Clofarabine in Children with Refractory/Relapsed Acute Leukemia: Results of 2 Phase II Open Label Studies.
Authors: Jeha Sima , Razzouk Bassem , Gaynon Paul , Rytting Michael , Kadota Richard , Rheingold Susan , Luchtman-Jones Lori , Arceci Robert , Steinherz Peter 
Published: April 2020

Abstract
Background: Clofarabine is a second generation purine nucleoside analogue synthesized to improve the properties of its congeners, fludarabine and cladribine. Clofarabine inhibits DNA polymerase alpha and ribonucleotide reductase, leading to the depletion of intracellular deoxynucleotide triphosphate pools, disruption of mitochondrial function and apoptosis.
Methods: Clofarabine was administered by IV infusion over 2 hrs for 5 days at 52 mg/m2/day and repeated every 2–6 weeks based on bone marrow response and recovery of normal hematopoiesis. An independent review panel confirmed all results.
Results: The median age of the 103 children (61 with ALL and 42 with AML) was 12 years (range 1–22 yrs).
ALL: The overall remission rate (CR+CRp) was 20%; 30% (18/61) of patients showed a response (7CR, 5CRp, 6PR). Responses were noted in 15 of 50 (30%) patients with B- lineage ALL, 2 of 6 (33%) with T-cell ALL. Responders received a median of 3 prior induction regimens; 50% (9/18) had prior HSCT and 50% (9/18) were refractory to the preceding induction regimen. Response rate in refractory patients was 26% (9/35). After clofarabine treatment, 10 patients proceeded to transplant (including 8 responders). 6 of 10 patients who received a transplant were alive at last follow up (survival range: 30.1+ – 145.1+ wks). Response duration in 6 patients with CR or CRp who did not receive a transplant ranged from 4.3 to 58.6 weeks; 2 patients maintained CR for 47.9 and 58.6 weeks after clofarabine therapy. Median overall survival for the patients who achieved at least a PR was 66.6 weeks compared to 12.9 weeks for all patients.
AML: The response rate for AML patients was 26% (1 CRp, 10 PR). Responders had received a median of 2 prior induction regimens, 36% (4/11) had prior HSCT and 55% (6/11) patients were refractory to the preceding induction regimen. Response rate in refractory patients was 21% (6/28). One patient who had received 5 prior induction regimens achieved CRp. 13 (31%) patients (1CRp, 6PR, 3NE, 3TF) underwent HSCT after completing clofarabine therapy, 5 of whom were alive at last follow-up (survival range: 62.7+ – 160.1+ wks). Many patients proceeded to HSCT as soon as a donor was identified without waiting for the patient to go into remission, making remission difficult to assess. Median overall survival for patients who achieved at least a PR was 32.1 wks compared to 23.4 wks for all patients.
Safety: The side effect profile was not unexpected in this heavily pretreated population. The ≥ gr 3 drug related AEs occurring in ≥10% patients included febrile neutropenia for ALL patients; febrile neutropenia, pyrexia, nausea, neutropenia, and hypotension for AML patients.
Conclusion: Clofarabine shows significant activity in heavily pretreated children with multiply relapsed acute leukemia, allowing otherwise refractory patients to proceed to HSCT. Durable responses were seen in ALL patients with no donor options who continued therapy with single agent clofarabine. Combination studies incorporating clofarabine in pediatric patients with relapsed ALL and AML are ongoing.