The Role of TET2 Mutation in Patients with Myeloproliferative Neoplasms and Thrombosis in Unusual Sites (Splanchnic Thrombosis and Cerebral Thrombosis)

Introduction:

Myeloproliferative neoplasms (MPNs) associated with unusual site thrombosis (UST) exhibit a distinct clinical profile, particularly in cases of splanchnic vein thrombosis (SVT) and cerebral vein thrombosis (CVT), requiring meticulous interdisciplinary collaboration. This study aims to characterize the molecular features of MPN-UST using next-generation sequencing (NGS), with a particular emphasis on the TET2 mutation.

Methods:

We reviewed clinical and morphological data and analyzed mutational profiles via NGS in 44 consecutive MPN patients (PV [n = 11], ET [n = 12], PMF [n = 14], and MPN-U [n = 7]) admitted to the Hematology Units at AOU delle Marche and Pescara between July 1992 and November 2020, who developed SVT or CVT either at diagnosis or during follow-up.

Results:

A total of 44 patients were included in the study, with CVT accounting for 13.6% of all thromboses (n = 6) and SVT representing 86.4% (n = 38). Half of the patients presented with thrombosis at the time of MPN diagnosis. A higher proportion of patients with MPN-U was observed among those with SVT, aligning with literature findings. Molecularly, 86.4% of patients had the JAK2 V617F mutation as the driver mutation, with a median JAK2 V617F VAF of 16.7% (range, 1.89-91.0). JAK2 was the sole mutation detected by NGS in 51.35% of cases. Conversely, in JAK2 non-mutated patients, the driver mutation was the only genetic lesion found in 16.67% of cases. The primary findings in NGS included mutations in TET2 (22.7%), followed by KIT (18.2%), ASXL1 (9.1%), SETBP1 (9.1%), RUNX1 (6.8%), and GATA2 (6.8%). In 34.1% of cases, three or more mutations were present.

No differences were observed between MPN-SVT and MPN-CVT patients in terms of sex, type of MPN, or symptoms. However, a higher percentage of MPN-CVT patients had a TET2 mutation (66.6% vs. 15.7%; p = 0.0057).

With a median follow-up of 8.7 years, 9 patients died. In our cohort, age at diagnosis (HR 1.03, 95% CI 1.02-1.05, p = 0.00813) and the presence of a TET2 mutation (HR 1.25, 95% CI 1.18-1.52, p = 0.0458) were associated with poorer survival in multivariable analysis.

Discussion:

This study highlights the significant role of TET2 mutations in patients with MPN associated with UST. Our findings indicate that TET2 mutations are notably more prevalent in patients with CVT compared to those with SVT. Moreover, the presence of a TET2 mutation is associated with poorer survival, underscoring its potential as a prognostic marker. These insights emphasize the importance of molecular profiling in MPN-UST patients for better risk stratification and tailored therapeutic approaches.

Kordasti:Boston Biomed: Consultancy; Pfizer: Consultancy, Speakers Bureau; Celgene: Research Funding; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; API: Consultancy; Alexion: Consultancy; MorphoSys: Research Funding; Beckman Coulter: Speakers Bureau.