Combined Cyclophosphamide, Fludarabine, Alemtuzumab, and Rituximab (CFAR), an Active Regimen for Heavily Treated Patients with CLL.

Chemoimmunotherapy is based on enhanced therapeutic activity with combined cytotoxics and monoclonal antibodies (mAbs); these regimens have demonstrated activity in patients (pts) refractory to chemotherapy and mAb alone. FCR is an active chemoimmunotherapy regimen for initial and salvage treatment of pts with CLL. Additionally, alemtuzumab, the mAb against CD52, is highly effective at clearing disease from bone marrow, the usual site of residual disease following purine analogue-based treatment. This formed the rationale for the CFAR regimen for previously treated patients with CLL. CFAR consists of C-250mg/m² d3–5; F-25mg/m² d3–5; A-30mg IV d1,3,5, and R-375–500mg/m² d2, each 28 days for 6 intended courses. Methylprednisone (125mg) on d1 and hydrocortisone 50mg on d2,3,5 were given for mAb premedication. Tumor lysis prophylaxis was allopurinol 300 mg/d for 7 d, course 1 only. Antibiotic prophylaxis was TMP-SMZ DS twice daily 2–3 d/wk and valacyclovir or valgancyclovir during treatment and for 2 months after completion. CMV antigen in blood was monitored before each course. To date, 79 pts have been registered on this trial, 74 have completed treatment, of whom, 59 were male. The median number of prior treatments=3(1–14); age=58(39–79)yrs; ALC=46(.04–320)K/μL; PLT=124(14–349)K/μL; HGB=11.7(8.2–15.5)gm/dL; and β2M=4.1(1.7–11.3)mg/L. Pts received a median of 3(1–6) courses. Of the 74 pts, 18 (24%) achieved CR, 2 nPR, 28 PR (OR=65%); 22 were non-responders, 1 could not be evaluated for response, and 3 were early deaths. Bone marrow was free of residual disease by 2-color flow analysis in 18/18 pts in CR, 1/2 in nPR, and 14/28 in PR. Of 40 pts with Rai high-risk disease, 25% achieved CR and 30% PR; of 34 with low-risk disease, 24% achieved CR and 53% PR. Among the 32 fludarabine-refractory pts, 13% achieved CR and 38% PR. Responses in pts with unfavorable cytogenetics [17p del (16), 11q del (15), complex (5), and 6q del (1)] included 14% CR and 50% PR; 44% of pts with 17p del responded. Of the 43 pts previously treated with FCR, 19% achieved CR, 37% PR; and for the 10 pts previously treated with FC, 10% achieved CR and 60% PR. Neutropenia, G3 and G4, occurred in 20% and 39% of 231 courses, respectively and thrombocytopenia, G3 and G4, occurred in 17% and 15% of 231 courses, respectively. CMV reactivation requiring treatment occurred in 12 pts, screening did not identify pts at risk for reactivation. The median follow-up time for all patients is 12 mo. The median time to progression for all responders is 26 mo, 32 mo for CR and 18 mo for PR pts. The median survival time for all patients is 19 mo, 35+ mo for CR, 18 mo for PR and 7 mo for non-responders. This regimen is also being evaluated as frontline treatment for pts with high-risk CLL. CFAR is an active regimen in heavily pre-treated patients with CLL, including those previously treated with chemoimmunotherapy.