Hematopoietic Stem Cell Transplantation Outcomes for High-Risk AML: A Report From the Children's Oncology Group

Abstract

Purpose: Hematopoietic stem cell transplantation (HSCT) is used as consolidation for pediatric patients with high-risk AML in first complete remission (CR1). The definition of high-risk AML has evolved considerably over the past two decades with the successive identification of new unfavorable risk factors. We conducted a cross-study analysis to determine whether HSCT improves the outcomes of patients with contemporarily defined high-risk AML.

Methods: We combined data from AAML0531 and AAML1031, the last two phase III clinical trials completed by the Children's Oncology Group (COG). These two trials established the prognostic importance of measurable residual disease (MRD) and several high-risk cryptic cytogenetic/molecular (CM) alterations, which were applied to reclassify patients in the current COG phase III clinical trial, AAML1831. We compared the outcomes after HSCT in CR1 with those after chemotherapy alone in CR1 in the redefined high-risk group.

Results: Our study cohort comprised 463 patients with high-risk CM alterations and 72 patients with standard-risk (SR) CM results with positive MRD at end of induction I. In all, 33.9% and 45.8% of these groups underwent HSCT in CR1, respectively. HSCT was associated with decreased relapse and improved disease-free survival (DFS) in both groups. In the high-risk CM group, 5-year DFS was 26.0% (95% CI, 20.6 to 31.6) and 49.8% (95% CI, 41.7 to 57.4; P < .001) in patients receiving chemotherapy alone and HSCT, respectively. In the SR CM and MRD+ groups, DFS was 16.9% (95% CI, 4.3 to 36.7) compared with 50.9% (95% CI, 32.7 to 66.5; P = .032). HSCT was also associated with improvement in outcomes based on multivariable analysis and across subgroups defined by clinical trial and by high-risk CM subtype, with the exception of chromosome 7 or 5 loss.

Conclusion: HSCT was associated with improved outcomes in pediatric patients with contemporarily defined high-risk AML.

Trial registration: ClinicalTrials.gov NCT00372593 NCT01371981.

FIG 1.

(A) Flow diagram of COG clinical trials, CM biomarker development, reclassification based on high-throughput sequencing, and methodology. (B) Alluvial diagram comparing historical risk stratification with contemporary CM risk stratification preceding further assignment by measurable residual disease status within the study cohort. ^aRetrospective. ^bMLLT1, MLLT2, MLLT4, MLLT10, ABI1. ^c≥90 days of age at diagnosis. BM, bone marrow; CCG, Children's Cancer Group; CM, cytogenetic/molecular; COG, Children's Oncology Group; CR1, first complete remission; HSCT, hematopoietic stem cell transplantation; MRC, Medical Research Council; MRD, measurable residual disease; PB, peripheral blood; POG, Pediatric Oncology Group.

FIG 2.

Flow diagram of study cohort. CM, cytogenetic/molecular; CR1, first complete remission; HSCT, hematopoietic stem cell transplantation; MRD, measurable residual disease; SR, standard-risk.

FIG 3.

Kaplan-Meier estimates of OS, DFS, and CIR based on contemporary CM risk stratification (standard and high) and MRD status (positive for SR), comparing patients who received chemotherapy alone versus hematopoietic stem cell transplant in first complete remission. CIR, cumulative incidence of relapse; CM, cytogenetic/molecular; DFS, disease-free survival; HSCT, hematopoietic stem cell transplantation; MRD, measurable residual disease; OS, overall survival; SR, standard-risk.