Background: Despite excellent outcomes in pediatric ALL, multiply relapsed patients have low response rates and low OS. The prognosis for relapsed/refractory AML is also poor. Clofarabine and Mitoxantrone have proven efficacy in children with leukemia and offer possible synergistic activity. Objective: To determine the maximal tolerated dose and overall response rate of clofarabine in combination with mitoxantrone as reinduction therapy for refractory/relapsed acute leukemia. Methods: Patients 0-30.99yr old with ALL, AML or NHL in relapse OR induction failure were given clofarabine (escalating doses 20, 30, 35 and 40mg/m²/day) Day 1-5, in combination with mitoxantrone 12mg/m²/day on Day 3-6. Dose escalation 3+3 design. CNS prophylaxis with intrathecal liposomal AraC. Patients allowed up to 3 cycles pending response and anthracycline exposure. Results: A total of 18 patients. Median Age is 13yrs (8months-23yrs); 11 ALL (3 = IF, 6 = Relapse 1, 2 = Relapse 2), 6 AML (4 = IF, 1 = Relapse 1, 1 = Relapse 2), 1 NHL (PD). There were 2 Grade III/IV toxicities at Dose Level 4 (Clofarabine 40mg/m2) (1 hepatic toxicity, 1 prolonged myelosuppression) hence 3 additional patients were enrolled at Dose Level 3 (Clofarabine 35mg/m2). Median time to neutrophil recovery was 24 days. Fourteen of 17 (82%) leukemia patients achieved a CR after 1 cycle of therapy. Of these, 93% achieved MRD negativity ( < 0.1%). Thirteen of 14 patients achieving CR went on to receive alloHSCT with continued remission at a median follow up time of 444 days (range 73-761) with a 1 year OS 64.2% (CI95: 36.8-82.2). Conclusions: The combination of clofarabine and mitoxantrone reinduction therapy is safe and well tolerated in children, adolescents and young adults with poor risk hematologic malignancies. The Phase I MTD of this combination has been established at 35mg/m²/dose Clofarabine. Efficacy data from the Phase I portion is encouraging with an 82% CR rate, 93% negative MRD and 64% 1 year OS in these high risk acute leukemia patients. An extended multicenter Phase II Study is ongoing. Clinical trial information: NCT01843672.