AALL1631: International Phase 3 trial in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) testing imatinib in combination with two different cytotoxic chemotherapy backbones.
What is the goal of the study?
ABSTRACT Approximately 3-5% of pediatric ALL patients present with the Philadelphia chromosome (Ph+ ALL). Historically, patients with Ph+ ALL had a poor prognosis and were considered candidates for allogeneic hematopoietic stem cell transplant (HSCT) in first complete remission (CR1). Studies conducted by COG and the European EsPhALL consortium over the last decade have demonstrated that the majority of pediatric Ph+ ALL patients are effectively treated with the combination of a tyrosine kinase inhibitor (TKI) and chemotherapy, without HSCT in CR1. However, the cytotoxic chemotherapy backbone administered in these trials was more intensive than is standardly used for non-Ph+ pediatric B-ALL, resulting in high rates of treatment-related toxicities (including life-threatening infections) and mortality, as well as increased risk of late effects. Reduction in treatment-related toxicities, if achievable without compromising disease free survival (DFS), would represent an important advance for this patient population. AALL1631 is an international collaborative protocol conducted by COG and EsPhALL with the primary objective of reducing treatment-related morbidity and mortality without adversely impacting disease-free survival (DFS) in Ph+ ALL patients classified as Standard Risk (SR) based on low MRD at week 10-12 of therapy. Ph+ ALL patients will enter the trial at Day 15 of Induction IA and begin daily imatinib at that time. After the Induction IB phase (week 10-12), minimal residual disease (MRD) will be assessed by immunoglobulin/T-cell receptor (IgH-TCR) PCR, and patients will be classified as SR (those with MRD < 5 x 10-4) or High Risk (HR; MRD > 5 x 10-4). SR patients will be randomized to receive one of two cytotoxic chemotherapy backbones: 1) the EsPhALL backbone (Arm A) used in previous EsPhALL protocols and COG AALL1122 or 2) a less intensive regimen similar to those typically administered to non-Ph+ ALL HR patients on COG trials (Arm B). Patients on both arms will continue to receive imatinib until the completion of all planned chemotherapy (two years of treatment). For HR patients (approximately 15-20% of patients), allogeneic HSCT in CR1 is still considered the treatment of choice. On AALL1631, HR patients will receive the EsPhALL chemotherapy backbone and proceed to HSCT after completion of the three consolidation blocks. Because there is variability in clinical practice regarding the use of TKI’s post-HSCT in Ph+ ALL, and controversy regarding their impact on toxicity, graft-versus-host disease (GVHD) and event free survival (EFS), we will test the feasibility and describe the outcome of post-HSCT imatinib administration in HR pediatric Ph+ ALL patients. Imatinib will be administered to all HR patients from Day +56 until Day +365 post-HSCT. This single-arm, Phase 3 study will be the largest prospective trial of a pediatric population uniformly treated with imatinib pre- and post-HSCT. At COG sites, adherence to imatinib, 6-mercaptopurine and methotrexate will be assessed in SR patients and to post-HSCT imatinib in HR patients in order to determine the prevalence, predictors and prognostic relevance of non-adherence in this patient population.
Who can participate in the study?
Please contact the study team listed below to learn more.