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- Title
Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes.
- Authors
Aguirre, Luis E.; Jain, Akriti; Ball, Somedeb; Ali, Najla Al; Volpe, Virginia O.; Tinsley-Vance, Sara; Sallman, David; Sweet, Kendra; Lancet, Jeffrey; Padron, Eric; Yun, Seongseok; Kuykendall, Andrew; Komrokji, Rami
- Abstract
Triple-negative myelofibrosis (MF) constitutes a distinct disease subset marked by aggressive clinical features, higher rates of leukemic transformation, shorter duration of response to ruxolitinib and poor survival. Mutations affecting epigenetic modification, RNA splicing and signaling likely drive its hostile course and may account for suboptimal responses to JAK inhibition. Background: Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms. About 90% of cases are driven by constitutive activation of 1 of 3 genes impacting the JAK/STAT pathway: JAK2, CALR, and MPL. Triple-negative myelofibrosis (TN-MF) accounts for only 5%-10% of cases and carries the worst outcomes. Little has been described about this subset of disease. Given the marked heterogeneity surrounding disease biology, clonal architecture, clinical presentation, and poor outcomes in TN-MF, identification of features of interest and assessment of treatment response are areas in need of further investigation. Patients and methods: We collected and evaluated baseline clinical and molecular parameters from 626 patients with a diagnosis of myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa (Florida, US) between 2003 and 2021 and compared them based on presence or absence of the three classical phenotypic driver mutations. Results: A small proportion of patients (6%) harbored TN-MF which correlated with inferior outcomes, marked by a 4-year reduction in overall survival time compared to the non-TN cohort (mOS 37.4 months vs. 85.7 months; P = .009) and higher rates of leukemic transformation. More pronounced thrombocytopenia and anemia, lower LDH, EPO levels, as well as lower percentage of marrow blasts at baseline were more commonly seen in TN-MF (P < .05). Similarly, patients with TN-MF had higher risk disease per DIPSS+ and GIPSS. Mutations impacting RNA splicing, epigenetic modification and signaling, specifically SRSF2, SETBP1, IDH2, CBL, and GNAS. were more commonly seen among those lacking a classical phenotypic driver. The prevalence of co-mutant ASXL1/SRSF2 clones was significantly higher in TN-MF as was trisomy 8. TN patients had fewer responses (46.2% vs. 63.4%) and shorter duration of response to ruxolitinib. Conclusion: TN-MF is invariably associated with significantly decreased survival and more aggressive clinical behavior with higher rates of leukemic transformation and shorter duration of response to ruxolitinib. Mutations impacting RNA splicing, epigenetic modification and signaling (SRSF2, SETBP1, IDH2, CBL, and GNAS) are more common in TN-MF, which likely drive its aggressive course and may account for suboptimal responses to JAK inhibition.
- Publication
Clinical Lymphoma, Myeloma & Leukemia, 2024, Vol 24, Issue 7, p459
- ISSN
2152-2650
- Publication type
Article
- DOI
10.1016/j.clml.2024.03.001