A SEQUENTIAL USE OF TKI, CHEMOTHERAPY AND TRANSPLANT IS ASSOCIATED WITH HIGH COMPLETE REMISSION RATES, DISEASE-FREE AND OVERALL SURVIVAL IN ADULT PH+ ALL. RESULTS OF THE GIMEMA 0904 PROTOCOL

Background: The clinical scenario of Ph+ ALL, considered the most aggres- sive form of leukemia, has changed profoundly following the introduction of 1st and 2nd generation tyrosine kinase inhibitors (TKI). In adult Ph+ ALL, TKI have been administered as part of the backbone of induction chemotherapy together with conventional drugs or, as in two earlier GIMEMA studies, alone in combination with steroids. The use of TKI has enabled high rates of complete hematological remissions (CHR), also in elderly patients. In the GIMEMA 0904 protocol, adult Ph+ ALL patients (≤60 years) were initially treated in induction and consolidation with Imatinib together with chemotherapy. This combination was associated with unacceptable toxicity and the protocol was amended. Imatinib was given as single agent, in combination with steroids, as induction therapy, while chemotherapy was added as consolidation. Aims: Aim of the study was to verify in adult Ph+ ALL the feasibility and efficacy of a sequential scheme based on an induction phase with Imatinib plus steroids, followed by a consolidation with chemotherapy plus Imatinib and, when applicable, by a transplant procedure. Methods: The steroid pre-phase was started from day -6, to allow central molecular screening, up to day 31. Imatinib (600 mg) was administered from day 1 to day 50. Patients who achieved a CHR received as consolidation therapy a cycle of HAM, without discontinuing Imatinib. HAM+Imatinib was planned also for non-responsive cases, followed by a further cycle of chemotherapy. Eligible patients received an allogeneic or autologous stem cell transplant (allo-SCT, auto-SCT). BCR-ABL1 transcript levels were normalized to the number of ABL1 control gene and expressed as a percentage of ABL1. Results: From July 2007 to April 2010, 51 patients have been enrolled; 23 were males and 28 females. The median age was 45.9 years (range: 16.9- 59.7) and the median WBC 28.0 ¥ 109/L (range: 1.4-597). Thirty-nine patients had a p190 fusion transcript, 7 a p210 and 5 had both. Two patients went offstudy for medical decision and toxicity, respectively. After the steroid pre- phase, 38 patients (79%) had a blast reduction ≥75%. At the end of induction (day 50), 47 patients (96%) had achieved a CHR, 1 had a partial response and 1 did not respond. After HAM, also the latter 2 cases obtained a CHR. No deaths in induction were recorded. Of the 43 patients who received HAM, 23 underwent a SCT procedure (20 allo-SCT, 3 auto-SCT), while 20 did not: so far, 3 relapses have occurred in the transplanted group (13%) and 8 in the non-transplanted group (40%). Disease-free survival (DFS) and overall survival (OS) at 36 months are 50.5% and 69.1%, respectively. SCT had no significant impact on DFS, while a trend was observed for overall survival OS (P=0.06). BCR-ABL1 transcript levels decreased during induction therapy, with a highly significant reduction (P<0.0001) between the onset and the end of induction. A further, non-significant, reduction was induced by HAM. Interestingly, a log reduction >1.3 at day 50 (end of induction) was associated with an improved DFS (P=0.03) and a decreased cumulative incidence of relapse (P=0.004). Summary and Conclusions: A sequential approach with Imatinib alone in induction, consolidated by chemotherapy plus Imatinib and followed by a SCT, is a feasible strategy for the management of adult Ph+ ALL patients. We confirm the very high CHR rates following induction with a TKI as single agent with steroids and no deaths in induction. This sequential therapeutic approach is associated with promising DFS and OS rates.