Results of the ALL-IC REL 2016 Registry Trial: 1st Relapses of Childhood ALL Treated in High-Middle Income Countries

BACKGROUND The Acute Lymphoblastic Leukemia Inter-Continental (ALL-IC) Study Group is currently conducting its 3rd academic randomized study to treat first-line pediatric ALL. By standardizing and continuously updating therapeutic guidelines and employing flow cytometry-based minimal residual disease (MRD) for treatment stratification, patient outcomes have improved. Nevertheless, relapse occurs in 10-20% of cases. When examined in 2014, survival rate of relapses fell short of benchmarks set by top-tier published studies. OBJECTIVES To establish a unified treatment framework for children experiencing their first relapse of ALL across the ALL-IC network. To analyze the post-relapse outcomes of these children and report findings from an observational registry trial. METHODS The IntReALL 2010 protocol was adapted to best fit ALL-IC countries. Patients were stratified as standard-risk (SR) or high-risk (HR) based on relapse characteristics and genetic profiles. High-risk criteria included T-cell immunophenotype, very early relapse, early isolated bone marrow relapse, relapse post-SCT, and specific genetic alterations. Standard-risk was assigned to all others. Allogeneic stem cell transplant (SCT) eligibility was extended to all HR patients, and among SR patients to those with poor response (marrow flow MRD ≥ 0.1% on induction day 29). Data were collected using an open-access registry on the REDCap platform. RESULTS Not all full-member groups of the frontline ALL-IC trials participated in this project or filled the registry. However, some observer countries did. Argentina (GATLA group), Bulgaria, Chile, Greece, Hungary, Romania, Slovenia and Turkey registered cases. To our knowledge, the ALL-IC REL protocol has also been used in Armenia, Bosnia-Herzegovina, Croatia, Georgia, Lebanon, Montenegro, Russia, Serbia, and Ukraine, though these countries didn't contribute to the registry. Recently, additional countries from the Middle East have shown interest. Of the 500 registered patients, 473 were included (median age 8.2 years, range 0.8 to 21; 38% female). Regarding immunophenotype, 47 T-ALL and 2 MPAL cases were there besides 424 B-ALL children. At initial diagnosis, 91% received ALL IC-BFM 2009 protocol treatment. Among relapses, 25.2% occurred very early, 31.5% early, 43.3% occurred late. CNS involvement was identified in 23.9% of the relapses, and testicular involvement in 4.2%. Upon relapse, 48% of patients were classified as SR and 52% as HR. Post-induction, complete remission rates were 73% in SR and 48% in HR groups. End of induction MRD < 0.1% was achieved by 52.2% of SR and 28.7% of HR patients. The 2-year overall survival rate was estimated at 55% for all patients, with 86% for SR and 26% for HR groups. Notably, the HR group faced a stark prognosis with significant mortality attributed to disease progression, treatment related complications and post-transplant complications. A surprisingly low proportion (39%) of HR patients were treated with SCT, likely due to limited or difficult access to this procedure. Among HR patients who did not receive SCT, there were virtually no long-term survivors. CONCLUSION This inaugural report from the ALL-IC REL Consortium highlights the promising outcomes for SR patients within our middle-income countries, paralleling those observed in the IntReALL study consortium. However, outcomes for the HR group fall much below the results of the ALL REZ BFM 2002 trial's HR arm - partly due to limited access to SCT in some regions. At other centers, integrating novel therapies, particularly immunotherapies, into the ALL-IC REL 2024 protocol may reduce leukemia-related and toxic death rates.