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Leukemic transformation in patients with polycythemia vera (PV) and essential thrombocythemia (ET) is considered a leading long-term complication, occurring in 2─5% of cases at 15 years. Patients who develop secondary acute myeloid leukemia (AML) have a poor prognosis, and the identification of PV and ET patients at high risk of leukemic transformation would help in monitoring and treating these patients, however it remains difficult.
Mutations in TP53, ASXL1, RUNX1, EZH2, IDH1/2, and SH2B3 are associated with high risk of leukemic transformation, but little is known about predictors of time to leukemic evolution. To better understand genetic mechanisms associated with leukemia development, Damien Luque Paz and colleagues, in a study published in Blood Advances, performed molecular analyses at different time points during disease evolution (at diagnosis, during the chronic phase, and at transformation) in patients with PV or ET who developed AML.1
Patients included in the study had previously been diagnosed with PV (n = 24) or ET (n = 25) and showed leukemic evolution. Molecular analyses were performed by next-generation sequencing on DNA samples obtained at the time of leukemic evolution and at diagnosis, or at the chronic phase (the earliest available sample was used if the sample at diagnosis was unavailable; Figure 1). In addition, a control cohort of 80 patients with PV (n = 37) or ET (n = 43) who did not develop AML after ≥ 8 years of follow-up was studied to investigate the prognosis of additional mutations during the chronic phase.
Figure 1. Cohort description1
AML, acute myeloid leukemia; ET, essential thrombocythemia; PV, polycythemia vera.The characteristics of 49 patients with PV or ET who developed AML are shown in Table 1.
Table 1. Patient characteristics1
ET, essential thrombocythemia; PV, polycythemia vera. |
|||
Characteristic |
Entire cohort |
PV |
ET |
---|---|---|---|
Median age at diagnosis, years (range) |
63 (26─82) |
65 (42─81) |
59 (26─82) |
Hemoglobin at diagnosis, g/dL (range) |
16 (10─20.7) |
18.1 (16─20.7) |
14.4 (10─16.6) |
Platelets at diagnosis, ×109/L (range) |
624 (139─1,575) |
404 (139─748) |
800 (471─1,575) |
Leukocytes at diagnosis, ×109/L (range) |
9.17 (3─27.8) |
10.6 (5.1─27.8) |
8.4 (3─17.3) |
Driver mutation, n (%) |
|
|
|
JAK2V617F |
39 (80) |
24 (100) |
15 (60) |
CALR |
6 (12) |
— |
6 (24) |
MPL |
2 (4) |
— |
2 (8) |
Triple negative |
2 (4) |
— |
2 (8) |
Time to leukemic transformation, years (range) |
12 (1─30) |
11 (2─30) |
12 (1─30) |
Karyotype at leukemic transformation, n (%) |
n = 35 |
n = 17 |
n = 18 |
Normal |
13 (37) |
6 (35) |
7 (39) |
Abnormal not complex |
6 (17) |
4 (24) |
2 (11) |
Complex |
9 (26) |
5 (29) |
4 (22) |
Monosomal |
7 (20) |
2 (12) |
5 (28) |
The total number of additional mutations (in addition to driver mutations) detected in the entire cohort was 191, with the most frequently mutated genes being TP53, TET2, RUNX1, ASXL1, and EZH2. At least one additional mutation was present in all patients with a median number of four mutations. The time to leukemic transformation was variable among patients and seemed to be related to the genes affected by additional mutations. Through sparse partial least squares discriminant analysis and using a hierarchical classification, the authors identified three groups of patients with different time to leukemic evolution (Figure 2):
Figure 2. Molecular landscape1
To better understand the mutations and allele burden evolution between the chronic and leukemic phases, matched samples obtained at diagnosis or during the chronic phase, available for 29 patients (Figure 1), were evaluated:
In addition, samples between diagnosis and leukemic transformation were analyzed in seven patients:
To evaluate the impact of additional mutations during the chronic phase on the risk of transformation, 29 patients with post-PV or -ET AML with a sample obtained during the chronic phase were compared with 80 stable patients with myeloproliferative neoplasms (PV, n = 37; ET, n = 43) who did not develop AML during ≥ 8 years of follow-up (range, 8─29 years):
The prognostic impact of additional mutations in TET2, ASXL1, RUNX1, and TP53 was examined in ten patients at leukemic transformation. Patients with mutated TP53 had a worse OS compared with patients with wild-type TP53 (12-month OS, 18% vs 48%, respectively; p = 0.05).
In this study, the authors evaluated not only the presence/absence of mutations at leukemic transformation, but also the allele burden. The findings suggested that mutations that show an increasing allele burden are likely to contribute to the risk of transformation to AML. They identified three molecular groups associated with different time to transformation:
Some of these mutations were already present at diagnosis/chronic phase, either with a significant allele burden or with a very low allele burden (especially TP53 mutations). An allele burden > 50% or a second mutation involving TP53 was observed in most leukemic transformation events, which may explain the inferior outcome to intensive therapy. Taken together these results suggest that the leukemic transformation of PV and ET involves different time-dependent molecular mechanisms, however further functional studies and larger cohorts are required to better understand these mechanisms.
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