Single Arm, Multi-Center, Phase II Study Of Clofarabine In Chinese Pediatric Patients With Refractory Or Relapsed Acute Lymphoblastic Leukemia

Background Clofarabine is a second generation purine nucleoside which inhibits DNA polymerase alpha and ribonucleotide reductase, leading to the depletion of intracellular deoxynucleotide triphosphate pools, disruption of mitochondrial function and apoptosis. A phase II study was conducted to evaluate the safety and efficacy of clofarabine in pediatric patients with refractory or relapsed acute lymphoblastic leukemia (ALL) in China. Method Patients aged 1-21 years with histologically confirmed, relapsed and/or refractory ALL were eligible. Clofarabine was administered intravenously for 5 days at 52 mg/m2/d during induction and consolidation. The primary end point was overall remission rate (ORR; complete remission [CR] plus CR with incomplete counts [CRi]). Blood samples were obtained from patients who agreed to blood drawing for pharmacokinetic determinations. Results A total of 44 patients were treated in this study, in which 43 were evaluable for response. The median age was 13 years (range: 5 to 22 years), and the majority were B cell-ALL (75%, 33/44). The overall remission rate was 44.2% (19/43), including two complete remissions (CR), and 17 CRis. 39 patients had progressive disease at cut-off time, the overall median remission duration was 2.9 months, and the median remission duration was 3.4 months for patients achieved CR or CRi. Seven CR/CRi patients had chance to got HSCT after clofarabine treatment. Subgroup analysis showed that patients younger than 14 years and with B cell-ALL had a higher ORR than patients older than 14 years and with T cell-ALL, and the difference were statistically significant (age < 14 years vs. age ≥14 years: 60.9% vs. 25%, p =0.0308; B cell-ALL vs. T cell-ALL: 57.6% vs. 0, p=0.002). The most common (≥10%) adverse reactions (ADR) were hematological toxicity, gastrointestinal reaction, and abnormal liver function, and the most common grade 3/4 non-hematologic ADRs was ALT elevation (13.6%). PK analysis demonstrated that after multiple administrations the mean elimination half-life of clofarabine was 6.43 h, and the Tmax was around 2 h. The mean Cmax and exposure to clofarabine over the dosing period (AUC 0-24) achieved 581 ug/L and 2602.56 ug/L, respectively. It seems that there is no significant difference of PK profiles between Chinese and Caucasian patients. Conclusion Single clofarabine treatment is effective in Chinese pediatric patients with multiple relapsed or refractory ALL with acceptable safety profiles. Disclosures: No relevant conflicts of interest to declare.