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1.
Int J Mol Sci ; 22(9)2021 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-34068690

RESUMO

Genetic studies in the past decade have improved our understanding of the molecular basis of the BCR-ABL1-negative myeloproliferative neoplasm (MPN) polycythaemia vera (PV). Such breakthroughs include the discovery of the JAK2V617F driver mutation in approximately 95% of patients with PV, as well as some very rare cases of familial hereditary MPN caused by inherited germline mutations. Patients with PV often progress to fibrosis or acute myeloid leukaemia, both associated with very poor clinical outcome. Moreover, thrombosis and major bleeding are the principal causes of morbidity and mortality. As a result of increasingly available and economical next-generation sequencing technologies, mutational studies have revealed the prognostic relevance of a few somatic mutations in terms of thrombotic risk and risk of transformation, helping to improve the risk stratification of patients with PV. Finally, knowledge of the molecular basis of PV has helped identify targets for directed therapy. The constitutive activation of the tyrosine kinase JAK2 is targeted by ruxolitinib, a JAK1/JAK2 tyrosine kinase inhibitor for PV patients who are resistant or intolerant to cytoreductive treatment with hydroxyurea. Other molecular mechanisms have also been revealed, and numerous agents are in various stages of development. Here, we will provide an update of the recent published literature on how molecular testing can improve the diagnosis and prognosis of patients with PV and present recent advances that may have prognostic value in the near future.


Assuntos
Janus Quinase 2/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Policitemia Vera/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Humanos , Janus Quinase 2/antagonistas & inibidores , Mutação/genética , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/genética , Transtornos Mieloproliferativos/patologia , Policitemia Vera/diagnóstico , Policitemia Vera/genética , Policitemia Vera/patologia , Prognóstico , Trombose/tratamento farmacológico , Trombose/genética , Trombose/patologia
2.
Int J Mol Sci ; 22(7)2021 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-33805426

RESUMO

Myeloproliferative neoplasms (MPNs) are a group of disorders characterized by clonal expansion of abnormal hematopoietic stem cells leading to hyperproliferation of one or more myeloid lineages. The main complications in MPNs are high risk of thrombosis and progression to myelofibrosis and leukemia. MPN patients with high risk scores are treated by hydroxyurea (HU), interferon-α, or ruxolitinib, a tyrosine kinase inhibitor. Polycythemia vera (PV) is an MPN characterized by overproduction of red blood cells (RBCs). ABCG2 is a member of the ATP-binding cassette superfamily transporters known to play a crucial role in multidrug resistance development. Proteome analysis showed higher ABCG2 levels in PV RBCs compared to RBCs from healthy controls and an additional increase of these levels in PV patients treated with HU, suggesting that ABCG2 might play a role in multidrug resistance in MPNs. In this work, we explored the role of ABCG2 in the transport of ruxolitinib and HU using human cell lines, RBCs, and in vitro differentiated erythroid progenitors. Using stopped-flow analysis, we showed that HU is not a substrate for ABCG2. Using transfected K562 cells expressing three different levels of recombinant ABCG2, MPN RBCs, and cultured erythroblasts, we showed that ABCG2 potentiates ruxolitinib-induced cytotoxicity that was blocked by the ABCG2-specific inhibitor KO143 suggesting ruxolitinib intracellular import by ABCG2. In silico modeling analysis identified possible ruxolitinib-binding site locations within the cavities of ABCG2. Our study opens new perspectives in ruxolitinib efficacy research targeting cell types depending on ABCG2 expression and polymorphisms among patients.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Eritrócitos/metabolismo , Proteínas de Neoplasias/metabolismo , Policitemia Vera/tratamento farmacológico , Pirazóis/farmacologia , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/química , Apoptose/efeitos dos fármacos , Sítios de Ligação , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Simulação por Computador , Dicetopiperazinas/farmacologia , Eritrócitos/efeitos dos fármacos , Células Eritroides/efeitos dos fármacos , Compostos Heterocíclicos de 4 ou mais Anéis/farmacologia , Humanos , Hidroxiureia/metabolismo , Hidroxiureia/farmacologia , Interferon-alfa/farmacologia , Células K562 , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/patologia , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/química , Fosfatidilserinas/metabolismo , Policitemia Vera/sangue , Policitemia Vera/patologia , Pirazóis/química , Pirazóis/metabolismo , Pirazóis/farmacocinética
3.
Clin Drug Investig ; 41(4): 391-404, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33725322

RESUMO

BACKGROUND AND OBJECTIVES: Ropeginterferon alfa-2b is a novel monopegylated recombinant interferon alfa-2b for the treatment of patients with polycythemia vera. The objectives of this study were to evaluate the pharmacokinetics, pharmacodynamics, safety, and tolerability of ropeginterferon alfa-2b in healthy Japanese subjects compared with Caucasian subjects. METHODS: In this multicenter, parallel-group phase I study, a cohort consisting of six Japanese and six Caucasian subjects was designated to receive a single subcutaneous dose of ropeginterferon alfa-2b (100, 200, 300, and 450 µg). Pharmacokinetic and pharmacodynamic parameters, and immunogenicity were evaluated. Safety was assessed throughout the study. RESULTS: Cohort 4 (450-µg dose) was not initiated because the primary objective of this study was achieved based on the three completed cohorts. A total of 36 enrolled subjects (18 Japanese and 18 Caucasian) in three cohorts were included in the safety, pharmacokinetic, and pharmacodynamic analysis sets. Ropeginterferon alfa-2b exposure in terms of the area under the serum concentration-time curve (AUC) from time zero extrapolated to infinity and the AUC from time zero to the time of the last quantifiable concentration was approximately 1.7-fold and two-fold higher in Japanese subjects than in Caucasian subjects, respectively. Across the same dose range, the maximum serum concentration was approximately 1.25-fold higher in Japanese subjects than in Caucasian subjects. The time to reach the median maximum serum concentration was similar between ethnicities (approximately 96-111 h). The terminal half-life was 48-57 h in Japanese subjects and 31-75 h in Caucasian subjects. The slope of the relationship between dose and drug exposure was greater than 1 in both ethnicities. The dose-dependent induction of beta-2 microglobulin and neopterin expression was observed in both ethnicities, and the two groups showed similar pharmacodynamic parameters. At the end of the study, 22.2% of Japanese subjects and 11.1% of Caucasian subjects developed anti-ropeginterferon alfa-2b-binding antibodies. The neutralizing capacity of these antibodies was not tested. Ropeginterferon alfa-2b up to 300 µg was safe and well tolerated, with no unexpected safety findings based on previous experiences with ropeginterferon alfa-2b and other forms of interferon. CONCLUSIONS: Ropeginterferon alfa-2b exposure was higher in Japanese subjects than in Caucasian subjects. The increase in ropeginterferon alfa-2b exposure was greater than the dose proportion in the dose range of 100-300 µg. Ropeginterferon alfa-2b was safe and well tolerated. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03546465, registered on 6 June, 2018.


Assuntos
Antivirais/administração & dosagem , Interferon alfa-2/administração & dosagem , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Adulto , Área Sob a Curva , Grupo com Ancestrais do Continente Asiático , Grupo com Ancestrais do Continente Europeu , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Policitemia Vera/tratamento farmacológico , Proteínas Recombinantes/administração & dosagem , Adulto Jovem
4.
Cell Stem Cell ; 28(3): 502-513.e6, 2021 03 04.
Artigo em Inglês | MEDLINE | ID: mdl-33621485

RESUMO

The implications of stem cell heterogeneity for disease pathogenesis and therapy are poorly defined. JAK2V617F+ myeloproliferative neoplasms (MPNs), harboring the same mutation in hematopoietic stem cells (HSCs), display diverse phenotypes, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These chronic malignant disorders are ideal models to analyze the pathological consequences of stem cell heterogeneity. Single-cell gene expression profiling with parallel mutation detection demonstrated that the megakaryocyte (Mk)-primed HSC subpopulation expanded significantly with enhanced potential in untreated individuals with JAK2V617F+ ET, driven primarily by the JAK2 mutation and elevated interferon signaling. During treatment, mutant HSCs were targeted preferentially in the Mk-primed HSC subpopulation. Interestingly, homozygous mutant HSCs were forced to re-enter quiescence, whereas their heterozygous counterparts underwent apoptosis. This study provides important evidence for the association of stem cell heterogeneity with the pathogenesis and therapeutic response of a malignant disease.


Assuntos
Transtornos Mieloproliferativos , Neoplasias , Policitemia Vera , Células-Tronco Hematopoéticas , Humanos , Janus Quinase 2 , Mutação/genética , Transtornos Mieloproliferativos/tratamento farmacológico , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética
5.
Lancet Haematol ; 8(3): e175-e184, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33476571

RESUMO

BACKGROUND: There is no evidence that phlebotomy alone is sufficient to steadily maintain haematocrit on target level in low-risk patients with polycythaemia vera. This study aimed to compare the efficacy and safety of ropeginterferon alfa-2b on top of the standard phlebotomy regimen with phlebotomy alone. METHODS: In 2017, we launched the Low-PV study, a multicentre, open-label, two-arm, parallel-group, investigator-initiated, phase 2 randomised trial with a group-sequential adaptive design. The study involved 21 haematological centres across Italy. Participants were recruited in a consecutive order. Participants enrolled in the study were patients, aged 18-60 years, with a diagnosis of polycythaemia vera according to 2008-16 WHO criteria. Eligible patients were randomly allocated (1:1) to receive either phlebotomy and low-dose aspirin (standard group) or ropeginterferon alfa-2b on top of the standard treatment (experimental group). Randomisation sequence was generated using five blocks of variable sizes proportional to elements of Pascal's triangle. Allocation was stratified by age and time from diagnosis. No masking was done. Patients randomly allocated to the standard group were treated with phlebotomy (300 mL for each phlebotomy to maintain the haematocrit values of lower than 45%) and low-dose aspirin (100 mg daily), if not contraindicated. Patients randomly allocated to the experimental group received ropeginterferon alfa-2b subcutaneously every 2 weeks in a fixed dose of 100 µg on top of the phlebotomy-only regimen. The primary endpoint was treatment response, defined as maintenance of the median haematocrit values of 45% or lower without progressive disease during a 12-month period. Analyses were done by intention-to-treat principle. The study was powered assuming a higher percentage of responders in the experimental group (75%) than in the standard group (50%). Here we report results from the second planned interim analysis when 50 patients had been recruited to each group. The trial is ongoing, and registered with ClinicalTrials.gov, NCT03003325. FINDINGS: Between Feb 2, 2017, and March 13, 2020, 146 patients were screened, and 127 patients were randomly assigned to the standard group (n=63) or the experimental group (n=64). The median follow-up period was 12·1 months (IQR 12·0-12·6). For the second pre-planned interim analysis, a higher response rate in the experimental group was seen (42 [84%] of 50 patients) than in the standard group (30 [60%] of 50 patients; absolute difference 24%, 95% CI 7-41%, p=0·0075). The observed z value (2·6001) crossed the critical bound of efficacy (2·5262), and the stagewise adjusted p value early showed superiority of experimental treatment. Thus, the data safety monitoring board decided to stop patient accrual for overwhelming efficacy and to continue the follow-up, as per protocol, for 2 years. Under the safety profile, no statistically significant difference between groups in frequency of adverse events of grade 3 or higher was observed; the most frequently reported adverse events were neutropenia (four [8%] of 50 patients) in the experimental group and skin symptoms (two [4%] of 50 patients) in the standard group. No grade 4 or 5 adverse events occurred. INTERPRETATION: Supplementing phlebotomy with ropeginterferon alfa-2b seems to be safe and effective in steadily maintaining haematocrit values on target in low-risk patients with polycythaemia vera. Findings from the current study might have implications for changing the current management of low-risk patients with polycythaemia vera. FUNDING: AOP Orphan Pharmaceuticals, Associazione Italiana per la Ricerca sul Cancro.


Assuntos
Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Flebotomia , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Adolescente , Adulto , Medula Óssea/patologia , Feminino , Humanos , Interferon alfa-2/efeitos adversos , Interferon-alfa/efeitos adversos , Janus Quinase 2/genética , Janus Quinase 2/metabolismo , Masculino , Pessoa de Meia-Idade , Neutropenia/etiologia , Polietilenoglicóis/efeitos adversos , Polimorfismo de Nucleotídeo Único , Qualidade de Vida , Proteínas Recombinantes/efeitos adversos , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Adulto Jovem
7.
Am J Hematol ; 95(12): 1599-1613, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32974939

RESUMO

DISEASE OVERVIEW: Polycythemia vera (PV) and essential thrombocythemia (ET) are myeloproliferative neoplasms (MPN) respectively characterized by clonal erythrocytosis and thrombocytosis; other disease features include leukocytosis, splenomegaly, thrombosis, bleeding, microcirculatory symptoms, pruritus and risk of leukemic or fibrotic transformation. DIAGNOSIS: Bone marrow morphology remains the cornerstone of diagnosis. In addition, the presence of JAK2 mutation is expected in PV while approximately 90% of patients with ET express mutually exclusive JAK2, CALR or MPL mutations (so called driver mutations). In ET, it is most important to exclude the possibility of prefibrotic myelofibrosis. SURVIVAL: Median survivals are approximately 15 years for PV and 18 years for ET; the corresponding values for patients age 40 or younger were 37 and 35 years. Certain mutations (mostly spliceosome) and abnormal karyotype might compromise survival in PV and ET. Life-expectancy in ET is inferior to the control population. Driver mutations have not been shown to affect survival in ET but risk of thrombosis is higher in JAK2 mutated cases. Leukemic transformation rates at 10 years are estimated at <1% for ET and 3% for PV. THROMBOSIS RISK: In PV, two risk categories are considered: high (age > 60 years or thrombosis history present) and low (absence of both risk factors). In ET, four risk categories are considered: very low (age ≤ 60 years, no thrombosis history, JAK2 wild-type), low (same as very low but JAK2 mutation present), intermediate (age > 60 years, no thrombosis history, JAK2 wild-type) and high (thrombosis history present or age > 60 years with JAK2 mutation). RISK-ADAPTED THERAPY: The main goal of therapy in both PV and ET is to prevent thrombohemorrhagic complications. All patients with PV require phlebotomy to keep hematocrit below 45% and once-daily or twice-daily aspirin (81 mg), in the absence of contraindications. Very low risk ET might not require therapy while aspirin therapy is advised for low risk disease. Cytoreductive therapy is recommended for high-risk ET and PV, but it is not mandatory for intermediate-risk ET. First-line drug of choice for cytoreductive therapy, in both ET and PV, is hydroxyurea and second-line drugs of choice are interferon-α and busulfan. We do not recommend treatment with ruxolutinib in PV, unless in the presence of severe and protracted pruritus or marked splenomegaly that is not responding to the aforementioned drugs. NEW TREATMENT DIRECTIONS: Controlled studies are needed to confirm the clinical outcome value of twice-daily vs once-daily aspirin dosing and the therapeutic role of pegylated interferons and direct oral anticoagulants.


Assuntos
Aspirina/uso terapêutico , Bussulfano/uso terapêutico , Interferon-alfa/uso terapêutico , Policitemia Vera , Trombocitemia Essencial , Fatores Etários , Aspirina/efeitos adversos , Bussulfano/efeitos adversos , Calreticulina/genética , Intervalo Livre de Doença , Humanos , Interferon-alfa/efeitos adversos , Janus Quinase 2/genética , Mutação , Policitemia Vera/diagnóstico , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Policitemia Vera/mortalidade , Receptores de Trombopoetina/genética , Medição de Risco , Fatores de Risco , Taxa de Sobrevida , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/genética , Trombocitemia Essencial/mortalidade
8.
Vnitr Lek ; 66(5): 309-313, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32942868

RESUMO

Interferon alfa (IFNα) has been used in the treatment of myeloproliferative disorders for more than 30 years. IFNα has been shown to induce clinical, hematological, molecular, and histopathological remission, but its toxicity has remained a limitation of its more widespread use. The development of pegylated forms with a better tolerance has brought new options for patients. Phase III clinical trials, ropeginterferonα versus hydroxyurea: PROUD-PV and CONTINUATION-PV, have shown long-term superiority in the efficacy and safety when comparing ropeginterferon alfa-2 b with hydroxyurea. Therapeutic use of interferons is a necessary part of the treatment regimen in younger at-risk patients in the first line, but until now, no SPC of a non-pegylated or pegylated interferon included treatment of patients with polycythemia vera. Ropeginterferon alfa-2 b (Besremi®) is the first and only one to have obtained registration and is available in the European Union as well as the Czech Republic for the treatment of patients with polycythemia vera without symptomatic splenomegaly.


Assuntos
Transtornos Mieloproliferativos , Policitemia Vera , República Tcheca , Humanos , Hidroxiureia , Interferon-alfa , Policitemia Vera/tratamento farmacológico
9.
Drugs Today (Barc) ; 56(3): 195-202, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32282866

RESUMO

Ropeginterferon alfa-2b is a novel mono-PEGylated alfa interferon. It is the first interferon approved for the treatment of patients with polycythemia vera (PV) and the first and only approved treatment for PV independent of previous hydroxyurea exposure. In contrast to other interferons, the drug has to be subcutaneously injected every 2 weeks only, with intervals of 4 weeks being possible after prolonged use. It is generally well tolerated and can lead to deep molecular responses. In this article, we provide a review of available preclinical and clinical data of ropeginterferon alfa-2b leading to its E.U. approval and give an outlook on future clinical trials involving this drug.


Assuntos
Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Humanos , Hidroxiureia , Interferon alfa-2/administração & dosagem , Interferon-alfa/administração & dosagem , Polietilenoglicóis/administração & dosagem , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico
11.
J Oncol Pharm Pract ; 26(5): 1285-1288, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32054413

RESUMO

INTRODUCTION: Polycythemia vera is a myeloproliferative neoplasm (MPN) characterized by increased red blood cell mass. The natural evolution of this MPN is to progress to an anemic/cytopenic phase also known as "spent" phase prior to transformation into an accelerated and/or an overt leukemic phase. CASE REPORT: Herein, we describe a case of a patient with polycythemia vera transitioning though a "spent" phase to an MPN in accelerated phase (MPN-AP). The patient had anemia, thrombocytopenia, neutrophilia and increased blasts in the bone marrow. Management and outcome: Upon treatment with four cycles of 5-azacitidine, the patient's polycythemia vera reversed back to the proliferative phase. Serial phlebotomies were again required. DISCUSSION: Reversal of a "spent" phase by 5-azacitidine back to a proliferative polycythemia vera phase requiring phlebotomies has not been previously reported in the scientific literature. We might witness similar cases in the literature in the future years, which could lead to yet another therapeutic indication of this important pharmacologic agent.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Flebotomia/métodos , Policitemia Vera/tratamento farmacológico , Idoso de 80 Anos ou mais , Anemia/sangue , Anemia/tratamento farmacológico , Anemia/terapia , Azacitidina/farmacologia , Medula Óssea/efeitos dos fármacos , Medula Óssea/metabolismo , Feminino , Humanos , Transtornos Mieloproliferativos/sangue , Transtornos Mieloproliferativos/tratamento farmacológico , Transtornos Mieloproliferativos/terapia , Policitemia Vera/sangue , Policitemia Vera/terapia
12.
Lancet Haematol ; 7(3): e196-e208, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32014125

RESUMO

BACKGROUND: The PROUD-PV and CONTINUATION-PV trials aimed to compare the novel monopegylated interferon ropeginterferon alfa-2b with hydroxyurea, the standard therapy for patients with polycythaemia vera, over 3 years of treatment. METHODS: PROUD-PV and its extension study, CONTINUATION-PV, were phase 3, randomised, controlled, open-label, trials done in 48 clinics in Europe. Patients were eligible if 18 years or older with early stage polycythaemia vera (no history of cytoreductive treatment or less than 3 years of previous hydroxyurea treatment) diagnosed by WHO's 2008 criteria. Patients were randomly assigned 1:1 to ropeginterferon alfa-2b (subcutaneously every 2 weeks, starting at 100 µg) or hydroxyurea (orally starting at 500 mg/day). After 1 year, patients could opt to enter the extension part of the trial, CONTINUATION-PV. The primary endpoint in PROUD-PV was non-inferiority of ropeginterferon alfa-2b versus hydroxyurea regarding complete haematological response with normal spleen size (longitudinal diameter of ≤12 cm for women and ≤13 cm for men) at 12 months; in CONTINUATION-PV, the coprimary endpoints were complete haematological response with normalisation of spleen size and with improved disease burden (ie, splenomegaly, microvascular disturbances, pruritus, and headache). We present the final results of PROUD-PV and an interim analysis at 36 months of the CONTINUATION-PV study (per statistical analysis plan). Analyses for safety and efficacy were per-protocol. The trials were registered on EudraCT, 2012-005259-18 (PROUD-PV) and 2014-001357-17 (CONTINUATION-PV, which is ongoing). FINDINGS: Patients were recruited from Sept 17, 2013 to March 13, 2015 with 306 enrolled. 257 patients were randomly assigned, 127 were treated in each group (three patients withdrew consent in the hydroxyurea group), and 171 rolled over to the CONTINUATION-PV trial. Median follow-up was 182·1 weeks (IQR 166·3-201·7) in the ropeginterferon alfa-2b and 164·5 weeks (144·4-169·3) in the standard therapy group. In PROUD-PV, 26 (21%) of 122 patients in the ropeginterferon alfa-2b group and 34 (28%) of 123 patients in the standard therapy group met the composite primary endpoint of complete haematological response with normal spleen size. In CONTINUATION-PV, complete haematological response with improved disease burden was met in 50 (53%) of 95 patients in the ropeginterferon alfa-2b group versus 28 (38%) of 74 patients in the hydroxyurea group, p=0·044 at 36 months. Complete haematological response without the spleen criterion in the ropeginterferon alfa-2b group versus standard therapy group were: 53 (43%) of 123 patients versus 57 (46%) of 125 patients, p=0·63 at 12 months (PROUD-PV), and 67 (71%) of 95 patients versus 38 (51%) of 74 patients, p=0·012 at 36 months (CONTINUATION-PV). The most frequently reported grade 3 and grade 4 treatment-related adverse events were increased γ-glutamyltransferase (seven [6%] of 127 patients) and increased alanine aminotransferase (four [3%] of 127 patients) in the ropeginterferon alfa-2b group, and leucopenia (six [5%] of 127 patients) and thrombocytopenia (five [4%] of 127 patients) in the standard therapy group. Treatment-related serious adverse events occurred in three (2%) of 127 patients in the ropeginterferon alfa-2b group and five (4%) of 127 patients in the hydroxyurea group. One treatment-related death was reported in the standard therapy group (acute leukaemia). INTERPRETATION: In patients with early polycythaemia vera, who predominantly presented without splenomegaly, ropeginterferon alfa-2b was effective in inducing haematological responses; non-inferiority to hydroxyurea regarding haematological response and normal spleen size was not shown at 12 months. However, response to ropeginterferon alfa-2b continued to increase over time with improved responses compared with hydroxyurea at 36 months. Considering the high and durable haematological and molecular responses and its good tolerability, ropeginterferon alfa-2b offers a valuable and safe long-term treatment option with features distinct from hydroxyurea. FUNDING: AOP Orphan Pharmaceuticals AG.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antivirais/uso terapêutico , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Idoso , Estudos de Equivalência como Asunto , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Policitemia Vera/patologia , Prognóstico , Proteínas Recombinantes/uso terapêutico
14.
Lancet Haematol ; 7(3): e226-e237, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31982039

RESUMO

BACKGROUND: Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. METHODS: We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov, NCT01243944. FINDINGS: We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9-12·3) in the ruxolitinib group and 9·3 years (4·9-13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51-88). The probability of maintaining complete haematological remission was 55% (95% CI 32-73) and the probability of maintaining overall clinicohaematological responses was 67% (54-77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4-95·9) with ruxolitinib therapy and 91·0% (82·8-95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment. INTERPRETATION: We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population. FUNDING: Novartis Pharmaceuticals Corporation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Pirazóis/uso terapêutico , Quinazolinas/uso terapêutico , Antivirais/uso terapêutico , Quimioterapia Combinada , Fibrinolíticos/uso terapêutico , Seguimentos , Humanos , Hidroxiureia/administração & dosagem , Pipobromano/administração & dosagem , Prognóstico , Proteínas Recombinantes/uso terapêutico , Taxa de Sobrevida , Fatores de Tempo
16.
Leuk Res ; 88: 106272, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31778911

RESUMO

Ruxolitinib, a selective JAK1/JAK2 inhibitor, is the current first line therapy for myelofibrosis (MF), which reduces symptomatology and splenomegaly, but does not clearly modify disease course. Panobinostat, a histone deacetylase inhibitor, was shown to be safe and tolerable in phase I and II trials and demonstrated clinical activity in approximately a third of treated patients. Combination therapy of ruxolitinib and panobinostat showed synergistic activity in a preclinical MF model, which prompted clinical evaluation of this combination in both ruxolitinib naïve and treated MF patients. Herein, we report the results of an investigator-initiated, dose escalation, phase I trial of ruxolitinib and panobinostat in 15 patients with primary MF and post-polycythemia vera/essential thrombocythemia MF. This combination treatment proved to be safe and tolerable without dose limiting thrombocytopenia and a maximum tolerated dose of both agents in combination was not determined. The majority of patients maintained stable disease with this combination treatment and 40 % attained a clinical improvement (spleen n = 5, anemia n = 1) by modified IWG-MRT at the end of 6 cycles. This is one of the first attempts of rationally designed, JAK inhibitor-based, combination therapy studies and exemplifies the feasibility of such an approach in patients with advanced MF.


Assuntos
Panobinostat/administração & dosagem , Panobinostat/efeitos adversos , Policitemia Vera/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Pirazóis/administração & dosagem , Pirazóis/efeitos adversos , Trombocitemia Essencial/tratamento farmacológico , Idoso , Estudos de Coortes , Relação Dose-Resposta a Droga , Esquema de Medicação , Quimioterapia Combinada/efeitos adversos , Feminino , Humanos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Policitemia Vera/complicações , Mielofibrose Primária/etiologia , Trombocitemia Essencial/complicações , Resultado do Tratamento
17.
Rinsho Ketsueki ; 61(12): 1670-1672, 2020.
Artigo em Japonês | MEDLINE | ID: mdl-33441519

RESUMO

Hydroxycarbamide is a widely used cytoreductive agent for treating polycythemia vera and essential thrombocythemia. Although hydroxycarbamide is usually well tolerated by most patients for long periods, some patients experience mucosal or cutaneous adverse events. Furthermore, a series of case report have indicated an association of hydroxycarbamide use with the development of non-melanoma skin cancer, especially in western countries. Here, we present the case of an elderly Japanese polycythemia vera patient who developed squamous cell carcinoma of the skin on the scalp after 10 years of exposure to hydroxyurea.


Assuntos
Carcinoma de Células Escamosas , Policitemia Vera , Trombocitemia Essencial , Idoso , Carcinoma de Células Escamosas/induzido quimicamente , Humanos , Hidroxiureia/efeitos adversos , Policitemia Vera/tratamento farmacológico , Couro Cabeludo , Trombocitemia Essencial/tratamento farmacológico
18.
Hematology Am Soc Hematol Educ Program ; 2019(1): 407-414, 2019 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-31808852

RESUMO

The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) share a common pathobiology of constitutive activation of the JAK and STAT pathway, despite having the 3 distinct phenotypes of essential thrombocythemia, polycythemia vera, and primary myelofibrosis. Targeting the JAK-STAT pathway has led to remarkable clinical benefit, including reduction in splenomegaly, amelioration of cytokine-driven symptoms, improvement in quality of life, and even some improvement in survival. However, targeting this pathway has not resulted in consistent disease modification by current metrics, including a reduction in mutant allele burden or reversal of fibrosis. Moreover, targeting JAK-STAT can lead to limiting treatment-emergent side effects, such as anemia and thrombocytopenia. Continued discovery points to a complex system of pathogenesis beyond JAK-STAT driving the formation and evolution of MPNs. This article reviews the successes and limitations of JAK-STAT inhibition, surveys the strategies behind emerging therapies, and discusses the challenges that are present in moving beyond JAK-STAT.


Assuntos
Policitemia Vera/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Transdução de Sinais , Trombocitemia Essencial/tratamento farmacológico , Idoso , Humanos , Janus Quinases/genética , Janus Quinases/metabolismo , Masculino , Policitemia Vera/genética , Policitemia Vera/metabolismo , Policitemia Vera/patologia , Mielofibrose Primária/genética , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/metabolismo , Trombocitemia Essencial/genética , Trombocitemia Essencial/metabolismo , Trombocitemia Essencial/patologia
19.
Exp Hematol ; 79: 26-34, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31563618

RESUMO

The myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal neoplastic disorders. Driver mutations in JAK2, CALR, and MPL genes have been identified in the majority of cases. Alongside these, an increasing number of genes are repeatedly identified as mutated in MPN. These, including ASXL1, TET2, DMNT3A, and EZH2, have key roles in epigenetic regulation. Dysregulation of epigenetic processes is therefore a key feature of MPN. Vorinostat is a pan histone deacetylase inhibitor (HDACi) that has been investigated in MPN. DNA methylation (DNAm) is a well-defined epigenetic mechanism of transcription modification. It is known to be affected by ageing, lifestyle, and disease. Epigenetic ageing signatures have been previously described allowing calculation of a methylation age (MA). In this study we examined the effect of vorinostat on MA in MPN cell lines and in patients with polycythaemia vera (PV) and essential thrombocythaemia (ET) treated with vorinostat as part of a clinical trial. An older MA was observed in patients with a higher JAK2 V617F allele burden and those with a longer duration of disease. PV patients had a MA older than that predicted whilst MA was younger than predicted in ET. Treatment with vorinostat resulted in a younger MA in PV patients and older MA in ET patients, in both cases a trend towards the normal chronological age. When MA change was compared against response, nonresponse was associated with a younger than predicted MA in ET patients and a higher than predicted MA in PV patients. The link between MA and JAK2 mutant allele burden implies that allele burden has a role not only in clinical phenotype and disease evolution in MPN patients, but also in the overall methylation landscape of the mutated cells.


Assuntos
Metilação de DNA/efeitos dos fármacos , DNA de Neoplasias/metabolismo , Epigênese Genética/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas de Neoplasias/biossíntese , Policitemia Vera , Trombocitemia Essencial , Vorinostat/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Linhagem Celular Tumoral , Metilação de DNA/genética , DNA de Neoplasias/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Policitemia Vera/tratamento farmacológico , Policitemia Vera/genética , Policitemia Vera/metabolismo , Policitemia Vera/patologia , Trombocitemia Essencial/tratamento farmacológico , Trombocitemia Essencial/genética , Trombocitemia Essencial/metabolismo , Trombocitemia Essencial/patologia
20.
In Vivo ; 33(5): 1667-1669, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31471421

RESUMO

Merkel cell carcinoma (MCC) is a rare neuroendocrine carcinoma of the skin. It is highly aggressive and represents the second most common cause of skin cancer-related death. Ruxolitinib is an orally administered selective inhibitor of Janus associated kinases1 and 2, which is used in the management of patients with symptomatic myelofibrosis and polycythemia vera who are non-responders or intolerant to hydroxyurea. Herein, we report the case of a 47-year-old woman with a 14-year history of chronic myeloproliferative syndrome initially treated with hydroxyurea for 4 years. She was then enrolled in the Response trial and treated for 7 years with ruxolitinib subsequently developing an MCC. This report shows the possibility of development of MCC in patients treated with ruxolitinib. Periodic skin examination is indicated in patients who undergo ruxolitinib therapy, especially if they have a history of skin cancer; dermatologists and oncohematologists should be aware of this possibility in order to introduce appropriate preventive strategies.


Assuntos
Carcinoma de Célula de Merkel/etiologia , Inibidores de Janus Quinases/efeitos adversos , Segunda Neoplasia Primária/etiologia , Pirazóis/efeitos adversos , Neoplasias Cutâneas/etiologia , Carcinoma de Célula de Merkel/diagnóstico , Feminino , Humanos , Inibidores de Janus Quinases/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Segunda Neoplasia Primária/diagnóstico , Policitemia Vera/tratamento farmacológico , Pirazóis/uso terapêutico , Neoplasias Cutâneas/diagnóstico
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