, Volume 66, Issue 6, pp 791-820
Date: 17 Sep 2012

Rituximab

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Summary

Abstract

Rituximab (MabThera®, Rituxan®) is an anti-CD20 monoclonal antibody that induces lysis and apoptosis of normal and malignant human B cells, and sensitises malignant B cells to the cytotoxic effect of chemotherapy. In phase III trials in patients with indolent or aggressive B-cell non-Hodgkin’s lymphoma (NHL), intravenous rituximab in combination with chemotherapy was more effective as first- or second-line therapy than chemotherapy alone in providing tumour remission and patient survival. Likewise, in patients with chronic lymphocytic leukaemia (CLL), rituximab in combination with chemotherapy appeared more effective than chemotherapy alone as either first- or second-line treatment. In addition, rituximab maintenance therapy was shown to significantly prolong tumour remission and patient survival in patients with indolent B-cell NHL or CLL. The combination of rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) was cost effective as first-line therapy for advanced-stage diffuse large B-cell NHL compared with CHOP alone. Rituximab, either alone or in combination with chemotherapy, was generally well tolerated in patients with NHL or CLL. Overall, rituximab in combination with chemotherapy, is a valuable option for first- and second-line therapy in patients with advanced-stage indolent or aggressive B-cell NHL, and possibly those with B-cell CLL, and is included in current treatment guidelines for these indications. The drug is also potentially useful as maintenance therapy in patients with indolent B-cell NHL or CLL.

Pharmacological Properties

Rituximab is a chimaeric murine/human monoclonal antibody directed against the surface antigen CD20 expressed on all normal and >90% of NHL and =14% of CLL malignant B cells. It induces lysis and apoptosis of all CD20-positive B cells and also sensitises malignant B cells to the cytotoxic effect of chemotherapy. At the recommended dose, rituximab causes rapid and profound B-cell lymphopenia in the majority of patients that lasts for up to 6 months and recovers (from haematopoietic stem cells) within 9–12 months after treatment. As maintenance therapy, rituximab would continue suppression of the B-cell population, including the malignant variety.

Following intravenous administration of rituximab in patients with B-cell NHL, drug serum concentrations increase in a dose-proportional manner (within clinically relevant dosage range), are positively correlated with clinical tumour responses (i.e. they are significantly higher in patients responding to rituximab monotherapy than in nonresponders) and are inversely correlated to the absolute level of circulating peripheral B cells and the tumour bulk measurements at baseline. The pharmacokinetics of rituximab are also characterised by accumulation of the drug with repeated administrations (reflecting the change in the population of CD20-positive B cells) and wide interindividual variability (caused by variable tumour responsiveness and burden between patients). Clinically relevant drug concentrations are present in the serum ≤6 months after, and were also found in the CNS during treatment with rituximab. The pharmacokinetics of rituximab appear to be similar in patients with follicular or diffuse large B-cell NHL, and are unaffected by the coadministration of CHOP.

Significantly lower serum concentrations of rituximab were found in patients with a lymphomatous form of B-cell CLL, compared with values in patients with B-cell NHL.

Therapeutic Efficacy

Indolent NHL: In phase III trials in patients with previously untreated advanced-stage follicular NHL, the addition of rituximab 375 mg/m2 (as an intravenous infusion) to 6–8 cycles of standard chemotherapy regimens was more effective in achieving tumour remission (i.e. complete response [CR]) and short-term (2.5-year) event-free survival (EFS) rates than chemotherapy alone. In combination with cyclophosphamide, vincristine and prednisone (CVP), rituximab also significantly prolonged the duration of tumour response (>2-fold), failure-free (≈4-fold) and disease-free survival (DFS) [>2-fold], and more than doubled the time to disease progression. At the estimated 3-year follow-up, these effects have not yet translated into a significantly greater overall survival (OS) rate compared with CVP alone (89% vs 81%), although both results are clinically relevant. Importantly, however, patients receiving rituximab in addition to CVP spent significantly longer time without disease symptoms or toxicity, and had a substantially improved quality-adjusted survival than patients receiving CVP alone. In patients with advanced follicular NHL, first-line therapy with rituximab in combination with mitoxantrone, chlorambucil and prednisone (MCP) also resulted in significantly longer progression-free survival (PFS) and OS rates than MCP alone.

As a second-line therapy in patients with relapsed or refractory follicular NHL, the addition of a single dose of rituximab to each of six cycles of CHOP or four cycles of fludarabine, cyclophosphamide and mitoxantrone (FCM) regimens significantly improved CR and objective response (OR) rates and prolonged PFS compared with chemotherapy alone in two phase III trials. A significantly improved 4-year OS rate was also reported in a trial with FCM.

The significant survival benefit of adding rituximab to first- or second-line chemotherapy regimens in patients with follicular NHL was confirmed in a meta-analysis of data from several randomised, phase III trials

As monotherapy, four once-weekly intravenous infusions of rituximab 375 mg/m2 produced clinically relevant CR and OR rates in two phase II trials in patients with mucosa-associated lymphoid tissue B-cell NHL. One of the trials showed ≈2-fold longer (p ≈ 0.001) failure-free survival in chemotherapy-naive than in chemotherapy-experienced patients receiving rituximab monotherapy.

Likewise, maintenance therapy with single-agent rituximab 375 mg/m2 (four once-weekly doses repeated every 6 months or single infusion every 2–3 months, for up to 2 years or until relapse), significantly increased CR and/or OR rates, and prolonged duration of remission, EFS and/or PFS after induction therapy in patients with follicular NHL or CLL (lymphomatous form), compared with rituximab re-treatment (at disease progression) [in a phase II trial] or observation (i.e. no further treatment) [in three phase III trials]. Rituximab maintenance therapy provided significantly greater 3- and 4-year PFS and OS rates in both previously treated and untreated patients with follicular NHL, compared with no further treatment. The estimated 3-year OS rates were high with both the rituximab maintenance and re-treatment approach, but results were not statistically significantly different (72% vs 68%) in previously untreated patients.

Aggressive NHL: The combination of rituximab 375 mg/m2 intravenous infusions with a CHOP or a CHOP-like regimen, administered in 6–8 cycles, was more effective than chemotherapy alone as the first-line treatment in patients with advanced-stage, diffuse large B-cell NHL or mantle cell lymphoma (MCL), in several phase III trials. Irrespective of the age of patients with diffuse, large B-cell NHL, the addition of rituximab resulted in significantly greater CR, 2- to 3-year failure-free survival and 2- to 5-year OS rates (the latter effect was observed only in low-risk patients). A significantly greater 5-year PFS rate was also reported with rituximab plus CHOP in a trial in older patients (age ≥60 years) irrespective of disease prognosis. In younger patients (age <60 years) with low-risk disease, rituximab plus CHOP or CHOP-like regimen significantly decreased the relative risk of treatment failure (by 64%) compared with chemotherapy alone.

Significantly greater 1-year failure-free or 4-year OS rates were observed in patients with MCL receiving intravenous infusions of rituximab 375 mg/m2 in combination with first-line CHOP (six cycles) or second-line FCM (four cycles), than those receiving chemotherapy alone, in two randomised, phase III trials. Meta-analysis of data from both trials confirmed the OS benefit of adding rituximab to chemotherapy in patients with MCL, both previously untreated or those with relapsed or refractory MCL.

Rituximab did not improve either tumour response or survival rates in patients with HIV-related, aggressive B-cell NHL, while increasing the risk of infectious death, in a randomised, phase III trial. By contrast, the findings of previous phase I and II trials suggested that rituximab therapy may be beneficial in this patient population.

Rituximab maintenance therapy was effective in patients with diffuse large B-cell NHL, only when the drug was not part of an induction regimen, and was ineffective in patients with MCL.

CLL: Standard rituximab monotherapy (i.e. four intravenous infusions of 375 mg/m2 once weekly) was less effective than fludarabine monotherapy in phase II trials in patients with B-cell CLL. However, the addition of rituximab 375 or 500 mg/m2 to six cycles of fludarabine (with or without cyclophosphamide) significantly improved response (CR and/or OR) and survival (2- to 4-year PFS and/or OS) rates in these patients, compared with chemotherapy alone in retrospective comparative analyses of several phase II and III trials.

Tolerability

Rituximab, alone or in combination with various chemotherapy regimens, was generally well tolerated in clinical trials in patients with advanced-stage indolent or aggressive B-cell NHL or B-cell CLL. The most common types of adverse events in these trials were infusion-related reactions, haematological adverse events and infections. Infusion-related reactions that occur in the majority of patients, most within 2 hours of the first infusion, are generally mild to moderate flu-like symptoms that usually resolve upon slowing or stopping the infusion, and become less frequent with subsequent infusions. Severe (grade 3/4) reactions, including severe cytokine release syndrome, occur in ≈10% of patients and may also require supportive care (e.g. analgesic, antihistamine, oxygen, intravenous fluids, bronchodilators, vasopressors and/or corticosteroids).

In comparison with chemotherapy, rituximab is associated with a substantially lower incidence of severe neutropenia and infections. Furthermore, the addition of rituximab does not increase the toxicity of chemotherapy in patients with NHL or CLL of B-cell origin. The tolerability profile of rituximab, in combination with chemotherapy, is similar in patients with indolent or aggressive NHL. In addition, the US manufacturer’s prescribing information for rituximab includes boxed warnings for fatal infusion reactions, tumour lysis syndrome and severe mucocutaneous reactions.

Various sections of the manuscript reviewed by: J.H. Best, Department of Pharmacy, University of Washington, Seattle, Washington, USA; A. Engert, Department of Internal Medicine I, University Hospital of Cologne, Köln, Germany; M. Fanale, Department of Lymphoma/Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA; P. Feugier, Hematology Department, Centre Hospitalier Universitaire de Brabois, Vandoeuvre les Nancy, France; S. O’Brien, Leukemia Department, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA; M. Pfreundschuh, Med. Klinik I, Saarland University, Homburg/Saar, Germany; P.L. Zinzani, Istituto di Ematologia e Oncologia Medica ‘L. e A. Seràgnoli’, University of Bologna, Bologna, Italy.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘rituximab’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE search terms were ‘rituximab’ or ’MabThera’ or ‘monoclonal-antibody-IDEC-C2B8’ or ‘anti-CD20 antibodies’ and ‘non-Hodgkin’s lymphoma’ or ‘lymphoma non-Hodgkin’s’ or ‘chronic lymphocytic leukaemia’. EMBASE search terms were ‘rituximab’ or ‘MabThera’ or ‘monoclonal-antibody-IDEC-C2B8’ and ‘non-Hodgkin’s lymphoma’ or ‘chronic lymphocytic leukaemia/leukaemia’. AdisBase search terms were ‘rituximab’ or ‘monoclonal-antibody IDEC-C2B8’ or ‘MabThera’ or ‘anti-CD20 antibodies’ or ‘IDEC-C2B8’ and ‘non-Hodgkin’s lymphoma’ or ‘chronic-lymphocytic-leukaemia’ or ‘chronic lymphatic leukaemia’. Searches were last updated on 6 April 2006.
Selection: Studies in patients with who received rituximab. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Rituximab, B-cell, T-cell, lymphoma, non-Hodgkin’s lymphoma (NHL), indolent, aggressive, follicular, mantle cell, mucosa-associated lymphoid tissue (MALT), chronic lymphocytic leukaemia (CLL), pharmacodynamics, pharmacokinetics, pharmacoeconomics, therapeutic use, cost effectiveness, induction, tolerability.