Science.gov

Sample records for i-131 rituximab chimeric

  1. I-131-MIBG therapies.

    PubMed

    Vöö, Stefan; Bucerius, Jan; Mottaghy, Felix M

    2011-11-01

    Metaiodobenzylguanidine (MIBG) is a tracer that selectively targets neuroendocrine cells. On this basis, radiolabeled iodinated-MIBG (I-131-MIBG) has been introduced as a molecular nuclear therapy in the management of neuroendocrine tumors, including neuroblastoma, pheochromocytoma, paraganglioma, neuroendocrine carcinomas, and other rare neuroendocrine tumors. Extensive work has been addressed to develop I-131-MIBG therapy: doses, therapeutic schemes, and efficiency. In this paper, we present an overview on I-131-MIBG therapy, with main focus on different aspects how to perform this treatment. Copyright © 2011 Elsevier Inc. All rights reserved.

  2. 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

  3. 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

  4. Radioactive Iodine (I-131) Therapy for Hyperthyroidism

    MedlinePlus

    ... Physician Resources Professions Site Index A-Z Radioactive Iodine (I-131) Therapy Radioiodine therapy is a nuclear ... thyroid cancer. When a small dose of radioactive iodine I-131 (an isotope of iodine that emits ...

  5. Recurrent thyrotoxicosis after I-131 induced hypothyroidism

    SciTech Connect

    Liu, L.; Borowski, G.D.; Shtasel, P.; Rose, L.I.

    1984-01-01

    The first clinically and biochemically documented case of recurrent thyrotoxicosis after I-131 induced hypothyroidism in a patient with Graves' disease is reported. Two months after the administration of 9.2 mCi of I-131, the subject developed hypothyroidism. One month later, the patient became euthyroid. Then, nine months following ablation, the patient again developed thyrotoxicosis. A second dose of I-131 of 12.5 mCi was required to finally produce permanent hypothyroidism. This case illustrates the recurrence of hypothyroidism after what had seemed to have been adequate I-131 radiation.

  6. Tositumomab and Iodine I 131 Tositumomab

    Cancer.gov

    This page contains brief information about tositumomab and iodine I 131 tositumomab and a collection of links to more information about the use of this drug combination, research results, and ongoing clinical trials.

  7. Successful treatment with a chimeric anti-CD20 monoclonal antibody (IDEC-C2B8, rituximab) for a patient with relapsed mantle cell lymphoma who developed a human anti-chimeric antibody.

    PubMed

    Maeda, T; Yamada, Y; Tawara, M; Yamasaki, R; Yakata, Y; Tsutsumi, C; Onimaru, Y; Kamihira, S; Tomonaga, M

    2001-07-01

    Mantle cell lymphoma (MCL) has a poor prognosis without cure; the median overall survival ranges only from 3 to 4 years irrespective of conventional therapeutic regimens. IDEC-C2B8 (rituximab), a chimeric monoclonal antibody against the B-cell-specific antigen CD20, induces an evaluable clinical response in patients with MCL with mild toxicities. However, the single agent rituximab cannot cure MCL. Due to its low immunogenicity, an antibody against IDEC-C2B8 (human antichimeric antibody [HACA]) has rarely been produced in vivo. We report a patient with relapsed MCL who was successfully treated with IDEC-C2B8 for over a year although she developed HACA 6 months after the initial administration of IDEC-C2B8 in the phase II clinical trial conducted by Zenyaku Kogyo Co. Ltd. We followed the pharmacokinetics of IDEC-C2B8, the serum HACA titer, and the number of B lymphocytes in the peripheral blood in relation to clinical response. The HACA became undetectable soon after subsequent administrations of IDEC-C2B8. When the serum level of IDEC-C2B8 was kept elevated, clinical responses were apparently observed and HACA disappeared during this response period. There were no significant clinical toxicities related to the appearance of HACA. The present findings suggested that IDEC-C2B8 is effective and safe even in patients who have developed HACA.

  8. I-131 MIBG imaging of carcinoid tumors

    SciTech Connect

    Blinder, R.A.; Feldman, J.M.; Coleman, R.E.

    1985-05-01

    The potential of I-131 MIBG to image carcinoid tumors was evaluated in nine patients with pathologically proven carcinoid. Three patients with foregut carcinoid tumors (2 bronchial and one pancreatic), had abnormal urinary 5-HIAA, and one had the carcinoid syndrome. Six patients had midgut carcinoid tumors (5 ileal and 1 cecal), 5 had abnormal urinary 5-HIAA, and 4 had the carcinoid syndrome. All of the patients with midgut carcinoids had metestatic disease to the liver and/or mesentery. Two hundred microcuries of I-131 MIBG were injected intravenously and the patients were studied at 24 and 48 hours. In all patients except those with bronchial carcinoids Tc-99m sulfur colloid liver exams with computer subtraction were performed during the study. The patients with bronchial carcinoids showed no uptake in the tumors. The patient with a pancreatic carcinoid who had carcinoid syndrome demonstrated tumor uptake in hepatic metastases. Of the six patients with midgut carcinoids, 4 demonstrated MIBG uptake in tumors. One patient with mesenteric disease did not have definitive tumor uptake. A second patient with liver involvement at surgery was negative on the MIBG study. Hepatic CT and scintigraphy were negative and the patient's 5-HIAA was normal. The 4 patients with carcinoid syndrome had abnormal MIBG scans. I-131 MIBG demonstrated tumor in 4 of six patients with midgut carcinoids. MIBG was not concentrated in two carcinoids of bronchial origin. The five patients with carcinoid syndrome had positive scans. MIBG has potential as a diagnostic agent in carcinoid tumors.

  9. Scintigraphic imaging of neuroblastoma with I-131-meta-iodobenzylguanidine (I-131-MIBG)

    SciTech Connect

    Feine, U.; Treuner, J.; Schauenburg, W.M.; Niethammer, D.; Meinke, J.; Elbach, E.; Dopfer, R.; Klingebiel, T.

    1984-01-01

    I-131MIBG is commonly used for the scintigraphic localization of phaeochromocytoma. The authors present data which indicate that the neuroblastoma may show a similar or even higher accumulation of I-131-MIBG. Four children were examined quantitatively by 8'' crystal dual head whole body scanner interfaced to a computer. Scans were performed 4 h, to 21 dp.i. of 1-4 MBq (25-100 ..mu..Ci) I-131-MIBG. Three of the four children aged 2 months to 2.8 years had large tumor masses in the abdomen or diffuse infiltration of the enlarged liver and high catecholamine levels in 24 h urine samples. They showed high tumor uptake of the tracer already in the 4 h scans. The uptake level correlated well with the catecholamine excretion. The biological half live was in all three cases for about 4 days. In the following days contrast between tumor and non tumor tissues became excellent. The fourth child was clinically free of tumor one year after cytostatic treatment and had normal catecholamine levels. The MIBG-scans did not show any tumor uptake but the myocardium and the salivary glands show pronounced tracer uptake according to the results of a previous study. The authors conclude that MIBG may not be only a diagnostic-tracer for neuroblastoma but may perhaps permit therapy.

  10. Scintigraphic depiction of an insulinoma by I-131 metaiodobenzylguanidine

    SciTech Connect

    Geatti, O.; Shapiro, B.; Barillari, B. )

    1989-12-01

    Scintigraphy with I-131 metaiodobenzylguanidine (MIBG) was effective in depicting a pancreatic insulinoma in a patient suffering from intermittent hypoglycemia. This observation widens the range of neuroendocrine tumors that take up to I-131 MIBG and supports the concept that many tumors of the amine precursor uptake and decarboxylation system may be imaged in this way.

  11. 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.

  12. 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

  13. 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.

  14. [Efficacy of treatment with I(131) in paediatric Graves disease].

    PubMed

    Enes Romero, P; Martín-Frías, M; de Jesús, M; Caballero Loscos, C; Alonso Blanco, M; Barrio Castellanos, R

    2014-01-01

    Radioiodine is an important therapeutic option in young patients with Grave's disease (GD). In the United States it is a widespread therapy, but in Europe its use in paediatrics is still controversial. To report our experience in radioiodine therapy of paediatric GD patients and analyse its effectiveness and safety. We retrospectively studied our paediatric population (<18 years of age) with GD, diagnosed from 1982 to 2012. A curative option was offered to patients who did not respond to anti-thyroid drug (AT) at puberty. We analysed, the patient characteristics, TSH, T4, T3 and thyroid antibodies levels, AT response, remission post I(131), side effects, and hypothyroidism rates. A total of 50 patients were diagnosed with GD from 1982 to 2012. All patients received AT as initial treatment (mean duration: 35.3±25.9 months). Permanent remission was achieved in 46%. Thyroidectomy was performed in 5 patients, and 14 patients received I(131) (mean dose: 10.9±1.09 mCi). Remission with I(131) was obtained in 100%. The rate of permanent hypothyroidism was 90%. There was no progression of ophthalmopathy or side effects in any patients treated with I(131.) Radioiodine treatment of paediatric GD patients is safe, leads to complete remission at the expense of hypothyroidism, and does not exacerbate ophthalmopathy. It can be considered in patients older than 5 years, who do no not respond to AT or with significant side effects with this medication. Copyright © 2012 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

  15. Scintigraphy of a neuroblastoma with I-131 meta-iodobenzylguanidine

    SciTech Connect

    Kimmig, B.; Brandeis, W.E.; Eisenhut, M.; Bubeck, B.; Hermann, H.J.; zum Winkel, K.

    1984-07-01

    Radioiodinated m-iodobenzylguanidine has been applied mainly for the diagnosis of pheochromocytoma and blastoma. In this paper the author shows that an ontogenetically related tumor, the neuroblastoma, is also scintigraphically visualized by its high uptake of I-131 MIBG. Because of the kinetic findings and the high uptake of more than 30% of the injected activity, it is likely that the neuroblastoma, by analogy with pheochromocytoma, is susceptible to specific radionuclide therapy.

  16. Scintigraphy of a neuroblastoma with I-131 meta-iodobenzylguanidine

    SciTech Connect

    Kimmig, B.; Brandeis, W.E.; Eisenhut, M.; Bubeck, B.; Hermann, H.J.; Zum Winkel, K.

    1984-07-01

    Radioiodinated m-iodobenzylguanidine has been applied mainly for the diagnosis of pheochromocytoma and blastoma. In this paper the authors show that an ontogenetically related tumor, the neuroblastoma, is also scintigraphically visualized by its high uptake of I-131 MIBG. Because of the kinetic findings and the high uptake of more than 30% of the injected activity, it is likely that the neuroblastoma, by analogy with pheochromocytoma, is susceptible to specific radionuclide therapy.

  17. Microwave assistance of labeling hippuric acid by I-131.

    PubMed

    Sherlock Huang, Lin-Chiang; Wu, Kou-Hung; Ko, Pi-Wen; Hsieh, Cheng-Ying; Pao, Kuan-Chuan; Chou, Shih-Ching; Shieh, Fa-Kuen; Sureshbabu, Radhakrishnan; Hsu, Ming-Hua

    2014-07-01

    This work presents a novel approach for labeling hippuric acid with I-131 using microwaves. It utilizes copper(II) acetate as a catalyst of the labeling. The process involves the use of this catalytic copper(II) acetate at low dilutions that were nevertheless sufficient to produce labeled hippuric acid with high radiochemical purity in a short time. Therefore, the novel technique overcomes the limitations of previously reported conventional methods that involve heating. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. The Purity of Radioiodide-I131 Assessed by in Vivo and in Vitro Methods

    PubMed Central

    Fawcett, D. M.; Olde, G. L.; McLeod, L. E.

    1962-01-01

    Between 41 and 94% of the radioactivity of 24 preparations of I131 supplied without cysteine preservative was non-iodide on chromatographic analysis. Extraneous radio-activity was essentially absent from I131 supplied with cysteine. It was converted to iodide-I131 by 10-3 M cysteine or iodide but not by incubation at pH 2. The average thyroid uptake of I131 containing extraneous radioactivity was significantly lower than the uptake of I131 free from non-iodide impurity in 16 human subjects measured under controlled conditions and in a random group of 669 patients. Incubation of samples of I131 containing non-iodide radioactivity with tyrosine and cupric chloride resulted in the non-enzymatic formation of monoiodotyrosine-I131 either in the presence or absence of thyroid homogenate. Enzymatic formation of monoiodotyrosine-I131 by thyroid homogenates could be demonstrated only when I131 free from extraneous activity was used. ImagesFig. 1Fig. 2 PMID:13891874

  19. The detection of thrombosis using I-131 labeled thrombospondin

    SciTech Connect

    Perlman, S.B.; Folts, J.D.; Hammes, R.J.; Besozzi, M.C.; Mosher, D.F.

    1985-05-01

    There are methods available for detecting intravascular thrombosis (IVT) but none are noninvasive, rapid and accurate. Iodine-131 labeled thrombospondin (I-TSP) is being evaluated as a method of detecting IVT. Thrombospondin is obtained from human platelet concentrate and labeled with I-131 using the chloramine-T technique. Anesthetized dogs are known to develop thrombi in stenosed arteries and veins with or without moderate initial damage. IVT is detected by blood flow declines as measured with an electromagnetic flow meter (EMF) probe on the vessel being studied. Undamaged comparable vessels were used as controls. After IVT is initiated, I-TSP is given IV. Vessels with thrombi are harvested at various times, weighed and counted in a gamma counter to determine if the thrombi accumulated labeled I-TSP. Vessels with thrombi harvested at 30, 45 or 60 minutes after injection of I-TSP did not accumulate I-TSP whereas vessels obtained at 90 and 150 minutes after injection did accumulate I-TSP when compared to their control vessels or whole blood. The ratios of I-TSP in the stenosed vessels with thrombi, compared to whole blood or the control undamaged vessels ranged from 2.33/1 to 6.92/1. The ratio of counts for vessels with intimal damage alone ranged from 0.88/1 to 1.05/1 while the ratio of counts from control vessels was 0.98/1 to 1.09/1.

  20. Impact of reconstruction parameters on quantitative I-131 SPECT

    NASA Astrophysics Data System (ADS)

    van Gils, C. A. J.; Beijst, C.; van Rooij, R.; de Jong, H. W. A. M.

    2016-07-01

    Radioiodine therapy using I-131 is widely used for treatment of thyroid disease or neuroendocrine tumors. Monitoring treatment by accurate dosimetry requires quantitative imaging. The high energy photons however render quantitative SPECT reconstruction challenging, potentially requiring accurate correction for scatter and collimator effects. The goal of this work is to assess the effectiveness of various correction methods on these effects using phantom studies. A SPECT/CT acquisition of the NEMA IEC body phantom was performed. Images were reconstructed using the following parameters: (1) without scatter correction, (2) with triple energy window (TEW) scatter correction and (3) with Monte Carlo-based scatter correction. For modelling the collimator-detector response (CDR), both (a) geometric Gaussian CDRs as well as (b) Monte Carlo simulated CDRs were compared. Quantitative accuracy, contrast to noise ratios and recovery coefficients were calculated, as well as the background variability and the residual count error in the lung insert. The Monte Carlo scatter corrected reconstruction method was shown to be intrinsically quantitative, requiring no experimentally acquired calibration factor. It resulted in a more accurate quantification of the background compartment activity density compared with TEW or no scatter correction. The quantification error relative to a dose calibrator derived measurement was found to be  <1%,-26% and 33%, respectively. The adverse effects of partial volume were significantly smaller with the Monte Carlo simulated CDR correction compared with geometric Gaussian or no CDR modelling. Scatter correction showed a small effect on quantification of small volumes. When using a weighting factor, TEW correction was comparable to Monte Carlo reconstruction in all measured parameters, although this approach is clinically impractical since this factor may be patient dependent. Monte Carlo based scatter correction including accurately simulated CDR

  1. Impact of reconstruction parameters on quantitative I-131 SPECT.

    PubMed

    van Gils, C A J; Beijst, C; van Rooij, R; de Jong, H W A M

    2016-07-21

    Radioiodine therapy using I-131 is widely used for treatment of thyroid disease or neuroendocrine tumors. Monitoring treatment by accurate dosimetry requires quantitative imaging. The high energy photons however render quantitative SPECT reconstruction challenging, potentially requiring accurate correction for scatter and collimator effects. The goal of this work is to assess the effectiveness of various correction methods on these effects using phantom studies. A SPECT/CT acquisition of the NEMA IEC body phantom was performed. Images were reconstructed using the following parameters: (1) without scatter correction, (2) with triple energy window (TEW) scatter correction and (3) with Monte Carlo-based scatter correction. For modelling the collimator-detector response (CDR), both (a) geometric Gaussian CDRs as well as (b) Monte Carlo simulated CDRs were compared. Quantitative accuracy, contrast to noise ratios and recovery coefficients were calculated, as well as the background variability and the residual count error in the lung insert. The Monte Carlo scatter corrected reconstruction method was shown to be intrinsically quantitative, requiring no experimentally acquired calibration factor. It resulted in a more accurate quantification of the background compartment activity density compared with TEW or no scatter correction. The quantification error relative to a dose calibrator derived measurement was found to be  <1%,-26% and 33%, respectively. The adverse effects of partial volume were significantly smaller with the Monte Carlo simulated CDR correction compared with geometric Gaussian or no CDR modelling. Scatter correction showed a small effect on quantification of small volumes. When using a weighting factor, TEW correction was comparable to Monte Carlo reconstruction in all measured parameters, although this approach is clinically impractical since this factor may be patient dependent. Monte Carlo based scatter correction including accurately simulated CDR

  2. 76 FR 81517 - Agency Information Collection Activities: Form I-131, Revision of an Existing Information...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-12-28

    ... the Form/Collection: Application for Travel Document. (3) Agency form number, if any, and the... SECURITY U.S. Citizenship and Immigration Services Agency Information Collection Activities: Form I-131... Collection Under Review: Form I- 131, Application for Travel Document. The Department of Homeland Security,...

  3. 77 FR 15787 - Agency Information Collection Activities: Form I-131, Revision of an Existing Information...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-03-16

    ... the Form/Collection: Application for Travel Document. (3) Agency Form Number, if any, and the... SECURITY U.S. Citizenship and Immigration Services Agency Information Collection Activities: Form I-131... Collection Under Review: Form I- 131, Application for Travel Document. The Department of Homeland Security,...

  4. Pregnancy Outcome After I-131 Therapy for Patients With Thyroid Cancer

    PubMed Central

    Ko, Kuan-Yin; Yen, Ruoh-Fang; Lin, Cheng-Li; Cheng, Mei-Fang; Huang, Wen-Sheng; Kao, Chia-Hung

    2016-01-01

    Abstract The aim of this study was to evaluate the influence of I-131 therapy on pregnancy outcome in patients that received therapeutic I-131 doses for thyroid cancer in Taiwan. This nationwide population-based cohort study was based on data from 1998 to 2010 obtained from the Taiwanese National Health Insurance Research Database. We identified 11,708 women with thyroid cancer (≥15 and ≤50 years of age) by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Patients were divided into 2 cohorts: I-131 therapy cohort and non-I-131 therapy cohort. The mean follow-up period was 6.08 years for the I-131 cohort and 6.87 years for the non-I-131 cohort. The case cohort and the control cohort comprised 775 and 716 pregnant patients, respectively. The overall incidence of pregnancy was significantly lower in the I-131 cohort (adjusted HR = 0.77, 95% CI = 0.70–0.86) and it was also observed when the patients were stratified according to age (HR = 0.73, 95% CI = 0.64–0.83 in 25–34 years; HR = 0.63, 95% CI = 0.49–0.82 in 35–44 years). Patients in the I-131 cohort had a lower successful delivery rate, particularly among patients in 25 to 34 years (OR = 0.60, 95% CI = 0.45–0.80). No significant difference was observed for adverse pregnancy conditions between 2 cohorts. I-131 therapy is associated with decreased pregnancy and successful delivery rates. The underlying mechanism likely involves physician recommendation, patient's psychological issue, and potential impact of I-131 treatment on reproductive health. Further investigation is needed. PMID:26844507

  5. Clinical comparison of I-131 orthoiodohippurate and the kit formulation of Tc-99m mercaptoacetyltriglycine

    SciTech Connect

    Taylor, A. Jr.; Ziffer, J.A.; Steves, A.; Eshima, D.; Delaney, V.B.; Welchel, J.D.

    1989-03-01

    Previous studies in animals and humans have shown that technetium-99m mercaptoacetyltriglycine (MAG3) purified by high-performance liquid chromatography is a renal tubular agent with characteristics similar to those of iodine-131 orthoiodohippurate (OIH). A kit formulation for Tc-99m MAG3 has been developed and compared with I-131 OIH in 17 patients with suspected renal dysfunction and three potential kidney donors. There were no adverse reactions. Tc-99m MAG3 images were of good quality and consistently better than I-131 OIH images. There was no significant difference in the relative renal uptake of Tc-99m MAG3 and I-131 OIH. The 30-minute urinary excretion of Tc-99m MAG3 was 36.4%, versus 40.4% for I-131 OIH. The average plasma clearance of Tc-99m MAG3 (138 mL/min +/- 117) was less than that of I-131 OIH (272 mL/min +/- 205) (P less than .001); however, there was good correlation between the Tc-99m MAG3 and I-131 OIH clearances (r = .87). The volume of distribution of Tc-99m MAG3 (5.96 L +/- 1.94) was less than that of I-131 OIH (9.41 L +/- 3.73) (P less than .001). These characteristics and the advantages of a simple kit formulation should lead to widespread clinical use.

  6. Normal and abnormal distribution of the adrenomedullary imaging agent m-(I-131)iodobenzylguanidine (I-131 MIBG) in man; evaluation by scintigraphy

    SciTech Connect

    Nakajo, M.; Shapiro, B.; Copp, J.; Kalff, V.; Gross, M.D.; Sisson, J.C.; Beierwaltes, W.H.

    1983-08-01

    The scintigraphic distribution of m-(/sup 131/I)iodobenzylguanidine (I-131 MIBG), an adrenal medullary imaging agent, was studied to determine the patterns of uptake of this agent in man. The normal distribution of I-131 MIBG includes clear portrayal of the salivary glands, liver, spleen, and urinary bladder. The heart, middle and lower lung zones, and colon were less frequently or less clearly seen. The upper lung zones and kidneys were seldom visualized. The thyroid appeared only in cases of inadequate thyroidal blockade. The normal adrenal glands were seldom seen and faintly imaged in 2% at 24 h after injection and in 16% at 48 h, in patients shown not to have pheochromocytomas, whereas intra-adrenal, extra-adrenal, and malignant pheochromocytomas usually appeared as intense focal areas of I-131 MIBG uptake at 24 through 72 h.

  7. Cystic thyroid mass following I-131 treatment of papillary thyroid carcinoma: An unusual complication

    SciTech Connect

    Morrish, D.W.; Jackson, F.I.; Lalani, Z.H.; Catz, Z.; Sloboda, R. )

    1989-12-01

    Several unusual complications of I-131 therapy for thyroid carcinoma are known. Two patients who developed a further unusual event that consisted of a palpable mass and cystic degeneration are described.

  8. Late presentation of metastatic pheochromocytoma: A problem case solved by I-131 MIBG scintigraphy

    SciTech Connect

    Geatti, O.; Shapiro, B.; Virgolini, L. )

    1990-02-01

    A patient presented with recurrent pheochromocytoma 10 years following the apparently successful surgical cure of a right adrenal pheochromocytoma. Conventional medical imaging techniques, (chest radiograph, abdominal ultrasound, and abdominal CT) suggested local recurrence for which surgery was planned. I-131 MIBG scintigraphy revealed disseminated metastatic disease that rendered attempts at surgical cure futile. The patient was treated with three therapeutic doses of I-131 MIBG with good symptomatic palliation and improvement of some biochemical parameters.

  9. Role of gambogic acid and NaI131 in A549/DDP cells

    PubMed Central

    Huang, Jing; Zhu, Xiaoli; Wang, Huan; Han, Shuhua; Liu, Lu; Xie, Yan; Chen, Daozhen; Zhang, Qiang; Zhang, Li; Hu, Yue

    2017-01-01

    Resistance to platinum in tumor tissue is a considerable barrier against effective lung cancer treatment. Radionuclide therapy is the primary adjuvant treatment, however, the toxic side effects limit its dosage in the clinical setting. Therefore, the present study aimed to determine whether an NaI131 radiosensitizer could help reduce the toxic side effects of radionuclide therapy. In vitro experiments were conducted to determine whether NaI131 can inhibit platinum resistance in A549/DDP cells, which are cisplatin-resistant non-small cell lung cancer cells, and whether gambogic acid (GA) is an effective NaI131 radiosensitizer. Cell proliferation following drug intervention was analyzed using MTT and isobolographic analysis. Apoptosis was assessed by flow cytometry. In addition, the mechanisms of drug intervention were analyzed by measuring the expression of P-glycoprotein (P-gP), B cell lymphoma 2 (Bcl-2), Bcl2-associated X protein (Bax) and P53 using western blot analysis and immunocytochemistry. According to isobolographic analysis, a low concentration of NaI131 combined with GA had a synergistic effect on the inhibition of A549/DDP cell proliferation, which was consistent with an increased rate of apoptosis. Furthermore, the overexpression of Bax, and the downregulation of P-gP, P53 and Bcl-2 observed demonstrated the potential mechanism(s) of NaI131 and GA intervention. NaI131 may induce apoptosis in A549/DDP cells by regulating apoptosis-related proteins. A low concentration combination of NaI131 and GA was able to significantly inhibit A549/DDP cell proliferation and induce cell apoptosis. Thus, the two drugs appear to have a synergistic effect on apoptosis of A549/DDP cells. PMID:28123519

  10. Monte Carlo simulation of the RBE of I-131 radiation using DNA damage as biomarker.

    PubMed

    Ezzati, Ahad Ollah; Mahmoud-Pashazadeh, Ali; Studenski, Matthew T

    2017-04-10

    In general, a weighting factor of one is applied for low linear energy transfer radiations. However, several studies indicate that relative biological effectiveness (RBE) of low energy photons and electrons is greater than one. The aim of this current study was calculating the RBE of I-131 radiation relative to Co-60 gamma photons in 100 μm spheroid cells using Monte Carlo (MC) simulations. These calculations were compared to experimentally measured results. MCNPX2.6 was used to simulate the I-131 and Co-60 irradiation setups and calculate the secondary electron spectra at energies higher than 1 keV with varying oxygen concentrations. The electron spectra at energies lower than 1 keV were obtained by extrapolation (down to 10 eV). The calculated electron spectra were input into the MCDS micro-dosimetric Monte Carlo code to calculate the DSB induction and related RBE. The calculated RBE of I-131 radiation relative to Co-60 photons, as the reference radiation recommended by the International Commission on Radiation Protection (ICRP), was 1.06, 1.03 and 1.02 for oxygen concentrations of 0, 5 and 100%, respectively. Results of MC simulations indicate the RBE of I-131 is greater than one. This finding, despite a 10% discrepancy with the findings of the previous in vitro study of one of the authors of this paper, reemphasizes that I-131 radiation induces more severe biological damage than current ICRP recommendations.

  11. Is thyroid scintigraphy necessary before I-131 therapy for hyperthyroidism. Concise Communication

    SciTech Connect

    Ripley, S.D.; Freitas, J.E.; Nagle, C.E.

    1984-06-01

    To assess the value of routine thyroid scintigraphy in the differential diagnosis of hyperthyroidism and as a guide to I-131 therapy, the authors prospectively examined 100 consecutive hyperthyroid patients referred for a 24-hr radioiodine uptake and I-131 therapy. The nuclear medicine physician recorded his preimaging diagnostic impression and therapeutic plan for each patient. After the (/sup 99m/Tc) pertechnetate image, the patient was reassessed to determine whether the image induced any change in the diagnosis or therapeutic plan. Seventy-nine of 80 patients with diffuse goiter to palpation, had scintigrams demonstrating no discrete focal defects and were diagnosed as Graves' disease; thus the scintigram did not contribute useful information. In 17 of 20 patients with uninodular or multinodular goiters, the image was necessary to clarify the final diagnosis and therapeutic plan. Thus, selective use of thyroid scintigraphy should decrease the number of scintigrams performed before I-131 therapy for hyperthyroidism, without compromising diagnostic accuracy or therapeutic success.

  12. False positive I-131 MIBG due to dilated renal pelvis: a case report

    SciTech Connect

    Bahar, R.H.; Mahmoud, S.; Ibrahim, A.; al-Gazzar, A.H.

    1988-12-01

    A case of false positive I-131 MIBG imaging for detection of pheochromocytoma is presented. There was an area of increased tracer uptake in the left renal region that showed steadily reducing activity over a period of three days. This raised the suspicion of a dilated renal pelvis, which was later confirmed by Tc-99m DTPA imaging. It is advisable in cases of ambiguous I-131 MIBG imaging to use Tc-99m DTPA rather than Tc-99m DMSA for localizing the kidneys and renal pelvis.

  13. 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

  14. 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

  15. Pheochromocytoma in the organ of Zukerkandl: I-131 MIBG scintigraphic localization

    SciTech Connect

    el-Desouki, M.; al-Nuaim, A.; Mofti, A.; Shanna, A.

    1989-06-01

    Scintigraphic localization of an extra-adrenal pheochromocytoma in a 27 year-old female with clinical and biochemical evidence of the disease is presented. While both ultrasonography and computed tomography were negative, I-131 MIBG scintigraphy successfully localized the extra-adrenal lesion in the organ of Zukerkandl.

  16. Effects of Dosimetrically Guided I-131 Therapy on Hematopoiesis in Patients With Differentiated Thyroid Cancer

    PubMed Central

    Bikas, Athanasios; Schneider, Mark; Desale, Sameer; Atkins, Frank; Mete, Mihriye; Burman, Kenneth D.; Wartofsky, Leonard

    2016-01-01

    Objective: The objective of the study was to evaluate the effects of dosimetrically guided I-131 prescribed activities on hematopoiesis reflected by changes in complete blood counts (CBCs). Design: This was a retrospective analysis. Setting: The study was conducted at an academic center. Patients: A total of 152 patients with differentiated thyroid cancer who had 185 dosimetrically guided I-131 treatments. Interventions: There were no interventions. Main Outcome Measures: Repeated-measure ANOVA was used for the analysis of the differences in the averages of CBCs that were documented at baseline and 1, 6, 12, 24–36, and 48–60 months after I-131 treatment. Results: All parameters decreased to their respective nadir at 1 month and then gradually returned toward baseline values. White blood cells (WBCs) and platelets (PLTs) were the most significantly affected cells. At 1 month, the decrease was 29.6% (P < .0001) for WBCs and 25% (P < .0001) for PLTs, whereas at 12 months, the decrease was 15.5% (P < .0001) and 13% (P < .0001), respectively. Lymphocytes appeared to be more susceptible to I-131 than neutrophils (ANCs). The decreases were small in absolute numbers for red blood cells, hematocrit and hemoglobin not surpassing 10%. Multivariate analysis demonstrated that the ratio of administered prescribed activity-to-maximum tolerated activity was associated with the decreases in WBCs (P = .0038), ANCs (P = .0063), and red blood cells (P = .029), with borderline significance for PLTs (P = .057) and hemoglobin (P = .057). Conclusions: Dosimetrically guided I-131 resulted in statistically significant decreases in CBC parameters, which were more prominent in WBCs and PLTs. Lymphocytes were more severely affected than ANCs, whereas all parameters reached a nadir at 1 month and then gradually returned toward baseline values over the 5-year follow-up of our study. PMID:26900639

  17. Rapid thyroidal iodine turnover in hyperthyroid patients: Incidence and impact on outcome of I-131 therapy (Rx)

    SciTech Connect

    Aktay, R.; Rezai, K.; Kirchner, P.T.

    1995-05-01

    It has been suggested that rapid thyroidal iodine turnover (RTIT) may be frequent in hyperthyroid patients and that it could cause not only I-131 therapy failures but also high radiation doses to the blood from circulating protein bound I-131 (JNM 73;14:379A). We investigated the incidence and importance of this phenomenon by comparing 4 hr to 24 hr uptake ratios with the success of I-131 therapy (3.7-5.5 MBq/gm of thyroid). Of 525 hyperthyroid patients treated at our institution between 1980 and 1993, 460 had both 4 and 24 hr uptake measurements: 370 were female, 90 male, mean age 42 years. Clinical diagnosis was Graves` disease in 402, non-Graves` disease in 58. Of the 460, 27 patients were lost to follow-up after the first I-131 Rx, 6 after the second Rx. Defining rapid turnover as early uptake {ge} late uptake, we found 71 of 460 hyperthyroids (15%) to have rapid thyroidal I-131 turnover with all but 2 in patients with Graves` disease. Of 22 patients with RTIT who failed 1st I-131 Rx, 18 (82%) were successfully treated with 2nd I-131 Rx; and of 29 with nonrapid turnover, 27 (93%) had a successful 2nd I-131 Rx. 17 of 24 (71%) patients were converted to nonrapid after the 1st I-131 Rx. The results (a) confirm a relatively high incidence of rapid thyroidal iodine turnover in hyperthyroid patients, (b) reveal a near 50% failure rate for first I-131 Rx in such patients vs. 11% for non-RTIT, (c) demonstrate a reversion to non-RTIT for most RTIT patients after first I-131 Rx, (d) show the 4 to 24 hour uptake ratios to be a guide for treatment outcome.

  18. The therapeutic efficacy of I131-PSCA-mAb in orthotopic mouse models of prostate cancer

    PubMed Central

    2013-01-01

    Background Prostate stem cell antigen (PSCA) is upregulated in prostate cancer tissues. Here we aimed to study the therapeutic efficacy of a monoclonal antibody of PSCA-labeled I131 (I131-PSCA-mAb) in orthotopic mouse models of prostate cancer. Methods The proliferation, apoptosis and invasion abilities of PC-3 and LNCaP cells treated with I131-PSCA-mAb were measured by methyl thiazolyl tetrazolium assay, flow cytometry and transwell culture, respectively. The human prostate cancer models were established by orthotopic implantation of PC-3 and LNCaP cells in nude mice. I131-PSCA-mAb distribution and tumor cell apoptosis in the tumor-bearing nude mice were measured. Results The inhibitory and apoptosis rates of PC-3 and LNCaP cells treated with I131-PSCA-mAb reached a maximum of 84%, 80% and 50%, 46%, respectively, which were obviously higher than in the cells treated with I131-IgG or PSCA-mAb. The invaded number of PC-3 and LNCaP cells treated with I131-PSCA-mAbe was significantly reduced (P < 0.01) compared with the control group. The ratios of I131-PSCA-mAb in tumor to intramuscular I131-PSCA-mAb (T/NT) in tumor-bearing nude mice were increased with time and reached the highest level after 8 h. T/NT stayed above 3.0 after 12 h, and the tumor could still be developed after 24 h. The number of apoptotic cells in tumor tissue of nude mice treated with I131-PSCA-mAb was larger than that in the control group. Conclusion I131-PSCA-mAb has the potential to become a new targeted therapy drug for the treatment of prostate cancer. PMID:24330823

  19. Development of gamma-photon/Cerenkov-light hybrid system for simultaneous imaging of I-131 radionuclide

    NASA Astrophysics Data System (ADS)

    Yamamoto, Seiichi; Suzuki, Mayumi; Kato, Katsuhiko; Watabe, Tadashi; Ikeda, Hayato; Kanai, Yasukazu; Ogata, Yoshimune; Hatazawa, Jun

    2016-09-01

    Although iodine 131 (I-131) is used for radionuclide therapy, high resolution images are difficult to obtain with conventional gamma cameras because of the high energy of I-131 gamma photons (364 keV). Cerenkov-light imaging is a possible method for beta emitting radionuclides, and I-131 (606 MeV maximum beta energy) is a candidate to obtain high resolution images. We developed a high energy gamma camera system for I-131 radionuclide and combined it with a Cerenkov-light imaging system to form a gamma-photon/Cerenkov-light hybrid imaging system to compare the simultaneously measured images of these two modalities. The high energy gamma imaging detector used 0.85-mm×0.85-mm×10-mm thick GAGG scintillator pixels arranged in a 44×44 matrix with a 0.1-mm thick reflector and optical coupled to a Hamamatsu 2 in. square position sensitive photomultiplier tube (PSPMT: H12700 MOD). The gamma imaging detector was encased in a 2 cm thick tungsten shield, and a pinhole collimator was mounted on its top to form a gamma camera system. The Cerenkov-light imaging system was made of a high sensitivity cooled CCD camera. The Cerenkov-light imaging system was combined with the gamma camera using optical mirrors to image the same area of the subject. With this configuration, we simultaneously imaged the gamma photons and the Cerenkov-light from I-131 in the subjects. The spatial resolution and sensitivity of the gamma camera system for I-131 were respectively 3 mm FWHM and 10 cps/MBq for the high sensitivity collimator at 10 cm from the collimator surface. The spatial resolution of the Cerenkov-light imaging system was 0.64 mm FWHM at 10 cm from the system surface. Thyroid phantom and rat images were successfully obtained with the developed gamma-photon/Cerenkov-light hybrid imaging system, allowing direct comparison of these two modalities. Our developed gamma-photon/Cerenkov-light hybrid imaging system will be useful to evaluate the advantages and disadvantages of these two

  20. Is it safe to treat hyperthyroid patients with I-131 without fear of thyroid storm?

    PubMed

    Vijayakumar, Vani; Nusynowwitz, M L; Ali, S

    2006-07-01

    Thyroid storm is extremely rare. However, hyperthyroid patients with severe thyrotoxicosis are frequently not treated immediately with I-131 for fear of thyroid storm but are placed on thiouracil drugs for varying periods of time. We demonstrate herein that it is safe to treat these patients with 1-131, without pretreatment with thiouracil drugs, provided they do not have complicating intercurrent disease. Our definition of severe hyperthyroidism includes marked signs and symptoms of thyrotoxicosis, suppressed TSH, markedly elevated free T4 and/or free T3 and elevated radioactive iodine uptake (RAIU) (>30%) at 4 or 24 hours. Our diagnostic criteria for thyroid storm include two or more findings of fever (>38 degrees C, 100 degrees F), severe tachycardia, high pulse pressure, agitation with tremors, flushing, sweating, heart failure, nausea, vomiting, diarrhea, jaundice associated with high free T4 and/or free T3. Patients were selected retrospectively for the period between August 2003 and December 2004. One hundred and twenty-two patient visits were identified. These patients were treated with 370-740 MBq (10-20 mCi) of I-131 and were evaluated for any evidence of thyroid storm. Most of the patients were placed on beta blocker drugs at the time of initial I-131 therapy; these were continued for at least two months, when the first follow-up visit occurred. At the time of I-131 therapy, it is our policy to educate the patients to seek immediate medical attention for exacerbation of symptoms of thyrotoxicosis. Not one of these patients developed thyroid storm. A subset of 25% of these cases with higher potential for thyroid storm (RAIU more than 65%, very marked signs and symptoms, and very markedly elevated free T4 and/or free T3) also tolerated the I-131 therapy well with marked clinical improvement and no exacerbation of the thyrotoxic state. It is safe to administer I-131 to patients who are severely hyperthyroid without fear of thyroid storm, provided beta

  1. Comparison of image quality of different iodine isotopes (I-123, I-124, and I-131).

    PubMed

    Rault, Erwann; Vandenberghe, Stefaan; Van Holen, Roel; De Beenhouwer, Jan; Staelens, Steven; Lemahieu, Ignace

    2007-06-01

    I-131 is a frequently used isotope for radionuclide therapy. This technique for cancer treatment requires a pre-therapeutic dosimetric study. The latter is usually performed (for this radionuclide) by directly imaging the uptake of the therapeutic radionuclide in the body or by replacing it by one of its isotopes, which are more suitable for imaging. This study aimed to compare the image quality that can be achieved by three iodine isotopes: I-131 and I-123 for single-photon emission computed tomography imaging, and I-124 for positron emission tomography imaging. The imaging characteristics of each isotope were investigated by simulated data. Their spectrums, point-spread functions, and contrast-recovery curves were drawn and compared. I-131 was imaged with a high-energy all-purpose (HEAP) collimator, whereas two collimators were compared for I-123: low-energy high-resolution (LEHR) and medium energy (ME). No mechanical collimation was used for I-124. The influence of small high-energy peaks (>0.1%) on the main energy window contamination were evaluated. Furthermore, the effect of a scattering medium was investigated and the triple energy window (TEW) correction was used for spectral-based scatter correction. Results showed that I-123 gave the best results with a LEHR collimator when the scatter correction was applied. Without correction, the ME collimator reduced the effects of high-energy contamination. I-131 offered the worst results. This can be explained by the large amount of septal penetration from the photopeak and by the collimator, which gave a low spatial resolution. I-124 gave the best imaging properties owing to its electronic collimation (high sensitivity) and a short coincidence time window.

  2. 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

  3. 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.

  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. 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

  6. [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.

  7. 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

  8. Loss of immunoreactivity of I-131 labeled monoclonal antibody with storage is related to radiation damage

    SciTech Connect

    Reynolds, J.; Fejka, R.; Rotman, M.; Farkas, R.; Larson, S.

    1985-05-01

    In order to use a single preparation of I-131 monoclonal antibody on more than one day, it is important to determine the shelf life of these compounds. Fifteen I-131 (.128 to 15 mCi/ml) preparations of IgG or Fab fragments of antimelanoma antibody (96.5 or 48.7) were stored at 0-4/sup 0/C in pharmaceutical vials. Daily aliquots were tested for total immunoreactivity (IR) (JNM 24:123,1983), TCA precipitability and fractions using size exclusion HPLC. Loss of IR ranges from 0-54% during the first 24 hours to 0-92% over 6 days. Loss of IR occurred with both Fab and IgG. The rate of loss of IR correlated with the initial specific concentration (r = .8,p < .01) and specific activity (r = .78,p < .01) but dilution of the concentrated solution by 1000x or more stopped the deterioration process (p < .01) suggesting specific concentration to be the important variable. When mM cysteamine or cystamine were added to the concentrated solutions the loss of IR with time was inhibited (X/sup 2/,p < .001). TCA precipitation and HPLC analysis showed loss of antibody associated radioactivity but not to the extent of the change in IR. There can be significant loss of IR of I-131 monoclonal antibody during storage at 0-4/sup 0/C. and high concentration solutions (>5 mCi/ml.) must be used within 24 hours of labeling to assure an active preparation. The inhibition of IR loss by dilution or by addition of radioprotectors suggests that the process is due to radiation effects on the antibody.

  9. I-131 Dose Response for Incident Thyroid Cancers in Ukraine Related to the Chornobyl Accident

    PubMed Central

    Tronko, Mykola D.; Hatch, Maureen; Bogdanova, Tetyana I.; Oliynik, Valery A.; Lubin, Jay H.; Zablotska, Lydia B.; Tereschenko, Valery P.; McConnell, Robert J.; Zamotaeva, Galina A.; O’Kane, Patrick; Bouville, Andre C.; Chaykovskaya, Ludmila V.; Greenebaum, Ellen; Paster, Ihor P.; Shpak, Victor M.; Ron, Elaine

    2011-01-01

    Background: Current knowledge about Chornobyl-related thyroid cancer risks comes from ecological studies based on grouped doses, case–control studies, and studies of prevalent cancers. Objective: To address this limitation, we evaluated the dose–response relationship for incident thyroid cancers using measurement-based individual iodine-131 (I-131) thyroid dose estimates in a prospective analytic cohort study. Methods: The cohort consists of individuals < 18 years of age on 26 April 1986 who resided in three contaminated oblasts (states) of Ukraine and underwent up to four thyroid screening examinations between 1998 and 2007 (n = 12,514). Thyroid doses of I-131 were estimated based on individual radioactivity measurements taken within 2 months after the accident, environmental transport models, and interview data. Excess radiation risks were estimated using Poisson regression models. Results: Sixty-five incident thyroid cancers were diagnosed during the second through fourth screenings and 73,004 person-years (PY) of observation. The dose–response relationship was consistent with linearity on relative and absolute scales, although the excess relative risk (ERR) model described data better than did the excess absolute risk (EAR) model. The ERR per gray was 1.91 [95% confidence interval (CI), 0.43–6.34], and the EAR per 104 PY/Gy was 2.21 (95% CI, 0.04–5.78). The ERR per gray varied significantly by oblast of residence but not by time since exposure, use of iodine prophylaxis, iodine status, sex, age, or tumor size. Conclusions: I-131–related thyroid cancer risks persisted for two decades after exposure, with no evidence of decrease during the observation period. The radiation risks, although smaller, are compatible with those of retrospective and ecological post-Chornobyl studies. PMID:21406336

  10. Treatment of metastatic para-aortic paraganglioma by surgery, radiotherapy and I-131 mIBG.

    PubMed

    Ball, A B; Tait, D M; Fisher, C; Sinnett, H D; Harmer, C L

    1991-10-01

    A patient with a malignant, functioning, aortico-sympathetic paraganglioma and a solitary bone metastasis causing paraplegia was treated by spinal decompression, irradiation of the metastasis, surgical excision of the primary tumour and systemic I-131 meta-iodobenzyl-guanidine (mIBG). Sixteen months after treatment there was no clinical, radiological or biochemical evidence of residual disease and neurological function was restored. The case supports the use of combined treatment incorporating mIBG in patients with metastatic neuroendocrine tumours which demonstrate mIBG uptake.

  11. Severe hyponatremia in association with I(131) therapy in a patient with metastatic thyroid cancer.

    PubMed

    Nozu, Tsukasa; Yoshida, Yuri; Ohira, Masumi; Okumura, Toshikatsu

    2011-01-01

    Hyponatremia is a common clinical problem that results from various causes. Hypothyroidism is known to be one of the causes of this disorder. We report a case of metastatic thyroid cancer presenting with severe hyponatremia in association with hypothyroidism induced by pretreatment of I(131) therapy, such as a low-iodine diet and withdrawal of thyroid hormone. Serum arginine vasopressin (AVP) was elevated and urine osmolality was higher than that of serum. Saline infusion and thyroid hormone replacement normalized serum sodium and AVP. Inappropriate secretion of AVP in hypothyroid state was thought to be one of the causes of this hyponatremia.

  12. 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

  13. 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.

  14. Calibration of the Accuscan II In Vivo System for I-131 Thyroid Counting

    SciTech Connect

    Orval R. Perry; David L. Georgeson

    2011-07-01

    This report describes the March 2011 calibration of the Accuscan II HpGe In Vivo system for I-131 thyroid counting. The source used for the calibration was an Analytics mixed gamma source 82834-121 distributed in an epoxy matrix in a Wheaton Liquid Scintillation Vial with energies from 88.0 keV to 1836.1 keV. The center of the detectors was position 64-feet from the vault floor. This position places the approximate center line of the detectors at the center line of the source in the thyroid tube. The calibration was performed using an RMC II phantom (Appendix J). Validation testing was performed using a Ba-133 source and an ANSI N44.3 Phantom (Appendix I). This report includes an overview introduction and records for the energy/FWHM and efficiency calibrations including verification counting. The Accuscan II system was successfully calibrated for counting the thyroid for I-131 and verified in accordance with ANSI/HPS N13.30-1996 criteria.

  15. Carcinoid tumors: CT and I-131 meta-iodo-benzylguanidine scintigraphy

    SciTech Connect

    Adolph, J.M.; Kimmig, B.N.; Georgi, P.; zum Winkel, K.

    1987-07-01

    The diagnostic value of computed tomography (CT) and iodine-131 meta-iodo-benzylguanidine (MIBG) scintiscanning was studied in nine patients with histologically proved carcinoid tumors of intestinal (n = 4), bronchial (n = 3), or thymic (n = 2) origin. CT scans clearly depicted the tumors and metastases in relation to surrounding vital structures but did not provide findings specific for carcinoids. The appearance on CT of an abdominal soft-tissue mass with a radiating pattern of linear densities was found to be highly suggestive of intestinal carcinoid tumors. I-131 MIBG scintiscans disclosed intense tracer uptake in the tumors and metastases in five patients. MIBG studies correctly depicted nine of nine tumor manifestations in intestinal carcinoids and four of six tumor manifestations in bronchus carcinoids. No MIBG concentration was found in thymus carcinoids. Because of its selective uptake mechanism, I-131 MIBG scintigraphy can allow specific detection and localization of neuroendocrine tumor tissue in patients with suspected carcinoid tumors. MIBG scintigraphy has diagnostic potential as a screening procedure in carcinoid tumors, especially those of intestinal origin.

  16. Neuroblastoma: Imaging evaluation by sequential Tc-99m MDP, I-131 MIBG, and Ga-67 citrate studies

    SciTech Connect

    Garty, I.; Friedman, A.; Sandler, M.P.; Kedar, A. )

    1989-07-01

    Fourteen children with histopathologically confirmed neuroblastoma underwent sequential correlative imaging studies using I-131 MIBG, Tc-99m MDP, and Ga-67 citrate during various stages of the disease. Of the patients 86% showed I-131 MIBG accumulation in the primary tumoral site, whereas 71% showed Tc-99m MDP and 79% Ga-67 citrate uptake. In 86% at least one of the two latter radiopharmaceuticals concentrated in the primary tumor. The use of all three radiopharmaceuticals raised the detection rate to 93%. Of the osseous or extraosseous metastases 100% were detected by Tc-99m MDP studies. The I-131 MIBG studies were positive in 71% of the osseous metastases and in 70% of the extraosseous metastases. No Ga-67 citrate uptake was demonstrated in osseous metastases, although one extraosseous lung metastasis concentrated this radiopharmaceutical. Tc-99m MDP bone imaging was the best method for diagnosing metastatic spread of the disease and for monitoring the results of treatment. Primary tumor uptake was best indicated by I-131 MIBG. Both Ga-67 citrate and I-131 MIBG were superior to Tc-99m MDP with regard to accurately demonstrating the extent of primary tumors. Only Tc-99m MDP indicated the relationship of these tumors to the kidneys and neighboring osseous structures, providing early screening of kidney compression. Ga-67 citrate study was mainly indicated in tumors with catecholamine depletion, which failed to concentrate the other two radiopharmaceuticals. I-131 MIBG proved especially useful in detecting neuroblastoma with negative Tc-99m MDP and Ga-67 citrate studies and also proved to be helpful with those cases in which I-131 MIBG was planned for therapy. The following strategy is suggested for evaluating neuroblastoma.

  17. Complex chimerism

    PubMed Central

    Ma, Kimberly K.; Petroff, Margaret G.; Coscia, Lisa A.; Armenti, Vincent T.; Adams Waldorf, Kristina M.

    2013-01-01

    Thousands of women with organ transplantation have undergone successful pregnancies, however little is known about how the profound immunologic changes associated with pregnancy might influence tolerance or rejection of the allograft. Pregnant women with a solid organ transplant are complex chimeras with multiple foreign cell populations from the donor organ, fetus, and mother of the pregnant woman. We consider the impact of complex chimerism and pregnancy-associated immunologic changes on tolerance of the allograft both during pregnancy and the postpartum period. Mechanisms of allograft tolerance are likely dynamic during pregnancy and affected by the influx of fetal microchimeric cells, HLA relationships (between the fetus, pregnant woman and/or donor), peripheral T cell tolerance to fetal cells, and fetal minor histocompatibility antigens. Further research is necessary to understand the complex immunology during pregnancy and the postpartum period of women with a solid organ transplant. PMID:23974274

  18. Fetal radiation dose estimates for I-131 sodium iodide in cases where conception occurs after administration

    SciTech Connect

    Sparks, R.B.; Stabin, M.G.

    1999-01-01

    After administration of I-131 to the female patient, the possibility of radiation exposure of the embryo/fetus exists if the patient becomes pregnant while radioiodine remains in the body. Fetal radiation dose estimates for such cases were calculated. Doses were calculated for various maternal thyroid uptakes and time intervals between administration and conception, including euthyroid and hyperthyroid cases. The maximum fetal dose calculating was about 9.8E-03 mGy/MBq, which occurred with 100% maternal thyroid uptake and a 1 week interval between administration and conception. Placental crossover of the small amount of radioiodine remaining 90 days after conception was also considered. Such crossover could result in an additional fetal dose of 9.8E-05 mGy/MBq and a maximum fetal thyroid self dose of 3.5E-04 mGy/MBq.

  19. A PROGRESSIVE REACTION OCCURRING WITH A RADIOACTIVE HEMOLYSIN, SODIUM OLEATE-I131

    PubMed Central

    Ponder, Eric; Ponder, Ruth V.

    1958-01-01

    Sodium oleate reacts progressively with human red cells at pH 7. By progressive is meant a reaction which is not adequately described as reversible or irreversible; such reactions cannot be stopped once they are under way, and are probably associated with a more or less stable "internal" lysin phase at the cell surfaces. The uptake of the lysin and the effect of dilution on the uptake can be studied by converting sodium oleate into the radioactive form, sodium oleate-I131. The uptake is a parabolic function of the lysin initially present in the system, and the effect of a tenfold dilution of systems in which red cells have remained in contact with the lysin for 2 minutes is to reduce the lysin taken up at the cell surfaces twofold. The lysin rapidly forms a relatively stable layer at the cell interfaces, and this layer is little affected by the dilution of the system as a whole. PMID:13491825

  20. 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

  1. Medically-derived I-131: a potential tool for understanding the fate of wastewater nitrogen in aquatic systems

    NASA Astrophysics Data System (ADS)

    Rose, P. S.; Smith, J. P.; Aller, R. C.; Cochran, J. K.; Swanson, R. L.; Murthy, S. N.; Coffin, R. B.

    2010-12-01

    Iodine-131(t1/2 = 8 days) has been measured in Potomac River water and sediments in the vicinity of the Blue Plains Water Pollution Control Plant (WPCP), Washington, DC. The source of I-131 is medical, where it is commonly used to treat thyroid cancer and hyperthyroidism. Iodine is metabolized by patients and eliminated primarily in urine. While other medical radioisotopes may enter the environment via sewage effluent, the nature and quantity of treatments using I-131 cause it to account for much of the radioactivity in sewage effluent. Natural iodine in aquatic systems is biologically cycled similar to other nutrients, such as nitrogen. Iodine-131 concentrations measured in sewage effluent from Blue Plains WPCP and in the Potomac River suggest a relatively continuous discharge of this isotope. Dissolved I-131 shows a strong, positive correlation with δ15N values of nitrate in the river. The range of I-131 concentrations detected in surface waters is 0.18 ± 0.01 to 0.68 ± 0.02 Bq/L. Surface water δ15NO3 values ranged from 8.7 ± 0.3 to 33.4 ± 7.3 ‰ with NO3+NO2 concentrations between 0.38 ± 0.02 and 2.79 ± 0.13 mgN/L. Sediment profiles of particulate I-131 and δ15N indicate rapid mixing or sedimentation and in many cases remineralization of a heavy nitrogen source consistent with wastewater nitrogen. Iodine-131 concentrations in sediments ranged from 1.31 ± 0.8 to 117 ± 2 Bq/kg dry weight. Values of δ15N in sediments ranged from 4.7 ± 0.1 ‰ to 9.3 ± 0.1 ‰. We propose that I-131 coupled with δ15N can be an excellent tracer for the short-term fate of wastewater nitrogen in this system. However, the utility of I-131 as a tracer is not limited to use in the Potomac River. Other studies have documented the presence of I-131 in several aquatic systems and continuous discharges of this radioisotope in sewage effluent are likely to be widespread in urban environments.

  2. Use of fusion images of I-131 metaiodobenzylguanidine, SPECT, and magnetic resonance studies to identify a malignant pheochromocytoma.

    PubMed

    Fujita, A; Hyodoh, H; Kawamura, Y; Kanegae, K; Furuse, M; Kanazawa, K

    2000-06-01

    Pheochromocytoma is a chromaffin tumor in which 10% are extra-adrenal and 10% are malignant. I-131 metaiodobenzylguanidine (MIBG) scintigraphy has an important role in the identification of these tumors and investigation of metastatic lesions. The authors describe a 36-year-old woman who underwent resection of a malignant left adrenal pheochromocytoma who was thought to have metastases in the liver and para-aortic lymph nodes. Fusion images of I-131 MIBG SPECT and magnetic resonance studies were obtained to properly identify the metastatic lesions. These fusion images helped greatly in subsequent surgery.

  3. Sialadenitis following low dose I-131 diagnostic thyroid scan with Thyrogen® (recombinant human thyroid stimulating hormone - thyrotropin alfa)

    PubMed Central

    Gonzalez, Marta E; Muttikkal, Thomas Jose Eluvathingal; Rehm, Patrice K

    2015-01-01

    Salivary dysfunction and sialadenitis are well known complications of radioiodine treatment for thyroid cancer. The parotid gland is more frequently affected and the salivary gland injury is dose related. The symptoms may develop shortly after therapeutic Iodine 131(I-131) administration or months later and progress with time. The development of unilateral parotiditis following a low dose, diagnostic I-131 scan performed following Thyrogen stimulation in a patient without prior history of sialadenitis is rare in our experience, and has not been reported in the medical literature. PMID:26622936

  4. 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

  5. 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.

  6. 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

  7. Iodine-131 metaiodobenzylguanidine (I-131 MIBG) diagnosis and therapy of pheochromocytoma and paraganglioma: current problems, critical issues and presentation of a sample case.

    PubMed

    Castellani, M R; Aktolun, C; Buzzoni, R; Seregni, E; Chiesa, C; Maccauro, M; Aliberti, G L; Vellani, C; Lorenzoni, A; Bombardieri, E

    2013-06-01

    Iodine-131 metaiodobenzylguanidine (I-131 MIBG) has been used for the diagnosis and treatment of malignant pheochromocytomas (PHEO) and paragangliomas (PGL) since 1980's. Despite increasing amount of experience with iodine-131 (I-131) MIBG therapy, many important questions still exist. In this article, we will discuss the current problems learned from clinical experience in diagnosis and therapy of PHEO/PGL with I-131 MIBG, and present a sample case to emphasize the critical aspects for an optimal treatment strategy.

  8. Implementation of iodine biokinetic model for interpreting I-131 contamination in breast milk after the Fukushima nuclear disaster

    NASA Astrophysics Data System (ADS)

    Tani, Kotaro; Kurihara, Osamu; Kim, Eunjoo; Yoshida, Satoshi; Sakai, Kazuo; Akashi, Makoto

    2015-07-01

    After the accident at the Fukushima Daiichi Nuclear Power Plant run by Tokyo Electric Power Company in 2011, breast milk samples obtained from volunteers living in Fukushima and neighboring prefectures were examined and small amounts of I-131 (2.2-36.3 Bq/kg) were detected in some samples. In this work, the I-131 concentrations in breast milk from nursing mothers in Ibaraki prefecture were calculated based on the iodine biokinetic model during lactation together with time-variable intake scenarios by inhalation of ambient air and ingestion of tap water, using the authors’ code. The calculated I-131 concentrations in breast milk generally agreed with those measured for the volunteers. Based on the results, thyroid equivalent doses to breast-fed infants were estimated for each place of residence of the volunteers on the assumption that these infants consumed 800 ml of breast milk every day, resulting in 10-11 mSv for Mito and Kasama cities and 1.1-1.8 mSv for Tsukuba and Moriya cities. It was suggested that breast milk consumption could be a major contributor to internal dose of breast-fed infants in areas with mild I-131 pollution; however, further studies considering personal behavior surveys would be necessary to estimate individual doses.

  9. Implementation of iodine biokinetic model for interpreting I-131 contamination in breast milk after the Fukushima nuclear disaster

    PubMed Central

    Tani, Kotaro; Kurihara, Osamu; Kim, Eunjoo; Yoshida, Satoshi; Sakai, Kazuo; Akashi, Makoto

    2015-01-01

    After the accident at the Fukushima Daiichi Nuclear Power Plant run by Tokyo Electric Power Company in 2011, breast milk samples obtained from volunteers living in Fukushima and neighboring prefectures were examined and small amounts of I-131 (2.2–36.3 Bq/kg) were detected in some samples. In this work, the I-131 concentrations in breast milk from nursing mothers in Ibaraki prefecture were calculated based on the iodine biokinetic model during lactation together with time-variable intake scenarios by inhalation of ambient air and ingestion of tap water, using the authors’ code. The calculated I-131 concentrations in breast milk generally agreed with those measured for the volunteers. Based on the results, thyroid equivalent doses to breast-fed infants were estimated for each place of residence of the volunteers on the assumption that these infants consumed 800 ml of breast milk every day, resulting in 10–11 mSv for Mito and Kasama cities and 1.1–1.8 mSv for Tsukuba and Moriya cities. It was suggested that breast milk consumption could be a major contributor to internal dose of breast-fed infants in areas with mild I-131 pollution; however, further studies considering personal behavior surveys would be necessary to estimate individual doses. PMID:26198990

  10. Empirical shielding design data for facilities administering I131 for thyroid carcinoma.

    PubMed

    Groth, M J

    1998-12-01

    Retrospective review of the records for 434 post thyroidectomy patients receiving I131 therapy for thyroid carcinoma revealed approximately 75% of the patients were discharged within 48 hours and 90% within 72 hours. Criterion for discharge was an external radiation dose below 25 muSv/hr, measured at one metre anterior to the patient's neck. The time-averaged average dose rate one metre anterior to the neck of a typical patient during the isolation period was 72 muSv/hr, with 90% of the patients below 82 muSv/hr. After correcting for the effects of patient size and scatter, the effective design dose rate from a patient in an isolation room treating two or three patients/week is 105 muSv.m2.hr-1, or 75 muSv.m.hr-1 where only one patient is treated each week. Concrete is the most economical shielding material, with 190 mm filled concrete block walls and 150 mm concrete floors as the minimum recommended shielding for a radioiodine therapy suite. Additional shielding will be required if the suite adjoins (including areas immediately above and below) areas with a high occupancy factor.

  11. Application of a medium-energy collimator for I-131 imaging after ablation treatment of differentiated thyroid cancer.

    PubMed

    Kobayashi, Masato; Wakabayashi, Hiroshi; Kayano, Daiki; Konishi, Takahiro; Kojima, Hironori; Yoneyama, Hiroto; Okuda, Koichi; Tsushima, Hiroyuki; Onoguchi, Masahisa; Kawai, Keiichi; Kinuya, Seigo

    2014-07-01

    High-energy (HE) collimators are usually applied for I-131 imaging after ablation treatment of differentiated thyroid cancer (DTC). However, purchase of HE collimators has been avoided in many nuclear medicine departments because the HE collimators are more expensive than other collimators. In this study, we compared the I-131 imaging using HE- and medium-energy (ME) collimators, which is more versatile than HE collimators. To simulate DTC patients with extra-thyroid beds, a phantom of acrylic containers containing I-131 was used. To simulate patients with thyroid beds, four phantoms representing extra-thyroid beds were arranged around the phantom representing normal thyroid tissues. Patients administered 1.11 or 3.70 GBq NaI-131 were also evaluated. Whole-body imaging and SPECT imaging of the phantoms and patients performed using HE-general-purpose (HEGP) and ME-low-penetration (MELP) collimators, and full-width at half maximum (FWHM) and percent coefficient of variation (%CV) were measured. In the extra-thyroid beds, FWHM and %CV with MELP were negligibly different from those with HEGP in whole-body imaging. Although FWHM with MELP was a little different from that with HEGP in SPECT imaging, %CV with MELP was significantly higher than that with HEGP. In the thyroid beds, only an extra-thyroid bed including higher radioactivity was identified in whole-body imaging with both collimators. Although SPECT images with MELP could not clarify extra-thyroid beds with low radioactivity, HEGP could identify them. In patients, although some whole-body images with MELP could not detect extra-thyroid beds, whole-body imaging with HEGP and SPECT imaging with both collimators could detect them. Although HEGP is the best collimator for I-131 imaging, MELP is applicable for not only whole-body imaging but also SPECT imaging.

  12. 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.

  13. Use of radioactive iodine I-131 and monitoring of radioactivity in patients with chronic kidney disease on haemodialysis.

    PubMed

    Gallegos-Villalobos, Angel; García-López, Fernando; Escalada, Carmen; Ortiz, Juan J; Cardona, Jorge; Medina, Amparo; Portolés, José

    2014-05-21

    Thyroid carcinoma is a neoplasia with a higher incidence in patients with chronic kidney disease. In recent years advances have been made in diagnostic and therapeutic trials. Dialysis patients are a particular group, their cancer being detected indirectly in the study of secondary hyperparathyroidism and during the study prior to renal transplantation. Thyroidectomy is the definitive treatment, but in patients with risk of recurrence, ablative therapy is required using radioactive iodine I-131, which is predominantly eliminated by renal excretion, therefore its use in patients on dialysis poses a problem in terms of dosage. Two cases are presented of patients on haemodialysis undergoing radioablation with radioactive iodine I-131, which with multidisciplinary treatment had the expected results in the patients.

  14. Sialoendoscopy combined with an internal stent and postoperative massage as a comprehensive treatment of delayed I(131)-induced parotitis.

    PubMed

    Meng, Q; Fang, W; Long, X; Deng, M; Li, J; Ke, J

    2017-09-01

    A common complication of radioiodine (I(131)) treatment of thyroid cancer is parotitis. Here we describe our clinical experience in treating delayed I(131)-induced parotitis using sialoendoscopy together with an internal stent and postoperative massage. In this retrospective cohort study we reviewed 32 patients who were treated in that way under general anaesthesia between July 2010 and March 2015. Their age, sex, and the time to development of the parotitis were collected from the hospital's database. All patients were evaluated using a visual analogue scale (VAS), sialography, and computed tomography preoperatively. The analyses of VAS scores were made during postoperative follow-up visits. We used the paired Student's t test and one-way ANOVA to assess the significance of differences, and probabilities of < 0.05 were accepted as significant. The mean (SD) age of the 32 patients was 50 (11) years, and they developed symptoms of delayed parotitis after a mean (SD) of 12 (11) months. The mean time between treatment with I(131) and sialoendoscopy was 26 (10) months. Ductal stenosis was the most common sialoendoscopic feature, together with mucous plugs and fibrosis. Fifty of the 56 ducts were successfully dilated by sialoendoscopy, and VAS scores significantly decreased from a preoperative 7.3 (1.1) to a postoperative 3.3 (2.1) (p=0.000) during follow-up of 3 - 41 months. Sialoendoscopic interventions combined with an internal stent and postoperative massage may be optimal comprehensive treatment for delayed I(131)-induced parotitis. Copyright © 2017 The British Association of Oral and Maxillofacial Surgeons. Published by Elsevier Ltd. All rights reserved.

  15. 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.

  16. 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.

  17. 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

  18. Three-dimensional cellular dosimetry of I-131 mIBG in neuroblastoma with EGS4 Monte Carlo code

    SciTech Connect

    Gouriou, J.; Ricard, M.; Lumbroso, J.; Aubert, B. |

    1995-05-01

    The adequate distribution of radiation dose to tumor cells is the most important factor for the outcome of internal (metabolic) radiotherapy. This study investigates the dosimetry of I-131 meta-iodobenzyl-guanidine at the cellular level in neuroblastoma. We developed a program based on the EGS4 Monte Carlo code allowing the computation of basic dosimetric parameters such as absorbed and cumulated fractions, scaled dose point kernels and dose rates, especially for radionuclides with therapeutic potential. It can be applied to various types of 3-D radionuclide tumor distributions. Geometrical parameters and mIBG uptake in xenografted tumors (nude mice, SK-N-SH) were obtained from micro-autoradiographies and SIMS microscopy images. The tumor could be simulated by a spheroid (500 {mu}m in radius) made up of spherical cells (9 {mu}m in radius) with a 1 {mu}m cytoplasm. Among this cell population, only 3% bound mIBG with local maximal rates of up to 16%. The radiation doses were calculated for I-131, since this radionuclide is the most widely used for labelling mIBG for a therapeutic potential. It can be applied to various types of 3-D radionuclide tumor distributions. Geometrical parameters and mIBG uptake in xenografted tumors (nude mice, SK-N-SH) were obtained from micro-autoradiographies and SIMS microscopy images.

  19. RET/PTC and PAX8/PPARγ chromosomal rearrangements in post-Chernobyl thyroid cancer and their association with I-131 radiation dose and other characteristics

    PubMed Central

    Leeman-Neill, Rebecca J.; Brenner, Alina V.; Little, Mark P.; Bogdanova, Tetiana I.; Hatch, Maureen; Zurnadzy, Liudmyla Y.; Mabuchi, Kiyohiko; Tronko, Mykola D.; Nikiforov, Yuri E.

    2012-01-01

    Background Childhood exposure to I-131 from the 1986 Chernobyl accident led to a sharp increase in papillary thyroid carcinoma (PTC) incidence in regions surrounding the reactor. Data concerning the association between genetic mutations in PTCs and individual radiation doses are limited. Methods We performed mutational analysis of 62 PTCs diagnosed in a Ukrainian cohort of patients who were <18 y.o. in 1986 and received 0.008-8.6 Gy of I-131 to the thyroid and explored associations between mutation types and I-131 dose and other characteristics. Results RET/PTC rearrangements were most common (35%), followed by BRAF (15%) and RAS (8%) point mutations. Two tumors carrying PAX8/PPARγ rearrangement were identified. We found a significant negative association with I-131 dose for BRAF and RAS point mutations and a significant concave association with I-131 dose, with an inflection point at 1.6 Gy and odds ratio 2.1, based on a linear-quadratic model for RET/PTC and PAX8/PPARγ rearrangements. The trends with dose were significantly different between tumors with point mutations and rearrangements. Compared to point mutations, rearrangements were associated with residence in the relatively iodine deficient Zhytomyr region, younger age at exposure or surgery, and male gender. Conclusions Our results provide the first demonstration of PAX8/PPARγ rearrangements in post-Chernobyl tumors and show different associations for point mutations and chromosomal rearrangements with I-131 dose and other factors. These data support the relationship between chromosomal rearrangements, but not point mutations, and I-131 exposure and point to a possible role of iodine deficiency in generation of RET/PTC rearrangements in these patients. PMID:23436219

  20. Marrow Ablative and Immunosuppressive Effects of I-131-anti-CD45 Antibody in Congenic and H2-Mismatched Murine Transplant Models

    SciTech Connect

    Matthews, D. C.; Martin, P J.; Nourigat, C.; Appelbaum, F. R.; Fisher, Darrell R. ); Bernstein, I. D.

    1998-12-01

    Targeted hematopoietic irradiation delivered by I-131-anti-CD45 antibody has been combined with conventional marrow transplant preparative regimens in an effort to decrease relapse. Before increasing the proportion of therapy delivered by radiolabeled antibody, the myeloablative and immunosuppressive effects of such low dose rate irradiation must be quantitated. We have examined the ability of I-131-anti-CD45 antibody to facilitate engraftment in Ly5-congenic and H2-mismatched murine marrow transplant models. Recipient B6-Ly5-a mice were treated with 30F11 antibody labeled with 0.1 to 1.5 mCi I-131 and/or total body irradiation (TBI), followed by T-cell-depleted marrow from Ly5-b-congenic (C57BL/6) or H2-mismatched (BALB/c) donors. Engraftment was achieved readily in the Ly5-congenic setting, with greater than 80% donor granulocytes and T cells after 0.5 mCi I-131 (estimated 17 Gy to marrow) or 8 Gy TBI. A higher TBI dose (14 Gy) was required to achieve engraftment of H2-mismatched mar row, and engraftment occurred in only 3 of 11 mice receiving 1.5 mCi I-131 delivered by anti-CD45 antibody. Engraftment of H2-mismatched marrow was achieved in 22 of 23 animals receiving 0.75 mCi I-131 delivered by anti-CD45 antibody combined with 8 Gy TBI. Thus, targeted radiation delivered via I-131-anti-CD45 antibody can enable engraftment of congenic marrow and can partially replace TBI when transplanting T-cell-depleted H2-mismatched marrow.

  1. Second malignancies in patients with differentiated thyroid carcinoma treated with low and medium activities of radioactive I-131

    PubMed Central

    PICIU, DOINA; PESTEAN, CLAUDIU; BARBUS, ELENA; LARG, MARIA IULIA; PICIU, ANDRA

    2016-01-01

    Background and aim This study aimed at determining whether there is a risk regarding the development of second primary malignancies after patient exposure to the low and medium radioiodine activity used during the treatment of differentiated thyroid cancers (DTC). Methods Second primary malignancies that occurred after DTC were detected in 1,990 patients treated between 1970 and 2003. The mean long-term follow-up period was 182 months. Results Radioiodine I-131was administrated at a mean dose of 63.2 mCi. There were 93 patients with at least one second primary malignancy. The relative risk of development of second malignancy in DTC patients was increased (p<0.0001) for breast, uterine and ovarian cancers compared with the general population. Conclusions The overall risk concerning the development of second primary malignancies was related to the presence of DTC, but not to exposure to the low and medium activities of radioiodine administered as adjuvant therapy. PMID:27547058

  2. 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.

  3. 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

  4. Preparation of clinical-scale (177) Lu-Rituximab: Optimization of protocols for conjugation, radiolabeling and freeze-dried kit formulation.

    PubMed

    Guleria, Mohini; Das, Tapas; Kumar, Chandan; Amirdhanayagam, Jeyachitra; Sarma, Haladhar D; Banerjee, Sharmila

    2017-02-08

    Rituximab is a monoclonal chimeric antibody which has been approved by US FDA for immunotherapy of Non-Hodgkins' lymphoma (NHL). Bexxar and Zevalin are the two other approved radiolabeled antibodies for radioimmunotherapy of NHL; however the fact that they are of murine origin reduces their treatment efficacy. To circumvent this, efforts have been made to radiolabel Rituximab with various therapeutic radioisotopes. In the present study, an effort has been made to optimize the conjugation (BFCA and antibody) and radiolabeling procedures for the preparation of clinical-scale (177) Lu-labeled Rituximab. An attempt was also made to prepare the freeze-dried Rituximab kit for the easy and convenient clinical translation of the agent. Clinical-scale (177) Lu-Rituximab (40 mCi, 1.48 GBq) was prepared with >95% radiochemical purity using the kit. Biological evaluation of (177) Lu-Rituximab was carried out by in-vitro cell binding studies in Raji cell lines, which showed satisfactory binding at 4 and 37 °C. Pharmacokinetic behaviour of the agent, evaluated by biodistribution studies in normal Swiss mice, revealed high blood and liver uptake at the initial time points; although it exhibited slow and gradual clearance with time. The study indicates that clinical-scale (177) Lu-Rituximab could be conveniently formulated using the methodology described in the present article.

  5. 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.

  6. 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.

  7. 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.

  8. Comparison of internal dosimetry factors for three classes of adult computational phantoms with emphasis on I-131 in the thyroid.

    PubMed

    Lamart, Stephanie; Bouville, Andre; Simon, Steven L; Eckerman, Keith F; Melo, Dunstana; Lee, Choonsik

    2011-11-21

    The S values for 11 major target organs for I-131 in the thyroid were compared for three classes of adult computational human phantoms: stylized, voxel and hybrid phantoms. In addition, we compared specific absorbed fractions (SAFs) with the thyroid as a source region over a broader photon energy range than the x- and gamma-rays of I-131. The S and SAF values were calculated for the International Commission on Radiological Protection (ICRP) reference voxel phantoms and the University of Florida (UF) hybrid phantoms by using the Monte Carlo transport method, while the S and SAF values for the Oak Ridge National Laboratory (ORNL) stylized phantoms were obtained from earlier publications. Phantoms in our calculations were for adults of both genders. The 11 target organs and tissues that were selected for the comparison of S values are brain, breast, stomach wall, small intestine wall, colon wall, heart wall, pancreas, salivary glands, thyroid, lungs and active marrow for I-131 and thyroid as a source region. The comparisons showed, in general, an underestimation of S values reported for the stylized phantoms compared to the values based on the ICRP voxel and UF hybrid phantoms and relatively good agreement between the S values obtained for the ICRP and UF phantoms. Substantial differences were observed for some organs between the three types of phantoms. For example, the small intestine wall of ICRP male phantom and heart wall of ICRP female phantom showed up to eightfold and fourfold greater S values, respectively, compared to the reported values for the ORNL phantoms. UF male and female phantoms also showed significant differences compared to the ORNL phantom, 4.0-fold greater for the small intestine wall and 3.3-fold greater for the heart wall. In our method, we directly calculated the S values without using the SAFs as commonly done. Hence, we sought to confirm the differences observed in our S values by comparing the SAFs among the phantoms with the thyroid as a

  9. Comparison of internal dosimetry factors for three classes of adult computational phantoms with emphasis on I-131 in the thyroid

    NASA Astrophysics Data System (ADS)

    Lamart, Stephanie; Bouville, Andre; Simon, Steven L.; Eckerman, Keith F.; Melo, Dunstana; Lee, Choonsik

    2011-11-01

    The S values for 11 major target organs for I-131 in the thyroid were compared for three classes of adult computational human phantoms: stylized, voxel and hybrid phantoms. In addition, we compared specific absorbed fractions (SAFs) with the thyroid as a source region over a broader photon energy range than the x- and gamma-rays of I-131. The S and SAF values were calculated for the International Commission on Radiological Protection (ICRP) reference voxel phantoms and the University of Florida (UF) hybrid phantoms by using the Monte Carlo transport method, while the S and SAF values for the Oak Ridge National Laboratory (ORNL) stylized phantoms were obtained from earlier publications. Phantoms in our calculations were for adults of both genders. The 11 target organs and tissues that were selected for the comparison of S values are brain, breast, stomach wall, small intestine wall, colon wall, heart wall, pancreas, salivary glands, thyroid, lungs and active marrow for I-131 and thyroid as a source region. The comparisons showed, in general, an underestimation of S values reported for the stylized phantoms compared to the values based on the ICRP voxel and UF hybrid phantoms and relatively good agreement between the S values obtained for the ICRP and UF phantoms. Substantial differences were observed for some organs between the three types of phantoms. For example, the small intestine wall of ICRP male phantom and heart wall of ICRP female phantom showed up to eightfold and fourfold greater S values, respectively, compared to the reported values for the ORNL phantoms. UF male and female phantoms also showed significant differences compared to the ORNL phantom, 4.0-fold greater for the small intestine wall and 3.3-fold greater for the heart wall. In our method, we directly calculated the S values without using the SAFs as commonly done. Hence, we sought to confirm the differences observed in our S values by comparing the SAFs among the phantoms with the thyroid as a

  10. Chimeric Pestivirus Experimental Vaccines.

    PubMed

    Reimann, Ilona; Blome, Sandra; Beer, Martin

    2016-01-01

    Chimeric pestiviruses have shown great potential as marker vaccine candidates against pestiviral infections. Exemplarily, we describe here the construction and testing of the most promising classical swine fever vaccine candidate "CP7_E2alf" in detail. The description is focused on classical cloning technologies in combination with reverse genetics.

  11. 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

  12. Cellular and molecular effects of beta radiation from I-131 on human tumor cells: a comparison with gamma radiation.

    PubMed

    Kumar, Chandan; Jayakumar, Sundarraj; Pandey, Badri N; Samuel, Grace; Venkatesh, Meera

    2014-01-01

    To study the comparative effects of beta radiation emitted from Na(131)I with equivalent dose of (60)Co γ- radiation across a range of tumor types and underlying mechanism of cytotoxicity. Different tumor cell lines of various tissue origin viz. Raji, U937, A431 and MCF-7 were irradiated with beta radiation emitted from Na(131)I and equivalent dose of (60)Co γ- radiation (0.4 Gy). Cellular toxicity and apoptosis study were carried out in four cell lines and the effects were compared. Gene expression studies of P21, RAD51 and BAX genes were analyzed by q-PCR after β- and γ-irradiation. Cell viability (trypan blue assay) and apoptosis (DNA fragmentation and cleavage of PARP assays) studies for both types of radiation showed that among the four cell lines, A431 is most radio-resistant while MCF-7 and U937 are moderately radiation resistant and Raji cells showed maximum radiosensitivity. However, irradiation of cells with beta radiation from I-131 resulted in enhanced toxicity and apoptosis in tumor cells compared to equivalent dose of γ- rays. Gene expression studies in Raji cells showed difference in magnitude and kinetics of RAD51 and P21 expression after β- and γ-irradiation. Our results showed higher efficacy of beta radiation in induction of tumor cell cytotoxicity and apoptosis compared to an equivalent dose of γ-radiation, which may be associated with differential DNA damage and subsequent repair kinetics in tumor cells after these radiations.

  13. False Positive Findings on I-131 WBS and SPECT/CT in Patients with History of Thyroid Cancer: Case Series

    PubMed Central

    Hannoush, Zeina C.; Palacios, Juan D.; Kuker, Russ A.

    2017-01-01

    Introduction. Although whole body scan (WBS) with I-131 is a highly sensitive tool for detecting normal thyroid tissue and metastasis of differentiated thyroid cancer (DTC), it is not specific. Additional information, provided by single photon emission computed tomography combined with X-ray computed tomography (SPECT/CT) and by the serum thyroglobulin level, is extremely useful for the interpretation of findings. Case Presentation. We report four cases of false positive WBS in patients with DTC: ovarian uptake corresponding to an endometrioma, scrotal uptake due to a spermatocele, rib-cage uptake due to an old fracture, and hepatic and renal uptake secondary to a granuloma and simple cyst, respectively. Conclusions. Trapping, organification, and storage of iodine are more prominent in thyroid tissue but not specific. Physiologic sodium-iodine symporter expression in other tissues explains some, but not all, of the WBS false positive cases. Other proposed etiologies are accumulation of radioiodine in inflamed organs, metabolism of radiodinated thyroid hormone, presence of radioiodine in body fluids, and contamination. In our cases nonthyroidal pathologies were suspected since the imaging findings were not corroborated by an elevated thyroglobulin level, which is considered a reliable tumor marker for most well-differentiated thyroid cancers. Clinicians should be aware of the potential pitfalls of WBS in DTC to avoid incorrect management. PMID:28246564

  14. Radionuclide I-131 Labeled Albumin-Paclitaxel Nanoparticles for Synergistic Combined Chemo-radioisotope Therapy of Cancer

    PubMed Central

    Tian, Longlong; Chen, Qian; Yi, Xuan; Wang, Guanglin; Chen, Jie; Ning, Ping; Yang, Kai; Liu, Zhuang

    2017-01-01

    Development of biocompatible/biodegradable materials with multiple functionalities via simple methods for cancer combination therapy has attracted great attention in recent years. Herein, paclitaxel (PTX), a popular anti-tumor chemotherapeutic drug, is used to induce the self-assembly of human serum albumin (HSA) pre-labeled with radionuclide I-131, obtaining 131I-HSA-PTX nanoparticles for combined chemotherapy and radioisotope therapy (RIT) of cancer. Such 131I-HSA-PTX nanoparticles show prolonged blood circulation time, high tumor specific uptake and excellent intra-tumor penetration ability. Interestingly, as revealed by in vivo photoacoustic imaging and ex vivo immunofluorescence staining, PTX delivered into the tumor by HSA-nanoparticle transportation can remarkably enhance the tumor local oxygen level and suppress the expression of HIF-1α, leading to greatly relieved tumor hypoxia. As the results, the combined in vivo chemotherapy & RIT with 131I-HSA-PTX nanoparticles in the animal tumor model offers excellent synergistic therapeutic efficacy, likely owing to the greatly modulated tumor microenvironment associated with PTX-based chemotherapy. Therefore, in this work, a simple yet effective therapeutic agent is developed for synergistic chemo-RIT of cancer, promising for future clinic translations in cancer treatment. PMID:28255354

  15. Thymic uptake after high-dose I-131 treatment in patients with differentiated thyroid carcinoma: a brief review of possible causes and management.

    PubMed

    Arce, Manrique Borbón; Molina, Teresa Cambil; Hernández, Tomás Martín; de la Cinta Calvo Morón, María; Herrero, Cristina Hernández; De La Riva Pérez, Pablo Antonio; Montaño, Juan Castro

    2015-01-01

    To report five cases of patients diagnosed with differentiated thyroid carcinoma (DTC) with uptake in the thymic area after high-dose treatment with I-131 and to evaluate the potential causes and therapeutic management. Five cases of young female patients with a mean age of 36.6 years (24-43) who had been treated with a mean dose of 106 mCi of I-131 (100-150 mCi) showing tracer uptake in the thymic area are reported. An I-131 whole-body scan (131I-WBS) was performed 7 days after therapeutic dose administration to each patient. Anterior and posterior planar images, followed by SPECT/CT of the head, neck and superior mediastinum were acquired in all patients. Thyroglobulin levels were measured with and without hormone replacement therapy in all cases. Samples taken from the superior mediastinum were sent to pathology for analysis, which confirmed the presence of thymic tissue. Two patients underwent elective total thymectomy due to the gross characteristics of the gland, local 131-I uptake, and high thyroglobulin levels. The remaining three patients had already undergone thymectomy as part of neck dissection during initial surgery, and no further invasive interventions were therefore performed. Pathological examination revealed no metastases in these five patients. Thymus visualization in young patients after administration of therapeutic doses of I-131 seems to be a more common finding than usually thought. Absence of metastasis in the thymus despite high thyroglobulin levels was confirmed in all cases. Based on these results, we suggest that a more expectant and less aggressive therapeutic approach could be used. We also suggest that I-131 therapy for DTC should be considered in classification of the potential causes of true thymic hyperplasia in the subgroup of patients recovering from a stressor. Copyright © 2013 SEEN. Published by Elsevier Espana. All rights reserved.

  16. 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.

  17. Comparison of I-131 radioimmunotherapy tumor dosimetry: unit density sphere model versus patient-specific Monte Carlo calculations.

    PubMed

    Howard, David M; Kearfott, Kimberlee J; Wilderman, Scott J; Dewaraja, Yuni K

    2011-10-01

    High computational requirements restrict the use of Monte Carlo algorithms for dose estimation in a clinical setting, despite the fact that they are considered more accurate than traditional methods. The goal of this study was to compare mean tumor absorbed dose estimates using the unit density sphere model incorporated in OLINDA with previously reported dose estimates from Monte Carlo simulations using the dose planning method (DPMMC) particle transport algorithm. The dataset (57 tumors, 19 lymphoma patients who underwent SPECT/CT imaging during I-131 radioimmunotherapy) included tumors of varying size, shape, and contrast. OLINDA calculations were first carried out using the baseline tumor volume and residence time from SPECT/CT imaging during 6 days post-tracer and 8 days post-therapy. Next, the OLINDA calculation was split over multiple time periods and summed to get the total dose, which accounted for the changes in tumor size. Results from the second calculation were compared with results determined by coupling SPECT/CT images with DPM Monte Carlo algorithms. Results from the OLINDA calculation accounting for changes in tumor size were almost always higher (median 22%, range -1%-68%) than the results from OLINDA using the baseline tumor volume because of tumor shrinkage. There was good agreement (median -5%, range -13%-2%) between the OLINDA results and the self-dose component from Monte Carlo calculations, indicating that tumor shape effects are a minor source of error when using the sphere model. However, because the sphere model ignores cross-irradiation, the OLINDA calculation significantly underestimated (median 14%, range 2%-31%) the total tumor absorbed dose compared with Monte Carlo. These results show that when the quantity of interest is the mean tumor absorbed dose, the unit density sphere model is a practical alternative to Monte Carlo for some applications. For applications requiring higher accuracy, computer-intensive Monte Carlo calculation is

  18. Immunoscintigraphy of human pancreatic carcinoma in nude mice with I-131-F(ab')/sub 2/-fragments of monoclonal antibodies

    SciTech Connect

    Senekowitsch, R.; Maul, F.D.; Wenisch, H.J.C.; Kriegel, H.; Hor, G.

    1985-05-01

    In the present study radioiodinated F(ab')/sub 2/-fragments of CA19-9 and antibody that reacts specifically with human gastrointestinal cancer were examined for their ability to detect human pancreatic carcinoma hosted in nude mice. Tumor-bearing mice received 80..mu..Ci of I-131-F(ab')/sub 2/ with a specific activity of 1.8..mu..Ci/..mu..g. All mice were imaged after the injection and every 24hr up to 6 days. The retained radioactivity was also registered with a whole-body counter immediately after imaging. As a control F(ab's)/sub 2/ of a nonspecific antibody were administered in parallel to another group of animals bearing the same tumor. Three animals of each group were killed at 1,2,4 and 8 days for determination of the distribution of both labeled antibody-fragments. On scintigraphic images obtained with the CA19-9-F(ab')/sub 2/ the tumors could be visualized 24hr after injection, the best dilineation however was achieved 96hr p.i.. The biodistribution data exhibited a more rapid blood clearance for the specific fragments compared to that for the unspecific ones. Tumors showed an increase in uptake up to 48hr reaching 1.7% of the injected dose per gram, declining to values of 0.08%/g at day 6 p.i.. The highest tumor-to-blood ratios were found after 96h. They were 7 for the CA19-9-fragments compared to 1.5 for the unspecific fragments. The whole body counting revealed a more rapid excretion for the fragments of the specific monoclonal antibodies than for the unspecific ones. In summary the authors were able to show that CA19-9-F(ab')/sub 2/-fragments can be used for immunodetection of human pancreatic carcinoma hosted in nude mice.

  19. Combination anti-CD74 (milatuzumab) and anti-CD20 (rituximab) monoclonal antibody therapy has in vitro and in vivo activity in mantle cell lymphoma

    PubMed Central

    Alinari, Lapo; Yu, Bo; Christian, Beth A.; Yan, Fengting; Shin, Jungook; Lapalombella, Rosa; Hertlein, Erin; Lustberg, Mark E.; Quinion, Carl; Zhang, Xiaoli; Lozanski, Gerard; Muthusamy, Natarajan; Prætorius-Ibba, Mette; O'Connor, Owen A.; Goldenberg, David M.; Byrd, John C.; Blum, Kristie A.

    2011-01-01

    Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmunotherapy. Rituximab, a chimeric anti–CD20 monoclonal antibody (mAb), has shown only modest activity as single agent in MCL. The humanized mAb milatuzumab targets CD74, an integral membrane protein linked with promotion of B-cell growth and survival, and has shown preclinical activity against B-cell malignancies. Because rituximab and milatuzumab target distinct antigens and potentially signal through different pathways, we explored a preclinical combination strategy in MCL. Treatment of MCL cell lines and primary tumor cells with immobilized milatuzumab and rituximab resulted in rapid cell death, radical oxygen species generation, and loss of mitochondrial membrane potential. Cytoskeletal distrupting agents significantly reduced formation of CD20/CD74 aggregates, cell adhesion, and cell death, highlighting the importance of actin microfilaments in rituximab/milatuzumab–mediated cell death. Cell death was independent of caspase activation, Bcl-2 family proteins or modulation of autophagy. Maximal inhibition of p65 nuclear translocation was observed with combination treatment, indicating disruption of the NF-κB pathway. Significant in vivo therapeutic activity of combination rituximab and milatuzumab was demonstrated in a preclinical model of MCL. These data support clinical evaluation of combination milatuzumab and rituximab therapy in MCL. PMID:21228331

  20. Combination anti-CD74 (milatuzumab) and anti-CD20 (rituximab) monoclonal antibody therapy has in vitro and in vivo activity in mantle cell lymphoma.

    PubMed

    Alinari, Lapo; Yu, Bo; Christian, Beth A; Yan, Fengting; Shin, Jungook; Lapalombella, Rosa; Hertlein, Erin; Lustberg, Mark E; Quinion, Carl; Zhang, Xiaoli; Lozanski, Gerard; Muthusamy, Natarajan; Prætorius-Ibba, Mette; O'Connor, Owen A; Goldenberg, David M; Byrd, John C; Blum, Kristie A; Baiocchi, Robert A

    2011-04-28

    Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy with a median survival of 3 years despite chemoimmunotherapy. Rituximab, a chimeric anti-CD20 monoclonal antibody (mAb), has shown only modest activity as single agent in MCL. The humanized mAb milatuzumab targets CD74, an integral membrane protein linked with promotion of B-cell growth and survival, and has shown preclinical activity against B-cell malignancies. Because rituximab and milatuzumab target distinct antigens and potentially signal through different pathways, we explored a preclinical combination strategy in MCL. Treatment of MCL cell lines and primary tumor cells with immobilized milatuzumab and rituximab resulted in rapid cell death, radical oxygen species generation, and loss of mitochondrial membrane potential. Cytoskeletal distrupting agents significantly reduced formation of CD20/CD74 aggregates, cell adhesion, and cell death, highlighting the importance of actin microfilaments in rituximab/milatuzumab-mediated cell death. Cell death was independent of caspase activation, Bcl-2 family proteins or modulation of autophagy. Maximal inhibition of p65 nuclear translocation was observed with combination treatment, indicating disruption of the NF-κB pathway. Significant in vivo therapeutic activity of combination rituximab and milatuzumab was demonstrated in a preclinical model of MCL. These data support clinical evaluation of combination milatuzumab and rituximab therapy in MCL.

  1. 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

  2. Inverse relationship between cardiac accumulation of meta-(/sup 131/I)iodobenzylguanidine (I-131 MIBG) and circulation catecholamines in suspected pheochromocytoma

    SciTech Connect

    Nakajo, M.; Shapiro, B.; Glowniak, J.; Sisson, J.C.; Beierwaltes, W.H.

    1983-12-01

    Heart intensity (HI) in the 24- and 48-hr images of meta-(/sup 131/I)iodobenzylguanidine (I-131 MIBG), a pheochromocytoma-seeking guanethidine analog, were compared with concentrations of plasma and urinary catecholamines and their metabolites in nonpheochromocytoma and pheochromocytoma patients. HI was inversely related to plasma concentrations and urinary excretion rates of the hormones. Plasma norepinephrine had the highest inverse correlation with HI (r = -0.73 at 24 hr, -0.63 at 48 hr) and urinary metanephrine the lowest (r = -0.23 at 24 hr, -0.28 at 48 hr). A similar relationship was observed in the intensity of salivary-gland visualization, but with less marked variations. HI was much higher in ninpheochromocytoma patients than in pheochromocytoma patients. HI in an I-131 MIGB image provides useful information in the diagnosis of pheochromocytoma, and may provide a tool for the study of the influence of catecholamines on the heart.

  3. Tumor dosimetry for I-131 trastuzumab therapy in a Her2+ NCI N87 xenograft mouse model using the Siemens SYMBIA E gamma camera with a pinhole collimator

    NASA Astrophysics Data System (ADS)

    Lee, Young Sub; Kim, Jin Su; Deuk Cho, Kyung; Kang, Joo Hyun; Moo Lim, Sang

    2015-07-01

    We performed imaging and therapy using I-131 trastuzumab and a pinhole collimator attached to a conventional gamma camera for human use in a mouse model. The conventional clinical gamma camera with a 2-mm radius-sized pinhole collimator was used for monitoring the animal model after administration of I-131 trastuzumab The highest and lowest radiation-received organs were osteogenic cells (0.349 mSv/MBq) and skin (0.137 mSv/MBq), respectively. The mean coefficients of variation (%CV) of the effective dose equivalent and effective dose were 0.091 and 0.093 mSv/MBq respectively. We showed the feasibility of the pinholeattached conventional gamma camera for human use for the assessment of dosimetry. Mouse dosimetry and prediction of human dosimetry could be used to provide data for the safety and efficacy of newly developed therapeutic schemes.

  4. A simple low-cost of liquid I-131 dispenser for routine radiopharmaceutical dispensing at nuclear medicine department, Institut Kanser Negara

    SciTech Connect

    Said, M. A.; Suhaimi, N. E. F.; Ashhar, Z. N.; Zainon, R.

    2016-01-22

    In routine radiopharmaceutical Iodine-131 ({sup 131}I) dispensing, the amount of radiation dose received by the personnel depends on the distance between the personnel and the source, the time spent manipulating the source and the amount of shielding used to reduce the dose rate from the source. The novel iRAD-I131 dispenser using recycle {sup 131}I liquid lead pot will lead into low cost production, less maintenance and low dose received by the personnel that prepared the {sup 131}I. The new fabricated of low cost {sup 131}I dispenser was tested and the dose received by personnel were evaluated. The body of lead material is made from 2.5 cm lead shielded coated with epoxy paint to absorb the radiation dose up to 7.4 GBq of {sup 131} I. The lead pot was supported with two stainless steel rod. The Optically Stimulated Luminescence (OSL) nanodot was used in this study to measure the dose rate at both extremities for every personnel who prepared the {sup 131}I. Each OSL nanodot was attached at the fingertip. Three different personnel (experienced between one to ten years above in preparing the radiopharmaceuticals) were participated in this study. The average equivalent dose at right and left hand were 122.694 ± 121.637 µSv/GBq and 77.281 ± 62.146 µSv/GBq respectively. This study found that the dose exposure received using iRAD-I131 was less up to seven times compared to the conventional method. The comparison of experimental data using iRAD-I131 and established radiopharmaceutical dispenser was also discussed. The innovation of {sup 131}I dispenser is highly recommended in a small radiopharmaceutical facility with limited budget. The novel iRAD-I131 enables implementation of higher output liquid dispensing with low radiation dose to the personnel.

  5. A simple low-cost of liquid I-131 dispenser for routine radiopharmaceutical dispensing at nuclear medicine department, Institut Kanser Negara

    NASA Astrophysics Data System (ADS)

    Said, M. A.; Ashhar, Z. N.; Suhaimi, N. E. F.; Zainon, R.

    2016-01-01

    In routine radiopharmaceutical Iodine-131 (131I) dispensing, the amount of radiation dose received by the personnel depends on the distance between the personnel and the source, the time spent manipulating the source and the amount of shielding used to reduce the dose rate from the source. The novel iRAD-I131 dispenser using recycle 131I liquid lead pot will lead into low cost production, less maintenance and low dose received by the personnel that prepared the 131I. The new fabricated of low cost 131I dispenser was tested and the dose received by personnel were evaluated. The body of lead material is made from 2.5 cm lead shielded coated with epoxy paint to absorb the radiation dose up to 7.4 GBq of 131 I. The lead pot was supported with two stainless steel rod. The Optically Stimulated Luminescence (OSL) nanodot was used in this study to measure the dose rate at both extremities for every personnel who prepared the 131I. Each OSL nanodot was attached at the fingertip. Three different personnel (experienced between one to ten years above in preparing the radiopharmaceuticals) were participated in this study. The average equivalent dose at right and left hand were 122.694 ± 121.637 µSv/GBq and 77.281 ± 62.146 µSv/GBq respectively. This study found that the dose exposure received using iRAD-I131 was less up to seven times compared to the conventional method. The comparison of experimental data using iRAD-I131 and established radiopharmaceutical dispenser was also discussed. The innovation of 131I dispenser is highly recommended in a small radiopharmaceutical facility with limited budget. The novel iRAD-I131 enables implementation of higher output liquid dispensing with low radiation dose to the personnel.

  6. In Thyroidectomized Thyroid Cancer Patients, False-Positive I-131 Whole Body Scans Are Often Caused by Inflammation Rather Than Thyroid Cancer

    PubMed Central

    Garger, Yana Basis; Winfeld, Mathew; Friedman, Kent; Blum, Manfred

    2016-01-01

    Objective. To show that I-131 false-positive results on whole-body scans (WBSs) after thyroidectomy for thyroid cancer may be a result of inflammation unassociated with the cancer. Methods. We performed a retrospective image analysis of our database of thyroid cancer patients who underwent WBS from January 2008 to January 2012 to identify and stratify false positives. Results. A total of 564 patients underwent WBS during the study period; 96 patients were referred for 99 I-131 single-photon emission computed tomography (SPECT/CT) scans to better interpret cryptic findings. Among them, 73 scans were shown to be falsely positive; 40/73 or 54.7% of false-positive findings were a result of inflammation. Of the findings, 17 were in the head, 1 in the neck, 4 in the chest, 3 in the abdomen, and 14 in the pelvis; 1 had a knee abscess. Conclusions. In our series, inflammation caused the majority of false-positive WBSs. I-131 SPECT/CT is powerful in the differentiation of inflammation from thyroid cancer. By excluding metastatic disease, one can properly prognosticate outcome and avoid unnecessary, potentially harmful treatment of patients with thyroid cancer. PMID:26977418

  7. Engineering Chimeric Antigen Receptors

    PubMed Central

    Kulemzin, S. V.; Kuznetsova, V. V.; Mamonkin, M.; Taranin, A. V.; Gorchakov, A. A.

    2017-01-01

    Chimeric antigen receptors (CARs) are recombinant protein molecules that redirect cytotoxic lymphocytes toward malignant and other target cells. The high feasibility of manufacturing CAR-modified lymphocytes for the therapy of cancer has spurred the development and optimization of new CAR T cells directed against a broad range of target antigens. In this review, we describe the main structural and functional elements constituting a CAR, discuss the roles of these elements in modulating the anti-tumor activity of CAR T cells, and highlight alternative approaches to CAR engineering. PMID:28461969

  8. 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.

  9. 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

  10. 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

  11. 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.

  12. 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.

  13. Development of rituximab-resistant B-NHL clones: an in vitro model for studying tumor resistance to monoclonal antibody-mediated immunotherapy.

    PubMed

    Jazirehi, Ali R; Bonavida, Benjamin

    2011-01-01

    Therapeutic strategies for cancer include chemotherapy, immunotherapy, and radiation. Such therapies result in significant short-term clinical responses; however, relapses and recurrences occur with no treatments. Targeted therapies using monoclonal antibodies have improved responses with minimal toxicities. For instance, Rituximab (chimeric anti-CD20 monoclonal antibody) was the first FDA-approved monoclonal antibody for the treatment of patients with non-Hodgkin's lymphoma (NHL). The clinical response was significantly improved when used in combination with chemotherapy. However, a subset of patients does not respond or becomes resistant to further treatment. Rituximab-resistant (RR) clones were used as a model to address the potential mechanisms of resistance. In this chapter, we discuss the underlying molecular mechanisms by which rituximab signals the cells and modifies several intracellular survival/antiapoptotic pathways, leading to its chemo/immunosensitizing activities. RR clones were developed to mimic in vivo resistance observed in patients. In comparison with the sensitive parental cells, the RR clones are refractory to rituximab-mediated cell signaling and chemosensitization. Noteworthy, interference with the hyperactivated survival/antiapoptotic pathways in the RR clones with various pharmacological inhibitors mimicked rituximab effects in the parental cells. The development of RR clones provides a paradigm for studying resistance by other anticancer monoclonal antibodies in various tumor models.

  14. 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.

  15. Long-Term Quality of Life and Pregnancy Outcomes of Differentiated Thyroid Cancer Survivors Treated by Total Thyroidectomy and I131 during Adolescence and Young Adulthood

    PubMed Central

    Metallo, Melanie; Groza, Lelia; Brunaud, Laurent; Klein, Marc; Weryha, Georges; Feigerlova, Eva

    2016-01-01

    Introduction. Differentiated thyroid cancer (DTC) is rare and confers good prognosis. Long-term health related quality of life (HRQoL) and pregnancy outcomes are not well known in subjects treated during adolescence and young adulthood. Methods. Cross-sectional analysis of HRQoL and global self-esteem, using SF-36 and ISP-25 surveys, and of pregnancy outcomes in female survivors of DTC treated by total thyroidectomy and I131 before age of 25 years. Results. Forty-five of 61 patients (74%) responded to the survey. Cumulative I131 activity was ≤3.85 GBq in 18 subjects and >3.85 GBq in 27 subjects. Mean time from diagnosis was 7.6 ± 5.2 years for the group ≤ 3.85 GBq versus 16.9 ± 11.6 years for the group > 3.85 GBq (P < 0.05). No significant alteration in long-term HRQoL and global self-esteem was observed. Thirty pregnancies after I131 were noted in patients from the group > 3.85 GBq and 10 in patients from the group ≤ 3.85 GBq. Frequency of miscarriages was of 17% (group > 3.85 GBq) and 10% (group ≤ 3.85 GBq) with 9 and 24 live births, respectively. No congenital malformations or first year mortality was noted. Conclusion. Long-term HRQoL, global self-esteem, and pregnancy outcomes are not affected in young female survivors of DTC. PMID:26977147

  16. Doses to the hand during the administration of radiolabeled antibodies containing Y-90, Tc-99m, I-131, and Lu-177

    SciTech Connect

    Barber, D.E.; Carsten, A.L.; Kaurin, D.G.L.; Baum, J.W.

    1997-02-01

    Exposure of the hands of medical personnel administering radiolabeled antibodies (RABs) was evaluated on the basis of (a) observing and photo-documenting administration techniques, and (b) experimental data on doses to thermoluminescent dosimeters (TLDs) on fingers of phantom hands holding syringes, and on syringes, with radionuclides in the syringes in each case. Actual exposure data for I-131 and Lu-177 were obtained in field studies. Variations in handling and administration techniques were identified. Dose rates measured using TLDs on the surface of loaded syringes were adjusted for differences in electronic stopping power, absorption coefficients, and attenuation between dosimeters and tissue to estimate dose-to-skin averaged over 1 cm{sup 2} at 7 mg cm{sup {minus}2} depth for Y-90, Tc-99m, I-131, and Lu-177. Dose rate coefficients to the skin, if in contact with the syringe wall, were 89, 1.9, 3.8, and 0.41 {micro}Sv s{sup {minus}1} per 37 MBq (1 mCi) for Y-90, Tc-99m, I-131, and Lu-177, respectively. For dose reduction, when using Y-90 the importance was clearly indicated of (a) avoiding direct contact with syringes containing RABs, if practical, and (b) using a beta-particle shield on the syringe. In using a syringe for injection, doses can best be approximated for the geometry studied by (a) wearing a finger dosimeter on the middle finger, toward the outside of the hand, on the hand operating the plunger, and (b) wearing finger dosimeters on the inner (palm) side of the finger on the hand that supports the syringe for energetic beta-particle emitters, such as Y-90 and Re-188.

  17. 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.

  18. Utility of SPECT/CT as an adjunct to planar whole body I-131 imaging: liver metastasis from papillary thyroid cancer.

    PubMed

    Agriantonis, Demetrios J; Hall, Lance; Wilson, Michael A

    2009-04-01

    One of the major limitations of planar I-131 imaging is its lack of anatomic precision. SPECT/CT offers the benefit of precise anatomic localization that planar imaging lacks. Whether for confirmation of physiologic uptake or true pathology, SPECT/CT has an important role to play in clarifying equivocal findings. We present a case of papillary thyroid cancer metastatic to the liver, a relatively rare scenario. SPECT/CT allowed definitive lesion characterization at the time of the patient's visit to the nuclear medicine department.

  19. 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.

  20. 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.

  1. 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.

  2. 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.

  3. The standardization methods of radioactive sources (125I, 131I, 99mTc, and 18F) for calibrating nuclear medicine equipment in Indonesia

    NASA Astrophysics Data System (ADS)

    Wurdiyanto, G.; Candra, H.

    2016-03-01

    The standardization of radioactive sources (125I, 131I, 99mTc and 18F) to calibrate the nuclear medicine equipment had been carried out in PTKMR-BATAN. This is necessary because the radioactive sources used in the field of nuclear medicine has a very short half-life in other that to obtain a quality measurement results require special treatment. Besides that, the use of nuclear medicine techniques in Indonesia develop rapidly. All the radioactive sources were prepared by gravimetric methods. Standardization of 125I has been carried out by photon- photon coincidence methods, while the others have been carried out by gamma spectrometry methods. The standar sources are used to calibrate a Capintec CRC-7BT radionuclide calibrator. The results shows that calibration factor for Capintec CRC-7BT dose calibrator is 1,03; 1,02; 1,06; and 1,04 for 125I, 131I, 99mTc and 18F respectively, by about 5 to 6% of the expanded uncertainties.

  4. Effects of bone marrow cell transplant on thyroid function in an I131-induced low T4 and elevated TSH rat model

    PubMed Central

    Guajardo-Salinas, Gustavo E; Carvajal, Juan A; Gaytan-Ramos, Ángel A; Arroyo, Luis; López-Reyes, Alberto G; Islas, José F; Cano, Beiman G; Arroyo-Currás, Netzahualcoyótl; Dávalos, Alfredo; Madrid, Gloria; Moreno-Cuevas, Jorge E

    2007-01-01

    Background We developed a study using low dose radioactive iodine creating an animal model of transient elevation of thyroid stimulating hormone (TSH). Male derived bone marrow cells were transplanted to asses their effect on thyroid function and their capability to repair the thyroid parenchyma. Results At 40 an 80 days after I131 treatment, the study groups TSH and T4 serum values both increased and decreased significantly respectively compared to the negative control group. Eight weeks after cell transplantation, neither TSH nor T4 showed a significant difference in any group. The mean number of SRY gene copies found in group I (Left Intracardiac Transplant) was 523.3 and those in group II (Intrathyroid Transplant) were only 73. Group III (No Transplant) and IV had no copies. Group I presented a partial restore of the histological pattern of rat thyroid with approximately 20% – 30% of normal-sized follicles. Group II did not show any histological differences compared to group III (Positive control). Conclusion Both a significant increase of TSH and decrease of T4 can be induced as early as day 40 after a low dose of I131 in rats. Restore of normal thyroid function can be spontaneously achieved after using a low dose RAI in a rat model. The use of BM derived cells did not affect the re-establishment of thyroid function and might help restore the normal architecture after treatment with RAI. PMID:17233913

  5. Invasiveness, chimerism and genetic diversity.

    PubMed

    Ben-Shlomo, Rachel

    2017-09-26

    Adaptation for invasiveness should comprise the capability to exploit and prosper in a wide range of ecological conditions, and is therefore expected to be associated with a certain level of genetic diversity. Paradoxically, however, invasive populations are established by only a few founders, resulting in low genetic diversity. As a conceivable way of attaining high genetic diversity and high variance of gene expression even when a small number of founders is involved in invasiveness, I suggest here chimerism, a fusion between different individuals-a common phenomenon found in numerous phyla. The composite entity offers the chimeric organism genetic flexibility and higher inclusive fitness that depends on the joint genomic fitness of the original partners. The ability to form a chimeric entity is also applied to subsequent generations and, consequently, the level of genetic diversity does not decline over generations of population establishment following invasion. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  6. 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

  7. 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.

  8. How should chimerism be decoded?

    PubMed

    Ferrand, Christophe; Perruche, Sylvain; Robinet, Eric; Martens, Anton; Tiberghien, Pierre; Saas, Philippe

    2003-05-15

    To date, the significance of chimerism has not been fully understood. In particular, microchimerism can be associated with allograft acceptance or rejection. Several factors may influence the immunologic consequences of chimerism. In this review, the major factors influencing these consequences are briefly described. Subsequently, the different methods available for detecting and tracking donor-derived cells are listed. These techniques have been mainly developed concomitantly with nonmyeloablative hematopoietic allografts to monitor immunosuppression. Finally, the authors suggest how these methods may help to improve the understanding of microchimerism in solid organ transplantation.

  9. 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

  10. Chimeric enzymes with improved cellulase activities

    DOEpatents

    Xu, Qi; Baker, John O; Himmel, Michael E

    2015-03-31

    Nucleic acid molecules encoding chimeric cellulase polypeptides that exhibit improved cellulase activities are disclosed herein. The chimeric cellulase polypeptides encoded by these nucleic acids and methods to produce the cellulases are also described, along with methods of using chimeric cellulases for the conversion of cellulose to sugars such as glucose.

  11. 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.

  12. 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.

  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. 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

  15. 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.

  16. 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.

  17. Mechanisms of tolerance induced via mixed chimerism.

    PubMed

    Sykes, Megan

    2007-05-01

    Mixed hematopoietic chimerism provides a powerful means of inducing robust, donor-specific tolerance. In this article, the minimal requirements for achieving mixed chimerism, the development of new reagents that promote its achievement, and the mechanisms by which peripheral and intrathymic tolerance are achieved via mixed chimerism are discussed. An emerging understanding of these mechanisms, along with the development of new immunosuppressive reagents, is allowing advancement toward clinical application of this approach.

  18. 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

  19. 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

  20. 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.

  1. 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

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. Rituximab for the treatment of refractory simultaneous anti-glomerular basement membrane (anti-GBM) and membranous nephropathy.

    PubMed

    Bandak, Ghassan; Jones, Bruce A; Li, Jian; Yee, Jerry; Umanath, Kausik

    2014-02-01

    Antibody-mediated anti-glomerular basement membrane (anti-GBM) disease occurs rarely in the presence of another B-cell disorder, membranous nephropathy. The coexistence of these two autoimmune disorders would be anticipated to require differing, specific therapies targeted to each disease process. We describe a case of concomitant membranous nephropathy and anti-GBM disease in which conventional therapy, including steroids, plasmapheresis and cyclophosphamide, failed to attenuate the anti-GBM disease, yet responded to an alternative treatment of rituximab. This B-cell directed, monoclonal, chimeric antibody treatment substantially reduced anti-GBM antibody titers and led to discontinuation of plasmapheresis, while maintaining the remission of membranous nephropathy and anti-GBM disease.

  8. 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

  9. 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

  10. Physicochemical Evaluation of Lyophilized Formulation of p-SCN-Bn-DOTA- and p-SCN-Bn-DTPA-rituximab for NHL Radio Immunotherapy.

    PubMed

    Ackova, Darinka Gjorgieva; Smilkov, Katarina; Janevik-Ivanovska, Emilija

    2016-01-01

    Radioimmunotherapy (RIT) of Non-Hodgkin's lymphoma (NHL) is said to be more advantageous compared to unlabelled therapeutic antibodies. To this date, radiolabelled murine anti-CD20 mAbs, Zevalin(®) and Bexxar(®) have been approved for imaging and therapy. A preparation containing rituximab, chimeric mAb radio immunoconjugate suitable for Lu-177 labeling, could provide better imaging and therapeutic profile at the same time. This study was conducted to evaluate prepared lyophilized formulations of two rituximab immune conjugates, intended for immediate Lu-177 labeling, for imaging and therapy. The characterization of the conjugates and demonstration of the integrity of the protein and purity after conjugation and lyophilization was performed by SDS-PAGE, FT-IR and MALDI-TOF-MS. The results showed preserved antibody structure and average of 6.1 p-SCN-Bn-DOTA and 8.8 p-SCN-Bn-DTPA groups per antibody molecule which is suitable for successful labeling. These results support the possibility of developing a "ready-to-label" rituximab immune conjugates for NHL imaging/therapy.

  11. Physicochemical Evaluation of Lyophilized Formulation of p-SCN-Bn-DOTA- and p-SCN-Bn-DTPA-rituximab for NHL Radio Immunotherapy

    PubMed Central

    Ackova, Darinka Gjorgieva; Smilkov, Katarina; Janevik-Ivanovska, Emilija

    2016-01-01

    Radioimmunotherapy (RIT) of Non-Hodgkin’s lymphoma (NHL) is said to be more advantageous compared to unlabelled therapeutic antibodies. To this date, radiolabelled murine anti-CD20 mAbs, Zevalin® and Bexxar® have been approved for imaging and therapy. A preparation containing rituximab, chimeric mAb radio immunoconjugate suitable for Lu-177 labeling, could provide better imaging and therapeutic profile at the same time. This study was conducted to evaluate prepared lyophilized formulations of two rituximab immune conjugates, intended for immediate Lu-177 labeling, for imaging and therapy. The characterization of the conjugates and demonstration of the integrity of the protein and purity after conjugation and lyophilization was performed by SDS-PAGE, FT-IR and MALDI-TOF-MS. The results showed preserved antibody structure and average of 6.1 p-SCN-Bn-DOTA and 8.8 p-SCN-Bn-DTPA groups per antibody molecule which is suitable for successful labeling. These results support the possibility of developing a “ready-to-label” rituximab immune conjugates for NHL imaging/therapy. PMID:27980563

  12. 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

  13. 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.

  14. 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

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. Chlorambucil-rituximab as first-line therapy in patients affected by follicular non-Hodgkin's lymphoma: a retrospective single-centre study.

    PubMed

    Martinelli, Giovanni; Montoro, Juan; Vanazzi, Anna; Andreola, Giovanna; Liptrott, Sarah; Radice, Davide; Negri, Mara; Preda, Lorenzo; Pruneri, Giancarlo; Laszlo, Daniele

    2015-12-01

    Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, has been shown to be active in newly diagnosed and relapsed patients with follicular lymphoma (FL), both as monotherapy and in combination with chemotherapy. Many studies suggest that the prognosis of patients with FL may improve when it is used in combination with chemotherapy. Despite these advances, the disease remains essentially incurable with standard therapy, and novel approaches to treatment are needed because optimal therapy is not defined. The combination of chlorambucil-rituximab is one of several standard treatment options for FL. Here, we considered data arising from 75 patients with newly diagnosed FL at the European Institute of Oncology treated with the combination of rituximab plus chlorambucil. The aim of this study was to evaluate the efficacy and safety of chlorambucil and rituximab, delivered 6 mg/m(2) /day orally for 6 weeks and 375 mg/m(2) in a standard 4-weekly schedule, respectively. Patients responding to the induction therapy received a prolonged therapy with four additional cycles of chlorambucil plus rituximab. Seventy-one patients (94.6%) completed the treatment; four patients discontinued treatment because of grade 3-4 hematological toxicity. The overall response rate was 97.3% including 74.7% of complete responses. Only two patients had a stable disease at revaluation after treatment. With a median follow-up of 57 months, 72 patients (96%) are alive. Median event-free survival (EFS) and median overall survival (OS) were not reached; 5-year OS rate was 98.4%. The 5-year EFS was 71.3%. By univariate and multivariate analyses, elevated beta-2 microglobulin levels and partial responses to therapy were correlated with worse EFS. These results suggest that the combination of chlorambucil and rituximab is an active and safe regimen in patients with newly diagnosed FL, principally in those with low tumour burden and favourable prognostic factors. Copyright

  2. Organ S values and effective doses for family members exposed to adult patients following I-131 treatment: A Monte Carlo simulation study

    SciTech Connect

    Han, Eun Young; Lee, Choonsik; Mcguire, Lynn; Brown, Tracy L. Y.; Bolch, Wesley E.

    2013-08-15

    Purpose: To calculate organ S values (mGy/Bq-s) and effective doses per time-integrated activity (mSv/Bq-s) for pediatric and adult family members exposed to an adult male or female patient treated with I-131 using a series of hybrid computational phantoms coupled with a Monte Carlo radiation transport technique.Methods: A series of pediatric and adult hybrid computational phantoms were employed in the study. Three different exposure scenarios were considered: (1) standing face-to-face exposures between an adult patient and pediatric or adult family phantoms at five different separation distances; (2) an adult female patient holding her newborn child, and (3) a 1-yr-old child standing on the lap of an adult female patient. For the adult patient model, two different thyroid-related diseases were considered: hyperthyroidism and differentiated thyroid cancer (DTC) with corresponding internal distributions of {sup 131}I. A general purpose Monte Carlo code, MCNPX v2.7, was used to perform the Monte Carlo radiation transport.Results: The S values show a strong dependency on age and organ location within the family phantoms at short distances. The S values and effective dose per time-integrated activity from the adult female patient phantom are relatively high at shorter distances and to younger family phantoms. At a distance of 1 m, effective doses per time-integrated activity are lower than those values based on the NRC (Nuclear Regulatory Commission) by a factor of 2 for both adult male and female patient phantoms. The S values to target organs from the hyperthyroid-patient source distribution strongly depend on the height of the exposed family phantom, so that their values rapidly decrease with decreasing height of the family phantom. Active marrow of the 10-yr-old phantom shows the highest S values among family phantoms for the DTC-patient source distribution. In the exposure scenario of mother and baby, S values and effective doses per time-integrated activity to

  3. 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

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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.

  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. 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. 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.

  12. 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.

  13. 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.

  14. [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.

  15. [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.

  16. 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

  17. Allogeneic hematopoietic cell transplantation after conditioning with I-131-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome.

    SciTech Connect

    Pagel, John M.; Gooley, T. A.; Rajendran, Joseph G.; Fisher, Darrell R.; Wilson, Wendy A.; Sandmaier, B. M.; Matthews, D. C.; Deeg, H. Joachim; Gopal, Ajay K.; Martin, P. J.; Storb, R.; Press, Oliver W.; Appelbaum, Frederick R.

    2009-12-24

    We conducted a study to estimate the maximum tolerated dose (MTD) of I-131-anti-CD45 antibody (Ab; BC8) that can be combined with a standard reduced-intensity conditioning regimen before allogeneic hematopoietic cell transplantation. Fifty-eight patients older than 50 years with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were treated with (131)I-BC8 Ab and fludarabine plus 2 Gy total body irradiation. Eighty-six percent of patients had AML or MDS with greater than 5% marrow blasts at the time of transplantation. Treatment produced a complete remission in all patients, and all had 100% donor-derived CD3(+) and CD33(+) cells in the blood by day 28 after the transplantation. The MTD of I-131-BC8 Ab delivered to liver was estimated to be 24 Gy. Seven patients (12%) died of nonrelapse causes by day 100. The estimated probability of recurrent malignancy at 1 year is 40%, and the 1-year survival estimate is 41%. These results show that CD45-targeted radiotherapy can be safely combined with a reduced-intensity conditioning regimen to yield encouraging overall survival for older, high-risk patients with AML or MDS. This study was registered at www.clinicaltrials.gov as #NCT00008177.

  18. Chimeric polypeptides having cellulolytic enhancing activity and polynucleotides encoding same

    DOEpatents

    Wogulis, Mark; Sweeney, Matthew; Heu, Tia

    2017-06-14

    The present invention relates to chimeric GH61 polypeptides having cellulolytic enhancing activity. The present invention also relates to polynucleotides encoding the chimeric GH61 polypeptides; nucleic acid constructs, vectors, and host cells comprising the polynucleotides; and methods of using the chimeric GH61 polypeptides.

  19. 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

  20. 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.

  1. 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

  2. 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

  3. 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

  4. 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

  5. Efficacy and Safety of Rituximab in Connective Tissue Disease related Interstitial Lung Disease.

    PubMed

    Fitzgerald, Deirdre Brigid; Moloney, Fiachra; Twomey, Maria; O'Connell, John Oisin; Cronin, Owen; Harty, Len; Harney, Sinead; Henry, Michael T

    2015-09-14

    Pulmonary complications of connective tissue disease are being identified more frequently with the advent of more sophisticated radiological investigations. Limited previous studies have suggested Rituximab (RTX), a chimeric monoclonal antibody with activity against CD-20, may benefit connective tissue disease patients with pulmonary complications. We performed a retrospective analysis of the efficacy and safety of RTX in patients attending a tertiary referral centre. Ten patients treated with RTX for pulmonary complications of CTD in our institution were identified. Baseline demographics, pre- and post-treatment investigations and adverse events were documented with an average follow up time-frame of 12.3 months (range: 3 - 27). Statistical analysis was performed using the Wilcoxan Signed-Rank test in SPSS. There was a statistically significant improvement in pulmonary function, with a mean increase of 19% in DLCO (median DLCO (ml/min/mmHg) pre-treatment vs. post-treatment: 13.94 vs. 19.34, p=0.028) and a mean increase of 13% in FVC (median FVC (L) pre-treatment vs. post-treatment: 3.47 vs.3.6, p=0.28). For patients with pulmonary fibrosis (n=7), CT severity was improved on post-treatment scan, though this did not reach statistical significance. There was a reduction in the number of nodules seen on the follow-up scans of two patients without fibrosis. No patient had a severe adverse reaction to RTX. Treatment with RTX resulted in an objective, measurable improvement in pulmonary function and/or radiological severity for the majority of patients included in the series. This was statistically significant despite the small numbers included. These results indicate a positive response to RTX with few complications of treatment.  

  6. Assessment of liver stiffness in patients with HCV and mixed cryoglobulinemia undergoing rituximab treatment.

    PubMed

    Stasi, Cristina; Triboli, Elisa; Arena, Umberto; Urraro, Teresa; Petrarca, Antonio; Gragnani, Laura; Laffi, Giacomo; Zignego, Anna Linda

    2014-01-24

    Mixed cryoglobulinemia (MC) is a HCV-related lymphoproliferative disorder generally associated with advanced liver disease. Liver stiffness has been significantly correlated with histopathological stage of fibrosis. Moreover, it was influenced by necroinflammatory activity. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody inducing transient B lymphocytes depletion that was shown to be useful and safe in the majority of HCV MC patients, leading also to improvement of cirrhotic syndrome. Aim of this study was to evaluate the modifications of liver stiffness following RTX treatment in HCV-related MC patients. Fourteen consecutive patients (10 F, 4 M; mean age 60.43 ± 43) with HCV-related chronic hepatitis (n = 10) or cirrhosis (n = 4) and MC, eligible for RTX treatment, were prospectively enrolled. Intravenous injection of 1 g of RTX was performed at day 0 and at day 15. Assessment of stiffness was carried out by Fibroscan (Echosens, Paris-France) at baseline, 15 days after the first infusion, and at month 1, 3 and 6 after therapy. MC symptoms significantly improved during the study, especially during the first 3 months. Liver stiffness observed 3 months after treatment was significantly reduced when compared with pre-treatment values (p = 0.01). This difference disappeared after 6 months of follow-up. Cytofluorimetric analysis showed a decrease of CD19+ peripheral blood cells, with the nadir at month 3 after therapy and B cell compartment reconstitution after 6 months. This study, for the first time showed that RTX-treatment in HCV-related MC induces a reduction of liver stiffness that is strictly associated with the B-cell depletion.

  7. Assessment of liver stiffness in patients with HCV and mixed cryoglobulinemia undergoing rituximab treatment

    PubMed Central

    2014-01-01

    Introduction Mixed cryoglobulinemia (MC) is a HCV-related lymphoproliferative disorder generally associated with advanced liver disease. Liver stiffness has been significantly correlated with histopathological stage of fibrosis. Moreover, it was influenced by necroinflammatory activity. Rituximab (RTX) is a chimeric anti-CD20 monoclonal antibody inducing transient B lymphocytes depletion that was shown to be useful and safe in the majority of HCV MC patients, leading also to improvement of cirrhotic syndrome. Aim of this study was to evaluate the modifications of liver stiffness following RTX treatment in HCV-related MC patients. Materials and methods Fourteen consecutive patients (10 F, 4 M; mean age 60.43 ± 43) with HCV-related chronic hepatitis (n = 10) or cirrhosis (n = 4) and MC, eligible for RTX treatment, were prospectively enrolled. Intravenous injection of 1 g of RTX was performed at day 0 and at day 15. Assessment of stiffness was carried out by Fibroscan® (Echosens, Paris-France) at baseline, 15 days after the first infusion, and at month 1, 3 and 6 after therapy. Results MC symptoms significantly improved during the study, especially during the first 3 months. Liver stiffness observed 3 months after treatment was significantly reduced when compared with pre-treatment values (p = 0.01). This difference disappeared after 6 months of follow-up. Cytofluorimetric analysis showed a decrease of CD19+ peripheral blood cells, with the nadir at month 3 after therapy and B cell compartment reconstitution after 6 months. Conclusion This study, for the first time showed that RTX-treatment in HCV-related MC induces a reduction of liver stiffness that is strictly associated with the B-cell depletion. PMID:24456582

  8. 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.

  9. [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.

  10. 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.

  11. [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.

  12. 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.

  13. 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

  14. 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.

  15. Long-Term Response and Possible Cure of Patients With B-Cell Malignancies With Dose-Escalated Rituximab

    PubMed Central

    Jacobs, Lauren M.; Wiernik, Peter H.; Dutcher, Janice P.; Muxi, Pablo

    2017-01-01

    Rituximab (R), a chimeric monoclonal antibody targeting CD20 antigen on B-cells, has become a standard of care in the treatment of B-cell malignancies, most often in conjunction with cytotoxic chemotherapy. Activity has been demonstrated in many subtypes of B-cell lymphoma, including diffuse large cell lymphoma, follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), lymphocyte-predominant Hodgkin lymphoma, and Waldenström macroglobulinemia (WM). Additionally, dose escalation of R as a single agent has demonstrated improved activity in previously treated/poor prognosis CLL. We present 4 cases of B-cell malignancy (2 CLL variants/MCL, 1 FL, 1 WM) who received dose-escalated R as a single agent and achieved complete response (3 patients) and stable disease/partial response (1 patient) of 6.5+ to 15+ years duration. They have been off treatment for 6.5+ to 15+ years. Toxicity was minimal, with initial infusion reactions similar to those observed with standard dose infusions. There were no serious treatment-related adverse events or infections. Dose escalated R as a single agent may possibly be curative for some patients with B-cell malignancies, unlike the standard empiric dose of 375 mg/m2, and deserves further study. PMID:28203581

  16. 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.

  17. 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.

  18. Transcriptome Sequencing for the Detection of Chimeric Transcripts.

    PubMed

    Chu, Hsueh-Ting

    2016-01-01

    The occurrence of chimeric transcripts has been reported in many cancer cells and seen as potential biomarkers and therapeutic targets. Modern high-throughput sequencing technologies offer a way to investigate individual chimeric transcripts and the systematic information of associated gene expressions about underlying genome structural variations and genomic interactions. The detection methods of finding chimeric transcripts from massive amount of short read sequence data are discussed here. Both assembly-based and alignment-based methods are used for the investigation of chimeric transcripts.

  19. Humanization of excretory pathway in chimeric mice with humanized liver.

    PubMed

    Okumura, Hirotoshi; Katoh, Miki; Sawada, Toshiro; Nakajima, Miki; Soeno, Yoshinori; Yabuuchi, Hikaru; Ikeda, Toshihiko; Tateno, Chise; Yoshizato, Katsutoshi; Yokoi, Tsuyoshi

    2007-06-01

    The liver of a chimeric urokinase-type plasminogen activator (uPA)(+/+)/severe combined immunodeficient (SCID) mouse line recently established in Japan could be replaced by more than 80% with human hepatocytes. We previously reported that the chimeric mice with humanized liver could be useful as a human model in studies on drug metabolism and pharmacokinetics. In the present study, the humanization of an excretory pathway was investigated in the chimeric mice. Cefmetazole (CMZ) was used as a probe drug. The CMZ excretions in urine and feces were 81.0 and 5.9% of the dose, respectively, in chimeric mice and were 23.7 and 59.4% of the dose, respectively, in control uPA(-/-)/SCID mice. Because CMZ is mainly excreted in urine in humans, the excretory profile of chimeric mice was demonstrated to be similar to that of humans. In the chimeric mice, the hepatic mRNA expression of human drug transporters could be quantified. On the other hand, the hepatic mRNA expression of mouse drug transporters in the chimeric mice was significantly lower than in the control uPA(-/-)/SCID mice. In conclusion, chimeric mice exhibited a humanized profile of drug excretion, suggesting that this chimeric mouse line would be a useful animal model in excretory studies.

  20. Phase III Randomized Intergroup Trial of CHOP Plus Rituximab Compared With CHOP Chemotherapy Plus 131Iodine-Tositumomab for Previously Untreated Follicular Non-Hodgkin Lymphoma: SWOG S0016

    PubMed Central

    Press, Oliver W.; Unger, Joseph M.; Rimsza, Lisa M.; Friedberg, Jonathan W.; LeBlanc, Michael; Czuczman, Myron S.; Kaminski, Mark; Braziel, Rita M.; Spier, Catherine; Gopal, Ajay K.; Maloney, David G.; Cheson, Bruce D.; Dakhil, Shaker R.; Miller, Thomas P.; Fisher, Richard I.

    2013-01-01

    Purpose Advanced follicular lymphomas (FL) are considered incurable with conventional chemotherapy and there is no consensus on the best treatment approach. Southwest Oncology Group (SWOG) and Cancer and Leukemia Group B compared the safety and efficacy of two immunochemotherapy regimens for FL in a phase III randomized intergroup protocol (SWOG S0016) that enrolled 554 patients with previously untreated, advanced-stage FL between March 1, 2001, and September 15, 2008. Patients and Methods Patients were eligible for the study if they had advanced-stage (bulky stage II, III, or IV) evaluable FL of any grade (1, 2, or 3) and had not received previous therapy. In one arm of the study, patients received six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy at 3-week intervals with six doses of rituximab (CHOP-R). In another arm of the study, patients received six cycles of CHOP followed by consolidation with tositumomab/iodine I-131 tositumomab radioimmunotherapy (RIT). Results After a median follow-up period of 4.9 years, the 2-year estimate of progression-free survival (PFS) was 76% on the CHOP-R arm and 80% on the CHOP-RIT arm (P = .11). The 2-year estimate of overall survival (OS) was 97% on the CHOP-R arm and 93% on the CHOP-RIT arm (P = .08). Conclusion There was no evidence of a significant improvement in PFS comparing CHOP-RIT with CHOP-R. However, PFS and OS were outstanding on both arms of the study. Future studies are needed to determine the potential benefits of combining CHOP-R induction chemotherapy with RIT consolidation and/or extended rituximab maintenance therapy. PMID:23233710

  1. 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.

  2. 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.

  3. 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

  4. 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

  5. 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.

  6. [Radioactivity for 137Cs, 125I, 131I, 59Fe, y 57Co windows from foods included in the basic alimentary basket and in the water, consumed in the state of Carabobo, Venezuela].

    PubMed

    Torres, Annabell; Tovar, María; Malpica, Oscar; Eblen-Zajjur, Antonio

    2002-01-01

    One of the input ways of radionucleids into the organism is through food intake. The aim of the present study is to measure the radioactivity levels in food and water samples within energy windows corresponding to 137Cs, 125I, 131I, 59Fe, and 57Co. Samples were taken from local and imported food belonging to the venezuelan basic alimentary basket and included: beef meat, hen egg, chicken bone, tomato, black bean, rice, powder milk from local dealers or imported from Italy and New Zeeland, potable water from the Valencia city aqueduct and bottled water from local sources or imported from Portugal. Radioactivity was measured with a well type Nal (TI) scintillation counter. Analyzed foods and water presented levels lower than the minimal detectable activity for 137Cs, 131I, 59Fe, 57Co, but it was detected in the Valencia city aqueduct water and in bottled water imported from Portugal, levels greater than the minimal detectable activity for the 125I energy window. These results strongly suggest the need of repeated multienergy windows monitoring of radioactivity of basic alimentary basket foods and potable water.

  7. Radioactive Iodine (I-131) Therapy for Hyperthyroidism

    MedlinePlus

    ... of your treatment team. top of page What equipment is used? There is no equipment used during ... iodine therapy. top of page Who operates the equipment? There is no equipment used during radioactive iodine ...

  8. Interspecies Chimerism with Mammalian Pluripotent Stem Cells.

    PubMed

    Wu, Jun; Platero-Luengo, Aida; Sakurai, Masahiro; Sugawara, Atsushi; Gil, Maria Antonia; Yamauchi, Takayoshi; Suzuki, Keiichiro; Bogliotti, Yanina Soledad; Cuello, Cristina; Morales Valencia, Mariana; Okumura, Daiji; Luo, Jingping; Vilariño, Marcela; Parrilla, Inmaculada; Soto, Delia Alba; Martinez, Cristina A; Hishida, Tomoaki; Sánchez-Bautista, Sonia; Martinez-Martinez, M Llanos; Wang, Huili; Nohalez, Alicia; Aizawa, Emi; Martinez-Redondo, Paloma; Ocampo, Alejandro; Reddy, Pradeep; Roca, Jordi; Maga, Elizabeth A; Esteban, Concepcion Rodriguez; Berggren, W Travis; Nuñez Delicado, Estrella; Lajara, Jeronimo; Guillen, Isabel; Guillen, Pedro; Campistol, Josep M; Martinez, Emilio A; Ross, Pablo Juan; Izpisua Belmonte, Juan Carlos

    2017-01-26

    Interspecies blastocyst complementation enables organ-specific enrichment of xenogenic pluripotent stem cell (PSC) derivatives. Here, we establish a versatile blastocyst complementation platform based on CRISPR-Cas9-mediated zygote genome editing and show enrichment of rat PSC-derivatives in several tissues of gene-edited organogenesis-disabled mice. Besides gaining insights into species evolution, embryogenesis, and human disease, interspecies blastocyst complementation might allow human organ generation in animals whose organ size, anatomy, and physiology are closer to humans. To date, however, whether human PSCs (hPSCs) can contribute to chimera formation in non-rodent species remains unknown. We systematically evaluate the chimeric competency of several types of hPSCs using a more diversified clade of mammals, the ungulates. We find that naïve hPSCs robustly engraft in both pig and cattle pre-implantation blastocysts but show limited contribution to post-implantation pig embryos. Instead, an intermediate hPSC type exhibits higher degree of chimerism and is able to generate differentiated progenies in post-implantation pig embryos.

  9. Lung rejection occurs in lung transplant recipients with blood chimerism.

    PubMed

    Knoop, C; Andrien, M; Defleur, V; Antoine, M; de Francquen, P; Goldman, M; Estenne, M

    1997-07-15

    It has been postulated that chimerism after transplantation might promote graft acceptance. In the present study, we prospectively assessed blood chimerism in 10 lung transplant recipients during the first posttransplant year and investigated whether chimerism was associated with an immunologically stable situation of the graft. The recipients' peripheral blood mononuclear cells were obtained before transplantation and at various time points during the first postoperative year. Donor cells were detected using nested polymerase chain reaction amplification of a donor-specific HLA-DRB1 allele. Clinical graft acceptance was determined by the number of rejection episodes. The incidence of blood chimerism was high during the first 3 postoperative months and then decreased over time. All patients experienced at least one acute rejection episode, and three patients developed chronic rejection. We, thus, conclude that rejection of the lung allograft may occur in the presence of blood chimerism.

  10. 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

  11. 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.

  12. 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.

  13. 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.

  14. 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.

  15. 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

  16. 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.

  17. 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

  18. 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.

  19. Vectors expressing chimeric Japanese encephalitis dengue 2 viruses.

    PubMed

    Wei, Y; Wang, S; Wang, X

    2014-01-01

    Vectors based on self-replicating RNAs (replicons) of flaviviruses are becoming powerful tool for expression of heterologous genes in mammalian cells and development of novel antiviral and anticancer vaccines. We constructed two vectors expressing chimeric viruses consisting of attenuated SA14-14-2 strain of Japanese encephalitis virus (JEV) in which the PrM/M-E genes were replaced fully or partially with those of dengue 2 virus (DENV-2). These vectors, named pJED2 and pJED2-1770 were transfected to BHK-21 cells and produced chimeric viruses JED2V and JED2-1770V, respectively. The chimeric viruses could be passaged in C6/36 but not BHK-21 cells. The chimeric viruses produced in C6/36 cells CPE 4-5 days after infection and RT-PCR, sequencing, immunofluorescence assay (IFA) and Western blot analysis confirmed the chimeric nature of produced viruses. The immunogenicity of chimeric viruses in mice was proved by detecting DENV-2 E protein-specific serum IgG antibodies with neutralization titer of 10. Successful preparation of infectious clones of chimeric JEV-DENV-2 viruses showed that JEV-based expression vectors are fully functional.

  20. chimeraviz: a tool for visualizing chimeric RNA.

    PubMed

    Lågstad, Stian; Zhao, Sen; Hoff, Andreas M; Johannessen, Bjarne; Lingjærde, Ole Christian; Skotheim, Rolf I

    2017-09-15

    Advances in high-throughput RNA sequencing have enabled more efficient detection of fusion transcripts, but the technology and associated software used for fusion detection from sequencing data often yield a high false discovery rate. Good prioritization of the results is important, and this can be helped by a visualization framework that automatically integrates RNA data with known genomic features. Here we present chimeraviz , a Bioconductor package that automates the creation of chimeric RNA visualizations. The package supports input from nine different fusion-finder tools: deFuse, EricScript, InFusion, JAFFA, FusionCatcher, FusionMap, PRADA, SOAPfuse and STAR-FUSION. chimeraviz is an R package available via Bioconductor ( https://bioconductor.org/packages/release/bioc/html/chimeraviz.html ) under Artistic-2.0. Source code and support is available at GitHub ( https://github.com/stianlagstad/chimeraviz ). rolf.i.skotheim@rr-research.no. Supplementary data are available at Bioinformatics online.

  1. 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.

  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. 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

  4. 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.

  5. [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.

  6. 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

  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. Stable mixed chimerism and tolerance to human organ transplants.

    PubMed

    Strober, Samuel

    2015-04-03

    Tolerance to combined kidney and hematopoietic cell transplant has been achieved in humans after establishment of mixed chimerism allowing for the withdrawal of immunosuppressive drugs. The seminal contributions of Ray Owen provided the scientific basis for the human protocol.

  9. Chimeric alignment by dynamic programming: Algorithm and biological uses

    SciTech Connect

    Komatsoulis, G.A.; Waterman, M.S.

    1997-12-01

    A new nearest-neighbor method for detecting chimeric 16S rRNA artifacts generated during PCR amplification from mixed populations has been developed. The method uses dynamic programming to generate an optimal chimeric alignment, defined as the highest scoring alignment between a query and a concatenation of a 5{prime} and a 3{prime} segment from two separate entries from a database of related sequences. Chimeras are detected by studying the scores and form of the chimeric and global sequence alignments. The chimeric alignment method was found to be marginally more effective than k-tuple based nearest-neighbor methods in simulation studies, but its most effective use is in concert with k-tuple methods. 15 refs., 3 figs., 1 tab.

  10. 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.

  11. 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.

  12. 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

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. Chimeric mitochondrial peptides from contiguous regular and swinger RNA.

    PubMed

    Seligmann, Hervé

    2016-01-01

    Previous mass spectrometry analyses described human mitochondrial peptides entirely translated from swinger RNAs, RNAs where polymerization systematically exchanged nucleotides. Exchanges follow one among 23 bijective transformation rules, nine symmetric exchanges (X ↔ Y, e.g. A ↔ C) and fourteen asymmetric exchanges (X → Y → Z → X, e.g. A → C → G → A), multiplying by 24 DNA's protein coding potential. Abrupt switches from regular to swinger polymerization produce chimeric RNAs. Here, human mitochondrial proteomic analyses assuming abrupt switches between regular and swinger transcriptions, detect chimeric peptides, encoded by part regular, part swinger RNA. Contiguous regular- and swinger-encoded residues within single peptides are stronger evidence for translation of swinger RNA than previously detected, entirely swinger-encoded peptides: regular parts are positive controls matched with contiguous swinger parts, increasing confidence in results. Chimeric peptides are 200 × rarer than swinger peptides (3/100,000 versus 6/1000). Among 186 peptides with > 8 residues for each regular and swinger parts, regular parts of eleven chimeric peptides correspond to six among the thirteen recognized, mitochondrial protein-coding genes. Chimeric peptides matching partly regular proteins are rarer and less expressed than chimeric peptides matching non-coding sequences, suggesting targeted degradation of misfolded proteins. Present results strengthen hypotheses that the short mitogenome encodes far more proteins than hitherto assumed. Entirely swinger-encoded proteins could exist.

  18. 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

  19. 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.

  20. 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

  1. 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.

  2. 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

  3. 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

  4. [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.

  5. 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.

  6. 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.

  7. 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.

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. Chimeric Antigen Receptor Therapy for Cancer

    PubMed Central

    Barrett, David M.; Singh, Nathan; Porter, David L.; Grupp, Stephan A.; June, Carl H.

    2014-01-01

    Improved outcomes for patients with cancer hinge on the development of new targeted therapies with acceptable short-term and long-term toxicity. Progress in basic, preclinical, and clinical arenas spanning cellular immunology, synthetic biology, and cell-processing technologies has paved the way for clinical applications of chimeric antigen receptor– based therapies. This new form of targeted immunotherapy merges the exquisite targeting specificity of monoclonal antibodies with the potent cytotoxicity and long-term persistence provided by cytotoxic T cells. Although this field is still in its infancy, clinical trials have already shown clinically significant antitumor activity in neuroblastoma, chronic lymphocytic leukemia, and B cell lymphoma, and trials targeting a variety of other adult and pediatric malignancies are under way. Ongoing work is focused on identifying optimal tumor targets and on elucidating and manipulating both cell- and host-associated factors to support expansion and persistence of the genetically engineered cells in vivo. The potential to target essentially any tumor-associated cell-surface antigen for which a monoclonal antibody can be made opens up an entirely new arena for targeted therapy of cancer. PMID:24274181

  14. Generating chimeric zebrafish embryos by transplantation.

    PubMed

    Kemp, Hilary A; Carmany-Rampey, Amanda; Moens, Cecilia

    2009-07-17

    One of the most powerful tools used to gain insight into complex developmental processes is the analysis of chimeric embryos. A chimera is defined as an organism that contains cells from more than one animal; mosaics are one type of chimera in which cells from more than one genotype are mixed, usually wild-type and mutant. In the zebrafish, chimeras can be readily made by transplantation of cells from a donor embryo into a host embryo at the appropriate embryonic stage. Labeled donor cells are generated by injection of a lineage marker, such as a fluorescent dye, into the one-cell stage embryo. Labeled donor cells are removed from donor embryos and introduced into unlabeled host embryos using an oil-controlled glass pipette mounted on either a compound or dissecting microscope. Donor cells can in some cases be targeted to a specific region or tissue of the developing blastula or gastrula stage host embryo by choosing a transplantation site in the host embryo based on well-established fate maps.

  15. Structure aided design of chimeric antibiotics.

    PubMed

    Karoli, Tomislav; Mamidyala, Sreeman K; Zuegg, Johannes; Fry, Scott R; Tee, Ernest H L; Bradford, Tanya A; Madala, Praveen K; Huang, Johnny X; Ramu, Soumya; Butler, Mark S; Cooper, Matthew A

    2012-04-01

    The rise of antibiotic resistance is of great clinical concern. One approach to reducing the development of resistance is to co-administer two or more antibiotics with different modes of action. However, it can be difficult to control the distribution and pharmacokinetics of two drugs to ensure both concentrations remain within the range of therapeutic efficacy whilst avoiding adverse effects. Hybrid drugs, where two drugs are linked together with a flexible linker, have been explored, but the resultant large, flexible molecules can have poor bioavailability. We have developed a chimeric approach using click chemistry where the pharmacophores of two drugs are overlapped into a single smaller, more drug-like molecule. Design and selection of compounds were assisted by in silico structural docking. We prepared a series of compounds that include candidates showing activity against the targets of both trimethoprim; dihydrofolate reductase, and ciprofloxacin; DNA gyrase and topoisomerase IV. The resultant triazole containing molecules show modest, but broad spectrum activities against drug sensitive and resistant Gram-negative and Gram-positive bacteria, with no observable cytotoxicity.

  16. Syngeneic Transplants with Modified Chimeric Hematopoietic Tumors.

    PubMed

    Hemann, Michael

    2015-08-03

    This protocol describes strategies to rapidly transduce tumor cells ex vivo and then transplant modified cells into immunocompetent-recipient mice. Inherent in the definition of a bona fide murine hematopoietic malignancy, unlike a myelo- or lympho-proliferative disease, is the ability to transplant tumors and give rise to a malignancy in recipient animals. This characteristic of hematopoietic disease makes these tumors a tractable model for examining the role of specific genes in tumor growth, dissemination, or therapeutic response. Additionally, because of the systemic nature of hematopoietic malignancies, transplanted tumors are frequently pathologically indistinguishable from donor malignancies-allowing one to perform decisive therapy studies on large cohorts of transplant recipients. Finally, following ex vivo manipulation, transplanted tumors can be made chimeric for the presence of defined retrovirally induced alterations. Thus, these malignancies can be made to resemble genetically heterogeneous human tumors that are in the process of acquiring new capabilities. In these experiments, fluorescent markers serve as a surrogate marker for the expression of a defined alteration, and the change in the percentage of fluorescent cells in a tumor population over time or in response to therapy can be used to gauge the impact of specific alterations on tumor behavior.

  17. 4-1BB chimeric antigen receptors.

    PubMed

    Campana, Dario; Schwarz, Herbert; Imai, Chihaya

    2014-01-01

    In addition to T-cell receptor signals, T lymphocytes require costimulatory signals for robust activation. Among these, those mediated by 4-1BB (CD137, TNFRSF9) are critical for tumor immunity. 4-1BB is expressed in T-cell receptor-activated lymphocytes as well as natural killer cells and other hematopoietic and nonhematopoietic cells. 4-1BB ligation induces a signaling cascade that results in cytokine production, expression of antiapoptotic molecules, and enhanced immune responses. In line with the described function of 4-1BB, its addition to CD3ζ chimeric antigen receptors (CARs) increases their capacity to provoke T-cell expansion and antitumor activity. The results of preclinical studies with 4-1BB CARs have been corroborated by encouraging results from clinical trials. Advantages and disadvantages of 4-1BB CARs versus CARs bearing other costimulatory components remain to be fully elucidated. In this review, we discuss the properties of 4-1BB, the design of 4-1BB CARs, and the function of T lymphocytes and natural killer cells expressing them.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. Baseline autoantibody profiles predict normalization of complement and anti-dsDNA autoantibody levels following rituximab treatment in systemic lupus erythematosus.

    PubMed

    Tew, G W; Rabbee, N; Wolslegel, K; Hsieh, H-J; Monroe, J G; Behrens, T W; Brunetta, P G; Keir, M E

    2010-02-01

    B cells are thought to play a major role in the pathogenesis of systemic lupus erythematosus (SLE). Rituximab (RTX), a chimeric anti-CD20 mAb, effectively depletes CD20( +) peripheral B cells. Recent results from EXPLORER, a placebo-controlled trial of RTX in addition to aggressive prednisone and immunosuppressive therapy, showed similar levels of clinical benefit in patients with active extra-renal SLE despite effective B cell depletion. We performed further data analyses to determine whether significant changes in disease activity biomarkers occurred in the absence of clinical benefit. We found that RTX-treated patients with baseline autoantibodies (autoAbs) had decreased anti-dsDNA and anti-cardiolipin autoAbs and increased complement levels. Patients with anti-dsDNA autoAb who lacked baseline RNA binding protein (RBP) autoAbs showed increased complement and decreased anti-dsDNA autoAb in response to RTX. Other biomarkers, such as baseline BAFF levels or IFN signature status did not predict enhanced effects of RTX therapy on complement or anti-dsDNA autoAb levels. Finally, platelet levels normalized in RTX-treated patients who entered the study with low baseline counts. Together, these findings demonstrate clear biologic activity of RTX in subsets of SLE patients, despite an overall lack of incremental clinical benefit with RTX in the EXPLORER trial.

  3. Steroid metabolism in chimeric mice with humanized liver.

    PubMed

    Lootens, Leen; Van Eenoo, Peter; Meuleman, Philip; Pozo, Oscar J; Van Renterghem, Pieter; Leroux-Roels, Geert; Delbeke, Frans T

    2009-11-01

    Anabolic androgenic steroids are considered to be doping agents and are prohibited in sports. Their metabolism needs to be elucidated to allow for urinary detection by gas chromatography-mass spectrometry (GC-MS) or liquid chromatography-tandem mass spectrometry (LC-MS/MS). Steroid metabolism was assessed using uPA(+/+) SCID mice with humanized livers (chimeric mice). This study presents the results of 19-norandrost-4-ene-3,17-dione (19-norAD) administration to these in vivo mice. As in humans, 19-norandrosterone and 19-noretiocholanolone are the major detectable metabolites of 19-norAD in the urine of chimeric mice.A summary is given of the metabolic pathways found in chimeric mice after administration of three model steroid compounds (methandienone, androst-4-ene-3,17-dione and 19-norandrost-4-ene-3,17-dione). From these studies we can conclude that all major metabolic pathways for anabolic steroids in humans are present in the chimeric mouse. It is hoped that, in future, this promising chimeric mouse model might assist the discovery of new and possible longer detectable metabolites of (designer) steroids.

  4. Assessment of chimerism in epithelial cancers in transplanted patients.

    PubMed

    Leboeuf, Christophe; Ratajczak, Philippe; Vérine, Jérôme; Elbouchtaoui, Morad; Plassa, François; Legrès, Luc; Ferreira, Irmine; Sandid, Wissam; Varna, Mariana; Bousquet, Guilhem; Verneuil, Laurence; Janin, Anne

    2014-01-01

    Cancer is now the most severe complication in the long term in transplant recipients. As most solid-organ or hematopoietic stem-cell transplantations are allogeneic, chimerism studies can be performed on cancers occurring in recipients. We summarize here the different methods used to study chimerism in cancers developing in allogeneic-transplant recipients, analyze their respective advantages and report the main results obtained from these studies. Chimerism analyses of cancers in transplant recipients require methods suited to tissue samples. In the case of gender-mismatched transplantation, the XY chromosomes can be explored using fluorescent in situ hybridization on whole-tissue sections or Y-sequence-specific PCR after the laser microdissection of tumor cells. For cancers occurring after gender-matched transplantation, laser microdissection of tumor cells enables studies of microsatellite markers and high-resolution melting analysis of mitochondrial DNA on genes with marked polymorphism, provided these are different in the donor and the recipient. The results of different studies address the cancers that develop in both recipients and in transplants. The presence of chimeric cells in these two types of cancer implies an exchange of progenitor/stem-cells between transplant and recipient, and the plasticity of these progenitor/stem-cells contributes to epithelial cancers. The presence of chimeric cells in concomitant cancers and preneoplastic lesions implies that the oncogenesis of these cancers progresses through a multistep process.

  5. 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.

  6. 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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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.

  12. 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

  13. Facilitating cells: Translation of hematopoietic chimerism to achieve clinical tolerance

    PubMed Central

    Ildstad, Suzanne T.; Leventhal, Joseph; Wen, Yujie; Yolcu, Esma

    2015-01-01

    ABSTRACT For over 50 y the association between hematopoietic chimerism and tolerance has been recognized. This originated with the brilliant observation by Dr. Ray Owen that freemartin cattle twins that shared a common placental blood supply were red blood cell chimeras, which led to the discovery that hematopoietic chimerism resulted in actively acquired tolerance. This was first confirmed in neonatal mice by Medawar et al. and subsequently in adult rodents. Fifty years later this concept has been successfully translated to solid organ transplant recipients in the clinic. The field is new, but cell-based therapies are being used with increasing frequency to induce tolerance and immunomodulation. The future is bright. This review focuses on chimerism and tolerance: past, present and prospects for the future. PMID:26745761

  14. 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

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. 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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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

  8. 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.

  9. 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

  10. 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.

  11. 78 FR 16505 - Prospective Grant of Exclusive License: Chimeric West Nile/Dengue Viruses

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-15

    ...: Chimeric West Nile/Dengue Viruses AGENCY: Centers for Disease Control and Prevention (CDC), Department of... Application 61/049,342, filed 4/30/2008, entitled ``Engineered, Chimeric West Nile/Dengue Viruses;'' PCT..., filed 10/29/2010, entitled ``Chimeric West Nile/Dengue Viruses;'' and all related continuing and foreign...

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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

  20. 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.

  1. Therapeutic use of chimeric bacteriophage (phage) lysins in staphylococcal endophthalmitis

    USDA-ARS?s Scientific Manuscript database

    Purpose: Phage endolysins are peptidoglycan hydrolases that are produced at the end of the phage lytic cycle to digest the host bacterial cell wall, facilitating the release of mature phage progeny. The aim of this study is to determine the antimicrobial activity of chimeric phage lysins against cli...

  2. Adaptive impact of the chimeric gene Quetzalcoatl in Drosophila melanogaster.

    PubMed

    Rogers, Rebekah L; Bedford, Trevor; Lyons, Ana M; Hartl, Daniel L

    2010-06-15

    Chimeric genes, which form through the genomic fusion of two protein-coding genes, are a significant source of evolutionary novelty in Drosophila melanogaster. However, the propensity of chimeric genes to produce adaptive phenotypic changes is not fully understood. Here, we describe the chimeric gene Quetzalcoatl (Qtzl; CG31864), which formed in the recent past and swept to fixation in D. melanogaster. Qtzl arose through a duplication on chromosome 2L that united a portion of the mitochondrially targeted peptide CG12264 with a segment of the polycomb gene escl. The 3' segment of the gene, which is derived from escl, is inherited out of frame, producing a unique peptide sequence. Nucleotide diversity is drastically reduced and site frequency spectra are significantly skewed surrounding the duplicated region, a finding consistent with a selective sweep on the duplicate region containing Qtzl. Qtzl has an expression profile that largely resembles that of escl, with expression in early pupae, adult females, and male testes. However, expression patterns appear to have been decoupled from both parental genes during later embryonic development and in head tissues of adult males, indicating that Qtzl has developed a distinct regulatory profile through the rearrangement of different 5' and 3' regulatory domains. Furthermore, misexpression of Qtzl suppresses defects in the formation of the neuromuscular junction in larvae, demonstrating that Qtzl can produce phenotypic effects in cells. Together, these results show that chimeric genes can produce structural and regulatory changes in a single mutational step and may be a major factor in adaptive evolution.

  3. Ray Owen and the history of naturally acquired chimerism

    PubMed Central

    Martin, Aryn

    2015-01-01

    abstract This article interweaves a history of Ray Owen's early work with a broader account of the conceptual landscape of immunology in the mid 1950's. In particular, Owen's openness to the very possibility of chimeric phenomena is recognized. PMID:27093621

  4. Systematic evaluation of atmospheric chemistry-transport model CHIMERE

    NASA Astrophysics Data System (ADS)

    Khvorostyanov, Dmitry; Menut, Laurent; Mailler, Sylvain; Siour, Guillaume; Couvidat, Florian; Bessagnet, Bertrand; Turquety, Solene

    2017-04-01

    Regional-scale atmospheric chemistry-transport models (CTM) are used to develop air quality regulatory measures, to support environmentally sensitive decisions in the industry, and to address variety of scientific questions involving the atmospheric composition. Model performance evaluation with measurement data is critical to understand their limits and the degree of confidence in model results. CHIMERE CTM (http://www.lmd.polytechnique.fr/chimere/) is a French national tool for operational forecast and decision support and is widely used in the international research community in various areas of atmospheric chemistry and physics, climate, and environment (http://www.lmd.polytechnique.fr/chimere/CW-articles.php). This work presents the model evaluation framework applied systematically to the new CHIMERE CTM versions in the course of the continuous model development. The framework uses three of the four CTM evaluation types identified by the Environmental Protection Agency (EPA) and the American Meteorological Society (AMS): operational, diagnostic, and dynamic. It allows to compare the overall model performance in subsequent model versions (operational evaluation), identify specific processes and/or model inputs that could be improved (diagnostic evaluation), and test the model sensitivity to the changes in air quality, such as emission reductions and meteorological events (dynamic evaluation). The observation datasets currently used for the evaluation are: EMEP (surface concentrations), AERONET (optical depths), and WOUDC (ozone sounding profiles). The framework is implemented as an automated processing chain and allows interactive exploration of the results via a web interface.

  5. Chimeric Genes in Deletions and Duplications Associated with Intellectual Disability

    PubMed Central

    Monfort, Sandra; Roselló, Mónica; Oltra, Silvestre; Caro-Llopis, Alfonso

    2017-01-01

    We report on three nonrelated patients with intellectual disability and CNVs that give rise to three new chimeric genes. All the genes forming these fusion transcripts may have an important role in central nervous system development and/or in gene expression regulation, and therefore not only their deletion or duplication but also the resulting chimeric gene may contribute to the phenotype of the patients. Deletions and duplications are usually pathogenic when affecting dose-sensitive genes. Alternatively, a chimeric gene may also be pathogenic by different gain-of-function mechanisms that are not restricted to dose-sensitive genes: the emergence of a new polypeptide that combines functional domains from two different genes, the deregulated expression of any coding sequence by the promoter region of a neighboring gene, and/or a putative dominant-negative effect due to the preservation of functional domains of partially truncated proteins. Fusion oncogenes are well known, but in other pathologies, the search for chimeric genes is disregarded. According to our findings, we hypothesize that the frequency of fusion transcripts may be much higher than suspected, and it should be taken into account in the array-CGH analyses of patients with intellectual disability. PMID:28630856

  6. Synthesis of a heterogeneous artificial metallolipase with chimeric catalytic activity.

    PubMed

    Filice, M; Romero, O; Gutiérrez-Fernández, J; de Las Rivas, B; Hermoso, J A; Palomo, J M

    2015-06-07

    A solid-phase strategy using lipase as a biomolecular scaffold to produce a large amount of Cu(2+)-metalloenzyme is proposed here. The application of this protocol on different 3D cavities of the enzyme allows creating a heterogeneous artificial metallolipase showing chimeric catalytic activity. The artificial catalyst was assessed in Diels-Alder cycloaddition reactions and cascade reactions showing excellent catalytic properties.

  7. Construction of yellow fever-influenza A chimeric virus particles.

    PubMed

    Oliveira, B C E P D; Liberto, M I M; Barth, O M; Cabral, M C

    2002-12-01

    In order to obtain a better understanding of the functional mechanisms involved in the fusogenesis of enveloped viruses, the influenza A (X31) and the yellow fever (17DD) virus particles were used to construct a chimeric structure based on their distinct pH requirements for fusion, and the distinct malleability of their nucleocapsids. The malleable nucleocapsid of the influenza A virus particle is characterized by a pleomorphic configuration when observed by electron microscopy. A heat inactivated preparation of X31 virus was used as a lectin to interact with the sialic acid domains present in the 17DD virus envelope. The E spikes of 17DD virus were induced to promote fusion of both envelopes, creating a double genome enveloped structure, the chimeric yellow fever-influenza A virus particle. These chimeric viral particles, originally denominated 'partículas virais quiméricas' (PVQ), were characterized by their infectious capacity for different biological systems. Cell inoculation with PVQ resulted in viral products that showed similar characteristics to those obtained after 17DD virus infections. Our findings open new opportunities towards the understanding of both virus particles and aspects of cellular physiologic quality control. The yellow fever-influenza A chimeric particles, by means of their hybrid composition, should be a valuable tool in the study of cell biology and the function of viral components.

  8. 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

  9. 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

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. [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.

  15. Chimeric aptamers in cancer cell-targeted drug delivery

    PubMed Central

    Kanwar, Jagat R; Roy, Kislay; Kanwar, Rupinder K

    2011-01-01

    Aptamers are single-stranded structured oligonucleotides (DNA or RNA) that can bind to a wide range of targets ("apatopes") with high affinity and specificity. These nucleic acid ligands, generated from pools of random-sequence by an in vitro selection process referred to as systematic evolution of ligands by exponential enrichment (SELEX), have now been identified as excellent tools for chemical biology, therapeutic delivery, diagnosis, research, and monitoring therapy in real-time imaging. Today, aptamers represent an interesting class of modern Pharmaceuticals which with their low immunogenic potential mimic extend many of the properties of monoclonal antibodies in diagnostics, research, and therapeutics. More recently, chimeric aptamer approach employing many different possible types of chimerization strategies has generated more stable and efficient chimeric aptamers with aptamer-aptamer, aptamer-nonaptamer biomacromolecules (siRNAs, proteins) and aptamer-nanoparticle chimeras. These chimeric aptamers when conjugated with various biomacromolecules like locked nucleic acid (LNA) to potentiate their stability, biodistribution, and targeting efficiency, have facilitated the accurate targeting in preclinical trials. We developed LNA-aptamer (anti-nucleolin and EpCAM) complexes which were loaded in iron-saturated bovine lactofeerin (Fe-blf)-coated dopamine modified surface of superparamagnetic iron oxide (Fe3O4) nanoparticles (SPIONs). This complex was used to deliver the specific aptamers in tumor cells in a co-culture model of normal and cancer cells. This review focuses on the chimeric aptamers, currently in development that are likely to find future practical applications in concert with other therapeutic molecules and modalities. PMID:21955150

  16. 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

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. 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

  5. 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.

  6. 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

  7. 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

  8. 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

  9. 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.

  10. 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.

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. [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.

  16. 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

  17. 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

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. 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.

  3. 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

  4. 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

  5. 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

  6. 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.

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. Novel Antiproliferative Chimeric Compounds with Marked Histone Deacetylase Inhibitory Activity

    PubMed Central

    2014-01-01

    Given our interest in finding potential antitumor agents and in view of the multifactorial mechanistic nature of cancer, in the present work, taking advantage of the multifunctional ligands approach, new chimeric molecules were designed and synthesized by combining in single chemical entities structural features of SAHA, targeting histone deacetylases (HDACs), with substituted stilbene or terphenyl derivatives previously obtained by us and endowed with antiproliferative and pro-apoptotic activity. The new chimeric derivatives were characterized with respect to their cytotoxic activity and their effects on cell cycle progression on different tumor cell lines, as well as their HDACs inhibition. Among the other, trans-6 showed the most interesting biological profile, as it exhibited a strong pro-apoptotic activity in tumor cell lines in comparison with both of its parent compounds and a marked HDAC inhibition. PMID:25221651

  13. Chimeric antigen receptors: driving immunology towards synthetic biology

    PubMed Central

    Sadelain, Michel

    2017-01-01

    The advent of second generation CARs and the CD19 paradigm have ushered a new therapeutic modality in oncology. In contrast to earlier forms of adoptive cell therapy, which were based on the isolation and expansion of naturally occurring T cells, CAR therapy is based on the design and manufacture of engineered T cells with optimized properties. A new armamentarium, comprising not only CARs but also chimeric costimulatory receptors, chimeric cytokine receptors, inhibitory receptors and synthetic Notch receptors, expressed in naïve, central memory or stem cell-like memory T cells, is being developed for clinical use in a wide range of cancers. Immunological principles are thus finding a new purpose thanks to advances in genetic engineering, synthetic biology and cell manufacturing sciences. PMID:27372731

  14. Birth of two chimeric genes in the Hominidae lineage.

    PubMed

    Courseaux, A; Nahon, J L

    2001-02-16

    How genes with newly characterized functions originate remains a fundamental question. PMCHL1 and PMCHL2, two chimeric genes derived from the melanin-concentrating hormone (MCH) gene, offer an opportunity to examine such an issue in the human lineage. Detailed structural, expression, and phylogenetic analysis showed that the PMCHL1 gene was created near 25 million years ago (Ma) by a complex mechanism of exon shuffling through retrotransposition of an antisense MCH messenger RNA coupled to de novo creation of splice sites. PMCHL2 arose 5 to 10 Ma by an event of duplication involving a large chromosomal region encompassing the PMCHL1 locus. The RNA expression patterns of those chimeric genes suggest that they have been submitted to strong regulatory constraints during primate evolution.

  15. Blood Chimerism in Dizygotic Monochorionic Twins During 5 Years Observation.

    PubMed

    Dziegiel, M H; Hansen, M H; Haedersdal, S; Barrett, A N; Rieneck, K; Main, K M; Hansen, A T; Clausen, F B

    2017-04-19

    Dizygotic monochorionic twin pregnancies can result in blood chimerism due to in utero twin-to-twin exchange of stem cells. In this case, we examined the proportion of allogeneic red blood cells by flow cytometry and the proportion of allogeneic nucleated cells by digital polymerase chain reaction at 7 months and again at 5 years. We found an increase in the proportion of allogeneic cells from 63% to 89% in one twin, and a similar increase in autologous cells in the other twin from 57% to 84%. A paradigm for stem cell therapy could be modeled on this case: induction of tolerance and chimerism by antenatal transfusion of donor stem cells. The procedure would hold the promise of transplantation and tolerance induction without myeloablative conditioning for inheritable benign hematological diseases such as sickle cell disease and thalassemia. © 2017 The American Society of Transplantation and the American Society of Transplant Surgeons.

  16. Characterization of chimeric plasmid cloning vehicles in Bacillus subtilis.

    PubMed

    Gryczan, T; Shivakumar, A G; Dubnau, D

    1980-01-01

    Restriction endonuclease cleavage maps of seven chimeric plasmids that may be used for molecular cloning in Bacillus subtilis are presented. These plasmids all carry multiple antibiotic resistance markers and were constructed by in vitro molecular cloning techniques. Several of the antibiotic resistance markers were shown to undergo insertional inactivation at specific restriction endonuclease sites. Kanamycin inactivation occurred at the BglII site of pUB110 derivatives, erythromycin inactivation occurred at the HpaI and BclI sites of pE194 derivatives, and streptomycin inactivation occurred at the HindIII site of pSA0501 derivatives. A stable mini-derivative of pBD12 was isolated and characterized. By using these plasmids, we identified proteins involved in plasmid-coded kanamycin and erythromycin resistance. The properties and uses of these chimeric plasmids in the further development of recombinant deoxyribonucleic acid technology in B. subtilis are discussed.

  17. Mechanisms of Tolerance Induction by Hematopoietic Chimerism: The Immune Perspective.

    PubMed

    Yolcu, Esma S; Shirwan, Haval; Askenasy, Nadir

    2017-03-01

    Hematopoietic chimerism is one of the effective approaches to induce tolerance to donor-derived tissue and organ grafts without administration of life-long immunosuppressive therapy. Although experimental efforts to develop such regimens have been ongoing for decades, substantial cumulative toxicity of combined hematopoietic and tissue transplants precludes wide clinical implementation. Tolerance is an active immunological process that includes both peripheral and central mechanisms of mutual education of coresident donor and host immune systems. The major stages include sequential suppression of early alloreactivity, establishment of hematopoietic chimerism and suppressor cells that sustain the state of tolerance, with significant mechanistic and temporal overlap along the tolerization process. Efforts to devise less toxic transplant strategies by reduction of preparatory conditioning focus on modulation rather than deletion of residual host immunity and early reinstitution of regulatory subsets at the central and peripheral levels. Stem Cells Translational Medicine 2017;6:700-712.

  18. Adaptive impact of the chimeric gene Quetzalcoatl in Drosophila melanogaster

    PubMed Central

    Rogers, Rebekah L.; Bedford, Trevor; Lyons, Ana M.; Hartl, Daniel L.

    2010-01-01

    Chimeric genes, which form through the genomic fusion of two protein-coding genes, are a significant source of evolutionary novelty in Drosophila melanogaster. However, the propensity of chimeric genes to produce adaptive phenotypic changes is not fully understood. Here, we describe the chimeric gene Quetzalcoatl (Qtzl; CG31864), which formed in the recent past and swept to fixation in D. melanogaster. Qtzl arose through a duplication on chromosome 2L that united a portion of the mitochondrially targeted peptide CG12264 with a segment of the polycomb gene escl. The 3′ segment of the gene, which is derived from escl, is inherited out of frame, producing a unique peptide sequence. Nucleotide diversity is drastically reduced and site frequency spectra are significantly skewed surrounding the duplicated region, a finding consistent with a selective sweep on the duplicate region containing Qtzl. Qtzl has an expression profile that largely resembles that of escl, with expression in early pupae, adult females, and male testes. However, expression patterns appear to have been decoupled from both parental genes during later embryonic development and in head tissues of adult males, indicating that Qtzl has developed a distinct regulatory profile through the rearrangement of different 5′ and 3′ regulatory domains. Furthermore, misexpression of Qtzl suppresses defects in the formation of the neuromuscular junction in larvae, demonstrating that Qtzl can produce phenotypic effects in cells. Together, these results show that chimeric genes can produce structural and regulatory changes in a single mutational step and may be a major factor in adaptive evolution. PMID:20534482

  19. Cord blood chimerism and relapse after haplo-cord transplantation.

    PubMed

    van Besien, Koen; Koshy, Nebu; Gergis, Usama; Mayer, Sebastian; Cushing, Melissa; Rennert, Hannah; Reich-Slotky, Ronit; Mark, Tomer; Pearse, Roger; Rossi, Adriana; Phillips, Adrienne; Vasovic, Liljana; Ferrante, Rosanna; Hsu, Yen-Michael; Shore, Tsiporah

    2017-02-01

    Haplo-cord stem cell transplantation combines the infusion of CD34 selected hematopoietic progenitors from a haplo-identical donor with an umbilical cord blood (UCB) graft from an unrelated donor and allows faster count recovery, with low rates of disease recurrence and chronic graft-versus-host disease (GVHD). But the contribution of the umbilical cord blood graft to long-term transplant outcome remains unclear. We analyzed 39 recipients of haplo-cord transplants with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), engrafted and in remission at 2 months. Median age was 66 (18-72) and all had intermediate, high, or very-high risk disease. Less than 20% UCB chimerism in the CD33 lineage was associated with an increased rate of disease recurrence (54% versus 11% p < 0.0001) and decrease in one year progression-free (20% versus 55%, p = 0.004) and overall survival (30% versus 62%, p = 0.02). Less than 100% UCB chimerism in the CD3 lineage was associated with increase rate of disease recurrence (46% versus 12%, p = 0.007). Persistent haplo-chimerism in the CD3 lineage was associated with an increased rate of disease recurrence (40% versus 15%, p = 0.009) Chimerism did not predict for treatment related mortality. The cumulative incidence of acute GVHD by day 100 was 43%. The cumulative incidence of moderate/severe chronic GVHD was only 5%. Engraftment of the umbilical cord blood grafts provides powerful graft-versus-leukemia (GVL) effects which protect against disease recurrence and is associated with low risk of chronic GVHD. Engraftment of CD34 selected haplo-identical cells can lead to rapid development of circulating T-cells, but when these cells dominate, GVL-effects are limited and rates of disease recurrence are high.

  20. Immunogenicity of candidate chimeric DNA vaccine against tuberculosis and leishmaniasis.

    PubMed

    Dey, Ayan; Kumar, Umesh; Sharma, Pawan; Singh, Sarman

    2009-08-13

    Mycobacterium tuberculosis and Leishmania donovani are important intracellular pathogens, especially in Indian context. In India and other South East Asian countries, both these infections are highly endemic and in about 20% cases co-infection of these pathogens is reported. For both these pathogens cell mediated immunity plays most important role. The available treatment of these infections is either prolonged or cumbersome or it is ineffective in controlling the outbreaks and spread. Therefore, potentiation of a common host defense mechanism can be used to prevent both the infections simultaneously. In this study we have developed a novel chimeric DNA vaccine candidate comprising the esat-6 gene of M. tuberculosis and kinesin motor domain gene of L. donovani. After developing this novel chimera, its immunogenicity was studied in mouse model. The immune response was compared with individual constructs of esat-6 and kinesin motor domain. The results showed that immunization with chimeric DNA vaccine construct resulted in stronger IFN-gamma and IL-2 response against kinesin (3012+/-102 and 367.5+/-8.92pg/ml) and ESAT-6 (1334+/-46.5 and 245.1+/-7.72pg/ml) in comparison to the individual vaccine constructs. The reciprocal immune response (IFN-gamma and IL-2) against individual construct was lower (kinesin motor domain: 1788+/-36.48 and 341.8+/-9.801pg/ml and ESAT-6: 867.0+/-47.23 and 170.8+/-4.578pg/ml, respectively). The results also suggest that using the chimeric construct both proteins yielded a reciprocal adjuvant affect over each other as the IFN-gamma production against chimera vaccination is statistically significant (p<0.0001) than individual construct vaccination. From this pilot study we could envisage that the chimeric DNA vaccine construct may offer an attractive strategy in controlling co-infection of leishmaniasis and tuberculosis and have important implication in future vaccine design.

  1. Chimeric Protein Complexes in Hybrid Species Generate Novel Phenotypes

    PubMed Central

    Piatkowska, Elzbieta M.; Naseeb, Samina; Knight, David; Delneri, Daniela

    2013-01-01

    Hybridization between species is an important mechanism for the origin of novel lineages and adaptation to new environments. Increased allelic variation and modification of the transcriptional network are the two recognized forces currently deemed to be responsible for the phenotypic properties seen in hybrids. However, since the majority of the biological functions in a cell are carried out by protein complexes, inter-specific protein assemblies therefore represent another important source of natural variation upon which evolutionary forces can act. Here we studied the composition of six protein complexes in two different Saccharomyces “sensu stricto” hybrids, to understand whether chimeric interactions can be freely formed in the cell in spite of species-specific co-evolutionary forces, and whether the different types of complexes cause a change in hybrid fitness. The protein assemblies were isolated from the hybrids via affinity chromatography and identified via mass spectrometry. We found evidence of spontaneous chimericity for four of the six protein assemblies tested and we showed that different types of complexes can cause a variety of phenotypes in selected environments. In the case of TRP2/TRP3 complex, the effect of such chimeric formation resulted in the fitness advantage of the hybrid in an environment lacking tryptophan, while only one type of parental combination of the MBF complex allowed the hybrid to grow under respiratory conditions. These phenotypes were dependent on both genetic and environmental backgrounds. This study provides empirical evidence that chimeric protein complexes can freely assemble in cells and reveals a new mechanism to generate phenotypic novelty and plasticity in hybrids to complement the genomic innovation resulting from gene duplication. The ability to exchange orthologous members has also important implications for the adaptation and subsequent genome evolution of the hybrids in terms of pattern of gene loss. PMID

  2. Chimeric plantibody passively protects mice against aerosolized ricin challenge.

    PubMed

    Sully, Erin K; Whaley, Kevin J; Bohorova, Natasha; Bohorov, Ognian; Goodman, Charles; Kim, Do H; Pauly, Michael H; Velasco, Jesus; Hiatt, Ernie; Morton, Josh; Swope, Kelsi; Roy, Chad J; Zeitlin, Larry; Mantis, Nicholas J

    2014-05-01

    Recent incidents in the United States and abroad have heightened concerns about the use of ricin toxin as a bioterrorism agent. In this study, we produced, using a robust plant-based platform, four chimeric toxin-neutralizing monoclonal antibodies that were then evaluated for the ability to passively protect mice from a lethal-dose ricin challenge. The most effective antibody, c-PB10, was further evaluated in mice as a therapeutic following ricin exposure by injection and inhalation.

  3. Prism adaptation changes perceptual awareness for chimeric visual objects but not for chimeric faces in spatial neglect after right-hemisphere stroke.

    PubMed

    Sarri, Margarita; Kalra, Lalit; Greenwood, Richard; Driver, Jon

    2006-06-01

    Prism adaptation can ameliorate some symptoms of left spatial neglect after right-hemisphere stroke. The mechanisms behind this remain unclear. Prism therapy may increase exploration towards the contralesional side, yet without improving perceptual awareness, as apparently for the left side of chimeric face stimuli (Ferber et al. 2003). However, other prism studies suggest that perceptual awareness might be improved (e.g., Maravita et al., 2003). We tested the impact of prism therapy on visual awareness for the left side of chimeric objects as well as chimeric faces, in three neglect patients. Prism therapy dramatically improved awareness for the identity of the left side of chimeric non-face objects, but had no effect on judging expressions for chimeric faces. The latter may thus be unique in showing no prism benefit.

  4. Xenobiotics, chimerism and the induction of tolerance following organ transplantation

    PubMed Central

    Delaney, C. P.; Thomson, A. W.; Demetris, A. J.; Starzl, T. E.

    2010-01-01

    Summary The successful results seen after organ transplantation are largely attributable to the potency and specificity of modern immunosuppressive agents. Although drug-free unresponsiveness to graft alloantigens has not been routinely achieved in clinical practice, recent appreciation of the importance of cell chimerism, which develops after the migration from donor to host of leukocytes contained in solid organ grafts, has introduced a concept which may explain the mechanism of graft tolerance. Recent evidence has indicated that immunosuppressive drugs may have a common potential to induce graft tolerance, even though they act through diverse mechanisms, and that this potential may be mediated by a permissive effect on the migration and survival of donor-derived leukocytes. This review briefly examines the mechanisms by which immunosuppressive drugs function and analyses the different methods which these agents might use to induce chimerism associated with graft tolerance. Furthermore, we describe ongoing clinical studies in which the chimerism produced after solid organ transplantation is augmented with donor bone marrow in an attempt to facilitate the induction of tolerance. PMID:7584491

  5. Chimeric antibodies with extended half-life in ferrets

    PubMed Central

    Nesspor, Thomas C; Scallon, Bernard

    2014-01-01

    Background Ferrets have long been used as a disease model for the study of influenza vaccines, but a more recent use has been for the study of human monoclonal antibodies directed against influenza viruses. Published data suggest that human antibodies are cleared unusually quickly from the ferret and that immune responses may be partially responsible. This immunogenicity increases variability within groups and may present an obstacle to long-term studies. Objective Our aim was to identify an antibody design with reduced immunogenicity and longer circulating half-life in ferrets. Methods The constant region coding sequences for ferret immunoglobulin G were cloned, and chimeric human/ferret antibodies were expressed and purified. Some of the chimeric antibodies included substitutions that have been shown to extend the half-life of human IgG antibodies. These chimeric antibodies were tested for binding to recombinant ferret FcRn receptor and then evaluated in pharmacokinetic studies in ferrets. Results A one-residue substitution in the ferret Fc domain, S252Y, was identified that increased binding affinity to the ferret neonatal receptor by 24-fold and extended half-life from 65 ± 27 to 206 ± 28 hours or ∼9 days. Ferrets dosed twice with this surrogate antibody showed no indications of an immune response. Conclusion Expressing the variable region of a candidate human therapeutic antibody with ferret constant regions containing the S252Y substitution can offer long half-life and limit immunogenicity. PMID:25074755

  6. Chimeric creatures in Greek mythology and reflections in science.

    PubMed

    Bazopoulou-Kyrkanidou, E

    2001-04-15

    "The Chimaera" in Homer's Iliad, "was of divine stock, not of men, in the forepart a lion, in the hinder a serpent, and in the midst a goat, ellipsis Bellerophon slew her, trusting in the signs of the gods." In Hesiod's Theogony it is emphasized that "Chimaera ellipsis had three heads, one of a grim-eyed lion, another of a goat, and another of a snakeellipsis". In addition to this interspecies animal chimera, human/animal chimeras are referred to in Greek mythology, preeminent among them the Centaurs and the Minotaur. The Centaurs, as horse/men, first appear in Geometric and early Archaic art, but in the literature not until early in the fifth century B.C. The bullheaded-man Minotaur, who is not certainly attested in the literary evidence until circa 500 B.C., first appears in art about 650 B.C. Attempts, in the fourth century B.C. and thereafter, to rationalize their mythical appearance were in vain; their chimeric nature retained its fascinating and archetypal form over the centuries. Early in the 1980s, experimental sheep/goat chimeras were produced removing the reproductive barrier between these two animal species. Late in the 1990s, legal, political, ethical, and moral fights loomed over a patent bid on human/animal chimeras. Chimeric technology is recently developed; however, the concept of chimerism has existed in literary and artistic form in ancient mythology. This is yet another example where art and literature precede scientific research and development.

  7. A modular strategy for engineering orthogonal chimeric RNA transcription regulators

    PubMed Central

    Takahashi, Melissa K.; Lucks, Julius B.

    2013-01-01

    Antisense RNA transcription attenuators are a key component of the synthetic biology toolbox, with their ability to serve as building blocks for both signal integration logic circuits and transcriptional cascades. However, a central challenge to building more sophisticated RNA genetic circuitry is creating larger families of orthogonal attenuators that function independently of each other. Here, we overcome this challenge by developing a modular strategy to create chimeric fusions between the engineered transcriptional attenuator from plasmid pT181 and natural antisense RNA translational regulators. Using in vivo gene expression assays in Escherichia coli, we demonstrate our ability to create chimeric attenuators by fusing sequences from five different translational regulators. Mutagenesis of these functional attenuators allowed us to create a total of 11 new chimeric attenutaors. A comprehensive orthogonality test of these culminated in a 7 × 7 matrix of mutually orthogonal regulators. A comparison between all chimeras tested led to design principles that will facilitate further engineering of orthogonal RNA transcription regulators, and may help elucidate general principles of non-coding RNA regulation. We anticipate that our strategy will accelerate the development of even larger families of orthogonal RNA transcription regulators, and thus create breakthroughs in our ability to construct increasingly sophisticated RNA genetic circuitry. PMID:23761434

  8. [Clinical translational research of chimeric antigen receptor-T (CAR-T) cells for the treatment of relapsed and refractory B-cell lymphoma/leukemia].

    PubMed

    Yuan, Shun-Zong; Su, Hang

    2014-08-01

    B-cell lymphoma and leukemia are the most common subtypes of malignant lymphomas. Relapse and refractory to multiple therapy are the main reasons of treatment failure. As the classical anti-tumor methods, surgery, radiation, chemotherapy and palliative therapy have cured lots of cancer patients. However, each year many patients still died of different kinds of hard-to-treat cancers. Although the ratio of complete remission of B-cell lymphoma/leukemia patients particularly with CD20 positive mature B cell malignancies has been largely increased after the application of Rituximab in clinic, nearly 20%-40% patients still died due to relapse and refractory to the treatment. During last five years, the development of chimeric antigen receptor-T (CAR-T) cells, especially CD19 CAR-T cells, which can recognize CD19 specifically expressed on B cells and have been demonstrated to be significantly effective to relapsed and refractory B cell lymphoma/leukemia in clinical trials, has gradually attracted extensively concerning from researchers and clinicians. Many medical institutions all over the world (besides in China) have registered the clinical trials for B-cell lymphoma/leukemia patients by use of CAR-T cells. In this review, we summarize the developmental history, the main ongoing clinical trials and proved potential adverse affects of CD19 CAR-T cells for the treatment of patients with B-cell lymphoma/leukemia.

  9. 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.

  10. 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.

  11. Dose-Adjusted EPOCH-Rituximab Combined With Fludarabine Provides an Effective Bridge to Reduced-Intensity Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Lymphoid Malignancies

    PubMed Central

    Salit, Rachel B.; Fowler, Daniel H.; Wilson, Wyndham H.; Dean, Robert M.; Pavletic, Steven Z.; Dunleavy, Kieron; Hakim, Frances; Fry, Terry J.; Steinberg, Seth M.; Hughes, Thomas E.; Odom, Jeanne; Bryant, Kelly; Gress, Ronald E.; Bishop, Michael R.

    2012-01-01

    Purpose There is currently no standard chemotherapy regimen for patients with lymphoid malignancies being considered for reduced-intensity conditioning allogeneic hematopoietic stem-cell transplantation (RIC-alloHSCT). The ideal regimen would provide disease control and result in lymphocyte depletion to facilitate engraftment. To this end, we developed a novel regimen by adding fludarabine to dose-adjusted continuous-infusion etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin plus with or without rituximab (DA-EPOCH-F/R). Patients and Methods One hundred forty-seven patients with lymphoid malignancy (median age, 50 years) who had heavily pretreated (median prior regimens, three) and chemo-refractory (47%) disease were treated with DA-EPOCH-F/R before RIC-alloHSCT. Patients received one to three consecutive cycles until achieving lymphocyte depletion (CD4+ count < 200/μL) or progressive disease. Results Overall response rate was 41%; 39% of patients had stable disease. Toxicity included grade 4 neutropenia in 65% and thrombocytopenia in 25% of patients. DA-EPOCH-F/R resulted in lymphocyte depletion (P < .001), which was inversely associated with serum interleukin (IL) 7 and IL-15 levels. Of 147 patients, 143 patients proceeded to RIC-alloHSCT. Patients with lower CD3+ (P < .001), CD4+ (P < .001), and CD8+ (P < .001) T-cell counts after DA-EPOCH-F/R were more likely to achieve full donor lymphoid chimerism by day +14 after transplant. Relative to nonresponders to DA-EPOCH-F/R, patients with complete and partial response had increased event-free survival (77.4 v 4.8 months; P < .001) and overall survival (98.5 v 16.2 months; P < .001). Conclusion DA-EPOCH-F/R safely provides tumor cytoreduction and lymphocyte depletion, thereby offering a bridge to RIC-alloHSCT in patients with aggressive lymphoid malignancies. PMID:22312100

  12. Lassa-vesicular stomatitis chimeric virus safely destroys brain tumors.

    PubMed

    Wollmann, Guido; Drokhlyansky, Eugene; Davis, John N; Cepko, Connie; van den Pol, Anthony N

    2015-07-01

    High-grade tumors in the brain are among the deadliest of cancers. Here, we took a promising oncolytic virus, vesicular stomatitis virus (VSV), and tested the hypothesis that the neurotoxicity associated with the virus could be eliminated without blocking its oncolytic potential in the brain by replacing the neurotropic VSV glycoprotein with the glycoprotein from one of five different viruses, including Ebola virus, Marburg virus, lymphocytic choriomeningitis virus (LCMV), rabies virus, and Lassa virus. Based on in vitro infections of normal and tumor cells, we selected two viruses to test in vivo. Wild-type VSV was lethal when injected directly into the brain. In contrast, a novel chimeric virus (VSV-LASV-GPC) containing genes from both the Lassa virus glycoprotein precursor (GPC) and VSV showed no adverse actions within or outside the brain and targeted and completely destroyed brain cancer, including high-grade glioblastoma and melanoma, even in metastatic cancer models. When mice had two brain tumors, intratumoral VSV-LASV-GPC injection in one tumor (glioma or melanoma) led to complete tumor destruction; importantly, the virus moved contralaterally within the brain to selectively infect the second noninjected tumor. A chimeric virus combining VSV genes with the gene coding for the Ebola virus glycoprotein was safe in the brain and also selectively targeted brain tumors but was substantially less effective in destroying brain tumors and prolonging survival of tumor-bearing mice. A tropism for multiple cancer types combined with an exquisite tumor specificity opens a new door to widespread application of VSV-LASV-GPC as a safe and efficacious oncolytic chimeric virus within the brain. Many viruses have been tested for their ability to target and kill cancer cells. Vesicular stomatitis virus (VSV) has shown substantial promise, but a key problem is that if it enters the brain, it can generate adverse neurologic consequences, including death. We tested a series of

  13. Lassa-Vesicular Stomatitis Chimeric Virus Safely Destroys Brain Tumors

    PubMed Central

    Wollmann, Guido; Drokhlyansky, Eugene; Davis, John N.; Cepko, Connie

    2015-01-01

    ABSTRACT High-grade tumors in the brain are among the deadliest of cancers. Here, we took a promising oncolytic virus, vesicular stomatitis virus (VSV), and tested the hypothesis that the neurotoxicity associated with the virus could be eliminated without blocking its oncolytic potential in the brain by replacing the neurotropic VSV glycoprotein with the glycoprotein from one of five different viruses, including Ebola virus, Marburg virus, lymphocytic choriomeningitis virus (LCMV), rabies virus, and Lassa virus. Based on in vitro infections of normal and tumor cells, we selected two viruses to test in vivo. Wild-type VSV was lethal when injected directly into the brain. In contrast, a novel chimeric virus (VSV-LASV-GPC) containing genes from both the Lassa virus glycoprotein precursor (GPC) and VSV showed no adverse actions within or outside the brain and targeted and completely destroyed brain cancer, including high-grade glioblastoma and melanoma, even in metastatic cancer models. When mice had two brain tumors, intratumoral VSV-LASV-GPC injection in one tumor (glioma or melanoma) led to complete tumor destruction; importantly, the virus moved contralaterally within the brain to selectively infect the second noninjected tumor. A chimeric virus combining VSV genes with the gene coding for the Ebola virus glycoprotein was safe in the brain and also selectively targeted brain tumors but was substantially less effective in destroying brain tumors and prolonging survival of tumor-bearing mice. A tropism for multiple cancer types combined with an exquisite tumor specificity opens a new door to widespread application of VSV-LASV-GPC as a safe and efficacious oncolytic chimeric virus within the brain. IMPORTANCE Many viruses have been tested for their ability to target and kill cancer cells. Vesicular stomatitis virus (VSV) has shown substantial promise, but a key problem is that if it enters the brain, it can generate adverse neurologic consequences, including death. We

  14. Utilizing chimeric proteins for exploring the cellular fate of endogenous proteins.

    PubMed

    Ben-Yehudah, Ahmi; Aqeilan, Rami; Belostotsky, Ruth; Azar, Yehudith; Lorberboum-Galski, Haya

    2002-01-11

    We recently designed and constructed chimeric proteins for the elimination of specific cell populations. These chimeric proteins are composed of a targeting component fused to an apoptotic protein as the killing moiety. However, chimeric proteins can serve not only to eliminate cell populations, but also as "biological tools" for studying the fate of endogenous proteins. We show here that upon entering their target cell, a variety of chimeric proteins composed of an endogenous protein as their killing moiety reach the subcellular location of their endogenous counterpart. In contrast, bacterial-based killing domains head for the subcellular site of their substrate. Moreover, the chimeric protein acts similarly to the endogenous protein, while causing the cell to die. Therefore, chimeric proteins may serve as a unique tool for investigating cellular proteins and their intracellular localization, without the need to overexpress them.

  15. Rotavirus VP7 epitope chimeric proteins elicit cross-immunoreactivity in guinea pigs.

    PubMed

    Zhao, Bingxin; Pan, Xiaoxia; Teng, Yumei; Xia, Wenyue; Wang, Jing; Wen, Yuling; Chen, Yuanding

    2015-10-01

    VP7 of group A rotavirus (RVA) contains major neutralizing epitopes. Using the antigenic protein VP6 as the vector, chimeric proteins carrying foreign epitopes have been shown to possess good immunoreactivity and immunogenicity. In the present study, using modified VP6 as the vector, three chimeric proteins carrying epitopes derived from VP7 of RVA were constructed. The results showed that the chimeric proteins reacted with anti-VP6 and with SA11 and Wa virus strains. Antibodies from guinea pigs inoculated with the chimeric proteins recognized VP6 and VP7 of RVA and protected mammalian cells from SA11 and Wa infection in vitro. The neutralizing activities of the antibodies against the chimeric proteins were significantly higher than those against the vector protein VP6F. Thus, development of chimeric vaccines carrying VP7 epitopes using VP6 as a vector could be a promising alternative to enhance immunization against RVAs.

  16. 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.

  17. 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

  18. Chimeric Proteins to Detect DNA Damage and Mismatches

    SciTech Connect

    McCutchen-Maloney, S; Malfatti, M; Robbins, K M

    2002-01-14

    The goal of this project was to develop chimeric proteins composed of a DNA mismatch or damage binding protein and a nuclease, as well as methods to detect DNA mismatches and damage. We accomplished this through protein engineering based on using polymerase chain reactions (PCRs) to create chimeras with novel functions for damage and mismatch detection. This project addressed fundamental questions relating to disease susceptibility and radiation-induced damage in cells. It also supported and enhanced LLNL's competency in the emerging field of proteomics. In nature, DNA is constantly being subjected to damaging agents such as exposure to ultraviolet (UV) radiation and various environmental and dietary carcinogens. If DNA damage is not repaired however, mutations in DNA result that can eventually manifest in cancer and other diseases. In addition to damage-induced DNA mutations, single nucleotide polymorphisms (SNPs), which are variations in the genetic sequence between individuals, may predispose some to disease. As a result of the Human Genome Project, the integrity of a person's DNA can now be monitored. Therefore, methods to detect DNA damage, mutations, and SNPs are useful not only in basic research but also in the health and biotechnology industries. Current methods of detection often use radioactive labeling and rely on expensive instrumentation that is not readily available in many research settings. Our methods to detect DNA damage and mismatches employ simple gel electrophoresis and flow cytometry, thereby alleviating the need for radioactive labeling and expensive equipment. In FY2001, we explored SNP detection by developing methods based on the ability of the chimeric proteins to detect mismatches. Using multiplex assays with flow cytometry and fluorescent beads to which the DNA substrates where attached, we showed that several of the chimeras possess greater affinity for damaged and mismatched DNA than for native DNA. This affinity was demonstrated in

  19. Expression and purification of toxic anti-breast cancer p28-NRC chimeric protein

    PubMed Central

    Soleimani, Meysam; Mirmohammad-Sadeghi, Hamid; Sadeghi-Aliabadi, Hojjat; Jahanian-Najafabadi, Ali

    2016-01-01

    Background: Chimeric proteins consisting of a targeting moiety and a cytotoxic moiety are now under intense research focus for targeted therapy of cancer. Here, we report cloning, expression, and purification of such a targeted chimeric protein made up of p28 peptide as both targeting and anticancer moiety fused to NRC peptide as a cytotoxic moiety. However, since the antimicrobial activity of the NRC peptide would intervene expression of the chimeric protein in Escherichia coli, we evaluated the effects of two fusion tags, that is, thioredoxin (Trx) and 6x-His tags, and various expression conditions, on the expression of p28-NRC chimeric protein. Materials and Methods: In order to express the chimeric protein with only 6x-His tag, pET28 expression plasmid was used. Cloning in pET32 expression plasmid was performed to add both Trx and 6x-His tags to the chimeric protein. Expression of the chimeric protein with both plasmids was evaluated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis following optimization of expression conditions and host strains. Results: Expression of the chimeric protein in pET28a was performed. However, expression yield of the chimeric protein was low. Optimization of culture conditions and host strains led to reasonable expression yield of the toxic chimeric protein in pET32a vector. In cases of both plasmids, approximately 10 kDa deviation of the apparent molecular weight from the theoretical one was seen in SDS-PAGE of purified chimeric proteins. Conclusions: The study leads to proper expression and purification yield of p28-NRC chimeric protein with Trx tag following optimizing culture conditions and host strains. PMID:27169101

  20. Establishment of Donor Chimerism Using Allogeneic Bone Marrow with AMP Cell Co-infusion

    DTIC Science & Technology

    2016-09-01

    AWARD NUMBER: W81XWH-15-1-0234 TITLE: “Establishment of donor Chimerism Using Allogeneic Bone Marrow with AMP Cell Co-infusion” PRINCIPAL...Form 298 (Rev. 8-98) Prescribed by ANSI Std. Z39.18 Megan.sykes@columbia.edu Establishment of donor Chimerism Using Allogeneic Bone Marrow with AMP...promote the induction of durable mixed allogeneic chimerism in non-human primates. To this end, we have performed bone marrow transplantation in two

  1. [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.

  2. 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.

  3. 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.

  4. 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

  5. Germ-line chimerism and paternal care in marmosets (Callithrix kuhlii).

    PubMed

    Ross, C N; French, J A; Ortí, G

    2007-04-10

    The formation of viable genetic chimeras in mammals through the transfer of cells between siblings in utero is rare. Using microsatellite DNA markers, we show here that chimerism in marmoset (Callithrix kuhlii) twins is not limited to blood-derived hematopoietic tissues as was previously described. All somatic tissue types sampled were found to be chimeric. Notably, chimerism was demonstrated to be present in germ-line tissues, an event never before documented as naturally occurring in a primate. In fact, we found that chimeric marmosets often transmit sibling alleles acquired in utero to their own offspring. Thus, an individual that contributes gametes to an offspring is not necessarily the genetic parent of that offspring. The presence of somatic and germ-line chimerism may have influenced the evolution of the extensive paternal and alloparental care system of this taxon. Although the exact mechanisms of sociobiological change associated with chimerism have not been fully explored, we show here that chimerism alters relatedness between twins and may alter the perceived relatedness between family members, thus influencing the allocation of parental care. Consistent with this prediction, we found a significant correlation between paternal care effort and the presence of epithelial chimerism, with males carrying chimeric infants more often than nonchimeric infants. Therefore, we propose that the presence of placental chorionic fusion and the exchange of cell lines between embryos may represent a unique adaptation affecting the evolution of cooperative care in this group of primates.

  6. Thionin-D4E1 chimeric protein protects plants against bacterial infections

    DOEpatents

    Stover, Eddie W; Gupta, Goutam; Hao, Guixia

    2017-08-08

    The generation of a chimeric protein containing a first domain encoding either a pro-thionon or thionin, a second domain encoding D4E1 or pro-D4E1, and a third domain encoding a peptide linker located between the first domain and second domain is described. Either the first domain or the second domain is located at the amino terminal of the chimeric protein and the other domain (second domain or first domain, respectively) is located at the carboxyl terminal. The chimeric protein has antibacterial activity. Genetically altered plants and their progeny expressing a polynucleotide encoding the chimeric protein resist diseases caused by bacteria.

  7. 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

  8. 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

  9. 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.

  10. 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

  11. 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.

  12. 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.

  13. 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

  14. 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

  15. 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.

  16. 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.

  17. 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

  18. Novel nanocomposites from spider silk–silica fusion (chimeric) proteins

    PubMed Central

    Wong Po Foo, Cheryl; Patwardhan, Siddharth V.; Belton, David J.; Kitchel, Brandon; Anastasiades, Daphne; Huang, Jia; Naik, Rajesh R.; Perry, Carole C.; Kaplan, David L.

    2006-01-01

    Silica skeletal architectures in diatoms are characterized by remarkable morphological and nanostructural details. Silk proteins from spiders and silkworms form strong and intricate self-assembling fibrous biomaterials in nature. We combined the features of silk with biosilica through the design, synthesis, and characterization of a novel family of chimeric proteins for subsequent use in model materials forming reactions. The domains from the major ampullate spidroin 1 (MaSp1) protein of Nephila clavipes spider dragline silk provide control over structural and morphological details because it can be self-assembled through diverse processing methods including film casting and fiber electrospinning. Biosilica nanostructures in diatoms are formed in aqueous ambient conditions at neutral pH and low temperatures. The R5 peptide derived from the silaffin protein of Cylindrotheca fusiformis induces and regulates silica precipitation in the chimeric protein designs under similar ambient conditions. Whereas mineralization reactions performed in the presence of R5 peptide alone form silica particles with a size distribution of 0.5–10 μm in diameter, reactions performed in the presence of the new fusion proteins generate nanocomposite materials containing silica particles with a narrower size distribution of 0.5–2 μm in diameter. Furthermore, we demonstrate that composite morphology and structure could be regulated by controlling processing conditions to produce films and fibers. These results suggest that the chimeric protein provides new options for processing and control over silica particle sizes, important benefits for biomedical and specialty materials, particularly in light of the all aqueous processing and the nanocomposite features of these new materials. PMID:16769898

  19. Novel nanocomposites from spider silk-silica fusion (chimeric) proteins.

    PubMed

    Wong Po Foo, Cheryl; Patwardhan, Siddharth V; Belton, David J; Kitchel, Brandon; Anastasiades, Daphne; Huang, Jia; Naik, Rajesh R; Perry, Carole C; Kaplan, David L

    2006-06-20

    Silica skeletal architectures in diatoms are characterized by remarkable morphological and nanostructural details. Silk proteins from spiders and silkworms form strong and intricate self-assembling fibrous biomaterials in nature. We combined the features of silk with biosilica through the design, synthesis, and characterization of a novel family of chimeric proteins for subsequent use in model materials forming reactions. The domains from the major ampullate spidroin 1 (MaSp1) protein of Nephila clavipes spider dragline silk provide control over structural and morphological details because it can be self-assembled through diverse processing methods including film casting and fiber electrospinning. Biosilica nanostructures in diatoms are formed in aqueous ambient conditions at neutral pH and low temperatures. The R5 peptide derived from the silaffin protein of Cylindrotheca fusiformis induces and regulates silica precipitation in the chimeric protein designs under similar ambient conditions. Whereas mineralization reactions performed in the presence of R5 peptide alone form silica particles with a size distribution of 0.5-10 microm in diameter, reactions performed in the presence of the new fusion proteins generate nanocomposite materials containing silica particles with a narrower size distribution of 0.5-2 microm in diameter. Furthermore, we demonstrate that composite morphology and structure could be regulated by controlling processing conditions to produce films and fibers. These results suggest that the chimeric protein provides new options for processing and control over silica particle sizes, important benefits for biomedical and specialty materials, particularly in light of the all aqueous processing and the nanocomposite features of these new materials.

  20. Characterization of chimeric Bacillus thuringiensis Vip3 toxins.

    PubMed

    Fang, Jun; Xu, Xiaoli; Wang, Ping; Zhao, Jian-Zhou; Shelton, Anthony M; Cheng, Jiaan; Feng, Ming-Guang; Shen, Zhicheng

    2007-02-01

    Bacillus thuringiensis vegetative insecticidal proteins (Vip) are potential alternatives for B. thuringiensis endotoxins that are currently utilized in commercial transgenic insect-resistant crops. Screening a large number of B. thuringiensis isolates resulted in the cloning of vip3Ac1. Vip3Ac1 showed high insecticidal activity against the fall armyworm Spodoptera frugiperda and the cotton bollworm Helicoverpa zea but very low activity against the silkworm Bombyx mori. The host specificity of this Vip3 toxin was altered by sequence swapping with a previously identified toxin, Vip3Aa1. While both Vip3Aa1 and Vip3Ac1 showed no detectable toxicity against the European corn borer Ostrinia nubilalis, the chimeric protein Vip3AcAa, consisting of the N-terminal region of Vip3Ac1 and the C-terminal region of Vip3Aa1, became insecticidal to the European corn borer. In addition, the chimeric Vip3AcAa had increased toxicity to the fall armyworm. Furthermore, both Vip3Ac1 and Vip3AcAa are highly insecticidal to a strain of cabbage looper (Trichoplusia ni) that is highly resistant to the B. thuringiensis endotoxin Cry1Ac, thus experimentally showing for the first time the lack of cross-resistance between B. thuringiensis Cry1A proteins and Vip3A toxins. The results in this study demonstrated that vip3Ac1 and its chimeric vip3 genes can be excellent candidates for engineering a new generation of transgenic plants for insect pest control.

  1. Chimeric antibodies with extended half-life in ferrets.

    PubMed

    Nesspor, Thomas C; Scallon, Bernard

    2014-09-01

    Ferrets have long been used as a disease model for the study of influenza vaccines, but a more recent use has been for the study of human monoclonal antibodies directed against influenza viruses. Published data suggest that human antibodies are cleared unusually quickly from the ferret and that immune responses may be partially responsible. This immunogenicity increases variability within groups and may present an obstacle to long-term studies. Our aim was to identify an antibody design with reduced immunogenicity and longer circulating half-life in ferrets. The constant region coding sequences for ferret immunoglobulin G were cloned, and chimeric human/ferret antibodies were expressed and purified. Some of the chimeric antibodies included substitutions that have been shown to extend the half-life of human IgG antibodies. These chimeric antibodies were tested for binding to recombinant ferret FcRn receptor and then evaluated in pharmacokinetic studies in ferrets. A one-residue substitution in the ferret Fc domain, S252Y, was identified that increased binding affinity to the ferret neonatal receptor by 24-fold and extended half-life from 65 ± 27 to 206 ± 28 hours or ~9 days. Ferrets dosed twice with this surrogate antibody showed no indications of an immune response. Expressing the variable region of a candidate human therapeutic antibody with ferret constant regions containing the S252Y substitution can offer long half-life and limit immunogenicity. © 2014 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.

  2. Chimeras taking shape: Potential functions of proteins encoded by chimeric RNA transcripts

    PubMed Central

    Frenkel-Morgenstern, Milana; Lacroix, Vincent; Ezkurdia, Iakes; Levin, Yishai; Gabashvili, Alexandra; Prilusky, Jaime; del Pozo, Angela; Tress, Michael; Johnson, Rory; Guigo, Roderic; Valencia, Alfonso

    2012-01-01

    Chimeric RNAs comprise exons from two or more different genes and have the potential to encode novel proteins that alter cellular phenotypes. To date, numerous putative chimeric transcripts have been identified among the ESTs isolated from several organisms and using high throughput RNA sequencing. The few corresponding protein products that have been characterized mostly result from chromosomal translocations and are associated with cancer. Here, we systematically establish that some of the putative chimeric transcripts are genuinely expressed in human cells. Using high throughput RNA sequencing, mass spectrometry experimental data, and functional annotation, we studied 7424 putative human chimeric RNAs. We confirmed the expression of 175 chimeric RNAs in 16 human tissues, with an abundance varying from 0.06 to 17 RPKM (Reads Per Kilobase per Million mapped reads). We show that these chimeric RNAs are significantly more tissue-specific than non-chimeric transcripts. Moreover, we present evidence that chimeras tend to incorporate highly expressed genes. Despite the low expression level of most chimeric RNAs, we show that 12 novel chimeras are translated into proteins detectable in multiple shotgun mass spectrometry experiments. Furthermore, we confirm the expression of three novel chimeric proteins using targeted mass spectrometry. Finally, based on our functional annotation of exon organization and preserved domains, we discuss the potential features of chimeric proteins with illustrative examples and suggest that chimeras significantly exploit signal peptides and transmembrane domains, which can alter the cellular localization of cognate proteins. Taken together, these findings establish that some chimeric RNAs are translated into potentially functional proteins in humans. PMID:22588898

  3. 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.

  4. 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

  5. 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

  6. 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

  7. [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.

  8. 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

  9. 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

  10. Bioengineered Chimeric Spider Silk-Uranium Binding Proteins

    PubMed Central

    Krishnaji, Sreevidhya Tarakkad; Kaplan, David L.

    2014-01-01

    Heavy metals constitute a source of environmental pollution. Here, novel functional hybrid biomaterials for specific interactions with heavy metals are designed by bioengineering consensus sequence repeats from spider silk of Nephila clavipes with repeats of a uranium peptide recognition motif from a mutated 33-residue of calmodulin protein from Paramecium tetraurelia. The self-assembly features of the silk to control nanoscale organic/inorganic material interfaces provides new biomaterials for uranium recovery. With subsequent enzymatic digestion of the silk to concentrate the sequestered metals, options can be envisaged to use these new chimeric protein systems in environmental engineering, including to remediate environments contaminated by uranium. PMID:23212989

  11. Chimeric transcripts resulting from complex duplications in chromosome Xq28.

    PubMed

    Zuccherato, Luciana W; Alleva, Benjamin; Whiters, Marjorie A; Carvalho, Claudia M B; Lupski, James R

    2016-02-01

    Gene fusions have been observed in somatic alterations in cancer and in schizophrenia. However, the underlying mechanism(s) for their formation are poorly understood. We experimentally demonstrated the expression of splicing variants of in silico predicted chimeric genes F8/CSAG1 and BCAP31/TEX28 in two individuals with de novo complex genomic rearrangements of Xq28; F8/CSAG1 includes exonization of an ERVL-MaLR intronic repetitive element. We provide evidence that replicative repair may contribute to exon shuffling processes and diversify the repertoire of expressed transcripts.

  12. The basic principles of chimeric antigen receptor (CAR) design

    PubMed Central

    Sadelain, Michel; Brentjens, Renier; Riviere, Isabelle

    2013-01-01

    CARs are recombinant receptors that provide both antigen-binding and T cell activating functions. A multitude of CARs has been reported over the past decade, targeting an array of cell surface tumor antigens. Their biological functions have dramatically changed following the introduction of tri-partite receptors comprising a costimulatory domain, termed second generation CARs. These have recently demonstrated clinical benefit in patients treated with CD19-targeted autologous T cells. CARs may be combined with costimulatory ligands, chimeric costimulatory receptors or cytokines to further enhance T cell potency, specificity and safety. CARs represent a new class of drugs with exciting potential for cancer immunotherapy. PMID:23550147

  13. 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

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 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

  19. 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.

  20. 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.

  1. Chimeric honeybees (Apis mellifera) produced by transplantation of embryonic cells into pre-gastrula stage embryos and detection of chimerism by use of microsatellite markers.

    PubMed

    Bergem, M; Norberg, K; Roseth, A; Meuwissen, T; Lien, S; Aamodt, R H

    2006-04-01

    The production of chimeras, by use of cell transplantation, has proved to be highly valuable in studies of development by providing insights into cell fate, differentiation, and developmental potential. So far, chimeric honeybees have been created by nuclear transfer technologies. We have developed protocols to produce chimeric honeybees by use of cell transplantation. Embryonic cells were transplanted between pre-gastrula stage embryos (32-34 hr after oviposition) and hatched larvae were reared in vitro for 4 days. Chimeric individuals were detected by use of microsatellite analysis and a conservative estimation approach. 4.8% of embryos, posteriorly injected with embryonic cells, developed into chimeric honeybee larvae. By injection of cells pre-stained with fluorescent cell tracer dye, we studied the integration of transplanted cells in the developing embryos. Number of injected cells varied from 0 to 50 and cells remained and multiplied mainly in the area of injection.

  2. Chimeric Genes as a Source of Rapid Evolution in Drosophila melanogaster

    PubMed Central

    Rogers, Rebekah L.; Hartl, Daniel L.

    2012-01-01

    Chimeric genes form through the combination of portions of existing coding sequences to create a new open reading frame. These new genes can create novel protein structures that are likely to serve as a strong source of novelty upon which selection can act. We have identified 14 chimeric genes that formed through DNA-level mutations in Drosophila melanogaster, and we investigate expression profiles, domain structures, and population genetics for each of these genes to examine their potential to effect adaptive evolution. We find that chimeric gene formation commonly produces mid-domain breaks and unites portions of wholly unrelated peptides, creating novel protein structures that are entirely distinct from other constructs in the genome. These new genes are often involved in selective sweeps. We further find a disparity between chimeric genes that have recently formed and swept to fixation versus chimeric genes that have been preserved over long periods of time, suggesting that preservation and adaptation are distinct processes. Finally, we demonstrate that chimeric gene formation can produce qualitative expression changes that are difficult to mimic through duplicate gene formation, and that extremely young chimeric genes (dS < 0.03) are more likely to be associated with selective sweeps than duplicate genes of the same age. Hence, chimeric genes can serve as an exceptional source of genetic novelty that can have a profound influence on adaptive evolution in D. melanogaster. PMID:21771717

  3. Development of a chimeric DNA-RNA hammerhead ribozyme targeting SARS virus.

    PubMed

    Fukushima, Akiko; Fukuda, Noboru; Lai, Yimu; Ueno, Takahiro; Moriyama, Mitsuhiko; Taguchi, Fumihiro; Iguchi, Akifumi; Shimizu, Kazushi; Kuroda, Kazumichi

    2009-01-01

    Severe acute respiratory syndrome (SARS) is a severe pulmonary infectious disease caused by a novel coronavirus. To develop an effective and specific medicine targeting the SARS-coronavirus (CoV), a chimeric DNA-RNA hammerhead ribozyme was designed and synthesized using a sequence homologous with the mouse hepatitis virus (MHV). Chimeric DNA-RNA hammerhead ribozyme targeting MHV and SARS-CoV were designed and synthesized.To confirm its activity, in vitro cleavage reactions were performed with the synthesized ribozyme. Effects of the chimeric ribozyme were evaluated on multiplication of MHV. Effects of the chimeric ribozyme on expression of SARS-CoV were evaluated in cultured 3T3 cells. The synthetic ribozyme cleaved the synthetic target MHV and SARS-CoV RNA into fragments of predicted length. The chimeric DNA-RNA hammerhead ribozyme targeting SARS-CoV significantly inhibited multiplication of MHV in DBT cells by about 60%. The chimeric DNA-RNA hammerhead ribozyme targeting SARS-CoV significantly inhibited the expression of SARS-CoV RNA in 3T3 cells transfected with the recombinant plasmid. The chimeric DNA-RNA ribozyme targeting SARS-CoV significantly inhibited MHV viral activity and expression of recombinant SARS RNA in vitro. These findings indicate that the synthetic chimeric DNA-RNA ribozyme could provide a feasible treatment for SARS. Copyright (c) 2009 S. Karger AG, Basel.

  4. 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.

  5. 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

  6. [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.

  7. 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

  8. 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.

  9. 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.

  10. 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.

  11. 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

  12. 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.

  13. 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

  14. Chimeric antigen receptor engineered stem cells: a novel HIV therapy.

    PubMed

    Zhen, Anjie; Carrillo, Mayra A; Kitchen, Scott G

    2017-03-01

    Despite the success of combination antiretroviral therapy (cART) for suppressing HIV and improving patients' quality of life, HIV persists in cART-treated patients and remains an incurable disease. Financial burdens and health consequences of lifelong cART treatment call for novel HIV therapies that result in a permanent cure. Cellular immunity is central in controlling HIV replication. However, HIV adopts numerous strategies to evade immune surveillance. Engineered immunity via genetic manipulation could offer a functional cure by generating cells that have enhanced antiviral activity and are resistant to HIV infection. Recently, encouraging reports from several human clinical trials using an anti-CD19 chimeric antigen receptor (CAR) modified T-cell therapy for treating B-cell malignancies have provided valuable insights and generated remarkable enthusiasm in engineered T-cell therapy. In this review, we discuss the development of HIV-specific chimeric antigen receptors and the use of stem cell based therapies to generate lifelong anti-HIV immunity.

  15. [Neutralizing Monoclonal and Chimeric Antibodies to Human IFN-γ].

    PubMed

    Larina, M V; Aliev, T K; Solopova, O N; Pozdnyakova, L P; Korobova, S V; Yakimov, S A; Sveshnikov, P G; Dolgikh, D A; Kirpichnikov, M P

    2015-01-01

    Autoiminune disorders are chronic diseases characterized by abnormal immune response directed against self-antigens that leads to tissue damage and violation of its normal functioning. Such diseases often result in disability or even death of patients. Nowadays a number of monoclonal antibodies to pro-inflammatory cytokines and their receptors are successfully used for the targeted treatment of autoimmune diseases. One of the perspective targets in autoimmune disease therapy is interferon gamma, a key cytokine in Th1 cells differentiation, activation of macrophages, and inflammation. In the present work, 5 monoclonal antibodies to human IFN-γ were obtained. For the development of potential therapeutic agent, we have performed neutralizing activity and affinity analysis of the antibodies. Based on the data obtained, the monoclonal antibody F1 was selected. This antibody has a dissociation constant 1.7 x 10(-9) M and IC90 = 8.9 ± 2.0 nM measured upon antibody inhibition of the IFN-γ-induced HLA-DR expression on the surface of U937 cells. We have constructed a bicistronic vector for the production of recombinant chimeric Fab fragment F1 chim in E. coli cells. The recombinant chimeric Fab fragment Fl chim neutralizes IFN-γ activity in vitro and has a dissociation constant 1.8 x 10(-9) M.

  16. Chimeric behavior of excited thioxanthone in protic solvents: II. Theory.

    PubMed

    Rai-Constapel, Vidisha; Villnow, Torben; Ryseck, Gerald; Gilch, Peter; Marian, Christel M

    2014-12-18

    The chimeric behavior of thioxanthone in protic solvents has been investigated employing computational chemistry methods. In particular, methanol and 2,2,2-trifluoroethanol have been chosen in this study. The solvent environment has been modeled using microsolvation in combination with a conductor-like screening model. The vertical excitation spectrum within the same solvent is seen to depend on the number of specific bonds formed between the chromophore and the solvent molecules. Two different models have been discussed in this work, namely, one and two H-bond models. In particular, the formation of the second H-bond causes the energy gap between the πHπL* and nOπL* states to increase further. Excited-state absorption spectra for the photophysically relevant electronic states have been theoretically determined for comparison with the time-resolved spectra recorded experimentally [Villnow, T.; Ryseck, G.; Rai-Constapel, V.; Marian, C. M.; Gilch, P. J. Phys. Chem. A 2014]. The equilibration of the 1(πHπL*) and 3(nOπL*) states holds responsible for the chimeric behavior. This equilibrium sets in with a calculated time constant of 23 ps in methanol and 14 ps in TFE (5 and 10 ps in experiment, respectively). The radiative decay from the optically bright 1(πHπL*) state is computed to occur with a time constant of 25 ns in both solvents (14–25 ns in experiment).

  17. Preliminary analgesic properties of deltorphin-5-methoxytryptamine chimeric opioid peptides.

    PubMed

    Wang, Jing; Wang, Li; Li, Meixing; Jin, Qiaoying; Dong, Shouliang

    2011-05-01

    To further understand the relationship between melatonin (MT) and deltorphins (Dels) in pain modulation, two chimeric peptides (Del I-5-methoxytryptamine and Del II-5-methoxytryptamine) both containing 5-methoxytryptamine at the carboxyl-terminal of Dels mimicking MT were designed, synthesized and characterized by tail-flick assay in mice. Results showed that intracerebroventricular (i.c.v.) administration of Del I-5-methoxytryptamine (YaFDVVG-X, X is 5-methoxytryptamine, 5, 50 nmol/kg) or Del II-5-methoxytryptamine (YaFEVVG-X, X is 5-methoxytryptamine, 5, 50 nmol/kg) produced stronger analgesia than deltorphins (Del I or Del II alone), and acting even longer and stronger than cocktails containing Del I or Del II (50 nmol/kg) and MT (50 nmol/kg). Naloxone (i.p., 100 nmol/kg) could totally block the analgesic effects induced by the chimeric peptides, while luzindole (specific antagonist of melatonin receptor, i.p., 250 nmol/kg) could only partially inhibit the effects down to that induced by Dels alone. Interestingly, Del I-5-methoxytryptamine and Del II-5-methoxytryptamine act weaker with δ receptor than Dels in vitro but could induce much longer analgesia through co-activating δ opioid receptor and melatonin receptor.

  18. Mixed chimerism to induce tolerance for solid organ transplantation

    SciTech Connect

    Wren, S.M.; Nalesnik, M.; Hronakes, M.L.; Oh, E.; Ildstad, S.T. )

    1991-04-01

    Chimerism, or the coexistence of tissue elements from more than one genetically different strain or species in an organism, is the only experimental state that results in the induction of donor-specific transplantation tolerance. Transplantation of a mixture of T-cell-depleted syngeneic (host-type) plus T-cell-depleted allogeneic (donor) bone marrow into a normal adult recipient mouse (A + B----A) results in mixed allogeneic chimerism. Recipient mice exhibit donor-specific transplantation tolerance, yet have full immunocompetence to recognize and respond to third-party transplantation antigens. After complete hematolymphopoietic repopulation at 28 days, animals accept a donor-specific skin graft but reject major histocompatibility complex (MHC) locus-disparate third-party grafts. We now report that permanent graft acceptance can also be achieved when the graft is placed at the time of bone marrow transplantation. Histologically, grafts were viable and had only minimal inflammatory changes. This model may have potential future clinical application for the induction of donor-specific transplantation tolerance.

  19. Chimeric Antisense Oligonucleotide Conjugated to α-Tocopherol

    PubMed Central

    Nishina, Tomoko; Numata, Junna; Nishina, Kazutaka; Yoshida-Tanaka, Kie; Nitta, Keiko; Piao, Wenying; Iwata, Rintaro; Ito, Shingo; Kuwahara, Hiroya; Wada, Takeshi; Mizusawa, Hidehiro; Yokota, Takanori

    2015-01-01

    We developed an efficient system for delivering short interfering RNA (siRNA) to the liver by using α-tocopherol conjugation. The α-tocopherol–conjugated siRNA was effective and safe for RNA interference–mediated gene silencing in vivo. In contrast, when the 13-mer LNA (locked nucleic acid)-DNA gapmer antisense oligonucleotide (ASO) was directly conjugated with α-tocopherol it showed markedly reduced silencing activity in mouse liver. Here, therefore, we tried to extend the 5′-end of the ASO sequence by using 5′-α-tocopherol–conjugated 4- to 7-mers of unlocked nucleic acid (UNA) as a “second wing.” Intravenous injection of mice with this α-tocopherol–conjugated chimeric ASO achieved more potent silencing than ASO alone in the liver, suggesting increased delivery of the ASO to the liver. Within the cells, the UNA wing was cleaved or degraded and α-tocopherol was released from the 13-mer gapmer ASO, resulting in activation of the gapmer. The α-tocopherol–conjugated chimeric ASO showed high efficacy, with hepatic tropism, and was effective and safe for gene silencing in vivo. We have thus identified a new, effective LNA-DNA gapmer structure in which drug delivery system (DDS) molecules are bound to ASO with UNA sequences. PMID:25584900

  20. CHIMERE-2017: from urban to hemispheric chemistry-transport modeling

    NASA Astrophysics Data System (ADS)

    Mailler, Sylvain; Menut, Laurent; Khvorostyanov, Dmitry; Valari, Myrto; Couvidat, Florian; Siour, Guillaume; Turquety, Solène; Briant, Régis; Tuccella, Paolo; Bessagnet, Bertrand; Colette, Augustin; Létinois, Laurent; Markakis, Kostantinos; Meleux, Frédérik

    2017-06-01

    CHIMERE is a chemistry-transport model designed for regional atmospheric composition. It can be used at a variety of scales from local to continental domains. However, due to the model design and its historical use as a regional model, major limitations had remained, hampering its use at hemispheric scale, due to the coordinate system used for transport as well as to missing processes that are important in regions outside Europe. Most of these limitations have been removed in the CHIMERE-2017 version, allowing its use in any region of the world and at any scale, from the scale of a single urban area up to hemispheric scale, with or without polar regions included. Other important improvements have been made in the treatment of the physical processes affecting aerosols and the emissions of mineral dust. From a computational point of view, the parallelization strategy of the model has also been updated in order to improve model numerical performance and reduce the code complexity. The present article describes all these changes. Statistical scores for a model simulation over continental Europe are presented, and a simulation of the circumpolar transport of volcanic ash plume from the Puyehue volcanic eruption in June 2011 in Chile provides a test case for the new model version at hemispheric scale.

  1. Donor Chimerism Early after Reduced-intensity Conditioning Hematopoietic Stem Cell Transplantation Predicts Relapse and Survival

    PubMed Central

    Koreth, John; Kim, Haesook T.; Nikiforow, Sarah; Milford, Edgar L.; Armand, Philippe; Cutler, Corey; Glotzbecker, Brett; Ho, Vincent T.; Antin, Joseph H.; Soiffer, Robert J.; Ritz, Jerome; Alyea, Edwin P.

    2015-01-01

    The impact of early donor cell chimerism on outcomes of T-replete reduced-intensity conditioning (RIC) hematopoietic stem cell transplantation (HSCT) is ill-defined. We evaluated day 30 (D30) and 100 (D100) total donor cell chimerism after RIC HSCT undertaken between 2002 and 2010 at our institution, excluding patients who died or relapsed before D30. When available, donor T-cell chimerism was also assessed. The primary outcome was overall survival (OS). Secondary outcomes included progression-free survival (PFS), relapse and non-relapse mortality (NRM). 688 patients with hematologic malignancies (48% myeloid; 52% lymphoid) and a median age of 57 years (range, 18-74) undergoing RIC HSCT with T-replete donor grafts (97% peripheral blood; 92% HLA-matched) and median follow-up of 58.2 months (range, 12.6-120.7) were evaluated. In multivariable analysis total donor cell and T-cell chimerism at D30 and D100 each predicted RIC HSCT outcomes, with D100 total donor cell chimerism most predictive. D100 total donor cell chimerism <90% was associated with increased relapse (HR 2.54, 95% CI 1.83-3.51, p<0.0001), impaired PFS (HR 2.01, 95% CI 1.53-2.65, p<0.0001) and worse OS (1.50, 95% CI 1.11-2.04, p=0.009), but not NRM (HR 0.76; 95% CI 0.44-2.27, p=0.33). There was no additional utility of incorporating sustained D30-D100 total donor cell chimerism, or T-cell chimerism. Low donor chimerism early after RIC HSCT is an independent risk factor for relapse and impaired survival. Donor chimerism assessment early after RIC HSCT can prognosticate for long-term outcomes and help identify high-risk patient cohorts that may benefit from additional therapeutic interventions. PMID:24907627

  2. 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.

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

    PubMed Central

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

    2013-01-01

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

  5. 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.

  6. 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.

  7. Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia

    PubMed Central

    Maude, Shannon L.; Frey, Noelle; Shaw, Pamela A.; Aplenc, Richard; Barrett, David M.; Bunin, Nancy J.; Chew, Anne; Gonzalez, Vanessa E.; Zheng, Zhaohui; Lacey, Simon F.; Mahnke, Yolanda D.; Melenhorst, Jan J.; Rheingold, Susan R.; Shen, Angela; Teachey, David T.; Levine, Bruce L.; June, Carl H.; Porter, David L.; Grupp, Stephan A.

    2014-01-01

    BACKGROUND Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor–modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. METHODS We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×106 to 20.6×106 CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. RESULTS A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti–interleukin-6 receptor antibody tocilizumab. CONCLUSIONS Chimeric antigen receptor–modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by

  8. Chimeric antigen receptor T cells for sustained remissions in leukemia.

    PubMed

    Maude, Shannon L; Frey, Noelle; Shaw, Pamela A; Aplenc, Richard; Barrett, David M; Bunin, Nancy J; Chew, Anne; Gonzalez, Vanessa E; Zheng, Zhaohui; Lacey, Simon F; Mahnke, Yolanda D; Melenhorst, Jan J; Rheingold, Susan R; Shen, Angela; Teachey, David T; Levine, Bruce L; June, Carl H; Porter, David L; Grupp, Stephan A

    2014-10-16

    Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease. We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells. A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab. Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 Clinical

  9. 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

  10. 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.

  11. 78 FR 63226 - GlaxoSmithKline LLC; Withdrawal of Approval of the Indication for Treatment of Patients With...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-10-23

    ... (tositumomab and iodine I 131 tositumomab) Injection held by GlaxoSmithKline LLP, P.O. Box 5089, 1250 South... and iodine I 131 tositumomab) Injection because the postmarketing study intended to verify clinical... rituximab-na ve indication for BEXXAR (tositumomab and iodine I 131 tositumomab) Injection from the...

  12. A technical application of quantitative next generation sequencing for chimerism evaluation

    PubMed Central

    Aloisio, Michelangelo; Licastro, Danilo; Caenazzo, Luciana; Torboli, Valentina; D'eustacchio, Angela; Severini, Giovanni Maria; Athanasakis, Emmanouil

    2016-01-01

    At present, the most common genetic diagnostic method for chimerism evaluation following hematopoietic stem cell transplantation is microsatellite analysis by capillary electrophoresis. The main objective was to establish, through repeated analysis over time, if a complete chimerism was present, or if the mixed chimerism was stable, increasing or decreasing over time. Considering the recent introduction of next generation sequencing (NGS) in clinical diagnostics, a detailed study evaluating an NGS protocol was conducted, coupled with a custom bioinformatics pipeline, for chimerism quantification. Based on the technology of Ion AmpliSeq, a 44-amplicon custom chimerism panel was designed, and a custom bioinformatics pipeline dedicated to the genotyping and quantification of NGS data was coded. The custom chimerism panel allowed identification of an average of 16 informative recipient alleles. The limit of detection of the protocol was fixed at 1% due to the NGS background (<1%). The protocol followed the standard Ion AmpliSeq library preparation and Ion Torrent Personal Genome Machine guidelines. Overall, the present study added to the scientific literature, identifying novel technical details for a possible future application of NGS for chimerism quantification. PMID:27499173

  13. 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.

  14. 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.

  15. [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.

  16. 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

  17. 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.

  18. 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.

  19. 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

  20. Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy

    PubMed Central

    Dai, Hanren; Wang, Yao; Lu, Xuechun

    2016-01-01

    The genetic modification and characterization of T-cells with chimeric antigen receptors (CARs) allow functionally distinct T-cell subsets to recognize specific tumor cells. The incorporation of costimulatory molecules or cytokines can enable engineered T-cells to eliminate tumor cells. CARs are generated by fusing the antigen-binding region of a monoclonal antibody (mAb) or other ligand to membrane-spanning and intracellular-signaling domains. They have recently shown clinical benefit in patients treated with CD19-directed autologous T-cells. Recent successes suggest that the modification of T-cells with CARs could be a powerful approach for developing safe and effective cancer therapeutics. Here, we briefly review early studies, consider strategies to improve the therapeutic potential and safety, and discuss the challenges and future prospects for CAR T-cells in cancer therapy. PMID:26819347

  1. Humanized chimeric mouse models of hepatitis B virus infection.

    PubMed

    Sun, Suwan; Li, Jun

    2017-06-01

    Hepatitis B virus (HBV) infection is associated with an increased risk of hepatic cirrhosis, hepatocellular carcinoma, fulminant hepatitis and end-stage hepatic failure. Despite the availability of anti-HBV therapies, HBV infection remains a major global public health problem. Developing an ideal animal model of HBV infection to clarify the details of the HBV replication process, the viral life cycle, the resulting immunoresponse and the precise pathogenesis of HBV is difficult because HBV has an extremely narrow host range and almost exclusively infects humans. In this review, we summarize and evaluate animal models available for studying HBV infection, especially focusing on humanized chimeric mouse models, and we discuss future development trends regarding immunocompetent humanized mouse models that can delineate the natural history and immunopathophysiology of HBV infection. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  2. Chimeric Antigen Receptors Modified T-Cells for Cancer Therapy.

    PubMed

    Dai, Hanren; Wang, Yao; Lu, Xuechun; Han, Weidong

    2016-07-01

    The genetic modification and characterization of T-cells with chimeric antigen receptors (CARs) allow functionally distinct T-cell subsets to recognize specific tumor cells. The incorporation of costimulatory molecules or cytokines can enable engineered T-cells to eliminate tumor cells. CARs are generated by fusing the antigen-binding region of a monoclonal antibody (mAb) or other ligand to membrane-spanning and intracellular-signaling domains. They have recently shown clinical benefit in patients treated with CD19-directed autologous T-cells. Recent successes suggest that the modification of T-cells with CARs could be a powerful approach for developing safe and effective cancer therapeutics. Here, we briefly review early studies, consider strategies to improve the therapeutic potential and safety, and discuss the challenges and future prospects for CAR T-cells in cancer therapy.

  3. The pharmacology of second-generation chimeric antigen receptors.

    PubMed

    van der Stegen, Sjoukje J C; Hamieh, Mohamad; Sadelain, Michel

    2015-07-01

    Second-generation chimeric antigen receptors (CARs) retarget and reprogramme T cells to augment their antitumour efficacy. The combined activating and co-stimulatory domains incorporated in these CARs critically determine the function, differentiation, metabolism and persistence of engineered T cells. CD19-targeted CARs that incorporate CD28 or 4-1BB signalling domains are the best known to date. Both have shown remarkable complete remission rates in patients with refractory B cell malignancies. Recent data indicate that CD28-based CARs direct a brisk proliferative response and boost effector functions, whereas 4-1BB-based CARs induce a more progressive T cell accumulation that may compensate for less immediate potency. These distinct kinetic features can be exploited to further develop CAR-based T cell therapies for a variety of cancers. A new field of immunopharmacology is emerging.

  4. Chimeric Antigen Receptor T Cell Therapy in Hematology.

    PubMed

    Ataca, Pınar; Arslan, Önder

    2015-12-01

    It is well demonstrated that the immune system can control and eliminate cancer cells. Immune-mediated elimination of tumor cells has been discovered and is the basis of both cancer vaccines and cellular therapies including hematopoietic stem cell transplantation. Adoptive T cell transfer has been improved to be more specific and potent and to cause less off-target toxicity. Currently, there are two forms of engineered T cells being tested in clinical trials: T cell receptor (TCR) and chimeric antigen receptor (CAR) modified T cells. On 1 July 2014, the United States Food and Drug Administration granted 'breakthrough therapy' designation to anti-CD19 CAR T cell therapy. Many studies were conducted to evaluate the benefits of this exciting and potent new treatment modality. This review summarizes the history of adoptive immunotherapy, adoptive immunotherapy using CARs, the CAR manufacturing process, preclinical and clinical studies, and the effectiveness and drawbacks of this strategy.

  5. Chimeric antigen receptor T-cell therapy for ALL.

    PubMed

    Maude, Shannon L; Shpall, Elizabeth J; Grupp, Stephan A

    2014-12-05

    Relapsed and refractory leukemias pose substantial challenges in both children and adults, with very little progress being made in more than a decade. Targeted immunotherapy using chimeric antigen receptor (CAR)-modified T cells has emerged as a potent therapy with an innovative mechanism. Dramatic clinical responses with complete remission rates as high as 90% have been reported using CAR-modified T cells directed against the B-cell-specific antigen CD19 in patients with relapsed/refractory acute lymphoblastic leukemia. Supraphysiologic T-cell proliferation, a hallmark of this therapy, contributes to both efficacy and the most notable toxicity, cytokine release syndrome, posing a unique challenge for toxicity management. Further studies are necessary to identify additional targets, standardize approaches to cytokine release syndrome management, and determine the durability of remissions. © 2014 by The American Society of Hematology. All rights reserved.

  6. How Chimeric Antigen Receptor Design Affects Adoptive T Cell Therapy.

    PubMed

    Gacerez, Albert T; Arellano, Benjamine; Sentman, Charles L

    2016-12-01

    Chimeric antigen receptor (CAR) T cells have been developed to treat tumors and have shown great success against B cell malignancies. Exploiting modular designs and swappable domains, CARs can target an array of cell surface antigens and, upon receptor-ligand interactions, direct signaling cascades, thereby driving T cell effector functions. CARs have been designed using receptors, ligands, or scFv binding domains. Different regions of a CAR have each been found to play a role in determining the overall efficacy of CAR T cells. Therefore, this review provides an overview of CAR construction and common designs. Each CAR region is discussed in the context of its importance to a CAR's function. Additionally, the review explores how various engineering strategies have been applied to CAR T cells in order to regulate CAR T cell function and activity. J. Cell. Physiol. 231: 2590-2598, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  7. 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 e