WASHINGTON – European patients with sickle cell disease (SCD) are tolerating hydroxyurea treatment well, 9 years into a 10-year prospective cohort study.

CDC/Janice Haney Carr

Fewer than one in five adults have experienced treatment-related adverse events and there have been low overall rates of discontinuation.

ESCORT-HU (European Sickle Cell Disease Cohort – Hydroxyurea) is slated to enroll 2,000 children and adults over the study period to assess the long-term safety and efficacy of hydroxyurea (HU) as a treatment for SCD.

“Hydroxyurea is still underused in sickle cell disease” both in Europe and the United States, said Bernard Dauvergne, PharmD, executive director of Addmedica, which markets hydroxyurea as Siklos. In part, fears about toxicity and side effects contribute to this underuse, Dr. Dauvergne said at a top abstracts session of the annual meeting of the Foundation for Sickle Cell Disease Research.

ESCORT-HU was designed as a purely observational, noninterventional study of patients treated with HU. It was initiated as part of the European Medicines Agency risk management plan, conceived at the time of the drug’s approval for SCD, explained Dr. Dauvergne.

“This prospective cohort study could enable the identification of delayed rare adverse events in real life, occurring in between 1 in 10,000 and 1 in 1,000 patients,” Dr. Dauvergne said. However, “no new safety information has been detected ... and no secondary cancer has been reported.”

At the last data analysis cutpoint of June 2017, 1,921 patients had been enrolled. Patients have come from 63 centers in France, Germany, Greece, and Italy, Dr. Dauvergne reported.

Of the 1,829 patients with data available for analysis, 804 were under the age of 18. The pediatric patients were a mean 9 years of age, and the adult patients were a mean 33 years old at enrollment. Most enrollees (84%) have the HbSS genotype.

At baseline, the pediatric patients were dosed at a mean 17.2 mg/kg per day of HU; for adult patients, the figure was 15.54 mg/kg per day. More than one-third (35.4%) of pediatric patients had been on HU at the time of study enrollment, for a mean of 4.5 years. In contrast, more than half (60.4%) of adults had been taking hydroxyurea for a mean of 6.25 years at enrollment.

The 1,002 adult patients with recently reported safety data were on a mean HU dose of 20.2 mg/kg per day. About 40% of adults reported at least one adverse event (AE), and a total of 334 AEs in 16.3% of adult patients were judged to be related to HU.

Skin and subcutaneous tissue reactions occurred in about 1 in 10 patients, with 153 reported incidences of skin dryness, skin reactions, alopecia, or changes in skin pigmentation. The next most common adverse events were blood and lymphatic system disorders, mostly neutropenia or thrombocytopenia, occurring in 9.6% of patients.

Discontinuation rates have been low, with an overall dropout rate of 3.8%.

The ESCORT-HU data “confirm that HU is an efficient and well-tolerated drug in both children and adults,” Dr. Dauvergne said. Over the short term, adverse events are related to the expected dose dependent myelosuppression that’s key to the drug’s mechanism of action. This makes sense given the narrow therapeutic index, with a tight range between an efficacious dose and a cytotoxic one, he said. “And the lower the [patient] weight is, the more sensitive the dose variations become,” Dr. Dauvergne said.

Being flexible about fine-tuning doses is key to finding the balance between tolerability and efficacy, “and consequently, for compliance,” he said.

Data collection for the study will end in 2018, with safety and efficacy data expected in 2019.

koakes@mdedge.com

Hydroxyurea well tolerated in longitudinal European study