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Blood ; 127(20): 2411-5, 2016 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-26968534

RESUMO

Although agents targeting B-cell receptor signaling have provided practice-changing results in relapsed chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), they require prolonged administration and provide incomplete responses. Given synergistic preclinical activity with phosphatidylinositol 3-kinase δ and spleen tyrosine kinase inhibition, this phase 2 study evaluated the safety and efficacy of the combination of idelalisib and entospletinib. Eligible patients with relapsed or refractory CLL or NHL underwent intrapatient dose escalation with each agent. With a median treatment exposure of 10 weeks, 60% and 36% of patients with CLL or follicular lymphoma, respectively, achieved objective responses. However, the study was terminated early because of treatment-emergent pneumonitis in 18% of patients (severe in 11 of 12 cases). Although most patients recovered with supportive measures and systemic steroids, 2 fatalities occurred and were attributed to treatment-emergent pneumonitis. Increases of interferon-γ and interleukins 6, 7, and 8 occurred over time in patients who developed pneumonitis. Future studies of novel combinations should employ conservative designs that incorporate pharmacodynamics/biomarker monitoring. These investigations should also prospectively evaluate plasma cytokine/chemokine levels in an attempt to validate biomarkers predictive of response and toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01796470.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Indazóis/efeitos adversos , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Linfoma não Hodgkin/tratamento farmacológico , Pneumonia/induzido quimicamente , Inibidores de Proteínas Quinases/efeitos adversos , Purinas/efeitos adversos , Pirazinas/efeitos adversos , Quinazolinonas/efeitos adversos , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Citocinas/metabolismo , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Indazóis/administração & dosagem , Leucemia Linfocítica Crônica de Células B/enzimologia , Linfoma não Hodgkin/enzimologia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/antagonistas & inibidores , Inibidores de Proteínas Quinases/administração & dosagem , Purinas/administração & dosagem , Pirazinas/administração & dosagem , Quinazolinonas/administração & dosagem , Quinase Syk/antagonistas & inibidores
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