Risk of Second Malignancies Not Elevated Among Older MPN Patients Treated With Hydroxyurea

The risk of second malignancy was similar among patients aged 66 and older who were treated with and without hydroxyurea.

The use of hydroxyurea to treat patients with myeloproliferative neoplasms (MPNs) does not appear to increase the risk of secondary malignancies among older patients, according to a new report.

The new data may help add clarity to a long-simmering question of whether exposure to hydroxyurea might itself convey a cancer risk. The new study was published in Blood Advances.

Both the National Comprehensive Cancer Network and the European LeukemiaNet guidelines call for the use of hydroxyurea as a frontline cytoreductive therapy for patients with high-risk MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and hyperproliferative myelofibrosis (MF), noted the study authors.

“Hydroxyurea not only reduces the incidence of thrombosis but also improves survival among older patients with ET and PV,” they wrote.

Yet, because the therapy interferes with DNA synthesis, the investigators noted that some worry the therapy may have mutagenic and leukemogenic potential, especially among high-risk patients. Previous studies on the matter have yielded conflicting results.

In the new report, they decided to analyze the association between hydroxyurea and secondary malignancy in a large cohort of older patients (those aged 66 and older).

They pulled data from 4023 cases of MPN reported in the Surveillance, Epidemiology, and End Results (SEER) Medicare–linked database between 2010 and 2017. Most of the cases were either PV (1688 cases) or ET (1976 cases). There were 359 cases of MF in the cohort. The patients had a median age of 77 years at the time of their MPN diagnosis.

A total of 489 patientsin the cohort went on to develop a second malignancy after a median follow-up of 3.25 years. Most of the second malignancies were solid malignancies (346); 73 cases were lymphoid malignancies, and 70 were myeloid malignancies.

Most patients in the cohort (2683 patients) were given hydroxyurea. Among those patients, the incidence probability of a second malignancy was 19.88% (95% CI, 17.16%-22.75%). Among the patients not receiving hydroxyurea, the incidence probability of a second malignancy was 22.31% (95% CI, 17.51%-27.47%). Thus, the authors said, patients who took hydroxyurea did not appear to be at an increased risk of a new malignancy.

On the other hand, the authors said other variables did appear to affect a patient’s risk of a second malignancy.

“Patients diagnosed with MPN at the age of ≥ 85 years, as well as patients with a disability, were less likely to develop any secondary malignancy and solid secondary malignancy when compared with those diagnosed at the age of 66 to 69 years and without disability, respectively, which may be because of an increase in the competing risk of death in these groups,” they wrote.

They noted that a new therapy—ropeginterferon α-2b—has been approved in the United States and Europe as a cytoreductive therapy for people with PV. The European LeukemiaNet 2021 expert opinion guidelines suggest that younger patients with PV be treated with the newer therapy due to the perceived increased risk of a second malignancy, the study authors noted. However, they said given the mixed evidence behind the hydroxyurea/second malignancy claim and the significantly higher cost of the new therapy, cost-effectiveness studies are warranted to better understand which cytoreductive therapy would be better for which patients.

The authors said their study was limited by several factors, including a lack of reliable records in the SEER database related to nonmelanoma skin cancers, which some research has linked with hydroxyurea use.

Despite those limitations, the investigators said the available data do not support a link between hydroxyurea use and second malignancies in older patients.


Wang R, Shallis RM, Stempel JM, et al. Second malignancies among older patients with classical myeloproliferative neoplasms treated with hydroxyurea. Blood Adv. 2023;7(5):734-743. doi:10.1182/bloodadvances.2022008259

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