Blood Advances in a Different Vein
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
Adverse Variants/Mutations and Effect
on Survival Outcomes
TABLE.
Adverse Variants/
Mutations
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)
IDH2
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ASH Clinical News
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. ●
Myelofibrosis-free survival: 27.2 (2.7-274.3)
REFERENCE
Leukemia-free survival: 55.5 (3.5-887.4)
Tefferi A, Lasho TL, Guglielmelli P, et al. Targeted deep sequencing in polycythemia vera and essential thrombocythemia.
Blood Adv. 2016 November 22.
December 2016