The watch-and-wait approach for patients with juvenile myelomonocytic leukemia: results of the French cohort

Abstract

Juvenile myelomonocytic leukemia (JMML) is a rare, aggressive pediatric myeloproliferative neoplasm for which hematopoietic stem cell transplantation (HSCT) is currently the only established curative therapy. However, a watch-and-wait (W&W) approach has shown promise for long-term survival in selected cases. In this real-world study, we analyzed outcomes of JMML patients initially managed with a W&W strategy within a nationwide cohort of 161 genetically characterized cases. W&W was chosen for 35 patients, with increasing adoption over time, reaching 39% in the 2016-2021 period. Most patients carried mutations in CBL (43%), NRAS (34%), or homozygous germline SH2B3 (14%). Over a median follow-up of 6.5 years, 86% (30/35) achieved long-term survival with partial or complete resolution of myeloproliferative symptoms, although clonal hematopoiesis persisted in nearly all survivors (28/30). Disease progression occurred in five patients (CBL: n=3, NRAS: n=1, PTPN11: n=1), mostly within two years post-diagnosis. Overall, in the W&W cohort, the 5-year OS and EFS were 93.1% and 84.5%. In NRAS-mutated cases, age <30 months, normal to slightly elevated fetal hemoglobin, platelet >45x109/L, the absence of additional somatic mutations and low DNA methylation profile were associated with favorable outcomes. In CBL-driven JMML, no predictive factor of adverse evolution was identified. Notably, W&W was effective in all patients with homozygous germline SH2B3, regardless of clinical or biological presentation. These findings support W&W as a viable alternative in up to 30% of JMML patients, potentially sparing them from HSCT-associated risks. Given the persistence of clonal hematopoiesis and the risk of extra-hematological complications, long-term monitoring remains essential.