Surveillance for Second Primary Malignancy Recommended in Select Patients With Myelofibrosis Treated With Ruxolitinib

Patients with myelofibrosis who receive ruxolitinib appear to face a higher risk of second primary malignancy; these risks are suggested to be even higher in men and patients with a history of arterial thrombosis and prolonged hydroxycarbamide exposure.

Patients with myelofibrosis (MF) who receive ruxolitinib (Jakafi) appear to face a higher risk of second primary malignancy (SPM); these risks are suggested to be even higher in men and patients with a history of arterial thrombosis and prolonged hydroxycarbamide (hydroxyurea; Hydrea) exposure, a new real-world study shows. As such, the authors of the report, published in the British Journal of Haematology, said active skin surveillance is recommended for patients with MF treated with ruxolitinib.

Patients with MF, like patients with all types of myeloproliferative neoplasms (MPNs), face a higher-than-average risk of SPM, and existing research shows SPM is a major cause of morbidity and mortality in patients with MF.

Ruxolitinib is a selective Janus kinase 1 and 2 (JAK1/2) inhibitor used to treat MF-related splenomegaly and symptoms. The drug is effective in the majority of cases, but it has been linked with an increased risk of non-melanoma skin cancers (NMSCs).

Corresponding author Nicola Polverelli, MD, PhD, of the University of Brescia, in Italy, and colleagues collected real-world data on the incidence, type, and timing of SPMs in patients with MF who received ruxolitinib therapy in order to better understand risk factors and survival rates.

The investigators pulled data retrospectively from a database of patients with chronic-phase MF who were treated with ruxolitinib between 2011 and January 2020 at one of 20 European hematology centers.

Polverelli and colleagues pulled a range of clinical data for patients and contacted participating cancer centers to find out information about all malignancies occurring before or after ruxolitinib therapy. Myelodysplasia and acute leukemia were excluded from the analysis, since they are possible natural evolutions of MF.

A total of 700 patients were identified, all of whom had MF and were treated with ruxolitinib. The median follow-up post-initiation of ruxolitinib therapy was 2.9 years (range, 0.1-8.4).

Among the 700 patients, 80 (11.4%) went on to develop a total of 87 SPMs following initiation of ruxolitinib. SPMs were developed a median of 2.8 years after the start of ruxolitinib therapy (range, 0.3-32.2); the incidence rates also tended to increase over time. NMSCs were the most common malignancy, representing just over half (50.6%) of the SPMs. No aggressive lymphomas were reported.

The investigators then conducted a multivariate analysis to determine risk factors for SPMs. They found that men had a higher risk of SPM (hazard ratio [HR], 2.37; 95% CI, 1.22-4.60; P = .01). Patients with thrombocytosis >400 x 109/L at the start of ruxolitinib therapy also had heightened risk (HR, 1.98; 95% CI, 1.10-4.60; P = .02).

For NMSC specifically, male sex and a duration of hydroxyurea and ruxolitinib therapy exceeding 5 years were risk factors, with HRs of 3.14, 3.20, and 2.93, respectively.

In other types of SPMs, risk factors for SPMs were male sex (HR, 2.41; 95% CI, 1.11-5.25; P = .03), platelet counts above 400 x 109/L (HR, 3.30; 95% CI, 1.67-6.50; P = .001), and previous arterial thromboses (HR, 3.47; 95% CI, 1.48-8.14; P = .004).

The authors reported that 7.5% of patients died due to a second cancer, a figure somewhat higher than data reported prior to the approval of ruxolitinib, although the authors admitted that this is challenged by the risk status of patients included in the analysis.

In discussing their findings, Polverelli and colleagues noted that men have already been found to be at higher risk for most neoplasia, including NMSC.

Similarly, they said the risk of SPM has long been shown to be higher in patients with thrombocytosis and previous arterial thrombosis. The authors wrote that both conditions are characterized by inflammation, and in the study data, both were present long before the start of ruxolitinib in most patients. “Therefore, the underlying inflammatory process causing thrombocytosis and arterial events has persisted over time, creating the substrate favorable to the accumulation of genetic damages, from which second cancers may result,” they wrote.

In terms of clinical practice, the authors said careful skin surveillance is essential for all patients with MF who undergo ruxolitinib therapy, and especially for those who also are exposed to hydroxyurea for long periods of time. Patients with a history of arterial thrombosis should be screened for second cancers, and clinicians should consider the patient’s gender when assessing risk.

“Further collection of data on [ruxolitinib] therapy in patients stratified by sex will probably contribute to the development of personalized strategies for the management of therapy- and disease-related complications,” they concluded.


Polverelli N, Elli EM, Abruzzese E, et al. Second primary malignancy in myelofibrosis patients treated with ruxolitinib. Br J Haematol. Published online November 21, 2020. doi:10.1111/bjh.17192