Late Bone Marrow Relapse Risk Stratification in Pediatric Patients With B-Cell Acute Lymphoblastic Leukemia

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In an analysis of the German ALL-REZ BFM 2002 trial, reported in the Journal of Clinical Oncology, Eckert et al found that postinduction minimal residual disease (MRD)-based treatment stratification resulted in “excellent survival” in pediatric patients with late relapse of B-cell precursor acute lymphoblastic leukemia (BCP-ALL).

Study Details

The analysis included 413 children and adolescents (median age = 9.7 years at relapse diagnosis; 30 patients aged ≥ 18 years) treated for late bone marrow BCP-ALL relapse diagnosed between January 2002 and December 2015. Patients with MRD of 10−3 or greater at relapse after standard induction therapy were recommended to receive allogeneic hematopoietic stem cell transplantation (HSCT) in second complete remission; those with MRD less than 103 continued to receive consolidation and maintenance chemotherapy (but could receive allogeneic HSCT from a matched sibling donor). MRD was assessed after induction treatment and at intervals during relapse until HSCT.

Key Findings

Event-free survival was good among both patients with favorable response (MRD less than 103) and poor response to induction treatment, with 10-year rates of 72% vs 65% being observed; 10-year overall survival was 82% vs 74%. Patients with MRD of 102 or greater after induction had poorer 10-year event-free survival (56%). 

Early nonresponders—defined as patients with ≥ 25% leukemic blasts after induction—had the poorest prognosis (10-year event-free survival = 22%). Late nonresponders—defined as patients with MRD of 103 or greater before HSCT—had 10-year event-free survival of 50% and 10-year overall survival of 63%. The investigators noted that these outcomes in principle justify use of allogeneic HSCT in such patients.

From a panel of candidate genes, TP53 alterations (present in 8% of patients with available data) were the only alterations with independent prognostic value in MRD-based response subgroups. On multivariate analysis, significantly poorer event-free survival was observed for TP53 loss/alteration (12 of 132 patients) in patients with good response to induction (hazard ratio [HR] = 3.37, P = .004); TP53 loss (4 of 106 patients) in patients with poor response (HR = 4.51, P = .016); and TP53 loss/mutation (20 of 245 patients) in those with good or poor response (HR = 2.51, P = .005).

The investigators concluded, “After induction treatment, MRD-based treatment stratification resulted in excellent survival in patients with late relapsed BCP-ALL. Prognosis could be further improved in very poor responders by intensifying treatment directly after induction. TP53 alterations can be defined as a novel genetic high-risk marker in all MRD response groups in late relapsed BCP-ALL. Here, we identified early and late nonresponders to be considered as events in future trials.”

Cornelia Eckert, PhD, of the Department of Pediatric Oncology and Hematology, Charité-Universitätsmedizin Berlin, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported by the German Childhood Cancer Foundation, German Federal Ministry of Education and Research, and others. For full disclosures of the study authors, visit

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