In patients with myelofibrosis (MF), driver mutation status, presence of additional mutations (especially of high-molecular risk, HMR) and adverse karyotype all have prognostic value and, as a result, have been incorporated into recent prognostic models.

Published data from several real-world studies on momelotinib-treated (MMB) MF patients confirm its efficacy—particularly in improving anemia and reducing transfusion dependence. The MOMGEMFIN study included 154 MF patients treated with MMB, 76.6% of which had prior JAK inhibitor exposure. At baseline, 70.1% were transfusion-dependent (TD). MMB led to a sustained improvement in anemia, with achievement of transfusion independence (TI) in 48.4% of TD patients at 3 months. However, there is still limited data regarding predictors of response based on patients' mutational profiles.

In this context, we present the results of the molecular sub-analysis from the MOMGEMFIN project, which studied the impact of genetic profile on response to (MMB). The main variables analyzed were driver gene mutations and presence of additional mutations, evaluated with next-generation sequencing (NGS) using a myeloid gene panel. HMR were defined as presence of pathogenic/probable pathogenic mutation in ASXL1, EZH2, IDH1/2, SRSF2, U2AF1 genes.

NGS data was available in 108 patients prior to MMB start. Sixty-two percent were male, with a median follow-up of 4.95 months. The most frequent driver mutation genotype was JAK2 (63%), followed by CALR (22.7%), triple negative (TN) (6.5%), MPL (5.8%), and unknown (1.9%). Among patients with NGS data, 63.9% harbored additional mutations, the most common being ASXL1 (34.3%), TET2 (14.8%), U2AF1 (11.1%), SRSF2 (8.3%), EZH2 (8.3%), SF3B1 (8.3%), RAS (7.4%), and IDH1/2 (3.7%).

Among 122 patients with baseline anemia, no association was observed between anemia response (according to 2024 IWG-ELN criteria) and driver mutations. However, patients with additional mutations showed a trend toward poorer anemia response (>1 g/dL, p=0.013; >1.5 g/dL, p=0.002; Pearson), particularly those with a HMR. Statistical significance was not reached for individual genes, likely due to the small sample size, with the exception of U2AF1.

Driver mutations had no significant impact on transfusion independence (TI, according to 2024 IWG-ELN criteria). However, only a third of patients with additional mutations achieved transfusion independence (15/45, 33.3%), compared to 55.6% of patients without an additional mutation (p=0.103). This decreased further to just 16.7% of patients with more than one HRM mutation (p=0.023). The presence of a U2AF1 mutation was significantly associated with not reaching TI (p=0.022).

For the group of patients previously treated with JAK inhibitors (n=118), JAK2 mutation was associated with TI (p=0.008), whereas TN and MPL were negative predictors (p=0.067 and p=0.155). This trend was not observed for the JAK inhibitor-naïve group (p=0.053), likely due to the small sample size.

Overall survival from the initiation of MMB differed significantly according to driver mutation status (p = 0.023; Log-rank test). Longer survival was observed in patients with JAK2 (mean: 11.7 months) and CALRmutations (mean: 13.7 months), whereas patients with MPL mutations or TN had shorter survival (mean: 7.0 and 7.1 months, respectively). Presence of additional mutation was not significant, but a negative trend was observed with U2AF1 and HMR. JAK2mut patients who had received prior JAK inhibitor treatment also showed superior OS compared to other driver mutations (p=0.042).

The positive impact of JAK2mut on OS (p=0.034 Log-rank, JAK2mut vs. JAK2WT) was completely negated if patients also harbored a U2AF1 mutation (n=12 JAK2/U2AF1 co-mutated), with survival significantly reduced from MMB initiation (p=0.037) and from the time of diagnosis (p<0.001).

Importantly, TI was associated with improved overall survival, both from diagnosis (p=0.012) and from MMB start (p=0.007).

Conclusion

These data show that U2AF1mut correlates with a lower probability of TI in MMB treated patients. The JAK2 driver mutation was associated with a better response to MMB with the exception of those with a U2AF1 co-mutation. Transfusion dependence negatively impacted overall survival, consistent with published data.

This content is only available as a PDF.
2025
Sign in via your Institution