First-Line Treatment Options for Chronic Lymphocytic Leukemia: FCR and Beyond
Introduction
During the past decade, the chemotherapy combination of fludarabine/cyclophosphamide (FC) emerged as standard therapy for the first-line treatment of chronic lymphocytic leukemia (CLL). More recently, the addition of rituximab (FCR) resulted in improved overall survival over FC, leading to approval by the US Food and Drug Administration (FDA) of FCR for use as both first- and second-line treatment. On the basis of these results, FCR is fast becoming the standard of care for healthy, fit patients with CLL. At the same time, however, a number of other agents, such as bendamustine, ofatumumab, GA101, alemtuzumab, Bcl-2 antagonists (ABT-263, oblimersen), lenalidomide, and flavopiridol, are emerging as treatment options for CLL. Whether these new agents will be reserved for cases in which FC or FCR is not appropriate or whether one or more may emerge as a viable alternative option to FC or FCR is still not clear, but research is under way. This article explores recent research into existing and emerging therapies for CLL.Standard Therapy for CLL
Several randomized trials[1-3] comparing FC with fludarabine monotherapy demonstrated improved complete response (CR) and overall response (OR) rates, as well as progression-free survival (PFS), with the use of FC, leading to the emergence of FC as the preferred chemotherapy combination for the treatment of previously untreated patients with CLL. With preclinical studies showing evidence for a synergy between rituximab and fludarabine,[4] the monoclonal antibody rituximab was added to fludarabine-based regimens and investigated in several phase 2 trials.[5-8] Results suggested improved ORs and CRs, as well as improved PFS and overall survival (OS), leading the German CLL Study Group to initiate a randomized, phase 3 trial comparing FCR with FC.In the German CLL trial,[9,10] 817 patients (median age, 61 years) with good physical fitness were randomly assigned to receive 6 courses of FC (n = 409) or FCR (n = 408). The study included 64% of patients at Binet stage B, 32% Binet C, and 5% Binet A. FCR induced a higher OR rate (92.8 vs 85.4%) and more CR (44.5 vs 22.9) (P < .001) than FC. In the initial analysis,[9] PFS at 2 years was 76.6% in the FCR arm and 62.3% in the FC arm (P < .01). FCR treatment was more frequently associated with grade 3 and 4 neutropenia (FCR 34%; FC 21%), while other side effects were not increased. Treatment-related mortality occurred in 2.0% in the FCR and 1.5% in the FC arm. A systematic analysis of prognostic factors including molecular cytogenetics showed that the positive effect of FCR applied for most prognostic subgroups. However, FCR did not improve the PFS or OS of patients with a del(17p). These data were updated at the 2009 American Society of Hematology (ASH) annual meeting[10] with a longer median observation time of 37.7 months. In the prolonged data, FCR continued to induce a higher OR rate (95.1% vs 88.4%) and more CRs (44.1% vs 21.8%; P < .001) than FC, as well as an improved PFS of 51.8 months vs 32.8 months for the FC group (P < .001). Most significantly, patients in the FCR arm had an improved OS compared with those in the FC arm. At 37.7 months, patients in the FCR arm had an OS of 84.1% vs 79% (P = .01) in the FC arm. In both arms, the median OS was not reached. For both PFS and OS, the largest benefit for FCR was observed in Binet stage A and B. As with the earlier reports, more patients in the FCR arm had hematologic adverse events, particularly neutropenia, but they did not have an increased infection rate. There were more deaths in the FC arm (86/396, 21.7%) than the FCR arm (65/404, 16.1%).
Taken together, the results show that FCR is superior to FC in the first-line treatment of physically fit patients with CLL. Therefore, the German CLL Study Group currently considers this combination to be standard of care for this group of patients.
Alternative Chemoimmunotherapy Combinations
Recently, an older chemotherapy option, bendamustine, and 2 new monoclonal antibodies, ofatumumab and alemtuzumab, were approved for treatment of CLL. Other novel therapies are also under consideration. In what appears to be a promising combination for first-line treatment, bendamustine has been combined with rituximab (BR), while results have been more mixed in some of the first-line chemoimmunotherapy combinations involving ofatumumab and alemtuzumab.Bendamustine
The German CLL Study Group initially studied BR in patients with relapsed CLL.[11] Results showed an OR rate of 77%, CR rate of 15%, and grade 3/4 neutropenia and thrombocytopenia rates of 12% and 9%, respectively -- response rates that were similar to those of the FCR regimen but with less neutropenia than the FCR regimen historically has had. On the strength of those results, the German CLL Study Group initiated a trial of BR in 117 patients (median age, 64 years) with previously untreated CLL.[12] Results of the phase 2 trial were presented at ASH 2009. At a median follow-up of 15.4 months, patients had an OR of 91%, CR of 33%, and 85% were in remission. Major side effects were low, with grade 3/4 neutropenia and thrombocytopenia occurring in 6.5% and 6% of courses, respectively. On the basis of these promising results, the German CLL Study Group is currently conducting the CLL10 study, a randomized comparison of FCR and BR in patients with previously untreated CLL. At present, FCR remains the preferred option, but the results of this study are anxiously awaited.
Monoclonal Antibodies
Building on the success of the antiCD20 antigen rituximab, researchers have been investigating a number of other monoclonal antibodies. These include ofatumumab, a fully human CD20 antibody that binds to a different site on CD20 than rituximab; alemtuzumab, a recombinant, fully humanized, monoclonal antibody against the CD52 antigen; and lumiliximab, a primatized anti-CD23 antibody that recently failed in a randomized trial.
Alemtuzumab has been studied most closely as a therapeutic option for patients with poor prognostic features. Monotherapy has produced response rates starting at 33% in patients with advanced or refractory CLL,[13-15] and it has proven efficacy in patients with high-risk genetic markers such as deletions of chromosome 11 or 17 (del(11q) and del(17p)), and p53 mutations.[16,17] As such, it is under investigation in a number of combinations for first-line therapy. However, results of alemtuzumab combined with FC (FCA) have been disappointing so far, with FCA proving more toxic and less efficacious than FCR.[18]
Presenters at ASH 2009[19] reported on the combination of cyclophosphamide, fludarabine, alemtuzumab, and rituximab (CFAR) in high-risk patients with previously untreated CLL. Results in 60 patients were similar to those seen previously with FCR, with 92% OR, 70% CR rate, and comparable PFS and overall survival. Toxicities were increased, however, suggesting that this regimen does not add significantly to FCR but may be more toxic. Synergistic activity between fludarabine and alemtuzumab (FA) was investigated in a phase 2 trial enrolling patients with relapsed CLL.[20] This combination proved feasible, safe, and effective. The German CLL Study Group is studying FCA in patients with relapsed/refractory CLL.[21]
What role, if any, alemtuzumab has in first-line therapy will become more clear once the results from 2 phase 3 trials are presented. Unfortunately, one of the studies, a trial from the French study[18] group comparing FCA with FCR in first-line therapy, was closed prematurely due to the higher toxicity observed in the FCA arm. In the other study, a first-line trial from the HOVON group, high-risk patients have been randomly assigned to receive either FC or FCA. Efficacy and toxicity results are awaited.
Ofatumumab has shown somewhat promising activity in patients with advanced CLL refractory to both fludarabine and alemtuzumab and in patients with fludarabine-refractory CLL inappropriate for alemtuzumab treatment.[22] Response rates in these populations were 58% and 47%, respectively. Consequently, it has raised interest for its potential as first-line therapy in patients with high-risk CLL. A phase 2 study presented at ASH 2009 assessed ofatumumab in combination with FC (FCO) in a high-risk, previously untreated CLL population.[23] OR was between 73% and 77%, with CR in 32% and 50% of patients (2 doses were assessed). These results were somewhat disappointing when compared with FCR, in particular with the high number of neutropenias observed for FCO in this trial. Ofatumumab does not seem to add much to current treatment options in CLL.
Lumiliximab showed a good safety profile with limited clinical activity in a phase 1 protocol.[24] Preliminary results of a phase 1/2 study evaluating lumiliximab plus fludarabine, cyclophosphamide, and rituximab (L + FCR) in 31 patients with relapsed CD23+ CLL demonstrated an overall response rate of 71%, with 48% CR, 10% PR, and 13% unconfirmed PR,[25] suggesting a possible improvement over the FCR regimen. However, an ongoing phase 3 study was closed early due to a lack of improvement over the FCR arm. It is unclear whether lumiliximab will have a role in CLL therapy.
Variations to FCR
The main drawback of FCR has been its myelotoxicity, particularly in elderly patients who have comorbidities. Therefore, variations on FCR have been investigated.
One such approach has been to use a dose-modified "FCR-Lite" regimen. This regimen -- which employs a reduced dose of the 2 cytostatic agents (fludarabine to 20 mg/m2 and cyclophosphamide to 150 mg/m2 days 2-4 during cycle 1 and days 1-3 in cycle 2-6) and an increased dose of rituximab (day 1 of cycle 1 at a dose of 375 mg/m2; cycles 2-6 on day 1 at 500 mg/m2 preceding chemotherapy and on day 14 of each cycle) -- was investigated in a study of 50 untreated patients with CLL (median age, 58 years).[26] Maintenance rituximab at 500 mg/m2 was given every 3 months until progression. Responses were determined using the International Workshop on Chronic Lymphocytic Leukemia 2008 guidelines.[27] In the study, the CR rate was 77%, with an OR rate of 100%. At a median follow-up of 2.4 years, all complete responders remained in CR, except for 1 patient who died of a myocardial infarction while still in remission. Five patients with PRs died within 2 years of completing FCR-Lite. Grade 3/4 neutropenia was documented in only 13% of cycles, a lower rate than that observed with the usual FCR regimen. With its lower toxicity but maintained efficacy, this regimen appears promising. However, it requires further testing in larger trials.
Another attempt at lowering the toxicity of FCR involved the substitution of pentostatin for fludarabine in FCR (a regimen known as PCR). A phase 3 randomized trial[28] of FCR vs PCR in previously untreated and minimally treated CLL patients revealed no statistical differences between treatments in OS or response. However, there also were no significant differences in infection rate (fever > 101° F requiring antibiotics) -- the primary endpoint of this study -- between the 2 arms (31% in FCR and 34% in PCR).
Conclusions
At the present time, when choosing treatment, there are 3 potentially relevant points to consider:- The physical condition (fitness and comorbidity) of the patient (independent of calendar age);
- The prognostic risk of the leukemia as determined by genetic and other prognostic factors; and
- The Rai or Binet stage of the disease.
This activity is supported by an independent educational grant from Cephalon Oncology.
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