Page 19 - Haematologica May 2022

Lymphoblastic leukaemia, paediatric, clofarabine
Introduction
The prevention of relapse without increasing toxicity is a challenging goal of frontline treatment in acute lymphoblas- tic leukemia (ALL), which is unlikely to be achieved by recombination or intensification of established chemothera- peutic agents. Besides immunotherapeutical approaches, novel compounds must be probed to prevent the develop- ment of resistant clones or to efficiently overcome those that already exist.
To this end, we evaluated clofarabine as one of the latest chemotherapeutic drugs to receive authoritative approval for the treatment of relapsed/refractory ALL in childhood. Clofarabine is a second-generation purine nucleoside ana- logue that combines the positive characteristics of first-gen- eration purine nucleosides fludarabine and cladribine by retaining 2-halogenated adenines, resulting in improved resistance against deamination and phosphorolysis.1-3 Several studies have been launched which scrutinized clofarabine in combination with other cytostatic drugs as second- or third- line therapy, or as a bridging regimen to hematopoietic stem cell transplantation.4-6
In the Children’s Oncology Group (COG) trial AALL1131, clofarabine was administered in combination with etoposide and cyclophosphamide, which were associated with severe infections and persistent myelotoxicity leading to premature closure of the experimental clofarabine arm.7
In order to assess the value of the frontline usage of clofara- bine, the Cooperative Acute Lymphoblastic Leukemia Study Group (CoALL) conducted a sequential phase II/III trial embedded into the CoALL 08-09 regimen for newly diag- nosed ALL patients for whom end-of-induction (EOI) mini- mal residual disease (MRD) imposed a greater risk of relapse.
During the non-randomized phase II, all eligible patients with quantifiable EOI MRD received the combination of clo- farabine 5x40 mg/m2 and pegylated asparaginase (PEG-ASP) 2,500 IU/m2 as early consolidation treatment. The results were compared to a high-dose cytarabine (HIDAC)/PEG- ASP control group in predecessor trial CoALL 03-07. Combined administration of clofarabine and PEG-ASP was feasible and exhibited acceptable toxicities without unex- pected severe side effects.8
Herein, we describe the results of the subsequent phase III trial within CoALL 08-09, comparing the efficacy and tolera- bility of clofarabine/PEG-ASP versus HIDAC/PEG-ASP at early consolidation in a randomized fashion.
Methods
Study design and patients
CoALL 08-09 was a multi-center, randomized trial for patients under the age of 18 years with a confirmed diagnosis of acute B- or T-cell precursor leukemia. Accrual was open from 1 October 2010 to 31 December 2019. The study was approved by the competent ethics boards (Online Supplementary Table S1) and conducted in accordance with the Declaration of Helsinki. The efficacy of clofara- bine/PEG-ASP was compared with HIDAC/PEG-ASP in a random- ized fashion as a primary study objective. An additional randomiza- tion of anthracyclines in delayed intensification was conducted from 2010 to 2016 with the primary objective of comparing toxicities.9
Stratification and treatment
All patients received the same three-drug induction with four weekly doses of daunorubicin (36 mg/m2) and vincristine (1.5
mg/m2) along with oral methylprednisolone (60 mg/m2) over 28 days and a single dose of age-adapted intrathecal methotrexate. BCP-ALL with a discernible, but non-quantifiable, or quantifiable EOI MRD and T-ALL with ≥10-3 EOI MRD were eligible for ran- domization, receiving either clofarabine 5x40 mg/m2 or HIDAC 4x3 g/m2 in combination with PEG-ASP 2,500 IU/m2 as the first or second course of consolidation in the treatment of BCP-ALL or T- ALL, respectively (Figure 1A).
Further treatment was administered according to respective strata (Figure 1B). By protocol, enrolled patients who achieved MRD-negativity at the end of induction or inversely showed an induction failure were not eligible for randomization (see the Online Supplementary Appendix for additional information).
Randomization
The randomization was performed by the coordinating trial center after stratification had been finalized according to EOI MRD status. Each stratum (high risk [HR] patients were subdivid- ed according to immunophenotype) underwent independent ran- domization on the basis of randomly permuted blocks to avoid imbalances within risk strata.
Analysis of minimal residual disease
Real-time quantitative polymerase chain reaction (PCR) analy- ses were performed targeting immunoglobulin heavy chain (IGH) and T-cell receptor (TCR) gene rearrangements to assess MRD. Data were interpreted according to the guidelines developed by the European Study Group for MRD detection in ALL (EuroMRD ALL).10
Statistical analyses
The probability of event-free (pEFS) and overall survival (pOS) was estimated using the Kaplan-Meier method and compared between subgroups using the log-rank test.11 Cumulative inci- dence functions of isolated CNS or any (isolated and combined) CNS relapse, as well as testicular relapse, treatment-related sec- ondary malignancies and toxicity-related death were calculated using the Kalbfleisch and Prentice method and compared using Gray’s test.12 A c2 test, a Fisher’s exact test, and Spearman’s rank correlation analyses were applied to compare the distribution of parameters between subgroups and correlation between parame- ters.13 A c2 test was applied to determine the difference in the rate of MRD-positive patients, as provided in the study protocol. This was complemented by a one-sided Fisher’s exact test and a Cochran-Armitage trend test, the latter of which compared the trend in MRD values between randomized groups.14
The status of patients was monitored annually. The database was newly updated (1 December 2020) prior to usage for analysis. Analyses were carried out using SAS version 9.4. Further details of statistical analyses are provided in the Online Supplementary Appendix.
Results
Overall, 303 study patients were eligible and random- ized, allocating 151 patients toward clofarabine/PEG-ASP and 152 patients toward HIDAC/PEG-ASP (Figure 2; Table 1; Online Supplementary Appendix). Of those patients, the main endpoint (i.e., MRD after randomized intervention) was reached by 296 patients, in close approximation to the planned sample size (n=295) (Table 2). There were no differences in patient characteristics regarding known risk factors other than a more frequent occurrence of ETV6- RUNX1 in the clofarabine-treated cohort (Table 1). The
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