Integration Analysis of JAK2 or RUNX1 Mutation With Bone Marrow Blast Can Improve Risk Stratification in the Patients With Lower Risk Myelodysplastic Syndrome.

Ying Fang,Ling-Yun Wu,Chun-Kang Chang,Zheng Zhang,Juan Guo,Dong Wu,Lu-Xi Song,You-Shan Zhao

doi:10.3389/fonc.2020.610525

Ying Fang, Ling-Yun Wu + Show 6 more

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https://doi.org/10.3389/fonc.2020.610525

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Abstract

Despite the improvements in prognostication of the revised International Prognostic Scoring System (IPSS-R) in myelodysplastic syndrome (MDS), there remain a portion of patients with lower risk (low/intermediate risk, LR) but poor prognostics. This study aimed to evaluate the relative contribution of mutational status when added to the IPSS-R, for estimating overall survival (OS) and progression-free survival (PFS) in patients with LR-MDS. We retrospectively analyzed clinical and laboratory variables of 328 patients diagnosed with MDS according to the FAB criteria. Twenty-nine-gene NGS assay was applied to bone marrow samples obtained at diagnosis. 233 (71.04%) patients were classified as LR-MDS. Univariate analysis showed association between inferior outcome (OS and PFS) and presence of JAK2 (p = 0.0177, p = 0.0002), RUNX1 (p = 0.0250, p = 0.0387), and U2AF1 (p = 0.0227, p = 0.7995) mutations. Multivariable survival analysis revealed JAK2 (p < 0.0001) and RUNX1 (p = 0.0215) mutations were independently prognostic for PFS in LR-MDS. Interestingly, bone marrow blast >1.5% could further predict disease progression of patients with LR-MDS (HR 8.06, 95%CI 2.95–22.04, p < 0.0001). Incorporation of JAK2, RUNX1 mutation and bone marrow blast in the IPSS-R can improve risk stratification in patients with LR-MDS. In summary, our result provided new risk factors for LR-MDS prognostics to identify candidates for early therapeutic intervention.

Highlights

Myelodysplastic syndrome (MDS) represents a heterogeneous group of clonal hematopoietic disorders with diverse clinical manifestations such as ineffective bone marrow (BM) hematopoiesis, peripheral blood cytopenia and variable propensity to progress to acute myeloid leukemia (AML) [1].Risk Factors for LR-MDS30% of MDS patients may progress to acute myeloid leukemia [2, 3]
We further investigate the prognostic influence of tumor mutation burden (TMB, ≥2 mutations) and recurrent mutations, univariate analysis indicated that TMB ≥2, RUNX1 and JAK2 mutations were associated with inferior overall survival (OS) and progression-free survival (PFS), and U2AF1 mutations was associated with inferior OS [hazard ratio (HR) > 1.5, p < 0.0500, Figure 2B]
Multivariable survival analysis revealed JAK2 [HR 6.58, 95%confidence interval (CI) 2.72–15.91, p < 0.0001] and RUNX1 [HR 3.25, 95%CI 1.19–8.89, p = 0.0215] mutations were independently prognostic for PFS in LR-MDS

Summary

Introduction

Myelodysplastic syndrome (MDS) represents a heterogeneous group of clonal hematopoietic disorders with diverse clinical manifestations such as ineffective bone marrow (BM) hematopoiesis, peripheral blood cytopenia and variable propensity to progress to acute myeloid leukemia (AML) [1]. 30% of MDS patients may progress to acute myeloid leukemia [2, 3]. This emphasizes the need to stratify MDS patients into low or high risk for progression to guide optimal MDS treatment. Patients with lower-risk (low/intermediate risk according to IPSS-R) myelodysplastic syndrome (LR-MDS) account for approximately two-thirds of patients with MDS. There remains a proportion of patients with lower risk but poor prognosis [5]. With the advance of generation sequencing (NGS), a number of driver mutations were found in MDS [6] with diverse prognosis under the standard immunochemotherapy [7, 8]

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