Elsevier

Cancer Treatment Reviews

Volume 31, Issue 6, October 2005, Pages 456-473
Cancer Treatment Reviews

Complications of treatment
Tolerability and safety of rituximab (MabThera®)

https://doi.org/10.1016/j.ctrv.2005.05.007Get rights and content

Summary

Rituximab, a human/mouse chimeric anti-CD20 antibody, has become part of standard therapy for patients with CD20-expressing B-cell lymphoma, and is currently under investigation for other indications including autoimmune diseases, in particular rheumatoid arthritis (RA). Its characteristic tolerability profile was established soon after clinical testing began and compares favourably with chemotherapy. The majority of patients experience mild to moderate infusion-related reactions (IRRs) during the first administration of rituximab, but the incidence decreases markedly with subsequent infusions. Current data suggest that the type of adverse events in patients with RA are similar to those in lymphoma, but that adverse events related to the rituximab infusions are less severe and less frequent.

Rituximab induces a rapid depletion of normal CD20-expressing B-cells in the peripheral blood, and levels remain low or undetectable for 2–6 months before returning to pretreatment levels, generally within 12 months. Serum immunoglobulin levels remain largely stable, although a reduction in IgM has been described. T-cells are unaffected by rituximab and consequently opportunistic infections rarely occur in association with rituximab therapy.

When used in combination with a variety of chemotherapeutic regimens, rituximab does not add to the toxicity of chemotherapy, with the exception of a higher rate of neutropenia. However, this does not translate into a higher infection rate.

Over 540 000 patients worldwide have now received rituximab and serious adverse reactions have occurred in a small minority of patients, but for the great majority of patients, rituximab is safe and well tolerated.

Introduction

Rituximab (MabThera®, Hoffmann-La Roche AG; Rituxan®, Genentech/Biogen Idec) is a chimeric human/mouse monoclonal antibody that has emerged in recent years as an effective therapy for non-Hodgkin’s lymphoma (NHL) and other B-cell malignancies. Rituximab binds avidly to the CD20 antigen, an attractive target for monoclonal antibody therapy, as it is expressed on almost all malignant B-cells. The antigen is however, also expressed on normal differentiated B-lymphocytes and pre-B-cells, but not on stem cells or plasma cells. Unlike murine monoclonal antibodies to CD20, rituximab persists in the circulation for long periods, interacts with human effector cells and rarely generates human anti-mouse antibody responses. Rituximab destroys B-cells by multiple mechanisms including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), induction of apoptosis and sensitisation to chemotherapy.1

Rituximab was first approved for the treatment of relapsed or refractory indolent CD20-positive NHL in the USA in 1997, then in Europe in 1998 for patients with advanced-stage chemoresistant or relapsed follicular lymphoma. More recently, rituximab has been approved for use in combination with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) chemotherapy for the treatment of aggressive NHL. In 2004, rituximab received European approval for the first-line treatment of patients with indolent lymphoma, in combination with conventional chemotherapy. Clinical evaluation of rituximab in a variety of lymphoid malignancies is continuing and it is also being tested for activity in other conditions, such as autoimmune disorders, notably rheumatoid arthritis. The present review focuses on the tolerability of rituximab in NHL and B-cell chronic lymphatic leukaemia (B-CLL), though safety data from trials in rheumatoid arthritis will be briefly discussed.

Section snippets

Methods

Over 540 000 patients have received rituximab worldwide,2 including children.3, 4, 5 A few pregnant women have also been treated.6, 7 The current knowledge of the safety and tolerability of rituximab was reviewed, using information gathered from both published and unpublished clinical trial data, data presented at scientific congresses, postmarketing surveillance reports, case histories, and other information included in the European8 and US9 prescribing information for rituximab.

Rituximab as monotherapy

Early testing of rituximab showed dramatic clinical activity in certain patients with CD20-positive lymphomas with minimal accompanying toxicity.10, 11, 12 In the subsequent pivotal trial of single-agent rituximab in indolent lymphoma, 166 patients received intravenous rituximab, 375 mg/m2 once weekly, for four consecutive weeks. Rituximab was generally well tolerated, but 84% of patients experienced an adverse event during rituximab therapy or within the first 30 days following therapy.

Rituximab in combination with chemotherapy

Rituximab has been combined with a variety of chemotherapeutic agents, based on the different mechanisms of action of rituximab and chemotherapy, synergistic activity demonstrated in vitro,20, 21, 22 and minimal overlapping toxicities. Rituximab in combination with standard-dose CHOP as first-line treatment for a small series of 40 patients with indolent NHL achieved response rates approaching 100%, with a median time to disease progression of almost seven years.23, 24 IRRs occurred in 19% of

Rituximab in combination with immunotherapy

Rituximab has been rationally combined with immune system modulators including interferon-alpha (IFN-α),36, 37, 38, 39 interleukin-2 (IL-2),40, 41 IL-1242 and G-CSF.43 Mechanisms by which immune modulators may increase the effectiveness of rituximab include potentiation of expression of CD20, increasing Fc receptor density on effector cells, and increasing numbers of effector cells.44 In a trial of rituximab plus IFN-α in 38 patients with relapsed or refractory indolent NHL, no unexpected

Rituximab in transplantation

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is potentially curative in younger patients with relapsed aggressive NHL, and is also being evaluated in indolent NHL. However, between 40% and 70% of patients relapse after ASCT because of residual tumour in the patient or contamination of tumour cells in the stem cell product.45 A number of strategies, including in vivo and in vitro purging have been used to purify grafts and thus minimise the risk of reinfusing

Rituximab in rheumatoid arthritis

The efficacy and safety of rituximab in severe RA was recently evaluated in a double-blind, placebo-controlled trial.64 One hundred and sixty-one patients were randomised in a four arm trial to receive either methotrexate (plus placebos for cyclophosphamide and rituximab infusion), rituximab (plus placebos for methotrexate and cyclophosphamide), rituximab plus methotrexate (plus placebo for cyclophosphamide) or rituximab plus cyclophosphamide (plus placebo for methotrexate). Rituximab dosing

Infusion-related reactions

Therapeutic infusions of monoclonal antibodies are typically associated with characteristic toxicity syndromes. As discussed above, early experience with rituximab in the pivotal trial in NHL revealed a characteristic infusion-related syndrome, usually occurring within a few hours of starting the first infusion.13, 65 The most prevalent IRRs were flu-like symptoms (fever, chills and rigors). Less common reactions included hypotension, bronchospasm, pruritus and rash. A cytokine release may be

Haematological side effects

In the pivotal study of rituximab monotherapy, haematological abnormalities occurred in a minority of patients and were usually mild and reversible. Grade 3/4 thrombocytopenia and neutropenia were reported in only 1.7% and 4.2% of patients respectively, and severe anaemia was reported in 1.1% of patients.13 This contrasts with the relatively high incidence of neutropenia, thrombocytopenia and anaemia occurring in association with purine analogue therapy and combination chemotherapy.79, 80

Infectious complications

As discussed above, rituximab efficiently kills both malignant and non-malignant CD20-positive cells, and normal B-cells are rapidly depleted following administration of the drug.11 Levels of normal peripheral B-cells remain low for 2–6 months, followed by recovery to pretreatment levels by 12 months. Despite this depletion of B-cells, mean serum immunoglobulin levels remain stable following administration of a conventional cycle of rituximab therapy (four weekly infusions of rituximab 375 mg/m2

Mucocutaneous reactions

Many chemotherapeutic agents induce mucocutaneous toxicity, most commonly alopecia, stomatitis and hyperpigmentation. These cause significant morbidity and psychological distress to patients. Patients receiving rituximab do not generally experience cutaneous toxicities, but there have been occasional reports of serious mucocutaneous adverse events. The incidence in 125 000 patients receiving rituximab between 1997 and 2001 is 0.0008% (Fig. 3), much lower than the expected incidence of serious

Pulmonary adverse events

There have been several reports of pulmonary reactions in patients receiving rituximab alone or in combination with chemotherapy. Kanelli and colleagues reviewed 27 patients who received rituximab and described a patient with MCL who developed bilateral pulmonary infiltrates 6 days after a single dose of rituximab. He required mechanical ventilation but recovered fully, with a normal chest X-ray being obtained 2 months later.129 In a study of rituximab and fludarabine in B-CLL, there were 3

Safety of extended dosing

As previously discussed, multiple courses of rituximab do not result in an increased incidence of adverse events.100 In a study assessing eight consecutive weekly infusions of patients with refractory NHL, extending rituximab therapy did not delay B-cell recovery, stimulate an increased incidence of HACA, or result in an increased incidence of infections compared with the standard regimen.99

Long-term follow-up data from patients who entered a Phase II trial of rituximab as first-line and

Long-term safety

Long-term follow-up of the use of rituximab in combination with other therapies does not reveal any consistent pattern of adverse events. Long-term follow-up data from three studies of rituximab in combination with CHOP have been reported.24, 136, 137 Thirty-three patients with previously untreated aggressive NHL have been followed for a median of 62 months and no long-term complications of R-CHOP therapy have been reported.136 Thirty-eight patients with indolent NHL received 6 cycles of R-CHOP

Summary and conclusions

The extensive clinical experience with rituximab as monotherapy and in combination with chemotherapy has yielded consistent data concerning side effects. The majority of patients receiving their first infusion of rituximab experience flu-like symptoms; other common symptoms include nausea, headache, fatigue and rash. These symptoms can be treated with paracetamol and antihistamines. About 10% of patients experience more severe symptoms such as bronchospasm, hypoxia and hypotension. Rituximab

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