Final results of CA180-372/COG AALL1122 phase 2 trial of dasatinib and chemotherapy in pediatric patients with newly-diagnosed Philadelphia chromosome positive acute lymphoblastic leukemia (PH plus ALL)

Abstract

Background and Aims: We administered EsPhALL chemotherapy plus dasatinib 60 mg/m 2 (starting day 15) at COG (North America and Aus- tralia) and EsPhALL (Italy and UK) sites. Patients (>1-17.99 years) with MRD 0.05% following induction Ib or MRD-positive follow- ing three additional high-risk (HR) chemotherapy blocks were allo- cated to CR1 HSCT. The remaining patients received chemother- apy plus dasatinib for 2 years. Only CNS3 patients received cranial irradiation. Methods: Enrollment was 109 patients (3/2012-5/2014); 3 were ineli- gible and received no trial therapy. Results: All 106 treated-patients achieved CR. With database lock 6/29/19, 48/106 had events including 38 relapses (24 marrow, 4 CNS, 4 marrow+CNS, 4 other, 2 marrow+other), 9 treatment-related deaths (7 in chemotherapy-assigned patients, 2 post-HSCT), and one malignancy. Nineteen (17.9%) patients met HSCT criteria, 15 (14.2%) received CR1 HSCT with 9 remaining event-free, 2 transplant-related deaths (6 weeks, 7 months), and 4 relapses (3 alive, 1 died). Among the four not transplanted, 2 were event-free, 1 relapsed and died, and 1 had an astrocytoma. The remaining 87 patients were assigned to chemotherapy plus dasatinib, with 47 remaining event-free. Seven died in CR1, 5 on-therapy (3 in HR3, 1 reinduction 2, 1 continuation) and 2 post-therapy (21 and 31 months). Thirty-three relapsed, 3 on-therapy at 16-23 months (all alive) and 30 post-therapy (18 12 months, 12 >12 months; 22 alive and 8 deceased). The primary toxicities were febrile neutropenia and infection; one chemotherapy patient discon- tinued dasatinib (allergy) and one discontinued post-HSCT (myelosup- pression). Conclusions: Dasatinib plus EsPhALL chemotherapy is safe and effec- tive in pediatric Ph +ALL. With only 14% of patients undergoing CR1 HSCT, as compared to 81% in the EsPhALL 2004 and 38% in the EsPhALL2010 imatinib trials, this trial demonstrates similar outcomes with 5-year EFS 54.6% (95% CI, 44.5-63.6) and OS 81.7% (95% CI, 82.8-87.9) versus 60.3%/71.5% in EsPhALL 2004, and 57%/71.8% in EsPhALL 2010