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  1. Rituximab

    PubMed Central

    Storz, Ulrich

    2014-01-01

    Because drug development is not a static process, a drug’s market authorisation may change over time. In many cases, the number of indications for which a drug is approved increases. Because this facet of drug development also comes at significant costs, a corresponding patent filing strategy is required to protect these investments. The strategy as applied to rituximab, which is approved for a variety of indications, is discussed in this review. PMID:24866199

  2. Rituximab therapy for primary glomerulonephritis: Report on two cases

    PubMed Central

    Fabrizi, Fabrizio; Cresseri, Donata; Fogazzi, Giovanni B; Moroni, Gabriella; Passerini, Patrizia; Martin, Paul; Messa, Piergiorgio

    2015-01-01

    The evidence in the medical literature on the efficacy and safety of rituximab therapy for primary glomerulonephritis is limited and controversial. We describe two male Caucasian patients with rapidly progressive kidney failure due to primary proliferative glomerulonephritis. Both of them received high-dose intravenous corticosteroids and oral cyclophosphamide with limited benefit. The first patient (hepatitis C virus-negative mixed cryoglobulinemia) underwent plasma-exchange with intravenous immunoglobulins; he showed significant benefit on kidney function (he became dialysis independent with serum creatinine going back to 1.6 mg/dL) after one rituximab pulse even if urinary abnormalities were still present. No improvement in renal function or urinary changes occurred in the second patient. Both these individuals developed sepsis over the follow-up, the first patient died two months after rituximab therapy. This report is in keeping with the occurrence of severe infections after rituximab therapy in patients with renal impairment at baseline and concomitant high-dose steroids. PMID:26301235

  3. Rituximab-induced interstitial lung disease: five case reports.

    PubMed

    Naqibullah, Matiuallah; Shaker, Saher B; Bach, Karen S; Bendstrup, Elisabeth

    2015-01-01

    Rituximab (RTX), a mouse/human chimeric anti-CD20 IgG1 monoclonal antibody has been effectively used as a single agent or in combination with chemotherapy regimen to treat lymphoma since 1997. In addition, it has been used to treat idiopathic thrombocytopenic purpura, systemic lupus erythematous, rheumatoid arthritis, and autoimmune hemolytic anemia. Recently, RTX has also been suggested for the treatment of certain connective tissue disease-related interstitial lung diseases (ILD) and hypersensitivity pneumonitis. Rare but serious pulmonary adverse reactions are reported. To raise awareness about this serious side effect of RTX treatment, as the indication for its use increases with time, we report five cases of probable RTX-ILD and discuss the current literature on this potentially lethal association. PMID:26557260

  4. Safety and efficacy of rituximab treatment for vasculitis in hepatitis B virus-associated type II cryoglobulinemia: a case report

    PubMed Central

    2012-01-01

    Introduction Systemic B-cell depletion and clinical remission of the systemic effects of cryoglobulins have already been achieved using rituximab in hepatitis C virus-positive immunocompetent patients. Conversely, to the best of our knowledge there are no reports in the literature regarding the use of rituximab in hepatitis B virus-associated cryoglobulinemia. Case presentation We report here the case of a 60-year-old Caucasian man who presented with hepatitis B virus-associated type II cryoglobulinemia with severe multisystem disease, including membranoproliferative glomerulonephritis with acute renal failure. The vasculitis was refractory to conventional and antiviral therapy but rituximab use led to a fall in cryoglobulin levels and disease control. The B-cell depletion was safe and efficient to induce a complete remission of the disease. Conclusion Our case highlights the benefit and the efficacy of rituximab in association with antiviral therapy in small vessel vasculitis related to hepatitis B virus-associated mixed cryoglobulinemia. PMID:22284897

  5. Successful therapy with rituximab of refractory acute humoral renal transplant rejection: a case report.

    PubMed

    Celik, A; Saglam, F; Cavdar, C; Sifil, A; Atila, K; Sarioglu, S; Bora, S; Gulay, H; Camsari, T

    2008-01-01

    Acute humoral rejection (AHR) is generally less responsive to conventional anti-rejection treatment with consequent allograft losses. Therapeutic options include antilymphocyte antibody (ATG), intravenous immunglobulin (IVIG), plasmapheresis, or immunoadsorption with protein A together with intensification of immunsuppression with a tacrolimus/mycophenolate mofetil combination. This report describes a transplant recipient who responded to rituximab therapy as treatment for steroid-, ATG-, IVIG-, and plasmapheresis-resistant AHR. PMID:18261611

  6. Progressive multifocal leukoencephalopathy after rituximab therapy in HIV-negative patients: a report of 57 cases from the Research on Adverse Drug Events and Reports project

    PubMed Central

    Carson, Kenneth R.; Evens, Andrew M.; Richey, Elizabeth A.; Habermann, Thomas M.; Focosi, Daniele; Seymour, John F.; Laubach, Jacob; Bawn, Susie D.; Gordon, Leo I.; Winter, Jane N.; Furman, Richard R.; Vose, Julie M.; Zelenetz, Andrew D.; Mamtani, Ronac; Raisch, Dennis W.; Dorshimer, Gary W.; Rosen, Steven T.; Muro, Kenji; Gottardi-Littell, Numa R.; Talley, Robert L.; Sartor, Oliver; Green, David; Major, Eugene O.

    2009-01-01

    Rituximab improves outcomes for persons with lymphoproliferative disorders and is increasingly used to treat immune-mediated illnesses. Recent reports describe 2 patients with systemic lupus erythematosus and 1 with rheumatoid arthritis who developed progressive multifocal leukoencephalopathy (PML) after rituximab treatment. We reviewed PML case descriptions among patients treated with rituximab from the Food and Drug Administration, the manufacturer, physicians, and a literature review from 1997 to 2008. Overall, 52 patients with lymphoproliferative disorders, 2 patients with systemic lupus erythematosus, 1 patient with rheumatoid arthritis, 1 patient with an idiopathic autoimmune pancytopenia, and 1 patient with immune thrombocytopenia developed PML after treatment with rituximab and other agents. Other treatments included hematopoietic stem cell transplantation (7 patients), purine analogs (26 patients), or alkylating agents (39 patients). One patient with an autoimmune hemolytic anemia developed PML after treatment with corticosteroids and rituximab, and 1 patient with an autoimmune pancytopenia developed PML after treatment with corticosteroids, azathioprine, and rituximab. Median time from last rituximab dose to PML diagnosis was 5.5 months. Median time to death after PML diagnosis was 2.0 months. The case-fatality rate was 90%. Awareness is needed of the potential for PML among rituximab-treated persons. PMID:19264918

  7. Rituximab for refractory subcutaneous Sweet's syndrome in chronic lymphocytic leukemia: A case report

    PubMed Central

    HASHEMI, SEYED MEHDI; FAZELI, SEYED AMIRHOSSEIN; VAHEDI, ABDOLBASET; GOLABCHIFARD, REZA

    2016-01-01

    Sweet's syndrome is a neutrophilic dermatosis characterised by sudden onset of fever, neutrophilia, erythematous skin rashes and neutrophilic infiltration of the dermis. Subcutaneous Sweet's syndrome, or Sweet's panniculitis, is an uncommon variant of the classic syndrome, with hypodermal neutrophilic infiltration. The association of Sweet's syndrome with various malignancies has been reported. The most common underlying hematological malignancies are of myeloid origin; however, there have been several reports of the classic Sweet's syndrome in patients with a lymphoproliferative disorder, although the association of subcutaneous Sweet's syndrome with lymphoproliferative disorders has not been well-documented thus far. Herein, we present the case of a 48-year-old man with a 2-year history of chronic lymphocytic leukemia who developed fever and skin rashes, without any evidence of a relapse. The clinical and pathological investigation resulted in the diagnosis of subcutaneous Sweet's syndrome. The patient exhibited no significant response to conventional therapeutic measures; however, following two subsequent doses of rituximab, his general condition and skin rash improved. The follow-up skin biopsy demonstrated dermal neutrophilic infiltrations in conjunction with prior mixed lobular and septal panniculitis, suggesting evolution of subcutaneous Sweet's syndrome to its classic form. To the best of our knowledge, this is one of the first reports of rituximab as a novel biological treatment for Sweet's syndrome. However, further randomized trials are required to evaluate the efficacy and safety of such biological therapies for Sweet's syndrome. PMID:26998300

  8. Delayed-onset grade 4 neutropenia associated with rituximab therapy in a patient with lymphoma: case report and literature review.

    PubMed

    Motl, Susannah E; Baskin, Reed C

    2005-08-01

    A 53-year-old man developed delayed-onset neutropenia 6 weeks after completing first-line therapy with rituximab, cyclophosphamide, mitoxantrone, vincristine, and prednisone for high-grade B-cell lymphoma. Bone marrow biopsy demonstrated hypercellular marrow with normal maturation. He also developed interstitial pneumonitis, an adverse event associated with rituximab use. Infiltrates of T cells were found in the patient's lungs. For the next 6 months, the patient required subcutaneous granulocyte colony-stimulating factor 300 mug twice/week to maintain a granulocyte count above 1000 cells/mm3. He also received oral antibiotics for mouth sores and thrush. Based on the existing evidence, monitoring blood counts for as long as 8 weeks after rituximab therapy may be advisable, although the literature reports that neutropenia can develop up to 1 year after treatment. The development of a registry and uniform testing may help uncover the cause of this delayed-onset neutropenia. PMID:16207108

  9. Could we use a lower dose of rituximab to treat rheumatoid arthritis in clinical practice: pros and cons?

    PubMed

    Ferraccioli, Gianfranco; Tolusso, Barbara; Gremese, Elisa

    2016-01-01

    The CERERRA database provides evidence that low-dose rituximab performs as well as the conventional dose in the real world, thus highlighting the possible pharmacoeconomic impact. In clinical trials, it has been shown that rituximab 500 mg twice, performs as well as 1 g twice, 2 weeks apart, in terms of the American College of Rheumatology (ACR)20 and ACR50, but not the ACR70. The choice should always be made after considering that the IMAGE trial has demonstrated similar radiographic progression after the first 6 months, but with less control, with low-dose rituximab in the first 6 months. A possible alternative can be hypothesized. PMID:27255529

  10. [Rituximab therapy in the treatment of anti-neutrophil cytoplasmic antibody (ANCA) -positive interstitial pneumonia: case report].

    PubMed

    Miyaoka, Tokiko; Itabashi, Mitsuyo; Kumon, Saeko; Akiyama, Kenichi; Iwabuchi, Yuko; Kataoka, Hiroshi; Moriyama, Takahito; Takei, Takashi; Nitta, Kosaku

    2016-01-01

    We report a patient treated with rituximab for interstitial pneumonia (IP) associated with microscopic polyangiitis (MPA) and who was undergoing hemodialysis. A 59-year-old woman who had been treated with tacrolimus for 1 year for rheumatic arthritis was referred to the Department of Nephrology for fatigue, fever, weight loss, and rapidly developing renal dysfunction. On the first admission, severe renal dysfunction, proteinuria, hematuria, and an elevated titer of MPO-ANCA were observed, and the woman was diagnosed with rapidly progressive glomerulonephritis because of MPA. At that point, IP was found to be present but not active. Although steroid semipulse therapy following an initial prednisolone (PSL) administration of 40 mg/day, IVCY, and plasma exchange were administered, renal dysfunction did not recover, and the patient required maintenance hemodialysis. Upon discharge, a high titer of MPO-ANCA was continuously observed. Nine months after the initiation of hemodialysis, respiratory discomfort and desaturation developed. Interstitial shadow and ground glass opacity were seen on a CT scan, and the patient was diagnosed with exacerbation of interstitial pneumonia caused by MPA recurrence. At the second admission, acute findings identified by imaging techniques had improved. However, the high titer of MPO-ANCA continued in spite of the steroid semi-pulse therapy following PSL administration, and rituximab corresponding to 200 mg/weekly for 1 month was also administered. The dose of rituximab was decreased subsequently because the patient was judged to be compromised by the hemodialysis. At the same time, internal administration of sulfamethoxazole/trimethoprim was initiated. After the rituximab treatment, MPO-ANCA antibodies gradually decreased, and the respiratory condition improved. Five months after the rituximab treatment, respiratory dysfunction recurred. Based on the CT findings and a high level of β-D-glycan, the patient was diagnosed with ARDS due to

  11. Successful Treatment of Life-Threatening Interstitial Lung Disease Secondary to Antisynthetase Syndrome Using Rituximab: A Case Report and Review of the Literature.

    PubMed

    Dasa, Osama; Ruzieh, Mohammed; Oraibi, Omar

    2016-01-01

    We are presenting a case of antisynthetase syndrome (ASS) that manifested with severe interstitial pneumonitis in the presence of anti-Jo-1 and Ro (SSA) antibodies. Our patient developed respiratory failure with high oxygen requirements despite treatment by high-dose steroids. The patient was then treated with rituximab. This treatment led to significant improvement in the patient condition, with resolution of the ground glass opacities on high-resolution computerized tomography and near normalization of pulmonary function tests. In this communication, we performed a literature review and summarized previous reports pertinent to using of rituximab to treat interstitial lung disease (ILD) secondary to ASS by searching the PubMed database from 1980 to 2014. We were able to find 14 reports that included total of 45 patients with ILD secondary to ASS. A significant improvement in ILD was reported in the majority of reported patients who received rituximab, while there was only 1 mortality-related to Pneumocystis jirovecii pneumonia. Rituximab treatment was tolerated well in the majority of cases. It is our conclusion that rituximab can be considered a therapeutic option in ILD secondary to ASS based on our experience with this case and the currently available evidence in the literature. Nevertheless, there is a need for additional controlled studies to assess the efficacy and safety of rituximab in ILD secondary to ASS compared with other immunosuppressive regimens. PMID:25830868

  12. Granulomatosis with polyangiitis (Wegener's granulomatosis) with hard palate and bronchial perforations treated with rituximab - a case report.

    PubMed

    Kosałka, Joanna; Bazan-Socha, Stanisława; Zugaj, Anna; Ignacak, Maria; Zuk, Joanna; Sokołowska, Barbara; Musiał, Jacek

    2014-01-01

    We present a case of a 57-year-old woman suffering from granulomatosis with polyangiitis (GPA), who in the seventh months of immunosuppressive treatment (cyclophosphamide) progressed with new pulmonary changes and perforations of the hard palate and bronchi. Rituximab was introduced resulting in B-cell depletion and disappearance of anti-PR3 antibody. Palatal holes have substantially diminished and all bronchial perforations disappeared, covered by fibrous tissue. In the fourth month after rituximab administration, large scarring obstruction of the right main bronchus with upper and middle lobes atelectasis emerged. Because of increasing dyspnoea, stenotic bronchus was re-opened by bronchoscopy. Intervention was complicated by bilateral pneumothorax and later, on the seventh day, by fatal pulmonary bleeding. To our knowledge, this is the first report of GPA refractory to cyclophosphamide complicated by palatal and bronchial perforations. PMID:25133814

  13. Effectiveness of Rituximab in Severe Wegener’s Granulomatosis: Report of Two Cases and Review of the Literature

    PubMed Central

    Oristrell, Joaquim; Bejarano, Guillermina; Jordana, Rosa; Monteagudo, Manuel; Marí, Begoña; Casanovas, Arnau; Tolosa, Carles

    2009-01-01

    We hereby describe the satisfactory evolution of rituximab treatment in two patients with Wegener’s granulomatosis (WG). Rituximab was indicated for refractoriness to standard treatment in one case and life-threatening myelotoxicity due to alkylating agents in the other. A brief review of previous experience with the use of rituximab in the treatment of WG is presented. PMID:19590594

  14. Rituximab for the Treatment of IgG4-Related Tubulointerstitial Nephritis: Case Report and Review of the Literature.

    PubMed

    McMahon, Blaithin A; Novick, Tessa; Scheel, Paul J; Bagnasco, Serena; Atta, Mohamed G

    2015-08-01

    Immunoglobulin type gamma 4 (IgG4)-related disease is a relatively newly described clinical entity characterized by a distinctive histopathological appearance, increased numbers of IgG4 positive plasma cells and often, but not always, elevated serum IgG4 concentrations. The most common renal manifestation of IgG4-related disease is tubulointerstitial nephritis marked with proteinuria, hematuria, decreased kidney function, hypocomplementemia, and radiologic abnormalities. Renal biopsy characteristics include dense lymphoplasmacytic tubulointerstitial nephritis that stains for IgG4, storiform fibrosis, and immune complex deposition in the interstitium and along tubule basement membranes. Treatment traditionally consists of prolonged glucocorticoids but cases refractory to glucocorticoids have been reported.We report a case of a 58-year-old Caucasian man who presented with fatigue, 50 pound weight loss, dyspnea, lymphadenopathy, and nephromegaly. The patient was first misdiagnosed as chronic interstitial nephritis secondary to renal sarcoid and was treated with repeated doses of prednisone. On his third relapse, he underwent a repeat renal biopsy and a diagnosis of IgG4-tubulointerstitial nephritis was confirmed. He was refractory to treatment with prednisone. The patient received Rituximab and had prompt sustained improvement in renal function. At 1 year post Rituximab treatment, his serum creatinine remains at baseline and imaging study revealed reduction in his kidney size.This is the first case report using Rituximab as a steroid sparing option for refractory IgG4-tubulointerstitial nephritis. More information is needed on the long-term effects of using of B-cell depleting agents for glucocorticoid resistant IgG4-tubulointerstitial nephritis. PMID:26266393

  15. Four cases of rituximab-associated melanoma.

    PubMed

    Velter, Charles; Pagès, Cécile; Schneider, Pierre; Osio, Amélie; Brice, Pauline; Lebbé, Céleste

    2014-08-01

    Biological agents have transformed the management of inflammatory and proliferative disorders. Safety issues have been raised, particularly the increased risk of opportunistic infections and secondary cancers. We report four cases of melanoma worsening or occurring after rituximab treatment for associated B-cell lymphoma, and discuss the accountability of the molecule in this process. In three cases, melanoma was diagnosed before or at the same time as a B-cell lymphoma treated with rituximab associated with chemotherapy and we observed rapid metastatic progression. In the last case, melanoma appeared after 5 years treatment with rituximab for a follicular lymphoma. Although it is premature to conclude on the role of rituximab in melanoma, careful follow-up and registration of such cases are important to gain further insight on this topic. PMID:24743053

  16. Rituximab use in adult primary glomerulopathy: where is the evidence?

    PubMed Central

    Mallat, Samir G; Itani, Houssam S; Abou-Mrad, Rana M; Abou Arkoub, Rima; Tanios, Bassem Y

    2016-01-01

    Rituximab is a chimeric anti-CD20 antibody that results in depletion of B-cell lymphocytes. It is currently used in the treatment of a variety of autoimmune diseases, in addition to CD20-positive lymphomas. The use of rituximab in the treatment of the adult primary glomerular diseases has emerged recently, although not yet established as first-line therapy in international guidelines. In patients with steroid-dependent minimal change disease or frequently relapsing disease, and in patients with idiopathic membranous nephropathy (IMN), several retrospective and prospective studies support the use of rituximab to induce remission, whereas in idiopathic focal and segmental glomerulosclerosis (FSGS), the use of rituximab has resulted in variable results. Evidence is still lacking for the use of rituximab in patients with immunoglobulin A nephropathy (IgAN) and idiopathic membranoproliferative glomerulonephritis (MPGN), as only few reports used rituximab in these two entities. Randomized controlled trials (RCTs) are warranted and clearly needed to establish the definitive role of rituximab in the management of steroid-dependent and frequently relapsing minimal change disease, IMN, both as first-line and second-line treatment, and in MPGN. We await the results of an ongoing RCT of rituximab use in IgAN. Although current evidence for the use of rituximab in patients with idiopathic FSGS is poor, more RCTs are needed to clarify its role, if any, in the management of steroid-resistant or steroid-dependent FSGS. PMID:27621641

  17. Rituximab: Uses in Dermatology.

    PubMed

    Gleghorn, K; Wilson, J; Wilkerson, M

    2016-09-01

    Rituximab is an anti-CD20 monoclonal antibody with considerable potential in dermatology due to an increase in off-label indications. Chronic graft-versus-host disease and pemphigus vulgaris are two of the most promising indications for off-label use of rituximab. It is a generally safe alternative that should be considered when traditional therapy with corticosteroids or immunosuppressants has failed or caused significant intolerance. Currently, rituximab is only FDA-approved for treatment of follicular and diffuse large B-cell non-Hodgkin's lymphoma, rheumatoid arthritis, chronic lymphocytic leukemia, granulomatosis with polyangiitis (formerly Wegener's granulomatosis) and microscopic polyangiitis. Herein, off-label uses of rituximab and its efficacy in the treatment of cutaneous diseases are reviewed. PMID:27603326

  18. Pancreas-protective effect of rituximab for acute-onset type 1 diabetes in the honeymoon period: a case report

    PubMed Central

    Kurozumi, Akira; Okada, Yosuke; Arao, Tadashi; Miyazaki, Yusuke; Yoshikawa, Maiko; Torimoto, Keiichi; Kubo, Satoshi; Nakayamada, Shingo

    2016-01-01

    Summary A randomized controlled study of rituximab demonstrated that the drug protects pancreatic function in patients with acute-onset type 1 diabetes mellitus (AOT1DM). However, the mechanism of this protective effect is poorly understood. We examined the effects of rituximab in two patients with AOT1DM in the honeymoon period and the mechanism of these effects. Case 1 was a 40-year-old man and Case 2 was a 45-year-old man, both diagnosed with AOT1DM. Various tests indicated intact capacity for endogenous insulin secretion and that they were in the honeymoon phase of AOT1DM. Treatment with rituximab protected against pancreatic β-cell damage and maintained somewhat the endogenous insulin secretion. In Case 2, HbA1c level was maintained below 6.5% up to 24 months after treatment. However, in Case 1, the patient showed a gradual increase in HbA1c level starting around 9 months but fell at 12 months to >9.0% and required an insulin dose about twice greater than that of Case 2. High spleen tyrosine kinase (Syk) levels were recorded in the two patients before rituximab administration and after the treatment, the levels were further increased in Case 1, but decreased in Case 2. Both patients require continuous careful follow-up for glycemic control, insulin secretion capacity, and adverse reactions in the future. Although the clinical relevance of high Syk levels in AOT1DM patients remains unclear, the difference in the change in Syk level between the two patients may explain the different clinical courses. Learning points We described the pancreas-protective effect of rituximab in two patients with acute-onset type 1 diabetes mellitus in the honeymoon period and investigated the possible mechanism of action. The present study demonstrated that treatment with rituximab maintained endogenous insulin secretion capacity for 2 years in the two patients. The phosphorylated-spleen tyrosine kinase (p-Syk) data suggest that the differences in HbA1c level and the required

  19. Progressive multifocal leukoencephalopathy (PML) in a patient with lymphoma treated with rituximab: A case report and literature review.

    PubMed

    Al-Tawfiq, Jaffar A; Banda, Ramzi W; Daabil, Riyadh A; Dawamneh, M F

    2015-01-01

    Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease caused by reactivation of a latent JC polyoma virus. The first cases of PML were described 50 years ago in patients with lymphoma. PML typically occurs in immunocompromised individuals, particularly those infected with HIV. We present a 52-year-old male with lymphoma who was treated with R-CHOP (R: Rituximab; C: Cyclophosphamide; H: Doxorubicin; O: Vincristine; P: Prednisone). After six cycles of therapy, the patients developed tonic-clonic seizure. MRI of the brain showed multiple brain lesions. The pathology of a brain biopsy was diagnostic for PML. We review radiographic and histopathological features of the disease. The literature on PML and its association with immunosuppressant agents is reviewed, and the impact of rituximab and other biological agents in the setting is highlighted. PMID:25666327

  20. Discovery – Development of Rituximab

    Cancer.gov

    NCI funded the development of rituximab, one of the first monoclonal antibody cancer treatments. With the discovery of rituximab, more than 70 percent of patients diagnosed with non-hodgkin lymphoma now live five years past their initial diagnosis.

  1. Acute Respiratory Distress Syndrome and Posterior Reversible Encephalopathy Syndrome following Rituximab Therapy.

    PubMed

    Wardrope, Katrina E; Manson, Lynn; Metcalfe, Wendy; Sullivan, Eoin D O

    2016-01-01

    The anti-CD20 monoclonal antibody rituximab is associated with rare but significant adverse events, notably posterior reversible encephalopathy syndrome (PRES) and acute respiratory distress syndrome (ARDS). We report a case of concomitant ARDS and PRES developing after rituximab therapy for treatment of cryoglobulinaemic vasculitis. There are 7 reported cases of PRES complicating rituximab use. PRES onset varied from immediate to 21 days after administration. All patients recovered completely, and rituximab was reintroduced in half of the cases. The occurrence of ARDS in association with rituximab is rarer. Only 3 confirmed cases exist, and ARDS may occur as a delayed reaction. PMID:27275457

  2. Acute Respiratory Distress Syndrome and Posterior Reversible Encephalopathy Syndrome following Rituximab Therapy

    PubMed Central

    Wardrope, Katrina E.; Manson, Lynn; Metcalfe, Wendy; Sullivan, Eoin D. O

    2016-01-01

    The anti-CD20 monoclonal antibody rituximab is associated with rare but significant adverse events, notably posterior reversible encephalopathy syndrome (PRES) and acute respiratory distress syndrome (ARDS). We report a case of concomitant ARDS and PRES developing after rituximab therapy for treatment of cryoglobulinaemic vasculitis. There are 7 reported cases of PRES complicating rituximab use. PRES onset varied from immediate to 21 days after administration. All patients recovered completely, and rituximab was reintroduced in half of the cases. The occurrence of ARDS in association with rituximab is rarer. Only 3 confirmed cases exist, and ARDS may occur as a delayed reaction.

  3. Idiopathic Nonviral Cryoglobulinemia Treated Successfully With Rituximab.

    PubMed

    Kamel, Mahmoud; Thajudeen, Bijin; Bracamonte, Erika; Madhrira, Machaiah

    2016-01-01

    Cryoglobulinemia is a systemic inflammatory syndrome that generally involves small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. The therapeutic management of idiopathic cryoglobulinemic vasculitis has yet to be defined because no study has evaluated the best strategies. However, treatment of severe vasculitis is traditionally based on a combination of corticosteroids and immunosuppressants or plasmapheresis, and more recently rituximab. We report a case of 77-year-old female patient diagnosed with idiopathic cryoglobulinemia, treated successfully with 6 months prednisone tapering and 2 doses of rituximab (1 g each dose). After receiving the above-mentioned treatment, her creatinine went back to normal with resolution of proteinuria and hematuria, normalization of serum complements, and significant improvement in her clinical picture. We conclude that rituximab could be an effective treatment for idiopathic cryoglobulnemia. PMID:24914502

  4. Improved outcome of adult Burkitt lymphoma/leukemia with rituximab and chemotherapy: report of a large prospective multicenter trial

    PubMed Central

    Walewski, Jan; Döhner, Hartmut; Viardot, Andreas; Hiddemann, Wolfgang; Spiekermann, Karsten; Serve, Hubert; Dührsen, Ulrich; Hüttmann, Andreas; Thiel, Eckhard; Dengler, Jolanta; Kneba, Michael; Schaich, Markus; Schmidt-Wolf, Ingo G. H.; Beck, Joachim; Hertenstein, Bernd; Reichle, Albrecht; Domanska-Czyz, Katarzyna; Fietkau, Rainer; Horst, Heinz-August; Rieder, Harald; Schwartz, Stefan; Burmeister, Thomas; Gökbuget, Nicola

    2014-01-01

    This largest prospective multicenter trial for adult patients with Burkitt lymphoma/leukemia aimed to prove the efficacy and feasibility of short-intensive chemotherapy combined with the anti-CD20 antibody rituximab. From 2002 to 2011, 363 patients 16 to 85 years old were recruited in 98 centers. Treatment consisted of 6 5-day chemotherapy cycles with high-dose methotrexate, high-dose cytosine arabinoside, cyclophosphamide, etoposide, ifosphamide, corticosteroids, and triple intrathecal therapy. Patients >55 years old received a reduced regimen. Rituximab was given before each cycle and twice as maintenance, for a total of 8 doses. The rate of complete remission was 88% (319/363); overall survival (OS) at 5 years, 80%; and progression-free survival, 71%; with significant difference between adolescents, adults, and elderly patients (OS rate of 90%, 84%, and 62%, respectively). Full treatment could be applied in 86% of the patients. The most important prognostic factors were International Prognostic Index (IPI) score (0-2 vs 3-5; P = .0005), age-adjusted IPI score (0-1 vs 2-3; P = .0001), and gender (male vs female; P = .004). The high cure rate in this prospective trial with a substantial number of participating hospitals demonstrates the efficacy and feasibility of chemoimmunotherapy, even in elderly patients. This trial was registered at www.clinicaltrials.gov as #NCT00199082. PMID:25359988

  5. Rituximab for the treatment of rheumatoid arthritis: an update

    PubMed Central

    Mok, Chi Chiu

    2014-01-01

    Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule expressed on the surface of B cells. It was first used in the treatment of non-Hodgkin’s lymphoma and later approved for the treatment of rheumatoid arthritis (RA) that does not respond adequately to disease-modifying antirheumatic drugs, including the anti-tumor-necrosis-factor (TNF) biologics. Sustained efficacy in RA can be achieved by repeated courses of rituximab. However, the optimal dose and retreatment schedule of rituximab in RA remains to be established. Seropositivity, complete B cell depletion shortly after treatment, and previous failure to no more than one anti-TNF agent are three factors associated with greater clinical benefits to rituximab. Infusion reaction to the first dose of rituximab occurs in approximately 25% of RA patients, and the incidence reduces with subsequent exposure. Immunogenicity to the chimeric compound occurs in 11% of RA patients, but this does not correlate with its efficacy in B cell depletion. Extended observation of randomized controlled trials in RA does not reveal a significant increase in the incidence of serious infections related to rituximab compared to placebo groups, and the infection rate remains static over time. Repeated treatment with rituximab is associated with hypogammaglobulinemia, which may increase the risk of serious, but rarely opportunistic, infections. Reactivation of occult hepatitis B infection has been reported in RA patients receiving rituximab, but no increase in the incidence of tuberculosis was observed. Screening for baseline serum immunoglobulin G level and hepatitis B status (including occult infection) is important, especially in Asian countries where hepatitis B infection is prevalent. The rare but fatal progressive multifocal leukoencephalopathy linked to the use of rituximab has to be noted. Postmarketing surveillance and registry data, particularly in Asia, are necessary to establish the long-term efficacy and

  6. [PET-CT documented remission of multicentric Castleman disease after treatment with rituximab: case report and review].

    PubMed

    Adam, Zdeněk; Szturz, Petr; Koukalová, Renata; Řehák, Zdeněk; Pour, Luděk; Krejčí, Marta; Šmardová, Lenka; Eid, Michal; Volfová, Pavlína; Čermáková, Zdeňka; Křen, Leoš; Sokol, Filip; Hanke, Ivo; Michalková, Eva; Král, Zdeněk; Mayer, Jiří

    2015-03-01

    We describe a case of multicentric Castleman disease with generalized lymphadenopathy and splenomegaly, accompanied by typical B symptoms - loss of 15 kg, fever of non-infectious origin, night sweats, symptoms of anemia. Histological examination of the nodes with the highest accumulation of fluorodeoxyglucose, taken from mediastinum by thoracoscopy, revealed plasmocellular type of Castleman disease. Tests for HIV and human herpesvirus 8 (HHV-8) were negative. Three recurrences of herpes zoster indicating an alteration of immunity preceded the dia-gnosis of disease. Treatment was initiated with combination of thalidomide, dexamethasone, and cyclophosphamide. The response after 2 months therapy was not clear and patient doesn't tolerated the therapy well. Therefore, this treatment was terminated and R-CHOP (Mabthera - rituximab, cyclophosphamide, adriamycin, vincristine, and prednisone) was selected as a second-line therapy. Lymphadenopathy and splenomegaly were reduced during the 2 cycles of treatment, however, serious infectious complications accompanied the therapy. Therefore, only use of Mabthera monotherapy 375 mg /m2 was administered in 28-day intervals. This treatment has shown efficacy and tolerability. PET-CT scan has demonstrated disappearance of lymphadenopathy and splenomegaly, in addition, normalized accumulation of fluorodeoxyglucose. Monotherapy with Mabthera has proved to be effective and well tolerated drug in this case. Currently, there are more effective therapeutic alternatives in multicentric Castleman disease: treatment with monotherapy of rituximab or in combination therapy with immunomodulatory drugs (thalidomide or lenalidomide, treatment with anti-IL-6 (siltuximab) or against its receptor (tocilizumab). In the case of ineffectiveness of one treatment option must be tested other alternative. In this case the therapy based on thalidomide wasn't successful, whereas the treatment with Mabthera has achieved disappearance of disease symptoms. PMID

  7. Rituximab therapy in nephrotic syndrome due to AH amyloidosis.

    PubMed

    Katoh, Nagaaki; Matsuda, Masayuki; Miyazaki, Daigo; Gono, Takahisa; Yazaki, Masahide; Ikeda, Shu-Ichi

    2009-01-01

    We report a patient with AH amyloidosis associated with lymphoplasmacytic leukemia that has remained in a stable state with a nephrotic syndrome for 17 months since the commencement of cyclic rituximab therapy aimed at suppression of pathogenetic gamma heavy chains. Free light chains in serum and CD20-positive cells in peripheral blood were useful as hematological markers in the patient. Rituximab might be a potent therapeutic option for AH amyloidosis associated with a B-cell lymphoproliferative disorder. PMID:19590993

  8. Prolonged Remission in Neuromyelitis Optica Following Cessation of Rituximab Treatment.

    PubMed

    Weinfurtner, Kelley; Graves, Jennifer; Ness, Jayne; Krupp, Lauren; Milazzo, Maria; Waubant, Emmanuelle

    2015-09-01

    Neuromyelitis optica is an autoimmune disease characterized by acute episodes of transverse myelitis and optic neuritis. Several small, open-label studies suggest rituximab, a monoclonal antibody against CD20, prevents relapses in neuromyelitis optica; however, there is little consensus on timing or duration of treatment. Here we report four patients with severe relapsing neuromyelitis optica who were stabilized on rituximab and, after discontinuing treatment, continued to experience prolonged remission of their disease. Remission ranged from 4.5 to 10.5 years total, including 3 to 9 years off all therapies. The patients had sustained clinical responses despite normal B-lymphocyte levels and, in at least 2 patients, continued seropositivity for aquaporin-4 antibodies. These cases suggest that rituximab may induce prolonged remission in certain neuromyelitis optica patients, and they highlight the need for further elucidation of rituximab's mechanism in neuromyelitis optica. PMID:25387545

  9. Objective cerebrospinal fluid response to intraventricular rituximab in indolent CNS lymphoma

    PubMed Central

    Strowd, Roy E; Abuali, Inas A; Grossman, Stuart A

    2016-01-01

    SUMMARY Indolent CNS lymphomas (CNSLs) are rare and no guidelines exist for management. Recent literature highlights the potential for safe and tolerable intrathecal (IT) delivery of rituximab, a large anti-CD20 monoclonal antibody, for aggressive CNSL. We report a patient with relapsed indolent CNSL who failed systemic rituximab and could not tolerate IT chemotherapies, but had an objective response of 6 months duration to IT rituximab. PMID:25905905

  10. Stiff-person syndrome treated with rituximab

    PubMed Central

    Lobo, Marcelo Evangelista; Araújo, Marx Lincoln Barros; Tomaz, Carlos Alberto Bezerra; Allam, Nasser

    2010-01-01

    Stiff-person syndrome (SPS) is a rare neurological condition consisting of progressive and fluctuating rigidity of the axial muscles combined with painful spasms. The pathophysiology of SPS is not fully understood, but there seems to be an autoimmune component. The use of rituximab, a chimeric monoclonal antibody targeting CD20 protein in the surface of mature B cells, for the treatment of SPS is a recent therapeutical approach showing promising results. The authors present a case report of a 41-year-old female patient diagnosed with SPS who was treated with rituximab in a public hospital in Brasília, Brazil, showing a good and safe response to the treatment so far. Our data go along with some recent articles published in the literature. PMID:22802263

  11. Rituximab efficiently depletes B cells in lung tumors and normal lung tissue

    PubMed Central

    Joly-Battaglini, Albane; Hammarström, Clara; Stankovic, Branislava; Aamodt, Henrik; Stjärne, Johan; Brustugun, Odd Terje; Helland, Åslaug; Øynebråten, Inger; Corthay, Alexandre

    2016-01-01

    Rituximab is a monoclonal antibody that targets the CD20 B-cell-specific antigen and is widely used as therapy for B-cell lymphoma. Since rituximab depletes both malignant and normal B cells, it is increasingly being used to treat various conditions in which normal B cells have a pathogenic role, such as rheumatoid arthritis and multiple sclerosis. It is well-established that rituximab efficiently eliminates B cells in blood, lymph nodes, and spleen. In contrast, the effect of rituximab in non-lymphoid tissues remains poorly documented and is debated. Here, we report a rheumatoid arthritis patient who was treated with rituximab before receiving thoracic surgery for non-small cell lung cancer. Using flow cytometry and immunohistochemistry, we show that rituximab efficiently depleted CD20-positive B cells in a primary lung tumor, in lung-associated lymph nodes, and in normal lung tissue. We conclude that rituximab may be very efficient at depleting normal B cells in the lungs. This property of rituximab may potentially be exploited for the treatment of conditions in which pathogenic B cells reside in the lungs. On the other hand, the clearance of lung B cells may provide an explanation for the rare cases of severe non-infectious pulmonary toxicity of rituximab. PMID:27081474

  12. [Cold agglutinin disease -  no response to glucocorticoids and rituximab, what treatment is best for the 3rd line of therapy? Case report and review of the literature].

    PubMed

    Adam, Z; Pejchalová, A; Chlupová, G; Ríhová, L; Pour, L; Krejčí, M; Cervinek, L; Král, Z; Mayer, J

    2013-09-01

    Acquired autoimmune haemolytic anaemia is divided according to the characteristics of immunoglobulin causing haemolysis. The most frequent are haemolytic anaemia with thermal antibodies. They bind to erythrocytes and initiate their destruction in the reticuloendothelial system cells, leading to extravascular haemolysis. Cold agglutinin disease differs significantly from haemolytic anaemia with thermal antibodies. Agglutination is caused by monoclonal antibodies, in most cases class IgM and very rarely class IgG. Under cold conditions they bind to erythrocytes and cause their agglutination and subsequent disorder of blood circulation in body parts with a lower temperature. Agglutinins binding initiate the binding of the complement to the erythrocytes. Under warm conditions the binding becomes loose but the parts of the complement, which are already bound, cause haemolysis, which is mainly of an intravascular nature. The loose haemoglobin causes haemoglobinuria. Description of a patient with the disease. The 1st symptoms of the disease, i.e. anaemia + circulatory disorders in the acral parts of the body, disappearing under warm conditions followed with haemoglobinuria, led to the dia-gnosis of cold agglutinin disease. The 1st line treatment, prednison, did not show any response. The 2nd line treatment used was rituximab and dexametazon. Rituximab was administered in doses of 500 mg/ m2 to 4 times in a row in weekly intervals. Dexametazon was administered in doses of 40 mg from 1st to 4th day and from 15th to 18th day of the cycle. This treatment, however, did not show any response either. Therefore this article brings an overview of all publications regarding the disease treatment with the aim of choosing the most effective treatment options in the case of failure of the monotherapy using rituximab. The 1st line treatment for cold agglutinin disease is rituximab in monotherapy, usually administered once per week at least for 4 weeks. This treatment shows a response

  13. Rituximab in the treatment of shrinking lung syndrome in systemic lupus erythematosus.

    PubMed

    Peñacoba Toribio, Patricia; Córica Albani, María Emilia; Mayos Pérez, Mercedes; Rodríguez de la Serna, Arturo

    2014-01-01

    Shrinking lung syndrome (SLS) is a rare manifestation of systemic lupus erythematosus. We report the case of a patient with non-responding SLS (neither to glucocorticoids nor immunosupresors), who showed remarkable improvement after the onset of treatment with rituximab. Although there is a little evidence, treatment with rituximab could be proposed in SLS when classical treatment fails. PMID:24315464

  14. Two cases of refractory Wegener's granulomatosis successfully treated with rituximab.

    PubMed

    Tamura, Naoto; Matsudaira, Ran; Hirashima, Mika; Ikeda, Makoto; Tajima, Michiko; Nawata, Masuyuki; Morimoto, Shinji; Kaneda, Kazuhiko; Kobayashi, Shigeto; Hashimoto, Hiroshi; Takasaki, Yoshinari

    2007-01-01

    Conventional therapy for Wegener's granulomatosis, steroid and cyclophosphamide, fails to control disease activity in some refractory patients and has treatment-related toxicity. B cell depletion therapy using rituximab, a chimeric anti-CD20 monoclonal antibody, has been shown to be effective for certain autoimmune diseases including antineutrophil cytoplasmic antibody (ANCA) -associated systemic vasculitis. We report two refractory cases of Wegener's granulomatosis: one with bronchial and pulmonary involvement and retroorbital granuloma, the other with retroorbital granuloma and hypertrophic pachymeningitis causing severe headache. Rituximab was effective in both cases, with diminished granuloma and reduced ANCA titers, allowing steroids to be tapered. No adverse effects were detected. PMID:17409608

  15. Rituximab in combination with multiagent chemotherapy for pediatric follicular lymphoma.

    PubMed

    Kumar, Riten; Galardy, Paul J; Dogan, Ahmet; Rodriguez, Vilmarie; Khan, Shakila P

    2011-08-01

    Given the rarity of follicular lymphoma (FL) in children, there is limited data on which to base treatment recommendations. Herein, we report our institutional experience of using rituximab with multiagent chemotherapy for pediatric FL. Six pediatric patients were diagnosed with FL from 2000 to 2009. All patients received rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for varying durations. Five of the six patients remain in remission with a median follow-up of 31 months. Larger randomized trials are indicated to establish the efficacy of this regimen for pediatric FL patients. PMID:21462303

  16. Sarcoidosis following successful treatment of pemphigus vulgaris with rituximab: a rituximab-induced reaction further supporting B-cell contribution to sarcoidosis pathogenesis?

    PubMed

    Galimberti, F; Fernandez, A P

    2016-06-01

    The anti-CD20 peripheral B-cell depleting monoclonal antibody, rituximab, has been shown to be a safe and effective treatment for refractory pemphigus vulgaris (PV), a potentially fatal autoimmune blistering disease. We report a patient who developed skin nodules and arthralgias following successful treatment of refractory PV with rituximab. Clinical, serological and histological findings were consistent with a diagnosis of sarcoidosis. The nodules promptly responded to treatment with corticosteroids, and resolved without recurrence when the medication was tapered several months later. The temporal onset of sarcoidosis following treatment with rituximab and the eventual resolution, coupled with the remarkable similarities between the B-cell immunological environment expected in our patient during the post-rituximab period and the immunological environment described in patients with idiopathic sarcoidosis, strongly implicates exposure to rituximab as the trigger for sarcoidosis development in our patient. We propose that rituximab-induced sarcoidal granulomas may be a rare adverse effect of treatment with this medication, providing further support for an important role of B cells in the pathogenesis of sarcoidosis. With better understanding of the circumstances surrounding sarcoidosis development following rituximab administration, this medication could potentially be used to induce sarcoidosis in animal research models to study the immunopathogenesis of this disease. PMID:26800651

  17. Progressive multifocal leukoencephalopathy secondary to rituximab-induced immunosuppression and the presence of John Cunningham virus: a case report and literature review.

    PubMed

    Kelly, Deirdre; Monaghan, Bernadette; McMahon, Eileen; Watson, Geoffrey; Kavanagh, Eoin; O'Rourke, Killian; McCaffrey, John; Carney, Desmond

    2016-09-01

    We present the case of a 60-year-old man who developed subacute neurologic changes, in the setting of stage III non-Hodgkin's follicular lymphoma, and was treated with induction chemotherapy, followed by a year of maintenance rituximab. Magnetic resonance imaging of the brain with gadolinium was pathognomonic for progressive multifocal leukoencephalopathy (PML). He was treated with sequential plasmapheresis and intravenous immunoglobulin with clinical improvement. A literature review of the diagnostic workup of rituximab-induced PML was undertaken. This case and the literature review demonstrate the important role of magnetic resonance imaging of the brain in diagnosis and follow-up of rituximab-induced PML. Specific radiologic features in combination with cerebrospinal fluid can be diagnostic and avoid the morbidity and mortality of a diagnostic brain biopsy. Plasmapheresis and intravenous immunoglobulin have a therapeutic role and demonstrate symptom improvement and disease control. Follow-up imaging in combination with clinical response is important in demonstrating a treatment response. PMID:27594961

  18. Improving testing for hepatitis B before treatment with rituximab

    PubMed Central

    Jopson, Laura; Ng, Sarah; Lowery, Matthew; Harwood, Jayne; Waugh, Sheila; Valappil, Manoj; McPherson, Stuart

    2016-01-01

    Aims/Objectives/Background Individuals with current or previous infection with the hepatitis B virus (HBV) can experience viral reactivation when treated with immunosuppression. Rituximab, an anti-CD20 antibody used to treat many diseases, has potent immunosuppressant effects with a high risk of causing HBV reactivation. Reactivation can range from elevated liver enzymes to acute severe hepatitis with liver failure and a significant mortality risk. HBV screening and appropriate use of prophylactic antiviral therapy can prevent reactivation. This work describes the introduction of a local policy for HBV testing in patients before rituximab treatment and assesses its impact. Methods and Results A baseline review (before policy introduction) of 90 patients showed that only 21 (23%) had hepatitis B surface antigen (HBsAg) and 17 (19%) had hepatitis B core antibody (anti-HBcAb) tested before receiving rituximab. Following introduction of the policy (on the basis of international guidelines), improved laboratory reporting protocols and targeted education sessions, two further reviews of HBV testing rates among patients being initiated onto rituximab were performed. There was a marked increase in pre-rituximab testing for HBsAg from 23 to 79% and for anti-HBcAb from 19 to 78%. Throughout the study period, a total of one (0.8%) HBsAg-positive and six (4.7%) anti-HBcAb-positive patients were identified. Conclusions This work clearly indicates that simple strategies can markedly improve appropriate HBV screening. In our cohort, 6% (of whom only 43% had recognized HBV risk factors) required antiviral prophylaxis, which emphasizes the importance of universal screening before rituximab. Reinforcement of the guidelines and ongoing education is needed to further increase testing rates. PMID:27388147

  19. A systematic review of the use of rituximab as induction therapy in renal transplantation.

    PubMed

    Macklin, Philip S; Morris, Peter J; Knight, Simon R

    2015-04-01

    Rituximab is a B-lymphocyte depleting agent used to treat lymphoma and autoimmune diseases. There has been recent interest in its use both for management of highly-sensitised and ABO-incompatible recipients but also for induction therapy before transplantation. This systematic review evaluates the evidence for its use as part of induction protocols in ABO-compatible, non-sensitised recipients. 4 databases and 3 trial registries were searched for studies of the use of rituximab as part of induction protocols. The small number of identified studies precluded meta-analysis and thus a narrative review was conducted. 12 manuscripts met the inclusion criteria, relating to 5 individual studies. No significant improvements in patient and graft survival or acute rejection rates were identified with rituximab induction. A single small study reported a trend towards improved graft function with the addition of rituximab induction to a standard immunosuppressive regimen. Rituximab was not found to be associated with increased infectious complications in any study but concerns were raised over possible associations with leukopaenia and cardiovascular mortality. Overall, no convincing benefit of rituximab induction was found and some safety concerns were identified. The results of on-going trials are awaited but further studies may be required before we can draw firm conclusions regarding the efficacy and safety of rituximab in this setting. PMID:25555541

  20. Rituximab-associated acute thrombocytopenia: an under-diagnosed phenomenon.

    PubMed

    Ram, Ron; Bonstein, Lilach; Gafter-Gvili, Anat; Ben-Bassat, Isaac; Shpilberg, Ofer; Raanani, Pia

    2009-04-01

    Acute infusion reactions are the most common documented adverse reactions reported with rituximab, with overt cytokine release syndrome, and hematological adverse events being much rarer. The clinical course of a patient with mantle cell lymphoma, who developed acute thrombocytopenia and leukopenia following rituximab administration, is described and the literature reviewed. Serum complement and the levels of three cytokines--TNF-alpha, IL-6, and IL-1, were measured 2 days after the infusion of rituximab by using ELISA assay. Drug-dependent antibodies against platelets were evaluated by two procedures as follows: an immunofluorescence test applying flow cytometry and Monoclonal Antibody Immobilization of Platelet Antigen (MAIPA). Serum levels of TNF-a were significantly increased compared with normal, whereas those of IL-6 and IL-1 were not increased significantly. Flow cytometry assay and the MAIPA assay failed to detect rituximab-dependent antibodies against platelets. Complement levels were decreased compared with normal. Literature search yielded 10 publications reporting on another 15 patients. The most common type of lymphoma was mantle cell lymphoma, six patients had bone marrow involvement, and 10 patients had splenomegaly. In 10 patients, acute cytopenia was preceded by cytokine release syndrome or infusion-related symptoms. Usually, thrombocytopenia was not associated with bleeding manifestations. Thrombocytopenia was the most commonly acute cytopenia reported. The postulated pathogenesis is associated with cytokine release syndrome and complement activation. Patients with potential risk factors like splenomegaly and bone marrow involvement, who develop clinical manifestations compatible with cytokine release syndrome, should be closely monitored for rituximab-associated cytopenia. PMID:19260124

  1. Remission of late-onset post-heart transplantation lymphoproliferative disorder following treatment with rituximab and modified mini-CHOP chemotherapy: A case report

    PubMed Central

    HUANG, QIANG; YANG, TIANXIN; JIN, XING; NI, XUMING; QI, HAIYAN; YAN, ZHIKUN

    2016-01-01

    Post-transplant lymphoproliferative disorder (PTLD) is one of the most frequent secondary malignancies that can follow immunosuppressive therapy for solid organ transplantation, and may result in severe morbidities and even mortality. A middle-aged Han Chinese patient, prescribed with immunosuppressive cyclosporine and prednisone, developed PTLD that manifested as a painless cervical lymph node enlargement, 12 years following heart transplantation. Histology revealed monomorphic B-cell PTLD (diffuse large-cell lymphoma); as a result the immunosuppressive regimen of the patient was changed to tacrolimus and mycophenolate mofetil. In addition, the patient was changed to 6-cycle rituximab with a modified mini-CHOP (R-mini-CHOP) regimen for induction, and 8-cycle quarterly rituximab treatment and maintenance therapy. R-mini-CHOP therapy was well tolerated, and no allograft rejection occurred. The patient exhibited clinical remission as demonstrated by the results of the positron emission tomography-computed tomography at the 5-year follow-up visit following R-mini-CHOP therapy. In conclusion, R-mini-CHOP therapy following reduced immunosuppression is effective and safe for the treatment of late-onset PTLD following heart transplantation. PMID:27347047

  2. Is rituximab an effective treatment of refractory calcinosis?

    PubMed

    Dubos, Maria; Ly, Kim; Martel, Clothilde; Fauchais, Anne Laure

    2016-01-01

    Calcinosis, the deposition of calcified material in soft tissues, is frequently seen in systemic sclerosis and dermatomyositis. Treatment options are limited, with disappointing results. Some recent case reports suggest that rituximab may be an attractive therapeutic option. In case 1, a 54-year-old woman who presented with rheumatoid arthritis in association with scleromyositis was treated with rituximab for rheumatoid arthritis. Despite this, she developed multiple progressive calcinosis, necessitating extracorporeal shock wave lithotripsy to limit calcinosis extension and pain. In case 2, a 38-year-old man, previously treated for an anti-Pm/Scl-positive polymyositis/scleroderma overlap syndrome, presented with multiple tumoural periarticular calcinosis, which progressed despite bisphosphonates, sodium thiosulfate and thalidomide. We decided to start rituximab. Progression of calcinosis was still evident 6 and 12 months after anti-CD20 treatment. Many treatments have been tried to treat calcinosis without demonstrated effectiveness. Presently, rituximab cannot be recommended for this indication in the absence of successful controlled trials. PMID:27247203

  3. Rituximab for the treatment of IgG4-related orbital disease: experience from five cases

    PubMed Central

    Wu, A; Andrew, N H; Tsirbas, A; Tan, P; Gajdatsy, A; Selva, D

    2015-01-01

    Purpose To review the clinical efficacy and safety of rituximab for treatment of IgG4-related orbital disease (IgG4-ROD). Design Retrospective multicentre interventional case series. Methods Chart review for five cases of biopsy-confirmed IgG4-ROD (IgG4+>10/HPF, ratio of IgG4+/IgG+>40%) treated with rituximab. Information retrieved included the dosing schedule, adverse events and the magnitude, temporality, and duration of the clinical response. Results All cases of IgG4-ROD were either steroid dependent or steroid resistant. Rituximab doses for induction therapy included two doses of 1000 mg at 2-weekly intervals, and four doses at 375 mg/m2 at weekly intervals. Two months after starting rituximab, three cases achieved complete clinical resolution and two cases achieved partial clinical resolution. Complete radiological resolution occurred in one case, and partial radiological resolution in three cases. Three cases received rituximab maintenance therapy and one case was commenced on mycophenolate. No relapse occurred during a mean follow-up of 33 months (range: 7–65 months). One disease relapse occurred when the dosing interval of rituximab maintenance therapy was extended to 6–monthly intervals; remission was swiftly achieved with rituximab reinduction therapy. The only adverse effects reported were one episode of fatigue lasting 1 week and two episodes of orbital discomfort. Conclusion Rituximab may be an effective treatment option for IgG4-ROD that is steroid dependent or steroid intolerant. Rituximab therapy resulted in swift clinical and radiological improvement, many months free of relapse, and few side effects. PMID:25341435

  4. Barriers to the Access and Use of Rituximab in Patients with Non-Hodgkin's Lymphoma and Chronic Lymphocytic Leukemia: A Physician Survey.

    PubMed

    Baer Ii, William H; Maini, Archana; Jacobs, Ira

    2014-01-01

    Biologics such as rituximab are an important component of oncology treatment strategies, although access to such therapies is challenging in countries with limited resources. This study examined access to rituximab and identified potential barriers to its use in the United States, Mexico, Turkey, Russia, and Brazil. The study also examined whether availability of a biosimilar to rituximab would improve access to, and use of, rituximab. Overall, 450 hematologists and oncologists completed a survey examining their use of rituximab in patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Less than 40% of physicians considered rituximab as easy to access from a cost perspective. Furthermore, many physicians chose not to treat, were unable to treat, or had to modify treatment with rituximab despite guidelines recommending its use in NHL and CLL patients. Insurance coverage, reimbursement, and cost to patient were commonly reported as barriers to the use of rituximab. Across all markets, over half of physicians reported that they would increase use of rituximab if a biosimilar was available. We conclude that rituximab use would increase across all therapy types and markets if a biosimilar was available, although a biosimilar would have the greatest impact in Brazil, Mexico, and Russia. PMID:24810947

  5. Persistence of babesiosis for >2 years in a patient on rituximab for rheumatoid arthritis.

    PubMed

    Raffalli, John; Wormser, Gary P

    2016-06-01

    We report a patient who was being treated with rituximab for rheumatoid arthritis who developed Babesia microti infection that persisted for 26 months despite prolonged anti-babesia drug therapy. The explanation for the persistence was likely to have been the long-term immunocompromising effects of rituximab, as evidenced by seronegativity for B. microti antibodies that lasted for more than 1 year after onset of infection. PMID:27036977

  6. Vulvovaginal pyoderma gangrenosum secondary to rituximab therapy.

    PubMed

    Dixit, Shreya; Selva-Nayagam, Priya; Hamann, Ian; Fischer, Gayle

    2015-01-01

    Rituximab is being used increasingly for the treatment of B-cell malignancies and nonmalignant conditions. Pyoderma gangrenosum is a rare neutrophilic dermatosis, which can be either idiopathic or associated with underlying systemic inflammatory conditions. We present a series of 4 patients who presented with ulcerative pyoderma gangrenosum in the vulvovaginal area after treatment with rituximab. PMID:24769650

  7. Rituximab in immunologic glomerular diseases

    PubMed Central

    Ejaz, A Ahsan; Asmar, Abdo; Alsabbagh, Mourad M

    2012-01-01

    Experimental data suggest that the B-cell antigen CD20 may play a significant role in the pathogenesis of many diseases including glomerular diseases. These and other findings underpin the central concept of B-cell-depleting therapies that target CD20 antigen as treatments for lupus nephritis, idiopathic membranous nephropathy, focal segmental glomerulosclerosis, cryglobulinemic glomerulonephritis, antibody mediated renal allograft rejection and recurrent glomerulonephritis in renal allograft. Use of rituximab as a B-cell depleting therapy has been associated with clinical improvement and has emerged as a possible adjunct or alternative treatment option in this field of nephrology. PMID:22377738

  8. Early-onset neutropenia induced by rituximab in a patient with lupus nephritis and hemolytic anemia.

    PubMed

    Arroyo-Ávila, Mariangelí; Fred-Jiménez, Ruth M; Vilá, Luis M

    2015-01-01

    Rituximab is an anti-CD20 monoclonal antibody that has been used to treat several complications of systemic lupus erythematosus (SLE) including nephritis, cerebritis, and hematological disorders. Neutropenia is among the adverse events associated with rituximab; this usually occurs several weeks after therapy. However, early-onset neutropenia has been reported only in a few cases. Herein, we describe a 36-year-old Hispanic SLE woman who developed severe early-onset neutropenia (0.3 × 10(9)/L) after the second weekly rituximab infusion (375 mg/m(2) weekly × 4) given for nephritis and hemolytic anemia. She also had early-onset thrombocytopenia after rituximab therapy. Both hematological disorders resolved 12 days after the fourth and final dose. This case, together with few others, suggests that early-onset neutropenia may occur during rituximab therapy. Even though rituximab-induced neutropenia seems to be transient, it may predispose SLE patients to severe complications such as infections. PMID:25767732

  9. Early-Onset Neutropenia Induced by Rituximab in a Patient with Lupus Nephritis and Hemolytic Anemia

    PubMed Central

    Arroyo-Ávila, Mariangelí; Fred-Jiménez, Ruth M.; Vilá, Luis M.

    2015-01-01

    Rituximab is an anti-CD20 monoclonal antibody that has been used to treat several complications of systemic lupus erythematosus (SLE) including nephritis, cerebritis, and hematological disorders. Neutropenia is among the adverse events associated with rituximab; this usually occurs several weeks after therapy. However, early-onset neutropenia has been reported only in a few cases. Herein, we describe a 36-year-old Hispanic SLE woman who developed severe early-onset neutropenia (0.3 × 109/L) after the second weekly rituximab infusion (375 mg/m2 weekly × 4) given for nephritis and hemolytic anemia. She also had early-onset thrombocytopenia after rituximab therapy. Both hematological disorders resolved 12 days after the fourth and final dose. This case, together with few others, suggests that early-onset neutropenia may occur during rituximab therapy. Even though rituximab-induced neutropenia seems to be transient, it may predispose SLE patients to severe complications such as infections. PMID:25767732

  10. Favorable outcome of granulocyte colony-stimulating factor use in neuromyelitis optica patients presenting with agranulocytosis in the setting of rituximab.

    PubMed

    Mealy, Maureen A; Levy, Michael

    2015-10-15

    Neuromyelitis optica is a severe autoimmune condition affecting the central nervous system characterized by a relapsing disease course. Rituximab is a chimeric monoclonal antibody against the protein CD20, and is one of the most utilized medications for management of this disease. A known complication of rituximab use is neutropenia. We report on two patients who developed symptomatic early-onset rituximab-induced agranulocytosis who safely received granulocyte colony-stimulating factor. Neutrophil counts recovered quickly and both patients continue to receive rituximab without further incident. PMID:26439958

  11. Rituximab-Induced Splenic Rupture and Cytokine Release

    PubMed Central

    Nair, Ranjit; Gheith, Shereen; Lamparella, Nicholas

    2016-01-01

    Patient: Female, 55 Final Diagnosis: Mantle cell lymphoma Symptoms: Cytokine release syndrome • hypoglycemia • hypotension • splenic rupture • splenomegaly • vision loss Medication: — Clinical Procedure: Case Report Specialty: Oncology Objective: Unusual clinical course Background: Rituximab is a therapeutic monoclonal antibody that is used for many different lymphomas. Post-marketing surveillance has revealed that the risk of fatal reaction with rituximab use is extremely low. Splenic rupture and cytokine release syndrome are rare fatal adverse events related to the use of therapeutic monoclonal antibodies, especially in aggressive malignancies with high tumor burden. Case Report: A 55-year-old woman presented with abdominal pain and type B symptoms and was diagnosed with mantle cell lymphoma. Initial peripheral blood flow cytometry showed findings that mimicked features of chronic lymphocytic leukemia. Further treatment with rituximab led to catastrophic treatment complications that proved to be fatal for the patient. Conclusions: Severe cytokine release syndrome associated with biologics carries a very high morbidity and case fatality rate. With this case report we aim to present the diagnostic challenge with small B-cell neoplasms, especially mantle cell lymphoma and chronic lymphocytic lymphomas, and underscore the importance of thorough risk assessment for reactions prior to treatment initiation. PMID:26972227

  12. Rituximab Retreatment for Low-Tumor Burden Follicular Lymphoma

    Cancer.gov

    A summary of results from a randomized clinical trial of patients with low–tumor burden follicular lymphoma that compared maintenance therapy with rituximab versus retreatment with rituximab only when there was evidence of disease progression.

  13. Long-term remission with rituximab in refractory leucine-rich glioma inactivated 1 antibody encephalitis.

    PubMed

    Brown, J William L; Martin, Peter J; Thorpe, John W; Michell, Andrew W; Coles, Alasdair J; Cox, Amanda L; Vincent, Angela; Zandi, Michael S

    2014-06-15

    Autoimmune encephalitis associated with antibodies to leucine-rich glioma inactivated 1 (LGI1) is recently described and there is a lack of detailed reports on the treatment of relapsing or refractory cases and long-term outcomes. Two case reports are presented. Both cases had faciobrachial dystonic seizures (FBDS) and received rituximab after relapsing or refractory disease. Both cases achieved sustained clinical remission of up to 15 and 56 months respectively. Rituximab use allowed withdrawal of corticosteroids and was well tolerated. Randomized clinical trials are needed in LGI1 encephalitis and other autoimmune encephalitides. PMID:24703099

  14. Practical considerations on the use of rituximab in autoimmune neurological disorders

    PubMed Central

    Kosmidis, Mixalis L.; Dalakas, Marinos C.

    2010-01-01

    Rituximab (Mabthera, Rituxan) is a chimeric human/murine monoclonal antibody against CD-20 surface antigen expressed on B-cells. Rituximab, by causing B-cell depletion, appears to be effective in several autoimmune disorders; it has been approved for rheumatoid arthritis and is a promising new agent in the treatment of several autoimmune neurological disorders. A controlled study in patients with relapsing remitting multiple sclerosis has shown that rituximab significantly reduces the number of new MRI lesions and improves clinical outcome; it also showed some promise in a subset of patients with primary progressive MS. The drug is also effective in a number of patients with Devic’s disease, myasthenia gravis, autoimmune neuropathies, and inflammatory myopathies. The apparent effectiveness of rituximab has moved B-cells into the center stage of clinical and laboratory investigation of autoimmune neurological disorders. We review the evidence-based effectiveness of rituximab in neurological disorders based on controlled trials and anecdotal reports, including our own experience, and address the immunobiology of B-cells in autoimmune central nervous system (CNS) and peripheral nervous system (PNS) disorders. In addition, we provide practical guidelines on how best to use this drug in clinical practice and highlight its potential toxicity. PMID:21179602

  15. Rituximab for subcutaneous delivery: Clinical management principles from a nursing perspective.

    PubMed

    Carlson, Julia; Cox, Keith; Bedwell, Kylie; Ku, Mathew

    2015-12-01

    Nurses play an integral role in administering treatments to patients with non-Hodgkin's lymphomas. Intravenous (IV) rituximab was approved by the Australian Therapeutic Goods Administration in 1998, and a novel subcutaneous (SC) formulation was approved in 2014. Fixed-dose SC rituximab is highly concentrated; co-formulation with a fully human recombinant vorhyaluronidase alfa enzyme helps overcome the physiological barriers of the SC space, facilitating drug dispersion. Despite a different pharmacokinetic profile to the IV preparation, SC rituximab demonstrates a comparable efficacy/safety profile. Most frequently occurring rituximab-related adverse events include neutropenia, nausea and constipation, and administration-related reactions are more frequent with the SC preparation. Compared with IV, SC delivery reduces treatment times and nurse workload, and patients report greater comfort and convenience. This article sets out nursing considerations for optimal administration of SC rituximab, including premedication, drug handling/preparation, injection technique, after-care and management of adverse events, particularly administration-related reactions. PMID:26681664

  16. Successful rituximab treatment in an elderly patient with recurrent thrombotic thrombocytopenic purpura.

    PubMed

    Matsubara, Etsuko; Yamanouchi, Jun; Hato, Takaaki; Takeuchi, Kazuto; Niiya, Toshiyuki; Yasukawa, Masaki

    2016-07-01

    An 81-year-old man presenting with fever, neurological symptoms, thrombocytopenia, and hemolytic anemia was diagnosed with acquired idiopathic thrombotic thrombocytopenic purpura (TTP). His disintegrin-like and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) activity was <1% and the ADAMTS13 inhibitor titer was 3.2 BU/ml. He received plasma exchange and steroid administration until remission was achieved. Seven months later, he suffered from paralysis of the right hand, hemolytic anemia, and thrombocytopenia. We confirmed TTP recurrence based on ADAMTS13 activity <1% and an ADAMTS13 inhibitor titer of 19.4 BU/ml. Four infusions of rituximab were administered in addition to plasma exchange and steroid pulse therapy. Platelet count recovery was observed within 5 days. No severe side effects related to rituximab occurred. Although rituximab has not been approved for TTP in Japan, we report the efficacy and safety of rituximab in an elderly patient with recurrent TTP. We suggest that rituximab therapy should be started as soon as possible for recurrent TTP in patients with high titers of ADAMTS13 inhibitor. PMID:27498731

  17. Rituximab and biosimilars – equivalence and reciprocity

    PubMed Central

    Qureshi, Zaina P; Magwood, Jametta S; Singh, Sarveshwari; Bennett, Charles L

    2014-01-01

    Cancer is a debilitating disease affecting millions of people daily. Over the years, cancer treatment has advanced in leaps and bounds. Antibodies are important breakthrough therapeutic agents for cancer. These agents, proteins produced by B lymphocytes of the immune system in response to antigens, bind to receptors on cell surfaces so that the antigen–antibody complexes can be recognized and destroyed by phagocytes. While each B cell synthesizes only one kind of antibody, an entire population of different types of B cells and their respective antibodies are produced in response to various antigens to which the organism had been exposed. However, to be useful clinically, substantial amounts of a single antibody must be generated from a single ancestral B cell. These antibodies produced by a specific population of B cells are the monoclonal antibodies that have become the cornerstone of treatment for cancer and many immunologic illnesses. The purpose of this report is to provide an overview of the clinical development of biosimilars in clinical oncology, focusing on rituximab and like biosimilars. PMID:24829884

  18. Acquired Hemophilia A Successfully Treated with Rituximab

    PubMed Central

    D’Arena, Giovanni; Grandone, Elvira; Di Minno, Matteo Nicola Dario; Musto, Pellegrino; Di Minno, Giovanni

    2015-01-01

    Acquired hemophilia A (AHA) is a rare bleeding disorder due to the development of specific autoantibodies against factor VIII. The anti-CD20 monoclonal antibody Rituximab has been proven to be effective in obtaining a long-term suppression of inhibitors of AHA, besides other immunosuppressive standard treatments. Here we describe a case of idiopathic AHA in a 60-year old man successfully treated with rituximab. He showed a complete clinical response with a normalization of clotting parameters after 5 weekly courses of rituximab given at a dose of 375 mg/sqm., but after stopping rituximab, an initial worsening of coagulation parameters induced the addition of 3 further courses. At present, the patient is in complete clinical and hematological remission after 200 days. This case confirms that Rituximab may be a safe and useful tool to treat AHA and, a prolonged administration can overcome the initial resistance. However, the precise position of this drug in the therapeutic strategy (first or second-line, alone or in combination with other drugs) remains to be established and warrants further investigation. PMID:25745551

  19. Selective response to rituximab in a young child with MuSK-associated myasthenia gravis.

    PubMed

    Govindarajan, Raghav; Iyadurai, Stanley J; Connolly, Anne; Zaidman, Craig

    2015-08-01

    Neuromuscular junction disorders in children are either genetic, such as congenital myasthenic syndrome, or autoimmune with circulating antibodies most commonly against acetylcholine receptors. There is limited experience recognizing and treating children with myasthenia associated with muscle-specific tyrosine kinase antibodies. We report a seven-year-old child with intermittent esotropia since age 3 months, and two years of progressive and severe diplopia, dysarthria, dysphagia, and facial weakness. Acetylcholine receptor antibodies and genetic testing for congenital myasthenic syndrome were negative. Muscle specific tyrosine kinase antibodies were significantly elevated. Ophthalmoplegia and bulbar weakness were refractory to treatment with acetylcholinesterase inhibitors, corticosteroids and IVIg but completely resolved following treatment with rituximab. Her neurologic examination remained normal at the most recent follow-up, 15 months after initiation of rituximab. Children with MuSK myasthenia, like adults, can respond to rituximab despite long standing disease and failure to improve on other immunosuppressant medications. PMID:25998611

  20. Rituximab off label use for difficult-to-treat auto-immune diseases: reappraisal of benefits and risks.

    PubMed

    Sailler, Laurent

    2008-02-01

    Rituximab is increasingly used off label for difficult-to-treat auto-immune diseases. We reviewed the main case series or clinical studies to identify the best indications of rituximab and the situations at substantial risks for adverse events. Refractory immune thrombocytopenic purpura was the main indication. However, the long term benefit-to-risk ratio of rituximab treatment before or after splenectomy is unknown. A single 375 mg/m2 infusion may be as efficacious as the classical four infusions cycle. Rituximab is the best treatment for cold agglutinin disease. In warm agglutinin auto-immune anaemia, its efficacy has essentially been reported in chronic lymphocytic leukemia (CLL) patients and in children. In CLL patients, lethal adverse events occurred in patients also receiving cyclophosphamide. Rituximab seems to have an interesting benefit-to-risk ratio in Wegener granulomatosis (excepted in granulomatous lesions), HCV-associated symptomatic cryoglobulinemia in patients unresponsive to anti-viral therapy, pemphigus and thrombotic thrombocytopenic purpura. Efficacy and safety data in lupus are difficult to interpret. Serum sickness disease is not exceptional in immune thrombocytopenic purpura (ITP), lupus and sicca syndrome patients. A substantial infectious risk has been reported in pemphigus patients and in post-renal transplant cryoglobulinemia. Double-blind randomised controlled trials and phase IV studies are mandatory in most clinical settings to confirm the overall favourable perception of rituximab benefit to risk ratio. PMID:18270863

  1. Analysis of the effectiveness and safety of rituximab in patients with refractory lupus nephritis: a chart review.

    PubMed

    Contis, Anne; Vanquaethem, Helene; Truchetet, Marie-Elise; Couzi, Lionel; Rigothier, Claire; Richez, Christophe; Lazaro, Estibaliz; Duffau, Pierre

    2016-02-01

    Lupus nephritis is a life-threatening complication of systemic lupus erythematosus. The standard treatment for this condition, including corticosteroids and cyclophosphamide, results in a 70 % remission rate at 12 months, but it is also associated with significant morbidity. Rituximab, a chimeric anti-CD20 antibody, could be useful, given the central role of B cells in the pathogenesis of systemic lupus erythematosus. Case reports and retrospective series have reported that rituximab is effective for refractory lupus nephritis. However, the double-blind, placebo-controlled LUNAR trial failed to meet its end point. We studied clinical, biological, and immunological data on 17 patients who received rituximab as an induction treatment for refractory lupus nephritis at the University Hospital Center of Bordeaux. A complete treatment response was defined as a normal serum creatinine with inactive urinary sediment and 24-h urinary albumin <0.5 g and a partial response (PR) as a >50 % improvement in all of the renal parameters that were abnormal at baseline, with no deterioration in any parameter. Seventeen patients received rituximab as induction treatment for lupus nephritis refractory to standard treatment by cyclophosphamide. After a follow-up of 12 months, complete or partial renal remission was achieved in 53 % patients. Rituximab therapy resulted in a significant improvement in proteinuria and steroid dose tapering in all patients. Rituximab should be considered as a treatment option for refractory lupus glomerulonephritis. PMID:26762196

  2. Recurrent inflammatory pseudotumor of the jaw with perineural intracranial invasion demonstrating sustained response to Rituximab.

    PubMed

    Garcia, Bryan A; Tinsley, Sarah; Schellenberger, Thomas; Bobustuc, George C

    2012-12-01

    Corticosteroids are the mainstay of treatment of inflammatory pseudotumor (IPT) of the head and neck; however, involvement of the skull base and mandible can be unresponsive to steroids and require surgical resection. IPT is known to usually contain a CD20+ lymphocyte subgroup. Rituximab, a chimeric anti-CD20 antibody, has been successfully utilized in the treatment of other CD20+ diseases, including the similar idiopathic orbital inflammatory disease. This is the first report to describe successful treatment with Rituximab of a recurrent IPT of the mandible with trigeminal spread and leptomeningeal involvement with clinical and radiologic evidence demonstrating a sustained response to therapy. PMID:22161155

  3. Herpetic tracheitis in association with rituximab therapy.

    PubMed

    Thong, Lorraine; Plant, Barry J; McCarthy, Julie; Murphy, Desmond M

    2016-07-01

    A 58-year old lady under active follow-up with the respiratory services at our institution for bronchiectasis secondary to hypogammaglobulinaemia presented with hoarseness and haemoptysis. She was also receiving rituximab maintenance therapy for follicular lymphoma. Bronchoscopy demonstrated vesicular lesions on her vocal cords and trachea, confirmed as herpes simplex virus (HSV) on cytological analysis of brushings. She responded well to intravenous valacyclovir. Rituximab is increasingly utilised in the treatment of haematological and auto-immune disorders. This case highlights the potential of this drug to potentiate susceptibility to infection in an already immunocompromised individual. PMID:27512561

  4. Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis

    PubMed Central

    2013-01-01

    Introduction The objective of the study was to investigate the impact of newer biologic treatments including rituximab, abatacept and tocilizumab on antibody response following pneumococcal vaccination using a 7-valent conjugate vaccine in patients with established rheumatoid arthritis (RA). Methods Patients with RA receiving rituximab, abatacept or tocilizumab as monotherapy or combined with methotrexate (MTX) participated in the study. Specific IgG antibodies against 23F and 6B serotypes were measured at vaccination and 4 to 6 weeks after vaccination using standardised ELISA. Geometric mean antibody levels (GML) were calculated. Antibody response (AR) was defined as the ratio between post- and pre-vaccination antibody levels and a positive antibody response (posAR) was AR ≥2. Results In total, 88 patients were enrolled in the study. Of 55 patients treated with rituximab, 26 (46%) were on concomitant MTX. Of patients receiving abatacept (n = 17) and tocilizumab (n = 16) biologic treatment was given in combination with MTX in 13 (76%) and 9 (56%) patients, respectively. Patients treated with rituximab had significantly lower AR compared to those on tocilizumab, as well as compared to previously reported RA patients on MTX and controls (spondylarthropathy patients treated with NSAIDs and/or analgesics). In total, 10.3% of patients on rituximab monotherapy and no patient on rituximab + MTX had posAR for both serotypes. For abatacept and tocilizumab the corresponding figures were 17.6% and 50%. Conclusion In this cohort of patients with established RA, treatment with rituximab and abatacept was associated with diminished antibody response but this was most pronounced for rituximab. Pneumococcal conjugate vaccine administrated during ongoing tocilizumab treatment seems to be associated with sufficient antibody response. Pneumococcal vaccination should preferably be encouraged before initiation of rituximab or abatacept treatment. Trial registration NCT

  5. A Study of Rituximab and Ifosfamide, Carboplatin, and Etoposide Chemotherapy in Children with Recurrent/Refractory B-cell (CD20+) Non-Hodgkin Lymphoma and Mature B-Cell Acute Lymphoblastic Leukemia: A Report from the Children's Oncology Group

    PubMed Central

    Griffin, Timothy C.; Weitzman, Sheila; Weinstein, Howard; Chang, Myron; Cairo, Mitchell; Hutchison, Robert; Shiramizu, Bruce; Wiley, Joseph; Woods, Deborah; Barnich, Margaret; Gross, Thomas G.

    2009-01-01

    Background To estimate the response rate and therapy related toxicities of the anti-CD20 monoclonal antibody rituximab when combined with chemotherapy including ifosfamide, carboplatin, and etoposide (ICE) in patients with relapsed and refractory B-cell non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia (B-ALL). Methods Patients received rituximab and ICE for 1 to 3 cycles, depending upon response. Rituximab (375 mg/m2) was given on day 1 and 3 of each cycle (day 1 only for cycle 3), with ifosfamide (3000 mg/m2) and etoposide (100 mg/m2) given on days 3, 4, and 5 and carboplatin (635 mg/m2) given on day 3 only. Results Twenty-one patients were enrolled, of whom 20 were eligible and evaluable. Although hematologic toxicities were common, only one patient was removed from study due to prolonged myelosuppression. Toxicities related to infusions of rituximab were frequent but manageable. Of the 6 eligible patients with diffuse large B-cell lymphoma, 3 achieved complete remission (CR), 1 had stable disease (SD), and 2 had progressive disease (PD). Of the 14 eligible patients with Burkitt lymphoma and B-ALL, there were 4 complete responses (CR), 5 partial responses (PR), 1 SD and 4 with PD. Thus the CR/PR rate for the entire group was 12/20 (60%). Following completion of protocol therapy 6 patients were able to proceed to consolidation with high-dose therapy and stem cell rescue. Conclusions The combination of rituximab and ICE chemotherapy was associated with an encouraging objective response rate and an acceptable toxicity profile. PMID:18816698

  6. A Randomized Controlled Trial of Rituximab Following Failure of Antiviral Therapy for Hepatitis C-Associated Cryoglobulinemic Vasculitis

    PubMed Central

    Sneller, Michael C.; Hu, Zonghui; Langford, Carol A.

    2011-01-01

    OBJECTIVES To report on the results of a randomized controlled trial of rituximab in hepatitis C virus (HCV)-associated mixed cryoglobulinemic vasculitis. METHODS We conducted an open-label single center randomized controlled trial of rituximab (375 mg/m2 per week for 4 weeks) compared to best available therapy for treatment of patients with HCV-associated cryoglobulinemic vasculitis in whom antiviral therapy failed to induce remission. The primary endpoint was remission at 6 months from study entry. RESULTS A total of 24 patients were enrolled. Baseline disease activity and organ involvement were similar in the two groups. Ten patients in the rituximab group (83%) were in remission at study month 6, compared with 1 patient in the control group (8%), a result that met criterion for stopping the study (P<0.001). The median duration of remission for rituximab-treated patients reaching the primary endpoint was 7 months. No adverse effect of rituximab on HCV plasma viremia or hepatic transaminase levels was observed. CONCLUSIONS Therapy with rituximab was well tolerated and effective treatment for patients with HCV-associated cryoglobulinemic vasculitis in whom antiviral therapy fails to induce remission. PMID:22147444

  7. Rituximab treatment for Epstein-Barr virus DNAemia after alternative-donor hematopoietic stem cell transplantation.

    PubMed

    Coppoletta, Stefania; Tedone, Elisabetta; Galano, Barbara; Soracco, Monica; Raiola, Anna Maria; Lamparelli, Teresa; Gualandi, Francesca; Bregante, Stefania; Ibatici, Adalberto; di Grazia, Carmen; Dominietto, Alida; Varaldo, Riccardo; Bruno, Barbara; Frassoni, Francesco; Van Lint, Maria Teresa; Bacigalupo, Andrea

    2011-06-01

    We report 55 patients undergoing an alternative-donor hematopoietic stem cell transplantation (HSCT) who developed Epstein-Barr virus (EBV) DNAemia, with >1000 EBV copies/10(5) peripheral blood mononuclear cells (PBMCs), and were treated with rituximab (375 mg/m(2)). The median patient age was 47 years (range, 20-65 years), and graft sources were mismatched family members (n = 4), unrelated donors (n = 46), and unrelated cord blood (n = 5). The conditioning regimen included antithymocyte globulin (ATG) in all patients. The median time to development of EBV DNAemia was day 27 post-HSCT (range, day 5 to day 242), with a median of 60 EBV copies/10(5) PBMCs (range, 1-5770 copies/10(5) PBMCs). The number of EBV copies was reduced to <1000/10(5) PBMCs on day +7 after initiation of rituximab therapy in 51% of the patients, on day +14 in 73% of the patients, and on +21 in 92% of the patients. Overall, 50 of 55 patients (91%) cleared EBV after one dose (n = 25) or more than one dose (n = 25) of rituximab. Factors predicting transplantation-related mortality (TRM) in multivariate analysis were a reduction to <1000 EBV copies/10(5) PBMCs by day +7 of treatment (relative risk [RR], 0.2; P = .01) and disease phase in remission (RR, 0.3; P = .05). TRM was 23% in the 40 patients with none or one of the negative predictors and 60% in the 15 patients with both negative predictors (P = .001). Of these latter 15 patients, 3 developed clinical posttransplantation lymphoproliferative disorder (PTLD). All 3 of these patients had a high EBV load on day +7 of rituximab therapy. This study confirms the effectiveness of rituximab in controlling EBV DNAemia in patients undergoing allogeneic HSCT. Patients with increasing EBV copies despite rituximab therapy are at high risk for EBV PTLD and may be considered for alternative therapies. PMID:20950702

  8. Role of Rituximab and Rituximab Biosimilars in Diffuse Large B-Cell Lymphoma.

    PubMed

    Coleman, Morton; Lammers, Philip E; Ciceri, Fabio; Jacobs, Ira A

    2016-04-01

    Diffuse large B-cell lymphoma (DLBCL), an aggressive non-Hodgkin lymphoma (NHL), is the most-common subtype of NHL. DLBCL can be classified into at least 3 major immunologically distinct types, which contributes to considerable variation in disease prognosis and response to treatment. DLBCL potentially is curable, even when diagnosed at advanced stages. The current standard of care for most patients with untreated or relapsed/refractory DLBCL is chemoimmunotherapy containing rituximab, an anti-CD20 monoclonal antibody. With advanced understanding of the molecular mechanisms involved in the pathogenesis of DLBCL and specific signaling pathways that are activated in different subtypes, potential new therapeutic targets have been identified, some of which are at the late stages of clinical development. This review summarizes the critical role of rituximab in the current standard of care treatment for DLBCL and discusses why rituximab is likely to remain an important component of treatment options for DLBCL in the foreseeable future. In addition, current and emerging therapeutic agents, including potential benefits of rituximab biosimilars, for patients with DLBCL are discussed. The advent of rituximab biosimilars may facilitate accessibility of rituximab-based chemotherapies to patients with DLBCL and has potential cost-saving benefits for healthcare systems globally. PMID:26906106

  9. Treatment of recurrent focal segmental glomerulosclerosis in pediatric kidney transplant recipients: effect of rituximab.

    PubMed

    Sethna, Christine; Benchimol, Corinne; Hotchkiss, Hilary; Frank, Rachel; Infante, Lulette; Vento, Suzanne; Trachtman, Howard

    2011-01-01

    Recurrence of focal segmental glomerulosclerosis (FSGS) after renal transplantation is a complication that often leads to graft loss. There is no consensus on the optimal treatment of recurrent FSGS. Rituximab, a monoclonal antibody to CD20, may be a useful treatment of this complication. Methods. We report four pediatric cases of recurrent FSGS treated with rituximab and plasmapheresis. Results. Four children (2M/2F), age 15.3 ± 2.6, with recurrent FSGS posttransplant were identified. Four doses of rituximab were administered 171 ± 180 days posttransplant and 114 ± 169 days after the start of plasmapheresis. Three children responded with complete remission, one of whom relapsed after four months. One child had a partial response with a decrease in proteinuria that was not sustained. No adverse side effects were reported during treatment or followup (mean 22.5 months). Conclusions. Rituximab is a safe and well-tolerated ancillary treatment for recurrent FSGS in pediatric patients in conjunction with plasmapheresis. PMID:21577271

  10. Treatment of Recurrent Focal Segmental Glomerulosclerosis in Pediatric Kidney Transplant Recipients: Effect of Rituximab

    PubMed Central

    Sethna, Christine; Benchimol, Corinne; Hotchkiss, Hilary; Frank, Rachel; Infante, Lulette; Vento, Suzanne; Trachtman, Howard

    2011-01-01

    Recurrence of focal segmental glomerulosclerosis (FSGS) after renal transplantation is a complication that often leads to graft loss. There is no consensus on the optimal treatment of recurrent FSGS. Rituximab, a monoclonal antibody to CD20, may be a useful treatment of this complication. Methods. We report four pediatric cases of recurrent FSGS treated with rituximab and plasmapheresis. Results. Four children (2M/2F), age 15.3 ± 2.6, with recurrent FSGS posttransplant were identified. Four doses of rituximab were administered 171 ± 180 days posttransplant and 114 ± 169 days after the start of plasmapheresis. Three children responded with complete remission, one of whom relapsed after four months. One child had a partial response with a decrease in proteinuria that was not sustained. No adverse side effects were reported during treatment or followup (mean 22.5 months). Conclusions. Rituximab is a safe and well-tolerated ancillary treatment for recurrent FSGS in pediatric patients in conjunction with plasmapheresis. PMID:21577271

  11. Treatment of myelitis in Behçet's disease with rituximab

    PubMed Central

    Messina, Maria Josè; Rodegher, Mariaemma; Scotti, Roberta; Martinelli, Vittorio

    2014-01-01

    Behçet's disease (BD) is a chronic inflammatory disorder that involves the parenchymal central nervous system (neuro-BD, NBD) approximately in 5–49% of patients, causing lesions rarely located in the spinal cord (SC). We report the first case of NBD-myelitis treated with intravenous rituximab. A 41-year-old man affected by BD presented with mild paraparesis with a miliary involvement and a ‘net-like’ gadolinium enhancement (Gde) of the SC. After a therapeutic attempt with pulsed cyclophosphamide and intravenous methylprednisolone, the clinical and neuroradiological course worsened. A progressive improvement was observed after rituximab administration associated with low doses of oral prednisone. No disease activity was detected and the patient reported no adverse event. After six rituximab cycles, cervical MRI was normal while thoracic MRI showed a slight T2–weighted hyperintensity of D4–D10 spinal tract without Gde. A combined use of rituximab and oral steroids resulted in a long-term suppression of NBD activity without any safety concern. PMID:24879733

  12. Rituximab in the treatment of autoimmune haemolytic anaemia.

    PubMed

    Rodrigo, Chaturaka; Rajapakse, Senaka; Gooneratne, Lallindra

    2015-05-01

    Rituximab is a B-cell depleting monoclonal antibody that is gaining popularity as an effective therapy for many autoimmune cytopenias. This article systematically evaluates its therapeutic efficacy in the treatment of different types of autoimmune haemolytic anaemia. We conclude that there is sufficient evidence to recommend it as a second line therapy for warm autoimmune haemolytic anaemia (wAIHA) either as monotherapy or combined therapy. Evidence from a single randomized controlled trial suggests that it may also be more efficacious as first line therapy in combination with steroids than steroids alone. A fewer number of studies have assessed its role in cold autoimmune haemolytic anaemia (cAIHA) and cold agglutinin disease (CAD) with success rates varying from 45-66%. In the absence of alternative definitive therapy, rituximab should be considered for patients with symptomatic CAD and significant haemolysis. Case reports of its efficacy in mixed autoimmune haemolytic anaemias are available but evidence from case series or larger cohorts are nonexistent. PMID:25139610

  13. Common variable immunodeficiency, immune thrombocytopenia, rituximab and splenectomy: important considerations.

    PubMed

    Arays, Ruta; Goyal, Sahil; Jordan, Kim M

    2016-08-01

    Common variable immunodeficiency (CVID) is readily considered in patients presenting with recurrent sino-pulmonary infections, however this disease has a broad range of clinical manifestations and diagnosis can be delayed by several years. We present the case of a 44-year-old postpartum female who presented with nausea, vomiting and abdominal distension. Four years prior, she was hospitalized for treatment of immune thrombocytopenia (ITP) with splenectomy and rituximab followed by two episodes of bacterial meningitis despite immunizations. The recurrent meningitis had been attributed to splenectomy and immunotherapy. During this hospitalization, extensive workup for gastrointestinal pathology was negative and she was diagnosed with intestinal pseudo-obstruction. Her hospital course was complicated by development of severe pseudomonas pneumonia, and subsequent immunoglobulin testing and impaired antibody response to vaccines were consistent with CVID. We review the clinical presentation of CVID, its association with autoimmune disease, and treatment implications, specifically the impact of rituximab therapy and splenectomy on immunoglobulin function and risk of serious infection. Intestinal pseudo-obstruction has been reported in children with CVID, but literature search failed to reveal similar presentation in adults. Physicians must consider the heterogeneous clinical manifestations of CVID to avoid delay in diagnosis and treatment. Institution of appropriate therapy with immunoglobulin replacement is important to decrease risk of serious infection. PMID:27276370

  14. Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma.

    PubMed

    Boland, A; Bagust, A; Hockenhull, J; Davis, H; Chu, P; Dickson, R

    2009-09-01

    This paper presents a summary of the evidence review group report into the clinical effectiveness and cost-effectiveness of rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma (NHL), in accordance with the licensed indication, based upon the evidence submission from Roche Products Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence included two randomised controlled trials [European Organisation for Research and Treatment of Cancer (EORTC) and German Low Grade Lymphoma Study Group - Fludarabine, Cyclophosphamide and Mitoxantrone and (GLSG-FCM)] comparing the clinical effects of chemotherapy with or without rituximab in the induction of remission at first or second relapse and the clinical benefits of rituximab maintenance therapy versus the NHS's current clinical practice of observation for follicular lymphoma (FL) patients. Both trials showed that in patients with relapsed FL the addition of rituximab to chemotherapy induction treatment increased overall response rates. Furthermore, rituximab maintenance therapy increased the median length of remission when compared with observation only. Safety data from the two trials showed that while the majority of patients reported some adverse events, the number of patients withdrawing from treatment in the EORTC trial was low, with rates not being reported for the GLSG-FCM trial. The most commonly reported adverse events were blood/bone marrow toxicity, skin rashes and allergies. The ERG reran the manufacturer's economic model after altering several of the assumptions and parameter values in order to recalculate the cost-utility ratios, quality-adjusted life-years (QALYs) and estimates of benefits. The manufacturer reported that maintenance therapy with rituximab was cost-effective compared with observation against commonly applied thresholds, with an incremental

  15. Rapid exacerbation of neuromyelitis optica after rituximab treatment.

    PubMed

    Dai, Yongqiang; Lu, Tingting; Wang, Yuge; Fang, Ling; Li, Rui; Kermode, Allan G; Qiu, Wei

    2016-04-01

    Studies have shown the efficacy of immunosuppressants against neuromyelitis optica (NMO). Rituximab is recommended as an off-label prescription to treat refractory NMO. However, we describe two such patients who were suboptimally responsive to rituximab and whose symptoms worsened after treatment. Our cautionary cases highlight that in a small proportion of patients with refractory NMO, rituximab may either fail or induce rapid relapse of NMO. This suggests we need to consider new treatment strategies for refractory NMO. PMID:26704780

  16. Late Occurrence of PML in a Patient Treated for Lymphoma with Immunomodulatory Chemotherapies, Bendamustine, Rituximab, and Ibritumomab Tiuxetan

    PubMed Central

    Lane, Michael A.; Renga, Vijay; Pachner, Andrew R.; Cohen, Jeffrey A.

    2015-01-01

    PML caused by John Cunningham (JC) virus is a rare but an increasingly recognized entity. With the advent of newer immunomodulatory therapies with monoclonal antibodies, there is an increasing incidence of PML. Initially concern was restricted to patients treated for multiple sclerosis with natalizumab but more case reports are being reported during treatment for other conditions like Crohn's disease and lymphoma with agents such as rituximab. We report the case of a 66-year-old woman who developed PML a year after completion of therapy with rituximab, ibritumomab, and bendamustine. PMID:25705531

  17. Use of rituximab as a treatment for systemic lupus erythematosus: retrospective review

    PubMed Central

    Machado, Roberta Ismael Lacerda; Scheinberg, Morton Aaron; de Queiroz, Maria Yvone Carlos Formiga; de Brito, Danielle Christinne Soares Egypto; Guimarães, Maria Fernanda Brandao de Resende; Giovelli, Raquel Altoé; Freire, Eutilia Andrade Medeiros

    2014-01-01

    ABSTRACT Objective: To report the experience in three Brazilian institutions with the use of rituximab in patients with different clinical forms of lupus erythematosus systemic in activity. Methods: The study consisted of a sample of 17 patients with LES, who were already being treated, but that at some stage of the disease showed refractory symptoms. The patients were subdivided into groups according to the clinical manifestation, and the responses for the use of rituximab were rated as complete, partial or no response. Data were collected through a spreadsheet, and used specific parameters for each group. The treatment was carried on by using therapeutic dose of 1g, and repeating the infusion within an interval of 15 days. Results: The clinical responses to rituximab of the group only hematological and of the group only osteoarticular were complete in all cases. In the renal group there was a clinical complete response, two partial and one absent. In the renal and hematological group complete response, there was one death and a missing response. The pulmonary group presented a complete response and two partial. Conclusion: The present study demonstrated that rituximab can bring benefits to patients with lupus erythematosus systemic, with good tolerability and mild side effects; it presented, however, variable response according to the system affected. PMID:24728244

  18. Target-directed development and preclinical characterization of the proposed biosimilar rituximab GP2013

    PubMed Central

    Kronthaler, Ulrich; Koppenburg, Vera; Fink, Martin; Meyer, Ines; Papandrikopoulou, Anastassia; Hofmann, Matthias; Stangler, Thomas; Visser, Jan

    2014-01-01

    Biosimilar development involves a target-directed iterative process to ensure a similar product to the originator. Here we report the preclinical development of the proposed biosimilar rituximab (GP2013). Post-translational modifications and bioactivities of GP2013 versus originator rituximab were engineered and monitored to ensure similar pharmacological profiles. Antibody-dependent cellular cytotoxicity (ADCC) was used to illustrate how different glycosylation patterns and structure–function relationships were controlled during process development. Pharmacological comparability between GP2013 and originator rituximab were confirmed in preclinical studies using clinical scale drug product. Similar in vitro ADCC potency was demonstrated when compared in a dose–response manner against two lymphoma cell lines using freshly purified human natural killer (NK) cells. In vivo efficacy was demonstrated in two well characterized mouse xenograft models, testing at sensitive sub-therapeutic dose levels. Pharmacokinetics and pharmacodynamics (CD20 cell depletion) were likewise comparable in cynomolgus monkeys. This preclinical comparability exercise confirms that GP2013 and originator rituximab are pharmacologically similar. PMID:24024472

  19. Safety and efficacy of intrathecal rituximab in children with B cell lymphoid CD20+ malignancies: An international retrospective study.

    PubMed

    Ceppi, Francesco; Weitzman, Sheila; Woessmann, Wilhelm; Davies, Kimberly; Lassaletta, Alvaro; Reismüller, Bettina; Mellgren, Karin; Uyttebroeck, Anne; Maia, Iris; Abdullah, Shaker; Miakova, Natasha; Glaser, Darryl; Cohn, Richard; Abla, Oussama; Attarbaschi, Andishe; Alexander, Sarah

    2016-05-01

    Central nervous system (CNS) involvement in patients with mature B non-Hodgkin lymphoma, post-transplantation proliferative disorder and acute lymphoblastic leukemia confers a significantly inferior prognosis as compared to patients without CNS disease. Intrathecal (IT) or intraventricular administration of rituximab is an option for this group of patients. We report 25 children with CNS involvement of CD20+ B lymphoid malignancies who received in total 163 IT/intraventricular rituximab doses. The median number of doses received by each patient was 6, with a median dose of 25 mg. The most common adverse events were Grades 1 and 2 peripheral neuropathies in five patients (20%), allergy in two patients, and headache in two patients. These events were self-limited, occurring in the 48 hours after treatment and resolving within 24 hr. Three patients presented with more severe though transient side effects, one with a Grade III neuropathy and two with seizure. Eighteen patients (72%) of those treated with IT/intraventricular rituximab, with or without other CNS directed treatment, achieved a CNS remission. This case series suggests that IT/intraventricular rituximab has therapeutic efficacy and relatively limited toxicity. Prospective trials of IT/intraventricular rituximab for patients with CNS involvement of CD20 + B lymphoid malignancies are warranted. Am. J. Hematol. 91:486-491, 2016. © 2016 Wiley Periodicals, Inc. PMID:26872652

  20. Rituximab Desensitization in Pediatric Patients: Results of a Case Series

    PubMed Central

    Lee, Joyce P.; Platt, Craig D.

    2016-01-01

    Rituximab is a monoclonal antibody (mAb) primarily used to treat oncologic and autoinflammatory conditions. Although hypersensitivity reactions (HSRs) and desensitization protocols to mAbs have been well described in adults, the experience in the pediatric population is very limited. We sought to determine the safety and efficacy of desensitization to rituximab in the pediatric population at our institution. We retrospectively reviewed the experience with HSRs and desensitization to rituximab during a 5-year period in our tertiary care pediatric center, including reaction evaluation, premedication regimens, and desensitization procedures and protocols. A total of 17 desensitizations to rituximab were performed in three patients. A 14-year-old patient underwent successful desensitization to rituximab using a published adult protocol without incident. Two younger patients (ages 7 years and 23 months) experienced significant reactions during initial desensitization attempts. Therefore, we designed a modified desensitization protocol to rituximab, with particular attention to the rate of infusion as mg/kg/h. This new patient weight-based protocol was successfully used in a total of 13 desensitizations in these two patients. Desensitization to rituximab was a safe and effective procedure in our pediatric population. We present a new patient weight-based desensitization protocol for pediatric patients who develop HSRs to rituximab, with particular usefulness for younger pediatric patients and potential utility in pediatric patients with HSRs to other mAbs.

  1. Rituximab and chemotherapy in diffuse large B-cell lymphoma.

    PubMed

    Sonet, Anne; Bosly, André

    2009-06-01

    Rituximab is an anti-CD20 chimeric monoclonal antibody with activity in nearly all subtypes of B-cell lymphomas. Association of rituximab with chemotherapy (mostly the cyclophosphamide, doxorubicin, vincristine and prednisolone [CHOP] regimen) in diffuse large B-cell lymphoma (DLBCL) represents an extraordinary revolution in the prognosis of DLBCL, and is the new standard of therapy in elderly and young, low-risk patients. Despite the lack of randomized, clinical trials in younger patients with high risk, rituximab is also a standard of care in these patients in clinical practice, at least in North America. The practice is based on observational trials (e.g., the British Columbia Registry) and the missing logic in classifying patients as 'younger' or 'older': 60 years old or 65 years old. In Europe, trials are ongoing to establish the best treatment for young, high-risk patients. Association of rituximab and chemotherapy deeply modifies prognostic factors defined before the rituximab era. PMID:19496708

  2. [Recurrent infections in an ITP patient treated with rituximab].

    PubMed

    Rosenberg-Bezalel, Shira; Asher, Ilan; Sthoeger, Zev

    2012-11-01

    Common variable immunodeficiency (CVID) is a heterogeneous group of disorders characterized by hypogammaglobulinemia and recurrent infections. Various mechanisms have been implied in the disease pathophysiology. Patients with CVID are at increased risk of developing ITP (Immune Thrombocytopenia Purpura) and/ or AIHA (Autoimmune Haemolytic Anemia). Rituximab, a humanized anti-CD20 monoclonal antibody, is increasingly being used for autoimmune cytopenias including ITP and AIHA. This is a case history of a patient treated with Rituximab due to refractory ITP. A year after completion of therapy the patient started suffering from an increased frequency of infections. Six years after treatment with Rituximab the patient was diagnosed with CVID and IVIG replacement treatment was started. The main possibilities that this patient presents include aggravation of CVID, first presented as ITP, after Rituximab treatment versus CVID secondary to Rituximab treatment. PMID:23367730

  3. A Case of Fulminant Hepatitis due to Echovirus 9 in a Patient on Maintenance Rituximab Therapy for Follicular Lymphoma

    PubMed Central

    Thomson, S. J.; Legg, Joanne; Narat, Santosh

    2015-01-01

    Rituximab is a CD20 monoclonal antibody commonly used in the treatment of haematological malignancies. It causes lymphopenia with subsequent compromised humoral immunity resulting in an increased risk of infection. A number of infections and viral reactivations have been described as complicating Rituximab therapy. We report an apparently unique case of echovirus 9 (an enterovirus) infection causing an acute hepatitis and significant morbidity in an adult patient on maintenance treatment of Rituximab for follicular lymphoma. We also describe potential missed opportunities to employ more robust screening for viral infections which may have prevented delays in the appropriate treatment and thus may have altered the patient's clinical course. We also make suggestions for lowering the threshold of viral testing in similar patients in the future. PMID:26106492

  4. Rituximab in B-Lineage Adult Acute Lymphoblastic Leukemia.

    PubMed

    Maury, Sébastien; Chevret, Sylvie; Thomas, Xavier; Heim, Dominik; Leguay, Thibaut; Huguet, Françoise; Chevallier, Patrice; Hunault, Mathilde; Boissel, Nicolas; Escoffre-Barbe, Martine; Hess, Urs; Vey, Norbert; Pignon, Jean-Michel; Braun, Thorsten; Marolleau, Jean-Pierre; Cahn, Jean-Yves; Chalandon, Yves; Lhéritier, Véronique; Beldjord, Kheira; Béné, Marie C; Ifrah, Norbert; Dombret, Hervé

    2016-09-15

    Background Treatment with rituximab has improved the outcome for patients with non-Hodgkin's lymphoma. Patients with B-lineage acute lymphoblastic leukemia (ALL) may also have the CD20 antigen, which is targeted by rituximab. Although single-group studies suggest that adding rituximab to chemotherapy could improve the outcome in such patients, this hypothesis has not been tested in a randomized trial. Methods We randomly assigned adults (18 to 59 years of age) with CD20-positive, Philadelphia chromosome (Ph)-negative ALL to receive chemotherapy with or without rituximab, with event-free survival as the primary end point. Rituximab was given during all treatment phases, for a total of 16 to 18 infusions. Results From May 2006 through April 2014, a total of 209 patients were enrolled: 105 in the rituximab group and 104 in the control group. After a median follow-up of 30 months, event-free survival was longer in the rituximab group than in the control group (hazard ratio, 0.66; 95% confidence interval [CI], 0.45 to 0.98; P=0.04); the estimated 2-year event-free survival rates were 65% (95% CI, 56 to 75) and 52% (95% CI, 43 to 63), respectively. Treatment with rituximab remained associated with longer event-free survival in a multivariate analysis. The overall incidence rate of severe adverse events did not differ significantly between the two groups, but fewer allergic reactions to asparaginase were observed in the rituximab group. Conclusions Adding rituximab to the ALL chemotherapy protocol improved the outcome for younger adults with CD20-positive, Ph-negative ALL. (Funded by the Regional Clinical Research Office, Paris, and others; ClinicalTrials.gov number, NCT00327678 .). PMID:27626518

  5. Mutational profile and prognostic significance of TP53 in diffuse large B-cell lymphoma patients treated with R-CHOP: report from an International DLBCL Rituximab-CHOP Consortium Program Study.

    PubMed

    Xu-Monette, Zijun Y; Wu, Lin; Visco, Carlo; Tai, Yu Chuan; Tzankov, Alexander; Liu, Wei-min; Montes-Moreno, Santiago; Dybkaer, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L; Hsi, Eric D; Zhao, X Frank; Choi, William W L; Zhao, Xiaoying; van Krieken, J Han; Huang, Qin; Huh, Jooryung; Ai, Weiyun; Ponzoni, Maurilio; Ferreri, Andrés J M; Zhou, Fan; Kahl, Brad S; Winter, Jane N; Xu, Wei; Li, Jianyong; Go, Ronald S; Li, Yong; Piris, Miguel A; Møller, Michael B; Miranda, Roberto N; Abruzzo, Lynne V; Medeiros, L Jeffrey; Young, Ken H

    2012-11-01

    TP53 mutation is an independent marker of poor prognosis in patients with diffuse large B-cell lymphoma (DLBCL) treated with cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (CHOP) therapy. However, its prognostic value in the rituximab immunochemotherapy era remains undefined. In the present study of a large cohort of DLBCL patients treated with rituximab plus CHOP (R-CHOP), we show that those with TP53 mutations had worse overall and progression-free survival compared with those without. Unlike earlier studies of patients treated with CHOP, TP53 mutation has predictive value for R-CHOP-treated patients with either the germinal center B-cell or activated B-cell DLBCL subtypes. Furthermore, we identified the loop-sheet-helix and L3 motifs in the DNA-binding domain to be the most critical structures for maintaining p53 function. In contrast, TP53 deletion and loss of heterozygosity did not confer worse survival. If gene mutation data are not available, immunohistochemical analysis showing > 50% cells expressing p53 protein is a useful surrogate and was able to stratify patients with significantly different prognoses. We conclude that assessment of TP53 mutation status is important for stratifying R-CHOP-treated patients into distinct prognostic subsets and has significant value in the design of future therapeutic strategies. PMID:22955915

  6. Preparation & in vitro evaluation of 90Y-DOTA-rituximab

    PubMed Central

    Kameswaran, Mythili; Pandey, Usha; Dash, Ashutosh; Samuel, Grace; Venkatesh, Meera

    2016-01-01

    Background & objectives: Radioimmunotherapy is extensively being used for the treatment of non-Hodgkin's lymphoma (NHL). Use of rituximab, a chimeric anti-CD20 antibody directed against the CD20 antigen in combination with suitable beta emitters is expected to result in good treatment response by its cross-fire and bystander effects. The present work involves the conjugation of p-isothiocyanatobenzyl DOTA (p-SCN-Bn-DOTA) to rituximab, its radiolabelling with 90Y and in vitro and in vivo evaluation to determine its potential as a radioimmunotherapeutic agent. Methods: Rituximab was conjugated with p-SCN-Bn-DOTA at 1:1 antibody: DOTA molar ratio. The number of DOTA molecules linked to one molecule of rituximab was determined by radioassay and spectroscopic assay. Radiolabelling of rituximab with 90Y was carried out and its in vitro stability was evaluated. In vitro cell binding studies were carried out in Raji cells expressing CD20 antigen. Biodistribution studies were carried out in normal Swiss mice. Results: Using both radioassay and spectroscopic method, it was determined that about five molecules of DOTA were linked to rituximab. Radiolabelling of the rituximab conjugate with 90Y and subsequent purification on PD-10 column gave a product with radiochemical purity (RCP) > 98 per cent which was retained at > 90 per cent up to 72 h when stored at 37°C. In vitro cell binding experiments of 90Y-DOTA-rituximab with Raji cells exhibited specific binding of 20.7 ± 0.1 per cent with 90Y-DOTA-rituximab which reduced to 15.5 ± 0.2 per cent when incubated with cold rituximab. The equilibrium constant Kd for 90Y-DOTA-Rituximab was determined to be 3.38 nM. Radiolabelled antibody showed clearance via hepatobiliary and renal routes and activity in tibia was found to be quite low indicating in vivo stability of 90Y-DOTA-rituximab. Interpretation & conclusions: p-SCN-Bn-DOTA was conjugated with rituximab and radiolabelling with 90Y was carried out. In vitro studies carried

  7. Fatal haemoptysis in a case of lymphomatoid granulomatosis treated with rituximab.

    PubMed

    Jaffre, S; Jardin, F; Dominique, S; Duet, E; Hubscher, Ph; Genevois, A; Corne, F; Bota, S; Nouvet, G; Thiberville, L

    2006-03-01

    Lymphomatoid granulomatosis is a rare angiocentric and angiodestructive disease, which commonly involves the lungs but also the brain, kidneys, liver and skin. This report describes the case of a 33-yr-old female with an aggressive form of lymphoid granulomatosis treated with an anti-CD20 antibody. Dramatic radiological improvement was seen at the fourth week. However, the patient died at home 1 month after the last rituximab administration from a massive haemoptysis. PMID:16507866

  8. Successful Management of Refractory Dialysis Independent Wegener's Granulomatosis with Combination of Therapeutic Plasma Exchange and Rituximab.

    PubMed

    Malhotra, Sheetal; Dhawan, Hari Krishan; Sharma, Ratti Ram; Marwaha, Neelam; Sharma, Aman

    2016-06-01

    Wegeners granulomatosis (WG) is an autoimmune, antineutrophil cytoplasmic antibody mediated necrotizing vasculitis involving renal, and upper and lower respiratory systems. Treatment relies on a combination of immunosuppressive drugs and tapering regimen of glucocorticoids. Therapeutic plasma exchange (TPE) has been recognized as a second line treatment. We report the successful use of TPE in combination with rituximab in achieving remission in a patient with WG (dialysis independent) not responding to conventional therapy. PMID:27408429

  9. The spectrum of use of rituximab in chronic lymphocytic leukemia

    PubMed Central

    Tedeschi, Alessandra; Vismara, Eleonora; Ricci, Francesca; Morra, Enrica; Montillo, Marco

    2010-01-01

    The monoclonal chimeric anti-CD20 antibody, rituximab, has considerably improved therapeutic outcome in B-cell chronic lymphocytic leukemia. Rituximab has limited clinical activity when used as a single agent. The combination of the monoclonal antibody with fludarabine-based regimens clearly demonstrated, in Phase II and randomized trials, an increase in clinical efficacy in previously untreated and pretreated patients. Furthermore the addition of rituximab enabled the eradication of minimal residual disease, which is correlated with the prognosis in a high proportion of patients. Although the combination of rituximab with fludarabine-based regimens increased myelosuppression and immunosuppression, incidence of infections did not increase. The benefit of adding rituximab to other purine analogs or other chemotherapeutic combination regimens has also been explored. Moreover there could be a role for achieving better quality of responses with the combination of different monoclonal antibodies, considering that they target different antigens and exert different mechanism of action. Although the role of rituximab as maintenance therapy in low grade non-Hodgkin’s lymphomas has been determined, the benefit and optimal schedule in chronic lymphocytic leukemia are still under investigation. This review brings together knowledge of the pharmacokinetics, mechanism of action and clinical use of rituximab in chronic lymphocytic leukemia. PMID:21289858

  10. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis

    PubMed Central

    Fornoni, Alessia; Sageshima, Junichiro; Wei, Changli; Merscher-Gomez, Sandra; Robier, Aguillon-Prada; Jauregui, Alexandra N.; Li, Jing; Mattiazzi, Adela; Ciancio, Gaetano; Chen, Linda; Zilleruelo, Gaston; Abitbol, Carolyn; Chandar, Jayanthi; Seeherunvong, Wacheree; Ricordi, Camillo; Ikehata, Masami; Rastaldi, Maria Pia; Reiser, Jochen; Burke, George W.

    2013-01-01

    Focal segmental glomerulosclerosis (FSGS) is a prevalent glomerular disease characterized by proteinuria, progression to end stage renal disease and recurrence of proteinuria after kidney transplantation in approximately one third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab recognizes CD20 on B-lymphocytes but might also bind sphingomyelin-phosphodiesterase-acid-like-3b (SMPDL-3b) and regulates acid-sphyngomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. Incidence of nephrotic-range proteinuria and change in estimated glomerular filtration rate (ΔeGFR) were analyzed. SMPDL-3b immunostaining was performed in post-reperfusion kidney biopsies. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of post-transplant proteinuria and decreased ΔeGFR. The number of SMPDL-3b+ podocytes in post-reperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase downregulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Either SMPDL-3b overexpression or treatment with rituximab prevented disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where the gene encoding SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b–dependent manner. PMID:21632984

  11. Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis.

    PubMed

    Fornoni, Alessia; Sageshima, Junichiro; Wei, Changli; Merscher-Gomez, Sandra; Aguillon-Prada, Robier; Jauregui, Alexandra N; Li, Jing; Mattiazzi, Adela; Ciancio, Gaetano; Chen, Linda; Zilleruelo, Gaston; Abitbol, Carolyn; Chandar, Jayanthi; Seeherunvong, Wacheree; Ricordi, Camillo; Ikehata, Masami; Rastaldi, Maria Pia; Reiser, Jochen; Burke, George W

    2011-06-01

    Focal segmental glomerulosclerosis (FSGS) is a glomerular disease characterized by proteinuria, progression to end-stage renal disease, and recurrence of proteinuria after kidney transplantation in about one-third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab not only recognizes CD20 on B lymphocytes, but might also bind sphingomyelin phosphodiesterase acid-like 3b (SMPDL-3b) protein and regulate acid sphingomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of posttransplant proteinuria and stabilization of glomerular filtration rate. The number of SMPDL-3b(+) podocytes in postreperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase down-regulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Overexpression of SMPDL-3b or treatment with rituximab was able to prevent disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b-dependent manner. PMID:21632984

  12. Primary renal lymphoma: long-term results of two patients treated with a chemotherapy + rituximab protocol.

    PubMed

    Vázquez-Alonso, F; Puche-Sanz, I; Sánchez-Ramos, C; Flores-Martín, J; Vicente-Prados, J; Cózar-Olmo, J M

    2012-01-01

    Primary renal lymphoma (PRL) is a rare disease of which the etiology and pathogenesis remain controversial, and there is currently no standard treatment for it. We present the results of a long-term followup of two patients who were diagnosed with PRL and treated with cyclophosphamide, adriamycin, vincristine, prednisolone and rituximab (CHOP + R) regimen. Both patients reached a complete response, and there is no evidence of recurrence after 4.5- and 5-year followup periods. Based on our experience and other recently published studies, we recommend the combination of CHOP + rituximab as the elective treatment for this disease. To our knowledge, this is the longest followup period with a complete response that has been reported with this modality of treatment. PMID:22997596

  13. False Positive B-Cells Crossmatch after Prior Rituximab Exposure of the Kidney Donor

    PubMed Central

    Desoutter, Judith; Apithy, Marie-Joëlle; Bartczak, Ségolène; Guillaume, Nicolas

    2016-01-01

    Crossmatching is essential prior to kidney transplantation to confirm compatibility between the donor and the recipient, particularly to prevent acute antibody-mediated rejection. An unexpected positive crossmatch may be obtained in recipients with an autoimmune disease or preexisting antibodies not detected by single-antigen bead array due to complement interference or who have been previously treated by desensitization protocols such as rituximab, antithymocyte globulin, or intravenous immunoglobulins. We report donor and recipient investigations that revealed unexpected positive B-cells crossmatch, probably due to donor cells, as the donor had received rituximab therapy shortly before organ harvesting, in a context of severe idiopathic thrombocytopenic purpura. We consequently detected unexpected Class II IgG complement-dependent cytotoxicity for all sera tested. Other laboratory investigations failed to elucidate the reasons for this recipient-related positivity.

  14. Rituximab-induced neutropenia in a patient with inflammatory myopathy and systemic sclerosis overlap disease

    PubMed Central

    Roberts, Mark; Oddis, Chester; Herrick, Arianne; Chinoy, Hector

    2016-01-01

    Rituximab (RTX) is a monoclonal chimeric antibody directed against the CD20 antigen of B lymphocytes. Late onset neutropenia (LON) is a recognised complication of rituximab usually occurring 4 weeks after the last dose and is reported in both haematological and rheumatological conditions. However, it has never been described in a patient with myositis and systemic sclerosis overlap disease. We describe a case of LON in a 54-year-old man who was diagnosed with myositis and then systemic sclerosis overlap disease. It resolved within 7 days, and the patient did not suffer neutropenic sepsis or any other complications. We propose similar mechanisms for LON as described in other conditions and routine blood monitoring in such patients. PMID:27407275

  15. Cost-effectiveness of rituximab in refractory cold agglutinin disease.

    PubMed

    Panwar, U; Mathews, C; Cullis, J O

    2008-08-01

    Cold haemagglutinin disease (CHAD) is an uncommon condition frequently associated with B-cell lymphoproliferative disorders and is refractory to conventional treatments used in autoimmune haemolytic anaemia. Rituximab has been used in this condition with favourable and lasting responses. Cost has been a major limitation to its use in such indication. We present cost-effectiveness analysis of the use of rituximab in two patients with CHAD. Rituximab successfully controlled haemolysis in both cases of CHAD and was found to be cost-effective through reducing transfusion needs. PMID:18665831

  16. Rituximab monitoring and redosing in pediatric neuromyelitis optica spectrum disorder

    PubMed Central

    Nosadini, Margherita; Alper, Gulay; Riney, Catherine J.; Benson, Leslie A.; Mohammad, Shekeeb S.; Ramanathan, Sudarshini; Nolan, Melinda; Appleton, Richard; Leventer, Richard J.; Deiva, Kumaran; Brilot, Fabienne; Gorman, Mark P.; Waldman, Amy T.; Banwell, Brenda

    2016-01-01

    Objective: To study rituximab in pediatric neuromyelitis optica (NMO)/NMO spectrum disorders (NMOSD) and the relationship between rituximab, B cell repopulation, and relapses in order to improve rituximab monitoring and redosing. Methods: Multicenter retrospective study of 16 children with NMO/NMOSD receiving ≥2 rituximab courses. According to CD19 counts, events during rituximab were categorized as “repopulation,” “depletion,” or “depletion failure” relapses (repopulation threshold CD19 ≥10 × 106 cells/L). Results: The 16 patients (14 girls; mean age 9.6 years, range 1.8–15.3) had a mean of 6.1 events (range 1–11) during a mean follow-up of 6.1 years (range 1.6–13.6) and received a total of 76 rituximab courses (mean 4.7, range 2–9) in 42.6-year cohort treatment. Before rituximab, 62.5% had received azathioprine, mycophenolate mofetil, or cyclophosphamide. Mean time from rituximab to last documented B cell depletion and first repopulation was 4.5 and 6.8 months, respectively, with large interpatient variability. Earliest repopulations occurred with the lowest doses. Significant reduction between pre- and post-rituximab annualized relapse rate (ARR) was observed (p = 0.003). During rituximab, 6 patients were relapse-free, although 21 relapses occurred in 10 patients, including 13 “repopulation,” 3 “depletion,” and 4 “depletion failure” relapses. Of the 13 “repopulation” relapses, 4 had CD19 10–50 × 106 cells/L, 10 had inadequate monitoring (≤1 CD19 in the 4 months before relapses), and 5 had delayed redosing after repopulation detection. Conclusion: Rituximab is effective in relapse prevention, but B cell repopulation creates a risk of relapse. Redosing before B cell repopulation could reduce the relapse risk further. Classification of evidence: This study provides Class IV evidence that rituximab significantly reduces ARR in pediatric NMO/NMOSD. This study also demonstrates a relationship between B cell repopulation

  17. Screening for viral hepatitis prior to rituximab chemotherapy.

    PubMed

    Leonard, A N; Love, B L; Norris, L B; Siddiqui, S K; Wallam, M N; Bennett, C L

    2016-01-01

    In 2008, the CDC published guidelines recommending screening of all persons undergoing treatment with rituximab to identify persons at risk of hepatitis B virus (HBV) reactivation. We evaluated implementation of this recommendation in veterans, who are at increased risk of HBV, and determined characteristics of those screened. We also evaluated a control setting, rates of hepatitis C virus (HCV) screening among the same rituximab-treated patients. There are no guidelines that recommend HCV screening prior to initiation of rituximab. Medical records of patients receiving rituximab between January 2006 and December 2012 were reviewed according to two time periods: 2006-2008 (period 1, pre-guidelines) and 2009-2012 (period 2, post-guidelines). Patient demographics, concomitant chemotherapy regimen (protocol, dose, duration), treatment indication, risk factors for hepatitis infection (substance abuse, homelessness, human immunodeficiency virus (HIV)), and HBV/HCV screening status were documented. During the study period, 102 patients were treated with rituximab (49 in period 1 and 53 in period 2). During periods 1 and 2, 22 and 32 % of rituximab-treated patients were screened for HBV, respectively (p = 0.375). Treatment during 2009 was the only significant predictor of HBV screening in the adjusted model (p = 0.01). For HCV during periods 1 and 2, 22 and 21 % of patients were screened, respectively (p = 1.00). There were no significant predictors of HCV screening. Rates of screening for HBV among rituximab-treated patients were low, both before and after dissemination of guidelines recommending universal HBV screening of rituximab-treated patients. PMID:26382277

  18. Brain Abscess following Rituximab Infusion in a Patient with Pemphigus Vulgaris

    PubMed Central

    Al-Harbi, Talal M.; Muammer, Shahad A.; Ellis, Ronald J.

    2015-01-01

    Patient: Female, 52 Final Diagnosis: Brain abscess Symptoms: Fever • headache • weakness, left sided Medication: Prednisolone • Azathioprine • Rituximab Clinical Procedure: Stereotactic brain biopsy and LP Specialty: Neurology Objective: Rare disease Background: Immunocompromised patients are at increased risk for developing meningitis or, rarely, brain abscess with opportunistic organisms like Listeria monocytogenes. Case Report: A 52 year-old Saudi Arabian woman who was diagnosed with pemphigus vulgaris and diabetes and had been on prednisolone and azathioprine for about 4 years. She presented with headache, low-grade fever, and left-sided weakness 2 weeks after receiving the second dose of rituximab infusion. Magnetic resonance imaging revealed an enhanced space-occupying lesion with multiple small cyst-like structures and vasogenic edema in the right temporoparietal area. Her blood culture was positive for Listeria monocytogenes, and a brain biopsy showed necrotic tissues with pus and inflammatory cells. She recovered after a 6-week course of antibiotics with ampicillin and gentamycin. Conclusions: Brain abscess due to Listeria monocytogenes is a risk that should be considered when adding rituximab to the regimen of a patient who is already Immunocompromised. PMID:25659437

  19. Clinical review: Serious adverse events associated with the use of rituximab - a critical care perspective

    PubMed Central

    2012-01-01

    The advent of biologic agents has provided a more specific and targeted approach to the treatment of various hematological malignancies and other autoimmune disorders. Such biologic agents have been relatively well tolerated with fewer adverse events reported as compared with many other chemotherapeutic agents. Rituximab is a monoclonal antibody to the B-cell marker CD20 and is a common biologic agent widely used for the treatment of B-cell lymphoma, lymphoproliferative disorders, and inflammatory conditions that are refractory to conventional treatment, including rheumatoid arthritis and some vasculitides. However, through randomized controlled trials and post-marketing surveillance, an increasing number of serious adverse events are being associated with the use of rituximab, often leading to or complicating an intensive care unit admission. The purpose of this review is to focus on the severe complications that are associated with the use of rituximab and that require critical care. Management and prevention strategies for the most common complications along with some examples of its uses within the critical care setting are also discussed. PMID:22967460

  20. Long-term outcomes to fludarabine and rituximab in Waldenström macroglobulinemia

    PubMed Central

    Branagan, Andrew R.; Ioakimidis, Leukothea; Soumerai, Jacob D.; Patterson, Christopher J.; Turnbull, Barry; Wasi, Parveen; Emmanouilides, Christos; Frankel, Stanley R.; Lister, Andrew; Morel, Pierre; Matous, Jeffrey; Gregory, Stephanie A.; Kimby, Eva

    2009-01-01

    We report the long-term outcome of a multicenter, prospective study examining fludarabine and rituximab in Waldenström macroglobulinemia (WM). WM patients with less than 2 prior therapies were eligible. Intended therapy consisted of 6 cycles (25 mg/m2 per day for 5 days) of fludarabine and 8 infusions (375 mg/m2 per week) of rituximab. A total of 43 patients were enrolled. Responses were: complete response (n = 2), very good partial response (n = 14), partial response (n = 21), and minor response (n = 4), for overall and major response rates of 95.3% and 86.0%, respectively. Median time to progression for all patients was 51.2 months and was longer for untreated patients (P = .017) and those achieving at least a very good partial response (P = .049). Grade 3 or higher toxicities included neutropenia (n = 27), thrombocytopenia (n = 7), and pneumonia (n = 6), including 2 patients who died of non–Pneumocystis carinii pneumonia. With a median follow-up of 40.3 months, we observed 3 cases of transformation to aggressive lymphoma and 3 cases of myelodysplastic syndrome/acute myeloid leukemia. The results of this study demonstrate that fludarabine and rituximab are highly active in WM, although short- and long-term toxicities need to be carefully weighed against other available treatment options. This study is registered at clinicaltrials.gov as NCT00020800. PMID:19015393

  1. Navitoclax (ABT-263) and bendamustine ± rituximab induce enhanced killing of non-Hodgkin's lymphoma tumours in vivo

    PubMed Central

    Ackler, S; Mitten, MJ; Chen, J; Clarin, J; Foster, K; Jin, S; Phillips, DC; Schlessinger, S; Wang, B; Leverson, JD; Boghaert, ER

    2012-01-01

    BACKGROUND AND PURPOSE Bendamustine with or without rituximab provides an effective and more tolerable alternative to the polytherapy cyclophosphamide–doxorubicin–vincristine–prednisolone (CHOP) in the treatment of haematological tumours and is currently approved for the treatment of many haematological malignancies. Navitoclax (ABT-263) is a potent inhibitor of Bcl-2, Bcl-xL and Bcl-w, which has demonstrated efficacy in haematological tumours alone and in combination with other agents. This paper describes the in vivo efficacy of combining either bendamustine or bendamustine plus rituximab (BR) with navitoclax in xenograft models of non-Hodgkin's lymphoma EXPERIMENTAL APPROACH Activity was tested in xenograft models of diffuse large B-cell lymphoma (DoHH-2, SuDHL-4), mantle cell lymphoma (Granta 519) and Burkitt's lymphoma (RAMOS). Activity was also monitored in a systemic model of Granta 519. KEY RESULTS Navitoclax potentiated bendamustine activity in all cell lines tested. Bendamustine activated p53 in Granta 519 tumours, concurrent with activation of caspase 3. Navitoclax also improved responses to bendamustine-rituximab (BR) in a subset of tumours. CONCLUSIONS AND IMPLICATIONS Navitoclax in combination with bendamustine and BR is a viable combination strategy for use in the clinic and demonstrated superior efficacy compared with previously reported data for navitoclax plus CHOP and rituximab-CHOP. PMID:22624727

  2. Impact of dose intensity on outcome of fludarabine, cyclophosphamide, and rituximab regimen given in the first-line therapy for chronic lymphocytic leukemia

    PubMed Central

    Bouvet, Emmanuelle; Borel, Cécile; Obéric, Lucie; Compaci, Gisèle; Cazin, Bruno; Michallet, Anne-Sophie; Laurent, Guy; Ysebaert, Loic

    2013-01-01

    Fludarabine-cyclophosphamide-rituximab is the most efficient first-line treatment for chronic lymphocytic leukemia patients. Many dose adjustments of the original MD Anderson Cancer Center regimen have been proposed. However, whether fludarabine-cyclophosphamide-rituximab relative dose intensity may have an impact on outcome has not yet been investigated. We retrospectively assessed relative dose intensity in 106 community-based patients included in our regional healthcare network from 2004-11, all receiving fludarabine-cyclophosphamide-rituximab as first-line treatment outside clinical trials. Dose reductions were observed in 51.4% of patients, mainly decided by the individual physician and not based on recommendations (52.7%), while there were fewer reports of toxicity or dose reduction because of impaired renal function. Progression-free survival was significantly reduced in patients who had a reduction in dose intensity of more than 20% in fludarabine-cyclophosphamide and/or rituximab. Multivariate analysis showed dose of rituximab had a significant impact on minimal residual disease and progression-free survival. Although prophylactic granulocyte-colony stimulating factor significantly reduced the rate of grade 3-4 neutropenia and febrile neutropenia, it had no impact on relative dose intensity and outcome. This study shows that, in routine clinical practice, there is low adherence to the original MD Anderson Cancer Center fludarabine-cyclophosphamide-rituximab schedule, and that the decision to modify dosage was mostly taken by the individual physician and was based on anticipated toxicity. This study shows that reduction of fludarabine-cyclophosphamide and, more importantly, of rituximab doses seriously interferes with progression-free survival. PMID:23065520

  3. Efficacy and safety of front-line therapy with fludarabine-cyclophosphamide-rituximab regimen for chronic lymphocytic leukemia outside clinical trials: the Israeli CLL Study Group experience.

    PubMed

    Herishanu, Yair; Goldschmidt, Neta; Bairey, Osnat; Ruchlemer, Rosa; Fineman, Riva; Rahimi-Levene, Naomi; Shvidel, Lev; Tadmor, Tamar; Ariel, Aviv; Braester, Andrea; Shapiro, Mika; Joffe, Erel; Polliack, Aaron

    2015-05-01

    This study aimed to evaluate the efficacy and safety of the fludarabine-cyclophosphamide-rituximab regimen for young physically fit patients with chronic lymphocytic leukemia in the "real-life" setting. We specifically focused on the impact of dose reduction on patient outcomes. The patient cohort consisted of 128 patients with chronic lymphocytic leukemia (≤ 70 years) treated at 10 Israeli centers with front-line fludarabine-cyclophosphamide-rituximab. We defined reduced chemotherapy as two-thirds or less of the total indicated dose. Patients treated with rituximab were divided into two groups and compared: those who received full dosages of 375 mg/m(2) or 500 mg/m(2), and patients given less than six cycles with either dose. Overall and clinical complete response rates (92.8% and 70.4%), as well as toxicities and overall survival (median not reached at 6 years), were similar to other reported clinical trials, but progression-free survival was shorter (42.5 months). Almost 50% of patients had some dose reduction of chemotherapy, 21% receiving less than two-thirds of the indicated dose, while close to 30% did not complete six cycles of rituximab. Reduced doses of chemotherapy and rituximab were independently associated with shorter progression-free survival (hazard ratio 3.6, P<0.0001 for reduced chemotherapy; hazard ratio 2.5, P=0.003 for incomplete-treatment with rituximab). Achieving a complete response was associated with longer overall survival but was not linked to the given dose of chemoimmunotherapy. In younger physically fit patients, front-line fludarabine-cyclophosphamide-rituximab therapy in the "real-life" setting achieves long remissions (albeit shorter than in clinical trials) and prolonged overall survival. However, dose reductions are commonly administered and may impact outcome. PMID:25661442

  4. Idelalisib and Rituximab in Relapsed Chronic Lymphocytic Leukemia

    PubMed Central

    Cheson, Bruce D.; Pagel, John M.; Hillmen, Peter; Barrientos, Jacqueline C.; Zelenetz, Andrew D.; Kipps, Thomas J.; Flinn, Ian; Ghia, Paolo; Eradat, Herbert; Ervin, Thomas; Lamanna, Nicole; Coiffier, Bertrand; Pettitt, Andrew R.; Ma, Shuo; Stilgenbauer, Stephan; Cramer, Paula; Aiello, Maria; Johnson, Dave M.; Miller, Langdon L.; Li, Daniel; Jahn, Thomas M.; Dansey, Roger D.; Hallek, Michael; O’Brien, Susan M.

    2014-01-01

    BACKGROUND Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemo-therapy. Effective therapies with acceptable side-effect profiles are needed for this patient population. METHODS In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta iso-form of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy. RESULTS The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P = 0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab. CONCLUSIONS The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemo-therapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.) PMID:24450857

  5. Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis

    PubMed Central

    Stone, John H.; Merkel, Peter A.; Spiera, Robert; Seo, Philip; Langford, Carol A.; Hoffman, Gary S.; Kallenberg, Cees G.M.; St. Clair, E. William; Turkiewicz, Anthony; Tchao, Nadia K.; Webber, Lisa; Ding, Linna; Sejismundo, Lourdes P.; Mieras, Kathleen; Weitzenkamp, David; Ikle, David; Seyfert-Margolis, Vicki; Mueller, Mark; Brunetta, Paul; Allen, Nancy B.; Fervenza, Fernando C.; Geetha, Duvuru; Keogh, Karina A.; Kissin, Eugene Y.; Monach, Paul A.; Peikert, Tobias; Stegeman, Coen; Ytterberg, Steven R.; Specks, Ulrich

    2011-01-01

    BACKGROUND Cyclophosphamide and glucocorticoids have been the cornerstone of remission-induction therapy for severe antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis for 40 years. Uncontrolled studies suggest that rituximab is effective and may be safer than a cyclophosphamide-based regimen. METHODS We conducted a multicenter, randomized, double-blind, double-dummy, noninferiority trial of rituximab (375 mg per square meter of body-surface area per week for 4 weeks) as compared with cyclophosphamide (2 mg per kilogram of body weight per day) for remission induction. Glucocorticoids were tapered off; the primary end point was remission of disease without the use of prednisone at 6 months. RESULTS Nine centers enrolled 197 ANCA-positive patients with either Wegener’s granulomatosis or microscopic polyangiitis. Baseline disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. Sixty-three patients in the rituximab group (64%) reached the primary end point, as compared with 52 patients in the control group (53%), a result that met the criterion for noninferiority (P<0.001). The rituximab-based regimen was more efficacious than the cyclophosphamide-based regimen for inducing remission of relapsing disease; 34 of 51 patients in the rituximab group (67%) as compared with 21 of 50 patients in the control group (42%) reached the primary end point (P = 0.01). Rituximab was also as effective as cyclophosphamide in the treatment of patients with major renal disease or alveolar hemorrhage. There were no significant differences between the treatment groups with respect to rates of adverse events. CONCLUSIONS Rituximab therapy was not inferior to daily cyclophosphamide treatment for induction of remission in severe ANCA-associated vasculitis and may be superior in relapsing disease. (Funded by the National Institutes of Allergy and Infectious Diseases, Genentech, and Biogen; Clinical

  6. B-Lymphocyte Depletion in Myalgic Encephalopathy/ Chronic Fatigue Syndrome. An Open-Label Phase II Study with Rituximab Maintenance Treatment

    PubMed Central

    Fluge, Øystein; Risa, Kristin; Lunde, Sigrid; Alme, Kine; Rekeland, Ingrid Gurvin; Sapkota, Dipak; Kristoffersen, Einar Kleboe; Sørland, Kari; Bruland, Ove; Dahl, Olav; Mella, Olav

    2015-01-01

    Background Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We previously reported a pilot case series followed by a small, randomized, placebo-controlled phase II study, suggesting that B-cell depletion using the monoclonal anti-CD20 antibody rituximab can yield clinical benefit in ME/CFS. Methods In this single-center, open-label, one-armed phase II study (NCT01156909), 29 patients were included for treatment with rituximab (500 mg/m2) two infusions two weeks apart, followed by maintenance rituximab infusions after 3, 6, 10 and 15 months, and with follow-up for 36 months. Findings Major or moderate responses, predefined as lasting improvements in self-reported Fatigue score, were detected in 18 out of 29 patients (intention to treat). Clinically significant responses were seen in 18 out of 28 patients (64%) receiving rituximab maintenance treatment. For these 18 patients, the mean response durations within the 156 weeks study period were 105 weeks in 14 major responders, and 69 weeks in four moderate responders. At end of follow-up (36 months), 11 out of 18 responding patients were still in ongoing clinical remission. For major responders, the mean lag time from first rituximab infusion until start of clinical response was 23 weeks (range 8–66). Among the nine patients from the placebo group in the previous randomized study with no significant improvement during 12 months follow-up after saline infusions, six achieved a clinical response before 12 months after rituximab maintenance infusions in the present study. Two patients had an allergic reaction to rituximab and two had an episode of uncomplicated late-onset neutropenia. Eight patients experienced one or more transient symptom flares after rituximab infusions. There was no unexpected toxicity. Conclusion In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed

  7. Improvement in Gemcitabine-Induced Thrombotic Microangiopathy with Rituximab in a Patient with Ovarian Cancer: Mechanistic Considerations

    PubMed Central

    Murugapandian, Sangeetha; Bijin, Babitha; Mansour, Iyad; Daheshpour, Sepehr; Pillai, Biju G.; Thajudeen, Bijin; Salahudeen, Abdulla K.

    2015-01-01

    Gemcitabine is a potent and widely used anticancer drug. We report a case of gemcitabine-induced thrombotic microangiopathy (GCI-TMA), a known but not widely recognized complication of gemcitabine use, and our experience of treating GCI-TMA with rituximab. A 74-year-old woman was referred to our clinic for an evaluation of worsening renal function. She has recently been treated for ovarian cancer (diagnosed in 2011) with surgery (tumor debulking and bilateral salpingo-oophorectomy) along with cisplatin chemotherapy in 2012, followed by carboplatin/doxorubicin in 2013 and recent therapy for resistant disease with gemcitabine. Laboratory tests showed anemia, normal platelets and elevated lactate dehydrogenase. A peripheral smear revealed numerous schistocytes, and a kidney biopsy showed acute as well as chronic TMA. The patient continued on gemcitabine therapy, and treatment with plasma exchange was started. Since there was no response to treatment even after 5 sessions of plasma exchange, one dose of rituximab was given, which was associated with a drop in the creatinine level to 2 mg/dl. The pathogenesis of renal injury could be the effect of direct injury to the endothelium mediated by cytokines. Usual treatment includes withdrawing the drug and initiation of treatment with plasmapheresis with or without steroids. In cases resistant to plasmapheresis, treatment with rituximab can be tried. The mechanism of action of rituximab might be due to the reduced production of B-cell-dependent cytokines that drive endothelial dysfunction by depleting B cells. Patients receiving gemcitabine chemotherapy should be monitored for the development of TMA, and early treatment with plasma exchange along with rituximab might benefit these patients who already have a bad prognosis. PMID:26266248

  8. A randomized phase II crossover study of imatinib or rituximab for cutaneous sclerosis after hematopoietic cell transplantation

    PubMed Central

    Arai, Sally; Pidala, Joseph; Pusic, Iskra; Chai, Xiaoyu; Jaglowski, Samantha; Khera, Nandita; Palmer, Jeanne; Chen, George L; Jagasia, Madan H; Mayer, Sebastian A; Wood, William A; Green, Michael; Hyun, Teresa S.; Inamoto, Yoshihiro; Storer, Barry E; Miklos, David B; Shulman, Howard M.; Martin, Paul J; Sarantopoulos, Stefanie; Lee, Stephanie J; Flowers, Mary E D

    2015-01-01

    Purpose Cutaneous sclerosis (CS) occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life. Experimental design We conducted a prospective, multi-center, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m2 intravenously weekly × 4 doses, repeatable after 3 months) for treatment of CS diagnosed within 18 months (NCT01309997). The primary endpoint was significant clinical response (SCR) at 6 months, defined as quantitative improvement in skin sclerosis or joint range of motion. Treatment success was defined as SCR at 6 months without crossover, recurrent malignancy or death. Secondary end points included changes of B cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and non-responders with each therapy. Results SCR was observed in 9 of 35 (26%, 95% CI 13-43%) participants randomized to imatinib and 10 of 37 (27%, 95% CI 14-44%) randomized to rituximab. Six (17%, 95% CI 7-34%) patients in the imatinib arm and 5 (14%, 95% CI 5-29%) in the rituximab arm had treatment success. Higher percentages of activated B cells (CD27+) were seen at enrollment in rituximab-treated patients who had treatment success (p = 0.01), but not in imatinib-treated patients. Conclusion These results support the need for more effective therapies for CS and suggest that activated B cells define a subgroup of patients with CS who are more likely to respond to rituximab. PMID:26378033

  9. Low absolute lymphocyte count and addition of rituximab confer high risk for interstitial pneumonia in patients with diffuse large B-cell lymphoma.

    PubMed

    Huang, Yu-Chung; Liu, Chia-Jen; Liu, Chun-Yu; Pai, Jih-Tung; Hong, Ying-Chung; Teng, Hao-Wei; Hsiao, Liang-Tsai; Chao, Ta-Chung; Gau, Jyh-Pyng; Liu, Jin-Hwang; Hsu, Hui-Chi; Chiou, Tzeon-Jye; Chen, Po-Min; Yu, Yuan-Bin; Tzeng, Cheng-Hwai

    2011-10-01

    Several small-scale studies have reported pulmonary toxicity among patients with diffuse large B-cell lymphoma (DLBCL) receiving rituximab-containing chemotherapy, though whether the use of rituximab predisposes to interstitial pneumonia (IP) remains unclear. This retrospective study was intended to identify the characteristics and risk factors of IP in patients with DLBCL. Between 2000 and 2009, 529 consecutive patients with DLBCL receiving first-line tri-weekly COP- or CHOP-based chemotherapy with or without rituximab were enrolled as subjects. IP was defined as diffuse pulmonary interstitial infiltrates found on computed tomography scans in conjunction with respiratory symptoms. IP was observed in 26 patients (4.9%), six of whom were confirmed with Pneumocystis jirovecii pneumonia. The median number of chemotherapy courses before IP was four cycles. Using multivariate analysis, absolute lymphocyte count less than 1×10(9)/l at diagnosis [odds ratio (OR) 2.75, p=0.014] and the addition of rituximab to chemotherapy (OR 4.56, p=0.003) were identified as independent risk factors for IP. In conclusion, the incidence of IP is increased in patients with DLBCL receiving rituximab-containing chemotherapy. Specific subgroups with lymphopenia at diagnosis may justify close scrutiny to detect pulmonary complications. PMID:21647583

  10. Is rituximab sub-optimally dosed in indolent B cell lymphoma?

    PubMed

    Sawalha, Yazeed; Rouphail, Basel; Jia, Xuefei; Dean, Robert M; Hill, Brian T; Jagadeesh, Deepa; Pohlman, Brad L; Smith, Mitchell R

    2016-09-01

    Rituximab pharmacokinetics are affected by gender, age and weight and can affect outcomes in aggressive B cell lymphoma. Less is known about the pharmacokinetics of rituximab in indolent B cell lymphoma (iNHL). We analysed the effects of gender, age, weight and body surface area on the outcomes of 303 patients treated with first line rituximab-based regimens for iNHL. The patients were divided into 3 treatment cohorts: rituximab only, rituximab + chemotherapy (R-CTX) and R-CTX followed by rituximab maintenance; furthermore, each cohort was subdivided as follicular (FL) or non-FL, based on histology. Older males and patients with higher weight had worse outcomes when treated with R-CTX, probably due to faster rituximab clearance. Our results concur with studies of R-CTX for DLBCL. As this effect was not observed in patients treated with rituximab alone or R-CTX followed by rituximab maintenance, we hypothesize that higher rituximab levels reached with weekly rituximab and/or prolonged exposure achieved with maintenance therapy exceed the therapeutic threshold, even with faster clearance, which nullifies the negative effect of higher weight and male gender. In conclusion, under current practices, a subset of patients with iNHL, i.e., FL treated with R-CTX, may be sub-optimally dosed with rituximab. PMID:27136331

  11. Rituximab for the Treatment of IgG4-Related Tubulointerstitial Nephritis

    PubMed Central

    McMahon, Blaithin A.; Novick, Tessa; Scheel, Paul J.; Bagnasco, Serena; Atta, Mohamed G.

    2015-01-01

    Abstract Immunoglobulin type gamma 4 (IgG4)-related disease is a relatively newly described clinical entity characterized by a distinctive histopathological appearance, increased numbers of IgG4 positive plasma cells and often, but not always, elevated serum IgG4 concentrations. The most common renal manifestation of IgG4-related disease is tubulointerstitial nephritis marked with proteinuria, hematuria, decreased kidney function, hypocomplementemia, and radiologic abnormalities. Renal biopsy characteristics include dense lymphoplasmacytic tubulointerstitial nephritis that stains for IgG4, storiform fibrosis, and immune complex deposition in the interstitium and along tubule basement membranes. Treatment traditionally consists of prolonged glucocorticoids but cases refractory to glucocorticoids have been reported. We report a case of a 58-year-old Caucasian man who presented with fatigue, 50 pound weight loss, dyspnea, lymphadenopathy, and nephromegaly. The patient was first misdiagnosed as chronic interstitial nephritis secondary to renal sarcoid and was treated with repeated doses of prednisone. On his third relapse, he underwent a repeat renal biopsy and a diagnosis of IgG4-tubulointerstitial nephritis was confirmed. He was refractory to treatment with prednisone. The patient received Rituximab and had prompt sustained improvement in renal function. At 1 year post Rituximab treatment, his serum creatinine remains at baseline and imaging study revealed reduction in his kidney size. This is the first case report using Rituximab as a steroid sparing option for refractory IgG4-tubulointerstitial nephritis. More information is needed on the long-term effects of using of B-cell depleting agents for glucocorticoid resistant IgG4-tubulointerstitial nephritis. PMID:26266393

  12. Developmental immunotoxicology assessment of rituximab in cynomolgus monkeys.

    PubMed

    Vaidyanathan, Anu; McKeever, Kathleen; Anand, Banmeet; Eppler, Steve; Weinbauer, Gerhard F; Beyer, Joseph C

    2011-01-01

    Rituximab is a chimeric murine/human-engineered immunoglobulin (Ig) G1 anti-CD20 monoclonal antibody, selectively depleting CD20-expressing cells in peripheral blood and lymphoid tissues. As part of the rituximab registration-enabling program for rheumatoid arthritis, cynomolgus monkey embryo-fetal development and pre- and postnatal developmental toxicity studies were performed. In both studies, female cynomolgus monkeys were administered rituximab iv at doses of 0/0, 15/20, 37.5/50, and 75/100 mg/kg (loading dose/study dose) from gestation day (GD) 20 to 50 for the embryo-fetal development study and GD 20 to postpartum (pp) day 28 for the pre- and postnatal study. In the embryo-fetal development study, although maternal dosing ended during the first trimester at GD 50, placental transfer of rituximab to fetuses was demonstrated at GD 100. Consequently, fetuses demonstrated B-cell depletion in lymphoid tissues at GD 100. Repletion of B cells was demonstrated in infants in a follow-up pre- and postnatal study following fetal and neonatal exposure. In the pre- and postnatal study, despite B-cell depletion, there was no significant functional consequence on the infant's ability to mount T-cell-dependent antibody responses following vaccination or antigenic challenge. Overall, rituximab was well tolerated at maximum feasible doses up to 100 mg/kg in pregnant cynomolgus monkeys and their infants after exposure from the period of organogenesis throughout pregnancy, parturition, and postnatal development. Importantly, the preclinical data have been concordant with the clinical data in children for cases where rituximab was administered during pregnancy. PMID:20937725

  13. A phase 2 study of inotuzumab ozogamicin in patients with indolent B-cell non-Hodgkin lymphoma refractory to rituximab alone, rituximab and chemotherapy, or radioimmunotherapy.

    PubMed

    Goy, Andre; Forero, Andres; Wagner-Johnston, Nina; Christopher Ehmann, W; Tsai, Michaela; Hatake, Kiyohiko; Ananthakrishnan, Revathi; Volkert, Angela; Vandendries, Erik; Ogura, Michinori

    2016-08-01

    This phase 2 study evaluated the efficacy and safety of inotuzumab ozogamicin (InO) in patients with indolent B-cell non-Hodgkin lymphoma (NHL) refractory to rituximab alone, rituximab plus chemotherapy or anti-CD20 radioimmunotherapy. Patients received InO 1·8 mg/m(2) intravenously on a 28-d cycle for a planned 4-8 cycles. The initial InO dose and schedule could be adjusted for tolerability and patients were allowed to receive 2 additional cycles (up to 8 total) after achieving a complete response (CR). The primary endpoint was overall response. Eighty-one patients were enrolled, among whom 48 (59%) received ≥3 InO cycles and 13 (16%) completed the treatment phase. The overall response rate was 67% (CR, 31%). Median (95% confidence interval) progression-free survival was 12·7 (8·9-26·9) months; median overall survival was not reached. Haematological adverse events (AEs) were common, particularly thrombocytopenia (74%) and neutropenia (56%). These were also the most common AEs leading to treatment discontinuation (37% and 11%, respectively); 58% of patients reported AEs leading to treatment discontinuation. InO demonstrated robust activity in these heavily pretreated patients, although treatment duration was limited by haematological toxicities. Additional studies may determine dosing regimens that allow for reduced toxicity. PMID:27101934

  14. Improvement of paraneoplastic limbic encephalitis after systemic treatment with rituximab in a patient with B-cell chronic lymphocytic leukemia.

    PubMed

    Nogai, Hendrik; Israel-Willner, Heike; Zschenderlein, Rolf; Pezzutto, Antonio

    2013-01-01

    Limbic encephalitis is an inflammatory disease of the central nervous system characterized by diverse neurologic symptoms including mnestic disturbances, hallucinations, and seizures as well as behavioral symptoms like depression, personality changes, and acute confusional states resembling dementia. Several antibodies have been described in the pathogenesis of limbic encephalitis. It is often a paraneoplastic syndrome associated with small cell lung cancer, breast cancer, or Hodgkin's lymphoma among others. Here, we report a patient with B-cell chronic lymphocytic leukemia (B-CLL), presenting with otherwise unexplained neurologic symptoms consistent with limbic encephalitis. Despite intensive diagnostic procedures, no causing agent could be identified. Pleocytosis consisting of T cells was detected in the cerebrospinal fluid (CSF). We initiated anti-B-cell therapy with Rituximab for B-CLL with quick and durable resolution of symptoms. We speculate that disruption of interaction between autoreactive T and malignant B cells is responsible for the therapeutic effect of Rituximab. PMID:23984126

  15. Drug-induced progressive multifocal leukoencephalopathy: Lessons learned from contrasting natalizumab and rituximab.

    PubMed

    Vermeer, N S; Straus, S M J M; Mantel-Teeuwisse, A K; Hidalgo-Simon, A; Egberts, A C G; Leufkens, H G M; De Bruin, M L

    2015-11-01

    Progressive multifocal leukoencephalopathy (PML) has been identified as a serious adverse drug reaction (ADR) of several immunomodulatory biologicals. In this study, we contrasted the reporting patterns of PML for two biologicals for which the risk was identified at different points in their lifecycle: natalizumab (before reapproval) and rituximab (nine years postapproval). We found that, apart from the differences in clinical characteristics (age, gender, indication, time to event, fatality), which reflect the diversity in context of use, PML reports for natalizumab were more complete and were received sooner after occurrence. This study serves as an important reminder that spontaneous reports should only be used with great caution to quantify and compare safety profiles across products over time. The observed variability in reporting patterns and heterogeneity of PML cases presents challenges to such comparisons. Lumping uncharacterized PML reports together without taking these differences into account may result in biased comparisons and flawed conclusions about differential safety. PMID:26347128

  16. Time Savings with Rituximab Subcutaneous Injection versus Rituximab Intravenous Infusion: A Time and Motion Study in Eight Countries

    PubMed Central

    De Cock, Erwin; Kritikou, Persefoni; Sandoval, Mariana; Tao, Sunning; Wiesner, Christof; Carella, Angelo Michele; Ngoh, Charles; Waterboer, Tim

    2016-01-01

    Background Rituximab is a standard treatment for non-Hodgkin lymphoma. The SABRINA trial (NCT01200758) showed that a subcutaneous (SC) rituximab formulation did not compromise efficacy or safety compared with intravenous (IV) infusion. We aimed to quantify active healthcare professional (HCP) time and patient chair time for rituximab SC and IV, including potential time savings. Methods This non-interventional time and motion study was run in eight countries and 30 day oncology units. Rituximab SC data were collected alongside the MabCute trial (NCT01461928); IV data were collected per routine real-world practice. Trained observers recorded active HCP time for pre-specified tasks (stopwatch) and chair time (time of day). A random intercept model was used to analyze active HCP time (by task and for all tasks combined) in the treatment room and drug preparation area, drug administration duration, chair time and patient treatment room time by country and/or across countries. Active HCP and chair time were extrapolated to a patient’s first year of treatment (11 rituximab sessions). Results Mean active HCP time was 35.0 and 23.7 minutes for IV and SC process, respectively (-32%, p <0.0001). By country, relative reduction in time was 27–58%. Absolute reduction in extrapolated active HCP time (first year of treatment) was 1.1–5.2 hours. Mean chair time was 262.1 minutes for IV, including 180.9 minutes infusion duration, vs. 67.3 minutes for SC, including 8.3 minutes SC injection administration (-74%, p <0.0001). By country, relative reduction was 53–91%. Absolute reduction in extrapolated chair time for the first year of treatment was 3.1–5.5 eight-hour days. Conclusions Compared with rituximab IV, rituximab SC was associated with reduced chair time and active HCP time. The latter could be invested in other activities, whereas the former may lead to more available appointments, reducing waiting lists and increasing the efficiency of day oncology units. Trial

  17. Radioimmunotherapy of relapsed indolent non-Hodgkin lymphoma with 131I-rituximab in routine clinical practice: 10-year single-institution experience of 142 consecutive patients.

    PubMed

    Leahy, Michael F; Turner, J Harvey

    2011-01-01

    Radioimmunotherapy of indolent non-Hodgkin lymphoma (NHL) has achieved objective response rates in clinical trials comparable with standard rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, but is relatively underused in routine practice. In this article, we report our clinical experience in 142 consecutive patients who received iodine-131 rituximab radioimmunotherapy for low-grade, predominantly follicular, relapsed NHL. Objective response rates of 67%, with complete response (CR) in 50% and median overall survival of 32 months, matched the response rates in a phase 2 clinical trial of (131)I-rituximab radioimmunotherapy and compares favorably with those reported for (131)I-tositumomab or (90)Y-ibritumomab tiuxetan. Progression-free survival was 18 months overall and 32 months in CR or CR-unconfirmed patients. Our patients comprised 107 (75%) follicular lymphoma, 21 (15%) small lymphocytic lymphoma, 6 (4%) mucosa-associated lymphoid tissue/marginal zone lymphoma, and 8 (6%) mantle-cell lymphoma, with median follow-up of 32 months and 8-year overall survival of 48%. Toxicity was limited to hematologic grade 4 neutropenia, occurring in 10% and thrombocytopenia in 6%. There were no episodes of bleeding or infection requiring hospital admission. Radioimmunotherapy with (131)I-rituximab in routine clinical outpatient practice provides cost-effective, safe treatment of relapsed/refractory indolent NHL, with half of patients achieving durable, complete remission with potential for repeat radioimmunotherapy on relapse. PMID:20864582

  18. CD20-positive primary gastric T-cell lymphoma poorly responding to initial treatment with rituximab plus CHOP, and a literature review.

    PubMed

    Kakinoki, Yasutaka; Hashiguchi, Junichi; Ishio, Takashi; Chiba, Koji; Niino, Daisuke; Ohshima, Koichi

    2015-12-01

    There have been rare reported cases of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) that co-expressed CD20. A 44-year-old Japanese male was initially misdiagnosed as CD20-positive diffuse large B-cell lymphoma with a background of reactive CD3-positive T-cells in the stomach. After four cycles of R-CHOP [rituximab plus cyclophosphamide (CY), doxorubicin, vincristine, and prednisolone (PSL)], total gastrectomy with regional lymph node dissection was performed due to the poor response to R-CHOP. A final diagnosis of CD20-positive primary gastric PTCL-NOS was made based on the immunohistochemical, flow cytometric, and molecular genetic findings. In the present case, CD20 immunostaining for T-cell lymphoma cells in tumor tissue varied; in a large part, these were strong to weak-positive, and in some parts, absent. We additionally reviewed the literature focusing on CD20-positive PTCL-NOS treated with rituximab. The administration of rituximab has been performed as an initial treatment in 11 cases, including the case reported here. The response was good in cases with high expression of CD20, while it was poor in cases with variable intensity in CD20 staining, which is consistent with our experience in the present case. The efficacy of rituximab may be associated with intensity of CD20 expression in T cells and its homogeneity in the tumor tissue. PMID:26251099

  19. Meeting Report: Breath Biomarkers Networking Sessions at PittCon 2010, Orlando, Florida

    EPA Science Inventory

    The Pittsburgh Conference and Exposition, or "PittCon" (www.pittcon.org/), is one of the largest international conferences for analytical chemistry and instrumentation typically attracting about 25,000 attendees and 1,000 commercial exhibitors. PittCon began in 1950 as a small sp...

  20. Rituximab add-on therapy for breakthrough relapsing multiple sclerosis

    PubMed Central

    Naismith, R.T.; Piccio, L.; Lyons, J.A.; Lauber, J.; Tutlam, N.T.; Parks, B.J.; Trinkaus, K.; Song, S.K.; Cross, A.H.

    2010-01-01

    Objective: B cells and the humoral immune system have been implicated in the pathogenesis of multiple sclerosis (MS). This study sought to evaluate the efficacy, safety, and tolerability of add-on therapy with rituximab, a monoclonal antibody that depletes circulating B cells, in subjects with relapsing MS with breakthrough disease defined by clinical and MRI activity (Class III evidence). Methods: Thirty subjects with a relapse within the past 18 months despite use of an injectable disease-modifying agent, and with at least 1 gadolinium-enhancing (GdE) lesion on any of 3 pretreatment MRIs, received rituximab administered at 375 mg/m2 weekly × 4 doses. Three monthly posttreatment brain MRI scans were obtained beginning 12 weeks after the first infusion. Multiple Sclerosis Functional Composite (MSFC) and Expanded Disability Status Scale (EDSS) were obtained at baseline and throughout the posttreatment follow-up. Results: GdE lesions were reduced after treatment with rituximab, with 74% of posttreatment MRI scans being free of GdE activity compared with 26% free of GdE activity at baseline (p < 0.0001). Median GdE lesions were reduced from 1.0 to 0, and mean number was reduced from 2.81 per month to 0.33 after treatment (88% reduction). MSFC improved as well (p = 0.02). EDSS remained stable. Conclusion: Rituximab add-on therapy was effective based upon blinded radiologic endpoints in this phase II study. In combination with standard injectable therapies, rituximab was well-tolerated with no serious adverse events. B-cell–modulating therapy remains a potential option for treatment of patients with relapsing MS with an inadequate response to standard injectable therapies. Classification of evidence: This study provides Class III evidence that add-on rituximab reduces gadolinium-enhancing brain lesions in multiple sclerosis. GLOSSARY DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale; FOV = field of view; GdE = gadolinium-enhancing; HACA = human

  1. Therapeutic effectiveness of rituximab in a patient with unresponsive autoimmune pulmonary alveolar proteinosis.

    PubMed

    Amital, Anat; Dux, Shlomo; Shitrit, David; Shpilberg, Ofer; Kramer, Mordechai R

    2010-11-01

    Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterised by the accumulation of lung surfactant in the alveoli. In most cases it is an autoimmune disease with antibodies directed against the growth factor granulocyte-macrophage colony stimulating factor (GM-CSF). Standard of care consists of whole lung lavages in symptomatic patients. An alternative treatment is GM-CSF injections. The case history is reported of a patient with PAP and severe dyspnoea and hypoxaemia. Whole lung lavages and GM-CSF initially resulted in partial remission. However, the patient's condition deteriorated and her saturation during rest with high-flow oxygen treatment was 85%. The patient was treated with an anti-CD20 antibody rituximab which resulted in dramatic improvement. Room air saturation increased to 98% with exercise and she no longer required supplemental oxygen. The diffusion capacity for carbon monoxide increased from 27% to 48% of predicted and the chest x-rays improved. Rituximab may be useful in the treatment of patients with unresponsive PAP. PMID:20855439

  2. Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia

    PubMed Central

    Badoux, Xavier C.; Keating, Michael J.; Wang, Xuemei; O'Brien, Susan M.; Ferrajoli, Alessandra; Faderl, Stefan; Burger, Jan; Koller, Charles; Lerner, Susan; Kantarjian, Hagop

    2011-01-01

    Patients with relapsed chronic lymphocytic leukemia (CLL) and high-risk features, such as fludarabine refractoriness, complex karyotype, or abnormalities of chromosome 17p, experience poor outcomes after standard fludaradine-based regimens. Alemtuzumab is a chimeric CD52 monoclonal antibody with activity in CLL patients with fludarabine-refractory disease and 17p deletion. We report the outcome for 80 relapsed or refractory patients with CLL enrolled in a phase 2 study of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR). All patients were assessed for response and progression according to the 1996 CLL-working group criteria. For the intention-to-treat analysis, the overall response rate was 65%, including 29% complete response. The estimated progression-free survival was 10.6 months and median overall survival was 16.7 months. Although we noted higher complete response in high-risk patients after CFAR compared with a similar population who had received fludarabine, cyclophosphamide, and rituximab as salvage therapy, there was no significant improvement in progression-free survival and overall survival appeared worse. CFAR was associated with a high rate of infectious complications with 37 patients (46%) experiencing a serious infection during therapy and 28% of evaluable patients experiencing late serious infections. Although CFAR produced good response rates in this highly pretreated high-risk group of patients, there was no benefit in survival outcomes. PMID:21670470

  3. Lymphomatoid granulomatosis treated successfully with rituximab in a renal transplant patient.

    PubMed

    Castrale, Cindy; El Haggan, Wael; Chapon, Françoise; Reman, Oumedaly; Lobbedez, Thierry; Ryckelynck, Jean Philippe; Hurault de Ligny, Bruno

    2011-01-01

    Lymphomatoid granulomatosis (LYG) in renal transplant recipients is rare multisystemic angiocentric lymphoproliferative disorder with significant malignant potential. Here, we describe LYG in a 70-year-old renal allograft recipient who, 4 years after transplantation, on tacrolimus and mycophenolate mofetil and prednisone maintenance immunosuppression, complained of low-grade fever, persistent headache and gait disturbance. The MRI of the brain revealed diffuse periventricular cerebral and cerebellar contrast-enhanced lesions. The CT scan of the thorax showed multiple pulmonary nodular opacities in both lung fields. The patient was diagnosed LYG based on the cerebral biopsy showing perivascular infiltration of CD20-positive B-lymphocytes with granulomatous lesions and immunofluorescence staining with anti-EBV antibodies. With careful reduction of the immunossuppression combined with the use of rituximab, our patient showed a complete disappearance of LYG, and she is clinically well more than 4 years after the diagnosis, with good kidney function. No recurrence has been observed by radiological imaging until now. This is the first report of a durable (>4 years) complete remission of LYG after treatment with rituximab in renal transplantation. PMID:21559262

  4. Rituximab plus liposomal doxorubicin in HIV-infected patients with KSHV-associated multicentric Castleman disease.

    PubMed

    Uldrick, Thomas S; Polizzotto, Mark N; Aleman, Karen; Wyvill, Kathleen M; Marshall, Vickie; Whitby, Denise; Wang, Victoria; Pittaluga, Stefania; O'Mahony, Deirdre; Steinberg, Seth M; Little, Richard F; Yarchoan, Robert

    2014-12-01

    Kaposi sarcoma (KS) herpesvirus-associated multicentric Castleman disease (KSHV-MCD) is a lymphoproliferative disorder, most commonly seen in HIV-infected patients, that has a high mortality if untreated. Concurrent KS is common. Although rituximab has reported activity in KSHV-MCD, its use is often associated with KS progression. Within a natural history study of KSHV-MCD, we prospectively evaluated rituximab 375 mg/m(2) combined with liposomal doxorubicin 20 mg/m(2) (R-Dox) every 3 weeks in 17 patients. Patients received a median of 4 cycles (range 3-9). All received antiretroviral therapy, 11 received consolidation interferon-α, and 6 received consolidation high-dose zidovudine with valganciclovir. Using NCI KSHV-MCD response criteria, major clinical and biochemical responses were attained in 94% and 88% of patients, respectively. With a median 58 months' potential follow-up, 3-year event-free survival was 69% and 3-year overall survival was 81%. During R-Dox therapy, cutaneous KS developed in 1 patient, whereas 5 of 6 patients with it had clinical improvement. R-Dox was associated with significant improvement in anemia and hypoalbuminemia. KSHV viral load, KSHV viral interleukin-6, C-reactive protein, human interleukin-6, and serum immunoglobulin free light chains decreased with therapy. R-Dox is effective in symptomatic KSHV-MCD and may be useful in patients with concurrent KS. This trial was registered at www.clinicaltrials.gov as #NCT00092222. PMID:25331113

  5. Neuromyelitis optica: Contribution of therapeutic responses markers monitoring in patients given rituximab.

    PubMed

    Romero, G; Ticchioni, M; Cohen, M; Rosenthal-Allieri, M A; Mondot, L; Lebrun Frenay, C

    2016-03-01

    Neuromyelitis optica (NMO) is a central nervous system inflammatory autoimmune disease characterized by medullary and/or optical nerve damage. It is rare but life-threatening. Concerning the treatment of NMO, many drugs have been used in background therapy. Some studies have shown efficacy of rituximab (an antiCD20 monoclonal anti-body) either on the reduction of the annual number of exacerbation or the mean score EDSS. In 2013, a Korean team reported a new protocol during which they administered rituximab only when memory B lymphocytes CD27+ were detectable in the bloodstream. In our patient, institution of this protocol led to clinical benefit with a major decrease in the EDSS score over time (7 in August 2012 vs. 1 in October 2015), a reduction of the total administered dose (4g in 2013 vs. 1.375g in 2014 vs. 0g in 2015) and side effects. Compared with the rate of theoretical administration, health expenditure savings reached 1700 Euros per month over the 11-month treatment. Monitoring therapeutic response markers with memory B lymphocyte counts appear to be an efficient cost-effective way to measure clinical efficiency, reduce total doses, and limit side effects. PMID:26915311

  6. [Hepatitis B virus reactivation after cessation of prophylactic lamivudine therapy in B-cell lymphoma patients treated with rituximab combined CHOP therapy].

    PubMed

    Mimura, Naoya; Tsujimura, Hideki; Ise, Mikiko; Sakai, Chikara; Kojima, Hiroshige; Fukai, Kenichi; Yokosuka, Osamu; Takagi, Toshiyuki; Kumagai, Kyoya

    2009-12-01

    Here we report three cases of hepatitis B virus (HBV) reactivation after cessation of preemptive lamivudine therapy in B-cell lymphoma patients treated with rituximab plus CHOP (R-CHOP). Two patients received eight cycles of R-CHOP, and one received two cycles of R-CHOP followed by two courses of rituximab. As all the patients were HBV surface antigen (HBsAg) positive, lamivudine was administered simultaneously with R-CHOP to prevent virus reactivation. All the patients developed hepatitis due to HBV reactivation 6, 8 and 13 months after completion of chemotherapy, and 4, 2 and 2 months after cessation of lamivudine, respectively. They were treated with either lamivudine or entecavir and all achieved full recovery. When HBV carriers undergo immunosuppressive anticancer treatment, prophylactic antiviral therapy is well recognized as effective. However, the optimal method of prophylaxis has not yet been established. Since the introduction of rituximab, new problems such as delayed HBV reactivation from HBsAg positive patients and de novo hepatitis B from HBsAg negative patients have emerged. Guidelines for prophylactic antiviral therapy in the era of rituximab need to be established. PMID:20068280

  7. Protein biochip array technology to monitor rituximab in rheumatoid arthritis

    PubMed Central

    Fabre, S; Guisset, C; Tatem, L; Dossat, N; Dupuy, A M; Cohen, J D; Cristol, J P; Daures, J P; Jorgensen, C

    2009-01-01

    In rheumatoid arthritis (RA) there are currently no good indicators to predict a clinical response to rituximab. The purpose of this study was to monitor and determine the role of peripheral blood cytokine profiling in differentiating between a good versus poor response to rituximab in RA. Blood samples were collected at baseline and at 3 months from 46 RA patients who were treated with rituximab. Responders are defined by the presence of three of four American College of Rheumatology criteria: ≥ 20% decrease in C-reactive protein, visual analogical score of disease activity, erythrocyte sedimentation rate and improvement of the disease activity score (28) (four values) by ≥ 1·2 obtained at 3 months. Twelve cytokines were measured from serum collected on days 0 and 90 by proteomic array, including interleukin-6 (IL-6), tumour necrosis factor-α, IL-1a, IL-1b, IL-2, IL-8, interferon-γ, IL-4, IL-10, monocyte chemoattractant protein-1, epidermal growth factor and vascular growth factor. We showed that C-reactive protein and IL-6 levels decrease significantly at 3 months in the responder group compared with baseline. At day 90 we identified a cytokine profile which differentiates responders and non-responders. High serum levels of two proinflammatory cytokines, monocyte chemoattractant protein-1 and epidermal growth factor, were significantly higher in the responder group at day 90 compared with non-responders. However, we were not able to identify a baseline cytokine profile predictive of a good response at 3 months. These findings suggest that cytokine profiling by proteomic analysis may be a promising tool for monitoring rituximab and may help in the future to identify responder RA patients. PMID:19220830

  8. Rituximab does not reset defective early B cell tolerance checkpoints

    PubMed Central

    Chamberlain, Nicolas; Massad, Christopher; Oe, Tyler; Cantaert, Tineke; Herold, Kevan C.; Meffre, Eric

    2015-01-01

    Type 1 diabetes (T1D) patients show abnormalities in early B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive B cells in their blood. Treatment with rituximab, an anti-CD20 mAb that depletes B cells, has been shown to preserve β cell function in T1D patients and improve other autoimmune diseases, including rheumatoid arthritis and multiple sclerosis. However, it remains largely unknown how anti–B cell therapy thwarts autoimmunity in these pathologies. Here, we analyzed the reactivity of Abs expressed by single, mature naive B cells from 4 patients with T1D before and 52 weeks after treatment to determine whether rituximab resets early B cell tolerance checkpoints. We found that anti–B cell therapy did not alter the frequencies of autoreactive and polyreactive B cells, which remained elevated in the blood of all patients after rituximab treatment. Moreover, the limited proliferative history of autoreactive B cells after treatment revealed that these clones were newly generated B cells and not self-reactive B cells that had escaped depletion and repopulated the periphery through homeostatic expansion. We conclude that anti–B cell therapy may provide a temporary dampening of autoimmune processes through B cell depletion. However, repletion with autoreactive B cells may explain the relapse that occurs in many autoimmune patients after anti–B cell therapy. PMID:26642366

  9. The risk of infections in hematologic patients treated with rituximab is not influenced by cumulative rituximab dosage - a single center experience

    PubMed Central

    2014-01-01

    Background Rituximab, a monoclonal antibody directed against CD20, is approved for the treatment of CD20-positive B-cell Non-Hodgkin’s lymphoma and rheumatologic disorders. Due to its potent activity in depleting CD20-positive lymphocytes, the influence on opportunistic infections is still under discussion. Thus, we analyzed the impact of rituximab either as monotherapy or in combination with other chemotherapeutic regimens to elucidate its role in contributing to infectious complications. Methods The records of consecutive patients (n = 125, 141 treatment episodes) treated with rituximab alone or in combination with chemotherapy and corticosteroids were analyzed retrospectively for the incidence, spectrum and outcome of infections during treatment and 6 months after the last course of rituximab. Univariate analysis of cofactors such as steroid medication, antiinfective prophylaxis, underlying disease and remission status were performed. Results Altogether 80 therapy episodes were associated with infections, the median number of infections per patient being 1 (range 1–7). The number of infectious complications was significantly higher in patients receiving a combination of rituximab and chemotherapy compared to rituximab monotherapy (p < 0.001). There was no statistically significant difference regarding number of rituximab courses or cumulative rituximab dosage between episodes with and without infections, respectively.Mean cumulative prednisone dosage between the cohort with infections and the one without infections showed a trend towards higher dosage of prednisone in the patients with infections (mean difference 441 mg, p > 0.14). Conclusions Rituximab in induction treatment, either as monotherapy or combined with chemotherapy by itself does not increase the incidence or change the spectrum of infections in hematologic patients. However the possible influence of higher dosages of concomitant steroid medication on frequency of infections

  10. Catastrophic multiple organ ischemia due to an anti-Pr cold agglutinin developing in a patient with mixed cryoglobulinemia after treatment with rituximab.

    PubMed

    Ruch, Joshua; McMahon, Brandon; Ramsey, Glenn; Kwaan, Hau C

    2009-02-01

    Cold agglutinin disease occurring with cryoglobulinemia is a rare occurrence. Here, we report a patient with mixed cryoglobulinemia that was treated with rituximab and, after response, developed an anti-Pr cold agglutinin that manifested with hemolysis and microvascular occlusion causing mesenteric ischemia and cerebral infarction. Unlike previous reports of patients with cryoglobulinemia and cold agglutinin disease, our patient did not have a detectable cryoprecipitate when his cold agglutinin manifested. PMID:19097173

  11. Case report: Sodium dichloroacetate (DCA) inhibition of the "Warburg Effect" in a human cancer patient: complete response in non-Hodgkin's lymphoma after disease progression with rituximab-CHOP.

    PubMed

    Strum, Stephen B; Adalsteinsson, Orn; Black, Richard R; Segal, Dmitri; Peress, Nancy L; Waldenfels, James

    2013-06-01

    The uptake of fluorodeoxyglucose Positron Emission Tomography in the tumors of various cancer types demonstrates the key role of glucose in the proliferation of cancer. Dichloroacetate is a 2-carbon molecule having crucial biologic activity in altering the metabolic breakdown of glucose to lactic acid. Human cell line studies show that dichloroacetate switches alter the metabolomics of the cancer cell from one of glycolysis to oxidative phosphorylation, and in doing so restore mitochondrial functions that trigger apoptosis of the cancer cell. Reports of dichloroacetate in human subjects are rare. The authors contacted individuals from Internet forums who had reported outstanding anti-cancer responses to self-medication with dichloroacetate. With informed consent, complete medical records were requested to document response to dichloroacetate, emphasizing the context of monotherapy with dichloroacetate. Of ten patients agreeing to such an evaluation, only one met the criteria of having comprehensive clinic records as well as pathology, imaging and laboratory reports, along with single agent therapy with dichloroacetate. That individual is the focus of this report. In this case report of a man with documented relapse after state-of-the-art chemotherapy for non-Hodgkin's lymphoma, a significant response to dichloroacetate is documented with a complete remission, which remains ongoing after 4 years. Dichloroacetate appears to be a novel therapy warranting further investigation in the treatment of cancer. PMID:23263938

  12. The Effect of Rituximab on Vaccine Responses in Patients with Immune Thrombocytopenia

    PubMed Central

    Nazi, Ishac; Kelton, John G.; Larché, Mark; Snider, Denis P.; Heddle, Nancy M.; Crowther, Mark A.; Cook, Richard J.; Tinmouth, Alan T.; Mangel, Joy; Arnold, Donald M.

    2013-01-01

    B-cell depletion therapy may impair vaccine responses and increase infection risk in patients with immune thrombocytopenia (ITP). Capitalizing on a multicenter randomized placebo-controlled trial, we investigated the effects of rituximab on the antibody and cellular responses to Streptococcus pneumoniae polysaccharide vaccine and Haemophilus influenzae type b (Hib) conjugate vaccine in ITP patients. Of 60 patients in the main trial, 24 patients received both vaccines 6 months after rituximab (n=17) or placebo (n=7). Among 20 evaluable patients, 3/14 (21%) in the rituximab group and 4/6 (67%) in the placebo group achieved a 4-fold increase in anti-pneumococcal antibodies (p=0.12). For anti-Hib antibodies, 4/14 (29%) and 5/6 (83%), respectively, achieved a 4-fold increase (p<0.05). Fewer patients in the rituximab group demonstrated functional Hib killing (2/14 [14%] versus 5/6 [83%], p<0.05). Three of 14 rituximab-treated patients failed to respond to vaccines by any criteria. After vaccinations, pre-plasma cell blasts and interferon-γ secreting T-cells were reduced in rituximab-treated patients. We found that antibody responses were impaired for at least 6 months after rituximab. Cellular immunity was reduced in parallel with the depleted B-cell pool. These findings have implications for the timing of vaccinations and the mechanism of infection after rituximab in patients with ITP. PMID:23851398

  13. Retroperitoneal fibrosis due to B-cell non-Hodgkin lymphoma: Responding to rituximab!

    PubMed

    Alvarez Argote, Juliana; Bauer, Frank A; Posteraro, Anthony F; Dasanu, Constantin A

    2016-02-01

    Retroperitoneal fibrosis is a rare disease manifesting as chronic soft tissue fibrosis in the retroperitoneum, with potential anatomic and/or functional compromise of adjacent organs. It can be primary (idiopathic) or secondary to other conditions such as cancers, autoimmune disorders, or drugs. We report herein a 66-year-old patient with symptomatic retroperitoneal fibrosis leading to bilateral hydronephrosis and renal failure, in whom, after a complex diagnostic work-up and protracted clinical course, a B-cell non-Hodgkin lymphoma in the retroperitoneal space and several vertebral bodies was identified. The patient was treated with radiation therapy and weekly rituximab infusions, with resolution of hydronephrosis and lower back pain. We include a thorough literature review on etiopathogenesis, diagnosis, therapy, and prognosis of retroperitoneal fibrosis. A meticulous search for malignancy is necessary in this rare condition that, if positive, may have significant therapeutic and prognostic implications. PMID:25013186

  14. Efficiency of treatment with rituximab in platelet transfusion refractoriness: a study of 7 cases

    PubMed Central

    Liu, Wenbin; Wu, Dijiong; Hu, Tonglin; Ye, Baodong

    2015-01-01

    Objective: The purpose of our study was to evaluate the efficacy and safety of rituximab in treatment of immune PR. Methods: We retrospective analysis 7 paitents (5 aplastic anemia, 2 myelodysplastic syndrome) with immune PR who received at least 3 weekly infusions of rituximab (375 mg/m2). Results: All enrolled patients acquired improvement of platelets transfusion more than 2 months (CCI ≥ 4.5 × 109/L). We first found that there were 2 patterns of response to rituximab treatment in patients with immune PR, which the early but transient after the first rituximab administration and the late but continuous beginning to appear at 3 weeks from the start of treatment. Conclusion: Rituximab is a promising treatment in patients with immune PR and giving the opportunity and time for cure the disease. PMID:26550372

  15. Rituximab, cyclophosphamide-fractionated, vincristine, doxorubicin and dexamethasone alternating with rituximab, methotrexate and cytarabine overcomes risk features associated with inferior outcomes in treatment of newly diagnosed, high-risk diffuse large B-cell lymphoma.

    PubMed

    Mato, Anthony; Feldman, Tatyana; Zielonka, Tania; Singavi, Arun; Gadaletta, Gabriella; Waksmundzki, Kathryn; Bhattacharyya, Pritish; Chow, Kar Fai; Yang, Xiao; Panush, David; Agress, Harry; Rosario, Maria; Howlett, Christina; Pecora, Andrew; Goy, Andre

    2013-12-01

    Subtypes of diffuse large B-cell lymphoma (DLBCL) that have inferior outcomes after front-line therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) have been identified. While it is agreed that R-CHOP is probably not adequate in these patients, there is no standard treatment approach for patients with DLBCL with high-risk features. We present results of a retrospective cohort study of high-risk DLBCL (defined as having at least one unfavorable risk factor: non-germinal center [GC] subtype by immunohistochemistry [IHC], Ki-67 ≥ 80%, high International Prognostic Index [IPI], c-MYC rearrangement) treated with R-HCVAD/R-MTX-AraC (rituximab, cyclophosphamide-fractionated, vincristine, doxorubicin and dexamethasone alternating with rituximab, methotrexate and cytarabine; R-HCVAD) as front-line therapy. With a median follow-up of 25.3 months, the 3-year PFS and OS estimates are 79% (95% confidence interval [CI], 65-88%) and 76% (95% CI, 61-86%), respectively, which are higher than those for historical comparisons with R-CHOP data for high-risk patients. These data are in accord with other recent reports of dose-intense front-line therapy of high-risk DLBCL. This analysis represents the largest reported cohort of patients with DLBCL treated with R-HCVAD. These data suggest that R-HCVAD can overcome traditional poor risk features such as high IPI, high Ki-67 and non-GC IHC pattern. Future work will focus on identifying molecular markers for failure in patients with DLBCL treated with dose-intensive regimens. PMID:23488604

  16. Rituximab for troublesome cases of childhood nephrotic syndrome

    PubMed Central

    Safdar, Osama Y; Aboualhameael, Adila; Kari, Jameela A

    2014-01-01

    Nephrotic syndrome (NS) is the most common glomerular disease of childhood. Steroid-dependent and steroid-resistant nephrotic syndrome present challenges in their pharmaceutical management; patients may need several immunosuppressive medication for optimum control, each of which medication has its own safety profile. Rituximab (RTX) is a monoclonal antibody that targets B cells and has been used successfully for management of lymphoma and rheumatoid arthritis. Recent clinical studies showed that rituximab may be an efficacious and safe alternative for the treatment of complicated nephrotic syndrome. In this review article, we aim to review the efficacy and safety of RTX therapy in nephrotic syndrome. We reviewed the literature pertaining to this topic by searching for relevant studies on PubMed and Medline using specific keywords. The initial search yielded 452 articles. These articles were then examined to ensure their relevance to the topic of research. We focused on multicenter randomized controlled trials with relatively large numbers of patients. A total of 29 articles were finally identified and will be summarized in this review. The majority of clinical studies of RTX in complicated pediatric NS showed that rituximab is effective in approximately 80% of patients with steroid-dependent NS, as it decreases the number of relapses and steroid dosage. However, RTX is less effective at achieving remission in steroid-resistant NS. RTX use was generally safe, and most side effects were transient and infusion-related. More randomized, double-blinded clinical studies are needed to assess the role of RTX in children with nephrotic syndrome. PMID:25512892

  17. Successful treatment of severe myasthenia gravis developed after allogeneic hematopoietic stem cell transplantation with plasma exchange and rituximab.

    PubMed

    Unal, Sule; Sag, Erdal; Kuskonmaz, Baris; Kesici, Selman; Bayrakci, Benan; Ayvaz, Deniz C; Tezcan, Ilhan; Yalnızoglu, Dilek; Uckan, Duygu

    2014-05-01

    Myasthenia gravis is among the rare complications after allogeneic hematopoietic stem cell transplantation and is usually associated with chronic GVHD. Herein, we report a 2-year and 10 months of age female with Griscelli syndrome, who developed severe myasthenia gravis at post-transplant +22nd month and required respiratory support with mechanical ventilation. She was unresponsive to cyclosporine A, methylprednisolone, intravenous immunoglobulin, and mycophenolate mofetil and the symptoms could only be controlled after plasma exchange and subsequent use of rituximab, in addition to cyclosporine A and mycophenolate mofetil maintenance. She is currently asymptomatic on the 6th month of follow-up. PMID:24307660

  18. Mound-ACT*DE*CON{sup SM} feasibility study. Phase 2: Final report

    SciTech Connect

    1994-12-01

    A portion of the abandoned Miami-Erie Canal paralleling the Greater Miami River receives the runoff and storm-water discharge from Mound Laboratory. In 1969, a low-level plutonium leak contaminated sediment as far away as 1.5 mi from the Mound site along the old canal system. An estimated one million cubic feet of sediment requires remediation. The technology being evaluated for the remediation of the low-level plutonium-238 contamination of the sediment involves two processes: washing the sediments with ACT*DE*CON{sup SM} solution to dissolve the contaminant, followed by extraction of the solution and processing with the MAG*SEP{sup SM} process to concentrate the contaminant and allow reuse of the ACT*DE*CON{sup SM} solution. The processes are being optimized for pilot-scale and field demonstration. Phase 2 of the project primarily involved identification at the laboratory scale of the optimal ACT*DE*CON{sup SM} formulation, identification of the ion-exchanger and MAG*SEP{sup SM} particles, verification of the plutonium mobility in the treated soil, and evaluation of other process parameters according to a series of tasks.

  19. Rituximab's new therapeutic target: the podocyte actin cytoskeleton.

    PubMed

    Chan, Andrew C

    2011-06-01

    Therapeutic off-target activities are well recognized for small-molecule drugs. In contrast, monoclonal antibodies (mAbs) traditionally are believed to act specifically and lack off-target therapeutic effects. In this issue of Science Translational Medicine, Fornoni et al. show therapeutic benefit, through an off-target-mediated mechanism, of the mAb drug rituximab in recurrent focal segmental glomerulosclerosis (FSGS) after kidney transplantation. These data shed new light on FSGS pathogenesis and suggest new therapeutic interventions for proteinuric diseases. PMID:21632983

  20. Treatment of Rheumatoid Arthritis with Biologic DMARDS (Rituximab and Etanercept)

    PubMed Central

    Gashi, Afrim A.; Rexhepi, Sylejman; Berisha, Idriz; Kryeziu, Avni; Ismaili, Jehona; Krasniqi, Gezim

    2014-01-01

    ABSTRACT Goal: To determine efficacy and safety of treatment with Rituximab and Etanercept plus Methotrexate in patients with active Rheumatoid Arthritis (RA), who had an inadequate response to nonbiologic DMARDS therapies and to explore the pharmacogenetics and pharmacodynamics of Rituximab and Etanercept in our populations. Study was done at Rheumatology Clinic of University Clinical Centre in Prishtina during 2009-2011 years. Methods: We evaluated primary efficacy and safety at 24 weeks in patients enrolled in the study of long term efficacy of Rituximab and Etanercept. Patients with active Rheumatoid Arthritis and an inadequate response to 1 or more non biologic DMARDS were randomized to receive intravenous Rituximab (1 course consisting of 2 infusions of 1.000 mg each –one group, and Etanercept 25 mg twice weekly –second group, but both groups with background MTX. The primary efficacy end point was a response on the ACR 20%, improvement criteria at 24 weeks, Secondary end points were responses on the ACR 50 and ACR 70, improvement criteria, the DAS 28, and EULAR response criteria at 24 weeks. Results: During our investigations we treated 20 patients, 15 females and 5 males, in the treated group with RTX and 13 patients 8 females and 5 males in the treated group with ETN. Patients of group 1 and group 2 were of ages 37-69 years old and 19-69 years old (average 47-44) Most of the patients belong in 2nd and 3 rd functional stage according to Steinbrocker. All ACR response parameters were significantly improved in RTX treated patients who also had clinically meaningful improvement in fatigue, disability and quality of life. Patients showed a trend less progression in radiographic end points. Most adverse events occurred with the first RTX infusion and were mild to moderate severity. Conclusion: At 24 weeks, a single course of RTX and ETN provided significant and clinically meaningful improvements in disease activity in patients with active, longstanding RA who

  1. Disseminated juvenile xanthogranuloma associated with follicular lymphoma in an adult: successful treatment with chemotherapy and rituximab. A review of the literature.

    PubMed

    Narváez-Moreno, B; Pulpillo-Ruiz, Á; De Zulueta-Dorado, T; Conejo-Mir, J

    2013-04-01

    Juvenile xanthogranuloma is a non-Langerhans cell histiocytosis that typically affects children, but several cases have been reported in adults, some in connection with hematologic malignancies. We present the case of a 61-year-old woman with multiple xanthogranulomas who developed a follicular lymphoma after 4 years of follow-up. After 6 months of treatment with chemotherapy and rituximab, the cutaneous lesions disappeared and the patient achieved remission from lymphoma. We highlight this case because xanthogranuloma is a rare disorder that is difficult to diagnose in adults and also because this is the first report of an association between xanthogranuloma and follicular lymphoma. Excellent response was achieved with chemotherapy and rituximab. Finally, given the possible association between xanthogranulomas and hematologic diseases, these lesions may be a cutaneous manifestation of an occult malignancy. PMID:22681714

  2. TECHNOLOGY EVALUATION REPORT: INTERNATIONAL WASTE TECHNOLOGIES/GEO-CON IN SITU STABILIZATION/SOLIDIFICATION - VOLUME IV - UPDATE REPORT

    EPA Science Inventory

    The long-term performance tests provide information on the first follow-up sampling and analysis on the SITE program demonstration of the International Waste Technologies additive, and the Geo-Con deep soil mixing equipment. he samples containing PCBs, were collected one year aft...

  3. TECHNOLOGY EVALUATION REPORT: INTERNATIONAL WASTE TECHNOLOGIES/GEO-CON IN SITU STABILIZATION/SOLIDIFICATION - VOLUME III - UPDATE REPORT

    EPA Science Inventory

    The long-term performance tests provide information on the first follow-up sampling and analysis on the SITE program demonstration of the International Waste Technologies additive, and the Geo-Con deep soil mixing equipment. he samples containing PCBs, were collected one year aft...

  4. Successful Curative Therapy With Rituximab and Allogeneic Haematopoietic Stem Cell Transplantation for MALT Lymphoma Associated With STK4-Mutated CD4+ Lymphocytopenia.

    PubMed

    Lum, Su Han; Bonney, Denise; Cheesman, Edmund; Wrignt, Neville B; Hughes, Stephen; Wynn, Robert

    2016-09-01

    Idiopathic CD4+ lymphocytopenia and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) are rare diseases in children. We report the first case of a child with STK4-mutated CD4+ lymphocytopenia who developed Epstein-Barr virus associated MALT lymphoma arising in the salivary gland. The child achieved complete remission with rituximab, and her immunodeficiency was cured by haematopoietic stem cell transplantation. The child remained well 24 months post transplantation. PMID:27163767

  5. Rituximab for treatment of inhibitors in haemophilia A. A Phase II study.

    PubMed

    Leissinger, C; Josephson, C D; Granger, S; Konkle, B A; Kruse-Jarres, R; Ragni, M V; Journeycake, J M; Valentino, L; Key, N S; Gill, J C; McCrae, K R; Neufeld, E J; Manno, C; Raffini, L; Saxena, K; Torres, M; Marder, V; Bennett, C M; Assmann, S F

    2014-09-01

    The development of antibodies against infused factor VIII (FVIII) in patients with haemophilia A is a serious complication leading to poorly controlled bleeding and increased morbidity. No treatment has been proven to reduce high titre antibodies in patients who fail immune tolerance induction or are not candidates for it. The Rituximab for the Treatment of Inhibitors in Congenital Hemophilia A (RICH) study was a phase II trial to assess whether rituximab can reduce anamnestic FVIII antibody (inhibitor) titres. Male subjects with severe congenital haemophilia A and an inhibitor titre ≥5 Bethesda Units/ml (BU) following a FVIII challenge infusion received rituximab 375 mg/m² weekly for weeks 1 through 4. Post-rituximab inhibitor titres were measured monthly from week 6 through week 22 to assess treatment response. Of 16 subjects who received at least one dose of rituximab, three (18.8%) met the criteria for a major response, defined as a fall in inhibitor titre to <5 BU, persisting after FVIII re-challenge. One subject had a minor response, defined as a fall in inhibitor titre to <5 BU, increasing to 5-10 BU after FVIII re-challenge, but <50% of the original peak inhibitor titre. Rituximab is useful in lowering inhibitor levels in patients, but its effect as a solo treatment strategy is modest. Future studies are indicated to determine the role of rituximab as an adjunctive therapy in immune tolerisation strategies. PMID:24919980

  6. In vivo B-cell depletion with rituximab for alternative donor hemopoietic SCT.

    PubMed

    Dominietto, A; Tedone, E; Soracco, M; Bruno, B; Raiola, A M; Van Lint, M T; Geroldi, S; Lamparelli, T; Galano, B; Gualandi, F; Frassoni, F; Bacigalupo, A

    2012-01-01

    We retrospectively analyzed 55 patients given a fixed dose of rituximab (200 mg) on day+5 after an alternative donor transplant, to prevent EBV DNA-emia; 68 alternative transplants who did not receive prophylactic rituximab served as controls. The two groups were comparable for donor type, and all patients received anti-thymocyte globulin in the conditioning regimen. Rituximab patients had a significantly lower rate of EBV DNA-emia 56 vs 85% (P=0.0004), a lower number of maximum median EBV copies (91 vs 1321/10(5) cells, P=0.003) and a significantly lower risk of exceeding 1000 EBV copies per 10(5)cells (14 vs 49%, P=0.0001). Leukocyte and lymphocyte counts were lower on day +50 and+100 in rituximab patients, whereas Ig levels were comparable. The cumulative incidence of grade II-IV acute GvHD was significantly reduced in rituximab patients (20 vs 38%, P=0.02). Chronic GvHD was comparable. There was a trend for a survival advantage for patients receiving rituximab (46 vs 40%, P=0.1), mainly because of lower transplant mortality (25 vs 37%, P=0.1). Despite the drawback of a retrospective study, these data suggest that a fixed dose of rituximab on day +5 reduces the risk of a high EBV load, and also reduces acute GvHD. PMID:21460867

  7. Salvage Regimens With Autologous Transplantation for Relapsed Large B-Cell Lymphoma in the Rituximab Era

    PubMed Central

    Gisselbrecht, Christian; Glass, Bertram; Mounier, Nicolas; Singh Gill, Devinder; Linch, David C.; Trneny, Marek; Bosly, Andre; Ketterer, Nicolas; Shpilberg, Ofer; Hagberg, Hans; Ma, David; Brière, Josette; Moskowitz, Craig H.; Schmitz, Norbert

    2010-01-01

    Purpose Salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT) is the standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL). Salvage regimens have never been compared; their efficacy in the rituximab era is unknown. Patients and Methods Patients with CD20+ DLBCL in first relapse or who were refractory after first-line therapy were randomly assigned to either rituximab, ifosfamide, etoposide, and carboplatin (R-ICE) or rituximab, dexamethasone, high-dose cytarabine, and cisplatin (R-DHAP). Responding patients received high-dose chemotherapy and ASCT. Results The median age of the 396 patients enrolled (R-ICE, n = 202; R-DHAP, n = 194) was 55 years. Similar response rates were observed after three cycles of R-ICE (63.5%; 95% CI, 56% to 70%) and R-DHAP (62.8%; 95 CI, 55% to 69%). Factors affecting response rates (P < .001) were refractory disease/relapse less than versus more than 12 months after diagnosis (46% v 88%, respectively), International Prognostic Index (IPI) of more than 1 versus 0 to 1 (52% v 71%, respectively), and prior rituximab treatment versus no prior rituximab (51% v 83%, respectively). There was no significant difference between R-ICE and R-DHAP for 3-year event-free survival (EFS) or overall survival. Three-year EFS was affected by prior rituximab treatment versus no rituximab (21% v 47%, respectively), relapse less than versus more than 12 months after diagnosis (20% v 45%, respectively), and IPI of 2 to 3 versus 0 to 1 (18% v 40%, respectively). In the Cox model, these parameters were significant (P < .001). Conclusion In patients who experience relapse more than 12 months after diagnosis, prior rituximab treatment does not affect EFS. Patients with early relapses after rituximab-containing first-line therapy have a poor prognosis, with no difference between the effects of R-ICE and R-DHAP. PMID:20660832

  8. Validated LC/MS Bioanalysis of Rituximab CDR Peptides Using Nano-surface and Molecular-Orientation Limited (nSMOL) Proteolysis.

    PubMed

    Iwamoto, Noriko; Takanashi, Megumi; Hamada, Akinobu; Shimada, Takashi

    2016-07-01

    Presently, monoclonal antibodies (mAbs) therapeutics have big global sales and are starting to receive competition from biosimilars. We previously reported that the nano-surface and molecular-orientation limited (nSMOL) proteolysis which is optimal method for bioanalysis of antibody drugs in plasma. The nSMOL is a Fab-selective limited proteolysis, which utilize the difference of protease nanoparticle diameter (200 nm) and antibody resin pore diameter (100 nm). In this report, we have demonstrated that the full validation for chimeric antibody Rituximab bioanalysis in human plasma using nSMOL proteolysis. The immunoglobulin fraction was collected using Protein A resin from plasma, which was then followed by the nSMOL proteolysis using the FG nanoparticle-immobilized trypsin under a nondenaturing condition at 50°C for 6 h. After removal of resin and nanoparticles, Rituximab signature peptides (GLEWIGAIYPGNGDTSYNQK, ASGYTFTSYNMHWVK, and FSGSGSGTSYSLTISR) including complementarity-determining region (CDR) and internal standard P14R were simultaneously quantified by multiple reaction monitoring (MRM). This quantification of Rituximab using nSMOL proteolysis showed lower limit of quantification (LLOQ) of 0.586 µg/mL and linearity of 0.586 to 300 µg/mL. The intra- and inter-assay precision of LLOQ, low quality control (LQC), middle quality control (MQC), and high quality control (HQC) was 5.45-12.9% and 11.8, 5.77-8.84% and 9.22, 2.58-6.39 and 6.48%, and 2.69-7.29 and 4.77%, respectively. These results indicate that nSMOL can be applied to clinical pharmacokinetics study of Rituximab, based on the precise analysis. PMID:27150271

  9. Molecular characterization of a variant virus that caused de novo hepatitis B without elevation of hepatitis B surface antigen after chemotherapy with rituximab.

    PubMed

    Miyagawa, Masami; Minami, Masahito; Fujii, Kota; Sendo, Rei; Mori, Kojiro; Shimizu, Daisuke; Nakajima, Tomoaki; Yasui, Kohichiroh; Itoh, Yoshito; Taniwaki, Masafumi; Okanoue, Takeshi; Yoshikawa, Toshikazu

    2008-12-01

    Hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg)-negative patients following treatment with rituximab has been reported increasingly. The aim of this study was to investigate the molecular mechanisms underlying HBV reactivation in an HBsAg-negative patient. HBV was reactivated in a 75-year-old man following chemotherapy with rituximab, without elevation of HBsAg. The patient's full-length HBV genome was cloned and the entire sequence was determined. Transfection studies were performed in vitro using recombinant wild-type HBV (wild-type), the patient's HBV (patient), and two chimeric HBV constructs, in which the preS/S region of the patient and wild-type virus had been exchanged with one another. Secreted HBsAg and intra- and extra-cellular HBV DNA were measured. The number of amino acid substitutions in HBV from this patient was much higher than in previous reports of HBV mutants, such as occult HBV and vaccine escape HBV mutants. Levels of HBsAg and HBV DNA production in vitro were significantly lower in the patient compared to wild-type transfections. From analyses of the chimeric constructs, the altered preS/S region was responsible mainly for this impairment. These results show that highly mutated HBV can reactivate after chemotherapy with rituximab, despite an unusually large number of mutations, resulting in impaired viral replication in vitro. Severe immune suppression, probably caused by rituximab, may permit reactivation of highly mutated HBV. These findings have important clinical implications for the prevention and management of HBV reactivation and may explain partially the mechanism of recent, unusual cases of HBV reactivation. PMID:19040281

  10. Progressive Multifocal Leukoencephalopathy Following Treatment with Rituximab in an HIV-Negative Patient with Non-Hodgkin Lymphoma

    PubMed Central

    Felli, Valentina; Di Sibio, Alessandra; Anselmi, Monica; Gennarelli, Antonio; Sucapane, Patrizia; Splendiani, Alessandra; Catalucci, Alessia; Marini, Carmine; Gallucci, Massimo

    2014-01-01

    Summary Progressive multifocal leukoencephalopathy (PML) is a rare rapidly progressive demyelinating disease of the central nervous system caused by reactivation of latent John Cunningham (JC) polyomavirus (JCV) infection. We describe an unusual case of PML in a 54-year-old patient with follicular non-Hodgkin lymphoma who received rituximab plus cyclophosphamide, hydroxydaunorubicin, oncovicin and prednisolone (R-CHOP) therapy. She started to notice gradual progressive neurological symptoms about two months after completion of rituximab treatment and was therefore admitted to hospital. On admission, brain CT and MRI showed widespread lesions consistent with a demyelinating process involving the subcortical and deep white matter of the cerebral and cerebellar hemispheres. CT and MRI findings were suggestive of PML, and JC virus DNA was detected by polymerase chain reaction assay of the cerebrospinal fluid and serum. The patient was treated supportively but reported a progressive worsening of the clinical and radiological findings. Our report emphasizes the role of CT and MRI findings in the diagnosis of PML and suggests that PML should be considered in patients with progressive neurological disorders involving the entire nervous system and mainly the white matter, especially in the presence of previous immunomodulatory treatment or immunosuppression. PMID:25489887

  11. Rituximab maintenance after autologous stem cell transplantation prolongs response duration in non-naive rituximab follicular lymphoma patients: a single institution experience.

    PubMed

    Bourcier, J; Gastinne, T; Leux, C; Moreau, A; Bossard, C; Mahé, B; Blin, N; Dubruille, V; Touzeau, C; Voldoire, M; Guillaume, T; Peterlin, P; Gallas, P; Garnier, A; Maisonneuve, H; Moreau, P; Juge-Morineau, N; Jardel, H; Chevallier, P; Moreau, P; Le Gouill, S

    2016-08-01

    We retrospectively evaluated the role of rituximab (R) in maintenance treatment after autologous stem cell transplantation performed in patients with relapsed follicular lymphoma. We compared the outcome of 67 follicular lymphoma (FL) patients according to the use of rituximab maintenance (RM) or not. All patients received rituximab plus chemotherapy before autologous stem-cell transplantation (ASCT). Patients received median of two lines of prior therapy. The RM schedule was one injection of rituximab every 3 months for 2 years. Median follow-up is 4.6 years. The 3-year progression-free survival (PFS) after ASCT was 86 % with RM vs. 46 % without (p = 0.0045). Median is not reached in the RM arm vs. 31 months in non-RM arm. The 3-year OS was 96 % with RM vs. 78 % without (p = 0.059). The present monocentric study shows that 2 years of RM after ASCT significantly increases response duration for non-naive rituximab relapsed FL patients compared with observation. PMID:27297970

  12. Clinical responses to rituximab in a case of neuroblastoma with refractory opsoclonus myoclonus ataxia syndrome.

    PubMed

    Alavi, Samin; Kord Valeshabad, Ali; Moradveisi, Borhan; Aminasnafi, Ali; Arzanian, Mohammad Taghi

    2012-01-01

    Opsoclonus myoclonus ataxia syndrome (OMS) is a rare neurologic syndrome. In a high proportion of children, it is associated with neuroblastoma. The etiology of this condition is thought to be immune mediated. In children, immunotherapy with conventional treatments such as corticosteroids, intravenous immunoglobulin, adrenocorticotropic hormone, and even antiepileptic drugs has been tried. Recently rituximab has been used safely for refractory OMS in children with neuroblastoma. Our patient was a 3.5-year-old girl referred for ataxia and dancing eye movements starting since 1.5 years ago. She was diagnosed with neuroblastoma on imaging studies on admission. The OMS was refractory to surgical resection, chemotherapy, corticosteroids, and intravenous immunoglobulin. Patient received rituximab simultaneously with chemotherapy. The total severity score decreased by 61.1% after rituximab. Patient's ataxia markedly improved that she was able to walk independently after 6 months. Our case confirmed the clinical efficacy and safety of rituximab in a refractory case of OMS. PMID:23198199

  13. Future therapies for pemphigus vulgaris: Rituximab and beyond.

    PubMed

    Huang, Amy; Madan, Raman K; Levitt, Jacob

    2016-04-01

    The conventional treatment for patients with pemphigus vulgaris (PV) centers on global immunosuppression, such as the use of steroids and other immunosuppressive drugs, to decrease titers of antidesmoglein autoantibodies responsible for the acantholytic blisters. Global immunosuppressants, however, cause serious side effects. The emergence of anti-CD20 biologic medications, such as rituximab, as an adjunct to conventional therapy has shifted the focus to targeted destruction of autoimmune B cells. Next-generation biologic medications with improved modes of delivery, pharmacology, and side effect profiles are constantly being developed, adding to the diversity of options for PV treatment. We review promising monoclonal antibodies, including veltuzumab, obinutuzumab (GA-101), ofatumumab, ocaratuzumab (AME-133v), PRO131921, and belimumab. PMID:26792592

  14. The role of rituximab and positron emission tomography in the treatment of primary mediastinal large B-cell lymphoma: experience on 74 patients.

    PubMed

    Zinzani, Pier Luigi; Broccoli, Alessandro; Casadei, Beatrice; Stefoni, Vittorio; Pellegrini, Cinzia; Gandolfi, Letizia; Maglie, Roberto; Argnani, Lisa; Pileri, Stefano; Fanti, Stefano

    2015-12-01

    Regarding primary mediastinal large B-cell lymphoma (PMLBCL), there are several controversial topics that warrant further investigation: the superiority of third-generation regimens, the impact of rituximab, the use of involved field radiotherapy (RT) and the assessment of clinical response by positron emission tomography (PET). We report our experience on 74 PMLBCL patients treated with a combination of a third-generation chemotherapy regimen (MACOP-B) and rituximab: an observational retrospective single-centre study was conducted on patients diagnosed and treated between February 2002 and July 2011. All patients were evaluated by computed tomography scan and PET scan; after the final PET evaluation, PET-negative patients were observed, whereas PET-positive patients underwent mediastinal RT. Sixty-one (82.4%) patients achieved a complete response after the MACOP-B plus rituximab regimen; 68.9% presented a positive final PET and were treated with local RT, whereas 31.1% had a negative PET. Five patients relapsed within 12 months. At 10 years, overall survival was 82%, progression-free survival was 87.6% and disease-free survival (DFS) was 90.5% (median follow-up 4 years). No statistically significant differences were observed in DFS between the patients treated also with RT (PET positive) and patients only observed (PET negative): 90.7% vs 90% (p = 0.85), respectively. In our experience, adding rituximab does not change the final results in terms of complete response and DFS utilizing third-generation regimen. Furthermore, the introduction of the PET-guided RT approach leads to a patient-tailored treatment, which preserves the outcome and, at the same time, allows reducing the use of RT. PMID:25256959

  15. Retrospective analysis of rituximab therapy and splenectomy in childhood chronic and refractory immune thrombocytopenic purpura.

    PubMed

    Ay, Yilmaz; Karapinar, Tuba H; Oymak, Yesim; Toret, Ersin; Demirag, Bengu; Ince, Dilek; Ozcan, Esin; Moueminoglou, Nergial; Koker, Sultan A; Vergin, Canan

    2016-06-01

    Immune thrombocytopenic purpura (ITP) results from accelerated platelet destruction mediated by autoantibodies to platelet glycoproteins. Some patients with chronic ITP are refractory to all therapies [steroids, intravenous immunoglobulin (IVIG), anti-D and immunosuppresive drugs] and have chronic low platelet counts and episodic bleeding. We retrospectively evaluated the efficacy and safety of rituximab treatment and splenectomy in paediatric patients diagnosed with chronic and refractory ITP who were unresponsive to steroids, IVIG, cyclosporine and mycophenolate mofetil. Records of patients with chronic and refractory ITP in 459 patients with primary ITP who were followed up in our hospital from January 2005 to December 2014 were reviewed. Fifteen of patients received rituximab and/or applied splenectomy. Fifteen chronic ITP patients (10 boys, five girls) with a mean age of 10 years were enrolled in the study. Two of these patients were suffering from Evans syndrome. The median time since diagnosis of ITP was 10 years. The median follow-up duration after starting Rituximab and splenectomy were 13 and 9.5 months, respectively.None of the seven patients who were treated with rituximab achieved a response. A splenectomy was performed in six of the seven patients who had been treated with rituximab. Complete and partial responses were achieved in 67 and 33% of the patients, respectively. We evaluated the clinical characteristics and responses of chronic ITP patients who did not receive rituximab therapy and underwent a splenectomy. The success rate was 100% in the eight patients with chronic and refractory ITP. Rituximab therapy might not be beneficial for some children with severe chronic ITP who are refractory to standard agents. A splenectomy might be useful and preferable to rituximab. PMID:26656905

  16. Combined therapy with rituximab plus cyclophosphamide/vincristine/prednisone for Sjogren's syndrome-associated B-cell non-Hodgkin's lymphoma.

    PubMed

    Carbone, J; Perez-Fernandez, R; Muñoz, A; Sabin, P; Carreño, L; Fernandez-Cruz, E

    2008-02-01

    Sjogren's syndrome (SS) is characterized by an increased risk of developing non-Hodgkin's lymphoma (NHL). Optimal treatment for NHL-complicating SS is not clearly established. NHL, which expresses the CD20 antigen on tumor cell surfaces, is a disease entity candidate to treatment with anti-CD20 monoclonal antibodies. We report clinical and immunological data of a patient with SS and NHL who was treated with a regimen consisting of cyclophosphamide/vincristine/prednisone (CVP) plus rituximab. A 68-year-old women had a 26-year history of SS and autoimmune thyroiditis. The clinical course of SS was complicated with severe splenomegaly. An increased percentage of CD19+ B cells (up to 30%) was detected in peripheral blood during follow-up. Clonal rearrangement of immunoglobulin heavy chain was detected. Low-grade B marginal zone lymphoma was diagnosed (peripheral blood immunophenotype: CD19+CD20+CD23+sIg+Kappa; bone marrow immunophenotype: 25% lymphocytes; CD19+CD20+CD79A/BCL2+). She received a total of six cycles of CVP plus rituximab (375 mg/m2). Therapy was well tolerated, and B lymphocytes were depleted from the peripheral blood. Splenomegaly normalized. No evidence of neoplastic infiltration was detected in bone marrow after completion of therapy, while certain symptoms of SS (sicca and arthralgia) improved with treatment. CVP plus rituximab proved effective in a patient with SS with NHL. PMID:18270861

  17. Impact of rituximab-associated B-cell defects on West Nile virus meningoencephalitis in solid organ transplant recipients

    PubMed Central

    Levi, Marilyn E.; Quan, Dianna; Ho, Joseph T.; Kleinschmidt-DeMasters, B. K.; Tyler, Kenneth L.; Grazia, Todd J.

    2010-01-01

    Evidence suggests that West Nile virus (WNV) neuroinvasive disease occurs more frequently in both solid organ and human stem cell transplant recipients. The effect of concomitant anti-B-cell therapy with rituximab, a CD20+ monoclonal antibody, on WNV infection in this population, however, has not been reported. We describe a case of a patient with alpha-1-antitrypsin deficiency who underwent single lung transplantation in 2005 and was maintained on tacrolimus, cytoxan and prednisone. More recently, she had received two courses of rituximab for recurrent A2–A3 grade rejection with concomitant capillaritis and presented six months later with rapid, fulminant WNV meningoencephalitis. Her diagnosis was made by cerebrospinal fluid (CSF) PCR but serum and CSF WNV IgM and IgG remained negative. She received WNV-specific hyperimmune globulin (Omr-Ig-Am®) through a compassionate protocol. She experienced a rapidly progressive and devastating neurological course despite treatment and died three wk after onset of her symptoms. Autopsy revealed extensive meningoencephalomyelitis. PMID:19659514

  18. A novel triple therapy for ITP using high-dose dexamethasone, low-dose rituximab, and cyclosporine (TT4)

    PubMed Central

    Choi, Philip Young-Ill; Roncolato, Fernando; Badoux, Xavier; Ramanathan, Sundra; Ho, Shir-Jing

    2015-01-01

    Promising reports of combination immunosuppression with high-dose dexamethasone and rituximab for the treatment of primary immune thrombocytopenia (ITP) have recently emerged. They suggest a potential to further optimize the efficacy of therapy. We investigate the use of a novel combination of conventional therapies in ITP given over 4 weeks. From 2011 to 2014, 20 patients were prospectively enrolled onto a single-arm phase 2b study to describe the safety, efficacy, and tolerability of oral dexamethasone 40 mg for days 1 to 4, oral cyclosporine 2.5 to 3 mg/kg daily for day 1 to 28, and intravenous low-dose rituximab 100 mg for days 7, 14, 21, and 28. There were no therapy-related serious adverse side effects, 6-month response rate was 60%, and treatment was well tolerated. Responders enjoyed relapse-free survivals of 92% and 76%, respectively, at 12 and 24 months. This study highlights the possibility of achieving an enduring remission from 4 weeks of therapy. This study is registered at www.anzctr.org.au (#ANZCTRN12611000015943). PMID:25972158

  19. Combination of cyclophosphamide, rituximab, and intratumoral CpG oligodeoxynucleotide successfully eradicates established B cell lymphoma.

    PubMed

    Betting, David J; Hurvitz, Sara A; Steward, Kristopher K; Yamada, Reiko E; Kafi, Kamran; van Rooijen, Nico; Timmerman, John M

    2012-09-01

    Rituximab plus chemotherapy is standard therapy for patients with non-Hodgkin B cell lymphoma, but often complete response or cure is not achieved. Toll-like receptor 9 agonist CpG oligodeoxynucleotides (CpG) can improve antibody-dependent cellular cytotoxicity and adaptive antitumor immune responses. Using a syngeneic murine B cell lymphoma expressing human CD20 (38C13-huCD20), we previously demonstrated that rituximab plus intratumoral CpG, but not systemic CpG, could eradicate up to half of 7-day established 38C13-huCD20 tumors. However, larger 10-day established tumors could not be cured with this regimen. We thus hypothesized that cytoreduction with cyclophosphamide (Cy) before immunotherapy might permit eradication of these more advanced tumor burdens. Pretreatment with Cy resulted in tumor eradication from 83% of animals treated with rituximab/CpG, whereas Cy/CpG or Cy/rituximab treatments only cured 30% or 17%, respectively (P<0.005). Tumor eradication depended on natural killer cells, but not T cells, macrophages, or complement. Only mice treated with Cy/rituximab/CpG partially resisted rechallenge with tumor cells. Foxp3 Treg and CD11bGr1 myeloid suppressor cells persisted within lymphoid organs after therapy, possibly influencing the ability to establish adaptive tumor immunity. In conclusion, cytoreduction with Cy permitted the cure of large, established lymphomas not otherwise responsive to rituximab plus intratumoral CpG immunotherapy. PMID:22892450

  20. Use of Rituximab in Children with Steroid- and Calcineurin-Inhibitor-Dependent Idiopathic Nephrotic Syndrome

    PubMed Central

    Ravani, Pietro; Ponticelli, Alessandro; Siciliano, Chiara; Fornoni, Alessia; Magnasco, Alberto; Sica, Felice; Bodria, Monica; Caridi, Gianluca; Wei, Changli; Belingheri, Mirco; Ghio, Luciana; Merscher-Gomez, Sandra; Edefonti, Alberto; Pasini, Andrea; Montini, Giovanni; Murtas, Corrado; Wang, Xiangyu; Muruve, Daniel; Vaglio, Augusto; Martorana, Davide; Pani, Antonello; Scolari, Francesco; Reiser, Jochen; Ghiggeri, Gian Marco

    2013-01-01

    In children with idiopathic nephrotic syndrome rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin-inhibitors. Long-term effects including number of repeated infusions to maintain remission are unknown. We treated with rituximab 46 consecutive children with idiopathic nephrotic syndrome lasting for at least one year (6.3±4.1 years), who were maintained in remission with oral prednisone and calcineurin inhibitors. They received 1–5 rituximab courses during a median follow-up of three years (range 1–5). Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and two-year-remission probabilities were respectively 20% and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months respectively following the first and subsequent courses. Time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20 or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Rituximab can be safely and repeatedly used as prednisone and calcineurin-inhibitor-sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further research is needed to identify patients who will benefit most from rituximab therapy. PMID:23739238

  1. Use of Rituximab for Refractory Cytopenias Associated with Autoimmune Lymphoproliferative Syndrome (ALPS)

    PubMed Central

    Rao, V. Koneti; Price, Susan; Perkins, Katie; Aldridge, Patricia; Tretler, Jean; Davis, Joie; Dale, Janet K.; Gill, Fred; Hartman, Kip R.; Stork, Linda C.; Gnarra, David J.; Krishnamurti, Lakshmanan; Newburger, Peter E.; Puck, Jennifer; Fleisher, Thomas

    2009-01-01

    Background ALPS is a disorder of apoptosis resulting in accumulation of autoreactive lymphocytes, leading to marked lymphadenopathy, hepatosplenomegaly and multilineage cytopenias due to splenic sequestration and/or autoimmune destruction often presenting in childhood. We summarize our experience of rituximab use during the last 8 years in twelve patients, 9 children and 3 adults, out of 259 individuals with ALPS, belonging to 166 families currently enrolled in studies at the National Institutes of Health. Methods Refractory immune thrombocytopenia (platelet count <20,000) in 9 patients and autoimmune hemolytic anemia (AIHA) in 3 patients led to treatment with rituximab. Among them, 7 patients had undergone prior surgical splenectomy; 3 had significant splenomegaly; and 2 had no palpable spleen. Results In 7 out of 9 patients with ALPS and thrombocytopenia, rituximab therapy led to median response duration of 21months (range 14–36 months). In contrast, none of the 3 children treated with rituximab for AIHA responded. Noted toxicities included profound and prolonged hypogammaglobulinemia in 3 patients requiring replacement IVIG, total absence of antibody response to polysaccharide vaccines lasting up to 4 years after rituximab infusions in 1 patient and prolonged neutropenia in 1 patient. Conclusion Toxicities including hypogammaglobulinemia and neutropenia constitute an additional infection risk burden, especially in asplenic individuals, and may warrant avoidance of rituximab until other immunosuppressive medication options are exhausted. Long term follow up of ALPS patients with cytopenias after any treatment is necessary to determine relative risks and benefits. PMID:19214977

  2. Anti-JC virus antibodies in rituximab-treated patients with neuromyelitis optica spectrum disorder.

    PubMed

    Kim, Su-Hyun; Hyun, Jae-Won; Jeong, In Hye; Joung, AeRan; Yeon, Joung-Lim; Dehmel, Thomas; Adams, Ortwin; Kieseier, Bernd C; Kim, Ho Jin

    2015-03-01

    Rituximab, a chimeric monoclonal anti-CD20 antibody, has been proposed to be effective for neuromyelitis optica spectrum disorder (NMOSD). A concern for developing progressive multifocal leukoencephalopathy (PML), which is caused by John Cunningham virus (JCV), has been suggested particularly in patients treated long term with rituximab. In this study, using a modified enzyme-linked immunosorbent assay with glutathione S-transferase-tagged VP1 as the antigen, we investigated the seroprevalence of anti-JCV antibodies among 78 Korean patients with NMOSD and the change in anti-JCV antibody serostatus following long-term rituximab treatment. The overall seroprevalence of anti-JCV antibodies was 69 % prior to rituximab administration. Over a mean of 4 years of repeated treatment with rituximab, no patient developed PML. Of 24 initially seronegative patients, none converted into seropositive, whereas six (11 %) of 54 initially seropositive patients converted into seronegative. Our results might support the safety of long-term rituximab treatment in patients with NMOSD with regard to the risk of developing PML. PMID:25559683

  3. Subcutaneous versus intravenous administration of rituximab: pharmacokinetics, CD20 target coverage and B-cell depletion in cynomolgus monkeys.

    PubMed

    Mao, Cheng-Ping; Brovarney, Martin R; Dabbagh, Karim; Birnböck, Herbert F; Richter, Wolfgang F; Del Nagro, Christopher J

    2013-01-01

    The CD20-specific monoclonal antibody rituximab (MabThera(®), Rituxan(®)) is widely used as the backbone of treatment for patients with hematologic disorders. Intravenous administration of rituximab is associated with infusion times of 4-6 hours, and can be associated with infusion-related reactions. Subcutaneous administration of rituximab may reduce this and facilitate administration without infusion-related reactions. We sought to determine the feasibility of achieving equivalent efficacy (measured by endogenous B-cell depletion) and long-term durability of CD20 target coverage for subcutaneously administered rituximab compared with intravenous dosing. In these preclinical studies, male cynomolgus monkeys were treated with either intravenous rituximab or novel subcutaneous formulation of rituximab containing human recombinant DNA-derived hyaluronidase enzyme. Peripheral blood samples were analyzed for serum rituximab concentrations, peripheral B-cell depletion, and CD20 target coverage, including subset analysis according to CD21+ status. Distal lymph node B-cell depletion and CD20 target coverage were also measured. Initial peak serum concentrations of rituximab were significantly higher following intravenous administration than subcutaneous. However, the mean serum rituximab trough concentrations were comparable at 2 and 7 days post-first dose and 9 and 14 days post-second dose. Efficacy of B-cell depletion in both peripheral blood and distal lymph nodes was comparable for both methods. In lymph nodes, 9 days after the second dose with subcutaneous and intravenous rituximab, B-cell levels were decreased by 57% and 42% respectively. Similarly, levels of peripheral blood B cells were depleted by >94% for both subcutaneous and intravenous dosing at all time points. Long-term recovery of free unbound surface CD20 levels was similar, and the duration of B-cell depletion was equally sustained over 2 months for both methods. These results demonstrate that, despite

  4. Subcutaneous versus Intravenous Administration of Rituximab: Pharmacokinetics, CD20 Target Coverage and B-Cell Depletion in Cynomolgus Monkeys

    PubMed Central

    Mao, Cheng-Ping; Brovarney, Martin R.; Dabbagh, Karim; Birnböck, Herbert F.; Richter, Wolfgang F.; Del Nagro, Christopher J.

    2013-01-01

    The CD20-specific monoclonal antibody rituximab (MabThera®, Rituxan®) is widely used as the backbone of treatment for patients with hematologic disorders. Intravenous administration of rituximab is associated with infusion times of 4–6 hours, and can be associated with infusion-related reactions. Subcutaneous administration of rituximab may reduce this and facilitate administration without infusion-related reactions. We sought to determine the feasibility of achieving equivalent efficacy (measured by endogenous B-cell depletion) and long-term durability of CD20 target coverage for subcutaneously administered rituximab compared with intravenous dosing. In these preclinical studies, male cynomolgus monkeys were treated with either intravenous rituximab or novel subcutaneous formulation of rituximab containing human recombinant DNA-derived hyaluronidase enzyme. Peripheral blood samples were analyzed for serum rituximab concentrations, peripheral B-cell depletion, and CD20 target coverage, including subset analysis according to CD21+ status. Distal lymph node B-cell depletion and CD20 target coverage were also measured. Initial peak serum concentrations of rituximab were significantly higher following intravenous administration than subcutaneous. However, the mean serum rituximab trough concentrations were comparable at 2 and 7 days post-first dose and 9 and 14 days post-second dose. Efficacy of B-cell depletion in both peripheral blood and distal lymph nodes was comparable for both methods. In lymph nodes, 9 days after the second dose with subcutaneous and intravenous rituximab, B-cell levels were decreased by 57% and 42% respectively. Similarly, levels of peripheral blood B cells were depleted by >94% for both subcutaneous and intravenous dosing at all time points. Long-term recovery of free unbound surface CD20 levels was similar, and the duration of B-cell depletion was equally sustained over 2 months for both methods. These results demonstrate that, despite

  5. Two hospitals report: the pros and cons of 12-hour shifts.

    PubMed

    Hasan-Stein, L

    1998-03-01

    Earlier last year, paediatric nurses and delivery suite midwives at two North Island hospitals took part in six-month trials working 12-hour shifts. In both cases the trials were successful and have resulted in a decision by staff to continue working longer hours. Staff at both hospitals report on the trials and the introduction of 12-hour shifts in their areas. PMID:10586729

  6. Association of rituximab with graphene oxide confers direct cytotoxicity for CD20-positive lymphoma cells

    PubMed Central

    Luo, Chengke; Deng, Zhenghao; Li, Lan; Clayton, Frederic; Chen, Alexander L.; Wei, Ran; Miles, Rodney; Stephens, Deborah M.; Glenn, Martha; Wang, Xiyang; Jensen, Peter E.; Chen, Xinjian

    2016-01-01

    Non-Hodgkin lymphoma (NHL) is one of the most common hematologic malignancies among adults for which the chimeric monoclonal anti-CD20 antibody (Ab) rituximab (RTX) is used as first-line therapy. As RTX itself is not directly cytotoxic but relies on host immune effector mechanisms or chemotherapeutic agents to attack target cells, its therapeutic capacity may become limited when host effector mechanisms are compromised. Currently, refractory disease and relapse with NHL are still common, highlighting the need for novel anti-CD20 antibody strategies with superior therapeutic efficacy over current protocols. We hypothesized that making RTX directly cytotoxic might improve the therapeutic efficacy. Graphene oxide (GO) has recently emerged as a highly attractive nanomaterial for biomedical applications; and several studies have reported cytotoxic effect of GO on benign and malignant cells in vitro. Herein, we report that RTX can be stably associated with GO, and that GO-associated RTX (RTX/GO) demonstrates remarkably high avidity for CD20. Binding of GO-associated RTX to CD20-positive lymphoma cells induces CD20 capping and target cell death through an actin dependent mechanism. In vivo, GO-associated RTX, but not free RTX, quickly eliminates high-grade lymphomas in the absence of host effector mechanisms in a xenograft lymphoma mouse model. Our findings represent the first demonstration of using GO-associated antibody as effective cytotoxic therapy for human B cell malignancies in the absence of chemotherapy, and these findings could have important clinical implications. PMID:26859679

  7. Real Time Analysis of Binding between Rituximab (anti-CD20 antibody) and B Lymphoma Cells

    PubMed Central

    Tan, Liang; Lin, Peiling; Chisti, Mohammad M.; Rehman, Abdul; Zeng, Xiangqun

    2013-01-01

    CD20, expressed on greater than 90% of B-lymphocytic lymphomas, is an attractive target for antibody therapy. Rituximab is a chimeric murine/human-engineered monoclonal antibody and can selectively deplete CD20-expressing cells in peripheral blood and lymphoid tissues. The immobilization of B-lymphoblast-like Burkitt's lymphoma Raji cells on the quartz crystal microbalance (QCM) gold electrode surface using RGD tripeptide was electrochemically confirmed. The real-time processes of attachment of Raji cells on the gold electrode and the subsequent binding of Rituximab to the cells were studied using QCM biosensor. The interaction between Rituximab and Raji cells led to the increased resonant frequency shifts (Δf0) in the studied antibody concentration range from 5 to 250 µg mL−1 following the Langmuir adsorption model. From these observations, the apparent binding constant between a single-layer of Rituximab and Raji cells was calculated to be 1.6×106 M−1. Control experiments using other therapeutic antibodies (i.e., Trastuzumab and Bevacizumab) and different cells (i.e., T cells and endothelial cells) proved the specific interaction between Rituximab and B cells. The effects of Ca2+ and Mn2+ ions on the Rituximab-Raji cell interaction were also studied providing the enhanced QCM signals, in particular, further indicating that CD20 is a calcium ion channel that can transport these metal ions into the cells and accelerate the cell lysis induced by Rituximab. Thus the real time capability of QCM and its simplicity of operation are highly suitable for multipurpose studies on living cells including cell-immobilization, cytotoxicity of drugs, and the cell action mechanisms. PMID:23926879

  8. Changes in B and T lymphocytes and chemokines with rituximab treatment in multiple sclerosis

    PubMed Central

    Piccio, Laura; Naismith, Robert T.; Trinkaus, Kathryn; Klein, Robyn S.; Parks, Becky J.; Lyons, Jeri A.; Cross, Anne H.

    2010-01-01

    Background B cells are implicated in the pathogenesis of multiple sclerosis (MS). A beneficial effect of B cell depletion using rituximab has been shown, but the complete mechanism of action for this drug is unclear. Objective To determine the relationship between T cells, B cells, and changes in CSF chemokines with rituximab, a monoclonal antibody that targets CD20. Design Phase II trial of rituximab as an add-on therapy. Setting The John L. Multiple Sclerosis Center, Washington University, St. Louis, Missouri. Patients Thirty relapsing-remitting MS subjects with clinical and MRI activity despite treatment with an immunomodulatory drug received four weekly doses of 375mg/m2 rituximab. Main Outcome Measures Lumbar puncture was performed before and after rituximab infusions in 26 subjects. CSF B and T lymphocytes were enumerated by flow cytometry, and chemoattractants were measured by ELISA. Results After rituximab administration, CSF B cells were decreased or undetectable in all subjects and CSF T cells were reduced in 81% of subjects. The mean reduction in CSF cellularity was 95% for B cells and 50% for T cells. After rituximab infusion, CSF CXCL13 and CCL19 decreased (P= 0.002, P=0.03, respectively). The proportional decline in CSF T cells correlated with the proportional decrease in CXCL13 (r=0.45;P=0.03), suggesting a possible relationship. CSF IgG index, IgG concentration, and oligoclonal band number were unchanged following treatment. Conclusions B cells are critical for T cell trafficking into the CNS in MS patients, and may alter T cell trafficking by influencing chemokine production within the CNS. PMID:20558389

  9. Gemcitabine enhances rituximab-mediated complement-dependent cytotoxicity to B cell lymphoma by CD20 upregulation.

    PubMed

    Hayashi, Kazumi; Nagasaki, Eijiro; Kan, Shin; Ito, Masaki; Kamata, Yuko; Homma, Sadamu; Aiba, Keisuke

    2016-05-01

    Although rituximab, a chimeric monoclonal antibody that specifically binds to CD20, has significantly improved the prognosis for diffuse large B cell lymphoma (DLBCL), one-third of DLBCL patients demonstrate resistance to rituximab or relapse after rituximab treatment. Thus, a novel approach to rituximab-based treatment is likely to be required to improve the efficacy of DLBCL treatment. As complement dependent cytotoxicity (CDC) is a key mechanism mediating rituximab's tumoricidal activity, rituximab binding to CD20 on tumor cells is a critical factor for effective rituximab-based treatments against DLBCL. We found that gemcitabine (GEM), but not lenalidomide (LEN) or azacitidine (AZA), can upregulate CD20 expression in TK and KML-1 cells, two human DLBCL cell lines. Treatment of TK and KML-1 cells with GEM enhanced CD20 expression at both the mRNA and protein levels. CD20 upregulation by GEM treatment was accompanied by increased rituximab binding to CD20. In TK cells, GEM treatment synergistically increased rituximab-mediated CDC activity in a dose-dependent manner. In KML cells, GEM treatment also induced upregulation of complement regulatory proteins, possibly leading to resistance to CDC. Treatment with LEN, a drug that did not upregulate CD20, did not enhance rituximab-mediated CDC activity. GEM treatment activated nuclear factor-kappa B (NF-kB) signaling in these cells. Furthermore, a specific inhibitor to NF-kB suppressed GEM-induced CD20 upregulation, indicating that GEM-induced NF-kB activation is closely associated with CD20 upregulation. These results suggest that when used in combination, GEM might enhance the antitumor efficacy of rituximab against DLBCL due to its unique ability to upregulate CD20. PMID:26920337

  10. Document-level classification of CT pulmonary angiography reports based on an extension of the ConText algorithm.

    PubMed

    Chapman, Brian E; Lee, Sean; Kang, Hyunseok Peter; Chapman, Wendy W

    2011-10-01

    In this paper we describe an application called peFinder for document-level classification of CT pulmonary angiography reports. peFinder is based on a generalized version of the ConText algorithm, a simple text processing algorithm for identifying features in clinical report documents. peFinder was used to answer questions about the disease state (pulmonary emboli present or absent), the certainty state of the diagnosis (uncertainty present or absent), the temporal state of an identified pulmonary embolus (acute or chronic), and the technical quality state of the exam (diagnostic or not diagnostic). Gold standard answers for each question were determined from the consensus classifications of three human annotators. peFinder results were compared to naive Bayes' classifiers using unigrams and bigrams. The sensitivities (and positive predictive values) for peFinder were 0.98(0.83), 0.86(0.96), 0.94(0.93), and 0.60(0.90) for disease state, quality state, certainty state, and temporal state respectively, compared to 0.68(0.77), 0.67(0.87), 0.62(0.82), and 0.04(0.25) for the naive Bayes' classifier using unigrams, and 0.75(0.79), 0.52(0.69), 0.59(0.84), and 0.04(0.25) for the naive Bayes' classifier using bigrams. PMID:21459155

  11. Clinical efficacy of combined rituximab treatment in a woman with severe Graves' ophthalmopathy

    PubMed Central

    Liu, Xiaomei; Guo, Hui; Liu, Juan; Shi, Bingyin

    2016-01-01

    The present study reports the case of a female Chinese patient with Graves' disease (GD) and severe Graves' ophthalmopathy (GO) in its active phase, who was treated with propylthiouracil and oral prednisolone for 2 months at a local hospital. However, a lack of improvement in symptoms meant that the patient was transferred to the First Affiliated Hospital of Xi'an Jiaotong University (Xi'an, China), whereupon the patient received high-dose intravenous methylprednisolone pulse therapy, although with limited efficacy. Subsequently, rituximab (RTX; anti-CD20 monoclonal antibody) combined with orbital irradiation treatment was initiated. The patient responded positively to the combined treatment; the clinical symptoms and enlargement of the extraocular muscles were ameliorated, and there were marked decreases in the clinical activity and NOSPECS grading scores. Furthermore, the serum levels of anti-thyrotropin receptor antibodies (TRAb) were markedly decreased at 2 months following RTX therapy. The patient was maintained in a euthyroid state by treatment with methimazole during and following RTX therapy. It was concluded that RTX treatment may attenuate severe GO by depleting lymphocytes, and may promote the recovery of GD by reducing the serum levels of TRAb. PMID:27446325

  12. Place in therapy of rituximab in the treatment of granulomatosis with polyangiitis and microscopic polyangiitis

    PubMed Central

    Shah, Shivani; Geetha, Duvuru

    2015-01-01

    Granulomatosis with polyangiitis and microscopic polyangiitis are small vessel vasculitides characterized by circulating antineutrophil circulating antibodies. Standard treatment for active severe disease has consisted of cyclophosphamide with glucocorticoids with or without plasmapheresis, which achieves approximately 75% sustained remission, but carries significant adverse effects such as malignancy, infertility, leukopenia, and infections. The role of B cells in the pathogenesis of anti-neutrophil circulating antibodies-associated vasculitis has been established, and as such, rituximab, a monoclonal anti-CD20 antibody, has been studied in treatment of active granulomatosis with polyangiitis and microscopic polyangiitis (induction) and in maintaining remission. Rituximab has been shown to be effective in inducing remission in several retrospective studies in patients with refractory disease or cyclophosphamide intolerance. The RAVE and RITUXVAS trials demonstrated rituximab is a noninferior alternative to standard cyclophosphamide-based therapy; however, its role in elderly patients and patients with severe renal disease warrants further investigation. Rituximab has been compared with azathioprine for maintaining remission in the MAINRITSAN trial and may be more efficacious in maintaining remission in patients treated with cyclophosphamide induction. Rituximab is not without risks and carries a similar adverse event risk rate as cyclophosphamide in randomized control trials. However, its use can be considered over cyclophosphamide in patients who have relapsing or refractory disease or in young patients seeking to preserve fertility.

  13. Rituximab as Single Agent in Primary MALT Lymphoma of the Ocular Adnexa

    PubMed Central

    Annibali, Ombretta; Chiodi, Francesca; Sarlo, Chiara; Cortes, Magdalena; Quaranta-Leoni, Francesco M.; Quattrocchi, Carlo; Bianchi, Antonella; Bonini, Stefano; Avvisati, Giuseppe

    2015-01-01

    Ocular Adnexal Lymphomas are the first cause of primary ocular malignancies, and among them the most common are MALT Ocular Adnexal Lymphomas. Recently systemic immunotherapy with anti-CD20 monoclonal antibody has been investigated as first-line treatment; however, the optimal management for MALT Ocular Adnexal Lymphomas is still unknown. The present study evaluated retrospectively the outcome of seven consecutive patients with primary MALT Ocular Adnexal Lymphomas, of whom six were treated with single agent Rituximab. All patients received 6 cycles of Rituximab 375 mg/mq every 3 weeks intravenously. The overall response rate was 100%; four patients (67%) achieved a Complete Remission, and two (33%) achieved a partial response. In four patients an additional Rituximab maintenance every 2-3 months was given for two years. After a median follow-up of 29 months (range 8–34), no recurrences were observed, without of therapy- or disease-related severe adverse events. None of the patients needed additional radiotherapy or other treatments. Rituximab as a single agent is highly effective and tolerable in first-line treatment of primary MALT Ocular adnexal Lymphomas. Furthermore, durable responses are achievable with the same-agent maintenance. Rituximab can be considered the agent of choice in the management of an indolent disease in whom the “quality of life” matter is of primary importance. PMID:26425558

  14. Rituximab for Non-Hodgkin’s Lymphoma: A Story of Rapid Success in Translation

    PubMed Central

    Harrison, Andrew M.; Thalji, Nassir M.; Greenberg, Alexandra J.; Tapia, Carmen J.; Windebank, Anthony J.

    2014-01-01

    Translational stories range from straightforward to complex. In this commentary, the story of the rapid and successful translation of rituximab therapy for the treatment of non-Hodgkin’s lymphoma (NHL) is examined. Development of this monoclonal antibody therapy began in the late 1980s. In 1994, rituximab received its first approval for the treatment of NHL by the United States Food and Drug Administration (FDA). Rituximab has since been approved for additional indications and has transformed medical practice. However, the social and political implications of these rapid successes are only beginning to become clear. In this commentary, key events in the rapid translation of rituximab from the bench to bedside are highlighted and placed into this historical framework. To accomplish this, the story of rituximab is divided into the following six topics, which we believe to be widely applicable to case studies of translation: (1) underlying disease, (2) key basic science, (3) key clinical studies in translation, (4) FDA approval process, (5) changes to medical practice, and (6) the social and political influences on translation. PMID:24528902

  15. Timing determines dexamethasone and rituximab induced synergistic cell death.

    PubMed

    Adem, Jemal; Eray, Mine; Eeva, Jonna; Nuutinen, Ulla; Pelkonen, Jukka

    2016-07-01

    Dysregulation of cell death signaling pathways in many cell types such as B lymphocytes (B-cells) can lead to cancer, for example to B-cell lymphomas. Rituximab (RTX) and glucocorticoids such as dexamethasone (Dex) are widely used to treat hematological malignancies including B-cell lymphomas. Although the combination of Dex and RTX improves the treatment outcome of lymphoma patients, most lymphomas remain incurable diseases. Therefore, a detailed investigation of Dex- and RTX-induced signaling might provide new insights into the therapeutic benefits of these drugs. In this paper, we describe Dex- and RTX-induced signaling pathways and their downstream target proteins/cells. In addition, we also overview how the signaling initiated by Dex and RTX modulate the outcome of Dex- and RTX-mediated cell death in lymphoma cells. The combination of Dex and RTX results in massive cell death in lymphoma cells. However, pretreatment of lymphoma cells or mononuclear cytotoxic cells with Dex followed by RTX leads to a decrease in apoptosis or it impairs antibody-dependent cellular cytotoxicity (ADCC). RTX-mediated ADCC is impaired by Dex-induced depletion of cytotoxic cells, whereas RTX-mediated short-term ERK1/2 activation decreases Dex-induced apoptosis. Therefore, the timing of the combination of Dex and RTX is a determining factor for the synergistic effect of these cell death inducing agents. PMID:27290654

  16. Rituximab as maintenance therapy for ANCA associated vasculitis: how, when and why?

    PubMed

    Alba, Marco A; Flores-Suárez, Luis Felipe

    2016-01-01

    ANCA-associated vasculitides (AAV) are chronic autoimmune diseases characterized by inflammation and destruction of small vessels. Rituximab is now licensed for use as a remission-induction agent in the treatment of these disorders. During recent years, several non-controlled studies have suggested that rituximab may be of value in maintaining disease remission in AAV. In these series, 3 techniques have been tried: "watch-and-wait", repeated cycles in fixed intervals, or administration based on proposed biomarkers. More importantly, the results of the MAINRITSAN trial showed that this anti-CD20 agent is superior to azathioprine for preventing major relapses in AAV. This review summarizes current information regarding the effectiveness, timing, dosing, duration and safety of rituximab as a valid option for remission maintenance. PMID:26255570

  17. A review of the current use of rituximab in autoimmune diseases.

    PubMed

    Gürcan, Hakan M; Keskin, Derin B; Stern, Joel N H; Nitzberg, Matthew A; Shekhani, Haris; Ahmed, A Razzaque

    2009-01-01

    Rituximab is a human/murine chimeric monoclonal antibody primarily used for treating non-Hodgkin's B-cell lymphoma. Recently it has also been used in the treatment of several autoimmune diseases. A literature review was conducted to determine the efficacy of rituximab in the treatment of some of these autoimmune diseases. Multiple mechanisms proposed for the rituximab mediated B cell depletion are also discussed. The efficacy of rituximab is well-established and it is FDA approved for treatment of Rheumatoid arthritis. In this review, data on the use of rituximab is presented from 92 studies involving 1197 patients with the following diseases: systemic lupus erythematosus, idiopathic thrombocytopenic purpura, anti-neutrophil cytoplasmic antibody associated vasculitis, Grave's disease, autoimmune hemolytic anemia, pemphigus vulgaris, hemophilia A, cold agglutinin disease, Sjogren's syndrome, graft vs. host disease, thrombotic thrombocytopenic purpura, cryoglobulinemia, IgM mediated neuropathy, multiple sclerosis, neuromyelitis optica, idiopathic membranous nephropathy, dermatomyositis, and opsoclonus myoclonus. The efficacy varies among different autoimmune diseases. The cumulative data would suggest that in the vast majority of studies in this review, RTX has a beneficial role in their treatment. While rituximab is very effective in the depletion of B cells, current research suggests it may also influence other cells of the immune system by re-establishing immune homeostasis and tolerance. The safety profile of RTX reveals that most reactions are infusion related. In patients with autoimmune diseases the incidence of serious and severe side effects is low. Systemic infection still remains a major concern and may result in death. PMID:19000786

  18. Sustained Elite Suppression of Replication Competent HIV-1 in a Patient Treated With Rituximab Based Chemotherapy

    PubMed Central

    Gaillard, Stephanie; Dinoso, Jason B.; Marsh, Julia A.; DeZern, Amy E.; O’Connell, Karen A; Spivak, Adam M.; Alwood, Karla; Durand, Christine M.; Ambinder, Richard F.; Blankson, Joel N.

    2011-01-01

    The mechanism of elite control of HIV-1 replication is not fully understood. While immunosuppression due to rituximab based chemotherapy has been associated with increased replication of HBV, CMV, and HIV-1, control of replication-competent HIV-1 was maintained in an elite controller/suppressor treated with a regimen that included vincristine, cyclophosphamide, prednisone, four rounds of plasmapheresis and ten cycles of rituximab. The data suggests that de-novo antibody responses do not play a significant role in the control of viral replication in these patients. PMID:21550842

  19. Novel Assessment Tools to Evaluate Clinical and Laboratory Responses in a Subset of Patients Enrolled in the Rituximab in Myositis Trial

    PubMed Central

    Rider, Lisa G.; Yip, Adrienne L.; Horkayne-Szakaly, Iren; Volochayev, Rita; Shrader, Joseph A.; Turner, Maria L.; Kong, Heidi H.; Jain, Minal S.; Jansen, Anna V.; Oddis, Chester V.; Fleisher, Thomas A.; Miller, Frederick W.

    2015-01-01

    Objective To assess changes in myositis core set measures and ancillary clinical and laboratory data from the National Institutes of Health’s subset of patients enrolled in the Rituximab in Myositis trial. Methods Eighteen patients (5 dermatomyositis, 8 polymyositis, 5 juvenile dermatomyositis) completed more in-depth testing of muscle strength and cutaneous assessments, patient-reported outcomes, and laboratory tests before and after administration of rituximab. Percent change in individual measures and in the definitions of improvement (DOIs) and standardized response means were examined over 44 weeks. Results Core set activity measures improved by 18–70% from weeks 0–44 and were sensitive to change. Fifteen patients met the DOI at week 44, 9 patients met a DOI 50% response, and 4 met a DOI 70% response. Muscle strength and function measures were more sensitive to change than cutaneous assessments. Constitutional, gastrointestinal, and pulmonary systems improved 44–70%. Patient-reported outcomes improved up to 28%. CD20+ B cells were depleted in the periphery, but B cell depletion was not associated with clinical improvement at week 16. Conclusions This subset of patients had high rates of clinical response to rituximab, similar to patients in the overall trial. Most measures were responsive, and muscle strength had a greater degree of change than cutaneous assessments. Several novel assessment tools, including measures of strength and function, extra-muscular organ activity, fatigue, and health-related quality of life, are promising for use in future myositis trials. Further study of B cell–depleting therapies in myositis, particularly in treatment-naïve patients, is warranted. PMID:25068290

  20. Greatly reduced risk of EBV reactivation in rituximab-experienced recipients of alemtuzumab-conditioned allogeneic HSCT.

    PubMed

    Burns, D M; Rana, S; Martin, E; Nagra, S; Ward, J; Osman, H; Bell, A I; Moss, P; Russell, N H; Craddock, C F; Fox, C P; Chaganti, S

    2016-06-01

    EBV-associated post-transplant lymphoproliferative disease (PTLD) remains an important complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). We retrospectively analysed the incidence and risk factors for EBV reactivation in 186 adult patients undergoing consecutive allo-HSCT with alemtuzumab T-cell depletion at a single centre. The cumulative incidence of EBV reactivation was 48% (confidence interval (CI) 41-55%) by 1 year, with an incidence of high-level EBV reactivation of 18% (CI 13-24%); 8 patients were concurrently diagnosed with PTLD. Amongst patients with high-level reactivation 31/38 (82%) developed this within only 2 weeks of first EBV qPCR positivity. In univariate analysis age⩾50 years was associated with significantly increased risk of EBV reactivation (hazard ratio (HR) 1.54, CI 1.02-2.31; P=0.039). Furthermore, a diagnosis of non-Hodgkin lymphoma (NHL) was associated with greatly reduced risk of reactivation (HR 0.10, CI 0.03-0.33; P=0.0001) and this was confirmed in multivariate testing. Importantly, rituximab therapy within 6 months prior to allo-HSCT was also highly predictive for lack of EBV reactivation (HR 0.18, CI 0.07-0.48; P=0.001) although confounding with NHL was apparent. Our data emphasise the risk of PTLD associated with alemtuzumab. Furthermore, we report the clinically important observation that rituximab, administered in the peri-transplant period, may provide effective prophylaxis for PTLD. PMID:26901708

  1. t(11;18)(q21;q21)-positive advanced-stage MALT lymphoma associated with monoclonal gammopathy: resistance to rituximab or rituximab-containing chemotherapy.

    PubMed

    Ohno, Hitoshi; Isoda, Kotaro

    2008-11-01

    Here we describe two cases of mucosa-associated lymphoid tissue (MALT) lymphoma with monoclonal immunoglobulins (Igs). The first case was a 77-year-old man with primary lymphoma of the lung. Immunoelectrophoresis detected IgM-kappa in serum and kappa light chain excretion into urine. Three months after treatment with single-agent rituximab, a large amount of pleural fluid was found to have accumulated. The fluid contained CD5(-), CD10(-), CD19(+), CD38(+) and CD138(-/+) lymphoma cells with lymphoplasmacytoid appearance. Although a small fraction of the cells were CD20(+), the majority of the lymphoma cells were negative and expressed surface-membrane IgM-kappa at low levels. The cells possessed a karyotype of 46, XY, t(11;18)(q21;q21). The second case was a 55-year-old man who underwent total gastrectomy due to gastric perforation. Surgical specimens demonstrated the histopathological features of MALT lymphoma associated with plasma cell differentiation. The lymphoma cells had a 46, XY, t(11;18)(q21;q21) karyotype. Monoclonal Igs detected were serum IgA (M)-kappa and urinary kappa light chain. The patient was subsequently treated with six cycles of R-CVP (rituximab, cyclophosphamide, vincristine and prednisolone) ; however, serum monoclonal Ig levels were not affected. The lymphoma cells in both cases may have contained two populations, a rituximab-sensitive CD20(+) population and a rituximab-resistant population that had differentiated into the Ig-secreting plasma cell stage. PMID:19039196

  2. A phase 2 study of Rituximab-Bendamustine and Rituximab-Cytarabine for transplant-eligible patients with mantle cell lymphoma.

    PubMed

    Armand, Philippe; Redd, Robert; Bsat, Jad; Mayuram, Sangeetha; Giardino, Angela; Fisher, David C; LaCasce, Ann S; Jacobson, Caron; Davids, Matthew S; Brown, Jennifer R; Weng, Li; Wilkins, Jennifer; Faham, Malek; Freedman, Arnold S; Joyce, Robin; Jacobsen, Eric D

    2016-04-01

    Chemoimmunotherapy followed by autologous stem cell transplantation (ASCT) is a standard therapy for transplant-eligible patients with newly diagnosed mantle cell lymphoma (MCL). The achievement of complete remission (CR) and minimal residual disease (MRD) negativity are associated with better outcomes. We tested an induction regimen of rituximab/bendamustine followed by rituximab/high-dose cytarabine (RB/RC). This phase 2 study (NCT01661881) enrolled 23 transplant-eligible patients aged 42-69, of whom 70% were MCL international prognostic index low-risk. Patients received three cycles of RB followed by three cycles of RC. The primary endpoint of the trial was the rate of CR after six cycles of therapy, with a rate of 75% considered promising. 96% of patients achieved a CR/unconfirmed CR after treatment, meeting the primary objective. One patient progressed on study, one declined ASCT in CR, and the remaining 21 underwent successful stem cell collection and ASCT. After a median follow-up of 13 months, the progression-free survival rate was 96%. Among 15 MRD-evaluable patients who completed treatment, 93% achieved MRD negativity after RB/RC. In conclusion, RB/RC achieves very high CR and MRD negativity rates in transplant-eligible patients, with a favourable safety profile. RB/RC warrants further comparative studies, and may become a useful alternative to RCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)-based induction regimens in this patient population. PMID:26729345

  3. Preserved Activity of CD20-Specific Chimeric Antigen Receptor-Expressing T Cells in the Presence of Rituximab.

    PubMed

    Rufener, Gregory A; Press, Oliver W; Olsen, Philip; Lee, Sang Yun; Jensen, Michael C; Gopal, Ajay K; Pender, Barbara; Budde, Lihua E; Rossow, Jeffrey K; Green, Damian J; Maloney, David G; Riddell, Stanley R; Till, Brian G

    2016-06-01

    CD20 is an attractive immunotherapy target for B-cell non-Hodgkin lymphomas, and adoptive transfer of T cells genetically modified to express a chimeric antigen receptor (CAR) targeting CD20 is a promising strategy. A theoretical limitation is that residual serum rituximab might block CAR binding to CD20 and thereby impede T cell-mediated anti-lymphoma responses. The activity of CD20 CAR-modified T cells in the presence of various concentrations of rituximab was tested in vitro and in vivo CAR-binding sites on CD20(+) tumor cells were blocked by rituximab in a dose-dependent fashion, although at 37°C blockade was incomplete at concentrations up to 200 μg/mL. T cells with CD20 CARs also exhibited modest dose-dependent reductions in cytokine secretion and cytotoxicity, but not proliferation, against lymphoma cell lines. At rituximab concentrations of 100 μg/mL, CAR T cells retained ≥50% of baseline activity against targets with high CD20 expression, but were more strongly inhibited when target cells expressed low CD20. In a murine xenograft model using a rituximab-refractory lymphoma cell line, rituximab did not impair CAR T-cell activity, and tumors were eradicated in >85% of mice. Clinical residual rituximab serum concentrations were measured in 103 lymphoma patients after rituximab therapy, with the median level found to be only 38 μg/mL (interquartile range, 19-72 μg/mL). Thus, despite modest functional impairment in vitro, the in vivo activity of CD20-targeted CAR T cells remains intact at clinically relevant levels of rituximab, making use of these T cells clinically feasible. Cancer Immunol Res; 4(6); 509-19. ©2016 AACRSee related Spotlight by Sadelain, p. 473. PMID:27197068

  4. Rituximab Plus Chlorambucil As First-Line Treatment for Chronic Lymphocytic Leukemia: Final Analysis of an Open-Label Phase II Study

    PubMed Central

    Hillmen, Peter; Gribben, John G.; Follows, George A.; Milligan, Donald; Sayala, Hazem A.; Moreton, Paul; Oscier, David G.; Dearden, Claire E.; Kennedy, Daniel B.; Pettitt, Andrew R.; Nathwani, Amit; Varghese, Abraham; Cohen, Dena; Rawstron, Andy; Oertel, Stephan; Pocock, Christopher F.E.

    2014-01-01

    Purpose Most patients with chronic lymphocytic leukemia (CLL) are elderly and/or have comorbidities that may make them ineligible for fludarabine-based treatment. For this population, chlorambucil monotherapy is an appropriate therapeutic option; however, response rates with chlorambucil are low, and more effective treatments are needed. This trial was designed to assess how the addition of rituximab to chlorambucil (R-chlorambucil) would affect safety and efficacy in patients with CLL. Patients and Methods Patients with first-line CLL were treated with rituximab (375 mg/m2 on day 1, cycle one, and 500 mg/m2 thereafter) plus chlorambucil (10 mg/m2/d all cycles; day 1 through 7) for six 28-day cycles. For patients not achieving complete response (CR), six additional cycles of chlorambucil alone could be administered. The primary end point of the study was safety. Results A total of 100 patients were treated with R-chlorambucil, with a median follow-up of 30 months. Median age of patients was 70 years (range, 43 to 86 years), with patients having a median of seven comorbidities. Hematologic toxicities accounted for most grade 3/4 adverse events reported, with neutropenia and lymphopenia both occurring in 41% of patients and leukopenia in 23%. Overall response rates were 84%, with CR achieved in 10% of patients. Median progression-free survival was 23.5 months; median overall survival was not reached. Conclusion These results compare favorably with previously published results for chlorambucil monotherapy, suggesting that the addition of rituximab to chlorambucil may improve efficacy with no unexpected adverse events. R-chlorambucil may improve outcome for patients who are ineligible for fludarabine-based treatments. PMID:24638012

  5. Targeting intratumoral B cells with rituximab in addition to CHOP in angioimmunoblastic T-cell lymphoma. A clinicobiological study of the GELA

    PubMed Central

    Delfau-Larue, Marie-Hélène; de Leval, Laurence; Joly, Bertrand; Plonquet, Anne; Challine, Dominique; Parrens, Marie; Delmer, Alain; Salles, Gilles; Morschhauser, Franck; Delarue, Richard; Brice, Pauline; Bouabdallah, Reda; Casasnovas, Olivier; Tilly, Hervé; Gaulard, Philippe; Haioun, Corinne

    2012-01-01

    Background In angioimmunoblastic T-cell lymphoma, symptoms linked to B-lymphocyte activation are common, and variable numbers of CD20+ large B-blasts, often infected by Epstein-Barr virus, are found in tumor tissues. We postulated that the disruption of putative B-T interactions and/or depletion of the Epstein-Barr virus reservoir by an anti-CD20 monoclonal antibody (rituximab) could improve the clinical outcome produced by conventional chemotherapy. Design and Methods Twenty-five newly diagnosed patients were treated, in a phase II study, with eight cycles of rituximab + chemotherapy (R-CHOP21). Tumor infiltration, B-blasts and Epstein-Barr virus status in tumor tissue and peripheral blood were fully characterized at diagnosis and were correlated with clinical outcome. Results A complete response rate of 44% (95% CI, 24% to 65%) was observed. With a median follow-up of 24 months, the 2-year progression-free survival rate was 42% (95% CI, 22% to 61%) and overall survival rate was 62% (95% CI, 40% to 78%). The presence of Epstein-Barr virus DNA in peripheral blood mononuclear cells (14/21 patients) correlated with Epstein-Barr virus score in lymph nodes (P<0.004) and the detection of circulating tumor cells (P=0.0019). Despite peripheral Epstein-Barr virus clearance after treatment, the viral load at diagnosis (>100 copy/μg DNA) was associated with shorter progression-free survival (P=0.06). Conclusions We report here the results of the first clinical trial targeting both the neoplastic T cells and the microenvironment-associated CD20+ B lymphocytes in angioimmunoblastic T-cell lymphoma, showing no clear benefit of adding rituximab to conventional chemotherapy. A strong relationship, not previously described, between circulating Epstein-Barr virus and circulating tumor cells is highlighted. PMID:22371178

  6. Occurrence of lymphoplasmacytic lymphoma 6 years after amelioration of primary cold agglutinin disease by rituximab therapy.

    PubMed

    Tanaka, Hiroaki; Hashimoto, Shinichiro; Sugita, Yasumasa; Sakai, Shio; Takeda, Yusuke; Abe, Daijiro; Takagi, Toshiyuki; Nakaseko, Chiaki

    2012-10-01

    Cold agglutinin disease (CAD) is a rare autoimmune hemolytic anemia, classified into primary and secondary types. Secondary CAD accompanies infection or malignant disease, most often lymphoma, whereas primary CAD frequently represents a lymphoproliferative bone marrow disorder characterized by clonal expansion of B cells. Here, I describe a case of lymphoplasmacytic lymphoma (LPL) developed 6 years after amelioration of primary CAD by rituximab monotherapy. A 54-year-old Japanese woman was diagnosed with primary CAD characterized by a small fraction of B lymphocytes and kappa laterality in the peripheral blood. M-protein was not detected by immuno-electrophoresis. The patient achieved remission following two courses of rituximab monotherapy. The level of IgM was specifically decreased, although levels of IgG and IgA were slightly increased. Six years after rituximab monotherapy, she developed LPL without CAD recurrence. Flow cytometry performed on bone marrow specimens revealed that lymphoma cells were positive for CD19 and CD20 with kappa laterality. The lymphoma may have transformed from clonal B lymphocytes at presentation of CAD. Rituximab monotherapy induced remission of CAD by specific decrease of IgM level, but did not eliminate the clonal B lymphocytes that may have progressed to LPL. This experience may provide clues toward the understanding of the pathophysiology of primary CAD with clonal lymphoproliferative disease of the bone marrow. PMID:22878940

  7. High in Vitro Anti-Tumor Efficacy of Dimeric Rituximab/Saporin-S6 Immunotoxin

    PubMed Central

    Bortolotti, Massimo; Bolognesi, Andrea; Battelli, Maria Giulia; Polito, Letizia

    2016-01-01

    The anti-CD20 mAb Rituximab has revolutionized lymphoma therapy, in spite of a number of unresponsive or relapsing patients. Immunotoxins, consisting of toxins coupled to antibodies, are being investigated for their potential ability to augment Rituximab efficacy. Here, we compare the anti-tumor effect of high- and low-molecular-weight Rituximab/saporin-S6 immunotoxins, named HMW-IT and LMW-IT, respectively. Saporin-S6 is a potent and stable plant enzyme belonging to ribosome-inactivating proteins that causes protein synthesis arrest and consequent cell death. Saporin-S6 was conjugated to Rituximab through an artificial disulfide bond. The inhibitory activity of HMW-IT and LMW-IT was evaluated on cell-free protein synthesis and in two CD20+ lymphoma cell lines, Raji and D430B. Two different conjugates were separated on the basis of their molecular weight and further characterized. Both HMW-IT (dimeric) and LMW-IT (monomeric) maintained a high level of enzymatic activity in a cell-free system. HMW-IT, thanks to a higher toxin payload and more efficient antigen capping, showed stronger in vitro anti-tumor efficacy than LMW-IT against lymphoma cells. Dimeric HMW-IT can be used for lymphoma therapy at least for ex vivo treatments. The possibility of using HMW-IT augments the yield in immunotoxin preparation and allows the targeting of antigens with low internalization rates. PMID:27338475

  8. High in Vitro Anti-Tumor Efficacy of Dimeric Rituximab/Saporin-S6 Immunotoxin.

    PubMed

    Bortolotti, Massimo; Bolognesi, Andrea; Battelli, Maria Giulia; Polito, Letizia

    2016-01-01

    The anti-CD20 mAb Rituximab has revolutionized lymphoma therapy, in spite of a number of unresponsive or relapsing patients. Immunotoxins, consisting of toxins coupled to antibodies, are being investigated for their potential ability to augment Rituximab efficacy. Here, we compare the anti-tumor effect of high- and low-molecular-weight Rituximab/saporin-S6 immunotoxins, named HMW-IT and LMW-IT, respectively. Saporin-S6 is a potent and stable plant enzyme belonging to ribosome-inactivating proteins that causes protein synthesis arrest and consequent cell death. Saporin-S6 was conjugated to Rituximab through an artificial disulfide bond. The inhibitory activity of HMW-IT and LMW-IT was evaluated on cell-free protein synthesis and in two CD20⁺ lymphoma cell lines, Raji and D430B. Two different conjugates were separated on the basis of their molecular weight and further characterized. Both HMW-IT (dimeric) and LMW-IT (monomeric) maintained a high level of enzymatic activity in a cell-free system. HMW-IT, thanks to a higher toxin payload and more efficient antigen capping, showed stronger in vitro anti-tumor efficacy than LMW-IT against lymphoma cells. Dimeric HMW-IT can be used for lymphoma therapy at least for ex vivo treatments. The possibility of using HMW-IT augments the yield in immunotoxin preparation and allows the targeting of antigens with low internalization rates. PMID:27338475

  9. Rituximab is an effective and safe treatment of relapse in elderly patients with resistant warm AIHA.

    PubMed

    Laribi, Kamel; Bolle, Delphine; Ghnaya, Habib; Sandu, Andrea; Besançon, Anne; Denizon, Nathalie; Truong, Catherine; Pineau-Vincent, Fabienne; de Materre, Alix Baugier

    2016-04-01

    We evaluated the efficacy and safety of rituximab for the treatment of 23 elderly patients (median age 78 years) with warm autoimmune haemolytic anaemia (AIHA). The median follow-up was 31 months. Patients had received one to five previous treatments. Rituximab was administered by intravenous infusion at a dose of 375 mg/m(2) once weekly for 4 weeks. The OR rate was 86.9 % (CR = 39.1 %, PR = 47.8 %). Median OS was 87 months. The median OS of patients who reached CR could not be calculated, and that of patients with PR was 67 months. At last follow-up, eight of the 20 responding patients, including one patient in CR and seven in PR, had relapsed after a median of 6 months. Failure to achieve CR was a risk factor for relapse (p = 0.028). We did not identify any pretreatment characteristics predictive of response to rituximab. In conclusion, rituximab is an effective treatment for elderly patients with refractory warm AIHA. PMID:26858026

  10. Responsiveness to reduced dosage of rituximab in Chinese patients with neuromyelitis optica

    PubMed Central

    Yang, Chun-Sheng; Yang, Li; Li, Ting; Zhang, Da-Qi; Jin, Wei-Na; Li, Min-Shu; Su, Ning; Zhangning, Nannan; Liu, Qiang; Shao, Zong-Hong; Yu, Chunshui

    2013-01-01

    Objective: To determine the effect of a lower dose of rituximab in depleting B lymphocytes, maintaining low B-cell counts, and relapse in patients with neuromyelitis optica (NMO) and NMO spectrum disorders. Methods: We treated 5 Chinese patients with deteriorating NMO and NMO spectrum disorders with a 100-mg IV infusion of rituximab once a week for 3 consecutive weeks, followed by additional infusion of the same dosage depending on circulating B-cell repopulation. Results: This reduced dosage of rituximab was sufficient to deplete B cells and maintain low B-cell counts. None of the treated patients experienced relapse, and all patients exhibited stabilized or improved neurologic function during the 1-year follow-up period. MRI revealed the absence of new lesions, no enhancement in spinal cord and brain, a significant shrinkage of spinal cord segments, and a reduction/disappearance of previous brain lesions. Conclusion: A lower dosage of rituximab may be sufficient in depleting B cells, maintaining low B-cell counts, and preventing disease progression in Chinese patients with NMO. PMID:23884041

  11. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic

    PubMed Central

    Richter, Maximilian; Yumul, Roma; Saydaminova, Kamola; Wang, Hongjie; Gough, Michael; Baldessari, Audrey; Cattaneo, Roberto; Lee, Frank; Wang, Chung-Huei Katherine; Jang, Haishan; Astier, Anne; Gopal, Ajay; Carter, Darrick; Lieber, André

    2016-01-01

    Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs). The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs) with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with rituximab in the

  12. Preclinical safety, pharmacokinetics, pharmacodynamics, and biodistribution studies with Ad35K++ protein: a novel rituximab cotherapeutic.

    PubMed

    Richter, Maximilian; Yumul, Roma; Saydaminova, Kamola; Wang, Hongjie; Gough, Michael; Baldessari, Audrey; Cattaneo, Roberto; Lee, Frank; Wang, Chung-Huei Katherine; Jang, Haishan; Astier, Anne; Gopal, Ajay; Carter, Darrick; Lieber, André

    2016-01-01

    Rituximab is a mouse/human chimeric monoclonal antibody targeted toward CD20. It is efficient as first-line therapy of CD20-positive B-cell malignancies. However, a large fraction of treated patients relapse with rituximab-resistant disease. So far, only modest progress has been made in treatment options for rituximab refractory patients. One of the mechanisms for rituximab resistance involves the upregulation of CD46, which is a key cell surface protein that blocks the activation of complement. We have recently developed a technology that depletes CD46 from the cell surface and thereby sensitizes tumor cells to complement-dependent cytotoxicity. This technology is based on a small recombinant protein, Ad35K++ that binds with high affinity to CD46. In preliminary studies using a 6 × histidinyl tagged protein, we had demonstrated that intravenous Ad35K++ injection in combination with rituximab was safe and increased rituximab-mediated killing of CD20-positive target cells in mice and nonhuman primates (NHPs). The presence of the tag, while allowing for easy purification by Ni-NTA chromatography, has the potential to increase the immunogenicity of the recombinant protein. For clinical application, we therefore developed an Ad35K++ protein without His-tag. In the present study, we performed preclinical studies in two animal species (mice and NHPs) with this protein demonstrating its safety and efficacy. These studies estimated the Ad35K++ dose range and treatment regimen to be used in patients. Furthermore, we showed that intravenous Ad35K++ injection triggers the shedding of the CD46 extracellular domain in xenograft mouse tumor models and in macaques. Shed serum CD46 can be measured in the serum and can potentially be used as a pharmacodynamic marker for monitoring Ad35K++ activity in patient undergoing treatment with this agent. These studies create the basis for an investigational new drug application for the use of Ad35K++ in combination with rituximab in the

  13. Rituximab in refractory myasthenia gravis: a prospective, open-label study with long-term follow-up.

    PubMed

    Anderson, Dustin; Phan, Cecile; Johnston, Wendy S; Siddiqi, Zaeem A

    2016-07-01

    We examined the clinical effectiveness of rituximab in fourteen patients with refractory myasthenia gravis (MG). Manual muscle testing (MMT) score was recorded at baseline and followed during the course of the study. Steroid dose, frequency of intravenous immunoglobulin (IVIG) infusions, and plasma exchange (PLEX) were also monitored throughout the duration of the study. All patients responded dramatically to rituximab, as measured by a change in MMT score, prednisone dose, or the frequency of IVIG infusions or PLEX. Rituximab appears safe and effective for the treatment of refractory MG. It should be considered as a therapeutic option in refractory patients. PMID:27386504

  14. Placebo-controlled trial of rituximab in IgM anti-myelin–associated glycoprotein neuropathy

    PubMed Central

    Viala, Karine; Nicolas, Guillaume; Créange, Alain; Vallat, Jean-Michel; Pouget, Jean; Clavelou, Pierre; Vial, Christophe; Steck, Andreas; Musset, Lucile; Marin, Benoit

    2013-01-01

    Objective: To determine whether rituximab 375 mg/m2 was efficacious in patients with immunoglobulin M (IgM) anti-myelin–associated glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating neuropathy). Methods: Fifty-four patients with IgM anti-MAG demyelinating neuropathy were enrolled in this randomized, double-blind, placebo-controlled trial. The inclusion criteria were inflammatory neuropathy cause and treatment (INCAT) sensory score (ISS) ≥4 and visual analog pain scale >4 or ataxia score ≥2. The primary outcome was mean change in ISS at 12 months. Results: Twenty-six patients were randomized to a group receiving 4 weekly infusions of 375 mg/m2 rituximab, and 28 patients to placebo. Intention-to-treat analysis, with imputation of missing ISS values by the last observation carried forward method, showed a lack of mean change in ISS at 12 months, 1.0 ± 2.7 in the rituximab group, and 1.0 ± 2.8 in the placebo group. However, changes were observed, in per protocol analysis at 12 months, for the number of patients with an improvement of at least 2 points in the INCAT disability scale (p = 0.027), the self-evaluation scale (p = 0.016), and 2 subscores of the Short Form–36 questionnaire. Conclusions: Although primary outcome measures provide no evidence to support the use of rituximab in IgM anti-MAG demyelinating neuropathy, there were improvements in several secondary outcomes in per protocol analysis. Level of evidence: This study provides Class I evidence that rituximab is ineffective in improving ISS in patients with IgM anti-MAG demyelinating neuropathy. PMID:23667063

  15. Rapid depletion of B lymphocytes by ultra-low-dose rituximab delivered intrathecally

    PubMed Central

    Bergman, Joakim; Dring, Ann; Vågberg, Mattias; Birgander, Richard; Lindqvist, Thomas; Gilthorpe, Jonathan; Bergenheim, Tommy

    2015-01-01

    Objective: We are conducting an open-label phase 1b study on the efficacy of intrathecal (IT) administration of rituximab, provided via an Ommaya reservoir, for the treatment of progressive multiple sclerosis (PMS). The objective of this initial study was to monitor B lymphocytes in peripheral blood (PB) and CSF from the first 10 patients 1 year posttreatment. Methods: Dose titration was performed with daily escalation from 1 mg to 25 mg IT rituximab (n = 3). Lymphocyte subpopulations were monitored daily during dose escalation in PB by flow cytometry and subsequently every 3 months for 1 year, after a total dose of 3 × 25 mg. PB B-lymphocyte subpopulations for the remaining patients (n = 7) were monitored at regular intervals. CSF lymphocyte subpopulations for all patients were monitored by flow cytometry every 2–3 months. Results: The PB B-lymphocyte count dropped rapidly after the first 2 injections (total dose of 3.5 mg IT rituximab) to undetectable levels. Three 25-mg doses given once per week depleted peripheral B lymphocytes entirely for the following 3–6 month period. Conclusions: Monoclonal antibodies seem to rapidly redistribute to the peripheral compartment following IT injection. Ultra-low doses of rituximab given IT are sufficient to cause complete depletion of peripheral B lymphocytes, indicating that low-dose IT treatment has the potential to be effective in both the CNS and systemic compartments. Classification of evidence: This study provides Class IV evidence that for patients with PMS, rituximab provided via an Ommaya reservoir depletes peripheral blood B lymphocytes. PMID:25745637

  16. Cold Autoimmune Hemolytic Anemia due to High-grade non Hodgkin's B cell Lymphoma with Weak Response to Rituximab and Chemotherapy Regimens

    PubMed Central

    Nazel Khosroshahi, Behzad; Jafari, Mohammad; Vazini, Hossein; Ahmadi, Alireza; Shams, Keivan; Kholoujini, Mahdi

    2015-01-01

    Autoimmune hemolytic anemia (AIHA) is characterized by shortening of red blood cell (RBC) survival and the presence of autoantibodies directed against autologous RBCs. Approximately 20% of autoimmune hemolytic anemia cases are associated with cold-reactive antibody. About half of patients with AIHA have no underlying associated disease; these cases are termed primary or idiopathic. Secondary cases are associated with underlying diseases or with certain drugs. We report herein a rare case of cold autoimmiune hemolytic anemia due to high-grade non-Hodgkin's lymphoma of B-cell type with weak response to rituximab and chemotherapy regimens. For treatment B cell lymphoma, Due to lack of treatment response, we used chemotherapy regimens including R- CHOP for the first time, and then Hyper CVAD, R- ICE and ESHAP were administered, respectively. For treatment of autoimmune hemolytic anemia, we have used the corticosteroid, rituximab, plasmapheresis and blood transfusion and splenectomy. In spite of all attempts, the patient died of anemia and aggressive lymphoma nine months after diagnosis. To our knowledge, this is a rare report from cold autoimmune hemolytic anemia in combination with high-grade non-Hodgkin's lymphoma of B-cell type that is refractory to conventional therapies. PMID:26261701

  17. Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells.

    PubMed

    Zent, Clive S; Taylor, Ronald P; Lindorfer, Margaret A; Beum, Paul V; LaPlant, Betsy; Wu, Wenting; Call, Timothy G; Bowen, Deborah A; Conte, Michael J; Frederick, Lori A; Link, Brian K; Blackwell, Sue E; Veeramani, Suresh; Baig, Nisar A; Viswanatha, David S; Weiner, George J; Witzig, Thomas E

    2014-07-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analog refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab-containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a Phase II trial testing the efficacy and tolerability of a short-duration regimen combining pentostatin, alemtuzumab, and low-dose high-frequency rituximab designed to decrease the risk of treatment-associated infections and to limit the loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n = 36) or previously untreated with 17p13 deletion (17p13-) (n = 3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional, and eight patients had purine analog refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy, with only five (13%) patients having treatment-limiting toxicity and no treatment-related deaths. Twenty-two (56%) patients responded to treatment, with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression-free survival was 7.2 months, time to next treatment was 9.1 months, and overall survival was 34.1 months. The majority of deaths (82%) were caused by progressive disease, including transformed diffuse large B-cell lymphoma (n = 6). Correlative studies showed that low-dose rituximab activates complement and natural killer cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that pentostatin, alemtuzumab, and low-dose high-frequency rituximab is a tolerable and effective therapy for CLL and that low-dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. PMID:24723493

  18. Epstein-Barr virus-driven B Cell Proliferation with CD4+ T Cell Expansion: A Lymphomatoid Granulomatosis-like Disease Related to Hyperinterleukin-10 Secretion of Remarkably Favourable Outcome with Rituximab.

    PubMed

    Cervera, P; Guihot, A; Gorochov, G; Lassoued, K; Coppo, P

    2015-12-01

    Granulomatous lymphomatosis is an Epstein-Barr virus (EBV)-driven B cell proliferation associated with an exuberant CD4(+) T cell reaction with usually histopathological pictures of angiocentrism. So far, the characteristics of CD4(+) T cells in granulomatous lymphomatosis and the mechanism leading to their expansion remain poorly explored. We report a 56-year-old female with a past history of cold agglutinin disease, which was successfully treated with 4 weekly infusions of rituximab. She presented one year later with features of granulomatous lymphomatosis that resulted in severe lung and bone marrow infiltration. We provide evidence that CD4(+) T cell expansion was oligoclonal, involved anergic cells and did not result from an EBV-driven stimulation. Rather, it resulted possibly from a high production of interleukin-10 by immunoblastic EBV-positive B cells. The outcome was remarkably favourable with rituximab and steroids. Our results suggest that an EBV-driven B cell proliferation should be investigated in patients presenting with a CD4(+) T cells alveolitis or other systemic manifestations resulting from a CD4(+) T cell expansion. These features should prompt to introduce an immunosuppressive therapy including steroids and rituximab. Our results deserve further investigations to confirm our pathophysiological hypotheses in CD4(+) T cell expansions associated with EBV-driven B cell proliferations and to assess whether granulomatous lymphomatosis could result from comparable mechanisms. PMID:26332210

  19. Imaging and measuring the rituximab-induced changes of mechanical properties in B-lymphoma cells using atomic force microscopy

    SciTech Connect

    Li, Mi; Liu, Lianqing; Xi, Ning; Wang, Yuechao; Dong, Zaili; Tabata, Osamu; Xiao, Xiubin; Zhang, Weijing

    2011-01-14

    Research highlights: {yields} Single B-lymphoma living cells were imaged by AFM with the assistance of microfabricated pillars. {yields} The apoptosis of B-lymphoma cells triggered by rituximab without cross-linking was observed by AO/EB double fluorescent staining. {yields} The B-lymphoma cells became dramatically softer after adding rituximab. -- Abstract: The topography and mechanical properties of single B-lymphoma cells have been investigated by atomic force microscopy (AFM). With the assistance of microfabricated patterned pillars, the surface topography and ultrastructure of single living B-lymphoma cell were visualized by AFM. The apoptosis of B-lymphoma cells induced by rituximab alone was observed by acridine orange/ethidium bromide (AO/EB) double fluorescent staining. The rituximab-induced changes of mechanical properties in B-lymphoma cells were measured dynamically and the results showed that B-lymphoma cells became dramatically softer after incubation with rituximab. These results can improve our understanding of rituximab'effect and will facilitate the further investigation of the underlying mechanisms.

  20. Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naïve with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE))

    PubMed Central

    Emery, P; Deodhar, A; Rigby, W F; Isaacs, J D; Combe, B; Racewicz, A J; Latinis, K; Abud-Mendoza, C; Szczepański, L J; Roschmann, R A; Chen, A; Armstrong, G K; Douglass, W; Tyrrell, H

    2010-01-01

    Objectives This phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naïve to prior biological treatment. Methods Patients with active disease on stable MTX (10–25 mg/week) were randomised to rituximab 2×500 mg (n=168), rituximab 2×1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) ≥2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2×500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48. Results At week 24, both doses of rituximab showed statistically superior efficacy (p<0.0001) to placebo (ACR20: 54%, 51% and 23%; rituximab (2×500 mg) + MTX, rituximab (2×1000 mg) + MTX and placebo + MTX, respectively). Secondary end points were also significantly improved for both rituximab groups compared with placebo. Further improvements in both rituximab arms were observed from week 24 to week 48. Rituximab + MTX was well tolerated, demonstrating comparable safety to placebo + MTX through to week 24, and between rituximab doses through to week 48. Conclusions Rituximab (at 2×500 mg and 2×1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses. PMID:20488885

  1. AFM analysis of the multiple types of molecular interactions involved in rituximab lymphoma therapy on patient tumor cells and NK cells.

    PubMed

    Li, Mi; Xiao, Xiubin; Zhang, Weijing; Liu, Lianqing; Xi, Ning; Wang, Yuechao

    2014-08-01

    Rituximab is a monoclonal antibody drug approved for the treatment of patients with lymphomas. Rituximab's main killing mechanism is antibody-dependent cellular cytotoxicity (ADCC). During ADCC, rituximab's fragment antigen binding (Fab) region binds to the CD20 antigen on the tumor cell and its fragment crystallizable (Fc) region binds to the Fc receptor (FcR) on the natural killer (NK) cells. In this study, two types of molecular interactions (CD20-rituximab, FcR-rituximab) involved in ADCC were measured simultaneously on cells prepared from biopsy specimens of lymphoma patients by utilizing atomic force microscopy (AFM) with functionalized tips carrying rituximab. NK cells were detected by specific NKp46 fluorescent labeling and tumor cells were detected by specific ROR1 fluorescent labeling. Based on the fluorescence recognition, the binding affinity and distribution of FcRs on NK cells, and CD20 on tumor cells, were quantitatively measured and mapped. The binding affinity and distribution of FcRs (on NK cells) and CD20 (on tumor cells) were associated with rituximab clinical efficacy. The experimental results provide a new approach to simultaneously quantify the multiple types of molecular interactions involved in rituximab ADCC mechanism on patient biopsy cells, which is of potential clinical significance to predict rituximab efficacy for personalized medicine. PMID:25117605

  2. Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study

    PubMed Central

    Padmanabhan, Swaminathan; Chan, Geoffrey W.; Gupta, Ira V.; Lisby, Steen; Österborg, Anders

    2011-01-01

    Ofatumumab, the human CD20 monoclonal antibody that binds a distinct epitope from rituximab, has demonstrated clinical benefit as monotherapy for patients with chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab (FA-ref) and patients refractory to fludarabine with bulky (> 5 cm) lymph nodes (BF-ref). To potentially gain insight into outcomes in patients previously treated with or refractory to rituximab, we performed an ad hoc retrospective analysis in the final 96 FA-ref and 111 BF-ref patients. There were 117 patients previously treated with rituximab (98 rituximab-refractory); 89 patients were rituximab-naive. For rituximab-treated, rituximab-refractory, and rituximab-naive patients, overall response rate was 43%, 44%, and 53%; median progression-free survival was 5.3, 5.5, and 5.6 months; and median overall survival was 15.5, 15.5, and 20.2 months. There were no significant differences in ofatumumab-related infusion reactions, or hematologic or infectious adverse events between subgroups. In summary, ofatumumab monotherapy was effective and well tolerated in patients with fludarabine-refractory chronic lymphocytic leukemia, including in patients with previous rituximab exposure. This trial was registered at www.clinicaltrials.gov as #NCT00349349. PMID:21856867

  3. B-cell targeted therapy with rituximab for thyroid eye disease: closer to the clinic.

    PubMed

    Shen, Sunny; Chan, Anita; Sfikakis, Petros P; Hsiu Ling, Andrea Low; Detorakis, Efstathios T; Boboridis, Kostas G; Mavrikakis, Ioannis

    2013-01-01

    The management of thyroid eye disease (TED) remains a therapeutic challenge. The current established therapies are unsatisfactory in one-third of the patients and have many limitations. Rituximab (RTX) is a CD20+ B-cell-depleting monoclonal antibody approved for the treatment of non-Hodgkin lymphomas, chronic lymphocytic leukemia, and rheumatoid arthritis. The early experience with RTX suggests that it is a promising alternative therapy for TED. Rituximab may compare favorably to the conventional glucocorticoid therapy and causes less collateral damage than retrobulbar orbital radiation and decompression surgery. In addition, the preliminary studies on RTX's proposed mechanism of action have revealed new insights into the pathogenic role of B-cells in TED. We summarize the current literature on the clinical application of RTX in TED and discuss its putative mechanisms of action. PMID:23253433

  4. Leuconostoc sp. Meningitis in a Patient Treated with Rituximab for Mantle Cell Lymphoma

    PubMed Central

    Holik, Hrvoje; Coha, Božena; Šiško, Marijan; Tomić-Paradžik, Maja

    2015-01-01

    We present a 64-year-old man who was treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemoimmunotherapy for mantle cell lymphoma and developed purulent meningitis, probably caused by Leuconostoc sp. The patient had severe hypogammaglobulinemia, which is a possible complication of rituximab therapy. To our knowledge and after reviewing the available medical literature, this is the first described case of purulent meningitis caused by Leuconostoc sp. in a patient with mantle cell lymphoma that appeared after treatment with the R-CHOP protocol. The diagnosis of purulent meningitis was based on clinical, laboratory and cytological cerebrospinal fluid findings, in addition to blood culture results in which we isolated Leuconostoc sp. The patient was treated with meropenem with full recovery. PMID:26376594

  5. Long-term Results of the Treatment of Patients With Mantle Cell Lymphoma With Cladribine (2-CDA) Alone (95-80-53) or 2-CDA and Rituximab (N0189) in the North Central Cancer Treatment Group

    PubMed Central

    Inwards, David J.; Fishkin, Paul A. S.; Hillman, David W.; Brown, David W.; Ansell, Stephen M.; Kurtin, Paul J.; Fonseca, Rafael; Morton, Roscoe F.; Veeder, Michael H.; Witzig, Thomas E.

    2012-01-01

    BACKGROUND The objective of this study was to test cladribine (2-CDA) alone and in combination with rituximab in patients with mantle cell lymphoma (MCL). METHODS Patients with MCL were treated on 2 sequential trials. In Trial 95-80-53, patients received 2-CDA as initial therapy or at relapse. In Trial N0189, patients received combination 2-CDA and rituximab as initial therapy. In both trials, 2-CDA was administered at a dose of 5 mg/m2 intravenously on Days 1 through 5 every 4 weeks for 2 to 6 cycles, depending on response. In Trial N0189, rituximab 375 mg/m2 was administered on Day 1 of each cycle. RESULTS Results were reported for 80 patients. Twenty-six previously untreated patients and 25 patients who had recurrent disease with a median age of 68 years received single-agent 2-CDA. The overall response rate (ORR) was 81% with 42% complete responses (CRs) in the previously untreated group. The median progression-free survival (PFS) was 13.6 months (95% confidence interval [95% CI], 7.2–22.1 months), and 81% of patients remained alive at 2 years. The ORR was 46% with a 21% CR rate in the recurrent disease group. The median PFS was 5.4 months (95% CI, 4.6–13.1 months), and 36% of patients remained alive at 2 years. Twenty-nine eligible patients with a median age of 70 years received 2-CDA plus rituximab. The ORR was 66% (19 of 29 patient), and the CR rate was 52% (15 of 29 patients). The median duration of response for patients who achieved a CR had not been reached at the time of the current report, and only 3 of the patients who achieved a CR developed recurrent disease at a median follow-up of 21.5 months. CONCLUSIONS 2-CDA had substantial single-agent activity in both recurrent and untreated MCL, and the results indicated that it may be administered safely to elderly patients. The addition of rituximab to 2-CDA may increase the duration of response. PMID:18470909

  6. Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)

    PubMed Central

    2011-01-01

    Introduction Evidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkin's lymphoma in a real-life clinical setting. Methods Patients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators. Results A total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physician's visual analogue scale; mean

  7. Rituximab: how approval history is reflected by a corresponding patent filing strategy.

    PubMed

    Storz, Ulrich

    2014-01-01

    Because drug development is not a static process, a drug's market authorisation may change over time. In many cases, the number of indications for which a drug is approved increases. Because this facet of drug development also comes at significant costs, a corresponding patent filing strategy is required to protect these investments. The strategy as applied to rituximab, which is approved for a variety of indications, is discussed in this review. PMID:24866199

  8. High-dose methotrexate with or without rituximab in newly diagnosed primary CNS lymphoma

    PubMed Central

    Ambady, Prakash; Abdelaziz, Ahmed; Sarai, Guneet; Bonekamp, David; Blakeley, Jaishri; Grossman, Stuart A.; Ye, Xiaobu

    2014-01-01

    Objective: To evaluate the efficacy of rituximab (R) when added to high-dose methotrexate (HD-MTX) in patients with newly diagnosed immunocompetent primary CNS lymphomas (PCNSLs). Methods: Immunocompetent adults with newly diagnosed PCNSL treated at The Johns Hopkins Hospital between 1995 and 2012 were investigated. From 1995 to 2008, patients received HD-MTX monotherapy (8 g/m2 initially every 2 weeks and after complete response [CR] monthly to complete 12 months of therapy). From 2008 to 2012, patients received the same HD-MTX with rituximab (375 mg/m2) with each HD-MTX treatment. CR rates and median overall and progression-free survival were analyzed for each patient cohort in this single-institution, retrospective study. Results: A total of 81 patients were identified: 54 received HD-MTX (median age 66 years) while 27 received HD-MTX/R (median age 65 years). CR rates were 36% in the HD-MTX cohort and 73% in the HD-MTX/R cohort (p = 0.0145). Median progression-free survival was 4.5 months in the HD-MTX cohort and 26.7 months in the HD-MTX/R cohort (p = 0.003). Median overall survival was 16.3 months in the HD-MTX cohort and has not yet been reached in the HD-MTX/R cohort (p = 0.01). Conclusions: The addition of rituximab to HD-MTX appears to improve CR rates as well as overall and progression-free survival in patients with newly diagnosed PCNSL. Comparisons of long-term survival in the 2 cohorts await further maturation of the data. Classification of evidence: This study provides Class III evidence that in immunocompetent patients with PCNSL, HD-MTX plus rituximab compared with HD-MTX alone improves CR and overall survival rates. PMID:24928128

  9. Effects of hypertonic buffer composition on lymph node uptake and bioavailability of rituximab, after subcutaneous administration

    PubMed Central

    Fathallah, Anas M.; Turner, Michael R.; Balu-Iyer, Sathy V.

    2015-01-01

    Subcutaneous administration of biologics is highly desirable; however, incomplete bioavailability after sc administration remains a major challenge. In this work we investigated the effects of excipient dependent hyper-osmolarity on lymphatic uptake and plasma exposure of rituximab as a model protein. Using Swiss Webster (SW) mice as our animal model, we compared the effects of NaCl, mannitol and, O-Phospho-L-Serine (OPLS) on plasma concentration of rituximab over 5 days after sc administration. We observed an increase in plasma concentrations in animals administered rituximab in hypertonic buffer solutions, as compared to isotonic buffer. Bioavailability, as estimated by our pharmacokinetic model, increased from 29% in isotonic buffer to 54% in hypertonic buffer containing NaCl, to almost complete bioavailability in hypertonic buffers containing high dose OPLS or mannitol. This improvement in plasma exposure is due to improved lymphatic trafficking as evident from the increase in the fraction of dose trafficked through the lymph node in the presence of hypertonic buffers. The fraction of the dose trafficked through the lymphatic, as estimated by the model, increased from 0.05 % in isotonic buffer to 13% in hyper-tonic buffer containing NaCl to about 30% for hypertonic buffers containing high dose OPLS and mannitol. Our data suggests that hypertonic solutions may be a viable option to improve sc bioavailability. PMID:25377184

  10. The anti-CD20 monoclonal antibody rituximab to treat acquired haemophilia A

    PubMed Central

    D’Arena, Giovanni; Grandone, Elvira; Di Minno, Matteo N.D.; Musto, Pellegrino; Di Minno, Giovanni

    2016-01-01

    Background Acquired haemophilia A (AHA) is a rare bleeding disorder caused by the development of specific autoantibodies against naturally occurring factor VIII (FVIII). Although about half of cases are idiopathic, AHA may be associated with several non-neoplastic conditions, autoimmune disorders, as well as haematological malignancies, such as chronic lymphocytic leukaemia and lymphoma. The long-term suppression of inhibitors is one of the mainstays of the treatment of AHA. Apart from standard immunosuppressive treatments, rituximab has been proven to be effective in AHA. Materials and methods The aim of this review is to provide a systematic description of data available in the literature on this topic. To do so, we performed a search using the indexed online database Medline/PubMed, without temporal limits, matching the words “rituximab” and “acquired h(a)emophilia”. Furthermore, additional published studies were identified in the reference list of the publications found in PubMed. Results The review of the literature confirms that rituximab may be a safe and useful treatment for AHA. Discussion Although rituximab is not a standard therapy for AHA, it may be useful in resistant cases. However, the definitive place of this monoclonal antibody in the therapeutic strategy for AHA (first or second-line, alone or in combination with other drugs) remains to be determined more precisely and warrants further investigation. PMID:26509821

  11. Assessment of physicochemical properties of rituximab related to its immunomodulatory activity.

    PubMed

    Miranda-Hernández, Mariana P; López-Morales, Carlos A; Ramírez-Ibáñez, Nancy D; Piña-Lara, Nelly; Pérez, Nestor O; Molina-Pérez, Aarón; Revilla-Beltri, Jorge; Flores-Ortiz, Luis F; Medina-Rivero, Emilio

    2015-01-01

    Rituximab is a chimeric monoclonal antibody employed for the treatment of CD20-positive B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. It binds specifically to the CD20 antigen expressed on pre-B and consequently on mature B-lymphocytes of both normal and malignant cells, inhibiting their proliferation through apoptosis, CDC, and ADCC mechanisms. The immunomodulatory activity of rituximab is closely related to critical quality attributes that characterize its chemical composition and spatial configuration, which determine the recognition of CD20 and the binding to receptors or factors involved in its effector functions, while regulating the potential immunogenic response. Herein, we present a physicochemical and biological characterization followed by a pharmacodynamics and immunogenicity study to demonstrate comparability between two products containing rituximab. The physicochemical and biological characterization revealed that both products fit within the same response intervals exhibiting the same degree of variability. With regard to clinical response, both products depleted CD20+ B-cells until posttreatment recovery and no meaningful differences were found in their pharmacodynamic profiles. The evaluation of anti-chimeric antibodies did not show differential immunogenicity among products. Overall, these data confirm that similarity of critical quality attributes results in a comparable immunomodulatory activity. PMID:25973441

  12. Recurrence of light chain deposit disease after renal allograft transplantation: potential role of rituximab?

    PubMed

    Kuypers, Dirk R J; Lerut, Evelyne; Claes, Kathleen; Evenepoel, Pieter; Vanrenterghem, Yves

    2007-04-01

    Light chain deposit disease (LCDD) is a monoclonal plasma cell disorder characterized by tissue deposition of nonamyloid immunoglobulin light chains, predominantly kappa chains, causing renal insufficiency. LCDD reoccurs almost invariably after renal grafting, leading to early graft loss, usually within a time span of months to years. We describe a female patient with LCDD who lost her first living donor graft after 1 year due to extensive recurrence of kappa chain deposition. Rituximab was administered on the seventh day after her second transplantation with a graft from a deceased donor, in order to prevent early recurrence of LCDD. The 2-year protocol biopsy - similarly to the completely normal 1-year protocol biopsy - revealed persistent absence of light chain deposition on light microscopy but immunohistochemical staining and electron microscopy showed very mild recurrence of light chain deposits. A second 4-week course of rituximab was repeated because of these electron microscopic findings. Subsequently, free kappa light chain concentration decreased from 693 to 74 mg/l and remained low 4 months after completion of therapy. Rituximab could be considered for delaying early LCDD recurrence in patients in whom treatment of the underlying bone marrow disorder failed or is contraindicated, but maintenance therapy is apparently necessary to consolidate this response. PMID:17326779

  13. Prognostic model for mantle cell lymphoma in the rituximab era: a nationwide study in Japan.

    PubMed

    Chihara, Dai; Asano, Naoko; Ohmachi, Ken; Kinoshita, Tomohiro; Okamoto, Masataka; Maeda, Yoshinobu; Mizuno, Ishikazu; Matsue, Kosei; Uchida, Toshiki; Nagai, Hirokazu; Nishikori, Momoko; Nakamura, Shigeo; Ogura, Michinori; Suzuki, Ritsuro

    2015-09-01

    Mantle cell lymphoma (MCL) is essentially incurable with conventional chemotherapy. The MCL International Prognostic Index (MIPI) is a validated specific prognostic index, but was derived from patients with advanced-stage disease primarily in the pre-rituximab era. We analysed 501 MCL patients (median age, 67 years; range 22-90) treated with rituximab-containing chemotherapy, and evaluated the prognostic factors adjusted by the treatment. Five-year overall survival (OS) in the low, intermediate and high MIPI groups was 74%, 70% and 35%, respectively. Additional to MIPI risk factors, multivariate analysis revealed that low serum albumin and bone-marrow involvement were also significantly associated with a poor outcome. The revised-MIPI (R-MIPI) was constructed using six factors, namely age, performance status, white blood cell count, serum lactate dehydrogenase, bone-marrow involvement and serum albumin, which is divided into four prognostic groups. Five-year OS in low, low-intermediate (L-I), high-intermediate (H-I) and high R-MIPI groups was 92%, 75%, 61% and 19%, respectively. Hazard ratio for OS of L-I, H-I and high risk to low risk patients were 5·4, 8·3 and 33·0, respectively. R-MIPI, a new prognostic index with easy application to the general patient population, shows promise for identifying low- and high-risk MCL patients in the rituximab era. PMID:25953436

  14. New insight in the mechanism of action of rituximab: the interferon signature towards personalized medicine.

    PubMed

    Verweij, Cornelis L; Vosslamber, Saskia

    2011-09-01

    Rheumatoid arthritis (RA) is the most common chronic inflammatory disorder of the musculoskeletal system that may cause permanent joint damage. The disease has a major impact on the quality of life of affected individuals, costs for the health care system, and society. Currently, no curative treatment is available, and patients are subjected to a prolonged course of treatment. Due to their role in the pathogenesis of RA, B cells have become an attractive target for therapy. Rituximab (Mabthera®/Rituxan®) is a therapeutic monoclonal antibody against CD20 expressed on B cells, which is effective in depleting B cells and approved worldwide for the treatment of RA. Rituximab was shown to be highly beneficial in decreasing clinical symptoms, safe, and well tolerated. However, clinical experience revealed that approximately 30-40% of RA patients do not respond to it. Given the destructive nature of RA, the risk of adverse effects, and considerable costs for therapy, there is a strong need to make predictions on the clinical outcome before the start of therapy. Since nearly all treated patients experience an effective depletion of circulating B cells, questions have been raised concerning the mechanism of action. In this review, novel developments, in particular the findings on the role of the interferon system, will be highlighted. This may add new and important information to our understanding of the mechanism that underlies the clinical outcome of rituximab treatment and may lead to the identification of biomarkers to predict the response. PMID:21955850

  15. Assessment of Physicochemical Properties of Rituximab Related to Its Immunomodulatory Activity

    PubMed Central

    Miranda-Hernández, Mariana P.; López-Morales, Carlos A.; Ramírez-Ibáñez, Nancy D.; Piña-Lara, Nelly; Pérez, Nestor O.; Molina-Pérez, Aarón; Revilla-Beltri, Jorge; Flores-Ortiz, Luis F.

    2015-01-01

    Rituximab is a chimeric monoclonal antibody employed for the treatment of CD20-positive B-cell non-Hodgkin's lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis and microscopic polyangiitis. It binds specifically to the CD20 antigen expressed on pre-B and consequently on mature B-lymphocytes of both normal and malignant cells, inhibiting their proliferation through apoptosis, CDC, and ADCC mechanisms. The immunomodulatory activity of rituximab is closely related to critical quality attributes that characterize its chemical composition and spatial configuration, which determine the recognition of CD20 and the binding to receptors or factors involved in its effector functions, while regulating the potential immunogenic response. Herein, we present a physicochemical and biological characterization followed by a pharmacodynamics and immunogenicity study to demonstrate comparability between two products containing rituximab. The physicochemical and biological characterization revealed that both products fit within the same response intervals exhibiting the same degree of variability. With regard to clinical response, both products depleted CD20+ B-cells until posttreatment recovery and no meaningful differences were found in their pharmacodynamic profiles. The evaluation of anti-chimeric antibodies did not show differential immunogenicity among products. Overall, these data confirm that similarity of critical quality attributes results in a comparable immunomodulatory activity. PMID:25973441

  16. Beneficial Effect of Rituximab in the Treatment of Recurrent Idiopathic Membranous Nephropathy after Kidney Transplantation

    PubMed Central

    Sprangers, Ben; Lefkowitz, George Ian; Cohen, Scott D.; Stokes, Michael Barry; Valeri, Antony; Appel, Gerald B.

    2010-01-01

    Background and objectives: Recurrence of the original kidney disease after renal transplantation is an increasingly recognized cause of allograft loss. Idiopathic membranous nephropathy (iMN) is a common cause of proteinuria that may progress to ESRD. It is known that iMN may recur after kidney transplantation, causing proteinuria, allograft dysfunction, and allograft loss. Limited data regarding the frequency and treatment of recurrent iMN are available. Design, setting, participants, & measurements: In this single-center study, all patients who had iMN and were receiving a first kidney transplant were included. We retrospectively assessed the incidence of biopsy-confirmed recurrent iMN and compared clinical characteristics of patients with and without recurrence. In addition, the effect of treatment with rituximab on proteinuria and renal allograft function in patients with recurrent iMN was examined Results: The incidence of recurrent iMN was 44%, and recurrences occurred at a median time of 13.6 months after transplantation. Two patterns of recurrence were identified: Early and late. No predictors of recurrence or disease progression could be identified. Treatment with rituximab was effective in four of four patients in stabilizing or reducing proteinuria and stabilizing renal function. Conclusions: Recurrence of iMN is common even in the era of modern immunosuppression. Rituximab seems to be a valuable treatment option for these patients, although lager studies are needed to confirm our data. PMID:20185599

  17. Association between -174 interleukin-6 gene polymorphism and biological response to rituximab in several systemic autoimmune diseases.

    PubMed

    Robledo, Gema; Dávila-Fajardo, Cristina Lucía; Márquez, Ana; Ortego-Centeno, Norberto; Callejas Rubio, José Luis; de Ramón Garrido, Enrique; Sánchez-Román, Julio; García-Hernández, Francisco J; Ríos-Fernández, Raquel; González-Escribano, Maria Francisca; Camps García, Maria Teresa; Castillo Palma, Maria Jesús; Ayala, Maria Del Mar; Martín, Javier

    2012-09-01

    Rituximab has become a pivotal treatment for systemic autoimmune diseases. The aim of this study was to determine whether the genetic variant -174 IL-6 contributes to differences in the response to rituximab in patients with systemic autoimmune diseases, including systemic lupus erythematosus (SLE), inflammatory myopathies, anti-neutrophil cytoplasmic antibody-mediated vasculitis, systemic sclerosis, Sjöegren's syndrome, rheumatoid arthritis, and autoimmune hemolytic anemia. DNA samples from 144 Spanish patients with different systemic autoimmune diseases receiving rituximab were genotyped for -174 IL-6 (rs1800795) gene polymorphism using the TaqMan(®) allelic discrimination technology. Six months after the first infusion with rituximab, we evaluated the response to the drug: 60.4% of the patients showed a complete response, partial 27.8%, and 11.8% did not respond to the treatment. The CC genotype frequency was significantly increased in nonresponders with respect to responders (23.5% vs. 7.1%, respectively; p=0.049; odds ratio (OR)=4.03, 95% confidence intervals (CI) 0.78-16.97). According to the genotype distribution, rituximab was effective in 69.2% of the CC carriers, 91.9% of the CG carriers, and 88.4% of the GG carriers. A similar trend was observed when SLE patients were analyzed separately (27.3% carried CC homozygosis in nonresponders and 6.9% in responders; p=0.066; OR=5.10, 95% CI 0.65-31.73). Rituximab was effective in 62.5% of the CC carriers, 88.9% of the GC carriers, and 90% of the GG carriers. These results suggest that -174 IL-6 (rs1800795) gene polymorphism plays a role in the response to rituximab in systemic autoimmune diseases. Validation of these findings in independent cohorts is warranted. PMID:22734797

  18. Anti-Apoptotic Effects of Lentiviral Vector Transduction Promote Increased Rituximab Tolerance in Cancerous B-Cells

    PubMed Central

    Ranjbar, Benyamin; Krogh, Louise Bechmann; Laursen, Maria Bach; Primo, Maria Nascimento; Marques, Sara Correia; Dybkær, Karen; Mikkelsen, Jacob Giehm

    2016-01-01

    Diffuse large B-cell lymphoma (DLBCL) is characterized by great genetic and clinical heterogeneity which complicates prognostic prediction and influences treatment efficacy. The most common regimen, R-CHOP, consists of a combination of anthracycline- and immuno-based drugs including Rituximab. It remains elusive how and to which extent genetic variability impacts the response and potential tolerance to R-CHOP. Hence, an improved understanding of mechanisms leading to drug tolerance in B-cells is crucial, and modelling by genetic intervention directly in B-cells is fundamental in such investigations. Lentivirus-based gene vectors are widely used gene vehicles, which in B-cells are an attractive alternative to potentially toxic transfection-based methodologies. Here, we investigate the use of VSV-G-pseudotyped lentiviral vectors in B-cells for exploring the impact of microRNAs on tolerance to Rituximab. Notably, we find that robust lentiviral transduction of cancerous B-cell lines markedly and specifically enhances the resistance of transduced germinal center B-cells (GCBs) to Rituximab. Although Rituximab works partially through complement-mediated cell lysis, increased tolerance is not achieved through effects of lentiviral transduction on cell death mediated by complement. Rather, reduced levels of PARP1 and persistent high levels of CD43 in Rituximab-treated GCBs demonstrate anti-apoptotic effects of lentiviral transduction that may interfere with the outcome and interpretation of Rituximab tolerance studies. Our findings stress that caution should be exercised exploiting lentiviral vectors in studies of tolerance to therapeutics in DLBCL. Importantly, however, we demonstrate the feasibility of using the lentiviral gene delivery platform in studies addressing the impact of specific microRNAs on Rituximab responsiveness. PMID:27045839

  19. Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome.

    PubMed

    Ruggenenti, Piero; Ruggiero, Barbara; Cravedi, Paolo; Vivarelli, Marina; Massella, Laura; Marasà, Maddalena; Chianca, Antonietta; Rubis, Nadia; Ene-Iordache, Bogdan; Rudnicki, Michael; Pollastro, Rosa Maria; Capasso, Giovambattista; Pisani, Antonio; Pennesi, Marco; Emma, Francesco; Remuzzi, Giuseppe

    2014-04-01

    The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered ≥2 recurrences over the previous year and were in steroid-induced remission for ≥1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19-0.60) to 0 mg/kg (IQR, 0-0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3±25.7 to 121.8±29.2 ml/min per 1.73 m(2) (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children. PMID:24480824

  20. MLN2238, a proteasome inhibitor, induces caspase-dependent cell death, cell cycle arrest, and potentiates the cytotoxic activity of chemotherapy agents in rituximab-chemotherapy-sensitive or rituximab-chemotherapy-resistant B-cell lymphoma preclinical models.

    PubMed

    Gu, Juan J; Hernandez-Ilizaliturri, Francisco J; Mavis, Cory; Czuczman, Natalie M; Deeb, George; Gibbs, John; Skitzki, Joseph J; Patil, Ritesh; Czuczman, Myron S

    2013-11-01

    To further develop therapeutic strategies targeting the proteasome system, we studied the antitumor activity and mechanisms of action of MLN2238, a reversible proteasome inhibitor, in preclinical lymphoma models. Experiments were conducted in rituximab-chemotherapy-sensitive cell lines, rituximab-chemotherapy-resistant cell lines (RRCL), and primary B-cell lymphoma cells. Cells were exposed to MLN2238 or caspase-dependent inhibitors, and differences in cell viability, alterations in apoptotic protein levels, effects on cell cycle, and the possibility of synergy when combined with chemotherapeutic agents were evaluated. MLN2238 showed more potent dose-dependent and time-dependent cytotoxicity and inhibition of cell proliferation in lymphoma cells than bortezomib. Our data suggest that MLN2238 can induce caspase-independent cell death in RRCL. MLN2238 (and to a much lesser degree bortezomib) reduced RRCL S phase and induced cell cycle arrest in the G2/M phase. Exposure of rituximab-chemotherapy-sensitive cell lines and RRCL to MLN2238 potentiated the cytotoxic effects of gemcitabine, doxorubicin, and paclitaxel and overcame resistance to chemotherapy in RRCL. MLN2238 is a potent proteasome inhibitor active in rituximab-chemotherapy-sensitive and rituximab-chemotherapy-resistant cell models and potentiates the antitumor activity of chemotherapy agents and has the potential of becoming an effective therapeutic agent in the treatment of therapy-resistant B-cell lymphoma. PMID:23995855

  1. Long-lasting uveitis remission and hearing loss recovery after rituximab in Vogt-Koyanagi-Harada disease.

    PubMed

    Caso, Francesco; Rigante, Donato; Vitale, Antonio; Costa, Luisa; Bascherini, Vittoria; Latronico, Eugenia; Franceschini, Rossella; Cantarini, Luca

    2015-10-01

    Vogt-Koyanagi-Harada disease (VKHD) is a multisystemic disorder characterized by granulomatous panuveitis variably combined with T cell-mediated neurologic and cutaneous manifestations. Early and aggressive treatment with systemic corticosteroids is the mainstay of treatment for VKHD. Additional use of immunosuppressants, intravenous immunoglobulins, and tumor necrosis factor-alpha inhibitors can help the most severely affected patients and work as corticosteroid-sparing agents. We report the case of a young woman with relapsing and multiresistant VKHD who demonstrated a stable remission of both uveitis and high-frequency hearing loss following rituximab intravenous administration (1 g. twice, 2 weeks apart, and 6 months later). A complete clinical response was observed 1 month since the first infusion, and no ocular relapses were recorded during the following year; in addition, audiometry showed a high-frequency hearing recovery in the right ear. Further observational studies are required to define the role of CD20 inhibition in the management of VKHD. PMID:25224382

  2. Tocilizumab for AA Amyloidosis after Treatment of Multicentric Castleman Disease with Steroids, Chemotherapy and Rituximab for Over 20 Years.

    PubMed

    Iijima, Takashi; Hoshino, Junichi; Suwabe, Tatsuya; Sumida, Keiichi; Mise, Koki; Kawada, Masahiro; Ueno, Toshiharu; Hamanoue, Satoshi; Hayami, Noriko; Hiramatsu, Rikako; Sawa, Naoki; Takaichi, Kenmei; Ubara, Yoshifumi

    2015-01-01

    We herein report the long-term outcome (30 years) of a human immunodeticiency virus- and human herpesvirus 8-negative Japanese man who was diagnosed to have multicentric Castleman disease (MCD) of the plasmacytic type after investigation of generalized lymphadenopathy at 34 of age in 1983. He received chemotherapy based on lymphoma regimens (combinations of prednisolone, vincristine, vindesine, cyclophosphamide, etoposide, melphalan, and ranimustine, etc.) for over 20 years. Although the systemic lymphadenopathy resolved, AA amyloidosis-related nephropathy occurred, with a serum creatinine (Cre) level of 0.9 mg/dL and urinary protein excretion (UP) of 7.5 g daily. Rituximab was started, but Cre increased to 2.6 mg/dL in 2010 and UP was unchanged. Therefore, treatment with tocilizmab was started. As a result, his hypergammaglobulinemia was well controlled, C-reactive protein became normal, UP decreased to 3.5 g daily, and Cre remained at 2.5 mg/dL in 2013. When AA amyloid nephropathy occurred after long-term chemotherapy, lituximab could not control it, but tocilizmab stopped the progression of nephropathy. This case suggests that MCD and AA amyloidosis may both have a close relationship to the overproduction of interleukin-6. PMID:26666616

  3. Bendamustine and Rituximab, as First Line Treatment, in Intermediate, High Risk Splenic Marginal Zone Lymphomas of Elderly Patients

    PubMed Central

    Castelli, Roberto; Gidaro, Antonio; Deliliers, Giorgio Lambertenghi

    2016-01-01

    Background Splenic marginal zone lymphoma (SMZL) is a chronic B-cell lymphoproliferative disorder, comprising less than 2% of non-Hodgkin’s lymphomas, and affecting mainly middle-aged and elderly patients with a median survival of >10 years. The typical clinical features of SMZL include splenomegaly. Treatment should be patient-tailored and can range from a ‘watchful waiting’ approach for asymptomatic patients without cytopenias to surgery, localized radiation therapy or immuno/chemotherapies. Recently, the combination of rituximab and Bendamustine (R-Benda) has been defined as highly active in patients with follicular lymphomas, but little is known about the efficacy of R-Benda in SMZL. Aim of the study The purpose of this retrospective study was to report our experience on the efficacy of R-Benda as first line treatment in 23 consecutive elderly SMZL patients. Results All patients had a complete resolution of splenomegaly along with restoration of their blood counts. Nineteen patients (83%) achieved a complete response (CR) to therapy; three patients (13%) achieved a partial response (PR).Ten patients (43%) obtained molecular remission. Toxicities were mild and mainly haematological and result in dose reductions for fourteen patients. Conclusions Our data suggest a high activity and good tolerance of R-Benda, despite dose reduction due to potential toxicity. PMID:27413523

  4. Phase II Study of Lenalidomide and Rituximab As Salvage Therapy for Patients With Relapsed or Refractory Chronic Lymphocytic Leukemia

    PubMed Central

    Badoux, Xavier C.; Keating, Michael J.; Wen, Sijin; Wierda, William G.; O'Brien, Susan M.; Faderl, Stefan; Sargent, Rachel; Burger, Jan A.; Ferrajoli, Alessandra

    2013-01-01

    Purpose Lenalidomide is an immunomodulatory drug active as salvage therapy for chronic lymphocytic leukemia (CLL). We combined lenalidomide with rituximab to improve response rates in patients with relapsed or refractory CLL. Patients and Methods Fifty-nine adult patients (age 42 to 82 years) with relapsed or refractory CLL were enrolled onto a phase II study of lenalidomide and rituximab. Patients had received prior fludarabine-based therapy or chemoimmunotherapy. Rituximab (375 mg/m2 intravenously) was administered weekly during cycle one and on day 1 of cycles three to 12. Lenalidomide was started on day 9 of cycle one at 10 mg orally and administered daily continuously. Each cycle was 28 days. Rituximab was administered for 12 cycles; lenalidomide could continue indefinitely if patients benefitted clinically. Results The overall response rate was 66%, including 12% complete responses and 12% nodular partial remissions. Time to treatment failure was 17.4 months. Median overall survival has not been reached; estimated survival at 36 months is 71%. The most common grade 3 or 4 toxicity was neutropenia (73% of patients). Fourteen patients (24%) experienced a grade 3 to 4 infection or febrile episode. There was one episode of grade 3 tumor lysis; one patient experienced renal failure during the first cycle of therapy, and one venous thromboembolic event occurred during the study. Conclusion The combination of lenalidomide and rituximab is active in patients with recurrent CLL and warrants further investigation. PMID:23270003

  5. Efficacy and safety of rituximab therapy for systemic lupus erythematosus: a systematic review and meta-analysis

    PubMed Central

    Lan, Lan; Han, Fei; Chen, Jiang-hua

    2012-01-01

    Objective: To review the efficacy and safety of rituximab therapy for systemic lupus erythematosus (SLE).Methods: We searched for randomized controlled trails and observational studies that evaluated the effect of rituximab based on the systemic lupus erythematosus disease activity index (SLEDAI), British Isles lupus assessment group index (BILAG), urine protein levels, and the prednisolone dose, and had adequate data to calculate the mean, standard deviation (SD), and 95% confidence intervals, and to systematically review and meta-analyze observational studies with fixed effects model or random effects model. Results: We included 2 randomized controlled studies and 19 observational clinical studies. We summarized the data from the 19 observational studies, analyzed the heterogeneity of the literature, and then used fixed effect model or random effect model for statistical analysis. The SLEDAI, BILAG, and urine protein levels and the prednisolone dosage were decreased after rituximab treatment, and the decreases in the BILAG, urine protein levels, and the prednisolone dose were found to be significant (P<0.05), when compared with baseline level. Rituximab’s adverse effects generally could be controlled with an effective dosing regimen. Conclusions: Although there are still controversies about rituximab’s treatment on SLE, but our study had showed that rituximab had favorable effects on refractory lupus. The long-term efficacy and safety of rituximab require further study. PMID:22949364

  6. Different sensitivity of rituximab-treatment to B-cells between ABO-incompatible kidney and liver transplantation.

    PubMed

    Morimoto, Hiroshi; Ide, Kentaro; Tanaka, Yuka; Ishiyama, Kohei; Ohira, Masahiro; Tahara, Hiroyuki; Akita, Tomonori; Tanaka, Junko; Ohdan, Hideki

    2016-06-01

    A desensitization protocol with rituximab is currently widely used for kidney transplantation (KT) and liver transplantation (LT) across the ABO blood group-incompatible (ABO-I) barrier. However, it remains to be elucidated whether rituximab is equally effective for B-cell and T-cell immune responses in both KT and LT recipients. To clarify these effects of rituximab, we enrolled 46 KT and 77 LT recipients in this study. The proportion of peripheral blood B-cells was determined at the perioperative period. T-cell responses to allostimulation were evaluated by a mixed lymphocyte reaction (MLR) assay. One week after rituximab administration, peripheral B-cells became undetectable in ABO-I KT recipients but remained detectable in some of the ABO-I LT recipients; B-cells were undetectable in both groups by week 2. B-cells remained below the detection limit throughout the first year in the ABO-I KT recipients, whereas they reappeared in the periphery after 6months in the ABO-I LT recipients. There were no significant differences in alloreactive T-cell responses based on MLR analyses between ABO-I and ABO-compatible groups. This study indicates that rituximab has differing B-cell sensitivity between KT and LT recipients and a minimal effect on the alloreactive T-cell responses in KT and LT recipients. PMID:27085793

  7. Suppression of Rituximab-resistant B-cell lymphoma with a novel multi-component anti-CD20 mAb nanocluster

    PubMed Central

    Zhao, He; Sun, Yun; Zhao, Mengxin; Chen, Di; Zhu, Xiandi; Zhang, Li; Li, Bohua; Dai, Jianxin; Li, Wei

    2015-01-01

    Although the anti-CD20 antibody Rituximab has revolutionized the treatment of Non-Hodgkin Lymphoma (NHL), resistance to treatment still existed. Thus, strategies for suppressing Rituximab-resistant NHLs are urgently needed. Here, an anti-CD20 nanocluster (ACNC) is successfully constructed from its type I and type II mAb (Rituximab and 11B8). These distinct anti-CD20 mAbs are mass grafted to a short chain polymer (polyethylenimine). Compared with parental Rituximab and 11B8, the ACNC had a reduced “off-rate”. Importantly, ACNC efficiently inhibited Rituximab-resistant lymphomas in both disseminated and localized human NHL xenograft models. Further results revealed that ACNC is significantly potent in inducing caspase-dependent apoptosis and lysosome-mediated programmed cell death (PCD). This may help explain why ACNC is effective in suppressing rituximab-resistant lymphoma while Rituximab and 11B8 are not. Additionally, ACNC experienced low clearance from peripheral blood and high intratumor accumulation. This improved pharmacokinetics is attributed to the antibody-antigen reaction (active targeting) and enhanced permeability and retention (ERP) effect (passive targeting). This study suggested that ACNC might be a promising therapeutic agent for treatment of rituximab-resistant lymphomas. PMID:26284588

  8. Lymphomatoid Granulomatosis of Central Nervous System and Lung Driven by Epstein Barr Virus Proliferation: Successful Treatment with Rituximab-Containing Chemotherapy

    PubMed Central

    Fernandez-Alvarez, Ruben; Gonzalez, ME; Fernandez, Almudena; Gonzalez-Rodriguez, AP; Sancho, JM; Dominguez, Francisco; Fernandez, Carmen

    2014-01-01

    Lymphomatoid granulomatosis (LYG) is a very rare Epstein-Barr virus (EBV) associated B-cell lymphoproliferative disorder. We report the case of a 41-year-old man who presented with fever and respiratory symptoms. Computed tomography showed multiple nodules in both lung fields. Polymerase chain reaction (PCR) analysis for EBV was positive in bronchoalveolar lavage and biopsy of lung node yielded a diagnosis of LYG, grade III. Shortly after initiation of treatment with agressive chemotherapy, neurological deterioration appeared. Neuroimaging findings revealed hydrocephalus and PCR analysis of the cerebrospinal fluid (CSF) was positive for EBV. Treatment with intravenous rituximab led to rapid reduction of EBV load in CSF, along with clinical and radiological improvement. After completion of treatment with immunochemotherapy, an autologous stem cell transplantation was performed. Patient stays in remission 18 months after diagnosis. PMID:24678394

  9. Diffuse large B-cell lymphoma transformed from mucosa-associated lymphoid tissue lymphoma arising in a female urethra treated with rituximab for the first time.

    PubMed

    Zahrani, A Al; Abdelsalam, M; Fiaar, A Al; Ibrahim, N; Al-Elawi, A; Muhammad, B

    2012-05-01

    A 30-year-old female patient presented to the gynecology clinic with a small (painless) swelling at the urethral orifice. She underwent surgical excision of the lesion. Pathological examination revealed non-Hodgkin's lymphoma of diffuse large B-cell type and mucosa-associated lymphoid tissue type, stage IE. The patient refused radiotherapy. Accordingly, we started CHOP-R chemotherapy. She received a total of 6 cycles of CHOP and 8 cycles of rituximab. Patient follow-up was done 3 months later through CT scan and cytoscopy confirming the complete remission. The patient has been disease-free for 4 years. We reviewed 26 cases of this rare entity reported previously. PMID:22679430

  10. Rapid infusion rituximab in combination with corticosteroid-containing chemotherapy or as maintenance therapy is well tolerated and can safely be delivered in the community setting.

    PubMed

    Sehn, Laurie H; Donaldson, Jane; Filewich, Allison; Fitzgerald, Catherine; Gill, Karamjit K; Runzer, Nancy; Searle, Barb; Souliere, Sheila; Spinelli, John J; Sutherland, Judy; Connors, Joseph M

    2007-05-15

    The increasing usage of rituximab in the management of non-Hodgkin lymphoma (NHL) has created huge logistical challenges with respect to the delivery of this time- and labor-intensive drug. To address these challenges, we developed and tested the feasibility of a 90-minute infusion schedule for rituximab (20% of the dose administered in the first 30 minutes, remaining 80% administered over 60 minutes). A safety analysis performed in 150 patients receiving rituximab with corticosteroid-containing chemotherapy and 56 patients receiving rituximab as maintenance therapy demonstrated that this schedule was well tolerated, with no grade 3 or 4 infusion reactions observed. In addition, no increase in minor reactions was noted. More than 1200 patients have been treated with this rapid rituximab infusion schedule in the province of British Columbia (BC), demonstrating its safety in the community setting. The adoption of this 90-minute schedule as standard practice has had a positive impact on resource utilization. PMID:17244675

  11. [Successful treatment with rituximab in two cases of IgM-monoclonal gammopathy of undetermined significance (MGUS) neuropathy].

    PubMed

    Koike, Michiaki; Sugimoto, Keiji; Tusui, Miyuki; Yahata, Yuriko

    2012-04-01

    A 66-year-old male was hospitalized with muscle weakness and gait disturbance. Examination revealed IgM 3,407 mg/dl (IgM, κ-type M protein) and he was diagnosed as having IgM-MGUS neuropathy. He suffered from paralysis of respiratory muscles and required a respirator support. Plasmapheresis and intravenous immunoglobulin were performed and he was weaned from the respirator. Rituximab given as 8 weekly infusions improved gait disturbance. A 71-year-old male was hospitalized with lumbago, numbness of lower extremities and gait disturbance. Examination revealed IgM 1,553 mg/dl (IgM, λ-type M protein) and he was diagnosed with IgM-MGUS neuropathy. Rituximab given as 8 weekly infusions improved gait disturbance. It was concluded that rituximab is a well-tolerated treatment that may be effective in some patients with IgM-MGUS neuropathy. PMID:22687979

  12. Rituximab Effectiveness and Safety for Treating Primary Sjögren’s Syndrome (pSS): Systematic Review and Meta-Analysis

    PubMed Central

    Souza, Francine Bertolais do Valle; Porfírio, Gustavo José Martiniano; Andriolo, Brenda Nazaré Gomes; de Albuquerque, Julia Vajda; Trevisani, Virginia Fernandes Moça

    2016-01-01

    Background Primary Sjögren’s Syndrome (pSS) is a systemic autoimmune disease that involves the exocrine glands and internal organs. pSS leads to destruction and loss of secretory function due to intense lymphoplasmacytic infiltration. Therapeutic options include mainly symptomatic and supportive measures, and traditional immunosuppressant drugs have shown no effectiveness in randomized trials. Rituximab (RTX) is a chimeric antibody anti-CD20 that leads to B cell depletion by diverse mechanisms. There is evidence that this drug may be effective for treating pSS. The objective of this systematic review was to evaluate Rituximab effectiveness and safety for treating pSS. Methods and Findings We conducted a systematic review of RCTs published until December 2015, with no language restriction. We registered a protocol on Plataforma Brasil (40654814.6.0000.5505) and developed search strategies for the following scientific databases: MEDLINE, EMBASE, CENTRAL and LILACS. We included adults with established pSS diagnosis and considered the use of Rituximab as intervention and the use of other drugs or placebo as control. Four studies met our eligibility criteria: three with low risk of bias and one with uncertain risk of bias. The total number of participants was 276 (145 RTX, 131 placebo). We assessed the risk of bias of each included study and evaluated the following as primary outcomes: lacrimal gland function, salivary gland function, fatigue improvement and adverse events. We found no significant differences between the groups in the Schirmer test at week 24 meta-analysis (MD 3.59, 95% CI -2.89 to 10.07). Only one study evaluated the lissamine green test and reported a statistically significant difference between the groups at week 24 (MD -2.00, 95% CI -3.52 to -0.48). There was a significant difference between the groups regarding salivary flow rate (MD 0.09, 95% CI 0.02 to 0.16) and improvement in fatigue VAS at weeks 6 (RR 3.98, 95% CI 1.61 to 9.82) and week 16

  13. Human Cytokine Genetic Variants Associated With HBsAg Reverse Seroconversion in Rituximab-Treated Non-Hodgkin Lymphoma Patients

    PubMed Central

    Hsiao, Liang-Tsai; Wang, Hao-Yuan; Yang, Ching-Fen; Chiou, Tzeon-Jye; Gau, Jyh-Pyng; Yu, Yuan-Bin; Liu, Hsiao-Ling; Chang, Wen-Chun; Chen, Po-Min; Tzeng, Cheng-Hwai; Chan, Yu-Jiun; Yang, Muh-Hwa; Liu, Jin-Hwang; Huang, Yi-Hsiang

    2016-01-01

    Abstract Hepatitis B virus (HBV) reactivation has been noted in HBV surface antigen (HBsAg)-seronegative patients with CD20+ B-cell non-Hodgkin lymphoma (NHL) undergoing rituximab treatment. Clinically, hepatitis flares are usually associated with the reappearance of HBsAg (reverse seroconversion of HBsAg, HBV-RS). It is unclear whether human genetic factors are related to rituximab-associated HBV reactivation. Unvaccinated HBsAg-seronegative adults (n = 104) with CD20+ NHL who had received rituximab-containing therapy without anti-HBV prophylaxis were enrolled. Eighty-nine candidate single nucleotide polymorphisms (SNPs) of 49 human cytokine genes were chosen and were analyzed using the iPLEX technique. Competing risk regression was used to identify the factors associated with HBV-RS. Participants had a median age of 66.1 years and 56.7% were male (n = 59). The anti-HBs and anti-HBc positivity rates were 82.4% and 94.1%, respectively, among patients for whom data were available (approximately 81%). A mean of 7.14 cycles of rituximab therapy were administered, and a total of 14 (13.4%) patients developed HBV-RS. Nine SNPs showed significant differences in frequency between patients with or without HBV-RS: CD40 rs1883832, IL4 rs2243248 and rs2243263, IL13 rs1295686, IL18 rs243908, IL20 rs1518108, and TNFSF13B rs12428930 and rs12583006. Multivariate analysis showed that ≥6 cycles of rituximab therapy, IL18 rs243908, and the IL4 haplotype rs2243248∼rs2243263 were independently associated with HBV-RS. The IL4 haplotype rs2243248∼rs2243263 was significantly associated with HBV-RS regardless of anti-HBs status. Polymorphisms in human cytokine genes impact the risk of rituximab-associated HBV-RS. PMID:26986131

  14. Characterization of Self-Assembled Monolayers of Peptide Mimotopes of CD20 Antigen and Their Binding with Rituximab.

    PubMed

    Leo, Norman; Shang, Yuqin; Yu, Jing-jiang; Zeng, Xiangqun

    2015-12-29

    CD20, expressed in greater than 90% of B-lymphocytic lymphomas, is a target for antibody therapy. Rituximab is a chimeric therapeutic monoclonal antibody (mAb) against the protein CD20, allowing it to destroy B cells and to treat lymphoma, leukemia, transplant rejection, and autoimmune disorder. In this work, the binding of rituximab to self-assembled monolayers (SAMs) of peptide mimotopes of CD20 antigen was systematically characterized. Four peptide mimotopes of CD 20 antigen were selected from the literature and redesigned to allow their SAM immobilizations on gold electrodes through a peptide linker with cysteine. The bindings of these peptides with rituximab and control mAbs (trastuzumab and bevacizumab) were characterized by quartz crystal microbalance (QCM). Among the four peptide mimotopes initially selected, the peptide designated as CN-14 (CGSGSGSWPRWLEN) was the most selective and sensitive for rituximab binding. The CN-14 SAM was further characterized by ellipsometry and atomic force microscopy. The thickness of the CN-14 SAM film was approximately 32 Å, and the CN-14 SAM is suggested to be stabilized by a salt bridge of Arg-10 and Glu-13 between CN-14 peptides. The CN-14 salt bridge was evaluated by a series of modifications to the CN-14 peptide sequence and characterized by QCM. The CN-14 amide variant produced a better affinity to rituximab than CN-14 without a significant impact on selectivity. As the pKa of the Glu residue of CN-14 increased, the affinity of the SAM to rituximab increased, whereas the selectivity decreased. This was attributed to the weakening of the salt bridge between the CN-14 Arg-10 and Glu-13 at higher pKa values for Glu-13. Our study shows that peptide mimotopes have potential benefits in sensor applications, as the peptide-peptide interactions in the SAMs can be manipulated by the addition of functional groups to the peptide to influence the binding of target proteins. PMID:26609837

  15. Rituximab in the Treatment of Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis: A Randomized, Placebo-phase Trial

    PubMed Central

    Oddis, Chester V.; Reed, Ann M.; Aggarwal, Rohit; Rider, Lisa G.; Ascherman, Dana P.; Levesque, Marc C.; Barohn, Richard J.; Feldman, Brian M.; Harris-Love, Michael O.; Koontz, Diane C.; Fertig, Noreen; Kelley, Stephanie S.; Pryber, Sherrie L.; Miller, Frederick W.; Rockette, Howard E.

    2012-01-01

    Objective To assess the safety and efficacy of rituximab in a randomized, double-blind, placebo-phase, trial of adult and pediatric myositis. Methods Adults with refractory polymyositis and adults and children with refractory dermatomyositis were enrolled. Entry criteria included muscle weakness and ≥2 additional abnormal core set measures (CSM) for adults. JDM patients required ≥ 3 abnormal CSM with or without muscle weakness. Patients were randomized to either ‘rituximab early’ or ‘rituximab late’ and glucocorticoid and immunosuppressive therapy were allowed at entry. The primary endpoint compared the time to achieve the preliminary International Myositis Assessment and Clinical Studies Group definition of improvement (DOI) between the 2 groups. The secondary endpoints were time to achieve ≥20% improvement in muscle strength, and the proportion of early and late rituximab patients achieving DOI at week 8. Results Among 200 randomized patients (76 PM/76 DM/48 JDM), 195 showed no difference in the time to DOI between the rituximab late (n=102) and rituximab early (n=93) groups (p=0.74, log rank) with a median time to DOI of 20.2 weeks and 20.0 weeks respectively. The secondary endpoints also did not significantly differ between the two treatment groups. However, 161 (83%) of randomized patients met the DOI and individual CSM improved in both groups throughout the 44-week trial. Conclusion Although there were no significant differences in the two treatment arms for the primary and secondary endpoints, 83% of refractory adult and juvenile myositis patients met the DOI. The role of B cell depleting therapies in myositis warrants further study with consideration for a different trial design. PMID:23124935

  16. Rituximab therapy for chonic and refractory immune thrombocytopenic purpura: a long-term follow-up analysis

    PubMed Central

    Garcia-Chavez, Jaime; Montiel-Cervantes, Laura; Esparza, Miriam García-Ruiz; Vela-Ojeda, Jorge

    2007-01-01

    The aim of this study was to evaluate the long-term response to rituximab in patients with chronic and refractory immune thrombocytopenic purpura (ITP). Adults with ITP fail to respond to conventional therapies in almost 30% of cases, developing a refractory disease. Rituximab has been successfully used in these patients. We used rituximab at 375 mg/m2, IV, weekly for a total of four doses in 18 adult patients. Complete remission (CR) was considered if the platelet count was >100 × 109/l, partial remission (PR) if platelets were >50 × 109/l, minimal response (MR) if the platelet count was >30 × 109/l and <50 × 109/l, and no response if platelet count remained unchanged. Response was classified as sustained (SR) when it was stable for a minimum of 6 months. Median age was 43.5 years (range, 17 to 70). Median platelet count at baseline was 12.5 × 109/l (range, 3.0 to 26.3). CR was achieved in five patients (28%), PR in five (28%), MR in four (22%), and two patients were classified as therapeutic failures (11%). Two additional patients were lost to follow-up. The median time between rituximab therapy and response was 14 weeks (range, 4 to 32). SR was achieved in 12 patients (67%). There were no severe adverse events during rituximab therapy. During follow-up (median, 26 months; range, 12 to 59), no other immunosuppressive drugs were used. In conclusion, rituximab therapy is effective and safe in adult patients with chronic and refractory ITP. Overall response rate achieved is high, long term, and with no risk of adverse events. PMID:17874322

  17. Cytomegalovirus infection in autologous stem cell transplant recipients in the era of rituximab.

    PubMed

    Jain, Tania; John, Jisha; Kotecha, Aditya; Deol, Abhinav; Saliminia, Tanaz; Revankar, Sanjay; Chandrasekar, Pranatharthi

    2016-08-01

    The incidence of cytomegalovirus (CMV) reactivation/disease after autologous stem cell transplant (ASCT) is much lower than that after allogeneic stem cell transplantation. With the recent use of rituximab during cancer chemotherapy or conditioning regimens prior to transplantation, there has been an increasing concern of opportunistic infections including CMV. In the present study, we reviewed the patients undergoing ASCT from December 2007 to December 2013 to identify those developing CMV reactivation/disease. Out of the 978 patients who underwent ASCT at the Karmanos Cancer Institute, 239 patients were tested for symptomatic CMV reactivation based on clinical suspicion. Of the tested patients, 7/239 (2.9 %) were documented to have CMV reactivation within 90 days of ASCT. The median time to develop CMV viremia was 32 days from transplantation. Of the 239 patients tested, CMV viremia was detected in 3 out of 72 patients who received rituximab as compared to 4 out of 167 patients who did not. Three of these seven viremic patients were treated with anti-viral drugs; viremia resolved in all patients at a median of 24 days. Three patients were found to develop other bacterial and/or fungal infections following CMV viremia. Two of the seven patients died during 1-year follow-up, due to primary disease progression or Candida sepsis. None of the patients developed proven tissue-invasive CMV disease. The study did not evaluate the incidence of asymptomatic CMV infection/reactivation. Despite prior publications based on limited data, rituximab does not appear to contribute to an increased frequency of symptomatic CMV reactivation following ASCT. PMID:27225264

  18. In Vitro Cytotoxicity of Low-Dose-Rate Radioimmunotherapy by the Alpha-Emitting Radioimmunoconjugate Thorium-227-DOTA-Rituximab

    SciTech Connect

    Dahle, Jostein; Krogh, Cecilie; Melhus, Katrine B.; Borrebaek, Jorgen; Larsen, Roy H.; Kvinnsland, Yngve

    2009-11-01

    Purpose: To determine whether the low-dose-rate alpha-particle-emitting radioimmunoconjugate {sup 227}Th-1,4,7,10-p-isothiocyanato-benzyl-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (DOTA)-rituximab can be used to inactivate lymphoma cells growing as single cells and small colonies. Methods and Materials: CD20-positive lymphoma cell lines were treated with {sup 227}Th-DOTA-rituximab for 1-5 weeks. To simulate the in vivo situation with continuous but decreasing supply of radioimmunoconjugates from the blood pool, the cells were not washed after incubation with {sup 227}Th-DOTA-rituximab, but half of the medium was replaced with fresh medium, and cell concentration and cell-bound activity were determined every other day after start of incubation. A microdosimetric model was established to estimate the average number of hits in the nucleus for different localizations of activity. Results: There was a specific targeted effect on cell growth of the {sup 227}Th-DOTA-rituximab treatment. Although the cells were not washed after incubation with {sup 227}Th-DOTA-rituximab, the average contribution of activity in the medium to the mean dose was only 6%, whereas the average contribution from activity on the cells' own surface was 78%. The mean dose rates after incubation with 800 Bq/mL {sup 227}Th-DOTA-rituximab varied from 0.01 to 0.03 cGy/min. The average delay in growing from 10{sup 5} to 10{sup 7} cells/mL was 15 days when the cells were treated with a mean absorbed radiation dose of 2 Gy alpha-particle radiation from {sup 227}Th-DOTA-rituximab, whereas it was 11 days when the cells were irradiated with 6 Gy of X-radiation. The relative biologic effect of the treatment was estimated to be 2.9-3.4. Conclusions: The low-dose-rate radioimmunoconjugate {sup 227}Th-DOTA-rituximab is suitable for inactivation of single lymphoma cells and small colonies of lymphoma cells.

  19. Risk of Reverse Seroconversion of Hepatitis B Virus Surface Antigen in Rituximab-Treated Non-Hodgkin Lymphoma Patients

    PubMed Central

    Hsiao, Liang-Tsai; Chiou, Tzeon-Jye; Gau, Jyh-Pyng; Yang, Ching-Fen; Yu, Yuan-Bin; Liu, Chun-Yu; Liu, Jin-Hwang; Chen, Po-Min; Tzeng, Cheng-Hwai; Chan, Yu-Jiun; Yang, Muh-Hwa; Huang, Yi-Hsiang

    2015-01-01

    Abstract Rituximab causes hepatitis B virus (HBV) reactivation in HBV surface antigen (HBsAg)-seronegative patients with CD20-positive B-cell non-Hodgkin lymphoma (CD20+ NHL), especially for those seropositive to the antibody of core antigen (anti-HBc). Clinical hepatitis usually develops after reverse seroconversion of HBsAg (HBV-RS), indicated by the reappearance of HBsAg in serum. Because of the relatively high prevalence of anti-HBc seropositivity in unvaccinated HBsAg-seronegative adults in an HBV hyperendemic area, we aimed to investigate additional factors influencing the development of rituximab-associated HBV-RS. Between January 2000 and December 2010, unvaccinated HBsAg-seronegative adults with CD20+ NHL who had received rituximab-containing therapy but not anti-HBV agents were enrolled. Patients with and without HBV-RS were compared in terms of clinical factors and treatments including the number of cycles of rituximab therapy, and transplantation. Competing risk regression was used to identify the factors associated with HBV-RS. For the 482 patients enrolled, the serological status of anti-HBc was available in 75.9%, with a seropositivity rate of 86.6%. At the last follow-up, a total of 33 (6.85%) patients had HBV-RS, with 95.8% anti-HBc seropositive, 78.9% anti-HBs seropositive, and none anti-HCV seropositive. HBV-RS patients have received more cycles (≥6) and prolonged durations of rituximab therapy, and hematopoietic stem cell transplantation. The overall survival was not different between patients with and those without HBV-RS. At the time of HBV-RS, a total of 25 (78.1%) patients had hepatitis flare, especially when HBV-RS appeared during/after induction therapy (100%, 10 of 10). Three (9.1%) patients had fulminant hepatitis, resulting in death in 1 (3%) patient. A higher rituximab cycle intensity was associated with a higher rate of hepatitis flare at the time of HBV-RS. When death in the absence of HBV-RS was considered as the competing risk

  20. Standard Operating Procedure for In-house Preparation of (131)I-rituximab for Radioimmunotherapy of Non-Hodgkin's Lymphoma.

    PubMed

    Pickford, Matthew D; Turner, J Harvey

    2012-09-01

    A Standard Operating Procedure (SOP) has been formulated for in-house preparation, quality control, dispensing and administration of (131)I-rituximab appropriate for the safe, effective, radioimmunotherapy of non-Hodgkin lymphoma. A decade of experience of semi-automated radioiodination of rituximab in our hospital radiopharmaceutical laboratory was analysed. The methodology was then refined for safe, practical, affordable application to radioimmunotherapy of lymphoma in departments of nuclear medicine in developing countries. This SOP has the potential to be incorporated into good laboratory practice conditions appropriate for local regulatory agency requirements. PMID:23372447

  1. Standard Operating Procedure for In-house Preparation of 131I-rituximab for Radioimmunotherapy of Non-Hodgkin's Lymphoma

    PubMed Central

    Pickford, Matthew D.; Turner, J. Harvey

    2012-01-01

    A Standard Operating Procedure (SOP) has been formulated for in-house preparation, quality control, dispensing and administration of 131I-rituximab appropriate for the safe, effective, radioimmunotherapy of non-Hodgkin lymphoma. A decade of experience of semi-automated radioiodination of rituximab in our hospital radiopharmaceutical laboratory was analysed. The methodology was then refined for safe, practical, affordable application to radioimmunotherapy of lymphoma in departments of nuclear medicine in developing countries. This SOP has the potential to be incorporated into good laboratory practice conditions appropriate for local regulatory agency requirements. PMID:23372447

  2. Protein-losing enteropathy associated with refractory systemic lupus erythematosus with a good response to rituximab.

    PubMed

    Sansinanea, Pierina; Carrica, Sebastián Augusto; Marcos, Josefina; García, Mercedes Argentina

    2016-01-01

    A case is presented of a protein-losing enteropathy (PLE) as the initial manifestation of systemic lupus erythematosus (SLE) in a 17 year-old female patient, who presented with ascites, edema and hypoalbuminemia. The diagnosis of SLE was based on the presence of: malar rash, oral ulcers, thrombocytopenia, antinuclear antibodies, IgM anticardiolipin antibody, and lupus anticoagulant. Renal and liver diseases were ruled out. The PLE diagnosis was confirmed with fecal alpha 1-antitrypsin clearance. The PLE was refractory to different lines of immunosuppressive agents like glucocorticoids, cyclophosphamide, azathioprine, and cyclosporine, showing a satisfactory and sustained response with rituximab, allowing steroid sparing and long term remission. PMID:25818375

  3. Steroid Refractory Autoimmune Haemolytic Anaemia Secondary to Sarcoidosis Successfully Treated with Rituximab and Mycophenolate Mofetil.

    PubMed

    Green, Sarah; Partridge, Erica; Idedevbo, Edore; Borg, Anton

    2016-01-01

    Autoimmune haemolytic anaemia is not a well-recognised complication of sarcoidosis. We describe the case of a 30-year-old female who presented with acute warm haemolytic anaemia and widespread lymphadenopathy. Sarcoidosis was diagnosed on lymph node biopsy and further investigation. The haemolytic anaemia responded only to a high dose of steroids. Evidence regarding treatment of steroid refractory autoimmune haemolysis secondary to sarcoidosis is lacking. Based on the emergent evidence that both disorders share common immunopathogenic mechanisms involving Th1 and Th17 lymphocytes, our patient was given rituximab and mycophenolate mofetil to successfully suppress the haemolysis and sarcoid activity. PMID:27563474

  4. Lenalidomide plus Rituximab as Initial Treatment for Mantle-Cell Lymphoma

    PubMed Central

    Ruan, Jia; Martin, Peter; Shah, Bijal; Schuster, Stephen J.; Smith, Sonali M.; Furman, Richard R.; Christos, Paul; Rodriguez, Amelyn; Svoboda, Jakub; Lewis, Jessica; Katz, Orel; Coleman, Morton; Leonard, John P.

    2015-01-01

    BACKGROUND Mantle-cell lymphoma is generally incurable. Initial treatment is not standardized but usually includes cytotoxic chemotherapy. Lenalidomide, an immunomodulatory compound, and rituximab, an anti-CD20 antibody, are active in patients with recurrent mantle-cell lymphoma. We evaluated lenalidomide plus rituximab as a first-line therapy. METHODS We conducted a single-group, multicenter, phase 2 study with induction and maintenance phases. During the induction phase, lenalidomide was administered at a dose of 20 mg daily on days 1 through 21 of every 28-day cycle for 12 cycles; the dose was escalated to 25 mg daily after the first cycle if no dose-limiting adverse events occurred during the first cycle and was reduced to 15 mg daily during the maintenance phase. Rituximab was administered once weekly for the first 4 weeks and then once every other cycle until disease progression. The primary end point was the overall response rate. Secondary end points included outcomes related to safety, survival, and quality of life. RESULTS A total of 38 participants were enrolled at four centers from July 2011 through April 2014. The median age was 65 years. On the basis of the Mantle Cell Lymphoma International Prognostic Index scores, the proportions of participants with low-risk, intermediate-risk, and high-risk disease at baseline were similar (34%, 34%, and 32%, respectively). The most common grade 3 or 4 adverse events were neutropenia (in 50% of the patients), rash (in 29%), thrombocytopenia (in 13%), an inflammatory syndrome (“tumor flare”) (in 11%), anemia (in 11%), serum sickness (in 8%), and fatigue (in 8%). At the median follow-up of 30 months (through February 2015), the overall response rate among the participants who could be evaluated was 92% (95% confidence interval [CI], 78 to 98), and the complete response rate was 64% (95% CI, 46 to 79); median progression-free survival had not been reached. The 2-year progression-free survival was estimated to be

  5. Steroid Refractory Autoimmune Haemolytic Anaemia Secondary to Sarcoidosis Successfully Treated with Rituximab and Mycophenolate Mofetil

    PubMed Central

    Idedevbo, Edore; Borg, Anton

    2016-01-01

    Autoimmune haemolytic anaemia is not a well-recognised complication of sarcoidosis. We describe the case of a 30-year-old female who presented with acute warm haemolytic anaemia and widespread lymphadenopathy. Sarcoidosis was diagnosed on lymph node biopsy and further investigation. The haemolytic anaemia responded only to a high dose of steroids. Evidence regarding treatment of steroid refractory autoimmune haemolysis secondary to sarcoidosis is lacking. Based on the emergent evidence that both disorders share common immunopathogenic mechanisms involving Th1 and Th17 lymphocytes, our patient was given rituximab and mycophenolate mofetil to successfully suppress the haemolysis and sarcoid activity. PMID:27563474

  6. Activity and safety of combined rituximab with chlorambucil in patients with mantle cell lymphoma.

    PubMed

    Bauwens, Deborah; Maerevoet, Marie; Michaux, Lucienne; Théate, Ivan; Hagemeijer, Anne; Stul, Michel; Danse, Etienne; Costantini, Sabrina; Vannuffel, Pascal; Straetmans, Nicole; Vekemans, Marie-Christiane; Deneys, Véronique; Ferrant, Augustin; Van Den Neste, Eric

    2005-11-01

    We evaluated the combination of rituximab with chlorambucil in patients with mantle cell lymphoma (MCL) not eligible for aggressive therapy. Fourteen patients (male/female: 9/5) were included (two newly diagnosed, 12 relapsed/refractory). The toxicities were neutropenia, thrombopenia and infection. Nine (64%) patients responded; five (36%) achieved complete remission and four (29%) achieved partial remission. The median progression-free survival for responders was 26 months (95% CI, 4-48). Marrow polymerase chain reaction negativity was attained in seven responders. These results suggest that this schedule may have notable antitumour activity in patients with MCL, including patients in relapse after autologous stem cell transplantation. PMID:16225653

  7. Consensus statement on the use of rituximab in patients with rheumatoid arthritis

    PubMed Central

    Smolen, J S; Keystone, E C; Emery, P; Breedveld, F C; Betteridge, N; Burmester, G R; Dougados, M; Ferraccioli, G; Jaeger, U; Klareskog, L; Kvien, T K; Martin‐Mola, E; Pavelka, K

    2007-01-01

    A large number of experts experienced in the treatment of rheumatoid arthritis were involved in formulating a consensus statement on the use of B cell‐targeted treatment with rituximab in patients with rheumatoid arthritis. The statement was supported by data from randomised controlled clinical trials and the substantial literature on oncology. The statement underwent three rounds of discussions until its ultimate formulation. It should guide clinicians in the use of this newly approved biological agent in treating patients with rheumatoid arthritis. PMID:17068064

  8. Immunreconstitution and Infectious Complications After Rituximab Treatment in Children and Adolescents: What Do We Know and What Can We Learn from Adults?

    PubMed Central

    Worch, Jennifer; Makarova, Olga; Burkhardt, Birgit

    2015-01-01

    Rituximab, an anti CD20 monoclonal antibody, is widely used in the treatment of B-cell malignancies in adults and increasingly in pediatric patients. By depleting B-cells, rituximab interferes with humoral immunity. This review provides a comprehensive overview of immune reconstitution and infectious complications after rituximab treatment in children and adolescents. Immune reconstitution starts usually after six months with recovery to normal between nine to twelve months. Extended rituximab treatment results in a prolonged recovery of B-cells without an increase of clinically relevant infections. The kinetic of B-cell recovery is influenced by the concomitant chemotherapy and the underlying disease. Intensive B-NHL treatment such as high-dose chemotherapy followed by rituximab bears a risk for prolonged hypogammaglobulinemia. Overall transient alteration of immune reconstitution and infections after rituximab treatment are acceptable for children and adolescent without significant differences compared to adults. However, age related disparities in the kinetic of immune reconstitution and the definitive role of rituximab in the treatment for children and adolescents with B-cell malignancies need to be evaluated in prospective controlled clinical trials. PMID:25643241

  9. Immunreconstitution and infectious complications after rituximab treatment in children and adolescents: what do we know and what can we learn from adults?

    PubMed

    Worch, Jennifer; Makarova, Olga; Burkhardt, Birgit

    2015-01-01

    Rituximab, an anti CD20 monoclonal antibody, is widely used in the treatment of B-cell malignancies in adults and increasingly in pediatric patients. By depleting B-cells, rituximab interferes with humoral immunity. This review provides a comprehensive overview of immune reconstitution and infectious complications after rituximab treatment in children and adolescents. Immune reconstitution starts usually after six months with recovery to normal between nine to twelve months. Extended rituximab treatment results in a prolonged recovery of B-cells without an increase of clinically relevant infections. The kinetic of B-cell recovery is influenced by the concomitant chemotherapy and the underlying disease. Intensive B-NHL treatment such as high-dose chemotherapy followed by rituximab bears a risk for prolonged hypogammaglobulinemia. Overall transient alteration of immune reconstitution and infections after rituximab treatment are acceptable for children and adolescent without significant differences compared to adults. However, age related disparities in the kinetic of immune reconstitution and the definitive role of rituximab in the treatment for children and adolescents with B-cell malignancies need to be evaluated in prospective controlled clinical trials. PMID:25643241

  10. Rituximab in the treatment of diffuse large B-cell lymphoma primary of the lung.

    PubMed

    Aviles, Agustin; Nambo, Maria J; Huerta-Guzman, Judith; Silva, Luis; Neri, Natividad

    2013-03-01

    Diffuse large B-cell lymphoma primary of lung (DLBCL-PL) is a rare presentation of extranodal lymphoma, in most cases chemotherapy-based anthracyclines: CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone) has been the treatment, with excellent outcome. The addition of rituximab to CHOP (R-CHOP) has been considered the gold standard in the treatment of nodal DLBCL. Thus, we assess in a large number of cases of DLBCL-PL whether the use of R-CHOP could improve survival in this setting of patients. Forty-two patients with DLBCL-PL, stage IE, age 65 years or younger, were treated with standard R-CHOP, no consolidation radiotherapy or maintenance therapy were considered. They were matched with patients who received CHOP alone to assess efficacy and toxicity. Complete response was observed in 35 patients (83%), and 7 patients were considered failure (16%). The study has a median follow-up of 42.8 months. Actuarial curves at 5 years showed that progression-free survival was 88 % and overall survival was 70 %. The results were not statistically different when compared retrospectively with patients who received CHOP alone. Treatment was well tolerated. The addition of rituximab to chemotherapy did not improve outcome in patients with DLBCL-PL. PMID:23394581

  11. Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy

    PubMed Central

    Al-Shammari, Ahmed Majeed; Rameez, Huda; Al-Taee, Maha F

    2016-01-01

    Hematological malignancies are important diseases that need more powerful therapeutics. Even with current targeting therapies, such as rituximab and other chemotherapeutic agents, there is a need to develop new treatment strategies. Combination therapy seems the best option to target the tumor cells by different mechanisms. Virotherapy is a very promising treatment modality, as it is selective, safe, and causes cancer destruction. The Iraqi strain of Newcastle disease virus (NDV) has proved to be effective both in vitro and in vivo. In the current work, we tested its ability on anti-hematological tumors and enhanced current treatments with combination therapy, and studied this combination using Chou–Talalay analysis. p53 concentration was measured to evaluate the mechanism of this proposed synergism. The results showed that NDV was synergistic with doxorubicin in low doses on plasmacytoma cells, with no involvement of p53 pathways, but involved p53 when the combination was used on non-Hodgkin lymphoma cells. NDV in combination with rituximab showed enhanced cytotoxicity that was p53-independent. In conclusion, this work proposes a novel combination modality for treatment of some hematological malignancies. PMID:27579294

  12. Outcomes 5 years after response to rituximab therapy in children and adults with immune thrombocytopenia

    PubMed Central

    Mahévas, Matthieu; Lee, Soo Y.; Stasi, Roberto; Cunningham-Rundles, Susanna; Godeau, Bertrand; Kanter, Julie; Neufeld, Ellis; Taube, Tillmann; Ramenghi, Ugo; Shenoy, Shalini; Ward, Mary J.; Mihatov, Nino; Patel, Vinay L.; Bierling, Philippe; Lesser, Martin; Cooper, Nichola; Bussel, James B.

    2012-01-01

    Treatments for immune thrombocytopenic purpura (ITP) providing durable platelet responses without continued dosing are limited. Whereas complete responses (CRs) to B-cell depletion in ITP usually last for 1 year in adults, partial responses (PRs) are less durable. Comparable data do not exist for children and 5-year outcomes are unavailable. Patients with ITP treated with rituximab who achieved CRs and PRs (platelets > 150 × 109/L or 50-150 × 109/L, respectively) were selected to be assessed for duration of their response; 72 adults whose response lasted at least 1 year and 66 children with response of any duration were included. Patients had baseline platelet counts < 30 × 109/L; 95% had ITP of > 6 months in duration. Adults and children each had initial overall response rates of 57% and similar 5-year estimates of persisting response (21% and 26%, respectively). Children did not relapse after 2 years from initial treatment whereas adults did. Initial CR and prolonged B-cell depletion predicted sustained responses whereas prior splenectomy, age, sex, and duration of ITP did not. No novel or substantial long-term clinical toxicity was observed. In summary, 21% to 26% of adults and children with chronic ITP treated with standard-dose rituximab maintained a treatment-free response for at least 5 years without major toxicity. These results can inform clinical decision-making. PMID:22566601

  13. Newcastle disease virus, rituximab, and doxorubicin combination as anti-hematological malignancy therapy.

    PubMed

    Al-Shammari, Ahmed Majeed; Rameez, Huda; Al-Taee, Maha F

    2016-01-01

    Hematological malignancies are important diseases that need more powerful therapeutics. Even with current targeting therapies, such as rituximab and other chemotherapeutic agents, there is a need to develop new treatment strategies. Combination therapy seems the best option to target the tumor cells by different mechanisms. Virotherapy is a very promising treatment modality, as it is selective, safe, and causes cancer destruction. The Iraqi strain of Newcastle disease virus (NDV) has proved to be effective both in vitro and in vivo. In the current work, we tested its ability on anti-hematological tumors and enhanced current treatments with combination therapy, and studied this combination using Chou-Talalay analysis. p53 concentration was measured to evaluate the mechanism of this proposed synergism. The results showed that NDV was synergistic with doxorubicin in low doses on plasmacytoma cells, with no involvement of p53 pathways, but involved p53 when the combination was used on non-Hodgkin lymphoma cells. NDV in combination with rituximab showed enhanced cytotoxicity that was p53-independent. In conclusion, this work proposes a novel combination modality for treatment of some hematological malignancies. PMID:27579294

  14. MRI assessment of suppression of structural damage in patients with rheumatoid arthritis receiving rituximab: results from the randomised, placebo-controlled, double-blind RA-SCORE study

    PubMed Central

    Peterfy, Charles; Emery, Paul; Tak, Paul P; Østergaard, Mikkel; DiCarlo, Julie; Otsa, Kati; Navarro Sarabia, Federico; Pavelka, Karel; Bagnard, Marie-Agnes; Gylvin, Lykke Hinsch; Bernasconi, Corrado; Gabriele, Annarita

    2016-01-01

    Objective To evaluate changes in structural damage and joint inflammation assessed by MRI following rituximab treatment in a Phase 3 study of patients with active rheumatoid arthritis (RA) despite methotrexate (MTX) who were naive to biological therapy. Methods Patients were randomised to receive two infusions of placebo (n=63), rituximab 500 mg (n=62), or rituximab 1000 mg (n=60) intravenously on days 1 and 15. MRI scans and radiographs of the most inflamed hand and wrist were acquired at baseline, weeks 12 (MRI only), 24 and 52. The primary end point was the change in MRI erosion score from baseline at week 24. Results Patients treated with rituximab demonstrated significantly less progression in the mean MRI erosion score compared with those treated with placebo at weeks 24 (0.47, 0.18 and 1.60, respectively, p=0.003 and p=0.001 for the two rituximab doses vs placebo) and 52 (−0.30, 0.11 and 3.02, respectively; p<0.001 and p<0.001). Cartilage loss at 52 weeks was significantly reduced in the rituximab group compared with the placebo group. Other secondary end points of synovitis and osteitis improved significantly with rituximab compared with placebo as early as 12 weeks and improved further at weeks 24 and 52. Conclusions This study demonstrated that rituximab significantly reduced erosion and cartilage loss at week 24 and week 52 in MTX-inadequate responder patients with active RA, suggesting that MRI is a valuable tool for assessing inflammatory and structural damage in patients with established RA receiving rituximab. Trial registration number NCT00578305 PMID:25355728

  15. Rituximab in combination with CODOX-M/IVAC: a retrospective analysis of 23 cases of non-HIV related B-cell non-Hodgkin lymphoma with proliferation index >95%.

    PubMed

    Mohamedbhai, Sajir G; Sibson, Keith; Marafioti, Teresa; Kayani, Irfan; Lowry, Lisa; Goldstone, Anthony H; Linch, David C; Ardeshna, Kirit M

    2011-01-01

    The safety and efficacy of rituximab with CODOX-M/IVAC (cyclophosphamide, doxorubicin, vincristine, methotrexate/ifosfamide, etoposide, high dose cytarabine) was retrospectively analysed in 23 patients with non-human immunodeficiency virus-related B-cell non-Hodgkin lymphoma with proliferation index >95% [14 with classical Burkitt lymphoma (BL), five with B-cell lymphoma unclassifiable, with features intermediate between diffuse large B cell lymphoma (DLBCL) and BL, and four with DLBCL]. Six (26%) low-risk (LR) patients received three cycles of CODOX-M and 17 (74%) high-risk (HR) cases were assigned to four cycles of alternating CODOX-M/IVAC. Rituximab 375 mg/m² was infused on days 1 and 10 of each cycle. Toxicity was comparable to that reported with CODOX-M/IVAC, with no treatment-related death. Two patients developed grade 3 rituximab-induced delayed neutropenia, with no adverse outcome. After completing treatment, 83% LR patients and 71% HR patients achieved CR by positron emission tomography-computerized tomography (PET-CT). Three (13%) patients received salvage treatment. At a median follow-up of 34 months (range = 18-75), 19 (83%) patients (100% LR and 74% HR) were alive, including one case undergoing salvage for late relapse. Four HR patients (17%) had died, three from primary progressive disease and one from treatment-refractory relapse 2 months after achieving CR. These results with R-CODOX-M/R-IVAC compare favourably with existing data using CODOX-M/IVAC and warrant further prospective studies. The potential pitfalls of PET-CT to assess response are highlighted. PMID:21092025

  16. Chemoimmunotherapy for Relapsed/Refractory and Progressive 17p13 Deleted Chronic Lymphocytic Leukemia (CLL) Combining Pentostatin, Alemtuzumab, and Low Dose Rituximab is Effective and Tolerable and Limits Loss of CD20 Expression by Circulating CLL Cells

    PubMed Central

    Zent, Clive S.; Taylor, Ronald P.; Lindorfer, Margaret A.; Beum, Paul V.; LaPlant, Betsy; Wu, Wenting; Call, Timothy G.; Bowen, Deborah A.; Conte, Michael J.; Frederick, Lori A.; Link, Brian K.; Blackwell, Sue E.; Veeramani, Suresh; Baig, Nisar A.; Viswanatha, David S.; Weiner, George J.; Witzig, Thomas E.

    2014-01-01

    Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) patients with purine analogue refractory disease or TP53 dysfunction still have limited treatment options and poor survival. Alemtuzumab containing chemoimmunotherapy regimens can be effective but frequently cause serious infections. We report a phase II trial testing the efficacy and tolerability of a short duration regimen combining pentostatin, alemtuzumab, and low dose high frequency rituximab (PAR) designed to decrease the risk of treatment associated infections and limit loss of CD20 expression by CLL cells. The study enrolled 39 patients with progressive CLL that was either relapsed/refractory (n=36) or previously untreated with 17p13 deletion (17p13-)(n=3). Thirteen (33%) patients had both 17p13- and TP53 mutations predicted to be dysfunctional and eight patients had purine analogue refractory CLL without TP53 dysfunction. Twenty-six (67%) patients completed therapy with only five (13%) patients having treatment limiting toxicity, and no treatment related deaths. Twenty-two (56%) patients responded to treatment with 11 (28%) complete responses (four with incomplete bone marrow recovery). Median progression free survival was 7.2 months, time to next treatment 9.1 months, and overall survival 34.1 months. The majority of deaths (82%) were caused by progressive disease including transformed diffuse large B cell lymphoma (n=6). Correlative studies showed that low dose rituximab activates complement and NK cells without a profound and sustained decrease in expression of CD20 by circulating CLL cells. We conclude that PAR is a tolerable and effective therapy for CLL and that low dose rituximab therapy can activate innate immune cytotoxic mechanisms without substantially decreasing CD20 expression. PMID:24723493

  17. Chemokine/cytokine profiling after rituximab: reciprocal expression of BCA-1/CXCL13 and BAFF in childhood OMS.

    PubMed

    Pranzatelli, Michael R; Tate, Elizabeth D; Travelstead, Anna L; Verhulst, Steven J

    2011-03-01

    The aim of the study was to test the hypothesis that B-cell repopulation following rituximab (anti-CD20) therapy is orchestrated by chemokines and non-chemokine cytokines. Twenty-five children with opsoclonus-myoclonus syndrome (OMS) received rituximab with or without conventional agents. A comprehensive panel of 40 chemokines and other cytokines were measured in serum by ELISA and multiplexed fluorescent bead-based immunoassay. Serum BAFF concentration changed dramatically (even after first infusion) and inversely with B-cell depletion/repopulation and CXCL13 concentration at 1, 3, and 6 months. Negative correlations were found for BAFF concentration vs blood B cell percentage and serum CXCL13 concentration; positive correlations with serum rituximab concentrations. Six months after initiation of therapy, no significant difference in the levels of APRIL, CXCL10, IL-6, or 17 other cytokines/chemokines were detected. These data reveal a major role for BAFF in peripheral B cell repopulation following rituximab-induced B-cell depletion, and novel changes in CXCL13. ClinicalTrials.gov NCT0024436. PMID:21211990

  18. High response rate and durable remissions following fludarabine and rituximab combination therapy for chronic cold agglutinin disease.

    PubMed

    Berentsen, Sigbjørn; Randen, Ulla; Vågan, Anne Marita; Hjorth-Hansen, Henrik; Vik, Anders; Dalgaard, Jakob; Jacobsen, Eva-Marie; Thoresen, Aud S; Beiske, Klaus; Tjønnfjord, Geir E

    2010-10-28

    Most patients diagnosed with primary chronic cold agglutinin disease (CAD) have a clonal lymphoproliferative bone marrow disorder. Treatment with rituximab is the only well-documented effective therapy, leading to 45%-60% partial responses (PR). Complete responses (CR) are rare, and median response duration is only 11 months. In a prospective multicenter trial, 29 patients received rituximab 375 mg/m(2) on days 1, 29, 57 and 85; and fludarabine orally, 40 mg/m(2) on days 1-5, 29-34, 57-61 and 85-89. Twenty-two patients (76%) responded, 6 (21%) achieving CR and 16 (55%) PR. Among 10 patients nonresponsive to rituximab monotherapy, 1 achieved CR and 6 PR. Median increase in hemoglobin level was 3.1 g/dL among the responders and 4.0 g/dL in those who achieved CR. Lower quartile of response duration was not reached after 33 months. Estimated median response duration was more than 66 months. Grade 3-4 hematologic toxicity occurred in 12 patients (41%). In conclusion, fludarabine and rituximab combination therapy is very efficient in patients with CAD. Toxicity may be a concern, and benefits should be carefully weighed against risks in very old and comorbid patients. It remains to be established whether the combination should be first-line or an efficient second-line therapy in CAD patients requiring treatment. PMID:20634373

  19. Standard Operating Procedure for Prospective Individualised Dosimetry for ([131])I-rituximab Radioimmunotherapy of Non-Hodgkin's Lymphoma.

    PubMed

    Calais, Phillipe J; Turner, J Harvey

    2012-09-01

    Radioimmunotherapy (RIT) is an attractive therapy for non-Hodgkin's lymphoma (NHL) as it allows targeted tumor irradiation which provides a cytotoxic effect significantly greater than that of the immune-mediated effects of a non-radioactive, or 'cold', antibody alone. Anti-CD20 antibodies such as rituximab are ideal for RIT, as not only is it easily iodinated, but the CD20 antigen is found on more than 95% of B-cell NHL. A standard operating procedure (SOP) has been formulated for personalized prospective dosimetry for safe, effective outpatient (131)I-rituximab RIT of NHL. Over five years, experience of treatment of outpatients with (131)I-rituximab was analyzed with respect to critical organ radiation dose in patients and radiation exposure of their carers. This radiation safety methodology has been refined; and offers the potential for safe, practical application to outpatient (131)I-rituximab RIT of lymphoma in general and in developing countries in particular. Given endorsement and sanction of this SOP by local regulatory authorities the personalized dosimetry paradigm will facilitate incorporation of RIT into the routine clinical practice of therapeutic nuclear oncology worldwide. PMID:23372448

  20. Plitidepsin (Aplidin) is a potent inhibitor of diffuse large cell and Burkitt lymphoma and is synergistic with rituximab.

    PubMed

    Barboza, Nora M; Medina, Daniel J; Budak-Alpdogan, Tulin; Aracil, Miguel; Jimeno, José M; Bertino, Joseph R; Banerjee, Debabrata

    2012-01-15

    Plitidepsin (Aplidin), an antitumor agent of marine origin, presently is undergoing phase II/III clinical trials, and has shown promise for the treatment of lymphoma. Here, we describe the antitumor effects of plitidepsin alone and in combination with rituximab and investigated the effects of each drug and the combination on the cell cycle and mechanism of cell death. Several Diffuse Large Cell Lymphoma (DLCL) lines and Burkitt cell lines were tested for sensitivity to plitidepsin and rituximab. All DLCL and Burkitt lymphoma cell lines were inhibited by plitidepsin in nanomolar concentrations, while rituximab sensitivity varied among different cell lines. Ramos and the RL cell lines proved sensitive to rituximab and were used to test the effects of each of the two drugs. The two agents exhibited synergism at all tested concentrations. For in vivo studies, irradiated athymic nude mice were engrafted with the Ramos lymphoma. Treatment was initiated when the tumors were ~0.5 cm in diameter, and toxic and therapeutic effects were monitored. In the in vivo study, additive effects of the combined two drugs, was demonstrated without an increase in host toxicity. The in vitro synergy and the in vivo additive antitumor effects without an increase in host toxicity with two relatively non-marrow suppressive agents encourages further development of this combination for treatment of aggressive B-cell lymphomas. PMID:22336911

  1. A phase II trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701

    PubMed Central

    Grant, Barbara W.; Jung, Sin-Ho; Johnson, Jeffrey L.; Kostakoglu, Lale; His, Eric; Byrd, John C.; Jones, Jeffrey; Leonard, John P.; Martin, S. Eric; Cheson, Bruce D.

    2013-01-01

    Rituximab combined with chemotherapy has improved the survival of previously untreated patients with follicular lymphoma (FL). Nevertheless, many patients neither want nor can tolerate chemotherapy, leading to interest in biological approaches. Epratuzumab is a humanized anti-CD22 monoclonal antibody with efficacy in relapsed FL. Since both rituximab and epratuzumab have single agent activity in FL, we evaluated the antibody combination as initial treatment of patients with FL. Patients and Methods Fifty-nine untreated patients with FL received epratuzumab 360 mg/m2 with rituximab 375 mg/m2 weekly for four induction doses. This combination was continued as extended induction in weeks 12, 20, 28, and 36. Response assessed by CT was correlated with clinical risk factors, FDG-PET findings at week 3, Fcg polymorphisms, immunohistochemical markers, and statin use. Results Therapy was well-tolerated with toxicities similar to expected with rituximab monotherapy. Fifty-two (88.2%) evaluable patients responded, including 25 complete responses (CR)(42.4%), and 27 partial responses (45.8%). At 3 years follow-up, 60% of patients remain in remission. Follicular Lymphoma International Prognostic Index (FLIPI) risk strongly predicted progression-free survival (p=0.022). Conclusions The high response rate and prolonged time to progression observed with this antibody combination are comparable to those observed after standard chemo-immunotherapies and further support the development of biologic, non-chemotherapeutic approaches for these patients. PMID:23922187

  2. Paraneoplastic pemphigus and myasthenia gravis, associated with inflammatory pseudotumor-like follicular dendritic cell sarcoma: response to rituximab.

    PubMed

    Wang, Lifang; Deng, Hui; Mao, Mei

    2016-08-01

    Paraneoplastic pemphigus (PNP) is an autoimmune blistering disease associated with neoplasms. The disease is most commonly of lymphoproliferative origin and presents high mortality. We describe a patient with PNP and myasthenia gravis associated with inflammatory pseudotumor-like follicular dendritic cell sarcoma, as well as the response to rituximab. PMID:27525088

  3. Prolonged B Cell Depletion With Rituximab is Effective in Treating Refractory Pulmonary Granulomatous Inflammation in Granulomatosis With Polyangiitis (GPA)

    PubMed Central

    Henderson, Scott R.; Copley, Susan J.; Pusey, Charles D.; Ind, Philip W.; Salama, Alan D.

    2014-01-01

    Abstract Pulmonary nodule formation is a frequent feature of granulomatosis with polyangiitis (GPA). Traditional induction therapy includes methotrexate or cyclophosphamide, however, pulmonary nodules generally respond slower than vasculitic components of disease. Efficacy of rituximab (RTX) solely for the treatment of pulmonary nodules has not been assessed. In this observational cohort study, we report patient outcomes with RTX in GPA patients with pulmonary nodules who failed to achieve remission following conventional immunosuppression. Patients (n = 5) with persistent pulmonary nodules were identified from our clinic database and retrospectively evaluated. Systemic manifestations, inflammatory markers, disease activity, concurrent immunosuppression, and absolute B cell numbers were recorded pre-RTX and at 6 monthly intervals following treatment. Chest radiographs at each time point were scored by an experienced radiologist, blinded to clinical details. Five patients with GPA and PR3-ANCA were evaluated (2 male, 3 female), mean age 34 (22–52) years. Pulmonary nodules (median 4, range 2–6), with or without cavitation were present in all patients. RTX induced initial B cell depletion (<5 cells/μL) in all patients but re-population was observed in 3 patients. Repeated RTX treatment in these 3 and persistent B cell depletion in the whole cohort was associated with further significant radiological improvement. Radiographic scoring at each time interval showed reduction in both number of nodules (P = <0.0001) and largest nodule diameter (P = <0.0001) in all patients for at least 18 months following B cell depletion. In summary, RTX therapy induces resolution of pulmonary granulomatous inflammation in GPA following prolonged B cell depletion. PMID:25501085

  4. Assessment of flares in lupus patients enrolled in a phase II/III study of rituximab (EXPLORER).

    PubMed

    Merrill, Jt; Buyon, Jp; Furie, Ra; Latinis, Km; Gordon, C; Hsieh, H-J; Brunetta, P

    2011-06-01

    The EXPLORER study was designed to assess the response to rituximab versus placebo in patients with moderate to severe extrarenal systemic lupus erythematosus (SLE) receiving background immunosuppression. The definition of response required reduced clinical activity without subsequent flares over 52 weeks, and the study did not meet its efficacy endpoint. The current exploratory analysis assessed flare rates in patients who achieved initial low disease activity response (British Isles Lupus Assessment Group [BILAG] C or better in all organs) during the study. Exploratory reanalysis of data from the EXPLORER trial was conducted, considering alternative definitions for flare. No difference was found between rituximab and placebo in preventing or delaying moderate to severe flares. However, when severe (BILAG A) flares alone were examined, rituximab reduced the risk of a subsequent first A flare (hazard ratio = 0.61; p = 0.052) and lowered mean ± SD annualized A flare rates (0.86 ± 1.47 vs. 1.41 ± 2.14; p = 0.038). Eighty-four (49.7%) rituximab-treated patients achieved low disease activity without subsequent A flares versus 31 (35.2%) placebo-treated patients (p = 0.027). Prednisone rescue for A flares was similar in rituximab- (24%) and placebo-treated (14%) patients (p = 0.204). This post hoc analysis evaluates the hypothesis that assessment of BILAG A flares may distinguish potential treatment effects with greater sensitivity than assessment of BILAG B flares. PMID:21478286

  5. Depletion of B‐Cells With Rituximab Improves Endothelial Function and Reduces Inflammation Among Individuals With Rheumatoid Arthritis

    PubMed Central

    Hsue, Priscilla Y.; Scherzer, Rebecca; Grunfeld, Carl; Imboden, John; Wu, Yuaner; del Puerto, Gus; Nitta, Elaine; Shigenaga, Judy; Schnell Heringer, Amanda; Ganz, Peter; Graf, Jonathan

    2014-01-01

    Background Individuals with rheumatoid arthritis (RA) are at increased risk for cardiovascular disease, partly due to systemic inflammation and endothelial dysfunction. B‐cells play an important pathogenic role in the inflammatory process that drives RA disease activity. Rituximab, a chimeric murine/human monoclonal antibody that depletes B‐cells, is an effective therapy for RA. The purpose of this study was to determine whether B‐cell depletion with rituximab reduces systemic inflammation and improves macrovascular (brachial artery flow‐mediated dilation, FMD) and microvascular (reactive hyperemia) endothelial function in RA patients. Methods and Results RA patients received a single course of rituximab (1000 mg IV infusion at baseline and on day 15). FMD, reactive hyperemia, inflammatory markers, and clinical assessments were performed at baseline, week 12, and week 24. Twenty patients (95% female, median age 54 years) completed the study. Following treatment, FMD improved from a baseline of 4.5±0.4% to 6.4±0.6% at 12 weeks (mean±SE; P<0.0001), followed by a decline at week 24; a similar pattern was observed for hyperemic velocity. Significant decreases in RA disease scores, high‐sensitivity C‐reactive protein, erythrocyte sedimentation rate, and circulating CD19+ B‐cells were sustained through week 24. Cholesterol and triglycerides became significantly although modestly elevated during the study. Conclusions Depletion of B‐cells with rituximab improved macrovascular and microvascular endothelial function and reduced systemic inflammation, despite modest elevation in lipids. Given these results, rituximab should be evaluated in the future for its possible role in reducing excess cardiovascular risk in RA. Clinical Trial Registration URL http://ClinicalTrials.gov. Unique identifier: NCT00844714. PMID:25336464

  6. Diminishing prognostic role of preexisting diabetes mellitus for patients with diffuse large B-cell lymphoma in the rituximab era.

    PubMed

    Lu, Hsueh-Ju; Huang, Yu-Chung; Liu, Chun-Yu; Hung, Man-Hsin; Hu, Ming-Hung; Wu, Chia-Yun; Hong, Ying-Chung; Hsiao, Liang-Tsai; Gau, Jyh-Pyng; Liu, Jin-Hwang; Hsu, Hui-Chi; Chiou, Tzeon-Jye; Tzeng, Cheng-Hwai; Yu, Yuan-Bin

    2013-11-01

    Rituximab reforms the treatment of diffuse large B-cell lymphoma (DLBCL) and the prognostic significance of baseline patient features should be reevaluated. Few population-based studies have investigated the association of diabetes mellitus (DM) and outcomes of lymphoma; however, the results remain inconclusive. From January 1, 2000 to December 31, 2009, a total of 468 consecutive newly diagnosed DLBCL patients receiving first-line chemotherapy with cyclophosphamide, vincristine, doxorubicin, and prednisolone (CHOP) or rituximab plus CHOP (R-CHOP) were enrolled. Pre-existing DM was defined according to medical history, use of antidiabetic medications, or any record of an abnormal hemoglobin A1c test. Progression-free survival (PFS) and overall survival (OS) were estimated and compared using the Kaplan-Meier method with a log-rank test. CHOP was administered in 194 patients, and 274 patients received R-CHOP. DM was identified in 16.2 % (76/468) of patients. Diabetic patients were older and more performance restricted, compared to the non-DM patients in both the CHOP and R-CHOP groups. In the CHOP group, 5-year PFS and OS were inferior in DM patients (PFS, 32.4 vs. 50.0 % (P = 0.039); OS, 38.2 vs. 62.5 % (P = 0.002)). However, outcomes were similar for both DM and non-DM patients in the context of R-CHOP treatment (PFS, 69.0 vs. 57.3 % (P = 0.179); OS, 76.2 vs. 69.8 % (P = 0.586)). The response rate of chemotherapy in DM patients was also improved to a level similar to non-DM patients with rituximab use. In conclusion, the prognostic significance of preexisting DM in DLBCL patients is changing in the rituximab era. The potentially additional benefit of rituximab in DM patients merits further investigation. PMID:23712292

  7. Long-Term Maintenance Therapy Using Rituximab-Induced Continuous B-Cell Depletion in Patients with ANCA Vasculitis

    PubMed Central

    Pendergraft, William F.; Cortazar, Frank B.; Wenger, Julia; Murphy, Andrew P.; Rhee, Eugene P.; Laliberte, Karen A.; Niles, John L.

    2014-01-01

    Background and objectives Remission in the majority of ANCA vasculitis patients is not sustained after a single course of rituximab, and risk of relapse warrants development of a successful strategy to ensure durable remission. Design, setting, participants, & measurements A retrospective analysis of ANCA vasculitis patients who underwent maintenance therapy using rituximab-induced continuous B-cell depletion for up to 7 years was performed. Maintenance therapy with rituximab was initiated after achieving remission or converting from other prior maintenance therapy. Continuous B-cell depletion was achieved in all patients by scheduled rituximab administration every 4 months. Disease activity, serologic parameters, adverse events, and survival were examined. Results In the study, 172 patients (mean age=60 years, 55% women, 57% myeloperoxidase–ANCA) treated from April of 2006 to March of 2013 underwent continuous B-cell depletion with rituximab. Median remission maintenance follow-up time was 2.1 years. Complete remission (Birmingham Vasculitis Activity Score [BVAS]=0) was achieved in all patients. Major relapse (BVAS≥3) occurred in 5% of patients and was associated with weaning of other immunosuppression drugs. Remission was reinduced in all patients. Survival mirrored survival of a general age-, sex-, and ethnicity-matched United States population. Conclusion This analysis provides evidence for long-term disease control using continuous B-cell depletion. This treatment strategy in ANCA vasculitis patients also seems to result in survival rates comparable with rates in a matched reference population. These findings suggest that prospective remission maintenance treatment trials using continuous B-cell depletion are warranted. PMID:24626432

  8. A multicenter randomized open-label study of rituximab plus rhTPO vs rituximab in corticosteroid-resistant or relapsed ITP

    PubMed Central

    Zhou, Hai; Xu, Miao; Qin, Ping; Zhang, Hai-yan; Yuan, Cheng-lu; Zhao, Hong-guo; Cui, Zhong-guang; Meng, Yue-sheng; Wang, Lei; Zhou, Fang; Wang, Xin; Li, Da-qi; Bi, Ke-hong; Zhu, Chuan-sheng; Guo, Cheng-shan; Chu, Xiao-xia; Wu, Qing-chao; Liu, Xin-guang; Dong, Xiao-yuan; Li, Jie; Peng, Jun

    2015-01-01

    This study aimed to compare the efficacy and safety of rituximab (RTX) plus recombinant human thrombopoietin (rhTPO) with RTX alone in patients with immune thrombocytopenia (ITP) who had failed to respond to corticosteroids or relapsed. Recruited patients were randomized at a ratio of 2:1 into 2 groups: the combination group (RTX + rhTPO, n = 77) and the monotherapy group (RTX, n = 38). Overall response was achieved in 79.2% of patients in the combination group vs 71.1% in the monotherapy group (P = .36), and the complete response (CR) rate was 45.4% in the combination group compared with 23.7% in the monotherapy group (P = .026). The combination group had significantly shorter time to response (TTR; median and range, 7 and 4-28 days) compared with the monotherapy group (28 and 4-90 days) (P < .01). There was no difference between these 2 groups in terms of the long-term response (P = .12). Our findings demonstrated that the combination of RTX and rhTPO significantly increased the CR rate and shortened TTR compared with RTX monotherapy in the treatment of corticosteroid-resistant or relapsed ITP but failed to show a beneficial effect on the long-lasting response. This study is registered at www.clinicaltrials.gov as #NCT01525836. PMID:25575541

  9. Corticosteroid-Free Primary Treatment of Chronic Extensive Graft-versus-Host Disease Incorporating Rituximab.

    PubMed

    Solomon, Scott R; Sizemore, Connie A; Ridgeway, Michelle; Zhang, Xu; Smith, Judith; Brown, Stacey; Holland, H Kent; Morris, Lawrence E; Bashey, Asad

    2015-09-01

    Chronic graft-versus-host disease (cGVHD) is a significant determinant of overall outcome and quality of life in survivors of allogeneic hematopoietic cell transplantation. Standard initial therapy of cGVHD is based on prolonged use of corticosteroids and a calcineurin inhibitor and has not changed for over 3 decades, despite limited efficacy and long-term toxicity. Rituximab is an attractive agent for the upfront treatment of cGVHD because of its favorable toxicity profile, efficacy in steroid-refractory cGVHD, and ability to serve as a steroid-sparing agent in autoimmune diseases. We hypothesized that a corticosteroid-free regimen incorporating rituximab would result in improved outcomes when used for the initial treatment of cGVHD. Twenty-five patients (median age, 56 years; range, 29 to 77) with extensive cGVHD were enrolled on a prospective phase II trial. Enrollment was limited to patients with first onset extensive cGVHD requiring systemic immunosuppression and without residual or concurrent acute graft-versus-host disease. cGVHD was classified as de novo, interrupted, and progressive in 12, 11, and 2 patients, respectively. cGVHD severity (National Institutes of Health grade) was mild, moderate, and severe in 3, 14, and 8 patients, respectively. All patients received rituximab 375 mg/m(2) × 4 weekly doses, then 1 dose every 3 months × 4 doses, in addition to mycophenolate mofetil and either tacrolimus or sirolimus. No other systemic immunosuppression was permitted, and only a short-course of steroids (≤4 weeks) was allowed at physician discretion; otherwise, treatment was deemed a failure and patients were treated off study. Twenty-two of 25 patients (88%) responded to treatment. Of the 22 responding patients, the median time to maximum response was 161 days (range, 35 to 300 days) with maximum response being complete in 21 of 22 patients and partial in 1 patient. Excluding the 3 patients taken off study for treatment failure, corticosteroids were used

  10. Successful use of rituximab in refractory idiopathic thrombocytopenic purpura in a patient with common variable immunodeficiency.

    PubMed

    Al-Ahmad, M; Al-Rasheed, M; Al-Muhani, A

    2010-01-01

    Idiopathic thrombocytopenic purpura (ITP) is a common autoimmune disease in patients with common variable immunodeficiency (CVID). We describe a 36-year-old woman with CVID. The clinical course of her disease was complicated by bronchiectasis, antiphospholipid antibody syndrome, and portal vein thrombosis. She developed recurrent attacks of ITP refractory to high doses of corticosteroid, intravenous immunoglobulin (IVIG), and splenectomy. She received a total of 5 doses of rituximab (375 mg/m2) and achieved an immediate and persistent response. Therapy was well tolerated. Her platelet count remained above 370,000/microL for 8 months of follow-up, despite repeated infections. During this period the patient remained off corticosteroids and on continuous IVIG replacement therapy. PMID:20635793

  11. Clopidogrel-induced refractory thrombotic thrombocytopenic purpura successfully treated with rituximab.

    PubMed

    Khodor, Sara; Castro, Miguel; McNamara, Colin; Chaulagain, Chakra P

    2016-06-01

    Thrombotic thrombocytopenic purpura (TTP) is a multisystem disorder characterized by microvascular aggregation of platelets and fibrin strands causing thrombocytopenia, microangiopathic hemolytic anemia, and organ dysfunction. TTP can develop as a result of a deficiency in ADAMTS13 enzyme activity due to either a genetic defect or, more commonly, the development of anti-ADAMTS13 autoantibodies. TTP can also be associated with pregnancy, organ transplant, lupus, infections, and drugs. Here, we present a case of TTP that developed shortly after the start of clopidogrel treatment for acute ischemic stroke and acute myocardial infarction, and describe the clinical presentation, refractory course of the disease, and successful induction of remission through the use of rituximab in a setting of pre-existing autoimmune diseases. PMID:26684918

  12. Rituximab for the Treatment of Relapses in ANCA-associated Vasculitis

    PubMed Central

    Miloslavsky, EM; Specks, U; Merkel, PA; Seo, P; Spiera, R; Langford, CA; Hoffman, GS; Kallenberg, CGM; St. Clair, EW; Tchao, NK; Viviano, L; Ding, L; Ikle, D; Villarreal, M; Jepson, B; Brunetta, P; Allen, NB; Fervenza, FC; Geetha, D; Keogh, K; Kissin, EY; Monach, PA; Peikert, T; Stegeman, C; Ytterberg, SR; Stone, JH

    2014-01-01

    Introduction Disease relapses are frequent in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). We evaluated the outcomes of patients re-treated with rituximab (RTX) and prednisone for severe disease relapses. Methods The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After achieving remission, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a pre-specified protocol. Investigators remained blinded to the original treatment assignment. Results Twenty-six patients received treatment with RTX for disease relapse after initially achieving remission on their originally assigned treatment. Fifteen patients were initially randomized to RTX and 11 to CYC/AZA. Thirteen (87%) of the patients originally assigned to RTX and 10 (91%) originally assigned to CYC/AZA achieved remission again with open-label RTX, an overall percentage of 88%. Half of the patients treated with open-label RTX were able to discontinue prednisone entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events/patient-year versus 11.8 adverse events/patient-year, respectively). Conclusion Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment. PMID:25047592

  13. Rituximab Injection

    MedlinePlus

    ... with another medication to treat the symptoms of rheumatoid arthritis (RA; a condition in which the body attacks ... and CLL by killing cancer cells. It treats rheumatoid arthritis, granulomatosis with polyangiitis, and microscopic polyangiitis by blocking ...

  14. Rituximab Injection

    MedlinePlus

    ... a condition in which the body attacks its own joints, causing pain, swelling, and loss of function) ... are conditions in which the body attacks its own veins and other blood vessels, which causes damage ...

  15. 90-yttrium-ibritumomab tiuxetan consolidation of fludarabine, mitoxantrone, rituximab in intermediate/high-risk follicular lymphoma: updated long-term results after a median follow-up of 7 years.

    PubMed

    Casadei, Beatrice; Pellegrini, Cinzia; Pulsoni, Alessandro; Annechini, Giorgia; De Renzo, Amalia; Stefoni, Vittorio; Broccoli, Alessandro; Gandolfi, Letizia; Quirini, Federica; Tonialini, Lorenzo; Morigi, Alice; Argnani, Lisa; Zinzani, Pier Luigi

    2016-06-01

    Radioimmunotherapy (RIT) after an induction phase with conventional chemoimmunotherapy became an attractive strategy of consolidation for patients with advanced follicular lymphoma: in particular, in many studies RIT was represented by yttrium-90-ibritumomab tiuxetan ((90) Y-IT). Independently by the different front-line treatment, updates on the long-term follow-up of these studies are needed because the disease course of follicular lymphoma is characterised by multiple relapses and progressively shorter durations of response. We report updated long-term efficacy and toxicity results of a multicenter phase II study on sequential treatment with four cycles of fludarabine, mitoxantrone, and rituximab followed by (90) Y-IT as front-line therapy for untreated patients with intermediate/high-risk follicular lymphoma. With a median follow-up of 84 months, only 19/49 (38.8%) complete response patients relapsed, yielding an estimated long-term disease-free survival of 62.6%. The 7-year overall survival was 72.7%. Four (7.3%) second acute myeloid leukemia occurred, with a median time following RIT of 42 months. A relevant patients' responsiveness to subsequent therapies occurred: approximately 65% of relapsed patients obtained a good clinical response after the second-line treatment. These data represented the first evidence of a real role even in the long period of 90Y-IT after a fludarabine-containing regimen plus rituximab in the treatment of high-risk follicular lymphoma. PMID:26990782

  16. Bendamustine in combination with rituximab for elderly patients with previously untreated B-cell chronic lymphocytic leukemia: A retrospective analysis of real-life practice in Italian hematology departments.

    PubMed

    Laurenti, Luca; Innocenti, Idanna; Autore, Francesco; Vannata, Barbara; Efremov, Dimitar G; Ciolli, Stefania; Del Poeta, Giovanni; Mauro, Francesca Romana; Cortelezzi, Agostino; Borza, Paola Anticoli; Ghio, Francesco; Mondello, Patrizia; Murru, Roberta; Gozzetti, Alessandro; Cariccio, Maria Rosa Lanza; Piccirillo, Nicola; Boncompagni, Riccardo; Cantonetti, Maria; Principe, Maria Ilaria Del; Reda, Gianluigi; Bongarzoni, Velia; Cervetti, Giulia; Pitini, Vincenzo; Foà, Robin; Sica, Simona; D'Arena, Giovanni

    2015-10-01

    The front-line therapy for CLL young and fit patients is chemo-immunotherapy with fludarabine-cyclophosphamide-rituximab (FCR). FCR regimen results in a significant myelosuppression and high rates of early and late infections especially in elderly patients. German CLL study group compared FCR vs. bendamustine-rituximab (BR) in fit untreated patients. The response rates with BR or FCR were comparable, BR could be an alternative 1st-line treatment for elderly patients. Here we report retrospective data of 70 elderly (≥65 years) CLL patients from 12 Italian centers treated with BR as front-line therapy. The primary end points were overall response rate (complete remission/partial remission) and safety. Forty-seven males and 23 females, with a median age of 72 years, were included in the study. Eight patients were unfit for CIRS. The OR rate was 88.6% (31.4% CR and 57.2% PR). Progression free survival, treatment free survival and overall survival rates at 2-years were 79%, 90.3% and 89.6%, respectively. Only del17 was independent unfavorable parameter on the response rate and PFS. Our results indicate that BR front-line at standard dose provides a high response rate with a good safety profile, even if more than 50% of patients experienced a bendamustine dose reduction until 70 mg/m2. PMID:26307523

  17. Rituximab does not improve clinical outcome in a randomized phase 3 trial of CHOP with or without rituximab in patients with HIV-associated non-Hodgkin lymphoma: AIDS-Malignancies Consortium Trial 010

    PubMed Central

    Kaplan, Lawrence D.; Lee, Jeannette Y.; Ambinder, Richard F.; Sparano, Joseph A.; Cesarman, Ethel; Chadburn, Amy; Levine, Alexandra M.; Scadden, David T.

    2005-01-01

    The addition of rituximab to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy results in significant improvement in clinical outcome for individuals with non–HIV-associated aggressive B-cell lymphoma. To assess the potential risks and benefits of the addition of rituximab to CHOP for HIV-associated non-Hodgkin lymphoma (HIV-NHL) 150 patients receiving CHOP for HIV-NHL were randomized (2:1) to receive 375 mg/m2 rituximab with each chemotherapy cycle (n = 99) or no immunotherapy (n = 50) in a multicenter phase 3 trial. The complete response rate (CR + CRu) was 57.6% for R-CHOP and 47% for CHOP (P = .147). With a median follow-up of 137 weeks, time to progression, progression-free survival, and overall survival times were 125, 45, and 139 weeks, respectively, for R-CHOP and 85, 38, and 110 weeks, respectively, for CHOP (P = not significant, all comparisons). Treatment-related infectious deaths occurred in 14% of patients receiving R-CHOP compared with 2% in the chemotherapy-alone group (P = .035). Of these deaths, 60% occurred in patients with CD4 counts less than 50/mm3. Progression-free survival was significantly influenced by CD4+ count (P < .001) and International Prognostic Index score (P = .022), but not bcl-2 status. The addition of rituximab to CHOP in patients with HIV-NHL may be associated with improved tumor responses. However, these benefits may be offset by an increase in infectious deaths, particularly in those individuals with CD4+ lymphocyte counts less than 50/mm3. PMID:15914552

  18. An update on the evidence for the efficacy and safety of rituximab in the management of neuromyelitis optica

    PubMed Central

    Collongues, Nicolas; de Seze, Jérôme

    2016-01-01

    Neuromyelitis optica spectrum disorders (NMOSDs) is a new concept which includes classical neuromyelitis optica (NMO) and partial forms of NMO such as recurrent optic neuritis with positive aquaporin-4 antibodies (AQP4) or brainstem symptoms (intractable hiccups or vomiting). This disease is clearly distinguished from multiple sclerosis (MS) and the therapeutic approach is clearly different. Rituximab is actually considered to be one of the most efficient treatments of NMOSD, even if class I studies are clearly lacking. In the present review, we describe the state of the art about rituximab treatment in NMOSD, including adults and children, plus its efficacy and tolerance and we also underline the questions that should be addressed in the near future. PMID:27134673

  19. An update on the evidence for the efficacy and safety of rituximab in the management of neuromyelitis optica.

    PubMed

    Collongues, Nicolas; de Seze, Jérôme

    2016-05-01

    Neuromyelitis optica spectrum disorders (NMOSDs) is a new concept which includes classical neuromyelitis optica (NMO) and partial forms of NMO such as recurrent optic neuritis with positive aquaporin-4 antibodies (AQP4) or brainstem symptoms (intractable hiccups or vomiting). This disease is clearly distinguished from multiple sclerosis (MS) and the therapeutic approach is clearly different. Rituximab is actually considered to be one of the most efficient treatments of NMOSD, even if class I studies are clearly lacking. In the present review, we describe the state of the art about rituximab treatment in NMOSD, including adults and children, plus its efficacy and tolerance and we also underline the questions that should be addressed in the near future. PMID:27134673

  20. [Successful treatment with rituximab in a patient with splenic marginal zone B-cell lymphoma accompanied by cold agglutinin disease].

    PubMed

    Yasuyama, Masako; Kawauchi, Kiyotaka; Otsuka, Kuniaki; Tamura, Hiroyuki; Fujibayashi, Mariko

    2014-01-01

    An 81-year-old man was admitted to our hospital due to dyspnea in July 2008. A physical examination revealed marked splenomegaly, and the results of laboratory tests were as follows: hemoglobin (Hb)=7.0 g/dL, Ret=6.4%, WBC=24,100/μL (Ly: 20,003/μL), indirect bilirubin=3.6 mg/dL, LDH=232 IU/L. The cold agglutinin titer was 1 : 8,192, and a direct antiglobulin test was positive. A PET scan showed abnormal accumulation in the spleen and bone marrow. A bone marrow aspirate examination and biopsy demonstrated diffuse involvement of abnormal lymphocytes that were found to be positive for CD20 and negative for CD5, CD10, and cyclin D1. The immunoglobulin genes were clonally rearranged. Based on these findings, splenic marginal zone B-cell lymphoma (SMZL) associated with cold agglutinin disease (CAD) was diagnosed. Because the patient refused splenectomy, he was treated with four cycles of rituximab therapy (375 mg/kg, once a week). The Hb level and lymphocyte count subsequently normalized and the splenomegaly resolved. One year later, he relapsed and was again treated with rituximab therapy with complete remission. CAD accompanied by SMZL is very rare. Rituximab may be chosen as an alternative and effective therapeutic option in patients with SMZL-particularly those with autoimmune hemolytic anemia. PMID:25749330

  1. Phase II trial of weekly bortezomib in combination with rituximab in untreated patients with Waldenström Macroglobulinemia.

    PubMed

    Ghobrial, Irene M; Xie, Wanling; Padmanabhan, Swaminathan; Badros, Ashraf; Rourke, Meghan; Leduc, Renee; Chuma, Stacey; Kunsman, Janet; Warren, Diane; Poon, Tiffany; Harris, Brianna; Sam, Amy; Anderson, Kenneth C; Richardson, Paul G; Treon, Steven P; Weller, Edie; Matous, Jeffrey

    2010-09-01

    This study aimed to determine the activity and safety of weekly bortezomib and rituximab in patients with untreated Waldenström Macroglobulinemia (WM). Patients with no prior therapy and symptomatic disease were eligible. Patients received bortezomib IV weekly at 1.6 mg/m(2) on days 1, 8, 15, q 28 days × 6 cycles, and rituximab 375 mg/m(2) weekly on cycles 1 and 4. Primary endpoint was the percent of patients with at least a minor response (MR). Twenty-six patients were treated. At least MR was observed in 23/26 patients (88%) (95% CI: 70-98%) with 1 complete response (4%), 1 near-complete response (4%), 15 partial remission (58%), and 6 MR (23%). Using IgM response evaluated by nephlometry, all 26 patients (100%) achieved at least MR or better. The median time to progression has not been reached, with an estimated 1-year event free rate of 79% (95% CI: 53, 91%). Common grade 3 and 4 therapy related adverse events included reversible neutropenia in 12%, anemia in 8%, and thrombocytopenia in 8%. No grade 3 or 4 neuropathy occurred. The combination of weekly bortezomib and rituximab exhibited significant activity and minimal neurological toxicity in patients with untreated WM. PMID:20652865

  2. Clinical experience with lenalidomide alone or in combination with rituximab in indolent B-cell and mantle cell lymphomas.

    PubMed

    Ruan, J; Shah, B; Martin, P; Schuster, S J

    2016-07-01

    Lenalidomide is an oral immunomodulatory drug with significant activity in indolent B-cell and mantle cell lymphomas. Lenalidomide has a manageable safety profile whether administered as a single agent or in combination with rituximab. The combination of lenalidomide with rituximab, known as the 'R(2)' regimen, enhances efficacy over what has been shown with monotherapy and has demonstrated activity in patients considered resistant to rituximab. Tolerability of these regimens has been consistent among studies. Asymptomatic neutropenia is the most common grade 3/4 adverse event, typically managed by dose interruption, followed by dose reduction once neutrophils have recovered. Nonhematologic toxicities (e.g. fatigue) are generally low-grade, manageable with concomitant treatment, and/or lenalidomide dose modification. More frequent with R(2), immune-related symptoms such as rash and tumor flare are important to recognize as lenalidomide-associated treatment effects in patients with lymphoma who require supportive care and potential dose modifications. Severe tumor flare reactions with painful lymphadenopathy are not typically observed outside of chronic lymphocytic leukemia/small lymphocytic lymphoma. Venous thromboembolism is uncommon in lymphomas, though prophylaxis is recommended. The general safety profile, differences between lenalidomide monotherapy and R(2) treatment, and optimal strategies for managing adverse events are discussed here. PMID:27052651

  3. Low-Dose Rituximab Therapy for Antibody-Mediated Rejection in a Highly Sensitized Heart-Transplant Recipient

    PubMed Central

    Aggarwal, Ashim; Pyle, Joseph; Hamilton, John; Bhat, Geetha

    2012-01-01

    Antibody-mediated rejection is the B-cell–mediated production of immunoglobulin G antibody against the transplanted heart. The currently available therapies for antibody-mediated rejection have had marginal success, and chronic manifestations of rejection can result in an increased risk of graft vasculopathy and perhaps require repeat transplantation. Rituximab, a monoclonal antibody directed against the CD20 receptor of B-lymphocytes and approved as therapy for lymphoma, can be used in heart-transplant patients for the management of antibody-mediated rejection. We present the case of a 52-year-old woman with high allosensitization (pre-transplantation panel reactive antibody level, 72%) who underwent successful orthotopic heart transplantation. Postoperatively, her acute antibody-mediated rejection with concomitant cellular rejection was successfully treated with low-dose rituximab. The patient died 5 months later because of multiple other medical problems. The present case suggests a role for low-dose rituximab as therapy for antibody-mediated rejection in heart-transplant patients. PMID:23304051

  4. Rituximab extended schedule or retreatment trial for low tumour burden non-follicular indolent B-cell non-Hodgkin lymphomas: Eastern Cooperative Oncology Group Protocol E4402.

    PubMed

    Williams, Michael E; Hong, Fangxin; Gascoyne, Randy D; Wagner, Lynne I; Krauss, John C; Habermann, Thomas M; Swinnen, Lode J; Schuster, Stephen J; Peterson, Christopher G; Sborov, Mark D; Martin, S Eric; Weiss, Matthias; Ehmann, W Christopher; Horning, Sandra J; Kahl, Brad S

    2016-06-01

    The rituximab extended schedule or retreatment trial (RESORT; E4402) was a phase 3 randomized prospective trial comparing maintenance rituximab (MR) versus a retreatment (RR) dosing strategy in asymptomatic, low tumour burden indolent lymphoma. A planned exploratory sub-study compared the two strategies for small lymphocytic (SLL) and marginal zone lymphomas (MZL). Patients responding to rituximab weekly × 4 were randomized to MR (single dose rituximab every 3 months until treatment failure) or RR (rituximab weekly × 4) at the time of each progression until treatment failure. The primary endpoint was time to treatment failure (TTTF). Patients with SLL (n = 57), MZL (n = 71) and unclassifiable small B-cell lymphoma (n = 3) received induction rituximab. The overall response rate (ORR) was 40% [95% confidence interval (CI) 31-49%; SLL ORR 22·8%; MZL ORR 52·1%]; all 52 responders were randomized. At a median of 4·3 years from randomization, treatment failure occurred in 18/23 RR and 15/29 MR. The median TTTF was 1·4 years for RR and 4·8 years for MR (P = 0·012); median time to first cytotoxic therapy was 6·3 years for RR and not reached for MR (P = 0·0002). Survival did not differ (P = 0·72). In low tumour burden SLL and MZL patients responding to rituximab induction, MR significantly improved TTTF as compared with RR. PMID:26970533

  5. Impact of Fc gamma-receptor polymorphisms on the response to rituximab treatment in children and adolescents with mature B cell lymphoma/leukemia.

    PubMed

    Burkhardt, Birgit; Yavuz, Deniz; Zimmermann, Martin; Schieferstein, Jutta; Kabickova, Edita; Attarbaschi, Andishe; Lisfeld, Jasmin; Reiter, Alfred; Makarova, Olga; Worch, Jennifer; Bonn, Bettina R; Damm-Welk, Christine

    2016-09-01

    Recent studies in adult lymphoma patients have indicated a correlation between polymorphisms of Fc gamma-receptors (FcγRs, encoded by the respective FCGR genes) and the response to rituximab treatment. In vitro, cells expressing FcγRIIIa-158V mediate antibody-dependent cellular cytotoxicity (ADCC) more efficiently than cells expressing FcγRIIIa-158F. The impact of the FCGR2A-131HR polymorphism is unclear. In this study, the FCGR polymorphisms FCGR3A-158VF and FCGR2A-131HR were analyzed in pediatric patients with mature aggressive B cell non-Hodgkin lymphoma/leukemia (B-NHL). Pediatric patients received a single dose of rituximab monotherapy. Response was evaluated on day 5 followed by standard chemotherapy for B-NHL. Among 105 evaluable patients, a response to rituximab was observed in 21 % of those homozygous for FcγRIIa-131RR (5/24) compared to 48 % of patients who were HH and HR FcγRIIa-131 allele carriers (18/34 and 21/47, respectively; p = 0.044). Among patients with the FCGR3A-158 polymorphism, those homozygous for the FF genotype had a significantly favorable rituximab response rate of 59 % (22/37) compared to 32 % in patients who were FcγRIIIa-158VV and FcγRIIIa-VF allele carriers (2/9 and 20/59, respectively; p = 0.022). A stringent phase II response evaluation of children and adolescents with B-NHL after one dose of rituximab monotherapy showed a significant association between the rituximab response rate and FCGR polymorphisms. These findings support the hypothesis that FCGR polymorphisms represent patient-specific parameters that influence the response to rituximab. PMID:27376362

  6. Value of Surveillance Studies for Patients With Stage I to II Diffuse Large B-Cell Lymphoma in the Rituximab Era

    SciTech Connect

    Hiniker, Susan M.; Pollom, Erqi L.; Khodadoust, Michael S.; Kozak, Margaret M.; Xu, Guofan; Quon, Andrew; Advani, Ranjana H.; Hoppe, Richard T.

    2015-05-01

    Background: The role of surveillance studies in limited-stage diffuse large B-cell lymphoma (DLBCL) in the rituximab era has not been well defined. We sought to evaluate the use of imaging (computed tomography [CT] and positron emission tomography [PET]-CT) scans and lactate dehydrogenase (LDH) in surveillance of patients with stage I to II DLBCL. Methods: A retrospective analysis was performed of patients who received definitive treatment between 2000 and 2013. Results: One hundred sixty-two consecutive patients with stage I to II DLBCL were treated with chemotherapy +/− rituximab, radiation, or combined modality therapy. The 5-year rates of overall survival (OS) and freedom from progression (FFP) were 81.2% and 80.8%, respectively. Of the 162 patients, 124 (77%) were followed up with at least 1 surveillance PET scan beyond end-of-treatment scans; of those, 94 of 124 (76%) achieved a complete metabolic response on PET scan after completion of chemotherapy, and this was associated with superior FFP (P=.01, HR=0.3) and OS (P=.01, HR 0.3). Eighteen patients experienced relapse after initial response to therapy. Nine relapses were initially suspected by surveillance imaging studies (8 PET, 1 CT), and 9 were suspected clinically (5 by patient-reported symptoms and 4 by symptoms and physical examination). No relapses were detected by surveillance LDH. The median duration from initiation of treatment to relapse was 14.3 months among patients with relapses suspected by imaging, and 59.8 months among patients with relapses suspected clinically (P=.077). There was no significant difference in OS from date of first therapy or OS after relapse between patients whose relapse was suspected by imaging versus clinically. Thirteen of 18 patients underwent successful salvage therapy after relapse. Conclusions: A complete response on PET scan immediately after initial chemotherapy is associated with superior FFP and OS in stage I to II DLBCL. The use of PET scans as

  7. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia

    PubMed Central

    Thompson, Philip A.; Tam, Constantine S.; O’Brien, Susan M.; Wierda, William G.; Stingo, Francesco; Plunkett, William; Smith, Susan C.; Kantarjian, Hagop M.; Freireich, Emil J.

    2016-01-01

    Accurate identification of patients likely to achieve long-progression-free survival (PFS) after chemoimmunotherapy is essential given the availability of less toxic alternatives, such as ibrutinib. Fludarabine, cyclophosphamide, and rituximab (FCR) achieved a high response rate, but continued relapses were seen in initial reports. We reviewed the original 300 patient phase 2 FCR study to identify long-term disease-free survivors. Minimal residual disease (MRD) was assessed posttreatment by a polymerase chain reaction-based ligase chain reaction assay (sensitivity 0.01%). At the median follow-up of 12.8 years, PFS was 30.9% (median PFS, 6.4 years). The 12.8-year PFS was 53.9% for patients with mutated immunoglobulin heavy chain variable (IGHV) gene (IGHV-M) and 8.7% for patients with unmutated IGHV (IGHV-UM). 50.7% of patients with IGHV-M achieved MRD-negativity posttreatment; of these, PFS was 79.8% at 12.8 years. A plateau was seen on the PFS curve in patients with IGHV-M, with no relapses beyond 10.4 years in 42 patients (total follow-up 105.4 patient-years). On multivariable analysis, IGHV-UM (hazard ratio, 3.37 [2.18-5.21]; P < .001) and del(17p) by conventional karyotyping (hazard ratio, 7.96 [1.02-61.92]; P = .048) were significantly associated with inferior PFS. Fifteen patients with IGHV-M had 4-color MRD flow cytometry (sensitivity 0.01%) performed in peripheral blood, at a median of 12.8 years posttreatment (range, 9.5-14.7). All were MRD-negative. The high rate of very long-term PFS in patients with IGHV-M after FCR argues for the continued use of chemoimmunotherapy in this patient subgroup outside clinical trials; alternative strategies may be preferred in patients with IGHV-UM, to limit long-term toxicity. PMID:26492934

  8. [Efficacy of CHOP+/-Rituximab-like therapy plus radiation therapy for patients with diffuse large B-cell lymphoma stage I].

    PubMed

    Ueda, Kyoko; Yokoyama, Masahiro; Asai, Hiroaki; Koudaira, Makoto; Yamada, Syuhei; Katsube, Atsushi; Mishima, Yuko; Sakajiri, Sakura; Takeuchi, Kengo; Saotome, Takashi; Terui, Yasuhito; Takahashi, Syunji; Hatake, Kiyohiko

    2010-05-01

    Clinically, R-CHOP-like therapy plus radiation therapy is commonly performed for patients with limited stage diffuse large B-cell lymphoma. However, the efficacy and the safety of the management have not been evaluated properly. In particular, we have few definitive reports about patients with stage I DLBCL. This time we evaluated the effect of CHOP+/-R-like therapy plus radiation therapy, by analyzing 28 patients with stage I DLBCL, retrospectively. 15 patients were treated with the RCHOP-like therapy, and 13 received CHOP-like therapy combined with radiation therapy. A complete response was observed in all of the patients. With a median follow-up time of 14 months, 1-year progression-free survival (PFS) was 100%, and the 1-year overall survival (OS) was 100% for the patients receiving the R-CHOP-like therapy. With a median follow-up time of 68 months, 5-year PFS was 84. 6%, and 5-year OS was 100% for patients receiving the CHOP-like therapy. Since the followup time was not enough and the patient numbers were too few, the benefit of the addition of Rituximab to the CHOP therapy could not be clarified. We need to assess the safety and the efficacy of the combined modality therapy for patients with limited-stage DLBCL by a larger prospective study. PMID:20495315

  9. The HELIOS trial protocol: a phase III study of ibrutinib in combination with bendamustine and rituximab in relapsed/refractory chronic lymphocytic leukemia.

    PubMed

    Hallek, Michael; Kay, Neil E; Osterborg, Anders; Chanan-Khan, Asher A; Mahler, Michelle; Salman, Mariya; Wan, Ying; Sun, Steven; Zhuang, Sen Hong; Howes, Angela

    2015-01-01

    Ibrutinib is an orally administered, covalent inhibitor of Bruton's tyrosine kinase with activity in B-cell malignancies based on Phase I/II studies. We describe the design and rationale for the Phase III HELIOS trial (trial registration: EudraCT No. 2012-000600-15; UTN No. U1111-1135-3745) investigating whether ibrutinib added to bendamustine and rituximab (BR) provides benefits over BR alone in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. Eligible patients must have relapsed/refractory disease measurable on CT scan and meet ≥ 1 International Workshop on Chronic Lymphocytic Leukemia criterion for requiring treatment; patients with del(17p) are excluded. All patients receive BR (maximum six cycles) as background therapy and are randomized 1:1 to placebo or ibrutinib 420 mg/day. Treatment with ibrutinib or placebo will start concomitantly with BR and continue until disease progression or unacceptable toxicity. The primary end point is progression-free survival. Secondary end points include safety, objective response rate, overall survival, rate of minimal residual disease-negative remissions, and patient-reported outcomes. Tumor response will be assessed using the International Workshop on Chronic Lymphocytic Leukemia guidelines. PMID:24901734

  10. IMPACT OF PRE-TRANSPLANT RITUXIMAB ON SURVIVAL AFTER AUTOLOGOUS HEMATOPOIETIC STEM CELL TRANSPLANTATION FOR DIFFUSE LARGE B-CELL LYMPHOMA

    PubMed Central

    Fenske, Timothy S.; Hari, Parameswaran N.; Carreras, Jeanette; Zhang, Mei-Jie; Kamble, Rammurti T.; Bolwell, Brian J.; Cairo, Mitchell S.; Champlin, Richard E.; Chen, Yi-Bin; Freytes, César O.; Gale, Robert Peter; Hale, Gregory A.; Ilhan, Osman; Khoury, H. Jean; Lister, John; Maharaj, Dipnarine; Marks, David I.; Munker, Reinhold; Pecora, Andrew L.; Rowlings, Philip A.; Shea, Thomas C.; Stiff, Patrick; Wiernik, Peter H.; Winter, Jane N.; Rizzo, J. Douglas; van Besien, Koen; Lazarus, Hillard M.; Vose, Julie M.

    2010-01-01

    Incorporation of the anti-CD20 monoclonal antibody rituximab into front-line regimens for diffuse large B-cell lymphoma (DLBCL) has resulted in improved survival. Despite this progress, many patients develop refractory or recurrent DLBCL and then receive autologous hematopoietic stem cell transplantation (AuHCT). It is unclear to what extent pre-transplant exposure to rituximab affects outcomes following AuHCT. Outcomes of 994 patients receiving AuHCT for DLBCL between 1996 and 2003 were analyzed according to whether rituximab was (n=176, “+R” group) or was not (n=818, “ −R” group) administered with front-line or salvage therapy prior to AuHCT. The +R group had superior progression-free survival (50% versus 38%, p=0.008) and overall survival (57% versus 45%, p=0.006) at 3 years. Platelet and neutrophil engraftment were not affected by exposure to rituximab. Non-relapse mortality (NRM) did not differ significantly between the +R and −R groups. In multivariate analysis, the +R group had improved progression-free survival (relative risk of relapse/progression or death 0.64, p<0.001) and improved overall survival (relative risk of death of 0.74, p=0.039). We conclude that pre-transplant rituximab is associated with a lower rate of progression and improved survival following AuHCT for DLBCL, with no evidence of impaired engraftment or increased NRM. PMID:19822306

  11. Rituximab is a safe and effective long-term treatment for children with steroid and calcineurin inhibitor-dependent idiopathic nephrotic syndrome.

    PubMed

    Ravani, Pietro; Ponticelli, Alessandro; Siciliano, Chiara; Fornoni, Alessia; Magnasco, Alberto; Sica, Felice; Bodria, Monica; Caridi, Gianluca; Wei, Changli; Belingheri, Mirco; Ghio, Luciana; Merscher-Gomez, Sandra; Edefonti, Alberto; Pasini, Andrea; Montini, Giovanni; Murtas, Corrado; Wang, Xiangyu; Muruve, Daniel; Vaglio, Augusto; Martorana, Davide; Pani, Antonello; Scolari, Francesco; Reiser, Jochen; Ghiggeri, Gian M

    2013-11-01

    In children with idiopathic nephrotic syndrome, rituximab can maintain short-term remission with withdrawal of prednisone and calcineurin inhibitors. Long-term effects including the number of repeated infusions to maintain remission are unknown. To test this, we treated 46 consecutive children with idiopathic nephrotic syndrome lasting for at least 1 year (mean 6.3 years), maintained in remission with oral prednisone and calcineurin inhibitors. They received 1-5 rituximab courses during a median follow-up of 3 years. Oral agents were tapered after each infusion, and completely withdrawn within 45 days. Rituximab was well tolerated. Six-month probabilities of remission were 48% after the first infusion and 37% after subsequent infusions. One- and 2-year-remission probabilities were, respectively, 20 and 10%. Median time intervals between complete oral-agent withdrawal and relapse were 5.6 and 8.5 months, respectively, following the first and subsequent courses. The time to reconstitution of CD20 cells correlated with the duration of remission, but was not associated with variation in FcyR, CD20, or SMPDL-3B polymorphisms. Podocyte Src phosphorylation was normal. Thus, rituximab can be safely and repeatedly used as a prednisone and calcineurin inhibitor-sparing therapy in a considerable proportion of children with dependent forms of idiopathic nephrotic syndrome. Further study is needed to identify patients who will benefit most from rituximab therapy. PMID:23739238

  12. Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma

    PubMed Central

    Bachy, Emmanuel; Houot, Roch; Morschhauser, Franck; Sonet, Anne; Brice, Pauline; Belhadj, Karim; Cartron, Guillaume; Audhuy, Bruno; Fermé, Christophe; Feugier, Pierre; Sebban, Catherine; Delwail, Vincent; Maisonneuve, Hervé; Le Gouill, Steven; Lefort, Sophie; Brousse, Nicole; Foussard, Charles; Salles, Gilles

    2013-01-01

    Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for patients treated with rituximab. However, no long-term follow up (i.e. > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-α2a or a similar chemotherapy-based regimen plus rituximab, and outcome was up-dated. With a median follow up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary end point) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P<0.0001 and P=0.001, respectively). Considering long-term toxicity, the addition of rituximab in the first-line setting was confirmed as safe with regards to development of secondary malignancies. Long-term follow up of patients with follicular lymphoma treated in the FL2000 study confirms the sustained clinical benefit of rituximab without long-term toxicity. This study was registered at ClinicalTrials.gov (Identifier:00136552). PMID:23645690

  13. Long-term follow up of the FL2000 study comparing CHVP-interferon to CHVP-interferon plus rituximab in follicular lymphoma.

    PubMed

    Bachy, Emmanuel; Houot, Roch; Morschhauser, Franck; Sonet, Anne; Brice, Pauline; Belhadj, Karim; Cartron, Guillaume; Audhuy, Bruno; Fermé, Christophe; Feugier, Pierre; Sebban, Catherine; Delwail, Vincent; Maisonneuve, Hervé; Le Gouill, Steven; Lefort, Sophie; Brousse, Nicole; Foussard, Charles; Salles, Gilles

    2013-07-01

    Anti-CD20-containing chemotherapy regimens have become the standard of care for patients with follicular lymphoma needing cytotoxic therapy. Four randomized trials demonstrated a clinical benefit for patients treated with rituximab. However, no long-term follow up (i.e. > 5 years) of these trials is yet available. Between May 2000 and May 2002, 358 newly diagnosed patients with high tumor burden follicular lymphoma were randomized to receive cyclophosphamide, adriamycin, etoposide and prednisolone plus interferon-α2a or a similar chemotherapy-based regimen plus rituximab, and outcome was up-dated. With a median follow up of 8.3 years, addition of rituximab remained significantly associated with prolonged event-free survival (primary end point) (P=0.0004) with a trend towards a benefit for overall survival (P=0.076). The Follicular Lymphoma International Prognostic Index score was strongly associated with outcome for both event-free and overall survival in univariate analysis and its prognostic value remained highly significant after adjusting for other significant covariates in multivariate models (P<0.0001 and P=0.001, respectively). Considering long-term toxicity, the addition of rituximab in the first-line setting was confirmed as safe with regards to development of secondary malignancies. Long-term follow up of patients with follicular lymphoma treated in the FL2000 study confirms the sustained clinical benefit of rituximab without long-term toxicity. PMID:23645690

  14. Immunologic effects of rituximab on the human spleen in immune thrombocytopenia

    PubMed Central

    Audia, Sylvain; Samson, Maxime; Guy, Julien; Janikashvili, Nona; Fraszczak, Jennifer; Trad, Malika; Ciudad, Marion; Leguy, Vanessa; Berthier, Sabine; Petrella, Tony; Aho-Glélé, Serge; Martin, Laurent; Maynadié, Marc; Lorcerie, Bernard; Rat, Patrick; Cheynel, Nicolas; Katsanis, Emmanuel; Larmonier, Nicolas

    2011-01-01

    Immune thrombocytopenia (ITP) is an autoimmune disease with a complex pathogenesis. As in many B cell–related autoimmune diseases, rituximab (RTX) has been shown to increase platelet counts in some ITP patients. From an immunologic standpoint, the mode of action of RTX and the reasons underlying its limited efficacy have yet to be elucidated. Because splenectomy is a cornerstone treatment of ITP, the immune effect of RTX on this major secondary lymphoid organ was investigated in 18 spleens removed from ITP patients who were treated or not with RTX. Spleens from ITP individuals had follicular hyperplasia consistent with secondary follicles. RTX therapy resulted in complete B-cell depletion in the blood and a significant reduction in splenic B cells, but these patients did not achieve remission. Moreover, whereas the percentage of circulating regulatory T cells (Tregs) was similar to that in controls, splenic Tregs were reduced in ITP patients. Interestingly, the ratio of proinflammatory Th1 cells to suppressive Tregs was increased in the spleens of patients who failed RTX therapy. These results indicate that although B cells are involved in ITP pathogenesis, RTX-induced total B-cell depletion is not correlated with its therapeutic effects, which suggests additional immune-mediated mechanisms of action of this drug. PMID:21876120

  15. Cladribine plus rituximab is an effective therapy for newly diagnosed mantle cell lymphoma.

    PubMed

    Spurgeon, Stephen E; Pindyck, Talia; Okada, Craig; Chen, Yiyi; Chen, Zunqiu; Mater, Elana; Abbi, Kamal; Epner, Elliot M

    2011-08-01

    Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma that is incurable with standard chemotherapy. There is no consensus on the best initial therapy, especially for elderly patients, who are not candidates for aggressive treatment approaches. Current National Comprehensive Cancer Network (NCCN) treatment guidelines include rituximab (R) plus cladribine for the initial treatment of MCL. However, few data are available to substantiate this recommendation. Therefore, to further define the role of R-cladribine for the initial treatment of MCL, we performed a retrospective chart review of 31 patients with MCL (median age, 67) treated with R-cladribine. The majority of responding patients also received R maintenance. The overall response rate was 87%, with 61% of patients achieving a complete remission (CR/CRu). The estimated median follow-up was 32.5 months, median PFS was 37.5 months, and median OS was 85.2 months. One of 19 (5.3%) subjects in CR/CRu relapsed (median follow-up of 23 months). CR/CRu was associated with improved survival (p < 0.0001), while a high mantle cell international prognostic index (MIPI) was associated with worse survival (p = 0.05). There was one toxic death (neutropenic pseudomonal sepsis) related to treatment. R-cladribine is an effective therapy for previously untreated MCL, and these results validate the use of R-cladribine for the initial treatment of MCL. PMID:21623691

  16. [Rituximab (MabThera)--a new biological medicine in rheumatoid arthritis therapy].

    PubMed

    Nemec, P

    2007-11-01

    Rheumatoid arthritis (RA) is a serious, chronic, inflammatory disorder that damages the joints. The chronic destructive process causes pain to patients with RA and leads to the development of permanent disability. At present, great emphasis is placed on timely and effective therapy for RA, which is able to halt or slow the development of the disorder. At present we do not have any means of curing RA, the main objective for treatment is to induce remission of the disorder and prevent structural damage to the joints and the development of permanent disability. The relatively frequent failure of disease modifying medications (DMARDs) lead to efforts to find new resources for the treatment of RA. So called biological medicines were recently introduced into therapeutic use. These were mainly TNFalpha blockers. Experience has shown that approximately a third of patients with RA do not respond even to treatment with such medicines. Rituximab (MabThera), a monoclonal antibody against CD20 positive B-lymphocytes, is a new biological medicine approved for RA therapy. It represents a new hope for patients with active RA, for whom earlier therapy with TNFa blockers has failed. PMID:18277630

  17. Radiolabelling rituximab with (99m)Tc in three steps procedure.

    PubMed

    Fontan, Charlotte; Bezombes, Christine; Salabert, Anne Sophie; Costes, Julien; Lopez, Raphael; Fournie, Jean-Jacques; Avet-Loiseau, Hervé; Coulais, Yvon; Payoux, Pierre; Tafani, Mathieu

    2015-06-15

    Lymphomas are the most frequent haematological malignancy. In non-Hodgkin's lymphomas (NHL), more than 90% of tumor cells express the cluster of differentiation (CD) 20 antigen. At the end of frontline therapy, the evaluation of remission is based on computed tomography (CT) and positron emission tomography coupled with computer tomography (PET/CT) with [(18)F]-fluorodeoxyglucose ([(18)F]FDG). Unfortunately, these techniques are not specific and cannot distinguish residual active tumor from inflammation. The aim of this study was to develop a specific radiotracer of NHL CD 20+ cells for clinical applications. The radiolabelling technique presented, based on the use of tricarbonyl compound, does not include an antibody reduction because this step could damage the protein. Actually, rituximab, an anti-CD 20 chimeric antibody used for the treatment of these NHL, was radiolabelled with Isolink® (99m)Tc-tricarbonyl compound in a three-step procedure without using a specific antibody reducer. Radiolabelling yield was greater than 97%. In vitro experiments showed a conservation of antibody integrity. In vivo experiments using Single-photon emission computed tomography/CT showed significant tumor targeting 24 h after injection of the radiotracer. It was consequently possible to develop an immunoradiolabelling method to specifically detect the residual disease. As this procedure is fast, reproducible and gentle, it will be possible to comply with Good Manufacturing Practices. PMID:26017396

  18. Effect of response quality and line of treatment with rituximab on overall and disease-free survival of patients with B-cell lymphoma

    PubMed Central

    Horvat, Mateja; Novakovic, Barbara Jezersek

    2010-01-01

    Background The introduction of rituximab into the treatment of patients with non-Hodgkin’s lymphomas has improved the overall response rate, as well as the response duration and the overall survival of patients with B-cell lymphomas. But only a few studies have addressed the question whether the better response (complete response) and the early introduction of rituximab into the treatment translate into the better survival. The aim of this retrospective study was to assess the potential relationship between either the quality of the response or the line of the rituximab treatment and the overall survival (OS) as well as the disease-free survival (DFS) of patients with B-cell lymphomas. Patients and methods. In the study, we analysed treatment outcomes in patients with different histological types of B-cell lymphomas who were treated at the Institute of Oncology between 2003 and 2007 with rituximab and chemotherapy. We included only patients who had the level of CD20 expression assessed prior to the introduction of the treatment with quantitative flow-cytometric measurements. The OS and DFS were evaluated by Kaplan-Meier survival curves. Results One hundred and fourteen patients were enrolled in the study. Patients who achieved a complete response after the rituximab containing treatment had a significantly longer OS than those reaching a partial response (hazard ratio [HR], 0.34; 95% CI, 0.05 to 0.91, P = 0.0375) and than patients with stable (hazard ratio [HR], 0.11; 95% CI, 0.0002 to 0.033, P < 0.0001) or progressive disease (hazard ratio [HR], 0.09; 95% CI, 0.003 to 0.03, P < 0.0001). Patients who achieved a complete response (CR; n = 70; 61.4%) had also a significantly longer DFS (hazard ratio [HR], 0.26; 95% CI, 0.021 to 0.538, P = 0.0068) than those reaching only a partial response (PR; n = 17; 14.9%). Patients treated with rituximab as the first-line treatment (n = 50; 43.9%) had a significantly longer OS than those treated with rituximab for the first

  19. Generation of biologically active linear and cyclic peptides has revealed a unique fine specificity of rituximab and its possible cross-reactivity with acid sphingomyelinase-like phosphodiesterase 3b precursor.

    PubMed

    Perosa, Federico; Favoino, Elvira; Caragnano, Maria Antonietta; Dammacco, Franco

    2006-02-01

    Heterogeneity of the effector functions displayed by rituximab and other anti-CD20 monoclonal antibodies (mAbs) apparently recognizing the same CD20 epitope suggests that additional mechanisms, probably related to mAb fine specificity, are responsible for B-cell depletion. To improve our understanding of rituximab's function, its fine specificity was investigated by means of phage display peptide library (PDPL)-expressing 7-mer cyclic (c7c) or 7-/12-mer linear peptides. Rituximab-specific c7c PDPL-derived clone insert sequences expressed the motif A(S)NPS overlapping the human CD20 170ANPS173. P172 was the most critical for rituximab binding, since its replacement with S172 (of mouse CD20) abolished the reactivity. The WPXWLE motif expressed by the linear PDPL-derived clone insert sequences could only be aligned to the reverse-oriented 161WPXWLE156 of acid sphingomyelinase-like phosphodiesterase 3b precursor (ASMLPD), though linear peptides bearing WPXWLE competed with cyclic ones for rituximab-paratope binding. Anti-CD20 mAb 1F5 only displayed a reactivity profile similar to that of rituximab, which also reacted with ASMLPD-derived peptides. Peptides induced antibodies with specificity and effector functions similar to those of rituximab. Our results show a unique fine specificity of rituximab, define the molecular basis for the lack of rituximab reactivity with mouse CD20 (mCD20), and the potential of targeting CD20 in an active immunotherapy setting. A possible rituximab interaction with ASMLPD is suggested. PMID:16223774

  20. Rituximab Maintenance Therapy After Autologous Stem-Cell Transplantation in Patients With Relapsed CD20+ Diffuse Large B-Cell Lymphoma: Final Analysis of the Collaborative Trial in Relapsed Aggressive Lymphoma

    PubMed Central

    Gisselbrecht, Christian; Schmitz, Norbert; Mounier, Nicolas; Singh Gill, Devinder; Linch, David C.; Trneny, Marek; Bosly, Andre; Milpied, Noel J.; Radford, John; Ketterer, Nicolas; Shpilberg, Ofer; Dührsen, Ulrich; Hagberg, Hans; Ma, David D.; Viardot, Andreas; Lowenthal, Ray; Brière, Josette; Salles, Gilles; Moskowitz, Craig H.; Glass, Bertram

    2012-01-01

    Purpose The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. Patients and Methods In total, 477 patients with CD20+ DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. Results After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P = .7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P < .05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01). Conclusion In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT. PMID:23091101

  1. Rituximab Extended Schedule or Re-Treatment Trial for Low–Tumor Burden Follicular Lymphoma: Eastern Cooperative Oncology Group Protocol E4402

    PubMed Central

    Kahl, Brad S.; Hong, Fangxin; Williams, Michael E.; Gascoyne, Randy D.; Wagner, Lynne I.; Krauss, John C.; Habermann, Thomas M.; Swinnen, Lode J.; Schuster, Stephen J.; Peterson, Christopher G.; Sborov, Mark D.; Martin, S. Eric; Weiss, Matthias; Ehmann, W. Christopher; Horning, Sandra J.

    2014-01-01

    Purpose In low–tumor burden follicular lymphoma (FL), maintenance rituximab (MR) has been shown to improve progression-free survival when compared with observation. It is not known whether MR provides superior long-term disease control compared with re-treatment rituximab (RR) administered on an as-needed basis. E4402 (RESORT) was a randomized clinical trial designed to compare MR against RR. Patients and Methods Eligible patients with previously untreated low–tumor burden FL received four doses of rituximab, and responding patients were randomly assigned to either RR or MR. Patients receiving RR were eligible for re-treatment at each disease progression until treatment failure. Patients assigned to MR received a single dose of rituximab every 3 months until treatment failure. The primary end point was time to treatment failure. Secondary end points included time to first cytotoxic therapy, toxicity, and health-related quality of life (HRQOL). Results A total of 289 patients were randomly assigned to RR or MR. With a median follow-up of 4.5 years, the estimated median time to treatment failure was 3.9 years for patients receiving RR and 4.3 years for those receiving MR (P = .54). Three-year freedom from cytotoxic therapy was 84% for those receiving RR and 95% for those receiving MR (P = .03). The median number of rituximab doses was four patients receiving RR and 18 for those receiving MR. There was no difference in HRQOL. Grade 3 to 4 toxicities were infrequent in both arms. Conclusion In low–tumor burden FL, a re-treatment strategy uses less rituximab while providing disease control comparable to that achieved with a maintenance strategy. PMID:25154829

  2. Chlorambucil-rituximab as first-line therapy in patients affected by follicular non-Hodgkin's lymphoma: a retrospective single-centre study.

    PubMed

    Martinelli, Giovanni; Montoro, Juan; Vanazzi, Anna; Andreola, Giovanna; Liptrott, Sarah; Radice, Davide; Negri, Mara; Preda, Lorenzo; Pruneri, Giancarlo; Laszlo, Daniele

    2015-12-01

    Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, has been shown to be active in newly diagnosed and relapsed patients with follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. Many studies suggest that the prognosis of patients with FL may improve when it is used in combination with chemotherapy. Despite these advances, the disease remains essentially incurable with standard therapy, and novel approaches to treatment are needed because optimal therapy is not defined. The combination of chlorambucil-rituximab is one of several standard treatment options for FL. Here, we considered data arising from 75 patients with newly diagnosed FL at the European Institute of Oncology treated with the combination of rituximab plus chlorambucil. The aim of this study was to evaluate the efficacy and safety of chlorambucil and rituximab, delivered 6 mg/m(2) /day orally for 6 weeks and 375 mg/m(2) in a standard 4-weekly schedule, respectively. Patients responding to the induction therapy received a prolonged therapy with four additional cycles of chlorambucil plus rituximab. Seventy-one patients (94.6%) completed the treatment; four patients discontinued treatment because of grade 3-4 hematological toxicity. The overall response rate was 97.3% including 74.7% of complete responses. Only two patients had a stable disease at revaluation after treatment. With a median follow-up of 57 months, 72 patients (96%) are alive. Median event-free survival (EFS) and median overall survival (OS) were not reached; 5-year OS rate was 98.4%. The 5-year EFS was 71.3%. By univariate and multivariate analyses, elevated beta-2 microglobulin levels and partial responses to therapy were correlated with worse EFS. These results suggest that the combination of chlorambucil and rituximab is an active and safe regimen in patients with newly diagnosed FL, principally in those with low tumour burden and favourable prognostic factors. PMID

  3. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma.

    PubMed

    Assouline, Sarit E; Nielsen, Torsten Holm; Yu, Stephen; Alcaide, Miguel; Chong, Lauren; MacDonald, David; Tosikyan, Axel; Kukreti, Vishal; Kezouh, Abbas; Petrogiannis-Haliotis, Tina; Albuquerque, Marco; Fornika, Daniel; Alamouti, Sepideh; Froment, Remi; Greenwood, Celia M T; Oros, Kathleen Klein; Camglioglu, Errol; Sharma, Ayushi; Christodoulopoulos, Rosa; Rousseau, Caroline; Johnson, Nathalie; Crump, Michael; Morin, Ryan D; Mann, Koren K

    2016-07-14

    The majority of diffuse large B-cell lymphoma (DLBCL) tumors contain mutations in histone-modifying enzymes (HMEs), indicating a potential therapeutic benefit of histone deacetylase inhibitors (HDIs), and preclinical data suggest that HDIs augment the effect of rituximab. In this randomized phase 2 study, we evaluated the response rate and toxicity of panobinostat, a pan-HDI administered 30 mg orally 3 times weekly, with or without rituximab, in 40 patients with relapsed or refractory de novo (n = 27) or transformed (n = 13) DLBCL. Candidate genes and whole exomes were sequenced in relapse tumor biopsies to search for molecular correlates, and these data were used to quantify circulating tumor DNA (ctDNA) in serial plasma samples. Eleven of 40 patients (28%) responded to panobinostat (95% confidence interval [CI] 14.6-43.9) and rituximab did not increase responses. The median duration of response was 14.5 months (95% CI 9.4 to "not reached"). At time of data censoring, 6 of 11 patients had not progressed. Of the genes tested for mutations, only those in MEF2B were significantly associated with response. We detected ctDNA in at least 1 plasma sample from 96% of tested patients. A significant increase in ctDNA at day 15 relative to baseline was strongly associated with lack of response (sensitivity 71.4%, specificity 100%). We conclude that panobinostat induces very durable responses in some patients with relapsed DLBCL, and early responses can be predicted by mutations in MEF2B or a significant change in ctDNA level at 15 days after treatment initiation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT01238692). PMID:27166360

  4. Cholestatic Liver Disease after Rituximab and Adalimumab and the Possible Role of Cross-Reacting Antibodies to Fab 2 Fragments

    PubMed Central

    Koetter, Ina; Schwab, Matthias; Fritz, Peter; Kimmel, Martin; Alscher, M. Dominik; Braun, Niko

    2013-01-01

    Background Millions of patients are treated with therapeutic monoclonal antibodies (Tmabs) for miscellaneous diseases. We investigated sera from six patients who received immune globulin, from one patient with refractory anti-neutrophil-cytoplasmic antibody (ANCA)-associated granulomatosis with polyangiitis (GPA) who developed two episodes of acute cholestatic liver disease, one after treatment with rituximab and a second after adalimumab and a healthy control group. Methods Three sera from the patient and six sera from patients who received immune globulin were analyzed for antibodies to rituximab and adalimumab by ELISA. Additionally, sera from the patients and from nine healthy blood donors were coated with the Fab fragment of an unrelated humanized monoclonal antibody, with human Fc proteins as well as a mouse IgG globulin. Results Viral serology for hepatitis A, B, C and autoantibodies specific for autoimmune liver disorders were negative. In all three sera from the patient antibodies to rituximab could be detected, but also antibodies to adalimumab were present even at time points when the patient had not yet received adalimumab, indicating cross reactivity between both substances. Testing against an unrelated human Fab fragment revealed positive results, indicating that the patient had antibodies against human Fab fragments in general. The Fc proteins were negative, and patients’ sera did also not react with mouse IgG globulins. Remarkably, 2 out of 5 patients which were treated with immune globulin had antibodies against human Fab fragments in general whereas in none of the samples from healthy controls antibodies to Fab fragment could be detected. Conclusion This is the first study demonstrating cholestatic liver disease induced by two different Tmabs. Cross - reacting antibodies to Fab2 fragments in general are probably involved. Further studies must show if these Fab2 antibodies in general are related with drug-induced side effects and accelerated drug

  5. Five years of experience with rituximab plus high-dose dexamethasone for relapsed/refractory chronic lymphocytic leukemia

    PubMed Central

    Šimkovič, Martin; Motyčková, Monika; Belada, David; Vodárek, Pavel; Kapoor, Rahul; Jaffar, Hamna; Vrbacký, Filip; Žák, Pavel

    2015-01-01

    Introduction High-dose methylprednisolone (HDMP) in combination with rituximab is active in the treatment of relapsed/refractory chronic lymphocytic leukemia (CLL), but serious infections are frequent. Recently published data suggested that high-dose dexamethasone might be equally effective as HDMP despite a lower cumulative dose. Material and methods We performed retrospective analysis of 60 patients with relapsed/refractory CLL (median age: 66 years; range: 37–86) treated with rituximab plus dexamethasone (R-dex) at a single tertiary center between September 2008 and October 2012. The schedule of R-dex consisted of rituximab 500 mg/m2 i.v. day 1 (375 mg/m2 in cycle 1) and dexamethasone 40 mg orally on days 1-4 and 10-13 repeated every 3 weeks for a maximum of 8 cycles. Unfavorable prognostic features were frequent (Rai stages III/IV in 67%, unmutated IgVH 82%, del 11q 43%, TP53 mutation/deletion 23%, bulky lymphadenopathy 58% of patients). Results Overall response (OR)/complete remission (CR) was achieved in 75/3%. At the median follow-up of 21 months, median progression-free survival (PFS) was 8 months, median time to next treatment 12.9 months and median overall survival 25.5 months. Refractoriness to fludarabine (p = 0.04) and age ≥ 65 years (p = 0.03) were significant predictors of shorter PFS. R-dex was successfully used for debulking before allogenic stem cell transplantation in 7 patients (12%). Serious (CTCAE grade III/IV) infections occurred in 27% of patients; 20% of patients developed steroid diabetes requiring temporary short-acting insulin. Conclusions Our results show that R-dex is an active and well-tolerated regimen for patients with relapsed/refractory CLL; however, major infections remain frequent despite combined antimicrobial prophylaxis.

  6. Phase 2 study of panobinostat with or without rituximab in relapsed diffuse large B-cell lymphoma

    PubMed Central

    Nielsen, Torsten Holm; Yu, Stephen; Alcaide, Miguel; Chong, Lauren; MacDonald, David; Tosikyan, Axel; Kukreti, Vishal; Kezouh, Abbas; Petrogiannis-Haliotis, Tina; Albuquerque, Marco; Fornika, Daniel; Alamouti, Sepideh; Froment, Remi; Greenwood, Celia M. T.; Oros, Kathleen Klein; Camglioglu, Errol; Sharma, Ayushi; Christodoulopoulos, Rosa; Rousseau, Caroline; Johnson, Nathalie; Crump, Michael; Morin, Ryan D.; Mann, Koren K.

    2016-01-01

    The majority of diffuse large B-cell lymphoma (DLBCL) tumors contain mutations in histone-modifying enzymes (HMEs), indicating a potential therapeutic benefit of histone deacetylase inhibitors (HDIs), and preclinical data suggest that HDIs augment the effect of rituximab. In this randomized phase 2 study, we evaluated the response rate and toxicity of panobinostat, a pan-HDI administered 30 mg orally 3 times weekly, with or without rituximab, in 40 patients with relapsed or refractory de novo (n = 27) or transformed (n = 13) DLBCL. Candidate genes and whole exomes were sequenced in relapse tumor biopsies to search for molecular correlates, and these data were used to quantify circulating tumor DNA (ctDNA) in serial plasma samples. Eleven of 40 patients (28%) responded to panobinostat (95% confidence interval [CI] 14.6-43.9) and rituximab did not increase responses. The median duration of response was 14.5 months (95% CI 9.4 to “not reached”). At time of data censoring, 6 of 11 patients had not progressed. Of the genes tested for mutations, only those in MEF2B were significantly associated with response. We detected ctDNA in at least 1 plasma sample from 96% of tested patients. A significant increase in ctDNA at day 15 relative to baseline was strongly associated with lack of response (sensitivity 71.4%, specificity 100%). We conclude that panobinostat induces very durable responses in some patients with relapsed DLBCL, and early responses can be predicted by mutations in MEF2B or a significant change in ctDNA level at 15 days after treatment initiation. This clinical trial was registered at www.ClinicalTrials.gov (#NCT01238692). PMID:27166360

  7. Therapeutic target of memory B cells depletion helps to tailor administration frequency of rituximab in myasthenia gravis.

    PubMed

    Lebrun, Christine; Bourg, Véronique; Bresch, Saskia; Cohen, Mikael; Rosenthal-Allieri, Maria Alessandra; Desnuelle, Claude; Ticchioni, Michel

    2016-09-15

    Rituximab (RTX) has demonstrated efficacy in limiting relapses in myasthenia gravis (MG). We investigated the interest of CD27+ memory B cell monitoring in patients as a biological marker of clinical relapse. Twenty-four patients have been treated with RTX (375mg/m(2)/week-month as an induction treatment). Maintenance treatment consisted with either systematic treatment every 3months or only when CD27+ memory B cells were detectable. After the induction treatment, the mean infusions were 1.3/year compared with 4/year. We suggest that RTX administration frequency can be decreased safely by monitoring the re-emerging CD27+ memory B cells. PMID:27609279

  8. Cost-effectiveness of adding rituximab to fludarabine and cyclophosphamide for treatment of chronic lymphocytic leukemia in Ukraine

    PubMed Central

    Mandrik, Olena; Corro Ramos, Isaac; Knies, Saskia; Al, Maiwenn; Severens, Johan L

    2015-01-01

    The aim of this study was to assess the cost-effectiveness, from a health care perspective, of adding rituximab to fludarabine and cyclophosphamide scheme (FCR versus FC) for treatment-naïve and refractory/relapsed Ukrainian patients with chronic lymphocytic leukemia. A decision-analytic Markov cohort model with three health states and 1-month cycle time was developed and run within a life time horizon. Data from two multinational, prospective, open-label Phase 3 studies were used to assess patients’ survival. While utilities were generalized from UK data, local resource utilization and disease-associated treatment, hospitalization, and side effect costs were applied. The alternative scenario was performed to assess the impact of lower life expectancy of the general population in Ukraine on the incremental cost-effectiveness ratio (ICER) for treatment-naïve patients. One-way, two-way, and probabilistic sensitivity analyses were conducted to assess the robustness of the results. The ICER (in US dollars) of treating chronic lymphocytic leukemia patients with FCR versus FC is US$8,704 per quality-adjusted life year gained for treatment-naïve patients and US$11,056 for refractory/relapsed patients. When survival data were modified to the lower life expectancy of the general population in Ukraine, the ICER for treatment-naïve patients was higher than US$13,000. This value is higher than three times the current gross domestic product per capita in Ukraine. Sensitivity analyses have shown a high impact of rituximab costs and a moderate impact of differences in utilities on the ICER. Furthermore, probabilistic sensitivity analyses have shown that for refractory/relapsed patients the probability of FCR being cost-effective is higher than for treatment-naïve patients and is close to one if the threshold is higher than US$15,000. State coverage of rituximab treatment may be considered a cost-effective treatment for the Ukrainian population under conditions of economic

  9. Cost-effectiveness of adding rituximab to fludarabine and cyclophosphamide for treatment of chronic lymphocytic leukemia in Ukraine.

    PubMed

    Mandrik, Olena; Corro Ramos, Isaac; Knies, Saskia; Al, Maiwenn; Severens, Johan L

    2015-01-01

    The aim of this study was to assess the cost-effectiveness, from a health care perspective, of adding rituximab to fludarabine and cyclophosphamide scheme (FCR versus FC) for treatment-naïve and refractory/relapsed Ukrainian patients with chronic lymphocytic leukemia. A decision-analytic Markov cohort model with three health states and 1-month cycle time was developed and run within a life time horizon. Data from two multinational, prospective, open-label Phase 3 studies were used to assess patients' survival. While utilities were generalized from UK data, local resource utilization and disease-associated treatment, hospitalization, and side effect costs were applied. The alternative scenario was performed to assess the impact of lower life expectancy of the general population in Ukraine on the incremental cost-effectiveness ratio (ICER) for treatment-naïve patients. One-way, two-way, and probabilistic sensitivity analyses were conducted to assess the robustness of the results. The ICER (in US dollars) of treating chronic lymphocytic leukemia patients with FCR versus FC is US$8,704 per quality-adjusted life year gained for treatment-naïve patients and US$11,056 for refractory/relapsed patients. When survival data were modified to the lower life expectancy of the general population in Ukraine, the ICER for treatment-naïve patients was higher than US$13,000. This value is higher than three times the current gross domestic product per capita in Ukraine. Sensitivity analyses have shown a high impact of rituximab costs and a moderate impact of differences in utilities on the ICER. Furthermore, probabilistic sensitivity analyses have shown that for refractory/relapsed patients the probability of FCR being cost-effective is higher than for treatment-naïve patients and is close to one if the threshold is higher than US$15,000. State coverage of rituximab treatment may be considered a cost-effective treatment for the Ukrainian population under conditions of economic

  10. [Successful treatment with rituximab and romiplostim for thrombocytopenia associated with Waldenström's macroglobulinemia initially presenting as Evans syndrome].

    PubMed

    Nozaki, Yumi; Koshiishi, Megumi; Sueki, Yuki; Kawashima, Ichirou; Yamamoto, Takeo; Nakajima, Kei; Mitsumori, Toru; Kirito, Keita

    2015-03-01

    A 60-year-old woman was admitted to our hospital with anemia and thrombocytopenia. Serum testing showed platelet-associated IgG elevation and she was positive on the direct and indirect Coombs tests. Together with bone marrow examination, these findings indicated a diagnosis of Evans syndrome. At diagnosis, she also had an IgM-κ type of monoclonal gammopathy of unknown significance. Initially, we administered steroids and her hemolytic anemia showed improvement. In contrast, only transient recovery of platelet counts was observed and her platelet counts rapidly decreased after steroid dose reduction. Thus, we treated her with a TPO-agonist, romiplostim. During the clinical course, she showed gradual serum IgM elevation. We thus performed another bone marrow biopsy and diagnosed her as having Waldenström's macroglobulinemia (WM). We started treatment with rituximab for WM. Together with the serum IgM reduction, she showed marked improvement of thrombocytopenia. This is a very rare case of WM initially presenting as autoimmune hemolytic anemia and immunethrombocytopenia associated with IgG class auto-antibody. Our experience suggests the usefulness of rituximab and romiplostim for the treatment of immunethrombocytopenia associated with WM. PMID:25876786

  11. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia.

    PubMed

    O'Brien, Susan M; Lamanna, Nicole; Kipps, Thomas J; Flinn, Ian; Zelenetz, Andrew D; Burger, Jan A; Keating, Michael; Mitra, Siddhartha; Holes, Leanne; Yu, Albert S; Johnson, David M; Miller, Langdon L; Kim, Yeonhee; Dansey, Roger D; Dubowy, Ronald L; Coutre, Steven E

    2015-12-17

    Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m(2) weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930. PMID:26472751

  12. A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia

    PubMed Central

    Lamanna, Nicole; Kipps, Thomas J.; Flinn, Ian; Zelenetz, Andrew D.; Burger, Jan A.; Keating, Michael; Mitra, Siddhartha; Holes, Leanne; Yu, Albert S.; Johnson, David M.; Miller, Langdon L.; Kim, Yeonhee; Dansey, Roger D.; Dubowy, Ronald L.; Coutre, Steven E.

    2015-01-01

    Idelalisib is a first-in-class oral inhibitor of PI3Kδ that has shown substantial activity in patients with relapsed/refractory chronic lymphocytic leukemia (CLL). To evaluate idelalisib as initial therapy, 64 treatment-naïve older patients with CLL or small lymphocytic leukemia (median age, 71 years; range, 65-90) were treated with rituximab 375 mg/m2 weekly ×8 and idelalisib 150 mg twice daily continuously for 48 weeks. Patients completing 48 weeks without progression could continue to receive idelalisib on an extension study. The median time on treatment was 22.4 months (range, 0.8-45.8+). The overall response rate (ORR) was 97%, including 19% complete responses. The ORR was 100% in patients with del(17p)/TP53 mutations and 97% in those with unmutated IGHV. Progression-free survival was 83% at 36 months. The most frequent (>30%) adverse events (any grade) were diarrhea (including colitis) (64%), rash (58%), pyrexia (42%), nausea (38%), chills (36%), cough (33%), and fatigue (31%). Elevated alanine transaminase/aspartate transaminase was seen in 67% of patients (23% grade ≥3). The combination of idelalisib and rituximab was highly active, resulting in durable disease control in treatment-naïve older patients with CLL. These results support the further development of idelalisib as initial treatment of CLL. This study is registered at ClinicalTrials.gov as #NCT01203930. PMID:26472751

  13. The role of radiotherapy for patients over age 60 with diffuse large B-cell lymphoma in the rituximab era.

    PubMed

    Cassidy, R J; Jegadeesh, N; Switchenko, J; Danish, H; Esiashvili, N; Flowers, C R; Khan, M K

    2016-08-01

    The role of consolidative radiotherapy (RT) in patients ≥60 years old with DLBCL in the rituximab era is controversial. We examined the impact on disease control and overall survival by the addition of consolidative RT after completion of chemotherapy, while adjusting for known adverse risk factors. Retrospective chart review from 2004 to 2012 of 83 consecutive patients ≥60 years old with DLBCL treated in the rituximab era, 68 of which had a complete response to chemotherapy, was performed. Amongst patients with a complete response, consolidative RT use was associated with 100% 5-year local control, improved progression-free survival (p = 0.047), and a trend for overall survival (p = .098) on multivariate analysis. Amongst all patients, the use of consolidative RT was associated with improved overall survival (p = 0.03). The use of consolidative RT should be considered for patients ≥60 years old independent of stage and response to chemotherapy. PMID:26759182

  14. The immunological phenotype of rituximab-sensitive chronic graft-versus-host disease: a phase II study

    PubMed Central

    van Dorp, Suzanne; Resemann, Henrike; te Boome, Liane; Pietersma, Floor; van Baarle, Debbie; Gmelig-Meyling, Frits; de Weger, Roel; Petersen, Eefke; Minnema, Monique; Lokhorst, Henk; Ebeling, Saskia; Beijn, Scott J.P.; Knol, Edward F.; van Dijk, Marijke; Meijer, Ellen; Kuball, Jürgen

    2011-01-01

    Chronic graft-versus-host disease is the major long-term complication after allogeneic stem cell transplantation with a suboptimal response rate to current treatments. Therefore, clinical efficacy and changes in lymphocyte subsets before and after rituximab treatment were evaluated in a prospective phase II study in patients with steroid-refractory chronic graft-versus-host disease. Overall response rate was 61%. Only responding patients were found to have increased B-cell numbers prior to treatment. B cells had a naïve-antigen-presenting phenotype and were mainly CD5 negative or had a low CD5 expression. Normal B-cell homeostasis was reestablished in responding patients one year after ritxumab treatment and associated with a significant decline in skin-infiltrating CD8+ T cells, suggesting that host B cells play a role in maintaining pathological CD8+ T-cell responses. Imbalances in B-cell homeostasis could be used to identify patients a priori with a higher chance of response to rituximab treatment (Eudra-CT 2008-004125-42). PMID:21546493

  15. A multicenter phase II study of sepantronium bromide (YM155) plus rituximab in patients with relapsed aggressive B-cell Non-Hodgkin lymphoma.

    PubMed

    Papadopoulos, Kyriakos P; Lopez-Jimenez, Javier; Smith, Scott E; Steinberg, Joyce; Keating, Anne; Sasse, Carolyn; Jie, Fei; Thyss, Antoine

    2016-08-01

    This phase II study evaluated YM155, a novel small-molecule survivin suppressant, in combination with rituximab in patients with relapsed aggressive B-cell non-Hodgkin lymphoma (NHL) who failed or were not candidates for autologous stem cell transplant (ASCT). During 14-day cycles, 41 patients received YM155 (5mg/m(2)/d) by continuous intravenous (IV) infusion for 168 hours (day 1-7), and rituximab (375mg/m(2)) IV on days 1 and 8 during cycles 1-4 and repeated for 4 cycles every 10 cycles. Forty patients (97.6%) had prior rituximab and 15 patients (36.6%) prior ASCT. Most frequent grade 3-4 adverse events were neutropenia (19.5%) and thrombocytopenia (12.2%). In the per-protocol set (n = 34), objective response rate was 50% and median progression-free survival 17.9 months. Median overall survival was not reached at study termination (median follow-up, 23 months). YM155 in combination with rituximab was tolerable with encouraging antitumor activity and durable responses in relapsed aggressive B-cell NHL patients. PMID:26857688

  16. Phase II multicenter study of oblimersen sodium, a Bcl-2 antisense oligonucleotide, in combination with rituximab in patients with recurrent B-cell non-Hodgkin lymphoma.

    PubMed

    Pro, Barbara; Leber, Brian; Smith, Mitchell; Fayad, Luis; Romaguera, Jorge; Hagemeister, Fredrick; Rodriguez, Alma; McLaughlin, Peter; Samaniego, Felipe; Zwiebel, James; Lopez, Adriana; Kwak, Larry; Younes, Anas

    2008-11-01

    Oblimersen sodium plus rituximab was evaluated in relapsed/refractory B-cell non-Hodgkin lymphoma (NHL) patients. Oblimersen was administered as a continuous intravenous infusion at a daily dose of 3 mg/kg/d for 7 d on alternate weeks for 3 weeks. Rituximab was given at a weekly dose of 375 mg/m(2) for six doses. Patients with stable disease or objective response were allowed to receive a second course of treatment. The overall response rate (ORR) was 42% with 10 complete responses (CR) and eight partial responses (PR). Twelve (28%) patients achieved a minimal response or stable disease. Among the 20 patients with follicular lymphoma the ORR was 60% (eight CR, four PR). Three of the responders were refractory to prior treatment with rituximab, and two of the responses occurred in patients who had failed an autologous stem cell transplant. Median duration of response was 12 months. Most toxicities were low grade and reversible. In conclusion, oblimersen sodium can be safely combined with rituximab. The combination appears to be most beneficial in patients with indolent NHL and warrants further investigation in a large randomized trial. PMID:18764869

  17. Randomized trial of bendamustine-rituximab or R-CHOP/R-CVP in first-line treatment of indolent NHL or MCL: the BRIGHT study.

    PubMed

    Flinn, Ian W; van der Jagt, Richard; Kahl, Brad S; Wood, Peter; Hawkins, Tim E; Macdonald, David; Hertzberg, Mark; Kwan, Yiu-Lam; Simpson, David; Craig, Michael; Kolibaba, Kathryn; Issa, Samar; Clementi, Regina; Hallman, Doreen M; Munteanu, Mihaela; Chen, Ling; Burke, John M

    2014-05-01

    This randomized, noninferiority (NI), global, phase 3 study evaluated the efficacy and safety of bendamustine plus rituximab (BR) vs a standard rituximab-chemotherapy regimen (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone [R-CHOP] or rituximab plus cyclophosphamide, vincristine, and prednisone [R-CVP]) for treatment-naive patients with indolent non-Hodgkin's lymphoma or mantle cell lymphoma. Investigators preassigned the standard treatment regimen they considered most appropriate for each patient; patients were randomized to receive BR (n = 224) or standard therapy (R-CHOP/R-CVP, n = 223) for 6 cycles; 2 additional cycles were permitted at investigator discretion. Response was assessed by a blinded independent review committee. BR was noninferior to R-CHOP/R-CVP, as assessed by the primary end point of complete response rate (31% vs 25%, respectively; P = .0225 for NI [0.88 margin]). The overall response rates for BR and R-CHOP/R-CVP were 97% and 91%, respectively (P = .0102). Incidences of vomiting and drug-hypersensitivity reactions were significantly higher in patients treated with BR (P < .05), and incidences of peripheral neuropathy/paresthesia and alopecia were significantly higher in patients treated with standard-therapy regimens (P < .05). These data indicate BR is noninferior to standard therapy with regard to clinical response with an acceptable safety profile. This trial was registered at www.clinicaltrials.gov as #NCT00877006. PMID:24591201

  18. Rituximab as Successful Adjunct Treatment in a Patient With Disseminated Nontuberculous Mycobacterial Infection Due to Acquired Anti–Interferon-γ Autoantibody

    PubMed Central

    Czaja, Christopher A.; Merkel, Patricia A.; Chan, Edward D.; Lenz, Laurel L.; Wolf, Molly L.; Alam, Rafeul; Frankel, Stephen K.; Fischer, Aryeh; Gogate, Shaila; Perez-Velez, Carlos M.; Knight, Vijaya

    2014-01-01

    An acquired immune deficiency due to interferon gamma (IFN-γ) autoantibodies was diagnosed in a 78-year-old Japanese man with treatment-refractory disseminated nontuberculous mycobacterial infection. In addition to standard antimycobacterial therapy, he was successfully treated with rituximab to eliminate B cells and thereby the autoantibody. Subsequently, he obtained a sustained remission from infection. PMID:24336756

  19. Single dose of rituximab in children with steroid-dependent minimal change nephrotic syndrome

    PubMed Central

    Niu, Xiao-Ling; Hao, Sheng; Wang, Ping; Zhang, Wei; Guo, Gui-Mei; Wu, Ying; Kuang, Xin-Yu; Zhu, Guang-Hua; Huang, Wen-Yan

    2016-01-01

    Rituximab (RTX) can be used in children with nephrotic syndrome, particularly in those with steroid-dependent nephrotic syndrome (SDNS). However, at present there is no unified standard of how to use RTX, with regard to the amount of doses and frequency, in children with nephrotic syndrome. The study aimed to investigate the therapeutic efficacy of a single dose of RTX in children with steroid-dependent minimal change nephrotic syndrome (SD-MCNS). The patients with biopsy-proven minimal change disease (MCD) and clinical features of SDNS received a single dose of RTX (375 mg/m2). The toxicity and side effects of RTX were also observed. The study included 19 patients (10 males and 9 females). Follow-up of the patients was 1–50 months (28.1±16.6 months). B-cell depletion was achieved with RTX infusion (CD20<0.5%) and lasted 1–6 months (mean, 2.92±1.57 months). During follow-up, 10 patients remained in complete remission and did not relapse without administration of oral steroids or immunosuppressants for 4–50 months (mean, 30.1±12.6 months), despite recovery of the B-cell count. Nine patients relapsed in the process of reducing steroids, thus, treatment was maintained at a lower dosage (T=0, P<0.05) than prior to use of RTX. The number of relapses also decreased significantly (T=95, P<0.05). Five of the patients relapsed after stopping steroid for several months. At the end of follow-up, the efficacy of a single induction of RTX was 47.4% (9/19). There were no significant side effects associated with administration of RTX. In conclusion, RTX is a safe and effective alternative for children with SD-MCNS. RTX is an effective treatment for the rapid induction of remission and reduces relapse and steroid dependency. A single dose of RTX for children with SD-MCNS is recommended for rapid induction of remission, reduction of long-term steroid dosage, and decrease in the number of relapses, as it has few side effects. PMID:27446549

  20. Retrospective analysis of primary gastric diffuse large B cell lymphoma in the rituximab era: a multicenter study of 95 patients in Japan.

    PubMed

    Tanaka, Tsutomu; Shimada, Kazuyuki; Yamamoto, Kazuhito; Hirooka, Yoshiki; Niwa, Yasumasa; Sugiura, Isamu; Kitamura, Kunio; Kosugi, Hiroshi; Kinoshita, Tomohiro; Goto, Hidemi; Nakamura, Shigeo

    2012-03-01

    Primary gastric diffuse large B cell lymphoma (PG-DLBCL) is common subtype of extranodal non-Hodgkin lymphoma. The optimal treatment strategy for PG-DLBCL in the rituximab era still remains unknown. To evaluate clinical outcomes of PG-DLBCL in the rituximab era, we conducted a retrospective, multicenter analysis of 95 patients with PG-DLBCL. In 58 patients with localized disease, 3-year progression-free survival (PFS) and overall survival (OS) were 91% and 91% for patients with six cycles of rituximab plus CHOP (R-CHOP) and 92% and 95% for patients with three to four cycles of R-CHOP plus radiotherapy (Log-rank test, P = 0.595 and P = 0.278, respectively). In 37 patients with advanced disease, 3-year PFS and 3-year OS were 43% and 64% for patients with R-CHOP chemotherapy with or without radiotherapy. On multivariate analysis, advanced stage and elevated serum LDH levels were independent predictors of survival in patients with PG-DLBCL. One patient with localized disease relapsed in lymph node, and eight patients with advanced disease relapsed in lymph node (n = 3), stomach (n = 2), central nervous system (CNS; n = 2), and duodenum (n = 1). Intriguingly, CNS relapse developed within 6 months after initial series of treatment (4.9 and 5.8 months, respectively), and stomach relapse developed in later phase (27.2 and 32.9 months, respectively). Clinical outcomes of PG-DLBCL were extremely favorable for localized-stage patients in the rituximab era, although these might be poor for advanced-stage patients even in the rituximab era. Further prospective analyses are warranted. PMID:21822617

  1. Estimating the Population Benefits and Costs of Rituximab Therapy in the United States from 1998 to 2013 Using Real-World Data

    PubMed Central

    Reyes, Carolina M.; Gleeson, Michelle L.; Halperin, Marc; Skettino, Sandra L.; Mikhael, Joseph

    2016-01-01

    Background: Rituximab was approved in 1997 and is regularly one of the largest drug expenditures for Medicare; however, its benefits and costs have not been estimated from a population perspective. Objectives: To estimate both the clinical and the economic outcomes of rituximab for its approved hematological uses at the population level. Research Design: Analyses using cancer registry incidence data from the Surveillance, Epidemiology, and End Results (SEER) program, and outcomes data from SEER data linked with Medicare administrative claims (SEER-Medicare data). These results were incorporated into an epidemiological simulation model of the population over time. Subjects: We modeled all United States patients from 1998 to 2013 diagnosed with diffuse large B-cell lymphoma, follicular lymphoma, or chronic lymphocytic leukemia. Measures: Using this model, we estimated the life-years saved, as well as their economic benefit, in the United States population. We also estimated the incremental cost of adding rituximab to chemotherapy. All economic inputs were based on Medicare reimbursed amounts inflated to 2013 dollars. Results: There were 279,704 cumulative life-years saved which were valued at $25.44 billion. The incremental direct medical cost of rituximab was estimated to be $8.92 billion, resulting in an incremental economic gain of $16.52 billion. Conclusions: These analyses, based on real-world evidence, show that the introduction of rituximab into clinical practice has produced a substantial number of incremental life-years. Importantly, the economic benefit of the life-years gained greatly exceeds the added costs of treatment. PMID:26759977

  2. Rituximab as first choice for patients with refractory rheumatoid arthritis: cost-effectiveness analysis in Iran based on a systematic review and meta-analysis.

    PubMed

    Ahmadiani, Saeed; Nikfar, Shekoufeh; Karimi, Somayeh; Jamshidi, Ahmad Reza; Akbari-Sari, Ali; Kebriaeezadeh, Abbas

    2016-09-01

    The aim of this study was to evaluate the effectiveness and cost-effectiveness of using rituximab as first line for patients with refractory rheumatoid arthritis in comparison with continuing conventional DMARDs, from a perspective of health service governors. A systematic review was implemented through searching PubMed, Scopus and Cochrane Library. Quality assessment was performed by Jadad scale. After meta-analysis of ACR index results, QALY gain was calculated through mapping ACR index to HAQ and utility index. To measure the direct and indirect medical costs, a set of interviews with patients were applied. Thirty-two patients were selected from three referral rheumatology clinics in Tehran with definite diagnosis of refractory rheumatoid arthritis in the year before and treatment regimen of either rituximab or DMARDs within last year. Incremental cost-effectiveness ratio was calculated for base case and scenario of generic rituximab. Threefold of GDP per capita was considered as threshold of cost-effectiveness. Four studies were eligible to be considered in this systematic review. Total risk differences of 0.3 for achieving ACR20 criteria, 0.21 for ACR50 and 0.1 for ACR70 were calculated. Also mean of total medical costs of patients for 24 weeks were $3985 in rituximab group and $932 for DMARDs group. Thus, the incremental cost per QALY ratio will be $45,900-$70,223 in base case and $32,386-$49,550 for generic scenario. Rituximab for treatment of patients with refractory rheumatoid arthritis is not considered as cost-effective in Iran in none of the scenarios. PMID:27136919

  3. Validation of 64Cu-DOTA-rituximab injection preparation under good manufacturing practices: a PET tracer for imaging of B-cell non-Hodgkin lymphoma.

    PubMed

    Natarajan, Arutselvan; Arksey, Natasha; Iagaru, Andrei; Chin, Frederick T; Gambhir, Sanjiv Sam

    2015-01-01

    Manufacturing of 64Cu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-rituximab injection under good manufacturing practices (GMP) was validated for imaging of patients with CD20+ B-cell non-Hodgkin lymphoma. Rituximab was purified by size exclusion high performance liquid chromatography (HPLC) and conjugated to DOTA-mono-(N-hydroxysuccinimidyl) ester. 64CuCl2, buffers, reagents, and other raw materials were obtained as high-grade quality. Following a semi-automated synthesis of 64Cu-DOTA-rituximab, a series of quality control tests was performed. The product was further tested in vivo using micro-positron emission tomography/computed tomography (PET/CT) to assess targeting ability towards human CD20 in transgenic mice. Three batches of 64Cu-DOTA-rituximab final product were prepared as per GMP specifications. The radiolabeling yield from these batches was 93.1 ± 5.8%; these provided final product with radiopharmaceutical yield, purity, and specific activity of 59.2 ± 5.1% (0.9 ± 0.1 GBq of 64Cu), > 95% (by HPLC and radio-thin layer chromatography), and 229.4 ± 43.3 GBq/µmol (or 1.5 ± 0.3 MBq/µg), respectively. The doses passed apyrogenicity and human serum stability specifications, were sterile up to 14 days, and retained > 60% immunoreactivity. In vivo micro-PET/CT mouse images at 24 hours postinjection showed that the tracer targeted the intended sites of human CD20 expression. Thus, we have validated the manufacturing of GMP grade 64Cu-DOTA-rituximab for injection in the clinical setting. PMID:25762106

  4. De novo CD5+ diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort.

    PubMed

    Alinari, Lapo; Gru, Alejandro; Quinion, Carl; Huang, Ying; Lozanski, Arletta; Lozanski, Gerard; Poston, Jacqueline; Venkataraman, Girish; Oak, Eunhye; Kreisel, Friederike; Park, Steven I; Matthews, Stephanie; Abramson, Jeremy S; Iris Lim, Hana; Martin, Peter; Cohen, Jonathon B; Evens, Andrew; Al-Mansour, Zeina; Singavi, Arun; Fenske, Timothy S; Blum, Kristie A

    2016-06-01

    De novo CD5+ diffuse large B-cell lymphomas (DLBCL) are a distinct subgroup of DLBCL with poor prognosis. However the role of rituximab-containing therapy and salvage stem cell transplantation in this patients' population remain to be defined. We retrospectively reviewed clinical features and outcomes of 102 patients with de novo CD5+ DLBCL treated with rituximab-containing therapy at nine different institutions. By Hans' criteria, 64 patients had activated B-cell (ABC) subtype, 24 germinal center B-cell (GCB) subtype, and 14 were not evaluated. No patients had a myc translocation. Eighty-three patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), 7 with rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, prednisone (R-EPOCH), and 6 with R-CHOP with methotrexate, 3 g/m(2) . The overall response rate to front-line therapy was 85%. The 3-year progression free survival (PFS) and overall survival (OS) for all patients were 40 and 65%, respectively. The 3-year PFS for ABC- and GCB-subtypes was 34 and 45%, respectively. The 3-year OS for ABC- and GCB-subtypes was 62 and 67%, respectively. The median time to second treatment failure was 3 months and 1 month for ABC- and GCB-subtypes, respectively. Twenty of 28 (71%) transplanted patients with autologous, allogeneic, or both, relapsed. This study confirms the poor prognosis of de novo CD5+ DLBCL in a large multi-center cohort despite initial rituximab-containing chemotherapy and suggests that stem cell transplantation fails to salvage the majority of these patients. Approaches to prevent recurrence and/or novel therapies for relapsed disease are needed for this subgroup of DLBCL patients. PMID:26800311

  5. An approach for conjugation of 177Lu- DOTA-SCN- Rituximab (BioSim) & its evaluation for radioimmunotherapy of relapsed & refractory B-cell non Hodgkins lymphoma patients

    PubMed Central

    Thakral, Parul; Singla, Suhas; Yadav, Madhav Prasad; Vasisht, Atul; Sharma, Atul; Gupta, Santosh Kumar; Bal, C.S.; Snehlata; Malhotra, Arun

    2014-01-01

    Background & objectives: The prerequisite of radioimmunotherapy is stable binding of a radionuclide to monoclonal antibodies, which are specific to the tumour-associated antigen. Most B-cell lymphomas express CD20 antigen on the surface of the tumour cells, making it a suitable target for therapeutic radioactive monoclonal antibodies. In the present study, the immunoconjugate of biosimilar Rituximab (Reditux™) and macrocyclic chelator, p-SCN-Bz-DOTA, was prepared and radiolabelled with Lutetium-177 followed by quality control procedures. Methods: Rituximab(BioSim) was desalted with sodium bicarbonate (0.1M, pH 9.0) and incubated with DOTA-SCN (1:50). The effectiveness of the conjugation was evaluated by determining the number of chelators per antibody molecule. This conjugate was radiolabelled with Lutetium-177 and purified using PD10 column. The quality control parameters like pH, clarity, radiochemical purity, in vitro stability and sterility were studied. Immunoreactivity of 177Lu-DOTA-Rituximab (BioSim) was assessed using RAMOS cells. The radioimmunoconjugate (RIC) after stringent quality assurance was injected in three patients and the biodistribution profile was analysed. Results: An average of 4.25 ± 1.04 p-SCN-Bz-DOTA molecules could be randomly conjugated to a single molecule of Rituximab (BioSim). The radiochemical purity of the labelled antibody was > 95 per cent with preserved affinity for CD20 antigen. The final preparation was stable up to about 120 h when tested under different conditions. A favourable biodistribution profile was observed with liver showing the maximum uptake of the RIC. Interpretation & conclusions: A favourable radiochemical purity, stability and biodistribution of the radiolabelled immunoconjugate indicate that clinical trials for evaluation of toxicity and efficacy of 177Lu-DOTA-antiCD20 antibody-Rituximab (BioSim) in patients of relapsed and refractory non Hodgkin's lymphoma can be considered. PMID:24927340

  6. Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/hepatitis B core antibody positive patients receiving rituximab-containing combination chemotherapy without routine antiviral prophylaxis.

    PubMed

    Koo, Yu Xuan; Tay, Matthew; Teh, Yii Ean; Teng, David; Tan, Daniel S W; Tan, Iain B H; Tai, David W M; Quek, Richard; Tao, Miriam; Lim, Soon Thye

    2011-10-01

    The use of rituximab has been associated with increased risk of hepatitis B virus (HBV) reactivation in patients who are hepatitis B surface antigen (HBsAg) negative and antihepatitis B core antibody (anti-HBc) positive. We aim to determine the rate of HBV reactivation in this group of patients who received rituximab-containing combination chemotherapy without concomitant antiviral prophylaxis and to identify potential risk factors for reactivation. Sixty-two HBsAg negative/anti-HBc positive patients with B-cell lymphoma treated with rituximab-based immunochemotherapy from 2006 to 2009 were included. None of the patients received concomitant antiviral prophylaxis. In this cohort, 48 (77%) patients received rituximab with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), eight (13%) received rituximab with cyclophosphamide, vincristine and prednisolone, and six (10%) received other chemotherapy regimens. Two patients suffered HBV reactivation; both were above 70 years of age, received R-CHOP chemotherapy and were negative for antihepatitis B surface antibody (anti-HBs) at baseline. One of the two patients reactivated shortly after completion of R-CHOP chemotherapy while the other reactivated during rituximab maintenance treatment. Thus, the overall reactivation rate in this cohort of patients is 3% (2/62), 4% (2/48), and 25% (1/4) in patients who received R-CHOP chemotherapy and who received rituximab maintenance, respectively. The rate of HBV reactivation is low in patients who are HBsAg negative/anti-HBc positive receiving rituximab-based combination chemotherapy without concomitant antiviral prophylaxis. However, elderly patients, particularly those without anti-HBs, seemed particularly at risk. PMID:21520001

  7. Fludarabine-Mitoxantrone-Rituximab regimen in untreated indolent non-follicular non-Hodgkin's lymphoma: experience on 143 patients.

    PubMed

    Zinzani, Pier Luigi; Pellegrini, Cinzia; Broccoli, Alessandro; Gandolfi, Letizia; Stefoni, Vittorio; Casadei, Beatrice; Maglie, Roberto; Argnani, Lisa; Pileri, Stefano

    2015-09-01

    Indolent non-follicular lymphomas (inFLs) are generally regarded as incurable, apart from extranodal mucosa-associated lymphatic tissue lymphomas, which can be partially cured by surgery, local radiotherapy, or antibiotic treatment. The aim of the present study was to test the degree of effectiveness and the safety of the regimen containing fludarabine, mitoxantrone, and rituximab (FMR) in inFL patients considering all the different entities belonging to this group. An observational retrospective study was conducted on 143 inFL patients providing that their first chemoimmunotherapy performed was FMR regimen and diagnosis from September 2000 to March 2011. There were 32 small lymphocytic lymphomas and 111 marginal zone lymphomas. At the end of treatment, overall response rate was 96.5% with 88% of complete responses (CR) and 8.5% of partial responses. With a median follow-up of 48 months, 10 out of 125 (8%) CR patients had disease relapse, yielding an estimated 9-year disease-free survival (DFS) of 74.9% and an estimated 10-year overall survival of 92.8%. The estimated 9-year progression free survival was 70.5%. The 10 relapsed patients showed lymphoma recurrence within 52 months: after this time, the DFS curve presented a plateau configuration. Only two (1.4%) patients developed a secondary hematological neoplasia. This study showed promising findings for the use of a fludarabine-based regimen in combination with rituximab in the front-line treatment of symptomatic inFL with a noteworthy high percentage of CR associated to an interesting long-term DFS and favorable acute and long-term safety profile. PMID:24986783

  8. Grandparents' Rights. Report from the Committee on Education and Labor. House of Representatives, Ninety-Ninth Congress, First Session. To Accompany H. Con. Res. 67.

    ERIC Educational Resources Information Center

    Congress of the U.S., Washington, DC. House Committee on Education and Labor.

    This document is a report on a resolution recommending that states develop and adopt a Uniform Grandparent's Visitation Act which would allow grandparents to petition state courts for the right to visit their grandchildren after the dissolution of the grandchildren's parents' marriage (by divorce, separation, or death). The resolution calls for…

  9. A multicenter phase II study incorporating high-dose rituximab and liposomal doxorubicin into the CODOX-M/IVAC regimen for untreated Burkitt's lymphoma

    PubMed Central

    Evens, A. M.; Carson, K. R.; Kolesar, J.; Nabhan, C.; Helenowski, I.; Islam, N.; Jovanovic, B.; Barr, P. M.; Caimi, P. F.; Gregory, S. A.; Gordon, L. I.

    2013-01-01

    Background Despite improvement with intensive multi-agent chemotherapy, 2-year progression-free survival (PFS) rates for adults with high-risk Burkitt's lymphoma (BL) remains <55%. Patients and methods We conducted a phase II trial for newly diagnosed classic BL utilizing liposomal doxorubicin (Adriamycin) in lieu of doxorubicin and incorporating intravenous rituximab (at 500 mg/m2 twice/cycle) into the CODOX-M/IVAC regimen. Correlative analyses included paired serum and cerebrospinal fluid (CSF) rituximab levels and close examination of cardiac function. Results Among 25 BL patients, the median age was 44 years (23–70) and 4 patients were HIV positive. There were 20 high-risk and 5 low-risk patients. At baseline, 40% of high-risk patients had bone marrow involvement, 35% had bulky disease and 15% had central nervous system involvement. The overall response rate was 100% (complete remission 92%). At 34-month median follow-up, the 2-year PFS and overall survival (OS) rates for all patients were 80% and 84%, respectively (low-risk: both 100%; high-risk: 76% and 81%, respectively). Furthermore, the 2-year PFS, OS, and disease-specific survival (DSS) rates for high-risk, HIV-negative patients were 84%, 89% and 100%, respectively. Adverse events (AEs) appeared to be consistent with prior CODOX-M/IVAC data, although there were several grade 3 cardiac events noted (all declined ejection fraction without clinical symptoms). The mean serum rituximab levels at 24 h after cycles 1 and 3 for patients without relapse were 258 and 306 μg/ml, respectively, versus 131 and 193 μg/ml, respectively, for patients with early progression (P = 0.002 and 0.002, respectively). The mean CSF rituximab levels for all patients were 0.11 and 0.24 μg/ml, respectively, at cycle 1 (24/72 h), which equated to serum:CSF ratios of 0.05% and 0.20%, respectively. Conclusions The integration of rituximab into CODOX-M/IVAC for adult BL was feasible and tolerable, while changes in cardiac function

  10. Persistence and selection of an expanded B-cell clone in the setting of rituximab therapy for Sjögren’s syndrome

    PubMed Central

    2014-01-01

    Introduction Subjects with primary Sjögren’s syndrome (SjS) have an increased risk of developing B-cell lymphoma and may harbor monoclonal B-cell expansions in the peripheral blood. Expanded B-cell clones could be pathogenic, and their persistence could exacerbate disease or predispose toward the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B-cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B-cell clones in the blood of subjects with primary SjS who were treated with rituximab. Methods To determine whether circulating B-cell clones in subjects with primary SjS emerge or remain after B cell-depleting therapy with rituximab, we studied the antibody heavy-chain repertoire. We performed single-memory B-cell and plasmablast sorting and antibody heavy-chain sequencing in six rituximab-treated SjS subjects over the course of a 1-year follow-up period. Results Expanded B-cell clones were identified in four out of the six rituximab-treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH, and JH gene segments. We identified one SjS subject with a large expanded B-cell clone that was present prior to therapy and persisted after therapy. Somatic mutations in the clone were numerous but did not increase in frequency over the course of the 1-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection. Conclusions For some subjects with primary SjS, these data show that (a) expanded B-cell clones are readily identified in the peripheral blood, (b) some clones are not eliminated by rituximab, and (c) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an

  11. Long-term outcome of patients in the LNH-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d'Etudes des Lymphomes de l'Adulte.

    PubMed

    Coiffier, Bertrand; Thieblemont, Catherine; Van Den Neste, Eric; Lepeu, Gérard; Plantier, Isabelle; Castaigne, Sylvie; Lefort, Sophie; Marit, Gérald; Macro, Margaret; Sebban, Catherine; Belhadj, Karim; Bordessoule, Dominique; Fermé, Christophe; Tilly, Hervé

    2010-09-23

    We report the outcome of patients included in the LNH-98.5 study, which compared cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) to rituximab plus CHOP (R-CHOP) therapy in 399 patients with diffuse large B-cell lymphoma (DLBCL) aged 60 to 80 years, with a median follow-up time of 10 years. Clinical event information was updated in all living patients (with the exception of 3 patients) in 2009. Survival end points were improved in patients treated with R-CHOP: the 10-year progression-free survival was 36.5%, compared with 20% with CHOP alone, and the 10-year overall survival was 43.5% compared with 27.6%. The same risk of death due to other diseases, secondary cancers, and late relapses was observed in both study arms. Relapses occurring after 5 years represented 7% of all disease progressions. The results from the 10-year analysis confirm the benefits and tolerability of the addition of rituximab to CHOP. Our findings underscore the need to treat elderly patients as young patients, with the use of curative chemotherapy. PMID:20548096

  12. RoboCon: A general purpose telerobotic control center

    SciTech Connect

    Draper, J.V.; Noakes, M.W.; Schempf, H.; Blair, L.M.

    1997-02-01

    This report describes human factors issues involved in the design of RoboCon, a multi-purpose control center for use in US Department of Energy remote handling applications. RoboCon is intended to be a flexible, modular control center capable of supporting a wide variety of robotic devices.

  13. Breath Analysis Science at PittCon 2012, Orlando, Florida

    EPA Science Inventory

    Breath analysis science was featured in three organized sessions at this year’s Pittsburgh Conference and Exposition, or ‘PittCon 2012’ (http://www.pittcon.org/). As described in previous meeting reports, PittCon is one of the largest international conferences for analytical chem...

  14. Rituximab-CHOP-ESHAP vs CHOP-ESHAP-high-dose therapy vs conventional CHOP chemotherapy in high-intermediate and high-risk aggressive non-Hodgkin's lymphoma.

    PubMed

    Intragumtornchai, Tanin; Bunworasate, Udomsak; Nakorn, Thanyaphong Na; Rojnuckarin, Ponlapat

    2006-07-01

    With currently available combination chemotherapy regimens, the outcome of the patients newly diagnosed with aggressive non-Hodgkin's lymphoma (NHL) identified as 'high' and 'high-intermediate' risk groups according to the international prognostic index (IPI) is still unsatisfactory and a more innovative therapy is urgently required to improve the survival of the patients. The purpose of this study was to compare the efficacy of rituximab given in combination with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and ESHAP (etoposide, methylprednisolone, high-dose Ara-C, cisplatin) vs CHOP-ESHAP and upfront high-dose therapy (HDT) and autologous stem cell transplantation (ASCT) vs standard CHOP in patients aged < or = 65 years old newly diagnosed with 'high' and 'high-intermediate' risk aggressive lymphoma enrolled onto two consecutive treatment trials at the institute. Between May 1995 - July 2002, 84 patients, aged 15 - 65 years old, with newly diagnosed aggressive NHL and an age-adjusted IPI of 2 or 3 were enrolled. The median age of the patients was 38 years (range 15 - 65). The baseline demographic features, in particular the major prognostic variables, were similar between the treatment groups. Patients treated with rituximab-CHOP-ESHAP received eight cycles of rituximab (375 mg m(-2) on day 1 of cycles 1 - 6 and days 21 and 28 of cycle 7) plus CHOP (day 3 of cycles 1, 3 and 5) and ESHAP (day 3 of cycles 2, 4 and 6 and day 1 of cycle 7) at 21-day intervals. Patients enrolled onto the CHOP-ESHAP-HDT arm (n = 23) were treated with three courses of CHOP and then switched to two or four cycles of ESHAP followed by HDT. Patients treated with CHOP alone (n = 25) were treated with the standard eight cycles of CHOP. The rate of complete remission was significantly improved with rituximab-CHOP-ESHAP compared with either CHOP-ESHAP-HDT or CHOP alone (67% compared with 44% and 36%, respectively; p = 0.043). With a median follow-up time of 53 months, the 5

  15. Immune-mediated necrotising myopathy associated with antibodies to the signal recognition particle treated with a combination of rituximab and cyclophosphamide.

    PubMed

    Fernandes das Neves, Marisa; Caetano, Joana; Oliveira, Susana; Delgado Alves, José

    2015-01-01

    A 50-year-old man presented with dysphagia and proximal muscle weakness. He was diagnosed with immune-mediated necrotising myopathy associated with antibodies to the signal recognition particle. After an initial response following treatment with high-dose steroids, intravenous immunoglobulin and methotrexate, there was a relapse of the immune condition. The clinical deterioration occurred less than 2 months after disease onset. The refractoriness of this disease was characterised by an increase of the already severe muscle wasting that led to respiratory failure and progressive dysphagia, regardless of the immunosuppressant treatment. At this time the patient was referred to our department. He was restarted on intravenous pulses of methylprednisolone associated with intravenous cyclophosphamide, but with no effect. After 3 weeks, rituximab was started with a dramatic and progressive improvement. There were no complications associated with rituximab/cyclophosphamide treatment and the disease has been kept in remission, for the last 3 years. PMID:26240092

  16. Rituximab in combination with platinum-containing chemotherapy in patients with relapsed or primary refractory diffuse large B-cell lymphoma.

    PubMed

    Bieker, Ralf; Kessler, Torsten; Berdel, Wolfgang E; Mesters, Rolf M

    2003-01-01

    The aim of the study was to evaluate the efficacy of a regimen consisting of rituximab and a platinum-containing chemotherapy with either Ifosfamide, Carboplatin and Etoposide (ICE) or Cisplatin, high-dose Ara-C and Dexamethasone (DHAP) in patients with relapsed or primary refractory diffuse large B-cell lymphoma. Ten patients with relapsed or primary refractory diffuse large B-cell lymphoma were treated from June 2000 until May 2001 with a platinum-containing chemotherapy regimen according to the ICE- or DHAP-protocol in combination with rituximab at the University of Muenster. Two cycles of ICE or DHAP and rituximab were given. In case of at least a minor response after 2 cycles, 2 additional cycles of the same combination were applied. Response rate, remission duration and duration of survival were evaluated. All 10 patients could be analysed with respect to these endpoints. No treatment related mortality was observed. The response rate (CR/PR) was 60% (10/50%). Twenty percent of the patients had progressive disease. The median duration of remission and survival was 3 and 3.5 months, respectively (range: 1-6 and 1-7 months, respectively), the survival rate was 10%. Eight of 10 patients died because of their underlying disease with short remission duration, 1 patient died of complications of allogeneic transplantation in CR. In conclusion, the combination of platinum-containing chemotherapy (ICE or DHAP) with rituximab demonstrates significant activity in intensively pretreated patients with relapsed or primary refractory diffuse large B-cell lymphoma. Considering the short duration of remission and survival, respectively, other experimental therapeutic approaches (e.g. allogeneic stem cell transplantation, radioimmunotherapy) should be pursued following this treatment in order to induce long-term remission. PMID:14534718

  17. Survival impact of rituximab combined with ACVBP and upfront consolidation autotransplantation in high-risk diffuse large B-cell lymphoma for GELA

    PubMed Central

    Fitoussi, Olivier; Belhadj, Karim; Mounier, Nicolas; Parrens, Marie; Tilly, Hervé; Salles, Gilles; Feugier, Pierre; Ferme, Christophe; Ysebaert, Loic; Gabarre, Jean; Herbrecht, Raoul; Janvier, Maud; Van Den Neste, Eric; Morschhauser, Franck; Casasnovas, Olivier; Ghesquieres, Hervé; Anglaret, Bruno; Brechignac, Sabine; Haioun, Corinne; Gisselbrecht, Christian

    2011-01-01

    Background As rituximab combined with CHOP improves complete remission and overall survival in diffuse large B-cell lymphoma, intensified chemotherapy followed by autologous stem-cell transplantation has also been advocated for high-risk patients. The aim of this study was to establish whether or not combining rituximab with high-dose chemotherapy and auto-transplantation also benefits patient survival. Design and Methods The LNH2003-3 study was a phase II trial including diffuse large B-cell lymphoma patients with 2 or 3 International Prognostic Index factors. They received four cycles of intensive biweekly chemotherapy with rituximab, doxorubicine, cyclophosphamide, vindesine, bleomycine, prednisolone (R-ACVBP) followed by auto-transplantation in responding patients. Two hundred and nine patients under 60 years of age were included in the study and 155 responding patients underwent auto-transplantation. In addition, a case-control study was performed by matching (1:1) 181 patients treated with R-ACVBP with ACVBP patients not given rituximab but submitted to auto-transplantation from the previous LNH1998-3 trial. Results With a median follow up of 45 months, 4-year progression-free survival and overall survival were estimated at 76% (CI: 69–81) and 78% (CI: 72–83), respectively. There was no difference between patients with 2 or 3 International Prognostic Index factors. Four year progression-free survival was significantly higher in R-ACVBP than ACVBP patients (74% vs. 58%; P=0.0005). There was also a significant increase in 4-year overall survival (76% vs. 68%; P=0.0494). Conclusions In high-risk diffuse large B-cell lymphoma patients, treatment with R-ACVBP followed by auto-transplantation results in a 78% 4-year overall survival which should be compared to other approaches. (Clinicaltrials.gov identifier: NCT00144807) PMID:21546499

  18. RITPBC: B-cell depleting therapy (rituximab) as a treatment for fatigue in primary biliary cirrhosis: study protocol for a randomised controlled trial

    PubMed Central

    Jopson, Laura; Newton, Julia L; Palmer, Jeremy; Floudas, Achilleas; Isaacs, John; Qian, Jessica; Wilkinson, Jennifer; Trenell, Mike; Blamire, Andrew; Howel, Denise; Jones, David E

    2015-01-01

    Introduction Primary biliary cirrhosis (PBC) is an autoimmune liver disease with approximately 50% of patients experiencing fatigue. This can be a particularly debilitating symptom, affecting quality of life and resulting in social isolation. Fatigue is highlighted by patients as a priority for research and patient support groups were involved in designing this trial. This is the first randomised controlled trial to investigate a treatment for fatigue in PBC. The trial protocol is innovative as it utilises novel magnetic resonance spectroscopy (MRS) techniques as an outcome measure. The protocol will be valuable to research groups planning clinical trials targeting fatigue in PBC and also transferrable to other conditions associated with fatigue. Methods and analysis RITPBC is a Medical Research Council (MRC) and National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation Programme (EME)-funded project. It is a phase II, single-centre, randomised controlled, double-blinded trial comparing rituximab with placebo in fatigued PBC patients. 78 patients with PBC and moderate to severe fatigue will be randomised to receive two infusions of rituximab or placebo. The study aims to assess whether rituximab improves fatigue in patients with PBC, the safety, and tolerability of rituximab in PBC and the sustainability of any beneficial actions. The primary outcome will be an improvement in fatigue domain score of the PBC-40, a disease-specific quality of life measure, evaluated at 12-week assessment. Secondary outcome measures include novel MRS techniques assessing muscle bioenergetic function, physical activity, anaerobic threshold and symptom, and quality of life measures. The trial started recruiting in October 2012 and recruitment is ongoing. Ethics and dissemination The trial has ethical approval from the NRES Committee North East, has Clinical Trial Authorisation from MHRA and local R&D approval. Trial results will be communicated to participants

  19. Impaired Response to Influenza Vaccine Associated with Persistent Memory B Cell Depletion in Non-Hodgkin’s Lymphoma Patients Treated with Rituximab-Containing Regimens

    PubMed Central

    Bedognetti, Davide; Zoppoli, Gabriele; Massucco, Carlotta; Zanardi, Elisa; Zupo, Simonetta; Bruzzone, Andrea; Sertoli, Mario Roberto; Balleari, Enrico; Racchi, Omar; Messina, Marco; Caltabiano, Graziano; Icardi, Giancarlo; Durando, Paolo; Marincola, Francesco M.; Boccardo, Francesco; Ferrarini, Manlio; Ansaldi, Filippo; De Maria, Andrea

    2012-01-01

    Influenza vaccination is generally recommended for non-Hodgkin’s lymphoma (NHL) patients, but no data are available about the activity of this vaccine after treatment with rituximab-containing regimens. We evaluated the humoral response to the trivalent seasonal influenza vaccine in a group of NHL patients in complete remission for ≥6 mo (median, 29 mo) after treatment with rituximab-containing regimens (n = 31) compared with age-matched healthy subjects (n = 34). B cell populations and incidence of influenza-like illness were also evaluated. For each viral strain, the response was significantly lower in patients compared with controls and was particularly poor in patients treated with fludarabine-based regimens. In the patient group, the response to vaccination did not fulfill the immunogenic criteria based on the European Committee for Medicinal Products for Human Use requirements. Among the patients, CD27+ memory B cells were significantly reduced, and their reduction correlated with serum IgM levels and vaccine response. Episodes of influenza-like illness were recorded only in patients. These results showed that NHL patients treated with rituximab-containing regimens have persisting perturbations of B cell compartments and Ig synthesis and may be at particular risk for infection, even in long-standing complete remission. PMID:21498665

  20. Clinico-biological characterization and outcome of primary nodal and extranodal diffuse large B-cell lymphoma in the rituximab era.

    PubMed

    Gutiérrez-García, Gonzalo; Colomo, Lluis; Villamor, Neus; Arenillas, Leonor; Martínez, Antonio; Cardesa, Teresa; García-Herrera, Adriana; Setoain, Xavier; Rodríguez, Sonia; Ghita, Gabriela; Abrisqueta, Pau; Giné, Eva; Bosch, Francesc; Campo, Elías; Montserrat, Emilio; López-Guillermo, Armando

    2010-07-01

    To study the main clinico-biological characteristics and the outcome of patients with diffuse large B-cell lymphoma (DLBCL) according to the primary site (nodal vs. extranodal), we included 262 patients consecutively diagnosed with DLBCL in a single institution, 5 years before and after immunochemotherapy was considered as the standard treatment. Altogether 116 patients received CHOP (cyclophosphamide, adriamycin, vincristine, and prednisone) and 146 rituximab plus CHOP (R-CHOP). The primary site was the lymph node in 140 patients (53%), Waldeyer's ring (WR) in 22, gastrointestinal (GI) in 33, and other extranodal in 67. The addition of rituximab significantly improved the CR rate in nodal, but not in extranodal, lymphomas. Patients receiving R-CHOP showed higher OS than those treated with CHOP alone (5-year OS: 71% vs. 48%). This difference was maintained in primary nodal (5-year OS: 69% vs. 37%, p < 0.0001), but was not observed in primary extranodal (75% vs. 65%, p = 0.45) lymphomas. The IPI, treatment, and primary site were the main variables for OS in multivariate analysis. In nodal cases, IPI and treatment maintained value, whereas only IPI predicted OS in extranodal cases. In conclusion, immunochemotherapy treatment dramatically improved the outcome of patients with nodal DLBCL; however, its effect was less in primary extranodal cases, so the prognosis of patients with nodal and extranodal lymphomas has been equalized in the rituximab era. PMID:20497002

  1. Role of radiation therapy in primary mediastinal large B-cell lymphoma in rituximab era: A US population-based analysis.

    PubMed

    Giri, Smith; Bhatt, Vijaya Raj; Pathak, Ranjan; Bociek, R Gregory; Vose, Julie M; Armitage, James O

    2015-11-01

    The use of radiation (RT) in primary mediastinal large B-cell lymphoma (PMBCL) may predispose young patients to the risk of cardiopulmonary toxicities and secondary malignancies. We used Surveillance, Epidemiology and End Results (SEER) 18 database to compare the overall survival (OS) differences among adult patients treated with and without RT after rituximab approval in the US. Multivariate analyses were performed using Cox proportional hazards regression to compare OS based on the use of RT while adjusting for age, year of diagnosis, race, stage and gender. PMBCL patients (n = 258), who received RT (48%), were similar in terms of age, gender, race, and stage at diagnosis to patients who did not receive RT. The five year OS was similar between patients treated with versus without RT (82.5% vs. 78.6%, P = 0.47). In a multivariate analysis, the use of RT did not influence OS in the rituximab era (HR 0.83; 95% CI 0.43-1.59; P = 0.56). Rituximab may reduce the benefit of RT in select patients such as those who achieve a metabolic complete remission at the end of chemotherapy. PMID:26270899

  2. Long-term efficacy of rituximab in IgM anti-myelin-associated glycoprotein neuropathy: RIMAG follow-up study.

    PubMed

    Iancu Ferfoglia, Ruxandra; Guimarães-Costa, Raquel; Viala, Karine; Musset, Lucile; Neil, Jean; Marin, Benoit; Léger, Jean-Marc

    2016-03-01

    The Rituximab vs. Placebo in Polyneuropathy Associated With Anti-MAG IgM Monoclonal Gammopathy (RIMAG) study showed no improvement using the inflammatory neuropathy cause and treatment sensory score (ISS) as primary outcome in patients with IgM anti-myelin-associated glycoprotein neuropathy (IgM anti-MAG neuropathy) treated with rituximab, when compared with placebo. However, some secondary outcomes seemed to improve in the per protocol analysis. Patients from one participating center in the RIMAG study underwent a new evaluation after a median follow-up of 6 (interquartile range (IQR) 4.9; 6.5) years, using the same outcome measures used in the original study. Data were recorded in seven rituximab patients (group 1) and in eight placebo patients (group 2). In group 2, six of eight patients received immunotherapy during follow-up, while only two of seven did in group 1. No significant change was observed in either the ISS or the secondary outcomes in both groups, with the exception of worsening in the 10-m walk time in group 2 (p = 0.016). The RIMAG follow-up study failed to find any significant change in most outcome measures in patients from the RIMAG study, some of them having received new immunotherapies. This study stresses the lack of useful clinical scales sensitive enough to capture small, even meaningful, improvement in IgM anti-MAG neuropathy. PMID:26748872

  3. Cost-effectiveness of rituximab in addition to fludarabine and cyclophosphamide (R-FC) for the first-line treatment of chronic lymphocytic leukemia.

    PubMed

    Müller, Dirk; Fischer, Kirsten; Kaiser, Peter; Eichhorst, Barbara; Walshe, Ronald; Reiser, Marcel; Kellermann, Lenka; Borsi, Lisa; Civello, Daniele; Mensch, Alexander; Bahlo, Jasmin; Hallek, Michael; Stock, Stephanie; Fingerle-Rowson, Günter

    2016-05-01

    The cost-effectiveness of rituximab in combination with fludarabine/cyclophosphamide (R-FC) for the first line treatment of chronic lymphocytic leukemia (CLL) was evaluated. Based on long-term clinical data (follow-up of 5.9 years) from the CLL8-trial, a Markov-model with three health states (Free from disease progression, Progressive disease, Death) was used to evaluate the cost per quality-adjusted life-year (QALY) and cost per life years gained (LYG) of R-FC from the perspective of the German statutory health insurance (SHI). The addition of rituximab to FC chemotherapy results in a gain of 1.1 quality-adjusted life-years. The incremental cost-effectiveness ratio (ICER) of R-FC compared with FC was €17 979 per QALY (€15 773 per LYG). Results were robust in deterministic and probabilistic sensitivity analyses. From the German SHI perspective, rituximab in combination with FC chemotherapy represents good value for first-line treatment of patients with CLL and compares favorably with chemotherapy alone. PMID:26584689

  4. Chlorambucil plus Rituximab as Front-Line Therapy in Elderly/Unfit Patients Affected by B-Cell Chronic Lymphocytic Leukemia: Results of a Single-Centre Experience

    PubMed Central

    Laurenti, Luca; Vannata, Barbara; Innocenti, Idanna; Autore, Francesco; Santini, Francesco; Piccirillo, Nicola; Za, Tommaso; Bellesi, Silvia; Marietti, Sara; Sica, Simona; Efremov, Dimitar G.; Leone, Giuseppe

    2013-01-01

    The current standard first line therapy for fit patients with B-CLL/SLL is based on combination of fludarabine-cyclophosphamide and rituximab. However, elderly patients or patients with comorbidities poorly tolerate purine analogue-based chemotherapy and they are often treated with Chlorambucil (Chl) only. However, complete response (CR) and overall response (OR) rates with Chl are relatively low. We now investigated whether the addition of Rituximab to Chl will improve the efficacy without impairing the tolerability in elderly and unfit patients. We included in our study 27 elderly or unfit patients that had not received prior therapy. All patients were treated with Chl (1mg/Kg per 28-day cycle for 8 cycles) plus Rituximab (375 mg/m2 for the first course and 500 mg/m2 for subsequent cycles until the 6th cycle). We obtained an OR rate of 74%. The most frequent adverse effect was grade 3–4 neutropenia, which occurred in 18.5% of the patients. Infections or grade 3–4 extra-hematological side effects were not recorded. None of the patients required reduction of dose, delay of therapy or hospitalization. Overall, these data suggest that Chl-R is an effective and well tolerated regimen in elderly/unfit patients with CLL. PMID:23667729

  5. Nam Con Son Basin

    SciTech Connect

    Tin, N.T.; Ty, N.D.; Hung, L.T.

    1994-07-01

    The Nam Con Son basin is the largest oil and gas bearing basin in Vietnam, and has a number of producing fields. The history of studies in the basin can be divided into four periods: Pre-1975, 1976-1980, 1981-1989, and 1990-present. A number of oil companies have carried out geological and geophysical studies and conducted drilling activities in the basin. These include ONGC, Enterprise Oil, BP, Shell, Petro-Canada, IPL, Lasmo, etc. Pre-Tertiary formations comprise quartz diorites, granodiorites, and metamorphic rocks of Mesozoic age. Cenozoic rocks include those of the Cau Formation (Oligocene and older), Dua Formation (lower Miocene), Thong-Mang Cau Formation (middle Miocene), Nam Con Son Formation (upper Miocene) and Bien Dong Formation (Pliocene-Quaternary). The basement is composed of pre-Cenozoic formations. Three fault systems are evident in the basin: north-south fault system, northeast-southwest fault system, and east-west fault system. Four tectonic zones can also be distinguished: western differentiated zone, northern differentiated zone, Dua-Natuna high zone, and eastern trough zone.

  6. Immunochemotherapy for primary central nervous system lymphoma with rituximab, methotrexate, cytarabine and dexamethasone: Retrospective analysis of 18 cases

    PubMed Central

    LIU, JING; SUN, XUE-FEI; QIAN, JUN; BAI, XUE-YAN; ZHU, HONG; CUI, QU; LI, XIAO-YAN; CHEN, YUE-DAN; WANG, YA-MING; LIU, YUAN-BO

    2015-01-01

    The incidence of primary central nervous system lymphoma (PCNSL) has increased in the last two decades and the clinical research regarding the treatment for PCNSL patients has also increased. However, the optimal induction chemotherapy has not been fully established. In the present retrospective study, the aim was to analyze the outcome in PCNSL patients treated with the combination of rituximab, methotrexate (MTX), cytarabine (Ara-C) and dexamethasone (R-MAD). Eighteen patients from Beijing Tiantan Hospital (Beijing, China) between January 2010 and March 2014 were newly diagnosed with PCNSL [diffuse large B-cell lymphoma (DLBCL) type] and received R-MAD as first-line treatment. The dosage was as follows: 375 mg/m2 rituximab was administered on day 0, 3.5 g/m2 MTX was administered on day 1, 1 g/m2 Ara-C was administered on day 2 and 10 mg dexamethasone was administered on days 1–3, every 3 weeks. After 6 cycles, the overall response rate was 94.5%. Ten (55.6%) patients achieved complete response (CR), 7 (38.9%) achieved partial response (PR) and 1 (5.6%) had progressive disease (PD). Patients were followed up from the start of the treatment, median 24.2 months (range 6–48). The overall survival (OS) rate was 94.5% and progression-free survival rate was 94.5%. The median OS was 22 months (95% confidence interval, 19.4–24.6). The high level of serum lactate dehydrogenase (LDH) concentration was associated with a poor outcome. Among 5 patients with an abnormally high LDH concentration, 1 achieved CR, 3 had PR and 1 had PD. None of the patients experienced any grade 4 toxicity. These results indicated that the R-MAD immunochemotherapy regimen is effective in PCNSL patients without serious toxicity. A prospective investigation with more patients should be administered in order to understand the more accurate effect of the regimen. PMID:26171213

  7. Rituximab in combination with CHOP chemotherapy for the treatment of diffuse large B cell lymphoma in Japan: a retrospective analysis of 1,057 cases from Kyushu Lymphoma Study Group.

    PubMed

    Seki, Ritsuko; Ohshima, Koichi; Nagafuji, Koji; Fujisaki, Tomoaki; Uike, Naokuni; Kawano, Fumio; Gondo, Hisashi; Makino, Shigeyoshi; Eto, Tetsuya; Moriuchi, Yukiyoshi; Taguchi, Fumihiro; Kamimura, Tomohiko; Tsuda, Hiroyuki; Ogawa, Ryosuke; Shimoda, Kazuya; Yamashita, Kiyoshi; Suzuki, Keiko; Suzushima, Hitoshi; Tsukazaki, Kunihiro; Higuchi, Masakazu; Utsunomiya, Atae; Iwahashi, Masahiro; Imamura, Yutaka; Tamura, Kazuo; Suzumiya, Junji; Yoshida, Minoru; Abe, Yasunobu; Matsumoto, Tadashi; Okamura, Takashi

    2010-03-01

    We performed a retrospective analysis of patients with diffuse large B cell lymphoma treated with rituximab plus CHOP (cyclophosphamide, adriamycin, vincristine and prednisone) as a first-line therapy at 22 hospitals of the Kyushu Lymphoma Study Group. During the period 1996-2005, 1,057 patients (aged 22-90 years) were analyzed. Of these, 678 were treated with CHOP, and 379 were treated with rituximab plus CHOP (R-CHOP). The complete response rate was 59.9% in the CHOP group and 67.0% in the R-CHOP group (P < 0.001). Three-year progression-free survival (PFS) and overall survival (OS) rates were significantly higher in the R-CHOP group than in the CHOP group (61.3 vs. 45.6% for PFS, P < 0.001; 68.3 vs. 54.5% for OS, P < 0.001). The International Prognostic Index was a good prognostic marker for both groups; a survival benefit of rituximab addition was found for each risk subgroup and also for both age groups (60 years). Among 345 patients who received localized radiation therapy, the adding rituximab to CHOP attenuated the survival difference between CHOP and R-CHOP groups (P = 0.104), compared with no radiation group (P < 0.001). Results of this large-scale, multicenter study confirm that rituximab plus CHOP provided a greater survival benefit than CHOP alone. PMID:20066574

  8. Primary central nervous system lymphoma treated with high-dose methotrexate and rituximab: A single-institution experience

    PubMed Central

    LY, K. INA; CREW, LAURA L.; GRAHAM, CARRIE A.; MRUGALA, MACIEJ M.

    2016-01-01

    Rituximab (RTX) improves the outcome in patients with systemic diffuse large B-cell lymphoma (DLBCL), but its benefit in primary central nervous system lymphoma (PCNSL) is unclear. In the present study, a single-institution retrospective analysis was performed for 12 patients with newly diagnosed PCNSL treated with combined high-dose methotrexate (HD-MTX) and RTX. MTX was administered biweekly at 8 g/m2/dose until a complete response (CR) was achieved or for a maximum of eight doses. RTX was provided for a total of eight weekly doses at 375 mg/m2/dose. Following a median of 11 cycles of MTX, the radiographic overall response rate was 91% and the CR rate was 58%. A CR was achieved after a median 6 cycles of MTX. The median progression-free survival time was 22 months and the median overall survival time has not yet been attained. These results compare favorably to single-agent HD-MTX and suggest a role for immunochemotherapy in the treatment of PCNSL. PMID:27123138

  9. Epratuzumab with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy in patients with previously untreated diffuse large B-cell lymphoma

    PubMed Central

    Micallef, Ivana N. M.; Maurer, Matthew J.; Wiseman, Gregory A.; Nikcevich, Daniel A.; Kurtin, Paul J.; Cannon, Michael W.; Perez, Domingo G.; Soori, Gamini S.; Link, Brian K.; Habermann, Thomas M.

    2011-01-01

    Approximately 60% of patients with diffuse large B-cell non-Hodgkin lymphoma (DLBCL) are curable with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemoimmunotherapy. Epratuzumab (E) is an unlabeled anti-CD22 monoclonal antibody with efficacy in relapsed DLBCL. This phase 2 trial tested the safety and efficacy of combining E with R-CHOP (ER-CHOP) in untreated DLBCL. A secondary aim was to assess the efficacy of interim positron emission tomography (PET) to predict outcome in DLBCL. Standard R-CHOP with the addition of E 360 mg/m2 intravenously was administered for 6 cycles. A total of 107 patients were enrolled in the study. Toxicity was similar to standard R-CHOP. Overall response rate in the 81 eligible patients was 96% (74% CR/CRu) by computed tomography scan and 88% by PET. By intention to treat analysis, at a median follow-up of 43 months, the event-free survival (EFS) and overall survival (OS) at 3 years in all 107 patients were 70% and 80%, respectively. Interim PET was not associated with EFS or OS. Comparison with a cohort of 215 patients who were treated with R-CHOP showed an improved EFS in the ER-CHOP patients. ER-CHOP is well tolerated and results appear promising as a combination therapy. This study was registered at www.clinicaltrials.gov as #NCT00301821. PMID:21673350

  10. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia

    PubMed Central

    Terzi-di-Bergamo, Lodovico; De Paoli, Lorenzo; Cerri, Michaela; Ghilardi, Guido; Chiarenza, Annalisa; Bulian, Pietro; Visco, Carlo; Mauro, Francesca R.; Morabito, Fortunato; Cortelezzi, Agostino; Zaja, Francesco; Forconi, Francesco; Laurenti, Luca; Del Giudice, Ilaria; Gentile, Massimo; Vincelli, Iolanda; Motta, Marina; Coscia, Marta; Rigolin, Gian Matteo; Tedeschi, Alessandra; Neri, Antonino; Marasca, Roberto; Perbellini, Omar; Moreno, Carol; Del Poeta, Giovanni; Massaia, Massimo; Zinzani, Pier Luigi; Montillo, Marco; Cuneo, Antonio; Gattei, Valter; Foà, Robin; Gaidano, Gianluca

    2015-01-01

    Fludarabine, cyclophosphamide, and rituximab (FCR) has represented a significant treatment advancement in chronic lymphocytic leukemia (CLL). In the new scenario of targeted agents, there is an increasing interest in identifying patients who gain the maximum benefit from FCR. In this observational multicenter retrospective analysis of 404 CLL patients receiving frontline FCR, the combination of three biomarkers that are widely tested before treatment (IGHV mutation status, 11q deletion and 17p deletion; available in 80% of the study cohort) allowed to identify a very low-risk category of patients carrying mutated IGHV genes but neither 11q or 17p deletion that accounted for 28% of all cases. The majority of very low-risk patients (71%) remained free of progression after treatment and their hazard of relapse decreased after 4 years from FCR. The life expectancy of very low-risk patients (91% at 5 years) was superimposable to that observed in the matched normal general population, indicating that neither the disease nor complications of its treatment affected survival in this favorable CLL group. These findings need a prospective validation and may be helpful for the design of clinical trials aimed at comparing FCR to new targeted treatments of CLL, and, possibly, for optimized disease management. PMID:26276669

  11. Effects of pretransplant plasmapheresis and rituximab on recurrence of focal segmental glomerulosclerosis in adult renal transplant recipients

    PubMed Central

    Park, Hoon Suk; Hong, Yuah; Sun, In O; Chung, Byung Ha; Kim, Hyung Wook; Choi, Bum Soon; Park, Cheol Whee; Jin, Dong Chan; Kim, Yong Soo

    2014-01-01

    Background/Aims Recurrent focal segmental glomerulosclerosis (FSGS) following renal transplantation is relatively common. However, the risk factors and optimal pretransplant treatment preventing recurrence of FSGS remain controversial. Methods We retrospectively reviewed 27 adult renal transplant recipients with FSGS over a period of 10 years. We first compared possible risk factors for FSGS recurrence between the recurrence and nonrecurrence groups. Then we evaluated the effect of pretransplant plasmapheresis (PP; n = 4) and PP with rituximab (PP + RTX; n = 5) on recurrence of FSGS after transplantation compared to control patients that were not treated with these modalities. Results There were seven recurrences in 27 patients (25.9%), but there were no significant differences in possible risk factors for FSGS recurrence between the two groups. Recurrence rates between patients with pretransplant PP or PP + RTX and control patients were not significantly different (22.2% vs. 27.7%, p > 0.05). There was also no significant difference in recurrence between the pretransplant PP and PP + RTX groups (25% vs. 20%, p > 0.05). Conclusions Pretransplant PP or PP + RTX do not significantly decrease the recurrence of FSGS in adult renal transplant candidates. PMID:25045296

  12. First-line treatment with rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine and followed by consolidation with 90Y-ibritumomab-tiuxetan in patients with mantle cell lymphoma. Results of a multicenter, phase 2 pilot trial from the GELTAMO group

    PubMed Central

    Arranz, Reyes; García-Noblejas, Ana; Grande, Carlos; Cannata-Ortiz, Jimena; Sánchez, José J.; García-Marco, José-Antonio; Aláez, Concepción; Pérez-Calvo, Javier; Martínez-Sánchez, Pilar; Sánchez-González, Blanca; Canales, Miguel-Angel; Conde, Eulogio; Martín, Alejandro; Arranz, Eva; Terol, María-José; Salar, Antonio; Caballero, Dolores

    2013-01-01

    The prognosis for fit patients with mantle cell lymphoma has improved with intensive strategies. Currently, the role of maintenance/consolidation approaches is being tested as relapses continue to appear. In this trial we evaluated the feasibility, safety and efficacy of rituximab-hyperCVAD alternating with rituximab-methotrexate-cytarabine followed by consolidation with 90Y-ibritumomab tiuxetan. Patients received six cycles followed by a single dose of 90Y-ibritumomab tiuxetan. Thirty patients were enrolled; their median age was 59 years. Twenty-four patients finished the induction treatment, 23 achieved complete remission (77%, 95% confidence interval 60–93) and one patient had progressive disease (3%). Eighteen patients (60%), all in complete remission, received consolidation therapy. In the intent-to-treat population, failure-free, progression-free and overall survival rates at 4 years were 40% (95% confidence interval 20.4–59.6), 52% (95% confidence interval 32.4–71.6) and 81% (95% confidence interval 67.28–94.72), respectively. For patients who received consolidation, failure-free and overall survival rates were 55% (95% confidence interval 31.48–78.52) and 87% (95% confidence interval 70–100), respectively. Hematologic toxicity was significant during induction and responsible for one death (3.3%). After consolidation, grade 3–4 neutropenia and thrombocytopenia were observed in 72% and 83% of patients, with a median duration of 5 and 12 weeks, respectively. Six (20%) patients died, three due to secondary malignancies (myelodysplastic syndrome and bladder and rectum carcinomas). In conclusion, in our experience, rituximab-hyperCVAD alternated with rituximab-methotrexate-cytarabine and followed by consolidation with 90Y-ibritumomab tiuxetan was efficacious although less feasible than expected. The unacceptable toxicity observed, especially secondary malignancies, advise against the use of this strategy. Trial registration: clinical.gov identifier

  13. The addition of rituximab to fludarabine and cyclophosphamide chemotherapy results in a significant improvement in overall survival in patients with newly diagnosed mantle cell lymphoma: results of a randomized UK National Cancer Research Institute trial

    PubMed Central

    Rule, Simon; Smith, Paul; Johnson, Peter W.M.; Bolam, Simon; Follows, George; Gambell, Joanne; Hillmen, Peter; Jack, Andrew; Johnson, Stephen; Kirkwood, Amy A; Kruger, Anton; Pocock, Christopher; Seymour, John F.; Toncheva, Milena; Walewski, Jan; Linch, David

    2016-01-01

    Mantle cell lymphoma is an incurable and generally aggressive lymphoma that is more common in elderly patients. Whilst a number of different chemotherapeutic regimens are active in this disease, there is no established gold standard therapy. Rituximab has been used widely to good effect in B-cell malignancies but there is no evidence that it improves outcomes when added to chemotherapy in this disease. We performed a randomized, open-label, multicenter study looking at the addition of rituximab to the standard chemotherapy regimen of fludarabine and cyclophosphamide in patients with newly diagnosed mantle cell lymphoma. A total of 370 patients were randomized. With a median follow up of six years, rituximab improved the median progression-free survival from 14.9 to 29.8 months (P<0.001) and overall survival from 37.0 to 44.5 months (P=0.005). This equates to absolute differences of 9.0% and 22.1% for overall and progression-free survival, respectively, at two years. Overall response rates were similar, but complete response rates were significantly higher in the rituximab arm: 52.7% vs. 39.9% (P=0.014). There was no clinically significant additional toxicity observed with the addition of rituximab. Overall, approximately 18% of patients died of non-lymphomatous causes, most commonly infections. The addition of rituximab to fludarabine and cyclophosphamide chemotherapy significantly improves outcomes in patients with mantle cell lymphoma. However, these regimens have significant late toxicity and should be used with caution. This trial has been registered (ISRCTN81133184 and clinicaltrials.gov:00641095) and is supported by the UK National Cancer Research Network. PMID:26611473

  14. The addition of rituximab to fludarabine and cyclophosphamide chemotherapy results in a significant improvement in overall survival in patients with newly diagnosed mantle cell lymphoma: results of a randomized UK National Cancer Research Institute trial.

    PubMed

    Rule, Simon; Smith, Paul; Johnson, Peter W M; Bolam, Simon; Follows, George; Gambell, Joanne; Hillmen, Peter; Jack, Andrew; Johnson, Stephen; Kirkwood, Amy A; Kruger, Anton; Pocock, Christopher; Seymour, John F; Toncheva, Milena; Walewski, Jan; Linch, David

    2016-02-01

    Mantle cell lymphoma is an incurable and generally aggressive lymphoma that is more common in elderly patients. Whilst a number of different chemotherapeutic regimens are active in this disease, there is no established gold standard therapy. Rituximab has been used widely to good effect in B-cell malignancies but there is no evidence that it improves outcomes when added to chemotherapy in this disease. We performed a randomized, open-label, multicenter study looking at the addition of rituximab to the standard chemotherapy regimen of fludarabine and cyclophosphamide in patients with newly diagnosed mantle cell lymphoma. A total of 370 patients were randomized. With a median follow up of six years, rituximab improved the median progression-free survival from 14.9 to 29.8 months (P<0.001) and overall survival from 37.0 to 44.5 months (P=0.005). This equates to absolute differences of 9.0% and 22.1% for overall and progression-free survival, respectively, at two years. Overall response rates were similar, but complete response rates were significantly higher in the rituximab arm: 52.7% vs. 39.9% (P=0.014). There was no clinically significant additional toxicity observed with the addition of rituximab. Overall, approximately 18% of patients died of non-lymphomatous causes, most commonly infections. The addition of rituximab to fludarabine and cyclophosphamide chemotherapy significantly improves outcomes in patients with mantle cell lymphoma. However, these regimens have significant late toxicity and should be used with caution. This trial has been registered (ISRCTN81133184 and clinicaltrials.gov:00641095) and is supported by the UK National Cancer Research Network. PMID:26611473

  15. Vecinos y Rehabilitation: Assessing the Needs of Indigenous People with Disabilities in Mexico. Final Report [English Version] = Vecinos y Rehabilitation: Evaluacion de las Necesidades de los Indigenas con Discapacidades en Mexico. Reporte Final [Version en Espanol].

    ERIC Educational Resources Information Center

    Marshall, Catherine A.; And Others

    Available in English and Spanish, this document reports on a survey of the circumstances and needs of disabled indigenous people in Oaxaca state, Mexico. Assisted by a Oaxaca disabilities consumer organization and an advisory committee of government officials, health care educators, community service providers, and indigenous people with…

  16. The FCGR3A polymorphism predicts the response to rituximab-based therapy in patients with non-Hodgkin lymphoma: a meta-analysis.

    PubMed

    Liu, Duo; Tian, Yuyang; Sun, Donglin; Sun, Haiming; Jin, Yan; Dong, Mei

    2016-09-01

    Epidemiological studies have assessed the association between Fc gamma receptor IIIA (FCGR3A) 158 V/F and the response to rituximab-based therapy in patients with non-Hodgkin lymphoma (NHL), but the findings have been inconsistent. We performed this meta-analysis to obtain a better assessment of this relationship. Electronic database searches were conducted for relevant studies. A pooled odds ratio (OR) with a 95 % confidence interval (95 % CI) was used to assess the strength of the association. Analyses of the subgroup and publication bias were conducted. A total of 10 studies involving 1050 patients were analyzed. In all the genetic models, no clear relationship was found between the FCGR3A 158 V/F polymorphism and the response to rituximab-based therapy in NHL patients. When categorized by ethnicity, Asian individuals with the FCGR3A 158 V/V allele (OR = 4.37; 95 % CI = 1.07-17.73; P = 0.039) or the non-F/(FV + VV) (OR = 2.50; 95 % CI = 1.04-5.98; P = 0.040) allele have a significantly higher complete response rate (CR) compared to FF individuals. No obvious heterogeneities were observed. In addition, no statistical evidence for a publication bias was found. Our study suggested that the FCGR3A 158 V/F polymorphism can predict the treatment response to rituximab-based chemotherapy in NHL patients, especially for Asian individuals. PMID:27431582

  17. High titers of anti-HBs prevent rituximab-related viral reactivation in resolved hepatitis B patient with non-Hodgkin's lymphoma.

    PubMed

    Cho, Yuri; Yu, Su Jong; Cho, Eun Ju; Lee, Jeong-Hoon; Kim, Tae Min; Heo, Dae Seog; Kim, Yoon Jun; Yoon, Jung-Hwan

    2016-06-01

    Rituximab, an anti-CD20 monoclonal antibody, is associated with an increased risk of hepatitis B virus (HBV) reactivation. This study aimed to determine the predictive factors for rituximab-related HBV reactivation in resolved hepatitis B patients, defined as HBsAg-negative, anti-HBc-positive, and undetectable HBV DNA. Among 840 consecutive patients with CD20-positive B-cell lymphoma who received rituximab-based chemotherapy from 2003 through 2014 at Seoul National University Hospital, 732 patients were excluded because either anti-HBc was not assessed or they were HBsAg-seropositive. This retrospective study included 108 resolved hepatitis B patients. During a median 33.5-month follow-up period, eight cases of HBV reactivation occurred only among the patients with low anti-HBs titers (<100 mIU/ml) at baseline and those who did not receive antiviral prophylaxis. Using multivariate analyses, antiviral prophylaxis and baseline anti-HBs titers were the protective factors for HBV reactivation (hazard ratio [HR], 0.90 and 0.95, respectively). Among those who did not receive antiviral prophylaxis, patients with high baseline anti-HBs (≥100 mIU/ml) experienced significantly lower risk of HBV reactivation (HR, 0.49; P = 0.006) than the patients with low baseline anti-HBs (<100 mIU/ml) whose cumulative HBV reactivation rates at 6 and 24 months after chemotherapy were 8.3% and 17.3%, respectively. High anti-HBs titer at baseline and antiviral prophylaxis prevented HBV reactivation, suggesting antiviral prophylaxis should be considered according to baseline anti-HBs titer. Meticulous follow-up for ALT and HBV DNA without antiviral prophylaxis might be possible for the patients with high baseline anti-HBs (≥100 mIU/ml). J. Med. Virol. 88:1010-1017, 2016. © 2015 Wiley Periodicals, Inc. PMID:26531242

  18. Strikingly high false positivity of surveillance FDG-PET/CT scanning among patients with diffuse large cell lymphoma in the rituximab era.

    PubMed

    Avivi, Irit; Zilberlicht, Ariel; Dann, Eldad J; Leiba, Ronit; Faibish, Tal; Rowe, Jacob M; Bar-Shalom, Rachel

    2013-05-01

    Predictive value (PV) of surveillance fluorodeoxyglucose positron emission tomography (FDG-PET) in patients with diffuse large B-cell lymphoma (DLBCL) treated with chemotherapy-rituximab (R) versus chemotherapy only, remains unclear. The aim of the current study was to compare the performance of surveillance PET in DLBCL patients receiving CHOP (cyclophosphamide, hydroxydaunorubicin hydrochloride, vincristine, and prednisone) alone versus CHOP-R. Institutional database was retrospectively searched for adults with newly diagnosed DLBCL, receiving CHOP or CHOP-R, who achieved complete remission and underwent surveillance PETs. Follow-up (FU) PET was considered positive for recurrence in case of an uptake unrelated to physiological or known benign process. Results were confirmed by biopsy, imaging and clinical FU. One hundred nineteen patients, 35 receiving CHOP and 84 CHOP-R, who underwent 422 FU-PETs, were analyzed. At a median PET-FU of 3.4 years, 31 patients relapsed (17 vs. 14, respectively; P = 0.02). PET detected all relapses, with no false-negative studies. Specificity and positive PV (PPV) were significantly lower for patients receiving CHOP-R vs. CHOP (84% vs. 87%, P = 0.023; 23% vs. 74%, P < 0.0001), reflecting a higher false-positive (FP) rate in subjects receiving CHOP-R (77% vs. 26%, P < 0.001). In the latter group, FP-rate remained persistently high up to 3 years post-therapy. Multivariate analysis confirmed rituximab to be the most significant predictor for FP-PET. In conclusion, routine surveillance FDG-PET is not recommended in DLBCL treated with rituximab; strict criteria identifying patients in whom FU-PET is beneficial are required. PMID:23423884

  19. Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL

    PubMed Central

    Samoilova, Olga; Osmanov, Evgenii; Eom, Hyeon-Seok; Topp, Max S.; Raposo, João; Pavlov, Viacheslav; Ricci, Deborah; Chaturvedi, Shalini; Zhu, Eugene; van de Velde, Helgi; Enny, Christopher; Rizo, Aleksandra; Ferhanoglu, Burhan

    2015-01-01

    This phase 2 study evaluated whether substituting bortezomib for vincristine in frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy could improve efficacy in non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL), centrally confirmed by immunohistochemistry (Hans method). In total, 164 patients were randomized 1:1 to receive six 21-day cycles of rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, and doxorubicin 50 mg/m2, all IV day 1, prednisone 100 mg/m2 orally days 1-5, plus either bortezomib 1.3 mg/m2 IV days 1, 4, 8, 11 (rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib [VR-CAP]; n = 84) or vincristine 1.4 mg/m2 (maximum 2 mg) IV day 1 (R-CHOP; n = 80). There were no significant differences between VR-CAP and R-CHOP in complete response rate (64.5%, 66.2%; odds ratio [OR], 0.91; P = .80), overall response rate (93.4%, 98.6%; OR, 0.21; P = .11), progression-free survival (hazard ratio [HR], 1.12; P = .76), or overall survival (HR, 0.89; P = .75). Rates of grade ≥3 adverse events (AEs; 88%, 89%), serious AEs (38%, 34%), discontinuations due to AEs (7%, 3%), and deaths due to AEs (2%, 5%) were similar with VR-CAP and R-CHOP. Grade ≥3 peripheral neuropathy rates were 6% and 3%, respectively. VR-CAP did not improve efficacy vs R-CHOP in non-GCB DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT01040871. PMID:26232170

  20. Frontline rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib (VR-CAP) or vincristine (R-CHOP) for non-GCB DLBCL.

    PubMed

    Offner, Fritz; Samoilova, Olga; Osmanov, Evgenii; Eom, Hyeon-Seok; Topp, Max S; Raposo, João; Pavlov, Viacheslav; Ricci, Deborah; Chaturvedi, Shalini; Zhu, Eugene; van de Velde, Helgi; Enny, Christopher; Rizo, Aleksandra; Ferhanoglu, Burhan

    2015-10-15

    This phase 2 study evaluated whether substituting bortezomib for vincristine in frontline rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy could improve efficacy in non-germinal center B-cell-like diffuse large B-cell lymphoma (non-GCB DLBCL), centrally confirmed by immunohistochemistry (Hans method). In total, 164 patients were randomized 1:1 to receive six 21-day cycles of rituximab 375 mg/m(2), cyclophosphamide 750 mg/m(2), and doxorubicin 50 mg/m(2), all IV day 1, prednisone 100 mg/m(2) orally days 1-5, plus either bortezomib 1.3 mg/m(2) IV days 1, 4, 8, 11 (rituximab, cyclophosphamide, doxorubicin, and prednisone with bortezomib [VR-CAP]; n = 84) or vincristine 1.4 mg/m(2) (maximum 2 mg) IV day 1 (R-CHOP; n = 80). There were no significant differences between VR-CAP and R-CHOP in complete response rate (64.5%, 66.2%; odds ratio [OR], 0.91; P = .80), overall response rate (93.4%, 98.6%; OR, 0.21; P = .11), progression-free survival (hazard ratio [HR], 1.12; P = .76), or overall survival (HR, 0.89; P = .75). Rates of grade ≥3 adverse events (AEs; 88%, 89%), serious AEs (38%, 34%), discontinuations due to AEs (7%, 3%), and deaths due to AEs (2%, 5%) were similar with VR-CAP and R-CHOP. Grade ≥3 peripheral neuropathy rates were 6% and 3%, respectively. VR-CAP did not improve efficacy vs R-CHOP in non-GCB DLBCL. This trial was registered at www.clinicaltrials.gov as #NCT01040871. PMID:26232170

  1. Alisertib added to rituximab and vincristine is synthetic lethal and potentially curative in mice with aggressive DLBCL co-overexpressing MYC and BCL2.

    PubMed

    Mahadevan, Daruka; Morales, Carla; Cooke, Laurence S; Manziello, Ann; Mount, David W; Persky, Daniel O; Fisher, Richard I; Miller, Thomas P; Qi, Wenqing

    2014-01-01

    Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼ 10-20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼ 50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy. PMID:24893165

  2. Alisertib Added to Rituximab and Vincristine Is Synthetic Lethal and Potentially Curative in Mice with Aggressive DLBCL Co-Overexpressing MYC and BCL2

    PubMed Central

    Mahadevan, Daruka; Morales, Carla; Cooke, Laurence S.; Manziello, Ann; Mount, David W.; Persky, Daniel O.; Fisher, Richard I.; Miller, Thomas P.; Qi, Wenqing

    2014-01-01

    Pearson correlation coefficient for expression analysis of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP) demonstrated Aurora A and B are highly correlated with MYC in DLBCL and mantle cell lymphoma (MCL), while both Auroras correlate with BCL2 only in DLBCL. Auroras are up-regulated by MYC dysregulation with associated aneuploidy and resistance to microtubule targeted agents such as vincristine. Myc and Bcl2 are differentially expressed in U-2932, TMD-8, OCI-Ly10 and Granta-519, but only U-2932 cells over-express mutated p53. Alisertib [MLN8237 or M], a highly selective small molecule inhibitor of Aurora A kinase, was synergistic with vincristine [VCR] and rituximab [R] for inhibition of cell proliferation, abrogation of cell cycle checkpoints and enhanced apoptosis versus single agent or doublet therapy. A DLBCL (U-2932) mouse model showed tumor growth inhibition (TGI) of ∼10–20% (p = 0.001) for M, VCR and M-VCR respectively, while R alone showed ∼50% TGI (p = 0.001). M-R and VCR-R led to tumor regression [TR], but relapsed 10 days after discontinuing therapy. In contrast, M-VCR-R demonstrated TR with no relapse >40 days after stopping therapy with a Kaplan-Meier survival of 100%. Genes that are modulated by M-VCR-R (CENP-C, Auroras) play a role in centromere-kinetochore function in an attempt to maintain mitosis in the presence of synthetic lethality. Together, our data suggest that the interaction between alisertib plus VCR plus rituximab is synergistic and synthetic lethal in Myc and Bcl-2 co-expressing DLBCL. Alisertib plus vincristine plus rituximab [M-VCR-R] may represent a new strategy for DLBCL therapy. PMID:24893165

  3. Predictors of Local Recurrence After Rituximab-Based Chemotherapy Alone in Stage III and IV Diffuse Large B-Cell Lymphoma: Guiding Decisions for Consolidative Radiation

    SciTech Connect

    Jegadeesh, Naresh; Rajpara, Raj; Esiashvili, Natia; Shi, Zheng; Liu, Yuan; Okwan-Duodu, Derrick; Flowers, Christopher R.; Khan, Mohammad K.

    2015-05-01

    Purpose: The role of consolidative radiation therapy (RT) for stage III and IV diffuse large B-cell lymphoma (DLBCL) in the era of rituximab is not well defined. There is evidence that some patients with bulky disease may benefit, but patient selection criteria are not well established. We sought to identify a subset of patients who experienced a high local failure rate after receiving rituximab-based chemotherapy alone and hence may benefit from the addition of consolidative RT. Methods and Materials: Two hundred eleven patients with stage III and IV DLBCL treated between August 1999 and January 2012 were reviewed. Of these, 89 had a complete response to systemic therapy including rituximab and received no initial RT. Kaplan-Meier analysis and Cox proportional hazards regression were performed, with local recurrence (LR) as the primary outcome. Results: The median follow-up time was 43.9 months. Fifty percent of patients experienced LR at 5 years. In multivariate analysis, tumor ≥5 cm and stage III disease were associated with increased risk of LR. The 5-year LR-free survival was 47.4% for patients with ≥5-cm lesions versus 74.7% for patients with <5-cm lesions (P=.01). In patients with <5-cm tumors, the maximum standardized uptake value (SUVmax) was ≥15 in all patients with LR. The 5-year LR-free survival was 100% in SUV<15 versus 68.8% in SUV≥15 (P=.10). Conclusions: Advanced-stage DLBCL patients with stage III disease or with disease ≥5 cm appear to be at an increased risk for LR. Patients with <5-cm disease and SUVmax ≥15 may be at higher risk for LR. These patients may benefit from consolidative RT after chemoimmunotherapy.

  4. Early Failure of Frontline Rituximab-containing Chemoimmunotherapy in Diffuse Large B-Cell Lymphoma does not Predict Futility of Autologous Hematopoietic Cell Transplantation

    PubMed Central

    Hamadani, Mehdi; Hari, Parameswaran N.; Zhang, Ying; Carreras, Jeanette; Akpek, Görgün; Aljurf, Mahmoud D.; Ayala, Ernesto; Bachanova, Veronika; Chen, Andy I.; Chen, Yi-Bin; Costa, Luciano J.; Fenske, Timothy S.; Freytes, César O.; Ganguly, Siddhartha; Hertzberg, Mark S.; Holmberg, Leona A.; Inwards, David J.; Kamble, Rammurti T.; Kanfer, Edward J.; Lazarus, Hillard M.; Marks, David I.; Nishihori, Taiga; Olsson, Richard; Reddy, Nishitha M.; Rizzieri, David A.; Savani, Bipin N.; Solh, Melhem; Vose, Julie M.; Wirk, Baldeep; Maloney, David G.; Smith, Sonali M.; Montoto, Silvia; Saber, Wael

    2014-01-01

    The poor prognosis of diffuse large B-cell lymphoma (DLBCL) patients relapsing within 1-year of initial diagnosis after first-line rituximab-based chemoimmunotherapy has created controversy about the role of autologous transplantation (auto-HCT) in this setting. We compared auto-HCT outcomes of chemosensitive DLBCL patients between 2000 and 2011 in two cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1-year of initial diagnosis. The ERF cohort was compared with those relapsing >1-year after initial diagnosis (Late Rituximab Failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Non-relapse mortality (NRM), progression/relapse, progression-free survival (PFS) and overall survival (OS) of ERF vs. LRF cohorts at 3-years were 9% (95%CI 6–13) vs. 9% (95%CI 5–13), 47% (95%CI 41–52) vs. 39% (95%CI 33–46), 44% (95%CI 38–50) vs. 52% (95%CI 45–59) and 50% (95 CI 44–56) vs. 67% (95%CI 60–74), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk (RR) 1.31, p=0.34). ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR 2.08, p<0.001) and overall mortality (RR 3.75, p<0.001) within the first 9 months post auto-HCT. Beyond this period, PFS and OS were not significantly different between ERF and LRF cohorts. Auto-HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS 44%), and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse. PMID:25008330

  5. Early failure of frontline rituximab-containing chemo-immunotherapy in diffuse large B cell lymphoma does not predict futility of autologous hematopoietic cell transplantation.

    PubMed

    Hamadani, Mehdi; Hari, Parameswaran N; Zhang, Ying; Carreras, Jeanette; Akpek, Görgün; Aljurf, Mahmoud D; Ayala, Ernesto; Bachanova, Veronika; Chen, Andy I; Chen, Yi-Bin; Costa, Luciano J; Fenske, Timothy S; Freytes, César O; Ganguly, Siddhartha; Hertzberg, Mark S; Holmberg, Leona A; Inwards, David J; Kamble, Rammurti T; Kanfer, Edward J; Lazarus, Hillard M; Marks, David I; Nishihori, Taiga; Olsson, Richard; Reddy, Nishitha M; Rizzieri, David A; Savani, Bipin N; Solh, Melhem; Vose, Julie M; Wirk, Baldeep; Maloney, David G; Smith, Sonali M; Montoto, Silvia; Saber, Wael; Alpdogan, Onder; Cashen, Amanda; Dandoy, Christopher; Finke, Robert; Gale, Robert; Gibson, John; Hsu, Jack W; Janakiraman, Nalini; Laughlin, Mary J; Lill, Michael; Cairo, Mitchell S; Munker, Reinhold; Rowlings, Phil A; Schouten, Harry C; Shea, Thomas C; Stiff, Patrick J; Waller, Edmund K

    2014-11-01

    The poor prognosis for patients with diffuse large B cell lymphoma (DLBCL) who relapse within 1 year of initial diagnosis after first-line rituximab-based chemo-immunotherapy has created controversy about the role of autologous transplantation (HCT) in this setting. We compared autologous HCT outcomes for chemosensitive DLBCL patients between 2000 and 2011 in 2 cohorts based on time to relapse from diagnosis. The early rituximab failure (ERF) cohort consisted of patients with primary refractory disease or those with first relapse within 1 year of initial diagnosis. The ERF cohort was compared with those relapsing >1 year after initial diagnosis (late rituximab failure [LRF] cohort). ERF and LRF cohorts included 300 and 216 patients, respectively. Nonrelapse mortality (NRM), progression/relapse, progression-free survival (PFS), and overall survival (OS) of ERF versus LRF cohorts at 3 years were 9% (95% confidence interval [CI], 6% to 13%) versus 9% (95% CI, 5% to 13%), 47% (95% CI, 41% to 52%) versus 39% (95% CI, 33% to 46%), 44% (95% CI, 38% to 50%) versus 52% (95% CI, 45% to 59%), and 50% (95% CI, 44% to 56%) versus 67% (95% CI, 60% to 74%), respectively. On multivariate analysis, ERF was not associated with higher NRM (relative risk [RR], 1.31; P = .34). The ERF cohort had a higher risk of treatment failure (progression/relapse or death) (RR, 2.08; P < .001) and overall mortality (RR, 3.75; P <.001) within the first 9 months after autologous HCT. Beyond this period, PFS and OS were not significantly different between the ERF and LRF cohorts. Autologous HCT provides durable disease control to a sizeable subset of DLBCL despite ERF (3-year PFS, 44%) and remains the standard-of-care in chemosensitive DLBCL regardless of the timing of disease relapse. PMID:25008330

  6. SpeB proteolysis with imaged capillary isoelectric focusing for the characterization of domain-specific charge heterogeneities of reference and biosimilar Rituximab.

    PubMed

    Zhang, Zichuan; Perrault, Ronel; Zhao, Yun; Ding, Julia

    2016-05-01

    The charge variations of therapeutic monoclonal antibody reveal important information of the post-translational modifications that may potentially impact the potency and safety of pharmaceutical products, especially during the evaluation of biosimilarity of therapeutic proteins. In this work, a novel SpeB-based proteolysis strategy coupling with imaged capillary isoelectric focusing was developed for the determination of domain-specific charge heterogeneities of innovator and generic Rituximab drug products from United States, European and Indian markets. It was observed that innovator Rituximab from the United States and Europe share highly similar peak distributions and charge heterogeneities with 26.2-26.6% Fc/2, 28.9-29.3% LC and 44.4-44.5% Fd peak areas detected, respectively, while multiple basic variations of Fc/2 and less acidic LC and Fd species were found from generic Rituximab from India with 20.9% Fc/2, 32.3% LC and 46.9% Fd peak areas detected. It was also demonstrated that structural changes caused by Carboxypeptidase B treatment and deamidation study at pH extremes could be sensitively captured with the established method, with the results further indicating that the generic product's basic variations of Fc/2 were un-cleaved Lysine residues, while the lack of certain acidic peaks on LC and Fd probably was due to the lower level of deamidation. This new strategy could become a useful tool to reveal domain-specific charge heterogeneities profiles of a variety of therapeutic monoclonal antibodies in regulated environments. PMID:27038651

  7. Histological analysis on adhesive molecules of renal intravascular large B cell lymphoma treated with CHOP chemotherapy and rituximab.

    PubMed

    Kusaba, T; Hatta, T; Tanda, S; Kameyama, H; Tamagaki, K; Okigaki, M; Inaba, T; Shimazaki, C; Sasaki, S

    2006-03-01

    A 48-year-old man was admitted to our hospital for investigation of mild renal dysfunction. A blood examination revealed mild elevation of creatinine level (1.77 mg/dl). Urinary examination revealed mild protein excretion (0.54 g/day) and microhematuria; renal biopsy revealed the focal proliferation of large mononuclear cells with mitosis in glomerular capillaries. According to immunohistochemical analysis, the intravascular lymphomatous cells stained positively with anti-leukocyte common antigen (LCA: CD45) and CD20, indicating a B lymphocyte lineage. In electron microscopy, the glomerular capillary was filled with lymphoma cells and epithelial foot process fusion was noted. Immunohistochemical analysis on adhesive molecules revealed a lack of CD11a expression on lymphoma cells, but positive CD54 expression on endothelial cells. Systemic 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) revealed no abnormal uptake of isotopes. On the basis of these findings, we diagnosed intravascular diffuse large B cell lymphoma localized in the kidney. Despite treatment with rituximab and CHOP (prednisolone, doxorubicin, vincristine, cyclophosphamide) for 3 cycles at 1-month intervals, the renal dysfunction did not change. In histopathological analysis of the second biopsy, lymphoma cells disappeared, but focal segmental glomerulosclerosis and moderate interstitial fibrosis were noted. Electron microscopic findings revealed severe subendothelial edema with mesangial interposition, indicating severe endothelial damage. Epithelial foot process fusion was improved. These pathological analyses let us conclude that a lack of CD11a could be a candidate factor for prevention of the extravasation of lymphoma cells from blood vessels in our patient. We also presumed that the intraglomerular endothelial damage occurred due to chemotherapy-associated cell injury. PMID:16550755

  8. The Effects of Rituximab on Lipids, Arterial Stiffness and Carotid Intima-Media Thickness in Rheumatoid Arthritis

    PubMed Central

    2016-01-01

    The aim of the study was to examine lipid profiles, arterial stiffness (AS), carotid intima-media thickness (cIMT), in 55 women with RA without overt cardiovascular disease (СVD) treated with rituximab (RTX).The following parameters were recorded before and 24 weeks after RTX therapy (2 infusions of 500 or 1,000 mg RTX intravenously, fortnightly): plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, DAS 28-ESR, serum C-reactive protein (CRP), RF IgM, AS (SI - stiffness index, RI – reflection index) by digital volume pulse contour analysis (Micro Medical, UK), and common cIMT by high-resolution B-mode carotid ultrasound. Based on the European League Against Rheumatism (EULAR) criteria, patients were divided into two groups: 1) moderate/good response to RTX therapy after 24 weeks (41 patients, 75%), 2) no response to RTX therapy (14 patients, 25%). Effective RTX therapy resulted in 9% increase in TC, 23% increase in HDL-C and 14% decrease in atherogenic index, 57% decrease in SI and 24% decrease in RI. We observed a 9% decrease of cIMTmax at 24 weeks. The improvement of cardiovascular parameters was accompanied by statistically significant decreases of CRP, ESR, RF IgM and DAS 28 in group 1 (P < 0.05). There were not significant changes in lipid profile, AS parameters, and cIMT in group 2. Two infusions of RTX in case of moderate/good EULAR effect of therapy exerted favorable effects on lipid profile, AS and cIMT in women with RA without overt CVD. PMID:26839473

  9. Risk of secondary hypogammaglobulinaemia after Rituximab and Fludarabine in indolent non-Hodgkin lymphomas: A retrospective cohort study.

    PubMed

    De Angelis, Federico; Tosti, Maria Elena; Capria, Saveria; Russo, Eleonora; D'Elia, Gianna Maria; Annechini, Giorgia; Stefanizzi, Caterina; Foà, Robin; Pulsoni, Alessandro

    2015-12-01

    The occurrence of secondary hypogammaglobulinemia (SH) after chemo-immunotherapy represents a potential side effect in patients with indolent non-Hodgkin lymphomas (iNHL). Few data are available on SH occurring after chemotherapy and/or Rituximab (R). We retrospectively investigated the incidence and the risk factors for SH and infectious complications in patients with iNHL after chemo-immunotherapy. Two hundred and sixty six patients treated between 1993 and 2011 were studied. Patients with a basal hypogammaglobulinemia or a monoclonal component were excluded. The incidence of SH was 2.2×1000 person-years (95% CI 1.6-2.9). Exposure to Fludarabine-based schedules (Fbs)±R was associated with a hazard ratio (HR) of 18.1 (95% CI: 4.3-77.0). Conversely, exposure to CHOP±R or CVP±R was not a risk factor (HR 0.3, 95% CI: 0.1-0.8; HR 0.3, 95% CI: 0.08-1.4, respectively). The role of R was studied comparing cohorts differing only for R; no differences were found comparing R-CHOP/R-CVP versus CHOP/CVP (HR 1.07, 95% CI: 0.38-3.05) and R-Fbs versus Fbs (HR 2.07, 95% CI: 0.62-6.99). Autologous stem cell transplantation (ASCT) is also a risk factor (HR: 5.2, 95% CI 2.1-13.0). SH patients presented a high risk for pneumonia development (HR 7.07 95% CI: 2.68-18.44). We recommend monitoring of serum immunoglobulins in an attempt to reduce the probability of infection after Fbs or ASCT. PMID:26547259

  10. The Effects of Rituximab on Lipids, Arterial Stiffness and Carotid Intima-Media Thickness in Rheumatoid Arthritis.

    PubMed

    Novikova, Diana S; Popkova, Tatiana V; Lukina, Galina V; Luchikhina, Elena L; Karateev, Dmitry E; Volkov, Alexander V; Novikov, Alexander A; Aleksandrova, Elena N; Nasonov, Evgeny L

    2016-02-01

    The aim of the study was to examine lipid profiles, arterial stiffness (AS), carotid intima-media thickness (cIMT), in 55 women with RA without overt cardiovascular disease (СVD) treated with rituximab (RTX).The following parameters were recorded before and 24 weeks after RTX therapy (2 infusions of 500 or 1,000 mg RTX intravenously, fortnightly): plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, DAS 28-ESR, serum C-reactive protein (CRP), RF IgM, AS (SI - stiffness index, RI - reflection index) by digital volume pulse contour analysis (Micro Medical, UK), and common cIMT by high-resolution B-mode carotid ultrasound. Based on the European League Against Rheumatism (EULAR) criteria, patients were divided into two groups: 1) moderate/good response to RTX therapy after 24 weeks (41 patients, 75%), 2) no response to RTX therapy (14 patients, 25%). Effective RTX therapy resulted in 9% increase in TC, 23% increase in HDL-C and 14% decrease in atherogenic index, 57% decrease in SI and 24% decrease in RI. We observed a 9% decrease of cIMTmax at 24 weeks. The improvement of cardiovascular parameters was accompanied by statistically significant decreases of CRP, ESR, RF IgM and DAS 28 in group 1 (P < 0.05). There were not significant changes in lipid profile, AS parameters, and cIMT in group 2. Two infusions of RTX in case of moderate/good EULAR effect of therapy exerted favorable effects on lipid profile, AS and cIMT in women with RA without overt CVD. PMID:26839473

  11. Risk factors for developing infusion reaction after rituximab administration in patients with B-cell non-Hodgkin's lymphoma.

    PubMed

    Tachi, T; Yasuda, M; Usui, K; Umeda, M; Nagaya, K; Osawa, T; Ichihashi, A; Noguchi, Y; Goto, H; Kasahara, S; Takahashi, T; Goto, C; Teramachi, H

    2015-10-01

    Rituximab (RTX), a monoclonal antibody against CD20, is known to cause fewer side effects than conventional anti-cancer drugs; however, infusion reaction (IR), which is specific to monoclonal antibody therapy, is frequently triggered by RTX. Therefore, we designed this study to identify risk factors based on clinical test values for developing IR after RTX administration. Eighty-nine patients with B-cell non-Hodgkin's lymphoma who had received RTX for the first time between February 2010 and March 2013, at the Gifu Municipal Hospital were enrolled as subjects. Analysis of data was conducted for 87 patients, after excluding patients whose data were missing. Univariate analysis showed significant differences in the number of patients exhibiting a soluble interleukin-2 receptor (sLL-2R) level > 2,000 U/L and hemoglobin (Hb) < lower standard limit (LSL) between the IR and non-IR groups. Multivariate analysis showed significant differences with respect to slL-2R > 2,000 U/L [odds ratio (OR), 4.463; 95% confidence interval (Cl), 1.262-15.779; P = 0.020], Hb < LSL [OR, 3.568; 95% CI, 1.071-11.890; P = 0.038], and steroid administration [OR, 0.284; 95% Cl, 0.094-0.852; P = 0.025]. Our findings show that sIL-2R > 2,000 U/L, Hb < LSL, and a lack of steroid premedication are risk factors for developing IR following RTX treatment. PMID:26601425

  12. Ultrasound-detected joint inflammation and B cell count: related variables for rituximab-treated RA patients?

    PubMed

    Valor, Lara; Martínez-Estupiñán, Lina; Janta, Iustina; Nieto, Juan Carlos; Ovalles-Bonilla, Juan Gabriel; González-Fernández, Carlos; Del Rio, Tamara; Hernández-Flórez, Diana; Monteagudo, Indalecio; López-Longo, Francisco Javier; Naredo, Esperanza

    2016-06-01

    This cross-sectional observational study aimed to explore the relationship between B cell count and ultrasound (US)-detected synovitis, in patients with rheumatoid arthritis treated with rituximab. Thirty-seven consecutive RA patients treated with RTX were recruited for the study. The patients underwent clinical [i.e., Disease Activity Score 28 joints (DAS28)], laboratory, and US assessment of 12 joints. Each joint was semiquantitatively (0-3) scored on B-mode and power Doppler mode. The scores were summed, and a global index was created for BM (BMS) and PD scores (PDI) synovitis. BM subclinical synovitis was evident in all patients, with PD synovial signal detected in 16 patients (43.2 %). No correlation was found between DAS28 and US scores. B cells were detected in 27 (72.9 %) patients, but there was no association in the mean B cell count and disease activity as measured by DAS28 (DAS28 < 2.6 = 34.53, DAS28 > 2.6 = 49.45, p = 0.52) and PDI score (PDI < 1 = 49.48, PDI > 1 = 35.44, p = 0.54). There was no correlation between the B cell count and DAS28, BMS, and PDI (r = 0.020, p = 0.907; r = -0.151, p = 0.371; r = -0.099, p = 0.558, respectively). In RTX-treated RA patients, no relationship could be established between US-detected synovitis and peripheral blood B cell count. PMID:27072348

  13. AMC 048: modified CODOX-M/IVAC-rituximab is safe and effective for HIV-associated Burkitt lymphoma

    PubMed Central

    Lee, Jeannette Y.; Cesarman, Ethel; Ambinder, Richard; Baiocchi, Robert; Reid, Erin; Ratner, Lee; Wagner-Johnston, Nina; Kaplan, Lawrence

    2015-01-01

    The toxicity of dose-intensive regimens used for Burkitt lymphoma prompted modification of cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) for HIV-positive patients. We added rituximab, reduced and/or rescheduled cyclophosphamide and methotrexate, capped vincristine, and used combination intrathecal chemotherapy. Antibiotic prophylaxis and growth factor support were required; highly active antiretroviral therapy (HAART) was discretionary. Thirteen AIDS Malignancy Consortium centers enrolled 34 patients from 2007 to 2010. Median age was 42 years (range, 19-55 years), 32 of 34 patients were high risk, 74% had stage III to IV BL and CD4 count of 195 cells per μL (range, 0-721 cells per μL), and 5 patients (15%) had CD4 <100 cells per μL. Twenty-six patients were receiving HAART; viral load was <100 copies per mL in 12 patients. Twenty-seven patients had at least one grade 3 to 5 toxicity, including 20 hematologic, 14 infectious, and 6 metabolic. None had grade 3 to 4 mucositis. Five patients did not complete treatments because of adverse events. Eleven patients died, including 1 treatment-related and 8 disease-related deaths. The 1-year progression-free survival was 69% (95% confidence interval [CI], 51%-82%) and overall survival was 72% (95% CI, 53%-84%); 2-year overall survival was 69% (95% CI, 50%-82%). Modifications of the CODOX-M/IVAC regimen resulted in a grade 3 to 4 toxicity rate of 79%, which was lower than that in the parent regimen (100%), without grade 3 to 4 mucositis. Despite a 68% protocol completion rate, the 1-year survival rate compares favorably with 2 studies that excluded HIV-positive patients. This trial was registered at http://clinicaltrials.gov as #NCT00392834. PMID:25957391

  14. Rituximab for immune hemolytic anemia following T- and B-Cell-depleted hematopoietic stem cell transplantation.

    PubMed

    Corti, P; Bonanomi, S; Vallinoto, C; Balduzzi, A; Uderzo, C; Cazzaniga, G; Gaipa, G; Dassi, M; Perseghin, P; Rovelli, A

    2003-01-01

    The treatment of immune-mediated hemolytic anemia (IHA) complicating hematopoietic stem cell transplantation (HSCT) is often unsatisfactory. We report a case of IHA which occurred after T- and B-cell depleted unrelated donor HSCT carried out for mucopolysaccharidosis type I-H (Hurler syndrome) which was successfully treated with anti-CD20+ monoclonal antibody PMID:12486323

  15. Rationale and design of the RIACT–study: a multi-center placebo controlled double blind study to test the efficacy of RItuximab in Acute Cellular tubulointerstitial rejection with B-cell infiltrates in renal Transplant patients: study protocol for a randomized controlled trial

    PubMed Central

    2012-01-01

    Background Acute kidney allograft rejection is a major cause for declining graft function and has a negative impact on the long-term graft survival. The majority (90%) of acute rejections are T-cell mediated and, therefore, the anti-rejection therapy targets T-cell-mediated mechanisms of the rejection process. However, there is increasing evidence that intragraft B-cells are also important in the T-cell-mediated rejections. First, a significant proportion of patients with acute T-cell-mediated rejection have B-cells present in the infiltrates. Second, the outcome of these patients is inferior, which has been related to an inferior response to the conventional anti-rejection therapy. Third, treatment of these patients with an anti-CD20 antibody (rituximab) improves the allograft outcome as reported in single case observations and in one small study. Despite the promise of these observations, solid evidence is required before incorporating this treatment option into a general treatment recommendation. Methods/Design The RIACT study is designed as a randomized, double-blind, placebo-controlled, parallel group multicenter Phase III study. The study examines whether rituximab, in addition to the standard treatment with steroid-boli, leads to an improved one-year kidney allograft function, compared to the standard treatment alone in patients with acute T-cell mediated tubulointerstitial rejection and significant B-cell infiltrates in their biopsies. A total of 180 patients will be recruited. Discussion It is important to clarify the relevance of anti-B cell targeting in T-cell mediated rejection and answer the question whether this novel concept should be incorporated in the conventional anti-rejection therapy. Trial registration Clinical trials gov. number: NCT01117662 PMID:23101480

  16. A case of refractory thrombotic thrombocytopenic purpura treated with plasmapheresis and rituximab.

    PubMed

    Kirui, Nicholas; Sokwala, Ahmed

    2016-07-01

     Thrombotic thrombocytopenic purpura (TTP) is a rare, life-threatening disorder with no prevalence or incidence studies in sub-Saharan Africa. Acquired TTP has several causes, all of which lead to decreased activity of von Willebrand factor cleaving protease (ADAMTS13) due to autoantibodies that are directed towards ADAMTS13. We report a case of a 46-year-old man who presented with most of the classic clinical manifestations of TTP. PMID:27384362

  17. Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia

    PubMed Central

    Kay, Neil E.; Geyer, Susan M.; Call, Timothy G.; Shanafelt, Tait D.; Zent, Clive S.; Jelinek, Diane F.; Tschumper, Renee; Bone, Nancy D.; Dewald, Gordon W.; Lin, Thomas S.; Heerema, Nyla A.; Smith, Lisa; Grever, Michael R.; Byrd, John C.

    2007-01-01

    Building on the prior work of use of pentostatin in chronic lymphocytic leukemia (CLL), we initiated a trial of combined pentostatin (2 mg/m2), cyclophosphamide (600 mg/m2), and rituximab (375 mg/m2) for 65 symptomatic, previously untreated patients. Of 64 evaluable patients, 34 (53%) were high Rai risk, 71% were nonmutated for the immunoglobulin heavy-chain variable region gene, 34% were CD38+, and 34% were ZAP-70+. Thirty patients (52%) had one anomaly detected by fluorescence in situ (FISH) hybridization, and 21 (36%) had complex FISH defects. Thirty-eight patients (58%) had grade 3+ hematologic toxicity but minimal transfusion needs and no major infections. Responses occurred in 58 patients (91%), with 26 (41%) complete responses (CRs), 14 (22%) nodular partial responses (nodular PRs), and 18 (28%) partial responses (PRs). Many patients with a CR also lacked evidence of minimal residual disease by 2-color flow cytometry. Examination of prognostic factors demonstrated poor response in the 3 patients with del(17p). In contrast, we found this regimen was equally effective in young versus older (> 70 years) patients and in del(11q22.3) versus other favorable prognostic factors. Thus, this novel regimen of pentostatin, cyclophosphamide, and rituximab for previously untreated patients with CLL demonstrated significant clinical activity despite poor risk-based prognoses, achievement of minimal residual disease in some, and modest toxicity. PMID:17008537

  18. Prognostic significance of survivin and caspase-3 immunohistochemical expression in patients with diffuse large B-cell lymphoma treated with rituximab and CHOP.

    PubMed

    Mitrović, Zdravko; Ilić, Ivana; Aurer, Igor; Kinda, Sandra Bašić; Radman, Ivo; Dotlić, Snježana; Ajduković, Radmila; Labar, Boris

    2011-06-01

    Survivin is an inhibitor of apoptosis whose expression may be associated with inferior outcome in patients with diffuse large B-cell lymphoma (DLBCL) treated without rituximab. Caspase-3 is the final caspase of the apoptotic cascade and its pattern of expression may also be related to patients' outcome. In this study we investigated immunohistochemical expression of survivin and caspase-3 (CPP32) in 57 patients with DLBCL treated with rituximab and CHOP (R-CHOP). According to previously published criteria, we separately analyzed correlation of different types of survivin expression with patients' outcome. Nuclear survivin was expressed in only 26% of cases, cytoplasmic survivin was expressed in 81% of cases while application of immunoreactivity scoring system yielded 58% of survivin positive cases. Caspase-3 was expressed in 77% of cases. There were no significant correlations between any type of survivin expression and response to treatment or survival of the patients. The expression of caspase-3 was also not associated with patients' outcome. We conclude that survivin and caspase-3 have no significant prognostic significance in patients with DLBCL treated with R-CHOP. PMID:20853074

  19. Rituximab-conjugated and doxorubicin-loaded microbubbles combined with ultrasound irradiation inhibits proliferation and induces apoptosis in Raji cell lines.

    PubMed

    Zhou, Shoubing; Zheng, Shiya; Shan, Yongfeng; Li, Lulu; Zhang, Xiu; Wang, Cailian

    2016-02-01

    Doxorubicin (DOX) is one of the most important medicines used for the treatment for B cell lymphoma, yet its clinical efficacy is often limited by severe adverse effects. Drug-loaded microbubbles, combined with ultrasound (US) irradiation, has shown great promise in reducing DOX-induced side effects and improving therapeutic efficacy. Nevertheless, these drug-loaded microbubbles are non-targeted microbubbles with comparatively suboptimal efficiency. Therefore, we synthesized targeted and DOX-loaded microbubbles (DMs), combined with US irradiation, for triggering drug release in lymphoma B cells. DMs were coated with rituximab via a biotin-avidin linkage to target Raji cells that overexpress the CD-20 antigen. In the present study, the cell viability after treatment with rituximab-conjugated DMs (RDMs) containing 0.25, 0.5 and 1.0 µg/ml DOX + US was 45.69±6.85, 25.31±2.60 and 15.67±2.83%, respectively, which demonstrated that RDMs + US produced significantly higher cytotoxicity than the other treatments. The early apoptosis ratio in the Raji cells at 48 h after the treatment was 32.4±2.84%, which was notably higher than the ratio in the other treatment groups. The results confirm the hypothesis that US-mediated targeting of CD-20-positive B cell lymphoma and the use of DMs may improve the DOX therapeutic efficiency. PMID:26718487

  20. Long-term survival in a patient with progressive multifocal leukoencephalopathy after therapy with rituximab, fludarabine and cyclophosphamide for chronic lymphocytic leukemia.

    PubMed

    Garrote, Heidys; de la Fuente, Adolfo; Oña, Raquel; Rodríguez, Inmaculada; Echevarría, Juan E; Sepúlveda, Juan M; García, Juan F

    2015-01-01

    A 50-year-old male with chronic lymphocytic leukemia (CLL) was treated with fludarabine, cyclophosphamide and rituximab, which produced a complete remission. Eight months after the last dose of rituximab he had visual disturbance, diminished muscular strength in the right arm and vesicular-papular lesions in the left ophthalmic branch region of the V cranial nerve. These were initially interpreted as herpes virus encephalopathy (HVE), but brain magnetic resonance imaging (MRI) showed evidence of demyelination consistent with progressive multifocal leukoencephalopathy (PML). Cerebrospinal fluid (CSF) analysis was negative for varicella zoster virus (VZV) and John Cunningham virus (JCV) DNA. The clinical suggestion of PML prompted us to perform a brain biopsy and to start treatment with mefloquine. In the brain biopsy, histopathological features of demyelination were described and the polymerase chain reaction (PCR) identified JCV, confirming the diagnosis of PML. Treatment with mefloquine (250 mg/week) and dexamethasone (4 mg/day) was started and maintained for 6 months. A year later there was an almost complete resolution of the MRI lesions and the patient achieved a stable clinical state with persisting motor impairment and severe epilepsy. The patient is alive 38 months after diagnosis of PML, which is the longest known survival to date. PMID:25767742

  1. Expression of CD40 is a positive prognostic factor of diffuse large B-cell lymphoma treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)

    PubMed Central

    Song, Guoqi; Ni, Huiyun; Zou, Linqing; Wang, Shukui; Tian, Fuliang; Liu, Hong; Cho, William C

    2016-01-01

    Objectives The objective of this study was to investigate the expression level of CD40 and its role in the prognosis of patients with diffuse large B-cell lymphoma (DLBCL) who were treated with rituximab-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). Design and methods The immunohistochemical expressions of CD40 in 186 well-characterized DLBCL patients were evaluated by tissue microarrays, thereby revealing the relationship of the molecule CD40 with known tumor, patient-related variables, and survival rates. Results The results showed that CD40 expressions were not statistically different between the germinal center B-cell-like (GCB) type and the non-GCB type. We also analyzed the relationships of CD40 expression with overall survival (OS) and progression-free survival (PFS) in DLBCL patients who were uniformly treated with R-CHOP. A low expression of CD40 compared to high expression is related to poor OS and PFS. Conclusion Our findings indicate that the CD40 level at onset acts as an independent prognostic predictor of DLBCL patients treated with R-CHOP. PMID:27382316

  2. Rituximab Downregulates Gene Expression Associated with Cell Proliferation, Survival, and Proteolysis in the Peripheral Blood from Rheumatoid Arthritis Patients: A Link between High Baseline Autophagy-Related ULK1 Expression and Improved Pain Control

    PubMed Central

    Tchetina, Elena V.; Pivanova, Anastasya N.; Markova, Galina A.; Lukina, Galina V.; Aleksandrova, Elena N.; Aleksankin, Andrey P.; Makarov, Sergey A.; Kuzin, Aleksandr N.

    2016-01-01

    Objective. To clarify molecular mechanisms for the response to rituximab in a longitudinal study. Methods. Peripheral blood from 16 RA patients treated with rituximab for a single treatment course and 26 healthy controls, blood and knee articular cartilages from 18 patients with long-standing RA, and cartilages from 14 healthy subjects were examined. Clinical response was assessed using ESR, ACPA, CRP, RF, DAS28 levels, CD19+ B-cell counts, bone erosion, and joint space narrowing scores. Protein expression in PBMCs was quantified using ELISA. Gene expression was performed with quantitative real-time PCR. Results. A decrease (p < 0.05) in DAS28, ESR, and CRP values after rituximab treatment was associated with the downregulation of MTOR, p21, caspase 3, ULK1, TNFα, IL-1β, and cathepsin K gene expression in the peripheral blood to levels found in healthy subjects. MMP-9 expression remained significantly higher compared to controls although decreased (p < 0.05) versus baseline. A negative correlation between baseline ULK1 gene expression and the number of tender joints at the end of follow-up was observed. Conclusions. The response to rituximab was associated with decreased MTOR, p21, caspase 3, ULK1, TNFα, IL-1β, and cathepsin K gene expression compared to healthy subjects. Residual increased expression in MMP-9, IFNα, and COX2 might account for remaining inflammation and pain. High baseline ULK1 gene expression indicates a good response in respect to pain. PMID:27057353

  3. Rituximab Downregulates Gene Expression Associated with Cell Proliferation, Survival, and Proteolysis in the Peripheral Blood from Rheumatoid Arthritis Patients: A Link between High Baseline Autophagy-Related ULK1 Expression and Improved Pain Control.

    PubMed

    Tchetina, Elena V; Pivanova, Anastasya N; Markova, Galina A; Lukina, Galina V; Aleksandrova, Elena N; Aleksankin, Andrey P; Makarov, Sergey A; Kuzin, Aleksandr N

    2016-01-01

    Objective. To clarify molecular mechanisms for the response to rituximab in a longitudinal study. Methods. Peripheral blood from 16 RA patients treated with rituximab for a single treatment course and 26 healthy controls, blood and knee articular cartilages from 18 patients with long-standing RA, and cartilages from 14 healthy subjects were examined. Clinical response was assessed using ESR, ACPA, CRP, RF, DAS28 levels, CD19+ B-cell counts, bone erosion, and joint space narrowing scores. Protein expression in PBMCs was quantified using ELISA. Gene expression was performed with quantitative real-time PCR. Results. A decrease (p < 0.05) in DAS28, ESR, and CRP values after rituximab treatment was associated with the downregulation of MTOR, p21, caspase 3, ULK1, TNFα, IL-1β, and cathepsin K gene expression in the peripheral blood to levels found in healthy subjects. MMP-9 expression remained significantly higher compared to controls although decreased (p < 0.05) versus baseline. A negative correlation between baseline ULK1 gene expression and the number of tender joints at the end of follow-up was observed. Conclusions. The response to rituximab was associated with decreased MTOR, p21, caspase 3, ULK1, TNFα, IL-1β, and cathepsin K gene expression compared to healthy subjects. Residual increased expression in MMP-9, IFNα, and COX2 might account for remaining inflammation and pain. High baseline ULK1 gene expression indicates a good response in respect to pain. PMID:27057353

  4. Impact of Rituximab on Immunoglobulin Concentrations and B Cell Numbers after Cyclophosphamide Treatment in Patients with ANCA-Associated Vasculitides

    PubMed Central

    Salzer, Ulrich; Warnatz, Klaus; Peter, Hans Hartmut; Lebrecht, Dirk; Schlesier, Michael; Voll, Reinhard E.; Thiel, Jens

    2012-01-01

    Objective To assess the impact of immunosuppressive therapy with cyclophosphamide (CYC) and rituximab (RTX) on serum immunoglobulin (Ig) concentrations and B lymphocyte counts in patients with ANCA-associated vasculitides (AAVs). Methods Retrospective analysis of Ig concentrations and peripheral B cell counts in 55 AAV patients. Results CYC treatment resulted in a decrease in Ig levels (median; interquartile range IQR) from IgG 12.8 g/L (8.15-15.45) to 9.17 g/L (8.04-9.90) (p = 0.002), IgM 1.05 g/L (0.70-1.41) to 0.83 g/L (0.60-1.17) (p = 0.046) and IgA 2.58 g/L (1.71-3.48) to 1.58 g/L (1-31-2.39) (p = 0.056) at a median follow-up time of 4 months. IgG remained significantly below the initial value at 14.5 months and 30 months analyses. Subsequent RTX treatment in patients that had previously received CYC resulted in a further decline in Ig levels from pre RTX IgG 9.84 g/L (8.71-11.60) to 7.11 g/L (5.75-8.77; p = 0.007), from pre RTX IgM 0.84 g/L (0.63-1.18) to 0.35 g/L (0.23-0.48; p<0.001) and from pre RTX IgA 2.03 g/L (1.37-2.50) to IgA 1.62 g/L (IQR 0.84-2.43; p = 0.365) 14 months after RTX. Treatment with RTX induced a complete depletion of B cells in all patients. After a median observation time of 20 months median B lymphocyte counts remained severely suppressed (4 B-cells/µl, 1.25-9.5, p<0.001). Seven patients (21%) that had been treated with CYC followed by RTX were started on Ig replacement because of severe bronchopulmonary infections and serum IgG concentrations below 5 g/L. Conclusions In patients with AAVs, treatment with CYC leads to a decline in immunoglobulin concentrations. A subsequent RTX therapy aggravates the decline in serum immunoglobulin concentrations and results in a profoundly delayed B cell repopulation. Surveying patients with AAVs post CYC and RTX treatment for serum immunoglobulin concentrations and persisting hypogammaglobulinemia is warranted. PMID:22629432

  5. Involved Field Radiation After Autologous Stem Cell Transplant for Diffuse Large B-Cell Lymphoma in the Rituximab Era

    SciTech Connect

    Biswas, Tithi; Dhakal, Sughosh; Chen Rui; Hyrien, Ollivier; Bernstein, Steven; Friedberg, Jonathan W.; Fisher, Richard I.; Liesveld, Jane; Phillips, Gordon; Constine, Louis S.

    2010-05-01

    Purpose: For patients with recurrent or refractory large B-cell non-Hodgkin's lymphoma, high-dose chemotherapy and autologous stem cell transplant (ASCT) is the treatment of choice. We evaluated the role of involved field radiation therapy (IFRT) post-ASCT for patients initially induced with cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) or, more recently, rituximab-CHOP (R-CHOP). Materials and Methods: Between May 1992 and April 2005, 176 patients underwent ASCT for recurrent or refractory large B-cell non-Hodgkin's lymphoma; 164 patients were evaluable for endpoint analysis. Fifty percent of the CHOP group (n = 131), and 39% of the R-CHOP group (n = 33), received IFRT. Follow-up from the time of transplant was a median/mean of 1.7/3 years (range, 0.03-13 years). Results: The 5-year overall survival (OS) and disease-specific survival (DSS) improved with IFRT in both the R-CHOP (p = 0.006 and 0.02, respectively) and CHOP (p = 0.02 and p = 0.04, respectively) groups. IFRT was associated with a 10% (p = 0.17) reduction in local failure, alone or with a distant site. On univariate analysis, IFRT was associated with superior OS (hazard ratio [HR] = 0.50 [95% CI 0.32, 0.78]; p = 0.002) and DSS (HR = 0.53 [95% CI 0.33, 0.86]; p = 0.009). Presence of B symptoms was adverse (p = 0.03). On multivariate analysis, only IFRT was associated with significant improvement in OS (HR = 0.35 [0.18, 0.68]; p = 0.002) and DSS (HR = 0.39 [95% CI 0.18, 0.84]; p = 0.01). Conclusions: Recognizing that positive and negative patient selection bias exists for the use of IFRT post-ASCT, patients initially treated with CHOP or R-CHOP and who undergo ASCT for recurrent or refractory disease may benefit from subsequent IFRT presumably due to enhanced local control that can translate into a survival advantage.

  6. Radiation Therapy in Primary Mediastinal B-Cell Lymphoma With Positron Emission Tomography Positivity After Rituximab Chemotherapy

    SciTech Connect

    Filippi, Andrea Riccardo; Piva, Cristina; Giunta, Francesca; Bellò, Marilena; Chiappella, Annalisa; Caracciolo, Daniele; Zotta, Michela; Douroukas, Anastasios; Ragona, Riccardo; Vitolo, Umberto; Bisi, Gianni; Ricardi, Umberto

    2013-10-01

    Purpose: To investigate the role of radiation therapy (RT) in patients affected with primary mediastinal B-cell lymphoma (PMBCL) with residual {sup 18}fluorodeoxyglucose positron emission tomography ({sup 18}FDG-PET)-positive disease after rituximab chemotherapy (R-CT). Methods and Materials: Thirty-seven patients treated with R-CT and RT, all with {sup 18}FDG-PET scan at diagnosis and before RT, were included. All {sup 18}FDG-PET scans were reviewed, and responses were classified according to the Deauville 5-point scoring system. Outcomes measures were overall survival (OS) and progression-free survival (PFS), estimated for the whole cohort and for subgroups according to {sup 18}FDG-PET score after R-CT. Results: The median follow-up time was 40.9 months. Three patients were assigned to Deauville score 1 (8.1%), 9 to score 2 (24.3%), 7 to score 3 (19%), 14 to score 4 (37.8%), and 4 to score 5 (10.8%). After RT, all patients with score 3-4 experienced a complete response (CR). Among patients with score 5, 1 was in CR (25%), 2 had persistent positivity (50%), and 1 showed progressive disease (25%). A total of 4 patients experienced progression or relapse: 1 of 33 (3%) with scores 1-4, and 3 of 4 (75%) with score 5. The 3-year OS and PFS of the whole cohort were 89.8% and 88.7%, respectively. OS was significantly different between scores 1-3 and scores 4-5 (100% vs 77% at 3 years, P<.05). Patients with a score of 5 had a significantly worse outcome than did all other patients (OS at 2 years, 33.3% vs 100%). Conclusions: Approximately 50% of PMBCL patients show residual disease at {sup 18}FDG-PET scan after R-CT. RT is able to convert to CR approximately 85% of these patients, but those with a Deauville score of 5 (10%) appear at high risk of progression and death, and they might be candidates for intensified programs.

  7. Combination of bendamustine and rituximab as front-line therapy for patients with chronic lymphocytic leukaemia: multicenter, retrospective clinical practice experience with 279 cases outside of controlled clinical trials.

    PubMed

    Gentile, Massimo; Zirlik, Katja; Ciolli, Stefania; Mauro, Francesca R; Di Renzo, Nicola; Mastrullo, Lucia; Angrilli, Francesco; Molica, Stefano; Tripepi, Giovanni; Giordano, Annamaria; Di Raimondo, Francesco; Selleri, Carmine; Coscia, Marta; Musso, Maurizio; Orsucci, Lorella; Mannina, Donato; Rago, Angela; Giannotta, Angela; Ferrara, Felicetto; Herishanu, Yair; Shvidel, Lev; Tadmor, Tamar; Scortechini, Ilaria; Ilariucci, Fiorella; Murru, Roberta; Guarini, Attilio; Musuraca, Gerardo; Mineo, Giuseppe; Vincelli, Iolanda; Arcari, Annalisa; Tarantini, Giuseppe; Caparrotti, Giuseppe; Chiarenza, Annalisa; Levato, Luciano; Villa, Maria Rosaria; De Paolis, Maria Rosaria; Zinzani, Pier Luigi; Polliack, Aaron; Morabito, Fortunato

    2016-06-01

    Recently, encouraging results in terms of safety and efficacy have been obtained using bendamustine-rituximab (BR) in untreated chronic lymphocytic leukaemia (CLL) patients enrolled in a phase II study. Here, we report a retrospective international multicenter study of CLL patients treated with BR as front-line therapy. The cohort included 279 patients with progressive CLL from 33 centers (29 Italian, 3 Israeli and 1 German) who received at least 1 cycle of BR as first-line treatment during the 2008-2014 period. The primary objective of this study was to evaluate the efficacy and safety of BR administered as front-line therapy, outside of controlled clinical trials. Median age was 70 years (range, 43-86 years); 62.4% were males and 35.8% had Binet stage C. Forty-two patients (15.2%) were unfit (cumulative illness rating scale [CIRS] score ≥7), and 140 (50.2%) had creatinine clearance ≤70 ml/min. Fluorescent in situ hybridisation analysis, available for 192 cases, showed that 21 (10.9%) had del11q and 18 (9.4%) del17p. The overall response rate (ORR) was 86.4%, with a complete remission rate of 28%. Patients with del17p had an ORR of 66.7%. After median follow-up of 24 months, the 2-year progression-free survival (PFS) was 69.9%; CIRS ≥7, immunoglobulin heavy-chain variable-region (IGHV) unmutated status, del17p and BR dose intensity <80% were independently associated with shorter PFS. Grade III or IV neutropenia, thrombocytopenia, and anaemia were observed in 25.9%, 15.4%, and 15.1% of patients, respectively. Twenty-four patients (8.6%) had severe infections. BR is also an effective and safe regimen for untreated CLL patients, outside of controlled clinical trials. PMID:27127905

  8. Rituximab plus gemcitabine and oxaliplatin in patients with refractory/relapsed diffuse large B-cell lymphoma who are not candidates for high-dose therapy. A phase II Lymphoma Study Association trial.

    PubMed

    Mounier, Nicolas; El Gnaoui, Taoufik; Tilly, Hervé; Canioni, Danièle; Sebban, Catherine; Casasnovas, René-Olivier; Delarue, Richard; Sonet, Anne; Beaussart, Pauline; Petrella, Tony; Castaigne, Sylvie; Bologna, Serge; Salles, Gilles; Rahmouni, Alain; Gaulard, Philippe; Haioun, Corinne

    2013-11-01

    A previous pilot study with rituximab, gemcitabine and oxaliplatin showed promising activity in patients with refractory/relapsed B-cell lymphoma. We, therefore, conducted a phase II study to determine whether these results could be reproduced in a multi-institutional setting. This phase II study included 49 patients with refractory (n=6) or relapsing (n=43) diffuse large B-cell lymphoma. The median age of the patients was 69 years. Prior treatment included rituximab in 31 (63%) and autologous transplantation in 17 (35%) patients. International Prognostic Index at enrollment was >2 in 34 patients (71%). The primary endpoint was overall response rate after four cycles of treatment. Patients were planned to receive eight cycles if they reached at least partial remission after four cycles. After four cycles 21 patients (44%) were in complete remission and 8 (17%) in partial remission, resulting in an overall response rate of 61%. Factors significantly affecting overall response rate were early (<1 year) progression/relapse (18% versus 54%; P=0.001) and prior exposure to rituximab (23% versus 65%; P=0.004). Five-year progression-free and overall survival rates were 12.8% and 13.9%, respectively. Rituximab, gemcitabine and oxaliplatin were well tolerated with grade 3-4 infectious episodes in 22% of the cycles. These results are the first confirmation from a multicenter study that rituximab, gemcitabine and oxaliplatin provide a consistent response rate in patients with refractory/relapsed diffuse large B-cell lymphoma. This therapy can now be considered as a platform for new combinations with targeted treatments. This trial was registered at clinicaltrial.gov under #NCT00169195. PMID:23753028

  9. Rituximab plus gemcitabine and oxaliplatin in patients with refractory/relapsed diffuse large B-cell lymphoma who are not candidates for high-dose therapy. A phase II Lymphoma Study Association trial

    PubMed Central

    Mounier, Nicolas; El Gnaoui, Taoufik; Tilly, Hervé; Canioni, Danièle; Sebban, Catherine; Casasnovas, René-Olivier; Delarue, Richard; Sonet, Anne; Beaussart, Pauline; Petrella, Tony; Castaigne, Sylvie; Bologna, Serge; Salles, Gilles; Rahmouni, Alain; Gaulard, Philippe; Haioun, Corinne

    2013-01-01

    A previous pilot study with rituximab, gemcitabine and oxaliplatin showed promising activity in patients with refractory/relapsed B-cell lymphoma. We, therefore, conducted a phase II study to determine whether these results could be reproduced in a multi-institutional setting. This phase II study included 49 patients with refractory (n=6) or relapsing (n=43) diffuse large B-cell lymphoma. The median age of the patients was 69 years. Prior treatment included rituximab in 31 (63%) and autologous transplantation in 17 (35%) patients. International Prognostic Index at enrollment was >2 in 34 patients (71%). The primary endpoint was overall response rate after four cycles of treatment. Patients were planned to receive eight cycles if they reached at least partial remission after four cycles. After four cycles 21 patients (44%) were in complete remission and 8 (17%) in partial remission, resulting in an overall response rate of 61%. Factors significantly affecting overall response rate were early (<1 year) progression/relapse (18% versus 54%; P=0.001) and prior exposure to rituximab (23% versus 65%; P=0.004). Five-year progression-free and overall survival rates were 12.8% and 13.9%, respectively. Rituximab, gemcitabine and oxaliplatin were well tolerated with grade 3–4 infectious episodes in 22% of the cycles. These results are the first confirmation from a multicenter study that rituximab, gemcitabine and oxaliplatin provide a consistent response rate in patients with refractory/relapsed diffuse large B-cell lymphoma. This therapy can now be considered as a platform for new combinations with targeted treatments. This trial was registered at clinicaltrial.gov under #NCT00169195. PMID:23753028

  10. Relative Biologic Effects of Low-Dose-Rate {alpha}-Emitting {sup 227}Th-Rituximab and {beta}-Emitting {sup 90}Y-Tiuexetan-Ibritumomab Versus External Beam X-Radiation

    SciTech Connect

    Dahle, Jostein Bruland, Oyvind S.; Larsen, Roy H.

    2008-09-01

    Purpose: To determine the relative biologic effects (RBE) of {alpha}-particle radiation from {sup 227}Th-rituximab and of {beta}-radiation from {sup 90}Y-tiuexetan-ibritumomab (Zevalin) compared with external beam X-radiation in the Raji lymphoma xenograft model. Methods and Materials: Radioimmunoconjugates were administered intravenously in nude mice with Raji lymphoma xenografts at different levels of activity. Absorbed dose to tumor was estimated by separate biodistribution experiments for {sup 227}Th-rituximab and Zevalin. Tumor growth was measured two to three times per week after injection or X-radiation. Treatment-induced increase in growth delay to reach tumor volumes of 500 and 1,000 mm{sup 3}, respectively, was used as an end point. Results: The absorbed radiation dose-rate in tumor was slightly more than 0.1 Gy/d for the first week following injection of {sup 227}Th-rituximab, and thereafter gradually decreased to 0.03 Gy/d at 21 days after injection. For treatment with Zevalin the maximum dose-rate in tumor was achieved already 6 h after injection (0.2 Gy/d), and thereafter decreased to 0.01 Gy/d after 7 days. The relative biologic effect was between 2.5 and 7.2 for {sup 227}Th-rituximab and between 1 and 1.3 for Zevalin. Conclusions: Both at low doses and low-dose-rates, the {sup 227}Th-rituximab treatment was more effective per absorbed radiation dose unit than the two other treatments. The considerable effect at low doses suggests that the best way to administer low-dose-rates, {alpha}-emitting radioimmunoconjugates is via multiple injections.

  11. Comparability analysis of anti-CD20 commercial (rituximab) and RNAi-mediated fucosylated antibodies by two LC-MS approaches

    PubMed Central

    Li, Chen; Rossomando, Anthony; Wu, Shiaw-Lin; Karger, Barry L.

    2013-01-01

    In developing biosimilar or biobetter products, comparability to the reference product is required to claim similar integrity or intended purpose. In this work, an anti-CD20 monoclonal antibody developed using RNA interference to decrease core fucosylation (RNAi-mediated) was comprehensively characterized by LC-MS and compared with the commercially-available anti-CD20 rituximab (MabThera®). As anticipated, < 30% core fucose was found within the RNAi-produced molecule (compared with > 90% in rituximab), and the reduction in fucose resulting in a significant improvement in FcγRΙΙΙa binding and antibody-dependent cell-mediated cytotoxicity. Two mutations, S258Y (fully mutated) and F174I/L (partially mutated), however, were detected in the production of the RNAi-mediated molecule. An alternative LC-MS approach using dimethyl labeling (i.e., 2CH2 for rituximab and 2CD2 for the RNAi-mediated molecule) was developed to additionally compare the two mAbs and confirm the full sequence with the two mutation sites. Furthermore, disulfide linkages were found to be the same for the two antibodies, with a small portion of unpaired cysteines in both products. Disulfides were correctly linked if the samples were prepared at low pH (i.e., enzymatic digestion by pepsin at pH 2); however, trace amounts of scrambling were found by trypsin digestion at pH 6.8, and this scrambling increased significantly at pH 8. Typical modifications, such as pyro-Glu formation at the N-terminus, K clipping at the C-terminus, oxidation at Met, and deamidation at Asn, were also detected with no significant differences between the two products. Using the LC-MS approaches for the comparability study, product integrity with critical structure information was revealed for confirmation of intended purpose (core fucosylation), identification of critical parameters (e.g., sample pH), and correction as needed (amino acid mutation). PMID:23751726

  12. Paramagnetic-to-Ferromagnetic Transition in Con Under Pressure

    NASA Astrophysics Data System (ADS)

    Kasinathan, Deepa; Pickett, Warren

    2004-03-01

    Motivated by reports of synthesis of zincblende (ZB) structure CrAs in thin film form, strong interest has developed in understanding transition metal pnictides and their tendencies toward magnetic order.Literature on the experimental analysis of the structure of CoN is varied, with reports of both magnetically ordered NaCl structure CoN and non-magnetic ZB CoN. We present results of first principles analysis of electronic structure, magnetism and Murnaghan equation of state for both structures. The non-magnetic ZB structure, stable at ambient pressure transforms to a collapsed ferromagnetic NaCl phase at 10GPa (ΔV = -15%). These results will be compared to data and similarities/differences with other transition metal nitrides will be discussed.

  13. Dose-reduced fludarabine, cyclophosphamide and rituximab is well tolerated in older patients with chronic lymphocytic leukemia and has preserved therapeutic efficacy.

    PubMed

    Lew, Thomas E; Cheah, Chan Y; Carney, Dennis A; Prince, H Miles; Wolf, Max; Bazargan, Ali; Januszewicz, E Henry; Filshie, Robin; Westerman, David; Seymour, John F; Tam, Constantine S

    2016-05-01

    Despite its efficacy in prospective trials, full dose fludarabine, cyclophosphamide and rituximab (FCR) may be too toxic for elderly patients with chronic lymphocytic leukemia (CLL) in clinical practice. We retrospectively reviewed the impact of dose reductions in FCR therapy on the outcomes of 42 consecutive patients aged 65-87 (median 72) years. Despite a median cumulative fludarabine dose reduction of 50% from full dose, the objective response and complete response rates were 86% and 38% respectively (frontline 94%/59%; previously treated 80%/24%). Dose reductions of 25-75% were not significantly associated with inferior progression free survival compared to minimal reductions (≤25%) (p = 0.49), and did not preclude deep responses, including six cases (14%) of minimal residual disease negativity. Although hematological and infectious toxicities were common, treatment limiting adverse effects were infrequent. Dose attenuated FCR appears to have preserved efficacy and may be a viable therapeutic option for elderly patients with CLL. PMID:26464106

  14. V gamma 9 V delta 2 T cell cytotoxicity against tumor cells is enhanced by monoclonal antibody drugs--rituximab and trastuzumab.

    PubMed

    Tokuyama, Hirotake; Hagi, Tomomi; Mattarollo, Stephen R; Morley, Jacqueline; Wang, Qiao; So, Hang-Fai; Fai-So, Hang; Moriyasu, Fuminori; Nieda, Mie; Nicol, Andrew J

    2008-06-01

    V gamma 9 V delta 2 T cells exert potent cytotoxicity toward various tumor cells and adoptive transfer of V gamma 9 V delta 2 T cells is an attractive proposition for cell based immunotherapy. V gamma 9 V delta 2 T cells expanded in the presence of Zoledronate and IL-2 express CD16 (Fc gamma RIII), which raises the possibility that V gamma 9 V delta 2 T cells could be used in conjunction with tumor targeting monoclonal antibody drugs to increase antitumor cytotoxicity by antibody dependent cellular cytotoxicity (ADCC). Cytotoxic activity against CD20-positive B lineage lymphoma or chronic lymphocytic leukemia (CLL) and HER2-positive breast cancer cells was assessed in the presence of rituximab and trastuzumab, respectively. Cytotoxicity of V gamma 9 V delta 2 T cells against CD20-positive targets was higher when used in combination with rituximab. Similarly, V gamma 9 V delta 2 T cells used in combination with trastuzumab resulted in greater cytotoxicity against HER2-positive cells in comparison with either agent alone and this effect was restricted to the CD16(+)V gamma 9 V delta 2 T cell population. Our results show that CD16(+)V gamma 9 V delta 2 T cells recognize monoclonal antibody coated tumor cells via CD16 and exert ADCC similar to that observed with NK cells, even when target cells are relatively resistant to monoclonal antibodies or V gamma 9 V delta 2 T cells alone. Combination therapy involving ex vivo expanded CD16(+)V gamma 9 V delta 2 T cells and monoclonal antibodies may enhance the clinical outcomes for patients treated with monoclonal antibody therapy. PMID:18307255

  15. Dose-intensified CHOP with rituximab (R-Double-CHOP) followed by consolidation high-dose chemotherapies for patients with advanced diffuse large B-cell lymphoma.

    PubMed

    Kurita, Daisuke; Miura, Katsuhiro; Nakagawa, Masaru; Ohtake, Shimon; Sakagami, Masashi; Uchino, Yoshihito; Takahashi, Hiromichi; Kiso, Satomi; Hojo, Atsuko; Kodaira, Hitomi; Yagi, Mai; Hirabayashi, Yukio; Kobayashi, Yujin; Iriyama, Noriyoshi; Kobayashi, Sumiko; Hatta, Yoshihiro; Kura, Yoshimasa; Sugitani, Masahiko; Takei, Masami

    2015-06-01

    Even after the advent of rituximab, clinical outcomes of conventional immuno-chemotherapy for high-risk diffuse large B-cell lymphoma (DLBCL) remain unsatisfactory. We retrospectively evaluated the efficacy and safety of R-Double-CHOP (R-D-CHOP), consisting of rituximab (375 mg/m(2), day -2), cyclophosphamide (750 mg/m(2), day 1, 2), doxorubicin (50 mg/m(2), day 1, 2), vincristine [1.4 mg/m(2) (maximum 2.0 mg/body), day 1], and prednisolone (50 mg/m(2), day 1-5), followed by consolidation high-dose chemotherapy. This treatment was given to 51 de novo DLBCL patients with a median age of 54 (range 19-65), who were categorized as high/high-intermediate risk by the age-adjusted International Prognostic Index. Treatment was given every 3 weeks up to three courses. The overall response and the complete response rate for R-D-CHOP were 94 and 78 %, respectively. A total of 30 responders proceeded to high-dose chemotherapy followed by autologous stem cell transplantation (HDC/ASCT), whereas 16 received high-dose methotrexate (HD-MTX) alternatively. The 3-year overall survival and the event-free survival for all patients were 78 and 61 %, respectively. Major adverse events included hematological toxicities, but there were no treatment-related deaths during the observation period. We conclude that the R-D-CHOP regimen followed by HDC/ASCT or HD-MTX is a promising treatment option for younger patients with highly advanced DLBCL. PMID:25776837

  16. Efficacy and safety of rituximab combined with chemotherapy in the treatment of diffuse large B-cell lymphoma: a meta-analysis.

    PubMed

    Meng, Fanlu; Zhong, Diansheng; Zhang, Linlin; Shao, Yi; Ma, Qing

    2015-01-01

    The aim of this study is to systematically evaluate the safety and efficacy of rituximab plus CHOP (R-CHOP combined regimen) in patients with previously untreated diffuse large B cell lymphoma (DLBCL). Electronic database were searched for randomized-controlled studies only comparing R-CHOP to CHOP standard alone in patients with untreated DLBCL were included. The risk ratios (RRs) with their 95% corresponding intervals (95% CI) were employed to estimate the efficacy of overall response (OR), complete response (CR), risk of dying and relapse rate in followed-up period. Total ten case-control studies containing 2941 patients met the inclusion criteria. The addition of R to standard CHOP were showed to increase the proportion of CR (RR=1.23, 95% CI=1.13-1.35, P<0.00001) and OR (RR=1.39, 95% CI=1.24-1.55, P<0.00001) in a fixed-effect model, indicating that rituximab combined with CHOP regimen is efficacy than CHOP alone. It did not increase the overall risk of dying as a consequence of infection (RR=0.79, 95% CI=0.55-1.13, P=0.20). Furthermore, the relapse rates is significantly lower in R-CHOP (RR=0.52, 95% CI=0.38-0.71, P<0.0001). The adverse effects were also not significant (P>0.05). In summary, R-CHOP regimen is superior to standard CHOP in terms of overall response and complete response. It does not increase the incidence of adverse effects. However, more studies concerning different age groups and special patients are needed to discuss the potential role of R in DLBCL. PMID:26770342

  17. Excellent outcomes and lack of prognostic impact of cell of origin for localized diffuse large B-cell lymphoma in the rituximab era.

    PubMed

    Kumar, Anita; Lunning, Matthew A; Zhang, Zhigang; Migliacci, Jocelyn C; Moskowitz, Craig H; Zelenetz, Andrew D

    2015-12-01

    Therapeutic options for limited-stage diffuse large B cell lymphoma (DLBCL) include short- or full-course R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) ± radiotherapy. The optimal treatment remains unclear. The prognostic value of cell-of-origin (COO) in early stage DLBCL is unknown. Patients with limited-stage DLBCL (stage I or stage II, non-bulky) treated with R-CHOP ± involved field radiotherapy (IFRT) from 1999 to 2012 were included. COO by the Hans algorithm was analysed in a subset of patients. Of 261 patients, 30% were stage I (N = 82), 37% stage IE (N = 96), <1% stage IXEE (N = 1), 18% stage II (N = 46) and 14% stage IIE (N = 37). The stage-modified International Prognostic Index stratified patients into prognostically relevant groups. There was no significant difference in progression-free survival (PFS) or overall survival (OS) for patients in the germinal centre B-cell-like (GCB; n = 65) and non-GCB cohorts (n = 22). Seventeen patients received R-CHOP × 3-4 cycles (Arm A), 147 received R-CHOP × 3-4 cycles + IFRT (Arm B), 48 received R-CHOP × 6 cycles (Arm C), and 50 received R-CHOP × 6 cycles + IFRT (Arm D). The outcomes were excellent, with 5-year PFS of 82% and 5-year OS of 93%, and were similar across the 4 treatment groups. In the rituximab era, outcomes for limited-stage DLBCL, regardless of treatment approach, were excellent. Baseline COO was not a significant prognostic factor in patients treated with short-course R-CHOP + IFRT. PMID:26456939

  18. The presence of genomic imbalances is associated with poor outcome in patients with burkitt lymphoma treated with dose-intensive chemotherapy including rituximab.

    PubMed

    Forero-Castro, Maribel; Robledo, Cristina; Lumbreras, Eva; Benito, Rocio; Hernández-Sánchez, Jesús M; Hernández-Sánchez, María; García, Juan L; Corchete-Sánchez, Luis A; Tormo, Mar; Barba, Pere; Menárguez, Javier; Ribera, Jordi; Grande, Carlos; Escoda, Lourdes; Olivier, Carmen; Carrillo, Estrella; García de Coca, Alfonso; Ribera, Josep-María; Hernández-Rivas, Jesús M

    2016-02-01

    The introduction of Rituximab has improved the outcome and survival rates of Burkitt lymphoma (BL). However, early relapse and refractoriness are current limitations of BL treatment and new biological factors affecting the outcome of these patients have not been explored. This study aimed to identify the presence of genomic changes that could predict the response to new therapies in BL. Forty adolescent and adult BL patients treated with the Dose-Intensive Chemotherapy Including Rituximab (Burkimab) protocol (Spanish Programme for the Study and Treatment of Haematological Malignancies; PETHEMA) were analysed using array-based comparative genomic hybridization (CGH). In addition, the presence of TP53, TCF3 (E2A), ID3 and GNA13 mutations was assessed by next-generation sequencing (NGS). Ninety-seven per cent of the patients harboured genomic imbalances. Losses on 11q, 13q, 15q or 17p were associated with a poor response to Burkimab therapy (P = 0·038), shorter progression-free survival (PFS; P = 0·007) and overall survival (OS; P = 0·009). The integrative analysis of array-CGH and NGS showed that 26·3% (5/19) and 36·8% (7/19) of patients carried alterations in the TP53 and TCF3 genes, respectively. TP53 alterations were associated with shorter PFS (P = 0·011) while TCF3 alterations were associated with shorter OS (P = 0·032). Genetic studies could be used for risk stratification of BL patients treated with the Burkimab protocol. PMID:26567765

  19. Rituximab, bendamustine and lenalidomide in patients with aggressive B-cell lymphoma not eligible for anthracycline-based therapy or intensive salvage chemotherapy - SAKK 38/08.

    PubMed

    Hitz, Felicitas; Zucca, Emanuele; Pabst, Thomas; Fischer, Natalie; Cairoli, Anne; Samaras, Panagiotis; Caspar, Clemens B; Mach, Nicolas; Krasniqi, Fatime; Schmidt, Adrian; Rothermundt, Christian; Enoiu, Milica; Eckhardt, Katrin; Berardi Vilei, Simona; Rondeau, Stephanie; Mey, Ulrich

    2016-07-01

    An increasing number of older patients are suffering from aggressive lymphoma. Effective and more tolerable treatment regimens are urgently needed for this growing patient population. Patients with aggressive lymphoma not eligible for anthracycline-based first-line therapy or intensive salvage regimens were treated with the rituximab-bendamustine-lenalidomide (R-BL) regimen (rituximab 375 mg/m(2)  day 1, bendamustine 70 mg/m(2)  d 1, 2, lenalidomide 10 mg d 1-21) for six cycles every 4 weeks. Forty-one patients with a median age of 75 (range 40-94) years were enrolled: 33 patients had substantial co-morbidities. 13 patients were not eligible for anthracycline-based first-line chemotherapy, 28 patients had relapsed/refractory disease. The primary endpoint, overall response, was achieved by 25 (61%) patients (95% confidence interval 45-76%). Grade ≥ 3 toxicity comprised haematological (59%), skin (15%), constitutional (15%) and neurological (12%) events. 9 patients died during trial treatment: 5 from lymphoma progression, 2 from toxicity, 2 with sudden death. After a median follow-up of 25·9 (interquartile range 20·4-31·6) months, 13 patients were still alive. Median overall survival was 14·5 months. In conclusion, R-BL can be considered a treatment option for elderly patients with treatment naïve or relapsed/refractory aggressive lymphoma not eligible for standard aggressive regimens. PMID:27018242

  20. Bendamustine plus rituximab versus R-CHOP as first-line treatment for patients with indolent non-Hodgkin's lymphoma: evidence from a multicenter, retrospective study.

    PubMed

    Mondello, Patrizia; Steiner, Normann; Willenbacher, Wolfgang; Wasle, Ines; Zaja, Francesco; Zambello, Renato; Visentin, Andrea; Mauro, Endri; Ferrero, Simone; Ghione, Paola; Pitini, Vincenzo; Cuzzocrea, Salvatore; Mian, Michael

    2016-06-01

    The optimal first-line treatment for advanced low-grade non-Hodgkin lymphomas (LG-NHL) is still highly debated. Recently, the StiL and the BRIGHT trials showed that the combination of rituximab and bendamustine (R-B) is non-inferior to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) with a better toxicity profile. Utilizing a retrospective analysis, we compared the efficacy and safety of both regimens in clinical practice. From November 1995 to January 2014, 263 LG-NHL patients treated with either R-B or R-CHOP were retrospectively assessed in seven European cancer centers. Ninety patients were treated with R-B and 173 with R-CHOP. Overall response rate was 94 and 92 % for the R-B and the R-CHOP group, respectively. The percentage of complete response was similar for both groups (63 vs. 66 % with R-B and R-CHOP, respectively; p = 0.8). R-B was better tolerated and less toxic than R-CHOP. The median follow-up was 6.8 and 5.9 years for the R-CHOP and the R-B group, respectively. Overall, no difference in progression-free survival (PFS) (108 vs. 110 months; p = 0.1) was observed in the R-B group compared to the R-CHOP cohort. Nevertheless, R-B significantly prolonged PFS in FL patients (152 and 132 months in the R-B and R-CHOP group, respectively; p = 0.05). However, this result was not verified in multivariate analysis probably due to the limits of the present study. We confirm that the R-B regimen administered in patients with LG-NHL is an effective and less toxic therapeutic option than R-CHOP in clinical practice. PMID:27103007

  1. A phase II, single-arm, multicentre study of coltuximab ravtansine (SAR3419) and rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma.

    PubMed

    Coiffier, Bertrand; Thieblemont, Catherine; de Guibert, Sophie; Dupuis, Jehan; Ribrag, Vincent; Bouabdallah, Réda; Morschhauser, Franck; Navarro, Robert; Le Gouill, Steven; Haioun, Corinne; Houot, Roch; Casasnovas, Olivier; Holte, Harald; Lamy, Thierry; Broussais, Florence; Payrard, Sandrine; Hatteville, Laurence; Tilly, Hervé

    2016-06-01

    In this phase II, multicentre, single-arm study, 52 patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) received the anti-CD19 antibody-drug conjugate coltuximab ravtansine (55 mg/m(2) ) and rituximab (375 mg/m(2) ) weekly for 4 weeks, then every 2 weeks for 8 weeks. The primary endpoint was objective response rate (ORR) by International Working Group Criteria. The primary objective was to reject the null hypothesis of an ORR of ≤40%. Among 45 evaluable patients, the ORR was 31·1% (80% confidence interval [CI]: 22·0-41·6%) and the primary objective was not met. The ORR appeared higher in patients with relapsed disease (58·3% [80% CI: 36·2-78·1%]) versus those refractory to their last (42·9% [80% CI: 17·0-72·1%]) or first-line therapy (15·4% [80% CI: 6·9-28·4%]). Median progression-free survival, overall survival and duration of response were 3·9 [80% CI: 3·22-3·98], 9·0 [80% CI: 6·47-13·67] and 8·6 (range: 0-18) months, respectively. The pharmacokinetics of both drugs were unaffected by co-administration. Common adverse events included gastrointestinal disorders (52%) and asthenia (25%). No patients discontinued due to adverse events. In conclusion, coltuximab ravtansine with rituximab was well tolerated and yielded clinical responses in a subset of patients with relapsed/refractory DLBCL. PMID:27010483

  2. Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome.

    PubMed

    Lunde, Sigrid; Kristoffersen, Einar K; Sapkota, Dipak; Risa, Kristin; Dahl, Olav; Bruland, Ove; Mella, Olav; Fluge, Øystein

    2016-01-01

    Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We have previously suggested clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in a randomized and placebo-controlled study. Prolonged responses were then demonstrated in an open-label phase-II study with maintenance rituximab treatment. Using blood samples from patients in the previous two clinical trials, we investigated quantitative changes in T-lymphocyte subsets, in immunoglobulins, and in serum levels of two B-cell regulating cytokines during follow-up. B-lymphocyte activating factor of the tumor necrosis family (BAFF) in baseline serum samples was elevated in 70 ME/CFS patients as compared to 56 healthy controls (p = 0.011). There were no significant differences in baseline serum BAFF levels between patients with mild, moderate, or severe ME/CFS, or between responders and non-responders to rituximab. A proliferation-inducing ligand (APRIL) serum levels were not significantly different in ME/CFS patients compared to healthy controls at baseline, and no changes in serum levels were seen during follow-up. Immunophenotyping of peripheral blood T-lymphocyte subsets and T-cell activation markers at multiple time points during follow-up showed no significant differences over time, between rituximab and placebo groups, or between responders and non-responders to rituximab. Baseline serum IgG levels were significantly lower in patients with subsequent response after rituximab therapy compared to non-responders (p = 0.03). In the maintenance study, slight but significant reductions in mean serum immunoglobulin levels were observed at 24 months compared to baseline; IgG 10.6-9.5 g/L, IgA 1.8-1.5 g/L, and IgM 0.97-0.70 g/L. Although no functional assays were performed, the lack of significant associations of T- and NK-cell subset numbers with B-cell depletion, as well as the lack of associations to clinical responses, suggest that B

  3. Serum BAFF and APRIL Levels, T-Lymphocyte Subsets, and Immunoglobulins after B-Cell Depletion Using the Monoclonal Anti-CD20 Antibody Rituximab in Myalgic Encephalopathy/Chronic Fatigue Syndrome

    PubMed Central

    Lunde, Sigrid; Kristoffersen, Einar K.; Sapkota, Dipak; Risa, Kristin; Dahl, Olav; Bruland, Ove; Mella, Olav; Fluge, Øystein

    2016-01-01

    Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is a disease of unknown etiology. We have previously suggested clinical benefit from B-cell depletion using the monoclonal anti-CD20 antibody rituximab in a randomized and placebo-controlled study. Prolonged responses were then demonstrated in an open-label phase-II study with maintenance rituximab treatment. Using blood samples from patients in the previous two clinical trials, we investigated quantitative changes in T-lymphocyte subsets, in immunoglobulins, and in serum levels of two B-cell regulating cytokines during follow-up. B-lymphocyte activating factor of the tumor necrosis family (BAFF) in baseline serum samples was elevated in 70 ME/CFS patients as compared to 56 healthy controls (p = 0.011). There were no significant differences in baseline serum BAFF levels between patients with mild, moderate, or severe ME/CFS, or between responders and non-responders to rituximab. A proliferation-inducing ligand (APRIL) serum levels were not significantly different in ME/CFS patients compared to healthy controls at baseline, and no changes in serum levels were seen during follow-up. Immunophenotyping of peripheral blood T-lymphocyte subsets and T-cell activation markers at multiple time points during follow-up showed no significant differences over time, between rituximab and placebo groups, or between responders and non-responders to rituximab. Baseline serum IgG levels were significantly lower in patients with subsequent response after rituximab therapy compared to non-responders (p = 0.03). In the maintenance study, slight but significant reductions in mean serum immunoglobulin levels were observed at 24 months compared to baseline; IgG 10.6–9.5 g/L, IgA 1.8–1.5 g/L, and IgM 0.97–0.70 g/L. Although no functional assays were performed, the lack of significant associations of T- and NK-cell subset numbers with B-cell depletion, as well as the lack of associations to clinical responses, suggest that B

  4. [Type B lactic acidosis associated with marginal lymphoma of the spleen: report of one case].

    PubMed

    Vega, Jorge; Rodríguez, María de los Ángeles; Peña, Armando; Vásquez, Alejadro

    2012-02-01

    Lactic acidosis in the absence of hypoxia or tissue hypoperfusion (type B) is very rare and is associated with the use of some drugs or malignancy. We report a 79-year-old woman, with a marginal non-Hodgkin's lymphoma of the spleen that was subjected to a splenectomy one year ago. She presented with unexplained tachypnea associated with pancytopenia and elevation of IgM to 10 times over the higher normal limit. Laboratory tests showed the presence of metabolic acidosis and high lactic acid levels in the absence of infection, tissue hypoxia or hypoperfusion. She was treated with sodium bicarbonate and steroids without obtaining a reduction in lactate levels. Twelve days after admission, a single dose of Rituximab quickly normalized lactate concentrations and platelet count. After the fourth dose of Rituximab, pancytopenia disappeared and IgM fell to 25% of its baseline concentration. PMID:22739955

  5. [I costi farmacologici della terapia di conversione con farmaci biologici nel carcinoma del colon-retto con metastasi epatiche].

    PubMed

    Giuliani, Jacopo; Bonetti, Andrea

    2016-08-01

    Riassunto. Lo scopo di questo studio è quello di valutare i costi dei farmaci (con particolare riferimento alle terapie con farmaci biologici) utilizzati nella terapia di conversione in una popolazione non selezionata di pazienti affetti da carcinoma del colon-retto in stadio avanzato, al fine di ottenere una resezione epatica R0. In questa rassegna sono stati selezionati i report completi e gli aggiornamenti di tutti gli studi clinici randomizzati (di fase II e fase III) che confrontassero almeno 2 regimi di terapia con farmaci biologici in prima linea in pazienti affetti da carcinoma del colon-retto in stadio avanzato di malattia. I costi dei farmaci sono stati ricavati dalla nostra Farmacia Ospedaliera e sono espressi in euro (€). Il nostro studio inizia con la valutazione di 683 abstract. 48 tria sono stati considerati adeguati per una successiva analisi. Una valutazione più approfondita ha portato all'esclusione di 37 trial, lasciando alla valutazione finale 11 studi clinici randomizzati (3 trial di fase II, per un totale di 522 pazienti, e 8 studi di fase III, per un totale di 7191 pazienti). I costi dei farmaci utilizzati nella terapia di conversione aumentano con la sostituzione del 5-fluorouracile con la capecitabina e, in misura maggiore, con l'introduzione degli agenti biologici. In questo lavoro sono presentati due punti chiave. Primo, i costi degli agenti farmacologici utilizzati nei regimi di prima linea a base di agenti biologici più comunemente utilizzati nel trattamento del carcinoma del colon-retto in stadio avanzato sono molto variabili. Secondo, i dati di efficacia dei regimi pubblicati, in termini di tassi di resezione, dipendono dalla selezione dei pazienti, dalle caratteristiche del tumore e dal tipo di schema di terapia. PMID:27571559

  6. Synergistic anti-tumor activity of acadesine (AICAR) in combination with the anti-CD20 monoclonal antibody rituximab in in vivo and in vitro models of mantle cell lymphoma

    PubMed Central

    Montraveta, Arnau; Xargay-Torrent, Sílvia; López-Guerra, Mónica; Rosich, Laia; Pérez-Galán, Patricia; Salaverria, Itziar; Beà, Silvia; Kalko, Susana G.; de Frias, Mercè; Campàs, Clara; Roué, Gaël; Colomer, Dolors

    2014-01-01

    Mantle cell lymphoma (MCL) is considered one of the most challenging lymphoma, with limited responses to current therapies. Acadesine, a nucleoside analogue has shown antitumoral effects in different preclinical cancer models as well as in a recent phase I/II clinical trial conducted in patients with chronic lymphocytic leukemia. Here we observed that acadesine exerted a selective antitumoral activity in the majority of MCL cell lines and primary MCL samples, independently of adverse cytogenetic factors. Moreover, acadesine was highly synergistic, both in vitro and in vivo, with the anti-CD20 monoclonal antibody rituximab, commonly used in combination therapy for MCL. Gene expression profiling analysis in harvested tumors suggested that acadesine modulates immune response, actin cytoskeleton organization and metal binding, pointing out a substantial impact on metabolic processes by the nucleoside analog. Rituximab also induced changes on metal binding and immune responses. The combination of both drugs enhanced the gene signature corresponding to each single agent, showing an enrichment of genes involved in inflammation, metabolic stress, apoptosis and proliferation. These effects could be important as aberrant apoptotic and proinflammatory pathways play a significant role in the pathogenesis of MCL. In summary, our results suggest that acadesine exerts a cytotoxic effect in MCL in combination with rituximab, by decreasing the proliferative and survival signatures of the disease, thus supporting the clinical examination of this strategy in MCL patients. PMID:24519895

  7. A multi-centre, single-arm, open-label study evaluating the safety and efficacy of fixed dose rituximab in patients with refractory, relapsed or chronic idiopathic thrombocytopenic purpura (R-ITP1000 study).

    PubMed

    Tran, Huyen; Brighton, Tim; Grigg, Andrew; McRae, Simon; Dixon, Joanna; Thurley, Daniel; Gandhi, Maher K; Truman, Matt; Marlton, Paula; Catalano, John

    2014-10-01

    The efficacy of a fixed-dose rituximab schedule was prospectively explored in primary/acute refractory, relapsed or chronic (platelet count >10 × 10(9) /l and ≤50 × 10(9) /l) idiopathic thrombocytopenic purpura (ITP). Patients received two doses of rituximab (1000 mg) on days 1 and 15 and were followed-up on weeks 1-8, 12, 26, 39 and 52. A total of 122 patients were included in the safety population; efficacy was analysed in 108 patients. Overall response rate (ORR) at week 8, defined as the proportion of patients achieving complete response (CR; platelet count >150 × 10(9) /l) or partial response (PR; platelet count >50 × 10(9) /l) was 44%. Therapeutic response, defined as achieving a response at week 8, with at least a minor response (MR; platelet count >30 × 10(9) /l), sustained up to weeks 26 and 52 and accompanied by a reduction in ITP medications, was achieved in 44% (week 26) and 35% (week 52) of patients, respectively. Treatment was well tolerated with no safety concerns. While this study failed to meet its primary endpoint of an ORR of 50%, the efficacy of two fixed doses of rituximab appear to provide similar efficacy to the standard 375 mg/m(2) four-dose schedule in relapsed/chronic ITP. PMID:25041261

  8. Potential resource and cost saving analysis of subcutaneous versus intravenous administration for rituximab in non-Hodgkin’s lymphoma and for trastuzumab in breast cancer in 17 Italian hospitals based on a systematic survey

    PubMed Central

    Ponzetti, Clemente; Canciani, Monica; Farina, Massimo; Era, Sara; Walzer, Stefan

    2016-01-01

    Introduction Subcutaneous versions of different oncology therapies have been available for patients for a few years, yet patient-relevant and hospital benefits have not been assessed in real life. Methods In order to analyze the impact of subcutaneous administrations for rituximab or trastuzumab in comparison to the respective intravenous mode a primary research in Italy was executed. The study’s primary objectives were to analyze the resource and cost implications from different perspectives (patient, medical staff) in the real world. The route of administration was discussed and aligned with the participating centers in order to capture all relevant therapy parts. After the successful execution of a pilot study 19 centers in six regions in Italy were recruited to participate. Results Significant time savings might be achieved with the subcutaneous mode through significantly lower patient preparation time including less time preparing the actual dosing for each individual patient. The total time difference is 3.3 hours with rituximab in hematology (non-Hodgkin’s lymphoma), which adds up to 23.55 hours for a full course of treatment per patient (overall preparation time: 40.1 hours intravenous [95% confidence interval (CI): ±0.47] vs 16.6 hours subcutaneous [95% CI: ±0.2]). In early breast cancer (trastuzumab), the time saving might be 3.3 hours for the first cycle and the total time saving for patient preparation might be 17.2 hours (overall preparation time: 38.8 hours intravenous [95% CI: ±9.42] vs 21.6 hours subcutaneous [95% CI: ±9.9]). Furthermore, in both settings, the time of medical staff was reduced and could hence be used elsewhere. Finally, in case wastage was experienced with intravenous therapies, there were potential significant reductions in wastage through the subcutaneous administration (93%–100%) with cost savings of €6,057 with rituximab subcutaneous and €28,399 with trastuzumab subcutaneous administration for the full treatment

  9. Aggressive Lymphoma "Sarcoma Mimicker" Originating in the Gluteus and Adductor Muscles: A Case Report and Literature Review.

    PubMed

    Elkourashy, Sarah A; Nashwan, Abdulqadir J; Alam, Syed I; Ammar, Adham A; El Sayed, Ahmed M; Omri, Halima El; Yassin, Mohamed A

    2016-01-01

    Extranodal lymphoma (ENL) occurs in approximately 30%-40% of all patients with non-Hodgkin lymphoma and has been described in almost all organs and tissues. However, diffuse large B-cell lymphoma is the most common histological subtype of non-Hodgkin lymphoma, primarily arising in the retroperitoneal region. In this article, we report a rare case of an adult male diagnosed with primary diffuse large B-cell lymphoma of the gluteal and adductor muscles with aggressive bone involvement. All appropriate radiological and histopathological studies were done for diagnosis and staging. After discussion with the lymphoma multidisciplinary team, it was agreed to start on R-CHOP protocol (rituximab, cyclophosphamide, doxorubicin (Adriamycin), vincristine (Oncovin®), and prednisone) as the standard of care, which was later changed to R-CODOX-M/R-IVAC protocol (rituximab, cyclophosphamide, vincristine (Oncovin®), doxorubicin, and high-dose methotrexate alternating with rituximab, ifosfamide, etoposide, and high-dose cytarabine) due to inadequate response. Due to the refractory aggressive nature of the disease, subsequent decision of the multidisciplinary team was salvage chemotherapy and autologous stem cell transplant. The aim of this case report was to describe and evaluate the clinical presentation and important radiological features of extranodal lymphoma affecting the musculoskeletal system. PMID:27398038

  10. Aggressive Lymphoma “Sarcoma Mimicker” Originating in the Gluteus and Adductor Muscles: A Case Report and Literature Review

    PubMed Central

    Elkourashy, Sarah A.; Nashwan, Abdulqadir J.; Alam, Syed I.; Ammar, Adham A.; El Sayed, Ahmed M.; Omri, Halima El; Yassin, Mohamed A.

    2016-01-01

    Extranodal lymphoma (ENL) occurs in approximately 30%–40% of all patients with non-Hodgkin lymphoma and has been described in almost all organs and tissues. However, diffuse large B-cell lymphoma is the most common histological subtype of non-Hodgkin lymphoma, primarily arising in the retroperitoneal region. In this article, we report a rare case of an adult male diagnosed with primary diffuse large B-cell lymphoma of the gluteal and adductor muscles with aggressive bone involvement. All appropriate radiological and histopathological studies were done for diagnosis and staging. After discussion with the lymphoma multidisciplinary team, it was agreed to start on R-CHOP protocol (rituximab, cyclophosphamide, doxorubicin (Adriamycin), vincristine (Oncovin®), and prednisone) as the standard of care, which was later changed to R-CODOX-M/R-IVAC protocol (rituximab, cyclophosphamide, vincristine (Oncovin®), doxorubicin, and high-dose methotrexate alternating with rituximab, ifosfamide, etoposide, and high-dose cytarabine) due to inadequate response. Due to the refractory aggressive nature of the disease, subsequent decision of the multidisciplinary team was salvage chemotherapy and autologous stem cell transplant. The aim of this case report was to describe and evaluate the clinical presentation and important radiological features of extranodal lymphoma affecting the musculoskeletal system. PMID:27398038

  11. Synthetic slings: pros and cons.

    PubMed

    Staskin, David R; Plzak, Louis

    2002-10-01

    Historically, the choice of sling material for the treatment of urinary incontinence has been based on the surgeon's preference and experience. In general, pelvic surgeons have not differentiated artificial graft materials by their inherent qualities or for biocompatibility in the female pelvis and vaginal wall. The introduction of new artificial graft materials and new methods of implantation for the correction of genuine stress incontinence has generated renewed interest in the "pros and cons" associated with nonabsorbable material use. In this review, we discuss and differentiate sling materials and techniques. We consider some of the physical and biologic qualities of artificial graft materials, present theories and practices associated with the successful use of permanent grafts, and discuss the natural evolution of artificial graft slings to the current use of the tension-free vaginal tape and Suprapubic Arc Sling System (American Medical Systems, Minneapolis, MN). PMID:12354353

  12. Reduced-dose ICE chemotherapy ± rituximab is a safe and effective salvage therapy for fit elderly patients with diffuse large B-cell lymphoma.

    PubMed

    Sarid, Nadav; Joffe, Erel; Gibstein, Lili; Avivi, Irit; Polliack, Aaron; Perry, Chava; Herishanu, Yair

    2016-07-01

    The risk of developing non-Hodgkin lymphoma increases with age, yet elderly patients are under-represented in clinical trials. Here, we evaluate a combination regimen including ifosfamide, carboplatin and etoposide with or without rituximab (ICE ± R) in 32 fit elderly patients (median age 75.6 years) with relapsed or refractory diffuse large B-cell lymphoma. ICE ± R was generally administered in reduced doses and was well tolerated. The overall response rate (ORR) was 53.1% with a complete response (CR) rate of 40.6%. The median progression free survival (PFS) and overall survival (OS) were 3.9 and 17.0 months, respectively. Patients who responded to ICE ± R achieved median PFS of 47.2 months and OS of 78.9 months. Patients ineligible for autologous transplantation who responded to ICE ± R were treated with additional cycles, and achieved a median PFS of 18.9 months and OS of 21.7 months. Previous response to first-line therapy was the strongest predictor of response, PFS and OS to second-line treatment. PMID:26643787

  13. A Phase I Study of Pulse High-Dose Vorinostat (V) plus Rituximab (R), Ifosphamide, Carboplatin, and Etoposide (ICE) in Patients with Relapsed Lymphoma

    PubMed Central

    Budde, Lihua E.; Zhang, Michelle M.; Shustov, Andrei R.; Pagel, John M.; Gooley, Ted A.; Oliveira, George R.; Chen, Tara L.; Knudsen, Nancy L.; Roden, Jennifer E.; Kammerer, Britt E.; Frayo, Shani L.; Warr, Thomas A.; Boyd, Thomas E.; Press, Oliver W.; Gopal, Ajay K.

    2013-01-01

    SUMMARY Given the poor outcomes of relapsed aggressive lymphomas and preclinical data suggesting that ≥2.5 μM concentrations of vorinostat synergize with both etoposide and platinums, we hypothesized that pulse high-dose vorinostat could safely augment the anti-tumour activity of (R)ICE [(rituximab), ifosphamide, carboplatin, etoposide] chemotherapy. We conducted a phase I dose escalation study using a schedule with oral vorinostat ranging from 400 mg/d to 700 mg bid for 5 days in combination with the standard (R)ICE regimen (days 3, 4 and 5). Twenty-nine patients (median age 56 years, median 2 prior therapies, 14 chemoresistant [of 27 evaluable], 2 prior transplants) were enrolled and treated. The maximally tolerated vorinostat dose was defined as 500 mg twice daily × 5 days. Common dose limiting toxicities included infection (n=2), hypokalaemia (n=2), and transaminitis (n=2). Grade 3 related gastrointestinal toxicity was seen in 9 patients. The median vorinostat concentration on day 3 was 4.5 μM (range 4.2–6.0 μM) and in vitro data confirmed the augmented antitumour and histone acetylation activity at these levels. Responses were observed in 19 of 27 evaluable patients (70%) including 8 complete response/unconfirmed complete response. High-dose vorinostat can be delivered safely with (R)ICE, achieves potentially synergistic drug levels, and warrants further study, although adequate gastrointestinal prophylaxis is warranted. PMID:23356514

  14. Safety and efficacy of rituximab plus bendamustine in relapsed or refractory diffuse large B-cell lymphoma patients: an Italian retrospective multicenter study.

    PubMed

    Arcari, Annalisa; Chiappella, Annalisa; Spina, Michele; Zanlari, Luca; Bernuzzi, Patrizia; Valenti, Vanessa; Tani, Monica; Marasca, Roberto; Cabras, Maria Giuseppina; Zambello, Renato; Santagostino, Alberto; Ilariucci, Fiorella; Carli, Giuseppe; Musto, Pellegrino; Savini, Paolo; Marino, Dario; Ghio, Francesco; Gentile, Massimo; Cox, Maria Christina; Vallisa, Daniele

    2016-08-01

    Relapsed or refractory diffuse large B-cell lymphoma (DLBCL) not suitable for high dose chemotherapy with autologous stem cell transplantation (ASCT) has a dismal prognosis and no standard therapy. We designed an Italian multicenter retrospective study aimed at evaluating the safety and efficacy of rituximab plus bendamustine (R-B) as salvage treatment in patients not eligible for ASCT because of age and/or comorbidity or in patients with post-ASCT recurrence. Fifty-five patients with a median age of 76 years were included. The overall response rate was 50%, including 28% complete remission and 22% partial remission. The median overall survival (OS) was 10.8 months. The median progression free survival (PFS) was 8.8 months. Eleven patients are still alive and in complete remission at last follow-up (12-71 months). Toxicity was moderate, mainly grades 1 and 2. R-B showed promising efficacy results with an acceptable toxicity profile and should be further investigated, possibly in combination with novel drugs. PMID:26666433

  15. Interleukin (IL)-17-producing pathogenic T lymphocytes co-express CD20 and are depleted by rituximab in primary Sjögren's syndrome: a pilot study.

    PubMed

    Alunno, A; Carubbi, F; Bistoni, O; Caterbi, S; Bartoloni, E; Di Benedetto, P; Cipriani, P; Giacomelli, R; Gerli, R

    2016-06-01

    Compelling evidence suggests that interleukin (IL)-17 and IL-17-producing cells play a pivotal role in the pathogenesis of primary Sjögren's syndrome (pSS). We investigated phenotypical and functional effects of the anti-CD20 antibody rituximab (RTX) on circulating and glandular IL-17-producing T cells in pSS. RTX is able to deplete glandular IL-17(+) CD3(+) CD4(-) CD8(-) double-negative (DN) and CD4(+) Th17 cells as well as circulating IL-17(+) DN T cells. A fraction of glandular and circulating IL-17(+) DN cells and CD4(+) T helper type 17 (Th17) cells co-expresses CD20 on the cell surface explaining, at least in part, such depletive capacity of RTX. The exposure to RTX does not rescue the in-vitro corticosteroid resistance of IL-17(+) DN T cells. Our results support further the therapeutic role in pSS of RTX that, despite its B cell specificity, appears able to also hamper IL-17-producing T cells in this disease. PMID:26814615

  16. hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor for immunotherapy of uterine serous papillary carcinoma

    PubMed Central

    Cocco, E; Hu, Z; Richter, C E; Bellone, S; Casagrande, F; Bellone, M; Todeschini, P; Krikun, G; Silasi, D-A; Azodi, M; Schwartz, P E; Rutherford, T J; Buza, N; Pecorelli, S; Lockwood, C J; Santin, A D

    2010-01-01

    Background: Uterine serous papillary adenocarcinoma (USPC) is a highly aggressive variant of endometrial cancer. Human immuno-conjugate molecule (hI-con1) is an antibody-like molecule targeted against tissue factor (TF), composed of two human Factor VII (fVII) as the targeting domain, fused to human immunoglobulin (Ig) G1 Fc as an effector domain. We evaluated hI-con1 potential activity against primary chemotherapy-resistant USPC cell lines expressing different levels of TF. Methods: A total of 16 formalin-fixed, paraffin-embedded USPC samples were evaluated by immunohistochemistry (IHC) for TF expression. Six primary USPC cell lines, half of which overexpress the epidermal growth factor type II (HER2/neu) receptor at 3+ levels, were assessed by flow cytometry and real-time PCR for TF expression. Sensitivity to hI-con1-dependent cell-mediated cytotoxicity (IDCC) was evaluated in 5-hour-chromium release assays. Finally, to investigate the effect of interleukin-2 (IL-2) on IDCC, 5-h 51Cr assays were also conducted in the presence of low doses of IL-2 (i.e., 50–100 IU ml−1). Results: Cytoplasmic and/or membrane TF expression was observed in all 16 (100%) USPC samples tested by IHC, but not in normal endometrium. High expression of TF was found in 50% (three out of six) of the USPC cell lines tested by real-time PCR and flow cytometry when compared with normal endometrial cells (NECs; P<0.001). Uterine serous papillary adenocarcinoma cell lines overexpressing TF, regardless of their high or low HER2/neu expression, were highly sensitive to IDCC (mean killing±s.d., 65.6±3.7%, range 57.5–77.0%, P<0.001), although negligible cytotoxicity against USPC was seen in the absence of hI-con1 or in the presence of Rituximab control antibody. The addition of low doses of IL-2 further increased the cytotoxic effect induced by hI-con1 against chemotherapy-resistant USPC. Conclusion: hI-con1 induces strong cytotoxicity against primary chemotherapy-resistant USPC cell

  17. Investigation on the conA binding properties of Klebsiella pneumoniae.

    PubMed

    Anuar, A S S; Tay, S T

    2014-12-01

    Klebsiella pneumoniae is a healthcare-associated bacterial pathogen which causes severe diseases in immunocompromised individuals. Concanavalin A (conA), a lectin which recognizes proteins with mannose or glucose residues, has been reported to agglutinate K. pneumoniae and hence, is postulated to have therapeutical potential for K. pneumoniae-induced liver infection. This study investigated the conA binding properties of a large collection of clinical isolates of K. pneumoniae. ConA agglutination reaction was demonstrated by 94 (51.4%) of 183 K. pneumoniae isolates using a microtiter plate assay. The conA agglutination reactions were inhibited in the presence of 2.5 mg/ml D-mannose and 2.5 mg/ml glucose, and following pretreatment of the bacterial suspension with protease and heating at 80ºC. Majority of the positive isolates originated from respiratory specimens. Isolation of conA-binding proteins from K. pneumoniae ATCC 700603 strain was performed using conA affinity column and the conA binding property of the eluted proteins was confirmed by western blotting analysis using conA-HRP conjugates. Proteins with molecular weights ranging from 35 to 60 kDa were eluted from the conA affinity column, of which four were identified as outer membrane protein precursor A (37 kDa), outer membrane protein precursor C (40 kDa), enolase (45 kDa) and chaperonin (60 kDa) using mass spectrometry analysis. Several conA binding proteins (including 45 and 60 kDa) were found to be immunogenic when reacted with rabbit anti-Klebsiella antibody. The function and interplay of the conA binding proteins in bacterium-host cell relationship merits further investigation. PMID:25776607

  18. EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era.

    PubMed

    Fox, C P; Burns, D; Parker, A N; Peggs, K S; Harvey, C M; Natarajan, S; Marks, D I; Jackson, B; Chakupurakal, G; Dennis, M; Lim, Z; Cook, G; Carpenter, B; Pettitt, A R; Mathew, S; Connelly-Smith, L; Yin, J A L; Viskaduraki, M; Chakraverty, R; Orchard, K; Shaw, B E; Byrne, J L; Brookes, C; Craddock, C F; Chaganti, S

    2014-02-01

    EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based allo-SCT is a relatively uncommon and challenging clinical problem but has not received detailed study in a large cohort. Quantitative-PCR (qPCR) monitoring for EBV reactivation post allo-SCT is now commonplace but its diagnostic and predictive value remains unclear. Sixty-nine patients with PTLD following Alemtuzumab-based allo-SCT were studied. Marked clinicopathological heterogeneity was evident; lymphadenopathy was frequently absent, whereas advanced extranodal disease was common. The median viral load at clinical presentation was 49 300 copies/mL (50-65 200 000 copies/mL) and, notably, 23% and 45% of cases, respectively, had 10 000 and 40 000 copies/mL. The overall response rate to rituximab as first-line therapy was 70%. For rituximab failures, chemotherapy was ineffectual but DLIs were successful. A four-parameter prognostic index predicted response to therapy (OR 0.30 (0.12-0.74); P=0.009] and PTLD mortality (hazard ratio (HR) 1.81 (1.12-2.93) P=0.02) on multivariate analysis. This is the largest detailed series of EBV-associated PTLD after allo-SCT. At clinical presentation, EBV-qPCR values are frequently below customary thresholds for pre-emptive therapy, challenging current paradigms for monitoring and intervention. A four-point score identifies a proportion of patients at risk of rituximab-refractory disease for whom alternative therapy is needed. PMID:24212561

  19. Rituximab in combination with CHOP chemotherapy for the treatment of diffuse large B cell lymphoma in China: a 10-year retrospective follow-up analysis of 437 cases from Shanghai Lymphoma Research Group.

    PubMed

    Li, Xiaoyang; Liu, Zhao; Cao, Junning; Hong, Xiaonan; Wang, Jianmin; Chen, Fangyuan; Wang, Chun; Zou, Shanhua; Li, Junmin; Shen, Zhixiang

    2012-06-01

    The purpose of the study is to evaluate the 10 years follow-up of the efficacy in Chinese patients receiving cyclophosphamide, doxorubicin/epirubicin, vincristine, and prednisone (CHOP) or rituximab plus CHOP (R-CHOP) regimen as the initial treatment for diffuse large B cell lymphoma (DLBCL). We have retrospectively analyzed 437 patients with DLBCL who were newly diagnosed and received CHOP or R-CHOP regimen in six university hospitals and closely followed up after the completion of treatment. For all patients, there were significant differences between R-CHOP and CHOP for overall survival (OS) (median follow-up 86 months, 84.1% vs 70.2%, p = 0.018) and progression-free survival (PFS) (81.5% vs 66.7%, p = 0.015), while elder patients (>60 years old) received higher OS (median follow-up 66 months, 80.7% vs 53.0%, p = 0.011). But for younger patients (≤60 years old), the treatments with rituximab did not demonstrate a significant effect on OS (85.5% vs 79.4%, p = 0.428). In the R-CHOP group, International Prognostic Index (IPI) distinguished three risk groups instead of four risk groups. But in the CHOP group, IPI still distinguished four risk groups. Furthermore, for 212 of 437 patients diagnosed with extranodal involvement DLBCL, R-CHOP regimen provided a longer OS than CHOP regimen did (OS, 89.9% vs 71.7%, p = 0.014). Moreover, patients with extranodal lymphoma had a significant longer survival in rituximab era (OS, 89.9% vs 79.2% for extranodal and nodal, respectively; p = 0.048). The results of this large-scale study suggested that R-CHOP provided a greater survival benefit in the initial treatment of DLBCL. As for the patients with extranodal lymphoma, R-CHOP was also a good choice as first-line treatment. Extranodal disease seems to be an independent good prognostic factor in rituximab era. PMID:22160255

  20. Dose-Adjusted EPOCH-Rituximab Combined With Fludarabine Provides an Effective Bridge to Reduced-Intensity Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Lymphoid Malignancies

    PubMed Central

    Salit, Rachel B.; Fowler, Daniel H.; Wilson, Wyndham H.; Dean, Robert M.; Pavletic, Steven Z.; Dunleavy, Kieron; Hakim, Frances; Fry, Terry J.; Steinberg, Seth M.; Hughes, Thomas E.; Odom, Jeanne; Bryant, Kelly; Gress, Ronald E.; Bishop, Michael R.

    2012-01-01

    Purpose There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R). Patients and Methods One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4+ count < 200/μL) or progressive disease. Results Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3+ (P < .001), CD4+ (P < .001), and CD8+ (P < .001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P < .001) and overall survival (98.5 v 16.2 months; P < .001). Conclusion DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies. PMID:22312100

  1. Fludarabine-based versus CHOP-like regimens with or without rituximab in patients with previously untreated indolent lymphoma: a retrospective analysis of safety and efficacy

    PubMed Central

    Xu, Xiao-xiao; Yan, Bei; Wang, Zhen-xing; Yu, Yong; Wu, Xiao-xiong; Zhang, Yi-zhuo

    2013-01-01

    Fludarabine-based regimens and CHOP (doxorubicin, cyclophosphamide, vincristine, prednisone)-like regimens with or without rituximab are the most common treatment modalities for indolent lymphoma. However, there is no clear evidence to date about which chemotherapy regimen should be the proper initial treatment of indolent lymphoma. More recently, the use of fludarabine has raised concerns due to its high number of toxicities, especially hematological toxicity and infectious complications. The present study aimed to retrospectively evaluate both the efficacy and the potential toxicities of the two main regimens (fludarabine-based and CHOP-like regimens) in patients with previously untreated indolent lymphoma. Among a total of 107 patients assessed, 54 patients received fludarabine-based regimens (FLU arm) and 53 received CHOP or CHOPE (doxorubicin, cyclophosphamide, vincristine, prednisone, or plus etoposide) regimens (CHOP arm). The results demonstrated that fludarabine-based regimens could induce significantly improved progression-free survival (PFS) compared with CHOP-like regimens. However, the FLU arm showed overall survival, complete response, and overall response rates similar to those of the CHOP arm. Grade 3–4 neutropenia occurred in 42.6% of the FLU arm and 7.5% of the CHOP arm (P < 0.000). Moreover, the FLU arm also had a higher occurrence of infection than the CHOP arm (27.8% vs 8.5%; P = 0.034). Multi-factor regression of infection revealed that only age (>60 years) and presentation of grade 3–4 myelosuppression were the independent factors to infection, and the FLU arm had significantly higher myelosuppression. In conclusion, the present study revealed that the use of fludarabine-based regimens could induce high rates of myelosuppression over CHOP-like regimens, in spite of significant increases in PFS. PMID:24143112

  2. High cure rates in Burkitt lymphoma and leukemia: a Northern Italy Leukemia Group study of the German short intensive rituximab-chemotherapy program

    PubMed Central

    Intermesoli, Tamara; Rambaldi, Alessandro; Rossi, Giuseppe; Delaini, Federica; Romani, Claudio; Pogliani, Enrico Maria; Pagani, Chiara; Angelucci, Emanuele; Terruzzi, Elisabetta; Levis, Alessandro; Cassibba, Vincenzo; Mattei, Daniele; Gianfaldoni, Giacomo; Scattolin, Anna Maria; Di Bona, Eros; Oldani, Elena; Parolini, Margherita; Gökbuget, Nicola; Bassan, Renato

    2013-01-01

    We evaluate the long-term results of a prospective clinical study enrolling more than 100 adult patients with Burkitt lymphoma/leukemia. Depending on extent of disease, treatment consisted of six to eight rituximab infusions and four to six courses of intensive chemotherapy (attenuated in patients aged >55 years) with high-dose methotrexate, fractionated ifosfamide/cyclophosphamide, other drugs in rotation, and intrathecal chemoprophylaxis. One-hundred five patients were treated (median age 47 years, range 17–78 years); 48% had Burkitt leukemia, 25% were older than 60 years, 37% had an Eastern Cooperative Oncology Group performance score >1, and 14% were positive for human immunodeficiency virus. The complete response rate and 3-year overall and disease-free survival rates were 79%, 67% and 75%, respectively, ranging from 100% to 45% for survival (P=0.000) and from 100% to 60% for disease-free survival (P=0.01) in patients with low, intermediate and high adapted International Prognostic Index scores. In multivariate analysis, only age (≤ versus >60 years) and performance status (0–1 versus >1) retained prognostic significance, identifying three risk groups with overall and disease-free survival probabilities of 88% and 87.5%, 57% and 70.5%, 20% and 28.5% (P=0.0000 and P=0.0001), respectively. The relapse rate was only 7% in patients treated with an intercycle interval ≤25 days. This regimen achieved 100% curability in patients with low adapted International Prognostic Index scores (21% of total), and very close to 90% in patients aged ≤60 years with performance score 0–1 (48% of total). Rapid diagnosis of Burkitt lymphoma/leukemia with prompt referral of patients to prevent clinical deterioration, and careful supervision of treatment without chemotherapy delay can achieve outstanding therapeutic results. ClinicalTrials.gov ID, NCT01290120 PMID:23753030

  3. Rituximab as consolidation therapy did not improve outcome in patients with diffuse large B-cell lymphoma at complete response after dose-dense chemotherapy (CHOP-14).

    PubMed

    Avilès, Agustin; Nambo, Maria-Jesùs; Huerta-Guzmàn, Judith; Silva, Luis; Neri, Natividad

    2015-04-01

    The authors started a clinical trial to assess the efficacy and toxicity of rituximab (R) as consolidation in patients with diffuse large B-cell lymphoma, with poor prognostic factors, who were in complete response (CR) after dose-dense chemotherapy (CHOP-14). Four hundred sixty-five untreated patients, with advanced stages (III and IV), older (median age >60 years old), and high clinical risk, were treated with dose-dense CHOP-14 (cyclophosphamide 1500 mg/m(2), i.v., day 1; vincristine 2 mg, i.v., standard dose, day 1; epirubicin 120 mg/m(2), i.v., day 1; and prednisone 60 mg/m(2), p.o., days 1-5) every 14 days for six cycles. If CR was achieved, the patients were allocated to receive R (375 mg/m(2), days 1, 8, 15, and 22) at 3 and 9 months after chemotherapy. Three hundred twenty-five patients achieved CR (70%) and were allocated to receive R (151 patients) or not (174 patients). Actuarial curves at 5 years showed that progression-free survival (PFS) was 51% (95% confidence interval [CI]: 44%-58%) in the R group and 53% (95% CI: 47%-59%) in the observation group (p=0.8). Overall survival (OS) was 65% (95% CI: 58%-71%) and 66% (95% CI: 59%-72%), respectively (p=0.78). Late toxicities were more frequent in the R group. The authors showed that the use of R as a consolidation treatment was not useful to improve PFS and OS and toxicity secondary to R was frequent. They did not recommend the use of R as consolidation in this patient setting. PMID:25871407

  4. The Effect of Combination Therapy with Rituximab and Intravenous Immunoglobulin on the Progression of Chronic Antibody Mediated Rejection in Renal Transplant Recipients

    PubMed Central

    Yun, Jintak; Khvan, Marina; Park, Cheol Whee; Choi, Yeong Jin; Kim, Yong-Soo; Yang, Chul Woo

    2014-01-01

    The treatment for chronic active antibody-mediated rejection (CAMR) remains controversial. We investigated the efficacy of rituximab (RTX) and intravenous immunoglobulin (IVIg) for CAMR. Eighteen patients with CAMR were treated with RTX (375 mg/m2) and IVIg (0.4 g/kg) for 4 days. The efficacy of RTX/IVIg combination therapy (RIT) was assessed by decline in estimated glomerular filtration rate per month (ΔeGFR) before and after RIT. Patients were divided into responder and nonresponder groups based on decrease and no decrease in ΔeGFR, respectively, and their clinical and histological characteristics were compared. Response rate to RIT was 66.7% (12/18), and overall ΔeGFR decreased significantly to 0.4 ± 1.7 mL·min−1·1.73 m−2 per month 6 months after RIT compared to that observed 6 months before RIT (1.8 ± 1.0, P < 0.05). Clinical and histological features between the 12 responders and the 6 nonresponders were not significantly different, but nonresponders had a significantly higher proteinuria levels at the time of RIT (2.5 ± 2.5 versus 7.0 ± 3.5 protein/creatinine (g/g), P < 0.001). The effect of the RIT on ΔeGFR had dissipated in all patients by 1 year post-RIT. Thus, RIT delayed CAMR progression, and baseline proteinuria level was a prognostic factor for response to RIT. PMID:24741626

  5. Biochar Usage: Pros and Cons

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Soil fertility benefits of charcoal application have been reported as early as 1847 indicating that plant nutrients are sorbed within charcoal pores. The use of biomass-derived black carbon or biochar, the solid byproduct from the pyrolysis processing of any organic feedstock, has garnered recent a...

  6. Treatment of high-risk aggressive B-cell non-Hodgkin lymphomas with rituximab, intensive induction and high-dose consolidation: long-term analysis of the R-MegaCHOP-ESHAP-BEAM Trial.

    PubMed

    Pytlík, Robert; Belada, David; Kubáčková, Kateřina; Vášová, Ingrid; Kozák, Tomáš; Pirnos, Jan; Bolomská, Ingrid; Matuška, Milan; Přibylová, Jana; Campr, Vít; Burešová, Lucie; Sýkorová, Alice; Berková, Adéla; Klener, Pavel; Trněný, Marek

    2015-01-01

    We have studied the feasibility and efficacy of intensified R-MegaCHOP-ESHAP-BEAM therapy in high-risk aggressive B-cell lymphomas. Altogether 105 patients (19-64 years) with diffuse large B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBL) or follicular lymphoma grade 3 (FL3) with an age-adjusted International Prognostic Index of 2-3 were recruited. Treatment consisted of three cycles of high-dose R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), followed by three cycles of R-ESHAP (rituximab, etoposide, methylprednisolone, cytarabine, cisplatin) and high-dose consolidation with BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem cell transplant. The 5-year progression-free survival (PFS) was 72% (DLBCL 60%, PMBL 89%) and overall survival (OS) was 74% (DLBCL 61%, PMBL 89%) after a median follow-up of 85 months. However, an independent prognostic factor was age only, with patients ≤ 45 years having 5-year PFS 90% and patients > 45 years having PFS 54%. PMBL had better prognosis than DLBCL/FL3 in patients > 45 years (PFS, 88% vs. 48%), but not in younger patients (PFS, 91% vs. 94%). PMID:24628294

  7. Prior Rituximab Correlates with Less Acute Graft-versus-Host Disease and Better Survival in B-Cell Lymphoma Patients Who Received Allogeneic Peripheral Blood Stem Cell Transplantation (PBSCT)

    PubMed Central

    Ratanatharathorn, Voravit; Logan, Brent; Wang, Dan; Horowitz, Mary; Uberti, Joseph P.; Ringden, Olle; Gale, Robert Peter; Khoury, Hanna; Arora, Mukta; Spellman, Stephen; Cutler, Corey; Antin, Joseph; Bornhaüser, Martin; Hale, Gregory; Verdonck, Leo; Cairo, Mitchell; Gupta, Vikas; Steven, Pavletic

    2012-01-01

    Summary Prior therapy with rituximab might attenuate disparate histocompatibility antigen presentation by B cells, thus decreased the risk of acute graft-versus-host disease (GVHD) and improved survival. We tested this hypothesis by comparing the outcomes of 435 B-cell lymphoma patients who received allogeneic transplantation from 1999 to 2004 in the Center for International Blood and Marrow Transplant Research database: 179 subjects who received rituximab within 6 months prior to transplantation (RTX cohort) and 256 subjects who did not receive RTX within 6 months prior to transplantation (No-RTX cohort). The RTX cohort had a significantly lower incidence of treatment-related mortality (TRM) (relative risk [RR] = 0.68; 95% confidence interval [CI], 0.47 - 1.0; P = 0.05), lower acute grade II-IV (RR = 0.72; 95% CI, 0.53 - 0.97; P = 0.03) and III-IV GVHD (RR = 0.55; 95% CI, 0.34 - 0.91; P = 0.02). There was no difference in the risk of chronic GVHD, disease progression or relapse. Progression-free survival (PFS) (RR = 0.68; 95% CI 0.50 - 0.92; P = 0.01) and overall survival (OS) (RR = 0.63; 95% CI, 0.46 - 0.86; P = 0.004) were significantly better in the RTX cohort. Prior RTX therapy correlated with less acute GVHD, similar chronic GVHD, less TRM, better PFS and OS. PMID:19344418

  8. A European multicentre and open-label controlled randomized trial to evaluate the efficacy of Sequential treatment with TAcrolimus–Rituximab versus steroids plus cyclophosphamide in patients with primary MEmbranous Nephropathy: the STARMEN study

    PubMed Central

    Rojas-Rivera, Jorge; Fernández-Juárez, Gema; Ortiz, Alberto; Hofstra, Julia; Gesualdo, Loreto; Tesar, Vladimir; Wetzels, Jack; Segarra, Alfons; Egido, Jesus; Praga, Manuel

    2015-01-01

    Background Patients with primary membranous nephropathy (MN) and persistent nephrotic syndrome have a high risk of progression to end-stage renal disease. The Ponticelli protocol (steroids with alkylating agents) is the most effective immunosuppressive therapy for this condition, but it has severe adverse effects. Tacrolimus and rituximab have demonstrated efficacy for remission of nephrotic syndrome in MN with a safer profile. However, the published evidence is largely based on small or short-term observational studies, historical cohorts, comparisons with conservative therapy or clinical trials without appropriate control groups, and there is no head-to-head comparison with the Ponticelli protocol. Methods The STARMEN randomized clinical trial will compare the efficacy of sequential tacrolimus–rituximab therapy with a modified Ponticelli protocol (steroids plus cyclophosphamide). The trial will also evaluate the role of antibodies against the M-type phospholipase A2 receptor (anti-PLA2R) and other antibodies as markers of response to treatment and long-term prognosis. Results The trial has already started with 23 patients having been enrolled as of 1 April 2015, an estimated 21.7% of the estimated sample. PMID:26413273

  9. Mandated Mental Health Insurance: A Complex Case of Pros and Cons. Human Resources Series.

    ERIC Educational Resources Information Center

    Paterson, Andrea

    1986-01-01

    The pros and cons of state laws mandating mental health insurance are discussed in this report. The history of a 1985 Supreme Court case which held that states could mandate mental health benefits introduces the report. In an overview of the issue, the long-standing argument between the insurance industry and the mental health establishment is…

  10. Laboratory research in homeopathy: con.

    PubMed

    Moffett, John R; Arun, Peethambaran; Namboodiri, M A A

    2006-12-01

    Alternative medical approaches to human diseases such as cancer are becoming increasingly popular, but reports on their success rates have been highly variable. Homeopathy is an alternative medical practice often applied to less critical human diseases but one that has also been applied sporadically to the treatment of cancer. Animal studies on the use of homeopathy to treat experimental cancer are few and the evidence provided to date is far from conclusive. The debate presented here concerns the utility of animal studies on cancer treatment with homeopathic preparations. As part of a Point-Counterpoint feature, this review and its companion piece in this issue by Khuda-Bukhsh (Integr Cancer Ther. 2006;5:320-332) are composed of a thesis section, a response section in reaction to the companion thesis, and a rebuttal section to address issues raised in the companion response. PMID:17101762

  11. Pro/con a precessional geodynamo

    NASA Astrophysics Data System (ADS)

    Vanyo, J.

    2003-04-01

    The modest amount of research that exists on the ability, or lack of ability, of mantle precession to power a geodynamo developed mostly during the last half of the 1900s. Papers by Roberts and Stewartson (1965) and by Busse (1968) studied precession generally without a pro/con conclusion. Malkus in the late 1960s attempted to advance a positive role for precession through experiments and analysis. His experiments have survived criticism, but his analyses were discounted, especially by Rochester, Jacobs, Smylie, and Chong (1975) and by Loper (1975). Rochester, et al. critiqued existing analyses of precession, including those of Malkus, but did not reach a strong position either pro or con a precessional geodynamo. Loper argued emphatically that precession was not capable of powering the geodynamo. Explicit analyses that either critique or support Loper’s arguments have yet to appear in the literature. During the 1970s, Vanyo and associates studied energy dissipation during precession of satellite liquid fuels and its effect on satellite attitude stability. Engineers and scientists in every country that has launched satellites completed similar research. Some is published in the aerospace literature, more is available in company and government reports. Beginning in 1981, Vanyo and associates applied this knowledge to the very similar problem of energy dissipation and flow patterns in precessing mechanical models scaled geometrically and dynamically to the Earth’s liquid core. Energy experiments indicate massive amounts of mechanical energy are dissipated at the CMB, and flow experiments show complex motions within the boundary layer and axial flows with helicity throughout the interior. Analysis of Earth core precession also advanced, especially in several papers by Kerswell and by Tilgner in the late 1990s. Detail numerical models have yet to appear. Although progress in understanding the role of precession in Earth core motions has advanced, there remains a

  12. Efficacy and long-term toxicity of the rituximab-fludarabine-cyclophosphamide combination therapy in Waldenstrom's macroglobulinemia.

    PubMed

    Souchet, Laetitia; Levy, Vincent; Ouzegdouh, Maya; Tamburini, Jérôme; Delmer, Alain; Dupuis, Jehan; Le Gouill, Steven; Pégourié-Bandelier, Brigitte; Tournilhac, Olivier; Boubaya, Marouanne; Vargaftig, Jacques; Choquet, Sylvain; Leblond, Véronique

    2016-08-01

    Waldenstrom's macroglobulinemia is generally treated with alkylating agents, purine analogs and monoclonal antibodies, alone or in combination. We report the outcomes of 82 patients (median age 61 years) treated with the RFC combination. Twenty-five patients were treatment-naive. RFC was administered every 4 weeks, for a median of five cycles. At treatment discontinuation, the overall response rate was 85.4%. The responses improved after treatment discontinuation in 25 patients, with a median time to best response achievement of 10.8 months, raising the major response rate (PR, VGPR and CR) from 64.6% to 76.8%. With a median follow-up of 47 months, the median progression-free survival time had not been reached (67% PFS at 48 months) and was influenced by age and treatment status before RFC. Likewise, the median time to next therapy had not been reached. Two cases of myelodysplastic syndrome/AML and 3 cases of transformation to aggressive lymphoma occurred. Thirteen patients died. The 3-year overall survival rate was 90%. Long-lasting cytopenias occurred in 19 patients. The RFC combination thus gave a high response rate and durable responses, even in heavily treatment-experienced patients. The high incidence of long-lasting cytopenia might be reduced by giving fewer courses and thereby minimizing myelotoxicity. Am. J. Hematol. 91:782-786, 2016. © 2016 Wiley Periodicals, Inc. PMID:27135784

  13. Galaxias australes con núcleo doble

    NASA Astrophysics Data System (ADS)

    Gimeno, G.; Díaz, R.; Carranza, G.

    Se estudia una muestra de galaxias australes con núcleo doble a partir de una búsqueda extensiva en la literatura. Se analizan las características morfológicas, fotométricas y espectroscópicas de la muestra. Para algunas galaxias se han realizado observaciones con el espectrógrafo multifunción (EMF) de la Estación Astrofísica de Bosque Alegre a partir de las cuales se determinaron parámetros cinemáticos.

  14. InterCon Travel Health: Case B

    ERIC Educational Resources Information Center

    Truman, Gregory E.; Pachamanova, Dessislava A.; Goldstein, Michael A.

    2010-01-01

    InterCon provides services to health insurers of foreign tourists who travel to the United States and Canada. Management wants to implement a new information system that will deal with several operational problems, but it is having difficulty securing the capital resources to fund the system's development. After an initial failure, the chief…

  15. Ependimoma myxopapilar sacro gigante con osteolisis

    PubMed Central

    Ajler, Pablo; Landriel, Federico; Goldschmidt, Ezequiel; Campero, Álvaro; Yampolsky, Claudio

    2014-01-01

    Objetivo: la presentación de un caso de una paciente con un ependimoma sacro con extensa infiltración y destrucción ósea local. Descripción del caso: una mujer de 53 años acudió a la consulta por dolor lumbosacro y alteraciones sensitivas perineales y esfinterianas. La imágenes por Resonancia Magnética (IRM) y la Tomografía Axial Computada (TAC) mostraron una lesión expansiva gigante a nivel S2-S4 con extensa osteólisis e invasión de tejidos adyacentes. Se realizó una exéresis tumoral completa con mejoría del estatus funcional. La anatomía patológica informó ependimoma mixopapilar. Discusión: la extensión de la resección quirúrgica es el mejor predictor de buen pronóstico. El tratamiento radiante se reserva como opción adyuvante para las resecciones incompletas y recidiva tumoral. La quimioterapia sólo debería utilizarse en casos en que la cirugía y la radioterapia estén contraindicadas. Conclusión: Los ependimomas mixopapilares sacros con destrucción ósea y presentación intra y extradural son muy infrecuentes y deben ser tenidos en cuenta entre los diagnósticos diferenciales preoperatorios. Su resección total, siempre que sea posible, es la mejor alternativa terapéutica. PMID:25165615

  16. Safety and Clinical Activity of a Combination Therapy Comprising Two Antibody-Based Targeting Agents for the Treatment of Non-Hodgkin Lymphoma: Results of a Phase I/II Study Evaluating the Immunoconjugate Inotuzumab Ozogamicin With Rituximab

    PubMed Central

    Fayad, Luis; Offner, Fritz; Smith, Mitchell R.; Verhoef, Gregor; Johnson, Peter; Kaufman, Jonathan L.; Rohatiner, Ama; Advani, Anjali; Foran, James; Hess, Georg; Coiffier, Bertrand; Czuczman, Myron; Giné, Eva; Durrant, Simon; Kneissl, Michelle; Luu, Kenneth T.; Hua, Steven Y.; Boni, Joseph; Vandendries, Erik; Dang, Nam H.

    2013-01-01

    Purpose Inotuzumab ozogamicin (INO) is an antibody-targeted chemotherapy agent composed of a humanized anti-CD22 antibody conjugated to calicheamicin, a potent cytotoxic agent. We performed a phase I/II study to determine the maximum-tolerated dose (MTD), safety, efficacy, and pharmacokinetics of INO plus rituximab (R-INO) for treatment of relapsed/refractory CD20+/CD22+ B-cell non-Hodgkin lymphoma (NHL). Patients and Methods A dose-escalation phase to determine the MTD of R-INO was followed by an expanded cohort to further evaluate the efficacy and safety at the MTD. Patients with relapsed follicular lymphoma (FL), relapsed diffuse large B-cell lymphoma (DLBCL), or refractory aggressive NHL received R-INO every 4 weeks for up to eight cycles. Results In all, 118 patients received one or more cycles of R-INO (median, four cycles). Most common grade 3 to 4 adverse events were thrombocytopenia (31%) and neutropenia (22%). Common low-grade toxicities included hyperbilirubinemia (25%) and increased AST (36%). The MTD of INO in combination with rituximab (375 mg/m2) was confirmed to be the same as that for single-agent INO (1.8 mg/m2). Treatment at the MTD yielded objective response rates of 87%, 74%, and 20% for relapsed FL (n = 39), relapsed DLBCL (n = 42), and refractory aggressive NHL (n = 30), respectively. The 2-year progression-free survival (PFS) rate was 68% (median, not reached) for FL and 42% (median, 17.1 months) for relapsed DLBCL. Conclusion R-INO demonstrated high response rates and long PFS in patients with relapsed FL or DLBCL. This and the manageable toxicity profile suggest that R-INO may be a promising option for CD20+/CD22+ B-cell NHL. PMID:23295790

  17. Synergistic and persistent effect of T-cell immunotherapy with anti-CD19 or anti-CD38 chimeric receptor in conjunction with rituximab on B-cell non-Hodgkin lymphoma.

    PubMed

    Mihara, Keichiro; Yanagihara, Kazuyoshi; Takigahira, Misato; Kitanaka, Akira; Imai, Chihaya; Bhattacharyya, Joyeeta; Kubo, Takanori; Takei, Yoshifumi; Yasunaga, Shin'ichiro; Takihara, Yoshihiro; Kimura, Akiro

    2010-10-01

    Using artificial receptors, it is possible to redirect the specificity of immune cells to tumour-associated antigens, which is expected to provide a useful strategy for cancer immunotherapy. Given that B-cell non-Hodgkin lymphoma (B-NHL) cells invariably express CD19 and CD38, these antigens may be suitable molecular candidates for such immunotherapy. We transduced human peripheral T cells or a T-cell line with either anti-CD19-chimeric receptor (CAR) or anti-CD38-CAR, which contained an anti-CD19 or anti-CD38 antibody-derived single-chain variable domain respectively. Retroviral transduction led to anti-CD19-CAR or anti-CD38-CAR expression in T cells with high efficiency (>60%). The T cell line, Hut78, when transduced with anti-CD19-CAR or anti-CD38-CAR, exerted strong cytotoxicity against the B-NHL cell lines, HT and RL, and lymphoma cells isolated from patients. Interestingly, use of both CARs had an additive cytotoxic effect on HT cells in vitro. In conjunction with rituximab, human peripheral T cells expressing either anti-CD19-CAR or anti-CD38-CAR enhanced cytotoxicity against HT-luciferase cells in xenografted mice. Moreover, the synergistic tumour-suppressing activity was persistent in vivo for over 2 months. These results provide a powerful rationale for clinical testing of the combination of rituximab with autologous T cells carrying either CAR on aggressive or relapsed B-NHLs. PMID:20678160

  18. conF and conJ contribute to conidia germination and stress response in the filamentous fungus Aspergillus nidulans.

    PubMed

    Suzuki, Satoshi; Sarikaya Bayram, Özlem; Bayram, Özgür; Braus, Gerhard H

    2013-07-01

    Light induces various responses in fungi including formation of asexual and sexual reproductive structures. The formation of conidia in the filamentous fungus Aspergillus nidulans is regulated by red and blue light receptors. Expression of conidia associated con genes, which are widely spread in the fungal kingdom, increases upon exposure to light. We have characterized the light-inducible conF and conJ genes of A. nidulans which are homologs of con-6 and con-10 of Neurospora crassa. con genes are expressed during conidia formation in asexual development. Five minutes light exposure are sufficient to induce conF or conJ expression in vegetative mycelia. Similar to N. crassa there were no significant phenotypes of single con mutations. A double conF and conJ deletion resulted in significantly increased cellular amounts of glycerol or erythritol. This leads to a delayed germination phenotype combined with increased resistance against desiccation. These defects were rescued by complementation of the double mutant strain with either conF or conJ. This suggests that fungal con genes exhibit redundant functions in controlling conidia germination and adjusting cellular levels of substances which protect conidia against dryness. PMID:23644150

  19. Somatic cell nuclear transfer: pros and cons.

    PubMed

    Sumer, Huseyin; Liu, Jun; Tat, Pollyanna; Heffernan, Corey; Jones, Karen L; Verma, Paul J

    2009-01-01

    Even though the technique of mammalian SCNT is just over a decade old it has already resulted in numerous significant advances. Despite the recent advances in the reprogramming field, SCNT remains the bench-mark for the generation of both genetically unmodified autologous pluripotent stem cells for transplantation and for the production of cloned animals. In this review we will discuss the pros and cons of SCNT, drawing comparisons with other reprogramming methods. PMID:20232594

  20. 9 CFR 319.301 - Chili con carne with beans.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Chili con carne with beans. 319.301 Section 319.301 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE... Dehydrated Meat Food Products § 319.301 Chili con carne with beans. Chili con carne with beans shall...

  1. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2012 CFR

    2012-01-01

    ... 9 Animals and Animal Products 2 2012-01-01 2012-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  2. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2014 CFR

    2014-01-01

    ... 9 Animals and Animal Products 2 2014-01-01 2014-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  3. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2010 CFR

    2010-01-01

    ... 9 Animals and Animal Products 2 2010-01-01 2010-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  4. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2013 CFR

    2013-01-01

    ... 9 Animals and Animal Products 2 2013-01-01 2013-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  5. 9 CFR 319.300 - Chili con carne.

    Code of Federal Regulations, 2011 CFR

    2011-01-01

    ... 9 Animals and Animal Products 2 2011-01-01 2011-01-01 false Chili con carne. 319.300 Section 319.300 Animals and Animal Products FOOD SAFETY AND INSPECTION SERVICE, DEPARTMENT OF AGRICULTURE AGENCY... Products § 319.300 Chili con carne. “Chili con carne” shall contain not less than 40 percent of...

  6. Expression of Tissue factor in Adenocarcinoma and Squamous Cell Carcinoma of the Uterine Cervix: Implications for immunotherapy with hI-con1, a factor VII-IgGFc chimeric protein targeting tissue factor

    PubMed Central

    2011-01-01

    Background Cervical cancer continues to be an important worldwide health problem for women. Up to 35% of patients who are diagnosed with and appropriately treated for cervical cancer will recur and treatment results are poor for recurrent disease. Given these sobering statistics, development of novel therapies for cervical cancer remains a high priority. We evaluated the expression of Tissue Factor (TF) in cervical cancer and the potential of hI-con1, an antibody-like-molecule targeted against TF, as a novel form of immunotherapy against multiple primary cervical carcinoma cell lines with squamous- and adenocarcinoma histology. Methods Because TF is a transmembrane receptor for coagulation factor VII/VIIa (fVII), in this study we evaluated the in vitro expression of TF in cervical carcinoma cell lines by immunohistochemistry (IHC), real time-PCR (qRT-PCR) and flow cytometry. Sensitivity to hI-con1-dependent cell-mediated-cytotoxicity (IDCC) was evaluated in 5-hrs-51chromium-release-assays against cervical cancer cell lines in vitro. Results Cytoplasmic and/or membrane TF expression was observed in 8 out of 8 (100%) of the tumor tissues tested by IHC and in 100% (11 out of 11) of the cervical carcinoma cell lines tested by real-time-PCR and flow cytometry but not in normal cervical keratinocytes (p = 0.0023 qRT-PCR; p = 0.0042 flow cytometry). All primary cervical cancer cell lines tested overexpressing TF, regardless of their histology, were highly sensitive to IDCC (mean killing ± SD, 56.2% ± 15.9%, range, 32.4%-76.9%, p < 0.001), while negligible cytotoxicity was seen in the absence of hI-con1 or in the presence of rituximab-control-antibody. Low doses of interleukin-2 further increased the cytotoxic effect induced by hI-con1 (p = 0.025) while human serum did not significantly decrease IDCC against cervical cancer cell lines (p = 0.597). Conclusions TF is highly expressed in squamous and adenocarcinoma of the uterine cervix. hI-con1 induces strong cytotoxicity

  7. Energy Star program benefits Con Edison

    SciTech Connect

    1995-05-01

    Impressed with savings in energy costs achieved after upgrading the lighting and air conditioning systems at its Manhattan headquarters, Home Box Office (HBO) wanted to do more, James Flock, vice president for computer and office systems, contacted Con Edison Co. of New York in March 1991 to determine what the company could do to save money by reducing energy consumed by personal computers. Arthur Kressner, Con Edison Research and Development manager contacted industry organizations and manufacturers for advice, but was told only to shut off computers at night and on weekends. Kressner arranged a series of meetings with IBM and the Electric Power Research Institute (EPRI) to discuss the issue, then approached the U.S. Environmental Protection Agency (EPA), which was designing a program to promote the introduction and use of energy-efficient office equipment. In 1992, the EPA announced the Energy Star program for PCs, enabling manufacturers to display the Energy Star logo on machines meeting program criteria, including the ability to enter a sleep mode in which neither the computer nor monitor consume more than 30 W or electricity. Industry experts estimate national energy consumption by office equipment could double by the year 2000, but Energy Star equipment is expected to improve efficiency and help maintain electric loads.

  8. OIL POLLUTION REPORTS. VOLUME 5, NUMBER 4

    EPA Science Inventory

    OIL POLLUTION REPORTS (formerly OIL SPILL AND OIL POLLUTION REPORTS) is a quarterly compilation of abstracts of current oil pollution related literature, research projects, and conferences. Comprehensive coverage of terrestrial and aquatic oil pollution and its prevention and con...

  9. Reporters Report Reporters.

    ERIC Educational Resources Information Center

    MacDougall, Curtis D.

    This collection brings together 58 news stories by professional reporters who wrote of their own involvement in newsworthy events. Part One, "Reporters Are Like All of Us and Can Be Newsworthy Too," features accounts written by reporters who were employed by newspapers that went out of business, were victims of crimes, were accused of committing…

  10. Cervical disc arthroplasty: Pros and cons

    PubMed Central

    Moatz, Bradley; Tortolani, P. Justin

    2012-01-01

    Background: Cervical disc arthroplasty has emerged as a promising potential alternative to anterior cervical discectomy and fusion (ACDF) in appropriately selected patients. Despite a history of excellent outcomes after ACDF, the question as to whether a fusion leads to adjacent segment degeneration remains unanswered. Numerous US investigational device exemption trials comparing cervical arthroplasty to fusion have been conducted to answer this question. Methods: This study reviews the current research regarding cervical athroplasty, and emphasizes both the pros and cons of arthroplasty as compared with ACDF. Results: Early clinical outcomes show that cervical arthroplasty is as effective as the standard ACDF. However, this new technology is also associated with an expanding list of novel complications. Conclusion: Although there is no definitive evidence that cervical disc replacement reduces the incidence of adjacent segment degeneration, it does show other advantages; for example, faster return to work, and reduced need for postoperative bracing. PMID:22905327

  11. Pilot trial of yttrium-90 ibritumomab tiuxetan consolidation following rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone chemotherapy in patients with limited-stage, bulky diffuse large B-cell lymphoma.

    PubMed

    Yang, Deok-Hwan; Kim, Won Seog; Kim, Seok Jin; Kim, Jin Seok; Kwak, Jae-Yong; Chung, Joo Seop; Oh, Sung Yong; Suh, Cheolwon; Lee, Je-Jung

    2012-05-01

    The clinical efficacy and safety of yttrium-90 ((90)Y)-ibritumomab tiuxetan consolidation treatment following rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) chemotherapy was investigated in patients with limited-stage and bulky diffuse large B-cell lymphoma (DLBCL). This prospective, multi-center, pilot trial included 21 patients who were newly diagnosed with stage I/II, bulky DLBCL and achieved a complete or partial response after six cycles of R-CHOP. The median size of bulky disease was 10.0 × 7.0 cm. After a median follow-up of 28.8 months, the overall response rate after (90)Y-ibritumomab tiuxetan consolidation treatment was 80.9%, including 4.8% partial response. However, six patients (28.6%) experienced a progression or relapse. The 3-year overall and progression-free survival rates were 85.0 ± 8.0% and 75.0 ± 9.7%, respectively. Grade 3-4 adverse events were mainly hematologic toxicities, such as thrombocytopenia (35%) and neutropenia (60%). One patient experienced grade 3 Pneumocystis carinii pneumonitis. Thus, (90)Y-ibritumomab tiuxetan consolidation following six cycles of R-CHOP resulted in an acceptable response with tolerable toxicity in patients with limited-stage and bulky DLBCL. PMID:22035417

  12. Rituximab plus a CHOP-like regimen, central nervous system prophylaxis, and contralateral testicular irradiation for localized primary testicular diffuse large B-cell lymphoma lead to prolonged progression-free survival.

    PubMed

    Ichikawa, Kunimoto; Noguchi, Masaaki; Koike, Michiaki; Aritaka, Nanae; Sekiguchi, Yasunobu; Sunami, Yoshitaka; Tsutsui, Miyuki; Hosone, Masaru; Hirano, Takao; Gotoh, Akihiko; Komatsu, Norio

    2014-10-01

    We retrospectively evaluated the clinical features, management, and survival of 12 patients (age 51-84 years) with localized primary testicular diffuse large B-cell lymphoma (PTL). All 12 PTL patients underwent orchiectomy. Seven of the 12 patients were treated with strategy A, which consisted of at least six cycles of rituximab (R) plus a CHOP-like regimen, central nervous system (CNS) prophylaxis involving intrathecal chemotherapy (IT) and/or high-dose intravenous methotrexate, and contralateral scrotal irradiation (cRT). The other five patients were treated with strategy B, which included three regimens: orchiectomy alone, orchiectomy plus cRT and IT, and orchiectomy plus 3-4 cycles of R-CHOP plus cRT with or without IT. The median follow-up period was 48 months (range 19-123 months). The 4-year progression-free survival (PFS) rate for the seven patients treated with strategy A was 85.7 %, whereas that for the five patients treated with strategy B was 20 %. The patients treated with strategy A exhibited a significantly higher 4-year PFS rate than those treated with strategy B (P = 0.017). These results confirmed that the administration of a sufficient number of cycles of an R-containing chemotherapy regimen plus cRT plus CNS prophylaxis should be considered as a treatment for localized PTL. PMID:25085255

  13. Trazando la materia oscura con cúmulos globulares

    NASA Astrophysics Data System (ADS)

    Forte, J. C.

    Se describe la estrategia adoptada para mapear la distribución de materia oscura y bariónica en galaxias elípticas cuyos cúmulos globulares están siendo observados con los telescopios VLT y Gemini. Se ejemplifican los resultados con los datos obtenidos en el cúmulo de Fornax.

  14. ProCon - PROteomics CONversion tool.

    PubMed

    Mayer, Gerhard; Stephan, Christian; Meyer, Helmut E; Kohl, Michael; Marcus, Katrin; Eisenacher, Martin

    2015-11-01

    With the growing amount of experimental data produced in proteomics experiments and the requirements/recommendations of journals in the proteomics field to publicly make available data described in papers, a need for long-term storage of proteomics data in public repositories arises. For such an upload one needs proteomics data in a standardized format. Therefore, it is desirable, that the proprietary vendor's software will integrate in the future such an export functionality using the standard formats for proteomics results defined by the HUPO-PSI group. Currently not all search engines and analysis tools support these standard formats. In the meantime there is a need to provide user-friendly free-to-use conversion tools that can convert the data into such standard formats in order to support wet-lab scientists in creating proteomics data files ready for upload into the public repositories. ProCon is such a conversion tool written in Java for conversion of proteomics identification data into standard formats mzIdentML and Pride XML. It allows the conversion of Sequest™/Comet .out files, of search results from the popular and often used ProteomeDiscoverer® 1.x (x=versions 1.1 to1.4) software and search results stored in the LIMS systems ProteinScape® 1.3 and 2.1 into mzIdentML and PRIDE XML. This article is part of a Special Issue entitled: Computational Proteomics. PMID:26182917

  15. Combinación de radioterapia con quimioterapia mejora la supervivencia con raro cáncer cerebral

    Cancer.gov

    Los resultados de dos estudios clínicos de seguimiento a largo plazo confirman que ciertos pacientes viven substancialmente más si se les trata con una combinación de quimioterapia y radioterapia en comparación con radioterapia solamente.

  16. Bovine Spongiform Encephalopathy: Atypical Pros and Cons

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Transmissible spongiform encephalopathies (TSEs) are fatal neurologic diseases that affect several mammalian species including human beings. Four animal TSE agents have been reported: scrapie of sheep and goats; chronic wasting disease (CWD) of deer, elk, and moose; transmissible mink encephalopath...

  17. Confirmatory analysis of opinions regarding the pros and cons of mammography.

    PubMed

    Rakowski, W; Andersen, M R; Stoddard, A M; Urban, N; Rimer, B K; Lane, D S; Fox, S A; Costanza, M E

    1997-09-01

    This investigation extends prior research to apply decision-making constructs from the transtheoretical model (TTM) of behavior change to mammography screening. Study subjects were 8,914 women ages 50-80, recruited from 40 primarily rural communities in Washington State. Structural equation modeling showed that favorable and unfavorable opinions about mammography (i.e., pros and cons) fit the observed data. Analysis of variance supported the associations between readiness to obtain screening (i.e., stage of adoption) and opinions about mammography (i.e., decisional balance) previously found in research using smaller samples from another geographic region. This report extends these earlier studies by using structural equation modeling, opinion scales based both on principal component analyses and on a priori definitions, a developmental sample and a confirmatory sample, and by sampling from a different geographic region. It is recommended that future research examine whether opinions regarding the cons of mammography are more individually specific than the pros. PMID:9302540

  18. Molecular characteristics of diffuse large B-cell lymphoma in human immunodeficiency virus-infected and -uninfected patients in the pre-highly active antiretroviral therapy and pre-rituximab era.

    PubMed

    Morton, Lindsay M; Kim, Clara J; Weiss, Lawrence M; Bhatia, Kishor; Cockburn, Myles; Hawes, Debra; Wang, Sophia S; Chang, Cindy; Altekruse, Sean F; Engels, Eric A; Cozen, Wendy

    2014-03-01

    Human immunodeficiency virus (HIV) infection substantially elevates diffuse large B-cell lymphoma (DLBCL) risk, but its impact on the distinct DLBCL subtypes defined by cell of origin is unclear. We compared DLBCL molecular characteristics and prognosis in 51 HIV-infected and 116 HIV-uninfected cases diagnosed during 1977-2003. Using immunohistochemistry to classify cell of origin based on the Tally algorithm, activated B-cell (ABC)-DLBCL was substantially more common in HIV-infected (83%) than in HIV-uninfected (54%) cases (p < 0.001). Epstein-Barr virus (EBV) was detected in 63% of DLBCLs in HIV-infected cases, occurring almost exclusively in ABC-DLBCL (74% vs. 13% of germinal center B-cell [GCB]-DLBCL, p = 0.002), but was rarely detected in DLBCLs among HIV-uninfected cases (3%). Among HIV-uninfected cases, MYC/IgH [t(8;14)(q24;q32)] and IgH/BCL2 [t(14;18)(q32;q21)] translocations were significantly more common and BCL6/IgH [t(3;14)(q27;q32)] significantly less common in GCB-DLBCL than in ABC-DLBCL (p = 0.010, < 0.001 and = 0.039, respectively). Among HIV-infected cases, translocations other than MYC/IgH [t(8;14)(q24;q32)] (21%) were rare (≤ 6%) and unrelated to cell of origin. ABC-DLBCL was associated with adverse overall survival compared with GCB-DLBCL regardless of HIV status (pHIV-infected = 0.066; pHIV-uninfected = 0.038). Our data demonstrate key differences in the molecular characteristics, cell of origin and prognosis of DLBCL by HIV status in the pre-highly active antiretroviral therapy (HAART) and pre-rituximab era, supporting biologic differences in lymphomagenesis in the presence of HIV. PMID:23772639

  19. Early Relapse of Follicular Lymphoma After Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Defines Patients at High Risk for Death: An Analysis From the National LymphoCare Study

    PubMed Central

    Casulo, Carla; Byrtek, Michelle; Dawson, Keith L.; Zhou, Xiaolei; Farber, Charles M.; Flowers, Christopher R.; Hainsworth, John D.; Maurer, Matthew J.; Cerhan, James R.; Link, Brian K.; Zelenetz, Andrew D.; Friedberg, Jonathan W.

    2015-01-01

    Purpose Twenty percent of patients with follicular lymphoma (FL) experience progression of disease (POD) within 2 years of initial chemoimmunotherapy. We analyzed data from the National LymphoCare Study to identify whether prognostic FL factors are associated with early POD and whether patients with early POD are at high risk for death. Patients and Methods In total, 588 patients with stage 2 to 4 FL received first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Two groups were defined: patients with early POD 2 years or less after diagnosis and those without POD within 2 years, the reference group. An independent validation set, 147 patients with FL who received first-line R-CHOP, was analyzed for reproducibility. Results Of 588 patients, 19% (n = 110) had early POD, 71% (n = 420) were in the reference group, 8% (n = 46) were lost to follow-up, and 2% (n = 12) died without POD less than 2 years after diagnosis. Five-year overall survival was lower in the early-POD group than in the reference group (50% v 90%). This trend was maintained after we adjusted for FL International Prognostic Index (hazard ratio, 6.44; 95% CI, 4.33 to 9.58). Results were similar for the validation set (FL International Prognostic Index–adjusted hazard ratio, 19.8). Conclusion In patients with FL who received first-line R-CHOP, POD within 2 years after diagnosis was associated with poor outcomes and should be further validated as a standard end point of chemoimmunotherapy trials of untreated FL. This high-risk FL population warrants further study in directed prospective clinical trials. PMID:26124482

  20. Biweekly rituximab, cyclophosphamide, vincristine, non-pegylated liposome-encapsulated doxorubicin and prednisone (R-COMP-14) in elderly patients with poor-risk diffuse large B-cell lymphoma and moderate to high ‘life threat’ impact cardiopathy

    PubMed Central

    Corazzelli, Gaetano; Frigeri, Ferdinando; Arcamone, Manuela; Lucania, Anna; RosariaVilla, Maria; Morelli, Emanuela; Amore, Alfonso; Capobianco, Gaetana; Caronna, Antonietta; Becchimanzi, Cristina; Volzone, Francesco; Marcacci, Gianpaolo; Russo, Filippo; De Filippi, Rosaria; Mastrullo, Lucia; Pinto, Antonio

    2011-01-01

    This Phase II study assessed feasibility and efficacy of a biweekly R-COMP-14 regimen (rituximab, cyclophosphamide, non-pegylated liposome-encapsulated doxorubicin, vincristine and prednisone) in untreated elderly patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and moderate to high ‘life threat’ impact NIA/NCI cardiac comorbidity. A total of 208 courses were delivered, with close cardiac monitoring, to 41 patients (median age: 73 years, range: 62–82; 37% >75 years) at a median interval of 15·6 (range, 13–29) days; 67% completed all six scheduled courses. Response rate was 73%, with 68% complete responses (CR); 4-year disease-free survival (DFS) and time to treatment failure (TTF) were 72% and 49%, respectively. Failures were due to early death (n = 3), therapy discontinuations (no-response n = 2; toxicity n = 6), relapse (n = 6) and death in CR (n = 3). Incidence of cardiac grade 3–5 adverse events was 7/41 (17%; 95% confidence interval: 8–31%). Time to progression and overall survival at 4-years were 77% and 67%, respectively. The Age-adjusted Charlson Comorbidity Index (aaCCI) correlated with failures (P = 0·007) with patients scoring ≤7 having a longer TTF (66% vs. 29%; P = 0·009). R-COMP-14 is feasible and ensures a substantial DFS to poor-risk DLBCL patients who would have been denied anthracycline-based treatment due to cardiac morbidity. The aaCCI predicted both treatment discontinuation rate and TTF. PMID:21707585

  1. The Big Con: China's Historical Sabotage

    ERIC Educational Resources Information Center

    Terrence Cheng

    2009-01-01

    On June 4, 1989, the Chinese military, under orders from the highest levels of government, violently crushed peaceful civilian demonstrations in Beijing, most symbolically in and around Tiananmen Square. In the end, the Chinese government claimed that the death toll was approximately 200, but the Chinese Red Cross reported 2,000 to 3,000 deaths.…

  2. 53. SECONDARY CONNING STATION AFT LOOKING FORWARD ON CENTERLINE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    53. SECONDARY CONNING STATION - AFT LOOKING FORWARD ON CENTERLINE SHOWING ENGINE ORDER TELEGRAPH, HELM, RADAR, GYRO REPEATERS, PORTHOLE WITH BATTLE PORTS CLOSED. - U.S.S. HORNET, Puget Sound Naval Shipyard, Sinclair Inlet, Bremerton, Kitsap County, WA

  3. 52. SECONDARY CONNING STATION FORWARD LOOKING AFT ON CENTERLINE ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    52. SECONDARY CONNING STATION - FORWARD LOOKING AFT ON CENTERLINE SHOWING ENGINE ORDER TELEGRAPH, HELM, RADAR, GYRO REPEATERS, PORTHOLE WITH BATTLE PORTS CLOSED. - U.S.S. HORNET, Puget Sound Naval Shipyard, Sinclair Inlet, Bremerton, Kitsap County, WA

  4. View forward of interior of conning tower and steering station; ...

    Library of Congress Historic Buildings Survey, Historic Engineering Record, Historic Landscapes Survey

    View forward of interior of conning tower and steering station; helmsman or observer viewed action through narrow opening at top of photo. (p57) - USS Olympia, Penn's Landing, 211 South Columbus Boulevard, Philadelphia, Philadelphia County, PA

  5. [Cement augmentation of pedicle screws : Pros and cons].

    PubMed

    Schnake, K J; Blattert, T R; Liljenqvist, U

    2016-09-01

    Cement augmentation of pedicle screws biomechanically increases screw purchase in the bone. However, clinical complications may occur. The pros and cons of the technique are discussed from different clinical perspectives. PMID:27514827

  6. Planificación Neuroquirúrgica con Software Osirix

    PubMed Central

    Jaimovich, Sebastián Gastón; Guevara, Martin; Pampin, Sergio; Jaimovich, Roberto; Gardella, Javier Luis

    2014-01-01

    Introducción: La individualidad anatómica es clave para reducir el trauma quirúrgico y obtener un mejor resultado. Actualmente, el avance en las neuroimágenes ha permitido objetivar esa individualidad anatómica, permitiendo planificar la intervención quirúrgica. Con este objetivo, presentamos nuestra experiencia con el software Osirix. Descripción de la técnica: Se presentan 3 casos ejemplificadores de 40 realizados. Caso 1: Paciente con meningioma de la convexidad parasagital izquierda en área premotora; Caso 2: Paciente con macroadenoma hipofisario, operada previamente por vía transeptoesfenoidal en otra institución con una resección parcial; Caso 3: Paciente con lesiones en pedúnculo cerebeloso medio bilateral. Se realizó la planificación prequirúrgica con el software OsiriX, fusionando y reconstruyendo en 3D las imágenes de TC e IRM, para analizar relaciones anatómicas, medir distancias, coordenadas y trayectorias, entre otras funciones. Discusión: El software OsiriX de acceso libre y gratuito permite al cirujano, mediante la fusión y reconstrucción en 3D de imágenes, analizar la anatomía individual del paciente y planificar de forma rápida, simple, segura y económica cirugías de alta complejidad. En el Caso 1 se pudo analizar las relaciones del tumor con las estructuras adyacentes para minimizar el abordaje. En el Caso 2 permitió comprender la anatomía post-operatoria previa del paciente, para determinar la trayectoria del abordaje transnasal endoscópico y la necesidad de ampliar su exposición, logrando la resección tumoral completa. En el Caso 3 permitió obtener las coordenadas estereotáxicas y trayectoria de una lesión sin representación tomográfica. Conclusión: En casos de no contar con costosos sistemas de neuronavegación o estereotáxia el software OsiriX es una alternativa a la hora de planificar la cirugía, con el objetivo de disminuir el trauma y la morbilidad operatoria. PMID:25165617

  7. ConPADE: Genome Assembly Ploidy Estimation from Next-Generation Sequencing Data

    PubMed Central

    Margarido, Gabriel R. A.; Heckerman, David

    2015-01-01

    As a result of improvements in genome assembly algorithms and the ever decreasing costs of high-throughput sequencing technologies, new high quality draft genome sequences are published at a striking pace. With well-established methodologies, larger and more complex genomes are being tackled, including polyploid plant genomes. Given the similarity between multiple copies of a basic genome in polyploid individuals, assembly of such data usually results in collapsed contigs that represent a variable number of homoeologous genomic regions. Unfortunately, such collapse is often not ideal, as keeping contigs separate can lead both to improved assembly and also insights about how haplotypes influence phenotype. Here, we describe a first step in avoiding inappropriate collapse during assembly. In particular, we describe ConPADE (Contig Ploidy and Allele Dosage Estimation