ASXL1 Mutations Linked with Survival, Progression in Primary Myelofibrosis

A new meta-analysis confirms that ASXL1 mutations could be an important prognostic indicator in patients with myeloproliferative neoplasms.

Mutations of the additional sex combs like 1 (ASXL1) gene appear to have a significant adverse impact on the prognosis of patients with primary myelofibrosis (PMF), according to findings from a new meta-analysis that shows a higher probability of transformation to acute leukemia and shorter overall survival (OS) with alterations in ASXL1. The findings were published in the Annals of Hematology.

The prognosis for patients with PMF is typically calculated using the International Prognostic Scoring System (IPSS) or the Dynamic International Prognostic Scoring System (DIPSS) and DIPSS-Plus system. The problem, according to corresponding author Xiaomei Hu, MD, of the China Academy of Chinese Medical Sciences, and colleagues, is that such systems typically focus on clinical characteristics and karyotypes of patients.

“In recent years, more and more studies have begun to pay attention to the role of gene mutations in the pathogenic mechanism of hematologic diseases, and its influence on the progression and survival of PMF has gradually emerged,” Hu and colleagues wrote.

Such advances have created an urgent need to update prognostic stratification methods, the investigators added.

“With the rapid development of sequencing technology, in addition to the driver genes, varieties of somatic gene mutations have been discovered in PMF patients, which may play a significant role in the pathogenesis and clinical prognosis of PMF patients,” they said.

Somatic ASXL1 mutations are common in patients with PMF, with estimates suggesting mutations exist in between 13% and 38% of cases. Mutations can take the form of frameshift, nonsense, or missense mutations; frameshift mutations are the most common.

An increasing number of studies has suggested ASXL1 mutations play a significant role in patient prognosis, but Hu and colleagues said that stance remains controversial because it is unclear what exact role the mutations play.

In order to get a better sense of whether ASXL1 mutations are a meaningful prognostic indicator, the investigators conducted a meta-analysis of existing studies and trials that assessed the impact of ASXL1 mutations in PMF and included data on OS and/or progression to acute leukemia. The search eventually yielded 14 studies, which together included 4501 patients, 30.95% of whom had ASXL1 mutations.

All but one of the studies included OS data. Those studies involved 3527 patients. The meta-analysis showed that the overall hazard ratio (HR) for patients with the ASXL1 mutation was 2.30 (95% CI, 1.79-2.94; P <.00001) compared to those with wild-type ASXL1, suggesting patients with mutations have worse prognoses, Hu and colleagues said.

Three of the 14 studies included leukemia-free survival (LFS) as a metric; they showed an overall HR for LFS of 1.77 (95% CI, 1.30-2.42; P = .0003) in the mutated group versus the non-mutated group.

Finally, 6 studies looked at transformation rates to acute leukemia. Hu and colleagues used data from those studies to calculate an odds ratio (OR) of 2.06 (95% CI, 1.50-2.83; P <.00001) of transformation in patients with the mutation. The investigators said their data affirm earlier findings suggesting ASXL1 mutations play a role in disease severity in PMF.

In addition to ASXL1, many experts believe EZH2, SRSF2, and IDH1/IDH2 are also prognostically detrimental in PMF, putting patients in a high molecular risk category, with shorter OS and a greater likelihood of progression.

However, the authors also noted that the poor prognosis linked with ASXL1 could also have to do with the fact that the mutations are more common among patients older than 65 who are male and have a lower platelet count. They said insufficient data were available to conduct a full analysis of clinical features.

Hu and colleagues noted that the studies in their analysis were not uniform. They found significant heterogeneity in the results when it came to OS; however, when the team excluded 2 outlier studies from the data (due to the inclusion of more patients with overt PMF and lower risk DIPSS in these studies), they still found a significant correlation between ASXL1 mutations and OS, suggesting that their conclusion is reliable.

The investigators said their findings are subject to limitations, such as the fact that all included studies were retrospective, observational studies, rather than prospective, randomized, controlled trials. They also noted that the studies had different confounding factors in their multivariate analyses, potentially increasing heterogeneity into the results.

Hu and colleagues said there is significant evidence that ASXL1 should become an important molecular marker for risk stratification in PMF, though they said a large prospective cohort study is warranted to help solidify their findings.

“We believe that with the in-depth study of genetic variation and the development of next-generation sequencing technology, our understanding of the pathogenesis and risk factors for hematologic malignancies will be more profound,” they concluded.


Wang Z, Liu W, Wang M, et al. Prognostic value of ASXL1 mutations in patients with primary myelofibrosis and its relationship with clinical features: a meta-analysis. Ann Hematol. 2021;100(2):465-479. doi:10.1007/s00277-020-04387-7