LONG-TERM OUTCOME OF AN OBSERVATIONAL APPROACH IN PATIENTS WITH NRAS-MUTATED JUVENILE MYELOMONOCYTIC LEUKEMIA AND ABSENCE OF HIGH RISK FEATURES

Backgroung and Aimes: 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.Methods: This real-life study assessed the outcomes of JMML patients managed with a W&W strategy in a nationwide cohort of 161 genetically characterized cases.Clinical and molecular data were analyzed to identify prognostic factors that could guide patient selection for the W&W approach.Results: Between 2001 and 2021, the W&W strategy was implemented in 35 out of 161 patients (22%), with a significant increase over time.Notably, more than one-third of patients received W&W management between 2016 and 2021.Most patients had mutations in CBL (43%), NRAS (34%), or 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.In 28/30 long term survivors, clonal hematopoiesis with stable variant allele frequencies persisted while two showed a decrease in mutation burden.Five patients (CBL: n=3, NRAS: n=1, PTPN11: n=1) experienced disease progression mostly within two years post-diagnosis (4/5).Among them, three underwent HSCT and are currently alive while two were lost of follow up and died of disease.In CBL and homozygous germline SH2B3, no predictive factor of adverse outcomes were identified.In NRAS patients, younger age <30 months, normal to slightly elevated fetal hemoglobin, no additional somatic mutations, and low DNA methylation profile were associated with long-term survival.Conclusions: W&W is a feasible alternative for patients with CBL, NRAS and homozygous germline SH2B3, potentially sparing them from HSCT-associated risks.However, given the uncertain long-term effects of clonal hematopoiesis and possible extra-hematological complications, close monitoring remains crucial.