Painting a More Distinct Clinical Picture of MPN-U

A new study from the Mayo Clinic has shed light on one of the most challenging and poorly understood blood disorders. By highlighting its molecular diversity and vascular complications, the study is laying the groundwork for improved recognition and precision-based care of myeloproliferative neoplasms–unclassifiable (MPN-U), a rare condition that does not fit neatly into any existing diagnostic categories of myeloproliferative neoplasms (MPNs).1

Although survival outcomes appear comparable to ET, the thrombotic burden in MPN-U was disproportionately high. | Image credit: mdaros - stock.adobe.com

MPNs include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF), which share common genetic drivers, such as JAK2, but differ in their blood count patterns and risk profiles. Patients who exhibit overlapping or ambiguous features fall into the MPN-U category, a diagnosis that has persisted despite multiple revisions to international classification systems. The International Consensus Classification (ICC) and World Health Organization both recognize MPN-U as a distinct, albeit heterogeneous, entity.2,3

Researchers from the Mayo Clinic reviewed medical records from 181 patients evaluated between 2006 and 2025, 30 of whom met the strict ICC 2022 criteria for MPN-U, excluding cases complicated by severe myelofibrosis. Their data were compared with a control group of 658 patients with ET, allowing for direct assessment of clinical, molecular, and prognostic differences between the 2 conditions.

“At the time of this writing, the current study is the first to compare a well-characterized cohort of patients with MPN-U to those with ET,” detailed the researchers, who published their findings in the American Journal of Hematology.1

The hallmark laboratory distinction between the 2 groups was a lower platelet and white blood cell count in patients with MPN-U, coupled with a much higher incidence of venous thrombosis—43% vs 10% in ET. Notably, 77% of these thrombotic events occurred in unusual sites, such as the portal, mesenteric, or hepatic veins, emphasizing the vascular complications that can accompany MPN-U.

Genetic testing revealed important molecular contrasts. For example, JAK2 mutations were present in 87% of MPN-U cases, compared with 63% in ET, while CALR mutations were far less common (3% vs 25%). Beyond these canonical driver mutations, several high-risk non-driver mutations, including ASXL1 (29%), SRSF2 (14%), and EZH2 (14%), were significantly enriched in MPN-U. These mutations are known to correlate with adverse outcomes in other myeloid malignancies and may help explain the disease’s atypical features and aggressive clinical behavior, noted the researchers.

Despite these differences, the overall prognosis for MPN-U was similar to that of ET. After a median follow-up of 2.8 years, 20% of patients with MPN-U had died compared to 24% of patients with ET, with 15-year survival rates of 70% and 65%, respectively. However, MPN-U patients experienced higher rates of bleeding (23% vs 8%) and recurrent venous events even while on anticoagulation or aspirin therapy. Notably, none of the MPN-U cases progressed to myelofibrosis during follow-up, and only 1 patient (3%) developed acute leukemia.

Although survival outcomes appear comparable to ET, the thrombotic burden in MPN-U was disproportionately high, especially at atypical venous sites, prompting the researchers to recommend future studies that determine whether targeted therapies, such as JAK inhibitors or anti-fibrotic agents, could benefit this population.

When outcomes were analyzed by genetic subtype, JAK2-mutated patients with MPN-U demonstrated better overall survival than those with other driver mutations, suggesting a protective effect. Conversely, elevated white blood cell counts (≥20 × 10⁹/L), older age, SRSF2 mutations, and pre-existing venous thrombosis were associated with shorter survival. On multivariable analysis, only high leukocyte counts retained independent prognostic significance, identifying a subset of patients who may require closer monitoring or earlier intervention.

The findings also raise questions about therapeutic management, explained the researchers. Compared to patients with ET, those with MPN-U were less likely to receive cytoreductive therapy (37% vs 79%) or aspirin (77% vs 91%), possibly reflecting diagnostic uncertainty and the lack of consensus guidelines for this population. However, the high frequency of thrombosis suggests that aggressive vascular risk management is warranted, the researchers noted. The group emphasized the need for tailored treatment algorithms and refined diagnostic models that account for genetic heterogeneity and thrombotic risk.

References

1. Abdelaziz RRM, Faldu P, Fathima S, et al. Myeloproliferative neoplasm-unclassifiable (MPN-U): a carefully curated series of 30 Mayo Clinic patients. Am J Hematol. Published online September 23, 2025. doi:10.1002/ajh.70085

2. Gianelli U, Thiele J, Orazi A, et al. International consensus classification of myeloid and lymphoid neoplasms: myeloproliferative neoplasms. Virchows Arch. 2022;482(1):53-68. doi:10.1007/s00428-022-03480-8

3. Barbui T, Thiele J, Gisslingerr H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8(2):15. doi:10.1038/s41408-018-0054-y