Clinical Phenotype, Molecular Architecture, and Survival Follow-Up in NRAS- and KRAS-Mutated Juvenile Myelomonocytic Leukemia.
Juvenile myelomonocytic leukemia (JMML) is a rare RAS/MAPK-driven pediatric myelodysplastic/myeloproliferative neoplasm. The phenotype and survival relevance of NRAS/KRAS alterations remain difficult to interpret because of co-mutations, evolving sequencing, incomplete germline confirmation, and post-diagnostic HSCT.
We retrospectively reviewed 34 children with JMML and classifiable NRAS and/or KRAS alterations diagnosed between November 2010 and September 2022. Patients were classified as NRAS-only, KRAS-only, or NRAS/KRAS co-mutated. Direct comparisons used single-subtype cases. OS was analyzed in evaluable patients, with HSCT modeled as a time-dependent covariate.
The cohort included 20 NRAS-only, 12 KRAS-only, and 2 NRAS/KRAS co-mutated cases. KRAS-only cases had higher monocyte percentage (27.2% vs. 16.7%; p = 0.023) and lymphocyte percentage (48.1% vs. 39.0%; p = 0.018), whereas absolute monocyte count was comparable (4.0 vs. 4.0 × 109/L; p = 0.930). PTPN11 was the most frequent non-RAS co-mutation (7/34) and occurred in both NRAS/KRAS co-mutated cases. Methylation status was available in 11 patients and analyzed descriptively. NRAS/KRAS subtype did not significantly stratify OS (HR for KRAS-only vs. NRAS-only, 0.55; 95% CI, 0.18-1.62; p = 0.276). HbF did not significantly stratify OS, while diagnostic total hemoglobin showed only an exploratory univariable association. Exact HSCT dates were retrieved for all 11 transplanted patients; time-dependent Cox analysis showed a significant association between HSCT and better OS (HR, 0.11; 95% CI, 0.02-0.56; p = 0.007).
NRAS/KRAS status defined a limited diagnosis-time phenotype but did not independently stratify survival. JMML survival analyses should integrate co-mutations, germline and testing-era limitations, HbF/hemoglobin risk context, and time-dependent HSCT handling.
We retrospectively reviewed 34 children with JMML and classifiable NRAS and/or KRAS alterations diagnosed between November 2010 and September 2022. Patients were classified as NRAS-only, KRAS-only, or NRAS/KRAS co-mutated. Direct comparisons used single-subtype cases. OS was analyzed in evaluable patients, with HSCT modeled as a time-dependent covariate.
The cohort included 20 NRAS-only, 12 KRAS-only, and 2 NRAS/KRAS co-mutated cases. KRAS-only cases had higher monocyte percentage (27.2% vs. 16.7%; p = 0.023) and lymphocyte percentage (48.1% vs. 39.0%; p = 0.018), whereas absolute monocyte count was comparable (4.0 vs. 4.0 × 109/L; p = 0.930). PTPN11 was the most frequent non-RAS co-mutation (7/34) and occurred in both NRAS/KRAS co-mutated cases. Methylation status was available in 11 patients and analyzed descriptively. NRAS/KRAS subtype did not significantly stratify OS (HR for KRAS-only vs. NRAS-only, 0.55; 95% CI, 0.18-1.62; p = 0.276). HbF did not significantly stratify OS, while diagnostic total hemoglobin showed only an exploratory univariable association. Exact HSCT dates were retrieved for all 11 transplanted patients; time-dependent Cox analysis showed a significant association between HSCT and better OS (HR, 0.11; 95% CI, 0.02-0.56; p = 0.007).
NRAS/KRAS status defined a limited diagnosis-time phenotype but did not independently stratify survival. JMML survival analyses should integrate co-mutations, germline and testing-era limitations, HbF/hemoglobin risk context, and time-dependent HSCT handling.
Authors
Zhang Zhang, Liu Liu, Li Li, Wan Wan, Chen Chen, Guo Guo, Zhang Zhang, Zou Zou, Liu Liu, Chen Chen, Hu Hu, Zhang Zhang, Zhu Zhu, Yang Yang
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