A predictive classifier of poor prognosis in transplanted patients with juvenile myelomonocytic leukemia: a study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire

Abstract

Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric myeloproliferative neoplasm requiring hematopoietic stem cell transplantation (HSCT) in most cases. We retrospectively analyzed 119 JMML patients who underwent first allogeneic HSCT between 2002 and 2021. The majority (97%) carried a RAS-pathway mutation, and 62% exhibited karyotypic alterations or additional mutations in SETBP1, ASXL1, JAK3 and/or the RAS pathway. Relapse was the primary cause of death, with a 5-year cumulative incidence of 24.6% (95% CI: 17.1-32.9). Toxic deaths occurred in 12 patients, resulting in treatment-related mortality (TRM) of 9.0% (95% CI: 4.6-15.3). The 5-year overall (OS) and event-free survival were 73.6% (95% CI: 65.7-82.4) and 66.4% (95% CI: 58.2-75.8), respectively. Four independent adverse prognostic factors for OS were identified: age at diagnosis >2 years, time from diagnosis to HSCT ≥6 months, monocyte count at diagnosis >7.2x109/L, and the presence of additional genetic alterations. Based on these factors, we proposed a predictive classifier. Patients with 3 or more predictors (21% of the cohort) had a 5-year OS of 34.2%, whereas those with none (7%) had a 5-year OS of 100%. Our study demonstrates improved transplant outcomes compared to prior published data, which can be attributed to the synergistic impacts of a low TRM and a reduced, yet still substantial, relapse incidence. By integrating genetic information with clinical and hematologic features, we have devised a predictive classifier. This classifier effectively identifies a subgroup of patients who are at a heightened risk of unfavorable post-transplant outcomes who would benefit from novel therapeutic agents and post-transplant strategies.

Figure 1.

Flow chart of the transplanted juvenile myelomonocytic leukemia cohort. CR: complete remission; DOD: dead of disease; HSCT: hematopoietic stem cell transplant; JMML: juvenile myelomonocytic leukemia; N: number; TRM: treatment-related mortality.

Figure 2.

Estimated outcomes of the 119 transplanted patients. Overall survival (OS) (A) and event-free survival (EFS) (B) were analyzed using Kaplan-Meier methodology. Cumulative incidence function for relapse and treatment-related mortality (TRM) (C).

Figure 3.

Effect of monocyte count and initiating RAS-mutation on outcomes. Effect of monocyte count: (A) overall survival (OS) and (B) cumulative incidence function of relapse. Effect of initiating RAS-mutation: (C) OS and (D) event-free survival (EFS). OS and EFS were analyzed using Kaplan-Meier methodology. HSCT: hematopoietic stem cell transplant.

Figure 4.

Prognostic classifier for overall survival. This classifier defined 4 prognostic groups of patients according to the 4 predictor factors from the multivariate analysis. OS: overall survival; HSCT: hematopoietic stem cell transplant.