A pilot study of the Histone‐Deacetylase inhibitor Givinostat in patients with JAK2V617F positive chronic myeloproliferative neoplasms

Rambaldi, Alessandro; Dellacasa, Chiara Maria; Finazzi, Guido; Carobbio, Alessandra; Ferrari, Maria Luisa; Guglielmelli, Paola; Gattoni, Elisabetta; Salmoiraghi, Silvia; Finazzi, Maria Chiara; Tollo, Silvia Di; D’Urzo, Carmine; Vannucchi, Alessandro M.; Barosi, Giovanni; Barbui, Tiziano

doi:10.1111/j.1365-2141.2010.08266.x

Cited by 226 publications

(159 citation statements)

References 23 publications

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“…48 However, the hypomethylating agents azacitidine and decitabine did not produce discernible responses in small trials, 49,50 and the HDAC inhibitor ITF2357 (givinostat) was minimally effective in MF (unlike in most patients with PV). 51 Studies with the HDAC inhibitor LBH589 (panobinostat) in MF are ongoing, and preliminary results are of interest. 52…”

Section: Epigenetic Drugsmentioning

confidence: 99%

Management of Myelofibrosis

Vannucchi

2011

Hematology

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Myelofibrosis (MF), either primary or arising from previous polycythemia vera (PV) or essential thrombocythemia (ET), is the worst among the chronic myeloproliferative neoplasms in terms of survival and quality of life. Patients with MF have to face several clinical issues that, because of the poor effectiveness of medical therapy, surgery or radiotherapy, represent largely unmet clinical needs. Powerful risk stratification systems, applicable either at diagnosis using the International Prognostic Scoring System (IPSS) or during the variable course of illness using the Dynamic International Prognostic Scoring System (DIPSS) and DIPSS Plus, allow recognition of categories of patients with survival times ranging from decades to Ͻ 2 years. These scores are especially important for therapeutic decisions that include allogeneic stem cell transplantation (allogeneic SCT), the only curative approach that still carries a nonnegligible risk of morbidity and mortality even with newest reduced intensity conditioning (RIC) regimens. Discovery of JAK2V617F mutation prompted the development of clinical trials using JAK2 inhibitors; these agents overall have resulted in meaningful symptomatic improvement and reduction of splenomegaly that were otherwise not achievable with conventional therapy. Intriguing differences in the efficacy and tolerability of JAK2 inhibitors are being recognized, which could lead to a nonoverlapping spectrum of activity/safety. Other agents that do not directly target JAK2 and have shown symptomatic efficacy in MF are represented by inhibitors of the mammalian target of rapamycin (mTOR) and histone deacetylases (HDACs). Pomalidomide appears to be particularly active against MF-associated anemia. However, because these agents are all poorly effective in reducing the burden of mutated cells, further advancements are needed to move from enhancing our ability to palliate the disease to arriving at an actual cure for MF.

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Section: Epigenetic Drugsmentioning

confidence: 99%

Management of Myelofibrosis

Vannucchi

2011

Hematology

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“…Several pilot clinical studies suggest clinical activity in both early and late phases of the disease. [59][60][61][62][63] These agents also have the potential to harness an immunomodulatory effect that could synergize with the GVL effect, making them of additional interest. 64,65 The notion of administering these agents at a lower dose/intensity to harness their immunomodulatory effects, which include the upregulation of cancer testis antigens and augmentation of T-regulatory cells, following allo-SCT is additionally attractive.…”

Section: Impact Of Targeting the Jak/signal Transducers And Activatormentioning

confidence: 99%

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

Tamari

Mughal

Rondelli

et al. 2015

Bone Marrow Transplant

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At present, allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only curative treatment for patients with myelofibrosis (MF). Unfortunately a significant proportion of candidate patients are considered transplant ineligible due to their poor general condition and advanced age at time of diagnosis. The approval of the first JAK inhibitor, Ruxolitinib, for patients with advanced MF in 2011 has had a qualified impact on the treatment algorithm. The drug affords substantial improvement in MF-associated symptoms and splenomegaly but no major effect on the natural history. There has, therefore, been considerable support to assess the drug’s candidacy in the peri-transplant period. The drug’s precise impact on clinical outcome following allo-SCT is currently not known; nor is the drug’s long term efficacy and safety known. Considering the rarity of MF and the small proportion of patients who are undergoing allo-SCT, well designed collaborative efforts are required. In order to address some of the principal challenges, an expert panel of laboratory and clinical experts in this field was established, and an independent workshop held during the 54th American Society of Hematology’s meeting in New Orleans, USA, on 6th December 2013 and the European Hematology Association meeting in Milan, Italy on 13th June 2014. This document summarizes the results of these efforts.

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“…PV (with 99% of patients having a mutation somewhere in their JAK2) could well be the most straightforward target of JAK2 inhibition, and preliminary results of trials with XL019 98 , CEP-701 (Cephalon), 99 and ITF2347 97 show activity in decreasing erythrocytosis. However, these trials are too early in their accrual to allow any useful conclusions as to their efficacy.…”

Section: Jak2 Inhibitors For Pv and Etmentioning

confidence: 99%

“…On the other hand, a novel HDAC inhibitor, ITF2357, showed promising clinical activity in a Phase II trial, particularly in PV and ET patients, accompanied by evidence of a progressive decline of cells harboring the V617F allele. 82 In vitro, the drug significantly reduced proliferation of JAK2 V617F mutated cells, including endogenous erythroid colony formation, through the post-transcriptional downregulation of JAK2. 83 Orchestrating gene expression in normal adult cells and during development is one role of microRNAs (miRNAs), which is a large family of small non-coding RNAs.…”

Section: Novel Mechanisms In Mpdsmentioning

confidence: 99%

“…93 Although a well-tolerated drug, the suppression of the JAK-STAT pathway (including normal hematopoiesis which signals through this pathway) can lead to treatmentrelated thrombocytopenia and anemia. 92 Additional drugs being tested are early in their results (TG101348Fselective JAK2 inhibitor (TarGen, San Francisco, CA, USA), 94 XL019Fselective JAK2 inhibitor (Exelexis, San Francisco, CA, USA), 95 CEP-701 (TKI of JAK2 and FLT3) (Cephalon, Frazer, PA, USA), 96 ITF2357 (histone deacetylase inhibitor) (AQ18Italfarmaco, Italy) 97 but preliminary results also report improvements in splenomegaly and symptoms in MF patients (Table 1). No JAK2 inhibitor has yet reported a significant ability to improve cytopenias, fibrosis or histological changes associated with MF.…”

Section: Jak2 Inhibitors For Myelofibrosismentioning

confidence: 99%

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