Fludarabine, Cyclophosphamide, Rituximab for CLL
Abstract & Commentary
By Andrew Artz, MD, Division of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationships relevant to this field of study.
Synopsis: Tam et al report long-term data from 300 CLL patients treated with the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. Complete and overall response rates were 72% and 95%, respectively. The median time to progression was 80 months, and six-year overall survival was 77%. Late infection occurred in 10% after the first year of treatment, and almost 19% had persistent cytopenias after treatment. After adjusting for pre-treatment factors, FCR was associated with prolonged survival compared to other fludarabine regimens for initial treatment at the same center. The high activity and prolonged remissions suggest FCR as an excellent front-line regimen for CLL in select patients.
Source: Tam C, et al. Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood. 2008;112:975-980.
Chronic Lymphocytic Leukemia (CLL) has traditionally been considered an incurable disease, shy of allogeneic transplantation. In addition, complete responses and prolonged remissions were infrequent. The advent of more active agents, including purine analogues and antibody therapy, such as rituximab and alemtuzumab, has altered nihilistic perceptions of CLL therapy. For example, fludarabine plus cyclophosphamide induces a high response rate, although complete responses (CR) are only around 20-30%.1 The addition of the anti-CD20 antibody rituximab enhances response rates to fludarabine, or fludarabine and cyclophosphamide.2,3 In this report, Keating et al report on long-term data using the fludarabine, cyclophosphamide, and rituximab (FCR) combination.
Investigators at MD Anderson Cancer Center reviewed results from 300 patients 18 years and older receiving initial therapy for CLL on a phase II trial of FCR. Treatment entailed rituximab at 375-500 mg/m2 on day one combined with fludarabine 25-30 mg/m2 and cyclophosphamide 250-300 mg/m2 on days 1-3 of each course. Each cycle was repeated every four weeks, for a planned total of six courses. Responses were graded according to the NCI-WG 1996 criteria. The median age was 57 years, and 61% had either Rai stage I or II disease.
The overall response rate was 95% with 72% achieving a CR. Early death (n = 2) or induction resistance (n = 13) were infrequent. With a median follow-up for survivors of six years, six-year overall survival was 77% and progression free survival was 51%. Patients achieving CR had a median time to progression of 85 months.
Pre-treatment factors associated with lower CR rate were age 70 years and older (p = 0.02), elevated beta-2 microglobulin (p = 0.002), WBC > 150 K/uL (p = 0.02), and presence of chromosome 17 abnormalities (p = 0.01). Survival was adversely affected by these factors and elevated LDH. Older patients were much more likely to stop treatment earlier (79%) compared to younger adults (49%), primarily related to cytopenias, disease progression, or patient choice; early toxicity during treatment had been previously reported. Following completion of therapy, 19% of patients had persistent cytopenias lasting more than three months. The risk of serious infections was 10% during the first year of remission and 4% during the second year. Finally, Tam et al compared FCR to other fludarbine-based induction regimens for CLL. After adjusting for pre-treatment factors, FCR was associated with prolonged overall survival (p = <0.001).
Commentary
As the most common leukemia in western countries, management of CLL is a frequent concern of medical oncologists. The past decade witnessed the introduction of numerous agents and regimens offering enhanced activity, as evidenced by increased response rates. Purine analogs, especially fludarabine, have become the backbone of initial treatment for otherwise fit CLL patients. In a randomized study, the addition of cyclophosphamide to fludarabine improved CR rates from 4%-23%.4 By adding rituximab to the FC regimen (ie, the FCR regimen), phase II data from MD Anderson Cancer Center and others have demonstrated CR rates around 70%.3 However, long-term data and safety using this potentially more aggressive regimen have been lacking. The ideal initial regimen for CLL remains unknown.
In this series, Tam et al report on the long-term results using FCR. The responses were remarkable; overall and complete response rate were 95% and 72%, respectively. Median time to progression was 80 months, and six year overall survival was 77%. As expected, patients achieving CR had longer survival than those who did not. The present study was completed before routine use of techniques such as FISH or identification of IgVH mutation, and ZAP-70. However, traditional prognostic factors adversely impacted outcome such as age 70 years and older, elevated beta-2 microglobulin, and abnormalities of chromosome 17 by standard metaphase cytogenetics.
It is well-established that FCR is a highly myelosuppressive and immunosuppressive regimen. Confirming the myelosuppressive nature, persistent cytopenias occurred in 19% for three or more months after completion of therapy. In addition, Tam et al detail late toxicity, including serious or opportunistic infections, in 10% of patients after the first year of treatment and 4% in the second year. Lastly, 49% of patients in the under 70 cohort stopped treatment early. Most of the patients 70 years and older (79%) discontinued treatment early.
Compared to other patients at the same center treated with different fludarabine regimens, FCR was associated with improved survival after adjusting for pre-treatment prognostic factors. Tam et al conclude, "The FCR regimen has the highest CR rate, longest remission duration, and most favorable survival of frontline regimens for the treatment of CLL reported to date," leading them to suggest FCR should be considered the gold standard front-line regimen for CLL.
The response rates, remission duration, and survival data are provocative. Nevertheless, enthusiasm for this regimen must be tempered. Obviously, randomized, controlled studies would be ideal and should be forthcoming. The lack of a survival plateau curve indicates that most patients eventually relapse, suggesting maintenance strategies may be needed. The largest problem applying this data to clinical practice remains generalizability. We can assume patients eligible for this intensive treatment approach do not represent the typical CLL patient seen in practice. For example, the median age was 57 years and only 14% were over 70, whereas 70 years of age is the median age of diagnosis for CLL. Moreover, 97% of subjects had a performance status of 0 or 1. Secondly, the highly intensive nature of FCR mandates very close follow-up and aggressive infectious monitoring and prophylaxis that may be difficult in actual clinical practice.
For otherwise healthy CLL patients interested in aggressive therapy, the FCR regimen enables very high response rates, durable remissions, and might even prolong survival. Randomized trials will be required to conclude whether FCR improves long-term survival. The study raises a more challenging question about which patients should be given an aggressive regimen such as FCR.
References
1. Hallek M, et al. Fludarabine plus cyclophosphamide is an efficient treatment for advanced chronic lymphocytic leukaemia (CLL): results of a phase II study of the German CLL Study Group. Br J Haematol. 2001; 114:342-348.
2. Byrd JC, et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood. 2003;101:6-14.
3. Keating MJ, et al. Early results of a chemoimmuno-therapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23:4079-4088.
4. Flinn IW, et al. Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol. 2007;25:793-798.
Tam et al report long-term data from 300 CLL patients treated with the fludarabine, cyclophosphamide, and rituximab (FCR) regimen. Complete and overall response rates were 72% and 95%, respectively. The median time to progression was 80 months, and six-year overall survival was 77%. Late infection occurred in 10% after the first year of treatment, and almost 19% had persistent cytopenias after treatment. After adjusting for pre-treatment factors, FCR was associated with prolonged survival compared to other fludarabine regimens for initial treatment at the same center. The high activity and prolonged remissions suggest FCR as an excellent front-line regimen for CLL in select patients.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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