Reassessing the Prognostic Weight of Anemia Plus Thrombocytopenia in Primary Myelofibrosis

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by clonal stem cell proliferation and progressive bone marrow fibrosis, with median overall survival ranging from approximately 14 years in prefibrotic disease to around 7 years in overt PMF.¹ Accurate risk stratification is central to guiding pharmacologic and transplant-related decisions.

Several scoring models have been developed for this purpose, incorporating clinical, cytogenetic, and molecular variables.² Yet real-world application remains inconsistent, as roughly one-third of patients are never formally risk-stratified, and in nearly 40% of cases, the assigned category is incorrect.³ This gap highlights the need for more accessible prognostic tools that can reliably inform treatment decisions at the point of care.

Cytopenic Phenotype and Survival Findings

A recent prospective analysis from the European ERNEST-2 (NCT04153305) registry, enrolling 559 patients with overt PMF, found that 34% presented with anemia alone, 6% with isolated thrombocytopenia, and 10% with both cytopenias concurrently.⁴ Patients with the combined anemia-plus-thrombocytopenia phenotype had a median survival of fewer than 2 years, raising questions about whether this combination warrants greater weight in existing models.

The International Prognostic Scoring System already includes anemia as 1 of 5 adverse risk factors alongside age over 65, blood blasts of 1% or higher, white blood cell count greater than 25 × 10⁹/L, and constitutional symptoms,⁵ but the ERNEST-2 data suggested the co-occurrence of thrombocytopenia may amplify its prognostic significance considerably.

Validation Attempt and Discordant Results

To evaluate reproducibility, a retrospective analysis was performed of 530 overt PMF patients from the Pavia-CSM institutional database, published in Leukemia.¹ The proportion of patients with the myelodepletive phenotype was comparable between cohorts (49% vs 51%), but outcomes diverged sharply. In the Pavia cohort, the worst survival was observed in patients with severe anemia alone, not in those with concurrent thrombocytopenia.

Receiver operating characteristic analysis further undermined the combined phenotype's utility, yielding area-under-the-curve values of 0.52 in ERNEST-2 and 0.50 in Pavia—essentially no discriminative power above chance. Genotypic distributions also differed meaningfully, with JAK2 V617F prevalence and triple-negative genotype frequencies diverging across cytopenic subgroups in ways that likely contributed to the conflicting survival patterns.¹

Bias, Limitations, and the Road Ahead

Using the Quality in Prognosis Studies tool, the authors considered both populations of patients as very likely to produce misleading findings because of the risk of bias. The ERNEST-2 study was criticized for lack of disclosure of how patients were selected and not considering transplantation status; Pavia was critiqued for having an insufficient number of events compared to the size of the cohort, and the transplant confounding issue also arose.⁶

These results indicate that there is no evidence, either statistical or theoretical, that the anemia-plus-thrombocytopenia phenotype could serve as a stand-alone prognostic marker in overt PMF. For pharmacists in hematology settings, this evolving picture reinforces the importance of staying current with risk stratification frameworks that directly inform which patients are candidates for JAK inhibitor therapy, dose modification, or transplant referral.

REFERENCES

1. Barosi G, De Silvestri A, Gale RP, Rosti V. Prognostic value of anemia plus thrombocytopenia in primary myelofibrosis. Leukemia. 2026;40(3):698-701. doi:10.1038/s41375-026-02860-2

2. Mora B, Bucelli C, Cattaneo D, et al. Prognostic and predictive models in myelofibrosis. Curr Hematol Malig Rep. 2024;19(5):223-235. doi:10.1007/s11899-024-00739-6

3. Verstovsek S, Yu J, Kish JK, et al. Real-world risk assessment and treatment initiation among patients with myelofibrosis at community oncology practices in the United States. Ann Hematol. 2020;99(11):2555-2564. doi:10.1007/s00277-020-04055-w

4. Guglielmelli P, Ghirardi A, Carobbio A, et al. Cytopenic overt primary myelofibrosis at presentation: Analysis of outcomes in the prospective, real-world ERNEST-2 registry. Hemasphere. 2025;9(2):e70072. Published 2025 Jan 31. doi:10.1002/hem3.70072

5. Cervantes F, Dupriez B, Pereira A, et al. New prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment. Blood. 2009;113(13):2895-2901. doi:10.1182/blood-2008-07-170449

6. Hayden JA, van der Windt DA, Cartwright JL, Côté P, Bombardier C. Assessing bias in studies of prognostic factors. Ann Intern Med. 2013;158(4):280-286. doi:10.7326/0003-4819-158-4-201302190-00009