Variations on the fludarabine, cyclophosphamide, and rituximab combination in chronic lymphocytic leukemia therapy: what have we learned?

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. 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?” 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 al presents an FC dose-reduced, R dose-escalated version of the FCR regimen, termed “FCR-Lite,” whereas Lamanna et al introduce a sequential “F3C3R” regimen. 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 al to test a dose-reduced version of FCR, with the intent of maintaining efficacy. Fludarabine was dose reduced to 20 mg/m, and cyclophosphamide was reduced to 150 mg/m. Rituximab was increased to 500 mg/m 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 Table 1. Comparison of Three FCR Regimens