Trends in second primary malignancies in myelofibrosis pre- and post-JAK inhibitor era: A surveillance, epidemiology and end-Results database study

Abstract 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.