Clofarabine increases the eradication of minimal residual disease of primary Bprecursor acute lymphoblastic leukemia compared to high-dose cytarabine without improvement of outcome

Abstract

Novel treatment strategies are needed to improve cure for all children with acute lymphoblastic leukemia. To this end, we investigated the therapeutic potential of clofarabine in primary acute lymphoblastic leukemia in trial CoALL 08-09. The primary study objective was the minimal residual disease (MRD)-based comparative assessment of cytotoxic efficacies of clofarabine 5x40 mg/m2 versus high-dose cytarabine (HIDAC) 4x3g/m2, both in combination with PEG-ASP 2500 IU/m2 as randomized intervention in early consolidation. The secondary objective was an outcome analysis focused on treatment-arm dependence and MRD after randomized intervention. In B-cell precursor (BCP)-ALL, eradication of MRD was more profound after clofarabine compared to cytarabine, with 93 vs 79 of 143 randomized patients per arm reaching MRD-negativity (Chi-square test P=.03, left-sided P(Fisher’s exact test)=.04). MRD status of BCP-ALL after randomized intervention maintained its prognostic relevance, with a significant impact on event-free survival (EFS) and relapse rate. However, no difference in outcome regarding EFS and overall survival (OS) between randomized courses was observed (5- year EFS: clofarabine 85.7, SE=4.1 vs HIDAC 84.8, SE=4.7 (P=.96); OS: 95.7, SE=1.9 vs 92.2, SE=3.2 (P=.59)), independent of covariates or overall risk strata. Severe toxicities between randomized and subsequent treatment elements were also without significant difference. In conclusion, clofarabine/PEG-ASP is effective and safe, but greater cytotoxic efficacy of clofarabine compared to HIDAC did not translate into improved outcomes indicating a lack of surrogacy of post-intervention MRD at the trial level as opposed to the patient level, which hampers a broader implementation of this regimen in the frontline treatment of ALL.