Prior Cancer History Predicts Second Cancers in Polycythemia Vera, Essential Thrombocythemia

Patients with polycythemia vera (PV) or essential thrombocythemia (ET) who have survived 1 cancer face roughly double the risk of developing another cancer, according to a new single-center analysis, with nonmelanoma skin cancer emerging as the most common and most recurrent malignancy in this population.¹ The findings, published in Blood Cancer Journal, add granularity to a long-recognized but incompletely characterized link between myeloproliferative neoplasms (MPNs) and secondary cancers.

What Did the Mayo Clinic Cohort Demonstrate?

Investigators at Mayo Clinic and the University of Florence retrospectively followed 1968 consecutive patients with PV (n = 1001) or ET (n = 967) for a median of 11.2 years. Twenty percent of patients (n = 404) developed second cancers during follow-up, most often nonmelanoma skin cancer (47%), followed by lymphoid neoplasms and melanoma (10% each), prostate cancer (9%), and trachea/lung/bronchial cancer (8%).

Using competing-risk statistical methods that accounted for death, the researchers found that a prior cancer diagnosis nearly doubled the risk of a subsequent malignancy (subdistribution HR [sHR], 2.02; P < .001), even after adjusting for age, sex, MPN subtype, and cardiovascular risk factors. Older age (per 10 years, sHR, 1.20; P < .001), male sex (sHR, 1.39; P = .002), and hyperlipidemia (sHR, 1.41; P = .003) were independently associated with SC risk.

When nonmelanoma skin cancer was excluded from the outcome definition, prior cancer remained significantly associated with subsequent malignancy (sHR, 1.48; P = .048). In the most restrictive model, which excluded nonmelanoma skin cancer and blood cancers, only age (per 10 years, sHR, 1.13; P = .010) and male sex (sHR, 1.36; P = .038) retained independent significance.

Why Does Skin Cancer History Matter Most?

The strongest single signal in the study was the link between prior and subsequent nonmelanoma skin cancer. Patients who had already had nonmelanoma skin cancer had a 548% greater likelihood of developing another skin cancer compared with those with no cancer history (sHR, 6.48; P < .001), a magnitude of effect that exceeded every other variable examined, including age and sex.

Even a history of a non-skin cancer raised nonmelanoma skin cancer risk (sHR, 2.11; P < .001), suggesting that cancer susceptibility in this population may reflect a broader host predisposition rather than a skin-specific phenomenon, with potential links to cumulative ultraviolet exposure, immune surveillance changes, or genomic instability.

Molecular data, available in a subset of 620 patients, offered supporting but inconclusive signals: TET2 mutations showed a borderline association with nonmelanoma skin cancer risk (sHR, 1.73; P = .055), while TP53, SRSF2, and SF3B1 mutations were tied to skin cancer risk in unadjusted analyses but lost significance once clinical variables were factored in.

“In univariable analyses, mutations involving genes associated with clonal hematopoiesis and genomic instability, including TP53, SF3B1, and SRSF2, were associated with increased risk of [skin cancer],” the authors wrote. “However, these associations were attenuated in multivariable models, suggesting that molecular signals may partly reflect underlying clinical risk profiles rather than independent determinants.”

Does Hydroxyurea Raise Cancer Risk?

Because detailed longitudinal treatment records were not consistently available, the investigators could only evaluate baseline treatment exposure in a subgroup of 1211 patients treated with a single agent (1033 on hydroxyurea, 178 untreated). In that analysis, hydroxyurea was not associated with overall skin cancer risk (sHR, 0.94; P = .750), although there was a nonsignificant trend toward higher nonmelanoma skin cancer risk (sHR, 1.82; P = .110).

That result echoes previous research showing the incidence of second malignancies was similar among older patients with classical MPNs treated with and without hydroxyurea, even as the authors acknowledged that Surveillance, Epidemiology, and End Results data poorly captured nonmelanoma skin cancer specifically.² Data also show that ruxolitinib, an alternative cytoreductive option, carries its own documented association with higher nonmelanoma skin cancer rates vs the best available therapy.³

How Will This Impact Long-Term MPN Care?

The authors argue their findings support risk-adapted surveillance rather than changes to first-line treatment algorithms, with particular emphasis on regular dermatologic monitoring for patients with any cancer history and closer attention to metabolic risk factors such as hyperlipidemia.¹ The results build on knowledge of secondary primary malignancies in post-PV and post-ET myelofibrosis, which similarly called for identifying the patients who face the highest secondary-cancer risk and recommended monitoring cutaneous cancers before and during Janus kinase inhibitor treatment.⁴

Limitations include the single-center, retrospective design¹; inconsistent longitudinal treatment data; and molecular testing in only a third of the cohort. The authors called for prospective, molecularly annotated studies to refine risk stratification and clarify why prior cancer, especially skin cancer, so strongly forecasts what comes next for patients already managing a chronic blood cancer.

References

1. Loscocco GG, Aperna F, Iftikhas M, et al. Cancer history and second cancer risk in polycythemia vera and essential thrombocythemia. Blood Cancer J. Published online July 11, 2026. doi:10.1038/s41408-026-01560-5
2. Wang R, Shallis RM, Stempel JM, et al. Second malignancies among older patients with classical myeloproliferative neoplasms treated with hydroxyurea. Blood Adv. 2023;7(5):734-743. doi:10.1182/bloodadvances.2022008259
3. Caffrey M. Update: ruxolitinib beats best available therapy in treating polycythemia vera. AJMC^®. October 14, 2024. Accessed July 19, 2026. https://www.ajmc.com/view/update-ruxolitinib-beats-best-available-therapy-in-treating-polycythemia-vera
4. AJMC staff. Examining future malignancies after a secondary myelofibrosis. AJMC. July 4, 2019. Accessed July 19, 2026. https://www.ajmc.com/view/examining-future-malignancies-after-a-secondary-myelofibrosis