Second primary malignancies in ruxolitinib-treated myelofibrosis: Real-world evidence from 219 consecutive patients

Myeloproliferative neoplasms (MPNs) are clonal disorders that include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Patients with MPNs have a higher risk than the general population of developing a lymphoid neoplasm.1 It is still unclear whether this holds true for nonhematological second primary malignancies (SPMs).2-4 However, among 20 250 MPN patients included in the Surveillance, Epidemiology, and End Results (SEER) Program database, the 10-year cumulative incidence of SPMs was 12.7%, significantly higher than that expected in the general US population.5 Ruxolitinib (RUX) is an oral JAK inhibitor (JAKi) approved for International Prognostic Scoring System (IPSS)/Dynamic IPSS (DIPSS) intermediate- and high-risk myelofibrosis (MF)6,7 and for inadequately controlled PV. More than 2600 RUX-treated MF patients have been prospectively observed for at least 2 years within the 2 pivotal COMFORT trials8,9 and the expanded-access JUMP trial.10,11 Safety data from these trials underline a possibly increased incidence of nonmelanoma skin cancers (NMSCs), but no significant increase of lymphoproliferative neoplasms, similarly to what occurs in PV.12,13 Recently, Porpaczy et al alerted, however, on the possible 16-fold increased risk of developing aggressive lymphomas in MPN patients treated with JAKis, especially in the presence of a preexisting B-cell clone.14 The publication included a total of 1555 MPN patients, 126 of whom were treated with a JAKi (ruxolitinib, gandotinib, fedratinib, momelotinib), obtained assembling 2 broad academic data sets. In the well-described Viennese cohort, 3 of 31 MF patients treated with JAKi developed lymphomas. Median time from JAKi initiation to lymphoma diagnosis was 25 months. Subsequent analyses of other large academic data sets did, however, not confirm an increased risk of aggressive lymphoma development under JAKis in MPNs15,16 and in post-PV and post-ET MF (secondary MF [SMF]).17 These contradictory results were derived either from clinical trials with strict eligibility criteria, possibly at the expense of uncertainty about the generalizability of results, or from highly selected data sets of patients evaluated at referral centers, thus highlighting the need for real-world data (RWD). We consequently set out to assess the occurrence of SPMs, including lymphoproliferative neoplasms, in RUX-treated MF patients on the basis of RWD provided by the health authority of the Lombardy Region, integrated with institutional data.