In a trial of patients with relapsed/refractory pediatric leukemia, a reinduction therapy approach using mitoxantrone with clofarabine was shown to be safe and well tolerated at the recommended phase 2 dose for clofarabine. Additionally, most patients responded to treatment. These findings were presented in a poster at the 2022 American Society of Pediatric Hematology/Oncology Conference by Jessica Hochberg, MD, of New York Medical College, in Valhalla, NY, and colleagues.
The prospective, single-arm phase 1/2 trial (ClinicalTrials.gov Identifier: NCT01842672) included patients with acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML) who had relapse or induction failure. In phase 1, clofarabine was administered cycle days 1 through 5, with dose escalation up to a maximum of 40 mg/m2/day. Mitoxantrone (12 mg/m2/day) treatment was given from days 3 through 6.
The recommended phase 2 dose (RP2D) for clofarabine was established based on dose-limiting toxicities in phase 1. Primary objectives in phase 2 were determination of response rates and the minimal residual disease (MRD) rate. A secondary objective was to assess how many patients could proceed with hematopoietic stem cell transplantation (HSCT).
The study enrolled 39 patients, with 18 patients in phase 1 and 21 in phase 2. Patients had a median age of 13 years (range, 8 months to 23 years). There were 23 patients with ALL and 16 patients with AML in the study.
A complete response (CR) was reported in 33 patients, or 85% of the population. For 88% of the patients who reached CR, MRD negativity was also achieved at a level of <0.01%, as assessed by flow cytometry. The study investigators also reported that responders showed a 1-year overall survival rate of 85%.
Of the 33 patients reaching CR, 94% reportedly proceeded to HSCT. Fatalities were reported to have occurred in 1 patient prior to transplantation and in 8 patients following transplantation.
A total of 2 unexpected grade 3 or 4 toxicities during phase 1 were reported with clofarabine given at 40 mg/m2 per day; these included hepatic toxicity and prolonged myelosuppression. The RP2D for clofarabine was determined to be 35 mg/m2. In both trial phases, expected grade 4 myelosuppression was reported in all patients, and the median time to neutrophil recovery was 24 days in each phase.
The study investigators considered mitoxantrone and clofarabine to be safe and well tolerated in patients in this study, with clofarabine administered at its RP2D of 35 mg/m2. They also considered the CR rate with MRD negativity, and the 1-year overall survival rate among responders, to be encouraging. They indicated further research is underway.
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Hochberg J, Oesterheld J, Gardenswartz A, et al. Phase I/II trial of mitoxantrone and clofarabine in children with relapsed/refractory acute leukemia. Presented at: 2022 American Society of Pediatric Hematology/Oncology (ASPHO) Conference; May 4-7, 2022. Abstract 211.