RESUMO
Crovalimab, a novel C5 inhibitor, allows for low-volume, every-4- week, subcutaneous self-administration. COMMODORE 1 (NCT04432584) is a phase 3, global, randomized trial evaluating crovalimab versus eculizumab in C5 inhibitor-experienced patients with paroxysmal nocturnal hemoglobinuria (PNH). Adults with lactate dehydrogenase ≤1.5 × upper limit of normal and receiving approved eculizumab doses for ≥24 weeks were randomized 1:1 to receive crovalimab (weight-based tiered dosing) or continue eculizumab. The original primary study objective was efficacy; however, given the evolving treatment landscape, target recruitment was not met, and all efficacy endpoints became exploratory, with safety as the new primary objective. Exploratory efficacy endpoints included transfusion avoidance, hemolysis control, breakthrough hemolysis, hemoglobin stabilization, FACIT-Fatigue score, and patient preference (crovalimab vs. eculizumab). Eighty-nine patients were randomized (45 to crovalimab; 44 to eculizumab). During the 24-week primary treatment period, adverse events (AEs) occurred in 77% of patients receiving crovalimab and 67% receiving eculizumab. No AEs led to treatment withdrawal or death, and no meningococcal infections occurred. 16% of crovalimab-treated patients had transient immune complex reactions (also known as Type III hypersensitivity events), an expected risk when switching between C5 inhibitors that bind to different C5 epitopes; most were mild/moderate and all resolved without treatment modification. Crovalimab-treated patients had sustained terminal complement activity inhibition, maintained disease control, and 85% preferred crovalimab over eculizumab. Together with phase 3 COMMODORE 2 results in complement inhibitor-naive patients, these data support crovalimab's favorable benefit-risk profile. Crovalimab is a new C5 inhibitor for PNH that is potentially less burdensome than existing therapies for this lifelong disease.
Assuntos
Anticorpos Monoclonais Humanizados , Inativadores do Complemento , Hemoglobinúria Paroxística , Humanos , Hemoglobinúria Paroxística/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Feminino , Masculino , Pessoa de Meia-Idade , Adulto , Inativadores do Complemento/uso terapêutico , Inativadores do Complemento/efeitos adversos , Inativadores do Complemento/administração & dosagem , Idoso , Complemento C5/antagonistas & inibidores , Resultado do TratamentoRESUMO
INTRODUCTION:: In patients with essential thrombocythemia (ET), the vascular complications contribute to morbidity and mortality. To better predict the occurrence of thrombotic events, an International Prognostic Score for Thrombosis in Essential Thrombocythemia (IPSET-thrombosis) has recently been proposed. We present the application of this score and compare its results with the usual classification system. METHOD:: We retrospectively evaluated the characteristics and risk factors for thrombosis of 46 patients with a diagnosis of ET seen in the last 6 years at Faculdade de Medicina do ABC (FMABC). RESULTS:: Thrombosis in the arterial territory was more prevalent than in venous sites. We observed that cardiovascular risk factors (hypertension, hypercholesterolemia, diabetes mellitus, and smoking) were also risk factors for thrombosis (p<0.001). Age over 60 years and presence of JAK2 V617F mutation were not associated with the occurrence of thrombotic events. No patient classified by IPSET-thrombosis as low risk had a thrombotic event. Furthermore, using the IPSET-thrombosis scale, we identified two patients who had thrombotic events during follow-up and were otherwise classified in the low-risk group of the traditional classification. Leukocytosis at diagnosis was significantly associated with arterial thrombosis (p=0.02), while splenomegaly was associated with venous thrombotic events (p=0.01). CONCLUSION:: Cardiovascular risk factors and leukocytosis were directly associated with arterial thrombosis. IPSET-thrombosis appears to be better than the traditional classification at identifying lower risk patients who do not need specific therapy.
Assuntos
Medição de Risco/métodos , Trombocitemia Essencial/complicações , Trombose/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil , Complicações do Diabetes , Feminino , Hospitais Públicos/estatística & dados numéricos , Humanos , Hipertensão/complicações , Janus Quinase 2/genética , Masculino , Pessoa de Meia-Idade , Prognóstico , Valores de Referência , Estudos Retrospectivos , Fatores de Risco , Fumar/efeitos adversos , Trombose/diagnóstico , Adulto JovemRESUMO
Summary Introduction: In patients with essential thrombocythemia (ET), the vascular complications contribute to morbidity and mortality. To better predict the occurrence of thrombotic events, an International Prognostic Score for Thrombosis in Essential Thrombocythemia (IPSET-thrombosis) has recently been proposed. We present the application of this score and compare its results with the usual classification system. Method: We retrospectively evaluated the characteristics and risk factors for thrombosis of 46 patients with a diagnosis of ET seen in the last 6 years at Faculdade de Medicina do ABC (FMABC). Results: Thrombosis in the arterial territory was more prevalent than in venous sites. We observed that cardiovascular risk factors (hypertension, hypercholesterolemia, diabetes mellitus, and smoking) were also risk factors for thrombosis (p<0.001). Age over 60 years and presence of JAK2 V617F mutation were not associated with the occurrence of thrombotic events. No patient classified by IPSET-thrombosis as low risk had a thrombotic event. Furthermore, using the IPSET-thrombosis scale, we identified two patients who had thrombotic events during follow-up and were otherwise classified in the low-risk group of the traditional classification. Leukocytosis at diagnosis was significantly associated with arterial thrombosis (p=0.02), while splenomegaly was associated with venous thrombotic events (p=0.01). Conclusion: Cardiovascular risk factors and leukocytosis were directly associated with arterial thrombosis. IPSET-thrombosis appears to be better than the traditional classification at identifying lower risk patients who do not need specific therapy.
Resumo Introdução: em pacientes com trombocitemia essencial (TE), complicações vasculares contribuem para morbidade e mortalidade. Para melhor predizer a ocorrência de eventos trombóticos, um escore prognóstico internacional de trombose para TE (IPSET-trombose) foi recentemente desenvolvido. Apresentamos aqui a aplicação desse escore e comparamos seus resultados com o sistema de classificação usual. Método: avaliamos retrospectivamente as características e os fatores de risco para trombose em 46 pacientes com diagnóstico de TE que foram atendidos nos últimos 6 anos na Faculdade de Medicina do ABC. Resultados: trombose em território arterial é mais prevalente que em sítio venoso. Observamos que fatores de risco cardiovascular (hipertensão, hipercolesterolemia, diabetes mellitus e tabagismo) foram considerados fatores de risco para trombose (p<0,001). Idade > 60 anos e presença de mutação JAK2 V617F não se associaram à ocorrência de eventos trombóticos. Nenhum paciente classificado como baixo risco pelo IPSET-trombose apresentou evento trombótico. Quando comparado à classificação de risco tradicional, IPSET-trombose foi capaz de identificar dois pacientes que evoluíram com trombose no seguimento e estavam categorizados no grupo de baixo risco. Leucocitose ao diagnóstico foi mais prevalente em pacientes que apresentaram trombose arterial (p=0,02), e esplenomegalia, entre aqueles com evento trombótico venoso (p=0,01). Conclusão: fatores de risco cardiovascular e leucocitose se associaram de forma direta com trombose arterial. IPSET-trombose parece ser melhor que a classificação tradicional na identificação de pacientes de baixo risco que não precisam de terapia específica.
Assuntos
Humanos , Masculino , Feminino , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Adulto Jovem , Trombose/etiologia , Medição de Risco/métodos , Trombocitemia Essencial/complicações , Prognóstico , Valores de Referência , Trombose/diagnóstico , Brasil , Fumar/efeitos adversos , Estudos Retrospectivos , Fatores de Risco , Complicações do Diabetes , Janus Quinase 2/genética , Hospitais Públicos/estatística & dados numéricos , Hipertensão/complicações , Pessoa de Meia-IdadeRESUMO
Novel agents have provided a new foundation for multiple myeloma therapies. When combined with other anti-myeloma agents, these compounds significantly enhance clinical efficacy. High-dose steroids are frequently used in anti-myeloma combination regimens; however, the doses employed are often poorly tolerated, especially in patients with concurrent comorbid conditions. We hypothesized that a steroid-independent combination regimen could be developed without significant compromise of efficacy. The availability of such a regimen will be important for patients whose concurrent ailments make them poor candidates for steroid containing anti-myeloma regimens. A phase II single institute, non-randomized clinical trial was conducted to investigate a novel steroid-free three-drug combination of bortezomib (V), pegylated liposomal doxorubicin (D), and thalidomide (T), the VDT regimen. Forty-three newly diagnosed multiple myeloma patients requiring treatment were enrolled on this study. The overall response rate and complete response (CR) + near complete response (nCR) rate was 78% and 35%, respectively. Median time to progression was 29.5 months. Fatigue, rash, neuropathy, constipation and infections were the most common side effects. We concluded that VDT is a tolerable and an effective regimen capable of inducing high response rates and can be employed in patients considered to be poor candidates for steroid-based treatment regimens.
O mieloma mútliplo representa a segunda neoplasia hematológica mais frequente, cuja cura ainda permanece distante. A maioria dos esquemas para tratamento utiliza doses elevadas de corticoides que são altamente eficazes no controle da doença. No entanto, trata-se de doença que acomete preferencialmente idosos população sujeita a apresentar comorbidades que limitam o uso dos esteroides.Esse estudo avalia um esquema de tratamento que utiliza drogas sabidamente efetivas contra o mieloma bortezomibe, doxorrubicina lipossomal e talidomida porém sem o uso associado de corticoide. Apesar de se tratar de estudo com número reduzido de pacientes apenas 40 avaliados , a taxa de resposta global (78%) e as taxas de resposta completa e quase completa (35%), além da média de tempo livre de progressão da doença (29,5 meses), são consideráveis. Um ponto a ser destacado é que a associação de duas drogas potencialmente neurotóxicas bortezomibe e talidomida não aumentou significativamente a incidência de neuropatia.