Salvage Therapy with Combined Cyclophosphamide (C), Fludarabine (F), Alemtuzumab (A), and Rituximab (R) (CFAR) for Heavily Pre-Treated Patients with CLL.
Authors: Wierda William G. , OBrien S. , Ferrajoli A. , Faderl S. , Koller C. , Giles F. , Cortes J. , Thomas D. , Ravandi F. , Garcia-Manero G. , Andreeff M. , Lerner S. , Kantarjian H. , Keating M. 
Published: April 2020

Abstract
The availability of new and active agents for treatment of patients with CLL has led to an evolution in treatment from single-agent to combination regimens, resulting in improved response rates and possibly survival. The focus in developing new treatment regimens is to attain as high a complete remission (CR) rate as possible and to eliminate residual disease in bone marrow. The FCR regimen has significant activity in both chemotherapy-naïve and previously treated patients with CLL. Historic comparisons suggest a survival advantage for previously treated patients treated with FCR compared with F or FC. We combined alemtuzumab (A) with FCR to enhance the potentiation of mAb and chemotherapy in a phase II clinical trial for previously treated patients with CLL. The CFAR regimen consists of C-250mg/m2 day 3–5; F-25mg/m2 days 3–5; A-30mg days 1,3,5, and R-375–500mg/m2 day 2, each 28 days for 6 intended cycles. Methylprednisone 125 mg on day 1 and hydrocortisone 100 mg on days 2, 3, 5 were given with each course for mAb premedication. Allopurinol 300 mg daily was given for tumor lysis prophylaxis. Antibiotic prophylaxis was TMP-SMX DS twice daily 2–3 days/week and valacyclovir or valgancyclovir through all 6 cycles and 2 months after completion of treatment. Blood CMV antigen was monitored before each course. To date, 66 patients have been enrolled. There are 44 evaluable patients; 35 were male, 24 had Rai high-risk disease, the median # of prior treatments was 4 (1–9), 36% were fludarabine-refractory, 91% received prior R, 20% prior A, 16% had prior FC, and 48% had prior FCR. Pre-treatment karyotype of bone marrow cells was done in 38, 17 had complex abnormalities (7=17p-; 7=11q-); 16 were diploid. The median age=58yrs(41-79), ALC=428k/μL(.04–320), HGB=11.9g/dL(8.2–15.4), PLT=126k/μL(14–349), and β2m=4.5mg/L(2.5–11.3).
The CR, PR, and OR rates for the 44 patients were 27%, 38%, and 65%, respectively. There were 2 early deaths and 2 could not be evaluated for response. Higher CR and OR rates were seen in fludarabine-sensitive patients. Higher OR but not CR rate was seen in earlier-stage patients. Elimination of minimal residual disease by flow cytometry (&lt;5% CD5/19+) occurred in 92% and 50% of patients achieved CR and PR, respectively. 38 patients completed 3 or more cycles, 10 completed all 6 cycles. Myelosuppression was the most frequent reason for not receiving 6 cycles. Neutropenia, G3/4, occurred in 59% of cycles; thrombocytopenia, G3/4, in 29% of 156 evaluable cycles. Nearly all patients experienced at least one episode of G3/4 neutropenia and 57% experienced at least one episode of G3/4 thrombocytopenia. Infection was associated with 26% of 156 treatment cycles, 5% were major, 17% FUO, 2% herpes simplex, and 10% minor infections. 8 patients experienced reactivation of CMV, all resolved with treatment. Non-hematologic toxicities were ≤G3 and included fatigue, nausea/vomiting, constipation, or cough. The estimated median time to progression for all responders was 19+ mo; 20+ mo and 10+ mo for patients achieving CR and PR, respectively. The estimated median survival for all patients is 16 mo, 27+ mo for CR, 15 mo for PR, and 7 mo for non-responders. The median follow-up time for all patients is 10.5 mos. This study is on going. In summary, CFAR is an active regimen that is well tolerated for heavily pre-treated patients with CLL.