Newly Identified DNA Mutations Predict for Worse Survival Among Patients With Polycythemia Vera and Essential Thrombocythemia

The driver mutations JAK2, CALR, and MPL have prognostic and diagnostic significance for patients with the myeloproliferative neoplasms polycythemia vera (PV) and essential thrombocythemia (ET). In a next-generation sequencing (NGS) study published in Blood Advances, researchers have identified new sequence variants/mutations that can predict for worse overall, leukemia-free, or myelofibrosis-free survival in these patients.

“The study identifies prognostically important specific sequence variants/mutations and demonstrates the subsidiary role of the ‘number’ of mutations,” the authors, led by Ayalew Tefferi, MD, from the Division of Hematology at the Mayo Clinic in Rochester, Minnesota, wrote, adding that incorporating molecular information into prognostic models for PV and ET could help refine risk stratification. “The observations from the study are practically relevant and timely, considering the increasing use of targeted NGS in routine myeloid cancer practice,” the authors wrote.

The investigators developed a 27-gene myeloid neoplasm panel (consisting of genes that are commonly included in commercially available NGS panels) to sequence bone marrow or whole blood DNA from 316 patients diagnosed with PV (n=133) or ET (n=183). The panel included the following genes: TET2, DNMT3A, IDH1, IDH2, ASXL1, EZH2, SUZ12, SRSF2, SF3B1, ZRSR2, U2AF1, PTPN11, TP53, SH2B3, RUNX1, CBL, NRAS, JAK2, CSF3R, FLT3, KIT, CALR, MPL, NPM1, CEBPA, IKZF1, and SETBP1.

The “driver” mutations (JAK2, CALR, and MPL) were common among the patient population: The JAK2 mutation was present in 98 percent of patients with PV, while the JAK2 mutation was present in 52 percent, CALR was present in 26 percent, and MPL was present in 4 percent of patients with ET. More than half of patients with PV and ET had sequence variants/mutations other than the driver mutations: 70 (52.6%) patients with PV and 96 (52.5%) with ET.

The most frequent sequence variants/mutations in both disorders were TET2 and ASXL1. Notably, there were no significant associations between driver mutation status and the number or type of other sequence variants/mutations.

During follow-up, the numbers of documented deaths, leukemic transformations, and fibrotic progressions were 62 (47%), 7 (5.3%), and 14 (11%), respectively, for patients with PV, and 61 (33%), 6 (3.3%), and 27 (15%), respectively, for patients with ET.

Median survival among the patients was 14.2 years for those with PV and 19.9 years for those with ET (ranges not provided). The researchers identified three variants/mutations as “adverse” (meaning their presence was associated with lower overall, leukemia-free, or myelofibrosis-free survival) for patients with PV (ASXL1, SRSF2, and IDH2) and six adverse variants for patients with ET (SH2B3, IDH2, SF3B1, U2AF1, EZH2, TP53).

At least one of the three adverse variants/mutations was present in 20 (15%) of the 133 PV patients and, the more sequence variants/mutations a patient had (adverse or not adverse), the worse his or her survival. Patients who had three sequence variants/mutations (n=4) had significantly worse survival compared with those with two (n=26; p=0.04), one (n=40; p=0.003), or no (n=63; p=0.003) sequence variant/mutation. “The shorter survival seen in the four patients with three sequence variants/mutations was fully accounted for by the presence of adverse variants/mutations in all of them,” the authors noted.

Similar findings were reported for patients with ET: Patients without any mutation (n=87) had significantly longer survival compared with those with three or four mutations (n=7; p<0.0001) or one (n=75; p=0.0009) sequence variant, but not with those with two sequence variants (n=14; p=0.28).

In both groups, these adverse variants/mutations conferred a survival risk independent of age, risk level (determined by score on the International Working Group Prognostic Model), or karyotype.

Dr. Tefferi and authors confirmed their findings in an external validation cohort of 215 patients with PV and 174 patients with ET. For PV, the adverse variants/mutations were independently associated with poor overall survival (OS; hazard ratio [HR] = 2.41 for ASXL1; HR=3.84 for SRSF2) and myelofibrosis-free survival (HR=1.9 for ASXL1). For ET, the adverse variants/mutations also were independently associated with poor OS (HR=2.9 for U2AF1), myelofibrosis-free survival (HR=3.2 for U2AF1), and leukemia-free survival (HR=7.3 for TP53). See the TABLE for all adverse outcomes.

Additional studies are warranted “to refine and possibly expand the pool of clinically relevant DNA sequence variants/mutations that could be targeted by NGS,” the authors noted as limitations of the study. “Such a strategy would ideally also include sequence variants/mutations that identify patients with increased risk of thrombosis,” which the current study was not powered to detect.


Tefferi A, Lasho TL, Guglielmelli P, et al. Targeted deep sequencing in polycythemia vera and essential thrombocythemia. Blood Adv. 2016 November 22.

TABLE. Adverse Variants/Mutations and Effect on Survival Outcomes
Adverse Variant/ Mutation Survival Outcome

Hazard ratio (95% CI)

Essential Thrombocythemia
SH2B3 Overall survival: 3.0 (1.03-8.2)
IDH2 Overall survival: 22.1 (2.8-176.9)
SF3B1 Myelofibrosis-free survival: 8.1 (2.5-25.8)
U2AF1 Myelofibrosis-free survival: 30.3 (3.4-271.0)
EZH2 Leukemia-free survival: 146.8 (11.1-1935.6)
TP53 Leukemia-free survival: 82.8 (7.5-91.6)
Polycythemia Vera
ASXL1 Overall survival: 2.2 (1.1-4.3)
SRSF2 Overall survival: 6.1 (2.0-19.2)
Leukemia-free survival: 74.5 (4.4-1261.7)
Myelofibrosis-free survival: 27.2 (2.7-274.3)
IDH2 Leukemia-free survival: 55.5 (3.5-887.4)