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Investigational Treatment Provides Hope for Patients With PV

Investigational Treatment Provides Hope for Patients With PV
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Published on April 9, 2021

What We Know About Givinostat for the Treatment of PV

A new investigational drug has been shown to provide long-term results for patients with polycythemia vera (PV) without any serious side effects.

In an ongoing trial at multiple centers, givinostat, which belongs to a class of drugs called histone deacetylase (HDAC) inhibitors, was shown to be effective and safe over a four-year period in patients with PV who have a JAK2 V617F mutation. (Up to 95% of patients with PV have a mutation in the JAK2 gene.)

HDAC inhibitors are anti-cancer agents that block enzymes called HDACs, which are overexpressed in cancer cells. Inhibiting the activity of HDAC enzymes can activate tumor suppressor genes to help control cell division and slow down cancer progression.

Eighty percent of the patients in the trial had a partial or complete response to the treatment and the responses lasted throughout the follow-up period.

“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 Dr. Alessandro Rambaldi, professor of hematology at the University of Milan in Italy and lead author and investigator of the trial, in a press release.

He added: “The overall response rate, which continues to be persistent over the four-year mean follow-up, combined with the good safety profile, justifies the global pivotal phase 3 study (comparing givinostat to standard-of-care therapies) …to further evaluate givinostat and generate clinical evidence necessary to bring the drug to patients.”

Study Details

The results published in Blood Cancer Journal summarize the four-year mean follow-up of a long-term study that enrolled 51 patients with PV. These patients had received clinical benefit from givinostat in three previous studies by the manufacturer Italfarmaco, as well as in a compassionate use program.

Almost half had undergone at least one prior therapy. About 10% had received at least three, including antiplatelet therapy (e.g., clopidogrel) and cytoreductive treatments (e.g., hydroxyurea).

One patient failed PV screening. The remaining 50 patients received at least one dose of givinostat (range: 50 mg once a day to 100 mg twice a day). Fifteen patients also received hydroxyurea. For 10 patients, hydroxyurea was later discontinued.

The overall response rate was 92%. Four patients withdrew because of progression to either acute myeloid leukemia or PV-myelofibrosis. One withdrew because of a lack of response. Another two withdrew consent and there was one death from natural causes.

During the study, only five patients (10.0%) experienced Grade 3 adverse events (AEs) — severe or medically significant but not immediately life-threatening — and there were no treatment-related Grade 4 (life-threatening) or 5 (death) AEs. 

Most of the patients continued treatment with givinostat after the study ended, supporting its long-term use, the study authors wrote.

Why is Polycythemia Vera So Hard to Treat?

In PV, the bone marrow makes too many red cells or too many white blood cells, and platelets. Patients require treatment to stabilize their blood levels. This ranges from phlebotomy alone or in combination with low-dose aspirin, or treatments such as hydroxyurea, interferon (ropeginterferon) or the JAK inhibitor ruxolitinib (Jakafi).

While all of these can help mitigate PV symptoms, they don’t target the underlying cause of the disease. In addition, toxicity and side effects can limit the use of treatments like hydroxyurea and interferon.

“We know with ruxolitinib people actually live longer for a few years, but it does not eliminate disease,” said Dr. Srdan Verstovsek, director of the Clinical Research Center for MPNs at The University of Texas MD Anderson Cancer Center in Houston, in an interview with Patient Power co-founder Andrew Schorr. “It loses the control of these symptoms and these medications do not really improve the bone marrow function, the anemia persists, and it may be worse on the therapy with JAK inhibitors. So how do we improve that?”

Givinostat selectively targets the JAK2 mutation and reduces the proliferation of hematopoietic cells, which play a role in tumor growth and progression.

In the three previous studies, the HDAC inhibitor (either alone or in combination with hydroxyurea) was effective, with a high response rate (50-80% depending on the study and the dose administered) and a good safety profile. Most of the AEs were mild or moderate in severity.

Commenting on the Blood Cancer Journal study, Dr. Verstovsek said in a statement: “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.”

~Megan Trusdell


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