RESUMEN
T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive T-lymphoid malignancy usually refractory to current treatment strategies and associated with short overall survival. By applying next-generation functional testing of primary patient-derived lymphoma cells using a library of 106 US Food and Drug Administration (FDA)-approved anticancer drugs or compounds currently in clinical development, we set out to identify novel effective treatments for T-PLL patients. We found that the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax (ABT-199) demonstrated the strongest T-PLL-specific response when comparing individual ex vivo drug response in 86 patients with refractory hematologic malignancies. Mechanistically, responses to venetoclax correlated with protein expression of BCL-2 but not with expression of the BCL-2 family members myeloid cell leukemia 1 (MCL-1) and BCL-XL in lymphoma cells. BCL-2 expression was inversely correlated with the expression of MCL-1. Based on the ex vivo responses, venetoclax treatment was commenced in 2 late-stage refractory T-PLL patients resulting in clinical responses. Our findings demonstrate first evidence of single-agent activity of venetoclax both ex vivo and in humans, offering a novel agent in T-PLL.
Asunto(s)
Antineoplásicos/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas c-bcl-2/antagonistas & inhibidores , Sulfonamidas/uso terapéutico , Adulto , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Resistencia a Antineoplásicos , Femenino , Ensayos Analíticos de Alto Rendimiento , Humanos , Leucemia Prolinfocítica de Células T/diagnóstico , Leucemia Prolinfocítica de Células T/metabolismo , Masculino , Persona de Mediana Edad , Recurrencia , Sulfonamidas/farmacología , Resultado del TratamientoRESUMEN
The International Prognostic Index (IPI) has been used for decades in diffuse large B-cell lymphoma (DLBCL). A retrospective cancer registry analysis in North America showed significantly improved results when an enhanced IPI, the National Comprehensive Cancer Network (NCCN)-IPI was applied. This novel score puts more weight on age and high levels of lactate dehydrogenase (LDH). Nevertheless, it remains unclear if these results can be extrapolated to the general population. This retrospective bi-centre analysis included 499 unselected DLBCL patients who were treated with rituximab and anthracycline-based chemoimmunotherapy between 2004 and 2013. In our cohort, the NCCN-IPI was more accurate in identifying patients at low or high risk, despite older age, and more patients with increased LDH. Nevertheless, a modified scoring of the risk factors was required to more accurately identify elderly patients with a very favourable diagnosis, suggesting an impaired value of the original NCCN-IPI in the elderly. Serum ß2 -microglobulin and albumin were retained as independent prognostic factors for survival in a multivariate analysis. Our data confirm, for the first time, the superior prognostic power of the NCCN-IPI in an unselected, middle-European cohort. We furthermore propose a modified NCCN-IPI for more accurate prognostication in the elderly. Albumin and ß2 -microglobulin levels are likely to add significant information to the NCCN-IPI.