Notwithstanding the improved results with first-line therapy, CLL remains incurable, and patients are destined to relapse after primary treatment. The management of relapsed CLL pts is then dependent on several factors, including age, performance status, previous therapy, response and duration of response to therapy, and time from last therapy. Currently, the optimal treatment for pts with relapsed disease is not known. Bendamustine (BEN) demonstrated clinical activity in pre-treated hematological malignancies due to its unique mechanism of action distinct from standard alkylating agents. Alemtuzumab (CAM) is active in previously treated pts with CLL refractory to alkylating agents and purine nucleoside analogs. We designed a multicentric, single arm, dose escalation study to determine maximum tolerated dose (MTD) and to evaluate the efficacy and safety of Ben Cam combination in refractory/relapsed CLL pts.
Previously treated CLL pts requiring therapy were enrolled. In the first part of the study, the tolerability of a stepwise dose-escalation schedule of BEN along with an increasing dose of CAM has been determined. BEN was given at a starting dose of 50 mg/sqm for 2 consecutive days along with CAM 20 mg sc on days 1 to 3; if MTD was not reached within the 1st cohort, the 2nd cohort received an increased dose of CAM 30 mg with a subsequent further increase of BEN 70 mg/sqm if MTD was not reached. Treatment was repeated every 28 d up to 4 course. If one of 3 pts at each dose level experienced DLT three additional pts were added (max 6). If 5 of the 6 subjects were able to complete the first 2 courses without experiencing DLT, this level was considered tolerable and dose-escalation continued initiating the following cohort.
Between July 2008 and March 2012, 50 pts with previously treated CLL requiring therapy according to IWCLL criteria were enrolled in 9 Italian centres. The median age of our population was 67 years (range 46–82), 64% were male and all pts presented with Binet stage B or C. Pts' population was characterized by high risk biological and clinical disease profile: 44% were in Binet stage C, bulky lymph nodes were present in 24% of pts, refractory pts represented 26% of our population. According to hierarchical model, del17p was present in 28% and del11q in 24%; 66% were IGVH unmutated, 40% ZAP70+ and 36% CD38+. Median number of prior regimens was 2 (range, 1–4): 84% had previously received fludarabine-based treatment and 70% monoclonal antibodies in monotherapy or in combination. Twelve pts have been enrolled in the Phase I of this trial: 3 pts in each of the first 2 cohorts, 6 in the third cohort. BEN 70 mg/sqm and CAM 30 mg sc resulted as the MTD. Median number of courses administered was 4 (range, 1–4), 72% of pts completed treatment program being progression the major cause of discontinuation. At the time of writing 43 pts (86%) are evaluable for response, evaluation is pending in 7 pts who completed in all cases treatment program. Overall response rate resulted of 70% including 26% of CRs and 44% of PRs; 18% of pts maintained a stable disease; 12% showed a progression. Significant difference in response rate (P=0.009) was observed among pts with relapsed versus refractory disease. Previous treatment and unfavourable biological features did not affect response achievement. None of the variables considered showed to be significant in reaching a CR. In the whole series of treated pts grade III-IV hematological toxicity was: neutropenia in the 33% of courses, thrombocytopenia and anemia in 7 and 4% respectively. Febrile neutropenia developed in the 15% of courses. CMV reactivation occurred in 10% of courses without any organ involvement. We recorded 8 major infections: 3 sepsis, 4 pneumonias and 1 enteritis. Extra-hematological toxicity was mild. Median time to progression in responders was reached after a median follow-up of 15,5 months.
Analysis of results data collected on 43/50 pts treated with 4-weekly dosing BENCAM regimen suggests that this combination is effective in relapsed and refractory CLL pts, most of them carrying adverse prognostic factors. Hematologic toxicity was the only serious adverse event observed with a manageable myelosuppression. Major infections recorded were not superior in quantity and quality to those observed using other immuno-chemotherapeutic regimens in the same setting. No toxic deaths were recorded while on treatment.
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.