Paper Details

ABSTRACT

Background: Over the last two decades, clinical trials for pediatric Philadelphia chromosome-positive (Ph+) ALL have tested the combination of tyrosine kinase inhibitors (TKIs), either imatinib or dasatinib, with intensive chemotherapy backbones, resulting in 5-year (yr) event-free survival (EFS) rates of 50-60%. The intensity of therapy has led to high rates of serious adverse events (SAEs), primarily infection-related, with treatment-related mortality (TRM) of 8-15% on recent trials. The European Ph+ ALL intergroup (EsPhALL) and the Children’s Oncology Group (COG) jointly conducted the EsPhALL2017/COGAALL1631 phase 3 study, with the primary objective to determine if a less intensive chemotherapy backbone (based upon the COG augmented BFM regimen) would reduce the incidence of treatment-related toxicities compared to the standard EsPhALL regimen without adversely impacting disease-free survival (DFS) of pediatric Ph+ ALL patients (pts).

Methods: EsPhALL2017/COGAALL1631, sponsored by the University of Milano-Bicocca (Italy), enrolled pts aged 1-21 yrs with de novo Ph+ B- or T-ALL or mixed phenotype acute leukemia (MPAL). Blast phase CML was excluded. Pts entered the study on induction day 15 with addition of imatinib (imatinib prior to enrollment allowed). After induction and BFM phase IB, minimal residual disease (MRD) was assessed by real-time quantitative PCR of rearranged immunoglobulin/T-cell receptor genes. Pts with MRD ≥5x10^-4 were classified as high risk (HR), received 3 EsPhALL consolidation blocks with imatinib and were allocated to hematopoietic cell transplant in first complete remission (HCT in CR1). All others were classified as standard risk (SR) and randomized to continuous imatinib with either the COG or EsPhALL chemotherapy backbones, for an overall treatment duration of 2 yrs. The COG arm included 4 courses of HD-MTX, one delayed intensification phase, interim maintenance with escalating dose methotrexate and maintenance with vincristine/steroid pulses, while the EsPhALL arm used 3 intensive multiagent consolidation blocks, 2 BFM Protocol II phases and maintenance without pulses. The primary estimand was the hazard ratio of COG vs EsPhALL arm (intention-to-treat) based on DFS from randomization. The non-inferiority margin was set at hazard ratio=1.43. This final analysis is based on 463 pts (97% of target) and 198 events (target: 194), with a median follow-up of 3.8 yrs (range: 0.1–8.0).

Results: Between 2017-2024, 609 Ph+ pts were enrolled; 96% B-ALL, 2% T-ALL and 2% MPAL. The overall 5-yr EFS was 50.4% (95%CI 45.4–55.1), with plateau not yet observed, and overall survival (OS) was 85.6% (82.0–88.5). 573 pts were risk-stratified based on end-IB MRD: 40 (7%) were HR, 21 of whom received HCT in CR1 and 533 (93%) were SR, of whom 463 (87%) were randomized, 230 to COG and 233 to EsPhALL arm. The 5-yr DFS (95%CI) was 42.9% (34.8–50.6) for COG vs 52.8% (44.3–60.6) for EsPhALL arm. The hazard ratio was 1.197; the upper bound of the one-sided 95%CI was 1.514, which exceeded the pre-defined non-inferiority margin, indicating that non-inferiority of the COG arm was not demonstrated. The 5-yr cumulative incidence of relapse for COG vs EsPhALL arm ([CIR] n=101 vs 72 relapses) was 54.4% (95%CI 46.1–62.0) vs 38.9% (30.8–46.9). The most common serious adverse events (SAEs) were infections (CTCAE v5.0): 185 vs 354 in COG vs EsPhALL arm. The 5-yr cumulative incidence of TRM (n=3 vs 18 deaths, primarily due to infection) was 1.3% (0.4–3.5) for COG and 7.8% (4.8–11.8) for EsPhALL arm. The 5-yr OS (95%CI, n deaths) was 88.8% (82.1–93.0, n=19) for COG and 84.2% (78.2–88.6, n=35) for EsPhALL arm.

Conclusions: Compared with the EsPhALL arm, the less intensive COG arm was associated with a higher 5-yr CI of relapse but with fewer serious infections and a lower 5-yr CI of TRM. The 5-yr OS was similar between arms, reflecting the differential rates of TRM as well as effective salvage after relapse. Overall, this study demonstrates that the long-term EFS of pediatric Ph+ ALL treated with cytotoxic chemotherapy combined with TKI remains unsatisfactory. More innovative approaches, including immunotherapy and newer generation TKIs, should be evaluated to reduce relapses and minimize toxicity. To that end, the ongoing COGAALL2131/EsPhALL2022 collaborative study is testing a novel regimen consisting of dasatinib combined with a reduced-intensity chemotherapy backbone and 3 cycles of blinatumomab.