INTRODUCTION

There is sparse population-level data on the risk of second primary malignancy (SPM) and leukemic transformation in Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-MPNs) patients (pts) in the US. In this retrospective cohort study, we evaluated the risk of SPM and leukemic transformation over a 20-yr period for four distinct MPN entities – polycythemia vera (PV), MPN, not otherwise specified (MPN NOS), primary myelofibrosis (PMF) and essential thrombocythemia (ET).

METHODS

We queried Surveillance, Epidemiology and End Results 17 registries (2001-2021) to identify pts aged ≥15 years (yrs) with Ph- MPNs as the index cancer diagnosed from 2001-2020, who developed a SPM ≥6 months after MPN diagnosis. All third and higher-order cancers were excluded. SPMs excluded all leukemias except acute lymphocytic leukemia (ALL) and chronic lymphocytic leukemia (CLL). All cancers were identified using ICD-O-3/WHO-2008 diagnostic codes. The risks of SPM development and leukemic transformation were estimated by standardized incidence ratios (SIRs), defined as the ratio of observed number of SPM or leukemic transformation in the MPN population to the expected number of cases in the general US population adjusted for age, sex, race, & calendar year, using SEER*Stat software (version 8.4.5). As small case numbers can lead to unstable estimates, only those SPM sites with ≥20 cases were included for SIR and leukemic transformation analysis. Cumulative incidence (CI) of SPM and leukemic transformation were calculated using Fine-Gray competing risk regression analyses with death as a competing risk. Analyses were conducted in R 4.2.2 & SAS 9.4.

RESULTS

The incidence rates of SPMs per 100,000 person-years (p-yrs) varied by MPN subtypes – 1511 cases (95% CI: 1445-1561) for PV, 1562 cases (95% CI: 1369-1781) for MPN-NOS, 1539 cases (95% CI: 1358-1743) for PMF and 1369 cases (95% CI: 1303-1437) for ET. The median time to development of SPMs was 4.74 yrs [(Interquartile range (IQR): 2.42-8.5] in PV, 5.12 yrs (IQR: 2.68-9.63) in MPN-NOS, 3.04 yrs (IQR:1.75-5.84) in PMF, and 4.25 yrs (IQR:2.16-7.77) in ET.

A significant difference in CI of SPM was noted amongst the MPN subtypes (p<0.0001). The 10-yr CI of SPMs was 8.7% (95% CI: 7.5-10) for MPN-NOS and 8.1% (95% CI: 7.1-9.2) for PMF, plateauing thereafter. For PV and ET, the CI increased with time, from 11.5% (95% CI: 10.9-12) for PV and 10.6% (95% CI: 10.1-11.2) for ET at 10-yrs, to 18.7% (95% CI: 17.6-19.8) and 17.6% (95% CI: 16.4-18.8) respectively at 20 yrs, and still rising.

The 5 most prevalent SPM sites in MPN pts were respiratory tract (17.8%), male genital system (15.6%), gastrointestinal tract (15.6%), breast (10.6%), and urinary tract (9.5%). In PV pts, SIRs were significantly increased for skin (1.47, 95% CI: 1.25-1.72), respiratory tract (1.41, 95% CI: 1.27-1.56), ear, nose & throat (ENT) (1.31, 95% CI: 1.04-1.62), central nervous system (CNS) (1.63, 95% CI: 1.14-2.26), endocrine cancers (2.06, 95% CI: 1.55-2.69), lymphomas (1.29, 95% CI: 1.06-1.56) & chronic lymphocytic leukemia (CLL) (1.69, 95% CI: 1.21-2.3). In PMF pts, SIRs were significantly increased for skin cancers (1.69, 95% CI: 1.08-2.52) and lymphomas (2.87, 95% CI: 1.98-4.04). For ET pts, SIRs were significantly increased for ENT (1.61, 95% CI: 1.26-2.01), respiratory tract (1.17, 95% CI: 1.03-1.32), male genital system (1.33, 95% CI: 1.16-1.51), urinary tract (1.26, 95% CI: 1.08-1.46), lymphomas (1.39, 95% CI: 1.13-1.68), and CLL (1.5, 95% CI: 1.01-2.14). SIR for SPMs were not significantly elevated for MPN-NOS pts.

The incidence rates for leukemic transformation per 100,000 p-yrs was 207 cases (95% CI: 183-235) for PV, 429 cases (95% CI: 332-553) for MPN-NOS, 1121 cases (95% CI: 967-1297) for PMF & 299 cases (95% CI: 268.9-332.2) for ET. CI of leukemic transformation differed significantly amongst the MPN subtypes (p<0.0001): 10yr CI was highest for PMF at 6.2% (95% CI: 5.4-7.2), followed by 2.6% (95% CI: 2-3.5%) for MPN-NOS, 2.4% (95% CI: 2.1-2.7) for ET and 1.8% (95% CI: 1.6-2.1) for PV.

CONCLUSION

Compared to the general population, pts with PV, ET & PMF have an increased risk of developing several cancers, particularly skin, respiratory, ENT, CNS, male genital, urinary, endocrine, lymphomas & CLL. Notably, the risk of lymphoma was highest in PMF pts – 187% more observed cases than expected. The CI of SPM was highest in PV and ET, while the CI rates for leukemic transformation were highest for PMF.

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2025
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