Page 24 - Haematologica May 2022

G. Escherich et al.
Figure 4. Treatment-related toxicities in randomized patients according to treatment arm and common terminology criteria. HIDAC: high-dose cytarabine; WBC: white blood cell.
of MRD and well tolerated in the frontline treatment of ALL. In comparison to high-dose cytarabine/PEG-ASP, clo- farabine/PEG-ASP was superior in the overall reduction of an MRD burden. The frequency of MRD-positive BCP- ALL patients in the standard arm was lower than the pre- dicted rate of 60%, likely due to a smaller sample size and the different distribution of risk strata in the preceding trial, CoALL 03-07.
Although the prognostic impact of MRD in BCP-ALL is still clearly discernible in early consolidation after the ran- domized courses of clofarabine versus HIDAC, the greater cytotoxic efficacy of clofarabine did not translate into an obvious improvement of outcome at the trial level after a median follow-up period of 3.7 years. This lack of surroga- cy of MRD at early consolidation in a survival endpoint analysis could be explained by a small effect size, taking into account that only a single course of clofarabine was compared with high-dose cytarabine as a part of a complex multiagent chemotherapy backbone, the entirety of which determines treatment efficacy. Our trial design allowed for the detection of a ~10% difference in outcome between randomized treatment arms at a power of 80%. Hence, the small sample size has to be considered with regard to the number of randomized patients required in order to per- form a meaningful comparative analysis of survival in CoALL 08-09, which was a priori defined as a secondary objective in the study protocol.
Overall, clofarabine increased the rate of MRD negativi- ty by 25% compared to HIDAC, which is an incremental improvement with borderline significance in contrast to a statistically more robust overall reduction of MRD after clofarabine (Table 2; Online Supplementary Figure S1). The occurrence of relapsing disease in MRD-negative patients after clofarabine (and HIDAC) observed in this trial points
at MRD as a time-dependent variable. In this regard, early achievement of MRD negativity at the end of induction is more predictive of outcome than achievement of MRD negativity later in treatment, most likely due to the emer- gence of resistant clones, i.e., MRD negativity does not necessarily imply true eradication of the disease, but sim- ply reflects a decrease to a level below the detection limit of the PCR-based MRD assay. Inversely, MRD positivity more reliably reflects outcome when measured later in treatment.15,16
In addition, the rarity of events after treatment of ALL in childhood might generally compromise surrogacy of MRD as a prognostic marker of outcome at the trial level. A pre- vious multi-trial approach including 4,830 patients with ALL demonstrated that EOI MRD failed as a surrogate for treatment effects on EFS at the trial level, when dexam- ethasone and prednisone were compared in induction treatment of AIEOP-BFM ALL and COG trials.17-19 This meta-analysis raised caution with regard to MRD as a sur- rogate marker for treatment decisions in randomized trials. In contrast to these trials, in which the stratifying decision was made after randomization, we can exclude that the evaluation of MRD after randomized intervention impact- ed a decision on the subsequent treatment in CoALL 08-09, since the ultimate stratification had been done before ran- domization on d29 in BCP-ALL and on d43 in T-ALL.
In this trial, we applied clofarabine at a dose of 40 mg/m2 daily x 5 corresponding to the previously established single agent maximum-tolerated dose (MTD) in adult acute leukemia which is lower than the MTD of 52 mg/m2 x 5 determined in pediatric patients with acute leukemia.2,20 The administration of high-dose clofarabine in conjunction with PEG-asparaginase in early consolidation of CoALL 08-09 was feasible largely due to almost non-overlapping
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