Consolidation Therapy with Subcutaneous Alemtuzumab After Induction Treatment with Oral FC (Fludarabine and Cyclophosphamide) in Previously Untreated Patients Aged 65–70 Years with Advanced Stage Chronic Lymphocytic Leukemia (CLL): Final Results of a Phase II Study From the FCGCLL/WM,

Abstract 3900

Current treatment approaches in CLL aim at achieving the best clinical response without detectable minimal residual disease (MRD) in order to prolong the duration of response and potentially overall survival. Such a goal could be achieved by combining chemotherapy and monoclonal antibodies. This phase II trial was designed to evaluate the safety and the efficacy of alemtuzumab given as consolidation therapy after 3 courses of oral FC (F 40 mg/m² and C 250 mg/m² D1 to D3 every 4 weeks) in patients (pts) aged 65 to 70 years with previously untreated Binet stage B or C CLL. Pts who had achieved either complete response (CR) or partial response (PR) after FC were eligible for consolidation with alemtuzumab. Alemtuzumab was administered subcutaneously (SC) at the dose of 10 mg thrice a week for 8 consecutive weeks. CMV antigenemia was monitored every week and alemtuzumab should be discontinued in pts with more than 3 positive nuclei. Such stringent stopping rules for CMV reactivation, as well as the limitation of FC regimen to 3 courses and of the duration of alemtuzumab treatment to 8 weeks, were adopted in this trial targeting elderly patients in their first line treatment because of the severe infectious toxicities reported by others with similar strategies. MRD was evaluated by 6 color flow cytometry before, during and after alemtuzumab treatment and all samples were centralized in one center (RL & FC).

From June 2004 to January 2008, 55 patients with advanced (stage B or C) fully annotated CLL have been recruited in 14 french centers. Response to induction is evaluable in 51 of them (suicide before FC 1 pt and missing data 3 pts). A CR was achieved in 18 pts (34.6%) and a PR in 22 pts (42.3%) for an overall response rate (ORR) of 77% after 3 courses of FC. FC regimen was discontinued in 6 pts (progression 1 pt, renal carcinoma 1 pt, neutropenia 2 pts, PRCA 1 pt, myocardial infarction 1 pt) and a stable disease was observed in 5 pts. All the responding pts except two of them (onset of breast cancer in one CR pt and of lung carcinoma in one PR pt) proceeded to alemtuzumab consolidation after a planned 2 month period of rest (median 63 days, range 33 to 152). Alemtuzumab treatment was fully completed in 29/38 pts (76%) while it has been stopped prematurely (mainly between the 6th and 8th weeks) in 9 pts (24%). CMV reactivation occurred in 8 pts (21%) but it was associated with systemic symptoms in only one case (febrile pneumonia). A grade 3–4 neutropenia was observed in 9 pts at some point during alemtuzumab treatment. Eleven of the 21 PR pts (52%) converted from PR to CR after alemtuzumab consolidation while 2 patients went down from CR to PR. Overall, 26 pts were in CR after the whole treatment strategy (FC followed by alemtuzumab) accounting for 51% of the entire cohort. Blood MRD could be assessed sequentially in roughly two thirds of pts. While all patients but one (33/34 pts) were MRD positive after chemotherapy and before alemtuzumab treatment, only 8/22 pts (36%) had detectable MRD at the sensitivity level of 10-4 after the end of alemtuzumab consolidation, and 12 out of the 25 assessed pts (48%) still had undetectable MRD at 6 months after the end of treatment. With a median follow up of 34 months (range 2 to 58), only 6 out of the 38 pts (16%) who received FC followed by alemtuzumab consolidation, had CLL disease progression. Five patients have died but only one from CLL (solid tumors 3 pts, stroke 1 pt). No serious delayed infectious complication was observed and two patients developed auto-immune cytopenia (AIHA 1 pt and ITP 1 pt). Because of the few number of events (disease progression) observed so far, no correlation between the duration of response and the MRD data could be done by now.

In conclusion, three courses of FC only yielded a rather high response rate in previously untreated elderly CLL patients and a short (8 weeks) alemtuzumab consolidation course could thereafter be administered safely, leading to a high rate of PR to CR switches, a high proportion of patients with undetectable blood MRD after the end of treatment and durable responses.