Predicting survival using clinical risk scores and non-HLA immunogenetics

Abstract

Previous studies of non-histocompatibility leukocyte antigen (HLA) gene single-nucleotide polymorphisms (SNPs) on subgroups of patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) revealed an association with transplant outcome. This study further evaluated the association of non-HLA polymorphisms with overall survival in a cohort of 762 HSCT patients using data on 26 polymorphisms in 16 non-HLA genes. When viewed in addition to an already established clinical risk score (EBMT-score), three polymorphisms: rs8177374 in the gene for MyD88-adapter-like (MAL; P = 0.026), rs9340799 in the oestrogen receptor gene (ESR; P = 0.003) and rs1800795 in interleukin-6 (IL-6; P = 0.007) were found to be associated with reduced overall survival, whereas the haplo-genotype (ACC/ACC) in IL-10 was protective (P = 0.02). The addition of these non-HLA polymorphisms in a Cox regression model alongside the EBMT-score improved discrimination between risk groups and increased the level of prediction compared with the EBMT-score alone (gain in prediction capability for EBMT-genetic-score 10.8%). Results also demonstrated how changes in clinical practice through time have altered the effects of non-HLA analysis. The study illustrates the significance of non-HLA genotyping prior to HSCT and the importance of further investigation into non-HLA gene polymorphisms in risk prediction. Bone Marrow Transplantation INTRODUCTIONHaematopoietic stem cell transplantation (HSCT) is the major curative therapy for disorders of the blood and immune system. However, the rate of survival in patients with HSCT has remained at 40-60% for the last two decades, owing to post-transplant complications including infection, GvHD and relapse.Five relevant clinical factors influencing transplantation success in patients with haematological disorders, including CML, ALL and AML, have been identified by the European Group for Blood and Marrow Transplantation (EBMT). These risk factors (EBMT-factors) are patient age, sibling donor/matched unrelated donor (MUD), patient-donor gender combination, stage of disease and time from diagnosis to transplant. A clinical risk score (EMBT-score) utilising the EBMT-factors was proposed in order to aid the prediction and prevention of post-transplant complications.

Impact of genomic risk factors on survival after haematopoietic stem cell transplantation for patients with acute leukaemia

“…Allogeneic haematopoietic stem cell transplantation (HSCT) is the principal curative therapy for disorders of the haematopoietic system, but it is still associated with substantial morbidity and mortality (Copelan, ; Gratwohl et al ., ) with a survival rate of 40–60% (Balavarca et al ., ). Five main clinical factors influencing outcome after HSCT have been established by the European Group for Blood and Marrow Transplantation (EBMT).…”

The influence of glucocorticoid receptor single nucleotide polymorphisms on outcome after haematopoietic stem cell transplantation

“…In recent years several groups, including ourselves, have reported that non‐HLA gene polymorphisms are predictive of outcome in HSCT, Dickinson, Middleton, Rocha, Gluckman, and Holler (). We therefore decided to investigate SNPs in the GR gene, as they have been shown to be involved in the inflammatory process and autoimmune disease, Balavarca et al (), Pearce et al ().…”

Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes

“…Using a statistical analysis that included a bootstrap estimate of prediction error (179, 180), three further SNPs were associated with survival. A protective effect for the IL10 genotype ACC / ACC in the donors was observed, while estrogen receptor 1 ( ESR1 ) rs9340799 in the patient, IL6 rs18000795 in the donors, and TIRAP (or MAL ) rs177374 in the patient were associated with poorer survival (2). The subsequent clinical and genetic score assigned to each patient was shown to have a better predictive value than the EBMT score alone.…”

“…In addition, in a larger heterogeneous cohort, including CML and lymphoma (2), we developed a clinical and genetic score, which included the European Bone Marrow Transplantation (EBMT) Group score. This score incorporates clinical risk factors such as age of the patient and donor; time to transplant and type of transplant (175–178).…”

“…Outcomes such as acute and chronic graft-versus-host disease (aGvHD and cGvHD), relapse, and survival have been shown to be modified by functionally relevant polymorphisms in non-HLA genes that are involved in immune responses (1, 2). Such functional polymorphisms are complicated to pinpoint among other polymorphisms localized near these genes that have no direct effects on gene function.…”