Autologous Stem Cell Transplantation (ASCT) in CLL. Results of a Phase III Randomized Multicenter Trial.

We investigated, in a prospective randomized study, the place of ASCT in the frontline treatment of CLL.

From March 2001 to December 2007, 241 patients were included in the trial. Eligibility criteria were previously untreated stage B and C CLL patients under 66 years, characterized by Matutes score 4-5, absence of cyclin D1 expression, baseline flow assessment of ZAP 70 and CD38 expression, karyotype and FISH analysis, IgHv mutational status (centralized). Preceding randomization, initial chemotherapy consisted of 3 monthly courses of mini CHOP regimen as previously described, followed by 3 monthly courses of fludarabine, IV or oral. Patients achieving CR (NCI 1996 criteria plus normal CT scan) were randomized between observation and ASCT. Non CR patients were offered cisplatin/cytosine-arabinoside/dexamethasone (DHAP) rescue and randomized whatever the response between ASCT or 3 subsequent monthly IV courses of Fludarabine-Cyclophosphamide (FC). Conditioning regimen for ASCT consisted of cyclophosphamide IV (60 mg/sqm d-5-4) and fractionated total body irradiation (10 Gy). The primary end-point of the study was event-free survival at 3 years. Responses after initial treatment (i.e.before randomization) and after completion of therapy, overall survival, side effects, prognostic significance of clinical and biological characteristics at baseline were other endpoints.

Baseline characteristics were: gender (M/F: 3), age (median 56.4 years, range 33.3-66), stage B (185 patients) or C (56 patients). All enrolled cases but five (236 patients) started the treatment. Among them, 206 completed the six planned courses of initial chemotherapy. For the 236 patients, CR rate was 43.6%, and overall response was 89.8%. Forty two patients were not randomized because of treatment failure (19) or patient/physician decisions (23). After an observed median follow-up of 40.2 months (Q1-Q3, 17.9-47.9) at the reference date (1/1/2009), the overall survival for the 241 patients was 87.8% (95% CI, 83.3-92.6) at 3 years and 75.4% (95% CI, 66.2-88.6) at 5 years. For the 199 randomized patients, the overall survival was 90.9% (95% CI, 86.7-95.3) at 3 years. Among them 105 patients were in CR after initial treament and were allocated to ASCT (53 patients) or observation (52 patients) with a 3 years EFS of respectively 78.7% (95% CI, 67.7-91.4) and 31.3% (95% CI, 20.1-48.8) (p<0.00001). The median EFS from the start of the studied treatment was 26.2 months in the observation arm (not reached in the ASCT arm). Randomization (p=0.0001), mutational status (p<0.00001) and 11q deletion (p=0.001) remained independent prognostic factors for EFS in a multivariate analysis. There was no difference between ASCT and observation arms in terms of overall survival with 98% (95% CI, 94.3-100) and 97.5% (95% CI, 92.2-100)respectively. For the 94 patients not achieving CR and rescued with DHAP, the EFS at 3 years was 46.5% (95% CI, 33.6-66.3) in the ASCT arm (46 patients) and 43.2% (95% CI, 29.8-62.5) in the FC arm (48 patients). There was not statistical difference between these 2 arms but for the 34 patients actually autografted the EFS was 57.8% (95% CI, 41.7-80.2). The overall survival was not different for ASCT and FC arms: 81,2% (95% CI, 70.3-93.9) and 85,4% (95% CI, 75.1-97) respectively. In multivariate analysis, the only prognostic factor influencing the EFS (p=0.0001) and the overall survival (p=0.04) was the 17p deletion. The mutational status (non mutated) and the 17p deletion remained adverse prognostic factors in patients actually autografted. For the whole study, 28 patients allocated to ASCT did not receive this treatment mainly because of mobilisation failures (14 pts). Four MDS were recorded within the follow-up frame.

ASCT is a safe procedure which significantly improves response duration in patients attaining CR after a first line treatment. For patients not in CR, ASCT or consolidation with 3 FC courses provide similar results on response duration but ASCT could be considered in patients without 17p deletion or with mutated IGHV gene.

Van Den Neste:Roche: Research Funding.