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 chemotherapy-free 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.