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1.
BMJ Case Rep ; 14(9)2021 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-34479888

RESUMO

Nilotinib is used as standard treatment in managing chronic myeloid leukaemia (CML). A 23-year-old man with CML and on nilotinib was admitted to the intensive care unit due to respiratory failure. Three years prior, he developed pleural effusion from dasatinib therapy thus, his CML regimen was changed to nilotinib. Although the pleural effusion had once improved, the chest imaging revealed left-dominant bilateral pleural effusion. Endotracheal intubation and left thoracic drainage were performed. Nilotinib treatment was discontinued, and approximately 60 hours later, nilotinib concentrations of 927 and 2092 ng/mL were determined in his blood and pleural effusion, respectively. Severe pleural effusion may be induced in patients administering nilotinib, and nilotinib concentrations in blood and pleural effusion can be elevated in patients with nilotinib-related pleural effusion. Cross-occurrence of pleural effusions needs to be monitored precisely, especially in patients who are switched to other tyrosine kinase inhibitors after dasatinib treatment.


Assuntos
Antineoplásicos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Derrame Pleural , Adulto , Antineoplásicos/efeitos adversos , Dasatinibe/efeitos adversos , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Derrame Pleural/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas , Adulto Jovem
2.
Rinsho Ketsueki ; 62(8): 1024-1028, 2021.
Artigo em Japonês | MEDLINE | ID: mdl-34497188

RESUMO

BCR-ABL tyrosine kinase inhibitors (TKIs) have significantly improved the prognosis of chronic myeloid leukemia (CML). Currently, five BCR-ABL TKIs are approved for use in patients with CML, but the long-term use of these TKIs is associated with various cardiovascular events. Typical cardiovascular adverse events include pulmonary hypertension caused by dasatinib and arterial occlusive diseases caused by nilotinib and ponatinib. Although mechanisms of cardiovascular adverse events of BCR-ABL TKIs in the treatment of CML have not been clarified, differences in their inhibitory activities on off-target kinases, including those involved in vascular function, may be related to individual safety profiles. Arterial occlusive diseases are common in patients with a history of cardiovascular disease and risk of atherosclerosis. Arterial occlusive diseases, such as ischemic heart disease, ischemic cerebral disease, and peripheral arterial occlusive disease, worsen the prognosis and quality of life of patients with CML. Therefore, appropriate management strategies are required. This paper outlines cardiovascular adverse events associated with TKI treatment, including arterial obstructive diseases, pulmonary arterial hypertension, and QT interval prolongation.


Assuntos
Antineoplásicos , Hipertensão Pulmonar , Leucemia Mielogênica Crônica BCR-ABL Positiva , Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Proteínas de Fusão bcr-abl , Humanos , Hipertensão Pulmonar/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Qualidade de Vida
3.
Am J Case Rep ; 22: e932252, 2021 Sep 07.
Artigo em Inglês | MEDLINE | ID: mdl-34491978

RESUMO

BACKGROUND Osimertinib is an oral third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) approved as first-line therapy for advanced non-small cell lung cancer (NSCLC) with positive EGFR mutation. Rashes, nail toxicity, and diarrhea are common adverse events. Hematological adverse effects, including anemia, thrombocytopenia, and lymphocytopenia, have been reported. However, erythrocytosis has not been reported as an adverse event. To the best of our knowledge, we report the first case of acute lower extremity thrombosis presumably caused by osimertinib-induced erythrocytosis. CASE REPORT A 70-year-old man with epidermal EGFR-mutant advanced NSCLC presented with acute left sural pain. The patient's left foot was cold, and peripheral arterial Doppler signals were absent. He had developed erythrocytosis of unknown etiology during osimertinib therapy. Hemoglobin (Hb) and hematocrit were 22.6 g/dL and 62.5%, respectively. Contrast-enhanced computed tomography showed thrombotic occlusion of the popliteal artery. Other than erythrocytosis, there was no possible cause of arterial thrombosis. Osimertinib was discontinued immediately because the NSCLC started to resist treatment and was presumed to be the cause of erythrocytosis. He received endovascular treatment (EVT). Following serial EVT and debridement, his fourth toe was amputated for necrosis. Erythrocytosis persisted 8 months during osimertinib therapy. Hb levels decreased to 15.4 mg/dL due to blood loss complicated with catheter thrombectomy and remained normal for 20 months after osimertinib discontinuation. The patient died of cancer progression. CONCLUSIONS This case suggests the erythrocytosis was possibly caused by osimertinib. We may need to monitor Hb levels during osimertinib therapy and be alert to thrombosis once Hb starts to rise.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Policitemia , Trombose , Acrilamidas , Idoso , Compostos de Anilina , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Extremidade Inferior , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Mutação , Policitemia/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos
4.
Am J Clin Dermatol ; 22(5): 693-707, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34406619

RESUMO

BACKGROUND: Pivotal phase III studies demonstrated that abrocitinib, an oral, once-daily, JAK1-selective inhibitor, is effective treatment for moderate-to-severe atopic dermatitis (AD) as monotherapy and in combination with topical therapy. OBJECTIVE: The aim of this study was to evaluate the long-term safety of abrocitinib 200 mg and 100 mg in an integrated analysis of a phase IIb study, four phase III studies, and one long-term extension study. METHODS: Two cohorts were analyzed: a placebo-controlled cohort from 12- to 16-week studies and an all-abrocitinib cohort including patients who received one or more abrocitinib doses. Adverse events (AEs) of interest and laboratory data are reported. RESULTS: Total exposure in the all-abrocitinib cohort (n = 2856) was 1614 patient-years (PY); exposure was ≥ 24 weeks in 1248 patients and ≥ 48 weeks in 606 (maximum 108 weeks). In the placebo-controlled cohort (n = 1540), dose-related AEs (200 mg, 100 mg, placebo) were nausea (14.6%, 6.1%, 2.0%), headache (7.8%, 5.9%, 3.5%), and acne (4.7%, 1.6%, 0%). Platelet count was reduced transiently in a dose-dependent manner; 2/2718 patients (200-mg group) had confirmed platelet counts of < 50 × 103/mm3 at week 4. Incidence rates (IRs) were 2.33/100PY and 2.65/100 PY for serious infection, 4.34/100PY and 2.04/100PY for herpes zoster, and 11.83/100PY and 8.73/100PY for herpes simplex in the 200-mg and 100-mg groups, respectively. IRs for nonmelanoma skin cancer, other malignancies, and major adverse cardiovascular events were < 0.5/100PY for both doses. Five venous thromboembolism events occurred (IR 0.30/100PY), all in the 200-mg group. There were three deaths due to gastric carcinoma (diagnosed at day 43), sudden death, and COVID-19. CONCLUSION: Abrocitinib, with proper patient and dose selection, has a manageable tolerability and longer-term safety profile appropriate for long-term use in patients with moderate-to-severe AD. TRIAL REGISTRIES: ClinicalTrials.gov: NCT02780167, NCT03349060, NCT03575871, NCT03720470, NCT03627767, NCT03422822.


Assuntos
Dermatite Atópica/tratamento farmacológico , Infecções/epidemiologia , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Neoplasias Cutâneas/epidemiologia , Sulfonamidas/efeitos adversos , Acne Vulgar/induzido quimicamente , Adolescente , Adulto , Idoso , Doenças Cardiovasculares/epidemiologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Cefaleia/induzido quimicamente , Herpes Simples/epidemiologia , Herpes Zoster/epidemiologia , Humanos , Incidência , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Contagem de Plaquetas , Inibidores de Proteínas Quinases/administração & dosagem , Pirimidinas/administração & dosagem , Fatores de Risco , Sulfonamidas/administração & dosagem , Fatores de Tempo , Tromboembolia Venosa/epidemiologia , Adulto Jovem
5.
Lancet Neurol ; 20(9): 729-738, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34418400

RESUMO

BACKGROUND: Tolebrutinib is an oral, CNS-penetrant, irreversible inhibitor of Bruton's tyrosine kinase, an enzyme expressed in B lymphocytes and myeloid cells including microglia, which are major drivers of inflammation in multiple sclerosis. We aimed to determine the dose-response relationship between tolebrutinib and the reduction in new active brain MRI lesions in patients with relapsing multiple sclerosis. METHODS: We did a 16-week, phase 2b, randomised, double-blind, placebo-controlled, crossover, dose-finding trial at 40 centres (academic sites, specialty clinics, and general neurology centres) in ten countries in Europe and North America. Eligible participants were adults aged 18-55 years with diagnosed relapsing multiple sclerosis (either relapsing-remitting or relapsing secondary progressive multiple sclerosis), and one or more of the following criteria: at least one relapse within the previous year, at least two relapses within the previous 2 years, or at least one active gadolinium-enhancing brain lesion in the 6 months before screening. Exclusion criteria included a diagnosis of primary progressive multiple sclerosis or a diagnosis of secondary progressive multiple sclerosis without relapse. We used a two-step randomisation process to randomly assign eligible participants (1:1) to two cohorts, then further randomly assign participants in each cohort (1:1:1:1) to four tolebrutinib dose groups (5, 15, 30, and 60 mg administered once daily as an oral tablet). Cohort 1 received tolebrutinib for 12 weeks, then matched placebo (ie, identical looking tablets) for 4 weeks; cohort 2 received 4 weeks of placebo followed by 12 weeks of tolebrutinib. Participants and investigators were masked for dose and tolebrutinib-placebo administration sequence; investigators, study team members, and study participants did not have access to unmasked data. MRI scans were done at screening and every 4 weeks over 16 weeks. The primary efficacy endpoint was the number of new gadolinium-enhancing lesions detected on the scan done after 12 weeks of tolebrutinib treatment (assessed at week 12 for cohort 1 and week 16 for cohort 2), relative to the scan done 4 weeks previously, and compared with the lesions accumulated during 4 weeks of placebo run-in period in cohort 2. Efficacy data were analysed in a modified intention-to-treat population, using a two-step multiple comparison procedure with modelling analysis. Safety was assessed for all participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03889639), EudraCT (2018-003927-12), and WHO (U1111-1220-0572), and has been completed. FINDINGS: Between May 14, 2019, and Jan 2, 2020, we enrolled and randomly assigned 130 participants to tolebrutinib: 33 to 5 mg, 32 to 15 mg, 33 to 30 mg, and 32 to 60 mg. 129 (99%) completed the treatment regimen and 126 were included in the primary analysis. At treatment week 12, there was a dose-dependent reduction in the number of new gadolinium-enhancing lesions (mean [SD] lesions per patient: placebo, 1·03 [2·50]; 5 mg, 1·39 [3·20]; 15 mg, 0·77 [1·48]; 30 mg, 0·76 [3·31]; 60 mg, 0·13 [0·43]; p=0·03). One serious adverse event was reported (one patient in the 60 mg group was admitted to hospital because of a multiple sclerosis relapse). The most common non-serious adverse event during tolebrutinib treatment was headache (in one [3%] of 33 in the 5 mg group; three [9%] of 32 in the 15 mg group; one [3%] of 33 in the 30 mg group; and four [13%] of 32 in the 60 mg group). No safety-related discontinuations or treatment-related deaths occurred. INTERPRETATION: 12 weeks of tolebrutinib treatment led to a dose-dependent reduction in new gadolinium-enhancing lesions, the 60 mg dose being the most efficacious, and the drug was well tolerated. Reduction of acute inflammation, combined with the potential to modulate the immune response within the CNS, provides a scientific rationale to pursue phase 3 clinical trials of tolebrutinib in patients with relapsing and progressive forms of multiple sclerosis. FUNDING: Sanofi.


Assuntos
Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Sistema Nervoso Central/efeitos dos fármacos , Inflamação/tratamento farmacológico , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Inibidores de Proteínas Quinases/farmacologia , Adulto , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/imunologia , Sistema Nervoso Central/patologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Inflamação/diagnóstico por imagem , Inflamação/imunologia , Inflamação/patologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/patologia , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Recidiva , Adulto Jovem
6.
Medicine (Baltimore) ; 100(33): e26975, 2021 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-34414970

RESUMO

ABSTRACT: Dasatinib, a tyrosine kinase inhibitor (TKI), induces pulmonary hypertension (PH) in patients with chronic myeloid leukemia (CML). However, information on other TKIs is limited.We retrospectively analyzed PH prevalence by reviewing transthoracic echocardiography (TTE) findings in a population of Korean CML patients treated with TKI at a single hospital between 2003 and 2020. PH was defined as a high PH probability according to the European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines.Of the 189 patients treated with TKI(s) during the study period, 112 (59.3%) underwent TTE. Among the 112 patients treated with a TKI for a median of 40.4 months (range: 1.1-167.2 months), PH was found in 12 (10.7%), most frequently in those treated with dasatinib (ie, in 3 [7.5%] of 40 of those treated with imatinib, 1 [3.1%] of 32 of those treated with nilotinib, and 8 [21.6%] of 37 of those treated with dasatinib). PH resolved in 4 (50.0%) of the 8 dasatinib-treated patients after discontinuation of the agent. One nilotinib-treated and all three imatinib-treated patients recovered from PH. In multivariate analyses, age >60 years, dasatinib treatment, and positive cardiopulmonary symptoms/signs at the time of transthoracic echocardiography were statistically significant risk factors for developing PH.These results show that PH is induced not only by dasatinib, but also by imatinib and nilotinib. Careful screening for PH during any TKI treatment may thus be warranted in patients with CML.


Assuntos
Antineoplásicos/efeitos adversos , Dasatinibe/efeitos adversos , Hipertensão Pulmonar/induzido quimicamente , Mesilato de Imatinib/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Ecocardiografia , Feminino , Humanos , Hipertensão Pulmonar/diagnóstico por imagem , Mesilato de Imatinib/uso terapêutico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Pirimidinas/uso terapêutico , Estudos Retrospectivos , Adulto Jovem
7.
Bratisl Lek Listy ; 122(8): 531-537, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34282617

RESUMO

OBJECTIVES: The aim of this study was to assess cardiotoxicity and potential adverse effects related to lipid metabolism during treatment with tyrosine kinase inhibitors (TKIs) imatinib and nilotinib in patients with chronic myeloid leukemia (CML). PATIENTS AND METHODS: Eighty-two consecutive patients with CML, who received nilotinib and/or imatinib in a single haemato-oncological Slovak center between years 2002-2018 were evaluated in a retrospective study. The mean age was 55.8 years (range 22-77 years). Median of follow-up was 61.3 months. RESULTS: A significantly higher incidence of dyslipidemia, significantly higher levels of potential risk markers of cardiovascular disease small dense LDL cholesterol (sdLDL-CH) and a significant increase in total cholesterol were found in the patients during treatment with nilotinib in comparison to imatinib. Dyslipidemia led to drug therapy in 22 % of the patients in the nilotinib group. Fourteen percent of the patients in the nilotinib group had one or more cardiovascular events, including peripheral artery disease (10 %), myocardial infarction (4 %) and stroke (4 %). CONCLUSION: A higher risk of cardiovascular events and atherogenic dyslipidemia were associated with nilotinib therapy. Patients treated with TKI, especially nilotinib, require an early modification of cardiovascular risk factors and a careful cardiologic surveillance so that antileukemic therapy with this highly effective agent could continue (Tab. 4, Fig. 3, Ref. 32). Text in PDF www.elis.sk Keywords: tyrosine kinase inhibitors, cardiovascular events, dyslipidemia, small dense LDL-cholesterol, nilotinib, imatinib.


Assuntos
Antineoplásicos , Doenças Cardiovasculares , Leucemia Mielogênica Crônica BCR-ABL Positiva , Adulto , Idoso , Antineoplásicos/efeitos adversos , Doenças Cardiovasculares/induzido quimicamente , Doenças Cardiovasculares/epidemiologia , Humanos , Mesilato de Imatinib/efeitos adversos , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Lipídeos , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas , Estudos Retrospectivos , Adulto Jovem
8.
Orv Hetil ; 162(30): 1198-1207, 2021 07 25.
Artigo em Húngaro | MEDLINE | ID: mdl-34304154

RESUMO

Összefoglaló. A krónikus myeloid leukaemia ritka, klonális ossejt eredetu betegség. A myeloid sejtsor kóros muködését a 9-es és 22-es kromoszómák reciprok transzlokációja következtében kialakuló fúziós gén (BCR/ABL1) által kódolt patológiás (fokozott) aktivitású tirozin-kináz jelátviteli fehérje okozza. A tartós, gyakran élethosszig tartó BCR/ABL1 specifikus tirozin-kináz-gátló (TKI-) kezelés a betegek jelentos hányadában az egészséges populáció túlélését eléro teljes gyógyulást biztosít, melyhez folyamatos, a mindenkori szakmai ajánlásoknak megfelelo onkohematológiai ellenorzés szükséges. Az igen hatékony TKI-kezelés mellett azonban nemkívánatos mellékhatások jelentkezhetnek, melyek - számos szervrendszert érintve - a krónikus myeloid leukaemiás beteg kezelését multidiszciplináris együttmuködéssé szélesítik ki. Jelenleg Magyarországon ötféle TKI érheto el, melyek mellékhatásprofilja igen eltéro. A kezelés elindításakor, illetve terápiamódosítás esetén beteg- és kórképspecifikus szempontokat mérlegelve kell kiválasztani az adott TKI-kezelést. Tekintettel a tartós kezelés mellett elérheto kiváló túlélési eredményekre, egyre gyakoribb azoknak a krónikus myeloid leukaemiás betegeknek a száma, akiknél változó súlyosságú nemkívánatos mellékhatások jelentkeznek, melyek miatt a betegek sokszor nem a hematológus szakorvosnál jelentkeznek. A leggyakrabban észlelt szövodmények ismertetését saját beteganyagunk részletes elemzése kapcsán a mindennapi klinikai gyakorlatban is bemutatjuk. Igen fontos, hogy a társszakmák (háziorvos, belgyógyász, kardiológus, angiológus, diabetológus, tüdogyógyász, gasztroenterológus stb.) gyakorlói is tisztában legyenek az adott TKI-kezelés lehetséges mellékhatásaival, azok megelozésével, idoben történo felismerésével és hatékony kezelésével. Szakmai közremuködésük révén így segíthetik a klinikai hematológust a megfelelo terápia megtervezésében, valamint a betegek folyamatos kezelése kapcsán gyakran szükségessé váló szakmaspecifikus gondozásában is. Orv Hetil. 2021; 162(30): 1198-1207. Summary. Chronic myeloid leukemia is a rare clonal stem cell disorder. The pathological overproduction of the myeloid cell line is caused by abnormal function of a tyrosine kinase encoded by a fusion gene (BCR/ABL1) which is formed upon a reciprocal translocation of chromosomes 9 and 22. Long-term, often lifelong treatment with BCR/ABL1-specific tyrosine kinase inhibitors provides excellent disease control and overall survival rates close to the general survival of a healthy population in a significant proportion of patients. These patients require continuous oncohematological monitoring in accordance with the current diagnostic and treatment guidelines. However, undesirable side effects may occur that extend the treatment of the patients to a multidisciplinary approach involving a number of nonhematological specialities. Currently, five types of tyrosine kinase inhibitors are available in Hungary, with very different side effect profiles. At the start of treatment or in the event of a change in therapy, patient- and leukemia-specific assessments should be taken to select the most proper tyrosine kinase inhibitors treatment. Given the excellent survival outcomes achieved with long-term tyrosine kinase inhibitor treatment, there is an increasing number of patients who might experience adverse events of different kind or severity, which often results in patients ending up in different, nonhematological medical situations. The description of the most frequently observed complications in connection with a detailed cross-sectional analysis of our own patient cohort is also presented here resembling everyday clinical practice. It is very important that practitioners of other medical professions (general practitioner, internist, cardiologist, angiologist, diabetologist, pulmonologist, gastroenterologist, etc.) should be aware of the possible side effects of specific tyrosine kinase inhibitor therapies. They can help to assist the clinical hematologist in planning the appropriate tyrosine kinase inhibitor therapy as well as in professional caretaking of these patients. Orv Hetil. 2021; 162(30): 1198-1207.


Assuntos
Leucemia Mielogênica Crônica BCR-ABL Positiva , Leucemia Mieloide , Estudos Transversais , Humanos , Hungria , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Masculino , Inibidores de Proteínas Quinases/efeitos adversos
9.
Int J Mol Sci ; 22(13)2021 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-34202704

RESUMO

The aim of this study was to evaluate the effect of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, on red blood cell parameters in the context of iron homeostasis in patients with tuberous sclerosis complex (TSC) and evaluate its effect on cell size in vitro. Everolimus has a significant impact on red blood cell parameters in patients with TSC. The most common alteration was microcytosis. The mean MCV value decreased by 9.2%, 12%, and 11.8% after 3, 6, and 12 months of everolimus treatment. The iron level declined during the first 3 months, and human soluble transferrin receptor concentration increased during 6 months of therapy. The size of K562 cells decreased when cultured in the presence of 5 µM everolimus by approximately 8%. The addition of hemin to the cell culture with 5 µM everolimus did not prevent any decrease in cell size. The stage of erythroid maturation did not affect the response to everolimus. Our results showed that the mTOR inhibitor everolimus caused red blood cell microcytosis in vivo and in vitro. This effect is not clearly related to a deficit of iron and erythroid maturation. This observation confirms that mTOR signaling plays a complex role in the control of cell size.


Assuntos
Tamanho Celular/efeitos dos fármacos , Eritrócitos/efeitos dos fármacos , Eritrócitos/patologia , Inibidores de Proteínas Quinases/farmacologia , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Biomarcadores , Diferenciação Celular/efeitos dos fármacos , Linhagem Celular , Criança , Pré-Escolar , Índices de Eritrócitos , Eritrócitos/metabolismo , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Everolimo/farmacologia , Citometria de Fluxo , Humanos , Ferro/metabolismo , Células K562 , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos
10.
Expert Opin Drug Metab Toxicol ; 17(9): 1023-1030, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34275396

RESUMO

INTRODUCTION: The first-in-class BTK inhibitor ibrutinib has substantially changed the therapeutic landscape of chronic lymphocytic leukemia (CLL). The next-generation BTK inhibitor acalabrutinib is more selective and may have less off-target toxicities as compared to ibrutinib. Acalabrutinib has demonstrated safety and efficacy in CLL and has been approved to treat CLL. AREAS COVERED: Current clinical trials investigated acalabrutinib monotherapy or acalabrutinib-based combination therapies in relapsed/refractory and treatment-naive CLL. Data on the efficacy and safety of acalabrutinib in clinical trials were summarized in this review. The pharmacokinetic and pharmacodynamic data of acalabrutinib were also discussed. EXPERT OPINION: Acalabrutinib selectively inhibits BTK by covalent binding and shows rapid absorption and elimination. Acalabrutinib does not inhibit EGFR, TEC, or ITK and shows fewer off-target toxicities. Completed phase 3 trials have demonstrated that acalabrutinib improves the outcomes of patients with relapsed/refractory CLL and patients with treatment-naive CLL. The phase 3 trial that evaluates acalabrutinib versus ibrutinib has met its primary endpoint. Early phase studies suggested the combinations of acalabrutinib with a CD20 antibody and venetoclax led to high rates of undetectable minimal residual disease in the bone marrow in CLL patients and might provide a fixed-duration therapeutic option for patients with CLL.


Assuntos
Antineoplásicos/administração & dosagem , Benzamidas/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Pirazinas/administração & dosagem , Adenina/administração & dosagem , Adenina/efeitos adversos , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Benzamidas/efeitos adversos , Benzamidas/farmacocinética , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética , Pirazinas/efeitos adversos , Pirazinas/farmacocinética
11.
Expert Opin Drug Metab Toxicol ; 17(7): 803-821, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34278936

RESUMO

Introduction: Orally administered small molecule kinase inhibitors (KI) are a key class of targeted anti-cancer medicines that have contributed substantially to improved survival outcomes in patients with advanced disease. Since the introduction of KIs in 2001, there has been a building body of evidence that the benefit derived from these drugs may be further enhanced by individualizing dosing on the basis of concentration.Areas covered: This review considers the rationale for individualized KI dosing and the requirements for robust therapeutic drug monitoring (TDM). Current evidence supporting TDM-guided KI dosing is presented and critically evaluated, and finally potential approaches to address translational challenges for TDM-guided KI dosing and alternate approaches to support individualization of KI dosing are discussed.Expert opinion: Intuitively, the individualization of KI dosing through an approach such as TDM-guided dosing has great potential to enhance the effectiveness and tolerability of these drugs. However, based on current literature evidence it is unrealistic to propose that TDM-guided KI dosing should be routinely implemented into clinical practice.


Assuntos
Antineoplásicos/administração & dosagem , Monitoramento de Medicamentos/métodos , Inibidores de Proteínas Quinases/administração & dosagem , Administração Oral , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacocinética , Relação Dose-Resposta a Droga , Humanos , Neoplasias/tratamento farmacológico , Medicina de Precisão/métodos , Inibidores de Proteínas Quinases/efeitos adversos , Inibidores de Proteínas Quinases/farmacocinética
12.
Drugs Today (Barc) ; 57(7): 417-431, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34268530

RESUMO

Acalabrutinib was approved by the U.S. Food and Drug Administration (FDA) for treatment-naive (TN) and relapsed/refractory (R/R) use for patients with chronic lymphocytic leukemia (CLL) in November 2019 following the phase III ASCEND and ELEVATE-TN registration trials. Acalabrutinib is a second-generation Bruton tyrosine kinase inhibitor (BTKi) that was developed after ibrutinib, the first-in-class BTKi. Ibrutinib is usually well tolerated and provides durable remissions; however, some patients experience toxicities from the off-target effects that lead to treatment discontinuation. A recent press release of the phase III ELEVATE-RR trial comparing acalabrutinib to ibrutinib in relapsed high-risk CLL reported noninferior progression-free survival and statistically significantly lower rates of atrial fibrillation; however, publication of this data is pending. There is currently 53 months of follow-up for patients receiving acalabrutinib compared with 8 years for those on ibrutinib. Acalabrutinib is approved as monotherapy in the R/R or TN setting, and in the TN setting can be combined with the anti-CD20 monoclonal antibody obinutuzumab. The data for acalabrutinib development and clinical use are discussed in this review.


Assuntos
Leucemia Linfocítica Crônica de Células B , Benzamidas , Humanos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Pirazinas/efeitos adversos , Pirimidinas/efeitos adversos
13.
Crit Rev Oncol Hematol ; 163: 103393, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34119658

RESUMO

OBJECTIVE: We conducted a meta-analysis to synthesize the results of published randomized controlled trials conducted to evaluate the efficacy and safety of epidermal growth factor receptor - tyrosine kinase inhibitors (EGFR-TKIs) combined with chemotherapy or antiangiogenic therapy. METHODS: PubMed, EMBASE, Cochrane Library and ClinicalTrials.gov databases were searched and literatures from international conferences were read to identify eligible studies. The primary endpoints were objective response rate (ORR) and progression free survival (PFS). The secondary endpoints were disease control rate (DCR), overall survival (OS) and treatment-emergent adverse events (TEAEs). RESULTS: 10 studies, all on first-generation EGFR-TKI combination therapy, involving 2367 patients were included. Combination therapy resulted in significant improvements in ORR (RR: 1.11, 95% CI: 1.06-1.17, P < 0.001), DCR (RR: 1.03, 95% CI: 1.01-1.05, P = 0.007), PFS (HR: 0.56, 95% CI: 0.51-0.62, P < 0.001), OS (HR: 0.74, 95% CI: 0.64-0.84, P = 0.002) over monotherapy. This improvement was more apparent in the EGFR-TKIs combination chemotherapy group, and indirect comparisons revealed that EGFR-TKIs combined with chemotherapy appeared to be superior to combined with antiangiogenic therapy in ORR (RR: 1.19, 95% CI: 1.07-1.32), DCR (RR: 1.04, 95% CI: 1.02-1.08), and OS (HR: 0.79, 95% CI: 0.66-0.96). Of additional concern is the increased incidence of TEAEs in combination therapy. CONCLUSION: As a first-line treatment for patients with EGFR-mutated advanced non-small cell lung cancer (NSCLC), first-generation EGFR-TKIs combined with chemotherapy or antiangiogenic therapy was associated with significant improvement in ORR, DCR, PFS and OS compared with monotherapy.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Inibidores da Angiogênese/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Receptores ErbB/genética , Receptores ErbB/uso terapêutico , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Inibidores de Proteínas Quinases/efeitos adversos
15.
Aging (Albany NY) ; 13(12): 16425-16444, 2021 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-34156352

RESUMO

To identify novel prognostic and therapeutic targets for osteosarcoma patients, we compared the gene expression profiles of osteosarcoma and control tissues from the GSE42352 dataset in the Gene Expression Omnibus. Differentially expressed genes were subjected to Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, Gene Set Enrichment and protein-protein interaction network analyses. Survival curve analyses indicated that osteosarcoma patients with lower mRNA levels of cyclin-dependent kinase 1 (CDK1) and topoisomerase II alpha had better prognoses. Various computer-aided techniques were used to identify potential CDK1 inhibitors for osteosarcoma patients, and PHA-793887 was predicted to be a safe drug with a high binding affinity for CDK1. In vitro, MTT and colony formation assays demonstrated that PHA-793887 reduced the viability and clonogenicity of osteosarcoma cells, while a scratch assay suggested that PHA-793887 impaired the migration of these cells. Flow cytometry experiments revealed that PHA-793887 dose-dependently induced apoptosis in osteosarcoma cells. Western blotting and enzyme-linked immunosorbent assays indicated that CDK1 expression in osteosarcoma cells declined with increasing PHA-793887 concentrations. These results suggest that PHA-793887 could be a promising new treatment for osteosarcoma.


Assuntos
Biologia Computacional , Simulação de Acoplamento Molecular , Osteossarcoma/tratamento farmacológico , Pirazóis/uso terapêutico , Pirróis/uso terapêutico , Sítios de Ligação , Proteína Quinase CDC2/antagonistas & inibidores , Proteína Quinase CDC2/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Redes Reguladoras de Genes/efeitos dos fármacos , Humanos , Ligantes , Osteossarcoma/genética , Osteossarcoma/patologia , Mapas de Interação de Proteínas/genética , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/química , Pirazóis/farmacologia , Pirróis/química , Pirróis/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Análise de Sobrevida
16.
Neurology ; 97(7): e673-e683, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34088874

RESUMO

OBJECTIVE: To assess whether RAF and MEK inhibitors (RAFi/MEKi) can provide long-term clinical benefit in adult patients with BRAF V600-mutant glial and glioneuronal tumors (GGNTs), we analyzed tumor response and long-term outcome in a retrospective cohort. METHODS: We performed a retrospective search in the institutional databases of 6 neuro-oncology departments for adult patients with recurrent or disseminated BRAF V600-mutant GGNTs treated with RAFi/MEKi. RESULTS: Twenty-eight adults with recurrent or disseminated BRAF V600-mutant gangliogliomas (n = 9), pleomorphic xanthoastrocytomas (n = 9), and diffuse gliomas (n = 10) were included in the study. At the time that treatment with RAFi/MEKi was started, all tumors displayed radiologic features of high-grade neoplasms. Thirteen patients received RAFi as single agents (vemurafenib [n = 11], dabrafenib [n = 2]), and 15 received combinations of RAFi/MEKi (vemurafenib + cobimetinib [n = 5], dabrafenib + trametinib [n = 10]). Eleven patients achieved a partial or complete response (11 of 28, 39%), with a median reduction of -78% in their tumor burden. Responders experienced a median increase of 10 points in their Karnofsky Performance Status (KPS) score and a median progression-free survival of 18 months, which was longer than achieved with first-line treatment (i.e., 7 months, p = 0.047). Responders had better KPS score (p = 0.018) and tended to be younger (p = 0.061) and to be treated earlier (p = 0.099) compared to nonresponders. Five patients were rechallenged with RAFi/MEKi at progression, with novel tumor responses in 2. On univariate and multivariate analyses, response to RAFi/MEKi was an independent predictor of overall survival. CONCLUSIONS: Our study highlights the long-term clinical benefits of RAFi/MEKi in adult patients with BRAF V600-mutant GGNTs and encourages rechallenge in responders. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that, for adult patients with BRAF V600-mutant GGNT, RAFi/MEKi can reduce tumor burden and provide clinical benefit.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Glioma/tratamento farmacológico , Quinases de Proteína Quinase Ativadas por Mitógeno/antagonistas & inibidores , Avaliação de Resultados em Cuidados de Saúde , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas B-raf/genética , Adulto , Astrocitoma/tratamento farmacológico , Astrocitoma/genética , Azetidinas/farmacologia , Neoplasias Encefálicas/genética , Bases de Dados Factuais , Feminino , Ganglioglioma/tratamento farmacológico , Ganglioglioma/genética , Glioma/genética , Humanos , Imidazóis/farmacologia , Avaliação de Estado de Karnofsky , MAP Quinase Quinase Quinases/antagonistas & inibidores , Masculino , Pessoa de Meia-Idade , Oximas/farmacologia , Piperidinas/farmacologia , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Piridonas/farmacologia , Pirimidinonas/farmacologia , Estudos Retrospectivos , Vemurafenib/farmacologia , Quinases raf/antagonistas & inibidores
17.
Lancet Oncol ; 22(7): 946-958, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34143969

RESUMO

BACKGROUND: Despite advances in the first-line treatment of metastatic renal cell carcinoma (RCC), there is an unmet need for options to address disease progression during or after treatment with immune checkpoint inhibitors (ICIs). Pembrolizumab and lenvatinib are active as monotherapies in RCC; thus, we aimed to evaluate the combination of lenvatinib plus pembrolizumab in these patients. METHODS: We report results of the metastatic RCC cohort from an open-label phase 1b/2 study of lenvatinib plus pembrolizumab in patients aged at least 18 years with selected solid tumours and an Eastern Cooperative Oncology Group performance status of 0-1. Oral lenvatinib at 20 mg was given once daily along with intravenous pembrolizumab at 200 mg once every 3 weeks. Patients remained on study drug treatment until disease progression, development of unacceptable toxicity, or withdrawal of consent. Efficacy was analysed in patients with clear cell metastatic RCC receiving study drug by previous therapy grouping: treatment naive, previously treated ICI naive (previously treated with at least one line of therapy but not with an anti-PD-1 or anti-PD-L1 ICI), and ICI pretreated (ie, anti-PD-1 or anti-PD-L1) patients. Safety was analysed in all enrolled and treated patients. The primary endpoint was the objective response rate at week 24 per immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) by investigator assessment. This trial is registered with ClinicalTrials.gov (NCT02501096) and with the EU Clinical Trials Register (EudraCT2017-000300-26), and is closed to new participants. FINDINGS: Between July 21, 2015, and Oct 16, 2019, 145 patients were enrolled in the study. Two patients had non-clear cell RCC and were excluded from the efficacy analysis (one in the treatment-naive group and one in the ICI-pretreated group); thus, the population evaluated for efficacy comprised 143 patients (n=22 in the treatment-naive group, n=17 in the previously treated ICI-naive group, and n=104 in the ICI-pretreated group). All 145 enrolled patients were included in the safety analysis. The median follow-up was 19·8 months (IQR 14·3-28·4). The number of patients with an objective response at week 24 by irRECIST was 16 (72·7%, 95% CI 49·8-89·3) of 22 treatment-naive patients, seven (41·2%, 18·4-67·1) of 17 previously treated ICI-naive patients, and 58 (55·8%, 45·7-65·5) of 104 ICI-pretreated patients. Of 145 patients, 82 (57%) had grade 3 treatment-related adverse events and ten (7%) had grade 4 treatment-related adverse events. The most common grade 3 treatment-related adverse event was hypertension (30 [21%] of 145 patients). Treatment-related serious adverse events occurred in 36 (25%) patients, and there were three treatment-related deaths (upper gastrointestinal haemorrhage, sudden death, and pneumonia). INTERPRETATION: Lenvatinib plus pembrolizumab showed encouraging antitumour activity and a manageable safety profile and might be an option for post-ICI treatment of metastatic RCC. FUNDING: Eisai and Merck Sharp & Dohme.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Quinolinas/uso terapêutico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/secundário , Europa (Continente) , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Renais/imunologia , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Quinolinas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
18.
Lancet Oncol ; 22(7): 959-969, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34118197

RESUMO

BACKGROUND: Oncogenic alterations in RET have been identified in multiple tumour types, including 1-2% of non-small-cell lung cancers (NSCLCs). We aimed to assess the safety, tolerability, and antitumour activity of pralsetinib, a highly potent, oral, selective RET inhibitor, in patients with RET fusion-positive NSCLC. METHODS: ARROW is a multi-cohort, open-label, phase 1/2 study done at 71 sites (community and academic cancer centres) in 13 countries (Belgium, China, France, Germany, Hong Kong, Italy, Netherlands, Singapore, South Korea, Spain, Taiwan, the UK, and the USA). Patients aged 18 years or older with locally advanced or metastatic solid tumours, including RET fusion-positive NSCLC, and an Eastern Cooperative Oncology Group performance status of 0-2 (later limited to 0-1 in a protocol amendment) were enrolled. In phase 2, patients received 400 mg once-daily oral pralsetinib, and could continue treatment until disease progression, intolerance, withdrawal of consent, or investigator decision. Phase 2 primary endpoints were overall response rate (according to Response Evaluation Criteria in Solid Tumours version 1·1 and assessed by blinded independent central review) and safety. Tumour response was assessed in patients with RET fusion-positive NSCLC and centrally adjudicated baseline measurable disease who had received platinum-based chemotherapy or were treatment-naive because they were ineligible for standard therapy. This ongoing study is registered with ClinicalTrials.gov, NCT03037385, and enrolment of patients with treatment-naive RET fusion-positive NSCLC was ongoing at the time of this interim analysis. FINDINGS: Of 233 patients with RET fusion-positive NSCLC enrolled between March 17, 2017, and May 22, 2020 (data cutoff), 92 with previous platinum-based chemotherapy and 29 who were treatment-naive received pralsetinib before July 11, 2019 (efficacy enrolment cutoff); 87 previously treated patients and 27 treatment-naive patients had centrally adjudicated baseline measurable disease. Overall responses were recorded in 53 (61%; 95% CI 50-71) of 87 patients with previous platinum-based chemotherapy, including five (6%) patients with a complete response; and 19 (70%; 50-86) of 27 treatment-naive patients, including three (11%) with a complete response. In 233 patients with RET fusion-positive NSCLC, common grade 3 or worse treatment-related adverse events were neutropenia (43 patients [18%]), hypertension (26 [11%]), and anaemia (24 [10%]); there were no treatment-related deaths in this population. INTERPRETATION: Pralsetinib is a new, well-tolerated, promising, once-daily oral treatment option for patients with RET fusion-positive NSCLC. FUNDING: Blueprint Medicines.


Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Fusão Gênica , Neoplasias Pulmonares/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-ret/genética , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Pirimidinas/uso terapêutico , Idoso , Antineoplásicos/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Piridinas/efeitos adversos , Pirimidinas/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
19.
J Stroke Cerebrovasc Dis ; 30(8): 105883, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34090174

RESUMO

Nilotinib, a BCR-ABL tyrosine kinase inhibitor (TKI), has been associated with vascular events and accelerated arterial stenosis, presumably of atherosclerotic etiology. Studies of nilotinib-associated atherosclerosis are mainly associated with progressive peripheral artery occlusive disease (PAOD), and only a few cases of coronary artery disease (CAD), and cerebrovascular disease (CVD) have been reported. The mechanisms by which nilotinib promotes atherosclerosis are poorly understood but endothelial and perivascular factors, mast cell depletion, and metabolic factors such as promotion of dyslipidemia and impaired glucose metabolism are thought to play a role. We present a case of a patient with chronic myelogenous leukemia (CML) treated with nilotinib who developed intracranial atherosclerosis leading to acute onset of stroke. Our patient had no cardiovascular risk factors prior to treatment with nilotinib and developed accelerated atheromatous cerebrovascular disease with severe left middle cerebral artery (MCA) stenosis. These findings suggest that nilotinib may be associated with the development of intracranial atherosclerotic disease (ICAD) independently of any preexisting vascular risk factors leading to acute stroke. Clinicians should have increased awareness of the association between nilotinib and the development of progressive atheromatous disease and vascular adverse events including PAOD, CAD, and CVD. In certain patients, these events can be severe and life threatening. Thus, screening for vascular risk factors including CVD prior to starting nilotinib and close follow up during treatment is crucial.


Assuntos
Antineoplásicos/efeitos adversos , Infarto da Artéria Cerebral Média/etiologia , Arteriosclerose Intracraniana/induzido quimicamente , AVC Isquêmico/etiologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Estado Funcional , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/terapia , Arteriosclerose Intracraniana/diagnóstico por imagem , Arteriosclerose Intracraniana/terapia , AVC Isquêmico/diagnóstico por imagem , AVC Isquêmico/terapia , Masculino , Pessoa de Meia-Idade , Recuperação de Função Fisiológica , Fatores de Risco , Resultado do Tratamento
20.
Lancet Respir Med ; 9(9): 957-968, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34147142

RESUMO

BACKGROUND: The major complication of COVID-19 is hypoxaemic respiratory failure from capillary leak and alveolar oedema. Experimental and early clinical data suggest that the tyrosine-kinase inhibitor imatinib reverses pulmonary capillary leak. METHODS: This randomised, double-blind, placebo-controlled, clinical trial was done at 13 academic and non-academic teaching hospitals in the Netherlands. Hospitalised patients (aged ≥18 years) with COVID-19, as confirmed by an RT-PCR test for SARS-CoV-2, requiring supplemental oxygen to maintain a peripheral oxygen saturation of greater than 94% were eligible. Patients were excluded if they had severe pre-existing pulmonary disease, had pre-existing heart failure, had undergone active treatment of a haematological or non-haematological malignancy in the previous 12 months, had cytopenia, or were receiving concomitant treatment with medication known to strongly interact with imatinib. Patients were randomly assigned (1:1) to receive either oral imatinib, given as a loading dose of 800 mg on day 0 followed by 400 mg daily on days 1-9, or placebo. Randomisation was done with a computer-based clinical data management platform with variable block sizes (containing two, four, or six patients), stratified by study site. The primary outcome was time to discontinuation of mechanical ventilation and supplemental oxygen for more than 48 consecutive hours, while being alive during a 28-day period. Secondary outcomes included safety, mortality at 28 days, and the need for invasive mechanical ventilation. All efficacy and safety analyses were done in all randomised patients who had received at least one dose of study medication (modified intention-to-treat population). This study is registered with the EU Clinical Trials Register (EudraCT 2020-001236-10). FINDINGS: Between March 31, 2020, and Jan 4, 2021, 805 patients were screened, of whom 400 were eligible and randomly assigned to the imatinib group (n=204) or the placebo group (n=196). A total of 385 (96%) patients (median age 64 years [IQR 56-73]) received at least one dose of study medication and were included in the modified intention-to-treat population. Time to discontinuation of ventilation and supplemental oxygen for more than 48 h was not significantly different between the two groups (unadjusted hazard ratio [HR] 0·95 [95% CI 0·76-1·20]). At day 28, 15 (8%) of 197 patients had died in the imatinib group compared with 27 (14%) of 188 patients in the placebo group (unadjusted HR 0·51 [0·27-0·95]). After adjusting for baseline imbalances between the two groups (sex, obesity, diabetes, and cardiovascular disease) the HR for mortality was 0·52 (95% CI 0·26-1·05). The HR for mechanical ventilation in the imatinib group compared with the placebo group was 1·07 (0·63-1·80; p=0·81). The median duration of invasive mechanical ventilation was 7 days (IQR 3-13) in the imatinib group compared with 12 days (6-20) in the placebo group (p=0·0080). 91 (46%) of 197 patients in the imatinib group and 82 (44%) of 188 patients in the placebo group had at least one grade 3 or higher adverse event. The safety evaluation revealed no imatinib-associated adverse events. INTERPRETATION: The study failed to meet its primary outcome, as imatinib did not reduce the time to discontinuation of ventilation and supplemental oxygen for more than 48 consecutive hours in patients with COVID-19 requiring supplemental oxygen. The observed effects on survival (although attenuated after adjustment for baseline imbalances) and duration of mechanical ventilation suggest that imatinib might confer clinical benefit in hospitalised patients with COVID-19, but further studies are required to validate these findings. FUNDING: Amsterdam Medical Center Foundation, Nederlandse Organisatie voor Wetenschappelijk Onderzoek/ZonMW, and the European Union Innovative Medicines Initiative 2.


Assuntos
COVID-19/terapia , Mesilato de Imatinib/administração & dosagem , Inibidores de Proteínas Quinases/administração & dosagem , Respiração Artificial/estatística & dados numéricos , Insuficiência Respiratória/terapia , Idoso , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/virologia , Permeabilidade Capilar/efeitos dos fármacos , Terapia Combinada/efeitos adversos , Terapia Combinada/métodos , Método Duplo-Cego , Feminino , Humanos , Mesilato de Imatinib/efeitos adversos , Masculino , Pessoa de Meia-Idade , Países Baixos , Oxigênio/administração & dosagem , Placebos/administração & dosagem , Placebos/efeitos adversos , Inibidores de Proteínas Quinases/efeitos adversos , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/virologia , SARS-CoV-2/isolamento & purificação , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
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