A Pilot Study of Mitoxantrone in Combination with Clofarabine (MITCL) in Children, Adolescents and Young Adults (CAYA) with Refractory/Relapsed Acute Leukemia

BACKGROUND: Despite excellent outcomes in pediatric ALL, 20-30% of patients relapse or become refractory to frontline therapies with subsequent CR2 rates of only 60%. For multiply relapsed patients, response rates remain around 40%, with <10% overall survival in third complete response.(Gaynon, BJH 2005) In pediatric AML, five-year overall survival remains around 60% among children and adolescents but with a very poor prognosis for relapsed or refractory AML (<20% three-year OS).(Wells, JCO 2003) Clearly, novel combinations with improved complete response rates and long term outcomes are needed for these high risk patients. Several studies have supported the rationale for using either Clofarabine or Mitoxantrone in patients with refractory/relapsed acute leukemia.(Wells, JCO 2003; Jeha, JCO 2009) Mitoxantrone and clofarabine as single agents, have proven effective in children with relapsed/refractory ALL and AML 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 with mitoxantrone and clofarabine reinduction therapy.To further characterize the biology of childhood, adolescent and young adult refractory/relapsed acute leukemia.

DESIGN: Prospective, multi-center, treatment-based, non-randomized, open label, uncontrolled, single group assignment, safety and efficacy study (phase I/II). 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. (Figure 1) Patients were allowed subsequent cycles pending response and anthracycline exposure.

RESULTS: To date 15 patients have been enrolled on the safety portion of this study. Median Age is 16yrs (8months-23yrs); 9 ALL (3=Induction Failure, 4=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 we are currently enrolling at Dose Level 3 (Clofarabine 35mg/m²). Median time to neutrophil recovery is 24 days. Twelve of 14 (86%) evaluable leukemia patients achieved a CR after 1 cycle of therapy. Of these patients, 92% 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. Eleven of 12 patients achieving CR went on to receive an allogeneic HSCT with continued remission at a median follow up time of 224 days (range 31-593).

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 MTD or tolerable dose of this combination has yet to be reached. Hematopoietic recovery appears to be rapid and complete. Initial data from the first 15 patients enrolled is encouraging with an 86% CR rate in leukemic patients. Once the MTD or tolerable dose is reached, an extended multicenter Phase II Study will be initiated.