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Clinical Trial
. 2019 Dec 20;37(36):3493-3506.
doi: 10.1200/JCO.19.01694. Epub 2019 Oct 23.

Improving Stratification for Children With Late Bone Marrow B-Cell Acute Lymphoblastic Leukemia Relapses With Refined Response Classification and Integration of Genetics

Cornelia Eckert  1   2 , Stefanie Groeneveld-Krentz  1 , Renate Kirschner-Schwabe  1   2 , Nikola Hagedorn  1 , Christiane Chen-Santel  1 , Peter Bader  3 , Arndt Borkhardt  4 , Gunnar Cario  5 , Gabriele Escherich  6 , Renate Panzer-Grümayer  7 , Kathy Astrahantseff  1 , Angelika Eggert  1   2 , Lucie Sramkova  8 , Andishe Attarbaschi  7 , Jean-Pierre Bourquin  9 , Christina Peters  7 , Günter Henze  1 , Arend von Stackelberg  1 ; ALL-REZ BFM Trial Group
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Free article
Clinical Trial

Improving Stratification for Children With Late Bone Marrow B-Cell Acute Lymphoblastic Leukemia Relapses With Refined Response Classification and Integration of Genetics

Cornelia Eckert et al. J Clin Oncol. .
Free article

Abstract

Purpose: Minimal residual disease (MRD) helps to accurately assess when children with late bone marrow relapses of B-cell precursor (BCP) acute lymphoblastic leukemia (ALL) will benefit from allogeneic hematopoietic stem-cell transplantation (allo-HSCT). More detailed dissection of MRD response heterogeneity and the specific genetic aberrations could improve current practice.

Patients and methods: MRD was assessed after induction treatment and at different times during relapse treatment until allo-HSCT (indicated in poor responders to induction; MRD ≥ 10-3) for patients being treated for late BCP-ALL bone marrow relapses (n = 413; median follow-up, 9.4 years) in the ALL-REZ BFM 2002 trial/registry (ClinicalTrials.gov identifier: NCT00114348).

Results: Patients with both good (MRD < 10-3) and poor responses to induction treatment reached excellent event-free survival (EFS; 72% v 65%) and overall survival (OS; 82% v 74%). Patients with MRD of 10-2 or greater after induction had reduced EFS (56%), and their MRD persisted until allo-HSCT more frequently than it did in patients with MRD of 10-3 or greater to less than 10-2 (P = .037). Patients with 25% or more leukemic blasts after induction (early nonresponders) had the poorest prognosis (EFS, 22%). Interestingly, patients with MRD of 10-3 or greater before allo-HSCT (late nonresponders) still had an EFS of 50% and OS of 63%, which in principle justifies allo-HSCT in these patients. From a panel of selected candidate genes, TP53 alterations (frequency, 8%) were the only genetic alteration with independent prognostic value in any MRD-based response subgroup.

Conclusion: 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.

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