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Comparative Lesions Analysis Through a Targeted Sequencing Approach
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Comparative Lesions Analysis Through a Targeted Sequencing Approach

Published on: November 5, 2019

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Targeted deep sequencing in primary myelofibrosis

Ayalew Tefferi1, Terra L Lasho1, Christy M Finke1

  • 1Division of Hematology, Department of Internal Medicine.

Blood Advances
|January 4, 2018
PubMed

Insights

Genetic mutations beyond JAK2/CALR/MPL are common in primary myelofibrosis (PMF) and significantly impact patient survival. Identifying these adverse mutations improves prognostic accuracy for overall and leukemia-free survival in PMF patients.

Area of Science:

  • Hematology
  • Oncology
  • Genetics

Background:

  • Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by bone marrow fibrosis.
  • The prognostic significance of genetic mutations, particularly JAK2, CALR, and MPL, is well-established in PMF.
  • However, the role of other genetic variants in PMF prognosis requires further elucidation.

Purpose of the Study:

  • To investigate the prevalence and prognostic impact of DNA sequence variants/mutations other than JAK2/CALR/MPL in patients with PMF.
  • To identify specific adverse mutations and assess their contribution to overall survival (OS) and leukemia-free survival (LFS).
  • To evaluate the combined prognostic value of these additional mutations, independent of existing scoring systems.

Main Methods:

  • Next-generation sequencing (NGS) of a 27-gene panel was performed on bone marrow or whole blood DNA from 182 PMF patients.
  • Age-adjusted multivariable analysis was used to identify adverse variants/mutations impacting OS and LFS.
  • Statistical analyses, including survival curves and hazard ratios, were employed to assess prognostic significance.

Main Results:

  • 81% of patients harbored variants/mutations other than JAK2/CALR/MPL, with ASXL1, TET2, SRSF2, and U2AF1 being most frequent.
  • Adverse variants/mutations (ASXL1, SRSF2, CBL, KIT, RUNX1, SH2B3, CEBPA) were present in 56% of patients and associated with inferior OS (3.6 vs 8.5 years) and LFS (7-year risk, 25% vs 4%).
  • The prognostic impact of these adverse mutations was independent of the Dynamic International Prognostic Scoring System Plus and JAK2/CALR/MPL status, with a significant increase in risk for OS and LFS.

Conclusions:

  • DNA variants/mutations beyond JAK2/CALR/MPL are prevalent in PMF and carry significant prognostic information.
  • The number and specific types of adverse mutations identified provide additional predictive value for overall and leukemia-free survival.
  • These findings underscore the importance of comprehensive genetic profiling for improved risk stratification and management of PMF patients.

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