Impact of dose intensity on outcome of fludarabine, cyclophosphamide, and rituximab regimen given in the first-line therapy for chronic lymphocytic leukemia

Efficacy and safety of front-line therapy with fludarabine-cyclophosphamide-rituximab regimen for chronic lymphocytic leukemia outside clinical trials: the Israeli CLL Study Group experience

“…Interestingly, CR rates and PFS were also considerably higher in the only other study evaluating FCR outside of a clinical trial (CR+CRi of 99% and median PFS of 56 months) performed by Bouvet et al 11 These differences could be in part due to a patient population with milder disease [Binet stage C in only 18%, compared to 36% in our study and no patients with del(17p)] and exclusion of patients who did not complete six cycles of therapy. 11 Finally, in all the aforementioned studies, including ours, the median survival was not reached at six years, and the most common causes of death were infections and secondary malignancies. These observations reinforce the expected prolonged survival in CLL patients treated by FCR, but also suggest that outcomes may be poorer when administering FCR in the "real-life" setting as opposed to in a clinical trial.…”

“…Of note, previous studies of FCR employing the IWCL2008 response criteria for general practice showed similar response rates. 8,11 Regarding PFS, the median of our population (42.5 months) was lower compared to the clinical trial experience of CLL8 (51.8 months) and MDACC (approx. 80 months).…”

“…They too demonstrated a considerably reduced PFS in these patients. 11 Likewise, patients who received reduced doses generally had more severe disease and more comorbidities (as evident by a higher rate of Binet stage C and a reduced creatinine clearance). It is noteworthy that, in our study, reduced dose retained its statistical significance even after controlling for these covariates in a multivariate analysis.…”

“…This is contrary to previous retrospective studies that demonstrated a PFS benefit for higher doses of the drug. 11 In this respect, the optimal dose of rituximab in combination with chemotherapy has not been prospectively tested in CLL. Rituximab at a dosage of 500 mg/m 2 was empirically chosen on the basis of early studies of monotherapy which demonstrated that dose escalation to greater than 375 mg/m 2 resulted in better overall responses.…”

“…10 As a result, outside of formal clinical trials, patient adherence to the protocol is often compromised, and treating physicians are frequently tempted to decrease drug doses or reduce the number of treatment cycles. 11 Furthermore, the therapeutic concerns about toxicities become more problematic in older patients with comorbidities and renal dysfunction who have been under-represented in earlier clinical trials. Thus, there may be significant differences in outcome in patients treated with FCR within the framework of a clinical study when compared to patients treated in everyday life.…”