Complications of treatmentTolerability and safety of rituximab (MabThera®)
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knowledge of the safety and tolerability of rituximab was reviewed, using information gathered from both published and unpublished clinical trial data, data presented at scientific congresses, postmarketing surveillance reports, case histories, and other information included in the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
References (143)
- et al.
The mechanisms of action of rituximab in the elimination of tumor cells
Semin Oncol
(2003) - et al.
Phase I trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma
Blood
(1994) - et al.
IDEC-C2B8 (rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low grade non-Hodgkin’s lymphoma
Blood
(1997) - et al.
Prolonged treatment with rituximab in patients with follicular lymphoma significantly increases event-free survival and response duration compared with the standard 4-weekly schedule
Blood
(2004) - et al.
Homodimers but not monomers of Rituxan (chimeric anti-CD20) induce apoptosis in human B-lymphoma cells and synergize with a chemotherapeutic agent and an immunotoxin
Blood
(2001) - et al.
Rituximab in combination with CHOP or fludarabine in low-grade lymphoma
Semin Oncol
(2002) - et al.
randomized phase 2 study of fludarabine, with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukaemia Group B 9712 (CALGB 9712)
Blood
(2003) - et al.
Results of a Phase II multicenter trial of pentostatin and rituximab in Patients with low grade B-cell non-Hodgkin’s lymphoma: an effective and minimally toxic regimen
Clin Lymphoma
(2003) - et al.
The addition of rituximab to a combination of fludarabine, cyclophosphamide, mitoxantrone (FCM) significantly increases the response rate and prolongs survival compared to FCM alone in patients with relapsed and refractory follicular and mantle cell lymphoma – results of a prospective randomized studyBlood
Blood
(2004) - et al.
Rituximab: enhancing outcome of autologous stem cell transplantation in non-Hodgkin’s lymphoma
Semin Oncol
(2003)
Successful in vivo purging of CD34-containing peripheral blood harvests in mantle cell and indolent lymphoma: evidence for a role of both chemotherapy and rituximab infusion
Blood
Efficiency of in vivo purging with rituximab prior to autologous peripheral blood progenitor cell transplantation in B-cell non-Hodgkin’s lymphoma: a single institution study
Ann Oncol
Rituximab as adjuvant to high-dose therapy and autologous hematopoietic cell transplantation for aggressive non-Hodgkin lymphoma
Blood
Intensive chemotherapy and autologous stem-cell transplantation plus rituximab is superior to conventional chemotherapy for newly diagnosed advanced stage mantle cell lymphoma: a matched pair analysis
Ann Oncol
Rituximab and ICE (RICE) as second-line therapy prior to autologous stem cell transplantation for relapsed or primary refractory diffuse large B-cell lymphoma
Blood
Effective salvage therapy for lymphoma with cisplatin in combination with high-dose Ara-C and dexamethasone (DHAP)
Blood
OKT3 first-dose reaction: association with T cell subsets and cytokine release
Kidney Int
Cytokine-release syndrome in patients with B-cell chronic lymphocytic leukemia and high lymphocyte counts after treatment with an anti-CD20 monoclonal antibody (rituximab, IDEC-C2B8)
Blood
Rituximab: ongoing and future clinical development
Semin Oncol
Acute tumor lysis syndrome
Semin Oncol
Management of acute tumor lysis syndrome
Semin Oncol
Acute tumor lysis syndrome in patients with high-grade non-Hodgkin’s lymphoma
Am J Med
Rituximab in B-cell chronic lymphatic leukemia
Semin Oncol
Prolonged neutropenia following anti CD20 therapy in a patient with relapsed follicular non-Hodgkin’s lymphoma and corrected with IVIG
Ann Oncol
Agranulocytosis unresponsive to growth factors following in vivo purging
Blood
Evidence for T-large granular lymphocyte-mediated neutropenia in rituximab-treated lymphoma patients: report of two cases
Leuk Res
Anti-CD20 monoclonal antibody for the treatment of severe, immune-mediated pure red cell aplasia and hemolytic anemia
Blood
Successful treatment of pure red cell aplasia with rituximab in patients with chronic lymphocytic leukemia
Blood
Extended rituximab (anti CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin’s lymphoma
Ann Oncol
Treatment of monomorphic B-cell lymphoma with rituximab after liver transplantation in a child
Pediatr Transplant
Induction of long-term remission of a relapsed childhood B-acute lymphoblastic leukemia with rituximab chimaeric anti-CD20 monoclonal antibody and autologous stem cell transplantation
J Pediatr Hematol Oncol
Anti-CD20 monoclonal antibody (rituximab) for therapy of mediastinal CD20-positive large B-cell non-Hodgkin lymphoma with a local tumor extension into the lung of a 10-year-old girl
J Pediatr Hematol Oncol
Efficacy and safety of a combined rituximab chemotherapy during pregnancy
J Clin Oncol
Safety of rituximab therapy during the first trimester of pregnancy
Eur J Haematol
IDEC-CB8: results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin’s lymphoma
J Clin Oncol
Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program
J Clin Oncol
Rituximab as first-line and maintenance therapy for patients with indolent non-Hodgkin’s lymphoma
J Clin Oncol
Single agent rituximab as first-line and maintenance therapy for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. a phase II trial of the Minnie Pearl Cancer Research Network
J Clin Oncol
Standard-dose anti-CD20 antibody rituximab has efficacy in chronic lymphocytic leukaemia: results from a Nordic multicentre study
Eur J Haematol
Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs
Cancer Biother Radiopharm
Rituximab inactivates signal transducer and activation of transcription 3 (STAT3) activity in B-non-Hodgkin’s lymphoma through inhibition of the interleukin 10 autocrine/paracrine loop and results in down-regulation of Bcl-2 and sensitization to cytotoxic drugs
Cancer Res
Treatment of patients with low-grade B-cell lymphoma with the combination of chimaeric anti CD-20 monoclonal antibody and CHOP chemotherapy
J Clin Oncol
Prolonged clinical and molecular remission in patients with low-grade or follicular non-Hodgkin’s lymphoma treated with rituximab plus CHOP chemotherapy: 9-year follow-up
J Clin Oncol
CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma
N Engl J Med
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