The US Intergroup Trial E2997 was a phase 3 trial comparing two first-line chemotherapy regimens in patients with previously untreated chronic lymphocytic leukemia (CLL). A total of 278 patients were randomized to receive fludarabine (F) or fludarabine plus cyclophosphamide (FC) (click here to read the abstract). Consistent with a German CLL Study Group (GCLLSG) Trial (see abstract here), the results demonstrated that FC was associated with higher overall and complete response rate.
Importantly, neither E2997 nor the GCLLSG trial found a difference in overall survival despite the improvement in response rates. Since then, FC has been replaced by FCR (FC plus rituximab) on the basis of even better response rates demonstrated in subsequent trials. The role of cyclophosphamide in the FCR regimen, however, has been somewhat controversial. On the basis of historical comparison between trials, proponents of FCR suggest that it likely induces higher response rates than FR, especially in the group of patients deletion of the 11q (a common chromosomal abnormality in CLL cells). Other investigators point out that cyclphosphamide is a toxic chemotherapy drug that has never demonstrated an ability to improve overall survival.
Adding to this controversy is a recent publication. Dr. Mitchell Smith and colleagues re-evaluated the E2997 trial with over six-years of follow-up data and found that patients who had been randomized to the FC arm were almost twice as likely to experience a myeloid neoplasia (e.g., acute myeloid leukemia or myelodysplastic syndrome). Genetic analyses of these cancers suggested that they were associated with cyclophosphamide exposure. Importantly, the overall risk of secondary cancer in either arm was small, and the difference was not statistically significant. Nonetheless, the results certainly highlight the uncertainty regarding optimal first-line regimens.
The US Intergroup Trial CALGB 10404 is a phase 3 trial comparing FCR to FR in patients with previously untreated CLL. Update July 2013: the trial is no longer open to patient enrollment.