CFAR, An Active Frontline Regimen for High-Risk Patients with CLL, Including Those with Del 17p.

High-risk patients (pts) with CLL can be identified by prognostic factors. Traditional prognostic factors that identify high-risk pts include Rai stage, absolute lymphocyte count (ALC), rapid lymphocyte doubling time, and serum beta-2 microglobulin (β2M). Del 17p is associated with loss of the tumor suppressor gene TP53. Patients with del 17p also tend to have mutations in TP53, thereby providing a second mechanism for complete TP53 knockout. Pts with del 17p have poor response to purine analogue-based treatments. β2M greater than twice the upper limit of normal (2XULN) was an independent high-risk feature for pts treated with the frontline fludarabine (F), cyclophosphamide (C), rituximab (R) regimen (FCR). Pts younger than 70 years with β2M >2XULN treated with FCR had a complete remission (CR) rate of 60% and median time to progression (TTP) of 70 months, compared to 84% and 86 months for pts <70 yrs old with β2M <2XULN. We evaluated the CFAR regimen (F 20mg/m² d3–5; C 200mg/m² d3–5; R 375–500mg/ m² d2; and Alemtuzumab 30mg d1,3,5 of each 4-wk course) as frontline treatment in a high-risk group of pts with CLL. The trial completed planned enrollment of 60 pts; 48 are currently evaluable for response and follow-up. In this high-risk group, 28% of the 48 evaluable high-risk pts had del 17p prior to treatment by FISH analysis. Overall, the CR rate for the 48 pts was 69%, 54% CR for the 13 pts with del 17p. The overall response rates were 94% and 77% for the 48 pts and 13 pts with del 17p, respectively. CFAR was associated with more myelosuppression and fewer pts could receive all 6 intended courses compared with the historic high-risk group treated with FCR. However, a higher proportion of CFAR pts had no evidence of residual disease in the bone marrow by 2-color flow cytometry evaluation at response assessment. There is currently no difference in TTP or OS, comparing CFAR and FCR in this retrospective historical analysis with a short median follow-up time of 16 months for the CFAR group. There was no significant difference in incidence of infection during treatment with CFAR compared to FCR, with the exception of CMV reactivation. The CFAR regimen is active and tolerated in the highrisk group of pts with CLL, including those with del 17p. Follow-up continues for the pts treated on this trial in order to evaluate responses in all 60 enrolled pts and to evaluate time-to-event endpoints and compare with the historic FCR experience.