Cutaneous Toxicities Are Underestimated in Patients With MPNs Receiving Hydroxyurea

A prospective study from Germany has found that, in patients with BCRABL1-negative myeloproliferative neoplasms (MPNs), treatment with hydroxyurea (hydroxycarbamide) is associated with a substantially higher rate of cutaneous toxicities than reported in most retrospective studies, suggesting the incidence of cutaneous toxicities associated with hydroxyurea has been systematically underreported in these patients. Many of these cutaneous events occurred after years of therapy.

The findings of this study, published as a research letter in Leukemia by Frank Stegelmann, MD, of the University Hospital of Ulm in Germany, and colleagues, suggest that both clinicians and patients should be informed about the possible cutaneous side effects of hydroxyurea to prevent the occurrence of these events from “becoming a limiting factor for the long-term use of hydroxyurea in MPN management.”

This noninterventional trial from the German Study Group-MPN enrolled 172 patients with polycythemia vera (35%), essential thrombocythemia (35%), and primary or secondary myelofibrosis (25%) who were routinely seen at MPN outpatient clinics in two German cities.

At study entry and at every 3-month visit, the investigators collected information about each patient’s medical history, then assessed any possible relationship between cutaneous adverse events (CAEs) and cytoreductive therapy.

The median time from MPN diagnosis to study entry was 5.5 years (range = 0.1-32.6), while the median prospective follow-up duration from study entry to the data cutoff date was 4.0 years (range = 0.1-7.2).

A total of 305 cytoreductive treatment courses were recorded in the sample – 92 in the retrospective cohort and 213 in the prospective cohort. The most frequently used treatments included hydroxyurea (n=150), anagrelide (n=50), conventional or pegylated interferon-alpha (n=39), and ruxolitinib (n=66).

When the authors reviewed patients’ medical histories, they identified 115 CAEs overall.

This included 50 CAEs (43.5%) in the retrospective cohort, for a CAE rate of 5.4% per 100 patient-years. The median treatment time until a CAE occurred was 3.4 years (range = 0.1-32.5). Nearly all the CAEs (n=49/50) occurred during hydroxyurea treatment, after a median of 3.0 years (range = 0.1-22.7). Nearly one-third of patients (31.5%) discontinued hydroxyurea because of a CAE.

In the prospective portion of the study, 65 CAEs were recorded, and the overall incidence of CAEs during this period was 12.5% per 100 patient-years. In this group, 60 of the 65 drug-associated CAEs (92.3%) occurred with hydroxyurea, after a median treatment duration of 4.5 years (range = 0.2-15.3).

The most frequently reported events were ulcers (n=15) and skin rashes (n=14); squamous cell carcinoma and basal cell carcinoma occurred in 1 patient and 3 patients, respectively.

At the time of CAE occurrence, the median daily hydroxyurea dosage was 1,000 mg, and the cumulative median dosage until the first CAE was 1,533 g, the authors reported.

“Comparing the total numbers of prospectively recorded CAEs in hydroxyurea versus non-hydroxyurea treatment courses, we found a statistically higher incidence of CAE in hydroxyurea-treated patients versus non-hydroxyurea–treated patients (54.1% vs. 4.3%; p<0.0001),” the investigators wrote.

Hydroxyurea was more often discontinued due to CAEs, compared with non-hydroxyurea treatments: 19.8% (n=19/96 treatment courses) versus 0.9% (n=1/117 treatment courses; p<0.0001).

Overall, the authors concluded that, because the CAE incidence was twice as high when data were evaluated prospectively compared with retrospectively, hydroxyurea-related CAEs may be underdiagnosed. “To prevent the occurrence of CAE under hydroxyurea, we strongly recommend [informing] patients about possible CAE before treatment start [and] [examining] patients thoroughly before and during therapy,” they wrote.

Limitations of the study included its partial retrospective nature, as well as the inclusion of a small number of patients from a single country.

The authors report no relevant conflicts of interest.


Stegelmann F, Wille K, Busen H, et al. Significant association of cutaneous adverse events with hydroxyurea: results from a prospective non-interventional study in BCR-ABL1-negative myeloproliferative neoplasms (MPN) – on behalf of the German Study Group-MPN. Leukemia. 2020 July 3. [Epub ahead of print]