Prognostic Factors in Children with Acute Myeloid Leukemia Receiving the First Hematopoietic Stem Cell Transplantation in Second Remission

Introduction In children with acute myeloid leukemia (AML), hematopoietic stem cell transplantation (HSCT) during the first complete remission (CR1) is generally restricted to patients with a high risk of relapse. However, 30-40% of children with AML receiving chemotherapy will eventually relapse; these patients often undergo initial HSCT after achieving second CR (CR2) with re-induction chemotherapy. Previous studies have reported favorable prognostic factors in children with relapsed AML: no prior history of HSCT, longer duration of CR1, and achieving CR2 before HSCT. The identification of prognostic factors in children who received initial HSCT in CR2 may facilitate the refinement of risk stratification in first-line therapy, but they remain largely unknown.

In this study, we explored the prognostic factors of pediatric patients with AML who received initial HSCT in CR2.

Methods Data from 234 patients were collected from the Transplant Registry Unified Management Program sponsored by the Japanese Society for Transplantation and Cellular Therapy and the Japanese Data Center for Hematopoietic Cell Transplantation. The patients were selected according to the following criteria: (1) de novo AML, (2) age < 16 years and CR2 at the time of receiving HSCT, (3) no prior HSCT, and (4) HSCT performed between 2000 and 2019. Patients without information on survival and disease recurrence or those with Down syndrome (DS) were excluded. A myeloablative conditioning (MAC) regimen was defined as total-body irradiation (TBI) at > 8 Gy, melphalan > 140 mg/m², or busulfan ≥ 9 mg/kg. All other regimens were analyzed as reduced-intensity conditioning regimens. High-risk (HR) cytogenetics/genetics were defined as either 7-/7q-, 5q-, complex karyotype (three or more chromosomal abnormalities in the absence of one of the recurring translocations or inversions), t(6;11)(q27;q23), t(6;9)(p23;q34), t(16;21)(p11;q22), t(9:22)(q34;q11.2), or fms-like tyrosine kinase receptor 3 internal tandem duplication (FLT3-ITD).

Results The median age at HSCT was 7 years (range, 1-15), and the median follow-up period for survivors was 7.7 years (range, 0.2-19.2). The 5-year event-free survival (5y-EFS) and 5-year overall survival (5y-OS) rates were 63.5% (95% CI, 56.6-69.5%) and 66.9% (95% CI, 60.0-72.8%), respectively (Figure 1). The 5-year cumulative incidence of relapse was 24.7% (95% CI, 19.2-30.6%), whereas the 5-year cumulative incidence of non-relapse mortality was 11.8% (95% CI, 7.9-16.6%). The 5y-EFS was 72.6% (95% CI, 61.1-81.2%) for patients with core binding factor AML and 100% (95% CI unavailable owing to small patient number) for patients with t(15;17)(q22;q21). Patients with 11q23/KMT2A rearrangement and HR cytogenetics/genetics showed worse outcomes, with 5y-EFS rates of only 43.8% (95% CI, 21.4-64.3%) and 36.4% (95% CI, 17.8-55.3%), respectively. Among the French American British classification subtypes, patients with M7 AML showed inferior outcomes with a 5y-EFS of 18.8% (95% CI, 4.6-40.2%). For the conditioning regimens, aside from "other MAC,” which included only three patients, melphalan-based non-TBI MAC was associated with the most favorable outcomes, with a 5y-EFS of 77.1% (95% CI, 64.2-85.9%). Multivariate analysis identified duration of CR1 > 1 year and melphalan-based non-TBI MAC regimen as independent favorable prognostic factors, while M7 was identified as an independent adverse prognostic factor (hazard ratio 2.62, p = 0.033, Table 1).

Conclusion In the present study, approximately two-thirds of children who experienced relapse after chemotherapy remained in remission after HSCT in CR2. Melphalan-based non-TBI MAC is recommended as a conditioning regimen for this select population. Patients with t(15;17)(q22;q21) showed particularly excellent outcomes after initial HSCT in CR2, whereas those with HR cytogenetics/genetics or non-DS M7 were scarcely rescued with HSCT even after attaining CR2. Precise identification of high-risk populations among them with poor early treatment response and/or unfavorable genetic alterations will contribute to refining the risk stratification and indications for HSCT in CR1.

Atsuta:Astellas Pharma Inc.: Honoraria; AbbVie GK: Honoraria; Novartis Pharma KK: Honoraria; Meiji Seika Pharma Co, Ltd.: Honoraria; Mochida Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria.