Prognostic value of ASXL1 mutations in patients with primary myelofibrosis and its relationship with clinical features: a meta-analysis

Mingjing Wang,Jing Ming,Ziqing Wang,Erpeng Yang,Yujin Li,Xueying Wang,Richeng Quan,Weiyi Liu,Xiaomei Hu

doi:10.1007/s00277-020-04387-7

Abstract

Additional sex combs like 1 (ASXL1) mutations are one of the most common molecular biological abnormalities in patients with primary myelofibrosis (PMF), and the effect of these mutations on prognosis remains controversial. Hence, we conducted a meta-analysis to assess the prognostic value and clinical characteristics of ASXL1 mutations in PMF patients. Eligible studies were systematically searched from PubMed, Embase, and the Cochrane Library. We extracted the hazard ratios (HRs) and their 95% confidence intervals (CIs) of overall survival (OS) and leukemia-free survival (LFS), the number of patients transformed to acute leukemia, and clinical characteristics to carry out a meta-analysis by fixed effect model or random effect model according to the heterogeneity between studies. A total of 4501 PMF patients from 16 cohorts of 14 studies were included in this meta-analysis. The results revealed that ASXL1 mutations might predict a shorter OS (HR = 2.30, 95% CI: 1.79–2.94, P < 0.00001) and a higher probability of transformation to acute leukemia (LFS: HR = 1.77, 95% CI: 1.30–2.42, P = 0.0003; the rate of acute leukemia transformation: OR = 2.06, 95% CI: 1.50–2.83, P < 0.00001). Furthermore, ASXL1 mutations were correlated with patients older than 65 years old, male, a lower level of platelet counts, and a higher risk of the international prognostic score system. These findings indicate that ASXL1 mutations have a significant adverse impact on the prognosis of PMF patients and may contribute to risk stratification and prognostic assessment for PMF patients.

Highlights

Primary myelofibrosis (PMF) is a kind of breakpoint cluster region protein (BCR)-Abelson tyrosine-protein kinase (ABL)–negative myeloproliferative neoplasm (MPN) resulted from the clonal proliferation of abnormal hematopoietic stem cells
Studies were included in the meta-analysis if they met the following criteria: (1) original articles were prospective or retrospective cohort studies and clinical trials; (2) assessed the prognostic effect of Additional sex combs like 1 (ASXL1) mutations in PMF patients; (3) provided data on overall survival (OS), leukemia-free survival (LFS) or the number of cases transformed to acute leukemia, from which we could get the hazard ratios (HRs) and their 95% confidence intervals (CIs) or sufficient data to estimate; (4) papers published in English
The results revealed that ASXL1 mutations have a prominent adverse effect on the prognosis of PMF patients

Summary

Introduction

Primary myelofibrosis (PMF) is a kind of breakpoint cluster region protein (BCR)-Abelson tyrosine-protein kinase (ABL)–negative myeloproliferative neoplasm (MPN) resulted from the clonal proliferation of abnormal hematopoietic stem cells. It is mainly characterized by bone marrow fibrodysplasia, severe anemia, splenomegaly, constitutional symptoms (fatigue, night sweats, fever, cachexia), extramedullary hematopoiesis, progression to leukemia, and short survival [1]. More and more studies have begun to pay attention to the role of gene mutations in the pathogenic mechanism of hematological diseases, and its influence on the progression and survival of PMF has gradually emerged; in the meantime, the traditional prognostic stratification method needs to be improved urgently [7,8,9,10]. With the widespread application of next-generation sequencing technology in hematological malignancies, studies found that besides MPN driver gene mutations (JAK2, CALR, MPL), there were often other gene mutations in PMF patients, including histone modification genes (ASXL1 and EZH2), RNA splicing factor genes (SRSF2, U2AF1, and SF3B1), DNA methylation (DNMT3A, TET2, and IDH1/2), signal transduction genes (CBL and NRAS), and DNA repair genes (TP53), which may coexist with driver gene mutations or in patients without driver gene mutations, and some patients may carry two or more non-driver gene mutations at the same time, some of which may affect the evolution and prognosis of PMF [11,12,13]

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Results

Conclusion