Chronic lymphocytic leukaemia (CLL) is the commonest type of leukaemia in adults. Its clinical course and overall prognosis vary considerably; although there is no standard curative treatment, patients can live for years or even decades in remission. Most patients need treatment intermittently, with periods of remission between treatments that lessen over time.

There is, at least currently, an unmet medical need for therapies that provide long remissions in patients with relapsed and refractory disease. However, good responses in these patients can be obtained using regimens that include chemoimmunotherapeutic agents. A combination of the purine analogue fludarabine, the alkylating agent cyclophosphamide, and the monoclonal antibody rituximab (FCR) is becoming a standard treatment. A group of researchers from the U.T. M. D. Anderson Cancer Center in Houston, Texas, USA, led by William G. Wierda has now reported the final results from a Phase II clinical trial designed to test long-term responses to FCR treatment in patients with relapsed and refractory CLL.

A total of 288 patients with active, progressive CLL who had undergone differing numbers and types of prior treatment regimens were enrolled in the trial between 1999 and 2008. All received up to six four-week chemotherapy courses, each course involving all three drugs. The primary aim of the study was to evaluate the complete response rate in comparison with earlier regimens comprising fludarabine and cyclophosphamide (FC) or fludarabine alone; overall survival (OS), progression-free survival (PFS) and time to progression (TTP) were secondary outcomes. A group of 114 CLL patients on a trial of fludarabine and cyclophosphamide (FC) as salvage therapy was included as a historical comparison.

Two months after completion of therapy, a total of 211 patients (74% of the total) achieved a complete or partial remission, with 30% (81 patients) achieving complete remission. For the whole cohort, the estimated median progressions free survival time was 21 months and the median overall survival time was 47 months; these values compare very well with historical data from CLL patients with similar characteristics, including the comparison cohort receiving FC. Not surprisingly, patients who achieved a complete remission had significantly better PFS and OS times than those who did not. Toxicity was generally mild or moderate; the most commonly reported side effect was neutropenia, and the main toxicities reported by patients who failed to complete all six treatment courses were myelosuppression and infection. These side effects were all more common in patients over the age of 70.

The detailed trial results showed that patients who had received three or fewer prior regimens; patients who had previously been exposed to purine analogues or antibodies but not to alkylating agents; those who had not previously shown resistance to fludarabine; and those with chromosomal abnormalities classed as “low-risk” achieved the best outcomes in terms of response rate, progression-free and overall survival. In particular, patients with abnormalities in chromosome 17, which are regarded as high-risk in CLL, had poor survival times. Other clinical and demographic characteristics that were predictive of good response included younger age, higher platelet counts and lower serum creatinine levels.

Wierda and his co-workers concluded that the FCR regimen is both safe and effective in treating relapsed and refractory CLL in a significant subset of patients with no high-risk features. It is less satisfactory in treating high-risk patients and those over the age of 70, and further research will be needed to determine a suitable regimen for these.

Reference

Badoux, X.C., Keating, M.J., Wang, X. and 8 others (2011). Fludarabine, cyclophosphamide and rituximab chemoimmunotherapy highly effective treatment for relapsed patients with CLL. Blood, published online ahead of print 18 January 2011.