Abstract: Polycythemia Vera (PV) is a chronic myeloproliferative neoplasm primarily driven by the JAK2V617F mutation, characterized by excessive red blood cell production and a high risk of thrombotic and hemorrhagic complications. While conventional therapies such as phlebotomy and hydroxyurea focus on minimizing thrombotic risk, there is a critical need for disease-modifying agents that target the underlying malignant clone. Givinostat (ITF-2357) is an orally bioavailable, selective inhibitor of class I and II histone deacetylases (HDACs) that has emerged as a promising targeted therapy for PV. By selectively targeting JAK2V617F-mutated cells and downmodulating JAK2 protein expression, Givinostat restores normal hematopoiesis and reduces the mutant allele burden. Clinical trials have demonstrated significant hematological responses, symptom relief, and phlebotomy independence with an acceptable safety profile. This review summarizes the pharmacological activity, molecular mechanisms, current limitations, and future perspectives of Givinostat in the management of Polycythemia Vera based on recent literature.
1. Introduction
Polycythemia Vera (PV) is a BCR-ABL1-negative chronic myeloproliferative neoplasm (MPN) characterized by the clonal expansion of abnormal hematopoietic stem cells. It manifests clinically with elevated blood cell counts (particularly erythrocytes), a predisposition to thrombotic and hemorrhagic events, and a cumulative risk of fibrotic progression or leukemic evolution [1][2]. The pathophysiology of PV is predominantly driven by the JAK2V617F mutation, which is present in the vast majority of patients and leads to constitutive activation of the JAK-STAT signaling pathway [3][4].
Current management strategies are risk-adapted and primarily aim to prevent thrombotic complications. Standard therapies include low-dose aspirin and therapeutic phlebotomy to maintain hematocrit levels below 45% [2][4]. For high-risk patients, cytoreductive agents such as hydroxyurea (HU) or interferons are utilized as first-line treatments, while the JAK1/2 inhibitor ruxolitinib is approved for patients who are resistant or intolerant to HU [1][2]. Despite these options, conventional therapies often fail to eradicate the malignant clone or prevent disease progression, highlighting a significant unmet clinical need [1]. Givinostat (ITF-2357), a histone deacetylase (HDAC) inhibitor, has recently shown tremendous potential as a novel, disease-modifying therapeutic modality for PV [2][3]. Notably, the therapeutic scope of Givinostat extends beyond oncology, having also been investigated and recently approved for the treatment of Duchenne muscular dystrophy [6][7].
2. Pharmacological Activity
Givinostat has demonstrated robust pharmacological activity in PV patients, particularly those unresponsive to standard cytoreductive therapies. In a pilot phase IIA study involving JAK2V617F-positive MPN patients, Givinostat (administered at 50 mg daily) achieved one complete and six partial hematological responses among the 12 PV patients [1][2]. Notably, 70% of these patients achieved a phlebotomy-free status, and significant resolutions in splenomegaly (70%) and pruritus (90%) were observed, alongside a reduction in the JAK2V617F allele burden [2].
In a subsequent randomized phase II study of PV patients unresponsive to HU, Givinostat was evaluated at 50 mg once or twice daily in combination with HU at the maximum tolerated dose (MTD). Complete and partial responses were achieved in 55% and 50% of patients in the 50 mg and 100 mg/day groups, respectively, with pruritus control in over 64% of subjects [1][2]. A long-term follow-up study (median treatment duration of 4 years) reported complete and partial hematological remissions in 11% and 89% of patients, respectively. Furthermore, 56% of patients maintained a normal hematocrit without phlebotomy and exhibited normal spleen sizes [1][2].
More recently, a phase Ib/II study determined the MTD of Givinostat as monotherapy to be 100 mg twice daily. In this cohort, the overall response rate was 80.6%, with significant efficacy in symptom relief and a notable decrease in the JAK2V617F variant allele frequency (VAF) [1][2][4].
3. Molecular Mechanism of Action
The epigenome plays a central role in regulating gene expression, and histone modifications, particularly deacetylation catalyzed by histone deacetylases (HDACs), are known to silence tumor suppressor genes in various malignancies [1][2]. Givinostat is an orally bioavailable, potent, and selective inhibitor of class I and II HDACs [2][4].
In the context of PV, Givinostat acts directly on JAK2V617F-mutated cells. It reduces their proliferation through a mechanism that involves the downmodulation of the JAK2 protein and the subsequent inhibition of its downstream signaling pathways [1][2]. Importantly, Givinostat prevents the synthesis of the mutated JAK2 protein without affecting the wild-type protein [3]. By suppressing the clonogenic activity of these mutated cells, Givinostat promotes the outgrowth of non-mutated (wild-type) colonies, demonstrating a unique potential to restore normal hematopoiesis in PV patients [1][2]. Additionally, in vitro studies have shown that Givinostat induces apoptosis in neoplastic cells and inhibits the synthesis of numerous pro-inflammatory cytokines, which contributes to the alleviation of constitutional symptoms like pruritus [2][4].
4. Structure-Activity Relationship (SAR)
While the provided literature does not detail the specific chemical structure-activity relationship (SAR) modifications of the Givinostat molecule, it highlights the compound's functional selectivity profile derived from its structure. Givinostat is formulated as an orally bioavailable small molecule that selectively targets class I and II HDACs [2][4]. This specific HDAC inhibition profile translates into preferential cytotoxicity toward JAK2V617F-mutant cells both in vitro and in vivo, while exerting minimal effects on normal hematopoietic progenitors [4]. The selective activity is mediated through the targeted transcriptional repression of genes involved in cell cycle progression, cytokine signaling, and inflammatory responses, sparing normal cellular functions [4].
5. Current Limitations
Despite its promising efficacy, Givinostat therapy is associated with certain limitations and adverse effects. The most commonly reported adverse events (AEs) include gastrointestinal symptoms (such as diarrhea and nausea), mild thrombocytopenia, elevated liver enzymes, and increased serum creatinine levels [3][4]. In studies evaluating Givinostat in broader myeloproliferative contexts (such as myelofibrosis), gastrointestinal side effects were observed in up to 62% of patients [5].
However, in PV-specific clinical trials, the drug has generally been well tolerated. In the phase II combination study with HU, Grade 3 AEs were recorded in only about 4.5% of cases, and no Grade 4 toxicities were reported [1][2]. Similarly, during long-term treatment (median 4 years), only three Grade 3 toxicities and zero Grade 4 toxicities occurred, indicating an acceptable long-term safety profile [1][2]. Nevertheless, the presence of gastrointestinal and hematological toxicities requires careful monitoring and may necessitate dose adjustments in clinical practice.
6. Future Perspectives
Givinostat represents one of the most encouraging emerging treatments for Polycythemia Vera, offering a shift from mere symptom management to potential disease modification [2][3]. By targeting epigenetic dysregulation while sparing normal hematopoiesis, it provides a viable alternative to traditional cytoreductive therapies, particularly for patients who are resistant or intolerant to hydroxyurea [4].
Based on the successful efficacy and safety data from early-phase trials, a global phase III clinical study is currently planned or underway to evaluate the efficacy of Givinostat compared to hydroxyurea in high-risk PV patients [2][4]. If successful, Givinostat could redefine the standard of care by offering stable hematocrit control, reducing or eliminating the need for repeated phlebotomies, and lowering the mutant allele burden [4]. Furthermore, the recent FDA approval of Givinostat for Duchenne muscular dystrophy underscores its broad therapeutic potential and safety profile, paving the way for its expanded use in fibrotic, inflammatory, and neoplastic diseases [6][7].
