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Future Oncology
Drug Evaluation
Rituximab for the treatment of follicular lymphoma Chan Y Cheah1,2, Senthil Lingaratnam3 & John F Seymour*1,2 Department of Haematology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia University of Melbourne, Parkville, Victoria, Australia 3 Pharmacy Department, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia *Author for correspondence: Tel.: +61 3 9656 1076 n Fax: +61 3 9656 1408 n
[email protected] 1 2
Rituximab is the first and most widely adopted anti-CD20 monoclonal antibody, and has dramatically improved outcomes for patients with B-cell malignancies. Rituximab is active as a single agent and when combined with chemotherapy improves both response rates and survival compared with chemotherapy alone. This approach has become standard of care in this setting. A number of Phase III studies using extended applications of rituximab have demonstrated that patients achieve a significantly longer progression-free survival, at the cost of an increase in infective complications. This has resulted in the widespread adoption of maintenance rituximab following the completion of primary therapy. Rituximab is useful in both previously untreated patients and at relapse, although a subset of patients develop disease that is rituximab resistant, which along with histologic transformation remains a significant management problem for patients with follicular lymphoma. The toxicities are modest and manageable, including infusion reactions, late - onset neutropenia, impaired humoral immunit y, reactivation of hepatitis and possibly pulmonary toxicity.
Follicular lymphoma (FL) is the most common indolent lymphoma, with an estimated incidence of five to seven per 100,000 population each year. The median survival was 8–10 years prior to the introduction of rituximab (Mabthera®; Hoffman-La Roche, Basel, Switzerland; Rituxan®; Biogen-Idec, CA, USA; Genentech, CA, USA), however, outcomes with contemporary treatments have significantly improved [1]. Although typically initially chemosensitive, the clinical course is characterized by successively shorter durations of remission and eventually treatment resistance [2]. Approximately 25% of patients have stage I/II disease at presentation and although randomized studies are lacking, radiotherapy with curative intent has been consistently shown to attain truly durable disease eradication in 40–50% of patients, consistent with cure, and is considered standard of care [3]. However, the majority of patients have advanced stage disease at diagnosis and initation of treatment may be safely delayed until clear indications develop – a recommendation that is based on several studies that failed to show a survival benefit from early initation of therapy [4–7]. Two of these studies (the Groupe pour l’Etude de Lymphome Folliculaire [4] and British National Lymphoma Investigation [5]) employed criteria for determining which patients can be safely observed, and these have become the most widely accepted (Box 1). Once treatment is necessary, options are dependent on tumor burden, patient comorbidities and preference. Rituximab combined with 10.2217/FON.13.134 © 2013 Future Medicine Ltd
chemotherapy and followed by rituximab maintenance is considered standard of care for patients with symptomatic, high-tumor burden or disease otherwise requiring therapy, although the choice of chemotherapy backbone remains a matter of considerable debate. In this article, we summarize the key data supporting the use of rituximab in FL and provide our recommendations based on the available evidence. Areas of unmet need
Despite the considerable improvements achieved with the introduction of the anti-CD20 monoclonal antibody (mAb) rituximab, FL remains incurable with conventional treatment. Highlighting the heterogeneity of clinical outcome, patients treated with rituximab-containing regimens can be stratified according to the Follicular Lymphoma International Prognostic Index (FLIPI-2) with low-, intermediate- and high-risk groups achieving 5-year progression-free survival (PFS) rates of 80, 51 and 19%, respectively [8]. For high-risk patients, as discerned by FLIPI-2, improved treatment approaches are urgently required. Risk of histologic transformation
A dreaded event in the natural history of patients with FL is histologic transformation into a highgrade lymphoma. The risk of transformation has been estimated at approximately 3% per year, with an actuarial risk after 15 years of follow-up ranging from 22–45% in a large retrospective Future Oncol. (2013) 9(9), 1283–1298
Keywords adverse event n anti-CD20 chemotherapy n follicular lymphoma n monoclonal antibody n pharmacokinetic n review n rituximab n n
part of
ISSN 1479-6694
1283
Drug Evaluation
Cheah, Lingaratnam & Seymour
Box 1. Criteria for safely delaying the treatment of advanced-stage follicular lymphoma. GELF criteria [4] – All of the following: – Maximum diameter of disease
