Phase I/II Trial of Mitoxantrone and Clofarabine in Children With Relapsed/Refractory Acute Leukemia

Author Type(s)

Faculty

Document Type

Abstract

Publication Date

2022

DOI

10.1002/pbc.29735

Journal Title

Pediatric Blood and Cancer

Department

Pediatrics

Second Department

Medicine

Abstract

Background: Despite excellent outcomes in pediatric leukemias, multiply relapsed or refractory patients have low response rates to reinduction therapy and low overall long-term survival. Clo- farabine and Mitoxantrone have proven efficacy in children with leukemia. Objectives: We sought to determine the safety and overall response rate in a Phase I/II trial of clofarabine in combination with mitoxantrone as reinduction therapy for refractory/relapsed pediatric leukemia. Design/Method: Prospective, Phase I/II study (NCT01842672). Patients 0-30.99yr old with ALL or AML with relapse OR induction failure given 1 to 3 cycles of clofarabine (escalating doses 20, 30, 35 and 40mg/m2/day) Day 1-5, in combination with mitoxantrone 12mg/m2/day on Day 3-6. CNS prophylaxis with intrathecal cytarabine. MRD was defined by flow cytometry (≥ 0.01%). Results: Total of 39 patients enrolled (18 Phase I, 21 Phase II). Median Age 13yrs (8months-23yrs). Demographics 23 ALL (9 = IF, 11 = Relapse 1, 3 = Relapse 2), 16 AML (8 = IF, 6 = Relapse 1, 2 = Relapse 2). During Phase I, there were 2 Grade III/IV toxicities at Dose Level 4 (1 hepatic toxicity, 1 prolonged myelosuppression). Median time to neutrophil recovery was 24 days. The Phase I MTD (RP2D) of this combination was established at 35mg/m2/dose Clofarabine. In Phase II one patient developed Grade IV prolonged myelosuppression. Thirty three of 39 (85%) leukemia patients achieved a CR after 1 cycle of therapy. Of these, 88% achieved MRD negativity. Thirty one of 33 patients achieving CR went on to receive alloSCT. One patient died prior to transplant. Seven patients died of transplant complications. One patient died of recurrent disease post-transplant. The remaining 24 patients continue to demonstrate complete remission with MRD negativity. The overall and event free survival at 1 year and 3 years for patients who responded to therapy is 85% (CI95 0.84-0.97) and 77% (CI95 0.64-0.98), respectively at a median follow up time of 48 months (range 4-95). Conclusion: The combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute pediatric leukemia has been demonstrated to be safe and well tolerated at a RP2D of 35mg/m2 Clofarabine in children with poor risk acute leukemias. Our response data is encouraging with 85% CR rate with high MRD negativity in leukemic patients allowing patients to safely proceed to AlloHSCT with a 3yr EFS and OS of 77%. Long term follow up and a successor trial is planned and ongoing.

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