Imatinib Combined with Intensive HAM Chemotherapy as Consolidation of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph1-ALL). Preliminary Results of the AFR03 Phase I/II Study.

Abstract

In a large series of patients with Ph1-ALL treated in the LALA-94 trial, negative BCR-ABL minimal residual disease (MRD) and allogeneic donor availability were two independent good-risk factors for survival in those reaching hematological complete remission (HCR) after standard induction followed by intensive HAM consolidation (Dombret et al. Blood2002;100:2357). The HAM regimen included intermediate-dose cytarabine (1 g/m2/12h Day 1 to 4) and mitoxantrone (10 mg/m2 Day 3 to 5). The fraction of HCR patients in molecular CR (MCR) after HAM was 38%, with a median RT-PCR sensitivity of 10−5. In the present Phase I/II study, we combined increasing dosages of imatinib with HAM (HAMI regimen) in an attempt: 1) to increase the fraction of MCR patients from 38 to 75% (as primary objective); and 2) to evaluate the safety of the combination regimen and the feasibility of autologous peripheral blood stem cell (PBSC) collection after HAMI (as secondary objectives). Patients aged 18–60 years with Ph1-ALL in HCR after 1 or 2 cycles of chemotherapy were eligible in the absence of counter-indication for further stem cell transplantation. Imatinib was administered daily from Day 1 of HAM. MRD was assessed by RQ-PCR at Day 0 and Day 45 of HAMI. MCR was defined as a BCR-ABL level lower than 10−5 at Day 45. Twenty-two patients have been enrolled. Results observed in the first 18 patients treated in 3 consecutive 6-patient cohorts at 400, 600, and 800 mg/d imatinib, respectively, are available. Main results may be summarized as follows: 1) an excessive toxicity was observed in the 800 mg/d cohort leading to recommend the 600 mg/d dosage for further combinations of imatinib and intensive chemotherapy; 2) only 5 of the 15 patients tested (33%) reached MCR at Day 45 of HAMI and no clear correlations were found between molecular response and imatinib dosage or Day 0 MRD level; 3) after HAMI, PBSC collection was feasible under imatinib administration in 9 out of 14 patients (64%) with an apparent relationship between failure to collect and no MCR (P=.08); 4) only 3 patients were not able to receive allogeneic or autologous transplantation as further consolidation (1 early relapse, 1 severe infection, 1 too high MRD level); and 5) estimated 18-month disease-free and overall survival were 58% and 78%, respectively, with 8/15 patients receiving imatinib during the post-transplant period. In conclusion, failure to improve the MCR rate as compared to our no-imatinib historical control could be explained by the relatively short exposure to imatinib and/or by the absence of in vivo synergism between imatinib and cytarabine or mitoxantrone. More benefit might be anticipated by incorporating imatinib earlier in the treament i.e. first induction course. Further studies are needed to evaluate the role of post-transplant maintenance with imatinib.