Combined Chemotherapy Improves CLL Outcomes but Not Survival

SUTTON, England, July 20 -- Progression-free survival in chronic lymphocytic leukemia was extended significantly over monotherapy by combining fludarabine and cyclophosphamide, found an international study.
But five-year overall survival with the combination over fludarabine or chlorambucil monotherapy did not improve, Daniel Catovsky, M.D., of the Institute of Cancer Research here, and collaborators, in eight countries reported in the July 21 issue of The Lancet. The complete response rate was also significantly improved.
In a multicenter trial, five-year progression-free survival was 36% with the combination versus 10% for fludarabine or chlorambucil alone (P=0.00005), the investigators found.
The chemotherapy doublet led to complete responses in 38% of patients, more than double the number with fludarabine alone (P<0.0001) and five-fold more than with chlorambucil (P=0.006). Overall response rates also were significantly higher.
The combination was superior to monotherapy in all age groups and in prognostic groups defined by gene mutations and cytogenetics. However, overall survival, the primary endpoint of the trial, did not differ among treatment groups.
"Fludarabine plus cyclophosphamide should now become the standard treatment for CLL and the basis for new protocols that incorporate monoclonal antibodies," concluded the team.
Previous studies had shown that fludarabine plus cyclophosphamide resulted in a high response rate in CLL, but whether the combination offered a survival benefit compared with monotherapy remained unknown.
Investigators at 136 centers in eight countries randomized 777 previously untreated CLL patients in a 1:1:2 ratio to six courses of fludarabine or fludarabine plus cyclophosphamide for six courses or to 12 courses of chlorambucil. The primary endpoint was overall survival, and secondary endpoints were response rate, progression-free survival, toxicity, and quality of life. The primary statistical comparisons were combination therapy versus fludarabine alone and fludarabine versus chlorambucil.
After a median follow up of 41 months the overall response rate with the combination therapy was 94% compared with 80% for fludarabine alone (P<0.0001) and 72% for chlorambucil (P=0.04).
Patients randomized to the combination had a five-year survival of 54% compared with 52% with fludarabine alone and 59% with chlorambucil. Median survival was 43 months with the duo, 23 months with fludarabine, and 20 months with chlorambucil.
Immunoglobulin heavy chain gene (VH) mutation status and cytogenetics were assessed in more than 500 patients, and combination therapy resulted in the best outcomes for prognostic groups defined by those tests. Patients older than 70 also derived greater benefit from the duo than from either monotherapy.
They noted that although fludarabine and cyclophosphamide was a superior treatment overall, the combination did not effectively overcome the short progression-free survival in patients with a 17p13 deletion on FISH analysis. For this reason, they wrote that "fludarabine plus cyclophosphamide cannot, however, be recommended for poor-risk patients (6% in this study) characterized by 17p (p53) deletion, since they are unlikely to respond well to this combination."
Combination therapy was associated with more neutropenia and hospital days but less hemolytic anemia compared with monotherapy. Quality of life was better in patients who responded to therapy, but a preliminary analysis of the data showed no differences between groups.
Dr. Catovsky and colleagues performed a meta-analysis that included data from the current trial and from two previous comparisons of combination therapy and fludarabine monotherapy. The analysis revealed a consistent benefit for progession-free survival with fludarabine plus cyclophosphamide.
They pointed out that the absence of survival differences, despite the better responses and progression-free survival with fludarabine plus cyclophosphamide than with other combinations, relates to the effect of second-line treatments. Patients receiving the less effective treatment first are more likely to respond better than are those who receive it second.
In a commentary, Tait D. Shanafelt, M.D., and Neil E. Kay, M.D., of the Mayo Clinic in Rochester, Minn., pointed out that the Catovsky study is the first large clinical trial to examine response rates according to molecular risk variables. The results hint at the possibility of tailored therapy and emphasize the need for additional trials to evaluate therapy in specific CLL subgroups.
The results of this trial and of the meta-analysis should not be interpreted as showing that treatment had no impact on survival, Drs. Shanafelt and Kay continued.
"[A] reasonable interpretation of the randomized trials for patients with CLL is that the sequence of treatment might not affect survival if all treatment options are available to patients with progressive disease as a salvage therapy," they wrote. "Indeed this trial provides additional evidence that response to second-line therapy confounds interpretation of overall survival in trials of first-line therapy for patients with CLL."
Several investigators disclosed commercial relationships. The study was supported by Leukemia Research UK, Schering Health Care and Schering AG. Primary source: The LancetSource reference: Catovsky D et al. "Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukemia (the LRF CLL4 Trialk): a randomized controlled trial." Lancet 2007;370:230-239.