, Volume 63, Issue 8, pp 803-843
Date: 17 Sep 2012

Rituximab

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Summary

Abstract

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/m2 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/m2 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, hypotension). These reactions are usually reversible with appropriate interventions and supportive care but there have been rare reports of fatalities.

Conclusion: Clinical trials with rituximab indicate that the drug has broad application to B-cell malignancies, although further clarification is needed to determine its optimal use in many of these clinical settings. Importantly, rituximab in combination with CHOP chemotherapy has emerged as a new treatment standard for previously untreated diffuse large B-cell lymphoma, at least in elderly patients. Compared with conventional chemotherapy, rituximab is associated with markedly reduced haematological events such as severe neutropenia, as well as associated infections. Rituximab may be particularly suitable for elderly patients or those with poor performance status, and its tolerability profile facilitates its use in combination with cytotoxic drugs.

Pharmacodynamic Properties

Rituximab is a mouse/human chimaeric IgG1-κ monoclonal antibody that targets the CD20 antigen found on the surface of malignant and normal B lymphocytes. Although treatment with rituximab induces lymphopenia in most patients, typically lasting about 6 months, a full recovery of B lymphocytes in the peripheral blood is usually seen 9–12 months after therapy, as CD20 is not expressed on haematopoietic stem cells. CD20 is, however, expressed on >90% of B-cell non-Hodgkin’s lymphomas (NHL) and to a lesser degree on B-cell chronic lymphocytic leukaemia (CLL) cells.

Although not fully elucidated, the cytotoxic effects of rituximab on CD20-positive malignant B cells appears to involve complement-dependent cytotoxicity, complement-dependent cellular cytotoxicity, antibody-dependent cellular cytotoxicity and induction of apoptosis. In addition, in vitro data indicate that rituximab sensitises tumour cells to the effects of conventional chemotherapeutic drugs.

Pharmacokinetic Properties

Serum rituximab concentrations increased in proportion to dose across a wide range of single- and multiple-dose intravenous regimens in patients with B-cell NHL. When administered at a dose of 375 mg/m2 once weekly for 4 weeks in a pivotal trial in patients with relapsed or refractory indolent B-cell NHL (follicular or small lymphocytic subtypes), peak serum concentrations essentially doubled from the first (239.1 mg/L) to the fourth (460.7 mg/L) infusion, while elimination half-life (t1/2) increased from 76.3 to 205.8 hours (3.2 to 8.6 days). The concomitant increase in serum rituximab concentrations and t1/2 with each successive infusion may be due, at least in part, to the elimination of circulating CD20-positive B cells and reduction or saturation of CD20-binding sites after the initial infusions of rituximab. The pharmacokinetic properties of rituximab are also characterised by wide inter-individual variability, and serum drug concentrations that are correlated with clinical response.

Although pharmacokinetic data are limited in patients with aggressive forms of NHL, such as diffuse large B-cell lymphoma, rituximab appears to have a similar pharmacokinetic profile in these patients to that in patients with indolent B-cell NHL. The pharmacokinetics of rituximab are also reported to be similar whether the drug is administered with or without cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy.

Therapeutic Use

A number of studies have demonstrated efficacy of intravenous rituximab in patients with various lymphoid malignancies of B-cell origin, including indolent (e.g. follicular lymphoma) and aggressive (e.g. diffuse large B-cell lymphoma) forms of NHL, and CLL, but the drug has not yet been approved for use in CLL, and approved indications in NHL vary between countries. In the US, for example, rituximab is available for the treatment of patients with low-grade or follicular, relapsed or refractory, CD20-positive B-cell NHL. In Europe, the drug has similar approval for relapsed or refractory follicular NHL as in the US, but has also been approved for use in combination with CHOP chemotherapy for the most common aggressive form of NHL (CD20-positive, diffuse large B-cell lymphoma). Rituximab was approved for these indications primarily on the basis of results from two pivotal trials. In Japan, rituximab has been approved for indolent B-cell NHL and mantle cell lymphoma (an aggressive form of B-cell NHL), primarily on the basis of results of a Japanese phase II trial.

Indolent NHL: Results of several studies evaluating rituximab 375 mg/m2 once weekly for 4 weeks in patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic lymphomas) showed objective response (OR) rates ranging from approximately 40–60% in those receiving the drug for relapsed or refractory indolent B-cell NHL, and slightly higher (50–70%) for those receiving rituximab as first-line therapy. In a pivotal trial in 166 patients with relapsed or refractory low-grade or follicular B-cell NHL, intent-to-treat (ITT) analysis showed an OR rate of 48%, and a projected median time to progression of 13 months.

Encouraging data are also emerging on the use of rituximab in combination with chemotherapeutic agents (e.g. CHOP, fludarabine-containing regimens) or other drugs (e.g. interferon-α2a) in previously untreated patients with indolent forms of B-cell NHL (primarily follicular and small lymphocytic subtypes). Rates for OR were consistently around 95%, with the majority being complete responses (CRs). Follow-up data from a study in 40 patients with low-grade or follicular B-cell NHL treated with rituximab plus CHOP as first-line therapy showed that responses were durable with a progression-free survival and median duration of response >5 years.

Bcl-2 gene rearrangement (t14;18) occurs in malignant cells in up to 85% of patients with follicular lymphoma, and minimal residual disease in peripheral blood and bone marrow can be monitored using polymerase chain reaction (PCR). In several studies assessing blood and/or bone marrow, rituximab has achieved molecular response (conversion from PCR-positive to PCR-negative bc1-2 status) in at least half of the patients.

Aggressive NHL: Studies with rituximab as monotherapy in aggressive B-cell NHL, a potentially curable disorder, have generally been restricted to patients with relapsed or recurrent disease, since CHOP has traditionally been the standard first-line treatment regimen. However, promising results from phase II monotherapy studies prompted further clinical investigation of rituximab in conjunction with chemotherapy. Thus, most studies with rituximab in patients with aggressive forms of B-cell NHL have involved combination therapy, including a pivotal randomised trial comparing eight cycles of standard CHOP therapy plus rituximab 375 mg/m2 (one dose per cycle) versus CHOP alone in 399 previously untreated elderly patients (60–80 years of age) with diffuse large B-cell lymphoma. Results of the pivotal trial showed a clear advantage for rituximab plus CHOP versus CHOP in terms of event-free survival (primary endpoint) at 2 years (57% vs 38%, p < 0.001). Overall survival at 2 years (70% vs 57%, p < 0.01) and CR rate (76% vs 63%, p < 0.01) were also higher with the rituximab-CHOP combination. Other, smaller trials with rituximab in combination with CHOP or other chemotherapeutic regimens, either as first-line therapy or for patients with relapsed or refractory aggressive B-cell NHL, have also shown promising results in terms of clinical response rates.

CLL: In relatively small trials (n < 40) conducted primarily in patients with relapsed or refractory B-cell CLL, rituximab monotherapy (various regimens) achieved OR rates of 23–45%, with median duration of response ranging from approximately 3–10 months. In a larger, randomised trial in 104 previously untreated patients with B-cell CLL, concurrent treatment with six cycles of fludarabine plus rituximab 375 mg/m2 (seven doses in total) followed 2 months later by four weekly doses of rituximab achieved an OR rate of 90% compared with 77% for those who received sequential treatment using fludarabine induction followed 2 months later by rituximab 375 mg/m2 once weekly for 4 weeks. Although this difference was not statistically significant, there was a significant advantage for concurrent versus sequential treatment in terms of CR rates (47% vs 28%, p < 0.05). Several other studies using rituximab in combination with fludarabine-containing regimens, most of which are available only as abstracts, have shown good clinical response rates in previously untreated patients with CLL, as well as those with relapsed or refractory disease.

Tolerability

The majority of patients treated with rituximab will experience one or more adverse events, the most common being infusion-related reactions. Mild to moderate flu-like symptoms such as fever, chills and rigours occur in most patients during their first infusion of rituximab, although the incidence of infusion-related adverse events decreases with subsequent rituximab infusions. Severe (grade 3 or 4) infusion-related reactions occur in approximately 10% of patients, and may be accompanied by bronchospasm, hypotension, angioedema and/or hypoxia. In the vast majority of cases these adverse effects are reversible with interruption or discontinuation of rituximab along with supportive care. However, severe consequences of infusion-related reactions have been reported, including pulmonary infiltrates, acute respiratory distress syndrome and cardiovascular events. In patients who develop cytokine release syndrome associated with tumour lysis syndrome, renal, respiratory or multi-organ failure can occur. Infusion-related fatalities with rituximab have been rare (approximately 0.04-0.07% of patients).

Grade 3 or 4 haematological adverse effects generally occur infrequently with rituximab monotherapy, aside from severe lymphopenia which occurs in about 40% of patients, is related to the action of rituximab and does not appear to be associated with adverse consequences. Moreover, the risk of serious or opportunistic infections appears to be considerably less than that reported with conventional chemotherapy. Various other adverse events have been reported with rituximab, including rare reports of fatal mucocutaneous reactions.

Pharmacoeconomic Considerations

Several pharmacoeconomic analyses of rituximab in B-cell NHL have been conducted and most have been published only as abstracts. Cost analyses from the UK, France, the US and Spain indicate that rituximab is associated with total direct medical costs similar to or lower than those for fludarabine in patients with relapsed or refractory indolent B-cell NHL (usually follicular or small lymphocytic subtypes when histology was specified). The higher acquisition costs of rituximab compared with fludarabine were at least offset by reduced costs associated with adverse haematological effects (e.g. neutropenia) and drug administration. Although results were equivocal in cost comparisons between rituximab and CHOP chemotherapy in patients with relapsed or refractory indolent B-cell NHL, total direct medical costs appear to be broadly similar for rituximab and CHOP.

In cost-effectiveness analyses of rituximab in patients with aggressive B-cell NHL, investigators from France and the UK used medical resource consumption and survival data from the pivotal trial in patients with diffuse large B-cell lymphoma to determine the cost-effectiveness ratio for rituximab plus CHOP versus CHOP alone. When survival data from a protocol-scheduled interim analysis, or from 2-year follow-up data, of the pivotal trial were projected over 10 years using published long-term survival data, favourable cost-effectiveness ratios of approximately €22 150-€28 410 per life-year gained were calculated (year of costing not reported). Results were sensitive to the durability of the survival benefit and assumed that the survival benefit shown during the study period persists to 10 years.

Dosage and Administration

The standard dose of rituximab is 375 mg/m2 administered as an intravenous infusion to adult patients. However, the recommended dosage interval and duration of therapy varies between countries and for different indications (see Therapeutic Use summary section for approved indications in the US and Europe). For patients with relapsed or refractory follicular B-cell lymphoma (the most common histology of indolent NHL), rituximab is administered once weekly for 4 weeks (European recommendation) or for 4 or 8 weeks (US recommendation). For patients with diffuse large B-cell lymphoma (the most common aggressive form of NHL), rituximab is used in combination with CHOP chemotherapy for 6–8 cycles and is administered on day 1 of each cycle (European recommendation).

For the first dose of rituximab, the initial infusion rate should be 50 mg/h for the first 30 minutes, which is increased in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h. For subsequent doses, the initial infusion rate is 100 mg/h, which is increased by 100 mg/h increments at 30-minute intervals, to a maximum of 400 mg/h.

For patients who do not tolerate the first dose of rituximab well, subsequent rituximab doses should be administered according to recommendations for the first infusion (US recommendation). For patients who experience severe infusion-related reactions with rituximab, therapy should be interrupted and supportive care measures implemented. After complete resolution of symptoms, rituximab infusion can continue at half the previous rate in most patients.

Various sections of the manuscript reviewed by: S.M. Ansell, Division of Hematology, Mayo Clinic, Rochester, Minnesota, USA; K. U. Chow, Department of Internal Medicine III Hematology/Oncology, Johann Wolfgang Goethe-University, Frankfurt, Germany; M. Ghielmini, Divisione di Oncologia Medica, Ospedale Civico, Istituto Oncologico della Svizzera Italiana, Lugano, Switzerland; J.D. Hainsworth, Sarah Cannon Cancer Center, Nashville, Tennessee, USA; D. Huhn, Dept of Medicine/Hematology and Oncology, Charite Campus Virchow-Klinikum, Berlin, Germany; A. Rambaldi, Divisione di Ematologia, Ospedali Riuniti, Bergamo, Italy; K. Tobinai, Hematology Division, National Cancer Center Hospital, Tokyo, Japan.

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 ‘IDEC C2B8’ and (‘lymphoma-non-hodgkin’ or ‘leukemia lymphocytic chronic’). EMBASE search terms were ‘rituximab’ or ‘IDEC C2B8’ and (‘nonhodgkin-lymphoma’ or ‘lymphatic leukemia chronic’). AdisBase search terms were ‘rituximab’ or ‘IDEC-C2B8’ and (‘non-hodgkins-lymphoma’ or ‘chronic lymphocytic leukaemia’). Searches were last updated 6 March 2003.
Selection: Studies in patients with non-Hodgkin’s lymphoma or chronic lymphocytic leukaemia 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, non-Hodgkin’s lymphoma, chronic lymphocytic leukaemia, lymphoid malignancies, pharmacodynamics, pharmacokinetics, therapeutic use, tolerability, dosage and administration.