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Do High Molecular Risk Mutations Increase Leukemia Risk in Myelofibrosis?

By Melissa Badamo November 30, 2023

Concurrent high-molecular risk (HMR) mutations and lower mutant JAK2V617F allele burden were identified in patients with myelofibrosis (MF) with significantly reduced overall survival (OS) and high risk of leukemic transformation, according to a recent study.

The multicenter trial, led by Yu-Hung Wang, MD, MSc, of the University of Manchester in the United Kingdom, studied genetic mutations across three cohorts.

First, researchers recruited a discovery cohort of 122 patients with MF (median age, 61 years) with an available mutation profile determined by next-generation sequencing. Fifty-five patients (45%) had at least one HMR mutation such as ASXL1, EZH2, SRSF2, IDH, and U2AF1. ASXL1 was the most common genetic alteration (37%) other than driver mutations, followed by TET2 (16%) and EZH2 (12%). The most common driver mutation was JAK2V617F (64.8%), followed by CALR (18%) and MPL (9%).

Median OS after 28.2 months was not reached (NR), and patients with at least one HMR mutation had significantly shorter leukemia-free survival (LFS) and OS than those without (P<0.001).

Next, 79 JAK2-mutated patients were divided into either lower-allele (JAK2low) or higher-allele (JAK2high) burden groups. JAK2low patients had significantly lower OS than JAK2high patients (median 53 months vs NR; P=0.037), concurrent with previous data. Of all the JAK2-mutated patients, those with HMR mutations had a significantly shorter OS compared with those without HMR mutations (50 months vs NR; P<0.001).

When considering HMR mutations with JAK2V617F allele burden, researchers discovered that HMR alterations conferred worse LFS and OS in JAK2low patients, but not in JAK2high patients. Therefore, researchers determined that patients with simultaneous HMR mutations and lower mutant JAK2V617F allele burden had distinctively inferior OS.

Finally, the third cohort validated the link between HMR/JAK2 allele burden and LFS/OS. According to co-occurrence tests, “…there was no shared mutational co-occurrence pattern among the three cohorts, excluding the potential confounding influence of specific concurrent mutations,” Dr. Wang and colleagues noted. Therefore, they concluded that simultaneous HMR mutations and lower JAK2V617F allele burden is an adverse prognostic factor for MF regardless of age, risk stratification systems, and other mutations.


Wang Y, Gurnari C, Wei C, et al. HMR mutations drive poor prognosis in myelofibrosis patients with lower JAK2V617F allele burden but not in those with higher allele burden: results of a multicenter study. Abstract #627. Presented at the 65th ASH Annual Meeting and Exposition; December 9-12, 2023; San Diego, California.

Original Source: Do High Molecular Risk Mutations Increase Leukemia Risk in Myelofibrosis Patients? | Blood Cancers Today

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