Background: Essential thrombocythemia (ET) is a chronic Philadelphia chromosome negative myeloproliferative neoplasm characterized by thrombocytosis with risks of vascular complications and transformation to secondary myelofibrosis (SMF) or acute myeloid leukemia (AML). The impact of genetic mutations, karyotype abnormalities, and therapy on disease progression and vascular events remains incompletely understood.

Methods: We retrospectively reviewed 90 consecutive ET patients meeting WHO 2022 criteria at our institution, including only those diagnosed before 2015 to ensure adequate follow-up for rare progression events. Clinical, laboratory, cytogenetic, mutational, treatment, and outcome data were collected. All patients had to have genetic testing for driver mutations in JAK2, MPL, and CALR or a myeloid next-generation sequencing (NGS) panel during their disease course. Vascular events and disease progression were recorded. We used descriptive statistics for baseline characteristics, Fisher's exact or Chi-square tests for categorical variables, and calculated odds ratios where appropriate. Continuous variables are reported as means with ranges, and point-biserial correlation and Mann-Whitney U Test were used for analysis.

Results: Among 90 patients with ET, the median follow-up time was 15.5 years (interquartile range [IQR]: 11.0–18.6). Median age at diagnosis was 58.4 years (IQR: 49–70) and 37% were male. Baseline CBC data (n=31) showed mean WBC 9.3×10³/µL, platelets 857×10³/µL, and hemoglobin 13.1 g/dL. 8/68 had splenomegaly on physical exam or imaging and 10/68 patients had symptoms attributed to ET at baseline. 6 out of 49 patients (12%) with baseline karyotype available had structural abnormalities. JAK2 V617F mutation was present in 35/74 tested (47%), CALR in 12/44 (27%), MPL in 6/43 (14%), and 7/47 (15%) were triple-negative. NGS at time of initial diagnosis was available for 16 patients and showed mutations in TET2 (n=3), SRSF2 (n=1), ASXL1 (n=2), EZH2 (n=1), and TP53 (n=1).

Over follow-up, 11 patients (12%) progressed to AML after a median of 14.8 years, and 40 (44%) progressed to SMF after a median of 13.5 years. Splenomegaly was present in 64% of AML and 63% of SMF cases. Patients with abnormal karyotype had numerically higher rate of SMF progression compared to normal karyotype (50% (3/6) vs. 19% (7/36), p=0.09). Progression to AML and SMF was often accompanied by karyotype abnormalities in 72% (8/11) of AML and 46% (17/37) of SMF cases. While neither JAK2, CALR, MPL, nor triple-negative status was significantly associated with progression to AML or SMF, there was a non-significant trend toward higher progression to AML among MPL-mutated patients (p = 0.087, OR 8.75, 95% CI 0.95-80.26), while no significant association was observed with progression to SMF.

NGS was performed in 28 patients at transformation. The most common mutations detected were TET2 (n=7), TP53 (n=5), ASXL1 (n=3), DNMT3A (n=2), SF3B1 (n=2) for SMF and TP53 (n=3), TET2 (n=2), DNMT3A (n=2), ASXL1 (n=2) for AML.

76 patients received hydroxyurea, 6 received interferon, and 36 received anagrelide. There was no statistically significant association between type of treatment and disease progression.

Vascular events occurred in 33/90 patients (37%), with thrombosis in 64% and bleeding in 36%. The distribution of JAK2 V617F variant allele fractions (VAF) differed significantly between patients with and without vascular events (U = 21, z = −2.17, p = 0.03). A weak to moderate positive correlation was observed between JAK2 V617F VAF and vascular events (r = 0.38), which did not reach statistical significance (p = 0.065). Point-biserial correlation showed a moderate positive association between higher platelet counts and vascular events (r = 0.39, p = 0.007).

Conclusions: In this ET cohort with a median follow-up of over 15 years, we observed high transformation rates to SMF and AML. The higher-than-expected transformation rate may reflect selection bias, including an older cohort, tertiary referral patterns, longer follow-up, enrichment for higher-risk disease biology, and potential misclassification of prefibrotic or overt primary MF as ET. Transformation was associated with karyotype alterations and abnormal baseline karyotype. JAK2 V617F VAF differed significantly between patients with and without vascular events, indicating a possible association. Higher platelet counts at diagnosis showed a moderate positive correlation with vascular events.

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2025
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