Rational Response-Adapted Risk Stratification and Treatment for Children with Late Bone Marrow Relapses of B-Cell Precursor Acute Lymphoblastic Leukaemia: A Report from the <i>ALL-REZ BFM</i> Trial Group

Abstract

Background: Minimal residual disease (MRD) supports a more accurate assessment when children and adolescents with late bone marrow relapses of B-cell precursor (BCP) acute lymphoblastic leukaemia (ALL) will benefit from allogeneic haematopoietic stem cell transplantation (alloHSCT). A more detailed dissection of MRD heterogeneity, dynamics and the specific genetic aberrations involved promises to further improve treatment stratification. Methods: Patients treated according to the ALL-REZ BFM 2002 trial/registry protocol with late BCP ALL bone marrow relapses (n=413) were included. AlloHSCT was indicated for patients with MRD≥10-3 after induction treatment (poor response). Findings: Patients with good (MRD<10-3) or poor responses to induction reached excellent event-free survival (EFS) and overall survival (OS) probabilities. However, EFS probability was decreased in patients with a very poor response (MRD≥10-2) to induction, in whom MRD persisted (≥10-4) until directly before alloHSCT more frequently than in intermediate poor responders (MRD≥10-3to<10-2). Patients with MRD≥10-3 prior to alloHSCT had the poorest prognoses, and were defined as late nonresponders. Patients ≥25% leukaemic blasts after induction had a very poor probability for EFS and OS. Multivariable Cox regression identified only TP53 alterations, in any MRD-based response subgroup, as independent prognostic marker. Interpretation: The excellent survival in patients with late relapsed BCP-ALL was achieved because of post-induction MRD-based treatment stratification of patients for alloHSCT. Two nonresponder cut-offs were identified that predict patients after induction who will not benefit from conventional treatment intensification and after consolidation who will not benefit from alloHSCT. They should be shunted toward controlled trials for novel therapies. Funding Statement: German Childhood Cancer Foundation, German Jose Carreras Foundation. Declaration of Interests: The authors declare no conflict of interest. Ethics Approval Statement: The treatment protocols, including MRD assessments at the defined time points, were approved by local medical research ethics committees, and informed consent obtained from patients and/or guardians.