Safety and efficacy of the maximum tolerated dose of givinostat in polycythemia vera: a two-part Phase Ib/II study

Rambaldi, Alessandro; Iurlo, Alessandra; Vannucchi, Alessandro M.; Noble, Richard; Bubnoff, Nikolas von; Guarini, Attilio; Martino, Bruno; Pezzutto, Antonio; Carli, Giuseppe; Muro, Marianna De; Luciani, Stefania; McMullin, Mary Frances; Cambier, Nathalie; Marolleau, Jean Pierre; Mesa, Ruben A.; Tibes, Raoul; Pancrazzi, Alessandro; Gesullo, Francesca; Bettica, Paolo; Manzoni, Sara; Tollo, Silvia Di

doi:10.1038/s41375-020-0735-y

Cited by 36 publications

(26 citation statements)

References 14 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Modest improvements were also recorded in JAK2 V617F allele burden. Givinostat was well tolerated without safety concerns, as only two drug-related grade 3 AEs were recorded [ 100 ].…”

Section: Introductionmentioning

confidence: 99%

New Perspectives on Polycythemia Vera: From Diagnosis to Therapy

Iurlo

Cattaneo

Bucelli

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

Polycythemia vera (PV) is mainly characterized by elevated blood cell counts, thrombotic as well as hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. Major changes to its diagnostic criteria were made in the 2016 revision of the World Health Organization (WHO) classification, with both hemoglobin and hematocrit diagnostic thresholds lowered to 16.5 g/dL and 49% for men, and 16 g/dL and 48% for women, respectively. The main reason leading to these changes was represented by the recognition of a new entity, namely the so-called “masked PV”, as individuals suffering from this condition have a worse outcome, possibly owing to missed or delayed diagnoses and lower intensity of treatment. Thrombotic risk stratification is of crucial importance to evaluate patients’ prognosis at diagnosis. Currently, patients are stratified into a low-risk group, in the case of younger age (<60 years) and no previous thromboses, and a high-risk group, in the case of patients older than 60 years and/or with a previous thrombotic complication. Furthermore, even though they have not yet been formally included in a scoring system, generic cardiovascular risk factors, particularly hypertension, smoking, and leukocytosis, contribute to the thrombotic overall risk. In the absence of agents proven to modify its natural history and prevent progression, PV management has primarily been focused on minimizing the thrombotic risk, representing the main cause of morbidity and mortality. When cytoreduction is necessary, conventional therapies include hydroxyurea as a first-line treatment and ruxolitinib and interferon in resistant/intolerant cases. Each therapy, however, is burdened by specific drawbacks, underlying the need for improved strategies. Currently, the therapeutic landscape for PV is still expanding, and includes several molecules that are under investigation, like long-acting pegylated interferon alpha-2b, histone deacetylase inhibitors, and murine double minute 2 (MDM2) inhibitors.

show abstract

“…Modest improvements were also recorded in JAK2 V617F allele burden. Givinostat was well tolerated without safety concerns, as only two drug-related grade 3 AEs were recorded [ 100 ].…”

Section: Introductionmentioning

confidence: 99%

New Perspectives on Polycythemia Vera: From Diagnosis to Therapy

Iurlo

Cattaneo

Bucelli

et al. 2020

IJMS

Self Cite

View full text Add to dashboard Cite

show abstract

“…Eligible patients are JAK2 V617F -positive, ≥18 years of age, with an established diagnosis of MPN according to the revised World Health Organization criteria, who had tolerated previous givinostat treatment and achieved a clinical benefit at the end of either three core studies [21][22][23] and/or a compassionate use program, and provided written informed consent prior to any study-related procedure. The study was approved by the independent ethics committees at each institution, and was performed in accordance with the principles of the Declaration of Helsinki, and the International Conference on Harmonization notes for guidance on Good Clinical Practice (ICH/CPMP/135/95).…”

Section: Study Design and Patientsmentioning

confidence: 99%

Long-term safety and efficacy of givinostat in polycythemia vera: 4-year mean follow up of three phase 1/2 studies and a compassionate use program

et al. 2021

Self Cite

View full text Add to dashboard Cite

Polycythemia vera (PV) is a BCR-ABL1-negative myeloproliferative neoplasm (MPN) characterized by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow, mainly due to a Janus kinase 2 gene mutation (JAK2V617F). Givinostat, a histone-deacetylase inhibitor that selectively targets JAK2V617F cell growth, has demonstrated good efficacy and safety in three phase 1/2 studies in patients with PV. This manuscript focuses on the 4-year mean (2.8 year median) follow-up of an open-label, long-term study that enrolled 51 patients with PV (out of a total of 54 with MPN) who received clinical benefit from givinostat in these previous studies or on compassionate use, and who continued to receive givinostat at the last effective and tolerated dose. The primary objectives are to determine givinostat’s long-term safety and tolerability, and efficacy evaluated by the investigators according to internationally recognized response criteria. During follow-up, only 10% of PV patients reported Grade 3 treatment-related adverse events (AEs), while none had Grade 4 or 5 treatment-related AEs. The overall response rate for the duration of follow-up was always greater than 80% in patients with PV. In conclusion, givinostat demonstrated a good safety and efficacy profile in patients with PV, data supporting long-term use in this population.

show abstract

“…Efficacy is further demonstrated in a phase Ib clinical trial [ 301 ]. Although HDAC inhibitors exert multiple effects, poor tolerability remains a major issue [ 254 , 272 ] with the exception of treatment with givinostat in PV patients, which showed positive results in a few clinical trials [ 74 , 253 , 284 ] ( Table 3 ).…”

Section: Targeting Mpn Stem Cells Via Epigenetic Regulationmentioning

confidence: 99%

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

Yung

Lee

Chu

et al. 2021

IJMS

View full text Add to dashboard Cite

Myeloproliferative neoplasms (MPNs) are unique hematopoietic stem cell disorders sharing mutations that constitutively activate the signal-transduction pathways involved in haematopoiesis. They are characterized by stem cell-derived clonal myeloproliferation. The key MPNs comprise chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). CML is defined by the presence of the Philadelphia (Ph) chromosome and BCR-ABL1 fusion gene. Despite effective cytoreductive agents and targeted therapy, complete CML/MPN stem cell eradication is rarely achieved. In this review article, we discuss the novel agents and combination therapy that can potentially abnormal hematopoietic stem cells in CML and MPNs and the CML/MPN stem cell-sustaining bone marrow microenvironment.

show abstract

Safety and efficacy of the maximum tolerated dose of givinostat in polycythemia vera: a two-part Phase Ib/II study

Cited by 36 publications

References 14 publications

New Perspectives on Polycythemia Vera: From Diagnosis to Therapy

New Perspectives on Polycythemia Vera: From Diagnosis to Therapy

Long-term safety and efficacy of givinostat in polycythemia vera: 4-year mean follow up of three phase 1/2 studies and a compassionate use program

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

Contact Info

Product

Resources

About