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

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.

How I treat relapsed acute lymphoblastic leukemia in the pediatric population

“…Relapsed ALL therapies differ significantly between cooperative groups, but attain similar outcomes (Table 2). 10,11,[13][14][15][16] We would administer the United Kingdom (UKALL) R3 reinduction regimen (dexamethasone, vincristine, mitoxantrone, pegaspargase, and intrathecal methotrexate) 15 used in the recent COG AALL1331 first relapse B-ALL trial (NCT02101853) or another 4-drug reinduction regimen. Because infectious risk is high, 17,18 we would hospitalize her until count recovery and provide antibacterial, antifungal, and Pneumocystis jirovecii prophylaxis.…”

Outcomes after late bone marrow and very early central nervous system relapse of childhood B-acute lymphoblastic leukemia: a report from the Children's Oncology Group phase III study AALL0433

“…However, the UKALL R3 relapse protocol used the same 0.01% threshold, and showed improved progression-free survival for those receiving mitoxantrone (66%) vs. idarubicin (46%) despite no difference in MRD clearance between arms [17] [18]. A higher MRD threshold of 0.1% was highly predictive of outcome in BFM REZ P95/96/2002 [7] [37].…”

Risk factors and outcomes in children with high-risk B-cell precursor and T-cell relapsed acute lymphoblastic leukaemia: combined analysis of ALLR3 and ALL-REZ BFM 2002 clinical trials

“…Duration of first complete remission and immunophenotypes predict outcomes in patients with relapsed acute lymphoblastic leukaemia (ALL) [1e3]. B-cell precursor (BCP) ALL with bone marrow relapses occurring later than 6 months after stopping therapy has survival rates of more than 80% [4,5]. In contrast, patients with highrisk (HR) relapses defined as BCP-ALL relapses within 18 months of first diagnosis or with isolated medullary relapses occurring within 6 months of stopping therapy, and T-cell isolated or combined medullary relapses at any time, have survival rates between 15% and 30% [3,6,7] even after allogeneic haematopoietic stem cell transplantation (SCT) [2,3,8e10].…”