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

Background. Fludarabine-cyclophosphamide-rituximab is the most efficient first-line treatment for chronic lymphocytic leukemia patients. Many dose adjustments of the original MD Anderson Cancer Center regimen have been proposed. However, whether fludarabinecyclophosphamide-rituximab relative dose intensity may impact outcome has not been investigated before. Design and Methods. We retrospectively assessed relative dose intensity in 106 communitybased patients, included in our regional healthcare network from 2004-11, all receiving fludarabine-cyclophosphamide-rituximab first-line outside a clinical trial. Results. Dose reductions were noticed in 51.4% of patients, mainly due to physician’s individual decision not based on recommendation (52.7%) while documented toxicity or dose reduction because of impaired renal function played lesser roles. Progression-free survival was significantly reduced in patients who had a reduction of dose intensity greater than 20% in fludarabine-cyclophosphamide and/or rituximab. On multivariate analysis, dose of rituximab has significant impact on minimal residual disease and progression-free survival. Though prophylactic granulocyte-colony stimulating factor significantly reduced the rate of grade 3-4 neutropenia and febrile neutropenia, it had no impact on relative dose intensity and outcome. Conclusions. This study shows that, in routine clinical practice, the adherence rate to the original MD Anderson Cancer Center fludarabine-cyclophosphamide-rituximab schedule is low, mostly due to individual physician’s decision based on anticipated toxicity. This study shows that reduction of fludarabine-cyclophosphamide and, more importantly, of rituximab doses seriously interfere with progression-free survival. DOI: 10.3324/haematol.2012.070755