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Sample records for con rituximab reporte

  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. Pros and cons of rituximab maintenance in follicular lymphoma.

    PubMed

    Zhang, Lu; Ghielmini, Michele; Cheson, Bruce D; Ujjani, Chaitra

    2017-07-01

    Follicular lymphoma (FL) is the most prevalent indolent non-Hodgkin lymphoma. Most patients present with advanced disease and are incurable with current therapy. The approval of rituximab has revolutionized the treatment of follicular lymphoma when administered in the induction setting for high-tumor burden disease, but the use of rituximab as a maintenance therapy (MR) continues to be a point of controversy. In this article, we review the main data and arguments in favor and against MR in FL. In summary, most studies have demonstrated a significant benefit in progression-free or event-free survival in this notoriously recurrent disease; however, long-term outcomes could not consistently demonstrate to be improved with this intervention. In a meta-analysis of randomized trials overall survival (OS) showed a tendency to improvement when given to patients in relapse, but no single study reached a significant OS advantage. The risk of high-grade transformation does not seem to be reduced in prospective trials. On the other hand, MR clearly increases toxicity without an improvement in quality of life. Finally, MR is expensive, and it is not proven that the delayed relapse time can compensate for these costs. In conclusion, despite the proven increase in progression-free survival, MR can't be recommended as a standard for the treatment of FL. Copyright © 2017 Elsevier Ltd. All rights reserved.

  3. [Shock as an adverse reaction to rituximab: Case report].

    PubMed

    Palma, Estefanía; González, Vicente; Grünholz, Daniela; Landaeta, María; Mallea, María; Pérez, José; Armstrong, Tomás

    2017-02-01

    Rituximab is a plausible alternative first-line treatment of ANCA-associated vasculitis. Adverse effects related to its infusion are common and usually have a benign course. However, there have been reports of refractory cardiogenic shock simulating septic shock. We report an 81-year-old male with the diagnosis of ANCA associated vasculitis. Rituximab 500 mg was administered intravenously for a relapse. The infusion proceeded without incident. However, 24 hours after its administration the patient began with fever, chills, coughing and strong malaise. The patient was transferred to the critical patient unit where a septic shock was suspected and resuscitative measures were started. However, the fast response to moderate doses of vasoactive drugs and complementary tests did not support an infectious etiology for the shock. Antimicrobials were discontinued and systemic corticosteroids were maintained, achieving remission of the symptoms. Shock as an unusual adverse reaction to Rituximab was suspected.

  4. Rituximab-induced interstitial lung disease in a patient with follicular lymphoma: A rare case report

    PubMed Central

    Aagre, Suhas; Patel, Apurva; Kendre, Pradip; Anand, Asha

    2015-01-01

    Rituximab is a chimeric monoclonal antibody that targets CD-20 antigen expressed in more than 90% of all B cell non-Hodgkin's lymphoma (NHL). We report a case of 33-year-old female without any comorbidities, newly diagnosed with stage IIIB follicular lymphoma treated with rituximab-based chemotherapy. Patient developed exertional dyspnea and dry cough after the fourth cycle of rituximab-based chemotherapy. Diagnostic high-resolution computed tomography (HRCT) of the lungs revealed bilateral patchy ground glass opacities suggestive of interstitial lung disease (ILD). It was managed successfully with supplemental oxygen and corticosteroids with discontinuation of the Rituximab. Extensive review of the literature did not reveal ample of material on rituximab-induced ILD (RTX-ILD). PMID:26664173

  5. Treatment-resistant recurrent membranoproliferative glomerulonephritis in renal allograft responding to rituximab: case report.

    PubMed

    Farooqui, M; Alsaad, K; Aloudah, N; Alhamdan, H

    2015-04-01

    We report a case of idiopathic membranoproliferative glomerulonephritis (MPGN) recurring 2 years after a living-unrelated kidney transplantation. The disease was refractory to intravenous immunoglobulin and plasmapheresis. Treatment with 2 doses of rituximab resulted in remission of the disease. The disease relapsed 18 months later after an episode of cytomegalovirus pneumonitis. After treatment of the pneumonitis, a lung biopsy was performed owing to persistent chest symptoms, which revealed bronchiolitis obliterans with organizing pneumonia. Bone marrow examination and culture revealed presence of acid-fast bacilli, and culture grew Mycobacterium tuberculosis. A repeated course of rituximab was withheld because of infection with tuberculosis, the patient's chest symptoms, and rare reports of noninfectious lung disease after the use of rituximab. The patient continues to have proteinuria with impaired kidney function. Copyright © 2015 Elsevier Inc. All rights reserved.

  6. Individualized rituximab treatment for relapsing neuromyelitis optica: a pediatric case report.

    PubMed

    He, Dian; Yu, YunLi; Yan, WeiBo; Dai, QingQing; Xu, Zhu; Chu, Lan

    2014-08-01

    Neuromyelitis optica is an autoimmune inflammatory disorder of the central nervous system. Current therapeutic approaches are based on small uncontrolled trials, case series, or case reports. There are only a few case reports describing rituximab for pediatric neuromyelitis optica. A 7-year-old girl with neuromyelitis optica had high disease activity with recurrent myelitis and steroid dependence. A remarkable increase of CD19(+) B-cell count in the peripheral blood mononuclear cells and seropositivity for anti-aquaporin 4 antibody were detected at each attack. After induction therapy with rituximab, the CD19(+) B-cell number was significantly reduced and sustained at low levels. The level of serum anti-aquaporin 4 antibody normalized. She was relapse-free over 1-year follow-up period. An individualized maintenance therapy scheme is underway. Treatment with rituximab for relapsing neuromyelitis optica requires an individualized regimen to optimize the frequency and dosage of administration to maximize efficacy yet minimize overtreatment and cost. Personal levels of CD19(+) B cells in peripheral blood mononuclear cells at previous attacks and responsiveness to rituximab in induction therapy may be two useful indicators in establishing individualized maintenance therapy schemes for relapsing neuromyelitis optica. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. A pioneer experience in Malaysia on In-house Radio-labelling of (131)I-rituximab in the treatment of Non-Hodgkin's Lymphoma and a case report of high dose (131)I-rituximab-BEAM conditioning autologous transplant.

    PubMed

    Kuan, Jew Win; Law, Chiong Soon; Wong, Xiang Qi; Ko, Ching Tiong; Awang, Zool Hilmi; Chew, Lee Ping; Chang, Kian Meng

    2016-10-01

    Radioimmunotherapy is an established treatment modality in Non-Hodgkin's lymphoma. The only two commercially available radioimmunotherapies - (90)Y-ibritumomab tiuxetan is expensive and (131)I-tositumomab has been discontinued from commercial production. In resource limited environment, self-labelling (131)I-rituximab might be the only viable practical option. We reported our pioneer experience in Malaysia on self-labelling (131)I-rituximab, substituting autologous haematopoietic stem cell transplantation (HSCT) and a patient, the first reported case, received high dose (131)I-rituximab (6000MBq/163mCi) combined with BEAM conditioning for autologous HSCT.

  8. Targeted Therapy with Rituximab in Felty’s Syndrome: A Case Report

    PubMed Central

    Heylen, Line; Dierickx, Daan; Vandenberghe, Peter; Westhovens, René

    2012-01-01

    Felty’s syndrome is a rare, severe extra-articular manifestation of rheumatoid arthritis (RA). There is no standard therapy, and several disease-modifying antirheumatic drugs have been used with varying success. Only very few reports exist in literature on the use of biologicals in this indication and this with a variable efficacy. We report the case of a 53-year-old woman with severe refractory/partly undertreated RA who presented with Felty’s syndrome and pancytopenia, in whom treatment with rituximab led to an marked increase of red blood cells, neutrophils and thrombocytes. In addition, the RA disease activity status improved dramatically and treatment with steroids could be reduced. The current sparse literature on this topic is reviewed. PMID:23198005

  9. Catastrophic antiphospholipid syndrome associated with systemic lupus erythematosus treated with rituximab: case report and a review of the literature.

    PubMed

    Sukara, G; Baresic, M; Sentic, M; Brcic, L; Anic, B

    2015-01-01

    Catastrophic antiphospholipid syndrome (CAPS) is a rare, acute, life-threatening form of antiphospholipid syndrome. In the last several decades there has been a significant improvement in the treatment of patients with CAPS, but the overall mortality is still very significant. The use of rituximab has been reported in the treatment of refractory cases of CAPS but the data are still scarce and inconclusive. We report a case of 47-year old male patient with long standing SLE and secondary APS who presented with acute thromboembolic incident (partial thrombosis of superior mesenteric artery). During the first week of his hospitalization he met the criteria for probable CAPS. He was treated with anticoagulants, glucocorticoids, intravenous immunoglobulins and systemic antibiotics. Finally he was treated with rituximab. There was no response to the implemented treatment and he eventually died. Autopsy showed evidence of small vessel thrombosis in the lung microvasculature. With this the criteria for definitive CAPS were fulfilled. To our knowledge, at present time, this is the first ever reported case of definitive CAPS associated with SLE treated with rituximab. There is a great need for further investigation to evaluate the effectiveness of rituximab in treatment of CAPS.

  10. Rituximab in multiple sclerosis

    PubMed Central

    Svenningsson, Rasmus; Alping, Peter; Novakova, Lenka; Björck, Anna; Fink, Katharina; Islam-Jakobsson, Protik; Malmeström, Clas; Axelsson, Markus; Vågberg, Mattias; Sundström, Peter; Lycke, Jan; Piehl, Fredrik; Svenningsson, Anders

    2016-01-01

    Objective: To investigate the safety and efficacy of rituximab in multiple sclerosis (MS). Methods: In this retrospective uncontrolled observational multicenter study, off-label rituximab-treated patients with MS were identified through the Swedish MS register. Outcome data were collected from the MS register and medical charts. Adverse events (AEs) grades 2–5 according to the Common Terminology Criteria for Adverse Events were recorded. Results: A total of 822 rituximab-treated patients with MS were identified: 557 relapsing-remitting MS (RRMS), 198 secondary progressive MS (SPMS), and 67 primary progressive MS (PPMS). At baseline, 26.2% had contrast-enhancing lesions (CELs). Patients were treated with 500 or 1,000 mg rituximab IV every 6–12 months, during a mean 21.8 (SD 14.3) months. During treatment, the annualized relapse rates were 0.044 (RRMS), 0.038 (SPMS), and 0.015 (PPMS), and 4.6% of patients displayed CELs. Median Expanded Disability Status Scale remained unchanged in RRMS (p = 0.42) and increased by 0.5 and 1.0 in SPMS and PPMS, respectively (p = 0.10 and 0.25). Infusion-related AEs occurred during 7.8% of infusions and most were mild. A total of 89 AEs grades ≥2 (of which 76 infections) were recorded in 72 patients. No case of progressive multifocal leukoencephalopathy was detected. Conclusions: This is the largest cohort of patients with MS treated with rituximab reported so far. The safety, clinical, and MRI findings in this heterogeneous real-world cohort treated with different doses of rituximab were similar to those reported in previous randomized controlled trials on B-cell depletion therapy in MS. Classification of evidence: This study provides Class IV evidence that for patients with MS, rituximab is safe and effective. PMID:27760868

  11. Refractory relapsing polychondritis in a child treated with antiCD20 monoclonal antibody (rituximab): first case report.

    PubMed

    Abdwani, Reem; Kolethekkat, Arif Ali; Al Abri, Rashid

    2012-07-01

    To report the first case of refractory relapsing polychondritis in a child who was treated with the biological agent, rituximab, an antiCD20 monoclonal antibody. The case is reported with a review of the literature on the use of biological agents in the treatment of refractory relapsing polychondritis. A 10-year-old boy presented with relapsing polychondritis who was treated initially with prednisolone and methotrexate. As there was no response to the treatment, anti TNF antagonist infliximab was given but with a failed response. A subsequent therapy with rituximab produced significant clinical remission with no recurrence at 1 year. Relapsing polychondritis unresponsive to primary treatment modalities but treated with various biological agents in adult have been well described in adults but not reported in children age below 13 yrs. Hence we present this case report. Biological agents such as rituximab has promising role in children when primary treatment fails as reported in our case. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  12. Refractory thrombotic thrombocytopenic purpura associated with primary Sjogren syndrome treated with rituximab: a case report.

    PubMed

    Toumeh, Anis; Josh, Navpreet; Narwal, Rawan; Assaly, Ragheb

    2014-01-01

    Thrombotic thrombocytopenic purpura (TTP) is an uncommon, serious disease that involves multiple organs and is rapidly fatal if left untreated. TTP is associated with multisystem symptoms, such as thrombocytopenia, microangiopathic hemolytic anemia, renal impairment, central nervous system involvement, and fever. TTP is idiopathic in about 37% of the cases and can be associated with autoimmune diseases in 13% of the cases. Autoimmune disease-associated TTP can be refractory to plasma exchange and requires immunosuppressive therapy. We report a case of a previously healthy 55-year-old African American female who presented with shortness of breath, hemolytic anemia, renal impairment, and thrombocytopenia. The diagnosis of TTP was made, and plasmapheresis was initiated. However, recurrence happened 48 hours after plasmapheresis was stopped. Autoimmune workup for refractory TTP revealed positive antinuclear antibodies, Anti-SSA, and Anti-SSB. Lip biopsy revealed findings consistent with Sjogren syndrome. Treatment with Rituximab was started, and significant clinical and laboratory response was achieved. The patient remained asymptomatic thereafter. A high clinical suspicion of autoimmune diseases is important as TTP tends to be refractory to plasma exchange in these cases, and immunosuppressive therapy is a key.

  13. Rituximab-Induced Hypersensitivity Pneumonitis

    PubMed Central

    Tonelli, Adriano R.; Lottenberg, Richard; Allan, Robert W.; Sriram, P.S.

    2009-01-01

    Rituximab is a chimeric anti-CD20 monoclonal antibody used to treat CD20+ non-Hodgkin's lymphoma. Although pulmonary adverse reactions such as cough, rhinitis, bronchospasm, dyspnea and sinusitis are relatively common, other respiratory conditions like cryptogenic organizing pneumonia, interstitial pneumonitis and diffuse alveolar hemorrhage have rarely been reported. Only 2 possible cases of rituximab-associated hypersensitivity pneumonitis have been described to date. We present a case of hypersensitivity pneumonitis with classic radiographic and histopathologic findings in a patient treated with rituximab who responded to prednisone. PMID:18843175

  14. Early relapse after rituximab chemoimmunotherapy.

    PubMed

    Kiss, Flora; Buslig, Julia; Szegedi, Istvan; Scholtz, Beata; Kappelmayer, Janos; Kiss, Csongor

    2008-02-01

    In relapsed/refractory childhood acute lymphoblastic leukemia (ALL) of the B-cell lineage rituximab, a monoclonal anti-CD20 antibody was used successfully in some cases. We report on a 15-year-old female with relapsed CD20-positive B-cell progenitor ALL treated with rituximab because of positive minimal residual disease signals after chemotherapy, as checked by flow cytometry and real time quantitative-PCR. Rituximab eliminated the CD20-positive subpopulation, but not the more immature leukemic cells. The patient died with fulminant aspergillosis before hematopoietic stem cell transplantation could be performed.

  15. Desensitization protocol for rituximab-induced serum sickness.

    PubMed

    Fajt, Merritt L; Petrov, Andrej A

    2014-01-01

    Rituximab, a chimeric anti-CD20 monoclonal antibody, is used to treat rheumatologic and hematologic diseases. Serum sickness, a Type III delayed hypersensitivity reaction, has been reported with rituximab treatment. Traditionally, drug desensitization has been used to treat Type I IgE-mediated hypersensitivity reactions. We report the first case of successful drug desensitization to rituximab in a patient with medication-induced serum sickness. In our case, a 37-year-old woman with Sjogren's syndrome and papillary thyroid carcinoma developed serum sickness 72 hours following rituximab infusion for gastric mucosal associated lymphoma tissue (MALT). Her MALT progressed after stopping rituximab. She underwent a rapid 12-step intravenous rituximab desensitization without recurrence of serum sickness. Following the completion of 4 rituximab desensitizations, she had gastric MALT remission. She received 25 maintenance rituximab doses using this desensitization protocol quarterly without complications. This is the first report documenting rituximab desensitization for the treatment of delayed drug reactions like serum sickness.

  16. Refractory antineutrophil cytoplasmic antibody-associated vasculitis successfully treated with rituximab: a case report.

    PubMed

    Horai, Yoshiro; Miyamura, Tomoya; Takahama, Soichiro; Hirata, Akie; Nakamura, Masataka; Ando, Hitoshi; Minami, Rumi; Yamamoto, Masahiro; Suematsu, Eiichi

    2010-01-01

    A 63-year-old-man was diagnosed in March 2002 with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis because of mononeuritis multiplex, interstitial pneumonia and a positive finding for myeloperoxidase (MPO)-ANCA. Although treated with prednisolone and oral cyclophosphamide, he suffered repeated remission and deterioration of his conditon, which was complicated by hypertrophic pachymeningitis and sinusitis. In July 2006, he was diagnosed with an exacerbation of ANCA-associated vasculitis because of pyrexia, general malaise, numbness in his face and legs, and elevated serum CRP level. Steroid pulse therapy was thus initiated and the patient's clinical symptoms improved. However, serum CRP levels elevated again (5.18 mg/dl) in September 2006. We began administration of rituximab (500 mg/bodyx4 times) in November 2006 and his symptom and laboratory data significantly improved. The dose of prednisolone was slowly decreased without suffering a relapse. Rituximab has been administered every one year, and good disease control has been achieved. Diagnosis of Wegener's granulomatosis was made from the findings of a nodular lesion in the left lung. Rituximab should be considered for patients with refractory ANCA-associated vasculitis.

  17. IgG4-related disease with cutaneous manifestations treated with rituximab: case report and literature review.

    PubMed

    Jalilian, Chris; Prince, H Miles; McCormack, Chris; Lade, Stephen; Cheah, Chan Y

    2014-05-01

    Immunoglobulin type gamma 4 (Ig)G4-related disease (IgG4-RD) is a relatively recently described clinical entity characterised by elevated levels of serum IgG4 and tissue infiltration of IgG4+ plasma cells in various organ systems. Cutaneous involvement is rare but is becoming increasingly appreciated; typically presenting as erythematous papules and/or nodules that are commonly pruritic. We report a case of IgG4-RD presenting with persistent pruritic papules and unilateral parotid swelling. His serum IgG4 level was elevated and a histological examination of his skin biopsies found a lymphoplasmacytic infiltration with an excess of IgG4+ non-clonal plasma cells. The patient was intolerant of oral prednisolone, however complete resolution of the cutaneous lesions was achieved with the anti-CD20 antibody, rituximab.

  18. Longterm Safety of Rituximab: Final Report of the Rheumatoid Arthritis Global Clinical Trial Program over 11 Years.

    PubMed

    van Vollenhoven, Ronald F; Fleischmann, Roy M; Furst, Daniel E; Lacey, Stuart; Lehane, Patricia B

    2015-10-01

    Final evaluation of the longterm safety of rituximab (RTX) in rheumatoid arthritis (RA) up to 11 years. Pooled observed case analysis of data from patients with moderate to severe, active RA in a global clinical trial program. As of September 2012, 3595 patients received a mean of 4 courses (range 1-20) of RTX over 11 years [14,816 patient-years (PY)]. Of these, 1246 patients had > 5 years of followup (8970 PY). A pooled placebo population (n = 818) was included in the analysis. The overall serious infection event (SIE) rate was 3.76/100 PY (2.71/100 PY in patients observed for > 5 yrs) and comparable with rates reported previously at 9.5 years (3.94/100 PY and 3.26/100 PY, respectively). SIE rates continued to be similar before and during/after development of low immunoglobulin levels, and serious opportunistic infections remained rare. Rates of cardiac events remained consistent with previous analysis and with rates in the general RA population. No increased risk of malignancy over time was observed. This final report demonstrates that RTX remains well tolerated over time and multiple courses. No new safety risks were identified and there was no increase in the rate of any types of adverse events with prolonged exposure to RTX during 11 years of observation.

  19. Rituximab with chemotherapy in children and adolescents with central nervous system and/or bone marrow-positive Burkitt lymphoma/leukaemia: a Children's Oncology Group Report.

    PubMed

    Goldman, Stanton; Smith, Lynette; Galardy, Paul; Perkins, Sherrie L; Frazer, John Kimble; Sanger, Warren; Anderson, James R; Gross, Thomas G; Weinstein, Howard; Harrison, Lauren; Shiramizu, Bruce; Barth, Matthew; Cairo, Mitchell S

    2014-11-01

    Children and adolescents with Burkitt Lymphoma (BL) and combined central nervous system (CNS) and bone marrow involvement still have a poor prognosis with chemotherapy alone. We therefore investigated in children and adolescents with bone marrow (≥25% blasts) and/or CNS-positive Burkitt lymphoma the chemoimmunotherapy combination of rituximab (375 mg/m(2) ) and the standard chemotherapy arm of our previously reported French-American-British (FAB) Lymphome Malins de Burkitt (LMB) 96 trial. Central pathological and cytogenetic characterization was also performed. There were 40 evaluable patients with Burkitt histology (25 with leukaemia and 15 with CNS disease ± leukaemia). The chemoimmunotherapy regimen was well tolerated. The incidence of grade III/IV mucositis during induction cycles with combined chemotherapy and rituximab was 31% and 26%, respectively. The 3-year event-free survival (EFS)/overall survival (OS) was 90% (95% confidence interval [CI], 76-96%) in the entire cohort and 93% (95% CI, 61-99%) in patients with CNS disease. Based on the results of this trial, an international randomized study of FAB/LMB 96 chemotherapy ± rituximab for high-risk patients is currently under investigation.

  20. 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.

  1. Novel applications of Rituximab in dermatological disorders

    PubMed Central

    Bhandari, Prasan R.; Pai, Varadraj V.

    2014-01-01

    Rituximab is a monoclonal therapeutic anti-CD20 antibody that has been approved for use in lymphoma and rheumatoid arthritis. Over the past decade several reports based on case series and observational studies have recorded the benefits of rituximab in particular groups of dermatological patients. Off-label use of rituximab in many dermatological indications is not uncommon in many countries in the world. This article reviews the available data that may be of use to the practicing dermatologist. Because of its potential complications, paucity of clinical data, and cost considerations, rituximab is favoured only when standard systemic therapies fail or corticosteroids are absolutely contraindicated. Further research is required in this field. PMID:25165639

  2. Rituximab for Rheumatoid Arthritis.

    PubMed

    Cohen, Marc D; Keystone, Edward

    2015-12-01

    Rituximab is a chimeric monoclonal antibody directed at the CD20 molecule on the surfaces of some but not all B cells. It depletes almost all peripheral B cells, but other niches of B cells are variably depleted, including synovium. Its mechanism of action in rheumatoid arthritis (RA) is only partially understood. Rituximab was efficacious in clinical trials of patients with RA, including those who are methotrexate naïve, those with an incomplete response to methotrexate, and those with an incomplete response to tumor necrosis factor inhibitors. The need for a concomitant traditional disease-modifying drug, the optimal dose of rituximab, and the optimal interval for retreatment remain somewhat uncertain. Rituximab seems to be most efficacious in seropositive patients and those with an incomplete response to only one tumor necrosis factor inhibitor. Rituximab has a reasonable safety profile, with a small risk of serious infectious events, which is stable over time and repeat courses. Opportunistic infections are rare. Reactivation of hepatitis B remains a concern. The possible association of rituximab and progressive multifocal leukoencephalopathy may still require vigilance. Malignancies and cardiovascular events do not appear to be increased. Infusion reactions are more likely with the initial infusion, and are usually mild. Rituximab may cause hypogammaglobulinemia, but any risk of subsequent risk of increased infectious events is not yet well established. Before initiating rituximab, patient screening for hypersensitivity to murine proteins, infections, congestive heart failure, pregnancy, and hypogammaglobulinemia is imperative. Vaccinations should be administered prior to treatment whenever possible. Rituximab has been a significant addition to the rheumatologists' armamentarium for the treatment of RA.

  3. Treatment of refractory retrobulbar granuloma with rituximab in a patient with ANCA-negative Wegener's granulomatosis: a case report.

    PubMed

    Ooka, Seido; Maeda, Akihiko; Ito, Hiroshi; Omata, Masami; Yamada, Hidehiro; Ozaki, Shoichi

    2009-01-01

    Retrobulbar granuloma is one of the serious complications in Wegener's granulomatosis and often shows resistance to conventional therapy during long-term treatment. The outcome of this complication includes visual loss, orbital and facial deformity, fistula formation, as well as infection. There has been increasing evidence that shows the efficacy of rituximab, a chimeric anti-B cell mAb, for the treatment of autoimmune diseases including Wegener's granulomatosis. We present a 22-year-old Japanese woman who was diagnosed with Wegener's granulomatosis complicated by refractory retrobulbar granuloma. She was admitted to our hospital with pain of the right eye and right proptosis during treatment with monthly IVCY for Wegener's granulomatosis. We diagnosed refractory retrobulbar granuloma by computed tomography (CT) scan and biopsy. She showed a refractory growth of retrobulbar granuloma in spite of negative ANCA. She was also complicated with pulmonary granulomatous lesions in bilateral apices. After approval by an institutional ethical committee and informed consent of this patient, rituximab 375 mg/m2 was intravenously administered weekly four times. Concomitant prednisolone 0.5 mg/kg was also administered for 2 weeks and gradually tapered. Treatment of rituximab resulted in prompt relief of symptoms in this case and the reduction of the granuloma. BVAS score also improved from 6 to 0 at 3 months and was kept in remission for 12 months. Circulating CD19-positive cells were kept less than 0.1% during the follow-up. There were no serious adverse events. This case suggests that rituximab is effective for refractory retrobulbar granuloma complicated in Wegener's granulomatosis even when ANCA titers are negative.

  4. Mitomycin-C-Induced TTP/HUS Treated Successfully with Rituximab: Case Report and Review of the Literature

    PubMed Central

    Yamin, Hanah; Smith, Hedy

    2013-01-01

    Microangiopathic hemolytic anemia (MAHA), thrombocytopenia, fever, renal failure, and neurologic symptoms comprise the cardinal features of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Etiologies can include medications, infections, cancers, or transplantation. We present a patient with a history of rectal cancer treated with mitomycin-C who developed MAHA, acute kidney injury, and thrombocytopenia 6 months after completing therapy and to did not respond the plasmapheresis or steroids. She was treated with four weekly doses of rituximab with full recovery. PMID:23762670

  5. [Novel uses of rituximab].

    PubMed

    Frenzel, Laurent

    2013-12-01

    Since its approved by HAS in 1998, the use of rituximab increases every year. Marketed in France under the name MabThera, rituximab is used primarily in the treatment of B-cell malignancies including follicular lymphoma, diffuse large B-cell lymphoma and chronic lymphocytic leukemia and corresponding to the three main indications for treatment. However, given its action on B cells, rituximab also proves to be effective in rheumatoid arthritis. By extension as anti-B-cell, rituximab is actually used in other autoimmune diseases: in autoimmune cytopenias as idiopathic thrombocytopenic purpura and hemolytic anemia, in vasculitis, or multiple sclerosis, it is also used in organ transplantation as kidney in prophylaxy to rejection and treatment of EBV-mediated complications.

  6. Rituximab In Indolent Lymphomas

    PubMed Central

    Sousou, Tarek; Friedberg, Jonathan

    2010-01-01

    Indolent Non Hodgkin's lymphoma (NHL) comprises a group of incurable, generally slow growing lymphomas highly responsive to initial therapy with a relapsing and progressive course. Rituximab, an anti CD-20 antibody, has had a large impact on treatment of indolent NHL. Its effectiveness as a single agent and in conjunction with known chemotherapy regimens has made it a standard of care in the treatment of NHL. Analysis of data obtained from NHL clinical trials as well as data from the National Cancer Institute indicates that the overall survival of indolent NHL has improved since the discovery of rituximab. Given its effectiveness and tolerability, it is currently being investigated as a maintenance agent with encouraging results. This review summarizes several landmark trials utilizing rituximab as a single agent and in combination with chemotherapy for treatment of NHL. In addition, a review of the studied rituximab maintenance dosing schedules and its impact on NHL will also be presented. Overall, rituximab has changed the landscape for treatment of indolent NHL however additional research is necessary to identify the optimal dosing schedule as well as patients most likely to respond to prolonged rituximab therapy. PMID:20350660

  7. 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.

  8. Non-ischemic cardiomyopathy after rituximab treatment for membranous nephropathy

    PubMed Central

    Cheungpasitporn, Wisit; Kopecky, Stephen L.; Specks, Ulrich; Bharucha, Kharmen; Fervenza, Fernando C.

    2017-01-01

    Rituximab is an anti-CD20 monoclonal antibody frequently used for the treatment of non-Hodgkin’s lymphoma, chronic lymphocytic leukemia (CLL), rheumatoid arthritis (RA), and anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis. In addition, rituximab has recently been increasingly used as an off-label treatment in a number of inflammatory and systemic autoimmune diseases. It is advised that rituximab infusion may cause infusion reactions and adverse cardiac effects including arrhythmia and angina, especially in patients with prior history of cardiovascular diseases. However, its detailed cardiotoxicity profile and effects on cardiac function were not well described. We report a 51-year-old man who developed non-ischemic cardiomyopathy after rituximab treatment for membranous nephropathy. The patient experienced reduced cardiac functions within 48 hours after the initial infusion, which remained markedly reduced at 9-month follow-up. As the utility of rituximab expands, physicians must be aware of this serious cardiovascular adverse effect. PMID:28487867

  9. Nasal, pharyngeal, and laryngeal pemphigus vulgaris successfully treated with rituximab.

    PubMed

    Sami, Naveed

    2017-01-01

    Pemphigus vulgaris is a potentially fatal autoimmune blistering disease that can involve the nasopharyngeal and laryngeal tissues. The disease can be recalcitrant to conventional oral treatments, and treatment alternatives are limited. This retrospective study evaluated the efficacy of rituximab as a rescue agent in 5 patients with recalcitrant pemphigus vulgaris involving nasopharyngeal and laryngeal mucosa. All 5 patients were unresponsive to systemic steroids and at least one conventional oral immunosuppressive agent. The patients received rituximab infusions as a rescue agent because of recalcitrant disease. All 5 patients had a complete clinical response to rituximab and could discontinue systemic steroids and reduce the dosage of their initial immunosuppressive agent. No major adverse reactions were observed or reported with rituximab. Rituximab can be used as an effective rescue agent in the treatment of severe pemphigus vulgaris with nasopharyngeal and laryngeal involvement.

  10. Risks and Benefits of Rituximab in the Treatment of Hashimoto Encephalopathy in Children: Two Case Reports and a Mini Review.

    PubMed

    Maas, Annemieke; Braun, Kees P J; Geleijns, Karin; Jansen, Floor E; van Royen-Kerkhof, Annet

    2017-01-01

    Hashimoto encephalopathy is a rare condition, characterized by the association of encephalopathy with a variety of neurological symptoms and autoantibodies to the thyroid gland. Its etiology is unknown, and symptoms are usually treated with immune suppressive therapy, e.g., high doses of corticosteroids. Here, we report the long-term outcome in two steroid-refractory adolescents with Hashimoto encephalopathy who were treated with rituximab, a monoclonal antibody directed against CD20. In addition, we reviewed the literature regarding treatment strategies in Hashimoto encephalopathy. Anti-B-cell therapy can be of value in the treatment of Hashimoto encephalopathy, especially in steroid refractory cases, but side effects due to low levels of immunoglobulins warrant careful monitoring. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Successful treatment of relapsing autoimmune pancreatitis in primary Sjögren's syndrome with rituximab: report of a case and review of the literature.

    PubMed

    Rueda, Juan C; Duarte-Rey, Carolina; Casas, Nohemi

    2009-10-01

    Autoimmune pancreatitis (AIP) is a rare disorder often associated with multiple autoimmune diseases like rheumatoid arthritis, inflammatory bowel disease and Sjögren's syndrome (SS). Although knowledge of AIP has grown over the last few years, little is certain about its cause and pathogenesis. Positive immunologic markers like antinuclear antibodies (ANA) or elevated serum levels of IgG4, systemic autoimmune disease association and positive response to oral steroid therapy strongly supports the idea of autoimmune mechanisms involved in the pathogenesis of AIP. We describe the first case reported on the literature of a patient with primary SS who developed relapsing AIP to steroids but responded successfully to Rituximab (RTX) therapy. New theories about the role of B-cells activity in SS and other autoimmune diseases has encourage the use of RTX, proving tolerance and efficacy especially in extra-glandular manifestations.

  12. Post-transplant lymphoproliferative disorder presenting with skin ulceration in a renal transplant recipient who achieved sustained remission with rituximab therapy: A case report

    PubMed Central

    Law, Man Fai; Chan, Hay Nun; Lai, Ho Kei; Ha, Chung Yin; Ng, Celia; Yeung, Yiu Ming; Yip, Sze Fai

    2016-01-01

    Post-transplant lymphoproliferative disorder (PTLD) is associated with a variety of clinical presentations, but rarely involves the skin. We herein report a case of PTLD presenting with skin ulceration in a renal transplant recipient. A biopsy of the ulcer confirmed the diagnosis of diffuse large B-cell lymphoma. The patient was initially treated with immunosuppression reduction, but the skin ulcer persisted. He was then treated with two courses of chemotherapy, but his condition was complicated with cryptococcal infection. Antifungal agents were administered to control the fungal infection. The patient later developed lymphoma recurrence and was successfully treated with single-agent rituximab. The patient remains well 6 years after treatment, with no evidence of disease relapse. Therefore, PTLD may manifest as skin lesions and physicians must be aware of this rare presentation. PMID:27900097

  13. Rituximab Not Effective for Hearing Loss in Cogan's Syndrome

    PubMed Central

    Kerr, Leslie Dubin

    2016-01-01

    Importance. Rituximab was not effective in ameliorating the hearing loss in a patient with atypical Cogan's syndrome. Observations. We report the case of a patient who developed acute bilateral uveitis and sensorineural hearing loss. A diagnosis of atypical Cogan's syndrome was made. The patient's hearing loss did not improve despite high dose steroids and azathioprine. Rituximab was administered given a recent report of its efficacy in a patient with refractory disease; however, our patient's hearing loss did not improve. Conclusion. Hearing loss in Cogan's syndrome is difficult to treat. Though rituximab was ineffective in our case, earlier administration in the disease course could be effective for future patients. PMID:27843668

  14. Successful pregnancy after rituximab in a women with recurrent in vitro fertilisation failures and anti-phospholipid antibody positive.

    PubMed

    Ng, C T; O'Neil, M; Walsh, D; Walsh, T; Veale, D J

    2009-12-01

    We report a case of successful pregnancy after rituximab in a patient with a history of in vitro fertilisation (IVF) failures and positive anti-cardiolipin antibody (ACA). Following a course of rituximab, her ACA became negative and she successfully conceived with IVF treatment. This is the first case in literature describing the use of rituximab therapy in this clinical scenario.

  15. Update on the use of rituximab for intractable rheumatoid arthritis

    PubMed Central

    Looney, R John

    2009-01-01

    It has been 3 years since rituximab, a mouse x human chimeric anti-CD20 monoclonal antibody that selectively depleted B cells, was approved by the FDA for the treatment of moderate to severe rheumatoid arthritis (RA) with an inadequate response to anti-TNF therapies. Since approval rituximab has become a part of standard treatment, and additional data have become available on long-term efficacy and safety both from clinical trials and from post-marketing surveillance. In open long-term follow-up from clinical trials, patients treated with multiple courses of rituximab continued to respond in terms of signs and symptoms, and damage assessed radiographically was significantly inhibited. Moreover, the rate of serious infectious events was not increased as the number of courses increased. However, because of case reports of progressive multifocal leukoencephalopathy in patients treated with rituximab for non-malignant conditions, a black box warning has been added. Studies on the immunologic correlates of response to rituximab treatment including B cell subsets in peripheral blood and synovial biopsies are providing clues into how rituximab works for autoimmune disease. However, at this time we are not able to explain why some patients do not respond and cannot predict who will respond. Future challenges for the further development of rituximab for intractable RA will be discussed. PMID:27789983

  16. Understanding rituximab function and resistance: implications for tailored therapy.

    PubMed

    Amoroso, Alfredo; Hafsi, Sameh; Militello, Loredana; Russo, Alessia E; Soua, Zohra; Mazzarino, Maria C; Stivala, Franca; Libra, Massimo

    2011-01-01

    The addition of anti-CD20 monoclonal antibody (rituximab) to chemotherapy has significantly improved survival in B-cell lymphoma. However, a substantial number of patients relapse after treatment with rituximab. Understanding of anti-CD20 antibody molecular function may facilitate the development of pharmacologic strategies to overcome resistance. Cell death have been demonstrated to be caused by rituximab binding to CD20 throughout direct and indirect mechanisms. The direct mechanism comprises growth inhibition, induction of apoptosis and sensitization of cells to chemotherapy. While, the indirect mechanisms to Rituximab include complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC). However, these mechanisms are still poorly understood. To shed light on this issue, we have analyzed the most significant results showing the role of Rituximab as a signal-inducing antibody and as a chemosensitizing agent through negative regulation of major survival pathways. Mechanisms of resistance to Rituximab are also discussed. Additionally, studies here reported show that, cellular targets are modified after treatment with Rituximab and may become useful for novel therapeutic strategies in the treatment of patients resistant to standard therapy.

  17. Induction of thyroid remission using rituximab in a patient with type 3 autoimmune polyglandular syndrome including Graves' disease and type 1 diabetes mellitus: a case report.

    PubMed

    Kurozumi, Akira; Okada, Yosuke; Arao, Tadashi; Narisawa, Manabu; Torimoto, Keiichi; Yamamoto, Sunao; Tanaka, Yoshiya

    2015-01-01

    Rituximab (RTX) is a monoclonal antibody that targets the B-cell-specific CD20 antigen. Recent reports indicate that RTX is effective against type 1 diabetes mellitus (T1DM) and hematologic as well as autoimmune diseases. Other studies have indicated that RTX therapy leads to the remission of recurrent or active Graves' disease (GD). However, the efficacy of RTX in Japanese patients with autoimmune polyglandular syndrome (APS) has not been reported to date. Herein, we report the case of a patient with GD and T1DM with sustained endogenous insulin secretion capacity. To protect pancreatic β cells, we administered RTX at a dose of 500 mg (approximately 300 mg/m2) on 2 occasions 1 week apart. After treatment, no adverse effects were observed, and thyroid stimulating hormone receptor antibody (TRAb) was no longer detectable 4 months after RTX administration. In addition, the reduction in TRAb level improved thyroid function. Notably, the treatment induced remission over a period of 1 year after the diagnosis of GD.

  18. Two cases of idiopathic membranous nephropathy treated with rituximab

    PubMed Central

    Young Yoon, Jae; Tae Han, Seung; Cho, Ajin; Ryoun Jang, Hye; Eun Lee, Jung; Huh, Wooseong; Joong Kim, Dae; Young Oh, Ha; Kim, Yoon-Goo

    2013-01-01

    Idiopathic membranous nephropathy is a common cause of nephrotic syndrome, and has been reported as a cause of idiopathic primary glomerulonephropathy in up to 90% of patients. However, the treatment options remain controversial. We report two cases of idiopathic membranous nephropathy that were treated with rituximab. A 54-year-old man and a 64-year old man were admitted for rituximab therapy. They had previously been treated with combinations of immunosuppressive agents including cyclophosphamide, cyclosporine, mycophenolate, and steroids. However, the patients' heavy proteinuria was not resolved. Both patients received rituximab therapy, 2 weeks apart. After several months of follow-up and a second round of rituximab treatment for each patient, their proteinuria decreased and partial remission of disease was achieved in both patients. PMID:26877930

  19. Kinetics of Rituximab Excretion into Urine and Peritoneal Fluid in Two Patients with Nephrotic Syndrome

    PubMed Central

    Schwarz, Anke; Wagner, A. D.; Haller, Hermann; Schiffer, Mario

    2017-01-01

    Clinical observations suggest that treatment of Rituximab might be less effective in patients with nephrotic range proteinuria when compared to nonnephrotic patients. It is conceivable that the reason for this is that significant amounts of Rituximab might be lost in the urine in a nephrotic patient and that these patients require a repeated or higher dosage. However, this has not been systematically studied. In this case report we describe two different patients with nephrotic range proteinuria receiving Rituximab. The first patient received Rituximab for therapy resistant cryoglobulinemic membranoproliferative glomerulonephritis and the other for second line treatment of Felty's syndrome. We employed flow cytometry to determine the amount of Rituximab excretion in both urine and peritoneal fluid specimens in these patients following administration of Rituximab. We found that a significant amount of Rituximab is lost from the circulation by excretion into the urine. Furthermore we saw a close correlation of the excretion of Rituximab to the excretion of IgG molecules suggesting selectivity of proteinuria as the determining factor of Rituximab excretion. Further larger scale clinical studies could have the potential to evaluate an optimal cut-off value of IgG urinary loss before a possible administration of Rituximab therefore contributing to a more individualized treatment approach in patients with nonselective and nephrotic range proteinuria. PMID:28243475

  20. 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. © The Author(s) 2014.

  1. Rituximab in Neuromyelitis Optica Spectrum Disorders: Our Experience.

    PubMed

    Jade, Jui Dilip; Bansi, Srishti; Singhal, Bhim

    2017-01-01

    Neuromyelitis optica (NMO) is an inflammatory demyelinating central nervous system disease, with recurrent attacks of severe bilateral optic neuritis and longitudinally extensive transverse myelitis. Aggressive immunosuppression is essential to prevent clinical relapses and permanent disability. Rituximab, a monoclonal antibody to CD20, has been found effective in several reports and small uncontrolled studies. There is a paucity of data regarding its use in Indian patients. The aim of this study was to report the results of rituximab treatment in NMO spectrum disorders (NMOSDs) in the Indian scenario. This study is a retrospective, observational study including 13 NMOSD patients treated with rituximab. After initial therapy in the acute episode with IV methylprednisolone and if needed plasma exchange, therapy was initiated as a cycle of intravenous rituximab, two doses 2 weeks apart of 1 g each. Subsequent cycles were advised at intervals of every 6 months. The primary outcome measure was annualized relapse rate (ARR), defined as a number of clinical attacks per year. Clinical adverse events were recorded throughout the study. In the study, mean ARR reduced from 2.61 to 0.09 after therapy (P = 0.000685). Of 13 patients, 8 (61.54%) were completely relapse free after starting treatment with rituximab. Treatment was well tolerated and no serious adverse events were noted. The treatment of NMOSDs with rituximab in Indian patients reduces the frequency of relapses and is well tolerated.

  2. Rituximab in Neuromyelitis Optica Spectrum Disorders: Our Experience

    PubMed Central

    Jade, Jui Dilip; Bansi, Srishti; Singhal, Bhim

    2017-01-01

    Background: Neuromyelitis optica (NMO) is an inflammatory demyelinating central nervous system disease, with recurrent attacks of severe bilateral optic neuritis and longitudinally extensive transverse myelitis. Aggressive immunosuppression is essential to prevent clinical relapses and permanent disability. Rituximab, a monoclonal antibody to CD20, has been found effective in several reports and small uncontrolled studies. There is a paucity of data regarding its use in Indian patients. Objectives: The aim of this study was to report the results of rituximab treatment in NMO spectrum disorders (NMOSDs) in the Indian scenario. Methods: This study is a retrospective, observational study including 13 NMOSD patients treated with rituximab. After initial therapy in the acute episode with IV methylprednisolone and if needed plasma exchange, therapy was initiated as a cycle of intravenous rituximab, two doses 2 weeks apart of 1 g each. Subsequent cycles were advised at intervals of every 6 months. The primary outcome measure was annualized relapse rate (ARR), defined as a number of clinical attacks per year. Clinical adverse events were recorded throughout the study. Results: In the study, mean ARR reduced from 2.61 to 0.09 after therapy (P = 0.000685). Of 13 patients, 8 (61.54%) were completely relapse free after starting treatment with rituximab. Treatment was well tolerated and no serious adverse events were noted. Conclusions: The treatment of NMOSDs with rituximab in Indian patients reduces the frequency of relapses and is well tolerated. PMID:28904454

  3. Very low residual concentrations of rituximab long after infusion still induce positive B-cell complement-dependent cytotoxicity-crossmatch.

    PubMed

    Gatault, Philippe; Philippe, Gatault; Jollet, Isabelle; Isabelle, Jollet; Paintaud, Gilles; Gilles, Paintaud; Magdelaine, Charlotte; Charlotte, Magdelaine; Bridoux, Franck; Franck, Bridoux; Lebranchu, Yvon; Yvon, Lebranchu; Büchler, Matthias; Matthias, Büchler; Touchard, Guy; Guy, Touchard; Thierry, Antoine; Antoine, Thierry

    2013-12-01

    Rituximab may induce positive B-cell complement-dependent cytotoxicity crossmatch (CDC-XM) in the absence of donor-specific antibodies, as we report in these two cases. We retrospectively assessed the in vitro concentration-effect relationship of rituximab in sera. B-cell CDC-XM results were positive only in the presence of rituximab, even with low concentrations (inferior to 1 μg/mL). Moreover, rituximab neutralization with increasing concentration of an anti-rituximab-idiotype monoclonal antibody progressively reduced B-cell lysis. In conclusion, measurement of rituximab content may be useful to identify sera at risk of misinterpretation in immunized patients.

  4. 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.

  5. [Successful treatment with rituximab in a patient with refractory mixed-type autoimmune hemolytic anemia].

    PubMed

    Ono, Kaoru; Sato, Tsutomu; Iyama, Satoshi; Tatekoshi, Ayumi; Hashimoto, Akari; Kamihara, Yusuke; Horiguchi, Hiroto; Kikuchi, Shohei; Takada, Kohichi; Hayashi, Tsuyoshi; Miyanishi, Koji; Sato, Yasushi; Takimoto, Rishu; Kobune, Masayoshi; Kato, Junji

    2013-11-01

    The evidence that rituximab is effective therapy for refractory warm or cold autoimmune hemolytic anemia (AIHA) has been accumulating; however, the efficacy of rituximab for mixed-type AIHA is not evident. Herein, we report a case of mixed-type AIHA refractory to corticosteroids and splenectomy, but successfully treated with rituximab (375 mg/m(2)/day, once weekly, four times). She achieved a complete response, which has been maintained for 16 months, to date, despite steroid tapering. Our case suggests that rituximab therapy should be considered for refractory AIHA even of mixed-type.

  6. MDM2 phenotypic and genotypic profiling, respective to TP53 genetic status, in diffuse large B-cell lymphoma patients treated with rituximab-CHOP immunochemotherapy: a report from the International DLBCL Rituximab-CHOP Consortium Program.

    PubMed

    Xu-Monette, Zijun Y; Møller, Michael B; Tzankov, Alexander; Montes-Moreno, Santiago; Hu, Wenwei; Manyam, Ganiraju C; Kristensen, Louise; Fan, Lei; Visco, Carlo; Dybkaer, Karen; Chiu, April; Tam, Wayne; Zu, Youli; Bhagat, Govind; Richards, Kristy L; Hsi, Eric D; Choi, William W L; van Krieken, J Han; Huang, Qin; Huh, Jooryung; Ai, Weiyun; Ponzoni, Maurilio; Ferreri, Andrés J M; Wu, Lin; Zhao, Xiaoying; Bueso-Ramos, Carlos E; Wang, Sa A; Go, Ronald S; Li, Yong; Winter, Jane N; Piris, Miguel A; Medeiros, L Jeffrey; Young, Ken H

    2013-10-10

    MDM2 is a key negative regulator of the tumor suppressor p53, however, the prognostic significance of MDM2 overexpression in diffuse large B-cell lymphoma (DLBCL) has not been defined convincingly. In a p53 genetically-defined large cohort of de novo DLBCL patients treated with rituximab, cyclophosphamide, hydroxydaunorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, we assessed MDM2 and p53 expression by immunohistochemistry (n = 478), MDM2 gene amplification by fluorescence in situ hybridization (n = 364), and a single nucleotide polymorphism in the MDM2 promoter, SNP309, by SNP genotyping assay (n = 108). Our results show that MDM2 overexpression, unlike p53 overexpression, is not a significant prognostic factor in overall DLBCL. Both MDM2 and p53 overexpression do not predict for an adverse clinical outcome in patients with wild-type p53 but predicts for significantly poorer survival in patients with mutated p53. Variable p53 activities may ultimately determine the survival differences, as suggested by the gene expression profiling analysis. MDM2 amplification was observed in 3 of 364 (0.8%) patients with high MDM2 expression. The presence of SNP309 did not correlate with MDM2 expression and survival. This study indicates that evaluation of MDM2 and p53 expression correlating with TP53 genetic status is essential to assess their prognostic significance and is important for designing therapeutic strategies that target the MDM2-p53 interaction.

  7. 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.

  8. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin in the treatment of secondary hemophagocytic lymphohistiocytosis with classical Hodgkin lymphoma: a case report and review of the literature.

    PubMed

    Hu, Steve; Bansal, Pranshu; Lynch, David; Rojas Hernandez, Cristhiam Mauricio; Dayao, Zoneddy

    2016-12-20

    Hemophagocytic lymphohistiocytosis is becoming an increasingly recognized disorder in adults. Classical Hodgkin lymphoma is a relatively uncommon etiology of hemophagocytic lymphohistiocytosis and may complicate treatment options. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin are discussed here as a treatment regimen. A 66-year-old Hispanic man previously in good health presented with a 1-month history of recurrent fevers, chills, and night sweats and a 3-week history of new onset jaundice. A bone marrow biopsy revealed a normocellular bone marrow with increased histiocytes with areas of hemophagocytic activity. He met five out of eight criteria for hemophagocytic lymphohistiocytosis diagnosis including fevers, pancytopenia, hemophagocytosis, ferritin of 23,292 ng/mL (>500 ng/mL), and soluble-CD25 of 15,330 pg/mL (>1033 pg/mL). A right cervical lymph node biopsy revealed CD15, CD30, MUM-1, and Epstein-Barr virus-encoded small ribonucleic acid-positive cells with morphologic findings of classical Hodgkin lymphoma, lymphocyte-rich subtype. He completed 2 weeks of hemophagocytic lymphohistiocytosis-directed therapy with etoposide and dexamethasone, but then was switched to rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin due to minimal improvement in his pancytopenia and hepatic impairment. He completed one full cycle of rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin with notable improvement in serial hepatic function panels and had an undetectable Epstein-Barr virus viral load. However, he eventually died due to complications of Enterococcus faecalis bacteremia and colonic microperforation in the setting of persistent pancytopenia. This case discusses the challenges facing treatment of adult malignancy-associated hemophagocytic lymphohistiocytosis. Rituximab, etoposide, methylprednisolone, high-dose cytarabine, and cisplatin may be a viable option for patients with secondary

  9. Rituximab in the treatment of acquired factor VIII inhibitors.

    PubMed

    Wiestner, Adrian; Cho, Hearn J; Asch, Adam S; Michelis, Mary Ann; Zeller, Jack A; Peerschke, Ellinor I B; Weksler, Babette B; Schechter, Geraldine P

    2002-11-01

    Autoantibodies against factor VIII (FVIII) are rare but can cause life-threatening bleeding requiring costly factor replacement and prolonged immunosuppression. We report 4 consecutively treated patients whose acquired FVIII inhibitors responded rapidly to immunosuppressive regimens that included rituximab, a monoclonal antibody against CD20(+) B cells. Three patients had spontaneously occurring inhibitors. The fourth, a patient with mild hemophilia A, developed both an autoantibody and an alloantibody following recombinant FVIII treatment. Pretreatment FVIII activities ranged from less than 1% to 4% and inhibitor titers from 5 to 60 Bethesda units (BU). One patient with polymyalgia rheumatica who developed the inhibitor while receiving prednisone responded to single agent rituximab. The hemophilia patient had rapid resolution of the autoantibody, whereas the alloantibody persisted for months. Responses continue off treatment from more than 7 to more than 12 months. This report adds to the growing evidence that rituximab has efficacy in immune disorders resulting from autoantibody formation.

  10. Treatment of unicentric Castleman disease with neoadjuvant rituximab.

    PubMed

    Bandera, Bradley; Ainsworth, Craig; Shikle, James; Rupard, Erik; Roach, Michael

    2010-11-01

    Angiofollicular lymph node hyperplasia, known more commonly as Castleman disease, is a rare lymphoproliferative disorder. Castleman disease has two distinct clinical manifestations described as unicentric and multicentric disease. These presentations have distinct treatment algorithms and portend very different prognoses. Standard treatment of unicentric disease is complete surgical resection, which confers a cure rate approaching 100%. To our knowledge, this case report is the first to describe the use of neoadjuvant rituximab in the treatment of unicentric Castleman disease to enable a less morbid surgical resection. Given the vascularity of the tumor, proximity to the pulmonary artery and superior vena cava, and possible intimate association with the lung parenchyma, the tumor was treated preoperatively with rituximab, an anti-CD20 monoclonal antibody, at doses of 375 mg/m² weekly for 4 weeks. Rituximab therapy successfully decreased the diameter of the tumor from 4.79 cm×2.67 cm to 2.8 cm×1.5 cm, as confirmed by CT imaging. Postoperative surgical pathology confirmed the diagnosis of Castleman disease, hyaline vascular type, with negative margins. Notably, the lymph node tissue in the rituximab-treated specimen demonstrated reduced mantle zone thickness, decreased size of follicles, and increased hyalinization of vessels. Rituximab shows promise in neoadjuvant treatment of unresectable or partially resectable unicentric Castleman disease.

  11. [Castleman's disease: Rapid desensitization for hypersensitivity reaction to rituximab].

    PubMed

    Boin, C; Lambert, S; Thomann, P; Aujoulat, O; Kieffer, P

    2016-06-01

    Rapid desensitization allows secure administration of a drug and is indicated when there is no therapeutic alternative. We report a 49-year-old patient who presented with a hypersensitivity reaction following an infusion of rituximab (375mg/m(2)) in the context of a Castleman's syndrome. After a clinical flare (splenomegaly, adenopathies) despite treatment with tocilizumab, anakinra and valganciclovir, the reintroduction of rituximab was decided, according to the rapid desensitization protocol. Four full dose desensitizations were successfully performed allowing immediate clinical improvement (apyrexia, loss of sweating and lymphadenopathy, splenomegaly partial regression) and biological (negativation of HHV8 viral load, and disappearance of neutropenia, anemia and thrombocytopenia). Rapid desensitization is a promising method for the pursuit of rituximab therapy after a hypersensitivity reaction and should be considered in patients with no acceptable therapeutic alternative. Copyright © 2015 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier SAS. All rights reserved.

  12. Rituximab-induced Takotsubo syndrome: more cardiotoxic than it appears?

    PubMed Central

    Ng, Kien Hoe; Dearden, Claire; Gruber, Pascale

    2015-01-01

    Rituximab is used for treatment of multiple haematological cancers. Caution for use is advised in patients with significant cardiorespiratory disease due to known cases of exacerbations of angina and arrhythmias. However, its cardiotoxicity profile is not as well recognised as other monoclonal antibodies such as transtuzumab. We report a case of a 66-year-old man who developed Takotsubo's cardiomyopathy (TC) after an elective infusion of rituximab. This case is exceptional in that rituximab has not been linked to TC, and the vast majority of chemotherapy-linked and immunotherapy-linked TC reactions have occurred during initial infusions. We also discuss the different mechanisms which link TC to immunotherapy and chemotherapy, and propose that there may be a potential for risk-stratifying recipients of this frequently used immunotherapy prior to administering treatment. PMID:25733089

  13. Acute jugular vein thrombosis during rituximab administration: Review of the literature.

    PubMed

    Dada, Reyad; Zekri, Jamal; Ramal, Bilal; Ahmad, Kamel

    2016-02-01

    Rituximab, a chimeric monoclonal antibody is licensed for the treatment of CD20 positive lymphomas. Previous studies have found rituximab, in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone alone in the treatment of diffuse large B-cell lymphoma and many other B-cell lymphomas. Acute hypersensitivity reactions have been reported in patients receiving rituximab infusion and usually manifesting as headache, fever, chills, sweats, skin rash, dyspnea, mild hypotension, and nausea. Acute major venous thrombosis and seizures have not been reported as manifestation of acute hypersensitivity reaction. We report on a 22-year-old woman, who was diagnosed with stage III B CD20 positive B-cell diffuse large B-cell lymphoma. During the first cycle of treatment, she developed grand-mal seizure while receiving rituximab infusion without any other features of acute hypersensitivity reaction. Imaging confirmed new onset jugular vein thrombosis with normal coagulation parameters. These events were managed by anticonvulsants and anticoagulation therapy. The patient completed eight cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone without rituximab and achieved complete remission. No further complications were noted. To our knowledge, this is the first case in the literature describing grand-mal seizures and acute thrombosis while on rituximab treatment. Clinicians should be aware of this rare side effect, as stopping rituximab can prevent recurrence of these complications.

  14. Rituximab activates Syk and AKT in CD20-positive B cell lymphoma cells dependent on cell membrane cholesterol levels.

    PubMed

    Nozaki, Yumi; Mitsumori, Toru; Yamamoto, Takeo; Kawashima, Ichiro; Shobu, Yuki; Hamanaka, Satoshi; Nakajima, Kei; Komatsu, Norio; Kirito, Keita

    2013-08-01

    The introduction of rituximab, an anti-CD20 monoclonal antibody, has dramatically improved the treatment outcomes of patients with B cell lymphoma. Nevertheless, the clinical response to rituximab varies, and a subpopulation of patients does not respond well to this antibody. Although several molecular events have been shown to be involved in the mechanism of action of rituximab, recent studies have demonstrated that intracellular signaling pathways and the direct effects of rituximab on cell membrane components are responsible for the antilymphoma action of this drug. In the present study, we demonstrated that rituximab activated Syk and Akt, molecules with antiapoptotic functions, in several CD20-positive lymphoma cell lines. Notably, rituximab activated Syk and Akt in all the tested primary lymphoma samples from six patients. Our results show that the cholesterol levels in lymphoma cell membranes have a crucial role in the regulation of Syk and Akt. The depletion of cholesterol from the cell membrane completely blocked rituximab-induced Syk and Akt activation. Simvastatin, an inhibitor of cholesterol synthesis, also abrogated rituximab-mediated Syk and Akt activation. Finally, we report that rituximab inhibited the apoptosis induced by chemotherapeutic drugs, which was observed solely in Akt-activated cells. This work demonstrates for the first time that rituximab paradoxically works to suppress apoptosis under certain conditions in a manner that is dependent on the cell membrane cholesterol level. Our observations provide novel insights and suggest that the cell membrane cholesterol level represents a new biomarker for predicting patient response to rituximab. Furthermore, the modulation of lipid rafts could provide a new strategy for enhancing the antilymphoma action of rituximab. Copyright © 2013 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. All rights reserved.

  15. Idiopathic Relapsing Thrombotic Thrombocytopenic Purpura with Persistent ADAMTS13 Inhibitor Activity Treated Sequentially with Plasmapheresis, Rituximab, Cyclophosphamide and Splenectomy.

    PubMed

    Musa, Faisal; Baidas, Said

    2015-01-01

    We here describe a patient with an idiopathic thrombotic thrombocytopenic purpura (TTP) secondary to an ADAMTS13 inhibitor that continued to be dependent on plasmapheresis until the patient was treated with rituximab. TTP manifestations subsided with rituximab treatment in spite of a persistently low ADAMTS13 activity and continued a detectable inhibitor activity until the patient developed an intolerance to rituximab due to an allergic reaction when cyclophosphamide was added; this resulted in a normalization of ADAMTS13 activity and the disappearance of the inhibitor. Later, the patient developed an intolerance to rituximab due to a severe allergic reaction. Soon after stopping rituximab, the ADAMTS13 activity level dipped below 5% in addition to the appearance of the ADAMTS13 inhibitor. The patient had a splenectomy after rituximab and cyclophosphamide treatment; the medication was stopped based on several case reports of a complete remission of TTP after splenectomy. We believe that the reason TTP went into remission in our patient was because of rituximab treatment, in spite of both persistently low ADAMTS13 activity and a detectable inhibitor activity due to reducing the release of von Willebrand factor large multimers from the endothelial cells. We found that ADAMTS13 activity normalized and the inhibitor activity became undetectable when cyclophosphamide was added to rituximab. We suggest adding cyclophosphamide to rituximab for the treatment of patients with persistent ADAMTS13 inhibitors in order to prolong the remission period and lower the rate of relapse.

  16. Refractory cold agglutinin-immunohaemolytic anaemia associated to marginal zone lymphoma responding to rituximab.

    PubMed

    Petit, José; Clavo, Mercedes; de Sevilla, Alberto Fernández; González-Barca, Eva; Domingo-Doménech, Eva; Grañena, Albert

    2003-01-01

    Cold agglutinin immunohaemolytic anaemia (CAIA) responds poorly to standard treatment. We report a case of marginal zone lymphoma complicated by CAIA that responded to rituximab after failing to respond to corticosteroids and chlorambucil.

  17. Crescendo response to rituximab in oral pemphigus vulgaris: a case with 7-year follow-up.

    PubMed

    Greenblatt, D T; Benton, E C; Groves, R W; Setterfield, J F

    2016-07-01

    Pemphigus vulgaris (PV) is an autoimmune blistering disease affecting the skin and mucous membranes. Rituximab, a CD20 chimeric monoclonal antibody, has efficacy in PV management. We report a case of severe oral PV that showed a progressive response to repeated courses of rituximab, culminating in a rapid response within 4 weeks following severe relapse 4 years after initial therapy. It demonstrates the progressively shorter time to achieve partial or complete remission following rituximab infusions, combined with minimal adjuvant therapy over a 7-year follow-up period. © 2016 British Association of Dermatologists.

  18. Rituximab Treatment in a Patient with Active Graves’ Orbitopathy and Psoriasis

    PubMed Central

    Şimşek, Tülay; Yıldırım, Nilgün; Efe, Belgin; Kebapçı, Nur

    2017-01-01

    Management of Graves’ orbitopathy remains an important therapeutic challenge. Current therapeutic modalities are unsatisfactory in about one third of patients. Rituximab is a monoclonal antibody against CD20 antigen that is expressed in mature and immature B cells. Early experience with rituximab suggests that it is a promising alternative therapy for Graves’ orbitopathy. Here we report a case of a 49-year-old woman with Graves’ orbitopathy and psoriasis. The patient received 2 infusions of 1 g rituximab 2 weeks apart. Although there was improvement in inflammatory signs of the disease, proptosis did not change after the treatment. PMID:28182165

  19. Combined Treatment with Antiviral Therapy and Rituximab in Patients with Mixed Cryoglobulinemia: Review of the Literature and Report of a Case Using Direct Antiviral Agents-Based Antihepatitis C Virus Therapy

    PubMed Central

    Urraro, Teresa; Gragnani, Laura; Piluso, Alessia; Fabbrizzi, Alessio; Monti, Monica; Boldrini, Barbara; Ranieri, Jessica; Zignego, Anna Linda

    2015-01-01

    Mixed cryoglobulinemia (MC) is an autoimmune/B-cell lymphoproliferative disorder associated with Hepatitis C Virus (HCV) infection, manifesting as a systemic vasculitis. In the last decade, antiviral treatment (AT) with pegylated interferon (Peg-IFN) plus ribavirin (RBV) was considered the first therapeutic option for HCV-MC. In MC patients ineligible or not responsive to antivirals, the anti-CD20 monoclonal antibody rituximab (RTX) is effective. A combined AT plus RTX was also suggested. Since the introduction of direct acting antivirals (DAAs), few data were published about MC and no data about a combined schedule. Here, we report a complete remission of MC after a sustained virological response following a combined RTX/Peg-IFN+RBV+DAA (boceprevir) treatment and review the literature about the combined RTX/AT. PMID:25815218

  20. Pulmonary intravascular large B-cell lymphoma successfully treated with rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone immunochemotherapy: Report of a patient surviving for over 1 year

    PubMed Central

    Nishii-Ito, Shizuka; Izumi, Hiroki; Touge, Hirokazu; Takeda, Kenichi; Hosoda, Yuzuru; Yamasaki, Akira; Kuwamoto, Satoshi; Shimizu, Eiji; Motokura, Toru

    2016-01-01

    A 73-year-old man with a history of lethargy, fever and dyspnea was admitted to Tottori University Hospital. A computed tomography (CT) scan revealed splenomegaly and diffusely spreading ground-glass opacities (GGOs) in both lungs. A video-assisted thoracoscopic surgery (VATS)-guided lung biopsy revealed intravascular proliferation of large atypical lymphoid cells in the arteries, veins and alveolar walls. The patient was diagnosed with intravascular large B-cell lymphoma (IVLBCL); he received 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) immunochemotherapy and has remained in complete remission for >1 year. Although IVLBCL is a rare disease, it should be considered in the differential diagnosis of pulmonary diffuse lesions that present with GGOs on CT scans. PMID:28105347

  1. Pulmonary intravascular large B-cell lymphoma successfully treated with rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone immunochemotherapy: Report of a patient surviving for over 1 year.

    PubMed

    Nishii-Ito, Shizuka; Izumi, Hiroki; Touge, Hirokazu; Takeda, Kenichi; Hosoda, Yuzuru; Yamasaki, Akira; Kuwamoto, Satoshi; Shimizu, Eiji; Motokura, Toru

    2016-12-01

    A 73-year-old man with a history of lethargy, fever and dyspnea was admitted to Tottori University Hospital. A computed tomography (CT) scan revealed splenomegaly and diffusely spreading ground-glass opacities (GGOs) in both lungs. A video-assisted thoracoscopic surgery (VATS)-guided lung biopsy revealed intravascular proliferation of large atypical lymphoid cells in the arteries, veins and alveolar walls. The patient was diagnosed with intravascular large B-cell lymphoma (IVLBCL); he received 6 cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) immunochemotherapy and has remained in complete remission for >1 year. Although IVLBCL is a rare disease, it should be considered in the differential diagnosis of pulmonary diffuse lesions that present with GGOs on CT scans.

  2. Cholesterol depletion inhibits src family kinase-dependent calcium mobilization and apoptosis induced by rituximab crosslinking

    PubMed Central

    Unruh, Tammy L; Li, Haidong; Mutch, Cathlin M; Shariat, Neda; Grigoriou, Lana; Sanyal, Ratna; Brown, Christopher B; Deans, Julie P

    2005-01-01

    The monoclonal antibody (mAb) rituximab produces objective clinical responses in patients with B-cell non-Hodgkin's lymphoma and antibody-based autoimmune diseases. Mechanisms mediating B-cell depletion by rituximab are not completely understood and may include direct effects of signalling via the target antigen CD20. Like most but not all CD20 mAbs, rituximab induces a sharp change in the solubility of the CD20 protein in the non-ionic detergent Triton-X-100, reflecting a dramatic increase in the innate affinity of CD20 for membrane raft signalling domains. Apoptosis induced by rituximab hypercrosslinking has been shown to require src family kinases (SFK), which are enriched in rafts. In this report we provide experimental evidence that SFK-dependent apoptotic signals induced by rituximab are raft dependent. Cholesterol depletion prevented the association of hypercrosslinked CD20 with detergent-insoluble rafts, and attenuated both calcium mobilization and apoptosis induced with rituximab. CD20 cocapped with the raft-associated transmembrane adaptor LAB/NTAL after hypercrosslinking with CD20 mAbs, regardless of their ability to induce a change in the affinity of CD20 for rafts. Taken together, the data demonstrate that CD20 hypercrosslinking via rituximab activates SFKs and downstream signalling events by clustering membrane rafts in which antibody-bound CD20 is localized in a high-affinity configuration. PMID:16162271

  3. Rituximab for Treatment of Membranoproliferative Glomerulonephritis and C3 Glomerulopathies

    PubMed Central

    2017-01-01

    Membranoproliferative glomerulonephritis (MPGN) is a histological pattern of injury resulting from predominantly subendothelial and mesangial deposition of immunoglobulins or complement factors with subsequent inflammation and proliferation particularly of the glomerular basement membrane. Recent classification of MPGN is based on pathogenesis dividing MPGN into immunoglobulin-associated MPGN and complement-mediated C3 glomerulonephritis (C3GN) and dense deposit disease (DDD). Current guidelines suggest treatment with steroids, cytotoxic agents with or without plasmapheresis only for subjects with progressive disease, that is, nephrotic range proteinuria and decline of renal function. Rituximab, a chimeric B-cell depleting anti-CD20 antibody, has emerged in the last decade as a treatment option for patients with primary glomerular diseases such as minimal change disease, focal-segmental glomerulosclerosis, or idiopathic membranous nephropathy. However, data on the use of rituximab in MPGN, C3GN, and DDD are limited to case reports and retrospective case series. Patients with immunoglobulin-associated and idiopathic MPGN who were treated with rituximab showed partial and complete responses in the majorities of cases. However, rituximab was not effective in few cases of C3GN and DDD. Despite promising results in immunoglobulin-associated and idiopathic MPGN, current evidence on this treatment remains weak, and controlled and prospective data are urgently needed. PMID:28573137

  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

    2014-05-07

    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.

  5. A Case of Rituximab Use as an Induction and Maintenance of Remission in ANCA-Associated Vasculitis

    PubMed Central

    Hafiz, Shahd; Albeity, Abdurahman; Almoallim, Hani

    2016-01-01

    Antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV) is a multisystem autoimmune disease affecting mainly microscopic blood vessels due to circulating autoantibodies against neutrophil cytoplasmic antigens. We report a case of a 57-year-old female patient presenting with hemoptysis, sinusitis, and conjunctivitis. Based on lung biopsy, the diagnosis of antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV) was established. She was put on rituximab as induction and maintenance therapy. She responded initially to rituximab as induction therapy but failed to respond in the maintenance course of the drug. Rituximab was stopped and mycophenolate mofetil was administered. She responded as laboratory c-ANCA titers turned negative and symptoms subsided. There are no randomized clinical trials addressing rituximab effect in induction and remission at the same time. This case report doubts the efficacy of the use of rituximab therapy for both induction and maintenance of remission at the same time, waiting for the results of the ongoing trials. PMID:27006851

  6. Rituximab-Associated Progressive Multifocal Leukoencephalopathy in Rheumatoid Arthritis

    PubMed Central

    Clifford, David B.; Ances, Beau; Costello, Craig; Rosen-Schmidt, Shari; Andersson, Magnus; Parks, Deborah; Perry, Arie; Yerra, Raju; Schmidt, Robert; Alvarez, Enrique; Tyler, Kenneth L.

    2012-01-01

    Objective To describe the development of progressive multifocal leukoencephalopathy (PML) in patients with rheumatoid arthritis (RA) treated with rituximab. Design Case study. Setting Clinical care for patients with rheumatologic diseases. Most were referred to academic centers for care after diagnosis (Washington University, St Louis, Missouri; Karolinska Insitute, Stockholm, Sweden; and Royal Melbourne Hospital, Melbourne, Australia) while one was cared for in a neurology practice in Dallas, Texas, with consultation by an academic neurovirologist from the University of Colorado in Denver. Patients Four patients developing PML in the setting of rituximab therapy for RA. Intervention Rituximab therapy. Main Outcome Measures Clinical and pathological observations. Results Four patients from an estimated population of 129 000 exposed to rituximab therapy for RA are reported in whom PML developed after administration of this drug. All were women older than 50 years, commonly with Sjögren syndrome and a history of treatment for joint disease ranging from 3 to 14 years. One case had no prior biologic and minimal immunosuppressive therapy. Progressive multifocal leukoencephalopathy presented as a progressive neurological disorder, with diagnosis confirmed by detection of JC virus DNA in the cerebrospinal fluid or brain biopsy specimen. Two patients died in less than 1 year from PML diagnosis, while 2 remain alive after treatment withdrawal. Magnetic resonance scans and tissue evaluation confirmed the frequent development of inflammatory PML during the course of the disease. Conclusion These cases suggest an increased risk, about 1 case per 25 000 individuals, of PML in patients with RA being treated with rituximab. Inflammatory PML may occur in this setting even while CD20 counts remain low. PMID:21555606

  7. An evaluation of the potential for drug-drug interactions between bendamustine and rituximab in indolent non-Hodgkin lymphoma and mantle cell lymphoma.

    PubMed

    Darwish, Mona; Burke, John M; Hellriegel, Edward; Robertson, Philmore; Phillips, Luann; Ludwig, Elizabeth; Munteanu, Mihaela C; Bond, Mary

    2014-06-01

    Bendamustine plus rituximab has been reported to be effective in treating lymphoid malignancies. This analysis investigated the potential for drug-drug interactions between the drugs in patients with indolent non-Hodgkin lymphoma or mantle cell lymphoma. Data were derived from a bendamustine-rituximab combination therapy study, a bendamustine monotherapy study, and published literature on rituximab monotherapy and combination therapy. Analysis of the potential for rituximab to affect bendamustine systemic exposure included comparing bendamustine concentration-time profile following monotherapy to that following combination therapy and comparing model-predicted Bayesian bendamustine clearance in the presence and absence of rituximab. Analysis of the potential for bendamustine to affect rituximab systemic exposure included plotting observed minimum, median, and maximum serum rituximab concentrations at the end of rituximab infusion (EOI) and 24 h and 7 days post-infusion in patients receiving combination therapy versus concentrations reported in literature following rituximab monotherapy. The established population pharmacokinetic model following bendamustine monotherapy was evaluated to determine its applicability to combination therapy for the purpose of confirming lack of pharmacokinetic interaction. The model adequately described the bendamustine concentration-time profile following monotherapy and combination therapy in adults. There was no statistically significant difference in estimated bendamustine clearance either alone or in combination. Also, rituximab concentrations from EOI to 24 h and 7 days demonstrated a pattern of decline similar to that seen in rituximab studies without bendamustine, suggesting that bendamustine does not affect the rituximab clearance rate. Neither bendamustine nor rituximab appears to affect systemic exposure of the other drug when coadministered.

  8. 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.

  9. A case of essential mixed cryoglobulinemia and associated acquired von-Willebrand disease treated with rituximab.

    PubMed

    Pasa, Semir; Altintas, Abdullah; Cil, Timucin; Danis, Ramazan; Ayyildiz, Orhan; Muftuoglu, Ekrem

    2009-02-01

    Current treatment options of essential mixed cryoglobulinemia (EMC); include immunosuppressive approaches, such as corticosteroids, cyclophosphamide, plasma exchange, other cytotoxic drugs in moderate to severe manifestations. Some controlled studies have been carried out to assess the efficacy of anti-CD20 monoclonal antibody, rituximab in patients with hepatitis C (HCV) related cryoglobulinemia (CG) and in patients with autoimmune disorders. Recent trials and some case reports demonstrate a beneficial role for rituximab in HCV related mixed CG. Although, the published evidence for treatment of EMC with rituximab is restricted to case reports, which have shown positive results. Several diseases include lymphoproliferative and myeloproliferative disorders, solid tumors, immunological disorders, cardiovascular disorders and some drugs associated with acquired von Willebrand disease (avWD). CG, which is a kind of immune complex disease, may be related with development of autoantibodies to various autoantigens. In this present case report, we showed the efficacy of rituximab in a 21-year-old female patient, suffered from neuropathy and arthralgia related with EMC, and developed avWD, presented with mucosal bleeding associated with CG. von Willebrand factor activity of our patient also increased with controlling the underlying disease, EMC by rituximab. This case demonstrate that rituximab may be an effective treatment option in EMC and avWD mainly related to CG.

  10. Induction treatment of previously undiagnosed ANCA-associated vasculitis in a renal transplant patient with Rituximab

    PubMed Central

    Graham-Brown, M. P. M.; Aljayyousi, R.; Baines, R. J.; Burton, J. O.; Brunskill, N. J.; Furness, P.; Topham, P.

    2016-01-01

    We report the case of a 40-year-old female transplant patient with undiagnosed ANCA-associated vasculitis (AAV) and renal allograft dysfunction who achieved disease remission with restoration of transplant function following induction therapy with rituximab. There are currently no trial data looking at the use of rituximab for induction of remission of renal transplant patients with AAV. Although recurrence of AAV following renal transplantation is rare, such patients have invariably had multiple previous exposures to induction and maintenance immunosuppressive regimens, often limiting treatment options post-transplantation. In this case, rituximab was well tolerated with no side effects, and was successful in salvaging transplant function. Optimal treatment regimens for relapsed AAV in the transplant population are not known, and clinical trials are needed to evaluate the efficacy and safety of rituximab at inducing and maintaining disease remission in relapsed AAV following transplantation. PMID:27699052

  11. Acute neurological worsening after Rituximab treatment in patients with anti-MAG neuropathy.

    PubMed

    Sala, Emilie; Robert-Varvat, Florence; Paul, Stéphane; Camdessanché, Jean-Philippe; Antoine, Jean-Christophe

    2014-10-15

    Patients with peripheral neuropathy and anti-MAG monoclonal IgM may respond to Rituximab, a humanized monoclonal anti-CD20 antibody. We report on three patients with peripheral neuropathy and anti-MAG monoclonal IgM who deteriorated under Rituximab and reviewed seven previously published cases. Worsening was acute and severe, and occurred during the treatment period. All the patients improved after deterioration but at final evaluation only one was improved comparatively to baseline, five were worsened and four were stabilized. Deterioration was not clearly associated with an increase of the anti-MAG antibody titer. Two patients received Rituximab prior or after the course which induced worsening without adverse reaction. Although rare, acute worsening of the neuropathy can occur after Rituximab. The deterioration is however reversible within some weeks to several months. Copyright © 2014 Elsevier B.V. All rights reserved.

  12. Rituximab-Associated Inflammatory Progressive Multifocal Leukoencephalopathy

    PubMed Central

    Schofield, Christina; Harris, Penelope

    2016-01-01

    Progressive multifocal leukoencephalopathy (PML) is a rare disease of the immunosuppression that results from neurotropic invasion of the JC virus which leads to demyelination of oligodendrocytes. Immune reconstitution inflammatory syndrome (IRIS), on the other hand, is a condition of inflammation that develops as the immune system reconstitutes. This case report describes a case of a 35-year-old HIV-negative male who presented with three weeks of right lower extremity paresthesias as well as right upper extremity apraxia. He was diagnosed with PML complicated by IRIS secondary to Rituximab, which he had completed four months prior to presentation. Despite the condition's poor prognosis, the patient recovered with only minor deficits. PMID:27965904

  13. Cost effectiveness of rituximab for non-Hodgkin's lymphoma: a systematic review.

    PubMed

    Auweiler, Philipp W P; Müller, Dirk; Stock, Stephanie; Gerber, Andreas

    2012-07-01

    The monoclonal antibody rituximab has shown clinical effectiveness in combination with chemotherapy for the treatment of non-Hodgkin's lymphoma (NHL) in several randomized controlled studies. Rituximab maintenance therapy is associated with significant improvement in progression-free and overall survival in patients with NHL. However, treatment with rituximab causes considerable costs for healthcare systems. This article provides an overview of economic evaluations of rituximab and appraises their methodological quality. A systematic literature search of cost-effectiveness studies on rituximab was carried out in nine electronic databases: MEDLINE, EMBASE, Cochrane Database of Systematic Reviews (CDSR), the German Agency of Health Technology Assessment (DAHTA) database, German Institute for Quality Improvement (DIQ)-Literatur, DIQ-Projekte, Database of Abstracts of Reviews of Effects (DARE), Health Technology Assessments (HTA) database and Sozialmedizin (SOMED) [languages: English, German, Dutch, French, Spanish and Italian; publication period: 1998 to 2010]. Based on pre-specified inclusion criteria, cost-effectiveness studies were identified that compared standard chemotherapy with standard chemotherapy plus rituximab in patients with a subtype of NHL. The methodological quality of the studies was assessed using a quality checklist. Fourteen economic evaluations from seven different countries were included in the review. All economic evaluations reported incremental cost-effectiveness ratios (ICERs) for the add-on therapy with rituximab that were below the country-specific thresholds. The studies differed significantly in their characteristics and methodological rigour. Most studies lacked transparency regarding identification and justification of data. In several studies, the rationale for the model structure was not described appropriately. Adding rituximab to standard chemotherapy is considered a cost-effective treatment option for NHL. However, the results of

  14. [Cost per responder associated with romiplostim and rituximab treatment for adult primary immune thrombocytopenia in France].

    PubMed

    Chiche, L; Perrin, A; Stern, L; Kutikova, L; Cohen-Nizard, S; Lefrère, F

    2014-05-01

    This analysis compared the response rates and cost per responder associated with romiplostim and rituximab in adult immune thrombocytopenia from the French National Health System payer perspective. A decision analytic model was developed to estimate the cost per patient and per responder of treating adult immune thrombocytopenia patients with romiplostim versus rituximab over 6 months. A systematic literature review identified phase 3 randomized controlled trials. Published response rates were extracted (response definition: ≥50×10(9) platelets/liter). Resource utilization was based on French and international treatment guidelines, and clinical expert opinion. Unit costs were derived from literature and French reimbursement lists, and included the costs of routine physician visits, treatment administration, and emergency care. Non-responders incurred bleeding-related event costs. The literature review identified a phase 3 randomized controlled trial for romiplostim with a response rate of 83%. Due to a lack of phase 3 randomized controlled trials for rituximab, a systematic review of studies was selected as the best source, reporting a response rate of 62.5%. Romiplostim and rituximab were associated with similar treatment costs, with an estimated cost per patient for romiplostim of €17,456 and €17,068 for rituximab. Rituximab resulted in a 30% higher cost per responder (€27,308 for rituximab versus €21,031 for romiplostim). Romiplostim use reduced drug administration, intravenous immunoglobulin, and bleeding-related hospitalization costs compared to rituximab. Due to its high efficacy leading to lower bleeding-related costs, romiplostim represents an efficient use of resources for adult immune thrombocytopenia patients in the French healthcare system. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

  15. Rituximab in anti-GBM disease: A retrospective study of 8 patients.

    PubMed

    Touzot, Maxime; Poisson, Johanne; Faguer, Stanislas; Ribes, David; Cohen, Pascal; Geffray, Loic; Anguel, Nadia; François, Helene; Karras, Alexandre; Cacoub, Patrice; Durrbach, Antoine; Saadoun, David

    2015-06-01

    Anti-glomerular basement membrane (GBM) disease is a rare autoantibody-mediated disorder presenting as rapidly progressive glomerulonephritis, and often with pulmonary hemorrhage. Antibody removal with plasmapheresis and immunosuppressive drugs are the cornerstones of the treatment. Data regarding the use of specific B-cell depleting therapy such as rituximab are lacking. We conducted a retrospective observational study of 8 patients with severe and/or refractory GBM disease that received rituximab therapy. Eight patients (2 men, 6 women) with a mean age of 26 ± 13.1 years old were included. Seven had severe renal involvement [median creatinin level was 282 μmol/l, range (65-423)] requiring high immunosuppressive or plasmapheresis dependent, and two had relapse of pulmonary hemorrhage including one with renal failure. Patients received an initial immunosuppressive treatment including steroid and cyclosphosphamide (n = 8) and plasmapheresis (n = 5). Except one late relapse, rituximab therapy was started within two months after diagnosis. All patients except one received 4 weekly dose of rituximab (375 mg(2)). Anti-GBM antibodies were still present in 6/8 patients, at rituximab initiation. Complete remission was observed in 7 out of 8 patients, mostly 3 months after rituximab therapy. After a mean follow-up of 25.6 months (range 4-93), patient and renal survival were 100% and 75% respectively, but rituximab use did not improve GFR. Anti-GBM antibodies remained negative for all patients during follow-up. Only one patient developed a severe bacterial infection but no opportunistic or viral infections were reported. Rituximab may represent an additional and/or alternative therapy in the induction treatment of anti-GBM disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. 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

  17. Rituximab in early systemic sclerosis

    PubMed Central

    Boonstra, Maaike; Meijs, Jessica; Dorjée, Annemarie L; Marsan, Nina Ajmone; Schouffoer, Anne; Ninaber, Maarten K; Quint, Koen D; Bonte-Mineur, Femke; Huizinga, Tom W J; Scherer, Hans U; de Vries-Bouwstra, Jeska K

    2017-01-01

    Objectives (1) Hypothesis testing of the potency of rituximab (RTX) in preventing fibrotic complications and (2) assessing acceptability and feasibility of RTX in early systemic sclerosis (SSc). Methods A small, 24-month, randomised, double-blind, placebo-controlled, single-centre trial in patients with SSc diagnosed <2 years was conducted. Patients received RTX or placebo infusions at t=0, t=15 days and t=6 months. Patients were clinically evaluated every 3 months, with lung function tests and high-resolution CT every other visit. Skin biopsies were taken at baseline and month 3. Immunophenotyping of peripheral blood mononuclear cells was performed at every visit, except at months 9 and 18. Adverse events, course of skin and pulmonary involvement and B cell populations in skin and peripheral blood were evaluated. Results In total 16, patients (rituximab n=8, placebo n=8) were included. Twelve patients had diffuse cutaneous SSc. Eighty-eight adverse events (RTX n=53, placebo n=35, p=0.22) and 11 serious adverse events (RTX n=7, placebo n=4, p=0.36) occurred. No unexpected RTX-related events were observed. Mean skin score over time did not differ between the groups. Over time, forced vital capacity and extent of lung involvement slightly improved with RTX, but this difference was insignificant. In peripheral blood B cells depletion was demonstrated. Conclusions No unexpected safety issues were observed with RTX in early SSc. Although this small trial could not confirm or reject potential efficacy of RTX in these patients, future placebo-controlled trials are warranted, specifically in the subgroup of patients with pulmonary involvement. Trial registration number EudraCT 2008-07180-16; Results. PMID:28879049

  18. Rituximab in early systemic sclerosis.

    PubMed

    Boonstra, Maaike; Meijs, Jessica; Dorjée, Annemarie L; Marsan, Nina Ajmone; Schouffoer, Anne; Ninaber, Maarten K; Quint, Koen D; Bonte-Mineur, Femke; Huizinga, Tom W J; Scherer, Hans U; de Vries-Bouwstra, Jeska K

    2017-01-01

    (1) Hypothesis testing of the potency of rituximab (RTX) in preventing fibrotic complications and (2) assessing acceptability and feasibility of RTX in early systemic sclerosis (SSc). A small, 24-month, randomised, double-blind, placebo-controlled, single-centre trial in patients with SSc diagnosed <2 years was conducted. Patients received RTX or placebo infusions at t=0, t=15 days and t=6 months. Patients were clinically evaluated every 3 months, with lung function tests and high-resolution CT every other visit. Skin biopsies were taken at baseline and month 3. Immunophenotyping of peripheral blood mononuclear cells was performed at every visit, except at months 9 and 18. Adverse events, course of skin and pulmonary involvement and B cell populations in skin and peripheral blood were evaluated. In total 16, patients (rituximab n=8, placebo n=8) were included. Twelve patients had diffuse cutaneous SSc. Eighty-eight adverse events (RTX n=53, placebo n=35, p=0.22) and 11 serious adverse events (RTX n=7, placebo n=4, p=0.36) occurred. No unexpected RTX-related events were observed. Mean skin score over time did not differ between the groups. Over time, forced vital capacity and extent of lung involvement slightly improved with RTX, but this difference was insignificant. In peripheral blood B cells depletion was demonstrated. No unexpected safety issues were observed with RTX in early SSc. Although this small trial could not confirm or reject potential efficacy of RTX in these patients, future placebo-controlled trials are warranted, specifically in the subgroup of patients with pulmonary involvement. EudraCT 2008-07180-16; Results.

  19. Long-term effect of rituximab in a case with late-onset Rasmussen´s encephalitis with anti-ganglioside IgGQ1b and anti-GAD antibodies positivity. Case Report.

    PubMed

    Timarova, Gabriela; Lisa, Iveta; Kukumberg, Peter

    2016-07-01

    Rasmussen's encephalitis is a rare autoimmune encephalitis usually involving one brain hemisphere, presenting with refractory epileptic seizures, and neurological and cognitive decline. Only 10% of cases start later in adolescence/adulthood. The only effective treatment for refractory seizures in childhood is hemispherectomy. For late-onset cases with mild neurological deficit the hemispherectomy is usually postponed because of its severe consequences. Immunotherapy shows some temporal effect for seizure control and slowing the brain atrophy, mainly in late onset Rasmussen's encephalitis. We report a patient with late onset Rasmussen´s encephalitis with anti-ganglioside IgGQ1b and anti-GAD antibodies positivity, who failed immunotherapy with cytostatics, immunoglobulins and steroids. Anti-ganglioside IgGQ1b antibodies are typically associated with a Miller-Fisher variant of Guillain-Barre syndrome and Bickerstaff's brainstem encephalitis. The association with Rasmussen´s encephalitis was not described before. Patient´s neurological deficit was mild and hemispherectomy was refused. The treatment with rituximab, an anti-CD20+ monoclonal antibody, led to 36-month control of seizures without any signs of progression of neurological deficit and MRI brain atrophy. Although the treatment is associated with long term B-cells depletion, patient doesn´t suffer from any clinically relevant infection. The biological treatment with monoclonal antibodies might be the way to stabilize patients with Rasmussen´s encephalitis, mainly late-onset, to prevent them from harmful and devastating hemispherectomy.

  20. Bone marrow necrosis complicating post-transplant lymphoproliferative disorder: resolution with rituximab.

    PubMed

    Rossi, Davide; Ramponi, Antonio; Franceschetti, Silvia; Stratta, Piero; Gaidano, Gianluca

    2008-05-01

    Bone marrow necrosis is a rare cause of bone marrow failure. Malignancy is the most frequent cause of bone marrow necrosis. Among malignancies, non-Hodgkin lymphoma (NHL) accounts for 10% of cases of bone marrow necrosis. Virtually all reported cases of NHL-associated bone marrow necrosis have developed in immunocompetent hosts. We report on a case of bone marrow necrosis complicating post-transplant lymphoproliferative disorder (PTLD) and resolving after rituximab monotherapy. This case report provides the first evidence of (i) bone marrow necrosis as a complication of PTLD; (ii) rapid resolution of NHL-associated bone marrow necrosis after rituximab treatment.

  1. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease

    PubMed Central

    Brilot, Fabienne; Duffy, Lisa V.; Twilt, Marinka; Waldman, Amy T.; Narula, Sona; Muscal, Eyal; Deiva, Kumaran; Andersen, Erik; Eyre, Michael R.; Eleftheriou, Despina; Brogan, Paul A.; Kneen, Rachel; Alper, Gulay; Anlar, Banu; Wassmer, Evangeline; Heineman, Kirsten; Hemingway, Cheryl; Riney, Catherine J.; Kornberg, Andrew; Tardieu, Marc; Stocco, Amber; Banwell, Brenda; Gorman, Mark P.; Benseler, Susanne M.; Lim, Ming

    2014-01-01

    Objective: To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS. Methods: Multicenter retrospective study. Results: A total of 144 children and adolescents (median age 8 years, range 0.7–17; 103 female) with NMDA receptor (NMDAR) encephalitis (n = 39), opsoclonus myoclonus ataxia syndrome (n = 32), neuromyelitis optica spectrum disorders (n = 20), neuropsychiatric systemic lupus erythematosus (n = 18), and other neuroinflammatory disorders (n = 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05–9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range 0.1–8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0–2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0–2 was greater in patients given rituximab early in their disease course compared to those treated later. Conclusion: While limited by the retrospective nature of this analysis, our data support an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality. Classification of evidence: This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections. PMID:24920861

  2. A comprehensive analysis of treatment outcomes in patients with pemphigus vulgaris treated with rituximab.

    PubMed

    Ahmed, A Razzaque; Shetty, Shawn

    2015-04-01

    Approximately 500 treatment recalcitrant pemphigus vulgaris patients have been treated with rituximab. They were treated according to the lymphoma protocol (N=224) or rheumatoid arthritis protocol (RAP) (N=209) patients. Others were treated with modifications or combinations of the two. The mean duration of follow-up with the lymphoma protocol was 28.9months and 21.9 in the rheumatoid arthritis protocol. The majority of the patients received corticosteroids and immunosuppressive therapy before, during, and after rituximab therapy. A clinical remission on therapy was observed in 90%-95% of patients within less than six weeks. A complete resolution occurred within three to four months. A small percentage of patients were able to stay in clinical remission without the need for additional systemic therapy. The incidence of relapse was at least 50%. The number of patients who required additional rituximab was 60% to 90%. A majority of patients in clinical remission post-rituximab therapy, were still on CS and ISA, albeit at lower doses. Serious adverse events were reported in a mean of five patients (range 2-9), the most important was infection and frequently resulting in septicemia. The mortality rate related to rituximab was a mean of 2 patients (range 1-3). Hence, the preliminary conclusions that can be drawn are that rituximab is an excellent agent to induce early remission. The protocols that were used were not ideal for producing a prolonged and sustained remission without additional therapy. The advantages and specificity of targeting B-cells demonstrate that rituximab is one of the best biological agents, currently available for treating recalcitrant pemphigus. Its further use is encouraged. Future research needs to focus on modifying, improving and possibly adding additional agents, so that prolonged and sustained remissions can be obtained by its use.

  3. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease.

    PubMed

    Dale, Russell C; Brilot, Fabienne; Duffy, Lisa V; Twilt, Marinka; Waldman, Amy T; Narula, Sona; Muscal, Eyal; Deiva, Kumaran; Andersen, Erik; Eyre, Michael R; Eleftheriou, Despina; Brogan, Paul A; Kneen, Rachel; Alper, Gulay; Anlar, Banu; Wassmer, Evangeline; Heineman, Kirsten; Hemingway, Cheryl; Riney, Catherine J; Kornberg, Andrew; Tardieu, Marc; Stocco, Amber; Banwell, Brenda; Gorman, Mark P; Benseler, Susanne M; Lim, Ming

    2014-07-08

    To assess the utility and safety of rituximab in pediatric autoimmune and inflammatory disorders of the CNS. Multicenter retrospective study. A total of 144 children and adolescents (median age 8 years, range 0.7-17; 103 female) with NMDA receptor (NMDAR) encephalitis (n = 39), opsoclonus myoclonus ataxia syndrome (n = 32), neuromyelitis optica spectrum disorders (n = 20), neuropsychiatric systemic lupus erythematosus (n = 18), and other neuroinflammatory disorders (n = 35) were studied. Rituximab was given after a median duration of disease of 0.5 years (range 0.05-9.5 years). Infusion adverse events were recorded in 18/144 (12.5%), including grade 4 (anaphylaxis) in 3. Eleven patients (7.6%) had an infectious adverse event (AE), including 2 with grade 5 (death) and 2 with grade 4 (disabling) infectious AE (median follow-up of 1.65 years [range 0.1-8.5]). No patients developed progressive multifocal leukoencephalopathy. A definite, probable, or possible benefit was reported in 125 of 144 (87%) patients. A total of 17.4% of patients had a modified Rankin Scale (mRS) score of 0-2 at rituximab initiation, compared to 73.9% at outcome. The change in mRS 0-2 was greater in patients given rituximab early in their disease course compared to those treated later. While limited by the retrospective nature of this analysis, our data support an off-label use of rituximab, although the significant risk of infectious complications suggests rituximab should be restricted to disorders with significant morbidity and mortality. This study provides Class IV evidence that in pediatric autoimmune and inflammatory CNS disorders, rituximab improves neurologic outcomes with a 7.6% risk of adverse infections. © 2014 American Academy of Neurology.

  4. Stability of stock and diluted rituximab.

    PubMed

    Zhang, Yang; Vermeulen, Lee C; Kolesar, Jill M

    2013-03-01

    The stability of two rituximab preparations stored in polyvinyl chloride (PVC) bags at 4 °C for up to 14 days was investigated. Two types of test samples were prepared: (1) 10 mL of rituximab solution (10 mg/mL) drawn directly from the original manufacturer's vial and injected into sterile glass vials and (2) 3 mL of rituximab 10 mg/mL mixed with 17 mL of 0.9% sodium chloride injection and injected into sterile PVC bags. Samples were analyzed immediately after preparation and after storage at 4 °C for 3, 7, and 14 days. Rituximab activity at the designated time points was measured using a validated enzyme-linked immunosorbent assay (ELISA) method. Chemical stability was defined as the retention of ≥85% of the drug's initial activity. Physical stability was evaluated through visual inspection for color changes or precipitate formation under normal laboratory lighting. The results of ELISA testing (with spectrophotometric absorbance assessment) indicated that the percentage of initial rituximab activity retained was over 85% for both test preparations under the storage conditions evaluated; no changes in color or turbidity were observed in any of the test samples. These findings suggest that extending the expiration dating of both stock and diluted rituximab solutions beyond the manufacturer-specified limit of 24 hours is feasible. Rituximab 10 mg/mL undiluted in glass vials and 1.5 mg/mL diluted in 0.9% sodium chloride injection in PVC bags are stable at 4 °C for up to 14 days.

  5. 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.

  6. Rituximab: a review of its use in non-Hodgkin's lymphoma and chronic lymphocytic leukaemia.

    PubMed

    Plosker, Greg L; Figgitt, David P

    2003-01-01

    Rituximab is an anti-CD20 monoclonal antibody that has demonstrated efficacy in patients with various lymphoid malignancies, including indolent and aggressive forms of B-cell non-Hodgkin's lymphoma (NHL) and B-cell chronic lymphocytic leukaemia (CLL). While the optimal use of the drug in many clinical settings has yet to be clarified, two pivotal trials have established rituximab as a viable treatment option in patients with relapsed or refractory indolent NHL, and as a standard first-line treatment option when combined with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (the most common type of aggressive NHL). The former was a noncomparative trial in relapsed indolent NHL (follicular and small lymphocytic subtypes) with clinical responses achieved in about half of patients treated with rituximab 375 mg/m(2) intravenously once weekly for 4 weeks, which was similar to some of the most encouraging results reported with traditional chemotherapeutic agents. The latter was a randomised comparison of eight cycles of CHOP plus rituximab 375 mg/m(2) intravenously (one dose per cycle) versus CHOP alone in previously untreated elderly patients (60 to 80 years of age) with diffuse large B-cell lymphoma. In this pivotal trial, 2-year event-free and overall survival were significantly higher with rituximab plus CHOP, and there was no increase in clinically significant adverse effects compared with CHOP alone. Treatment with rituximab is generally well tolerated, particularly in terms of adverse haematological effects and serious or opportunistic infections relative to standard chemotherapy. Infusion-related reactions occur in the majority of patients treated with rituximab; these are usually mild to moderate flu-like symptoms that decrease in frequency with subsequent infusions. In approximately 10% of patients, however, severe infusion-related reactions develop (e.g. bronchospasm

  7. Rituximab: an emerging treatment for recurrent diffuse alveolar hemorrhage in systemic lupus erythematosus.

    PubMed

    Tse, J R; Schwab, K E; McMahon, M; Simon, W

    2015-06-01

    Diffuse alveolar hemorrhage (DAH) is a rare manifestation of systemic lupus erythematosus (SLE) and is associated with high mortality rates. Treatment typically consists of aggressive immunosuppression with pulse-dose steroids, cyclophosphamide, and plasma exchange therapy. Mortality rates remain high despite use of multiple medical therapies. We present a case of recurrent DAH in a 52-year-old female with SLE after a deceased donor renal transplant who was successfully treated with rituximab. Our report highlights the pathophysiologic importance of B-cell-mediated immunosuppression in SLE-associated DAH and suggests that rituximab may represent a viable alternative to cyclophosphamide in the treatment of this disease. We also review eight other reported cases of rituximab use in SLE-associated DAH. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.

  8. Successful rituximab therapy in a lupus patient with diffuse alveolar haemorrhage.

    PubMed

    Pottier, V; Pierrot, M; Subra, J F; Mercat, A; Kouatchet, A; Parrot, A; Augusto, J F

    2011-05-01

    Diffuse alveolar haemorrhage (DAH) is a rare but life-threatening complication of systemic lupus erythematosus (SLE). Specific therapy is based on a heavy immunosuppressive treatment that usually associates corticosteroid and cyclophosphamide boluses and plasma exchange. Despite this treatment, an early mortality rate of 20-50% is reported in the literature. Immunosuppression-related complications are responsible for further mortality and morbidity. Rituximab, a specific anti-CD20 antigen B-cell antibody, has been used with success for the treatment of several refractory autoimmune disorders, but rarely for SLE-induced DAH. We report here the first case of SLE-induced DAH treated successfully with rituximab without cyclophosphamide administration in a patient intolerant to cyclophosphamide. We review the two other cases of SLE-induced DAH managed with rituximab as a part of the immunosuppressive regimen.

  9. Severe Primary Raynaud's Disease Treated with Rituximab

    PubMed Central

    Almoallim, Hani

    2016-01-01

    Raynaud's phenomenon refers to reversible spasms of the peripheral arterioles that can be primary Raynaud's phenomenon (PRP) or secondary Raynaud's phenomenon (SRP) to underlying connective tissue disease, both of which are characterized by a triphasic color response triggered by cold exposure or stress. PRP is typically a benign disease, whereas SRP may progress into digital ulcers and/or gangrene. Here, we report a case of a 55-year-old female diagnosed with PRP 7 years ago. Treatment with first-line agents, including calcium channel blocker, aspirin, and phosphodiesterase inhibitor, did not control her symptoms, which progressed to digital ulceration and gangrene. There were no symptoms of underlying autoimmune disease or malignancy, and autoimmune, serology, and immunology test results were normal; a biopsy of her left little finger was negative for vasculitis. Development to critical digital ischemia necessitated treatment with intravenous iloprost and heparin infusion followed by angioplasty, which led to a partial improvement. Due to persistent symptoms, rituximab therapy was initiated and two cycles induced a complete resolution of symptoms. PMID:27651971

  10. Severe Primary Raynaud's Disease Treated with Rituximab.

    PubMed

    Shabrawishi, Mohammed; Albeity, Abdurahman; Almoallim, Hani

    2016-01-01

    Raynaud's phenomenon refers to reversible spasms of the peripheral arterioles that can be primary Raynaud's phenomenon (PRP) or secondary Raynaud's phenomenon (SRP) to underlying connective tissue disease, both of which are characterized by a triphasic color response triggered by cold exposure or stress. PRP is typically a benign disease, whereas SRP may progress into digital ulcers and/or gangrene. Here, we report a case of a 55-year-old female diagnosed with PRP 7 years ago. Treatment with first-line agents, including calcium channel blocker, aspirin, and phosphodiesterase inhibitor, did not control her symptoms, which progressed to digital ulceration and gangrene. There were no symptoms of underlying autoimmune disease or malignancy, and autoimmune, serology, and immunology test results were normal; a biopsy of her left little finger was negative for vasculitis. Development to critical digital ischemia necessitated treatment with intravenous iloprost and heparin infusion followed by angioplasty, which led to a partial improvement. Due to persistent symptoms, rituximab therapy was initiated and two cycles induced a complete resolution of symptoms.

  11. Rituximab in high-grade lymphoma.

    PubMed

    Zwick, Carsten; Murawski, Niels; Pfreundschuh, Michael

    2010-04-01

    In 1997, the approval of the anti-CD20 antibody rituximab heralded a new era of combined immunochemotherapy for the treatment of malignant lymphoma. Until then, a combination of cyclophosphamide, vincristine, doxorubicin, and prednisone (CHOP) had been the standard of treatment for aggressive B-cell lymphoma for more than 25 years. The addition of rituximab led to an impressive improvement of response rates and survival outcomes in patients with follicular and diffuse large B-cell lymphoma (DLBCL) that has been confirmed in several randomized trials. Remaining challenges in the rituximab era are the identification of the optimal chemotherapy partner with respect to synergistic effects, as well as to the lack of interference with its effector mechanisms. Finally, the question of the optimal dosage and schedule of rituximab has to be addressed in well-designed randomized trials. The outcome of patients relapsing after a rituximab-containing induction regimen is dismal even with high-dose therapy and autologous stem cell transplantation (ASCT). For these patients new modalities of second-line therapy are urgently warranted.

  12. Lenalidomide and rituximab in Waldenstrom's macroglobulinemia.

    PubMed

    Treon, Steven P; Soumerai, Jacob D; Branagan, Andrew R; Hunter, Zachary R; Patterson, Christopher J; Ioakimidis, Leukothea; Chu, Luis; Musto, Paul; Baron, Ari D; Nunnink, Johannes C; Kash, Joseph J; Terjanian, Terenig O; Hyman, Paul M; Nawfel, Elena L; Sharon, David J; Munshi, Nikhil C; Anderson, Kenneth C

    2009-01-01

    Thalidomide and its more potent immunomodulatory derivative lenalidomide enhance rituximab-mediated antibody-dependent cell-mediated cytotoxicity. We therefore evaluated lenalidomide and rituximab in symptomatic Waldenstrom's macroglobulinemia (WM) patients naive to either agent. Intended therapy consisted of 48 weeks of lenalidomide (25 mg/d for 3 weeks and then 1 week off) along with rituximab (375 mg/m(2)/wk) dosed on weeks 2 to 5 and 13 to 16. Sixteen patients were enrolled, 12 of whom were previously untreated. Unexpectedly, we observed an acute decrease in hematocrit in 13 of 16 patients (median hematocrit decrease, 4.8%), which was attributable to lenalidomide patients and which led to cessation of further enrollment on this study. Lenalidomide-related anemia was observed even at doses as low as 5 mg/d and occurred in the absence of hemolysis or other cytopenias. The overall response and major response (<50% decrease in serum IgM) rates were 50% and 25%, respectively, on an intent-to-treat basis. With a median follow-up of 31.3 months, 4 of 8 responding patients have progressed with a median time to progression of 18.9 months. Lenalidomide produces unexpected but clinically significant acute anemia in patients with WM. In comparison with our previous study with thalidomide and rituximab in an analogous patient population, the responses achieved in WM patients with lenalidomide and rituximab appear less favorable.

  13. Desensitization to rituximab in a multidisciplinary setting.

    PubMed

    Amorós-Reboredo, Patrícia; Sánchez-López, Jaime; Bastida-Fernández, Carla; do Pazo-Oubiña, Fernando; Borràs-Maixenchs, Núria; Giné, Eva; Valero, Antonio; Creus-Baró, Natàlia

    2015-10-01

    The need to offer first-line therapy to the increasing number of patients who have suffered an hypersensitivity reaction has stimulated the use of rapid desensitization protocols. To present our experience working as a multidisciplinary team using a rituximab rapid desensitization scheme. Patient demographics, allergic reaction, skin tests to rituximab, number of desensitizations, reactions during the desensitization protocol and actions taken, number of administered and completed cycles, were retrospectively collected in patients who received at least one desensitization to rituximab. Number of desensitizations successfully managed. Between 2012 and June 2013 five patients received a total of 19 desensitizations to rituximab using a 12 step rapid desensitization protocol. All patients received the scheduled chemotherapeutic cycles as inpatients, with no delay in administration dates. Three patients presented a hypersensitivity reaction during the first desensitization and in one patient the event occurred again during the second treatment cycle. All reactions occurred in the last step, when the infusion rate reached the maximum speed. The developed protocol for rapid desensitization was successful in five patients receiving rituximab. Patients could receive the full intended dose.

  14. Favorable outcome of Epstein-Barr virus-associated B-cell lymphoproliferative disorder complicated by immunoglobulin G4-related disease treated with rituximab-based therapy: a case report.

    PubMed

    Ueda, Koki; Ikeda, Kazuhiko; Ogawa, Kazuei; Sukegawa, Masumi; Sano, Takahiro; Kimura, Satoshi; Suzuki, Osamu; Hashimoto, Yuko; Takeishi, Yasuchika

    2016-08-24

    After acute infection of Epstein-Barr virus, Epstein-Barr virus-infected B cells survive but usually do not show clonal proliferation. However, Epstein-Barr virus-infected B cells occasionally acquire a proliferative capacity that provokes clonal lymphoproliferative disorders. We herein present a case with Epstein-Barr virus-infected CD30+ B cell and immunoglobulin G4+ plasmacytoid cell proliferation in the lymph nodes, suggesting a pathological and clinical interaction between Epstein-Barr virus-associated B-cell lymphoproliferative disorders and immunoglobulin G4-related disease. Immunoglobulin G4-related disease has been recognized as a benign disease with proliferation of IgG4-related disease+ plasmacytoid cells. Several studies have recently reported the coexistence of immunoglobulin G4-related disease+ plasmacytoid cells with Epstein-Barr virus-infected B cells in lymph nodes in some immunoglobulin G4-related disease cases. However, the pathogenic role of the clonal proliferation of Epstein-Barr virus-infected B cells in immunoglobulin G4-related disease, as well as the treatments for patients with both Epstein-Barr virus-infected B cells and immunoglobulin G4-related disease, have never been discussed. A 50-year-old Japanese man was referred to us for persistent fatigue and lymphadenopathy. His blood examination showed elevated IgG4, and detected high levels of Epstein-Barr virus DNA. A lymph node biopsy revealed IgG4+ plasmacytoid cells and infiltration of large lymphoid cells, which were positive for CD20, CD30, Epstein-Barr virus-related late membrane protein 1, and Epstein-Barr virus-encoded RNA, and were negative for IgG4. Based on the diagnosis of both Epstein-Barr virus-associated B-cell lymphoproliferative disorder and IgG4-related disease, the patient received eight cycles of rituximab combined with cyclophosphamide and prednisolone, which resulted in the complete disappearance of lymphadenopathy. Moreover, his serum IgG4 level was significantly

  15. 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

  16. Successful Rituximab Therapy in Steroid-Resistant, Cryptogenic Organizing Pneumonia: A Case Series.

    PubMed

    Shitenberg, Dorit; Fruchter, Oren; Fridel, Ludmila; Kramer, Mordechai R

    2015-01-01

    Cryptogenic organizing pneumonia (COP) is an interstitial lung disease that is usually responsive to corticosteroid treatment. The treatment of COP has not been studied in randomized controlled trials; thus, treatment decisions are based on practice guidelines. We herein present, for the first time, 4 cases of patients with biopsy-proven COP who did not respond to corticosteroids but benefited from rituximab therapy. This report consists of a retrospective case series of patients who experienced steroid-resistant, biopsy-proven COP. Patients included in this case series suffered from acute or chronic COP and did not respond to corticosteroid treatment for a few weeks to months but later responded to rituximab. In a series of 4 patients, 1 patient had a complete radiological and clinical response after rituximab therapy, and the steroids could be gradually tapered. Three patients had a chronic course but had been able to lower steroid dosage or even discontinue the drug after being treated with rituximab. Since 40% of the patients with COP do not respond to or stay dependent on steroids, we think that even the ability to lower the steroid dosage by using rituximab as a steroid-sparing agent with a good safety profile is worth the effort. However, further studies are warranted. © 2015 S. Karger AG, Basel.

  17. Rituximab in lymphocyte-predominant Hodgkin disease.

    PubMed

    Azim, Hatem A; Pruneri, Giancarlo; Cocorocchio, Emilia; Cinieri, Saverio; Raviele, Paola R; Bassi, Simona; Preda, Lorenzo; Martinelli, Giovanni; Peccatori, Fedro A

    2009-01-01

    Lymphocyte-predominant Hodgkin disease (LPHD) differs in biology and clinical behaviour from classic Hodgkin disease. Almost 100% of LPHD neoplastic cells express CD20 and thus rituximab could be effective; yet limited data are available. We performed a retrospective analysis on patients with LPHD who were treated with rituximab at our institution to determine the magnitude of benefit offered by this drug. Seven patients were identified; 4 received the drug as single agent while the rest received it in combination with chemotherapy. All except 2 received the drug in the salvage setting. Response rate was 100% with 6 of 7 patients achieving complete remission. At a median follow-up of 2 years, 4 patients are still disease free while the rest relapsed at a median time of 27 months. Rituximab is effective in LPHD and should be considered; however, the optimal schedule remains to be determined.

  18. Remission Time after Rituximab Treatment for Autoimmune Bullous Disease: A Proposed Update Definition.

    PubMed

    Iranzo, Pilar; Pigem, Ramon; Giavedoni, Priscila; Alsina-Gibert, Mercè

    2015-01-01

    A therapeutic endpoint is a very important tool to evaluate response in clinical trials. In 2005, a consensus statement identified two late endpoints of disease activity in pemphigus: complete remission off therapy and complete remission on therapy, both definitions applying to patients without lesions for at least 2 months. The same period of time was considered for partial remission off/on therapy. These definitions were later applied to bullous pemphigoid and are considered in most studies on autoimmune bullous disease. These endpoints were established for different adjuvant agents, but at that moment, rituximab was not considered. Rituximab is known for the long duration of its effect, and in most studies relapses have been reported later than 6 months after treatment. In our opinion, time to remission after rituximab treatment should be redefined.

  19. Successful treatment of refractory adult onset Still's disease with rituximab.

    PubMed

    Belfeki, N; Smiti Khanfir, M; Said, F; Hamzaoui, A; Ben Salem, T; Ben Ghorbel, I; Lamloum, M; Houman, M H

    2016-12-16

    Adult-onset Still's disease (AOSD) is an uncommon inflammatory condition of unknown origin. In chronic disease, joint involvement is often predominant and erosions are noted in one third of patients. Therapeutic strategies derive from observational data. Corticosteroids are usually the first-line treatment. With inadequate response to corticosteroids, methotrexate appears the best choice to control disease activity and allow for tapering of steroid use. For refractory disease, biological therapy seems the most promising. We report here the case of a 38-year-old female patient with AOSD refractory to cytotoxic agents, treated by rituximab infusion therapy with favorable outcome.

  20. Rituximab as potential therapy for paraneoplastic cerebellar degeneration in pediatric Hodgkin disease.

    PubMed

    Yeo, Kee Kiat; Walter, Andrew W; Miller, Robin E; Dalmau, Josep

    2012-06-01

    Paraneoplastic cerebellar degeneration (PCD) is a rare neurological syndrome associated with lung cancer, breast adenocarcinoma,ovarian adenocarcinoma, and Hodgkin disease. It is rarely seen in pediatrics. We report a case of a 10-year-old boy with a 2-year prodrome that led to a diagnosis of PCD in association with stage IV Hodgkin disease. He received radiation and chemotherapy for his Hodgkin disease with resolution of his lymphoma. Based on promising data in adults on the efficacy of rituximab over other immuno suppressive agents in paraneoplastic disorders, he was treated with rituximab with marked improvement of the cerebellar syndrome.

  1. Effective treatment of refractory pulmonary hemorrhage with monoclonal anti-CD20 antibody (rituximab).

    PubMed

    Pinto, Luis Fernando; Candia, Liliana; Garcia, Patricia; Marín, Juan Ignacio; Pachón, Ines; Espinoza, Luis R; Marquez, Javier

    2009-01-01

    We report a 19-year-old female with systemic lupus erythematosus and lupus nephritis who developed pulmonary hemorrhage (PH) refractory to conventional immunosuppressive treatment. She was initially treated with intravenous methylprednisolone and cyclophosphamide pulses. She required mechanical ventilation due to a lack of responsiveness and her disease was considered refractory to conventional treatment. Rituximab was administered and this was followed by clinical improvement in both PH and nephritis. Rituximab may be a useful therapeutic option for the treatment of refractory PH. Copyright 2008 S. Karger AG, Basel.

  2. Cladribine with immediate rituximab for the treatment of patients with variant hairy cell leukemia

    PubMed Central

    Kreitman, Robert J.; Wilson, Wyndham; Calvo, Katherine R.; Arons, Evgeny; Roth, Laura; Sapolsky, Jeffrey; Zhou, Hong; Raffeld, Mark; Stetler-Stevenson, Maryalice

    2013-01-01

    Purpose In contrast to the classic form, variant hairy cell leukemia (HCLv) responds poorly to single-agent purine analogs, expresses unmutated BRAF, has shorter overall survival, and lacks effective standard therapy. No treatment has achieved a high complete remission rate even in small series, and of 39 reported cases from 6 studies, overall response rate after cladribine was 44% with 8% complete remissions. Rituximab has been found to increase the sensitivity of malignant cells to cladribine, suggesting that combination with cladribine might improve response in HCLv. To test this hypothesis, HCLv patients were treated with simultaneous cladribine and rituximab. Experimental design HCLv patients with 0-1 prior courses of cladribine received cladribine 0.15 mg/Kg days 1–5, with 8 weekly doses of rituximab 375 mg/m2 beginning day 1. Restaging was performed, and minimal residual disease (MRD) in blood and marrow was quantified using PCR, immunohistochemistry, and flow cytometry. Results By 6 months, 9 (90%) of 10 patients achieved complete remission (CR), compared to 3 (8%) of 39 reported cases treated with cladribine alone (p<0.0001). Of the 9 CRs, 8 remain free of MRD at 12–48 (median 27) months of follow-up. No dose-limiting toxicities were observed when beginning cladribine and rituximab on the same day, although most patients required short-term steroids to prevent and treat rituximab infusion reactions. Cytopenias in CRs resolved in 7–211 (median 34) days without major infections. Conclusion Although cladribine alone lacks effectiveness for early or relapsed HCLv, cladribine with immediate rituximab achieves CRs without MRD and is feasible to administer. PMID:24277451

  3. Placebo-controlled trial of rituximab in IgM anti-myelin-associated glycoprotein antibody demyelinating neuropathy.

    PubMed

    Dalakas, Marinos C; Rakocevic, Goran; Salajegheh, Mohammad; Dambrosia, James M; Hahn, Angelika F; Raju, Raghavan; McElroy, Beverly

    2009-03-01

    Report a double-blind, placebo-controlled study of rituximab in patients with anti-MAG demyelinating polyneuropathy (A-MAG-DP). Twenty-six patients were randomized to four weekly infusions of 375 mg/m(2) rituximab or placebo. Sample size was calculated to detect changes of > or = 1 Inflammatory Neuropathy Course and Treatment (INCAT) leg disability scores at month 8. IgM levels, anti-MAG titers, B cells, antigen-presenting cells, and immunoregulatory T cells were monitored every 2 months. Thirteen A-MAG-DP patients were randomized to rituximab and 13 to placebo. Randomization was balanced for age, electrophysiology, disease duration, disability scores, and baseline B cells. After 8 months, by intention to treat, 4 of 13 rituximab-treated patients improved by > or = 1 INCAT score compared with 0 of 13 patients taking placebo (p = 0.096). Excluding one rituximab-randomized patient who had normal INCAT score at entry, and thus could not improve, the results were significant (p = 0.036). The time to 10m walk was significantly reduced in the rituximab group (p = 0.042) (intention to treat). Clinically, walking improved in 7 of 13 rituximab-treated patients. At month 8, IgM was reduced by 34% and anti-MAG titers by 50%. CD25+CD4+Foxp3+ regulatory cells significantly increased by month 8. The most improved patients were those with high anti-MAG titers and most severe sensory deficits at baseline. Rituximab is the first drug that improves some patients with A-MAG-DP in a controlled study. The benefit may be exerted by reducing the putative pathogenic antibodies or by inducing immunoregulatory T cells. The results warrant confirmation with a larger trial.

  4. Preliminary analysis of mortality associated with rituximab use in autoimmune diseases.

    PubMed

    Shetty, Shawn; Ahmed, A R

    2013-12-01

    Normal antibodies and pathogenic autoantibodies are produced by B-cells and plasma cells. Rituximab is a chimeric monoclonal antibody that targets the CD20 molecule on cells that express them on their surface and kills them. Rituximab has been increasingly used to treat several autoimmune diseases. Studies on fatal outcomes associated with rituximab therapy are lacking. A comprehensive and detailed analysis in which the multiple factors that could contribute to a fatal outcome in all the autoimmune diseases in which rituximab has been used would be cumbersome, lack uniformity and would prove difficult in making certain definitive conclusions and comparisons, but more importantly it would not allow to provide specific precautions and recommendations to prevent mortality. Hence, autoimmune mucocutaneous blistering diseases (AMBD) were used as model to study fatal outcomes in patients treated with rituximab between 2000 and 2013, using uniform 13 criteria. Fatal outcomes were found in 14 patients with autoimmune blistering diseases out of 134 patients (10.4%). Patients died due to infections (75%), gastrointestinal (17%) and cardiac events (8%). Causes of death were reported in 101 patients with other autoimmune diseases out of 4320 with a mortality rate of 2.4%. Among them, 44 patients (43.6%) died from infections. A statistical analysis of the data demonstrated that a statistically significant higher mortality rate was observed in patients with AMBD compared to patients with other autoimmune diseases. Similarly, a statistically significant higher rate of death due to infections was reported in patients with AMBD compared to patients with other autoimmune diseases. Use of systemic corticosteroids and immunosuppressive agents as concomitant therapy with rituximab enhanced immunosuppression. In many patients, B-cells were depleted for prolonged periods, even after clinical recovery was observed. Although its main action is depletion of B-cells, rituximab has a

  5. Immunotherapy with Rituximab in Follicular Lymphomas

    PubMed Central

    SAGUNA, Carmen; MUT, Ileana Delia; LUPU, Anca Roxana; TEVET, Mihaela; BUMBEA, Horia; DRAGAN, Cornel

    2011-01-01

    ABSTRACT Background: Non-Hodgkin Lymphomas (NHL) represent a recent and fascinating domain of hemato-oncology, in which remarkable progress has been made. The conventional treatments of indolent lymphomas do not extend the survival rate, nor do they cure. Recent directions are centered on using several new drugs that are capable of overcoming the mechanisms that are resistant to recovery. The initiation of immunotherapy (Rituximab in 1997) seems to have changed the natural evolution of follicular lymphomas (FL). It is possible that resistance to healing in follicular lymphomas may be neutralized with Rituximab by suppressing STAT-1 positive macrophages that are present in the cellular microenvironment.Thereinafter, the re-evaluation of recent models of prognostic and therapeutic paradigmas that were used in FL became compulsory. The purpose of the paper is to compare the evolution of patients with follicular lymphoma and the period of response, according to the treatments. Material and method: The study group consisted of the 71 patients diagnosed with follicular lymphoma, out of a total of 767 malignant lymphatic proliferations with B cells, for a period of 7 years (2002-2008), at the Hematology Department, Hospital Coltea, Bucharest and Hematology Department, Universitary Hospital, Bucharest Results and conclusions: Combining chemotherapy with Rituximab had better results compared to the same chemotherapy, administered alone, both in induction and in case of relapse. The overall response rate in our study group was 74.7%, out of which 42.3% complete remissions. The overall response rate was 84.61% in the Rituximab group, compared to 68.88% in patients without Rituximab. PMID:22205891

  6. Immunotherapy with rituximab in follicular lymphomas.

    PubMed

    Saguna, Carmen; Mut, Ileana Delia; Lupu, Anca Roxana; Tevet, Mihaela; Bumbea, Horia; Dragan, Cornel

    2011-04-01

    Non-Hodgkin Lymphomas (NHL) represent a recent and fascinating domain of hemato-oncology, in which remarkable progress has been made. The conventional treatments of indolent lymphomas do not extend the survival rate, nor do they cure. Recent directions are centered on using several new drugs that are capable of overcoming the mechanisms that are resistant to recovery. The initiation of immunotherapy (Rituximab in 1997) seems to have changed the natural evolution of follicular lymphomas (FL). It is possible that resistance to healing in follicular lymphomas may be neutralized with Rituximab by suppressing STAT-1 positive macrophages that are present in the cellular microenvironment.Thereinafter, the re-evaluation of recent models of prognostic and therapeutic paradigmas that were used in FL became compulsory.The purpose of the paper is to compare the evolution of patients with follicular lymphoma and the period of response, according to the treatments. The study group consisted of the 71 patients diagnosed with follicular lymphoma, out of a total of 767 malignant lymphatic proliferations with B cells, for a period of 7 years (2002-2008), at the Hematology Department, Hospital Coltea, Bucharest and Hematology Department, Universitary Hospital, BucharestResults and conclusions: Combining chemotherapy with Rituximab had better results compared to the same chemotherapy, administered alone, both in induction and in case of relapse. The overall response rate in our study group was 74.7%, out of which 42.3% complete remissions. The overall response rate was 84.61% in the Rituximab group, compared to 68.88% in patients without Rituximab.

  7. 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

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

    PubMed

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

    2014-05-30

    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.

  9. Neuromyelitis optica spectrum disorders: long-term safety and efficacy of rituximab in Caucasian patients.

    PubMed

    Radaelli, M; Moiola, L; Sangalli, F; Esposito, F; Barcella, V; Ferrè, L; Rodegher, M; Colombo, B; Fazio, R; Martinelli, V; Comi, G

    2016-04-01

    To assess the long-term benefit-risk profile of repeated courses of rituximab in Caucasian patients affected by neuromyelitis optica (NMO) and related disorders, in everyday clinical practice. This is a prospective observational study performed at San Raffaele Hospital, Milan, Italy. From February 2006, we recruited 21 patients affected by NMO and NMO spectrum of disorders (NMOSD) whom underwent at least one cycle of intravenous (i.v.) rituximab and then were followed for at least 2 years. At a mean follow-up time of 48 months, we observed a significant reduction of the annualized relapse rate (ARR), from 2.0 to 0.16 (p < 0.01); and of the median Expanded Disability Status Scale (EDSS), from 5.5 to 4.0 (p < 0.013). There were 12 patients (57%) who remained disease free during the follow-up period. Five patients (24%) reported mild hematological adverse events. Serious infectious adverse events were reported by another four patients: These were all wheelchair bound at the beginning of their rituximab treatment. A fixed treatment scheme of rituximab, with re-treatment every 6 months, was efficacious for NMO and NMOSD, with a good safety profile; however, to obtain an even better benefit-risk ratio, close monitoring of CD19(+) B cells should be performed before the re-treatment of patients with high-level disability, concomitant leukopenia and hypogammaglobulinemia. © The Author(s), 2015.

  10. 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.

  11. Rituximab in the treatment of autoimmune haemolytic anaemia

    PubMed Central

    Rodrigo, Chaturaka; Rajapakse, Senaka; Gooneratne, Lallindra

    2015-01-01

    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

  12. [Cost-per-responder analysis comparing romiplostim to rituximab in the treatment of adult primary immune thrombocytopenia in Spain].

    PubMed

    López, M Fernanda; Mingot, María Eva; Valcárcel, David; Vicente García, Vicente; Perrin, Allison; Campos Tapias, Ignasi

    2015-05-08

    Romiplostim, a thrombopoietin-receptor agonist, is approved for second-line use in idiopathic thrombocytopenic purpura (ITP) patients where surgery is contraindicated. Anti-CD20 rituximab, an immunosuppressant, is currently used off-label. This analysis compared the cost per responder for romiplostim versus rituximab in Spain. A decision analytic model was constructed to estimate the 6-month cost per responding patient (achieving a platelet count≥50×10(9)/l) according to the most robust published data. A systematic literature review was performed to extract response rates from phase 3 randomized controlled trials. Romiplostim patients received weekly injections; rituximab patients received 4 weekly intravenous infusions. Medical resource costs were obtained from Spanish reimbursement lists. Treatment non-responders incurred bleeding-related event (BRE) management costs as reported in clinical trials. Medical resource utilization and clinical practice were based on Spanish treatment guidelines and validated by local clinical experts. The literature review identified phase 3 romiplostim trials with a response rate of 83%. Due to a lack of phase 3 controlled rituximab trials, a systematic review of studies was selected as the best source, reporting a response rate of 62.5%. The mean cost per patient for romiplostim was €16,289 and €13,459 for rituximab. Rituximab resulted in a 10% higher cost per responder (€21,535 versus €19,625 for romiplostim). Romiplostim use reduced drug administration, intravenous immunoglobulin, and bleeding-related costs compared to rituximab. Due to its high level of efficacy leading to lower BRE costs, romiplostim represents an efficient use of resources for adult ITP patients in the Spanish Healthcare System. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

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

    PubMed

    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; Dale, Russell C

    2016-02-01

    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. 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 × 10(6) cells/L). 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 × 10(6) cells/L, 10 had inadequate monitoring (≤1 CD19 in the 4 months before relapses), and 5 had delayed redosing after repopulation detection. 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. 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 and relapses.

  14. Patients with diffuse large B-cell lymphoma of germinal center origin with BCL2 translocations have poor outcome, irrespective of MYC status: a report from an International DLBCL rituximab-CHOP Consortium Program Study.

    PubMed

    Visco, Carlo; Tzankov, Alexander; Xu-Monette, Zijun Y; Miranda, Roberto N; Tai, Yu Chuan; Li, Yan; Liu, Wei-min; d'Amore, Emanuele S G; Li, Yong; Montes-Moreno, Santiago; Dybkær, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Wang, Huan-You; Dunphy, Cherie H; His, Eric D; Zhao, X Frank; Choi, William W L; Zhao, Xiaoying; van Krieken, J Han; Huang, Qin; Ai, Weiyun; O'Neill, Stacey; Ponzoni, Maurilio; Ferreri, Andres J M; Kahl, Brad S; Winter, Jane N; Go, Ronald S; Dirnhofer, Stephan; Piris, Miguel A; Møller, Michael B; Wu, Lin; Medeiros, L Jeffrey; Young, Ken H

    2013-02-01

    Diffuse large B-cell lymphoma can be classified by gene expression profiling into germinal center and activated B-cell subtypes with different prognoses after rituximab-CHOP. The importance of previously recognized prognostic markers, such as Bcl-2 protein expression and BCL2 gene abnormalities, has been questioned in the new therapeutic era. We analyzed Bcl-2 protein expression, and BCL2 and MYC gene abnormalities by interphase fluorescence in situ hybridization in 327 patients with de novo disease treated with rituximab-CHOP. Isolated BCL2 and MYC rearrangements were not predictive of outcome in our patients as a whole, but only in those with the germinal center subtype of lymphoma. The prognostic relevance of isolated MYC rearrangements was weaker than that of BCL2 isolated translocations, but was probably limited by the rarity of the rearrangements. Seven of eight patients with double hit lymphoma had the germinal center subtype with poor outcome. The germinal center subtype patients with isolated BCL2 translocations had significantly worse outcome than the patients without BCL2 rearrangements (P=0.0002), and their outcome was similar to that of patients with the activated B-cell subtype (P=0.30), but not as bad as the outcome of patients with double hit lymphoma (P<0.0001). Bcl-2 protein overexpression was associated with inferior outcome in patients with germinal center subtype lymphoma, but multivariate analysis showed that this was dependent on BCL2 translocations. The gene expression profiling of patients with BCL2 rearrangements was unique, showing activation of pathways that were silent in the negative counterpart. BCL2 translocated germinal center subtype patients have worse prognosis after rituximab-CHOP, irrespective of MYC status, but the presence of combined gene breaks significantly overcomes the prognostic relevance of isolated lesions.

  15. A Case of Coronary Vasospasm after Repeat Rituximab Infusion

    PubMed Central

    Ke, Calvin; Khosla, Amit; Davis, Margot K.; Hague, Cameron; Toma, Mustafa

    2015-01-01

    Coronary artery vasospasm (CAV) can be triggered by medication reactions. CAV occurring after multiple exposures to rituximab has not been previously described. A 61-year-old woman with no cardiac risk factors was treated with the sixth cycle of gemcitabine, cisplatin, dexamethasone, and rituximab therapy. Fifteen minutes after rituximab infusion commenced, she developed typical cardiac chest pain with ST segment elevations on electrocardiogram. Angiogram revealed evidence of coronary vasospasm. The patient was successfully treated with amlodipine. This case underlines the importance of monitoring cardiac side effects of rituximab therapy, even after multiple cycles. PMID:25866684

  16. Rituximab maintenance versus observation alone in patients with chronic lymphocytic leukaemia who respond to first-line or second-line rituximab-containing chemoimmunotherapy: final results of the AGMT CLL-8a Mabtenance randomised trial.

    PubMed

    Greil, Richard; Obrtlíková, Petra; Smolej, Lukáš; Kozák, Tomáš; Steurer, Michael; Andel, Johannes; Burgstaller, Sonja; Mikušková, Eva; Gercheva, Liana; Nösslinger, Thomas; Papajík, Tomáš; Ladická, Miriam; Girschikofsky, Michael; Hrubiško, Mikuláš; Jäger, Ulrich; Fridrik, Michael; Pecherstorfer, Martin; Králiková, Eva; Burcoveanu, Cristina; Spasov, Emil; Petzer, Andreas; Mihaylov, Georgi; Raynov, Julian; Oexle, Horst; Zabernigg, August; Flochová, Emília; Palášthy, Stanislav; Stehlíková, Olga; Doubek, Michael; Altenhofer, Petra; Pleyer, Lisa; Melchardt, Thomas; Klingler, Anton; Mayer, Jiří; Egle, Alexander

    2016-07-01

    In many patients with chronic lymphocytic leukaemia requiring treatment, induction therapy with rituximab plus chemotherapy improves outcomes compared with chemotherapy alone. In this study we aimed to investigate the potential of rituximab maintenance therapy to prolong disease control in patients who respond to rituximab-containing induction regimens. In this randomised, international, multicentre, open-label, phase 3 clinical trial, we enrolled patients who had achieved a complete response (CR), CR with incomplete bone marrow recovery (CRi), or partial response (PR) to first-line or second-line rituximab-containing chemoimmunotherapy and randomly assigned them in a 1:1 ratio (central block randomisation in the electronic case report form system) to either intravenous rituximab 375 mg/m(2) every 3 months, or observation alone, for 2 years. Stratification was by country, line of treatment, type of chemotherapy added to the rituximab backbone, and degree of remission following induction. The primary endpoint was progression-free survival. Efficacy analysis was done in the intention-to-treat population. This is the final, event-triggered analysis. Final analysis was triggered by the occurrence of 92 events. This trial is registered with ClinicalTrials.gov, number NCT01118234. Between April 1, 2010, and Dec 23, 2013, 134 patients were randomised to rituximab and 129 to observation alone. Median observation times were 33·4 months (IQR 25·7-42·8) for the rituximab group and 34·0 months (25·4-41·9) for the observation group. Progression-free survival was significantly longer in the rituximab maintenance group (47·0 months, IQR 28·5-incalculable) than with observation alone (35·5 months, 95% CI 25·7-46·3; hazard ratio [HR] 0·50, 95% CI 0·33-0·75, p=0·00077). The incidence of grade 3-4 haematological toxicities other than neutropenia was similar in the two treatment groups. Grade 3-4 neutropenia occurred in 28 (21%) patients in the rituximab group and 14

  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. A mild form of rituximab-associated lung injury in two adolescents treated for nephrotic syndrome.

    PubMed

    Spatafora, Mario; Bellini, Tommaso; Giordano, Carmela; Ghiggeri, Gian Marco

    2015-12-09

    Rituximab is used as a steroid/calcineurin inhibitor-saving agent in patients with nephrotic syndrome. Safety is a crucial issue for justifying widespread use of the drug in this clinical setting. Rituximab-associated lung injury (RALI) is a severe and potentially life-threatening complication in oncohaematological and rheumatological patients, while it has only been anecdotally reported in association with idiopathic nephrotic syndrome (2 cases described, 1 with fatal outcome). We describe a benign form of RALI occurring in two adolescents treated with rituximab (single pulse of 375 mg/m(2)) for nephrotic syndrome. Before treatment, the patients were in good clinical condition while receiving a combination of steroids and calcineurin inhibitors (tacrolimus, case 1 and cyclosporine, case 2). The two patients developed full blown RALI (ie, ground-glass lesions on CT, negative bronchoscopy with bronchoalveolar lavage and deficit in diffusion lung CO transfer), 14 and 40 days after rituximab infusion, respectively. Recovery was rapid and complete after administering steroids in case 1 and with no therapy in case 2. We conclude that RALI may occur in stable non-immunocompromised patients with nephrotic syndrome and its frequency may be higher than expected. Clinical presentation may be mild and resolve after steroids, suggesting hypersensitivity as the main mechanism. Rapid recognition and prompt steroid therapy, if needed, are mandatory for resolution. 2015 BMJ Publishing Group Ltd.

  19. Rituximab as a first-line preventive treatment in pediatric NMOSDs

    PubMed Central

    Longoni, Giulia; Banwell, Brenda; Filippi, Massimo

    2014-01-01

    Objective: No established therapeutic protocol has been proposed to date for childhood-onset neuromyelitis optica (NMO) spectrum disorders (NMOSDs). We report the response of 5 NMO immunoglobulin (Ig)G–positive pediatric cases to a standardized B-cell–targeted first-line immunosuppressive protocol with rituximab for prevention of relapses. Methods: Retrospective observational cohort study. Results: All patients included in the study showed disease remission after rituximab induction. Relapses always occurred in conjunction with CD19+ B-cell repopulation and appeared less severe than prior to treatment. At the end of follow-up, neurologic disability and MRI findings stabilized or improved in all the patients, with only minor and transient side effects. Oral steroid discontinuation was possible in all the patients. Conclusions: Our protocol is well-tolerated and has provided encouraging results in terms of control of relapses and progression of disability. An early intervention with rituximab might affect the disease course in pediatric NMO-IgG–positive NMOSDs. Classification of evidence: This study provides Class IV evidence that for children with NMOSDs, rituximab is well-tolerated and stabilizes or improves neurologic disability. PMID:25520954

  20. Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL

    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

    Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) is dictated by patient characteristics, prior therapy, and response to prior therapy. We report the final analysis of combined fludarabine, cyclophosphamide, and rituximab (FCR) for previously treated patients with CLL and identify patients who benefit most from this therapy. We explore efficacy of FCR in patients beyond first relapse, patients with prior exposure to fludarabine and alkylating agent combinations, and patients with prior exposure to rituximab. The FCR regimen was administered to 284 previously treated patients with CLL. Patients were assessed for response and progression by 1996 National Cancer Institute–Working Group (NCI-WG) criteria for CLL and followed for survival. The overall response rate was 74%, with 30% complete remission. The estimated median overall survival was 47 months and median progression-free survival for all patients was 21 months. Subgroup analyses indicated that the following patients were most suitable for FCR treatment: patients with up to 3 prior treatments, fludarabine-sensitive patients irrespective of prior rituximab exposure, and patients without chromosome 17 abnormalities. FCR is an active and well-tolerated therapy for patients with relapsed CLL. The addition of rituximab to FC improved quality and durability of response in this patient population. PMID:21245487

  1. Rituximab use in the catastrophic antiphospholipid syndrome: descriptive analysis of the CAPS registry patients receiving rituximab.

    PubMed

    Berman, Horacio; Rodríguez-Pintó, Ignasi; Cervera, Ricard; Morel, Nathalie; Costedoat-Chalumeau, Nathalie; Erkan, Doruk; Shoenfeld, Yehuda; Espinosa, Gerard

    2013-09-01

    The catastrophic variant of the antiphospholipid syndrome (APS) is characterized by thrombosis in multiple organs developing over a short period of time. First-line treatment for the catastrophic APS is the combination of anticoagulation plus corticosteroids plus plasma exchange and/or intravenous immunoglobulin. Despite this regimen, the mortality remains high and new treatment options are needed. By a systematic review of the Catastrophic APS Registry (CAPS Registry), we identified 20 patients treated with rituximab. The purpose of this study is to describe the clinical manifestations, laboratory features, and outcomes of rituximab-treated CAPS patients. In addition, the rationale for using rituximab in catastrophic APS is discussed. Copyright © 2013 Elsevier B.V. All rights reserved.

  2. Improvement in liver cirrhosis after treatment of HCV-related mixed cryoglobulinemia with rituximab.

    PubMed

    Petrarca, Antonio; Rigacci, Luigi; Monti, Monica; Giannini, Carlo; Bernardi, Franco; Caini, Patrizio; Colagrande, Stefano; Bosi, Alberto; Laffi, Giacomo; Zignego, Anna Linda

    2007-09-01

    Mixed cryoglobulinemia (MC) is the most strictly virus-related extrahepatic HCV disease. Antiviral therapy is considered the first therapeutic option; however, MC patients are frequently excluded from treatment due to contraindications. The effectiveness of B-cell depletion by anti-CD20 monoclonal antibody (rituximab) has recently been described, but the possibility of an immunodepression- related increase in viral replication and aminotransferase values limits its use in patients with advanced liver disease. Unfortunately, MC patients frequently also have cirrhosis. To our knowledge, no data are available regarding the effect of rituximab therapy in patients with decompensated cirrhosis. We report the successful treatment with rituximab (4 weekly infusions of 375 mg/m 2) of two patients (a 58-year-old man, and a 65-year-old woman) with HCV-related MC syndrome and decompensated liver cirrhosis. These patients underwent at least 6 months of post-treatment follow-up. In both cases a consistent improvement of MC syndrome was evident after treatment. In addition, improvement of liver protidosynthetic activity, increased prothrombin time, impressive reduction or disappearance of ascites and encephalopathy were also observed, in spite of some increase in viral titers or in ALT values. The Child-Pugh score improved from B8 to A6 and from Cll to B7, respectively. Pre- and post-treatment transjugular liver biopsies were available in 1 patient, showing disappearance of lymphocytic infiltration after treatment. These case reports show the effectiveness and safety of rituximab in patients with HCV-related MC and advanced cirrhosis, and strongly suggest that the depletion of CD20+ B-cells induced by rituximab treatment may be responsible for liver function improvement. The mechanisms involved are unknown. Interesting working hypotheses may implicate a role played by B-cell infiltrates in conditioning liver damage. The improvement of Kupffer cell function due to the cryocrit

  3. Efficacy of rituximab and plasmapharesis in an adult patient with antifactor H autoantibody-associated hemolytic uremic syndrome

    PubMed Central

    Deville, Clemence; Garrouste, Cyril; Coppo, Paul; Evrard, Bertrand; Lautrette, Alexandre; Heng, Anne Elisabeth

    2016-01-01

    Abstract Antifactor H antibody (anti-CFHAb) is found in 6% to 25% cases of atypical hemolytic uremic syndrome (aHUS) in children, but has been only exceptionally reported in adults. There is no consensus about the best treatment for this type of aHUS. We report the case of an adult patient treated successfully with plasma exchange (PE), steroids, and rituximab. A 27-year-old Caucasian male presented to hospital with anemia, thrombocytopenia, and acute renal failure. One week earlier, he had digestive problems with diarrhea. The diagnosis of anti-CFHAb-associated aHUS (82,000 AU/mL) without CFHR gene mutations was established. He received Rituximab 375 mg/m2 (4 pulses) with PE and steroids. This treatment achieved renal and hematological remission at day (D) 31 and negative anti-CFHAb at D45 (<100 AU/mL). At D76, a fifth rituximab pulse was performed while CD19 was higher than 10/mm3. Steroids were stopped at month (M) 9. The patient has not relapsed during long-term follow-up (M39). Rituximab therapy can be considered for anti-CFHAb-associated aHUS. Monitoring of anti-CFHAb titer may help to guide maintenance therapeutic strategies including Rituximab infusion. PMID:27684863

  4. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: a report from the International DLBCL Rituximab-CHOP Consortium Program Study.

    PubMed

    Visco, C; Li, Y; Xu-Monette, Z Y; Miranda, R N; Green, T M; Li, Y; Tzankov, A; Wen, W; Liu, W-m; Kahl, B S; d'Amore, E S G; Montes-Moreno, S; Dybkær, K; Chiu, A; Tam, W; Orazi, A; Zu, Y; Bhagat, G; Winter, J N; Wang, H-Y; O'Neill, S; Dunphy, C H; Hsi, E D; Zhao, X F; Go, R S; Choi, W W L; Zhou, F; Czader, M; Tong, J; Zhao, X; van Krieken, J H; Huang, Q; Ai, W; Etzell, J; Ponzoni, M; Ferreri, A J M; Piris, M A; Møller, M B; Bueso-Ramos, C E; Medeiros, L J; Wu, L; Young, K H

    2012-09-01

    Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development-namely germinal center B-cell like and activated B-cell like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1 and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B cells. Cutoffs for each marker were obtained using receiver-operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1 and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy.

  5. Comprehensive gene expression profiling and immunohistochemical studies support application of immunophenotypic algorithm for molecular subtype classification in diffuse large B-cell lymphoma: A report from the International DLBCL Rituximab-CHOP Consortium Program Study

    PubMed Central

    Visco, Carlo; Li, Yan; Xu-Monette, Zijun Y.; Miranda, Roberto N.; Green, Tina M.; Li, Yong; Tzankov, Alexander; Wen, Wei; Liu, Wei-min; Kahl, Brad S.; d’Amore, Emanuele S. G.; Montes-Moreno, Santiago; Dybkær, Karen; Chiu, April; Tam, Wayne; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Winter, Jane N.; Wang, Huan-You; O’Neill, Stacey; Dunphy, Cherie H.; Hsi, Eric D.; Zhao, X. Frank; Go, Ronald S.; Choi, William W. L.; Zhou, Fan; Czader, Magdalena; Tong, Jiefeng; Zhao, Xiaoying; van Krieken, J. Han; Huang, Qing; Ai, Weiyun; Etzell, Joan; Ponzoni, Maurilio; Ferreri, Andres J. M.; Piris, Miguel A.; Møller, Michael B.; Bueso-Ramos, Carlos E.; Medeiros, L. Jeffrey; Wu, Lin; Young, Ken H.

    2013-01-01

    Gene expression profiling (GEP) has stratified diffuse large B-cell lymphoma (DLBCL) into molecular subgroups that correspond to different stages of lymphocyte development - namely germinal center B-cell-like and activated B-cell-like. This classification has prognostic significance, but GEP is expensive and not readily applicable into daily practice, which has lead to immunohistochemical algorithms proposed as a surrogate for GEP analysis. We assembled tissue microarrays from 475 de novo DLBCL patients who were treated with rituximab-CHOP chemotherapy. All cases were successfully profiled by GEP on formalin-fixed, paraffin-embedded tissue samples. Sections were stained with antibodies reactive with CD10, GCET1, FOXP1, MUM1, and BCL6 and cases were classified following a rationale of sequential steps of differentiation of B-cells. Cutoffs for each marker were obtained using receiver operating characteristic curves, obviating the need for any arbitrary method. An algorithm based on the expression of CD10, FOXP1, and BCL6 was developed that had a simpler structure than other recently proposed algorithms and 92.6% concordance with GEP. In multivariate analysis, both the International Prognostic Index and our proposed algorithm were significant independent predictors of progression-free and overall survival. In conclusion, this algorithm effectively predicts prognosis of DLBCL patients matching GEP subgroups in the era of rituximab therapy. PMID:22437443

  6. Rituximab and intermediate-purity plasma-derived factor VIII concentrate (Koate®) as adjuncts to therapeutic plasma exchange for thrombotic thrombocytopenic purpura in patients with an ADAMTS13 inhibitor.

    PubMed

    Pandey, Soumya; Nakagawa, Mayumi; Rosenbaum, Eric R; Arnaoutakis, Konstantinos; Hutchins, Laura F; Makhoul, Issam; Milojkovic, Natasha; Cottler-Fox, Michele

    2015-02-01

    Thrombotic thrombocytopenic purpura (TTP) results from a congenital or acquired deficiency of the von Willebrand factor (vWF)-cleaving protease ADAMTS13. The disease can be fatal and hence treatment should be initiated promptly. Therapeutic plasma exchange (TPE) remains the standard treatment along with adjunct therapies including steroids and immunosuppressive drugs. Addition of rituximab to TPE has been shown to be beneficial in refractory/relapsing TTP; however, TPE results in removal of rituximab from the circulation requiring more frequent dosing of rituximab to achieve a favorable outcome. The intermediate-purity plasma-derived Factor VIII concentrate (FVIII) Koate® contains the highest amount of ADAMTS13 activity yet reported and has been used successfully in treating congenital TTP. Here we report our experience with addition of this FVIII concentrate to rituximab, corticosteroids and TPE in three TTP patients with an ADAMTS13 inhibitor to permit withholding TPE for 48 h after rituximab infusion.

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

    PubMed Central

    Buch, Maya H; Smolen, Josef S; Betteridge, Neil; Breedveld, Ferdinand C; Burmester, Gerd; Dörner, Thomas; Ferraccioli, Gianfranco; Gottenberg, Jacques-Eric; Isaacs, John; Kvien, Tore K; Mariette, Xavier; Martin-Mola, Emilio; Pavelka, Karel; Tak, Paul P; van der Heijde, Desiree; van Vollenhoven, Ronald F; Emery, Paul

    2011-01-01

    Background Since initial approval for the treatment of rheumatoid arthritis (RA), rituximab has been evaluated in clinical trials involving various populations with RA. Information has also been gathered from registries. This report therefore updates the 2007 consensus document on the use of rituximab in the treatment of RA. Methods Preparation of this new document involved many international experts experienced in the treatment of RA. Following a meeting to agree upon the core agenda, a systematic literature review was undertaken to identify all relevant data. Data were then interrogated by a drafting committee, with subsequent review and discussion by a wider expert committee leading to the formulation of an updated consensus statement. These committees also included patients with RA. Results The new statement covers wide-ranging issues including the use of rituximab in earlier RA and impact on structural progression, and aspects particularly pertinent to rituximab such as co-medication, optimal dosage regimens, repeat treatment cycles and how to manage non-response. Biological therapy following rituximab usage is also addressed, and safety concerns including appropriate screening for hepatitis, immunoglobulin levels and infection risk. This consensus statement will support clinicians and inform patients when using B-cell depletion in the management of RA, providing up-to-date information and highlighting areas for further research. Conclusion New therapeutic strategies and treatment options for RA, a chronic destructive and disabling disease, have expanded over recent years. These have been summarised in general strategic suggestions and specific management recommendations, emphasising the importance of expedient disease-modifying antirheumatic drug implementation and tight disease control. This consensus statement is in line with these fundamental principles of management. PMID:21378402

  8. Fludarabine, Cyclophosphamide, and Multiple-Dose Rituximab as Frontline Therapy for Chronic Lymphocytic Leukemia

    PubMed Central

    Short, Nicholas J.; Keating, Michael J.; Wierda, William G.; Faderl, Stefan; Ferrajoli, Alessandra; Estrov, Zeev; Smith, Susan C.; O'Brien, Susan M.

    2016-01-01

    Background Fludarabine, cyclophosphamide and rituximab (FCR) results in durable responses in patients with previously untreated chronic lymphocytic leukemia (CLL). Previous reports suggest that in patients with relapsed CLL a dose-intensified rituximab regimen increases response rates compared to standard-dose rituximab. It is unknown whether rituximab intensification of the FCR regimen will result in improved response rates and patient outcomes in patients with previously untreated CLL. Methods We conducted a single-arm study to evaluate the safety and efficacy of a modified FCR regimen with multiple-dose rituximab (FCR3) in 65 patients with previously untreated CLL. Results were compared to an historical cohort treated with FCR. Results The overall response rate to FCR3 was 97%, with 75% of patients achieving a complete remission. Minimal residual disease negativity was achieved in 62% of patients by flow cytometry. Median time to progression (TTP) was 81 months, and median overall survival (OS) was not reached, with 58% of patients still alive at a median survivor follow-up of 9.7 years. Grade 3-4 neutropenia, grade 3-4 thrombocytopenia and major infection were observed with 45%, 5% and 1.9% of FCR3 courses, respectively. Therapy-related myelodysplastic syndrome (t-MDS) or acute myelogenous leukemia (t-AML) developed in 7 patients (11%) (P <0.01 compared to the historical FCR cohort). Conclusions In patients with previously untreated CLL, FCR3 resulted in similar response rates, TTP and OS compared to a historical cohort of patients treated with FCR. FCR3 was associated with an increased incidence of t-MDS/AML. PMID:26218678

  9. Comparative assessment of clinical response in patients with rheumatoid arthritis between PF-05280586, a proposed rituximab biosimilar, and rituximab.

    PubMed

    Williams, Jason H; Hutmacher, Matthew M; Zierhut, Matthew L; Becker, Jean-Claude; Gumbiner, Barry; Spencer-Green, George; Melia, Lisa A; Liao, Kai-Hsin; Suster, Matthew; Yin, Donghua; Li, Ruifeng; Meng, Xu

    2016-12-01

    To evaluate potential differences between PF-05280586 and rituximab sourced from the European Union (rituximab-EU) and USA (rituximab-US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF-05280586. A randomised, double-blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti-tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF-05280586, rituximab-EU or rituximab-US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab-EU and rituximab-US responses using longitudinal nonlinear mixed effects models. The analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group-to-group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF-05280586 vs. rituximab-EU or rituximab-US lie outside the reference ranges were low. No clinically meaningful differences were detected in DAS28 or ACR response between PF-05280586 and rituximab-EU or rituximab-US as the differences were within the pre-specified reference ranges. NCT01526057. © 2016 Pfizer Inc. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

  10. Demonstration of highly specific toxicity of the α-emitting radioimmunoconjugate211At-rituximab against non-Hodgkin's lymphoma cells

    PubMed Central

    Aurlien, E; Larsen, R H; Kvalheim, G; Bruland, Ø S

    2000-01-01

    The ability of an α-emitter conjugated to a chimaeric anti-CD20 monoclonal antibody to kill selectively human B-lymphoma cells in vitro is reported. Two B-lymphoma cell lines RAEL and K422, and normal haematopoietic progenitor cells from human bone marrow aspirates were incubated with211At-rituximab (Rituxan® or MabThera™) and plated in clonogenic assays for survival analyses. Following 1 h incubation with211At-rituximab, in concentrations which gave an initial activity of 50 kBq ml–1, a high tumour cell to normal bone marrow cell toxicity ratio was obtained; 4.1 to 1.0 log cell kill. Biodistribution studies of211At-rituximab in Balb/c mice showed similar stability as that of the iodinated analogue. The data indicate that testing of211At-rituximab in human patients is warranted. © 2000 Cancer Research Campaign PMID:11044364

  11. Rituximab in the treatment of inflammatory myopathies: a review.

    PubMed

    Fasano, Serena; Gordon, Patrick; Hajji, Raouf; Loyo, Esthela; Isenberg, David A

    2017-01-01

    Several uncontrolled studies have encouraged the use of rituximab (RTX) in patients with myositis. Unfortunately, the first placebo-phase trial to assess the efficacy of RTX in refractory myositis did not show a significant difference between the two treatment groups, and doubts have been expressed about its study design. In this review we present an up-to-date overview of the reported experiences of RTX therapy in myositis. A PubMed search was performed to find all the available cases of refractory myositis patients treated with RTX up to July 2015. The following terms were assessed: inflammatory myopathies OR anti-synthetase syndrome OR polymyositis OR dermatomyositis AND RTX. A total of 48 studies were included. We identified 458 patients with myositis treated with RTX. We found a rate of response to RTX of 78.3%. RTX can play a role in the management of patients with myositis, at least in those with positive myositis-specific autoantibodies.

  12. Rituximab therapy in pemphigus and other autoantibody-mediated diseases

    PubMed Central

    Ran, Nina A.; Payne, Aimee S.

    2017-01-01

    Rituximab, a monoclonal antibody targeting the B cell marker CD20, was initially approved in 1997 by the United States Food and Drug Administration (FDA) for the treatment of non-Hodgkin lymphoma. Since that time, rituximab has been FDA-approved for rheumatoid arthritis and vasculitides, such as granulomatosis with polyangiitis and microscopic polyangiitis. Additionally, rituximab has been used off-label in the treatment of numerous other autoimmune diseases, with notable success in pemphigus, an autoantibody-mediated skin blistering disease. The efficacy of rituximab therapy in pemphigus has spurred interest in its potential to treat other autoantibody-mediated diseases. This review summarizes the efficacy of rituximab in pemphigus and examines its off-label use in other select autoantibody-mediated diseases. PMID:28184292

  13. Treatment with rituximab in idiopathic membranous nephropathy

    PubMed Central

    Fiorentino, Marco; Tondolo, Francesco; Bruno, Francesca; Infante, Barbara; Grandaliano, Giuseppe; Gesualdo, Loreto

    2016-01-01

    Background Rituximab represents a valid therapeutic option to induce remission in patients with primary glomerulonephritis. Despite several studies proving its efficacy in improving outcomes in patients with membranous nephropathy (MN), its role in therapeutic protocols is not yet defined. Methods We studied 38 patients with idiopathic MN treated with rituximab (in 13 patients as first-line therapy, in the remaining 25 after conventional immunosuppressive therapy). The patients were analyzed for a 15-month median (interquartile range 7.7–30.2) follow-up, with serial monitoring of 24-h proteinuria, renal function and circulating CD19+ B cells. Results The percentages of patients who achieved complete remission, partial remission and the composite endpoint (complete or partial remission) were 39.5% (15 patients), 36.8% (14 patients) and 76.3% (29 patients), respectively. The 24-h proteinuria was reduced significantly during the entire period of follow-up (from a baseline value of 6.1 to 0.9 g/day in the last visit; P < 0.01), while albuminemia increased constantly (from a baseline value of 2.6 to 3.5 g/dL in the last observation; P < 0.01). Renal function did not significantly change during the observation period. Circulating CD19+ B cells were reduced significantly from the baseline value to the 24-month value (P < 0.01); data about anti-phospholipase A2 receptor antibodies were available in 14 patients, 10 of which experienced a decreasing trend after treatment. No significant adverse events were described during and after infusions. Conclusions The present study confirmed that treatment with rituximab was remarkably safe and allowed for a large percentage of complete or partial remissions in patients with MN. PMID:27994855

  14. 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

  15. B-lymphocyte reconstitution after repeated rituximab treatment in a child with steroid-dependent autoimmune hemolytic anemia

    PubMed Central

    van der Linde, Annelieke A.A.; Schatorjé, Ellen J.H.; van der Weij, Annemieke M.; Gemen, Eugenie F.A.; de Vries, Esther

    2011-01-01

    We report the detailed long-term reconstitution of B-lymphocyte subpopulations, immunoglobulins, and specific antibody production after two courses of rituximab in a young, previously healthy girl with steroid-dependent autoimmune hemolytic anemia. B-lymphocyte subpopulations were surprisingly normal directly after reconstitution. However, there was a slower reconstitution after the second rituximab course, especially of non-switched and switched memory B-lymphocytes, and a temporary decline in IgM below age-matched reference values. PMID:22355513

  16. Rituximab as first-line treatment for the management of adult patients with non-severe hemophilia A and inhibitors.

    PubMed

    Lim, M Y; Nielsen, B; Lee, K; Kasthuri, R S; Key, N S; Ma, A D

    2014-06-01

    The role of immunosuppression in the management of patients with congenital hemophilia and inhibitors is uncertain. The use of rituximab has been limited to case reports and case series. In most reports, rituximab was used as second-line or third-line treatment following failure of conventional immune tolerance induction therapy, and more commonly in pediatric patients. The objective of this study was to describe our experience with rituximab for the eradication of factor VIII inhibitors in adult patients with non-severe hemophilia A. We retrospectively reviewed the medical records of adult patients with non-severe hemophilia A and a diagnosis of FVIII inhibitor treated with rituximab (four weekly doses of 375 mg m(-2) ) as first-line treatment at our hemophilia center. We identified nine consecutive adult patients with hemophilia A (moderate, n = 5; mild, n = 4) at our institution between 2000 and 2013, with a median age of 54 years (range, 24-77 years) at the time of inhibitor diagnosis. No patient received concomitant immune tolerance induction therapy. All nine patients had successful eradication of FVIII inhibitors. The median time from the first dose of rituximab to a clinical response was 95 days (range, 12-278 days). The median follow-up was 56 months (range, 13-139 months). Following inhibitor eradication, eight patients were rechallenged with FVIII concentrates. Two patients developed inhibitor recurrence associated with surgery. This case series demonstrates that rituximab is a useful first-line treatment to achieve sustained inhibitor eradication in adult patients with non-severe hemophilia A. © 2014 International Society on Thrombosis and Haemostasis.

  17. 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.

  18. [Icteric hepatitis in a patient with non-Hodgkin's lymphoma treated by rituximab-based chemotherapy].

    PubMed

    Coppola, Nicola; Masiello, Addolorata; Tonziello, Gilda; Macera, Margherita; Iodice, Valentina; Caprio, Nunzio; Pasquale, Giuseppe

    2010-06-01

    We report the case of a patient with non-Hodgkin's lymphoma who, during chemotherapy according to the r-CHOP schedule (rituximab-cyclophosphamide-doxorubicin-vincristine and prednisone), showed a hepatic flare with jaundice. Given the patient's state of asymptomatic carrier of HBsAg, we began a treatment of telbivudine (600 mg/die), resulting in a regression of hepatitis flare and negativization of HBV viraemia.

  19. Successful treatment of cryoglobulinaemia with rituximab.

    PubMed

    Choudhry, M; Rao, N; Juneja, R

    2012-01-01

    Cryoglobulinaemia is a systemic inflammatory condition characterised by immune complex-mediated small-to-medium-sized vasculitis. It has a wide variety of presentations ranging from bruising, neuropathy, and hepatosplenomegaly to acute renal failure. Mixed cryoglobulinaemia is the most common type and is strongly associated with hepatitis C. Management approaches include use of cyclophosphamide, prednisolone, and plasmapheresis, with differing views on alternative treatments in resistant cases. Rituximab has emerged as an attractive option in resistant cases on account of its potent immunosuppressive effects on B cells. We describe a case of type 2 mixed cryoglobulinaemia in association with non-Hodgkin's lymphoma resistant to standard treatments which responded well to rituximab. This case is remarkable as mixed cryoglobulinaemia associated with non-Hodgkin's lymphoma presenting with nephritis is unusual, and, contrary to the high rate of recurrence in lymphoma-related cryoglobulinaemia, our patient has not shown any recurrence over 24 months. This highlights an alternative treatment modality which can be used in patients not responsive to existing managements for this condition with benefits of minimal side effects and no oncogenetic potential.

  20. Preclinical activity of the type II CD20 antibody GA101 (obinutuzumab) compared with rituximab and ofatumumab in vitro and in xenograft models.

    PubMed

    Herter, Sylvia; Herting, Frank; Mundigl, Olaf; Waldhauer, Inja; Weinzierl, Tina; Fauti, Tanja; Muth, Gunter; Ziegler-Landesberger, Doris; Van Puijenbroek, Erwin; Lang, Sabine; Duong, Minh Ngoc; Reslan, Lina; Gerdes, Christian A; Friess, Thomas; Baer, Ute; Burtscher, Helmut; Weidner, Michael; Dumontet, Charles; Umana, Pablo; Niederfellner, Gerhard; Bacac, Marina; Klein, Christian

    2013-10-01

    We report the first preclinical in vitro and in vivo comparison of GA101 (obinutuzumab), a novel glycoengineered type II CD20 monoclonal antibody, with rituximab and ofatumumab, the two currently approved type I CD20 antibodies. The three antibodies were compared in assays measuring direct cell death (AnnexinV/PI staining and time-lapse microscopy), complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cell-mediated phagocytosis (ADCP), and internalization. The models used for the comparison of their activity in vivo were SU-DHL4 and RL xenografts. GA101 was found to be superior to rituximab and ofatumumab in the induction of direct cell death (independent of mechanical manipulation required for cell aggregate disruption formed by antibody treatment), whereas it was 10 to 1,000 times less potent in mediating CDC. GA101 showed superior activity to rituximab and ofatumumab in ADCC and whole-blood B-cell depletion assays, and was comparable with these two in ADCP. GA101 also showed slower internalization rate upon binding to CD20 than rituximab and ofatumumab. In vivo, GA101 induced a strong antitumor effect, including complete tumor remission in the SU-DHL4 model and overall superior efficacy compared with both rituximab and ofatumumab. When rituximab-pretreated animals were used, second-line treatment with GA101 was still able to control tumor progression, whereas tumors escaped rituximab treatment. Taken together, the preclinical data show that the glyoengineered type II CD20 antibody GA101 is differentiated from the two approved type I CD20 antibodies rituximab and ofatumumab by its overall preclinical activity, further supporting its clinical investigation.

  1. Rituximab and chlorambucil versus rituximab alone in gastric mucosa-associated lymphoid tissue lymphoma according to t(11;18) status: a monocentric non-randomized observational study.

    PubMed

    Lévy, Michaël; Copie-Bergman, Christiane; Amiot, Aurélien; Dupuis, Jehan; Le Baleur, Yann; Belhadj, Karim; Hémery, François; Sobhani, Iradj; Delfau-Larue, Marie-Hélène; Leroy, Karen; Haioun, Corinne; Delchier, Jean-Charles

    2013-05-01

    Forty-nine patients, t(11;18)-positive (n = 31) and t(11;18)-negative (n = 18), were treated without randomization with rituximab-chlorambucil or rituximab alone. Evaluation was performed at week (W) 6, week (W) 25 and every 6 months (Wx). Comparing the rituximab-chlorambucil group to the rituximab-alone group, remission was obtained in 93% vs. 66% at W6 (p = 0.01), in 93% vs. 81% at W25 (p = 0.14) and in 93% vs. 76% at Wx (p = 0.07). Comparing the rituximab-chlorambucil group to the rituximab-alone group in t(11;18)-positive patients, remission was obtained in 100% vs. 45% at W6 (p = 0.0005), in 100% vs. 66% at W25 (p = 0.01) and in 96% vs. 55% at Wx (p = 0.01). Comparing the rituximab-chlorambucil group to the rituximab-alone group in t(11;18)-negative patients, remission was obtained in 66% vs. 83% at W6 (p = 0.32), in 66% vs. 92% at W25 (p = 0.22) and in 83% vs. 92% at Wx (p = 0.47). In conclusion, rituximab-chlorambucil is significantly more rapidly efficient than rituximab alone. In t(11;18)-positive patients, the combination is more efficient than rituximab alone. In t(11;18)-negative patients, rituximab alone is as efficient as rituximab-chlorambucil and may be an alternative treatment.

  2. 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

  3. Microcosting Study of Rituximab Subcutaneous Injection Versus Intravenous Infusion.

    PubMed

    Mihajlović, Jovan; Bax, Pieter; van Breugel, Erwin; Blommestein, Hedwig M; Hoogendoorn, Mels; Hospes, Wobbe; Postma, Maarten J

    2017-06-01

    The goal of this study is to identify and compare all direct costs of intravenous and subcutaneous rituximab given to patients with diffuse large B-cell lymphoma in the Netherlands. Using a prospective, observational, bottom-up microcosting study, we collected primary data on the direct medical costs of the preparation, administration, and acquisition of rituximab. Drug costs and costs of drug wastage, labor costs, material costs, and outpatient costs were identified using standardized forms, structured using prices from official pricelists, and compared for the intravenous and subcutaneous forms of rituximab. Measurements were taken on 53 rituximab administrations (33 intravenous and 20 subcutaneous) and on 13 rituximab preparation (7 intravenous and 6 subcutaneous). The mean total costs were €2176.77 for the intravenous infusion and €1911.09 for the subcutaneous injection. The estimated difference of €265.17 (95% CI, €231.99-`€298.35) per administration was mainly attributable to differences in time spent in the chemotherapy unit, related outpatient costs, drug wastage, and drug costs. Rituximab administered in the form of subcutaneous injection is less costly than its intravenous form. With their equal effectiveness taken into account, subcutaneous rituximab administration can result in significant savings when transferred to the total diffuse large B-cell lymphoma population in the Netherlands. Copyright © 2017 Elsevier HS Journals, Inc. All rights reserved.

  4. CD20 antigen imaging with ¹²⁴I-rituximab PET/CT in patients with rheumatoid arthritis.

    PubMed

    Tran, L; Huitema, A D R; van Rijswijk, M H; Dinant, H J; Baars, J W; Beijnen, J H; Vogel, W V

    2011-01-01

    Visualization of the CD20-antigen expression could provide a tool to localize sites of inflammation and could be of additive value in the diagnosis, and subsequently, in the treatment follow-up of patients with rheumatoid arthritis. In this study, an anti-CD20 monoclonal antibody, rituximab (Mabthera®), was radiolabeled with ¹²⁴Iodine. We report the first results of I¹²⁴-rituximab PET/CT in patients with rheumatoid arthritis. Eligible patients received 50 MBq ¹²⁴I-rituximab. Wholebody PET/CT imaging was performed at 10 min, 24 h, 48 h and 72-96 h post injection. Images were evaluated primarily on a visual basis and were correlated with disease activity as determined by physical examination and clinical measures. Joints with visually detectable targeting of ¹²⁴I-rituximab were observed in 4 out of 5 evaluable patients. Only the images at 24 h and later showed accumulation in joints, indicating that the visualized signal represented active targeting of rituximab to the CD20 antigen. Several images showed CD20 positive B-cell infiltration in joints which were clinically normal, while a few clinically diagnosed arthritis localizations were not visualized. This discrepancy suggests that infiltration of CD20 positive B-cells in synovium is a phenomenon that is at least partially independent of clinical inflammation. The level of uptake in joints was generally low, representing less than 0.5% of the injected dose. We have shown the feasibility of CD20 antigen imaging using ¹²⁴I-rituximab in patients with rheumatoid arthritis. Further research is needed to elucidate the clinical significance of demonstrated B-cell infiltration in rheumatic joints.

  5. 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

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

    PubMed

    Akram, Qasim; 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.

  7. Radioimmunotherapy ((90) Y-Ibritumomab Tiuxetan) for Posttransplant Lymphoproliferative Disorders After Prior Exposure to Rituximab.

    PubMed

    Rossignol, J; Terriou, L; Robu, D; Willekens, C; Hivert, B; Pascal, L; Guieze, R; Trappe, R; Baillet, C; Huglo, D; Morschhauser, F

    2015-07-01

    Posttransplantation lymphoproliferative disorders (PTLDs) are life-threatening complications after solid organ and hematopoietic stem cell transplantation. Only half of CD20-positive PTLDs respond to rituximab monotherapy, and outcomes remain poor for patients with relapsed/refractory disease, especially those who do not qualify for an anthracycline containing regimen due to frailty or comorbidities. Radioimmunotherapy (RIT) might be an option in this particular setting. We report a panel of eight patients with rituximab refractory/relapsed CD20-positive PTLDs including three ineligible for subsequent CHOP-like chemotherapy who received (90) Y-Ibritumomab tiuxetan as a single agent (n = 7) or combined to chemotherapy (n = 1). Five out of eight patients were kidney transplant recipients, while 2/8 had a liver transplant and 1/8 had a heart transplant. Patients received a median of two previous therapies. Overall response rate was 62.5%. Importantly, all responders achieved complete response. At a median follow-up of 37 months [5; 84], complete response was ongoing in four patients. Toxicity was predominantly hematological and easily manageable. No graft rejection was noticed concomitantly or following RIT administration despite immunosuppression reduction after diagnosis of PTLDs. This report emphasizes the potential efficiency of salvage RIT for early rituximab refractory PTLDs without any unexpected toxicity.

  8. Rituximab Can Induce Remission in a Patient with Ankylosing Spondylitis Who Failed Anti-TNF-α Agent

    PubMed Central

    AlDhaheri, Fahmi; Almteri, Talal; Dwid, Naji; Majdali, Ahd; Janoudi, Nahed; Almoallim, Hani

    2017-01-01

    Patient: Male, 38 Final Diagnosis: Ankylosing spondylitis Symptoms: Back pain • morning stiffness Medication: — Clinical Procedure: Not applicable Specialty: Rheuamatology Objective: Unusual or unexpected effect of treatment Background: Ankylosing spondylitis (AS) is a chronic inflammatory disease that predominantly affects the axial skeleton. The ability of anti-TNF-α agents to reduce disease activity in patients with axial spondyloarthritis (axSpA), including AS, has been demonstrated in multiple randomized trials and several meta-analyses. Reports on the efficacy of rituximab in treatment of AS have described good results. We report on a patient with AS who failed anti-TNF-α therapy but showed good clinical improvement with rituximab therapy. Case Report: A 38-year-old male patient was diagnosed with AS and showed poor response to sulfasalazine and non-steroidal anti-inflammatory drugs (NSAIDs). Infliximab was initiated with marked improvement as per the Bath ankylosing spondylitis disease activity index (BASDAI). Due to disease flare, the patient was switched to etanercept. He subsequently acquired papillary thyroid cancer and etanercept was discontinued. He underwent a total thyroidectomy followed by radioiodine therapy. For his ongoing active disease, NSAIDs and sulfasalazine were resumed with a lack of response (BASDAI=7.1). Rituximab was started and resulted in significant improvement (BASDAI=2.3). Conclusions: Rituximab can be a potential target therapy for patients who start to lose response to TNF-inhibitors or for those who develop solid malignancies. Further placebo-controlled studies are required. PMID:28179619

  9. Treatment with rituximab and brentuximab vedotin in a patient of common variable immune deficiency-associated classic Hodgkin lymphoma.

    PubMed

    Rael, Efren; Rakszawski, Kevin; Koller, Kristian; Bayerl, Michael; Butte, Manish; Zheng, Hong

    2016-01-01

    Patients with common variable immunodeficiency (CVID) have an increased risk of developing lymphoproliferative diseases, including non-Hodgkins lymphoma (Blood 116:1228-1234, 2010; Blood 119:1650-7, 2012). The incidence and prognosis of Hodgkin lymphoma in this population is not clear, with only a few case reports in the literature. Conventional cytotoxic chemotherapy, although highly efficacious in treating Hodgkin lymphoma in immune competent patients, is problematic in patients with CVID due to the increased risk of infectious complications (Ther Umsch 69:687-91, 2012; Pediatr Hematol Oncol 24:337-42, 2012). Rituximab and brentuximab vedotin are both targeted agents used to treat lymphomas that express CD20 and CD30, respectively. Compared to cytotoxic chemotherapy typically used in Hodgkin lymphoma, these agents are better tolerated with minimal side effects. This makes them an attractive option for treating lymphoma in patients who have significant co-morbidities, including those with immune deficiencies. Additionally, rituximab has been used safely to treat autoimmune cytopenias in patients with CVID5. However, the role of these targeted therapies in CVID-associated Hodgkin lymphoma has not been reported. Here we report the case of a 25 year old female diagnosed with CVID-associated classic Hodgkin lymphoma, who achieved a complete remission following treatment with rituximab followed by brentuximab vedotin. We demonstrate that rituximab and brentuximab are likely safe and effective in CVID-associated Hodgkin lymphoma, providing a feasible and potentially optimal treatment option for this patient population.

  10. Rituximab in severe skin diseases: target, disease, and dose

    PubMed Central

    Bennett, Daniel D; Ohanian, Maro; Cable, Christian T

    2010-01-01

    New clinical indications for rituximab seem to appear every day. This review will trace the use of this monoclonal antibody from lymphoid malignancy, to classic autoimmune disease, and specifically severe autoimmune skin diseases. The history leading to different dosing schema with associated pharmacokinetic data will be discussed. A case of livedoid vasculopathy (atrophie blanche) responding to rituximab will illustrate how the response to therapy can help to elucidate previously obscure pathophysiology. PMID:22291497

  11. Clinical evaluation of rituximab treatment for neuromyelitis optica.

    PubMed

    Fernández-Megía, M J; Casanova-Estruch, B; Pérez-Miralles, F; Ruiz-Ramos, J; Alcalá-Vicente, C; Poveda-Andrés, J L

    2015-10-01

    Neuromyelitis optica is an inflammatory and usually relapsing demyelinating autoimmune disease of the central nervous system that targets the optic nerves and spinal cord. Rituximab has been used for different neurological diseases that are probably immune-mediated or involving humoural immunity. The objective of this study is to evaluate the efficacy and safety of rituximab as treatment for neuromyelitis optica in a tertiary hospital. Retrospective study of patients with neuromyelitis optica treated with rituximab 1000mg on days 1 and 15, repeated every 6 to 8 months. We recorded EDSS score, relapse rate, overall condition, CD19+ count, presence of anti-NMO antibodies, and possible adverse reactions. Six patients were treated; all were women with a median age of 46 years (range, 38-58). Anti-NMO antibodies were detected in 3 patients (50%). Baseline EDSS was 4 (range 2.0-5.5). Two patients had previously been treated with an immunomodulatory drug. Median time from the first rituximab infusion to first relapse was 3.7 years (range 1.7-6.9). Two patients had infusion reactions after the first dose of rituximab. Four patients remained relapse-free and their EDSS score did not progress during rituximab treatment, one patient showed no clinical improvement, and one patient could not be evaluated. Rituximab can be considered an attractive therapeutic alternative for patients with neuromyelitis optica as there are no approved treatments for this disease. Further studies with rituximab are needed to establish the role of this drug in treating neuromyelitis optica. Copyright © 2013 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

  12. Rituximab in Lymphoma and Chronic Lymphocytic Leukaemia: A Practice Guideline.

    PubMed

    Prica, A; Baldassarre, F; Hicks, L K; Imrie, K; Kouroukis, T; Cheung, M

    2017-01-01

    Rituximab is the first monoclonal antibody to be approved for use by the US Food and Drug Administration in cancer. Its role in the treatment of non-Hodgkin lymphoma, including chronic lymphocytic leukaemia (CLL), has evolved significantly. We aimed to systematically review and update the literature on rituximab in lymphoma and CLL, and provide evidence-based consensus guidelines for its rational use. Validated methodology from the Cancer Care Ontario Program in Evidence-based Care was used. A comprehensive literature search was completed by a methodologist from the Hematology Disease Site Group of Cancer Care Ontario. Data were extracted from randomised controlled trials of rituximab-containing chemotherapy regimens for patients with lymphoma or CLL. Fifty-six primary randomised controlled trials were retrievable and met all inclusion criteria. Clinically important benefits in progression-free survival or overall survival were seen in the following settings: (i) addition of rituximab to combination chemotherapy for initial treatment of aggressive B-cell lymphomas, including diffuse large B-cell lymphoma, Burkitt lymphoma and HIV-related lymphoma with CD4 count ≥50/mm(3); (ii) addition of rituximab to combination chemotherapy for initial and subsequent treatment of follicular lymphoma and other indolent B-cell lymphomas; (iii) use of rituximab maintenance in patients with indolent B-cell lymphomas who have responded to chemoimmunotherapy; (iv) addition of rituximab to fludarabine-based chemotherapy or chlorambucil for initial treatment of CLL. The consensus opinion of the Hematology Disease Site Group is that rituximab is recommended for these indications. Copyright © 2016 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

  13. Lymph Node Flow Cytometry as a Prompt Recognition of Ultra Early Onset PTLD: A Successful Case of Rituximab Treatment

    PubMed Central

    Li, Xiaofan; Li, Nainong; Yang, Ting; Chen, Zhizhe; Hu, Jianda

    2015-01-01

    Ultra early posttransplantation lymphoproliferative disorder (PTLD) is a rare and fatal complication after hematopoietic stem cell transplantation (HSCT). Here we report, by lymph node (LN) flowcytometry, that we early recognized ultra early PTLD after an HLA-matched sibling allo-HSCT followed by a successful treatment with anti-CD20 antibody (rituximab) in a patient in progress disease for angioimmunoblastic T-cell lymphoma (AITL). The patient was conditioned with a reduced intensity conditioning (RIC) regimen. One week after transplantation, the patient developed high fever, generalized fatigue, high Epstein-Barr virus (EBV) load, and LN enlargement. An LN lymphocyte suspension and peripheral blood flowcytometry was performed to find majority of LN lymphocytes highly expressed CD20. By highly suspicious PTLD, 4 doses of rituximab (375 mg/m2 qw) were given immediately followed by reducing and withdrawing immunosuppressant reagent. PTLD was later confirmed by pathology. The patient had good response to rituximab, showing absence of fever, reduction in LN size, and no detectable EBV-DNA. Twenty months after HSCT, the patient remains well without evidence of AITL and PTLD. The current report is one of the earliest cases of PTLD after HSCT. Taken together, by LN flowcytometry as a prompt recognition, rituximab can be an effective preemptive therapy for ultra early developed PTLD. PMID:25878909

  14. Acquired haemophilia A in a patient with chronic hepatitis C virus infection receiving treatment with pegylated interferon plus ribarivin: role of rituximab.

    PubMed

    Fernández de Palencia Espinosa, M Á; Arocas Casañ, V; Garrido Corro, B; de la Rubia Nieto, A

    2013-01-01

    Antecedentes: la hemofilia adquirida es un trastorno infrecuente causado por el desarrollo de inhibidores del factor de coagulación. Para eliminarlos, se requiere tratamiento con corticoides y fármacos citotóxicos. Métodos: describimos el caso del uso de rituximab en hemofilia adquirida refractaria al tratamiento convencional en un hombre de 63 años con infección crónica por el virus de la hepatitis C y que estaba recibiendo tratamiento con interferón pegilado a-2a y ribarivina. Resultados: tras 21 semanas de tratamiento antivírico, el paciente fue ingresado en el hospital por un gran hematoma en la musculatura abdominal. La concentración de factor VIII era nula y el título de inhibidor fue de 345 unidades Bethesda. Se administró tratamiento inmunosupresor oral con metilprednisolona y ciclofosfamida durante 1 mes, con escasa mejoría. Así pues, se sustituyó la ciclofosfamida por una dosis semanal de rituximab intravenoso. Dos meses después, la concentración de factor VIII se normalizó y el título de inhibidor era indetectable. Conclusión: Rituximab puede ser útil en el tratamiento de la hemofilia adquirida resistente al tratamiento estándar.

  15. Design, expression and characterization of a single chain anti-CD20 antibody; a germline humanized antibody derived from Rituximab.

    PubMed

    Ahmadzadeh, Vahideh; Farajnia, Safar; Hosseinpour Feizi, Mohammad Ali; Khavarinejad, Ramazan Ali

    2014-10-01

    CD20 is a B cell lineage specific surface antigen involved in various B cell malignancies. So far, several murine and chimeric antibodies have been produced against this antigen among which Rituximab is a commercially approved antibody widely used in treatment of cancers associated with CD20 overexpression. The current study reports the production and characterization of a humanized single chain version of Rituximab through CDR grafting method. For either heavy or light chain variable domains, a human antibody with the highest sequence homology to Rituximab was selected from human germline sequences and used as framework donors. Vernier zone residues in framework regions were replaced with those of Rituximab to retain the antigen binding affinity of parental antibody. The reactivity of humanized single chain antibody with CD20 was examined by ELISA and dot blot assays. The ability of antibody to suppress the growth of CD20 overexpressing Raji cells was tested by MTT assay. Analysis of reactivity with CD20 antigen revealed that the humanized single chain antibody reacted to the target antigen with high affinity. Proliferation inhibition assay showed that humanized scFv could suppress the proliferation of Raji cells efficiently in a dose-dependent manner. This successful production of a humanized scFv with the ability to inhibit growth of CD20-expressing cancer cell may provide a promising alternative strategy for CD20 targeted therapy.

  16. 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

  17. Time-Dependent Structural Alteration of Rituximab Analyzed by LC/TOF-MS after a Systemic Administration to Rats

    PubMed Central

    Otani, Yuki; Tsuda, Masahiro; Imai, Satoshi; Ikemi, Yasuaki; Nakagawa, Shunsaku; Omura, Tomohiro; Nakagawa, Takayuki; Yano, Ikuko; Matsubara, Kazuo

    2017-01-01

    Therapeutic monoclonal antibodies (mAbs) have heterogeneities in their structures. Multiple studies have reported that the variety of post-translational modifications could affect the pharmacokinetic profiles or pharmacological potencies of therapeutic mAbs. Taking into the account that the structural modification of mAbs would affect the efficacy, it is worth investigating the structural alteration of therapeutic mAbs in the blood and the relationship between their structures and pharmacological effects. Herein, we have developed the method to isolate rituximab from plasma in which endogenous IgGs interfere the detection of rituximab, and successfully developed the analytical method with a liquid chromatograph time-of-flight mass spectrometer to detect the structure of rituximab in plasma with errors less than 30 parts per millions. Eight types of carbohydrate chains in rituximab were detected by this method. Interestingly, time-dependent changes in carbohydrate chains such as AAF (G2F) and GnGn (G0) were observed in rats, although the amino acids were stable. Additionally, these structural changes were observed via incubation in plasma as in the rat experiment, suggesting that a certain type of enzyme in plasma caused the alterations of the carbohydrate chains. The present analytical methods could clarify the actual pharmacokinetics of therapeutic mAbs, and help to evaluate the interindividual variations in pharmacokinetics and efficacy. PMID:28052138

  18. Population pharmacokinetics of rituximab with or without plasmapheresis in kidney patients with antibody-mediated disease

    PubMed Central

    Puisset, Florent; White-Koning, Mélanie; Kamar, Nassim; Huart, Antoine; Haberer, Frédérique; Blasco, Hélène; Le Guellec, Chantal; Lafont, Thierry; Grand, Anaïs; Rostaing, Lionel; Chatelut, Etienne; Pourrat, Jacques

    2013-01-01

    Aims Both rituximab and plasmapheresis can be associated in the treatment of immune-mediated kidney diseases. The real impact of plasmapheresis on rituximab pharmacokinetics is unknown. The aim of this study was to compare rituximab pharmacokinetics between patients requiring plasmapheresis and others without plasmapheresis. Methods The study included 20 patients receiving one or several infusions of rituximab. In 10 patients, plasmapheresis sessions were also performed (between two and six sessions per patient). Rituximab concentrations were measured in blood samples in all patients and in discarded plasma obtained by plasmapheresis using an enzyme-linked immunosorbent assay method. Data were analysed according to a population pharmacokinetic approach. Results The mean percentage of rituximab removed during the first plasmapheresis session ranged between 47 and 54% when plasmapheresis was performed between 24 and 72 h after rituximab infusion. Rituximab pharmacokinetics was adequately described by a two-compartment model with first-order elimination. Plasmapheresis had a significant impact on rituximab pharmacokinetics, with an increase of rituximab clearance by a factor of 261 (95% confidence interval 146–376), i.e. from 6.64 to 1733 ml h−1. Plasmapheresis performed 24 h after rituximab infusion decreased the rituximab area under the curve by 26%. Conclusions Plasmapheresis removed an important amount of rituximab when performed less than 3 days after infusion. The removal of rituximab led to a significant decrease of the area under the curve. This pharmacokinetic observation should be taken into account for rituximab dosing, e.g. an additional third rituximab infusion may be recommended when three plasmapheresis sessions are performed after the first rituximab infusion. PMID:23432476

  19. 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

  20. Rituximab tolerability when given before or after CHOP.

    PubMed

    Hannawa, Idan S; Bestul, Daniel J

    2011-12-01

    To determine the tolerability of rituximab, specifically cytokine release syndrome/acute infusion reactions (CRS), when it is administered before or after cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy in patients with non-Hodgkin's lymphoma (NHL). This study is a retrospective analysis of patients identified through pharmacy chemotherapy records. Inclusion criteria were diagnosis of NHL, first cycle of rituximab with CHOP or modified CHOP (mCHOP), treated between 1/1/04 and 6/30/09, age 18 years and greater, and inpatient status. Patients were excluded if their records/information were unavailable. Patients were divided into two groups based on practices observed at our institution: rituximab followed by CHOP (R-CHOP) or CHOP followed by rituximab (CHOP-R). Patient records were reviewed to determine demographic data, CRS, vital signs, evidence of chills/rigors, use of rescue medications, and rituximab infusion rates. One-hundred thirteen patients meeting the inclusion criteria were divided into two groups: R-CHOP (n=29) and CHOP-R (n=84). R-CHOP patients experienced numerically more CRS (65.5% vs. 42.9%, p=0.0517) and significantly more chills/rigors (p=0.0376). Maximum and minimum oxygen (O(2)) saturations were significantly lower in the R-CHOP group (p=0.0444 and 0.0165, respectively). Maximum temperature was significantly higher in the R-CHOP group (p=0.0047). There was no difference between groups in use of rescue medications (p=1). R-CHOP patients required significantly more rate reductions (p=0.0431) than CHOP-R patients, although there was no difference in final tolerated rate between groups. Patients with NHL who receive rituximab after CHOP experience significantly fewer chills/rigors, higher oxygen saturations, lower maximum temperatures, and fewer rate reductions than patients who receive rituximab before CHOP.

  1. 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

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

    PubMed

    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

    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. 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. 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. In a subgroup of ME/CFS patients, prolonged B-cell depletion with rituximab maintenance infusions was associated with sustained clinical responses. The observed patterns of delayed responses and relapse

  3. 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

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

    PubMed

    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.

  5. 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

  6. Risk of Infection Associated With Subsequent Biologic Agent Use After Rituximab: Results From a National Rheumatoid Arthritis Patient Registry.

    PubMed

    Harrold, Leslie R; Reed, George W; Karki, Chitra; Magner, Robert; Shewade, Ashwini; John, Ani; Kremer, Joel M; Greenberg, Jeffrey D

    2016-12-01

    To assess whether the time between the last rituximab infusion and initiation of a different biologic agent influenced infection risk in patients with rheumatoid arthritis (RA). Patients with RA who newly initiated rituximab within the Consortium of Rheumatology Researchers of North America registry were included if they switched to a nonrituximab biologic agent and had ≥1 followup visit within 12 months of switching. Patients were categorized by duration of time between their last rituximab infusion and initiation of a subsequent biologic agent (≤5 months, 6-11 months, and ≥12 months). The primary outcome was time to first infectious event. Adjusted Cox regression models estimated the association between time to starting a subsequent biologic agent and infection. A total of 44 overall infections (7 serious, 37 nonserious) were reported during the 12-month followup in the 215 patients included in this analysis (104 switched at ≤5 months, 67 at 6-11 months, and 44 at ≥12 months). Median (interquartile range) time to infection was 4 (2-5) months. Infection rates per patient-year in the ≤5-month, 6-11-month, and ≥12-month groups were 0.34 (95% confidence interval [95% CI] 0.22-0.52), 0.30 (95% CI 0.17-0.52), and 0.41 (95% CI 0.22-0.77), respectively. After adjustment, time to switch to a subsequent biologic agent was not associated with infection, which remained unchanged when number and rate of rituximab retreatments were included in the models. In this real-world cohort of patients with RA, infection rates ranged from 0.30 to 0.41 per patient-year, with no significant difference in the rate between patients who initiated a subsequent biologic agent earlier versus later after rituximab treatment. © 2016, The Authors. Arthritis Care & Research published by Wiley Periodicals, Inc. on behalf of the American College of Rheumatology.

  7. A Randomized Phase II Crossover Study of Imatinib or Rituximab for Cutaneous Sclerosis after Hematopoietic Cell Transplantation.

    PubMed

    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

    2016-01-15

    Cutaneous sclerosis occurs in 20% of patients with chronic graft-versus-host disease (GVHD) and can compromise mobility and quality of life. We conducted a prospective, multicenter, randomized, two-arm phase II crossover trial of imatinib (200 mg daily) or rituximab (375 mg/m(2) i.v. weekly × 4 doses, repeatable after 3 months) for treatment of cutaneous sclerosis 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 endpoints included changes of B-cell profiles in blood (BAFF levels and cellular subsets), patient-reported outcomes, and histopathology between responders and nonresponders with each therapy. SCR was observed in 9 of 35 [26%; 95% confidence interval (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. These results support the need for more effective therapies for cutaneous sclerosis and suggest that activated B cells define a subgroup of patients with cutaneous sclerosis who are more likely to respond to rituximab. ©2015 American Association for Cancer Research.

  8. Rituximab preserves vision in ocular mucous membrane pemphigoid.

    PubMed

    Rübsam, Anne; Stefaniak, Richard; Worm, Margitta; Pleyer, Uwe

    2015-07-01

    To study the effectiveness and safety of anti-CD20 B-cell antibody rituximab (RTX) in the treatment of ocular mucous membrane pemphigoid (MMP). Retrospective analysis of six MMP patients receiving RTX with or without concomitant immunosuppression. RTX was administered as a high dose regimen (1000 mg/infusion, day 0 and day 14/cycle). Five patients received more than one cycle. Main outcome measure was the treatment response, defined as complete remission (CR) or partial remission (PR), monitored at 16 and 24 weeks. As secondary outcome measure, drug-related adverse events were evaluated. All patients responded within 16 weeks. Initial treatment response vanished in five of six patients at a mean of 10 months (± 4.4 standard deviation [SD]). A second cycle was initiated thereafter (interval 12 months ± 6.4 SD) resulting in CR in two of five and PR in three of five patients. One patient stabilized only when additional immunosuppression was initiated. Mean follow up was 22 months (± 8.2 SD).Two individuals experienced infusion reactions. Our study adds long-term data to the very limited experience with biologicals in MMP, indicating that RTX is a promising option for patients with advanced disease. We report for the first time the high dose regimen of RTX applied in a consecutive series.

  9. Metabolomic profiling predicts outcome of rituximab therapy in rheumatoid arthritis

    PubMed Central

    Sweeney, Shannon R; Kavanaugh, Arthur; Lodi, Alessia; Wang, Bo; Boyle, David; Tiziani, Stefano; Guma, Monica

    2016-01-01

    Objective: To determine whether characterisation of patients' metabolic profiles, utilising nuclear magnetic resonance (NMR) and mass spectrometry (MS), could predict response to rituximab therapy. 23 patients with active, seropositive rheumatoid arthritis (RA) on concomitant methotrexate were treated with rituximab. Patients were grouped into responders and non-responders according to the American College of Rheumatology improvement criteria, at a 20% level at 6 months. A Bruker Avance 700 MHz spectrometer and a Thermo Scientific Q Exactive Hybrid Quadrupole-Orbitrap mass spectrometer were used to acquire 1H-NMR and ultra high pressure liquid chromatography (UPLC)–MS/MS spectra, respectively, of serum samples before and after rituximab therapy. Data processing and statistical analysis were performed in MATLAB. 14 patients were characterised as responders, and 9 patients were considered non-responders. 7 polar metabolites (phenylalanine, 2-hydroxyvalerate, succinate, choline, glycine, acetoacetate and tyrosine) and 15 lipid species were different between responders and non-responders at baseline. Phosphatidylethanolamines, phosphatidyserines and phosphatidylglycerols were downregulated in responders. An opposite trend was observed in phosphatidylinositols. At 6 months, 5 polar metabolites (succinate, taurine, lactate, pyruvate and aspartate) and 37 lipids were different between groups. The relationship between serum metabolic profiles and clinical response to rituximab suggests that 1H-NMR and UPLC–MS/MS may be promising tools for predicting response to rituximab. PMID:27651926

  10. Metabolomic profiling predicts outcome of rituximab therapy in rheumatoid arthritis.

    PubMed

    Sweeney, Shannon R; Kavanaugh, Arthur; Lodi, Alessia; Wang, Bo; Boyle, David; Tiziani, Stefano; Guma, Monica

    2016-01-01

    To determine whether characterisation of patients' metabolic profiles, utilising nuclear magnetic resonance (NMR) and mass spectrometry (MS), could predict response to rituximab therapy. 23 patients with active, seropositive rheumatoid arthritis (RA) on concomitant methotrexate were treated with rituximab. Patients were grouped into responders and non-responders according to the American College of Rheumatology improvement criteria, at a 20% level at 6 months. A Bruker Avance 700 MHz spectrometer and a Thermo Scientific Q Exactive Hybrid Quadrupole-Orbitrap mass spectrometer were used to acquire (1)H-NMR and ultra high pressure liquid chromatography (UPLC)-MS/MS spectra, respectively, of serum samples before and after rituximab therapy. Data processing and statistical analysis were performed in MATLAB. 14 patients were characterised as responders, and 9 patients were considered non-responders. 7 polar metabolites (phenylalanine, 2-hydroxyvalerate, succinate, choline, glycine, acetoacetate and tyrosine) and 15 lipid species were different between responders and non-responders at baseline. Phosphatidylethanolamines, phosphatidyserines and phosphatidylglycerols were downregulated in responders. An opposite trend was observed in phosphatidylinositols. At 6 months, 5 polar metabolites (succinate, taurine, lactate, pyruvate and aspartate) and 37 lipids were different between groups. The relationship between serum metabolic profiles and clinical response to rituximab suggests that (1)H-NMR and UPLC-MS/MS may be promising tools for predicting response to rituximab.

  11. Cytomegalovirus enterocolitis in a patient with diffuse large B-cell lymphoma after chemotherapy with rituximab.

    PubMed

    Seewoodhary, Jason

    2006-12-07

    Rituximab has been associated with the development of cytomegalovirus enterocolitis in immunosuppressed patients. A 51-year-old patient with diffuse large B-cell lymphoma who received a conditioning chemotherapy regimen (RCVP and RICE) consisting of rituximab before bone marrow transplantation went on to develop cytomegalovirus enterocolitis. This supports evidence from previously described cases that rituximab may be associated with cytomegalovirus enterocolitis.

  12. Results of a phase I-II study of fenretinide and rituximab for patients with indolent B-cell lymphoma and mantle cell lymphoma.

    PubMed

    Cowan, Andrew J; Stevenson, Phillip A; Gooley, Ted A; Frayo, Shani L; Oliveira, George R; Smith, Stephen D; Green, Damian J; Roden, Jennifer E; Pagel, John M; Wood, Brent L; Press, Oliver W; Gopal, Ajay K

    2017-02-01

    Fenretinide, a synthetic retinoid, induces apoptotic cell death in B-cell non-Hodgkin lymphoma (B-NHL) and acts synergistically with rituximab in preclinical models. We report results from a phase I-II study of fenretinide with rituximab for B-NHLs. Eligible diagnoses included indolent B-NHL or mantle cell lymphoma. The phase I design de-escalated from fenretinide at 900 mg/m(2) PO BID for days 1-5 of a 7-day cycle. The phase II portion added 375 mg/m(2) IV rituximab weekly on weeks 5-9 then every 3 months. Fenretinide was continued until progression or intolerance. Thirty-two patients were treated: 7 in phase I, and 25 in phase II of the trial. No dose-limiting toxicities were observed. The phase II component utilized fenretinide 900 mg/m(2) twice daily with rituximab. The most common treatment-related adverse events of grade 3 or higher were rash (n = 3) and neutropenia (n = 3). Responses were seen in 6 (24%) patients on the phase II study, with a median duration of response of 47 months (95% confidence interval, 2-56). The combination of fenretinide and rituximab was well tolerated, yielded a modest overall response rate, but with prolonged remission durations. Further study should focus on identifying the responsive subset of B-NHL. © 2017 John Wiley & Sons Ltd.

  13. 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...

  14. 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...

  15. Rituximab in the treatment of non-Hodgkin’s lymphoma

    PubMed Central

    Hauptrock, Beate; Hess, Georg

    2008-01-01

    Besides traditional cytostatic drugs the introduction of monoclonal antibodies has substantially influenced current treatment concepts of non-Hodgkin’s lymphoma (NHL). Rituximab, a monoclonal anti-CD20 chimeric antibody, now has been widely evaluated in the various B-cell lymphatic neoplasms. Large phase III studies helped to prove the value of this drug in follicular lymphoma as part of induction or relapse treatment as well as maintenance treatment. The addition of rituximab to the well established CHOP regimens has increased achievable cure rates in diffuse large cell lymphoma, and this combination is now accepted worldwide as standard of care. Although conflicting results are available, rituximab is widely used for the treatment of mantle cell lymphoma. For the less frequent lymphoma entities phase 2 studies show a considerable efficiency for most of these B-NHL variants. Current research focuses on combined chemoimmunotherapy approaches, optimization of dosing regimens, and combination with novel agents. PMID:19707443

  16. A case of granulomatosis with polyangiitis and pyoderma gangrenosum successfully treated with infliximab and rituximab.

    PubMed

    Donmez, Salim; Pamuk, Omer N; Gedik, Mustafa; A K, Recep; Bulut, Gulay

    2014-05-01

    Here, we present a young male patient who was admitted with alveolar hemorrhage, arthritis and cutaneous lesions, who later developed bilateral orbital involvement and pyoderma gangrenosum (PG). He also had pathergy test positivity. The patient was refractory to conventional immunosuppressive therapy. Therefore, multiple devastating PG lesions and disease activity in granulomatosis with polyangiitis (GPA) were controlled with infliximab. Later, rituximab was used with success to prevent recurrence of symptoms. The relationship of PG with various autoimmune diseases is known; however, PG in GPA has been only rarely reported. Biologic agents might prove to be effective in GPA and PG patients who are refractory to standard immunosuppressive therapy.

  17. [Successful treatment with rituximab in a refractory Stiff-person syndrome].

    PubMed

    Sevy, A; Franques, J; Chiche, L; Pouget, J; Attarian, S

    2012-04-01

    Stiff person syndrome is a rare autoimmune disorder characterized by axial and limb progressive stiffness with surimposed spasms and production of autoantibodies to glutamic acid decarboxylase (GAD). We report a case of a 50-year-old woman who developed a stiff person syndrome resistant to conventional immunosuppressive treatments. Eight months after treatment, indexes of stiffness and spasm frequency improved, while however, the blood and CSF rates of anti-GAD increased. This observation illustrates the complexity of stiff person syndrome immunopathogenesis as well as the relevance of rituximab in this indication.

  18. Benefit from B-Lymphocyte Depletion Using the Anti-CD20 Antibody Rituximab in Chronic Fatigue Syndrome. A Double-Blind and Placebo-Controlled Study

    PubMed Central

    Fluge, Øystein; Bruland, Ove; Risa, Kristin; Storstein, Anette; Kristoffersen, Einar K.; Sapkota, Dipak; Næss, Halvor; Dahl, Olav; Nyland, Harald; Mella, Olav

    2011-01-01

    Background Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients. Methods and Findings In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m2 or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients. The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8–44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6–10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening. Conclusion The delayed responses starting from 2–7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical

  19. Benefit from B-lymphocyte depletion using the anti-CD20 antibody rituximab in chronic fatigue syndrome. A double-blind and placebo-controlled study.

    PubMed

    Fluge, Øystein; Bruland, Ove; Risa, Kristin; Storstein, Anette; Kristoffersen, Einar K; Sapkota, Dipak; Næss, Halvor; Dahl, Olav; Nyland, Harald; Mella, Olav

    2011-01-01

    Chronic fatigue syndrome (CFS) is a disease of unknown aetiology. Major CFS symptom relief during cancer chemotherapy in a patient with synchronous CFS and lymphoma spurred a pilot study of B-lymphocyte depletion using the anti-CD20 antibody Rituximab, which demonstrated significant clinical response in three CFS patients. In this double-blind, placebo-controlled phase II study (NCT00848692), 30 CFS patients were randomised to either Rituximab 500 mg/m(2) or saline, given twice two weeks apart, with follow-up for 12 months. Xenotropic murine leukemia virus-related virus (XMRV) was not detected in any of the patients. The responses generally affected all CFS symptoms. Major or moderate overall response, defined as lasting improvements in self-reported Fatigue score during follow-up, was seen in 10 out of 15 patients (67%) in the Rituximab group and in two out of 15 patients (13%) in the Placebo group (p = 0.003). Mean response duration within the follow-up period for the 10 responders to Rituximab was 25 weeks (range 8-44). Four Rituximab patients had clinical response durations past the study period. General linear models for repeated measures of Fatigue scores during follow-up showed a significant interaction between time and intervention group (p = 0.018 for self-reported, and p = 0.024 for physician-assessed), with differences between the Rituximab and Placebo groups between 6-10 months after intervention. The primary end-point, defined as effect on self-reported Fatigue score 3 months after intervention, was negative. There were no serious adverse events. Two patients in the Rituximab group with pre-existing psoriasis experienced moderate psoriasis worsening. The delayed responses starting from 2-7 months after Rituximab treatment, in spite of rapid B-cell depletion, suggests that CFS is an autoimmune disease and may be consistent with the gradual elimination of autoantibodies preceding clinical responses. The present findings will impact future

  20. Successful early rituximab treatment in a case of systemic lupus erythematosus with potentially fatal diffuse alveolar hemorrhage.

    PubMed

    Na, Ju Ock; Chang, Sung Hae; Seo, Ki-Hyeon; Choi, Jae Sung; Lee, Ho Sung; Lyu, Ji Won; Nah, Seoung-Su

    2015-01-01

    Diffuse alveolar hemorrhage (DAH) is a rare but devastating complication of systemic lupus erythematosus (SLE) with a high early mortality rate. DAH seldom occurs without active organ involvement. Recently, rituximab (RTX), a B cell-targeted therapy, has been reported to be effective for life-threatening autoimmune diseases. We describe a SLE patient who presented with acute respiratory failure due to DAH without other active organ involvement. This condition was dramatically improved with RTX without cyclophosphamide. © 2014 S. Karger AG, Basel.

  1. Randomized Controlled Trial of Rituximab and Cost-Effectiveness Analysis in Treating Fatigue and Oral Dryness in Primary Sjögren's Syndrome.

    PubMed

    Bowman, Simon J; Everett, Colin C; O'Dwyer, John L; Emery, Paul; Pitzalis, Costantino; Ng, Wan-Fai; Pease, Colin T; Price, Elizabeth J; Sutcliffe, Nurhan; Gendi, Nagui S T; Hall, Frances C; Ruddock, Sharon P; Fernandez, Catherine; Reynolds, Catherine; Hulme, Claire T; Davies, Kevin A; Edwards, Christopher J; Lanyon, Peter C; Moots, Robert J; Roussou, Euthalia; Giles, Ian P; Sharples, Linda D; Bombardieri, Michele

    2017-07-01

    To investigate whether rituximab, an anti-B cell therapy, improves symptoms of fatigue and oral dryness in patients with primary Sjögren's syndrome (SS). We conducted a multicenter, randomized, double-blind, placebo-controlled, parallel-group trial that included health economic analysis. Anti-Ro-positive patients with primary SS, symptomatic fatigue, and oral dryness were recruited from 25 UK rheumatology clinics from August 2011 to January 2014. Patients were centrally randomized to receive either intravenous (IV) placebo (250 ml saline) or IV rituximab (1,000 mg in 250 ml saline) in 2 courses at weeks 0, 2, 24, and 26, with pre- and postinfusion medication including corticosteroids. The primary end point was the proportion of patients achieving a 30% reduction in either fatigue or oral dryness at 48 weeks, as measured by visual analog scale. Other outcome measures included salivary and lacrimal flow rates, quality of life, scores on the European League Against Rheumatism (EULAR) Sjögren's Syndrome Patient Reported Index and EULAR Sjögren's Syndrome Disease Activity Index, symptoms of ocular and overall dryness, pain, globally assessed disease activity, and cost-effectiveness. All 133 patients who were randomized to receive placebo (n = 66) or rituximab (n = 67) were included in the primary analysis. Among patients with complete data, 21 of 56 placebo-treated patients and 24 of 61 rituximab-treated patients achieved the primary end point. After multiple imputation of missing outcomes, response rates in the placebo and rituximab groups were 36.8% and 39.8%, respectively (adjusted odds ratio 1.13 [95% confidence interval 0.50, 2.55]). There were no significant improvements in any outcome measure except for unstimulated salivary flow. The mean ± SD costs per patient for rituximab and placebo were £10,752 ± 264.75 and £2,672 ± 241.71, respectively. There were slightly more adverse events (AEs) reported in total for rituximab, but there was

  2. Rituximab in Children with Resistant Idiopathic Nephrotic Syndrome

    PubMed Central

    Magnasco, Alberto; Ravani, Pietro; Edefonti, Alberto; Murer, Luisa; Ghio, Luciana; Belingheri, Mirco; Benetti, Elisa; Murtas, Corrado; Messina, Giovanni; Massella, Laura; Porcellini, Maria Gabriella; Montagna, Michela; Regazzi, Mario; Scolari, Francesco

    2012-01-01

    Idiopathic nephrotic syndrome resistant to standard treatments remains a therapeutic dilemma in pediatric nephrology. To test whether the anti-CD20 monoclonal antibody rituximab may benefit these patients, we conducted an open-label, randomized, controlled trial in 31 children with idiopathic nephrotic syndrome unresponsive to the combination of calcineurin inhibitors and prednisone. All children continued prednisone and calcineurin inhibitors at the doses prescribed before enrollment, and one treatment group received two doses of rituximab (375 mg/m2 intravenously) as add-on therapy. The mean age was 8 years (range, 2–16 years). Rituximab did not reduce proteinuria at 3 months (change, −12% [95% confidence interval, −73% to 110%]; P=0.77 in analysis of covariance model adjusted for baseline proteinuria). Additional adjustment for previous remission and interaction terms (treatment by baseline proteinuria and treatment by previous remission) did not change the results. In conclusion, these data do not support the addition of rituximab to prednisone and calcineurin inhibitors in children with resistant idiopathic nephrotic syndrome. PMID:22581994

  3. The BAFFling effects of rituximab in lupus: danger ahead?

    PubMed

    Ehrenstein, Michael R; Wing, Charlotte

    2016-06-01

    Suboptimal trial design and concurrent therapies are thought to account for the unexpected failure of two clinical trials of rituximab in patients with systemic lupus erythematosus (SLE). However, in this Opinion article we propose an alternative explanation: that rituximab can trigger a sequence of events that exacerbates disease in some patients with SLE. Post-rituximab SLE flares that are characterized by high levels of antibodies to double-stranded DNA are associated with elevated circulating BAFF (B-cell-activating factor, also known as TNF ligand superfamily member 13B or BLyS) levels, and a high proportion of plasmablasts within the B-cell pool. BAFF not only perpetuates autoreactive B cells (including plasmablasts), particularly when B-cell numbers are low, but also stimulates T follicular helper (TFH) cells. Moreover, plasmablasts and TFH cells promote each others' formation. Thus, repeated rituximab infusions can result in a feedback loop characterized by ever-rising BAFF levels, surges in autoantibody production and worsening of disease. We argue that B-cell depletion should be swiftly followed by BAFF inhibition in patients with SLE.

  4. Treatment of EBV-associated nodular sclerosing Hodgkin lymphoma in a patient with ataxia telangiectasia with brentuximab vedotin and reduced COPP plus rituximab.

    PubMed

    Meister, Michael T; Voss, Sandra; Schwabe, Dirk

    2015-11-01

    Patients with ataxia telangiectasia (AT) with malignancies face poor prognosis due to increased treatment-related toxicity. Here, we report a 14-year-old male with AT and Hodgkin lymphoma (HL) who received brentuximab vedotin and reduced COPP plus rituximab courses. This treatment resulted in complete remission and showed no severe toxicity. © 2015 Wiley Periodicals, Inc.

  5. Rapid complete response using intrathecal rituximab in a patient with leptomeningeal lymphomatosis due to mantle cell lymphoma.

    PubMed

    Villela, Luis; García, Mauricio; Caballero, Rocío; Borbolla-Escoboza, José R; Bolaños-Meade, Javier

    2008-10-01

    Mantle cell lymphoma (MCL) is a B-cell lymphoid tumor that expresses CD20 and is associated with a poor prognosis. Central nervous system involvement has been associated with particularly dismal outcome. We report a 62-year-old male with MCL and meningeal lymphomatosis. The patient was treated with intrathecal rituximab (IT-R) 25 mg every third day for five doses with clearance of tumor after the third dose. Systemic therapy consisted of R-HyperCVAD alternating with rituximab, high-dose methotrexate, and cytarabine every 21 days, with IT-R on day 1 of each chemotherapy cycle. The patient was consolidated with an autologous stem cell transplant and remains in remission 23 months later. The use of IT-R and conventional intrathecal chemotherapy in MCLs is discussed here.

  6. Rapid complete response using intrathecal rituximab in a patient with leptomeningeal lymphomatosis due to mantle cell lymphoma

    PubMed Central

    Villela, Luis; García, Mauricio; Caballero, Rocío; Borbolla-Escoboza, José R.; Bolaños-Meade, Javier

    2015-01-01

    Mantle cell lymphoma (MCL) is a B-cell lymphoid tumor that expresses CD20 and is associated with a poor prognosis. Central nervous system involvement has been associated with particularly dismal outcome. We report a 62-year-old male with MCL and meningeal lymphomatosis. The patient was treated with intrathecal rituximab (IT-R) 25mg every third day for five doses with clearance of tumor after the third dose. Systemic therapy consisted of R-HyperCVAD alternating with rituximab, high-dose methotrexate, and cytarabine every 21 days, with IT-R on day 1 of each chemotherapy cycle. The patient was consolidated with an autologous stem cell transplant and remains in remission 23 months later. The use of IT-R and conventional intrathecal chemotherapy in MCLs is discussed here. PMID:18766006

  7. Refractory heparin induced thrombocytopenia with thrombosis (HITT) treated with therapeutic plasma exchange and rituximab as adjuvant therapy.

    PubMed

    Schell, Amy M; Petras, Melissa; Szczepiorkowski, Zbigniew M; Ornstein, Deborah L

    2013-10-01

    We report a case of refractory heparin-induced thrombocytopenia with thrombosis (HITT) with prolonged thrombocytopenia and multiple thrombotic complications that failed to improve despite aggressive treatment. A 60 year old female with a prior history of venous thromboembolism was admitted with an acute pulmonary embolism, and developed HITT after several days on heparin therapy. She suffered multiple complications including bilateral venous limb gangrene, acute renal failure, and refractory thrombocytopenia, leading us to use multimodality therapy including therapeutic plasma exchange (TPE) and rituximab immunosuppression. The patient had transient improvements in her thrombocytopenia with TPE, and rituximab was added in an attempt to reduce antibody production. She eventually required bilateral limb amputation, and only after removal of the gangrenous limbs did her platelet count show sustained improvement. We discuss the possible contribution of infection to her prolonged course.

  8. B Cell Reconstitution after Rituximab Treatment in Idiopathic Nephrotic Syndrome

    PubMed Central

    Carsetti, Rita; Cascioli, Simona; Casiraghi, Federica; Perna, Annalisa; Ravà, Lucilla; Ruggiero, Barbara; Emma, Francesco; Vivarelli, Marina

    2016-01-01

    The pathogenesis of nephrotic syndrome is unclear. However, the efficacy of rituximab, a B cell–depleting antibody, in nephrotic syndrome suggests a pathogenic role of B cells. In this retrospective study, we determined by flow cytometry levels of B and T cell subpopulations before and after rituximab infusion in 28 pediatric patients with frequently relapsing or steroid–dependent nephrotic syndrome. At baseline, patients had lower median percentages of transitional and mature B cells than age–matched healthy controls (P<0.001). Rituximab induced full depletion of B cells (<1% of lymphocytes). At 1 year, most patients exhibited complete total and mature B cell recovery, whereas memory B cell subsets remained significantly depleted. Total T cell concentration did not change with rituximab, whereas the CD4+/CD8+ T cell ratio tended to increase. Fourteen patients relapsed within 24 months, with a median follow-up of 11.2 months (interquartile range, 8–17.7 months). We observed no difference at baseline between nonrelapsing and relapsing patients in several clinical parameters and cell subset concentrations. Reconstitution of all memory B cell subpopulations, number of immunosuppressive drugs, and dose of tacrolimus during the last 4 months of follow-up were predictive of relapse in univariate Cox regression analysis. However, only delayed reconstitution of switched memory B cells, independent of immunosuppressive treatment, was protective against relapse in multivariate (P<0.01) and receiver operator characteristic (P<0.01 for percentage of lymphocytes; P=0.02 for absolute count) analyses. Evaluation of switched memory B cell recovery after rituximab may be useful for predicting relapse in patients with nephrotic syndrome. PMID:26567244

  9. Comparability of Antibody-Mediated Cell Killing Activity Between a Proposed Biosimilar RTXM83 and the Originator Rituximab.

    PubMed

    Cuello, Hector A; Segatori, Valeria I; Alberto, Marina; Pesce, Analía; Alonso, Daniel F; Gabri, Mariano R

    2016-06-01

    Biosimilars are described as biological products that resemble the structure of original biologic therapeutic products, with no clinically meaningful differences in terms of safety and effectiveness from the original. A wide range of biosimilars are under development or are already licensed in many countries. Biosimilars are earning acceptance and becoming a reality for immunotherapy treatments mainly based on the alternatives for the commercial anti-CD20 monoclonal antibody rituximab. The most important mechanism of action reported for this antibody is the induction of antibody-dependent cell cytotoxicity (ADCC), which is associated with the polymorphisms present at the 158 position in the IgG receptor FcγRIIIa. The aim of the study was to validate the functional comparability between the proposed rituximab biosimilar RTXM83 and the original product. To achieve this we assessed the binding capacity and ADCC induction of this biosimilar, taking into account the different FcγRIIIa-158 polymorphisms. Binding capacity was evaluated by flow cytometry using CD20 positive cells and a wide range of antibody concentrations. The FcγRIIIa-158 polymorphisms were analyzed by polymerase chain reaction (PCR) followed by allele-specific restriction enzyme digestion. ADCC was measured by a colorimetric lactate dehydrogenase-release assay, using effector cells from donors with different FcγRIIIa-158 polymorphisms. Binding capacity assay showed no differences between both products. Regarding ADCC, a similar relative potency was obtained between both antibodies, showing a higher response for the FcγRIIIa-158 valine/valine (V/V) polymorphism compared to the phenylalanine/phenylalanine (F/F), for both rituximab and RTXM83. Our data strongly suggest the biocomparability between the proposed biosimilar and the originator rituximab, in antibody recognition and ADCC activity. Additionally, our results suggest that donors with the FcγRIIIa-158V/V polymorphism induce a higher ADCC

  10. Severe infection in patients with rheumatoid arthritis taking anakinra, rituximab, or abatacept: a systematic review of observational studies.

    PubMed

    Cabral, Vanderlea Poeys; Andrade, Carlos Augusto Ferreira de; Passos, Sonia Regina Lambert; Martins, Maria de Fátima Moreira; Hökerberg, Yara Hahr Marques

    2016-10-01

    A question is raised about an increased risk of severe infection from the use of biological drugs in patients with rheumatoid arthritis. This systematic review of observational studies aimed at assessing the risk of severe infection associated with the use of anakinra, rituximab, and abatacept in patients with rheumatoid arthritis. The following databases were searched: PubMed, Science Direct, Scopus, Web of Knowledge, Scirus, Cochrane, Exerpta Medica Database, Scielo, and Lilacs up to July 2010. Severe infections were defined as those life-threatening ones in need of the use of parenteral antibiotics or of hospitalization. Longitudinal observational studies were selected without language restriction, involving adult patients diagnosed with rheumatoid arthritis and who used anakinra, rituximab, or abatacept. In four studies related to anakinra, 129 (5.1%) severe infections were related in 2,896 patients, of which three died. With respect to rituximab, two studies reported 72 (5.9%) severe infections in 1,224 patients, of which two died. Abatacept was evaluated in only one study in which 25 (2.4%) severe infections were reported in 1046 patients. The main site of infection for these three drugs was the respiratory tract. One possible explanation for the high frequency of severe infections associated with anakinra may be the longer follow-up time in the selected studies. The high frequency of severe infections associated with rituximab could be credited to the less strict inclusion criteria for the patients studied. Therefore, infection monitoring should be cautious in patients with rheumatoid arthritis in use of these three drugs.

  11. Severe infection in patients with rheumatoid arthritis taking anakinra, rituximab, or abatacept: a systematic review of observational studies.

    PubMed

    Cabral, Vanderlea Poeys; Andrade, Carlos Augusto Ferreira de; Passos, Sonia Regina Lambert; Martins, Maria de Fátima Moreira; Hökerberg, Yara Hahr Marques

    A question is raised about an increased risk of severe infection from the use of biological drugs in patients with rheumatoid arthritis. This systematic review of observational studies aimed at assessing the risk of severe infection associated with the use of anakinra, rituximab, and abatacept in patients with rheumatoid arthritis. The following databases were searched: PubMed, Science Direct, Scopus, Web of Knowledge, Scirus, Cochrane, Exerpta Medica Database, Scielo, and Lilacs up to July 2010. Severe infections were defined as those life-threatening ones in need of the use of parenteral antibiotics or of hospitalization. Longitudinal observational studies were selected without language restriction, involving adult patients diagnosed with rheumatoid arthritis and who used anakinra, rituximab, or abatacept. In four studies related to anakinra, 129 (5.1%) severe infections were related in 2896 patients, of which three died. With respect to rituximab, two studies reported 72 (5.9%) severe infections in 1224 patients, of which two died. Abatacept was evaluated in only one study in which 25 (2.4%) severe infections were reported in 1046 patients. The main site of infection for these three drugs was the respiratory tract. One possible explanation for the high frequency of severe infections associated with anakinra may be the longer follow-up time in the selected studies. The high frequency of severe infections associated with rituximab could be credited to the less strict inclusion criteria for the patients studied. Therefore, infection monitoring should be cautious in patients with rheumatoid arthritis in use of these three drugs.

  12. 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

  13. Sustained clinical response to rituximab in a case of life-threatening overlap subepidermal autoimmune blistering disease.

    PubMed

    Li, Yaohan; Foshee, J B; Sontheimer, Richard D

    2011-04-01

    The conventional treatment for the autoimmune bullous skin diseases is broad-spectrum immunosuppressive regimen typically combining systemic corticosteroids with adjuvant immunosuppressive therapeutic agents. Orphan diseases in the pemphigus, pemphigoid, and epidermolysis bullosa acquisita groups of clinical disorders are often clinically severe, requiring long-term treatment with such drugs or drug combinations. Rituximab, a chimeric recombinant monoclonal antibody targeting CD20(+) B cells, has recently been suggested to be effective in the treatment of pemphigus with relatively few adverse effects. The clinical value of rituximab in other immune-mediated blistering diseases has been less thoroughly examined. We report a case of a woman who presented initially with the Brunsting-Perry phenotype of cicatricial pemphigoid who subsequently developed severe generalized subepidermal blisters healing with scarring and milia formation thought to be clinically compatible with epidermolysis bullosa acquisita, although type VII collagen autoantibodies were never identified. Treatment with a number of conventional systemic agents was unsuccessful and complicated by methicillin-resistant Staphylococcus aureus-induced cutaneous ulcers and near-fatal gram-negative sepsis. This woman has enjoyed an 18-month complete clinical remission after a single inductive 4-week cycle of intravenous rituximab. This outcome supports the idea that systemic memory B-cell depletion with drugs such as rituximab should be considered for therapeutically refractory subepidermal autoimmune blistering diseases in addition to intraepidermal autoimmune blistering diseases. A potential role for the immunologic phenomenon of epitope spreading in the generation of overlapping features of autoimmune blistering diseases, and its contribution to therapeutic refractoriness ("hardening"), is discussed.

  14. Eficiency of different doses of rituximab in rheumatoid arthritis.

    PubMed

    Mena-Vázquez, Natalia; Manrique-Arija, Sara; Ureña-Garnica, Inmaculada; Romero-Barco, Carmen M; Jiménez-Núñez, Francisco G; Coret, Virginia; Irigoyen-Oyarzábal, María Victoria; Fernández-Nebro, Antonio

    2016-01-01

    Evaluate the effectiveness, cost and safety of rituximab in patients with rheumatoid arthritis (RA) depending on the dose used. Retrospective observational study conducted on 52 patients with RA treated with at least one dose of rituximab for 135.3 patient-years were included. Three treatment groups were obtained: (G1) First course and following two 1g infusions separated by 15 days; (G2) First course 2 infusions of 1g followed by 2 infusions of 500mg; (G3) First course and followed by 2 infusions of 500mg separated by 15 days. Re-treatments were administered on-demand according to the clinical activity. The retention time (Log-Rank), retreats and adverse events rates (incidence rate ratio) and treatment costs per patient-month of rituximab were analysed by groups. Group 2 showed a better cost-effectiveness ratio than group 1, as it was associated with a longer retention of rituximab (mean [95% CI] 65.7 [60.8 to 70.7] months vs 33.5 [22.7 to 44.3]; P<.001) and a lower rate of severe adverse events with only a slight increase in the rate of retreatment (courses/patient-year [95% CI] 1.66 [1.39 to 1.93] vs. 1.01 [0.69 to 1.34]; P=.005), and in the costs (median/patient-month, €484.89 vs. €473.45). Although group 3 was €41.20/patient-month cheaper than group 2, it was associated with a higher rate of re-treatments and shorter retention of rituximab (P<.001). The use of full-dose rituximab at onset, followed by reduced doses in successive courses administered on-demand retreatment may be the most cost-effective option. Copyright © 2015 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  15. Combination of rituximab with chlorambucil as first line treatment in patients with mantle cell lymphoma: a highly effective regimen.

    PubMed

    Sachanas, Sotirios; Pangalis, Gerassimos A; Vassilakopoulos, Theodoros P; Korkolopoulou, Penelope; Kontopidou, Flora N; Athanasoulia, Maria; Yiakoumis, Xanthi; Kalpadakis, Christina; Georgiou, Georgios; Masouridis, Stavroula; Moschogiannis, Maria; Tsirkinidis, Pantelis; Pappis, Vassiliki; Kokoris, Styliani I; Siakantaris, Marina P; Panayiotidis, Panayiotis; Angelopoulou, Maria K

    2011-03-01

    The optimal treatment approach for patients with mantle cell lymphoma (MCL) is not well defined. Intensive therapeutic regimens result in high response rates and prolonged progression-free survival but at the expense of significant toxicity. We report here our results of the administration of rituximab plus chlorambucil (R-Chl) as first line treatment in patients with MCL. Twenty consecutively diagnosed patients were treated with this combination in which an induction and a maintenance arm were included. During induction, rituximab was administered at a dose of 375 mg/m(2) on day 1, while chlorambucil was given afterward at a dose of 10 mg/day for 10 consecutive days for eight cycles and then as a single agent for an additional four cycles. Maintenance consisted of rituximab administration every 2 months for 1 year. Most patients had indolent disease features such as a low mantle-cell international prognostic index (MIPI) score. The overall response rate was 95% (90% CR, 5% PR). Among patients in CR, 78% presented a molecular remission. The 3-year progression-free survival was 89%. There were no serious side effects. These results show that the R-Chl combination could be an effective therapeutic option as first line treatment in MCL, especially for patients with indolent disease characteristics.

  16. Combination Immunosuppressive Therapy Including Rituximab for Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis in Adult-Onset Still's Disease

    PubMed Central

    Schäfer, Eva Johanna; Jung, Wolfram

    2016-01-01

    Hemophagocytic lymphopcytosis (HLH) is a life-threatening condition. It can occur either as primary form with genetic defects or secondary to other conditions, such as hematological or autoimmune diseases. Certain triggering factors can predispose individuals to the development of HLH. We report the case of a 25-year-old male patient who was diagnosed with HLH in the context of adult-onset Still's disease (AOSD) during a primary infection with Epstein-Barr virus (EBV). During therapy with anakinra and dexamethasone, he was still symptomatic with high-spiking fevers, arthralgia, and sore throat. His laboratory values showed high levels of ferritin and C-reactive protein. His condition improved after the addition of rituximab and cyclosporine to his immunosuppressive regimen with prednisolone and anakinra. This combination therapy led to a sustained clinical and serological remission of his condition. While rituximab has been used successfully for HLH in the context of EBV-associated lymphoma, its use in autoimmune diseases is uncommon. We hypothesize that the development of HLH was triggered by a primary EBV infection and that rituximab led to elimination of EBV-infected B-cells, while cyclosporine ameliorated the cytokine excess. We therefore propose that this combination immunosuppressive therapy might be successfully used in HLH occurring in the context of autoimmune diseases. PMID:28018698

  17. Combination Immunosuppressive Therapy Including Rituximab for Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis in Adult-Onset Still's Disease.

    PubMed

    Schäfer, Eva Johanna; Jung, Wolfram; Korsten, Peter

    2016-01-01

    Hemophagocytic lymphopcytosis (HLH) is a life-threatening condition. It can occur either as primary form with genetic defects or secondary to other conditions, such as hematological or autoimmune diseases. Certain triggering factors can predispose individuals to the development of HLH. We report the case of a 25-year-old male patient who was diagnosed with HLH in the context of adult-onset Still's disease (AOSD) during a primary infection with Epstein-Barr virus (EBV). During therapy with anakinra and dexamethasone, he was still symptomatic with high-spiking fevers, arthralgia, and sore throat. His laboratory values showed high levels of ferritin and C-reactive protein. His condition improved after the addition of rituximab and cyclosporine to his immunosuppressive regimen with prednisolone and anakinra. This combination therapy led to a sustained clinical and serological remission of his condition. While rituximab has been used successfully for HLH in the context of EBV-associated lymphoma, its use in autoimmune diseases is uncommon. We hypothesize that the development of HLH was triggered by a primary EBV infection and that rituximab led to elimination of EBV-infected B-cells, while cyclosporine ameliorated the cytokine excess. We therefore propose that this combination immunosuppressive therapy might be successfully used in HLH occurring in the context of autoimmune diseases.

  18. Liver transplantation for HCV-related cirrhosis in a patient with gastric mucosa-associated lymphoma (MALToma) pretreated with rituximab.

    PubMed

    Foxton, Matthew R; Knight, Lisa; Knisely, Alex S; Mufti, Ghulam J; O'Grady, John; Muiesan, Paolo; Norris, Suzanne

    2005-07-01

    End-stage liver disease due to chronic hepatitis C virus (HCV) infection is now the most frequent indication for liver transplantation. HCV infection is associated with extrahepatic disease including cryoglobulinemia and lymphoma. The number of patients requiring liver transplantation (LT) for cirrhosis secondary to HCV infection has increased over the past 10 years; consequently, associated extrahepatic manifestations (in particular hematological malignancies) will be more commonly observed in this patient group. The management of patients with both end-stage liver disease and significant HCV-related extrahepatic disease is undefined. We report a 59-year-old man in whom extranodal marginal-zone B-cell lymphoma arising in gastric mucosa-associated lymphoid tissue (MALToma) was successfully eradicated by rituximab administration and gastrectomy at LT for HCV-related cirrhosis. Our experience with rituximab in this patient suggests that it can be used safely in the setting of severe liver disease due to HCV infection. Rituximab may be useful in preventing progression of NHL until surgical extirpation is possible.

  19. [Successful rituximab treatment for acquired amegakaryocytic thrombocytopenic purpura complicated with Coombs-negative autoimmune hemolytic anemia].

    PubMed

    Hashimoto, Akari; Fujimi, Akihito; Kanisawa, Yuji; Matsuno, Teppei; Okuda, Toshinori; Minami, Shinya; Doi, Tadashi; Ishikawa, Kazuma; Uemura, Naoki; Tomaru, Utano

    2013-06-01

    Acquired amegakaryocytic thrombocytopenic purpura (AATP) is a rare disorder characterized by severe thrombocytopenia associated with total absence or a selective decrease in bone marrow megakaryocytes. A 67-year-old male presented with a 2-month bleeding tendency. He was referred to our hospital because of severe thrombocytopenia. Bone marrow biopsy showed complete absence of megakaryocytes without dysplasia in cells of the myeloid and erythroid lineages. AATP was diagnosed. In addition, mild normocytic normochromic anemia and reticulocytosis were also observed and haptoglobin was below the detectable level. Coombs-negative autoimmune hemolytic anemia (AIHA) was diagnosed based on the high titer of RBC-bound IgG and negative direct and indirect coombs test results. He was first treated with cyclosporine 200 mg per day and subsequently with prednisolone but only slight temporary improvement was achieved. Administration of eight doses of rituximab 375 mg/m(2) per week ameliorated both thrombocytopenia and anemia. AATP should be considered in the differential diagnosis of thrombocytopenia, and immunosuppressive therapy is a potential first-line treatment. This is the first case report of AATP accompanied by AIHA successfully treated with rituximab.

  20. 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. Copyright © 2016. Published by Elsevier Masson SAS.

  1. 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

    2014-12-04

    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.

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

    PubMed Central

    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

    2014-01-01

    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/m2 combined with liposomal doxorubicin 20 mg/m2 (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

  4. Immunochemotherapy with rituximab, methotrexate, procarbazine, and lomustine for primary CNS lymphoma (PCNSL) in the elderly.

    PubMed

    Fritsch, K; Kasenda, B; Hader, C; Nikkhah, G; Prinz, M; Haug, V; Haug, S; Ihorst, G; Finke, J; Illerhaus, G

    2011-09-01

    Primary central nervous system lymphoma (PCNSL) is an aggressive extranodal non-Hodgkin lymphoma confined to the central nervous system. In this article, we report the results of a pilot trial adding rituximab to the established regimen consisting of methotrexate, procarbazine, and lomustine (R-MCP). PCNSL patients ≥65 years without Karnofsky performance score (KPS) limit were included. R-MCP regimen consisted of rituximab (375 mg/m(2) i.v. on days -6, 1, 15, and 29), methotrexate (3 g/m(2) i.v., days 2, 16, and 30) followed by folinic rescue, procarbazine (60 mg/m(2) orally, days 2-11), and lomustine (110 mg/m(2) orally, day 2). A maximum of three 43-day cycles were applied. Primary end point was response to treatment obtained by magnetic resonance imaging. Secondary end points were overall survival (OS) and progression-free survival (PFS). Twenty-eight patients were included (median age 75, median KPS 60%). Best documented response: complete remission in 18 of 28 (64%), partial remission in 5 of 28 (18%), stable disease in 1 of 28 (4%), and progressive disease in 2 of 28 (7%) patients. Response was not assessed in two patients. Two treatment-associated deaths were observed. After a median follow-up of 36 months, the 3-year PFS and OS was 31%. R-MCP regimen is well tolerated and active in elderly patients with newly diagnosed PCNSL.

  5. 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.

  6. [Optimizing rheumatoid arthritis treatment with rituximab--individualized patient approach].

    PubMed

    Novak, Srdan

    2010-01-01

    Disease activity assessment is a cornerstone of monitoring rheumatoid arthritis (RA) development and guidance for rituximab treatment. Beside clinical signs and symptoms biomarkers (RF and anti-CCP) are important early predictors of response to therapy and they can predict disease development. Autoantibody (RF and anti-CCP) seropositivity has been associated with positive response to rituximab (RTX) in antiTNF-IR patients, DMARD-IR patients and MTX-naive patients. Selecting therapy for TNF-IR patients providing most likely response it should be taken in consideration results form recently published assessments demonstrating for RTX treated patients significant improvement in DAS28 from baseline versus alternative TNF inhibitor treatment. Recently published NICE treatment guideline is recommending upon antiTNF failure RTX treatment (in combination with MTX) instead antiTNF cycling.

  7. Autologous transplant for relapsed follicular lymphoma: impact of pre-transplant rituximab sensitivity.

    PubMed

    Phipps, Colin; Gopal, Ajay K; Storer, Barry E; Cassaday, Ryan D; Press, Oliver W; Till, Brian G; Pagel, John M; Palanca-Wessels, Maria C; Philip, Mary; Bensinger, William I; Holmberg, Leona A; Shustov, Andrei R; Green, Damian J; Chauncey, Thomas; Maloney, David G; Libby, Edward N

    2015-01-01

    Patients with rituximab-refractory follicular lymphoma (FL) have limited options. Before the rituximab era, autologous stem cell transplant (ASCT) was shown to improve outcomes in chemotherapy-sensitive, relapsed FL, but the impact of rituximab-sensitivity on these results is unknown. We analyzed 194 consecutive relapsed patients with FL who underwent ASCT at out center and categorized them as rituximab-sensitive (RS, n = 35), rituximab-refractory (RR, n = 65) or no rituximab (NoR, n = 94) if transplanted before rituximab was used. Progression-free survival at 3 years was 85% in RS and 35% in RR patients (p = 0.0004). Only rituximab-sensitivity was significant on multivariate analysis with improved overall survival (OS) (hazard ratio [HR] 0.24, p = 0.01) and progression-free survival (PFS) (HR 0.35, p = 0.006) in RS patients and increased relapse in RR patients (HR 2.11, p = 0.01). Pre-transplant rituximab-sensitivity is a strong independent predictor of post-transplant outcomes in relapsed FL, although one-third of RR patients achieved a PFS of over 3 years with ASCT.

  8. Rapid-Infusion Rituximab in Lymphoma Treatment: 2-Year Experience in a Single Institution

    PubMed Central

    Atay, Sevcan; Barista, Ibrahim; Gundogdu, Fatma; Akgedik, Kiymet; Arpaci, Afey

    2012-01-01

    Purpose: Rituximab is a chimeric anti-CD20 monoclonal antibody. We aimed to explore the safety and tolerability of rapid infusion rituximab, (over 90 minutes) in patients with non-Hodgkin's lymphoma at Hacettepe University Department of Medical Oncology. Patients and Methods: Adult patients diagnosed with non-Hodgkin's lymphoma who were to receive rituximab were included in the study. The schedule of administration for cycle 1 was unaltered and delivered according to the product monograph. All subsequent cycles were administered over a total infusion time of 90 minutes (20% of the dose in the first 30 minutes, then the remaining 80% over 60 minutes, total dose delivered in 500 mL). All patients were observed for infusion-related reactions during the rituximab infusion, and vital signs were recorded every 15 minutes. Results: From July 2006 to December 2008, 75 patients with non-Hodgkin's lymphoma were treated with rituximab-based chemotherapy. A total of 372 infusions were administered. The majority of patients were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, or rituximab only. The 90-minute rituximab infusion schedule was well tolerated, with no grade 3 or 4 infusion-related adverse events observed. Conclusion: A rapid infusion rituximab over 90 minutes is well tolerated and safe when administered as the second and subsequent infusions in the course of therapy. PMID:22942806

  9. Response to rituximab: has the original hypothesis been confirmed?

    PubMed

    Cambridge, Geraldine; Torre, Inmaculada De La

    2015-01-01

    Before the use of rituximab, the strongest accepted evidence for an association between B-cells and rheumatoid arthritis (RA) was that clinical disease was associated with serum autoantibodies. The ability to remove B-cells with rituximab has also revealed the relative importance of the different immunological parameters that underlie the clinical symptoms of RA. First, seropositive patients have a significantly more predictable and favorable clinical response to rituximab than seronegative patients. Second, the kinetics of the clinical response, with a delay of weeks or months after depletion, suggest that it is a B-cell product (autoantibody) and not B-cells per se that need to be reduced for remission to occur. Third, removal of B-cells from joints may not be closely associated with clinical improvement, although maintenance of plasma cell counts in joints has been associated with poorer responses. The requirement of 'new' B-cells generated from the bone marrow for relapse to occur suggests that selection of autoreactive B-cell clones in the periphery may also be necessary for their survival and differentiation into autoantibody-producing cells. The initial hypothesis suggested that the autoimmune response underlying the pathogenesis of RA was self-sustaining. This would seem to be confirmed, as relapse inevitably follows a variable period of reduced clinical symptoms induced by rituximab. In addition, a dominant role for autoantibodies seems to have strong support from clinical practice. In addition to their possible role in the pathogenesis of RA in the form of immune complexes, further investigation is necessary to determine whether autoantibodies contribute to perpetuation of changes in central B-cell tolerance in these patients.

  10. Lenalidomide down-regulates the CD20 antigen and antagonizes direct and antibody-dependent cellular cytotoxicity of rituximab on primary chronic lymphocytic leukemia cells

    PubMed Central

    Lapalombella, Rosa; Yu, Bo; Triantafillou, Georgia; Liu, Qing; Butchar, Jonathan P.; Lozanski, Gerard; Ramanunni, Asha; Smith, Lisa L.; Blum, William; Andritsos, Leslie; Wang, Da-Sheng; Lehman, Amy; Chen, Ching-Shih; Johnson, Amy J.; Marcucci, Guido; Lee, Robert J.; Lee, L. James; Tridandapani, Susheela; Muthusamy, Natarajan

    2008-01-01

    Lenalidomide, an immunomodulatory agent that enhances antibody-dependent cellular cytotoxicity (ADCC), is currently being investigated as a therapy for chronic lymphocytic leukemia (CLL). The anti-CD20 antibody rituximab is active in CLL and represents a rational agent to combine with lenalidomide. We therefore examined whether lenalidomide combined with rituximab enhances direct apoptosis and ADCC in CLL cells. In contrast to previous reports using CD20-positive lymphoma cell lines, lenalidomide down-regulated CD20 surface antigen expression in CLL patient cells via enhanced internalization, without influencing transcription. The CD20 surface antigen internalization enhanced delivery of an oligonucleotide incorporated into anti-CD20 immunoliposomes. In addition, CD20 surface antigen down-modulation by lenalidomide in CLL was accompanied by diminished rituximab-mediated apoptosis and ADCC. These observations suggest a need for alternative sequencing strategies to avoid antagonism between lenalidomide and rituximab therapy in CLL. In addition, they suggest that lenalidomide therapy might be useful to enhance targeted delivery of RNAi-based therapies using CD20 immunoliposomes in B-cell malignancies. PMID:18772452

  11. Neutralization of (NK-cell-derived) B-cell activating factor by Belimumab restores sensitivity of chronic lymphoid leukemia cells to direct and Rituximab-induced NK lysis.

    PubMed

    Wild, J; Schmiedel, B J; Maurer, A; Raab, S; Prokop, L; Stevanović, S; Dörfel, D; Schneider, P; Salih, H R

    2015-08-01

    Natural killer (NK) cells are cytotoxic lymphocytes that substantially contribute to the therapeutic benefit of antitumor antibodies like Rituximab, a crucial component in the treatment of B-cell malignancies. In chronic lymphocytic leukemia (CLL), the ability of NK cells to lyse the malignant cells and to mediate antibody-dependent cellular cytotoxicity upon Fc receptor stimulation is compromised, but the underlying mechanisms are largely unclear. We report here that NK-cells activation-dependently produce the tumor necrosis factor family member 'B-cell activating factor' (BAFF) in soluble form with no detectable surface expression, also in response to Fc receptor triggering by therapeutic CD20-antibodies. BAFF in turn enhanced the metabolic activity of primary CLL cells and impaired direct and Rituximab-induced lysis of CLL cells without affecting NK reactivity per se. The neutralizing BAFF antibody Belimumab, which is approved for treatment of systemic lupus erythematosus, prevented the effects of BAFF on the metabolism of CLL cells and restored their susceptibility to direct and Rituximab-induced NK-cell killing in allogeneic and autologous experimental systems. Our findings unravel the involvement of BAFF in the resistance of CLL cells to NK-cell antitumor immunity and Rituximab treatment and point to a benefit of combinatory approaches employing BAFF-neutralizing drugs in B-cell malignancies.

  12. Treatment of Epstein Barr virus-induced haemophagocytic lymphohistiocytosis with rituximab-containing chemo-immunotherapeutic regimens.

    PubMed

    Chellapandian, DeepakBabu; Das, Rupali; Zelley, Kristin; Wiener, Susan J; Zhao, Huaqing; Teachey, David T; Nichols, Kim E

    2013-08-01

    Haemophagocytic lymphohistiocytosis (HLH) is a life threatening complication of Epstein-Barr virus (EBV) infection. The anti-CD20 antibody rituximab depletes B cells, leading to improved outcomes for patients with EBV-associated B-lymphoproliferative disorders. To gather data on the use of rituximab in EBV-HLH, we performed a retrospective investigation involving 42 EBV-HLH patients who had received treatment with rituximab-containing regimens. On average, patients received 3 rituximab infusions (range 1-10) at a median dose of 375 mg/m(2) . In all patients, rituximab was administered with other HLH-directed medications, including steroids, etoposide and/or ciclosporin. Rituximab-containing regimens appeared well tolerated and improved clinical status in 43% of patients. Examination of laboratory data obtained prior to and within 2-4 weeks after the first rituximab dose revealed significant reductions in EBV load (median load pre-rituximab: 114,200 copies/ml, median post-rituximab: 225 copies/ml, P = 0.0001) and serum ferritin levels (median ferritin pre-rituximab: 4260 μg/l, median post-rituximab: 1149 μg/l, P = 0.001). Thus, when combined with conventional HLH-directed therapies, rituximab improves symptoms, reduces viral load and diminishes inflammation. These data support the incorporation of rituximab into future prospective clinical trials for patients with EBV-HLH. © 2013 John Wiley & Sons Ltd.

  13. Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy.

    PubMed

    Zucca, Emanuele; Conconi, Annarita; Martinelli, Giovanni; Bouabdallah, Reda; Tucci, Alessandra; Vitolo, Umberto; Martelli, Maurizio; Pettengell, Ruth; Salles, Gilles; Sebban, Catherine; Guillermo, Armando Lopez; Pinotti, Graziella; Devizzi, Liliana; Morschhauser, Franck; Tilly, Hervé; Torri, Valter; Hohaus, Stefan; Ferreri, Andrés J M; Zachée, Pierre; Bosly, André; Haioun, Corinne; Stelitano, Caterina; Bellei, Monica; Ponzoni, Maurilio; Copie-Bergman, Christiane; Jack, Andrew; Campo, Elias; Mazzucchelli, Luca; Cavalli, Franco; Johnson, Peter; Thieblemont, Catherine

    2017-03-29

    Purpose There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and Methods Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m(2)/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m(2) intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm. Results At a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination ( P = .0009). Progression-free survival was also significantly better with the combination ( P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded. Conclusion Rituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival.

  14. Autologous Stem Cell Transplantation for Follicular Lymphoma: Favorable Long-Term Survival Irrespective of Pretransplantation Rituximab Exposure.

    PubMed

    Jiménez-Ubieto, Ana; Grande, Carlos; Caballero, Dolores; Yáñez, Lucrecia; Novelli, Silvana; Hernández-Garcia, Miguel Teodoro; Manzanares, María; Arranz, Reyes; Ferreiro, José Javier; Bobillo, Sabella; Mercadal, Santiago; Galeo, Andrea; López Jiménez, Javier; Moraleda, José María; Vallejo, Carlos; Albo, Carmen; Pérez, Elena; Marrero, Carmen; Magnano, Laura; Palomera, Luis; Jarque, Isidro; Martínez-Sánchez, Pilar; Martín, Alejandro; Coria, Erika; López-Guillermo, Armando; Salar, Antonio; Lahuerta, Juan José

    2017-10-01

    High-dose chemotherapy supported by autologous stem cell transplantation (HDT/ASCT) has contributed to modify the natural history of follicular lymphoma (FL); however, an overall survival (OS) benefit has been demonstrated at relapse only after a rituximab-free chemotherapy regimen. A total of 655 patients with FL were reported to the Spanish GELTAMO (Grupo Español de Linfomas y Trasplantes de Médula Ósea) registry and underwent first ASCT between 1989 and 2007. A total of 203 patients underwent ASCT in first complete response (CR1), 174 in second complete response (CR2), 28 in third complete response (CR3), 140 in first partial response (PR1), 81 in subsequent PR, and 29 with resistant/refractory disease; 184 patients received rituximab before ASCT. With a median follow-up of 12 years from ASCT, median progression-free survival (PFS) and overall survival (OS) were 9.7 and 21.3 years, respectively. Actuarial 12-year PFS and OS were 63% (95% confidence interval [CI], 58%-68%) and 73% (95% CI, 68%-78%), respectively, for patients in CR (with a plateau in the curve beyond 15.9 years), 25% (95% CI, 19%-28%) and 49% (95% CI 42%-56%), respectively, for patients in PR, and 23% (95% CI, 8%-48%) and 28% (95% CI, 9%-45%), respectively, for patients with resistant/refractory disease (P < .001). In patients who received rituximab before ASCT, the estimated 9-year PFS and OS from ASCT were 59.5% (95% CI, 51%-67%) and 75% (95% CI, 68%-83%), respectively. Interestingly, for patients who underwent transplantation in CR ≥2 or PR ≥2 who had received rituximab before ASCT (n = 90), 9-year PFS and OS were 61% (95% CI, 51%-73%) and 75% (95% CI, 65%-80%), respectively, with no relapses occurring beyond 5.1 years after ASCT. The cumulative incidence of second malignancies in the global series was 6.7% at 5 years and 12.8% at 10 years. This analysis strongly suggests that ASCT is a potentially curative option for eligible patients with FL. In the setting of relapse, it is

  15. Reactivation of latent viruses in individuals receiving rituximab for new onset type 1 diabetes.

    PubMed

    Kroll, Jing Lu; Beam, Craig; Li, Shaobing; Viscidi, Raphael; Dighero, Bonnie; Cho, Alice; Boulware, David; Pescovitz, Mark; Weinberg, Adriana

    2013-06-01

    Rituximab has been successfully used as an experimental therapy in different autoimmune diseases. Recently, a double-blind placebo-controlled phase-2 study in early onset type 1 diabetes showed that rituximab delayed progression of the disease. However, like with any immunosuppressive therapy, there is a concern of opportunistic viral reactivations with the use of rituximab, including herpes and polyomaviruses. To study the incidence of new infections and reactivations with BK, JC, Epstein-Barr and cytomegalovirus (BKV, JCV, EBV and CMV) in T1D participants in the phase-2 rituximab study. Subjects received 4 weekly doses of rituximab (N = 57) or placebo (N = 30) during the first month of study. Blood samples obtained at weeks 0, 12, 26, 56 and 78 were assayed for CMV, EBV, BKV and JCV by real-time DNA PCR and serology. EBV reactivations were diagnosed by PCR in 25% of placebo, but none of rituximab recipients (p < 0.01). There were no episodes of CMV viremia in either treatment group. BKV viremias were significantly more common in the rituximab recipients (9%) compared with placebo controls (0, p < 0.01). No JCV reactivations were detected in this study, but among 6 rituximab and 2 placebo recipients who seroconverted for JCV during the study, only one rituximab recipient had detectable viremia. All infections were asymptomatic. Four doses of rituximab administered to individuals with early onset T1D decreased the incidence of asymptomatic EBV reactivations, as predicted by the rituximab-mediated elimination of memory B-cells, but increased the frequency of asymptomatic viremias caused by polyomaviruses. Copyright © 2013 Elsevier B.V. All rights reserved.

  16. Real world costs and cost-effectiveness of Rituximab for diffuse large B-cell lymphoma patients: a population-based analysis.

    PubMed

    Khor, Sara; Beca, Jaclyn; Krahn, Murray; Hodgson, David; Lee, Linda; Crump, Michael; Bremner, Karen E; Luo, Jin; Mamdani, Muhammad; Bell, Chaim M; Sawka, Carol; Gavura, Scott; Sullivan, Terrence; Trudeau, Maureen; Peacock, Stuart; Hoch, Jeffrey S

    2014-08-12

    Current treatment of diffuse-large-B-cell lymphoma (DLBCL) includes rituximab, an expensive drug, combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy. Economic models have predicted rituximab plus CHOP (RCHOP) to be a cost-effective alternative to CHOP alone as first-line treatment of DLBCL, but it remains unclear what its real-world costs and cost-effectiveness are in routine clinical practice. We performed a population-based retrospective cohort study from 1997 to 2007, using linked administrative databases in Ontario, Canada, to evaluate the costs and cost-effectiveness of RCHOP compared to CHOP alone. A historical control cohort (n = 1,099) with DLBCL who received CHOP before rituximab approval was hard-matched on age and treatment intensity and then propensity-score matched on sex, comorbidity, and histology to 1,099 RCHOP patients. All costs and outcomes were adjusted for censoring using the inverse probability weighting method. The main outcome measure was incremental cost per life-year gained (LYG). Rituximab was associated with a life expectancy increase of 3.2 months over 5 years at an additional cost of $16,298, corresponding to an incremental cost-effectiveness ratio of $61,984 (95% CI $34,087-$135,890) per LYG. The probability of being cost-effective was 90% if the willingness-to-pay threshold was $100,000/LYG. The cost-effectiveness ratio was most favourable for patients less than 60 years old ($31,800/LYG) but increased to $80,600/LYG for patients 60-79 years old and $110,100/LYG for patients ≥ 80 years old. We found that post-market survival benefits of rituximab are similar to or lower than those reported in clinical trials, while the costs, incremental costs and cost-effectiveness ratios are higher than in published economic models and differ by age. Our results showed that the addition of rituximab to standard CHOP chemotherapy was associated with improvement in survival but at a higher cost, and was

  17. CD30 expression defines a novel subgroup of diffuse large B-cell lymphoma with favorable prognosis and distinct gene expression signature: a report from the International DLBCL Rituximab-CHOP Consortium Program Study

    PubMed Central

    Hu, Shimin; Xu-Monette, Zijun Y.; Balasubramanyam, Aarthi; Manyam, Ganiraju C.; Visco, Carlo; Tzankov, Alexander; Liu, Wei-min; Miranda, Roberto N.; Zhang, Li; Montes-Moreno, Santiago; Dybkær, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L.; Hsi, Eric D.; Choi, William W. L.; Han van Krieken, J.; Huang, Qin; Huh, Jooryung; Ai, Weiyun; Ponzoni, Maurilio; Ferreri, Andrés J. M.; Zhao, Xiaoying; Winter, Jane N.; Zhang, Mingzhi; Li, Ling; Møller, Michael B.; Piris, Miguel A.; Li, Yong; Go, Ronald S.; Wu, Lin; Medeiros, L. Jeffrey; Young, Ken H.

    2013-01-01

    CD30, originally identified as a cell-surface marker of Reed-Sternberg and Hodgkin cells of classical Hodgkin lymphoma, is also expressed by several types of non-Hodgkin lymphoma, including a subset of diffuse large B-cell lymphoma (DLBCL). However, the prognostic and biological importance of CD30 expression in DLBCL is unknown. Here we report that CD30 expression is a favorable prognostic factor in a cohort of 903 de novo DLBCL patients. CD30 was expressed in ∼14% of DLBCL patients. Patients with CD30+ DLBCL had superior 5-year overall survival (CD30+, 79% vs CD30–, 59%; P = .001) and progression-free survival (P = .003). The favorable outcome of CD30 expression was maintained in both the germinal center B-cell and activated B-cell subtypes. Gene expression profiling revealed the upregulation of genes encoding negative regulators of nuclear factor κB activation and lymphocyte survival, and downregulation of genes encoding B-cell receptor signaling and proliferation, as well as prominent cytokine and stromal signatures in CD30+ DLBCL patients, suggesting a distinct molecular basis for its favorable outcome. Given the superior prognostic value, unique gene expression signature, and significant value of CD30 as a therapeutic target for brentuximab vedotin in ongoing successful clinical trials, it seems appropriate to consider CD30+ DLBCL as a distinct subgroup of DLBCL. PMID:23343832

  18. 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

  19. Rituximab shows no effect on remission in patients with refractory nephrotic syndrome

    PubMed Central

    Yin, Supei; He, Ting; Li, Yi; Wang, Jingshuang; Zeng, Wei; Tang, Sha; Zhao, Jinghong

    2016-01-01

    Abstract To assess the efficacy of rituximab in treatment of refractory nephrotic syndrome (NS) compared with other agents. Studies were searched from Web of Science, PubMed, and CNKI up to April 2016. The standardized mean difference or relative risk or odds ratio and 95% confidence intervals were used to assess the efficacy of rituximab treatment compared with other agents in refractory NS. Totally, 8 studies were included. The present study showed that there was a significant higher relapse-free survival rate in rituximab group than that in the other agents group. Compared with other agents, rituximab did not significantly improve the complete and overall remission rate, serum albumin levels. Rituximab also did not decrease the serum creatinine, urinary protein, and serum cholesterol levels. However, compared with other agents, the adult patients had a higher serum cholesterol levels after treatment with rituximab. Rituximab promised to be a new agent in the treatment of refractory NS; it also could be used as an alternative to conventional immunosuppressive drugs-dependent or drugs-resistant. However, more high-quality, large sample, and multicenter randomized controlled trials are needed to further confirm the efficacy of rituximab in treatment of refractory NS. PMID:27977574

  20. Efficacy of rituximab in an aggressive form of multicentric Castleman disease associated with immune phenomena.

    PubMed

    Ocio, Enrique M; Sanchez-Guijo, Fermin M; Diez-Campelo, Maria; Castilla, Cristina; Blanco, Oscar J; Caballero, Dolores; San Miguel, Jesus F

    2005-04-01

    Multicentric Castleman disease (MCD) is an uncommon lymphoproliferative disorder for which the best therapeutic option is not yet well established. Immune-related disorders are rare complications of MCD. We report on an MCD case in a 23-year-old patient with extensive abdominal involvement and associated immune hemolytic anemia and Raynaud phenomenon. He was negative for human immunodeficiency virus (HIV) and human herpesvirus-8 (HHV-8). After 8 courses of the anti-CD20 monoclonal antibody (rituximab), the patient achieved complete remission. Interestingly, Raynaud phenomenon disappeared under treatment and no new hemolytic events occurred. Anti-CD20 antibody treatment could be an attractive therapeutic approach for MCD, mainly when immune-related disorders are associated.

  1. Assessment of Response to Lithium Maintenance Treatment in Bipolar Disorder: A Consortium on Lithium Genetics (ConLiGen) Report

    PubMed Central

    Manchia, Mirko; Adli, Mazda; Akula, Nirmala; Ardau, Raffaella; Aubry, Jean-Michel; Backlund, Lena; Banzato, Claudio EM.; Baune, Bernhard T.; Bellivier, Frank; Bengesser, Susanne; Biernacka, Joanna M.; Brichant-Petitjean, Clara; Bui, Elise; Calkin, Cynthia V.; Cheng, Andrew Tai Ann; Chillotti, Caterina; Cichon, Sven; Clark, Scott; Czerski, Piotr M.; Dantas, Clarissa; Zompo, Maria Del; DePaulo, J. Raymond; Detera-Wadleigh, Sevilla D.; Etain, Bruno; Falkai, Peter; Frisén, Louise; Frye, Mark A.; Fullerton, Jan; Gard, Sébastien; Garnham, Julie; Goes, Fernando S.; Grof, Paul; Gruber, Oliver; Hashimoto, Ryota; Hauser, Joanna; Heilbronner, Urs; Hoban, Rebecca; Hou, Liping; Jamain, Stéphane; Kahn, Jean-Pierre; Kassem, Layla; Kato, Tadafumi; Kelsoe, John R.; Kittel-Schneider, Sarah; Kliwicki, Sebastian; Kuo, Po-Hsiu; Kusumi, Ichiro; Laje, Gonzalo; Lavebratt, Catharina; Leboyer, Marion; Leckband, Susan G.; López Jaramillo, Carlos A.; Maj, Mario; Malafosse, Alain; Martinsson, Lina; Masui, Takuya; Mitchell, Philip B.; Mondimore, Frank; Monteleone, Palmiero; Nallet, Audrey; Neuner, Maria; Novák, Tomás; O’Donovan, Claire; Ösby, Urban; Ozaki, Norio; Perlis, Roy H.; Pfennig, Andrea; Potash, James B.; Reich-Erkelenz, Daniela; Reif, Andreas; Reininghaus, Eva; Richardson, Sara; Rouleau, Guy A.; Rybakowski, Janusz K.; Schalling, Martin; Schofield, Peter R.; Schubert, Oliver K.; Schweizer, Barbara; Seemüller, Florian; Grigoroiu-Serbanescu, Maria; Severino, Giovanni; Seymour, Lisa R.; Slaney, Claire; Smoller, Jordan W.; Squassina, Alessio; Stamm, Thomas; Steele, Jo; Stopkova, Pavla; Tighe, Sarah K.; Tortorella, Alfonso; Turecki, Gustavo; Wray, Naomi R.; Wright, Adam; Zandi, Peter P.; Zilles, David; Bauer, Michael; Rietschel, Marcella; McMahon, Francis J.

    2013-01-01

    Objective The assessment of response to lithium maintenance treatment in bipolar disorder (BD) is complicated by variable length of treatment, unpredictable clinical course, and often inconsistent compliance. Prospective and retrospective methods of assessment of lithium response have been proposed in the literature. In this study we report the key phenotypic measures of the “Retrospective Criteria of Long-Term Treatment Response in Research Subjects with Bipolar Disorder” scale currently used in the Consortium on Lithium Genetics (ConLiGen) study. Materials and Methods Twenty-nine ConLiGen sites took part in a two-stage case-vignette rating procedure to examine inter-rater agreement [Kappa (κ)] and reliability [intra-class correlation coefficient (ICC)] of lithium response. Annotated first-round vignettes and rating guidelines were circulated to expert research clinicians for training purposes between the two stages. Further, we analyzed the distributional properties of the treatment response scores available for 1,308 patients using mixture modeling. Results Substantial and moderate agreement was shown across sites in the first and second sets of vignettes (κ = 0.66 and κ = 0.54, respectively), without significant improvement from training. However, definition of response using the A score as a quantitative trait and selecting cases with B criteria of 4 or less showed an improvement between the two stages (ICC1 = 0.71 and ICC2 = 0.75, respectively). Mixture modeling of score distribution indicated three subpopulations (full responders, partial responders, non responders). Conclusions We identified two definitions of lithium response, one dichotomous and the other continuous, with moderate to substantial inter-rater agreement and reliability. Accurate phenotypic measurement of lithium response is crucial for the ongoing ConLiGen pharmacogenomic study. PMID:23840348

  2. Rituximab therapy in Greek patients with rheumatoid arthritis

    PubMed Central

    Tsiakalos, Aristotelis P; Avgoustidis, Nestor K; Moutsopoulos, Haralampos M

    2008-01-01

    Objective: An open-label, prospective, uncontrolled study created to investigate clinical response, serological changes and side effects in Greek patients with rheumatoid arthritis (RA), after B-cell depletion with rituximab. Methods: Patients with high disease activity (disease activity score [DAS]-28 > 5.1) were selected for treatment with rituximab and received two infusions, 1 gr each, 2 weeks apart. Different disease parameters (visual analog scale, DAS-28, C-reactive protein [CRP], erythrocyte sedimentation rate, health assessment questionnaire, complement (C3), C4, rheumatoid factor [RF], anti-cyclic citrullinated peptide antibody [anti-CCP], swollen joint count, tender joint count, immunoglobulin M [IgM], IgG, IgA) were performed at base line, 2, 4, and 6 months post-treatment. Response was defined according to the American College of Rheumatology (ACR) criteria. Results: Seventeen patients received therapy. Treatment led to a reduction in various disease parameters. ACR20 was achieved in 41.11% of patients by week 8, 52.94% by week 16, and 82.35% by week 24. ACR50 was achieved in 5.88% by week 8, 41.17% by week 16, and 64.7% by week 24. ACR70 was achieved only by week 24 in 23.52% of patients. Statistical analysis has shown no differences in clinical response, between RF positive/negative patients, and anti-CCP-positive/negative patients, while decline of RF was better correlated with reduction of DAS-28 than with anti-CCP. Conclusions: Rituximab is a well tolerated and effective treatment in RA. Response was not correlated to RF or anti-CCP positivity. Decline of RF was associated with clinical response and reduction of DAS-28 and CRP. PMID:19707469

  3. Refractory myasthenia gravis - clinical profile, comorbidities and response to rituximab.

    PubMed

    Sudulagunta, Sreenivasa Rao; Sepehrar, Mona; Sodalagunta, Mahesh Babu; Settikere Nataraju, Aravinda; Bangalore Raja, Shiva Kumar; Sathyanarayana, Deepak; Gummadi, Siddharth; Burra, Hemanth Kumar

    2016-01-01

    Introduction: Myasthenia gravis (MG) is an antibody mediated autoimmune neuromuscular disorder characterized by fatigable muscle weakness. A proportion of myasthenia gravis patients are classified as refractory due to non responsiveness to conventional treatment. This retrospective study was done to evaluate clinical profile, epidemiological, laboratory, and features of patients with MG and mode of management using rituximab and complications. Methods: Data of myasthenia gravis patients admitted or presented to outpatient department (previous medical records) with MG between January 2008 and January 2016 were included. A total of 512 patients fulfilled the clinical and diagnostic criteria of myasthenia gravis of which 76 patients met the diagnostic certainty for refractory myasthenia gravis and were evaluated. Results: Out of 76 refractory MG patients, 53 (69.73%) patients fulfilled all the three defined criteria. The median age of onset of the refractory MG group was 36 years with a range of 27-53 years. In our study 25 patients (32.89%) belonged to the age group of 21-30 years. Anti-MuSK antibodies were positive in 8 non-refractory MG patients (2.06%) and 36 refractory MG patients (47.36%). Mean HbA1C was found to be 8.6±2.33. The dose of administered prednisone decreased by a mean of 59.7% (p=3.3x10(-8)) to 94.6% (p=2.2x10(-14)) after the third cycle of rituximab treatment. Conclusion: The refractory MG patients are most commonly female with an early age of onset, anti-MuSK antibodies, and thymomas. Refractory MG patients have higher prevalence and poor control (HbA1C >8%) of diabetes mellitus and dyslipidemia probably due to increased steroid usage. Rituximab is very efficient in treatment of refractory MG with adverse effects being low.

  4. Should we consider MMF therapy after rituximab for nephrotic syndrome?

    PubMed

    Filler, Guido; Huang, Shih-Han Susan; Sharma, Ajay P

    2011-10-01

    The management of steroid-dependent nephrotic syndrome, especially in patients who have failed to respond to cytotoxic drugs, such as cyclophosphamide, remains challenging. Rituximab represents a new (off-label) therapeutic option. In a significant portion of patients, it has a short serum half-life following the recovery of CD20-positive cells. The addition of mycophenolate mofetil (MMF) as a maintenance therapy is also an attractive option, but one which requires testing in a prospective randomized clinical trial with therapeutic drug monitoring and mechanistic ancillary studies.

  5. Rheumatoid granulomatous disease and pachymeningitis successfully treated with rituximab.

    PubMed

    Moeyersoons, Anneleen; Verschueren, Patrick; Tousseyn, Thomas; De Langhe, Ellen

    2017-09-13

    Granulomatous disease and pachymeningitis rarely occur in rheumatoid arthritis patients and confer a challenging differential diagnosis. Our patient, treated with a tumor necrosis factor alpha inhibitor, presented with meningitis and diffuse granulomatous adenopathies. Opportunistic infections and malignancy were excluded after confirmation of negative broath serologic, molecular analysis, and negative cytology. Because of the time frame and the clinical presentation, this case was considered as a rare systemic manifestation of RA. He was treated with rituximab with beneficial clinical evolution. This case offers an excellent opportunity to focus on the diagnostic and therapeutic approach in pachymeningitis and granulomatous disease in rheumatoid arthritis patients.

  6. 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

  7. 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.

  8. Population pharmacokinetics of Reditux™, a biosimilar Rituximab, in diffuse large B-cell lymphoma.

    PubMed

    Gota, Vikram; Karanam, Ashwin; Rath, Sanhita; Yadav, Akanksha; Tembhare, Prashant; Subramanian, P; Sengar, Manju; Nair, Reena; Menon, Hari

    2016-08-01

    Rituximab (MabThera™, Roche) is a chimeric IgG1 monoclonal antibody targeting the CD20 surface antigen on normal and neoplastic B cells. It revolutionized the treatment of non-Hodgkin's lymphoma with superior progression-free and overall survival. However, its prohibitively high cost makes it inaccessible to majority of patients in developing countries. Reditux™ (Dr. Reddy's Laboratories, India), a biosimilar, was introduced in India in 2007 at nearly half the price of the innovator. However, there is a dearth of data regarding the pharmacokinetics and efficacy of Reditux™. Twenty-one patients of diffuse large B-cell lymphoma on R-CHOP regimen were enrolled for the study. Reditux™ was administered as a slow intravenous infusion at a dose of 375 mg/m(2) on day 1 of a 21-day cycle. Pharmacokinetic sampling was performed at pre-dose, post-infusion, 24, 48 h, 7 and 21 days. Rituximab levels were estimated by ELISA. Population pharmacokinetics was performed using NONMEM. In addition, B-cell count was determined at baseline and days 3 and 21 of the first cycle. Survival analysis was performed using Kaplan-Meier plots. The volume of distribution of central compartment and clearance of Reditux™ were estimated at 0.95 L and 5.98 mL/h, respectively. No covariate effects were seen. B-cell count was completely depleted by day 3 and remained so on day 21. Overall survival was 84.6 % at a median follow-up of 36 months. The pharmacokinetic profile and B-cell response to Reditux™ are comparable with those reported for MabThera™. Thus, MabThera™ can be substituted with Reditux™ for the treatment of B-cell lymphomas.

  9. Radiolabeling of rituximab with (188)Re and (99m)Tc using the tricarbonyl technology.

    PubMed

    Dias, Carla Roberta; Jeger, Simone; Osso, João Alberto; Müller, Cristina; De Pasquale, Christine; Hohn, Alexander; Waibel, Robert; Schibli, Roger

    2011-01-01

    The most successful clinical studies of immunotherapy in patients with non-Hodgkin's lymphoma (NHL) use the antibody rituximab (RTX) targeting CD20(+) B-cell tumors. Rituximab radiolabeled with β(-) emitters could potentiate the therapeutic efficacy of the antibody by virtue of the particle radiation. Here, we report on a direct radiolabeling approach of rituximab with the (99m)Tc- and (188)Re-tricarbonyl core (IsoLink technology). The native format of the antibody (RTX(wt)) as well as a reduced form (RTX(red)) was labeled with (99m)Tc/(188)Re(CO)(3). The partial reduction of the disulfide bonds to produce free sulfhydryl groups (-SH) was achieved with 2-mercaptoethanol. Radiolabeling efficiency, in vitro human plasma stability as well as transchelation toward cysteine and histidine was investigated. The immunoreactivity and binding affinity were determined on Ramos and/or Raji cells expressing CD20. Biodistribution was performed in mice bearing subcutaneous Ramos lymphoma xenografts. The radiolabeling efficiency and kinetics of RTX(red) were superior to that of RTX(wt) ((99m)Tc: 98% after 3 h for RTX(red) vs. 70% after 24 h for RTX(wt)). (99m)Tc(CO)(3)-RTX(red) was used without purification for in vitro and in vivo studies whereas (188)Re(CO)(3)-RTX(red) was purified to eliminate free (188)Re-precursor. Both radioimmunoconjugates were stable in human plasma for 24 h at 37 °C. In contrast, displacement experiments with excess cysteine/histidine showed significant transchelation in the case of (99m)Tc(CO)(3)-RTX(red) but not with pre-purified (188)Re(CO)(3)-RTX(red). Both conjugates revealed high binding affinity to the CD20 antigen (K(d) = 5-6 nM). Tumor uptake of (188)Re(CO)(3)-RTX(red) was 2.5 %ID/g and 0.8 %ID/g for (99m)Tc(CO)(3)-RTX(red) 48 h after injection. The values for other organs and tissues were similar for both compounds, for example the tumor-to-blood and tumor-to-liver ratios were 0.4 and 0.3 for (99m)Tc(CO)(3)-RTX(red) and for (188)Re(CO)(3)-RTX

  10. The role of rituximab in adults with warm antibody autoimmune hemolytic anemia.

    PubMed

    Dierickx, Daan; Kentos, Alain; Delannoy, André

    2015-05-21

    Warm antibody hemolytic anemia is the most common form of autoimmune hemolytic anemia. When therapy is needed, corticosteroids remain the cornerstone of initial treatment but are able to cure only a minority of patients (<20%). Splenectomy is usually proposed when a second-line therapy is needed. This classical approach is now challenged by the use of rituximab both as second-line and as first-line therapy. Second-line treatment with rituximab leads to response rates similar to splenectomy (∼70%), but rituximab-induced responses seem less sustained. However, additional courses of rituximab are most often followed by responses, at the price of reasonable toxicity. In some major European centers, rituximab is now the preferred second-line therapy of warm antibody hemolytic anemia in adults, although no prospective study convincingly supports this attitude. A recent randomized study strongly suggests that in first-line treatment, rituximab combined with steroids is superior to monotherapy with steroids. If this finding is confirmed, rituximab will emerge as a major component of the management of warm antibody hemolytic anemia not only after relapse but as soon as treatment is needed.

  11. Critical appraisal of rituximab in the maintenance treatment of advanced follicular lymphoma

    PubMed Central

    Aguiar-Bujanda, David; Blanco-Sánchez, María Jesús; Hernández-Sosa, María; Galván-Ruíz, Saray; Hernández-Sarmiento, Samuel

    2015-01-01

    Rituximab is an IgG1, chimeric monoclonal antibody specifically designed to recognize the CD20 antigen expressed on the surface of normal and malignant B-lymphocytes, from the B-cell precursor to the mature B-cells of the germinal center, and by most neoplasms derived from B-cells. After 2 decades of use, rituximab is firmly positioned in the treatment of follicular lymphoma (FL), both in the front line and in the relapsing disease, improving previous results by including it in classical chemotherapy regimens. However, the pharmacology of rituximab continues to generate controversial issues especially regarding the mechanisms of action in vivo. The contribution of rituximab as a maintenance treatment in FL has been significant progress in the management of this disease without an increase in side effects or a decrease in the quality of life of patients. With the widespread use of rituximab, there are new security alerts and side effects not previously detected in the pivotal trials that clinicians should learn to recognize and manage. In this article, we will review the pharmacokinetics and pharmacodynamics of rituximab, the management issues in the treatment of advanced FL focusing on maintenance rituximab, its long-term efficacy and safety profile, and its effect on the quality of life. PMID:26604821

  12. 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

  13. Addition of rituximab to chlorambucil produces superior event-free survival in the treatment of patients with extranodal marginal-zone B-cell lymphoma: 5-year analysis of the IELSG-19 Randomized Study.

    PubMed

    Zucca, Emanuele; Conconi, Annarita; Laszlo, Daniele; López-Guillermo, Armando; Bouabdallah, Reda; Coiffier, Bertrand; Sebban, Catherine; Jardin, Fabrice; Vitolo, Umberto; Morschhauser, Franck; Pileri, Stefano A; Copie-Bergman, Christiane; Campo, Elias; Jack, Andrew; Floriani, Irene; Johnson, Peter; Martelli, Maurizio; Cavalli, Franco; Martinelli, Giovanni; Thieblemont, Catherine

    2013-02-10

    Apart from localized gastric disease, there is no consensus on standard initial treatment of mucosa-associated lymphoid tissue lymphoma. The IELSG-19 study (Randomized Trial of Chlorambucil Versus Chlorambucil Plus Rituximab Versus Rituximab in MALT Lymphoma) was launched to compare chlorambucil alone versus chlorambucil plus rituximab in patients not previously given systemic anticancer therapy. Patients not responding to or not suitable for local therapy were eligible. In arm A, chlorambucil was given daily 6 mg/m(2) orally (PO) for 6 weeks. Responding patients and those with stable disease continued to be given daily chlorambucil 6 mg/m(2) PO for 14 consecutive days every 28 days for four cycles. In arm B, intravenous rituximab 375 mg/m(2) per day was added on days 1, 8, 15, 22, 56, 84, 112, and 140. After completion of the planned accrual, the protocol was amended to introduce a third arm with rituximab alone. We report the planned final analysis of the first two arms (113 patients in arm A and 114 in arm B). At a median follow-up of 62 months, the 5-year event-free survival (EFS) was significantly better for the patients treated in arm B (68% v 50%; P = .002) who, despite similar overall response rates (90% v 87%), achieved a higher complete remission rate (78% v 65%; P = .025). Progression-free survival was also improved but it did not reach statistical significance (P = .057). Five-year overall survival (OS) was 89% in both arms. Both treatments were well tolerated without unexpected toxicities. Both treatments were active; the better response rate and EFS obtained with the addition of rituximab did not translate into improved OS.

  14. Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients

    PubMed Central

    van Vollenhoven, Ronald F; Emery, Paul; Bingham, Clifton O; Keystone, Edward C; Fleischmann, Roy M; Furst, Daniel E; Tyson, Nicola; Collinson, Neil; Lehane, Patricia B

    2013-01-01

    Objectives Evaluation of long-term safety of rituximab in rheumatoid arthritis (RA). Methods Pooled observed case analysis of data from patients with moderate-to-severe, active RA treated with rituximab in a global clinical trial programme. Results As of September 2010, 3194 patients had received up to 17 rituximab courses over 9.5 years (11 962 patient-years). Of these, 627 had >5 years’ follow-up (4418 patient-years). A pooled placebo population (n=818) (placebo+methotrexate (MTX)) was also analysed. Serious adverse event and infection rates generally remained stable over time and multiple courses. The overall serious infection event (SIE) rate was 3.94/100 patient-years (3.26/100 patient-years in patients observed for >5 years) and was comparable with placebo+MTX (3.79/100 patient-years). Serious opportunistic infections were rare. Overall, 22.4% (n=717) of rituximab-treated patients developed low immunoglobulin (Ig)M and 3.5% (n=112) low IgG levels for ≥4 months after ≥1 course. SIE rates were similar before and during/after development of low Ig levels; however, in patients with low IgG, rates were higher than in patients who never developed low IgG. Rates of myocardial infarction and stroke were consistent with rates in the general RA population. No increased risk of malignancy over time was observed. Conclusions This analysis demonstrates that rituximab remains generally well tolerated over time and multiple courses, with a safety profile consistent with published data and clinical trial experience. Overall, the findings indicate that there was no evidence of an increased safety risk or increased reporting rates of any types of adverse events with prolonged exposure to rituximab during the 9.5 years of observation. PMID:23136242

  15. B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design

    PubMed Central

    2013-01-01

    B cells are believed to be central to the disease process in systemic lupus erythematosus (SLE), making them a target for new therapeutic intervention. In recent years there have been many publications regarding the experience in SLE of B-cell depletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells, reporting promising results in uncontrolled open studies and in routine clinical use. However, the two large randomised controlled trials in extra-renal lupus (EXPLORER study) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints. Based on the clinical experience with rituximab this failure was somewhat unexpected and raised a number of questions and concerns, not only into the true level of benefit of B-cell depletion in a broad population but also how to test the true level of effectiveness of an investigational agent as we seek to improve the design of therapeutic trials in SLE. A better understanding of what went wrong in these trials is essential to elucidate the underlying reasons for the disparate observations noted in open studies and controlled trials. In this review, we focus on various factors that may affect the ability to accurately and confidently establish the level of treatment effect of the investigational agent, in this case rituximab, in the two studies and explore hurdles faced in the randomised controlled trials investigating the efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based on the lessons learned from the clinical trials, we make suggestions that could be implemented in future clinical trial design to overcome the hurdles faced. PMID:23566295

  16. B-cell depletion in SLE: clinical and trial experience with rituximab and ocrelizumab and implications for study design.

    PubMed

    Reddy, Venkat; Jayne, David; Close, David; Isenberg, David

    2013-01-01

    B cells are believed to be central to the disease process in systemic lupus erythematosus (SLE), making them a target for new therapeutic intervention. In recent years there have been many publications regarding the experience in SLE of B-cell depletion utilising rituximab, an anti-CD20 mAb that temporarily depletes B cells,reporting promising results in uncontrolled open studies and in routine clinical use. However, the two large randomised controlled trials in extra-renal lupus (EXPLORER study) and lupus nephritis (LUNAR study) failed to achieve their primary endpoints. Based on the clinical experience with rituximab this failure was somewhat unexpected and raised a number of questions and concerns, not only into the true level of benefit of B-cell depletion in a broad population but also how to test the true level of effectiveness of an investigational agent as we seek to improve the design of therapeutic trials in SLE. A better understanding of what went wrong in these trials is essential to elucidate the underlying reasons for the disparate observations noted in open studies and controlled trials. In this review, we focus on various factors that may affect the ability to accurately and confidently establish the level of treatment effect of the investigational agent, in this case rituximab, in the tw studies and explore hurdles faced in the randomised controlled trials investigating the efficacy of ocrelizumab, the humanised anti-CD20 mAb, in SLE. Further, based on the lessons learned from the clinical trials, we make suggestions that could be implemented in future clinical trial design to overcome the hurdles faced.

  17. Evaluation of 89Zr-rituximab tracer by Cerenkov luminescence imaging and correlation with PET in a humanized transgenic mouse model to image NHL.

    PubMed

    Natarajan, Arutselvan; Habte, Frezghi; Liu, Hongguang; Sathirachinda, Ataya; Hu, Xiang; Cheng, Zhen; Nagamine, Claude M; Gambhir, Sanjiv Sam

    2013-08-01

    This research aimed to study the use of Cerenkov luminescence imaging (CLI) for non-Hodgkin's lymphoma (NHL) using 89Zr-rituximab positron emission tomography (PET) tracer with a humanized transgenic mouse model that expresses human CD20 and the correlation of CLI with PET. Zr-rituximab (2.6 MBq) was tail vein-injected into transgenic mice that express the human CD20 on their B cells (huCD20TM). One group (n=3) received 2 mg/kg pre-dose (blocking) of cold rituximab 2 h prior to tracer; a second group (n=3) had no pre-dose (non-blocking). CLI was performed using a cooled charge-coupled device optical imager. We also performed PET imaging and ex vivo studies in order to confirm the in vivo CLI results. At each time point (4, 24, 48, 72, and 96 h), two groups of mice were imaged in vivo and ex vivo with CLI and PET, and at 96 h, organs were measured by gamma counter. huCD20 transgenic mice injected with 89Zr-rituximab demonstrated a high-contrast CLI image compared to mice blocked with a cold dose. At various time points of 4-96 h post-radiotracer injection, the in vivo CLI signal intensity showed specific uptake in the spleen where B cells reside and, hence, the huCD20 biomarker is present at very high levels. The time-activity curve of dose decay-corrected CLI intensity and percent injected dose per gram of tissue of PET uptake in the spleen were increased over the time period (4-96 h). At 96 h, the 89Zr-rituximab uptake ratio (non-blocking vs blocking) counted (mean±standard deviation) for the spleen was 1.5±0.6 for CLI and 1.9±0.3 for PET. Furthermore, spleen uptake measurements (non-blocking and blocking of all time points) of CLI vs PET showed good correlation (R2=0.85 and slope=0.576), which also confirmed the corresponding correlations parameter value (R2=0.834 and slope=0.47) obtained for ex vivo measurements. CLI and PET of huCD20 transgenic mice injected with 89Zr-rituximab demonstrated that the tracer was able to target huCD20-expressing B cells. The in

  18. Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the AutoImmunity and Rituximab registry

    PubMed Central

    Salmon, J H; Cacoub, P; Combe, B; Sibilia, J; Pallot-Prades, B; Fain, O; Cantagrel, A; Dougados, M; Andres, E; Meyer, O; Carli, P; Pertuiset, E; Pane, I; Maurier, F; Ravaud, P; Mariette, X; Gottenberg, J E

    2015-01-01

    Objectives To evaluate the prevalence of late-onset neutropenia and its complications in patients treated with rituximab (RTX) for rheumatoid arthritis (RA) and other autoimmune diseases (AIDs) in a prospective registry. Methods The AutoImmunity and Rituximab registry is an independent 7-year prospective registry promoted by the French Society of Rheumatology. For each episode of neutropenia, data were validated by the clinician in charge of the patient. Results Among 2624 patients treated with RTX for refractory AIDs, and at least 1 follow-up visit (a total follow-up of 4179 patient-years in RA and 987 patient-years in AIDs), late-onset neutropenia was observed in 40 patients (25 RA (1.3% of patients with RA, 0.6/100 patient-years), and AIDs in 15 (2.3% of patients with AIDs, 1.5/100 patient-years)). 6 patients (15%) had neutrophils <500/mm3, 8 (20%) had neutrophils between 500 and 1000/mm3, and 26 (65%) had neutrophils between 1000 and 1500/mm3. Neutropenia occurred after a median period of 4.5 (3–6.5) months after the last RTX infusion in patients with RA, and 5 (3–6.5) months in patients with AIDs. 5 patients (12.5%), 4 of them with neutrophils lower than 500/mm3, developed a non-opportunistic serious infection and required antibiotics and granulocyte colony-stimulating factor injections, with a favourable outcome. After resolution of their RTX-related neutropenia, 19 patients (47.5%) were re-treated, and neutropenia reoccurred in 3 of them. Conclusions Late-onset neutropenia might occur after RTX and may result in serious infections. Thus, monitoring of white cell count should be performed after RTX. However, in this large registry of patients with AIDs, the frequency of RTX-induced neutropenia was much lower than that previously reported in patients treated for blood malignancies or AIDs. PMID:26509060

  19. Safety of surgery after rituximab therapy in 133 patients with rheumatoid arthritis: data from the autoimmunity and rituximab registry.

    PubMed

    Godot, S; Gottenberg, J-E; Paternotte, S; Pane, I; Combe, B; Sibilia, J; Flipo, R-M; Schaeverbeke, T; Ravaud, P; Toussirot, E; Berenbaum, F; Mariette, X; Wendling, D; Sellam, J

    2013-11-01

    We used data from the AutoImmunity and Rituximab (AIR) registry to investigate the safety of surgery for patients with rheumatoid arthritis receiving rituximab (RTX) in routine care. Data for patients included in the AIR registry and undergoing surgery during the year following an infusion of RTX were reviewed to describe the frequency of postsurgical complications, compare patients with and without complications, and identify factors associated with complications. We examined data for 133 patients with a known date of surgery and at least 1 followup visit, corresponding to 140 procedures, including 94 orthopedic surgeries (67%) and 23 abdominal surgeries (16.5%). The median delay between surgery and the last RTX infusion was 6.4 months (interquartile range 4.3– 8.7 months), without any difference between patients with and without complications. Nine patients (6.7%) experienced 12 complications (8.5%), including 8 surgical site infections (5.7%) and 1 death due to septic shock. Postoperative complications occurred after 4.3% of abdominal surgeries (1 of 23) and 7.4% of orthopedic surgeries (7 of 95). On univariate analysis, spine surgery was associated with postoperative complications (P = 0.048). In common practice, the risk of complications may be more important in case of spine surgery, but does not seem to be linked to the time between the last RTX infusion and surgery.

  20. Patient-Reported Outcomes and Survivorship in Radiation Oncology: Overcoming the Cons

    PubMed Central

    Siddiqui, Farzan; Liu, Arthur K.; Watkins-Bruner, Deborah; Movsas, Benjamin

    2014-01-01

    Purpose Although patient-reported outcomes (PROs) have become a key component of clinical oncology trials, many challenges exist regarding their optimal application. The goal of this article is to methodically review these barriers and suggest strategies to overcome them. This review will primarily focus on radiation oncology examples, will address issues regarding the “why, how, and what” of PROs, and will provide strategies for difficult problems such as methods for reducing missing data. This review will also address cancer survivorship because it closely relates to PROs. Methods Key articles focusing on PROs, quality of life, and survivorship issues in oncology trials are highlighted, with an emphasis on radiation oncology clinical trials. Publications and Web sites of various governmental and regulatory agencies are also reviewed. Results The study of PROs in clinical oncology trials has become well established. There are guidelines provided by organizations such as the US Food and Drug Administration that clearly indicate the importance of and methodology for studying PROs. Clinical trials in oncology have repeatedly demonstrated the value of studying PROs and suggested ways to overcome some of the key challenges. The Radiation Therapy Oncology Group (RTOG) has led some of these efforts, and their contributions are highlighted. The current state of cancer survivorship guidelines is also discussed. Conclusion The study of PROs presents significant benefits in understanding and treating toxicities and enhancing quality of life; however, challenges remain. Strategies are presented to overcome these hurdles, which will ultimately improve cancer survivorship. PMID:25113760

  1. [Successful treatment with rituximab for autoimmune hemolytic anemia associated with chronic lymphocytic leukemia].

    PubMed

    Tanaka, Yuko; Ito, Yoshikazu; Yoshizawa, Sei-ichiro; Fujimoto, Hiroaki; Gotoh, Moritaka; Tauchi, Tetsuzo; Kimura, Yukihiko; Ohyashiki, Kazuma

    2013-02-01

    A 68-year-old man was diagnosed with chronic lymphocytic leukemia (CLL) 3 years ago. His course was progressive, and he was complicated with autoimmune hemolytic anemia (AIHA). After the lack of efficacy of prednisone and cyclo-phosphamide, rituximab (375mg/m(2)) was administered based on the presence of CD20 positive leukemic cells by flow cytometric analysis of bone marrow. During 4 courses of rituximab administration, both anemia and hemolysis improved dramatically. Furthermore, the percentage of CLL cells in his peripheral blood was reduced. Rituximab may be one of the effective treatments for CLL associated AIHA in Japan as well as in foreign countries.

  2. Rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin's lymphoma.

    PubMed

    Dundar, Y; Bagust, A; Hounsome, J; McLeod, C; Boland, A; Davis, H; Walley, T; Dickson, R

    2009-06-01

    This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of rituximab for the first-line treatment of stage III/IV follicular non-Hodgkin's lymphoma (FNHL) based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The manufacturer's scope restricts the intervention to rituximab in combination with CVP (cyclophosphamide, vincristine and prednisolone) (R-CVP); the only comparator used was CVP alone. The evidence from the one included randomised controlled trial (RCT) suggests that the addition of rituximab to a CVP chemotherapy regimen has a positive effect on the outcomes of time to treatment failure, disease progression, overall tumour response, duration of response and time to new lymphoma treatment in patients with stage III/IV FNHL compared with CVP alone. Adverse events were comparable between the two arms. This study was confirmed as the only relevant RCT. The economic analyses provided by the manufacturer were modelled using a three-state Markov model with with the health states being defined as progression-free survival (PFS), progressed (in which patients have relapsed) and death (which is an absorbing state). The model generated results for a cohort of patients with an initial age of 53 and makes no distinction between men and women. The model is basic in design, with several serious design flaws and key parameter values that are probably incompatible. Attempting to rectify the identified errors and limitations of the model did not increase the incremental cost-effectiveness ratio (ICER) above 30,000 pounds. Although the cost-effectiveness results obtained appear to be compelling in support of R-CVP compared with CVP for the trial population the results may not be so convincing for a more representative population. The results of the ERG analysis on the impact of age suggest that ICERs increase

  3. 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.

  4. Chemoimmunotherapy With Fludarabine and Rituximab Produces Extended Overall Survival and Progression-Free Survival in Chronic Lymphocytic Leukemia: Long-Term Follow-Up of CALGB Study 9712

    PubMed Central

    Woyach, Jennifer A.; Ruppert, Amy S.; Heerema, Nyla A.; Peterson, Bercedis L.; Gribben, John G.; Morrison, Vicki A.; Rai, Kanti R.; Larson, Richard A.; Byrd, John C.

    2011-01-01

    Purpose The addition of rituximab to fludarabine-based regimens in chronic lymphocytic leukemia (CLL) has been shown to produce high response rates with extended remissions. The long-term follow-up of these regimens with respect to progression, survival, risk of secondary leukemia, and impact of genomic risk factors has been limited. Methods We report the long-term follow-up of the chemoimmunotherapy trial CALGB 9712 from the Cancer and Leukemia Group B, for which treatment regimen was previously reported, to examine end points of progression-free survival (PFS), overall survival (OS), impact of genomic features, and risk of therapy-related myeloid neoplasm (t-MN). Results A total of 104 patients were enrolled on this study and now have a median follow-up of 117 months (range, 66 to 131 months). The median OS was 85 months, and 71% of patients were alive at 5 years. The median PFS was 42 months, and 27% were progression free at 5 years. An estimated 13% remained free of progression at almost 10 years of follow-up. Multivariable models of PFS and OS showed that immunoglobulin heavy chain variable region mutational status was significant for both, whereas cytogenetic abnormalities were significant only for OS. No patient developed t-MN before relapse. Conclusion Long-term follow-up of CALGB 9712 demonstrates extended OS and PFS with fludarabine plus rituximab. Patients treated with fludarabine plus rituximab administered concurrently or sequentially have a low risk of t-MN. These long-term data support fludarabine plus rituximab as one acceptable first-line treatment for symptomatic patients with CLL. PMID:21321292

  5. Ibrutinib for patients with rituximab-refractory Waldenström's macroglobulinaemia (iNNOVATE): an open-label substudy of an international, multicentre, phase 3 trial.

    PubMed

    Dimopoulos, Meletios A; Trotman, Judith; Tedeschi, Alessandra; Matous, Jeffrey V; Macdonald, David; Tam, Constantine; Tournilhac, Olivier; Ma, Shuo; Oriol, Albert; Heffner, Leonard T; Shustik, Chaim; García-Sanz, Ramón; Cornell, Robert F; de Larrea, Carlos Fernández; Castillo, Jorge J; Granell, Miquel; Kyrtsonis, Marie-Christine; Leblond, Veronique; Symeonidis, Argiris; Kastritis, Efstathios; Singh, Priyanka; Li, Jianling; Graef, Thorsten; Bilotti, Elizabeth; Treon, Steven; Buske, Christian

    2017-02-01

    In the era of widespread rituximab use for Waldenström's macroglobulinaemia, new treatment options for patients with rituximab-refractory disease are an important clinical need. Ibrutinib has induced durable responses in previously treated patients with Waldenström's macroglobulinaemia. We assessed the efficacy and safety of ibrutinib in a population with rituximab-refractory disease. This multicentre, open-label substudy was done at 19 sites in seven countries in adults aged 18 years and older with confirmed Waldenström's macroglobulinaemia, refractory to rituximab and requiring treatment. Disease refractory to the last rituximab-containing therapy was defined as either relapse less than 12 months since last dose of rituximab or failure to achieve at least a minor response. Key exclusion criteria included: CNS involvement, a stroke or intracranial haemorrhage less than 12 months before enrolment, clinically significant cardiovascular disease, hepatitis B or hepatitis C viral infection, and a known bleeding disorder. Patients received oral ibrutinib 420 mg once daily until progression or unacceptable toxicity. The substudy was not prospectively powered for statistical comparisons, and as such, all the analyses are descriptive in nature. This study objectives were the proportion of patients with an overall response, progression-free survival, overall survival, haematological improvement measured by haemoglobin, time to next treatment, and patient-reported outcomes according to the Functional Assessment of Cancer Therapy-Anemia (FACT-An) and the Euro Qol 5 Dimension Questionnaire (EQ-5D-5L). All analyses were per protocol. The study is registered at ClinicalTrials.gov, number NCT02165397, and follow-up is ongoing but enrolment is complete. Between Aug 18, 2014, and Feb 18, 2015, 31 patients were enrolled. Median age was 67 years (IQR 58-74); 13 (42%) of 31 patients had high-risk disease per the International Prognostic Scoring System Waldenstr

  6. Symptom Burden and Quality of Life in Patients with Follicular Lymphoma undergoing Maintenance Treatment with Rituximab Compared with Observation

    PubMed Central

    Walker, Mark S.; Stepanski, Edward J.; Reyes, Carolina; Satram-Hoang, Sacha; Houts, Arthur C.; Schwartzberg, Lee S.

    2011-01-01

    Background: The impact on health related quality of life (HRQoL) of rituximab maintenance (R-M) versus observation (OBS) after induction for treatment of follicular lymphoma (FL) is unclear. Methods: We reviewed the charts of 137 patients (53% female, 87% White, age 61.0 ± 12.4 years) who received either R-M (n = 53) or OBS (n = 84) after chemotherapy induction for newly diagnosed FL at community oncology practices within the US. Patients (65% with advanced disease; 48% with a high FLIPI score [3–5]) had completed ≥1 Patient Care Monitor HRQoL survey in the period following front-line therapy, and were excluded if they had progressed during front-line therapy. Results: Linear mixed models showed that postinduction, most symptoms were stable, with patients on R-M reporting HRQoL that was equal to that reported by OBS patients. Conclusions: Among R-M patients, receipt of rituximab was associated with improved psychological symptoms. PMID:23556084

  7. 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.

  8. Drug-Induced Neutropenia: A Focus on Rituximab-Induced Late-Onset Neutropenia.

    PubMed

    Moore, Donald C

    2016-12-01

    Rituximab can cause late-onset neutropenia that may result in serious life-threatening complications. The author describes the pathophysiology, incidence, and management of this adverse reaction and presents two case histories.

  9. Rituximab Therapy Reduces Organ-Specific T Cell Responses and Ameliorates Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Monson, Nancy L.; Cravens, Petra; Hussain, Rehana; Harp, Christopher T.; Cummings, Matthew; de Pilar Martin, Maria; Ben, Li-Hong; Do, Julie; Lyons, Jeri-Anne; Lovette-Racke, Amy; Cross, Anne H.; Racke, Michael K.; Stüve, Olaf; Shlomchik, Mark; Eagar, Todd N.

    2011-01-01

    Recent clinical trials have established B cell depletion by the anti-CD20 chimeric antibody Rituximab as a beneficial therapy for patients with relapsing-remitting multiple sclerosis (MS). The impact of Rituximab on T cell responses remains largely unexplored. In the experimental autoimmune encephalomyelitis (EAE) model of MS in mice that express human CD20, Rituximab administration rapidly depleted peripheral B cells and strongly reduced EAE severity. B cell depletion was also associated with diminished Delayed Type Hypersensitivity (DTH) and a reduction in T cell proliferation and IL-17 production during recall immune response experiments. While Rituximab is not considered a broad immunosuppressant, our results indicate a role for B cells as a therapeutic cellular target in regulating encephalitogenic T cell responses in specific tissues. PMID:21359213

  10. Clinical Responses to Rituximab in a Case of Neuroblastoma with Refractory Opsoclonus Myoclonus Ataxia Syndrome

    PubMed Central

    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

  11. 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.

  12. Bendamustine and Rituximab in Relapsed and Refractory Hairy Cell Leukemia

    PubMed Central

    Burotto, Mauricio; Stetler-Stevenson, Maryalice; Arons, Evgeny; Zhou, Hong; Wilson, Wyndham; Kreitman, Robert J.

    2013-01-01

    Purpose To determine tolerability and for the first time explore efficacy of bendamustine plus rituximab (BR) in multiply relapsed/refractory hairy cell leukemia (HCL), using 2 different dose levels of bendamustine. Experimental design HCL patients with ≥2 prior therapies requiring treatment received rituximab 375 mg/m2 days 1 and 15, plus bendamustine 70 (n=6) or 90 (n=6) mg/m2, days 1 and 2, for 6 cycles at 4-week intervals. Results At 70 and 90 mg/m2/dose of bendamustine, overall response rate was 100%, with 3 (50%) and 4 (67%) complete remissions (CR) in each respective group. Minimal residual disease (MRD) was absent in 67% and 100% of CRs, respectively. All 6 without MRD remain in CR at 30–35 (median 31) months of follow-up. Soluble CD22 and CD25 levels decreased with all responses, with median values decreasing from 17.7 and 42 ng/ml at baseline to undetectable and 2 ng/ml after CR, respectively (p<0.001). Of 12 patients receiving 72 cycles of BR, the most common toxicities were hematologic, including thrombocytopenia (83%), lymphopenia (75%), leukopenia (58%) and neutropenia (42%). Grade 3–4 hematologic toxicity included lymphopenia and thrombocytopenia (each 75%), leukopenia (58%), and neutropenia (25%). No significant dose-related differences were detected in response or toxicity. Conclusion BR has significant activity in HCL. Bendamustine at either 70 or 90 mg/m2/dose was highly effective in multiply relapsed/refractory HCL, and could be considered for achieving durable CRs without MRD in patients after failure of standard therapies. Since it was not dose-limiting, 90 mg/m2/dose was chosen for future testing. PMID:24097860

  13. Efficacy and tolerability of rituximab in patients with rhupus.

    PubMed

    Andrade-Ortega, Lilia; Irazoque-Palazuelos, Fedra; Muñóz-López, Sandra; Rosales-Don Pablo, Victor Manuel

    2013-01-01

    Rhupus in an infrequent disease in which an overlap between lupus eritematosus and rheumatoid arthritis exists. Joint manifestations are prominent and treatment with non biological DMARDs is not always satisfactory, so immunosupressors and biological agents have been tried. A prospective, open clinical study was done to evaluate efficacy and tolerability of rituximab in patients with Rhupus. The main objective was a change in DAS28 at 6 months and secondary objectives were a change in MEX-SLEDAI at 6 months, change in DAS28 and MEX-SLEDAI during follow up, steroid requirements and detection of adverse events. We included 9 women with a mean age of 43 years and disease duration of 10 years. A significant reduction in DAS28 was observed (from 5.73 at baseline to 3.02 at 6 months, P<.001). Improvement in DAS28 was maintained during follow up. At 6 months, 3 patients were in remission and 3 had low disease activity. MEX-SLEDAI diminished from 5 points at baseline to 1.22 at 6 months (P<.001). There was a negative correlation between clinical improvement and anti-CCP levels (r=-0,794, P=.011). Mean prednisone dose was reduced from 11.66mg/day at baseline to 0,55 and 1.11mg/day at 12 and 24 months. Treatment was well tolerated. In this study rituximab was effective not only for joint affection but also for other manifestations of the disease. We consider that this biological agent can be a good therapeutic option for patients with rhupus.

  14. Efficacy and Safety of Rituximab in Moderately-to-Severely Active Systemic Lupus Erythematosus

    PubMed Central

    Merrill, Joan T.; Neuwelt, C. Michael; Wallace, Daniel J.; Shanahan, Joseph C.; Latinis, Kevin M.; Oates, James C.; Utset, Tammy O.; Gordon, Caroline; Isenberg, David A.; Hsieh, Hsin-Ju; Zhang, David; Brunetta, Paul G.

    2015-01-01

    Objective B cells are likely to contribute to the pathogenesis of systemic lupus erythematosus (SLE), and rituximab induces depletion of B cells. The Exploratory Phase II/III SLE Evaluation of Rituximab (EXPLORER) trial tested the efficacy and safety of rituximab versus placebo in patients with moderately-to-severely active extrarenal SLE. Methods Patients entered with ≥1 British Isles Lupus Assessment Group (BILAG) A score or ≥2 BILAG B scores despite background immunosuppressant therapy, which was continued during the trial. Prednisone was added and subsequently tapered. Patients were randomized at a ratio of 2:1 to receive rituximab (1,000 mg) or placebo on days 1, 15, 168, and 182. Results In the intent-to-treat analysis of 257 patients, background treatment was evenly distributed among azathioprine, mycophenolate mofetil, and methotrexate. Fifty-three percent of the patients had ≥1 BILAG A score at entry, and 57% of the patients were categorized as being steroid dependent. No differences were observed between placebo and rituximab in the primary and secondary efficacy end points, including the BILAG-defined response, in terms of both area under the curve and landmark analyses. A beneficial effect of rituximab on the primary end point was observed in the African American and Hispanic subgroups. Safety and tolerability were similar in patients receiving placebo and those receiving rituximab. Conclusion The EXPLORER trial enrolled patients with moderately-to-severely active SLE and used aggressive background treatment and sensitive cutoffs for nonresponse. No differences were noted between placebo and rituximab in the primary and secondary end points. Further evaluation of patient subsets, biomarkers, and exploratory outcome models may improve the design of future SLE clinical trials. PMID:20039413

  15. Cutaneous improvement in refractory adult and juvenile dermatomyositis after treatment with rituximab.

    PubMed

    Aggarwal, Rohit; Loganathan, Priyadarshini; Koontz, Diane; Qi, Zengbiao; Reed, Ann M; Oddis, Chester V

    2017-02-01

    The aim was to assess the efficacy of rituximab for the cutaneous manifestations of adult DM and JDM. Patients with refractory adult DM (n = 72) and JDM (n = 48) were treated with rituximab in a randomized placebo-phase-controlled trial [either rituximab early drug (week 0/1) or rituximab late arms (week 8/9), such that all subjects received study drug]. Stable concomitant therapy was allowed. Cutaneous disease activity was assessed using the Myositis Disease Activity Assessment Tool, which grades cutaneous disease activity on a visual analog scale. A myositis damage assessment tool, termed the Myositis Damage Index, was used to assess cutaneous damage. Improvement post-rituximab was evaluated in individual rashes as well as in cutaneous disease activity and damage scores. The χ(2) test, Student's paired t-test and Wilcoxon test were used for analysis. There were significant improvements in cutaneous disease activity from baseline to the end of the trial after rituximab administration in both adult DM and JDM subsets. The cutaneous visual analog scale activity improved in adult DM (3.22-1.72, P = 0.0002) and JDM (3.26-1.56, P <0.0001), with erythroderma, erythematous rashes without secondary changes of ulceration or necrosis, heliotrope, Gottron sign and papules improving most significantly. Adult DM subjects receiving rituximab earlier in the trial demonstrated a trend for faster cutaneous response (20% relative improvement from baseline) compared with those receiving B cell depletion later (P = 0.052). Refractory skin rashes in adult DM and JDM showed improvement after the addition of rituximab to the standard therapy in a clinical trial. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  16. CALGB 150905 (Alliance): Rituximab broadens the anti-lymphoma response by activating unlicensed NK cells

    PubMed Central

    Du, Juan; Lopez-Verges, Sandra; Pitcher, Brandelyn N.; Johnson, Jeffrey; Jung, Sin-Ho; Zhou, Lili; Hsu, Katharine; Czuczman, Myron S.; Cheson, Bruce; Kaplan, Lawrence; Lanier, Lewis L.; Venstrom, Jeffrey M.

    2014-01-01

    Natural killer (NK) cells contribute to clinical responses in patients treated with rituximab, but the rules determining NK cell responsiveness to mAb therapies are poorly defined. A deeper understanding of the mechanisms responsible for antibody-dependent cellular cytotoxicity (ADCC) could yield useful biomarkers for predicting clinical responses in patients. Unlicensed NK cells, defined as NK cells lacking expression of an inhibitory KIR for self-HLA class I ligands, are hypo-responsive in steady-state, but are potent effectors in inflammatory conditions. We hypothesized that antitumor antibodies such as rituximab can overcome NK cell dependence on licensing, making unlicensed NK cells important for clinical responses. Here we examined the influences of variations in KIR and HLA class I alleles on in vitro responses to rituximab. We tested the clinical significance in a cohort of follicular lymphoma patients treated with rituximab-containing mAb combinations and show that rituximab triggers responses from all NK cell populations regardless of licensing. Neither IL-2 nor accessory cells are required for activating unlicensed NK cells, but both can augment rituximab-mediated ADCC. Moreover, in 101 follicular lymphoma patients treated with rituximab-containing mAb combinations, a “missing ligand” genotype (predictive of unlicensed NK cells) is associated with higher progression-free survival. Our data suggest that the clinical efficacy of rituximab may be driven, in part, by its ability to broaden the NK cell repertoire to include previously hypo-responsive, unlicensed NK cells. A “missing ligand” KIR and HLA class I genotype may be predictive of this benefit, and useful for personalizing treatment decisions in lymphomas and other tumors. PMID:24958280

  17. Efficacy of rituximab in the setting of steroid-refractory chronic graft-versus-host disease: a systematic review and meta-analysis.

    PubMed

    Kharfan-Dabaja, Mohamed A; Mhaskar, Asmita R; Djulbegovic, Benjamin; Cutler, Corey; Mohty, Mohamad; Kumar, Ambuj

    2009-09-01

    Increased insight into the role of B lymphocytes in the pathophysiology of graft-versus-host disease has led to a number of studies assessing the efficacy of the anti-CD20 monoclonal antibody (mAb) rituximab in treating steroid-refractory chronic graft-versus-host disease (cGVHD). Findings vary greatly among these studies, however. We conducted a systematic review to summarize the totality of evidence on the efficacy of rituximab in steroid-refractory cGVHD. We performed a PubMed search and contacted experts in the field to identify relevant studies. Endpoints included overall response rate (including organ-specific) and ability of rituximab to allow dosage reduction of immunosuppressive therapies. Data were pooled under a random-effects model. Seven studies (3 prospective and 4 retrospective, with a total of 111 patients) met the inclusion criteria. The pooled proportion of overall response was 0.66 (95% confidence interval=0.57 to 0.74). There was no heterogeneity among the pooled studies. Response rates were 13% to 100% for cGVHD of the skin, 0 to 83% for cGVHD of the oral mucosa, 0 to 66% for cGVHD of the liver, and 0 to 38% for cGVHD of the lung. Common adverse events were related to infusion reactions or infectious complications. The relatively small number of patients and the varying criteria for reporting organ response and dosage reduction of steroids, among other limitations, hinders our ability to reach definitive conclusions on the overall efficacy of rituximab for cGVHD involving other organs.

  18. Complete response to post-transplant lymphoproliferative disorder by surgical resection and rituximab after living-donor liver re-transplantation for recurrent primary sclerosing cholangitis.

    PubMed

    Haruki, Koichiro; Shiba, Hiroaki; Shimada, Junichi; Okui, Norimitsu; Iida, Tomonori; Yanaga, Katsuhiko

    2017-02-01

    Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication of solid organ transplantation. We herein report a case of PTLD after living-donor liver re-transplantation (reLDLT) for recurrent primary sclerosing cholangitis (PSC), for which complete response was achieved by surgical resection and rituximab. A 47-year-old man, who had undergone living-donor liver transplantation (LDLT) twice at age of 43 and 45 years for end-stage liver disease firstly for PSC and secondary for recurrent PSC, suffered liver dysfunction due to an acute cellular rejection (ACR) 17 months after reLDLT. At reLDLT, a right liver lobe was donated from his spouse. Although steroid was effective for ACR, PTLD developed in the ileocecal area. The patient received rituximab for treatment of PTLD, and ileocecal resection for hemorrhage from ileocecal PTLD. The patient achieved complete response by rituximab and surgical resection for PTLD, but PSC recurred and hemophagocytic syndrome (HPS) developed with hyperbilirubinemia and elevated serum ferritin. The patient received steroid treatment for HPS, but thrombocytopenia and coagulopathy developed presumably due to thrombotic microangiopathy. Therefore, tacrolimus was switched to mycophenolate mofetil. Despite intensive treatment including plasmapheresis and platelet infusion, fungal infection of both lungs developed, and the patient died 22 months after reLDLT. Autopsy revealed complete response of PTLD, recurrence of PSC and persistance of HPS.

  19. The effect of rituximab on anti-platelet autoantibody levels in patients with immune thrombocytopenia.

    PubMed

    Arnold, Donald M; Vrbensky, John R; Karim, Nadia; Smith, James W; Liu, Yang; Ivetic, Nikola; Kelton, John G; Nazy, Ishac

    2017-07-01

    Rituximab is an effective therapy resulting in a platelet count improvement in 60% of patients with immune thrombocytopenia (ITP). Rituximab depletes B cells; thus, a reduction in platelet autoantibody levels would be anticipated in patients who achieve a clinical response to this treatment. The objectives of this study were to determine whether rituximab was associated with a reduction in platelet autoantibody levels, and to correlate the loss of autoantibodies with the achievement of a treatment response. We performed a case-control study nested within a previous randomized controlled trial of standard therapy plus adjuvant rituximab or placebo. We measured platelet-bound anti-glycoprotein (GP) IIbIIIa and anti-GPIbIX using the antigen capture test. Of 55 evaluable patients, 25 (45%) had a detectable platelet autoantibody at baseline. Rituximab was associated with a significant reduction in anti-GPIIbIIIa levels (P = 0·02) but not anti-GPIbIX levels (P = 0·51) compared with placebo. Neither the presence of an autoantibody at baseline nor the loss of the autoantibody after treatment was associated with a response to rituximab. The subset of patients with persistent autoantibodies after treatment failed to achieve a platelet count response, suggesting that persistence of platelet autoantibodies can be a marker of disease severity. © 2017 John Wiley & Sons Ltd.

  20. Effects of Low-Dose Rituximab Therapy in Patients With Primary Cytomegalovirus Infection.

    PubMed

    Ishihara, Hiroki; Ishida, Hideki; Toki, Daisuke; Omoto, Kazuya; Sirakawa, Hiroki; Shimizu, Tomokazu; Okumi, Masayoshi; Tanabe, Kazunari

    2015-12-01

    Cytomegalovirus infection is an important cause of morbidity and mortality among recipients undergoing hematopoietic stem cell and solid-organ transplant. The risk of cytomegalovirus infection is high in cytomegalovirus-seronegative recipients of cytomegalovirus-seropositive organs (donor positive/recipient negative) and recipients with strong immunosuppressive status such as those receiving rituximab induction or antirejection treatment. However, it remains unclear how rituximab affects patients with primary cytomegalovirus infection. We evaluated the effects of low-dose rituximab therapy on clinical and immunologic outcomes in recipients who were donor positive but recipient negative for primary cytomegalovirus infections. We conducted a retrospective review of patients with primary cytomegalovirus infections from January 2005 to March 2014. Patient outcomes were compared between groups administered given rituximab or given no intervention at the time of transplant. Our study group included 49 recipients with primary cytomegalovirus infection, including 32 who received rituximab therapy (group 1) and 17 who did not (group 2). No significant differences were observed between groups in the duration of cytomegalovirus seroconversion (P = .0570) and initial cytomegalovirus immunoglobulin G titers (P = .8418). Rituximab induction therapy does not affect clinical or immunologic outcomes of primary cytomegalovirus infection, even in high-risk recipients who are donor positive but recipient negative for primary cytomegalovirus infections.

  1. 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

  2. Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis.

    PubMed

    Saadoun, David; Rosenzwajg, Michelle; Landau, Dan; Piette, Jean Charles; Klatzmann, David; Cacoub, Patrice

    2008-06-01

    Rituximab, an anti-CD20 monoclonal antibody, has been used to treat autoimmune disorders such as mixed cryoglobulinemia (MC). However, its mechanisms of action as well as the effects on cellular immunity remain poorly defined. We investigated the changes of peripheral blood B- and T-cell subsets, the clonal VH1-69 cells, as well as the cytokine profile following rituximab therapy. The study involved 21 patients with hepatitis C-related MC who received rituximab, of whom 14 achieved a complete response. Compared with healthy and hepatitis C virus (HCV) controls, pretreatment abnormalities in MC patients included a decreased percentage of naive B cells (P < .05) and CD4(+)CD25(+)FoxP3(+) regulatory T cells (P = .02) with an increase in memory B cells (P = .03) and plasmablasts (P < .05). These abnormalities were reverted at 12 months after rituximab. Clonal VH1-69(+) B cells dramatically decreased following treatment (32% +/- 6% versus 8% +/- 2%, P = .01). Complete responders of rituximab exhibited an expansion of regulatory T cells (P < .01) accompanied with a decrease in CD8(+) T-cell activation (P < .01) and decreased production of interleukin 12 (IL-12; P = .02) and interferon-gamma (IFN-gamma; P = .01). Our findings indicate that in patients with MC, response to B-cell depletion induced by rituximab effectively normalizes many of the disturbances in peripheral B- and T-lymphocyte homeostasis.

  3. Is there a role for "watch and wait" in follicular lymphoma in the rituximab era?

    PubMed

    Kahl, Brad

    2012-01-01

    The paradigm of "watch and wait" for low-tumor-burden follicular lymphoma (LTB-FL) was established in an era when the treatment options were more limited. With the introduction of rituximab, it appears that the natural history of this incurable disease has changed. However, most of the contemporary treatment data have been generated in patients with high tumor burden, and it is unclear whether the improvements in outcome also apply to the LTB population. There are no published trials evaluating rituximab-chemotherapy combinations and just a few studies evaluating single-agent rituximab in this population. As a result, there are many unknowns in the management of LTB-FL. Would the application of rituximab-chemotherapy combination cure a fraction of patients? Would the application of rituximab-chemotherapy combination improve the overall survival of the population? Would treatment with single-agent rituximab improve the psychologic quality of life by avoiding a watch and wait interval or by delaying the time to first chemotherapy? This review, a mixture of data and opinion, will discuss goals of therapy for an LTB-FL patient, summarize existing data, and propose a management algorithm.

  4. 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

  5. Rituximab Treatment for PR3-ANCA-Positive Membranoproliferative Glomerulonephritis Associated with Adult-Onset Periodic Fever Syndrome

    PubMed Central

    Hamano, Yoshitomo; Yoshizawa, Hiromichi; Sugase, Taro; Miki, Takuya; Ohtani, Naoko; Hanawa, Shiho; Takeshima, Eri; Morishita, Yoshiyuki; Saito, Osamu; Takemoto, Fumi; Muto, Shigeaki; Yumura, Wako; Kusano, Eiji

    2012-01-01

    We report the case of a 36-year-old Japanese woman with nephrotic syndrome due to membranoproliferative glomerulonephritis (MPGN) Type I diagnosed after a 5-year history of periodic fever syndrome (PFS). Hypocomplementemia and elevation of anti-proteinase 3 anti-neutrophil cytoplasmic autoantibody (PR3-ANCA) were observed. HIV, and hepatitis B and C serology were negative. Nephrotic syndrome and periodic fever did not respond to oral steroid and intravenous steroid pulse therapies combined with cyclosporine, dipyridamole, warfarin and losartan. We tried immunotherapy using rituximab, a human-mouse chimeric monoclonal antibody directed against the CD20 antigen on mature B cells. This therapeutic approach led to improvement of renal function and remission of nephrotic syndrome and hypocomplementemia. However, it did not have a beneficial effect on periodic fever. Suspecting adult-onset hereditary PFS, we analyzed her genetic alteration of MEFV and TNFRSF1A genes. A rare genotype in intron 6 of TNFRSF1A was revealed. The etiological relationship between periodic fever and MPGN is discussed. Rituximab is a hopeful choice of induction therapy for refractory MPGN. PMID:23197963

  6. Experience With Rituximab Immunotherapy as an Early Intervention in Patients With Rai Stage 0 to II Chronic Lymphocytic Leukemia

    PubMed Central

    Ferrajoli, Alessandra; Keating, Michael J.; O’Brien, Susan; Cortes, Jorge; Thomas, Deborah A.

    2015-01-01

    BACKGROUND Management of asymptomatic early stage chronic lymphocytic leukemia (CLL) centered on expectant surveillance for active disease warranting chemotherapy. In CLL, elevated serum β-2 microglobulin (β2M) levels were associated with more rapid disease progression and shorter survival (OS). METHODS An early intervention trial was designed to assess response, time-to-progression (TTP), and OS after immunotherapy with standard-dose rituximab (375 mg/m2 intravenously weekly for 8 consecutive weeks) in 34 asymptomatic untreated early stage CLL with β2M level ≥ 2 mg/dL. RESULTS Long-term follow-up and results are reported. The overall response rate in 34 patients was 82% (9% complete [CR]), median TTP in the 28 responders was 23 months, the median time to subsequent treatment was 43 months, and the 8-year OS rate was 74% (median follow-up, 102 months). CONCLUSIONS Early treatment with rituximab was well tolerated and safe. Further studies are needed to determine if this intervention can decrease CLL-related morbidity and mortality. PMID:21246526

  7. 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

  8. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial.

    PubMed

    Salles, Gilles; Seymour, John Francis; Offner, Fritz; López-Guillermo, Armando; Belada, David; Xerri, Luc; Feugier, Pierre; Bouabdallah, Réda; Catalano, John Vincent; Brice, Pauline; Caballero, Dolores; Haioun, Corinne; Pedersen, Lars Moller; Delmer, Alain; Simpson, David; Leppa, Sirpa; Soubeyran, Pierre; Hagenbeek, Anton; Casasnovas, Olivier; Intragumtornchai, Tanin; Fermé, Christophe; da Silva, Maria Gomes; Sebban, Catherine; Lister, Andrew; Estell, Jane A; Milone, Gustavo; Sonet, Anne; Mendila, Myriam; Coiffier, Bertrand; Tilly, Hervé

    2011-01-01

    Patients with follicular lymphoma can have long survival times, but disease progression typically occurs 3-5 years after initial treatment. We assessed the potential benefit of 2 years of rituximab maintenance after first-line treatment in patients with follicular lymphoma receiving a rituximab plus chemotherapy regimen. The randomised, open-label PRIMA study was undertaken in 223 centres in 25 countries. 1217 patients with previously untreated follicular lymphoma needing systemic therapy received one of three non-randomised immunochemotherapy induction regimens used in routine practice. 1019 patients achieving a complete or partial response were then randomly assigned to receive 2 years of rituximab maintenance therapy (375 mg/m(2) every 8 weeks) or observation. Treatment was assigned equally by centralised block randomisation, stratified by induction regimen, response, region, and centre. Neither the participants nor those giving the interventions, assessing outcomes, and analysing data were masked to group assignments. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00140582. 505 patients were assigned to rituximab maintenance and 513 to observation (one patient died during randomisation). With a median follow-up of 36 months (IQR 30-42), PFS was 74·9% (95% CI 70·9-78·9) in the rituximab maintenance group (130 patients progressed) and 57·6% (53·2-62·0) in the observation group (218 progressed; hazard ratio [HR] 0·55, 95% CI 0·44-0·68, p<0·0001). 2 years after randomisation, 361 patients (71·5%) in the rituximab maintenance group were in complete or unconfirmed complete response versus 268 (52·2%) in the observation group (p=0·0001). Overall survival did not differ significantly between groups (HR 0·87, 95% CI 0·51-1·47). Grade 3 and 4 adverse events were recorded in 121 patients (24%) in the rituximab maintenance group and 84 (17%) in the

  9. Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study.

    PubMed

    Chanan-Khan, Asher; Cramer, Paula; Demirkan, Fatih; Fraser, Graeme; Silva, Rodrigo Santucci; Grosicki, Sebastian; Pristupa, Aleksander; Janssens, Ann; Mayer, Jiri; Bartlett, Nancy L; Dilhuydy, Marie-Sarah; Pylypenko, Halyna; Loscertales, Javier; Avigdor, Abraham; Rule, Simon; Villa, Diego; Samoilova, Olga; Panagiotidis, Panagiots; Goy, Andre; Mato, Anthony; Pavlovsky, Miguel A; Karlsson, Claes; Mahler, Michelle; Salman, Mariya; Sun, Steven; Phelps, Charles; Balasubramanian, Sriram; Howes, Angela; Hallek, Michael

    2016-02-01

    -free survival. Crossover to ibrutinib was permitted for patients in the placebo group with IRC-confirmed disease progression. Analysis was by intention-to-treat and is continuing for further long-term follow-up. The trial is registered with ClinicalTrials.gov, number NCT01611090. Between Sept 19, 2012, and Jan 21, 2014, 578 eligible patients were randomly assigned to ibrutinib or placebo in combination with bendamustine plus rituximab (289 in each group). The primary endpoint was met at the preplanned interim analysis (March 10, 2015). At a median follow-up of 17 months (IQR 13·7-20·7), progression-free survival was significantly improved in the ibrutinib group compared with the placebo group (not reached in the ibrutinib group (95% CI not evaluable) vs 13·3 months (11·3-13·9) in the placebo group (hazard ratio [HR] 0·203, 95% CI 0·150-0·276; p<0·0001). IRC-assessed progression-free survival at 18 months was 79% (95% CI 73-83) in the ibrutinib group and 24% (18-31) in the placebo group (HR 0·203, 95% CI 0·150-0·276; p<0·0001). The most frequent all-grade adverse events were neutropenia and nausea. 222 (77%) of 287 patients in the ibrutinib group and 212 (74%) of 287 patients in the placebo group reported grade 3-4 events; the most common grade 3-4 adverse events in both groups were neutropenia (154 [54%] in the ibrutinib group vs 145 [51%] in the placebo group) and thrombocytopenia (43 [15%] in each group). A safety profile similar to that previously reported with ibrutinib and bendamustine plus rituximab individually was noted. In patients eligible for bendamustine plus rituximab, the addition of ibrutinib to this regimen results in significant improvements in outcome with no new safety signals identified from the combination and a manageable safety profile. Janssen Research & Development. Copyright © 2016 Elsevier Ltd. All rights reserved.

  10. 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

  11. Changes in B- and T-lymphocyte and chemokine levels with rituximab treatment in multiple sclerosis.

    PubMed

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

    2010-06-01

    B cells are implicated in the pathogenesis of multiple sclerosis. A beneficial effect of B-cell depletion using rituximab has been shown, but the complete mechanism of action for this drug is unclear. To determine the relationship between T and B cells and changes in cerebrospinal fluid (CSF) chemokine levels with rituximab, a monoclonal antibody that targets CD20. Phase 2 trial of rituximab as an add-on therapy. The John L. Trotter Multiple Sclerosis Center, Washington University. Participants and Intervention Thirty subjects who had relapsing-remitting multiple sclerosis with clinical and magnetic resonance imaging activity despite treatment with an immunomodulatory drug received 4 weekly doses of rituximab (375 mg/m(2)). Lumbar puncture was performed before and after rituximab infusions in 26 subjects. Levels of B and T lymphocytes in the CSF were enumerated by flow cytometry, and chemoattractant levels were measured by enzyme-linked immunosorbent assay. After rituximab administration, CSF B-cell levels were decreased or undetectable in all subjects, and CSF T-cell levels were reduced in 21 subjects (81%). The mean reduction in CSF cellularity was 95% for B cells and 50% for T cells. After rituximab infusion, CSF CXCL13 and CCL19 levels decreased (P = .002 and P = .03, respectively). The proportional decline in CSF T-cell levels correlated with the proportional decrease in CXCL13 levels (r = 0.45; P = .03), suggesting a possible relationship. The CSF IgG index, IgG concentration, and oligoclonal band number were unchanged following treatment. In subjects with multiple sclerosis, B cells are critical for T-cell trafficking into the central nervous system and may alter the process by influencing chemokine production within the central nervous system.

  12. A Randomized, Controlled Trial of Rituximab in IgA Nephropathy with Proteinuria and Renal Dysfunction.

    PubMed

    Lafayette, Richard A; Canetta, Pietro A; Rovin, Brad H; Appel, Gerald B; Novak, Jan; Nath, Karl A; Sethi, Sanjeev; Tumlin, James A; Mehta, Kshama; Hogan, Marie; Erickson, Stephen; Julian, Bruce A; Leung, Nelson; Enders, Felicity T; Brown, Rhubell; Knoppova, Barbora; Hall, Stacy; Fervenza, Fernando C

    2017-04-01

    IgA nephropathy frequently leads to progressive CKD. Although interest surrounds use of immunosuppressive agents added to standard therapy, several recent studies have questioned efficacy of these agents. Depleting antibody-producing B cells potentially offers a new therapy. In this open label, multicenter study conducted over 1-year follow-up, we randomized 34 adult patients with biopsy-proven IgA nephropathy and proteinuria >1 g/d, maintained on angiotensin-converting enzyme inhibitors or angiotensin receptor blockers with well controlled BP and eGFR<90 ml/min per 1.73 m(2), to receive standard therapy or rituximab with standard therapy. Primary outcome measures included change in proteinuria and change in eGFR. Median baseline serum creatinine level (range) was 1.4 (0.8-2.4) mg/dl, and proteinuria was 2.1 (0.6-5.3) g/d. Treatment with rituximab depleted B cells and was well tolerated. eGFR did not change in either group. Rituximab did not alter the level of proteinuria compared with that at baseline or in the control group; three patients in each group had ≥50% reduction in level of proteinuria. Serum levels of galactose-deficient IgA1 or antibodies against galactose-deficient IgA1 did not change. In this trial, rituximab therapy did not significantly improve renal function or proteinuria assessed over 1 year. Although rituximab effectively depleted B cells, it failed to reduce serum levels of galactose-deficient IgA1 and antigalactose-deficient IgA1 antibodies. Lack of efficacy of rituximab, at least at this stage and severity of IgA nephropathy, may reflect a failure of rituximab to reduce levels of specific antibodies assigned salient pathogenetic roles in IgA nephropathy.

  13. Elevated autoantibody content in rheumatoid arthritis synovia with lymphoid aggregates and the effect of rituximab.

    PubMed

    Rosengren, Sanna; Wei, Nathan; Kalunian, Kenneth C; Zvaifler, Nathan J; Kavanaugh, Arthur; Boyle, David L

    2008-01-01

    The purpose of this study was to quantitatively evaluate the contribution of synovial lymphoid aggregates to autoantibody (rheumatoid factor [RF] and anti-cyclic citrullinated peptide [anti-CCP]) and total immunoglobulin (IgG and IgM) production in rheumatoid arthritis (RA) patients and the effect thereon of the B-cell-depleting antibody, rituximab, in the ARISE (Assessment of Rituximab's Immunomodulatory Synovial Effects) trial. Autoantibodies as well as total IgM and IgG were quantified by enzyme-linked immunosorbent assay in extracts of synovial tissues and matched serum from patients with RA or osteoarthritis (OA). Synovial biopsies and serum were obtained at baseline and 8 weeks following rituximab therapy in 14 RA patients. A synovial/serum index (SSI) was calculated as the ratio of synovial to serum antibody/albumin, with values above 1 representing synovial enrichment. Lymphoid aggregates were evaluated histologically. Anti-CCP IgG, but not RF-IgM, was significantly enriched in RA synovia compared with serum. Total IgM and IgG were also enriched in RA, but not in OA. SSI correlated significantly with mRNA content for both IgM and IgG, demonstrating that it reflected synovial immunoglobulin production. RA synovia with lymphocyte aggregates contained significantly elevated RF-IgM and anti-CCP IgG compared with tissues with diffuse lymphoid infiltration. Rituximab treatment did not affect synovial autoantibody or total immunoglobulin SSI overall. However, in aggregate-containing tissues, rituximab significantly reduced total IgM and IgG SSI as well as IgM and IgG1 mRNA. Surprisingly, RF-IgM and anti-CCP IgG SSIs were unchanged by rituximab in aggregate-containing synovia. Combined with earlier observations that synovial lymphoid aggregates are unaltered by rituximab treatment, these data suggest that lymphoid aggregates may provide a protective niche for autoantibody-producing cells.

  14. Rituximab as treatment for anti-MuSK myasthenia gravis: Multicenter blinded prospective review.

    PubMed

    Hehir, Michael K; Hobson-Webb, Lisa D; Benatar, Michael; Barnett, Carolina; Silvestri, Nicholas J; Howard, James F; Howard, Diantha; Visser, Amy; Crum, Brian A; Nowak, Richard; Beekman, Rachel; Kumar, Aditya; Ruzhansky, Katherine; Chen, I-Hweii Amy; Pulley, Michael T; LaBoy, Shannon M; Fellman, Melissa A; Greene, Shane M; Pasnoor, Mamatha; Burns, Ted M

    2017-09-05

    To evaluate the efficacy of rituximab in treatment of anti-muscle-specific kinase (MuSK) myasthenia gravis (MG). This was a multicenter, blinded, prospective review, comparing anti-MuSK-positive patients with MG treated with rituximab to those not treated with rituximab. The primary clinical endpoint was the Myasthenia Gravis Status and Treatment Intensity (MGSTI), a novel outcome that combines the Myasthenia Gravis Foundation of America (MGFA) postintervention status (PIS) and the number and dosages of other immunosuppressant therapies used. A priori, an MGSTI of level ≤2 was used to define a favorable outcome. Secondary outcomes included modified MGFA PIS of minimal manifestations or better, mean/median prednisone dose, and mean/median doses of other immunosuppressant drugs. Seventy-seven of 119 patients with anti-MuSK MG evaluated between January 1, 2005, and January 1, 2015, at 10 neuromuscular centers were selected for analysis after review of limited clinical data by a blinded expert panel. An additional 22 patients were excluded due to insufficient follow-up. Baseline characteristics were similar between the rituximab-treated patients (n = 24) and the controls (n = 31). Median follow-up duration was >3.5 years. At last visit, 58% (14/24) of rituximab-treated patients reached the primary outcome compared to 16% (5/31) of controls (p = 0.002). Number needed to treat for the primary outcome is 2.4. At last visit, 29% of rituximab-treated patients were taking prednisone (mean dose 4.5 mg/day) compared to 74% of controls (mean dose 13 mg/day) (p = 0.001 and p = 0.005). This study provides Class IV evidence that for patients with anti-MuSK MG, rituximab increased the probability of a favorable outcome. © 2017 American Academy of Neurology.

  15. Spotlight on rituximab in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis: current perspectives

    PubMed Central

    Moog, Philipp; Thuermel, Klaus

    2015-01-01

    A 54-year-old patient presented to his general practitioner because of strong muscle pain in both thighs. Inflammatory parameters (CRP 16.3 mg/dL) and white blood cells (15 g/L) were elevated. The patient reported a weight loss of 10 kg in 4 weeks. There was no fever or any other specific symptoms. Urine dipstick examination and computed tomography of the chest were unremarkable. Because of increasing symptoms, the patient was referred to our department. Magnetic resonance tomography showed diffuse inflammatory changes of the muscles of both thighs. Neurological examination and electrophysiology revealed axonal sensorimotor neuropathy and ground-glass opacities of both lungs had occurred. Serum creatinine increased to 229 μmol/L within a few days, with proteinuria of 3.3 g/g creatinine. Kidney biopsy showed diffuse pauci-immune proliferative glomerulonephritis. Proteinase 3-specific antineutrophil cytoplasmic antibodies were markedly increased. Birmingham Vasculitis Activity Score was 35. Within 2 days, serum creatinine further increased to 495 μmol/L. Plasma exchange, high-dose glucocorticosteroids, and hemodialysis were started. The patient received cyclophosphamide 1 g twice and rituximab 375 mg/m2 four times according to the RITUXVAS protocol. Despite ongoing therapy, hemodialysis could not be withdrawn and had to be continued over 3 weeks until diuresis normalized. Glucocorticosteroids were tapered to 20 mg after 2 months, and serum creatinine was 133 μmol/L. However, nephritic urinary sediment reappeared. Another dose of 1 g cyclophosphamide was given, and glucocorticosteroids were raised for another 4 weeks. After 6 months, the daily prednisolone dose was able to be tapered to 5 mg. Serum creatinine was 124 μmol/L, proteinuria further decreased to 382 mg/g creatinine, and the Birmingham Vasculitis Activity Score was 0. Maintenance therapy with rituximab 375 mg/m2 every 6 months was started. At the last visit after 8 months, the patient was still in

  16. Pharmacokinetics, safety, and efficacy of subcutaneous versus intravenous rituximab plus chemotherapy as treatment for chronic lymphocytic leukaemia (SAWYER): a phase 1b, open-label, randomised controlled non-inferiority trial.

    PubMed

    Assouline, Sarit; Buccheri, Valeria; Delmer, Alain; Gaidano, Gianluca; Trneny, Marek; Berthillon, Natalia; Brewster, Michael; Catalani, Olivier; Li, Sai; McIntyre, Christine; Sayyed, Pakeeza; Badoux, Xavier

    2016-03-01

    follow-up was 13·9 months (IQR 11·9-16·0) for patients in the subcutaneous group and 14·1 months (11·6-16·5) for patients in the intravenous group. At cycle five, the geometric mean trough serum concentration in patients given subcutaneous rituximab was non-inferior to that in patients given intravenous rituximab (97·5 μg/mL vs 61·5 μg/mL), with an adjusted geometric mean ratio of 1·53 (90% CI 1·27-1·85). In the safety analysis, the proportion of patients reporting adverse events was similar between the subcutaneous and intravenous groups (all grades: 82 [96%] of 85 patients and 81 [91%] of 89 patients; serious adverse events: 25 [29%] and 29 [33%] patients; grade ≥3: 59 [69%] and 63 [71%] patients, respectively). The most common adverse event of grade 3 or higher was neutropenia (48 [56%] patients in the subcutaneous group and 46 [52%] patients in the intravenous group); the most common serious adverse event was febrile neutropenia (n=9 [11%] and n=4 [4%], respectively). We recorded administration-related reactions in 37 (44%) patients given subcutaneous rituximab and 40 (45%) patients given the intravenous dose, with differences between administration routes for injection-site erythema (n=10 [12%] and n=0, respectively) and nausea (n=2 [2%] and n=11 [12%], respectively). More patients reported local cutaneous reactions after subcutaneous rituximab (n=36 [42%]) than after intravenous rituximab (n=2 [2%]); most of these reactions were grade 1 or 2. When combined with fludarabine and cyclophosphamide, subcutaneous rituximab 1600 mg achieved trough serum concentrations that were pharmacokinetically non-inferior to those achieved with intravenous rituximab 500 mg/m(2), with a similar safety and efficacy profile between the two groups. Treatment with subcutaneous rituximab should allow patients with chronic lymphocytic leukaemia to receive clinical benefit from the drug via a more convenient delivery method than the intravenous route, and might also be used in

  17. Rituximab maintenance therapy for patients with diffuse large B-cell lymphoma: A meta-analysis

    PubMed Central

    Li, Juan

    2017-01-01

    Purpose The addition of rituximab to standard chemotherapy has significantly improved survival in patients with lymphoma. Recently, maintenance therapy with rituximab has been shown to prevent relapse and provide survival benefits for patients with follicular or mantle cell lymphoma. However, the effects of rituximab in patients with diffuse large B-cell lymphoma (DLBCL) remain unclear. Two new studies involving rituximab in the treatment of DLBCL were performed this past year. We performed a meta analysis to evaluate the effects of rituximab maintenance treatment of patients with DLBCL. Methods Several databases (PubMed, MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials) databases were reviewed for relevant randomized controlled trials published prior to May, 2016. Two reviewers assessed the quality of the included studies and extracted data independently. The hazard ratios (HRs) for time-to-event data and relative risks (RRs) for the other data were pooled and estimated. Results Totally 5 studies including 1740 patients were eligible for the meta-analysis. Compared to the observation group, patients who received rituximab maintenance therapy had significantly improved event-free survival (EFS) (HR = 0.80, 95% CI: 0.65–0.98) and progression-free survival (PFS) (HR = 0.72, 95% CI: 0.54–0.94). However, there was no statistically significant difference in overall survival (OS) (HR = 0.66, 95% CI: 0.27–1.29). A subgroup analysis suggested that male patients may benefit from rituximab maintenance therapy with a better EFS (HR = 0.53, 95% CI: 0.34–0.82-), while this advantage was not observed in female patients (HR = 0.99, 95% CI: 0.64–1.52). Conclusions Rituximab maintenance may provide survival benefits beyond that afforded by first- and second-line chemotherapy alone, especially in male patients. However, maintenance rituximab treatment may cause more adverse events. It is recommended that both survival benefits and adverse events should

  18. Inflammation and autoantibody markers identify rheumatoid arthritis patients with enhanced clinical benefit following rituximab treatment.

    PubMed

    Lal, Preeti; Su, Zheng; Holweg, Cecile T J; Silverman, Gregg J; Schwartzman, Sergio; Kelman, Ariella; Read, Simon; Spaniolo, Greg; Monroe, John G; Behrens, Timothy W; Townsend, Michael J

    2011-12-01

    Rituximab significantly improves the signs and symptoms of rheumatoid arthritis (RA) and slows the progression of joint damage. The aim of this study was to identify clinical characteristics and biomarkers that identify patients with RA in whom the clinical benefit of rituximab may be enhanced. The study group comprised 1,008 RA patients from 2 independent randomized placebo-controlled phase III clinical trials (REFLEX [Randomized Evaluation of Long-Term Efficacy of Rituximab in Rheumatoid Arthritis] and SERENE [Study Evaluating Rituximab's Efficacy in Methotrexate Inadequate Responders]). A novel threshold selection method was used to identify baseline candidate biomarkers present in at least 20% of patients that enriched for placebo-corrected American College of Rheumatology 50% improvement (ACR50 response; a high clinical efficacy bar) at week 24 after the first course of rituximab. The presence of IgM rheumatoid factor (IgM-RF), IgG-RF, IgA-RF, and IgG anti-cyclic citrullinated peptide (anti-CCP) antibodies together with an elevated C-reactive protein (CRP) level were associated with enhanced placebo-corrected ACR50 response rates in the REFLEX patients with RA who had an inadequate response to anti-tumor necrosis factor therapies. These findings were independently replicated using samples from patients in SERENE who had an inadequate response to disease-modifying antirheumatic drug treatment. The combination of an elevated baseline CRP level together with an elevated level of any RF isotype and/or IgG anti-CCP antibodies was further associated with an enhanced benefit to rituximab. The presence of any RF isotype and/or IgG anti-CCP autoantibodies together with an elevated CRP level identifies a subgroup of patients with RA in whom the benefit of rituximab treatment may be enhanced. Although the clinical benefit of rituximab was greater in the biomarker-positive population compared with the biomarker-negative population, the clinical benefit of rituximab

  19. Lessons for the clinic from rituximab pharmacokinetics and pharmacodynamics

    PubMed Central

    Golay, Josée; Semenzato, Gianpietro; Rambaldi, Alessandro; Foà, Robin; Gaidano, Gianluca; Gamba, Enrica; Pane, Fabrizio; Pinto, Antonello; Specchia, Giorgina; Zaja, Francesco; Regazzi, Mario

    2013-01-01

    The anti-CD20 antibody rituximab (RTX; Rituxan®, MabThera®) was the first anti-cancer antibody approved by the US Food and Drug Administration in 1997 and it is now the most-studied unconjugated therapeutic antibody. The knowledge gained over the past 15 y on the pharmacodynamics (PD) of this antibody has led to the development of a new generation of anti-CD20 antibodies with enhanced efficacy in vitro. Studies on the pharmacokinetics (PK) properties and the effect of factors such as tumor load and localization, antibody concentration in the circulation and gender on both PK and clinical response has allowed the design of optimized schedules and novel routes of RTX administration. Although clinical results using newer anti-CD20 antibodies, such as ofatumumab and obinutuzumab, and novel administration schedules for RTX are still being evaluated, the knowledge gained so far on RTX PK and PD should also be relevant for other unconjugated monoclonal antibody therapeutics, and will be critically reviewed here. PMID:23933992

  20. Rituximab treatment for relapsed opsoclonus-myoclonus syndrome.

    PubMed

    Toyoshima, Daisaku; Morisada, Naoya; Takami, Yuichi; Kidokoro, Hiroyuki; Nishiyama, Masahiro; Nakagawa, Taku; Ninchoji, Takeshi; Nozu, Kandai; Takeshima, Yasuhiro; Takada, Satoshi; Nishio, Hisahide; Iijima, Kazumoto

    2016-03-01

    Opsoclonus-myoclonus syndrome (OMS) is a rare neurological disorder that is associated with paraneoplastic diseases. Because OMS can frequently relapse, patients may be inflicted with neurological problems for a long time. Recently, rituximab (RTX) was introduced as a drug to treat OMS. To assess RTX treatment, we studied a patient who experienced recurrence of OMS. A 2-year-old Japanese boy, who had left adrenal neuroblastoma, suddenly showed OMS symptoms, including ataxia and opsoclonus. Surgical resection of the tumor and subsequent steroid therapy ameliorated his symptoms. When OMS relapsed during the time when prednisolone was reduced, he was treated with full-dose RTX therapy (375 mg/m2/week) for 4 consecutive weeks. However, 1year later, he presented again with OMS symptoms. This time, we only administered an additional single dose of RTX treatment (375 mg/m2), allowing remission of OMS symptoms. During 2 years after the additional RTX treatment, OMS symptoms did not appear, even when prednisolone was reduced. He had no adverse events associated with RTX during the whole treatment period. An additional single-dose RTX therapy might be effective for relapsed OMS patients who were previously treated with full-dose RTX therapy. Copyright © 2015 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

  1. ABO-Incompatible Adult Living Donor Liver Transplantation Under the Desensitization Protocol With Rituximab.

    PubMed

    Song, G-W; Lee, S-G; Hwang, S; Kim, K-H; Ahn, C-S; Moon, D-B; Ha, T-Y; Jung, D-H; Park, G-C; Kim, W-J; Sin, M-H; Yoon, Y-I; Kang, W-H; Kim, S-H; Tak, E-Y

    2016-01-01

    ABO incompatibility is no longer considered a contraindication for adult living donor liver transplantation (ALDLT) due to various strategies to overcome the ABO blood group barrier. We report the largest single-center experience of ABO-incompatible (ABOi) ALDLT in 235 adult patients. The desensitization protocol included a single dose of rituximab and total plasma exchange. In addition, local graft infusion therapy, cyclophosphamide, or splenectomy was used for a certain time period, but these treatments were eventually discontinued due to adverse events. There were three cases (1.3%) of in-hospital mortality. The cumulative 3-year graft and patient survival rates were 89.2% and 92.3%, respectively, and were comparable to those of the ABO-compatible group (n = 1301). Despite promising survival outcomes, 17 patients (7.2%) experienced antibody-mediated rejection that manifested as diffuse intrahepatic biliary stricture; six cases required retransplantation, and three patients died. ABOi ALDLT is a feasible method for expanding a living liver donor pool, but the efficacy of the desensitization protocol in targeting B cell immunity should be optimized.

  2. Successful plasma exchange combined with rituximab therapy in aggressive APS-related cutaneous necrosis.

    PubMed

    Costa, Rubens; Fazal, Salman; Kaplan, Robert B; Spero, Joel; Costa, Ricardo

    2013-03-01

    Antiphospholipid antibody syndrome (APS) is a systemic autoimmune disorder characterized by venous and/or arterial thrombosis or recurrent fetal loss associated with the presence of antiphospholipid antibodies and/or a lupus anticoagulant. The skin appears to be an important target organ and many cases of APS may present with skin manifestations. These lesions may be manifold and may take the form of livedo reticularis, livedo racemosa, ulcerations, digital gangrene, subungeal splinter hemorrhages, superficial venous thrombosis, thrombocytopenic purpura, pseudovasculitic manifestations, extensive cutaneous necrosis, or primary anetoderma. We report a case of fulminant APS-related cutaneous necrosis. A 38-year-old Caucasian male with a past history of APS, multiple deep vein thrombi/pulmonary emboli, presented with necrotic lesions on his right upper and right lower extremities. Initially, baseline anticoagulation was increased without improvement. Subsequently, plasma exchange was initiated on a daily schedule. Furthermore, rituximab 1,000 mg IV was administered on days 1 and 15. After six consecutive daily sessions of plasma exchange, there was significant regression of the necrotic lesions. After a 22-day hospital stay, the patient was discharged to home on fondaparinux. The patient presented approximately 2 months later after missing follow-up appointments. At the time, his initial lesions looked remarkably improved.

  3. Long-term follow-up of different refractory systemic vasculitides treated with rituximab.

    PubMed

    Rees, Frances; Yazdani, Ramin; Lanyon, Peter

    2011-09-01

    There is increasing interest in rituximab (RTX) as an alternative to cyclophosphamide (CYC) for remission induction in systemic vasculitis. Recent studies have reported high remission rates, but it is not clear how long the initial remission lasts [1, 2]. A retrospective study was undertaken of 15 cases of refractory systemic vasculitis (11 Wegener's granulomatosis, 1 Churg-Strauss syndrome, 1 cutaneous polyarteritis nodosa and 2 cryoglobulinaemic vasculitis) treated with RTX, with a mean follow-up of 34 months. All had previously received CYC, and 14, at least one other immunosuppressive drug. All had active disease when treated (median Birmingham Vasculitis Activity Score (BVAS) 2003, 13). All cases achieved remission (BVAS 2003, 0). Thirteen required re-treatment, nine due to relapse (mean, 9 months after initial treatment) and four because of repopulation or rising ANCA in the context of CYC intolerance or previous CYC refractory disease. Relapsing cases have been successfully re-treated up to five further cycles, either at B cell repopulation or at six monthly intervals. Infections were rare. Mean IgG levels fell significantly, and IgM levels became subnormal in six cases. There were three cases of neutropenia, one severe at 10 months post-treatment. These results provide further evidence that RTX is an effective induction agent in systemic vasculitis. The optimal and long-term outcome of re-treatment remains to be defined.

  4. Off-label use of rituximab for systemic lupus erythematosus in Europe.

    PubMed

    Rydén-Aulin, Monica; Boumpas, Dimitrios; Bultink, Irene; Callejas Rubio, Jose Luis; Caminal-Montero, Luis; Castro, Antoni; Colodro Ruiz, Agustín; Doria, Andrea; Dörner, Thomas; Gonzalez-Echavarri, Cristina; Gremese, Elisa; Houssiau, Frederic A; Huizinga, Tom; Inanç, Murat; Isenberg, David; Iuliano, Annamaria; Jacobsen, Søren; Jimenéz-Alonso, Juan; Kovács, Lászlo; Mariette, Xavier; Mosca, Marta; Nived, Ola; Oristrell, Joaquim; Ramos-Casals, Manuel; Rascón, Javier; Ruiz-Irastorza, Guillermo; Sáez-Comet, Luis; Salvador Cervelló, Gonzalo; Sebastiani, Gian Domenico; Squatrito, Danilo; Szücs, Gabriella; Voskuyl, Alexandre; van Vollenhoven, Ronald

    2016-01-01

    Rituximab (RTX) is a biological treatment used off-label in patients with systemic lupus erythematosus (SLE). This survey aimed to investigate the off-label use of RTX in Europe and compare the characteristics of patients receiving RTX with those receiving conventional therapy. Data on patients with SLE receiving RTX were taken from the International Registry for Biologics in SLE retrospective registry and complemented with data on patients with SLE treated with conventional therapy. For nationwide estimates of RTX use in patients with SLE, investigators were asked to provide data through case report forms (CRFs). Countries for which no data were submitted through CRFs, published literature and/or personal communication were used, and for European countries where no data were available, estimates were made on the assumption of similarities with neighbouring countries. The estimated off-label use of RTX in Europe was 0.5%-1.5% of all patients with SLE. In comparison with patients with SLE on conventional therapy, patients treated with RTX had longer disease duration, higher disease activity and were more often treated with immunosuppressives. The most frequent organ manifestations for which either RTX or conventional therapy was initiated were lupus nephritis followed by musculoskeletal and haematological. The reason for treatment was, besides disease control, corticosteroid-sparing for patients treated with conventional therapy. RTX use for SLE in Europe is restrictive and appears to be used as a last resort in patients for whom other reasonable options have been exhausted.

  5. 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

  6. Off-label use of rituximab for systemic lupus erythematosus in Europe

    PubMed Central

    Rydén-Aulin, Monica; Boumpas, Dimitrios; Bultink, Irene; Callejas Rubio, Jose Luis; Caminal-Montero, Luis; Castro, Antoni; Colodro Ruiz, Agustín; Doria, Andrea; Dörner, Thomas; Gonzalez-Echavarri, Cristina; Gremese, Elisa; Houssiau, Frederic A; Huizinga, Tom; Inanç, Murat; Isenberg, David; Iuliano, Annamaria; Jacobsen, Søren; Jimenéz-Alonso, Juan; Kovács, Lászlo; Mariette, Xavier; Mosca, Marta; Nived, Ola; Oristrell, Joaquim; Ramos-Casals, Manuel; Rascón, Javier; Sáez-Comet, Luis; Salvador Cervelló, Gonzalo; Sebastiani, Gian Domenico; Squatrito, Danilo; Szücs, Gabriella; Voskuyl, Alexandre; van Vollenhoven, Ronald

    2016-01-01

    Objectives Rituximab (RTX) is a biological treatment used off-label in patients with systemic lupus erythematosus (SLE). This survey aimed to investigate the off-label use of RTX in Europe and compare the characteristics of patients receiving RTX with those receiving conventional therapy. Methods Data on patients with SLE receiving RTX were taken from the International Registry for Biologics in SLE retrospective registry and complemented with data on patients with SLE treated with conventional therapy. For nationwide estimates of RTX use in patients with SLE, investigators were asked to provide data through case report forms (CRFs). Countries for which no data were submitted through CRFs, published literature and/or personal communication were used, and for European countries where no data were available, estimates were made on the assumption of similarities with neighbouring countries. Results The estimated off-label use of RTX in Europe was 0.5%–1.5% of all patients with SLE. In comparison with patients with SLE on conventional therapy, patients treated with RTX had longer disease duration, higher disease activity and were more often treated with immunosuppressives. The most frequent organ manifestations for which either RTX or conventional therapy was initiated were lupus nephritis followed by musculoskeletal and haematological. The reason for treatment was, besides disease control, corticosteroid-sparing for patients treated with conventional therapy. Conclusions RTX use for SLE in Europe is restrictive and appears to be used as a last resort in patients for whom other reasonable options have been exhausted. PMID:27651920

  7. Rituximab for Non‐Hodgkin's Lymphoma: A Story of Rapid Success in Translation

    PubMed Central

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

    2013-01-01

    Abstract 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

  8. Novel use of rituximab in a case of Riedel's thyroiditis refractory to glucocorticoids and tamoxifen.

    PubMed

    Soh, Shui-Boon; Pham, Alan; O'Hehir, Robyn E; Cherk, Martin; Topliss, Duncan J

    2013-09-01

    A 42-year-old woman presented with a rapidly enlarging right-sided thyroid mass and underwent hemithyroidectomy. Riedel's thyroiditis was only diagnosed upon surgical decompression of the right carotid artery 2 years later. She became more symptomatic as Riedel's thyroiditis progressed, and mediastinal fibrosclerosis developed over the next 12 months. Oral prednisolone failed to improve her condition, and she was commenced on tamoxifen. Despite initial improvement, her symptoms recurred 2 years later, mainly arising from compression of the trachea and esophagus at the thoracic inlet. Fluorodeoxyglucose positron emission tomographic scan showed locally advanced active invasive fibrosclerosis in the neck and mediastinum. An elevated activin-A level of 218 pg/mL was consistent with active inflammation. IgG subtypes (including IgG4) were normal. Two courses of iv methylprednisolone were given but only produced transient improvement. Subsequently, the patient received 3 doses of i.v. rituximab at monthly intervals and had prompt sustained symptomatic improvement. Activin-A level decreased to 122 pg/mL 10 months after rituximab therapy. Fluorodeoxyglucose positron emission tomographic scan 6 weeks after therapy showed reduction in inflammation. A further scan at 10 months demonstrated ongoing response to rituximab. This is a case of refractory Riedel's thyroiditis with symptomatic, biochemical, and radiological improvement that has persisted 14 months after rituximab. The likelihood and duration of response to rituximab in Riedel's thyroiditis requires further study.

  9. Rituximab in induction therapy for anti-neutrophil cytoplasmic antibody (ANCA) vasculitis.

    PubMed

    Niles, J

    2011-05-01

    Anti-neutrophil cytoplasmic antibodies (ANCA) have been associated with a spectrum of vasculitis that includes granulomatous polyangiitis (formerly known as Wegener's granulomatosis), microscopic polyangiitis, the Churg-Strauss syndrome, primary pauciimmune necrotizing and crescentic glomerulonephritis and related forms of vasculitis. In vitro, in vivo and clinical evidence support the conclusion that ANCA participate in the pathophysiology of this disease spectrum. Rituximab is a potent tool that can interrupt B cell-mediated immunity without major compromise of T cell-mediated immunity. Thus, it has great appeal as a tool to interrupt antibody-mediated autoimmune disease. The results of two prospective randomized trials confirm that rituximab can be effective as part of induction therapy for active ANCA-associated vasculitis. The safety profile for rituximab appears favourable relative to cyclophosphamide and steroids. However, there remain many patients who require individualized adjustments of ancillary therapy, as breakthrough disease, relapses and infectious complications do occur. Based on our current knowledge, rituximab should now be incorporated as part of induction therapy in many patients with ANCA-associated vasculitis. However, more work is needed to determine how rituximab may best be integrated into the overall immunosuppression of these patients.

  10. Improved outcome with rituximab in patients with HIV-associated multicentric Castleman disease.

    PubMed

    Hoffmann, Christian; Schmid, Holger; Müller, Markus; Teutsch, Christian; van Lunzen, Jan; Esser, Stefan; Wolf, Timo; Wyen, Christoph; Sabranski, Michael; Horst, Heinz-August; Reuter, Stefan; Vogel, Martin; Jäger, Hans; Bogner, Johannes; Arasteh, Keikawus

    2011-09-29

    Although HIV-associated multicentric Castleman disease (HIV-MCD) is not classified as an AIDS-defining illness, mortality is high and progression to lymphoma occurs frequently. At present, there is no widely accepted recommendation for the treatment of HIV-MCD. In this retrospective (1998-2010), multicentric analysis of 52 histologically proven cases, outcome was analyzed with respect to the use of different MCD therapies and potential prognostic factors. After a mean follow-up of 2.26 years, 19 of 52 patients died. Median estimated overall survival (OS) was 6.2 years. Potential risk factors, such as older age, previous AIDS, or lower CD4 T cells had no impact on OS. Treatment was heterogeneous, consisting of cytostatic and/or antiviral agents, rituximab, or combinations of these modalities. There were marked differences in the outcome when patients were grouped according to MCD treatment. Patients receiving rituximab-based regimens had higher complete remission rates than patients receiving chemotherapy only. The mean estimated OS in patients receiving rituximab alone or in combination with cytostatic agents was not reached, compared with 5.1 years (P = .03). Clinical outcome and overall survival of HIV-MCD have markedly improved with rituximab-based therapies, considering rituximab-based therapies (with or without cytostatic agents) to be among the preferred first-line options in patients with HIV-MCD.

  11. Relapsed chronic lymphocytic leukemia retreated with rituximab: interim results of the PERLE study.

    PubMed

    Chaoui, Driss; Choquet, Sylvain; Sanhes, Laurence; Mahé, Béatrice; Hacini, Maya; Fitoussi, Olivier; Arkam, Yazid; Orfeuvre, Hubert; Dilhuydy, Marie-Sarah; Barry, Marly; Jourdan, Eric; Dreyfus, Brigitte; Tempescul, Adrian; Leprêtre, Stéphane; Bardet, Aurélie; Leconte, Pierre; Maynadié, Marc; Delmer, Alain

    2017-06-01

    This prospective non-interventional study assessed the management of relapsed/refractory CLL after one or two treatments with rituximab, and retreatment with a rituximab-based regimen. An interim analysis was performed at the end of the induction period in 192 evaluable patients. Median age was 72 years [35-89], first relapse (55%), and second relapse (45%). Rituximab administered during first (68%), second (92%), or both treatment lines (20%). R-bendamustine administered in 56% of patients, R-purine analogs (21%), and R-alkylating agents (19%). The overall response rate (ORR) was 74.6%, in favor of R-purine analogs (90%), R-bendamustine (75%), and R-alkylating agents (69%). Lower ORR in Del 17p patients (43%) and third time rituximab (31%). Most frequent adverse events were hematological (23% patients) including neutropenia (11%) and infections (12%); grade 3/4 AEs (23% patients), mainly hematological (18%); death during induction treatment (7%). This first large study focusing on relapsed/refractory CLL patients retreated with rituximab-based regimens is still ongoing.

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

    PubMed

    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.

  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 in treatment-resistant CIDP with antibodies against paranodal proteins

    PubMed Central

    Querol, Luis; Rojas-García, Ricard; Diaz-Manera, Jordi; Barcena, Joseba; Pardo, Julio; Ortega-Moreno, Angel; Sedano, Maria Jose; Seró-Ballesteros, Laia; Carvajal, Alejandra; Ortiz, Nicolau; Gallardo, Eduard

    2015-01-01

    Objective: To describe the response to rituximab in patients with treatment-resistant chronic inflammatory demyelinating polyneuropathy (CIDP) with antibodies against paranodal proteins and correlate the response with autoantibody titers. Methods: Patients with CIDP and IgG4 anti–contactin-1 (CNTN1) or anti–neurofascin-155 (NF155) antibodies who were resistant to IV immunoglobulin and corticosteroids were treated with rituximab and followed prospectively. Immunocytochemistry was used to detect anti-CNTN1 and anti-NF155 antibodies and ELISA with human recombinant CNTN1 and NF155 proteins was used to determine antibody titers. Results: Two patients had a marked improvement; another patient improved slightly after 10 years of stable, severe disease; and the fourth patient had an ischemic stroke unrelated to treatment and was lost to follow-up. Autoantibodies decreased in all patients after rituximab treatment. Conclusions: Rituximab treatment is an option for patients with CIDP with IgG4 anti-CNTN1/NF155 antibodies who are resistant to conventional therapies. Classification of evidence: This study provides Class IV evidence that rituximab is effective for patients with treatment-resistant CIDP with IgG4 anti-CNTN1 or anti-NF155 antibodies. PMID:26401517

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

    PubMed

    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.

  16. Role of Maintenance Rituximab (Rituxan) Therapy In the Treatment of Follicular Lymphoma

    PubMed Central

    Fowler, Nathan H.

    2011-01-01

    Although follicular lymphoma remains incurable, recent advances in first-line therapy have resulted in improved response rates and response duration. Maintenance therapy with rituximab (Rituxan) after induction treatment with rituximab alone or chemotherapy in combination with or without rituximab has resulted in further improvement in progression-free survival in both treatment-naive and previously treated patients. Efficacy results from the large phase 3, randomized Primary Rituximab and Maintenance (PRIMA) trial in the first-line setting have dem onstrated significant improvements in progression-free survival, in the rate of patients achieving complete remission, and in the proportion of patients remaining in complete remission using maintenance rituximab. The use of maintenance therapy is also under study in additional hematological malignancies, including diffuse large B-cell lymphoma and chronic lymphocytic leukemia. Clinical investigation is ongoing to address the optimal duration of maintenance therapy and the question of whether re-treatment upon disease progression is as beneficial as maintenance for follicular lymphoma. PMID:22346327

  17. Alternate virtual populations elucidate the type I interferon signature predictive of the response to rituximab in rheumatoid arthritis

    PubMed Central

    2013-01-01

    Background Mechanistic biosimulation can be used in drug development to form testable hypotheses, develop predictions of efficacy before clinical trial results are available, and elucidate clinical response to therapy. However, there is a lack of tools to simultaneously (1) calibrate the prevalence of mechanistically distinct, large sets of virtual patients so their simulated responses statistically match phenotypic variability reported in published clinical trial outcomes, and (2) explore alternate hypotheses of those prevalence weightings to reflect underlying uncertainty in population biology. Here, we report the development of an algorithm, MAPEL (Mechanistic Axes Population Ensemble Linkage), which utilizes a mechanistically-based weighting method to match clinical trial statistics. MAPEL is the first algorithm for developing weighted virtual populations based on biosimulation results that enables the rapid development of an ensemble of alternate virtual population hypotheses, each validated by a composite goodness-of-fit criterion. Results Virtual patient cohort mechanistic biosimulation results were successfully calibrated with an acceptable composite goodness-of-fit to clinical populations across multiple therapeutic interventions. The resulting virtual populations were employed to investigate the mechanistic underpinnings of variations in the response to rituximab. A comparison between virtual populations with a strong or weak American College of Rheumatology (ACR) score in response to rituximab suggested that interferon β (IFNβ) was an important mechanistic contributor to the disease state, a signature that has previously been identified though the underlying mechanisms remain unclear. Sensitivity analysis elucidated key anti-inflammatory properties of IFNβ that modulated the pathophysiologic state, consistent with the observed prognostic correlation of baseline type I interferon measurements with clinical response. Specifically, the effects of IFN

  18. Impact of rituximab desensitization on blood-type-incompatible adult living donor liver transplantation: a Japanese multicenter study.

    PubMed

    Egawa, H; Teramukai, S; Haga, H; Tanabe, M; Mori, A; Ikegami, T; Kawagishi, N; Ohdan, H; Kasahara, M; Umeshita, K

    2014-01-01

    We evaluated the effects of rituximab prophylaxis on outcomes of ABO-blood-type-incompatible living donor liver transplantation (ABO-I LDLT) in 381 adult patients in the Japanese registry of ABO-I LDLT. Patients underwent dual or triple immunosuppression with or without B cell desensitization therapies such as plasmapheresis, splenectomy, local infusion, intravenous immunoglobulin and rituximab. Era before 2005, intensive care unit-bound status, high Model for End-Stage Liver Disease score and absence of rituximab prophylaxis were significant risk factors for overall survival and antibody-mediated rejection (AMR) in the univariate analysis. After adjustment for era effects in the multivariate analysis, only absence of rituximab prophylaxis was a significant risk factor for AMR, and there were no significant risk factors for survival. Rituximab prophylaxis significantly decreased the incidence of AMR, especially hepatic necrosis (p < 0.001). In the rituximab group, other B cell desensitization therapies had no add-on effects. Multiple or large rituximab doses significantly increased the incidence of infection, and early administration had no advantage. In conclusion, outcomes in adult ABO-I LDLT have significantly improved in the latest era coincident with the introduction of rituximab.

  19. Rituximab antiproliferative effect in B-lymphoma cells is associated with acid-sphingomyelinase activation in raft microdomains.

    PubMed

    Bezombes, Christine; Grazide, Solène; Garret, Céline; Fabre, Claire; Quillet-Mary, Anne; Müller, Sabina; Jaffrézou, Jean-Pierre; Laurent, Guy

    2004-08-15

    Rituximab is a chimeric human immunoglobulin G1 (IgG1) anti-CD20 monoclonal antibody with significant activity against CD20+ malignant B cells. Rituximab is currently used with success in the treatment of B-cell-derived lymphoid neoplasias either alone or in combination with chemotherapy. However, the predominant mechanism by which rituximab exerts its antitumor properties in vivo remains unknown. In the present study, we demonstrate that in Daudi and RL B-lymphoma cells, rituximab (without cross-linking) used at the saturating dose of 10 microg/mL induced moderate accumulation in G1 phase, growth inhibition, and significant loss in clonogenic potential. However, in these cells, rituximab induced no apoptosis. Furthermore, we observed that treatment with rituximab resulted in a rapid and transient increase in acid-sphingomyelinase (A-SMase) activity and concomitant cellular ceramide (CER) generation in raft microdomains. We also observed that rituximab-treated cells externalized both A-SMase and CER that colocalized with the CD20 receptor. Finally, we present evidence that rituximab-induced growth inhibition may be mediated through a CER-triggered signaling pathway, leading to the induction of cell cycle-dependent kinase inhibitors such as p27Kip1 through a mitogen-activated protein kinase (MAPK)-dependent mechanism.

  20. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program

    PubMed Central

    Hu, Shimin; Xu-Monette, Zijun Y.; Tzankov, Alexander; Green, Tina; Wu, Lin; Balasubramanyam, Aarthi; Liu, Wei-min; Visco, Carlo; Li, Yong; Miranda, Roberto N.; Montes-Moreno, Santiago; Dybkaer, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L.; Hsi, Eric D.; Choi, William W. L.; Zhao, Xiaoying; van Krieken, J. Han; Huang, Qin; Huh, Jooryung; Ai, Weiyun; Ponzoni, Maurilio; Ferreri, Andrés J. M.; Zhou, Fan; Slack, Graham W.; Gascoyne, Randy D.; Tu, Meifeng; Variakojis, Daina; Chen, Weina; Go, Ronald S.; Piris, Miguel A.; Møller, Michael B.; Medeiros, L. Jeffrey; Young, Ken H.

    2013-01-01

    Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)–like and unfavorable activated B-cell (ABC)–like subtypes based on gene expression signatures. In this study, we analyzed 893 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We show that MYC/BCL2 protein coexpression occurred significantly more commonly in the ABC subtype. Patients with the ABC or GCB subtype of DLBCL had similar prognoses with MYC/BCL2 coexpression and without MYC/BCL2 coexpression. Consistent with the notion that the prognostic difference between the 2 subtypes is attributable to MYC/BCL2 coexpression, there is no difference in gene expression signatures between the 2 subtypes in the absence of MYC/BCL2 coexpression. DLBCL with MYC/BCL2 coexpression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 coexpression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. In conclusion, the data suggest that MYC/BCL2 coexpression, rather than cell-of-origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP. PMID:23449635

  1. MYC/BCL2 protein coexpression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program.

    PubMed

    Hu, Shimin; Xu-Monette, Zijun Y; Tzankov, Alexander; Green, Tina; Wu, Lin; Balasubramanyam, Aarthi; Liu, Wei-min; Visco, Carlo; Li, Yong; Miranda, Roberto N; Montes-Moreno, Santiago; Dybkaer, Karen; Chiu, April; Orazi, Attilio; Zu, Youli; Bhagat, Govind; Richards, Kristy L; Hsi, Eric D; Choi, William W L; Zhao, Xiaoying; van Krieken, J Han; Huang, Qin; Huh, Jooryung; Ai, Weiyun; Ponzoni, Maurilio; Ferreri, Andrés J M; Zhou, Fan; Slack, Graham W; Gascoyne, Randy D; Tu, Meifeng; Variakojis, Daina; Chen, Weina; Go, Ronald S; Piris, Miguel A; Møller, Michael B; Medeiros, L Jeffrey; Young, Ken H

    2013-05-16

    Diffuse large B-cell lymphoma (DLBCL) is stratified into prognostically favorable germinal center B-cell (GCB)-like and unfavorable activated B-cell (ABC)-like subtypes based on gene expression signatures. In this study, we analyzed 893 de novo DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). We show that MYC/BCL2 protein coexpression occurred significantly more commonly in the ABC subtype. Patients with the ABC or GCB subtype of DLBCL had similar prognoses with MYC/BCL2 coexpression and without MYC/BCL2 coexpression. Consistent with the notion that the prognostic difference between the 2 subtypes is attributable to MYC/BCL2 coexpression, there is no difference in gene expression signatures between the 2 subtypes in the absence of MYC/BCL2 coexpression. DLBCL with MYC/BCL2 coexpression demonstrated a signature of marked downregulation of genes encoding extracellular matrix proteins, those involving matrix deposition/remodeling and cell adhesion, and upregulation of proliferation-associated genes. We conclude that MYC/BCL2 coexpression in DLBCL is associated with an aggressive clinical course, is more common in the ABC subtype, and contributes to the overall inferior prognosis of patients with ABC-DLBCL. In conclusion, the data suggest that MYC/BCL2 coexpression, rather than cell-of-origin classification, is a better predictor of prognosis in patients with DLBCL treated with R-CHOP.

  2. [Successful treatment of B-cell prolymphocytic leukemia (B-PLL) with FCR-Lite (fludarabine, cyclophosphamide, rituximab) protocol].

    PubMed

    Telek, Béla; Batár, Péter; Rejto, László; Udvardy, Miklós

    2010-08-01

    B-cell prolymphocytic leukemia (B-PLL) is a rare disorder characterized by marked lymphocytosis in the peripheral blood, matured lymphocytic infiltration in the bone marrow and splenomegaly. It has a distinct immunophenotype (CD19, CD20, CD22, FMC7, intensive surface immunoglobulin positivity) which helps to differentiate from other lymphoproliferative malignancies. It has a poor prognosis and its treatment is unsettled. The authors present a case of a patient with typical B-PLL treated with FCR-Lite (fludarabine, cyclophosphamide, rituximab) protocol achieving complete hematological (and immunophenotypic) remission. The treatment was well tolerated. Neither major infective complication nor tumor lysis syndrome was observed. According to the author's experience the FCR-Lite protocol can not only be used in patients with CLL but it also can be effective in patients with B-PLL. No clinical experience has been reported yet in the literature with this protocol.

  3. 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.

  4. Rituximab and subcutaneous cladribine in chronic lymphocytic leukemia for newly diagnosed and relapsed patients.

    PubMed

    Bertazzoni, Paola; Rabascio, Cristina; Gigli, Federica; Calabrese, Liliana; Radice, Davide; Calleri, Angelica; Gregato, Giuliana; Negri, Mara; Liptrott, Sarah J; Bassi, Simona; Nassi, Luca; Sammassimo, Simona; Laszlo, Daniele; Preda, Lorenzo; Pruneri, Giancarlo; Orlando, Laura; Martinelli, Giovanni

    2010-08-01

    The aim of this study was to investigate the efficacy of combined treatment with rituximab and subcutaneous cladribine in patients with newly diagnosed and relapsed chronic lymphocytic leukemia (CLL). Forty-three patients with active CLL or small lymphocytic lymphoma received rituximab 375 mg/m(2) on day 1 and cladribine 0.1 mg/kg subcutaneously on days 2-6. The treatment was repeated every 4 weeks for a total of four cycles. Sixteen patients were pretreated. The overall response rate was 88% (50% complete remission and 38% partial remission). The median time to treatment failure was 37.9 months. Grade 4 neutropenia developed in 5% of patients. The data indicate that combination therapy with rituximab and cladribine is a valuable and safe treatment for patients with CLL.

  5. Rituximab in the treatment of primary cutaneous B-cell lymphoma: a review.

    PubMed

    Fernández-Guarino, M; Ortiz-Romero, P L; Fernández-Misa, R; Montalbán, C

    2014-06-01

    Rituximab is a chimeric mouse-human antibody that targets the CD20 antigen, which is found in both normal and neoplastic B cells. In recent years, it has been increasingly used to treat cutaneous B-cell lymphoma and is now considered an alternative to classic treatment (radiotherapy and surgery) of 2 types of indolent lymphoma, namely, primary cutaneous follicle center lymphoma and primary cutaneous marginal zone B-cell lymphoma. Rituximab is also administered as an alternative to polychemotherapy in the treatment of primary cutaneous large B-cell lymphoma, leg type. Its use as an alternative drug led to it being administered intralesionally, with beneficial effects. In the present article, we review the literature published on the use of rituximab to treat primary cutaneous B-cell lymphoma. Copyright © 2012 Elsevier España, S.L. and AEDV. All rights reserved.

  6. Rituximab exposure is influenced by baseline metabolic tumor volume and predicts outcome of DLBCL patients: a LYSA study.

    PubMed

    Tout, Mira; Casasnovas, Olivier; Meignan, Michel; Lamy, Thierry; Morschhauser, Franck; Salles, Gilles; Gyan, Emmanuel; Haioun, Corinne; Mercier, Mélanie; Feugier, Pierre; Boussetta, Sami; Paintaud, Gilles; Ternant, David; Cartron, Guillaume

    2017-03-01

    High variability in patient outcome after rituximab-based treatment is partly explained by rituximab concentrations, and pharmacokinetic variability could be influenced by tumor burden. We aimed at quantifying the influence of baseline total metabolic tumor volume (TMTV0) on rituximab pharmacokinetics and of TMTV0 and rituximab exposure on outcome in patients with diffuse large B-cell lymphoma (DLBCL). TMTV0 was measured by (18)F-FDG-PET/CT in 108 previously untreated DLBCL patients who received four 375 mg/m(2) rituximab infusions every 2 weeks in combination with chemotherapy in two prospective trials. A two-compartment population model allowed describing rituximab pharmacokinetics and calculating rituximab exposure (area under the concentration-time curve; AUC). The association of TMTV0 and AUC with metabolic response after 4 cycles, as well as progression-free survival (PFS) and overall survival (OS), was assessed using logistic regression and Cox models, respectively. Cutoff values for patient outcome were determined using ROC curve analysis. Exposure to rituximab decreased as TMTV0 increased (R(2)=0.41, P<.0001). A high AUC in cycle 1 (≥9400 mg.h/L) was associated with better response (OR, 5.56; P=.0006) and longer PFS (hazard ratio [HR], 0.38; P=.011) and OS (HR, 0.17; P=.001). A nomogram for rituximab dose needed to obtain optimal AUC according to TMTV0 was constructed, and the 375 mg/m(2) classical dose would be suitable for patients with TMTV0 <281 cm(3) In summary, rituximab exposure is influenced by TMTV0 and correlates with response and outcome of DLBCL patients. Dose individualization according to TMTV0 should be evaluated in prospective studies. Studies were registered at www.clinicaltrials.gov as NCT00498043 and NCT00841945.

  7. Aquaporin-4 antibody titration in NMO patients treated with rituximab

    PubMed Central

    Marnetto, Fabiana; Granieri, Letizia; Capobianco, Marco; Bertolotto, Antonio

    2016-01-01

    Objective: We undertook an observational retrospective study to investigate the usefulness of aquaporin-4 (AQP4) antibodies (Ab) titration in the management of patients with neuromyelitis optica (NMO) treated with rituximab (RTX) by studying (1) the correlation between AQP4-Ab titer and disease activity, (2) the influence of RTX on antibody levels, and (3) the association between AQP4-Ab levels and responsiveness to RTX. Methods: A cell-based assay was used for AQP4-Ab titration in 322 serum samples from 7 patients with NMO treated with RTX (median follow-up 65 months), according to a treatment-to-target approach. Serum samples were collected every month following standardized procedures. Results: (1) In group analysis, AQP4-Ab titers correlated with the disease activity, showing higher titers during and preceding relapses than during remission. However, in individual analysis, an increase in AQP4-Ab titers and CD19+ B cells did not always precede a relapse. (2) A reduction of AQP4-Ab titers in the short-term and long-term period was observed during RTX treatment. (3) Reduction of AQP4-Ab titers was observed in responder patients both 3 months after RTX infusion and in the long-term follow-up. In one nonresponder patient, AQP4-Ab levels never decreased during the treatment period. Conclusions: Titration of AQP4-Abs could be useful in the clinical management of patients with NMO treated with RTX: titration before each reinfusion and 3 months after each reinfusion may provide information about responsiveness to RTX. Although a relationship among AQP4-Ab levels, disease activity, and response to RTX was observed, the usefulness of AQP4-Ab titration to predict relapses is limited. PMID:28054001

  8. A rheumatoid factor paradox: inhibition of rituximab effector function

    PubMed Central

    2013-01-01

    Introduction Rituximab (RTX) therapy of rheumatoid arthritis (RA) exhibits enhanced effectiveness in seropositive patients. Using patient sera, we tested if this improved efficacy was associated with enhanced RTX mediated complement-dependent cytotoxicity (RTX-CDC). Methods We developed an in vitro assay for RTX-CDC using patient sera and the Daudi human B cell line. Using propidium iodide uptake and flow cytometry, we compared RTX-CDC with rheumatoid factor (RF)+ sera relative to normal volunteer, non-RA and RF- sera. Additional studies examined mixing studies of RF+ and RF- sera, as well as the effect of monoclonal IgA or IgM RF. Finally, the effect of RF on RTX mediated trogocytosis of normal B cells was evaluated. Results Using human sera, addition of RTX resulted in rapid and profound (> 50%) Daudi cell death that was complement dependent. Surprisingly, RF+ patient sera exhibited reduced RTX-CDC relative to RF- sera, with an inverse relationship of RTX-CDC and RF titer. Mixing studies indicated the presence of an inhibitor of RTX-CDC in RF+ sera. The addition of monoclonal IgM or IgA RF to RF- sera markedly inhibited RTX-CDC. This effect was specific for RF binding to the Fc portion of RTX as it was not apparent with the F(ab)' domains of RTX engineered onto IgG3 heavy chain. RF also modestly inhibited RTX mediated trogocytosis. Conclusions Contrary to expectations, RF+ sera exhibits reduced RTX-CDC due to the presence of RF. The enhanced efficacy of RTX in seropositive RA patients cannot be attributed to improved B cell depletion through CDC. This result indicates that high RF levels may potentially modulate the efficacy of any therapeutic monoclonal antibody dependent on Fc effector function. PMID:23351360

  9. Durability of the Rituximab Response in Acetylcholine Receptor Autoantibody-Positive Myasthenia Gravis.

    PubMed

    Robeson, Kimberly R; Kumar, Aditya; Keung, Benison; DiCapua, Daniel B; Grodinsky, Emily; Patwa, Huned S; Stathopoulos, Panos A; Goldstein, Jonathan M; O'Connor, Kevin C; Nowak, Richard J

    2017-01-01

    Myasthenia gravis (MG), an autoimmune disorder of neuromuscular transmission, is treated by an array of immunotherapeutics, many of which are nonspecific. Even with current therapies, a subset of patients has medically refractory MG. The benefits of B-cell-targeted therapy with rituximab have been observed in MG; however, the duration of these benefits after treatment is unclear. To evaluate the durability of response to rituximab in the treatment of acetylcholine receptor autoantibody-positive (AChR+) generalized MG. This retrospective case series study included 16 patients with AChR+ MG referred to an MG clinic from January 1, 2007, to December 31, 2015. The patients were treated with rituximab and followed up for 18 to 84 months after treatment. Assessment of long-term clinical response, durability of response and/or relapse rate, AChR autoantibody levels, adverse effects, and inflammatory markers. In the 16 patients (6 men and 10 women; median age, 42 [range, 18-69] years), clinical improvement was observed in parallel with complete withdrawal or reduction of other immunotherapies, with all patients achieving complete stable remission, pharmacologic remission, or minimal manifestations based on the Myasthenia Gravis Foundation of America postintervention status criteria. Nine patients (56%) had a relapse during a mean follow-up of 36 (range, 24-47) months. Seven patients (44%) remained relapse free with a mean follow-up of 47 (range, 18-81) months since the last rituximab treatment. All values were normalized to a pretreatment anti-AChR antibody level of 100% and the mean levels after each rituximab cycle were calculated. A 33% decrease was seen after cycle 1 of rituximab treatment (100% vs 67%; P = .004); 20% after cycle 2 (compared with cycle 1) (67% vs 47%; P = .008); and 17% after cycle 3 (compared with cycle 2) (47% vs 30%; P = .02). However, the serum cytokine levels measured were found to be unchanged. Rituximab therapy appears to be an

  10. [Recommendations on the use of rituximab for ANCA-associated vasculitis].

    PubMed

    Gause, A M; Rubbert-Roth, A

    2014-04-01

    Rituximab (Rtx) has been approved in Germany since April 2013 for treatment of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). This therapy can be used in severe manifestations of these diseases and in relapses. It is administered as infusions of 375 mg rituximab per m(2) every 4 weeks after high dose intravenous prednisolone for 3 days and continued parallel to concomitant oral prednisolone therapy. Recommendations for the indications and use for antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) are described in addition to previous publications on recommendations for rheumatoid arthritis.

  11. [Efficacy of rituximab combined with cyclophosphamide in a patient with systemic lupus erythematosus and peritoneal vasculitis refractory to conventional inmunosupressive therapy].

    PubMed

    Garrido Rasco, Rocío; García Hernández, Francisco José; González León, Rocío; Castillo Palma, María Jesús; Ocaña Medina, Celia; Sánchez Román, Julio

    2009-02-01

    Peritoneal vasculitis is a rare and severe clinical manifestation of systemic lupus erythematosus. We report a patient who presented with ascites due to peritoneal vasculitis and cutaneous, articular, hematological and renal inflammatory activity. Treatment with glucocorticoids and immunosuppressive drugs was ineffective. In view of the resistance to different therapies, 4 weekly infusions of 375mg/m2 of rituximab (RTX) were started, in association with cyclophosphamide pulses during the first and the third weeks. With this treatment strategy, the patient reached a complete response which was achieved in later flares of inflammatory activity (the second and third flares were multisystemic and with ascites again, and the fourth flare with nephritis).

  12. Comparative assessment of clinical response in patients with rheumatoid arthritis between PF‐05280586, a proposed rituximab biosimilar, and rituximab

    PubMed Central

    Williams, Jason H.; Hutmacher, Matthew M.; Zierhut, Matthew L.; Becker, Jean‐Claude; Gumbiner, Barry; Spencer‐Green, George; Melia, Lisa A.; Liao, Kai‐Hsin; Suster, Matthew; Li, Ruifeng; Meng, Xu

    2016-01-01

    Aims To evaluate potential differences between PF‐05280586 and rituximab sourced from the European Union (rituximab‐EU) and USA (rituximab‐US) in clinical response (Disease Activity Score in 28 Joints [DAS28] and American College of Rheumatology [ACR] criteria), as part of the overall biosimilarity assessment of PF‐05280586. Methods A randomised, double‐blind, pharmacokinetic similarity trial was conducted in patients with active rheumatoid arthritis refractory to anti‐tumour necrosis factor therapy on a background of methotrexate. Patients were treated with 1000 mg of PF‐05280586, rituximab‐EU or rituximab‐US on days 1 and 15 and followed over 24 weeks for pharmacokinetic, clinical response and safety assessments. Key secondary end points were the areas under effect curves for DAS28 and ACR responses. Mean differences in areas under effect curves were compared against respective reference ranges established by observed rituximab‐EU and rituximab‐US responses using longitudinal nonlinear mixed effects models. Results The analysis included 214 patients. Demographics were similar across groups with exceptions in some baseline disease characteristics. Baseline imbalances and group‐to‐group variation were accounted for by covariate effects in each model. Predictions from the DAS28 and ACR models tracked the central tendency and distribution of observations well. No point estimates of mean differences were outside the reference range for DAS28 or ACR scores. The probabilities that the predicted differences between PF‐05280586 vs. rituximab‐EU or rituximab‐US lie outside the reference ranges were low. Conclusions No clinically meaningful differences were detected in DAS28 or ACR response between PF‐05280586 and rituximab‐EU or rituximab‐US as the differences were within the pre‐specified reference ranges. TRIAL REGISTRATION Number: NCT01526057. PMID:27530379

  13. Chlorambucil plus rituximab with or without maintenance rituximab as first-line treatment for elderly chronic lymphocytic leukemia patients.

    PubMed

    Foà, Robin; Del Giudice, Ilaria; Cuneo, Antonio; Del Poeta, Giovanni; Ciolli, Stefania; Di Raimondo, Francesco; Lauria, Francesco; Cencini, Emanuele; Rigolin, Gian Matteo; Cortelezzi, Agostino; Nobile, Francesco; Callea, Vincenzo; Brugiatelli, Maura; Massaia, Massimo; Molica, Stefano; Trentin, Livio; Rizzi, Rita; Specchia, Giorgina; Di Serio, Francesca; Orsucci, Lorella; Ambrosetti, Achille; Montillo, Marco; Zinzani, Pier Luigi; Ferrara, Felicetto; Morabito, Fortunato; Mura, Maria Angela; Soriani, Silvia; Peragine, Nadia; Tavolaro, Simona; Bonina, Silvia; Marinelli, Marilisa; De Propris, Maria Stefania; Starza, Irene Della; Piciocchi, Alfonso; Alietti, Alessandra; Runggaldier, Eva Josephine; Gamba, Enrica; Mauro, Francesca Romana; Chiaretti, Sabina; Guarini, Anna

    2014-05-01

    In a phase II trial, we evaluated chlorambucil and rituximab (CLB-R) as first-line induction treatment with or without R as maintenance for elderly chronic lymphocytic leukemia (CLL) patients. Treatment consisted of eight 28-day cycles of CLB (8 mg/m(2) /day, days 1-7) and R (day 1 of cycle 3, 375 mg/m(2) ; cycles 4-8, 500 mg/m(2) ). Responders were randomized to 12 8-week doses of R (375 mg/m(2) ) or observation. As per intention-to-treat analysis, 82.4% (95% CI, 74.25-90.46%) of 85 patients achieved an overall response (OR), 16.5% a complete response (CR), 2.4% a CR with incomplete bone marrow recovery. The OR was similar across Binet stages (A 86.4%, B 81.6%, and C 78.6%) and age categories (60-64 years, 92.3%; 65-69, 85.2%; 70-74, 75.0%; ≥75, 81.0%). CLB-R was well tolerated. After a median follow-up of 34.2 months, the median progression-free survival (PFS) was 34.7 months (95% CI, 33.1-39.5). TP53 abnormalities, complex karyotype, and low CD20 gene expression predicted lack of response; SF3B1 mutation and BIRC3 disruption low CR rates. IGHV mutations significantly predicted PFS. R maintenance tended towards a better PFS than observation and was safe and most beneficial for patients in partial response and for unmutated IGHV cases. CLB-R represents a promising option for elderly CLL patients. Copyright © 2014 Wiley Periodicals, Inc.

  14. Rituximab treatment for spondyloarthritis. A nationwide series: data from the AIR registry of the French Society of Rheumatology.

    PubMed

    Wendling, Daniel; Dougados, Maxime; Berenbaum, Francis; Brocq, Olivier; Schaeverbeke, Thierry; Mazieres, Bernard; Marcelli, Christian; Leparc, Jean-Marie; Bertin, Philippe; Robin, Michèle; Sibilia, Jean; Lafforgue, Pierre; Prati, Clément; Combe, Bernard; Gottenberg, Jacques-Eric

    2012-12-01

    To evaluate the efficacy and safety of rituximab (RTX) in several subsets of spondyloarthritis (SpA) using the data of the AIR (Autoimmunity and Rituximab) registry. All patients receiving RTX for SpA, and prospectively included in the AIR registry from September 2005 to September 2010, were retrospectively analyzed. The response to treatment was evaluated by the Bath Ankylosing Spondylitis Disease Activity Index for axial disease, joint count for peripheral disease, and C-reactive protein reduction. Among the 595 patients included in the AIR registry, 26 patients with SpA from 13 centers were reported: ankylosing spondylitis (10), undifferentiated SpA (7), and psoriatic arthritis (9). Mean disease duration was 8.8 years (range 1-40). The extraarticular features found were psoriasis, 12 cases; uveitis, 4 cases; and Crohn's disease, 3 cases. The mean number of disease-modifying antirheumatic drugs before RTX was 2.4; previous anti-tumor necrosis factor (TNF) agents were taken in 23 cases. The mean number of RTX courses was 1.5 (range 1-5), with a total of 35.6 patient-years. Efficacy was noted in 11/23 cases: 3 out of 3 anti-TNF-naive patients and 8 out of 20 anti-TNF nonresponder patients. No predictive factors of response could be identified, particularly in diagnosis subsets or clinical presentation (axial or peripheral). In this nationwide study of several subsets of SpA, RTX had only a moderate efficacy that was more marked in patients who were anti-TNF-naive.

  15. 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. © 2016 John Wiley & Sons Ltd.

  16. Recombinant interleukin-2 significantly augments activity of rituximab in human tumor xenograft models of B-cell non-Hodgkin lymphoma.

    PubMed

    Lopes de Menezes, Daniel E; Denis-Mize, Kimberly; Tang, Yan; Ye, Helen; Kunich, John C; Garrett, Evelyn N; Peng, Jing; Cousens, Lawrence S; Gelb, Arnold B; Heise, Carla; Wilson, Susan E; Jallal, Bahija; Aukerman, Sharon L

    2007-01-01

    Recombinant interleukin-2 (rIL-2) is a pleiotropic cytokine that activates select immune effector cell responses associated with antitumor activity, including antibody-dependent cellular cytotoxicity (ADCC). Rituximab is an anti-CD20 monoclonal antibody that activates ADCC in non-Hodgkin lymphoma (NHL). The ability of rIL-2 to augment rituximab-dependent tumor responses was investigated. The efficacy of rIL-2 in combination with rituximab was evaluated in 2 NHL tumor xenograft models: the CD20hi, rituximab-sensitive, low-grade Daudi model and the CD20lo, aggressive, rituximab-resistant Namalwa model. Combination of rIL-2 plus rituximab was synergistic in a rituximab-sensitive Daudi tumor model, as evidenced by significant tumor regressions and increased time to tumor progression, compared with rIL-2 and rituximab single agents. In contrast, rituximab-resistant Namalwa tumors were responsive to single-agent rIL-2 and showed an increased response when combined with rituximab. Using in vitro killing assays, rIL-2 was shown to enhance activity of rituximab by activating ADCC and lymphokine-activated killer activity. Additionally, the activity of rIL-2 plus rituximab F(ab')2 was similar to that of rIL-2 alone, indicating a critical role for immunoglobulin G1 Fc-FcgammaR-effector responses in mediating ADCC. Antiproliferative and apoptotic tumor responses, along with an influx of immune effector cells, were observed by immunohistochemistry. Collectively, the data suggest that rIL-2 mediates potent tumoricidal activity against NHL tumors, in part, through activation and trafficking of monocytes and natural killer cells to tumors. These data support the mechanistic and therapeutic rationale for combination of rIL-2 with rituximab in NHL clinical trials and for single-agent rIL-2 in rituximab-resistant NHL patients.

  17. Fc gamma receptor 3A and 2A polymorphisms do not predict response to rituximab in follicular lymphoma

    PubMed Central

    Kenkre, Vaishalee P.; Hong, Fangxin; Cerhan, James R.; Lewis, Marcia; Sullivan, Leslie; Williams, Michael E.; Gascoyne, Randy D.; Horning, Sandra J.; Kahl, Brad S.

    2015-01-01

    Purpose Pre-clinical studies suggest that single nucleotide polymorphisms (SNPs) in the Fcγ receptor (FCGR) genes influence response to rituximab, but the clinical relevance of this is uncertain. Experimental Design We prospectively obtained specimens for genotyping in the RESORT study, where 408 previously untreated, low tumor burden follicular lymphoma (FL) patients were treated with single agent rituximab. Patients received rituximab in 4 weekly doses and responders were randomized to rituximab re-treatment (RR) upon progression versus maintenance rituximab (MR). SNP genotyping was performed in 321 consenting patients. Results Response rates to initial therapy and response duration were correlated with the FCGR3A SNP at position 158 (rs396991) and the FCGR2A SNP at position 131 (rs1801274). The response rate to initial rituximab was 71%. No FCGR genotypes or grouping of genotypes were predictive of initial response. 289 patients were randomized to RR (n = 143) or to MR (n = 146). With a median follow up of 5.5 years, the 3-yr response duration in the RR arm and the MR arm was 50% and 78%, respectively. Genotyping was available in 235 of 289 randomized patients. In patients receiving RR (n = 115) or MR (n =120), response duration was not associated with any FCGR genotypes or genotype combinations. Conclusions Based on this analysis of treatment-naïve, low tumor burden FL, we conclude that the FCGR3A and FCGR2A SNPs do not confer differential responsiveness to rituximab. PMID:26510856

  18. A clinical prediction model for infusion-related reactions to rituximab in patients with B cell lymphomas.

    PubMed

    Hayama, Tatsuya; Miura, Katsuhiro; Uchiike, Akihiro; Nakagawa, Masaru; Tsutsumi, Daisuke; Sakagami, Masashi; Yoshida, Yoshikazu; Takei, Masami

    2017-01-31

    Background Infusion-related reactions (IRRs) are a major adverse event of rituximab. Objective To develop a prediction model for IRRs to rituximab among patients with B cell non- Hodgkin's lymphomas (B-NHL). Setting A 1000-bed university hospital in Tokyo. Methods Patients with B-NHL treated with rituximab at our institution from 2004 to 2014 were retrospectively analysed. Chills, fever, rash, nausea, asthenia, headache, cardiovascular symptoms, and respiratory symptoms of any grade, in association with rituximab infusion, were identified as IRRs. Risk factors for IRRs to rituximab found in the intergroup analysis were subsequently evaluated by using multivariate analysis. Main outcome measure Occurrence of IRRs to rituximab. Results A total of 140 patients with various types of B-NHL, including 74% with diffuse large Bcell lymphoma, were analysed. Among them, 55 and 85 patients were assigned to the IRR group and the non-IRR group, respectively. Indolent histological subtypes, bulky disease (>10 cm), B symptoms, higher serum soluble interleukin-2 receptor concentration, and bone marrow involvement were more common in the IRR group. The multivariate logistic regression analysis identified low-grade lymphomas [odds ratio (OR) 2.81, p = 0.017] and bulky disease (OR 2.52, p = 0.037) as independent risk factors for IRRs to rituximab. The incidence rates of IRRs to rituximab among patients with neither, one, or both of these risk factors were 26, 54, and 78%, respectively (χ(2) = 16.4, p < 0.001). Conclusions A simple combination of histopathological subtype and bulkiness of disease could predict the risk of IRRs to rituximab among patients with B-NHL.

  19. 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 AACR

  20. Serum globulins as marker of immune restoration after treatment with high-dose rituximab for chronic lymphocytic leukemia.

    PubMed

    Alexandrescu, Doru T; Wiernik, Peter H

    2008-01-01

    An important biological alteration in chronic lymphocytic leukemia (CLL) is the dysregulation of immunoglobulin production, as a consequence of complex and yet incompletely understood interactions between plasma cells and the neoplastic B-cell clone. As a result, most patients develop severe hypogammaglobulinemia during the course of the disease. Fourteen patients were analyzed retrospectively for changes in globulins produced by antineoplastic treatments. During maximum response to fludarabine, chlorambucil, and overall rituximab, the mean levels of globulins were 2.500, 2.752, and 3.018 g/dl. The mean increase in globulins during clinical response to individual treatments compared to pre-treatment values were 0.050 g/dl for fludarabine, 0.302 g/dl for chlorambucil, 0.267 g/dl for low-dose rituximab, and 0.346 g/dl for high-dose rituximab. Overall, treatment with rituximab produced an average increase in globulins at clinical response of 11.6%, which increased further to 17.3% at maximum clinical response. Serum globulins increased significantly compared with pre-treatment values at maximum clinical response to rituximab overall (P=0.001) and high-dose rituximab (P=0.001), but no statistical significance occurred in the cases of fludarabine (P=0.5), chlorambucil/prednisone (P=0.14), and low-dose rituximab (P=0.07). Serum globulins levels correlate with disease status (complete responders versus partial responders and stable disease groups), but not with peripheral neoplastic load. Therefore, although rituximab is efficient in decreasing the tumor burden, additional mechanisms may be involved in relieving suppressive effects on immunoglobulin-producing cells, which especially manifest at high doses of the agent. Use of high doses of rituximab in CLL can avoid T-cell dysfunction and neutropenia, and is associated with humoral immunorestorative effects.

  1. A Phased Desensitization Protocol With Rituximab and Bortezomib for Highly Sensitized Kidney Transplant Candidates

    PubMed Central

    Ide, Kentaro; Tanaka, Yuka; Sasaki, Yu; Tahara, Hiroyuki; Ohira, Masahiro; Ishiyama, Kohei; Tashiro, Hirotaka; Ohdan, Hideki

    2015-01-01

    Background Desensitization protocols comprising plasmapheresis, IVIGs, and rituximab and/or bortezomib have allowed for successful kidney transplantation in some highly HLA-sensitized patients with end-stage renal disease. However, the optimal combination of these therapies and their proper timing remains entirely unknown. We propose a phased desensitization strategy using rituximab followed by bortezomib as a safer method. Methods Three sensitized kidney transplant candidates who could not be desensitized using our conventional protocol, which consists of a single rituximab dose combined with plasmapheresis, were enrolled in this study. When IgM+ CD27− naive B cells reappeared but IgM+ CD27+ memory B cells remained undetectable in their peripheral blood, the patients were treated with 1 cycle of bortezomib followed by plasmapheresis. Results After bortezomib treatment, patients' donor-specific anti-HLA antibodies (DSA) values were decreased, and cross-match tests were consistently negative. All 3 patients underwent living donor kidney transplantation. They showed immediate renal function, and both DSA and non-DSA were undetectable during the observation period. Neither antibody-mediated rejection nor severe acute cellular rejection was encountered in these patients after transplantation. Conclusions The present cases suggest that a phased use of rituximab and bortezomib can safely desensitize highly sensitized kidney transplant candidates. PMID:27500219

  2. Histopathologic features of transplant glomerulopathy associated with response to therapy with intravenous immune globulin and rituximab.

    PubMed

    Kahwaji, Joseph; Najjar, Reiad; Kancherla, Deepika; Villicana, Rafael; Peng, Alice; Jordan, Stanley; Vo, Ashley; Haas, Mark

    2014-05-01

    Transplant glomerulopathy (TG) is associated with poor long-term allograft survival and is often accompanied by microcirculation inflammation. Histopathologic scoring may inform prognosis and help guide therapy. We retrospectively assessed 33 patients with biopsy-proven TG. All biopsies were given a glomerulitis (g) and peritubular capillaritis (ptc) score. We determined allograft survival and serum creatinine stability in three different score groups: g < 2 and ≥ 2, ptc < 2 and ≥ 2, and (g + ptc) < 4 and ≥ 4. We assessed the impact of treatment with intravenous immune globulin (IVIG) and rituximab on outcomes. Graft survival and serum creatinine stability did not differ in each of the histopathologic score groups. Higher-score groups were associated with the presence of concomitant antibody-mediated rejection and were more likely to receive IVIG and rituximab. Treatment with IVIG and rituximab resulted in stability of serum creatinine within the higher-score groups, but not in the lower-score groups. Stabilization of serum creatinine was associated with an improvement in donor-specific antibody. Histopathologic scoring in kidney allograft biopsies with TG may help guide treatment. The combination of IVIG and rituximab appears to be beneficial in patients whose biopsies have moderate or severe microvascular injury.

  3. Acute Liver Failure Due to Echovirus 9 Associated With Persistent B-Cell Depletion From Rituximab

    PubMed Central

    Bajema, Kristina L; Simonson, Paul D; Greninger, Alex L; Çoruh, Basak; Pottinger, Paul S; Bhattacharya, Renuka; Liou, Iris W; Jalikis, Florencia G; Fligner, Corinne L

    2017-01-01

    Abstract We describe a case of fatal acute liver failure due to echovirus 9 in the setting of persistent B-cell depletion and hypogammaglobulinemia 3 years after rituximab therapy. Metagenomic next-generation sequencing further specified the etiologic agent. Early recognition may provide an opportunity for interventions including intravenous immunoglobulin and liver transplantation. PMID:28948184

  4. Efficacy and safety of rituximab treatment in children with primary glomerulonephritis.

    PubMed

    Zachwieja, Jacek; Silska, Magdalena; Ostalska-Nowicka, Danuta; Soltysiak, Jolanta; Lipkowska, Katarzyna; Blumczynski, Andrzej; Musielak, Anna

    2012-01-01

    The aim of our study was to analyze the efficacy and safety of rituximab, a chimeric monoclonal antibody against CD20 lymphocytes, as a nonstandard immunosuppressive therapy in children with different types of primary glomerulonephritis who were not eligible for routine treatment. The study group was composed of 16 children with proteinuric glomerulopathies, not responding to standard immunosuppressive therapy. The indications included steroid-resistant nephrotic syndrome (n=14) and steroid-dependent nephrotic syndrome (n=2). The dose of rituximab was established as 375 mg/m2 of body surface area, administered by intravenous infusion once weekly for 1 to 4 weeks, depending on the CD19 lymphocyte count. We evaluated proteinuria and plasma concentration of CD19 lymphocytes at intervals of 1, 3 and 6 months, after which patients received a single repeat dose. Remission, defined as proteinuria less than 150 mg per 24 hours, was observed in 7 of the 16 children. There were no statistically significant differences in leukocyte counts between single and multiple rituximab doses. We also did not observe any clinical or biochemical side effects. In conclusion, we postulate that alternative rituximab therapy should be taken into consideration in nephrotic patients not responding to standard therapy.

  5. Phase 2 study of cladribine followed by rituximab in patients with hairy cell leukemia

    PubMed Central

    O'Brien, Susan; Jorgensen, Jeffrey; Pierce, Sherry; Faderl, Stefan; Ferrajoli, Alessandra; Koller, Charles; Challagundla, Pramoda; York, Sergernne; Brandt, Mark; Luthra, Rajyalakshmi; Burger, Jan; Thomas, Deborah; Keating, Michael; Kantarjian, Hagop

    2011-01-01

    We conducted this study to determine the feasibility and safety of cladribine followed by rituximab in patients with hairy cell leukemia including the vari-ant form (HCLv). Cladribine 5.6 mg/m2 given IV over 2 hours daily for 5 days was followed ∼ 1 month later with rituximab 375 mg/m2 IV weekly for 8 weeks. Responses were recorded and BM minimal residual disease (MRD) was evaluated after the completion of rituximab. Thirty-six patients have been treated including 5 with HCLv. Median age was 57 years (range, 37-89). All patients (100%) have achieved complete response (CR), defined as presence of no hairy cells in BM and blood with normalization of counts (absolute neutrophil count [ANC]> 1.5 × 109/L, hemoglobin [Hgb] > 12.0 g/dL, platelets [PLT] > 100 × 109/L), as well as resolution of splenomegaly. There were no grade 3 or 4 nonhematologic adverse events directly related to the treatment. Only 1 patient (with HCLv) has relapsed; median CR duration has not been reached (range,1+-63+ months). Three patients with HCLv died including 1 with relapsed disease and 2 from unrelated malignancies. Median survival duration has not been reached (range, 2+-64+ months). Treatment with clad-ribine followed by rituximab is effective tk;4and may increase CR rate. This study was registered at www.clinicaltrials.gov as NCT00412594. PMID:21821712

  6. [Rituximab cost analysis for maintenance treatment of patients with follicular lymphoma].

    PubMed

    2008-01-01

    In patients with refractory or recurrent follicular lymphoma responding to induction therapy with CHOP or rituximab + CHOP, maintenance treatment with rituximab compared to the "observation" option improves both overall survival and progression-free survival. Estimate whether maintenance treatment with rituximab is a cost-effective intervention compared to the clinical practice of "observing" its evolution. the EORTC 20981 clinical trial population. Spanish National Health System (direct healthcare costs). Incremental cost-effectiveness analysis, with a transition model between states of health. cost of gaining a quality-adjusted life year (QALY), per life year gained (LYG) and per progression-free LYG. Premises of the basic case: Weibull distribution for survival extrapolation, 5 year duration of the benefits of the treatment, time horizon of 10 years and annual discount rate (costs and benefits) of 3.5%. These premises were modified in the sensitivity analyses. Deterministic analysis: the cost per QALY gained was 9,358 euro, 8,493 euro per LYG and 5,485 euro per progression-free LYG. Probabilistic and sensitivity analysis: they confirmed the stability of the deterministic analysis results. According to this model, maintenance treatment with rituximab is cost-effective (cost per LYG < 30,000 euro) in patients with resistant or recurrent follicular lymphoma responding to induction treatment, in comparison to the usual practice of observing patients' evolution.

  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. Effect of off-label use of oncology drugs on pharmaceutical costs: the rituximab experience.

    PubMed

    Kocs, Darren; Fendrick, A Mark

    2003-05-01

    While the off-label use of oncology interventions is widespread, the factors influencing off-label use and the resultant influence on oncology drug expenditures are not well understood. To assess the indications for rituximab use, a retrospective review was undertaken at a single academic center between September 1998 and June 2001. Patient diagnoses were linked to pharmacy records, and each administration of rituximab was classified as either on-label or off-label as defined by FDA-approved indications. The resultant utilization patterns were the foundation for a conceptual model designed to identify factors that influence off-label use of oncology-related therapeutics and forecast the effect of off-label use on aggregate oncology drug expenditures. One hundred one patients received a total of 428 rituximab administrations during the study period. Most (320, 75%) of the administrations were for off-label indications. Although the extent of off-label and on-label use grew at a similar rate initially, off-label utilization increased nearly exponentially over time as on-label uses lessened. A conceptual model that describes factors that promote, inhibit, or have a mixed influence on off-label use may help predict future patterns of off-label utilization and allow better forecasting of oncology drug expenditures. The off-label use of rituximab is substantial. Projections of oncology-related patterns of care and drug expenditures must account for the potential for off-label use.

  9. TMA secondary to SLE: rituximab improves overall but not renal survival.

    PubMed

    Sun, Fangfang; Wang, Xiaodong; Wu, Wanlong; Wang, Kaiwen; Chen, Zhiwei; Li, Ting; Ye, Shuang

    2017-08-30

    Thrombotic microangiopathy (TMA) includes a series of life-threatening disorders. Systemic lupus erythematosus (SLE) is one of the most common acquired causes. To identify predictors of prognosis in patients with TMA secondary to SLE, we conducted a single-center historical study. From January 2013 to June 2016, of 2182 SLE hospitalized patients in the Ren Ji Hospital, a total of 21 consecutive patients with TMA secondary to SLE were identified. The 90-day short-term mortality was 33.3%. The kidney involvement (66.7%) was associated with poor prognosis, while the administration of rituximab (n = 13) was an independent protective factor according to logistic regression analysis. Compared to conventional treatment, i.e., plasma exchange, high-dose glucocorticoids, and intravenous immunoglobulin, the overall survival is significantly higher among patients receiving rituximab add-on (92.2 vs 33.3%, p = 0.0173); however, five out of seven patients with renal involvement in the rituximab group were eventually hemodialysis dependent. Our data indicated that add-on rituximab in the background of conventional therapy may improve the overall but not the renal survival in SLE-TMA patients.

  10. Emergence of long-lived autoreactive plasma cells in the spleen of primary warm auto-immune hemolytic anemia patients treated with rituximab.

    PubMed

    Mahévas, Matthieu; Michel, Marc; Vingert, Benoit; Moroch, Julien; Boutboul, David; Audia, Sylvain; Cagnard, Nicolas; Ripa, Julie; Menard, Cédric; Tarte, Karin; Mégret, Jérôme; Le Gallou, Simon; Patin, Pauline; Thai, Lan; Galicier, Lionel; Bonnotte, Bernard; Godeau, Bertrand; Noizat-Pirenne, France; Weill, Jean-Claude; Reynaud, Claude-Agnès

    2015-08-01

    Primary warm autoimmune hemolytic anemia (wAIHA) is a rare autoimmune disease in which red blood cells are eliminated by IgG autoantibodies. We analyzed the antibody-secreting cells in the spleen and the peripheral blood of wAIHA patients in various contexts of treatment. Plasmablasts were observed in peripheral blood of newly diagnosed wAIHA patients and, accordingly, active germinal center reactions were present in the spleen of patients receiving short-term corticosteroid therapy. Long-term corticosteroid regimens markedly reduced this response while splenic plasma cells were able to persist, a fraction of them secreting anti-red blood cell IgG in vitro. In wAIHA patients treated by rituximab and who underwent splenectomy because of treatment failure, plasma cells were still present in the spleen, some of them being autoreactive. By using a set of diagnostic genes that allowed us to assess the plasma cell maturation stage, we observed that these cells displayed a long-lived program, differing from the one of plasma cells from healthy donors or from wAIHA patients with various immunosuppressant treatments, and more similar to the one of normal long-lived bone-marrow plasma cells. Interestingly, an increased level of B-cell activating factor (BAFF) was observed in the supernatant of spleen cell cultures from such rituximab-treated wAIHA patients. These results suggest, in line with our previous report on primary immune thrombocytopenia, that the B-cell depletion induced by rituximab promoted a suitable environment for the maturation and survival of auto-immune long-lived plasma cells in the spleen.

  11. 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

  12. Rituximab plus chlorambucil as first-line treatment for chronic lymphocytic leukemia: Final analysis of an open-label phase II study.

    PubMed

    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

    2014-04-20

    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 with first-line CLL were treated with rituximab (375 mg/m(2) on day 1, cycle one, and 500 mg/m(2) thereafter) plus chlorambucil (10 mg/m(2)/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. 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. 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.

  13. 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

  14. Repeated Administrations of Rituximab along with Steroids and Immunosuppressive Agents in Refractory Steroid-resistant Nephrotic Syndrome.

    PubMed

    Fujinaga, Shuichiro; Sakuraya, Koji

    2017-01-15

    A recent randomized control trial in children with steroid-resistant nephrotic syndrome revealed that two doses of rituximab did not reduce proteinuria. A 14-month-old boy developed refractory steroid-resistant nephrotic syndrome due to focal segmental glomerulosclerosis. The patient achieved complete remission 11 months after disease onset following eight doses of rituximab combined with steroids and cyclosporine. Long-lasting B cell depletion with repeated rituximab administrations may be required to achieve complete remission in patients with steroid-resistant nephrotic syndrome and massive proteinuria.

  15. Rituximab fails where eculizumab restores renal function in C3nef-related DDD.

    PubMed

    Rousset-Rouvière, Caroline; Cailliez, Mathilde; Garaix, Florentine; Bruno, Daniele; Laurent, Daniel; Tsimaratos, Michel

    2014-06-01

    Dense deposit disease (DDD), a C3 glomerulopathy (C3G), is a rare disease with unfavorable progression towards end-stage kidney disease. The pathogenesis of DDD is due to cytotoxic effects related to acquired or genetic dysregulation of the complement alternative pathway, which is at times accompanied by the production of C3 nephritic factor (C3NeF), an auto-antibody directed against the alternative C3 convertase. Available treatments include plasma exchange, CD20-targeted antibodies, and a terminal complement blockade via the anti-C5 monoclonal antibody eculizumab. We report here the case of an 8-year-old child with C3NeF and refractory DDD who presented with a nephritic syndrome. She tested positive for C3NeF activity; C3 was undetectable. Genetic analyses of the alternative complement pathway were normal. Methylprednisolone pulses and mycophenolate mofetil treatment resulted in complete recovery of renal function and a reduction in proteinuria. Corticosteroids were tapered and then withdrawn. Four months after corticosteroid discontinuation, hematuria and proteinuria recurred, and a renal biopsy confirmed an active DDD with a majority of extracapillary crescents. Despite an increase in immunosuppressive drugs, including methylprednisolone pulses and rituximab therapy, the patient suffered acute renal failure within 3 weeks, requiring dialysis. Eculizumab treatment resulted in a quick and impressive response. Hematuria very quickly resolved, kidney function improved, and no further dialysis was required. The patient received bimonthly eculizumab injections of 600 mg, allowing for normalization of renal function and reduction of proteinuria to <0.5 g per day. Since then, she continues to receive eculizumab. Complement regulation pathway-targeted therapy may be a specific and useful treatment for rapidly progressing DDD prior to the development of glomerulosclerosis. Our data provide evidence supporting the pivotal role of complement alternative pathway

  16. Impact of rituximab therapy on response to tetanus toxoid vaccination in kidney-transplant patients.

    PubMed

    Puissant-Lubrano, Benedicte; Rostaing, Lionel; Kamar, Nassim; Abbal, Michel; Fort, Marylise; Blancher, Antoine

    2010-03-01

    Rituximab is used after kidney transplant to prevention or treat kidney-allograft rejection. However, the impact of rituximab on the ability of patients to respond to tetanus toxoid vaccination has not yet been studied. The response to tetanus toxoid vaccination was analyzed in 39 kidney transplant recipients immunosuppressed by corticoids, antiproliferative agents, and/or calcineurin inhibitors. Thirteen patients had previously received rituximab (group 1), 26 patients had not (group 2). Response to control bacterial antigens and immunologic parameters (lymphocyte count, B-cell subsets, serum immunoglobulin level) were analyzed before and at 1 month after vaccination. Thirty healthy blood donors were used as controls for the before-vaccination immunologic parameters. Before vaccination, neither patient group differed from controls in serum levels of immunoglobulins and antibodies against bacterial antigens, but they did display lower levels of CD4 T cells and B cells compared with controls. Responders to the tetanus toxoid vaccination were slightly fewer in group 1 (4/13) than in group 2 (16/26), but the intensity of the anti-tetanus toxoid response was not significantly different between these 2 groups. None of the parameters studied at the time of vaccination (anti-tetanus toxoid level, peripheral B or CD4 T-cell count, memory B-cell subsets, treatment with rituximab, time since transplant) were associated with an ability to respond to vaccination. The ability to respond to vaccination and graft outcomes were not correlated in each patient group. Rituximab impaired the secondary immune response after tetanus toxoid vaccination, but did not abolish it in all patients.

  17. Effect of rituximab on human in vivo antibody immune responses.

    PubMed

    Pescovitz, Mark D; Torgerson, Troy R; Ochs, Hans D; Ocheltree, Elizabeth; McGee, Paula; Krause-Steinrauf, Heidi; Lachin, John M; Canniff, Jennifer; Greenbaum, Carla; Herold, Kevan C; Skyler, Jay S; Weinberg, Adriana

    2011-12-01

    B-lymphocyte depletion with rituximab has been shown to benefit patients with various autoimmune diseases. We have previously demonstrated that this benefit is also apparent in patients with newly diagnosed type 1 diabetes. The effect of rituximab on in vivo antibody responses, particularly during the period of B-lymphocyte depletion, is incompletely determined. This study was designed to assess this knowledge void. In patients with recent-onset type 1 diabetes treated with rituximab (n = 46) or placebo (n = 29), antibody responses to neoantigen phiX174 during B-lymphocyte depletion and with hepatitis A (as a second neoantigen) and tetanus/diphtheria (as recall antigens) after B-lymphocyte recovery were studied. Anti- tetanus, diphtheria, mumps, measles, and rubella titers were measured before and after treatment by means of ELISA. Antibody titers and percentage IgM versus percentage IgG to phiX174 were measured by means of phage neutralization. B-lymphocyte subsets were determined by means of flow cytometry. No change occurred in preexisting antibody titers. Tetanus/diphtheria and hepatitis A immunization responses were protective in the rituximab-treated subjects, although significantly blunted compared with those seen in the controls subjects, when immunized at the time of B-lymphocyte recovery. Anti-phiX174 responses were severely reduced during the period of B-lymphocyte depletion, but with B-lymphocyte recovery, anti-phiX174 responses were within the normal range. During the time of B-lymphocyte depletion, rituximab recipients had a decreased antibody response to neoantigens and significantly lower titers after recall immunization with diphtheria and tetanus toxoid. With recovery, immune responses return toward normal. Immunization during the time of B-lymphocyte depletion, although ineffective, does not preclude a subsequent response to the antigen. Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights

  18. Infectious Complications in Kidney-Transplant Recipients Desensitized with Rituximab and Intravenous Immunoglobulin

    PubMed Central

    Sinha, Aditi; Toyoda, Mieko; Ge, Shili; Reinsmoen, Nancy; Cao, Kai; Lai, Chih-Hung; Villicana, Rafael; Peng, Alice; Jordan, Stanley; Vo, Ashley

    2011-01-01

    Summary Background and objectives Rituximab and intravenous Ig (IVIG) are commonly used for desensitization of HLA and blood group–incompatible (ABOi) transplants. However, serious infections have been noted in association with rituximab administration. In this study, we retrospectively compared infectious outcomes in those who received rituximab plus IVIG for HLA or ABOi transplants (RIT group) with a group of nonsensitized, ABO-compatible transplant recipients (non-RIT group). Design, setting, participants, & measurements Patients undergoing kidney transplantation at Cedars-Sinai Medical Center were included in the analysis. A total of 361 patients were identified. All received antimicrobial prophylaxis and viral surveillance. The primary outcome was infection. Results Overall patient survival was 97 and 96%, and graft survival was 91 and 89% in the RIT and non-RIT groups, respectively, after an average follow-up of 18 months. There were equal rates of bacterial (34.7% versus 39.1%), viral (21.8% versus 25.1%), fungal (5.9% versus 5.2%), and serious infections (22.9% versus 25.5%) in the RIT and non-RIT groups respectively. Urinary tract infection was the most common infection, accounting for 50% of all bacterial infections. Cytomegalovirus viremia was nonsignificantly more common in the nonrituximab-treated group (15.2% versus 10%), whereas BK viremia was marginally more frequent in the rituximab-treated group (10.6% versus 5.8%). There were no graft losses caused by BK-associated nephropathy. There were two deaths in each group related to infection (1%). Conclusion Rituximab does not increase infection risk when used with intravenous Ig for desensitization. PMID:22157713

  19. Infectious complications in kidney-transplant recipients desensitized with rituximab and intravenous immunoglobulin.

    PubMed

    Kahwaji, Joseph; Sinha, Aditi; Toyoda, Mieko; Ge, Shili; Reinsmoen, Nancy; Cao, Kai; Lai, Chih-Hung; Villicana, Rafael; Peng, Alice; Jordan, Stanley; Vo, Ashley

    2011-12-01

    Rituximab and intravenous Ig (IVIG) are commonly used for desensitization of HLA and blood group-incompatible (ABOi) transplants. However, serious infections have been noted in association with rituximab administration. In this study, we retrospectively compared infectious outcomes in those who received rituximab plus IVIG for HLA or ABOi transplants (RIT group) with a group of nonsensitized, ABO-compatible transplant recipients (non-RIT group). Patients undergoing kidney transplantation at Cedars-Sinai Medical Center were included in the analysis. A total of 361 patients were identified. All received antimicrobial prophylaxis and viral surveillance. The primary outcome was infection. Overall patient survival was 97 and 96%, and graft survival was 91 and 89% in the RIT and non-RIT groups, respectively, after an average follow-up of 18 months. There were equal rates of bacterial (34.7% versus 39.1%), viral (21.8% versus 25.1%), fungal (5.9% versus 5.2%), and serious infections (22.9% versus 25.5%) in the RIT and non-RIT groups respectively. Urinary tract infection was the most common infection, accounting for 50% of all bacterial infections. Cytomegalovirus viremia was nonsignificantly more common in the nonrituximab-treated group (15.2% versus 10%), whereas BK viremia was marginally more frequent in the rituximab-treated group (10.6% versus 5.8%). There were no graft losses caused by BK-associated nephropathy. There were two deaths in each group related to infection (1%). Rituximab does not increase infection risk when used with intravenous Ig for desensitization.

  20. 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

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

    PubMed

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

    2013-06-11

    To determine whether rituximab 375 mg/m(2) was efficacious in patients with immunoglobulin M (IgM) anti-myelin-associated glycoprotein antibody demyelinating neuropathy (IgM anti-MAG demyelinating neuropathy). 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. Twenty-six patients were randomized to a group receiving 4 weekly infusions of 375 mg/m(2) 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. 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. This study provides Class I evidence that rituximab is ineffective in improving ISS in patients with IgM anti-MAG demyelinating neuropathy.

  2. Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases

    PubMed Central

    Gottenberg, J; Guillevin, L; Lambotte, O; Combe, B; Allanore, Y; Cantagrel, A; Larroche, C; Soubrier, M; Bouillet, L; Dougados, M; Fain, O; Farge, D; Kyndt, X; Lortholary, O; Masson, C; Moura, B; Remy, P; Thomas, T; Wendling, D; Anaya, J; Sibilia, J; Mariette, X; t for

    2005-01-01

    Objective: To assess the tolerance and efficacy of rituximab in patients with various autoimmune diseases seen in daily rheumatological practice. Methods: 866 rheumatology and internal medicine practitioners were contacted by email to obtain the files of patients treated with rituximab for systemic autoimmune diseases. Patients with lymphoma were analysed if the evolution of the autoimmune disease could be evaluated. Results: In all, 43 of 49 cases could be analysed, including 14 with rheumatoid arthritis (RA), 13 with systemic lupus erythematosus (SLE), six with primary Sjögren's syndrome (pSS), five with systemic vasculitis, and five with other autoimmune diseases. Rituximab was prescribed for lymphoma in two patients with RA and two with pSS. In the 39 other cases, rituximab was given because of the refractory character of the autoimmune disease. The mean follow up period was 8.3 months (range 2 to 26). There were 11 adverse events in 10 patients and treatment had to be discontinued in six. Efficacy was observed in 30 patients (70%): RA 11, SLE 9, pSS 5, vasculitis 2, antisynthetase syndromes 2, sarcoidosis 1. The mean decrease in corticosteroid intake was 9.5 mg/d (range 0 to 50) in responders. Seven patients experienced relapse after mean 8.1 months (5 to 15). Three patients died because of refractory autoimmune disease. Conclusions: Despite absence of marketing authorisation, rituximab is used to treat various refractory autoimmune diseases in daily rheumatological practice. This study showed good tolerance and short term clinical efficacy, with marked corticosteroid reduction in patients with SLE, pSS, vasculitis, and polymyositis. PMID:15550531

  3. Bone mineral density in systemic lupus erythematosus women one year after rituximab therapy.

    PubMed

    Mendoza Pinto, C; García Carrasco, M; Etchegaray Morales, I; Jiménez Hernández, M; Méndez Martínez, S; Jiménez Hernández, C; Briones Rojas, R; Ramos Alvarez, G; Rodríguez Gallegos, A; Montiel Jarquín, A; López Colombo, A; Cervera, R

    2013-10-01

    The objective of this study was to assess the effects of rituximab on bone mineral density (BMD) in women with systemic lupus erythematosus (SLE) 1 year after treatment. Thirty active female SLE patients treated with rituximab were compared with 43 SLE women not treated with rituximab. BMD was measured using dual energy X-ray absorptiometry (DEXA) before initiating biologic therapy and after 1 year. The mean age was 38.5 ± 2.1 years; median disease duration was 7 years. In the rituximab group, after 1 year of follow-up, BMD at the femoral neck (FN) decreased from 0.980 ± 0.130 g/cm(2) to 0.809 ± 0.139 g/cm(2) (-17.4%; p=0.001). Similarly, BMD at the lumbar spine (LS) decreased from 1.062 ± 0.137 g/cm(2) to 0.893 ± 0.194 g/cm(2) (-15.8%; p=0.001). In control subjects, BMD at the FN decreased from 0.914 ± 0.193 g/cm(2) to 0.890 ± 0.135 g/cm(2) (-2.6%; p=0.001), and BMD at the LS decreased from 0.926 ± 0.128 g/cm(2) to 0.867 ± 0.139 g/cm(2) (-6.2%; p=0.09). After 1 year, SLE patients had lower BMD at both the FN and LS, but the loss was greater in postmenopausal patients who had received rituximab therapy.

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

    PubMed

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

    2015-07-01

    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.

  5. Autoimmune polyendocrine syndrome type 1: Utility of KCNRG autoantibodies as a marker of active pulmonary disease and successful treatment with rituximab.

    PubMed

    Popler, Jonathan; Alimohammadi, Mohammad; Kämpe, Olle; Dalin, Frida; Dishop, Megan K; Barker, Jennifer M; Moriarty-Kelsey, Margaret; Soep, Jennifer B; Deterding, Robin R

    2012-01-01

    Autoimmune polyendocrine syndrome type 1 (APS-1), also known as Autoimmune Polyendocrinopathy Candidiasis and Ectodermal Dysplasia (APECD) is a disorder caused by mutations in the autoimmune regulator (AIRE) gene. In some APS-1 patients, significant pulmonary disease is observed. Autoantibodies directed against the potassium channel regulatory protein (KCNRG), found in epithelial cells of terminal bronchioles, have been suggested as a marker for pulmonary disease in APS-1 patients. We report two patients with APS-1; one with and one without lung disease. Patient 1 had multiple admissions for pneumonia and respiratory insufficiency, required non-invasive ventilation, and had findings of bronchiectasis on thoracic imaging and significant lymphocytic infiltrates of the airways on lung biopsy. To verify the autoimmune cause of pulmonary symptoms APS-1 patients, both were tested in a blinded manner for the presence of autoantibodies to KCNRG in serum. We found that only Patient 1 had autoantibodies present. Additionally, Patient 1 had progressive disease despite treatment with several immunomodulating agents, including corticosteroids, azathioprine, and mycophenolate. Patient 1 had a lung biopsy performed which was consistent with B cell lymphocytic aggregates. Rituximab treatment was initiated with apparent good response. This report illustrates the practical use of KCNRG autoantibodies to identify APS-1 patients with pulmonary risk and the successful use of the monoclonal antibody, Rituximab, to treat pulmonary disease in APS-1 patients.

  6. Development and biological studies of ¹⁷⁷Lu-DOTA-rituximab for the treatment of Non-Hodgkin's lymphoma.

    PubMed

    Massicano, Adriana V F; Pujatti, Priscilla B; Alcarde, Lais F; Suzuki, Miriam F; Spencer, Patrick J; Araújo, Elaine B

    2016-01-01

    The optimization of DOTA-NHS-ester conjugation to Rituximab using different Ab:DOTA molar ratios (1:10, 1:20, 1:50 and 1:100) was studied. High radiochemical yield, in vitro stability and immunoreactive fraction were obtained for the Rituximab conjugated at 1:50 molar ratio, resulting in the incorporation of an average number of 4.9 ± 1.1 DOTA per Rituximab molecule. Labeling with 177Lu was performed in high specific activity with great in vitro stability. Biodistribution in healthy and xenographed mice showed tumor uptake and high in vivo stability as evidenced by low uptake in bone. The properties of 177Lu-DOTA-Rituximab prepared from DOTA-NHS-ester suggest the potential for the application of the 177Lu-labeled antibody in preliminary clinical studies.

  7. Rituximab (MabThera) for aggressive non-Hodgkin's lymphoma: systematic review and economic evaluation.

    PubMed

    Knight, C; Hind, D; Brewer, N; Abbott, V

    2004-09-01

    To determine the clinical and cost-effectiveness of adding rituximab to the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy regime for adult patients with diffuse large B-cell lymphoma (DLBCL). Electronic bibliographic database. Comparative studies were selected for review if they addressed the clinical or cost-effectiveness of adding rituximab to CHOP in people aged at least 18 years with DLBCL. The internal validity of the study was assessed through the use of the validated Jadad scoring system. Data were abstracted into standardised data extraction forms. Costs were estimated through resource use data taken from the published trial and the unpublished sponsor submission. Unit costs were taken from published sources, where available. An economic evaluation was undertaken to evaluate the cost-effectiveness of R-CHOP compared with CHOP alone for patients with DLBCL using data sources and methodology similar to the manufacturer's submission. In the systematic review of effectiveness, one randomised controlled trial was identified. The study was, in most respects, methodologically rigorous and well conducted and the statistical evidence favoured the addition of rituximab to CHOP. The total cost of rituximab with CHOP (R-CHOP) and CHOP alone estimated from the model developed by ScHARR was 14,456 pounds and 5773 pounds, respectively, for patients aged 60 years and over, and 15,181 pounds and 7311 pounds for patients aged less than 60 years over a 15-year time horizon. The ScHARR model estimated that the addition of rituximab to CHOP generated an additional 0.82 QALY at an extra cost of 8683 pounds compared with CHOP alone therapy over a 15-year time horizon, a cost/quality-adjusted life-year (QALY) ratio of 10,596 pounds for patients aged 60 years or more. For patients aged under 60 years, 1.05 QALY were generated at an additional cost of 7870 pounds, a cost/QALY ratio of 7533 pounds. Assuming that the societal value of a QALY was 30

  8. [Successful rituximab monotherapy in a patient with mucosa-associated lymphoid tissue lymphoma of the rectum with trisomy 3, 18].

    PubMed

    Kagawa, Miwako; Okamura, Seisuke; Okamoto, Koichi; Kitamura, Shinji; Kimura, Tetsuo; Niki, Miyako; Kaji, Masako; Okahisa, Toshiya; Yano, Mitsuyasu; Kagawa, Seiko; Kudo, Eiji; Sano, Toshiaki; Imoto, Yoshitaka; Wada, Satoshi; Takayama, Tetsuji

    2010-04-01

    A 62-year-old man was referred to our hospital with enlargement of mucosa-associated lymphoid tissue (MALT) lymphoma of the rectum after the eradication of Helicobacter pylori. The patient was given a diagnosis of stage I MALT. Endoscopic observation revealed an enlarged rectal tumor with 3, 18 double trisomy. Rituximab monotherapy was given and complete remission was achieved. Rituximab monotherapy can be useful for MALT lymphoma of the rectum.

  9. Anxiety and Health-Related Quality of Life Among Patients With Low–Tumor Burden Non-Hodgkin Lymphoma Randomly Assigned to Two Different Rituximab Dosing Regimens: Results From ECOG Trial E4402 (RESORT)

    PubMed Central

    Wagner, Lynne I.; Zhao, Fengmin; Hong, Fangxin; Williams, Michael E.; Gascoyne, Randy D.; Krauss, John C.; Advani, Ranjana H.; Go, Ronald S.; Habermann, Thomas M.; Leach, Joseph W.; O'Connor, Brian; Schuster, Stephen J.; Cella, David; Horning, Sandra J.; Kahl, Brad S.

    2015-01-01

    Purpose The purpose of this study was to compare illness-related anxiety among participants in the Rituximab Extended Schedule or Retreatment Trial (RESORT) randomly assigned to maintenance rituximab (MR) versus rituximab re-treatment (RR). A secondary objective was to examine whether the superiority of MR versus RR on anxiety depended on illness-related coping style. Patients and Methods Patients (N = 253) completed patient-reported outcome (PRO) measures at random assignment to MR or RR (baseline); at 3, 6, 12, 24, 36, and 48 months after random assignment; and at rituximab failure. PRO measures assessed illness-related anxiety and coping style, and secondary end points including general anxiety, worry and interference with emotional well-being, depression, and health-related quality of life (HRQoL). Patients were classified as using an active or avoidant illness-related coping style. Independent sample t tests and linear mixed-effects models were used to identify treatment arm differences on PRO end points and differences based on coping style. Results Illness-related anxiety was comparable between treatment arms at all time points (P > .05), regardless of coping style (active or avoidant). Illness-related anxiety and general anxiety significantly decreased over time on both arms. HRQoL scores were relatively stable and did not change significantly from baseline for both arms. An avoidant coping style was associated with significantly higher anxiety (18% and 13% exceeded clinical cutoff points at baseline and 6 months, respectively) and poorer HRQoL compared with an active coping style (P < .001), regardless of treatment arm assignment. Conclusion Surveillance until RR at progression was not associated with increased anxiety compared with MR, regardless of coping style. Avoidant coping was associated with higher anxiety and poorer HRQoL. PMID:25605841

  10. Anxiety and health-related quality of life among patients with low-tumor burden non-Hodgkin lymphoma randomly assigned to two different rituximab dosing regimens: results from ECOG trial E4402 (RESORT).

    PubMed

    Wagner, Lynne I; Zhao, Fengmin; Hong, Fangxin; Williams, Michael E; Gascoyne, Randy D; Krauss, John C; Advani, Ranjana H; Go, Ronald S; Habermann, Thomas M; Leach, Joseph W; O'Connor, Brian; Schuster, Stephen J; Cella, David; Horning, Sandra J; Kahl, Brad S

    2015-03-01

    The purpose of this study was to compare illness-related anxiety among participants in the Rituximab Extended Schedule or Retreatment Trial (RESORT) randomly assigned to maintenance rituximab (MR) versus rituximab re-treatment (RR). A secondary objective was to examine whether the superiority of MR versus RR on anxiety depended on illness-related coping style. Patients (N = 253) completed patient-reported outcome (PRO) measures at random assignment to MR or RR (baseline); at 3, 6, 12, 24, 36, and 48 months after random assignment; and at rituximab failure. PRO measures assessed illness-related anxiety and coping style, and secondary end points including general anxiety, worry and interference with emotional well-being, depression, and health-related quality of life (HRQoL). Patients were classified as using an active or avoidant illness-related coping style. Independent sample t tests and linear mixed-effects models were used to identify treatment arm differences on PRO end points and differences based on coping style. Illness-related anxiety was comparable between treatment arms at all time points (P > .05), regardless of coping style (active or avoidant). Illness-related anxiety and general anxiety significantly decreased over time on both arms. HRQoL scores were relatively stable and did not change significantly from baseline for both arms. An avoidant coping style was associated with significantly higher anxiety (18% and 13% exceeded clinical cutoff points at baseline and 6 months, respectively) and poorer HRQoL compared with an active coping style (P < .001), regardless of treatment arm assignment. Surveillance until RR at progression was not associated with increased anxiety compared with MR, regardless of coping style. Avoidant coping was associated with higher anxiety and poorer HRQoL. © 2015 by American Society of Clinical Oncology.

  11. Biologic predictors of clinical improvement in rituximab-treated refractory myositis.

    PubMed

    Reed, Ann M; Crowson, Cynthia S; Hein, Molly; de Padilla, Consuelo Lopez; Olazagasti, Jeannette M; Aggarwal, Rohit; Ascherman, Dana P; Levesque, Marc C; Oddis, Chester V

    2015-09-17

    To examine the longitudinal utility of a biomarker signature in conjunction with myositis autoantibodies (autoAbs) as predictors of disease improvement in refractory myositis patients treated with rituximab. In the RIM Trial, all subjects received rituximab on 2 consecutive weeks. Using start of treatment as baseline, serum samples (n = 177) were analyzed at baseline and after rituximab with multiplexed sandwich immunoassays to quantify type-1 IFN-regulated and other pro-inflammatory chemokines and cytokines. Biomarker scores were generated for the following pathways: type-1 IFN-inducible (IFNCK), innate, Th1, Th2, Th17 and regulatory cytokines. Myositis autoAbs (anti-synthetase n = 28, TIF-γ n = 19, Mi-2 n = 25, SRP n = 21, MJ n = 18, non-MAA n = 24, unidentified autoantibody n = 9, and no autoantibodies n = 33) determined by immunoprecipitation at baseline, were correlated with outcome measures. Kruskal-Wallis rank sum tests were used for comparisons. The mean (SD) values for muscle disease and physician global disease activity VAS scores (0-100 mm) were 46 (22) and 49 (19). IFNCK scores (median values) were higher at baseline in subjects with anti-synthetase (43), TIF1-γ (31) and Mi-2 (30) compared with other autoAb groups (p < 0.001). At 16 weeks after rituximab, anti-synthetase and Mi-2 autoAb positive subjects and non-MAA had a greater improvement in IFNCK scores (- 6.7, - 6.1 and -7.2, p < .001). Both IFNCK high scores (>30) and autoAb group (Mi-2, non-MAA, and undefined autoantibody) demonstrated the greatest clinical improvement based on muscle VAS (muscle-interaction p = 0.075). Biomarker signatures in conjunction with autoAbs help predict response to rituximab in refractory myositis. Biomarker and clinical responses are greatest at 16 weeks after rituximab.

  12. Statins Impair Antitumor Effects of Rituximab by Inducing Conformational Changes of CD20

    PubMed Central

    Winiarska, Magdalena; Bil, Jacek; Wilczek, Ewa; Wilczynski, Grzegorz M; Lekka, Malgorzata; Engelberts, Patrick J; Mackus, Wendy J. M; Gorska, Elzbieta; Bojarski, Lukasz; Stoklosa, Tomasz; Nowis, Dominika; Kurzaj, Zuzanna; Makowski, Marcin; Glodkowska, Eliza; Issat, Tadeusz; Mrowka, Piotr; Lasek, Witold; Dabrowska-Iwanicka, Anna; Basak, Grzegorz W; Wasik, Maria; Warzocha, Krzysztof; Sinski, Maciej; Gaciong, Zbigniew; Jakobisiak, Marek; Parren, Paul W. H. I; Golab, Jakub

    2008-01-01

    Background Rituximab is used in the treatment of CD20+ B cell lymphomas and other B cell lymphoproliferative disorders. Its clinical efficacy might be further improved by combinations with other drugs such as statins that inhibit cholesterol synthesis and show promising antilymphoma effects. The objective of this study was to evaluate the influence of statins on rituximab-induced killing of B cell lymphomas. Methods and Findings Complement-dependent cytotoxicity (CDC) was assessed by MTT and Alamar blue assays as well as trypan blue staining, and antibody-dependent cellular cytotoxicity (ADCC) was assessed by a 51Cr release assay. Statins were found to significantly decrease rituximab-mediated CDC and ADCC of B cell lymphoma cells. Incubation of B cell lymphoma cells with statins decreased CD20 immunostaining in flow cytometry studies but did not affect total cellular levels of CD20 as measured with RT-PCR and Western blotting. Similar effects are exerted by other cholesterol-depleting agents (methyl-β-cyclodextrin and berberine), but not filipin III, indicating that the presence of plasma membrane cholesterol and not lipid rafts is required for rituximab-mediated CDC. Immunofluorescence microscopy using double staining with monoclonal antibodies (mAbs) directed against a conformational epitope and a linear cytoplasmic epitope revealed that CD20 is present in the plasma membrane in comparable amounts in control and statin-treated cells. Atomic force microscopy and limited proteolysis indicated that statins, through cholesterol depletion, induce conformational changes in CD20 that result in impaired binding of anti-CD20 mAb. An in vivo reduction of cholesterol induced by short-term treatment of five patients with hypercholesterolemia with atorvastatin resulted in reduced anti-CD20 binding to freshly isolated B cells. Conclusions Statins were shown to interfere with both detection of CD20 and antilymphoma activity of rituximab. These studies have significant

  13. High-dose therapy and autologous stem cell transplant for transformed non-Hodgkin lymphoma in the rituximab era

    PubMed Central

    Ban-Hoefen, Makiko; Kelly, Jennifer L.; Bernstein, Steven H.; Liesveld, Jane; Constine, Louis; Becker, Michael; Milner, Laurie; Phillips, Gordon; Friedberg, Jonathan W.

    2013-01-01

    The impact of rituximab on outcome of high dose therapy and autologous stem cell transplantation (HD-ASCT) for transformed NHL has not been previously described. We analyzed eighteen consecutive patients with indolent NHL who transformed to diffuse large B-cell lymphoma (DLBCL), received rituximab-containing therapy either before or after transformation and underwent subsequent HD-ASCT. With a median follow-up of 40 months, the 2-year PFS was 59% and the 2-year OS was 82%. Six patients did not receive rituximab pre-transformation; this group had a significantly better PFS at 2 years post HD-ASCT compared to 12 patients who were exposed to rituximab pre-transformation (p=0.03). HD-ASCT remains an effective therapeutic option for transformed NHL in the rituximab era. However, patients exposed to rituximab pre-transformation appear to have inferior HD-ASCT outcomes, and thus may benefit from novel conditioning and maintenance regimens in the setting of HD-ASCT. PMID:22023518

  14. Using health-system-wide data to understand hepatitis B virus prophylaxis and reactivation outcomes in patients receiving rituximab

    PubMed Central

    Schmajuk, Gabriela; Tonner, Chris; Trupin, Laura; Li, Jing; Sarkar, Urmimala; Ludwig, Dana; Shiboski, Stephen; Sirota, Marina; Dudley, R. Adams; Murray, Sara; Yazdany, Jinoos

    2017-01-01

    Abstract Hepatitis B virus (HBV) reactivation in the setting of rituximab use is a potentially fatal but preventable safety event. The rate of HBV screening and proportion of patients at risk who receive antiviral prophylaxis in patients initiating rituximab is unknown. We analyzed electronic health record (EHR) data from 2 health systems, a university center and a safety net health system, including diagnosis grouper codes, problem lists, medications, laboratory results, procedures codes, clinical encounter notes, and scanned documents. We identified all patients who received rituximab between 6/1/2012 and 1/1/2016. We calculated the proportion of rituximab users with inadequate screening for HBV according to the Centers for Disease Control guidelines for detecting latent HBV infection before their first rituximab infusion during the study period. We also assessed the proportion of patients with positive hepatitis B screening tests who were prescribed antiviral prophylaxis. Finally, we characterized safety failures and adverse events. We included 926 patients from the university and 132 patients from the safety net health system. Sixty-one percent of patients from the university had adequate screening for HBV compared with 90% from the safety net. Among patients at risk for reactivation based on results of HBV testing, 66% and 92% received antiviral prophylaxis at the university and safety net, respectively. We found wide variations in hepatitis B screening practices among patients receiving rituximab, resulting in unnecessary risks to patients. Interventions should be developed to improve patient safety procedures in this high-risk patient population. PMID:28353614

  15. 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.

  16. Phase II study of alemtuzumab-rituximab therapy in previously untreated patients with chronic lymphocytic leukemia: short- and long-term outcomes.

    PubMed

    Frankfurt, Olga; Ma, Shuo; Gordon, Leo; Winter, Jane N; Horowitz, Jeanne M; Rademaker, Alfred; Weitner, Bing Bing; Peterson, LoAnn C; Altman, Jessica K; Tallman, Martin S; Petrich, Adam; Rosen, Steven T

    2015-02-01

    We investigated the safety, efficacy, and long-term outcomes of alemtuzumab and rituximab (AR) combination therapy in previously untreated patients with CLL. Thirty patients, ages 28-80 years, 47% older than 60 years, 90% Rai clinical stages II-IV, and 67% without favorable cytogenetics received AR. Based on the NCI-WG 1996 criteria, OR was 100%, with 60% CR. With CT scans OR was 70%, with 23% CR, 47% PR, and 30% SD. Sixty-seven percent of patients showed no evidence of MRD in the bone marrow by 6-color flow cytometry. Median PFS, TFS, and 5-year OS were 24.4, 50.7 months, and 80%, respectively. Grade 3/4 neutropenia and thrombocytopenia were reported in 30% and 7% of patients, respectively. CMV reactivation, asymptomatic in all but one patient, occurred in 8 patients. Immunotherapy with alemtuzumab and rituximab results in robust responses and long asymptomatic therapy-free intervals. It is well tolerated with infrequent, predictable, and easily managed complications.

  17. 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

  18. Transient Impact of Rituximab in H1N1 Vaccination-associated Narcolepsy With Severe Psychiatric Symptoms.

    PubMed

    Sarkanen, Tomi; Alén, Reija; Partinen, Markku

    2016-09-01

    Narcolepsy type 1 is an organic sleep disorder caused by the destruction of hypocretin producing neurons in hypothalamus. In addition to daytime sleepiness, the spectrum and severity of symptoms are very variable. Psychiatric comorbidity and phenomena resembling psychotic symptoms are also common. Current treatment options for narcolepsy are symptomatic but there are few case reports of positive effect of immunotherapy. We report a very severely affected young boy treated with rituximab (RXB). A 12-year-old boy developed narcolepsy after Pandemrix H1N1 vaccination in 2010. He started to express severe psychiatric symptoms shortly after the onset. Cataplexy and sleepiness were devastatingly disabling. Conventional treatments did not have any effect on symptoms so we decided to try RXB, chimeric human monoclonal antibody against CD20 expressed in B lymphocytes. After the first treatment his condition ameliorated dramatically. Unfortunately, the effect lasted only for 2 months. Following attempts did not show any effect. Effect of RXB on narcolepsy has not been reported before. Remarkable but short-lasting effect of RXB in narcolepsy is intriguing as it could imply that there is still ongoing B cell-mediated autoimmune response possible contributing to symptoms in narcolepsy.

  19. Rituximab therapy in necrotizing autoimmune myopathy associated with anti-SRP antibody: A clinical case review.

    PubMed

    Nóvoa Medina, Francisco Javier; Gutiérrez Martínez, José; González González, Yeray; Romero Díaz, Beatriz; Machín García, Sergio; Rosas Romero, Antonio

    2017-04-04

    Necrotizing autoimmune myopathy (NAM) is a rare and emerging entity of idiopathic inflammatory myopathy (IIM). They have been associated with connective tissue disorders, viral infections, malignancy, anti-signal recognition particle (SRP) and anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase protein (with or without the use of statins). Anti-SRP associated NAM has different clinical and histological characteristics that differentiate them from other IIM, resulting in a poor prognosis. Very few cases treated with rituximab have been published, with varying clinical response. Here we describe a case of anti-SRP associated NAM refractory to conventional immunosuppressants and its successful long-term management with the combination of rituximab, corticosteroids and methotrexate. Copyright © 2017 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.

  20. Rituximab in diffuse cutaneous systemic sclerosis: should we be using it today?

    PubMed

    McQueen, Fiona M; Solanki, Kamal

    2015-05-01

    There is new evidence that B-cell depletion could be an effective intervention in patients with SSc. Observational case-control study data from the European League Against Rheumatism Scleroderma Trials and Research group has suggested that rituximab therapy may reduce progression of skin thickening and lung fibrosis, especially in a subgroup with early dcSSc. These positive data remain preliminary and need to be viewed with caution, recognizing the spontaneous regression of skin thickening that may occur during early disease. In this review, we summarize the clinical evidence for the therapeutic use of rituximab in SSc as well as the basic science evidence suggesting that B cells and autoantibodies are the primary drivers of fibrosis in skin and lung tissue. We have also reviewed the parallels between SSc and the other CTDs where B-cell depletion therapy is efficacious.

  1. 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

  2. Severe multi-resistant pemphigus vulgaris: prolonged remission with a single cycle of rituximab.

    PubMed

    Corral, Isabela Soubhia; Freitas, Thais Helena Proença de; Aquino, Renata Telles Rudge de; Koller, Daniella Abbruzzini S; Magliari, Maria Elisa Ruffolo; Muller, Helena

    2013-01-01

    Pemphigus vulgaris is an autoimmune bullous disease whose therapy is based on systemic corticosteroids, with or without immunosuppressants. Rituximab is a chimeric monoclonal antibody of the IgG class, directed at a specific CD20 B cell surface antigen, used in pemphigus vulgaris empirically since 2002, with success in 90% of the cases and long periods of remission. Male patient, 33 years old, diagnosed with pemphigus vulgaris, confirmed by histopathology and direct immunofluorescence. He was treated for seven months with numerous treatments, including immunosuppressive drugs, with an unsatisfactory response, until he had complete remission with the use of rituximab. During a 34-month follow-up period, the patient presented a slight clinical relapse, which was successfully controlled with prednisone in a daily dose of 120 mg, soon reduced to 20mg.

  3. Rituximab resistant evans syndrome and autoimmunity in Schimke immuno-osseous dysplasia

    PubMed Central

    2011-01-01

    Autoimmunity is often observed among individuals with primary immune deficiencies; however, the frequency and role of autoimmunity in Schimke immuno-osseous dysplasia (SIOD) has not been fully assessed. SIOD, which is caused by mutations of SMARCAL1, is a rare autosomal recessive disease with its prominent features being skeletal dysplasia, T cell deficiency, and renal failure. We present a child with severe SIOD who developed rituximab resistant Evans syndrome (ES). Consistent with observations in several other immunodeficiency disorders, a review of SIOD patients showed that approximately a fifth of SIOD patients have some features of autoimmune disease. To our best knowledge this case represents the first patient with SIOD and rituximab resistant ES and the first study of autoimmune disease in SIOD. PMID:21914180

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

    PubMed

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

    2015-09-01

    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.

  5. Is rituximab effective for induction of remission in ANCA-associated vasculitis?

    PubMed

    Rain, Carmen; Yáñez, Tatiana; Rada, Gabriel

    2015-08-13

    Adding rituximab to the treatment with corticosteroids has been proposed as a therapeutic alternative for inducing remission in anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, especially when fertility is a concern, or when there is contraindication or intolerance to cyclophosphamide. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified only one systematic review including three pertinent randomized controlled trials. We combined the evidence using meta-analysis and generated a summary of findings following the GRADE approach. We concluded rituximab may slightly increase induction of remission rate, but it may also increase the risk of infection. It is not clear whether it increases the risk of cancer, or whether increases or decreases mortality because the certainty of the evidence is very low.

  6. Long-term experience with rituximab in anti-synthetase syndrome-related interstitial lung disease.

    PubMed

    Andersson, Helena; Sem, Marthe; Lund, May Brit; Aaløkken, Trond Mogens; Günther, Anne; Walle-Hansen, Ragnhild; Garen, Torhild; Molberg, Øyvind

    2015-08-01

    To retrospectively evaluate the efficacy and safety of rituximab (Rtx) treatment in patients with anti-synthetase syndrome (ASS) and severe interstitial lung disease (ILD). Patients with severe ILD and >12 months follow-up post-Rtx were identified from the Oslo University Hospital ASS cohort (n = 112). Clinical data, including pulmonary function tests (PFTs), were retrospectively collected from medical reports. Extent of ILD pre-, and post-Rtx was scored on thin-section high-resolution CT (HRCT) images and expressed as a percentage of total lung volume. Muscle strength was evaluated by manual muscle testing of eight muscle groups (MMT8). Altogether, 34/112 ASS patients had received Rtx; 24/34 had severe ILD and >12 months follow-up post-Rtx (median 52 months). In these 24 patients, the median percentage of predicted forced vital capacity, forced expiratory volume in 1 s (FEV1) and diffusing capacity of the lungs for carbon monoxide (DLCO) increased by 24%, 22% and 17%, respectively, post-Rtx. Seven patients (all with disease duration <12 months and/or acute onset/exacerbation of ILD) had >30% improvement in all three PFTs. HRCT analysis showed a median 34% reduction in ILD extent post-Rtx. MMT8 score increased post-Rtx. During follow-up, 7/34 (21%) Rtx-treated ASS patients died; 6/7 deaths were related to infections. The mortality rate in the Rtx-treated group was comparable to that of the remaining ASS cohort (25/78 deceased; 32%). This study, which included 24 Rtx-treated ASS patients with severe ILD, reports improved PFTs after a median 52 months follow-up post-Rtx. The best outcome was observed in patients with a disease duration <12 months and/or acute onset/exacerbation of ILD. The study indicates that Rtx could be a treatment option for selected ASS patients, but infections should be given attention. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email

  7. Absence of Intragraft B Cells in Rejection Biopsies After Rituximab Induction Therapy: Consequences for Clinical Outcome

    PubMed Central

    van den Hoogen, Martijn W.F.; Steenbergen, Eric J.; Baas, Marije C.; Florquin, Sandrine; Hilbrands, Luuk B.

    2017-01-01

    Background The pathophysiological role of intragraft B cells during renal allograft rejection is unclear. Methods We studied B-cell infiltration during acute rejection in 53 patients who participated in a clinical trial in which adult renal transplant patients were randomized between a single intraoperative dose of rituximab (375 mg/m2) or placebo as induction therapy. Two independent pathologists scored all biopsies in a blinded fashion according to the Banff classification and scored for the presence of B cells and plasma cells using CD79a and CD138 as markers. Results The majority of acute rejections were T cell–mediated. The proportion of acute rejections with an antibody-mediated component tended to be lower in rituximab-treated patients (4/23, 17.4%) than in placebo-treated patients (11/30, 36.7%; P = 0.14). Biopsies of rituximab-treated patients had significantly lower scores for B cells (0.00; range, 0.00-0.50 vs 1.70; range, 0.60-3.30; P < 0.0001) and plasma cells (0.10; range, 0.00-1.90 vs 0.40; range, 0.00-7.50; P = 0.006). During acute rejection, intragraft clusters of B cells were not observed after rituximab induction therapy. However, the depletion of intragraft B cells during acute rejection did not affect steroid resistance, proteinuria, graft function at 2 years follow-up, or patient and graft survival at a median follow-up of 4.1 years (range, 2.0-6.2 years). Conclusions These data do not support a harmful influence of intragraft B cells present during acute allograft rejection on the clinical course within the first few years after renal transplantation. PMID:28405599

  8. Predictors of disease relapse in IgG4-related disease following rituximab

    PubMed Central

    Wallace, Zachary S.; Mattoo, Hamid; Mahajan, Vinay S.; Kulikova, Maria; Lu, Leo; Deshpande, Vikram; Choi, Hyon K.; Pillai, Shiv

    2016-01-01

    Objective. IgG4-related disease (IgG4-RD) is a relapsing–remitting condition responsible for fibroinflammatory lesions that can lead to organ damage and life-threatening complications at nearly any anatomical site. The duration of remission following treatment varies and predictors of relapse are unclear. The objectives of this study were to review our experience with rituximab as remission induction in IgG4-RD, to clarify the duration of efficacy and to identify predictors of flare following treatment. Methods. In this retrospective cohort study, all patients were treated with two doses of rituximab (1 g) separated by 15 days. Clinical, radiographic and laboratory data pertaining to rituximab response and disease relapse were collected from the electronic medical record. Kaplan–Meier curves were constructed to estimate the time to disease relapse. Log-rank analyses were performed to compare times to relapse among subgroups. Potential relapse predictors were evaluated with Cox regression analysis. Results. Fifty-seven of 60 patients (95%) had clinical responses to rituximab. Forty-one patients (68%) were treated without glucocorticoids. Twenty-one patients (37%) experienced relapses following treatment at a median time from the first infusion of 244 days. Baseline concentrations of serum IgG4, IgE and circulating eosinophils predicted subsequent relapses, with hazard ratios of 6.2 (95% CI: 1.2, 32.0), 8.2 (95% CI: 1.4, 50.0) and 7.9 (95% CI: 1.8, 34.7), respectively. The higher the baseline values, the greater the risk of relapse and the shorter the time to relapse. Only 10% of the patients had elevations of all three major risk factors, underscoring the importance of measuring all three at baseline. Conclusion. Baseline elevations in serum IgG4, IgE and blood eosinophil concentrations all predict IgG4-RD relapses independently. PMID:26888853

  9. Predictors of Clinical Improvement in Rituximab-Treated Refractory Adult and Juvenile Dermatomyositis and Adult Polymyositis

    PubMed Central

    Aggarwal, Rohit; Bandos, Andriy; Reed, Ann M.; Ascherman, Dana P.; Barohn, Richard J.; Feldman, Brian M.; Miller, Frederick W.; Rider, Lisa G.; Harris-Love, Michael O.; Levesque, Marc C.; Oddis, Chester V.

    2014-01-01

    Objective The aim was to identify the clinical and laboratory predictors of clinical improvement in a cohort of myositis patients treated with rituximab. Methods We analyzed data for 195 myositis patients [75 adult polymyositis/72 adult dermatomyositis/48 juvenile dermatomyositis (JDM)] in the Rituximab in Myositis trial. Clinical improvement was defined as 20% improvement in at least 3 of 6 core set measures (CSM) of disease activity: physician and patient/parent global disease activity, manual muscle testing, physical function, muscle enzymes, and extramuscular disease activity. We analyzed the association of the following baseline variables with improvement: myositis clinical subgroup, demographics, myositis damage, clinical and laboratory parameters, CSM, rituximab treatment, and myositis autoantibodies (anti-synthetase, -Mi-2, -SRP, -TIF1-γ, -MJ, other and no autoantibodies). All measures were univariately assessed for association with improvement using time-to-event analyses. A multivariable time-dependent proportional hazards model was used to evaluate the association of individual predictive factors with improvement. Results In the final multivariable model, the presence of an anti-synthetase [primarily anti-Jo-1 (HR 3.08, p<0.01)], anti-Mi-2 (HR 2.5, p<0.01), or other autoantibody (HR 1.4, p=0.14) predicted a shorter time to improvement compared to the autoantibody negative subset. Lower physician global damage (HR 2.32, p< 0.01) and JDM (vs. adult myositis, HR 2.45, p<0.01) also predicted improvement. Unlike the autoantibody subset, the predictive effect of physician global damage and JDM diminished by week 20. Rituximab treatment did not affect these associations. Conclusion The presence of an anti-synthetase and anti-Mi-2 autoantibodies, JDM subset and lower disease damage strongly predicted clinical improvement in refractory myositis patients. PMID:24574235

  10. Medical resource utilization in dermatomyositis/polymyositis patients treated with repository corticotropin injection, intravenous immunoglobulin, and/or rituximab

    PubMed Central

    Knight, Tyler; Bond, T Christopher; Popelar, Breanna; Wang, Li; Niewoehner, John W; Anastassopoulos, Kathryn; Philbin, Michael

    2017-01-01

    Background Dermatomyositis and polymyositis (DM/PM) are rare, incurable inflammatory diseases that cause progressive muscle weakness and can be associated with increased medical resource use (MRU). When corticosteroid treatment is unsuccessful, patients may receive intravenous immunoglobulin (IVIg), rituximab, or repository corticotropin injection (RCI). This study compared real-world, non-medication MRU between patients treated with RCI and those treated with IVIg and/or rituximab for DM/PM. Methods Claims of DM/PM patients were analyzed from the combination of three commercial health insurance databases in the United States from July 2009 to June 2014. Patients treated with RCI were propensity score matched to those treated with IVIg, rituximab, and both (IVIg+rituximab) based on demographics, prior clinical characteristics, and prior MRU. Per-patient per-month (PPPM) MRU and costs were compared using Poisson regression and generalized linear modeling, respectively. Results One-hundred thirty-two RCI, 1,150 IVIg, and 562 rituximab patients had an average age of 52.6, 46.6, and 51.7 years, respectively, and roughly two-thirds were female. After matching, there were no significant differences in demographics or prior clinical characteristics. RCI patients had fewer PPPM hospitalizations (0.09 vs 0.17; P=0.049), shorter length of stay (LOS; 3.24 days vs 4.55 days; P=0.004), PPPM hospital outpatient department (HOPD) visits (0.60 vs 1.39; P<0.001), and PPPM physician office visits (2.01 vs 2.33; P=0.035) than IVIg. RCI had fewer PPPM HOPD visits (0.56 vs 0.92; P<0.001) than rituximab. Patients treated with RCI had shorter LOS (2.18 days vs 5.15; P<0.001) and less PPPM HOPD visits (0.53 vs 1.26; P<0.001) than IVIg+rituximab. Total non-medication PPPM costs were 23%–75% lower for RCI compared to IVIg ($2,126 vs $3,964; P<0.001), rituximab ($2,008 vs $2,607; P=0.018), and IVIg+rituximab ($1,234 vs $4,858; P<0.001). Conclusion Patients treated with RCI had less PPPM

  11. Medical resource utilization in dermatomyositis/polymyositis patients treated with repository corticotropin injection, intravenous immunoglobulin, and/or rituximab.

    PubMed

    Knight, Tyler; Bond, T Christopher; Popelar, Breanna; Wang, Li; Niewoehner, John W; Anastassopoulos, Kathryn; Philbin, Michael

    2017-01-01

    Dermatomyositis and polymyositis (DM/PM) are rare, incurable inflammatory diseases that cause progressive muscle weakness and can be associated with increased medical resource use (MRU). When corticosteroid treatment is unsuccessful, patients may receive intravenous immunoglobulin (IVIg), rituximab, or repository corticotropin injection (RCI). This study compared real-world, non-medication MRU between patients treated with RCI and those treated with IVIg and/or rituximab for DM/PM. Claims of DM/PM patients were analyzed from the combination of three commercial health insurance databases in the United States from July 2009 to June 2014. Patients treated with RCI were propensity score matched to those treated with IVIg, rituximab, and both (IVIg+rituximab) based on demographics, prior clinical characteristics, and prior MRU. Per-patient per-month (PPPM) MRU and costs were compared using Poisson regression and generalized linear modeling, respectively. One-hundred thirty-two RCI, 1,150 IVIg, and 562 rituximab patients had an average age of 52.6, 46.6, and 51.7 years, respectively, and roughly two-thirds were female. After matching, there were no significant differences in demographics or prior clinical characteristics. RCI patients had fewer PPPM hospitalizations (0.09 vs 0.17; P=0.049), shorter length of stay (LOS; 3.24 days vs 4.55 days; P=0.004), PPPM hospital outpatient department (HOPD) visits (0.60 vs 1.39; P<0.001), and PPPM physician office visits (2.01 vs 2.33; P=0.035) than IVIg. RCI had fewer PPPM HOPD visits (0.56 vs 0.92; P<0.001) than rituximab. Patients treated with RCI had shorter LOS (2.18 days vs 5.15; P<0.001) and less PPPM HOPD visits (0.53 vs 1.26; P<0.001) than IVIg+rituximab. Total non-medication PPPM costs were 23%-75% lower for RCI compared to IVIg ($2,126 vs $3,964; P<0.001), rituximab ($2,008 vs $2,607; P=0.018), and IVIg+rituximab ($1,234 vs $4,858; P<0.001). Patients treated with RCI had less PPPM non-medication MRU and costs than those

  12. 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

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

    PubMed

    Fathallah, Anas M; Turner, Michael R; Mager, Donald E; Balu-Iyer, Sathy V

    2015-03-01

    The subcutaneous administration of biologics is highly desirable; however, incomplete bioavailability after s.c. administration remains a major challenge. In this work we investigated the effects of excipient dependent hyperosmolarity on lymphatic uptake and plasma exposure of rituximab as a model protein. Using Swiss Webster (SW) mice as the animal model, we compared the effects of NaCl, mannitol and O-phospho-L-serine (OPLS) on the plasma concentration of rituximab over 5 days after s.c. administration. An increase was observed in plasma concentrations in animals administered rituximab in hypertonic buffer solutions, compared with 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 the improved lymphatic trafficking as evident from the increase in the fraction of dose trafficked through the lymph nodes in the presence of hypertonic buffers. The fraction of the dose trafficked through the lymphatics, as estimated by the model, increased from 0.05% in isotonic buffer to 13% in hypertonic buffer containing NaCl to about 30% for hypertonic buffers containing high dose OPLS and mannitol. The data suggest that hypertonic solutions may be a viable option for improving s.c. bioavailability. Copyright © 2014 John Wiley & Sons, Ltd.

  14. IL2/IL21 region polymorphism influences response to rituximab in systemic lupus erythematosus patients.

    PubMed

    Márquez, Ana; Dávila-Fajardo, Cristina Lucía; Robledo, Gema; Rubio, José Luis Callejas; de Ramón Garrido, Enrique; García-Hernández, Francisco J; González-León, Rocío; Ríos-Fernández, Raquel; Barrera, José Cabeza; González-Escribano, Ma Francisca; García, Ma Teresa Camps; Palma, Ma Jesús Castillo; del Mar Ayala, Ma; Ortego-Centeno, Norberto; Martín, Javier

    2013-08-01

    To determine whether the IL2/IL21 region, a general autoimmunity locus, contributes to the observed variation in response to rituximab in patients with systemic lupus erythematosus as well as to analyze its influence in a cohort including other autoimmune diseases. rs6822844 G/T polymorphism at the IL2-IL21 region was analyzed by TaqMan assay in 84 systemic lupus erythematosus (SLE) and 60 different systemic autoimmune diseases Spanish patients receiving rituximab. Six months after the first infusion patients were classified, according to the EULAR criteria, as good responders, partial responders and non-responders. A statistically significant difference was observed in GG genotype frequency between responder (total and partial response) (83.56%) and non-responder (45.45%) SLE patients (p=0.010, odds ratio (OR)=6.10 [1.28-29.06]). No association with the response was evident in the group of patients with autoimmune diseases other than lupus. Furthermore, when both groups of patients were pooled in a meta-analysis, a reduced statistical significance of the association was observed (p=0.024, OR=3.53 [1.06-11.64]). Our results show for a first time that IL2-IL21 region seems to play a role in the response to rituximab in SLE patients but not in other autoimmune diseases.

  15. 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.

  16. 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

  17. Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura.

    PubMed

    Bennett, Carolyn M; Rogers, Zora R; Kinnamon, Daniel D; Bussel, James B; Mahoney, Donald H; Abshire, Thomas C; Sawaf, Hadi; Moore, Theodore B; Loh, Mignon L; Glader, Bertil E; McCarthy, Maggie C; Mueller, Brigitta U; Olson, Thomas A; Lorenzana, Adonis N; Mentzer, William C; Buchanan, George R; Feldman, Henry A; Neufeld, Ellis J

    2006-04-01

    We assessed safety and efficacy of rituximab in a prospective study of 36 patients, age 2.6 to 18.3 years, with severe chronic immune thrombocytopenic purpura (ITP). The primary outcome of sustained platelets above 50 x 10(9)/L (50,000/mm3) during 4 consecutive weeks, starting in weeks 9 to 12, was achieved by 11 of 36 patients (31%, confidence interval [CI], 16% to 48%). Median response time was 1 week (range, 1 to 7 weeks). Attainment of the primary outcome was not associated with age, prior pharmacologic responses, prior splenectomy, ITP duration, screening platelet count, refractoriness, or IgM reduction. First-dose, infusion-related toxicity was common (47%) despite premedication. Significant drug-related toxicities included third-dose hypotension (n = 1) and serum sickness (n = 2). Peripheral B cells were depleted in all subjects. IgM decreased 3.4% per week, but IgG did not significantly decrease. Rituximab was well tolerated, with manageable infusion-related side effects, but 6% of subjects developed serum sickness. Rituximab is beneficial for some pediatric patients with severe, chronic ITP.

  18. Prospective phase 1/2 study of rituximab in childhood and adolescent chronic immune thrombocytopenic purpura

    PubMed Central

    Bennett, Carolyn M.; Rogers, Zora R.; Kinnamon, Daniel D.; Bussel, James B.; Mahoney, Donald H.; Abshire, Thomas C.; Sawaf, Hadi; Moore, Theodore B.; Loh, Mignon L.; Glader, Bertil E.; McCarthy, Maggie C.; Mueller, Brigitta U.; Olson, Thomas A.; Lorenzana, Adonis N.; Mentzer, William C.; Buchanan, George R.; Feldman, Henry A.; Neufeld, Ellis J.

    2006-01-01

    We assessed safety and efficacy of rituximab in a prospective study of 36 patients, age 2.6 to 18.3 years, with severe chronic immune thrombocytopenic purpura (ITP). The primary outcome of sustained platelets above 50 × 109/L (50 000/mm3) during 4 consecutive weeks, starting in weeks 9 to 12, was achieved by 11 of 36 patients (31%, confidence interval [CI], 16% to 48%). Median response time was 1 week (range, 1 to 7 weeks). Attainment of the primary outcome was not associated with age, prior pharmacologic responses, prior splenectomy, ITP duration, screening platelet count, refractoriness, or IgM reduction. First-dose, infusion-related toxicity was common (47%) despite premedication. Significant drug-related toxicities included third-dose hypotension (n = 1) and serum sickness (n = 2). Peripheral B cells were depleted in all subjects. IgM decreased 3.4% per week, but IgG did not significantly decrease. Rituximab was well tolerated, with manageable infusion-related side effects, but 6% of subjects developed serum sickness. Rituximab is beneficial for some pediatric patients with severe, chronic ITP. PMID:16352811

  19. Rituximab induces sustained reduction of pathogenic B cells in patients with peripheral nervous system autoimmunity

    PubMed Central

    Maurer, Michael A.; Rakocevic, Goran; Leung, Carol S.; Quast, Isaak; Lukačišin, Martin; Goebels, Norbert; Münz, Christian; Wardemann, Hedda; Dalakas, Marinos; Lünemann, Jan D.

    2012-01-01

    The B cell–depleting IgG1 monoclonal antibody rituximab can persistently suppress disease progression in some patients with autoimmune diseases. However, the mechanism underlying these long-term beneficial effects has remained unclear. Here, we evaluated Ig gene usage in patients with anti–myelin-associated glycoprotein (anti-MAG) neuropathy, an autoimmune disease of the peripheral nervous system that is mediated by IgM autoantibodies binding to MAG antigen. Patients with anti-MAG neuropathy showed substantial clonal expansions of blood IgM memory B cells that recognized MAG antigen. The group of patients showing no clinical improvement after rituximab therapy were distinguished from clinical responders by a higher load of clonal IgM memory B cell expansions before and after therapy, by persistence of clonal expansions despite efficient peripheral B cell depletion, and by a lack of substantial changes in somatic hypermutation frequencies of IgM memory B cells. We infer from these data that the effectiveness of rituximab therapy depends on efficient depletion of noncirculating B cells and is associated with qualitative immunological changes that indicate reconfiguration of B cell memory through sustained reduction of autoreactive clonal expansions. These findings support the continued development of B cell–depleting therapies for autoimmune diseases. PMID:22426210

  20. Evaluation of AKT phosphorylation and PTEN loss and their correlation with the resistance of rituximab in DLBCL.

    PubMed

    Ma, Yihui; Zhang, Pengyu; Gao, Yi; Fan, Huijie; Zhang, Mingzhi; Wu, Jingjing

    2015-01-01

    Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of lymphoma with quite high mortality. PTEN/PI3K/AKT signal pathway is constitutively activated and plays an oncogenic role in most tumors including non-Hodgkin's lymphoma (NHL). Since rituximab used in chemotherapy has been proved to improve the survival of DLBCL patients, rituximab resistance is a common clinical challenge in the treatment of DLBCL. The aims of the present study are to determine the different levels of several important biomarkers of PTEN/PI3K/AKT pathway in DLBCL patients who are resistant or sensitive to rituximab treatment, and investigate the potential clinical application of these biomarkers. 48 patients with DLBCL who were treated by rituximab-based chemotherapy were divided into 2 groups according to their reactions to rituximab. The expression of p-AKT, PTEN, and Ki-67 protein in 48 DLBCL tissues were detected using immunohistochemistry and analyzed for the clinical pathological significance and the resistance to rituximab. Meanwhile, PTEN gene deletion was detected also by FISH, and mutation of PIK3CA was performed by sequencing analysis. Activation of p-AKT in 12 of 48 (25.0%) and loss expression of PTEN in 15 of 48 (31.3%) DLBCL species were observed. P-AKT activation (P<0.05) and loss of PTEN expression (P<0.05) were significantly associative with high Ki-67 index. P-AKT and PTEN expression showed a significant negative correlation in all 48 DLBCL patients (r=-0.450, P<0.05), and the Spearman correlation coefficient in the resistant group (r=-0.769, P<0.05) was greater than in the sensitive group (r=-0.691, P<0.05). Regulation of PTEN/PI3K/AKT signal pathway participates in the progression of DLBCL, and may be involved in the development of the resistance to rituximab for some DLBCL patients.

  1. Rituximab serum concentrations during immuno-chemotherapy of follicular lymphoma correlate with patient gender, bone marrow infiltration and clinical response

    PubMed Central

    Jäger, Ulrich; Fridrik, Michael; Zeitlinger, Markus; Heintel, Daniel; Hopfinger, Georg; Burgstaller, Sonja; Mannhalter, Christine; Oberaigner, Wilhelm; Porpaczy, Edit; Skrabs, Cathrin; Einberger, Christine; Drach, Johannes; Raderer, Markus; Gaiger, Alexander; Putman, Monique; Greil, Richard

    2012-01-01

    Background Treatment of follicular lymphoma with rituximab is currently recommended at a dose of 375 mg/m2. We aimed to provide a rationale for optimal dosing and scheduling of this anti-CD20 antibody based on pharmacokinetics. Design and Methods Clinical efficacy of immunochemotherapy with rituximab, fludarabine and mitoxantrone followed by 2-monthly rituximab maintenance was evaluated in 29 patients with previously untreated follicular lymphoma in a prospective phase II trial (AGMT-NHL9). Pharmacokinetic analysis was assessed in 17 patients. Results Induction treatment resulted in high clinical response rates (complete remission 66%; ORR 100%). Significantly higher complete remission rates were observed in female patients (86 vs. 47%; Odds Ratio 6.8, 95% CI: 1.12; 41.82; P=0.05). Rituximab pharmacokinetic analysis showed a high variability ranging over almost 1 order of magnitude at maintenance cycle 1 (area under the curve 1,540–12,025 g/L*days). Median area under the curve was lower in men (81%) and in patients with initial bone marrow infiltration (76%). Higher rituximab serum concentrations before next therapy (Ctrough) were associated with female sex (P=0.04) as well as with absence of initial bone marrow infiltration (P=0.001). Ctrough correlated with remission quality (complete vs. partial remission; P=0.005) and progression-free survival (P=0.03). A decline in rituximab Ctrough below 25,000 ng/mL was observed 9.5 to 62 months before clinical relapse (P=0.008). Conclusions The results of this pilot trial suggest that more differentiated dosing schedules based on gender and bone marrow infiltration should be explored for rituximab therapy for lymphoma. This study was registered in ClinicalTrials.gov (Identifier: NCT01560117). PMID:22511498

  2. Rituximab in Children with Steroid-Dependent Nephrotic Syndrome: A Multicenter, Open-Label, Noninferiority, Randomized Controlled Trial

    PubMed Central

    Rossi, Roberta; Bonanni, Alice; Quinn, Robert R.; Sica, Felice; Bodria, Monica; Pasini, Andrea; Montini, Giovanni; Edefonti, Alberto; Belingheri, Mirco; De Giovanni, Donatella; Barbano, Giancarlo; Degl’Innocenti, Ludovica; Scolari, Francesco; Murer, Luisa; Reiser, Jochen; Fornoni, Alessia; Ghiggeri, Gian Marco

    2015-01-01

    Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, noninferiority, randomized controlled trial at four sites in Italy tested whether rituximab is noninferior to steroids in maintaining remission in juvenile SDNS. We enrolled children age 1–16 years who had developed SDNS in the previous 6–12 months and were maintained in remission with high prednisone doses (≥0.7 mg/kg per day). We randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m2; intervention). Prednisone was tapered in both groups after 1 month. For noninferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m2 per day) within a prespecified noninferiority margin of three times the levels among controls (primary outcome). We followed participants for ≥1 year to compare risk of relapse (secondary outcome). Fifteen children per group (21 boys; mean age, 7 years [range, 2.6–13.5 years]) were enrolled and followed for ≤60 months (median, 22 months). Three-month proteinuria was 42% lower in the rituximab group (geometric mean ratio, 0.58; 95% confidence interval, 0.18 to 1.95 [i.e., within the noninferiority margin of three times the levels in controls]). All but one child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95% confidence interval, 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. In conclusion, rituximab was noninferior to steroids for the treatment of juvenile SDNS. PMID:25592855

  3. Rituximab in Children with Steroid-Dependent Nephrotic Syndrome: A Multicenter, Open-Label, Noninferiority, Randomized Controlled Trial.

    PubMed

    Ravani, Pietro; Rossi, Roberta; Bonanni, Alice; Quinn, Robert R; Sica, Felice; Bodria, Monica; Pasini, Andrea; Montini, Giovanni; Edefonti, Alberto; Belingheri, Mirco; De Giovanni, Donatella; Barbano, Giancarlo; Degl'Innocenti, Ludovica; Scolari, Francesco; Murer, Luisa; Reiser, Jochen; Fornoni, Alessia; Ghiggeri, Gian Marco

    2015-09-01

    Steroid-dependent nephrotic syndrome (SDNS) carries a high risk of toxicity from steroids or steroid-sparing agents. This open-label, noninferiority, randomized controlled trial at four sites in Italy tested whether rituximab is noninferior to steroids in maintaining remission in juvenile SDNS. We enrolled children age 1-16 years who had developed SDNS in the previous 6-12 months and were maintained in remission with high prednisone doses (≥0.7 mg/kg per day). We randomly assigned participants to continue prednisone alone for 1 month (control) or to add a single intravenous infusion of rituximab (375 mg/m(2); intervention). Prednisone was tapered in both groups after 1 month. For noninferiority, rituximab had to permit steroid withdrawal and maintain 3-month proteinuria (mg/m(2) per day) within a prespecified noninferiority margin of three times the levels among controls (primary outcome). We followed participants for ≥1 year to compare risk of relapse (secondary outcome). Fifteen children per group (21 boys; mean age, 7 years [range, 2.6-13.5 years]) were enrolled and followed for ≤60 months (median, 22 months). Three-month proteinuria was 42% lower in the rituximab group (geometric mean ratio, 0.58; 95% confidence interval, 0.18 to 1.95 [i.e., within the noninferiority margin of three times the levels in controls]). All but one child in the control group relapsed within 6 months; median time to relapse in the rituximab group was 18 months (95% confidence interval, 9 to 32 months). In the rituximab group, nausea and skin rash during infusion were common; transient acute arthritis occurred in one child. In conclusion, rituximab was noninferior to steroids for the treatment of juvenile SDNS.

  4. Initial evaluation of (227)Th-p-benzyl-DOTA-rituximab for low-dose rate alpha-particle radioimmunotherapy.

    PubMed

    Dahle, Jostein; Borrebaek, Jørgen; Melhus, Katrine B; Bruland, Oyvind S; Salberg, Gro; Olsen, Dag Rune; Larsen, Roy H

    2006-02-01

    Radioimmunotherapy has proven clinically effective in patients with non-Hodgkin's lymphoma. Radioimmunotherapy trials have so far been performed with beta-emitting isotopes. In contrast to beta-emitters, the shorter range and high linear energy transfer (LET) of alpha particles allow for more efficient and selective killing of individually targeted tumor cells. However, there are several obstacles to the use of alpha-particle immunotherapy, including problems with chelation chemistry and nontarget tissue toxicity. The alpha-emitting radioimmunoconjugate (227)Th-DOTA-p-benzyl-rituximab is a new potential anti-lymphoma agent that might overcome some of these difficulties. The present study explores the immunoreactivity, in vivo stability and biodistribution, as well as the effect on in vitro cell growth, of this novel radioimmunoconjugate. To evaluate in vivo stability, uptake in balb/c mice of the alpha-particle-emitting nuclide (227)Th alone, the chelated form, (227)Th-p-nitrobenzyl-DOTA and the radioimmunoconjugate (227)Th-DOTA-p-benzyl-rituximab was compared in a range of organs at increasing time points after injection. The immunoreactive fraction of (227)Th-DOTA-p-benzyl-rituximab was 56-65%. During the 28 days after injection of radioimmunoconjugate only, very modest amounts of the (227)Th had detached from DOTA-p-benzyl-rituximab, indicating a relevant stability in vivo. The half-life of (227)Th-DOTA-p-benzyl-rituximab in blood was 7.4 days. Incubation of lymphoma cells with (227)Th-DOTA-p-benzyl-rituximab resulted in a significant antigen-dependent inhibition of cell growth. The data presented here warrant further studies of (227)Th-DOTA-p-benzyl-rituximab.

  5. Rituximab response in follicular lymphoma is associated with the rs20575 polymorphism in TRAILR1 extrinsic apoptosis trigger.

    PubMed

    Gutiérrez-Cívicos, Rocío; Hurtado, Ana M; Torres-Moreno, Daniel; Sanchez-Blanco, José J; Español, Ignacio; Consuegra-Sánchez, Luciano; Perez-Ceballos, Elena; Gutiérrez-Meca, María D; Jerez, Andrés; Conesa-Zamora, Pablo

    2017-02-01

    Rituximab in combination with chemotherapy has been proven to increase progression-free and overall survival in follicular lymphoma (FL), but there is considerable interindividual variability in the response. Extrinsic pathway apoptosis triggered by death receptors seems to be involved in the mechanism of action of monoclonal antibodies. This study aimed to assess the association between TRAILR1/TRAIL polymorphisms (rs20575, rs20576, rs2230229, rs12488654) and rituximab response and the relationship with FASL rs763110, previously found to be associated with rituximab response. Polymorphisms were determined in a study cohort of 125 FL patients treated with rituximab as first-line treatment and correlated with response, which was scored according to the International Working Group Consensus Revised as complete response, partial response, stable disease, and progressive disease. No significant association with response was found for rs20576, rs2230229, and rs12488654 polymorphisms. In contrast, rs20575 GC/GG carriers were more partial/nonresponders (88.2%) than complete responders (72.5%), showing a trend toward statistical significance (P=0.064). In a multivariable setting, we found that female sex [odds ratio=0.355, 95% confidence interval (CI): 0.137-0.922, P=0.033] and the TRAILR1 rs20575 CC genotype (odds ratio=0.162, 95% CI: 0.035-0.757, P=0.021) were independent positive predictive factors of complete clinical response to rituximab, constructing a parsimonious model with good calibration [χ of 5.719 (d.f.=6, P=0.455)] and discrimination (C-statistic=0.739, 95% CI: 0.636-0.842). After studying the pharmacogenetic role of TRAILR1/TRAIL polymorphisms in rituximab-treated FL patients, we found that the rs20575 CC genotype is an independent predictive factor of better rituximab response, indicating the possible involvement of death receptors in anti-CD20 mechanisms of action.

  6. 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

  7. 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.

  8. Rituximab in Steroid-Dependent or Frequently Relapsing Idiopathic Nephrotic Syndrome

    PubMed Central

    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

    2014-01-01

    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/m2 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 m2 (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

  9. An experience with the Patient-Reported Outcomes Measurement Information System: pros and cons and unanswered questions.

    PubMed

    Badger, Terry A; Heitkemper, Margaret; Lee, Kathryn A; Bruner, Deborah Watkins

    2014-01-01

    The goal of the Patient-Reported Outcomes Measurement Information System (PROMIS) is to create efficient, reliable, and valid assessments of adult and child health. The nursing science literature in which PROMIS measures are used is rapidly expanding. Investigators have been encouraged to consider the integration of PROMIS measures into both descriptive studies and clinical trials. Doing this has created opportunities and challenges for investigators. This article highlights three projects to show the perspectives of nurse scientists who incorporated PROMIS measures into their research. The first project describes advantages of PROMIS to allow for comparisons of a study population with a national sample and to compliment legacy measures. The second project examines issues in the translation of tools for region-specific Hispanic populations. The third project provides a perspective on the use of PROMIS measures to capture cancer-related fatigue and to develop new components of a sexual function scale. As indicated by these three examples, nurse scientists can contribute an important role in moving the PROMIS initiative forward. Results from these types of projects also move symptom science forward within a more interdisciplinary approach to common measures of interest.

  10. CD99 expression and newly diagnosed diffuse large B-cell lymphoma treated with rituximab-CHOP immunochemotherapy.

    PubMed

    Hong, Junshik; Park, Sanghui; Park, Jinny; Jang, Seung Jun; Ahn, Hee Kyung; Sym, Sun Jin; Cho, Eun Kyung; Shin, Dong Bok; Lee, Jae Hoon

    2012-12-01

    In order to evaluate prognostic value of CD99 expression in patients with diffuse large B-cell lymphoma (DLBCL) who underwent treatment with rituximab-CHOP immunochemotherapy, immunohistochemistry for CD99/CD10/BCL-2/BCL-6/MUM-1 was performed on nodal DLBCL specimens from 70 patients. Patients were classified as either germinal center B-cell (GCB) subtype or non-GCB subtype according to the Muris algorithm. A superior 2-year event-free survival (EFS) was observed in patients with the GCB subgroup, compared to those with the non-GCB subgroup (p = 0.034). The distribution of CD99 expression (29 patients; 41.4 %) did not show deviation according to subtype and was not prognostic for survival in the entire patient population. Among patients with the GCB subgroup, better EFS and overall survival (OS) were observed in CD99+ patients, compared to CD99- patients. Conversely, among patients with the non-GCB subgroup, inferior EFS and OS were reported in CD99+ patients. Superior 2-year EFS (p = 0.004) and 2-year OS (p = 0.003) were observed in patients with GCB/CD99+ and non-GCB/CD99- compared to the others, and the combination classification was found to be an independent prognostic factor.

  11. A life-threatening case of TAFRO syndrome with dramatic response to tocilizumab, rituximab, and pulse steroids

    PubMed Central

    José, Fabio Freire; Kerbauy, Lucila Nassif; Perini, Guilherme Fleury; Blumenschein, Danielle Isadora; Pasqualin, Denise da Cunha; Malheiros, Denise Maria Avancini Costa; Campos Neto, Guilherme de Carvalho; de Souza Santos, Fabio Pires; Piovesan, Ronaldo; Hamerschlak, Nelson

    2017-01-01

    Abstract Rationale: This is the report of the first case of TAFRO syndrome (Thrombocytopenia, Anasarca, myelofibrosis, Renal dysfunction, Organomegaly) in Latin America. Patient concerns: The patient was a 61-year-old white woman of Ashkenazi Jewish descent, who presented with a history of 8 days of nausea, vomiting, and fever; severe pitting edema in both legs, ascites, splenomegaly, and palpable axillary lymph nodes. Diagnoses: Abdominal computed tomography (CT) showed bilateral pleural effusion and retroperitoneal lymph node enlargement. Interventions: Anasarca and worsening of renal function led to admission to the intensive care unit (ICU) with multiple organ failure, requiring mechanical ventilation, vasopressor medications, and continuous renal replacement therapy (CRRT). Diagnosis of TAFRO syndrome was made on day 18 after admission, based on clinical findings and results of bone marrow and lymph node biopsies. She was treated with methylprednisolone, tocilizumab, and rituximab. One week after the first tocilizumab dose, she had dramatic improvements in respiratory and hemodynamic status, and was weaned from ventilator support and vasopressor medications. Outcomes: After 2 weeks of therapy, CRRT was switched to intermittent hemodialysis. On day 46, the patient was discharged from the ICU to the general ward, and 3 months after admission, she went home. Lessons: Provided the interleukin-6 measurement is available, this approach is suggested in cases of TAFRO syndrome, in order to customize the treatment. PMID:28353560

  12. 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.

  13. Successful treatment of steroid and cyclophosphamide-resistant diffuse scleroderma-associated interstitial lung disease with rituximab.

    PubMed

    Yoo, Wan-Hee

    2012-03-01

    Scleroderma (SSc) is a multisystem disorder characterized by fibrosis and collagen deposition in the dermis, but affects multiple organ systems, leading to esophageal dysmotility, renal failure, and interstitial lung disease (ILD). ILD is common manifestation of diffuse type of SSc and may be life threatening, and require aggressive therapy with cytotoxic agents. Although high-dose steroid and cyclophosphamide are most commonly used therapy for SSc-associated ILD, the efficacy is questionable in some cases and more effective and less toxic therapies are needed. Rituximab (RTX) is a chimeric mAb against human CD20 that depletes peripheral B cells and introduced for systemic rheumatic diseases. However, there were no enough evidences for SSc-associated ILD. We report herein a case of 47-year-old female with diffuse type of SSc with steroid and cyclophosphamide-resistant ILD that was successfully treated with RTX. Thus, we suggested that RTX could be an efficacious therapeutic modality for severe, conventional treatment-resistant SSc-associated ILD.

  14. Intraorbital injection of rituximab: a new approach for active thyroid-associated orbitopathy, a prospective case series.

    PubMed

    Savino, G; Balia, L; Colucci, D; Battendieri, R; Gari, M; Corsello, S M; Pontecorvi, A; Dickmann, A

    2013-06-01

    The aim of this paper was to examine the efficacy and the safety of intraorbital administration of the monoclonal anti-CD20 antibody rituximab (RTX) to treat patients affected by thyroid-associated orbitopathy (TAO) unresponsive to conventional therapy. Five patients with active moderately-severe TAO unresponsive to systemic glucocorticoids were studied. After a complete ophthalmological examination, disease activity and severity were assessed by the clinical activity score (CAS) and the NO SPECS scoring system. Computed tomography scans were performed in all patients. Patients were treated with intraorbital injection of RTX 10 mg once a week for one month repeated once one month apart. The patients were followed every three months until 18 months. In all patients treated with RTX, CAS was significantly reduced (p< 0,005), inactive phase of TAO was reached in four out of five patients. No patients experienced major side effects, minor side effects were reported in two patients. Intraorbital injection of RTX is a safe and useful promising therapeutic option for active TAO.

  15. Second cancers in patients with chronic lymphocytic leukemia who received frontline fludarabine, cyclophosphamide and rituximab therapy: distribution and clinical outcomes.

    PubMed

    Benjamini, Ohad; Jain, Preetesh; Trinh, Long; Qiao, Wei; Strom, Sara S; Lerner, Susan; Wang, Xuemei; Burger, Jan; Ferrajoli, Alessandra; Kantarjian, Hagop; O'Brien, Susan; Wierda, William; Estrov, Zeev; Keating, Michael

    2015-06-01

    Patients with chronic lymphocytic leukemia (CLL) are known to have an increased incidence of second cancers, but the contribution of commonly used frontline therapies to the incidence of second cancers is unclear. We report on the characteristics, incidence, outcomes and factors associated with second cancers in 234 patients receiving fludarabine, cyclophosphamide and rituximab (FCR) based regimens in the frontline setting. The risk of second cancers was 2.38 times higher than the expected risk in the general population. Ninety-three patients (40%) had other cancers before and 66 patients (28%) after FCR. Rates of therapy related acute myeloid leukemia/myelodysplastic syndrome (t-AML/MDS) (5.1%) and Richter transformation (RT) (9%) were high, while solid tumors were not increased. Overall survival of patients with second cancers after frontline FCR was shorter (median of 4.5 years) compared to patients with and without prior cancers. Second cancer risk after frontline FCR is mainly due to high rates of t-AML/MDS and RT, and as speculated the survival of affected patients is shorter.

  16. Dual institution experience of nodal marginal zone lymphoma reveals excellent long-term outcomes in the rituximab era.

    PubMed

    Starr, Adam G; Caimi, Paolo F; Fu, PingFu; Massoud, Mira R; Meyerson, Howard; Hsi, Eric D; Mansur, David B; Cherian, Sheen; Cooper, Brenda W; De Lima, Marcos J G; Lazarus, Hillard M; Gerson, Stanton L; Jagadeesh, Deepa; Smith, Mitchell R; Dean, Robert M; Pohlman, Brad L; Hill, Brian T; William, Basem M

    2016-10-01

    Nodal marginal zone lymphoma (NMZL) is a rare non-Hodgkin lymphoma that arises from mature B-cells. We delineate outcomes, prognostic factors and treatment trends among a large cohort of patients with NMZL in the rituximab era. We identified 56 such patients treated at our institutions. The majority presented with advanced stage disease (78·6%). Over a median follow-up of 38·2 months, median progression-free survival (PFS) was 42·4 months and median overall survival (OS) was not reached. Kaplan-Meier estimates of OS at 120 months after diagnosis was 71·9%. High-risk follicular lymphoma international prognostic index (FLIPI) was associated with inferior PFS. Age >60 years and elevated serum lactate dehydrogenase (LDH) were associated with inferior OS. Transformation to diffuse large B-cell lymphoma occurred in 7 patients, 6 of who presented with advanced disease. OS was comparable to our previously reported extranodal MZL cohort. FLIPI score predicted for inferior PFS and OS when both cohorts were analysed together (n = 267). In summary, outcomes in NMZL are favourable with a large majority of patients surviving at 120 months. High risk FLIPI, age >60 years, and elevated serum LDH were associated with inferior outcomes.

  17. 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.

  18. 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

  19. Subcutaneous absorption of monoclonal antibodies: role of dose, site of injection, and injection volume on rituximab pharmacokinetics in rats.

    PubMed

    Kagan, Leonid; Turner, Michael R; Balu-Iyer, Sathy V; Mager, Donald E

    2012-02-01

    To determine the effect of dose, the anatomical site of injection, and the injection volume on subcutaneous absorption of rituximab in rats and to explore absorption mechanisms using pharmacokinetic modeling. Rituximab serum concentrations were measured following intravenous and subcutaneous administration at the back, abdomen, and foot of rats. Several pharmacokinetic models were developed that included linear and saturable absorption, and degradation and/or protective binding at the injection site. Rituximab exhibited linear kinetics following intravenous administration; however, bioavailability following subcutaneous injection was inversely related to the dose level. For the 1 mg/kg dose, bioavailability was approximately 70% at all tested injection sites, with faster absorption from the foot (T(max) = 12 h for foot vs. 4.6 days for back). Bioavailability for the 10 mg/kg dose was 44 and 31% for the abdomen and back sites and 18% for 40 mg/kg injected at the back. A pharmacokinetic model that included binding as part of the absorption mechanism successfully captured the nonlinearities in rituximab absorption. The anatomical site of subcutaneous injection influences the rate of absorption and bioavailability of rituximab in rats. Saturable binding may be a major determinant of the nonlinear absorptive transport of monoclonal antibodies.

  20. Long-term maintenance therapy using rituximab-induced continuous B-cell depletion in patients with ANCA vasculitis.

    PubMed

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

    2014-04-01

    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. 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. 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. 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.

  1. 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

  2. The impact of Fc gamma receptor IIa and IIIa gene polymorphisms on the therapeutic response of rituximab in Egyptian adult immune thrombocytopenic purpura.

    PubMed

    Ellithy, Hend N; Ahmed, Salwa H; Shahin, Gehan H; Matter, Mervat M; Talatt, Mohamed

    2017-08-31

    In chronic immune thrombocytopenic purpura (ITP), rituximab removes the harmful autoantibodies through antibody-dependent cellular cytotoxicity. The response to rituximab in ITP is variable; the effectiveness of rituximab is influenced by the process of activation of effector fragment C gamma receptors (FcγRs). Genetic factors may affect the response to rituximab. The influence of FcγRIIa (H131R) and FcγRIIIa (V158F) gene polymorphisms on the response to rituximab in ITP. One hundred ITP patients were genotyped for FcγRIIa (H131R) and FcγRIIIa (V158F) gene polymorphisms using the polymerase chain reaction-restriction fragment length polymorphism assay. The response at the end of the third month was assessed by direct platelets count. Polymorphisms were analyzed in relation to the response. The mean platelets count at end of weeks 1-4 of rituximab was statistically significantly higher in patients who achieved complete response (CR) than partial response or no response (P-value = .001). Although RR (44.4%) and HR (38.9%) genotypes were observed to be higher in patients who achieved CR compared with the wild (HH) genotype (16.7%), it was not statistically significantly different (P-value = .648). The higher platelet count achieved early is predictive for a better response to rituximab later. FCγRIIA polymorphisms did not significantly influence response to rituximab in ITP.

  3. 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.

  4. Toxicity of fludarabine and cyclophosphamide with or without rituximab as initial therapy for patients with previously untreated mantle cell lymphoma: results of a randomised phase II study.

    PubMed

    Eve, Heather E; Linch, David; Qian, Wendi; Ross, Moira; Seymour, John F; Smith, Paul; Stevens, Lindsey; Rule, Simon A J

    2009-02-01

    The National Cancer Research Network (NCRN) is currently coordinating a Phase III randomised study (LY05) comparing fludarabine and cyclophosphamide (FC) with or without rituximab (R) for previously untreated mantle cell lymphoma (MCL). The combination of FC is well-recognised as significantly immunosuppressive and there are concerns that adding rituximab may increase infection risk further. The impact of rituximab on other markers of toxicity is also unclear. We analysed the toxicity data on 139 patients treated within the NCRN LY05 trial. Non-hematological toxicity was similar between the two treatment arms. The only difference in hematological toxicity was a higher rate of lymphocytopenia with fludarabine cyclophosphamide and rituximab (FCR), which did not translate into increased febrile episodes or infections. In conclusion, the addition of rituximab to FC for previously untreated MCL has no significant impact on toxicity.

  5. [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.

  6. Central nervous system involvement in adult patients with diffuse large B-cell lymphoma: Influence of rituximab

    PubMed Central

    CAO, BING; ZHOU, XIAOYAN; JI, DONGMEI; CAO, JUNNING; GUO, YE; ZHANG, QUNLING; WU, XIANGHUA; LI, JUNMIN; WANG, JIANMIN; CHEN, FANGYUAN; WANG, CHUN; ZOU, SHANHUA; HONG, XIAONAN

    2012-01-01

    CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone)-like chemotherapy, in combination with rituximab (R-CHOP-like), improves outcome in patients with diffuse large B-cell lymphoma (DLBCL). We aimed to investigate the impact of rituximab on central nervous system (CNS) disease in adult patients. We studied 315 patients (aged 18–60 years old) from six hospitals between July 2003 and May 2008. All patients received CHOP-like (n=165) or R-CHOP-like (n=150) regimen every 3 weeks. With a median follow-up of 3.69 years, 10 patients (3.17%) developed CNS disease. The cumulative risk of CNS occurrence was not significantly different between the two treatment groups (P=0.871). We conclude that the addition of rituximab did not reduce the risk of CNS disease in adult patients with DLBCL. PMID:22970053

  7. Rituximab Faster Infusion for Patients With Non-Hodgkin's Lymphoma in the United States: Implications for Nursing Practice.

    PubMed

    Dawson, Keith

    2015-01-01

    The majority of follicular non-Hodgkin's lymphoma patients in the United States receive an initial treatment strategy that includes the infusion of rituximab. Data from a phase III multicenter clinical trial led to the 2012 US Food and Drug Administration approval of a 90-minute infusion of rituximab (Rituxan) starting at Cycle 2 for patients with non-Hodgkin's lymphoma who did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1. A review of literature was undertaken to identify existing evidence regarding both the safety of rituximab faster infusion and its impact on nursing practice. The aim of this article is to stimulate discussion and lead to implementation of evidence-based nursing practices to improve the delivery of patient care.

  8. Rituximab faster infusion for patients with non-Hodgkin's lymphoma in the United States: implications for nursing practice.

    PubMed

    Dawson, Keith

    2013-01-01

    The majority of follicular non-Hodgkin's lymphoma patients in the United States receive an initial treatment strategy that includes the infusion of rituximab. Data from a phase III multicenter clinical trial led to the 2012 US Food and Drug Administration approval of a 90-minute infusion of rituximab (Rituxan) starting at Cycle 2 for patients with non-Hodgkin's lymphoma who did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1. A review of literature was undertaken to identify existing evidence regarding both the safety of rituximab faster infusion and its impact on nursing practice. The aim of this article is to stimulate discussion and lead to implementation of evidence-based nursing practices to improve the delivery of patient care.

  9. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study

    PubMed Central

    Seymour, John F; Ma, Shuo; Brander, Danielle M; Choi, Michael Y; Barrientos, Jacqueline; Davids, Matthew S; Anderson, Mary Ann; Beaven, Anne W; Rosen, Steven T; Tam, Constantine S; Prine, Betty; Agarwal, Suresh K; Munasinghe, Wijith; Zhu, Ming; Lash, L Leanne; Desai, Monali; Cerri, Elisa; Verdugo, Maria; Kim, Su Young; Humerickhouse, Rod A; Gordon, Gary B; Kipps, Thomas J; Roberts, Andrew W

    2017-01-01

    Summary Background Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab. Methods Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200–600 mg) and then monthly rituximab commenced (375 mg/m2 in month 1 and 500 mg/m2 in months 2–6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616. Findings Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1–2 toxicities

  10. BCL2 predicts survival in germinal center B-cell-like diffuse large B-cell lymphoma treated with CHOP-like therapy and rituximab.

    PubMed

    Iqbal, Javeed; Meyer, Paul N; Smith, Lynette M; Johnson, Nathalie A; Vose, Julie M; Greiner, Timothy C; Connors, Joseph M; Staudt, Louis M; Rimsza, Lisa; Jaffe, Elaine; Rosenwald, Andreas; Ott, German; Delabie, Jan; Campo, Elias; Braziel, Rita M; Cook, James R; Tubbs, Raymond R; Gascoyne, Randy D; Armitage, James O; Weisenburger, Dennis D; Chan, Wing C

    2011-12-15

    We have previously shown the prognostic significance of BCL2 expression in the activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) patients treated with cyclophosphamide-Adriamycin-vincristine-prednisone (CHOP) or CHOP-like therapy. However, after the inclusion of rituximab (R) in the CHOP regimen, several conflicting observations about the prognostic value of BCL2 expression have been reported. We evaluated the R-CHOP cohort of 221 DLBCL cases with gene expression profiling data. BCL2 protein (n = 169), mRNA (n = 221) expression, and t(14;18) (n = 144) were correlated with clinical outcome. The CHOP cohort (n = 181) was used for comparative analysis. BCL2 protein expression has significant impact on overall survival (OS) and event-free survival (EFS) in DLBCL (OS, P = 0.009; EFS, P = 0.001) and GCB-DLBCL (OS, P = 0.03; EFS, P = 0.002) but not in ABC-DLBCL in the R-CHOP cohort. The survival differences for EFS in GCB-DLBCL were still observed in multivariate analysis. At the mRNA level, this correlation was observed in EFS in DLBCL (P = 0.006), but only a trend was observed in GCB-DLBCL (P = 0.09). The t(14;18) was detected in 34% of GCB-DLBCL but was not associated with significant differences in survival. Gene enrichment analysis identified significant enrichment of the DLBCL "stromal-1" signatures and hypoxia-inducible factor 1 (HIF1-α) signature in BCL2(-)GCB-DLBCL, whereas T(FH) cell signatures were enriched in BCL2(+)GCB-DLBCL. The prognostic significance of BCL2 has changed after inclusion of rituximab in the treatment protocol and is observed in the GCB-DLBCL rather than the ABC-DLBCL. Although rituximab has benefited patients in both DLBCL subgroups, the BCL2(+)GCB-DLBCL seems to receive less benefit from this treatment and may require other novel therapeutic intervention. ©2011 AACR.

  11. Durable responses with the metronomic rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide regimen in elderly patients with recurrent mantle cell lymphoma.

    PubMed

    Ruan, Jia; Martin, Peter; Coleman, Morton; Furman, Richard R; Cheung, Ken; Faye, Adam; Elstrom, Rebecca; Lachs, Mark; Hajjar, Katherine A; Leonard, John P

    2010-06-01

    Targeting the tumor microenvironment and angiogenesis is a novel lymphoma therapeutic strategy. The authors report safety, activity, and angiogenic profiling results with the rituximab and thalidomide plus prednisone, etoposide, procarbazine, and cyclophosphamide (RT-PEPC) regimen in patients with recurrent mantle cell lymphoma (MCL). RT-PEPC included induction (Months 1-3) of rituximab 4 times weekly, daily thalidomide (50 mg), and PEPC followed by maintenance thalidomide (100 mg), oral PEPC titrated to the neutrophil count, and rituximab every 4 months. Endpoints included safety, efficacy, quality of life (QoL), and translational studies, including tumor angiogenic phenotyping, plasma vascular endothelial growth factor (VEGF), and circulating endothelial cells. Twenty-five patients were enrolled, and 22 were evaluable. The median age was 68 years (range, 52-81 years), 24 patients (96%) had stage III or IV disease, 18 patients (72%) had an International Prognostic Index (IPI) score of 3 to 5, and 20 patients (80%) had high-risk Mantle Cell International Prognostic Index (MIPI) scores. Patients had received a median of 2 previous therapies (range, 1-7 previous therapies), and 15 patients (60%) had progressed on bortezomib. At a median follow-up of 38 months, the overall response rate was 73% (complete response [CR]/unconfirmed CR rate, 32%; partial response [PR] rate, 41%; n = 22 patients), and the median progression-free survival was 10 months. Four CRs were ongoing (> or =6 months, > or =31 months, > or =48 months, and > or =50 months). Toxicities included grade 1 and 2 fatigue, rash, neuropathy, and cytopenias, including grade 1 and 2 thrombocytopenia (64%) and grade 3 and 4 neutropenia (64%). Two thromboses and 5 episodes of grade 3 or 4 infections occurred. QoL was maintained or improved. Correlative studies demonstrated tumor autocrine angiogenic loop (expression of VEGF A and VEGF receptor 1) and heightened angiogenesis and lymphangiogenesis in stroma

  12. 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

  13. 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

  14. 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

  15. 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.

  16. Developing biomarkers for predicting clinical relapse in pemphigus patients treated with rituximab.

    PubMed

    Albers, Lauren N; Liu, Yuan; Bo, Na; Swerlick, Robert A; Feldman, Ron J

    2017-09-16

    Rituximab is an effective therapy for pemphigus, although relapses are common. To identify biomarkers to predict relapse of pemphigus following rituximab treatment. In this retrospective cohort study, 62 patients with pemphigus treated with 99 rituximab cycles provided longitudinal clinical scoring and biomarker data, including levels of CD19(+) B cells, CD4(+) T cells, and desmoglein 1 (Dsg1) and desmoglein 3 (Dsg3) autoantibodies. An extended time-variant Kaplan-Meier estimator and extended Cox model were applied. Relapse was rare before B-cell repopulation. Univariate analysis revealed low CD4 count (<400 cells/μL) to predict relapse (P < .001). A positive result of testing for Dsg1 (>20 IU) was predictive of relapse among patients with mucocutaneous disease (hazard ratio, 6.40; P = .019); a positive result of testing for Dsg3 (>20 IU) was predictive in patients with mucocutaneous and mucosal disease (hazard ratio, 32.92; P < .001). Multivariable analysis revealed that every CD4 value increase of 200 decreases the hazard ratio for relapse by 35% (P = .029). A positive result of testing for Dsg1 increases the risk for relapse by a factor of 12.32 in patients with mucocutaneous disease (P = .001); positive result of testing for Dsg3 increases risk for relapse by 28.38 in patients with mucosal and mucocutaneous disease (P = .006). Limitations include the retrospective design and inconsistent follow-up. Relapse is associated with B-cell repopulation, low CD4(+) T -cell count, and positive result of testing for Dsg1 and Dsg3. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  17. Efficacy, outcomes, and cost-effectiveness of desensitization using IVIG and rituximab.

    PubMed

    Vo, Ashley A; Petrozzino, Jeffrey; Yeung, Kai; Sinha, Aditi; Kahwaji, Joseph; Peng, Alice; Villicana, Rafael; Mackowiak, John; Jordan, Stanley C

    2013-03-27

    Transplantation rates are very low for the broadly sensitized patient (panel reactive antibody [PRA]>80%; HS). Here, we examine the efficacy, outcomes, and cost-effectiveness of desensitization using high-dose intravenous immunoglobulin (IVIG) and rituximab to improve transplantation rates in HS patients. From July 2006 to December 2011, 207 HS (56 living donors/151 deceased donors) patients (donor-specific antibody positive, PRA>80%) were desensitized using IVIG and rituximab. After desensitization, responsive patients proceeded to transplantation with an acceptable crossmatch. Cost and outcomes of desensitization were compared with dialysis. Of the 207 treated patients, 146 (71%) were transplanted. At 48 months, patient and graft survival by Kaplan-Meier were 95% and 87.5%, respectively. The total 3-year cost for patients treated in the desensitization arm was $219,914 per patient compared with $238,667 per patient treated in the dialysis arm. Thus, each patient treated with desensitization is estimated to save the U.S. healthcare system $18,753 in 2011 USD. Overall, estimated patient survival at the end of 3 years was 96.6% for patients in the desensitization arm of the model (based on Cedars-Sinai survival rate) compared with 79.0% for an age, end-stage renal disease etiology, and PRA matched group of patients remaining on dialysis during the study period. We conclude that desensitization with IVIG+rituximab is clinically and cost-effective, with both financial savings and an estimated 17.6% greater probability of 3-year survival associated with desensitization versus dialysis alone. However, the benefits of desensitization and transplantation are limited by organ availability and allocation policies.

  18. Refractory myasthenia gravis – clinical profile, comorbidities and response to rituximab

    PubMed Central

    Sudulagunta, Sreenivasa Rao; Sepehrar, Mona; Sodalagunta, Mahesh Babu; Settikere Nataraju, Aravinda; Bangalore Raja, Shiva Kumar; Sathyanarayana, Deepak; Gummadi, Siddharth; Burra, Hemanth Kumar

    2016-01-01

    Introduction: Myasthenia gravis (MG) is an antibody mediated autoimmune neuromuscular disorder characterized by fatigable muscle weakness. A proportion of myasthenia gravis patients are classified as refractory due to non responsiveness to conventional treatment. This retrospective study was done to evaluate clinical profile, epidemiological, laboratory, and features of patients with MG and mode of management using rituximab and complications. Methods: Data of myasthenia gravis patients admitted or presented to outpatient department (previous medical records) with MG between January 2008 and January 2016 were included. A total of 512 patients fulfilled the clinical and diagnostic criteria of myasthenia gravis of which 76 patients met the diagnostic certainty for refractory myasthenia gravis and were evaluated. Results: Out of 76 refractory MG patients, 53 (69.73%) patients fulfilled all the three defined criteria. The median age of onset of the refractory MG group was 36 years with a range of 27–53 years. In our study 25 patients (32.89%) belonged to the age group of 21–30 years. Anti-MuSK antibodies were positive in 8 non-refractory MG patients (2.06%) and 36 refractory MG patients (47.36%). Mean HbA1C was found to be 8.6±2.33. The dose of administered prednisone decreased by a mean of 59.7% (p=3.3x10–8) to 94.6% (p=2.2x10–14) after the third cycle of rituximab treatment. Conclusion: The refractory MG patients are most commonly female with an early age of onset, anti-MuSK antibodies, and thymomas. Refractory MG patients have higher prevalence and poor control (HbA1C >8%) of diabetes mellitus and dyslipidemia probably due to increased steroid usage. Rituximab is very efficient in treatment of refractory MG with adverse effects being low. PMID:27790079

  19. Autoantibody levels in myositis patients correlate with clinical response during B cell depletion with rituximab.

    PubMed

    Aggarwal, Rohit; Oddis, Chester V; Goudeau, Danielle; Koontz, Diane; Qi, Zengbiao; Reed, Ann M; Ascherman, Dana P; Levesque, Marc C

    2016-06-01

    To determine the longitudinal trends in serum levels of four myositis-associated autoantibodies: anti-Jo-1, -transcription intermediary factor 1 γ (TIF1-γ), -signal recognition particle (SRP) and -Mi-2, after B cell depletion with rituximab, and to determine the longitudinal association of these autoantibody levels with disease activity as measured by myositis core-set measures (CSMs). Treatment-resistant adult and pediatric myositis subjects (n = 200) received rituximab in the 44-week Rituximab in Myositis Trial. CSMs [muscle enzymes, manual muscle testing (MMT), physician and patient global disease activity, HAQ, and extramuscular disease activity] were evaluated monthly and anti-Jo-1 (n = 28), -TIF1-γ (n = 23), -SRP (n = 25) and -Mi-2 (n = 26) serum levels were measured using validated quantitative ELISAs. Temporal trends and the longitudinal relationship between myositis-associated autoantibodies levels and CSM were estimated using linear mixed models. Following rituximab, anti-Jo-1 levels decreased over time (P < 0.001) and strongly correlated with all CSMs (P < 0.008). Anti-TIF1-γ levels also decreased over time (P < 0.001) and were only associated with HAQ, MMT and physician and patient global disease activity. Anti-SRP levels did not change significantly over time, but were significantly associated with serum muscle enzymes. Anti-Mi-2 levels significantly decreased over time and were associated with muscle enzymes, MMT and the physician global score. Anti-Jo-1, anti-TIF1-γ and anti-Mi-2 levels in myositis subjects decreased after B cell depletion and were correlated with changes in disease activity, whereas anti-SRP levels were only associated with longitudinal muscle enzyme levels. The strong association of anti-Jo-1 levels with clinical outcomes suggests that anti-Jo-1 autoantibodies may be a good biomarker for disease activity. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights

  20. [Progressive multifocal leukoencephalopathy after rituximab therapy in a patient with mantle cell lymphoma].

    PubMed

    Ota, Ikuyo; Katsura, Yukitaka; Yoshida, Chikashi; Yoshizawa, Kazuo; Ohtani, Haruo; Sata, Tetsutaro; Komeno, Takuya

    2010-12-01

    A 74-year-old man, who had mantle cell lymphoma treated with several anticancer drugs including rituximab, was admitted to our hospital because of gait disturbance and progressive paralysis of the right lower limb. T2-weighted MR image showed multiple high intensity lesions in the left parietal lobe. Suspected of being cerebral invasion of lymphoma, high-dose methotrexate was begun, but the patient died of sepsis without neurological improvement. At autopsy, it was proven that neurological symptoms had been caused by progressive multifocal leukoencephalopathy (PML). PML should be considered as a possible complication of heavily treated lymphoma.

  1. 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.

  2. 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

  3. 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.

  4. Rituximab maintenance for patients with aggressive B-cell lymphoma in first remission: results of the randomized NHL13 trial

    PubMed Central

    Jaeger, Ulrich; Trneny, Marek; Melzer, Helen; Praxmarer, Michael; Nawarawong, Weerasak; Ben Yehuda, Dina; Goldstein, David; Mihaljevic, Bilijana; Ilhan, Osman; Ballova, Veronika; Hedenus, Michael; Hsiao, Liang-Tsai; Au, Wing-Yan; Burgstaller, Sonja; Weidinger, Gerhard; Keil, Felix; Dittrich, Christian; Skrabs, Cathrin; Klingler, Anton; Chott, Andreas; Fridrik, Michael A.; Greil, Richard

    2015-01-01

    We investigated rituximab maintenance therapy in patients with diffuse large B-cell lymphoma (n=662) or follicular lymphoma grade 3b (n=21) in first complete remission. Patients were randomized to rituximab maintenance (n=338) or observation (n=345). At a median follow-up of 45 months, the event-free survival rate (the primary endpoint) at 3 years was 80.1% for rituximab maintenance versus 76.5% for observation. This difference was not statistically significant for the intent-to-treat population (likelihood ratio P=0.0670). The hazard ratio by treatment arm was 0.79 (95% confidence interval 0.57–1.08; P=0.1433). The secondary endpoint, progression-free survival was also not met for the whole statistical model (likelihood ratio P=0.3646). Of note, rituximab maintenance was superior to observation when treatment arms only were compared (hazard ratio: 0.62; 95% confidence interval 0.43–0.90; P=0.0120). Overall survival remained unchanged (92.0 versus 90.3%). In subgroup analysis male patients benefited from rituximab maintenance with regards to both event-free survival (84.1% versus 74.4%) (hazard ratio: 0.58; 95% confidence interval 0.36–0.94; P=0.0267) and progression-free survival (89.0% versus 77.6%) (hazard ratio: 0.45; 95% confidence interval 0.25–0.79; P=0.0058). Women had more grade 3/4 adverse events (P=0.0297) and infections (P=0.0341). Men with a low International Prognostic Index treated with rituximab had the best outcome. In summary, rituximab maintenance in first remission after R-CHOP-like treatment did not prolong event-free, progression-free or overall survival of patients with aggressive B-non-Hodgkin lymphoma. The significantly better outcome of men warrants further studies prior to the routine use of rituximab maintenance in men with low International Prognostic Index. This trial is registered under EUDRACT #2005-005187-90 and www.clinicaltrials.gov as #NCT00400478. PMID:25911553

  5. 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

  6. Clinical and immunological effects of Rituximab in patients with lupus nephritis refractory to conventional therapy: a pilot study.

    PubMed

    Vigna-Perez, Mónica; Hernández-Castro, Berenice; Paredes-Saharopulos, Octavio; Portales-Pérez, Diana; Baranda, Lourdes; Abud-Mendoza, Carlos; González-Amaro, Roberto

    2006-01-01

    We studied the clinical and immunological effects of Rituximab (anti-CD20) therapy in patients with lupus nephritis. In an open clinical trial, 22 patients with active systemic lupus erythematosis and renal involvement (mainly class III and IV according to the WHO classification) that was refractory to conventional therapy were studied. In all these patients, Rituximab (0.5 to 1.0 g at days 1 and 15) was added to the immunosuppressive therapy and its therapeutic effect was evaluated. In addition, the levels and function of regulatory T lymphocytes and the apoptosis of immune cells were assessed. We found a significant reduction in disease activity (p < 0.05, MEX-SLEDAI index), and proteinuria (p < 0.05) at days 60 and 90 of Rituximab therapy. Although most patients showed improvement in creatinine clearance and erythrocyturia, no significant changes in these parameters were detected. In most patients (20/22), B cell depletion was observed, but no clear-cut effect of Rituximab on complement levels or auto-antibody titers was detected (p > 0.05 in all cases). One patient died at day 70 with invasive histoplasmosis. No important adverse effects of Rituximab therapy were registered in other patients. A significant enhancement in the levels of different CD4+ regulatory cells (TREG, Th3, Tr1), but not CD8+ Ts lymphocytes, was observed at day 30. This increase was sustained for TREG cells at day 90, and accompanied by an improvement in their regulatory function. In addition, we observed an unexpected increase in the apoptosis of T cells at day 30. Interestingly, the enhancement in the suppressive function of TREG cells was not observed in the two patients that showed the poorest clinical response to Rituximab. We conclude that the data obtained in this open clinical trial suggest that Rituximab is a promising candidate for randomized controlled trials in patients with lupus nephritis refractory to the conventional immunosuppressive therapy. The effects of Rituximab on

  7. Bendamustine and rituximab combination in the management of chronic lymphocytic leukemia-associated autoimmune hemolytic anemia: a multicentric retrospective study of the French CLL intergroup (GCFLLC/MW and GOELAMS).

    PubMed

    Quinquenel, Anne; Willekens, Christophe; Dupuis, Jehan; Royer, Bruno; Ysebaert, Loic; De Guibert, S; Michallet, Anne-Sophie; Feugier, Pierre; Guieze, Romain; Levy, Vincent; Delmer, Alain

    2015-03-01

    We report our experience on bendamustine and rituximab (BR) combination in 26 patients with chronic lymphocytic leukemia (CLL) complicated by autoimmune hemolytic anemia (AIHA). At the time of BR initiation, 88% of the patients had already been treated for AIHA and CLL was progressive regardless of AIHA in all patients but one. Overall response rates were 81% for AIHA and 77% for CLL. Median time to next treatment was 28.3 months and 26.2 months for AIHA and CLL, respectively. BR therapy may represent a good and safe therapeutic option in this setting where adequate control of CLL seems important for long-term AIHA response.

  8. Safety of rituximab in the routine treatment of rheumatoid arthritis in Italy in patients refractory to anti-TNFa drugs: results from the observational retrospective-prospective RUBINO study.

    PubMed

    Bazzichi, L; Biasi, D; Tinazzi, E; Muratore, M; Pellerito, R; Russo, R; Corsaro Santi, M; De Sandre, P; Epis, O; Granata, M; Kroegler, B; Meschini, C; Versace, F; Astolfi, C

    2014-11-06

    The paper reports the results from the observational retrospective-prospective RUBINO study conducted in Italy to assess the safety of rituximab in the treatment of rheumatoid arthritis (RA) in routine clinical practice. The percentage of patients who manifested at least one grade 3 or 4 adverse event (AE) assessed by the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v.3) during the observation period (primary objective) was evaluated. The percentage of patients manifesting a severe AE (SAE), clinical response to rituximab treatment, clinical remission according to disease activity score for 28 joints (DAS28) criteria, markers of disease and quality of life were also assessed. Fifty-three Italian rheumatology centers took part in the study. Patients with a diagnosis of RA and inadequate response to anti-tumor necrosis factor b (anti-TNFa) drugs were enrolled. Participating patients had previously received at least one cycle of rituximab, and treatment was still ongoing at the time of recruitment. Out of 205 patients enrolled, 60% manifested no form of AE, 14.2% had at least one grade 3 or 4 AE, and 11.2% patients reported an SAE. The overall percentage of patients manifesting AEs (40%) was lower compared to the DANCER (81% and 85%), REFLEX (85%) and RESET (85% and 69%) studies, but higher than that observed in the CERERRA registry (from 10.2% to 13.9%). This difference may be due to the shorter observation period applied in the CERERRA registry (only 12 months) compared to the RUBINO study (up to 3 years). All parameters of RA activity (erythrocyte sedimentation rate, C-reactive protein, health assessment questionnaire score, DAS28) improved significantly during the study.

  9. Síndrome antifosfolípidos catastrófico. Reporte de caso y revisión bibliográfica.

    PubMed

    Orantes, Luis Del Carpio; Martínez, Chantall Citlally Anaya; Casas, Elías Bonilla

    2017-01-01

    Se reporta un caso de una condición clínica sumamente rara, la cual cursa con falla multiorgánica aguda posterior a una tormenta trombótica relacionada con anticuerpos antifosfolípidos, el denominado síndrome antifosfolípidos (SAF) catastrófico, el cual comenzó como un cuadro recurrente de trombosis mesentérica, con antecedentes de insuficiencia venosa y úlceras distales probablemente asociadas a un SAF no identificado, ameritando manejo en terapia intensiva y la consulta por el experto mundial Dr. Ricard Cervera, quien confirmó el diagnóstico y recomendó tratar como tal. La evolución del paciente fue satisfactoria hasta el momento. Se hacen recomendaciones finales de diagnóstico y se comentan las opciones de tratamiento actuales, como rituximab o eculizumab. El presente caso fue agregado al registro internacional de SAF catastrófico (International CAPS Registry), que actualmente alberga alrededor de 500 casos en todo el mundo. The present document is the report of a case of a very rare clinical entity, which presents with acute multiorganic failure after a thrombotic storm related to antiphospholipid antibodies, the so-called catastrophic antiphospholipid syndrome, which began as a recurrent picture of mesenteric thrombosis, with a previous history of venous insufficiency and distal ulcers probably associated with an unidentified antiphospholipid; deserving management in intensive care and the consultation by the world expert, Dr. Ricard Cervera who confirmed the diagnosis and recommend treating as such entity, the patient's evolution was satisfactory so far. Final recommendations for diagnosis and current treatment options such as rituximab or eculizumab are made. The present case was added to the international registry that currently houses around 500 cases worldwide (International CAPS Registry).

  10. Long-term Follow-up of Treatment with Ibrutinib and Rituximab in Patients with High-Risk Chronic Lymphocytic Leukemia.

    PubMed

    Jain, Preetesh; Keating, Michael J; Wierda, William G; Sivina, Mariela; Thompson, Philip A; Ferrajoli, Alessandra; Estrov, Zeev; Kantarjian, Hagop; O'Brien, Susan; Burger, Jan A

    2016-10-19

    Background: Ibrutinib is an active therapy with an acceptable safety profile for patients with chronic lymphocytic leukemia (CLL), including high-risk patients with del17p or with TP53 mutations. Ibrutinib is broadly indicated for the treatment of patients with CLL and specifically including those with 17p deletion. The optimal use of ibrutinib in combination with other agents remains controversial.Methods: We report the long-term outcome [median follow-up of 47 months (range, 36-51 months)] of 40 patients with high-risk CLL, treated on the first ibrutinib combination trial with rituximab (IR). The majority of patients (36/40) were previously treated.Results: Median age was 65 years, and 21 patients (52%) had 17p deletion. Median duration on treatment was 41 months (range, 2-51 months), and median number of treatment cycles was 42 (range, 2-49). Overall response rate was 95%, and 9 patients (23%) attained a complete remission. Twenty-one patients discontinued treatment, 10 due to disease progression, 9 for other causes, and 2 due to stem cell transplantation; the remaining 19 patients continue on ibrutinib. Median progression-free survival for all patients was 45 months, which was significantly shorter in the subgroup of patients with del17p (n = 21, 32.3 months, P = 0.02). Fourteen patients (35%) died, five from progressive disease, five from infections, and four from other causes. Median overall survival has not been reached.Conclusions: IR combination therapy leads to durable remissions in high-risk CLL; the possible benefit from the addition of rituximab is currently explored in a randomized trial. Clin Cancer Res; 1-5. ©2016 AACR.

  11. A Canadian perspective on the subcutaneous administration of rituximab in non-Hodgkin lymphoma

    PubMed Central

    MacDonald, D.; Crosbie, T.; Christofides, A.; Assaily, W.; Wiernikowski, J.

    2017-01-01

    Rituximab is widely used for the treatment of non-Hodgkin lymphoma, being a key component in most therapeutic regimens. Administration of the intravenous (IV) formulation is lengthy and places a significant burden on health care resources and patient quality of life. A subcutaneous (sc) formulation that provides a fixed dose of rituximab is being examined in a number of studies. Results indicate that the pharmacokinetics are noninferior and response rates are comparable to those obtained with the IV formulation. Moreover, the sc formulation is preferred by patients and health care providers and reduces administration and chair time. Additional advantages include a lesser potential for dosing errors, shorter preparation time, reduced drug wastage, and fewer infusion-related reactions. Despite the success of the sc formulation, correct administration is needed to reduce administration-related reactions. By using a careful procedure, the sc formulation can be given safely and effectively, potentially reducing the burden on health care resources and improving quality of life for patients. PMID:28270723

  12. A Phase 2 Study of Concurrent Fludarabine and Rituximab for the Treatment of Marginal Zone Lymphomas

    PubMed Central

    Brown, Jennifer R; Friedberg, Jonathan W.; Feng, Yang; Scofield, Sarah; Phillips, Kimberly; Cin, Paola Dal; Joyce, Robin; Takvorian, Ronald W; Fisher, David C; Fisher, Richard I; Liesveld, Jane; Marquis, Diana; Neuberg, Donna; Freedman, Arnold S

    2009-01-01

    SUMMARY The marginal zone lymphomas are a recently defined group of related diseases likely arising from a common cell of origin, the marginal zone B cell. Data on therapy for subtypes other than gastric MALT has been largely limited to retrospective case series. We therefore undertook this prospective phase 2 study of fludarabine and rituximab for the treatment of marginal zone lymphomas. 26 patients were enrolled, 14 with nodal MZL, 8 with MALT lymphomas and 4 with splenic MZL; 81% were receiving initial systemic therapy. Only 58% (95% CI 37–77%) of patients completed the planned six cycles, due to significant hematologic, infectious and allergic toxicity. Four late toxic deaths occurred due to infections (15% (95% CI 4.3–35%), two related to delayed bone marrow aplasia and two related to MDS. Nonetheless, the ORR was 85% (95% CI 65–96%), with 54% CRs. The progression-free survival at 3.1 years of follow-up is 79.5% (95% CI, 63–96%). We conclude that although concurrent fludarabine and rituximab given at this dose and schedule is a highly effective regimen in the treatment of marginal zone lymphomas, the significant hematologic and infectious toxicity observed both during and after therapy is prohibitive in this patient population, emphasizing the need to study marginal zone lymphomas as a separate entity. PMID:19344412

  13. 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.

  14. Launching biosimilar rituximab: an industry opinion on biosimilar uptake in Europe.

    PubMed

    Trollope, Richard; Johnson, Sue; Ireland, Henry

    2017-06-01

    Richard Trollope and Sue Johnson talk with Henry Ireland, Senior Editor about the recent approval of biosimilar rituximab (Truxima(®)) & the current state of biosimilar uptake across Europe Richard Trollope, Head of Biosimilars, Mundipharma International Limited, qualified as a biochemist before joining Wyeth's commercial operations, prior to its acquisition by Pfizer. Richard later joined Yamanouchi Pharmaceuticals (now Astellas Pharma). His fascination with oncology led him to join Mundipharma in Europe and after joining the company's UK arm (Napp Pharmaceuticals Limited), Richard began his journey in biosimilars. He now heads up the biosimilar franchise at Mundipharma International as it launches biosimilar rituximab (Truxima(®)) - the first biosimilar monoclonal antibody for the treatment of cancer, which will be distributed by Napp Pharmaceuticals in the UK. Sue Johnson, PhD, Medical Insights at Mundipharma International Limited, is a scientist by background and completed her postdoc fellowship at Harvard Medical School. On returning to the UK, she began her career in the pharmaceutical industry, working in UK Medical Affairs before transitioning to a European role with Mundipharma 2 years ago, where she leads on Medical Insights for the biosimilars franchise.

  15. Economic evaluation of rituximab plus cyclophosphamide, vincristine and prednisolone for advanced follicular lymphoma

    PubMed Central

    Hornberger, John; Reyes, Carolina; Lubeck, Deborah; Valente, Nancy

    2008-01-01

    The addition of rituximab to cyclophosphamide, vincristine and prednisolone (CVP) for advanced follicular lymphoma increases median time to progression by 17 months. A US societal cost-effectiveness of R-CVP versus CVP is estimated for a representative 50-year-old patient. Progression-free survival (PFS) and overall survival are based on a randomized Phase III trial. Costs are estimated using Medicare reimbursement rates and published drug price data, and include drug and administration costs, adverse events, treatment of relapses, and end-of-life care. Utility estimates are derived from the literature and a 3% discount rate is employed. Mean overall survival is projected to be 1.51 years longer for patients assigned to R-CVP versus CVP. The cost per quality-adjusted year of life gained is $28,565. The utility associated with stable or progressive disease and the unit drug cost of rituximab most influence the findings. The cost-effectiveness ratio of R-CVP compared with CVP is projected to be cost-effective in the United States under a range of sensitivity analyses. PMID:18231908

  16. Treatment of synchronous mantle cell lymphoma and small lymphocytic lymphoma with bendamustine and rituximab.

    PubMed

    Kourelis, Taxiarchis V; Kahl, Brad S; Benn, Peter; Delach, Judith A; Bilgrami, Syed F

    2011-01-01

    Herein, we describe a case of a female patient in whom B cell chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL) were diagnosed simultaneously. She presented with anemia, thrombocytopenia and splenomegaly. Flow cytometry demonstrated two immunophenotypically distinct CD5-positive monoclonal B cell populations. Peripheral blood fluorescence in situ hybridization (FISH) was positive for IGH/CCND1, consistent with t(11;14) translocation. She received 6 cycles of bendamustine 70 mg/m(2)/day for 2 days and rituximab on the first day every 4 weeks along with granulocyte-colony stimulating factor. She had an excellent response, and repeat computed tomography after her third cycle of chemotherapy revealed no organomegaly or lymphadenopathy. Her peripheral blood lymphocytosis also resolved. Bone marrow examination revealed no detectable flow-cytometric evidence of MCL or CLL. Repeat cytogenetic and FISH analysis were also normal. The patient remains in complete remission 20 months after her initial diagnosis and is receiving maintenance rituximab 375 mg/m(2) weekly for 4 weeks every 6 months for 2 years.

  17. Obinutuzumab: A Review in Rituximab-Refractory or -Relapsed Follicular Lymphoma.

    PubMed

    Dhillon, Sohita

    2017-03-21

    Obinutuzumab (Gazyva(®), Gazyvaro(®)) is a recombinant, monoclonal, humanized and glycoengineered, type II, anti-CD20, IgG1 antibody. It has recently been granted an additional indication for the treatment of patients with follicular lymphoma who relapsed after, or are refractory to, a rituximab-containing regimen. In the primary anal