Background

Ruxolitinib, the first JAK inhibitor approved for the treatment of myelofibrosis in 2012, was

rapidly adopted into standard clinical practice. Since then, three additional JAK inhibitors have

received FDA approval. Emerging data, however, have raised concerns about an increased

incidence of second primary malignancies (SPMs), particularly non-melanoma skin cancers,

among patients receiving ruxolitinib. This study was conducted to compare the site-specific risk

of SPM and demographic factors associated with SPM in myelofibrosis patients since the

availability of JAK inhibitors.

Materials and Methods

A retrospective cohort study was conducted using the Surveillance, Epidemiology and End-

Results (SEER-17) database. Primary myelofibrosis (ICD-O-3 9961) patients, confirmed on

histopathology, diagnosed between 2000 and 2022 were included while those diagnosed through

death certificates or autopsies were excluded. A second cancer diagnosed more than 60 days

after the initial myelofibrosis diagnosis was defined as a SPM. Latency was defined as the time

interval between myelofibrosis and SPM diagnosis. Standardized incidence ratios (SIR) were

computed using the SEER*Stat software. Individual patient data was analyzed using SPSS.

Results

A total of 4,838 patients with myelofibrosis were included in the study, with SPMs identified in

689 patients (14.1%). A higher incidence of SPMs was observed in patients diagnosed prior to

2012 compared to those diagnosed in the post-ruxolitinib era (17.1% vs. 12%). Compared to the

general population, patients with myelofibrosis demonstrated a significantly elevated risk of

developing SPMs (SIR 2.03; 95% CI, 1.88–2.19). This elevated risk was observed regardless of

the diagnosis era—both pre-2012 (SIR 1.87; 95% CI, 1.68–2.08) and post-2012 (SIR 2.24; 95%

CI, 2.00–2.49).The risk of respiratory tract SPMs significantly increased in patients diagnosed

after 2012 (SIR 1.66; 95% CI, 1.16–2.31), but not in those diagnosed before 2012 (SIR 1.29;

95% CI, 0.91–1.77).

The risk of non-Hodgkin lymphoma and leukemia was elevated regardless of the year of

diagnosis. Patients diagnosed before 2012 had SIRs of 3.24 and 20.84, respectively, while those

diagnosed after 2012 had SIRs of 2.61 and 34.04, respectively. The risk of SPMs remained

consistently elevated across most subgroups defined by age, sex, race, and latency. Notable

exceptions included American Indian/Alaskan Native patients (SIR 4.79; 95% CI, 0.58–17.31)

and patients with a latency over 120 months diagnosed after 2012 (SIR 1.84; 95% CI,

0.05–10.27).

A multivariable binary logistic regression analysis demonstrated a significantly higher risk of

second primary malignancies (SPMs) in patients diagnosed after 2012 compared to those

diagnosed before 2012 (OR 2.46; 95% CI, 2.04–2.98; p<0.001), after adjusting for demographic

factors. Age over 75 years was associated with a significantly reduced risk of SPM (OR 0.78;

95% CI, 0.62–0.98). Sex, race, chemotherapy, and marital status were not significant predictors

of SPM risk.

Although overall survival (OS) and cancer-specific survival (CSS) did not significantly differ between patients with and without SPMs (OS: 58 vs. 53 months, p=0.529; CSS: 92 vs. 105

months, p=0.112), multivariable Cox regression analysis demonstrated that the presence of

SPMs adversely impacted CSS (HR 1.22; 95% CI, 1.08–1.38; p=0.001), but not OS (HR 1.10;

95% CI, 0.96–1.16; p=0.28).

Conclusion

The incidence of second primary malignancies (SPMs) was significantly higher in patients

diagnosed after the approval of ruxolitinib, with consistent trends across age, sex, race, and

latency subgroups. SPMs were associated with reduced cancer-specific survival. Although these

patterns suggest a potential link, the SEER database lacks detailed treatment information,

limiting causal inference. Prospective studies are warranted to clarify the relationship between

ruxolitinib exposure and SPM risk.

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2025
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