A B S T R A C T PurposeImatinib mesylate is a targeted agent that may be used against Philadelphia chromosome-positive (Phϩ) acute lymphoblastic leukemia (ALL), one of the highest risk pediatric ALL groups. Patients and MethodsWe evaluated whether imatinib (340 mg/m 2 /d) with an intensive chemotherapy regimen improved outcome in children ages 1 to 21 years with Phϩ ALL (N ϭ 92) and compared toxicities to PhϪ ALL patients (N ϭ 65) given the same chemotherapy without imatinib. Exposure to imatinib was increased progressively in five patient cohorts that received imatinib from 42 (cohort 1; n ϭ 7) to 280 continuous days (cohort 5; n ϭ 50) before maintenance therapy. Patients with human leukocyte antigen (HLA) -identical sibling donors underwent blood and marrow transplantation (BMT) with imatinib given for 6 months following BMT. ResultsContinuous imatinib exposure improved outcome in cohort 5 patients with a 3-year event-free survival (EFS) of 80% Ϯ 11% (95% CI, 64% to 90%), more than twice historical controls (35% Ϯ 4%; P Ͻ .0001). Three-year EFS was similar for patients in cohort 5 treated with chemotherapy plus imatinib (88% Ϯ 11%; 95% CI, 66% to 96%) or sibling donor BMT (57% Ϯ 22%; 95% CI, 30.4% to 76.1%). There were no significant toxicities associated with adding imatinib to intensive chemotherapy. The higher imatinib dosing in cohort 5 appears to improve survival by having an impact on the outcome of children with a higher burden of minimal residual disease after induction. ConclusionImatinib plus intensive chemotherapy improved 3-year EFS in children and adolescents with Phϩ ALL, with no appreciable increase in toxicity. BMT plus imatinib offered no advantage over BMT alone. Additional follow-up is required to determine the impact of this treatment on long-term EFS and determine whether chemotherapy plus imatinib can replace BMT.