A Phase II Study of the HDAC Inhibitor Givinostat In Combination with Hydroxyurea In Patients with Polycythemia Vera Resistant to Hydroxyurea Monotherapy

Several agents inhibiting the JAK2V617F mutation are actively investigated in patients with polycythemia vera (PV) and other chronic myeloproliferative neoplasms (MPN) with promising results. Givinostat, an HDAC inhibitor, specifically inhibits proliferation of cells bearing the JAK2V617F mutation and has shown significant activity with good tolerability in clinical studies in MPN patients. The aim of the present study was to evaluate safety and efficacy of two oral doses of Givinostat (50 or 100 mg daily) in combination with hydroxyurea (HU) in PV patients.

In this multicenter, randomized, open-label, phase II study, we treated 44 patients with JAK2V617F positive PV, non-responders (NR) to the maximum tolerated doses of HU monotherapy for at least 3 months. The clinical -hematological response criteria developed by the European LeukemiaNet (ELN) consensus conference (complete and partial response) were used to assess the primary endpoint after 12 weeks of treatment. Recruited patients were randomly assigned to receive Givinostat (50 or 100 mg/die) in combination with the maximum tolerated dose of HU. After week 12, NR patients increased the initial daily dose of Givinostat by 50 mg, while responders continued Givinostat at the initial daily dose. Overall, the treatment lasted up to a maximum of 24 cumulative weeks of drug administration.

Baseline demographic and hematological parameters were balanced between the two randomized groups. The mean weekly dose of HU at baseline was 6.75 (range 1.75–14) and 6.25 (1–14) grams and was reduced during the study to 6.25 (range 1.75–14) and 5.75 (0.75-12.25) grams, in the 50 (group A) and 100 mg (group B) Givinostat groups, respectively.

The combination of Givinostat and HU was well tolerated. Only five out of 44 evaluable patients dropped-out before week 12, respectively 2 in group A and 3 in group B. Reasons for treatment discontinuation were grade 2 thrombocytopenia and iperkalemia in group A and panic attack, withdrawal of consent and investigator decision due to safety reason (detection of familiar cardiac disorder unknown at recruitment) in group B. Only two grade 3 not drug related adverse events (AEs) were observed (hyperkalemia and platelet count increase), both occurring in group B. The most frequent grade 2 AEs were thrombocytopenia (4 cases, two in each group), leukopenia (2 cases both in group B) and diarrhea (2 cases, one in each group).

Complete (CR) plus partial (PR) response according to ELN response criteria was observed in 50% and 45% of patients in group A and B respectively. Moreover, a notable control of itching was observed at week 12 in most of the 21 evaluable patients affected by severe itching (grade ≥ 2) at baseline. Seven out of 11 (64%) and 8 out of 10 (80%) patients had a complete itching relief, in group A and B respectively.

The combined use of Givinostat and HU is well tolerated and about 50% of patients resistant to HU monotherapy achieved an overall ELN response (PR or CR). At week 12 no differences were found in the two randomized arms in term of hematological responses and itching relief. Givinostat confirms to be active in PV through the control of myeloproliferation and of some specific clinical needs, such as severe itching. Completed clinical and molecular data (after 24 cumulative weeks of treatment) will be presented at the meeting.

Rambaldi:Italfarmaco S.p.A.: Consultancy, Honoraria. Vannucchi:Italfarmaco S.p.A.: Consultancy, Honoraria. Barbui:Italfarmaco S.p.A.: Consultancy, Honoraria.