Triple-Negative Myelofibrosis Associated With Decreased Survival, Aggressive Clinical Behavior and Shorter Duration of Response to Ruxolitinib

According to recently published research in Clinical Lymphoma, Myeloma & Leukemia, triple-negative myelofibrosis (TN-MF) was found to be continually associated with decreased survival, enhanced aggressive clinical behavior with higher rates of leukemic transformation, and a shorter duration of response to ruxolitinib.

“Myelofibrosis is the most aggressive subtype among classical BCR::ABL1 negative myeloproliferative neoplasms...Triple-negative myelofibrosis accounts for only 5% [to] 10% of cases and carries the worst outcomes,” explained lead study author Luis Aguirre, MD, Dana-Farber Cancer Institute, Harvard Medical School, Cambridge, Massachusetts, and colleagues. They added, “Little has been described about this subset of disease…identification of features of interest and assessment of treatment response are areas in need of further investigation.”

Researchers evaluated baseline clinical and molecular parameters from 626 patients with myelofibrosis who presented to the H. Lee Moffitt Cancer Center in Tampa, Florida, between 2003 and 2021. These data were compared based on the presence or absence of the 3 classical phenotypic driver mutations.

Results demonstrated that 6% of patients harbored TN-MF which correlated with inferior outcomes, marked by a 4-year reduction in overall survival (OS) time compared to the non-TN cohort ([median] mOS 37.4 months vs 85.7 months; P = .009) and higher rates of leukemic transformation. Additionally, more pronounced thrombocytopenia and anemia, lower lactate dehydrogenase (LDH), erythropoietin (EPO) levels, and a lower percentage of marrow blasts at baseline were more commonly seen in TN-MF (P < .05). It was also noted that patients with TN-MF had a higher risk disease per Dynamic International Prognostic Scoring System Plus (DIPSS+) and Genetically Inspired Prognostic Scoring System (GIPSS).

Furthermore, mutations impacting RNA splicing, epigenetic modification and signaling, specifically SRSF2, SETBP1, IDH2, CBL, and GNAS, were more commonly seen among patients who were lacking a classical phenotypic driver. The prevalence of co-mutant ASXL1/SRSF2 clones was noticeably higher in TN-MF as was trisomy 8. Patients who were triple-negative had fewer responses (46.2% vs. 63.4%) and shorter duration of response to ruxolitinib.

“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,” concluded Dr Aguirre and colleagues.

“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,” they added.

Source:

Aguirre L, Jain A, Ball S, et al. Triple-negative myelofibrosis: Disease features, response to treatment and outcomes. Published online March 10, 2024. doi: 10.1016/j.clml.2024.03.001