Genetic Characteristics and Clinical Prognosis of JMML with RAS Mutations

Objective: Juvenile myelomonocytic leukemia (JMML) is a clonal malignant hematological tumor that occurs in childhood, characterized by increased infiltration of abnormal granulomonocytes in peripheral blood, bone marrow, and internal organs. The vast majority of children with JMML have mutations in the RAS/MAPK signaling pathway . The prognosis of JMML patients with different gene subtypes shows significant heterogeneity. This study aimed to explore the genomic features and prognostic factors of JMML with RAS mutations.

Method: This study retrospectively analyzed the genetic and clinical characteristics 34 cases of JMML with Ras mutations who were initially diagnosed at the Hematology Hospital of the Chinese Academy of Medical Sciences (Institute of Hematology) from January 2008 to November 2022.

Results: Among 34 JMML with Ras mutations, 21 had NRAS mutations, 12 had KRAS mutations, and 1 had NRAS and KRAS compound mutations. The median age of onset was 14.5 months (range: 3-60 months), with a male proportion of 79.4%. All patients had splenomegaly, with a median palpable size of 5 centimeters (range 2-16 centimeters) of the subcostal spleen. The median white blood cell count in peripheral blood of all patients was 20.9 × 10⁹/L (range: 5.9-170.8 × 10⁹/L), the median hemoglobin was 83.5g/L (range: 58.0-117.0g/L), the median platelet count was 35.5 × 10⁹/L (range: 9.0-147.0 × 10⁹/L), and the median fetal hemoglobin was 6.3g/L (range: 1.4-62.7 g/L). Among 34 JMML patients with Ras mutations, 28 patients completed karyotype testing, of which 23 (82.1%) had normal karyotypes, 2 (8.7%) had monomeric 7-karyotype, and 3 (10.7%) had other karyotype abnormalities. In terms of treatment, 11 out of 34 children (32.4%) underwent hematopoietic stem cell transplantation (HSCT), including 5 cases with NRAS mutations, 6 cases with KRAS mutations. Follow up until January 2023, with a median follow-up time of 13 months (1-103 months). The median overall survival (OS) was 11.5 months (1-102 months), with a median OS of 13 months (1-72 months) for patients with NRAS mutations and 16 months (1-102 months) for patients with KRAS mutations. The median OS of the transplant group was 13 months (8-60 months), and the median EFS was 9.5 months (3-33 months). The median OS in the non-transplant group was 11.5 months (1-102 months). The overall survival rate of children in the transplantation group was higher than that in the non-transplantation group (P=0.037). Univariate analysis showed that liver size (≥ 2cm below the rib) and initial PLT<40 × 10⁹/L were factors affecting the survival rate of non- transplanted JMML children with Ras mutations (P<0.05). The results of the multivariate Cox proportional hazards regression model analysis showed that liver size (≥ 2cm below the rib) was a factor affecting the survival rate of non-transplanted JMML children with Ras mutations (P<0.05).

Conclusion: In our study, we reported the clinical and genetic characteristics of JMML patients with Ras mutations. And it was found that liver size and PLT at initial diagnosis are prognostic factors affecting JMML patients with non-transplanted Ras mutations.