Post-Remission Therapy with Imatinib and HAM Improve MRD before Tansplant for Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ALL): Results of the GRAALL AFR03 Study.

Combination of Imatinib with chemotherapy has been reported as very promising for patients with Ph+ ALL. In this study, we attempted to minimize the MRD (Minimal Residual Disease) level before transplant for Ph+ ALL by combining Imatinib with HAM (HAMI). This regimen consisted to Cytarabine 2g/m²/12 hours between day1 and day4, Mitoxantrone 10mg/m²/day between day1 and day3 combinated with Imatinib (3 different doses) between day1 and day45. MRD was studied by RT-PCR at day1 (before treatment) and day45 (after treatment) and was exprimed by BCR-ABL/ABL levels. Between April 2002 and September 2005, 36 patients in complete remission (CR) after induction chemotherapy have been analysed. This group consisted of 13 females and 23 males with a median age of 42 years (19–60). Three doses of Imatinib (400 mg, 600 mg and 800 mg/day) have been tested for six patients in each cohort (the first eighteen patients). After an intermediate analysis, the dose of 800 mg per day has been shown to be toxic (one grade IV hypokaliemia), and a last cohort of 18 patients were treated with 600 mg/day. No toxic-death related to HAMI regimen was reported. Thirthy-one patients could be studied for MRD before and after HAMI consolidation. Four patients were in molecular remission (level of BCR-ABL/ABL<10⁻⁵) before treatment and 12 after. No difference between 3 cohorts of dose was observed. The median level of MRD was 10⁻³ (0–0.7) and 3 × 10⁻⁵ (0–0.004) before and after treatment respectively (p=0.0015). After a median follow-up of two years and for all patients, the estimated overall survival (OS) and disease free survival were respectively of 71% (51%–84%) and 52% (32%–69%). The cumulative incidence of relapse and the cumulative incidence of death in CR were respectively of 15% (6%–32%) and 31% (17%–52%). Twenty patients had allogenic matched transplantation (thirteen related, seven unrelated) and composed the group with donor. In this first group, seven patients obtained MRD negativity after HAMI treatment. The others sixteen patients composed the second group of patients without donor or older than 55 years. In this second group, eleven patients received autologous stem-cell transplant followed by imatinib for nine of them, and five received imatinib in maintenance with or without chemotherapy. In this group, six patients had obtained MRD negativity after HAMI. The two-years OS was identical for patients with or without donor (71%). In conclusion, imatinib combined with high dose chemotherapy improved molecular remission before transplantation and lead to an improve outcome.