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

Abstract

The EBMT risk score is an established tool successfully used in the prognosis of survival post-HSCT and is applicable for a range of haematological disorders. One of its main advantages is that score generation involves summation of clinical parameters that are available pretransplant. However, the EBMT risk score is recognized as not being optimal. Previous analyses, involving patients with various diagnoses, have shown that non-HLA gene polymorphisms influence outcome after allogeneic HSCT. This study is novel as it focuses only on patients having acute leukaemia (N = 458) and attempts to demonstrate how non-HLA gene polymorphisms can be added to the EBMT risk score in a Cox regression model to improve prognostic ability for overall survival. The results of the study found that three genetic factors improved EBMT risk score. The presence of MAL (rs8177374) allele T in the patient, absence of glucocorticoid receptor haplotype (consisting of rs6198, rs33389 and rs33388) ACT in the patient and absence of heat-shock protein 70-hom (+2437) (rs2227956) allele C in the patient were associated with decreased survival time. When compared to the EBMT risk score, the scores combining EBMT risk score with the genetic factors had an improved correlation with clinical outcome and better separation of risk groups. A bootstrapping technique, involving repeated testing of a model using multiple validation sets, also revealed that the newly proposed model had improved predictive value when compared to the EBMT risk score alone. Results support the view that non-HLA polymorphisms could be useful for pretransplant clinical assessment and provide evidence that polymorphisms in the recipient genotype may influence incoming donor cells, suppressing the initiation of the graft versus leukaemia effect and reducing survival.

Pharmacogenomic markers of glucocorticoid response in the initial phase of remission induction therapy in childhood acute lymphoblastic leukemia

“… 15 Moreover, CTA (rs33389-rs33388-rs6198) haplotype consisting of alleles found to be favorable for GC response on day 8 in our study, was associated with longer survival time in acute leukemia patients who underwent hematopoietic stem cell transplantation. 47 Interestingly however, in our cohort, CAA haplotype was associated with PGR. This result further points out favorable association of rs33389 C and rs6198 A alleles with lower blast count.…”

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

“…The subsequent clinical and genetic score assigned to each patient was shown to have a better predictive value than the EBMT score alone. In a more recent cohort studying acute leukemia transplant patients (181), three polymorphisms, presence of toll-interleukin 1 receptor domain containing adaptor protein ( TIRAP ) (alternatively named MAL ) allele T (rs8177374) in the patient, absence of the glucocorticoid receptor ( GCR ) haplotype (consisting of rs6198, rs33389, and rs33388) ACT in the patient and absence of HSPA1L (or HSP70-hom ) +2437 (rs2227956) allele C in the patient were associated with decreased survival. The subsequent clinical and genetic score assigned to each patient was shown to have a better predictive value than the EBMT score alone.…”