Combined Cyclophosphamide, Fludarabine, Alemtuzumab, and Rituximab (CFAR) Is Active for Relapsed and Refractory Patients with CLL.
Authors: Wierda William , Faderl Stefan , O’Brien Susan , Cortes Jorge , Ferrajoli Alessandra , Giles Francis , Andreff Michael , Koller Charles , Kantarjian Hagop , Keating Michael 
Published: October 2019

New combination regimens for patients with chronic lymphocytic leukemia (CLL) aim to improve complete remission (CR) rates and eliminate minimal residual disease detectible by flow cytomoetry or molecular (PCR) techniques in order to prolong progression-free and overall survival. The complete and overall (OR) response rates to single-agent fludarabine (F) in large phase II studies of previously treated patients with CLL are 12% and 50%, respectively. These rates are improved to 25% CR and 73% OR with chemoimmunotherapy combining F with cyclophosphamide (C) and rituximab (R) (FCR). With FCR, approximately a third of patients achieving CR are rendered negative in bone marrow for the clonal Ig gene by PCR (molecular remission). Alemtuzumab (A) has activity in treating F-refractory patients and in eliminating minimal residual disease. In this phase II study we combined A with FCR (CFAR) to improve response rates and survival in previously treated patients. The CFAR regimen consists of C-250mg/m2 d3-5; F-25mg/m2 d3-5; A-30mg d1,3,5; and rituximab 375–500mg/m2 d2, each 28 days for 6 intended cycles. Methylprednisolone (125mg) on d1 and hydrocortisone (50mg) d2,3,5 are given each course for mAb premedication. Allopurinol 300mg daily is given for tumor lysis syndrome prophylaxis. Antibiotic prophylaxis is TMP-SMX DS twice daily 2–3days/week and valacyclovir 500mg daily, both through all 6 cycles and for 2 months after completion of treatment. CMV antigen in blood is done before each course for monitoring. To date, 31 patients have been enrolled, 21 are evaluable for response, 2 patients are inevaluable, and there was 1 early death. Evaluable patients (17 males) have the following characteristics [median (range)]: age 58yr (46–72), WBC 41K/μl (2–220), HGB 11gm/dl (7.7–14.1), PLT 90K/μl (14–349), β2M 4mg/l (2.5–11.3), and # prior treatments 4 (1–8). Thirteen (62%) and 10 (48%) were refractory to alkylator and F therapy, respectively. Nineteen (90%) and 6 (29%) previously received R and A, respectively. Eleven (52%) previously received FCR and 2 (9%) previously underwent allo-/auto-SCT. At enrollment, 8 (38%) had unfavorable cytogenetics (17p-, 11q-, or complex) by metaphase karyotype. The CR, PR, and OR rates by NCI-WG criteria for these 21 patients were 14%, 38%, and 52% respectively. Five of 8 PRs were categorized as such due to prolonged cytopenia and had no morphologic or flow cytometry evidence of disease. All patients achieving CR were negative for residual disease in bone marrow by 2-color flow cytometry. The median number (range) of CFAR cycles administered were 3 (1–6). Twelve of 21 are currently alive with a median follow-up time of 21 mo. The most common non-hematologic toxicities were grade 1–2 and in order of frequency included fatigue, fever, rash/hives, nausea, URI symptoms, and sinusitis. Grade 3–4 toxicities were much less common and consisted of nausea/vomiting, fever/chills, fatigue, mucositis, consitipation, arthralgia, pneumonia, and shortness of breath. Grade 3 and 4 neutropenia occurred in 23% and 39% of 70 evaulable courses, respectively. Grade 3 and 4 thrombocytopenia occurred in 23% and 16% of 70 evaluable courses, respectively. CMV reactivation was noted in 5/21 of evaluable patients, all cases responded to therapy. This study is ongoing. Early analysis of relapsed or refractory patients with CLL treated with CFAR indicates that this is an active regimen that is well tolerated with expected toxicities.