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Hydroxyurea is a cytoreductive agent offered to patients with polycythemia vera (PV) for treating symptoms such as splenomegaly and leukocytosis.1 Unfortunately, hydroxyurea resistance occurs in 20–30% of patients with PV and is associated with increased risk of thrombosis, disease progression, and adverse survival outcomes. While genomic classification of myeloproliferative neoplasms (MPN) based on data from next-generation sequencing (NGS) has been used for prognosis predictions, the association between molecular characteristics and the risk of developing hydroxyurea resistance is yet to be explored.2
In a letter to the editor, Alberto Alvarez-Larrán and colleagues presented a study in Leukemia that aimed to characterize hydroxyurea-resistant patients with PV by molecular classification and to correlate results with disease progression and survival outcomes.2
Baseline patient characteristics are presented in Table 1
Table 1. Patient characteristics and molecular classification at diagnosis in patients with PV according to development of hydroxyurea-resistance versus controls2
Characteristics |
Hydroxyurea-resistant patients |
Controls |
p value |
---|---|---|---|
Age, years (range) |
66 (36-88) |
66 (20-84) |
0.3 |
Female, n (%) |
26 (43) |
25 (42) |
0.9 |
History of thrombosis, n (%) |
20 (33) |
16 (27) |
0.5 |
Hemoglobin, g/L (range) |
179 (145-223) |
170 (146-238) |
0.1 |
Leukocyte count, x 109/L (range) |
12.3 (5.3-26.6) |
11.1 (4.8-20.4) |
0.03 |
Platelet count, x 109/L (range) |
508 (123-1302) |
534 (163-974) |
0.6 |
JAK2 mutation: |
|
|
|
V617F, n (%) Exon 12, n (%) |
59 (96.7) 1 (1.6) |
59 (100) |
ns |
|
|||
Molecular Group |
Hydroxyurea-resistant patients |
Controls (n = 59) |
|
TP53 disruption or aneuploidy, n (%) |
10 (16.4) |
1 (1.7) |
|
Chromatin or spliceosome gene mutation, n (%) |
23 (37.7) |
7 (11.9) |
|
Homozygous JAK2 mutation, n (%) |
17 (27.9) |
26 (44.1) |
|
Heterozygous JAK2 mutation, n (%) |
10 (16.4) |
25 (42.4) |
|
No mutation, n (%) |
1 (1.6) |
0 |
|
In multivariate analysis, mutations listed in the genomic classification were associated with a higher risk of hydroxyurea resistance (HR, 2.2; 95% CI, 1.5–3.2; p < 0.0001). Also, after correcting for age, patients with TP53 disruption/aneuploidy or spliceosome/chromatin mutations had a higher risk of death when compared with patients with JAK2 heterozygous (HR, 4.2; 95% CI, 1.2–15.1; p = 0.026) and patients with JAK2 homozygous (HR, 2.1; 95% CI, 1.01–4.04; p = 0.046).
In summary, the data support the implementation of genetic classification by NGS for prognosis and clinical decision making in patients with PV. Molecular classification revealed patterns for the risk of disease progression and hydroxyurea therapy resistance for each molecular group, especially for TP53 and spliceosome/chromatin mutations.
This study highlights the need for novel drugs to treat high-risk molecular aberrations, since treatment with hydroxyurea is subject to resistance. Also, this study shows the need for thrombosis prevention in patients with a homozygous JAK2 mutation. In contrast, patients with a heterozygous JAK2 mutation may benefit from long-term treatment with hydroxyurea as demonstrated by the low rates of resistance, thrombosis, and disease progression. The main limitations of this study were the small patient cohort and the limited samples from PV diagnosis.
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