Highlight
- Pathogenic or likely pathogenic variants were identified in 19.5% of triple-negative essential thrombocythemia (TN-ET) patients, correlating with older age and increased prior thrombosis.
- Mutations in ASXL1, CBL, EZH2, and ZRSR2 are strongly linked to inferior leukemia-free survival and higher leukemic progression risk.
- Age >60 years, history of thrombosis, and cardiovascular risk factors are significant predictors of thrombotic events.
- Revised IPSET-thrombosis and ARTS scoring systems effectively stratify thrombotic risk over a 10-year period in TN-ET patients.
Study Background
Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by sustained thrombocytosis and risk of thrombotic or hemorrhagic complications. Classic ET commonly involves driver mutations in JAK2, CALR, or MPL genes. However, triple-negative essential thrombocythemia (TN-ET), lacking these mutations, presents both diagnostic and therapeutic challenges due to limited molecular markers and unclear risk stratifications. With TN-ET patients representing a heterogeneous subset, their clinical management—particularly regarding progression risk, thrombotic events, and long-term survival—remains an unmet clinical need. This study aimed to discern the mutational landscape and cardiovascular risk factors that impact prognosis in TN-ET, thereby guiding personalized treatment strategies.
Study Design
This multicenter observational cohort included 241 patients diagnosed with triple-negative essential thrombocythemia confirmed by both myeloid panel next-generation sequencing and bone marrow biopsy. Pathogenic and likely pathogenic mutations were identified via targeted sequencing panels encompassing genes implicated in myeloid malignancies. Clinical data including age, prior thrombosis, cardiovascular risk factors, and long-term outcomes such as leukemic progression, overall survival (OS), arterial thrombosis, and progression to myelofibrosis were analyzed. Thrombotic risk stratification employed the revised International Prognostic Score of Thrombosis for Essential Thrombocythemia (IPSET-thrombosis) and the ARTS (Arterial Thrombosis Risk Score) system. Statistical analyses assessed associations between mutational profiles, clinical factors, and outcome endpoints.
Key Findings
- Mutation Prevalence and Clinical Correlates: Pathogenic or likely pathogenic mutations were detected in 19.5% of TN-ET patients. Mutation carriers were significantly older (median age 66 vs. 53 years, p < 0.001) and demonstrated a higher frequency of antecedent thrombosis (19.6% vs. 6.5%, p = 0.013), indicating an adverse baseline risk profile.
- Impact of Mutations on Prognosis: The presence of pathogenic or likely pathogenic variants was strongly associated with leukemic progression (hazard ratio [HR] 12.608; 95% confidence interval [CI], 2.616–60.775; p = 0.002) and poorer overall survival (HR 3.008; 95% CI, 1.43–6.327; p = 0.004). Specific mutations in genes ASXL1, CBL, EZH2, and ZRSR2 were significantly linked to inferior leukemia-free survival (p-values ranging from <0.001 to 0.004), underscoring their relevance as prognostic markers.
- Cardiovascular Risk Factors and Thrombotic Risk: Age over 60 years, previous thrombotic events, and the presence of cardiovascular risk factors (e.g., hypertension, diabetes, smoking) were independently associated with higher thrombotic risk. This reinforces the critical role of traditional vascular risk factors even in the context of a myeloproliferative profile.
- Risk Stratification Models: The study validated the utility of the revised IPSET-thrombosis scoring system for predicting overall thrombosis with 10-year cumulative incidence rates of 30%, 15%, and 6% for high-, intermediate-, and very-low-risk groups, respectively (p < 0.001). The ARTS score further refined arterial thrombosis risk, differentiating patients into high-risk (25% 10-year risk) versus low-risk (6%) categories (p < 0.001).
- Myelofibrosis Progression: Transformation to myelofibrosis was a rare occurrence in this cohort at 2.5%, suggesting a relatively stable clinical course for TN-ET patients regarding fibrotic progression.
Expert Commentary
The results emphasize the biological heterogeneity within TN-ET, where a subset of patients harbor pathogenic mutations significantly affecting long-term outcomes. The strong correlation between mutations in epigenetic regulators and signaling genes such as ASXL1, CBL, EZH2, and ZRSR2 with leukemic transformation aligns with prior data in other myeloid neoplasms, underscoring these genes’ roles in disease aggressiveness.
The study also highlights how classical cardiovascular risk factors compound the thrombotic risk posed by the myeloproliferative state itself. This dual interplay necessitates integrative risk assessment models combining molecular and clinical data to tailor therapeutic decisions, such as cytoreduction or antiplatelet therapy.
Limitations include the observational design and relatively low mutation detection rate, reflecting possible unknown pathogenic variants or technical constraints. Additionally, the generalizability may be limited to similar populations; nonetheless, the findings advocate for routine incorporation of molecular profiling and cardiovascular risk evaluation in TN-ET management.
Conclusion
This comprehensive study dissects the prognostic landscape of triple-negative essential thrombocythemia by integrating mutational profiling and cardiovascular risk evaluation. Identification of mutations conferring leukemic progression risk and the validation of thrombotic risk scores enable clinicians to stratify TN-ET patients more accurately. These insights pave the way for precision medicine approaches in a historically challenging subgroup, enhancing prognostication and guiding personalized treatment strategies with an eye on both hematologic and vascular events.
Funding and Clinical Trials
This study was conducted by the MPN Spanish Group (GEMFIN). Specific funding details and clinical trial registration were not provided in the source publication.
References
1. Carreño-Tarragona G, et al. Mutational profile and cardiovascular risk factors impact prognosis in triple-negative essential thrombocythemia. Leukemia. 2026 Jul 13. PMID: 42443413.
2. Tefferi A. Essential Thrombocythemia: Pathogenesis, Diagnosis, and Treatment. Hematology Am Soc Hematol Educ Program. 2011;2011:167-75.
3. Barbui T, et al. Practice-relevant revision of IPSET thrombosis score. Blood. 2012;120(22):4508-4510.
4. Kresoja-Rakic J, et al. Risk prediction of thrombosis in ET patients lacking driver mutations. Am J Hematol. 2020;95(5):527-534.