Rituximab: a review of its use in chronic lymphocytic leukaemia, low-grade or follicular lymphoma and diffuse large B-cell lymphoma
ABSTRACT Rituximab (MabThera, Rituxan) is a chimeric mouse anti-human CD20 monoclonal antibody. This article reviews the use of intravenous rituximab in the treatment of chronic lymphocytic leukaemia (CLL), low-grade or follicular lymphoma, and diffuse large B-cell lymphoma. The addition of rituximab to fludarabine plus cyclophosphamide significantly prolonged progression-free survival both in previously untreated patients with CLL and in those with relapsed or refractory CLL, according to the results of two randomized, open-label, multicentre trials. In patients with previously untreated advanced follicular lymphoma, the addition of rituximab to chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone [CHOP], cyclophosphamide, vincristine and prednisone [CVP], mitoxantrone, chlorambucil and prednisolone, or cyclophosphamide, doxorubicin, etoposide and prednisolone) was generally associated with better outcomes than chemotherapy alone in randomized, multicentre trials. In a similarly designed trial, progression-free survival was significantly longer in previously untreated patients with follicular lymphoma, other indolent lymphomas or mantle-cell lymphoma who received rituximab plus bendamustine than in those receiving rituximab plus CHOP. Monotherapy with rituximab also demonstrated efficacy in patients with relapsed or refractory low-grade or follicular lymphoma, according to the results of noncomparative trials. In terms of maintenance therapy, progression-free survival was significantly prolonged with rituximab maintenance therapy versus observation alone in patients with advanced indolent lymphoma who had not progressed following first-line therapy with CVP and in patients with relapsed or refractory follicular lymphoma who had responded to CHOP (with or without rituximab), according to the results of randomized, open-label, multicentre trials. In four randomized, open-label, multicentre trials in younger or elderly patients with previously untreated diffuse large B-cell lymphoma, event-free survival, failure-free survival, progression-free survival and overall survival were generally improved to a significant extent by the addition of rituximab to CHOP or CHOP-like chemotherapy. Intravenous rituximab was generally well tolerated in patients with CLL, low-grade or follicular lymphoma, or diffuse large B-cell lymphoma, both as monotherapy and when administered in combination with chemotherapy. Infusion reactions were one of the most commonly occurring adverse events in patients receiving intravenous rituximab. The results of pharmacoeconomic modelling analyses demonstrated that rituximab appears to be cost effective in patients with previously untreated follicular lymphoma, in patients with follicular lymphoma receiving rituximab maintenance therapy following treatment for relapsed or refractory disease and in patients with previously untreated diffuse large B-cell lymphoma. In conclusion, rituximab remains a valuable therapy in patients with CLL, low-grade or follicular lymphoma and diffuse large B-cell lymphoma and, in a variety of treatment settings, represents the standard of care.
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- "The CD20-specific monoclonal antibody (mAb) rituximab (MabThera®, Rituxan®) was the first mAb approved for use in the treatment of cancer. Rituximab is widely used as the backbone of treatment for patients with non-Hodgkin’s lymphoma (NHL) and chronic lymphocytic leukemia (CLL) [1,2]. Rituximab is also approved in combination with methotrexate in adult patients with moderately to severely active rheumatoid arthritis who have inadequate response to one or more tumor necrosis factor antagonist therapies, and in combination with glucocorticoids for adult patients with Wegener’s granulomatosis and microscopic polyangiitis . "
ABSTRACT: The CD20-specific monoclonal antibody rituximab (MabThera(®), Rituxan(®)) is widely used as the backbone of treatment for patients with hematologic disorders. Intravenous administration of rituximab is associated with infusion times of 4-6 hours, and can be associated with infusion-related reactions. Subcutaneous administration of rituximab may reduce this and facilitate administration without infusion-related reactions. We sought to determine the feasibility of achieving equivalent efficacy (measured by endogenous B-cell depletion) and long-term durability of CD20 target coverage for subcutaneously administered rituximab compared with intravenous dosing. In these preclinical studies, male cynomolgus monkeys were treated with either intravenous rituximab or novel subcutaneous formulation of rituximab containing human recombinant DNA-derived hyaluronidase enzyme. Peripheral blood samples were analyzed for serum rituximab concentrations, peripheral B-cell depletion, and CD20 target coverage, including subset analysis according to CD21+ status. Distal lymph node B-cell depletion and CD20 target coverage were also measured. Initial peak serum concentrations of rituximab were significantly higher following intravenous administration than subcutaneous. However, the mean serum rituximab trough concentrations were comparable at 2 and 7 days post-first dose and 9 and 14 days post-second dose. Efficacy of B-cell depletion in both peripheral blood and distal lymph nodes was comparable for both methods. In lymph nodes, 9 days after the second dose with subcutaneous and intravenous rituximab, B-cell levels were decreased by 57% and 42% respectively. Similarly, levels of peripheral blood B cells were depleted by >94% for both subcutaneous and intravenous dosing at all time points. Long-term recovery of free unbound surface CD20 levels was similar, and the duration of B-cell depletion was equally sustained over 2 months for both methods. These results demonstrate that, despite initial peak serum drug level differences, subcutaneous rituximab has similar durability, pharmacodynamics, and efficacy compared with intravenous rituximab.PLoS ONE 11/2013; 8(11):e80533. DOI:10.1371/journal.pone.0080533 · 3.23 Impact Factor
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- "Therapeutic infusions of mAbs are associated with a characteristic infusion-related syndrome (8,10,17–19). Infusion reactions, predominantly occurring on the first or second administration of ofatumumab, were common, and the pattern was similar to what has been observed in other ofatumumab studies. Cytokine release may be responsible for the infusion-related reactions (20). "
ABSTRACT: Objectives: Ofatumumab is a human IgG1κ monoclonal antibody that targets a membrane proximal epitope encompassing the small and large loops of CD20. This Phase I study evaluated the safety, tolerability, efficacy and pharmacokinetics of ofatumumab monotherapy in Japanese patients with relapsed/refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma. Methods: Ofatumumab was administered intravenously weekly for a total of eight doses (dose escalation: 500 and 1000 mg). Six patients (two chronic lymphocytic leukemia and four small lymphocytic lymphoma) were enrolled into two dose cohorts (500 mg, three patients; 1000 mg, three patients). All six patients received 300 mg ofatumumab at the first infusion and either 500 or 1000 mg at seven subsequent weekly infusions. Results: No dose-limiting toxicities or serious adverse events were observed. Grade 3-4 adverse events observed were grade 3 lymphocytopenia (n = 1) and neutropenia (n = 1). Grade 1-2 infusion-related adverse events leading to temporary interruption of ofatumumab infusion were observed in all six patients on the first infusion day, and all patients completed the planned eight infusions. The overall response rate was 50% (3/6). Conclusions: Ofatumumab was well tolerated at doses up to 1000 mg and showed preliminary evidence of activity in relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma, warranting further investigations.Japanese Journal of Clinical Oncology 02/2013; 43(5). DOI:10.1093/jjco/hyt022 · 2.02 Impact Factor
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- "Rituximab, a chimeric mAb with human IgG1 Fc domains targets the CD20 antigen on the surface of mature B-cells, leading to cell lysis via complement-mediated cytotoxicity. It is used for treatment of Non-Hodgkin's lymphoma, leukaemias and some autoimmune disorders (Keating, 2010). In multiple sclerosis patients, its action appears to include an unusual mechanism involving functional inhibition of T cells after B cell depletion (Cross et al., 2006). "
ABSTRACT: Antibodies are well established in mainstream clinical practice and present an exciting area for collaborative research and development in industry and academia alike. In this review, we will provide an overview of the current market and an outlook to 2015, focussing on whole antibody molecules while acknowledging the next generation scaffolds containing variable fragments. The market will be discussed in the context of disease targets, particularly in the areas of oncology and immune disorders which generate the greatest revenue by a wide margin. Emerging targets include central nervous system disorders which will also stimulate new delivery strategies. It is becoming increasingly apparent that a better understanding of bioprocessing is required in order to optimize the steps involved in the preparation of a protein prior to formulation. The latter is outside the scope of this review and nor is it our intention to discuss protein delivery and pharmacokinetics. The challenges that lie ahead include the discovery of new disease targets and the development of robust bioprocessing operations.International Journal of Pharmaceutics 12/2011; 440(1). DOI:10.1016/j.ijpharm.2011.12.039 · 3.65 Impact Factor