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1.
Leukemia ; 32(4): 960-970, 2018 04.
Artículo en Inglés | MEDLINE | ID: mdl-28972595

RESUMEN

Ibrutinib, a covalent inhibitor of Bruton Tyrosine Kinase (BTK), is approved for treatment of patients with relapsed/refractory or treatment-naïve chronic lymphocytic leukemia (CLL). Besides directly inhibiting BTK, ibrutinib possesses immunomodulatory properties through targeting multiple signaling pathways. Understanding how this ancillary property of ibrutinib modifies the CLL microenvironment is crucial for further exploration of immune responses in this disease and devising future combination therapies. Here, we investigated the mechanisms underlying the immunomodulatory properties of ibrutinib. In peripheral blood samples collected prospectively from CLL patients treated with ibrutinib monotherapy, we observed selective and durable downregulation of PD-L1 on CLL cells by 3 months post-treatment. Further analysis showed that this effect was mediated through inhibition of the constitutively active signal transducer and activator of transcription 3 (STAT3) in CLL cells. Similar downregulation of PD-1 was observed in CD4+ and CD8+ T cells. We also demonstrated reduced interleukin (IL)-10 production by CLL cells in patients receiving ibrutinib, which was also linked to suppression of STAT3 phosphorylation. Taken together, these findings provide a mechanistic basis for immunomodulation by ibrutinib through inhibition of the STAT3 pathway, critical in inducing and sustaining tumor immune tolerance. The data also merit testing of combination treatments combining ibrutinib with agents capable of augmenting its immunomodulatory effects.


Asunto(s)
Linfocitos B Reguladores/efectos de los fármacos , Antígeno B7-H1/metabolismo , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Receptor de Muerte Celular Programada 1/metabolismo , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Factor de Transcripción STAT3/metabolismo , Microambiente Tumoral/efectos de los fármacos , Adenina/análogos & derivados , Anciano , Linfocitos B Reguladores/metabolismo , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Femenino , Humanos , Tolerancia Inmunológica/efectos de los fármacos , Inmunosupresores/uso terapéutico , Leucemia Linfocítica Crónica de Células B/metabolismo , Masculino , Persona de Mediana Edad , Piperidinas , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Tirosina Quinasas/metabolismo , Transducción de Señal/efectos de los fármacos
3.
Bone Marrow Transplant ; 50(9): 1187-94, 2015 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-26030050

RESUMEN

In allo-stem cell transplantation (SCT), it is unclear whether donor-specific anti-HLA Abs (DSAs) can actually mediate graft rejection or if they are simply surrogate markers for the cellular immunity that causes graft rejection. Here, we first analyzed a case of cord blood allograft rejection in which DSA and cytotoxic T lymphocyte (CTL) specific for donor HLA-B*54:01 were detected at the time of graft rejection. Both the DSA and CTL inhibited colony formation by unrelated bone marrow mononuclear cells sharing HLA-B*54:01, suggesting that the humoral and cellular immune responses were involved in the graft rejection. Interestingly, the DSA and CTL were also detected in cryopreserved pre-transplant patient blood, raising a hypothesis that the presence of anti-HLA Abs could be an indicator for corresponding HLA-specific T cells. We then evaluated the existence of HLA-specific CD8(+) T cells in other patient blood specimens having anti-HLA class I Abs. Interferon-γ enzyme-linked immunospot assays clearly confirmed the existence of corresponding HLA-specific T-cell precursors in three of seven patients with anti-HLA Abs. In conclusion, our data demonstrate that integrated humoral and cellular immunity recognizing the same alloantigen of the donor can mediate graft rejection in DSA-positive patients undergoing HLA-mismatched allo-SCT. Further studies generalizing our observation are warranted.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Trasplante de Células Madre de Sangre del Cordón Umbilical , Rechazo de Injerto/inmunología , Antígenos HLA-B/inmunología , Inmunidad Celular , Inmunidad Humoral , Leucemia Mieloide Aguda , Aloinjertos , Linfocitos T CD8-positivos/patología , Rechazo de Injerto/patología , Humanos , Leucemia Mieloide Aguda/inmunología , Leucemia Mieloide Aguda/patología , Leucemia Mieloide Aguda/terapia , Masculino , Persona de Mediana Edad
4.
Bone Marrow Transplant ; 48(1): 56-62, 2013 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-22705800

RESUMEN

Allogeneic hematopoietic SCT (allo-HCT) from matched sibling donor (MSD) is recommended for younger patients with intermediate cytogenetic risk AML in first CR (CR1), whereas the role of alternative donor transplants in these patients is unknown. We retrospectively analyzed 605 patients with intermediate-risk AML, who received myeloablative allo-HCT in CR1. The 4-year OS for MSD (n=290) and matched unrelated donor (MUD; n=141) was 65% and 68% (P=0.50), respectively. In multivariate analysis, MUD had a similar risk of overall mortality as MSD (hazard ratio=0.90; 95% confidence interval, 0.62-1.30; P=0.58), whereas older age, female donor/male recipient (FDMR) combination, and requiring more than one course of induction chemotherapy to achieve CR1 were poor prognostic factors for OS. Thus, OS after MUD HCT with sex combinations other than FDMR was significantly higher than that after MSD HCT from female donors to male recipients (4-year OS 72% versus 55%, P=0.04). These results suggest that HCT, not only from MSD, but also from MUD, should be considered in younger patients with intermediate-risk AML in CR1, and that the donor-recipient sex combination is more important than the donor type in donor selection.


Asunto(s)
Aberraciones Cromosómicas , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Leucemia Mieloide Aguda/terapia , Adolescente , Adulto , Factores de Edad , Donantes de Sangre , Trasplante de Médula Ósea/efectos adversos , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Humanos , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Inducción de Remisión , Estudios Retrospectivos , Caracteres Sexuales , Hermanos , Análisis de Supervivencia , Donantes de Tejidos , Trasplante Homólogo , Adulto Joven
5.
Bone Marrow Transplant ; 47(3): 387-94, 2012 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-21499316

RESUMEN

The effects of macrophage activation on the outcome of allogeneic hematopoietic SCT (allo-HSCT) have yet to be fully examined. A total of 70 adult patients who received a first allo-HSCT for hematological diseases were studied. We counted the number of hemophagocytic cells in BM clot sections on day +14±7, and analyzed its impact on subsequent outcome. In all, 23 patients were diagnosed as having increased numbers of hemophagocytic cells (HP group), whereas 47 were not (non-HP group). The HP group was not associated with an increased incidence of acute or chronic GVHD, but was associated with worse hematopoietic recovery than the non-HP group. The 2-year OS for the HP group and the non-HP group was 30 and 65% (P<0.01), respectively, and 2-year non-relapse mortality was 48% and 27% (P<0.01), respectively. Multivariate analysis confirmed that the HP group was associated with a lower OS (hazard ratio (HR)=2.3; 95% confidence interval (CI), 1.0-5.4; P=0.048) and higher non-relapse mortality (HR=4.0; 95% CI, 1.6-9.9; P<0.01). The HP group had higher incidences of death due to graft failure (P<0.01) and endothelial complications, such as sinusoidal obstruction syndrome and transplant-associated microangiopathy (P=0.01). Macrophage activation is a previously unrecognized complication with negative impact on outcome of allo-HSCT.


Asunto(s)
Trasplante de Células Madre Hematopoyéticas/métodos , Sistema Hematopoyético , Enfermedad Aguda , Adolescente , Adulto , Humanos , Activación de Macrófagos , Persona de Mediana Edad , Análisis Multivariante , Fagocitosis , Recurrencia , Acondicionamiento Pretrasplante , Trasplante Homólogo/métodos , Resultado del Tratamiento
6.
Ann Oncol ; 22(8): 1865-71, 2011 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-21289367

RESUMEN

BACKGROUND: Because of the less graft-facilitating effect by bone marrow (BM), we need to assess a dosage of conditioning more accurately particularly in combination with reduced-intensity conditioning. Thus we examined that modified continual reassessment method (mCRM) is applicable for deciding appropriate conditioning of allogeneic BM transplantation. PATIENTS AND METHODS: The conditioning regimen consisted of i.v. fludarabine (125 mg/m2) plus an examination dose of i.v. melphalan. The primary endpoint was a donor-type T-cell chimerism at day 28 with successful engraftment defined as >90% donor cells. Five patients per dose level were planned to be accrued and chimerism data were used to determine the next dose. RESULTS: Seventeen patients were enrolled at doses between 130 and 160 mg/m2. The dose was changed from 160 to 130 mg/m(2) (second level) after five full-donor chimerisms. With one patient of 0% chimera in the second level, the dose was increased to 135 mg/m2 (third level). Following five full-donor chimerisms in the third level, the study was complete as projected. CONCLUSIONS: mCRM was shown to be a relevant method for dose-finding of conditioning regimen. The melphalan dose of 135 mg/m2 was determined as the recommended phase II dose to induce initial full-donor chimerism.


Asunto(s)
Trasplante de Médula Ósea , Quimerismo/efectos de los fármacos , Neoplasias Hematológicas/cirugía , Melfalán/administración & dosificación , Agonistas Mieloablativos/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Vidarabina/análogos & derivados , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Masculino , Persona de Mediana Edad , Linfocitos T/efectos de los fármacos , Donantes de Tejidos , Trasplante Homólogo , Vidarabina/administración & dosificación
7.
Bone Marrow Transplant ; 46(11): 1444-9, 2011 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-21170090

RESUMEN

CTLA-4 is a negative regulator of activated T cells and the association of CTLA-4 polymorphisms with autoimmune diseases and transplant outcome has been reported. We evaluated the effect of donor CTLA-4 polymorphisms on outcome after allogeneic hematopoietic SCT (HSCT). We analyzed 147 Japanese HLA-matched sibling recipients and their donors who had undergone allogeneic HSCT. Genotyping of three single-nucleotide polymorphisms in CTLA-4 (-318, +49, CT60) was performed using TaqMan-PCR. According to the international HapMap database, only these three CTLA-4 haplotypes, classified as C-G-G, C-A-A and T-A-G, are present in the Japanese population. In this study, percentage expression of the C-G-G, C-A-A and T-A-G haplotypes was 59.5, 30.6 and 9.9%, respectively. Recipients of the C-A-A haplotype donor showed a significantly lower risk of relapse (HR: 0.54, 95% CI: 0.30-0.97, P=0.040) and a trend toward higher OS (HR: 0.61, 95% CI: 0.36-1.0, P=0.054) than did recipients of a donor without the C-A-A haplotype. The presence or absence of the C-A-A haplotype did not affect GVHD or non-relapse mortality. As the presence of the C-A-A haplotype reduced relapse risk and improved survival after allogeneic HSCT, this CTLA-4 haplotype may provide useful information for donor selection.


Asunto(s)
Antígeno CTLA-4/genética , Trasplante de Células Madre Hematopoyéticas , Adolescente , Adulto , Pueblo Asiatico/genética , Femenino , Frecuencia de los Genes , Enfermedad Injerto contra Huésped/prevención & control , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Recurrencia , Hermanos , Trasplante Homólogo/efectos adversos , Resultado del Tratamiento
8.
Bone Marrow Transplant ; 45(2): 371-7, 2010 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-19525984

RESUMEN

The prognostic significance of eosinophilia after allogeneic hematopoietic SCT (HSCT) and the relationship between eosinophilia and acute GVHD are not well studied. We retrospectively analyzed 201 adult patients who underwent their first allogeneic HSCT. Seventy-three (36%) patients developed eosinophilia within the first 100 days after HSCT. Eosinophilia was observed more frequently among those patients with acute GVHD than those without it (48 vs 25%, P=0.009). However, it was associated with milder acute GVHD and lower incidence of gut and liver acute GVHD. Among patients with acute GVHD, the 3-year OS for patients with and without eosinophilia was 63.4 and 47.2% (P=0.02), respectively, and 3-year nonrelapse mortality (NRM) was 20.2 and 37.5% (P=0.01), respectively. Multivariate analysis confirmed that eosinophilia was associated with a better OS (P=0.03) and lower NRM (P=0.046) in patients with acute GVHD, whereas it was not associated with a higher relapse rate (P=0.45). In contrast, eosinophilia was not associated with outcomes in those patients without acute GVHD. In conclusion, eosinophilia was associated with milder acute GVHD and better prognosis among patients with acute GVHD. The pathophysiology behind eosinophilia after allogeneic HSCT remains to be investigated.


Asunto(s)
Eosinofilia/complicaciones , Enfermedad Injerto contra Huésped/mortalidad , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Aguda , Adolescente , Adulto , Anciano , Eosinofilia/etiología , Eosinofilia/mortalidad , Femenino , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Resultado del Tratamiento
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