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Essential thrombocythemia (ET), a Ph-negative myeloproliferative neoplasm (MPN) is prone to higher risk of thrombohemorrhagic complications including progression to myelofibrosis (MF), which is associated with poorer prognosis. Most patients with ET harbor one of the three MPN-specific clonal markers, including JAK2V617F, calreticulin (CALR), and thrombopoietin receptor gene (MPL) mutations that are drivers of JAK-STAT signaling pathway. Previously a few studies have identified driver CALR and MPL mutations and additional SF3B1 and U2AF1 mutations as risk factors for progression to MF; however, data are limited on the risk of progression to MF.
Loscocco et al,1 recently published a retrospective cohort study in the American Journal of Hematology, identifying clinical and molecular variables predictive of inferior myelofibrosis-free survival (MFS) in patients with ET, defined by World Health Organization (WHO). The key findings are summarized here.
A retrospective, multicenter, cohort study utilizing three independent cohorts: University of Florence, Italy (n = 718) as the experimental cohort; Mayo Clinic, USA (n = 479), and Catholic University, Rome, Italy (n = 410) as two independent validation cohorts.
Median age at diagnosis was 57.9 years (range, 12.9−92.9) (Table 1) with a median follow-up of 106 months (range, 6−422) in the experimental Florence cohort. Palpable splenomegaly, constitutional symptoms, major thrombosis at diagnosis, major bleeding, and acute myeloid leukemia (AML) progression were not statistically significant variables at baseline.
Table 1. Clinical and laboratory variables of patients, stratified by their driver mutational status*
Variable |
All patients |
JAK2 |
CALR type 1/1-like |
CALR type 2/2-like |
MPL |
TN |
p value‡ |
---|---|---|---|---|---|---|---|
Age in year, |
57.9 |
62.0 |
52.6 |
48.9 |
54.8 |
49.2 |
<0.001 |
Age ≥60 years, % |
46.4 |
53.7 |
32.6 |
25.5 |
42.3 |
33.3 |
<0.001 |
Sex, females, % |
64.8 |
67.5 |
42.6 |
49.0 |
76.9 |
80.8 |
<0.001 |
WBC × 109/, |
8.3 |
8.7 |
8.2 |
7.2 |
6.8 |
7.6 |
<0.001 |
WBC ≥11 × 109/L |
16.4 |
19.6 |
12.8 |
4.2 |
20.0 |
7.7 |
0.01 |
Hb, g/dl, |
14.1 |
14.4 |
13.8 |
13.7 |
13.6 |
13.5 |
<0.001 |
Hematocrit, median (range) |
42.9 |
43.9 |
41.6 |
41.2 |
41.3 |
40.9 |
<0.001 |
Platelets × 109/L, |
739 |
698 |
823 |
886 |
852 |
794 |
<0.001 |
Platelets ≥ 1,000 × 109/L, % |
17.5 |
12.9 |
26.1 |
31.4 |
26.9 |
23.1 |
0.001 |
Major thrombosis before diagnosis |
6.2 |
8.6 |
1.2 |
0.0 |
0.0 |
3.8 |
0.01 |
Overall thrombosis at follow-up |
13.8 |
14.7 |
15.4 |
14.0 |
26.9 |
2.6 |
0.01 |
Cardiovascular risk factors |
52.9 |
59.5 |
44.7 |
34.1 |
48.0 |
39.7 |
<0.001 |
Microcirculatory symptoms |
33.1 |
32.0 |
28.1 |
36.0 |
61.5 |
34.6 |
0.03 |
MF progression, % |
7.4 |
4.9 |
21.7 |
7.9 |
19.2 |
1.3 |
<0.001 |
Death, % |
14.8 |
16.3 |
16.3 |
5.9 |
23.1 |
6.4 |
0.04 |
CALR, calreticulin; Hb, hemoglobin; JAK2, Janus kinase 2; MPL, myeloproliferative leukemia; MF, myelofibrosis; TN, triple negative; WBC, white blood cell. |
Table 2. Multivariate analysis of clinical and molecular risk factors for MFS*
Variables |
Multivariable analysis† |
Multivariable analysis‡ |
Multivariable analysis§ |
---|---|---|---|
Age > 60 years |
0.005 |
0.02 |
0.05 |
Sex, male |
0.02 |
0.3 |
0.01 |
Constitutional symptoms |
0.06 |
0.3 |
0.04 |
Palpable splenomegaly |
0.01 |
0.003 |
0.02 |
CALR 1/1-like/MPL |
< 0.001 |
— |
— |
JAK2V617F VAF >35% vs ≤35% |
— |
0.003 |
— |
CALR 1/1-like + MPL + JAK2V617F > 35% vs all the others |
— |
— |
< 0.0001 |
CALR, Calreticulin; JAK2, Janus kinase 2; MPL, myeloproliferative leukemia; VAF, variant allele frequency. |
The study showed useful risk signals for fibrotic transformation in patients with ET and enhanced the identification of patients who require close monitoring and appropriate counselling. However, the findings from the study should be interpreted with caution due to the certain caveats such as retrospective study leading to selection bias.
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