Rituximab for Chronic Lymphocytic Leukemia in Treatment-Naïve and Treatment-Experienced Patients

Ann Janssens, MD; Robin Foa, MD; Michael J. Keating, MD, BS; Iain Tatt, PhD; and Emma S. C. Carr, BSc, MSc, PhD
Published Online: Monday, January 23, 2012

Abstract

There has been a lack of meta-analyses and systematic reviews conducted in chronic lymphocytic leukemia (CLL). Structured searches were conducted in publication and conference databases to identify randomized controlled trials (RCTs) that are reporting efficacy data for treatment-naïve CLL and both RCTs and non-RCTs for relapsed/refractory CLL. Eight RCTs met prespecified inclusion criteria to permit a meta-analysis of fludarabine/cyclophosphamide/rituximab (FCR) with alemtuzumab, bendamustine, chlorambucil, fludarabine, and fludarabine/cyclophosphamide (FC). A mixed treatment comparison demonstrated that FCR significantly prolonged progression-free survival (PFS) compared with all other treatments (hazard ratios, 0.24-0.56) and significantly increased overall response rate (ORR) compared with all other treatments. FCR significantly increased the complete response (CR) rate compared with chlorambucil, fludarabine, and FC (odds ratios of 30.3, 10.1, and 2.7, respectively). For relapsed and refractory CLL, 9 RCTs and 86 non-RCTs were identified that reported efficacy data. A meta-analysis was deemed inappropriate due to trial heterogeneity. Overall, overall survival (OS) and PFS ranged from 24 to 33.8 months and from 6 to 30.6 months, respectively, depending on the therapy. Across all trials, FCR showed the greatest improvement in PFS, with robust ORR and CR rates. The identified studies indicated that FCR is highly efficacious for the treatment of both untreated and relapsed/refractory patients with CLL. These studies and the benefit of FCR are largely applicable to young and fit patients with CLL, and the best treatment for older patients could not be extracted from this analysis. Going forward, this evidence-based review should be updated with longer follow-up from trials to better determine OS benefit.

Introduction

Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in the Western world, with an incidence rate of approximately 3.9 per 100,000 persons per year.1 Approximately 14,570 patients will be diagnosed with CLL in the United States in 2011.2 Primarily a malignancy of the elderly, the median age at diagnosis is 72 years in the United States, and approximately 70% of patients are aged >65 years.3 The disease is largely characterized by a slow, often asymptomatic progression over several years as malignant cells gradually accumulate in the blood, bone marrow, and lymph nodes.4 Anemia, thrombocytopenia, and immunosuppression can accompany painless lymph node enlargement and organomegaly. Systemic symptoms, such as fever, sweating, and weight loss, may be rare. Patients with early disease are usually left untreated; however, most patients will eventually require treatment.5

The treatment of CLL has advanced rapidly over the past 2 decades due to the use of chlorambucil as standard first-line treatment and subsequent clinical determination that the purine-based analog fludarabine showed superior clinical benefit over alkylator- and anthracycline- based regimens.6-8 Initial treatment with fludarabine is associated with response rates of 63% to 80%, and when combined with cyclophosphamide (FC) showed increased response rates of 74% to 94%.9,10 Adding the anti-CD20 monoclonal antibody rituximab to FC (FCR) chemotherapy resulted in further improvements in the overall response rates (ORRs) and complete response (CR) rates.11,12 Additional biologic and chemical agents, including alemtuzumab, ofatumumab, and bendamustine, have been added to the CLL treatment armamentarium, and a number of investigational agents are undergoing study in the clinic. Treatment options for patients with relapsed or refractory CLL remain limited, and the prognosis for these patients is still poor.13 The management of CLL depends on a number of factors, and in the first-line setting it has been proposed that 3 overriding considerations dictate treatment: tumor load with or without symptomatic or progressive disease (ie, determined by Rai or Binet stage or by lymphocyte doubling time); the physical condition of the patient (ie, fitness and comorbidity); and the prognostic risk of the leukemia (ie, due to genetic and other molecular factors).14 For relapsed disease, these factors, in addition to the choice of prior therapy and the length of remission duration from first treatment, will influence treatment decisions. Despite treatment, the vast majority of patients relapse and CLL remains an incurable disease.15 Randomized controlled trials (RCTs) are needed to determine optimal treatment for appropriate patient types, depending on stage of disease, cytogenetics, performance status, and treatment status.

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