Comparative Study of Phenotype, Genotype, and Outcomes in Triple-Negative Primary Myelofibrosis
Overview
This study analyzed 92 patients with triple-negative primary myelofibrosis (PMF) and compared their clinical, genetic, and outcome profiles to 668 JAK2-mutated PMF patients. Key findings include distinct mutational patterns, a higher prevalence of severe anemia, and the significant prognostic impact of unfavorable karyotype and high molecular risk mutations in triple-negative PMF.
Background
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by mutations in JAK2, CALR, or MPL genes. Approximately 10–15% of PMF patients lack these mutations and are classified as triple-negative. Previous genomic studies have not identified recurrent novel mutations in triple-negative PMF but have found rare variants and other mutations that may influence disease phenotype and prognosis. This study aims to delineate the clinical and genetic features and outcomes of triple-negative PMF compared to JAK2-mutated cases.
Data Highlights
Parameter
Triple-Negative PMF (N=92)
JAK2-Mutated PMF (N=668)
p-value
Median Age (years)
65 (31–88)
66 (27–90)
NS
Male (%)
53%
61%
NS
Hemoglobin (g/dL)
9.4 (5–16)
10.7 (5–18.3)
<0.01
Transfusion-Requiring Anemia (%)
40%
23%
<0.01
Leukocytosis >11 × 10⁹/L (%)
33%
45%
0.01
Platelet Count (×10⁹/L)
157 (11–1100)
243 (11–2491)
0.01
Thrombocytopenia <100 × 10⁹/L (%)
34%
16%
<0.01
Severe Anemia (%)
47%
27%
<0.01
Moderate Anemia (%)
13%
20%
<0.01
Unfavorable Karyotype (%)
19%
Not specified
Not specified
High Molecular Risk Mutations (%)
29%
Not specified
Not specified
Deaths (%)
54%
52%
NS
Leukemic Transformation (%)
14%
10%
NS
Allogenic Stem Cell Transplant (%)
23%
16%
NS
Key Findings
Triple-negative PMF patients represent 8.5% of chronic phase PMF cases and present with more severe anemia and lower platelet counts compared to JAK2-mutated patients.
Unfavorable karyotype is present in 19% of triple-negative PMF and is an independent risk factor for overall survival, unlike in JAK2-mutated PMF.
High molecular risk mutations (ASXL1, SRSF2, U2AF1Q157) occur in 29% of triple-negative PMF and are associated with worse overall and leukemia-free survival.
Leukemic transformation rates and overall survival are similar between triple-negative and JAK2-mutated PMF patients.
In triple-negative PMF, unfavorable karyotype clusters with ASXL1 and EZH2 mutations, whereas in JAK2-mutated PMF, ASXL1 mutations cluster with favorable karyotype.
Multivariable analysis identified age >65, hemoglobin <10 g/dL, leukocyte count >25 × 10⁹/L, peripheral blood blasts ≥1%, and unfavorable karyotype as independent predictors of poorer survival in triple-negative PMF.
Clinical Implications
Clinicians should recognize that triple-negative PMF patients often present with more severe anemia and distinct genetic profiles that influence prognosis. The presence of unfavorable karyotype and high molecular risk mutations should prompt closer monitoring and may guide therapeutic decisions. Despite similar overall survival to JAK2-mutated PMF, triple-negative patients require tailored risk assessment incorporating these genetic factors.
Conclusion
Triple-negative PMF constitutes a distinct subgroup with unique clinical and genetic features that impact prognosis. Incorporating cytogenetic and molecular risk factors is essential for accurate prognostication and management in this population.
References
Tefferi et al. 2024 -- Comparative Study of Phenotype, Genotype, and Outcomes in Triple-Negative Primary Myelofibrosis
by Yassin A. Bashir, Ahmed A. Abdelrheem, Maymona Abdelmagid, Kaaren K. Reichard, Rong He, Cinthya J. Zepeda Mendoza, Animesh Pardanani, Naseema Gangat, Ayalew Tefferi
