Second Malignancies among Older Patients with Classical Myeloproliferative Neoplasms Treated with Ruxolitinib Open Access

• There is controversy surrounding the association of the use of RUX and risk of SM in patients with MPN

• Our study suggests that treatment with RUX does not increase the risk of developing a SM in older patients with MPN

Polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF) are classical Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) associated with an increased risk of development of second malignancies (SM). The reasons for solid and lymphoid SM are unclear, but a therapy-related effect has been invoked. While an increased risk of non-melanoma skin cancers is associated with the use of ruxolitinib (RUX), its influence on the development of other forms of SM remains controversial. We conducted a retrospective cohort analysis to assess associations between RUX and SM among older patients diagnosed with MPN from 2012-2019 in the Surveillance, Epidemiology, and End Results Medicare-linked database. We identified 6043 patients (2396 PV, 2944 ET, 703 MF) with median age of 76 (interquartile range [IQR]: 71-82) years. After a median follow-up of 3.66 (IQR: 2.25-5.17) years and 3.02 (IQR: 1.84-4.75) years for 513 RUX-users and 5530 non-users, respectively, 469 patients developed a SM: 383 solid and 86 lymphoid. In the multivariable proportional sub-distribution hazard regression model with death as a competing risk, the risk of developing any SM did not differ by RUX use status (hazard ratio [HR]= 0.96, 95% confidence interval [CI]: 0.65-1.42, p=0.84) nor proportion of days covered by RUX (every 10% increase: HR=1.00, 95% CI: 0.96-1.05, p=0.95). RUX exposure did not impact the risk of solid SM (HR=0.77, 95% CI: 0.48-1.23, p=0.27) or lymphoid SM (HR=1.73, 95% CI: 0.79-3.80, p=0.17). Our results suggest that the use of RUX does not increase the risk of SM in older patients with MPN.