Myelofibrosis is characterized by mutations in the JAK–STAT pathway, specifically in the myeloproliferative neoplasm (MPN) driver genes JAK2, CALR, and MPL. However, patients often have mutations in other MPN-related genes, influencing their disease’s clinical phenotype and treatment response.

In a letter to the editor published in the American Journal of Hematology, Alberto Hernández-Sánchez, MD, and coinvestigators shared their efforts to analyze the impact of nonMPN driver somatic mutations. Their study included 312 patients with primary myelofibrosis. The researchers evaluated 56 genes using next-generation sequencing (NGS). Of note, 72% of patients had non-MPN driver mutations, with 47% presenting two or more mutations. The most frequent mutations were in ASXL1 (34%), TET2 (22%), and SRSF2 (17%).

Per the findings, the presence of any NGS-detected mutation was associated with worse outcomes. Patients without mutations had a median OS of 12.4 years, compared to 8.7 years for those with a single non-MPN driver mutation and 4.4 years for those with two or more mutations. Specific mutations in SRSF2, CBL, SETBP1, TP53, U2AF1 Q157, NRAS, and EZH2 were significantly associated with shorter OS. The adverse impact of ASXL1 mutations on OS was significant only when the variant allele frequency exceeded 20%.

The researchers also examined the integration of mutations not included in the MIPSS70 model. Incorporating CBL, SETBP1, TP53, NRAS, and KRAS mutations improved the model’s discriminative capacity. In the MIPSS70 intermediate- and high-risk groups, the presence of these mutations was associated with significantly shorter OS. Using multivariate analysis, the investigators identified SRSF2, CBL, EZH2, SETBP1, and ASXL1 mutations with variant allele frequency >20% as independent prognostic factors for OS.

The researchers emphasized the significance of considering the variant allele frequency of ASXL1 mutations, particularly the >20% threshold, which could impact allogeneic HSCT decision-making. “To our knowledge, this is the first study to report that the prognostic value of ASXL1 mutations is dependent on variant allele frequency, exhibiting an incremental effect in which the higher the variant allele frequency the worse OS,” Dr. Hernández-Sánchez and colleagues concluded.