ITF2357 (Italfarmaco SpA, Cinisello Balsamo, Italy) is a new synthetic class I and II HDAC inhibitor with a potent anti-proliferative and pro-apoptotic activity against several hematologic malignancies both in vitro and in vivo. It also inhibits the production/release of several cytokines including TNFa, IL-1b, IL-12, IFNg, IL-6 and VEGF by neoplastic as well as endothelial and mesenchymal cells (Golay J et al., Leukemia 2007). Recently, we have shown that ITF2357 inhibits the autonomous proliferation of hematopoietic cells from patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) through a specific down modulation of the JAK2V617F mutated protein and inhibition of its downstream signaling (Guerini et al., Leukemia, 2008). For these latter properties we planned to evaluate the safety and efficacy of ITF2357 in the treatment of PV, ET as well as Myelofibrosis, both primary (PMF) or secondary to a previous PV or ET (post PV/ET MF). Eligible to this non-randomized, open label, phase II A study, were patients refractory to hydroxyurea or young patients in need of cytoreductive therapy. ITF2357, was given orally at a starting daily dose of 50 mg b.i.d that could be escalated to 50 mg t.i.d., in the absence of toxicity. The dose was reduced at 50 mg/daily or withdrawn in case of toxicity. The total duration of drug administration could not exceed 6 months. In PV and ET a complete response (CR) was defined as HCT< 45%, no need of phlebotomy, platelets < 450 x109/L, WBC <10 x109/L, no splenomegaly, no systemic symptoms (pruritus, fever, weight loss and micro circulatory symptoms). A partial response (PR) was defined if hematocrit was less than 45% without phlebotomy or if response of at least 3 of the above-mentioned criteria was achieved. A no response was defined if the above criteria were not met. For PMF and post PV/ET MF patients, responses were defined according to EUMNET criteria. A total of 26 patients (male/female, 12/14), with a median age of 56 (range 36–70) and a confirmed diagnosis of JAK2V617F positive PV (n= 12), ET (n= 1), PMF (n= 4) or post PV/ET MF (n= 9) were enrolled into this study. At the time of this analysis, all patients received at least 1 month of treatment but only 13 patients have completed at least 12 weeks of treatment. ITF2357 was well tolerated and no patient experienced grade III-IV toxicity. Reasons for dose reduction or transient suspension included on-target side effects (grade 2 thrombocytopenia and anemia were observed in 1 and 4 patients, respectively) and other grade 1 or 2 toxicities (diarrhea, gastric pain, liver enzymes elevation, fatigue, and transient QTc elongation) in 9 patients. In PV/ET patients, 3 complete, 8 partial and 3 no responses were documented. Noteworthy, a significant reduction of palpable spleen was observed in 6 of 8 splenomegalic patients and the disappearance of pruritus in most of them. Two major and 2 moderate responses (EUMNET criteria) were registered among the 13 MF patients. Molecular monitoring of the JAK2V617F mutated allele performed by quantitative PCR showed a median reduction of 8% (range 1–17%) in 10/17 patients and 12% (range 2–29%) in 7/8 patients analyzed after 12 and 24 weeks of treatment, respectively. In conclusion, treatment with ITF2357, a drug with a pleiotropic activity on chromatin structure and gene transcription, was followed by a rapid improvement of constitutional symptoms, spleen size and hematologic response in the great majority of PV/ET and in some MF patients. Different drug dosing and combinations are now under investigation.

Disclosures: Rambaldi: Italfarmaco, SpA, Cinisello Balsamo, Italy: Research Funding.

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