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Originally published as JCO Early Release 10.1200/JCO.2008.18.8698 on December 15 2008 © 2009 American Society of Clinical Oncology.
Variations on the Fludarabine, Cyclophosphamide, and Rituximab Combination in Chronic Lymphocytic Leukemia Therapy: What Have We Learned?Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA Fludarabine, cyclophosphamide, and rituximab (FCR) each have single-agent efficacy in the treatment of chronic lymphocytic leukemia (CLL). In combination, these agents are synergistic as demonstrated by the results of the FCR regimen developed by Michael Keating et al at The University of Texas M. D. Anderson Cancer Center, Houston, TX.1 Clearly, with high complete remission rates and long remission durations, the FCR regimen is among the frontline regimens for treatment of CLL. Indeed, the question has been raised, "Should FCR be considered the new gold standard for CLL therapy?"2
Unfortunately, the extraordinary biologic and clinical heterogeneity of CLL make it difficult to compare the results of clinical trials, so the answer to this question will require additional randomized clinical trials developed with attention to critical prognostic factors for risk stratification of patients with CLL. However, despite this limitation, we can, nevertheless, still learn much from comparing phase II trials of the FCR combination. In this issue of the Journal of Clinical Oncology, two small phase II trials aimed at reducing toxicity while preserving efficacy examine modifications of the FCR combination. The report by Foon et al3 presents an FC dose-reduced, R dose-escalated version of the FCR regimen, termed "FCR-Lite," whereas Lamanna et al4 introduce a sequential "F To evaluate these trials, it is important to recapitulate the recently reported long-term results of the 300 patients with CLL receiving FCR as initial therapy at M. D. Anderson Cancer Center (Table 1). Impressive clinical activity was noted, with a complete response (CR) rate of 72% and an overall response rate of 95%. Six-year overall survival and failure-free survival were 77% and 51%, respectively; median time to progression was 80 months. Evaluation for minimal residual disease (MRD) by flow cytometry (FL-C) at the end of treatment and polymerase chain reaction (PCR) correlated with improved overall survival. FL-C negativity was associated with superior time to progression (median, 85 months v 49 months) and survival (84% v 65% at 6 years). PCR applied to patients already known to be FL-C negative had little additional impact. Although it is noteworthy that two thirds of patients had intermediate-risk disease by Rai criteria, these are the most robust single-institution data to date in terms of CR rate, remission duration, and survival. In addition, these data reconfirm and emphasize the importance of MRD negativity after completion of treatment.
The efficacy of the combination of FCR, as well as the associated toxicities, led Foon et al3 to test a dose-reduced version of FCR, with the intent of maintaining efficacy. Fludarabine was dose reduced to 20 mg/m2, and cyclophosphamide was reduced to 150 mg/m2. Rituximab was increased to 500 mg/m2 on days 1 and 14 of a 28-day cycle, and rituximab maintenance was included after completion of six cycles of the combination. The authors report on 48 assessable patients, all of whom responded to treatment (100% overall response rate) with 38 CRs (79%). Of these 38 patients, 37 (97%) had a FL-C–negative CR. Although the authors state that none of the 38 patients achieving CR have relapsed at the time of report, the median duration of CR is 22.3 months with a range of 5.2 to 42.5 months, which is rather short follow-up at this point. Grade 3 to 4 toxicities were rare, with grade 3 or 4 neutropenia occurring in 13% of treatment cycles. The authors conclude that their results confirm the high response rate of the FCR regimen, albeit FCR-Lite, with a lower toxicity than reported for classic FCR. Moreover, they emphasize that 34 (68%) of 40 patients were treated by community oncologists. It should be noted that 84% of enrolled patients had intermediate-risk disease, and as such, the patient population was heavily skewed toward early-stage patients. It is challenging to extrapolate treatment for advanced stage (Rai III/IV) disease based on results in just eight patients. Finally, the authors fail to report any biologic markers beyond cytogenetics. The study does, however, raise two interesting questions: first, what is the minimum effective dose of fludarabine in this combination? And second, is there a role for rituximab maintenance? The answers to both of the questions are beyond the scope of this single-arm, phase II trial.
The second report by Lamanna et al4 and the Memorial Sloan-Kettering Cancer Center (MSKCC; New York, NY) group introduces the concept of sequential chemo-immunotherapy. Building on their prior experience with cyclophosphamide consolidation after fludarabine, the authors added rituximab to what was termed the F
The MSKCC study provides us with some intriguing insights. For example, the authors reported the molecular CR rate after each of the sequential treatment phases. Although all but one patient had detectable disease after fludarabine, seven patients had no disease by clonotypic PCR after cyclophosphamide consolidation. Interestingly, after completion of treatment, 12 patients were noted to have a molecular CR, suggesting rituximab had a significant impact on eradication of MRD in these patients. Similar to the FCR-Lite trial, the small number of patients included in this trial precludes any further conclusions beyond the generation of hypotheses. It seems, however, that sequential F Taken together, the studies reported by Foon et al3 and Lamanna et al4 confirm the efficacy of the FCR combination, but do not support the use of sequential FCR or FCR-Lite in practice outside of a clinical trial. They do, however, support the use of approaches for MRD detection for refining our definition of therapeutic response in clinical trials, and the Lamanna study supports the observation that even patients with adverse prognostic features can have durable remissions if they achieve CR. The question remains, how can we use the information from phase II trials of FCR to improve our treatment approach to patients with CLL, given the clinical and biologic diversity of this disease? To answer to this question, we will need to identify those patients who benefit most from this treatment approach, those patients (perhaps those with MRD at the end of therapy) who need additional therapeutic interventions, and those patients who might be better served by an alternative approach altogether. Part of the answer to this question will be forthcoming from the randomized phase II Intergroup trial that compares fludarabine and rituximab (FR), classical FCR, and FR followed by lenalidomide. This trial randomly assigns patients within strata defined by Rai stage and will examine the impact of tumor cell biology (interphase cytogenetic analysis, stimulated metaphase cytogenetic analysis, immunoglobulin VH gene mutational status, CD38 and CD49d expression, ZAP-70 expression, p53 dysfunction, gene expression profile, epigenetic changes in methylation) on treatment outcome and disease evolution. Although this Intergroup trial will not compare different versions of the FCR combination, it will identify which patients benefit most from a fludarabine-based combination as first therapy and should provide a rational basis for future trials in which treatments can be prospectively evaluated in biologically defined groups of patients with CLL. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Stephen J. Schuster Collection and assembly of data: Stephen J. Schuster Data analysis and interpretation: Tahamtan Ahmadi, Stephen J. Schuster Manuscript writing: Tahamtan Ahmadi, Stephen J. Schuster Final approval of manuscript: Tahamtan Ahmadi, Stephen J. Schuster Acknowledgment We thank Jim and Frannie Maguire for their enduring support of the Lymphoma Program at the University of Pennsylvania. REFERENCES
1. Tam CS, O'Brien S, Wierda W, et al: Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 112:975–980, 2008. 2. Montserrat E: Further progress in CLL therapy. Blood 112:924–925, 2008. 3. Foon KA, Boyiadzis M, Land SR, et al: Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 27:498–503, 2009.[CrossRef][Medline] 4. Lamanna N, Jurcic JG, Noy A, et al: Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: Molecular remissions predict for durable complete responses. J Clin Oncol 27:491–497, 2009.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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