A phase II study of <scp>G</scp>ivinostat in combination with hydroxycarbamide in patients with polycythaemia vera unresponsive to hydroxycarbamide monotherapy

Harrison

2017

Blood

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There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients’ major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibrosis. Raised awareness of the molecular abnormalities and cellular pathways involved in the pathogenesis of MPN is facilitating the development of clinical trials with novel target drugs, either alone or in combination with ruxolitinib. Although for most of these molecules a convincing preclinical rationale was provided, the results of early phase 1 and 2 clinical trials have been quite disappointing to date, and toxicities sometimes have been limiting. In this review, we critically illustrate the current landscape of novel therapies that are under evaluation for patients with MPN on the basis of current guidelines, patient risk stratification criteria, and previous experience, looking ahead to the chance of a cure for these disorders.

Section: Hdacimentioning

confidence: 99%

Emerging treatments for classical myeloproliferative neoplasms

Harrison

2017

Blood

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“…108 Givinostat proved promising in a phase II study for control of hematocrit and symptoms, 109 and was also tested in combination with hydroxyurea in patients who were refractory to this drug, producing responses in approximately half. 110 A phase Ib/II study to assess the safety and tolerability, and preliminary efficacy, in PV patients (clinicaltrials.gov identifier: 01901432) is ongoing. Overall, not much is available and the shelf is quite empty.…”

Section: What's Available?mentioning

confidence: 99%

From leeches to personalized medicine: evolving concepts in the management of polycythemia vera

2016

Haematologica

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© Ferrata Storti Foundationing to the level of knowledge we have now. Table 1 lists some of these landmark studies; due to space constraints, I will not be able to address all of them in detail. Evolving concepts in diagnosis Making a diagnosis of polycythemia veraThe World Health Organization (WHO) recently released a revised classification of MPN in which important changes to the 2008 version were introduced (Table 2). 8 In the 2008 version, the most compelling innovation had been the introduction of JAK2V617F and "similar" mutations (involving JAK2 exon 12 in 3%-4% of patients) as major diagnostic criteria.3-6 Although JAK2V617F mutation is associated with PV in more than 95% of cases, it does not represent a clear diagnosis since it is found also in 50%-60% of ET and PMF. However, the use of JAK2V617F as a marker of clonal myeloproliferation greatly facilitates the distinction of PV from reactive or congenital erythrocytosis.Considering that isotope-based assays for measuring red cell mass (RCM) and plasma volume are not routinely available even in most tertiary centers, the 2008 WHO classification listed a hemoglobin level more than 185 g/L and 165 g/L in men and women, respectively, as a strong surrogate marker of absolute increase of RCM. Since some PV patients do not fulfill such high levels, other criteria were added to facilitate diagnosis, including: 1) hemoglobin or hematocrit level that is more than 99 th percentile of reference range for age, sex, or altitude of residence; 2) an RCM that is more than 25% above mean normal predicted value;3) a hemoglobin level more than 170 g/L and 150 g/L in men and women, associated with a sustained increase of 20 g/L from baseline not attributable to correction of iron deficiency. According to the pragmatic British standards, hematocrit more than 52% in males and more than 48% in females, or an RCM more than 25% above predicted value, are sufficient to establish a diagnosis of PV if JAK2 mutation is present. 9 However, a reassessment of how far the WHO criteria can be applied in a real-life setting raised the issue of JAK2V617F mutated patients with only a borderline increase in hemoglobin. It was shown that BM morphology, according to WHO guidelines, accurately reflected a condition of increased RCM, since all patients with increased RCM also had a BM morphology consistent with PV.

“…The HDAC inhibitor givinostat has been used in 2 phase 2 clinical trials: the first included patients with PV and other MPNs who were intolerant or refractory to hydroxyurea, 96 and the second, envisioning the association of givinostat with low-dose hydroxyurea, enrolled PV patients who were unresponsive to the maximum tolerated dose of hydroxyurea. 97 These studies provided initial evidence of efficacy regarding Hct and phlebotomy control and symptom improvement, with a good safety profile; However, no phase 3 study is planned to date. Another HDAC inhibitor, vorinostat, showed efficacy in normalizing blood cell counts and reducing pruritus and splenomegaly in newly diagnosed and previously treated PV patients who were in need of cytoreduction or were intolerant to other therapies, but it caused notable side effects, leading to a high discontinuation rate.…”

Section: Investigational Agentsmentioning

confidence: 99%

How I treat polycythemia vera

2014

Blood

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Polycythemia vera (PV) is a chronic myeloproliferative neoplasm associated with JAK2 mutations (V617F or exon 12) in almost all cases. The World Health Organization has defined the criteria for diagnosis, but it is still unclear which parameter (hemoglobin or hematocrit) is the most reliable for demonstrating increased red cell volume and for monitoring response to therapy; also, the role of bone marrow biopsy is being revisited. PV is associated with reduced survival because of cardiovascular complications and progression to post-PV myelofibrosis or leukemia. Criteria for risk-adapted treatment rely on the likelihood of thrombosis. Controlled trials have demonstrated that incidence of cardiovascular events is reduced by sustained control of hematocrit with phlebotomies (low-risk patients) and/or cytotoxic agents (high-risk patients) and antiplatelet therapy with aspirin. Hydroxyurea and interferon may be used as first-line treatments, whereas busulfan is reserved for patients that are refractory or resistant to first-line agents. However, there is no evidence that therapy improves survival, and the significance of reduction of JAK2 mutated allele burden produced by interferon is unknown. PV is also associated with a plethora of symptoms that are poorly controlled by conventional therapy. This article summarizes my approach to the management of PV in daily clinical practice.