Givinostat Shows Promise for Long-Term Use in Patients With Polycythemia Vera

In patients with polycythemia vera (PV), long-term use of the histone deacetylase (HDAC) inhibitor givinostat may be warranted after the agent demonstrated tolerable safety and good efficacy over a 4-year period in an ongoing, multicenter, open-label, single-arm study (NCT01761968) of patients with a chronic myeloproliferative neoplasm (MPN) who are positive for a JAK2 V617F mutation.¹

The study was designed to determine the safety, tolerability, and efficacy of givinostat in patients with MPNs who were recruited from 3 core studies and a compassionate use program where givinostat was assessed as monotherapy or in combination with hydroxyurea. Safety and tolerability were determined by the incidence and severity of adverse events (AEs) observed in the study, and efficacy was assessed by investigators according to the objective response rate (ORR) and complete response (CR) rate achieved with the agent.

“These long-term results support the potential of givinostat as a disease-altering treatment in patients with PV who are currently confined to symptomatic care,” said Alessandro Rambaldi, MD, professor of hematology at the University of Milan; head of the Hematology and Bone Marrow Transplant Unit at ASST Papa Giovanni XXIII in Bergamo; and lead author and investigator of the trial, in a press release.²

Due to the increased levels of red cells, white blood cells, and platelets found in patients with PV, this population requires therapy that can stabilize blood levels. The use of the available treatment options for these patients is limited by toxicities and other safety concerns.

A total of 104 patients with PV were included in the study, making up 68.3% of the patient population. Those eligible were 18 years of age or older with an MPN diagnosis based on revised criteria from the World Health Organization. The patients enrolled had also tolerated prior treatment with givinostat.

For the purpose of the 4-year analysis, data were available for 50 patients with PV who had a median age of 59.0 years (range, 42.0-80.0). An even percentage of patients were under 60 years of age and 60 years of age or older (50%). The study population was largely male (62.0%), and all patients were White. Upon entry to the study, it had been a median of 7.2 years (±5.70) since the patients were diagnosed with PV. At baseline, investigators looked at hematologic levels, which showed that the median hemoglobin level in these patients was 136 g/l (range, 118-166), hematocrit was 45.05 (range, 40.9%-50.7%), platelets were 698 109/l (range, 264-1459), and the median white blood cell count was 13.44 109/l (range, 3.71-46.48). Testing at baseline showed that a JAK2 V617F mutation was present in all patients enrolled, with the median JAK2 V617F allele burden being 59.75% (range, 25.0-94.2).

In terms of prior therapy, the majority of the population received antiplatelet treatments (52.0%), while 60% received cytoreductive treatments. Notably, 46% of the study population had at least 1 prior therapy. Eight percent of patients were heavily pretreated with at least 3 prior therapies.

Givinostat was administered in one dose given at a dose range of 50 mg once a day to 100 mg twice a day. Fifteen patients in the study also received concomitant hydroxyurea. For 10 patients, hydroxyurea was later discontinued.

At the time of data cutoff, the patients with PV had been exposed to givinostat for a median of 2.8 years (range, 3 months-11 years). At the time, 62% of the population was still receiving therapy.

Givinostat led to a partial response or CR in 80% of the patients treated. It was notable that the responses observed lasted throughout the follow-up period. Only 4 patients in the study were nonresponders. The ORR observed with givinostat in the study was 92%.

“The overall response rate, which continues to be persistent over the 4-year mean follow-up, combined with the good safety profile, justifies the global pivotal phase 3 study, which will start this year, to further evaluate givinostat and generate clinical evidence necessary to bring the drug to patients,” Rambaldi stated, in the press release.

The safety analysis showed that 96% of patients experienced an adverse event (AE), but notably, the majority of AEs were less than grade 3 in severity. Treatment-related AEs (TRAEs) were also predominantly low grade even though they occurred in 94.1% of patients. Also, only 10% of patients had a grade 3 TRAE, and no TRAEs were grade 4 or 5. The most common AE categories of any grade observed in the study were blood and lymphatic system disorders (64.0%), gastrointestinal disorders (32.0%), and cardiac disorders (14.0%). The subgroup of patients who received concomitant hydroxyurea showed similar safety results to the intent-to-treat population.

Overall, 4 patients in the study withdrew as a result of disease progression. These patients progressed to either acute myeloid leukemia or PV-myelofibrosis. Another patient withdrew due to a lack of response to givinostat. Another 2 patients from the study withdrew consent and there was 1 patient death from natural causes.

“With over 100,000 polycythemia vera cases in the US and considering that these patients have an increased risk of developing myelofibrosis or acute myeloid leukemia, in addition to the day-to-day complications caused by the disease, the data announced today provide PV patients with hope for a new treatment option,” added Srdan Verstovsek, MD, PhD, professor of medicine; chief, Section for MPNs at the Department of Leukemia; and director at the Clinical Research Center for MPNs at The University of Texas MD Anderson Cancer Center in Houston, Texas, in a statement. “I value the opportunity to participate in the upcoming pivotal and global phase 3 trial, which will be the first of its kind in PV.”

_References:

_{1. Rambaldi A, lurlo A, Vannucch AM, et al. Long-term safety and efficacy of givinostat in polycythemia vera: 4-year mean follow up of three phase 1/2 studies and a compassionate use program. Blood Cancer J. 2021;11(53). doi:10.1038/s41408-021-00445-z}

_{2. Italfarmaco announces publication of positive long-term data for givinostat in polycythemia vera patients in Blood Cancer Journal. News release. Italfarmaco Group. March 18, 2021. Accessed}