RESUMEN
CpG oligodeoxynucleotides (CpG) and IL-21 are two promising agents for the treatment of B-cell chronic lymphocytic leukemia (B-CLL). Recently, we reported that the combination of CpG and IL-21 (CpG/IL-21) can induce granzyme B (GrB)-dependent apoptosis in B-CLL cells. Here, we demonstrate that treatment of B-CLL cells with CpG and IL-21 results in the development of antigen-presenting cell (APC)-like cells with cytotoxic features. These properties eventually give rise to B-CLL cell apoptosis, independently of their cytogenetic phenotype, whereas normal B-cell survival is not negatively affected by CpG/IL-21. APC- and CTL-typical molecules found to be up-regulated in CpG/IL-21-stimulated B-CLL cells include GrB, perforin, T-bet, monokine-induced by IFN-γ and IFN-γ-inducible protein 10 (IP-10), as well as molecules important for cell adhesion, antigen cross-presentation and costimulation. Also induced are molecules involved in GrB induction, trafficking and processing, whereas the GrB inhibitor Serpin B9 [formerly proteinase inhibitor-9 (PI-9)] is down-modulated by CpG/IL-21. In conclusion, CpG/IL-21-stimulated B-CLL cells acquire features that are reminiscent of killer dendritic cells, and which result in enhanced immunogenicity, cytotoxicity and apoptosis. Our results provide novel insights into the aberrant immune state of B-CLL cells and may establish a basis for the development of an innovative cellular vaccination approach in B-CLL.
Asunto(s)
Células Presentadoras de Antígenos/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Interleucinas/farmacología , Leucemia Linfocítica Crónica de Células B/inmunología , Activación de Linfocitos/efectos de los fármacos , Oligodesoxirribonucleótidos/farmacología , Anciano , Anciano de 80 o más Años , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/patología , Apoptosis/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos B/patología , Quimiocina CXCL10/genética , Quimiocina CXCL10/inmunología , Citotoxicidad Inmunológica/efectos de los fármacos , Femenino , Regulación Leucémica de la Expresión Génica , Granzimas/genética , Granzimas/inmunología , Humanos , Inmunofenotipificación , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Masculino , Persona de Mediana Edad , Perforina/genética , Perforina/inmunología , Cultivo Primario de Células , Proteínas Recombinantes/farmacología , Transducción de Señal , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/inmunologíaRESUMEN
The aim of this retrospective study was to investigate the safety and efficacy of allogeneic hematopoietic cell transplantation (alloHCT) in patients pre-treated with ibrutinib. Eligible were patients aged >18 years allotransplanted for chronic lymphocytic leukemia (CLL) or mantle cell lymphoma (MCL) after prior exposure to ibrutinib who were registered with the EBMT registry. Seventy patients (CLL 48, MCL 22) were included. At the time of alloHCT, 73% of the patients were ibrutinib responsive. All patients except one engrafted, and acute GVHD grade 2-4 (3-4) was observed in 49% (12%) of 68 evaluable patients. The cumulative incidence of chronic GVHD was 54% 1 year after transplant. In the CLL group, 12-month non-relapse mortality, relapse incidence (RI), progression-free survival (PFS), and overall survival (OS) were 10, 30, 60, and 72%, respectively, and in the MCL group 5, 19, 76, and 86%, respectively. Pre-transplant ibrutinib failure and poor performance status predicted inferior RI, PFS and OS in the CLL group. In conclusion, ibrutinib does not affect the safety of a subsequent alloHCT. While the relatively high post-transplant relapse risk in ibrutinib-exposed patients with CLL deserves further study, in patients with MCL consolidating disease responses to ibrutinib with alloHCT seems to be a promising option.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Leucemia Linfocítica Crónica de Células B , Linfoma de Células del Manto , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Adenina/análogos & derivados , Adulto , Anciano , Aloinjertos , Supervivencia sin Enfermedad , Femenino , Enfermedad Injerto contra Huésped/mortalidad , Enfermedad Injerto contra Huésped/prevención & control , Humanos , Leucemia Linfocítica Crónica de Células B/mortalidad , Leucemia Linfocítica Crónica de Células B/terapia , Linfoma de Células del Manto/mortalidad , Linfoma de Células del Manto/terapia , Masculino , Persona de Mediana Edad , Piperidinas , Tasa de SupervivenciaRESUMEN
This study was planned as a phase 3 trial to investigate low-dose fludarabine with or without darbepoetin alfa in older patients with previously untreated or treated chronic lymphocytic leukemia (CLL) and comorbidity. Due to slow recruitment, the study was terminated prematurely after accrual of 97 patients who, on average, were 74 years old and had a cumulative illness rating scale (CIRS) total score of 5. We report toxicity and efficacy of the study treatment. Grade 3-5 neutropenia and infection were observed in 25% and 10% of patients, respectively. Response was seen in 73% (5% complete remissions). Median event-free and overall survival was 12.2 and 44.8 months, respectively. No differences in outcome were found for patients treated with versus without darbepoetin alfa. In subjects with progressive/recurrent CLL during or after study treatment, overall survival was similar for patients receiving chemotherapy versus chemoimmunotherapy as salvage treatment.