A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia patients: final results of the GIMEMA LAL1509 protocol

The GIMEMA LAL1509 protocol, designed for adult (≥18-60 years) de novo Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) patients, was based on dasatinib plus steroids induction - with central nervous system prophylaxis - followed by dasatinib alone in patients in complete molecular response or by chemotherapy and/or allogeneic transplant in patients not reaching complete molecular response. Sixty patients (median age 41.9 years) were enrolled: 33 were p190+, 18 p210+ and nine p190/p210+. At the end of induction (day +85), 58 patients (97%) achieved complete hematologic remission. No deaths in induction were recorded. Eleven patients (18.3%) obtained complete molecular response. Among the incomplete molecular responders (n=47), 22 underwent an allogeneic transplant. Seventeen hematologic relapses occurred (median 7 months; range, 3-40.1): 13 during consolidation and four post-transplant. ABL1 mutations (five T315I, three V299L, one E281K and one G254E) were found in ten of 13 relapsed cases. With a median follow-up of 57.4 months (range, 4.2-75.6), overall survival and disease-free survival were 56.3% and 47.2%. A better disease-free survival was observed in patients who obtained a molecular response at day +85 compared to cases who did not. The presence of additional copy number aberrations - IKZF1 plus CDKN2A/B and/or PAX5 deletions - was the most important unfavorable prognostic factor on overall and disease-free survival (P=0.005 and P=0.0008). This study shows that in adult Ph+ ALL long-term survivals can be achieved with a total-therapy strategy based on a chemotherapyfree induction and, in complete molecular responders, also without further systemic chemotherapy. Finally, the screening of additional copy number aberrations should be included in the diagnostic work-up (clinicatrial gov. Identifier: EudraCT 2010-019119-39).