Primary myelofibrosis: Prognostic impact of non-driver mutations

Patients diagnosed with primary myelofibrosis (PMF) often present with non-driver mutations which are related to other myeloproliferative neoplasms. The presence of these non-driver mutations can influence the clinical phenotype and treatment response.

Recently, Hernández-Sánchez et al.¹ published results from a study in American Journal of Hematology investigating the impact of non-myeloproliferative neoplasm driver mutations in patients diagnosed with PMF. We summarize the key points below

Study design¹

• This study was performed across 60 Spanish sites (N = 312)
• Median age was 68 years
• A total of 20 genes out of 56 evaluated were consistently analyzed across all next-generation sequencing panels.
• Only pathogenic or likely-pathogenic variants with a variant allele frequency (VAF) of >1% were considered a mutation.

Key findings¹

• Non-driver mutations were identified in 72% of patients and 47% of patients had ≥2 non-driver mutations
• The most frequently identified non-driver mutation was ASXL1, followed by TET2 and SRSF2 (Figure 1)

*Adapted from Hernández-Sánchez, et al.¹

• The presence of any non-driver mutation resulted in a worse median overall survival (OS) vs patients with no non-driver mutations (p < 0.001)
  • 0 mutation: 12.4 years
  • 1 mutation: 8.7 years
  • ≥2 mutations: 4.4 years
• A VAF of >20% was shown to be an adverse prognostic factor

• Univariate analysis identified the following mutations to be associated with shorter OS: SRSF2 (p < 0.001), CBL (p < 0.001), SETBP1 (p = 0.012), TP53 (p = 0.016), U2AF1 Q157 (p = 0.021), NRAS (p = 0.032), and EZH2 (p = 0.034).
• Mutations identified as independent prognostic factors were: SRSF2 (p < 0.001), CBL (p = 0.003), EZH2 (p = 0.013), SETBP1 (p = 0.024), and ASXL1 with a VAF of >20% (p = 0.042).

Key learnings
Results confirm the adverse prognostic role of gene mutations included in current prognostic scores for PMF. The study supports the independent impact of CBL, TP53, and SETBP1 mutations on OS. The prognostic impact of ASXL1 mutations is dependent on VAF ≥20% which may aid future decisions regarding allogeneic hematopoietic stem cell transplantation.