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2.
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
3.
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
5.
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
6.
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
7.
Blood ; 134(18): 1498-1509, 2019 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-31515250

RESUMO

Prior studies have reported high response rates with recombinant interferon-α (rIFN-α) therapy in patients with essential thrombocythemia (ET) and polycythemia vera (PV). To further define the role of rIFN-α, we investigated the outcomes of pegylated-rIFN-α2a (PEG) therapy in ET and PV patients previously treated with hydroxyurea (HU). The Myeloproliferative Disorders Research Consortium (MPD-RC)-111 study was an investigator-initiated, international, multicenter, phase 2 trial evaluating the ability of PEG therapy to induce complete (CR) and partial (PR) hematologic responses in patients with high-risk ET or PV who were either refractory or intolerant to HU. The study included 65 patients with ET and 50 patients with PV. The overall response rates (ORRs; CR/PR) at 12 months were 69.2% (43.1% and 26.2%) in ET patients and 60% (22% and 38%) in PV patients. CR rates were higher in CALR-mutated ET patients (56.5% vs 28.0%; P = .01), compared with those in subjects lacking a CALR mutation. The median absolute reduction in JAK2V617F variant allele fraction was -6% (range, -84% to 47%) in patients achieving a CR vs +4% (range, -18% to 56%) in patients with PR or nonresponse (NR). Therapy was associated with a significant rate of adverse events (AEs); most were manageable, and PEG discontinuation related to AEs occurred in only 13.9% of subjects. We conclude that PEG is an effective therapy for patients with ET or PV who were previously refractory and/or intolerant of HU. This trial was registered at www.clinicaltrials.gov as #NCT01259856.


Assuntos
Antineoplásicos/uso terapêutico , Interferon-alfa/uso terapêutico , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Hidroxiureia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento
8.
Blood ; 134(6): 525-533, 2019 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-31167802

RESUMO

A limited number of drugs are available to treat patients with polycythemia vera (PV) and essential thrombocythemia (ET). We attempted to identify alternative agents that may target abnormalities within malignant hematopoietic stem (HSCs) and progenitor cells (HPCs). Previously, MDM2 protein levels were shown to be upregulated in PV/ET CD34+ cells, and exposure to a nutlin, an MDM2 antagonist, induced activation of the TP53 pathway and selective depletion of PV HPCs/HSCs. This anticlonal activity was mediated by upregulation of p53 and potentiated by the addition of interferon-α2a (IFN-α2a). Therefore, we performed an investigator-initiated phase 1 trial of the oral MDM2 antagonist idasanutlin (RG7388; Roche) in patients with high-risk PV/ET for whom at least 1 prior therapy had failed. Patients not attaining at least a partial response by European LeukemiaNet criteria after 6 cycles were then allowed to receive combination therapy with low-dose pegylated IFN-α2a. Thirteen patients with JAK2 V617F+ PV/ET were enrolled, and 12 (PV, n = 11; ET, n = 1) were treated with idasanutlin at 100 and 150 mg daily, respectively, for 5 consecutive days of a 28-day cycle. Idasanutlin was well tolerated; no dose-limiting toxicity was observed, but low-grade gastrointestinal toxicity was common. Overall response rate after 6 cycles was 58% (7 of 12) with idasanutlin monotherapy and 50% (2 of 4) with combination therapy. Median duration of response was 16.8 months (range, 3.5-26.7). Hematologic, symptomatic, pathologic, and molecular responses were observed. These data indicate that idasanutlin is a promising novel agent for PV; it is currently being evaluated in a global phase 2 trial. This trial was registered at www.clinicaltrials.gov as #NCT02407080.


Assuntos
Antineoplásicos/administração & dosagem , Policitemia Vera/tratamento farmacológico , Pirrolidinas/administração & dosagem , para-Aminobenzoatos/administração & dosagem , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/efeitos adversos , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Policitemia Vera/diagnóstico , Policitemia Vera/etiologia , Proteínas Proto-Oncogênicas c-mdm2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-mdm2/genética , Proteínas Proto-Oncogênicas c-mdm2/metabolismo , Pirrolidinas/efeitos adversos , Resultado do Tratamento , para-Aminobenzoatos/efeitos adversos
9.
Hematol Oncol ; 37(3): 291-295, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31050810

RESUMO

There have been some reports on a possible role of azacytidine (AZA) in the treatment of accelerated/blastic phase evolved from Philadelphia-negative myeloproliferative neoplasms (MPN-AP/BP), but results are conflicting. In this study, we analyzed a cohort of 39 patients with MPN-AP/BP treated frontline with AZA at the standard dosage (75 mg/m2 ). Median time from diagnosis to AP/BP evolution was 92.3 months (IR 29.9-180.1). All patients were evaluable for hematologic response: two patients (5.2%) died early after AZA initiation, 13 patients (33.3%) had a progressive or stable disease, nine (23.1%) had a hematologic improvement (HI), seven (17.9%) achieved a partial response (PR), and eight (20.5%) a complete response (CR). Overall, 24 patients achieved a clinical hematologic response (HI + PR + CR), with an overall response rate of 61.5%. Median overall survival (OS) from AZA start of the whole cohort was 13.5 months (95% CI, 8.2-18.7). There was no difference in median OS among patients with HI, PR, or CR (P = .908). These three subgroups as "responders" having been considered, a significantly better OS was observed in responder compared with nonresponder patients, with a median OS of 17.6 months (95% CI, 10.1-25.0) versus 4.1 months (95% CI, 0.4-10.0) (P = .001) Only female gender was significant for both achievement of response (.010) and OS duration (P = .002). In conclusion, AZA is useful for the management of MPN-AP/BP, with an overall response rate (HI + PR + CR) of 61.5% and a longer OS in responders.


Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Crise Blástica/tratamento farmacológico , Transtornos Mieloproliferativos/tratamento farmacológico , Idoso , Crise Blástica/diagnóstico , Feminino , Humanos , Hidroxiureia/uso terapêutico , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/diagnóstico , Leucemia Mieloide Crônica Atípica BCR-ABL Negativa/tratamento farmacológico , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mutação , Transtornos Mieloproliferativos/diagnóstico , Pipobromano/uso terapêutico , Policitemia Vera/diagnóstico , Policitemia Vera/tratamento farmacológico , Mielofibrose Primária/diagnóstico , Mielofibrose Primária/tratamento farmacológico , Prognóstico , Indução de Remissão , Estudos Retrospectivos , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/tratamento farmacológico , Resultado do Tratamento
10.
Leukemia ; 33(8): 1996-2005, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31142846

RESUMO

We conducted a large international nested case-control study including 1881 patients with Philadelphia-negative myeloproliferative neoplasms (MPN). Cases (n = 647) were patients with second cancer (SC: carcinoma, non-melanoma skin cancer, hematological second cancer, and melanoma) and controls (n = 1234) were patients without SC, matched with cases for sex, age at MPN diagnosis, date of MPN diagnosis, and MPN disease duration. The aim was to evaluate the risk of SC after exposure to cytoreductive drugs. Patients exposed to hydroxyurea (HU) (median: 3 years) had a risk of SC similar to unexposed patients (OR = 1.06, 95% CI 0.82-1.38). In contrast, in cancer-specific stratified multivariable analysis, HU had two-fold higher risk of non-melanoma (NM) skin cancer (OR = 2.28, 95% CI 1.15-4.51). A significantly higher risk of NM-skin cancer was also documented for pipobroman (OR = 3.74, 95% CI 1.00-14.01), ruxolitinib (OR = 3.87, 95% CI 1.18-12.75), and for drug combination (OR = 3.47, 95% CI 1.55-7.75). These three drugs did not show excess risk of carcinoma and hematological second cancer compared with unexposed patients. Exposure to interferon, busulfan, and anagrelide did not increase the risk. In summary, while it is reassuring that no excess of carcinoma was documented, a careful dermatologic active surveillance before and during the course of treatments is recommended.


Assuntos
Antineoplásicos/efeitos adversos , Segunda Neoplasia Primária/induzido quimicamente , Cromossomo Filadélfia , Policitemia Vera/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Trombocitemia Essencial/tratamento farmacológico , Estudos de Casos e Controles , Humanos , Hidroxiureia/efeitos adversos , Pipobromano/efeitos adversos , Policitemia Vera/genética , Pirazóis/efeitos adversos , Trombocitemia Essencial/genética
11.
Ann Hematol ; 98(6): 1421-1426, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30919072

RESUMO

Hydroxyurea (HU) resistance or intolerance occurs in 15 to 24% of patients with polycythemia vera (PV). Resistance to HU is associated with a shortened life expectancy, intolerance has no prognostic value. We assessed the occurrence of HU resistance or intolerance comparing the original (ELNo) versus the modified European Leukemia Net (ELNm) criteria as applied in recent large clinical trials including PV patients. We retrospectively analyzed 106 patients with PV treated with HU at the University Hospitals of Leuven between 1990 and 2016 for occurrence of HU resistance/intolerance when using both ELNo as ELNm. After a mean duration of treatment of 5.1 years, when applying the ELNo 20.7% of patients had shown resistance or intolerance to HU in comparison to 39.6% when using the ELNm. When using the ELNo 4.7% of patients were resistant to HU versus 23.6% when applying the ELNm. In total, 16.0% of patients were HU intolerant. This rate was identical when using both ELNo and ELNm. 20.7% of PV patients were considered as HU-resistant or intolerant when using the original ELN criteria. However, when applying the modified ELN criteria 39.6% of PV patients were resistant or intolerant to HU. In our hands, no patient received a minimum dose of 2 g HU a day, as such the ELNm seem better adapted for daily clinical use. However, the prognostic value of HU-resistance in PV, when defined by the ELNm, still needs to be confirmed.


Assuntos
Resistência a Medicamentos , Hidroxiureia/uso terapêutico , Policitemia Vera/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Febre/induzido quimicamente , Seguimentos , Humanos , Hidroxiureia/efeitos adversos , Hidroxiureia/farmacologia , Úlcera da Perna/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Mucosite/induzido quimicamente , Policitemia Vera/complicações , Policitemia Vera/mortalidade , Prognóstico , Estudos Retrospectivos , Trombose/epidemiologia , Trombose/etiologia
12.
BMC Infect Dis ; 19(1): 287, 2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30917797

RESUMO

BACKGROUND: Ruxolitinib is a highly potent janus kinase inhibitor that places its users at risk for various bacterial infections and viral reactivation. However new reports are also emerging that suggest greater immunosuppression and risk for fungal disease. CASE PRESENTATION: We report the case of a 51 year-old veteran from Guam, treated with ruxolitinib for polycythemia vera, who developed disseminated histoplasmosis and concurrent cryptococcal meningitis. CONCLUSION: This case draws attention to the degree of immunosuppression that may be seen with this drug and the need for heightened vigilance for opportunistic infections in those treated with inhibitors of janus kinase/signal transducers and activators of transcription (JAK/STAT) such as ruxolitinib.


Assuntos
Histoplasmose/induzido quimicamente , Infecções Fúngicas Invasivas/induzido quimicamente , Meningite Criptocócica/induzido quimicamente , Policitemia Vera/tratamento farmacológico , Pirazóis/efeitos adversos , Guam , Histoplasmose/complicações , Histoplasmose/patologia , Humanos , Tolerância Imunológica/efeitos dos fármacos , Hospedeiro Imunocomprometido , Infecções Fúngicas Invasivas/complicações , Infecções Fúngicas Invasivas/patologia , Masculino , Meningite Criptocócica/complicações , Meningite Criptocócica/patologia , Pessoa de Meia-Idade , Veteranos
13.
Int J Infect Dis ; 80: 134-136, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30639623

RESUMO

Ruxolitinib is a JAK-1/JAK-2 inhibitor indicated for the treatment of polycythemia vera and primary or secondary myelofibrosis. Only one patient (0.2%) was diagnosed with tuberculosis among the 485 patients receiving ruxolitinib in the four pivotal trials. Fourteen cases of tuberculosis have since been reported. We observed two (3%) mycobacterial infections (one due to Mycobacterium tuberculosis and one due to Mycobacterium avium complex) in our cohort of 65 patients receiving ruxolitinib. This observation suggests that the rate of mycobacterial infection might be higher than that observed in the pivotal trials and that atypical mycobacterial infections can also occur.


Assuntos
Infecções por Mycobacterium não Tuberculosas/tratamento farmacológico , Mielofibrose Primária/tratamento farmacológico , Pirazóis/uso terapêutico , Tuberculose/tratamento farmacológico , Idoso , Feminino , Humanos , Masculino , Mycobacterium avium/efeitos dos fármacos , Mycobacterium avium/isolamento & purificação , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/isolamento & purificação , Policitemia Vera/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico
14.
Am J Hematol ; 94(1): 5-9, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30252953

RESUMO

First-line cytoreductive drug of choice in high risk essential thrombocythemia (ET) is currently hydroxyurea, a practice based on the results of a randomized study; second-line drugs of choice include pegylated interferon-α, busulfan and anagrelide. Anagrelide clinical trials were pioneered by the late Murray N. Silverstein (1928-1998) of the Mayo Clinic whose studies led to FDA approval in March 1997. The current study represents a retrospective examination of the potential impact of anagrelide therapy on survival and disease complications in ET. 1076 patients with ET were considered (median age 58 years; females 63%); risk distribution, according to the international prognostic score for ET (IPSET), was 28% high, 42% intermediate, and 30% low. Overall (OS), myelofibrosis-free (MFFS) and thrombosis-free survival data were compared for ET patients diagnosed before and after the 1997 FDA approval date for anagrelide; a significant difference was apparent in OS (P = .006; HR 1.4, 95% CI 1.1-1.7) and MFFS (P < .001; HR 4.2, 95% CI 2.7-6.5), in favor of patients diagnosed prior to 1997; the difference was sustained during multivariable analysis that included IPSET. Similarly stratified survival data in polycythemia vera (n = 665) and primary myelofibrosis (n = 1282) showed no similar impact on survival (P = .3 and .17, respectively). The current study represents a retrospective analysis and suggests significantly decreased OS and MFFS in ET patients diagnosed after the FDA approval date of anagrelide. Whether or not anagrelide therapy was to blame for the worsening of OS and MFFS over time cannot be assumed and requires validation in a prospective study.


Assuntos
Inibidores da Agregação de Plaquetas/uso terapêutico , Quinazolinas/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Medula Óssea/patologia , Progressão da Doença , Intervalo Livre de Doença , Aprovação de Drogas , Feminino , Fibrose , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Inibidores da Agregação de Plaquetas/efeitos adversos , Policitemia Vera/tratamento farmacológico , Policitemia Vera/mortalidade , Mielofibrose Primária/tratamento farmacológico , Mielofibrose Primária/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Quinazolinas/efeitos adversos , Estudos Retrospectivos , Índice de Gravidade de Doença , Trombocitemia Essencial/mortalidade , Trombocitemia Essencial/patologia , Trombose/etiologia , Trombose/prevenção & controle , Resultado do Tratamento , Adulto Jovem
16.
Semin Immunopathol ; 41(1): 5-19, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30203226

RESUMO

The first clinical trials of the safety and efficacy of interferon-alpha2 (IFN-alpha2) were performed about 30 years ago. Since then, several single-arm studies have convincingly demonstrated that IFN-alpha2 is a highly potent anti-cancer agent in several cancer types but unfortunately not being explored sufficiently due to a high toxicity profile when using non-pegylated IFN-alpha2 or high dosages or due to competitive drugs, that for clinicians at first glance might look more attractive. Within the hematological malignancies, IFN-alpha2 has only recently been revived in patients with the Philadelphia-negative myeloproliferative neoplasms-essential thrombocytosis, polycythemia vera, and myelofibrosis (MPNs)-and in patients with chronic myelogenous leukemia (CML) in combination with tyrosine kinase inhibitors. In this review, we tell the IFN story in MPNs from the very beginning in the 1980s up to 2018 and describe the perspectives for IFN-alpha2 treatment of MPNs in the future. The mechanisms of actions are discussed and the impact of chronic inflammation as the driving force for clonal expansion and disease progression in MPNs is discussed in the context of combination therapies with potent anti-inflammatory agents, such as the JAK1-2 inhibitors (licensed only ruxolitinib) and statins as well. Interferon-alpha2 being the cornerstone treatment in MPNs and having the potential of inducing minimal residual disease (MRD) with normalization of the bone marrow and low-JAK2V617F allele burden, we believe that combination therapy with ruxolitinib may be even more efficacious and hopefully revert disease progression in many more patients to enter the path towards MRD. In patients with advanced and transforming disease towards leukemic transformation or having transformed to acute myeloid leukemia, "triple therapy" is proposed as a novel treatment modality to be tested in clinical trials combining IFN-alpha2, DNA-hypomethylator, and ruxolitinib. The rationale for this "triple therapy" is given, including the fact that even in AML, IFN-alpha2 as monotherapy may revert disease progression. We envisage a new and bright future with many more patients with MPNs obtaining MRD on the above therapies. From this stage-and even before-vaccination strategies may open a new horizon with cure being the goal for some patients.


Assuntos
Interferon-alfa/uso terapêutico , Transtornos Mieloproliferativos/tratamento farmacológico , Policitemia Vera/tratamento farmacológico , Progressão da Doença , Humanos , Vigilância Imunológica , Inflamação/diagnóstico , Inflamação/tratamento farmacológico , Interferon-alfa/administração & dosagem , Interferon-alfa/efeitos adversos , Mutação , Transtornos Mieloproliferativos/diagnóstico , Transtornos Mieloproliferativos/etiologia , Neoplasia Residual , Policitemia Vera/diagnóstico , Policitemia Vera/etiologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Resultado do Tratamento
18.
Vnitr Lek ; 64(10): 955-960, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30590943

RESUMO

Polycythemia vera is a chronic myeloproliferative neoplasm characterized by hematopoietic stem cell-derived clonal myeloproliferation resulting in erythrocytosis, leukocytosis and thrombocytosis. Survival is reduced compared with general population. Main reasons of death include thrombohemorrhagic complications, fibrotic progression and leuk-aemic transformation. Presence of Janus kinase (JAK2) gene mutations is a diagnostic marker and standard dia-gnostic criterion. World Health Organization 2016 diagnostic criteria focusing on hemoglobin levels, hematocrit, red cell mass and bone marrow morphology are mandatory. Therapeutic approach depends on stratification of patients according age and personal risk of thrombosis. Low-risk patients are treated first line with low-dose aspirin and phlebo-tomy. Cytoreduction is indicated in high-risk patients. Interferon-α has demonstrated efficacy in many clinical trials. Its pegylated form is well tolerated, enabling less frequent administration than standard interferon. Therefore it is therapy of choice based on Central European Myeloproliferative Neoplasm Organisation recommendation. Ropeginterferon α-2b has been shown to be more efficacious than hydroxyurea. Hydroxyurea is suspected of leukemogenic potential. JAK1/JAK2 inhibitor ruxolitinib is approved for hydroxyurea resistant/intolerant patients. Key words: diagnosis - polycythemia vera - therapy.


Assuntos
Inibidores Enzimáticos , Hidroxiureia , Policitemia Vera , Aspirina/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Humanos , Hidroxiureia/uso terapêutico , Inibidores da Agregação de Plaquetas/uso terapêutico , Policitemia Vera/complicações , Policitemia Vera/tratamento farmacológico , Trombocitose/etiologia , Trombose/etiologia
19.
Medicine (Baltimore) ; 97(52): e13880, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30593195

RESUMO

RATIONALE: Polycythemia vera (PV) is a cloned erythrocytotic disease manifested by high proliferation and apoptosis in the bone marrow. The clinical symptoms of PV are occult. In practice, patients with cerebral infarction caused by PV are prone to misdiagnosis and missed diagnosis. PATIENT CONCERNS: Here, we report a misdiagnosis of PV leading to cerebral infarction. The patient was a middle-aged woman who was diagnosed with acute cerebral infarction in the outpatient hospital. After treatment, the patient still had left hemiplegia, dizziness and other symptoms and was admitted to our hospital. DIAGNOSIS: We did not find sufficient evidence of atherosclerotic processes in the brain infarction. However, the patient's signs and laboratory examination indicated a high suspicion of PV. A series of further examinations confirmed the final diagnosis. INTERVENTIONS: Bone marrow suppression medications (oral hydroxyurea and subcutaneous injection of interferon) were given and subsequent prevention of cerebral infarction was implemented. OUTCOMES: Routine blood reexamination was normal and no further cerebral infarction occurred. LESSONS: Patients with acute cerebral infarction should be considered comprehensively, and rare causes should not be ignored. It is crucial that PV be diagnosed and treated as early as possible, which can significantly improve the prognosis of patients.


Assuntos
Infarto Cerebral/etiologia , Policitemia Vera/complicações , Feminino , Humanos , Hidroxiureia/uso terapêutico , Interferons/uso terapêutico , Pessoa de Meia-Idade , Policitemia Vera/tratamento farmacológico
20.
Clin Adv Hematol Oncol ; 16(11): 750-757, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30543590

RESUMO

Polycythemia vera (PV) is the most common Philadelphia chromosome-negative myeloproliferative neoplasm. Whereas low-risk patients are treated with aspirin and phlebotomy, high-risk patients receive cytoreductive therapy, which most commonly consists of hydroxyurea in the United States. Concerns about the long-term safety of hydroxyurea, as well as a desire for more efficacious and targeted therapy, have led to the development of novel therapies for high-risk patients with PV. Pegylated interferon (IFN) has shown promise in phase 2 studies of PV, and preliminary data from ongoing phase 3 studies suggest noninferiority as a frontline therapy. Efficient count control, tolerability, and even molecular responses as a salvage therapy have been demonstrated. Ropeginterferon-α-2b, a monopegylated IFN with a longer half-life and less frequent dose interval compared with recombinant or pegylated IFN, is an impressive agent in development. Ruxolitinib has a proven role as second-line therapy for PV, but an ongoing trial combining ruxolitinib and IFN as salvage therapy is under way. Early-phase clinical trials have also suggested that MDM2 inhibitors such as idasanutlin and histone deacetylase inhibitors should continue in their development. If these novel agents are able to modify the natural history of PV, the treatment paradigm in newly diagnosed patients will evolve from risk-adapted or reactive treatment toward early interventions.


Assuntos
Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Pirazóis/uso terapêutico , Pirrolidinas/uso terapêutico , para-Aminobenzoatos/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Meia-Vida , Humanos , Hidroxiureia/farmacocinética , Hidroxiureia/uso terapêutico , Interferon alfa-2/farmacocinética , Interferon-alfa/farmacocinética , Policitemia Vera/metabolismo , Policitemia Vera/patologia , Polietilenoglicóis/farmacocinética , Pirazóis/farmacocinética , Pirrolidinas/farmacocinética , Proteínas Recombinantes/farmacocinética , Proteínas Recombinantes/uso terapêutico , Terapia de Salvação/métodos , para-Aminobenzoatos/farmacocinética
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