Investigation of MHC gamma block C4A and C4B polymorphisms in unrelated hematopoietic stem cell transplantation.

BACKGROUND: Immunological life-threatening complications frequently occur in post-hematopoietic stem cell transplantation (HSCT), despite matching recipient and donor (R/D) pairs for classical human leukocyte antigens (HLA). Studies have shown that R/D non-HLA disparities within the major histocompatibility complex (MHC) are associated with adverse effects post-HSCT. METHODS: We investigated the impact of mismatches of single-nucleotide polymorphisms (SNPs) in C4A/C4B genes, for showing the highest diversity in the MHC gamma block, on 238 patients who underwent HLA 10/10 unrelated donor (URD) HSCT. The endpoints were acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD) and mortality. One hundred and twenty-nine R/D pairs had 23 C4-SNPs typed by PCR-SSP (Gamma-Type™v.1.0), and 109 R/D pairs had these 23 SNPs identified by next-generation sequencing (NGS) using the Illumina platform. RESULTS: The percentage of patients who received HSC from HLA 10/10 donors with 1-7 mismatches was 42.9%. The R/D pairs were considered C4mismatched when bearing at least one disparity. These mismatches were not found to be risk factors for aGVHD, cGVHD or mortality after unrelated HSCT when SNPs were analyzed together (matched or mm≥1), independently or according to the percentage of incompatibilities (full match for 23 SNPs; 1-3mm and >3mm). An exception was the association between 1-3 mismatches at the composite of SNPs C13193/T14952/T19588 with the development of aGVHD (P=0.012) and with grades III-IV of this disease (P=0.004). CONCLUSION: Our data are not consistent with the hypothesis that disparities in C4A/C4B SNPs increase the risks of post-HSCT adverse effects for the endpoints investigated in this study.

Investigation of MHC gamma block C4A and C4B polymorphisms in unrelated hematopoietic stem cell transplantation

ABSTRACT Background: Immunological life-threatening complications frequently occur in post-hematopoietic stem cell transplantation (HSCT), despite matching recipient and donor (R/D) pairs for classical human leukocyte antigens (HLA). Studies have shown that R/D non-HLA disparities within the major histocompatibility complex (MHC) are associated with adverse effects post-HSCT. Methods: We investigated the impact of mismatches of single-nucleotide polymorphisms (SNPs) in C4A/C4B genes, for showing the highest diversity in the MHC gamma block, on 238 patients who underwent HLA 10/10 unrelated donor (URD) HSCT. The endpoints were acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD) and mortality. One hundred and twenty-nine R/D pairs had 23 C4-SNPs typed by PCR-SSP (Gamma-Type™v.1.0), and 109 R/D pairs had these 23 SNPs identified by next-generation sequencing (NGS) using the Illumina platform. Results: The percentage of patients who received HSC from HLA 10/10 donors with 1-7 mismatches was 42.9%. The R/D pairs were considered C4 mismatched when bearing at least one disparity. These mismatches were not found to be risk factors for aGVHD, cGVHD or mortality after unrelated HSCT when SNPs were analyzed together (matched or mm ≥ 1), independently or according to the percentage of incompatibilities (full match for 23 SNPs; 1-3 mm and >3 mm). An exception was the association between 1-3 mismatches at the composite of SNPs C13193/T14952/T19588 with the development of aGVHD (P = 0.012) and with grades III-IV of this disease (P = 0.004). Conclusion: Our data are not consistent with the hypothesis that disparities in C4A/C4B SNPs increase the risks of post-HSCT adverse effects for the endpoints investigated in this study.

Tyrosine kinase inhibitors in patients with chronic myelogeneous leukemia: defining the role of social risk factors and non-adherence to treatment / Inhibidores de la tirosin-kinasa en pacientes con leucemia mielógena crónica: definir el papel de los factores de riesgo sociales y la no adherencia al tratamiento

Objective: To assess the role of social risk factors on adherence to tyrosine kinase inhibitors (TKI) therapy in chronic myeloid leukemia (CML) patients. Methods: This is a retrospective study and eligible patients were adults with CML on TKI treatment. Cases of no adherence to treatment were confirmed during pharmacists’ consultation (patient-reported adherence). Baseline characteristics between groups were compared between cases and controls groups. Risk factors identified in bivariate analysis (p<0.2) were included in multivariate model. A qualitative investigation assessed whether such predictors of non-adherence had causal relationship. Results: Of 151 patients with CML consulted by pharmacists, 21% had adherence problems. Despite patients with secondary school (p=0.03), most of investigated social risk factors did not differ between groups. However, by using a qualitative approach, patients’ level of education could not explain low adherence rates behavior. Conclusions: Social determinants of health, herein investigated, were unlikely to predict adherence to treatment. Regression techniques may lead to untrue statements, so future researches should consider investigating the causes, not only the statistical estimates (AU)

Objetivo: Evaluar el papel de los factores de riesgo sociales sobre la adherencia a los inhibidores de la tirosin-kinasa (TKI) en pacientes con leucemia mieloide crónica (CML). Métodos: Este es un estudio retrospectivo y los pacientes elegibles eran adultos con CML a tratamiento con TKI. Los casos de no adherencia se confirmaron durante las consultas farmacéuticas (adherencia reportada por el paciente). Se compararon las características al inicio entre grupos casos y controles. Los factores de riesgos identificados en un análisis bivariado (p<0,2) se incluyeron en un modelo multivariado. La investigación cualitativa evaluó si esos predictores de no adherencia tenían una relación causal. Resultados: De los 151 pacientes con CML consultados por los farmacéuticos, el 21% tenía problemas de adherencia. Excepto los pacientes con educación secundaria (p=0,03), la mayoría de los factores de riesgo sociales no diferían entre grupos. Sin embargo, al usar un abordaje cualitativo, el nivel educacional de los pacientes no pudo explicar los comportamientos de bajas tasas de adherencia. Conclusiones: Los determinantes sociales de salud, aquí estudiados, no fueron capaces de predecir la adherencia al tratamiento. Las técnicas de regresión pueden llevar a afirmaciones irreales, así que la futura investigación debería considerar investigar las causas, y no solo los resultados estadísticos (AU)

Transplante de células-tronco hematopoéticas em crianças e adolescentes com leucemia aguda: experiência de duas instituições brasileiras / Hematopoietic stem cell transplantation in children and adolescents with acute leukemia: experience of two Brazilian institutions

O transplante de células-tronco hematopoéticas (TCTH) é o tratamento de escolha para leucemias agudas de alto risco. Apesar da melhora na sobrevida destes pacientes, a recidiva continua sendo a maior causa de óbito pós-transplante de células-tronco hematopoéticas. O objetivo deste trabalho foi analisar os resultados dos transplantes realizados em crianças com leucemia aguda em duas instituições brasileiras. Realizou-se estudo retrospectivo de 208 pacientes transplantados entre 1990-2007. Mediana de idade: 9 anos; 119 pacientes com leucemia linfoide aguda (LLA) e 89 com leucemia mieloide aguda (LMA). Doença precoce: CR1 e CR2. ... 14/195 pacientes tiveram falha primária de pega (8 por cento). Não houve diferença na sobrevida global e sobrevida livre de recaída entre pacientes com leucemia linfoide aguda e leucemia mieloide aguda, entre transplantes aparentados e não aparentados, tampouco entre as fontes de células utilizadas. O desenvolvimento da doença do enxerto contra hospedeiro (DECH) aguda ou crônica também não influenciou a sobrevida global e sobrevida livre de recaída. Pacientes com leucemia linfoide aguda condicionados com irradiação corporal total (TBI) apresentaram melhor sobrevida global e sobrevida livre de recaída (p<0,001). Cento e dezoito pacientes morreram entre 1-1.654 dias pós-transplante de células-tronco hematopoéticas (M:160). Mortalidade relacionada a transplante (MRT) (dia+100): 16 por cento. Incidência cumulativa de recaída: 40 por cento (3 anos). Pacientes com doença avançada tiveram menor sobrevida global e sobrevida livre de recaída (três anos)(p<0,001). Na análise multivariada, o status da doença foi o principal fator associado ao aumento da sobrevida global e sobrevida livre de recaída. Nossos resultados mostram que é possível se atingir uma boa sobrevida para pacientes com doença precoce e também mostram a baixa eficácia naqueles com doença avançada.

Hematopoietic Stem Cell transplantation (HSCT) is the treatment of choice for patients with high-risk leukemia. In spite of this, relapse remains a major cause of death of these patients. Our objective was to analyze the outcomes of patients with acute leukemia submitted to hematopoietic stem cell transplantation in two Brazilian institutions... There were no differences in the overall survival and event free survival between patients with acute lymphocytic leukemia and acute myeloid leukemia, between sources of cells used or between those who developed acute or chronic graft-versus-host disease (GVHD). When comparing transplants from related and unrelated donors, there was no difference in the overall survival. Patients with acute lymphocytic leukemia receiving the total body irradiation (TBI) conditioning regimen had better overall survival and event free survival (p<0.001). One hundred and eighteen patients died between 0 and 1654 days after hematopoietic stem cell transplantation (M: 160 days). Transplantation-related-mortality (TRM) at D+100 was 16 percent and cumulative incidence of relapse was 40 percent (3 years). Patients with advanced disease had lower 3-year overall survival and event free survival (p<0.001). Multivariate analysis showed that disease status was the most significant factor associated with higher event free survival and overall survival . Our results show that children and adolescents transplanted with early disease can achieve considerable overall survival and also highlights the inefficacy of hematopoietic stem cell transplantation for patients with advanced disease.