BACKGROUND: Despite excellent outcomes in pediatric ALL, multiply relapsed patients have response rates ∼40%, with <10% OS in CR3.(Gaynon, BJH 2005) The prognosis for relapsed or refractory AML is ∼20% OS.(Wells, JCO 2003) Novel combinations with improved outcomes are needed. Clofarabine and Mitoxantrone have proven efficacy in children with leukemia and offer possible synergistic activity in vivo with less drug resistance.(Chow, Leukemia & Lymphoma 2000)

OBJECTIVES: To determine the maximal tolerated dose and overall response rate of clofarabine in combination with mitoxantrone as reinduction therapy for refractory/relapsed acute leukemia. To determine the percent of minimal residual disease (MRD) following reinduction.

DESIGN: Prospective, open label, uncontrolled, safety and efficacy study. Patients 0-30.99yr old with ALL, AML or NHL in 1st, 2nd or 3rd relapse OR primary induction failure were 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. Dexrazoxane was given prior to Mitoxantrone. Dose escalation was planned every 3 patients pending dose limiting toxicities. CNS prophylaxis was achieved with intrathecal liposomal cytarabine. Patients were allowed subsequent cycles pending response and anthracycline exposure.

RESULTS: To date 17 patients have been enrolled on the Phase I safety portion of this study. Median Age is 13yrs (8months-23yrs); 11 ALL (3 = Induction Failure, 6 = Relapse1, 2 = Relapse2), 5 AML (4 = Induction Failure, 1 = Relapse2), 1 NHL ( = Progressive Disease). There have been 2 prolonged Grade III/IV toxicities at Dose Level 4 (Clofarabine 40mg/m2) (1 hepatic toxicity, 1 prolonged myelosuppression) hence additional patients were enrolled at Dose Level 3 (Clofarabine 35mg/m2). Median time to neutrophil recovery was 24 days. Fourteen of 16 (88%) evaluable leukemia patients achieved a CR after 1 cycle of therapy. Of these patients, 94% achieved MRD negativity (<0.1%). Two patients with relapsed ALL had no response. One patient with relapsed/refractory NHL had progressive disease after 2 cycles. Thirteen of 14 patients achieving CR went on to receive an allogeneic HSCT with continued remission at a median follow up time of 275 days (range 40-634). Overall 1 year survival for leukemia patients is 78.7% (CI95: 47.2-92.5).

CONCLUSION: The combination of clofarabine and mitoxantrone reinduction therapy for relapsed or refractory acute leukemia appears to be safe and well tolerated in children, adolescents and young adults with poor risk hematologic malignancies. The Phase I MTD of this combination was found to be 35mg/m2 Clofarabine. Hematopoietic recovery appears to be rapid and complete. Initial data from the first 17 patients enrolled is encouraging with an 88% CR rate in leukemic patients. An extended multicenter Phase II Study is ongoing.

Citation Format: Jessica Hochberg, Javier Oesterheld, Olga Militano, Liana Klejmont, Lauren Harrison, Berkley Nickerson, Mitchell S. Cairo. Phase I results of mitoxantrone in combination with clofarabine in children with refractory/relapsed acute leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3203.