RESUMO
There is increasing evidence that endothelial dysfunction is involved in refractoriness of acute GvHD (aGvHD). Here we investigated the hypothesis that another endothelial complication, transplant-associated thrombotic microangiopathy (TMA), contributes to the pathogenesis of aGvHD refractoriness. TMA was retrospectively assessed in 771 patients after allogeneic stem cell transplantation (alloSCT). Incidences of TMA and refractory aGvHD were correlated with biomarkers of endothelial damage obtained before alloSCT for patients receiving or not receiving statin-based endothelial prophylaxis (SEP). Diagnostic criteria for TMA and refractory aGvHD were met by 41 (5.3%) and 76 (10%) patients, respectively. TMA was overrepresented in patients with refractory aGvHD (45.0 vs 2.3% in all other patients, P<0.001). TMA independently increased mortality. Elevated pretransplant suppressor of tumorigenicity-2 and nitrates along with high-risk variants of the thrombomodulin gene were associated with increased risk of TMA. In contrast, SEP abolished the unfavorable outcome predicted by pretransplant biomarkers on TMA risk. Patients on SEP had a significantly lower risk of TMA (P=0.001) and refractory aGvHD (P=0.055) in a multivariate multistate model. Our data provide evidence that TMA contributes to the pathogenesis of aGvHD refractoriness. Patients with an increased TMA risk can be identified pretransplant and may benefit from pharmacological endothelium protection.
Assuntos
Endotélio Vascular , Doença Enxerto-Hospedeiro , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Transplante de Células-Tronco , Microangiopatias Trombóticas , Doença Aguda , Adolescente , Adulto , Idoso , Aloenxertos , Intervalo Livre de Doença , Endotélio Vascular/lesões , Endotélio Vascular/metabolismo , Feminino , Seguimentos , Doença Enxerto-Hospedeiro/complicações , Doença Enxerto-Hospedeiro/tratamento farmacológico , Doença Enxerto-Hospedeiro/metabolismo , Doença Enxerto-Hospedeiro/mortalidade , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Taxa de Sobrevida , Microangiopatias Trombóticas/tratamento farmacológico , Microangiopatias Trombóticas/etiologia , Microangiopatias Trombóticas/metabolismo , Microangiopatias Trombóticas/mortalidadeAssuntos
Anticorpos Monoclonais Murinos/uso terapêutico , Antineoplásicos/uso terapêutico , Linfoma de Célula do Manto/tratamento farmacológico , Transplante de Células-Tronco , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Humanos , Linfoma de Célula do Manto/patologia , Masculino , Pessoa de Meia-Idade , RituximabRESUMO
Overexpression of BCR-ABL and P-glycoprotein (Pgp) are two of the known mechanisms of imatinib resistance. As combination therapy may allow to overcome drug resistance, we investigated the effect of combination treatment with imatinib and 17-allylamino-17-demethoxygeldanamycin (17-AAG), a heat-shock protein 90 (Hsp90) inhibitor, on different imatinib-sensitive and imatinib-resistant CML cell lines. In imatinib-sensitive cells, combination index (CI) values obtained using the method of Chou and Talalay indicated additive (CI=1) or marginally antagonistic (CI>1) effects following simultaneous treatment with imatinib and 17-AAG. In imatinib-resistant cells both drugs acted synergistically (CI<1). In primary chronic-phase CML cells additive or synergistic effects of the combination of imatinib plus 17-AAG were discernible. Annexin V/propidium iodide staining showed that the activity of imatinib plus 17-AAG is mediated by apoptosis. Combination treatment with imatinib plus 17-AAG was more effective in reducing the BCR-ABL protein level than 17-AAG alone. Monotherapy with 17-AAG decreased P-glycoprotein activity, which may increase intracellular imatinib levels and contribute to the sensitization of CML cells to imatinib. The results suggest that combination of imatinib and 17-AAG may be useful to overcome imatinib resistance in a clinical setting.
