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Influence of single nucleotide polymorphisms (SNPs) of HLA-DRB1 gene on outcomes of hematopoietic stem cell transplantation for sickle cell disease

Hematopoietic stem cell transplantation (HSCT) is, to date, the only curative therapy for sickle cell disease (SCD). It is now well known that patients transplanted with an HLA identical sibling donor have an overall survival (OS) between 92% and 94% and an event free survival event (EFS) between 84% and 92% (1,2,3).

The lack of an HLA identical donor is one of the several obstacles preventing a widespread application of HSCT for SCD.

In order to increase the number of sickle cell patients likely to benefit from HSCT, the possibility of using other sources of stem cells has been explored, in particular using: (i) unrelated donors ( marrow bone (BM), adult peripheral blood (PB) or cord blood (CB)), or (ii) haploidentical related donors.

The results of transplantations from unrelated donors for sickle cell disease have been recently described (4-9), revealing that the high toxicity linked to conditioning regimen and to chronic graft versus host disease (GvHD) are concerning factors in the setting of  HSCT for these patients.

Transplantation outcomes vary depending on the clinical characteristics of the patient, the type of donor and the transplant procedure itself. So far, strategies to improve transplantation outcomes include better disease control of patient's, the use of less intensive treatment protocols with decreased toxicity, and a search for the best HLA identity among donor and recipient in order to reduce the risk of GvHD (10-12). The greater the number of differences between patient and donor HLA, the higher the risk of post-transplant mortality, especially for specific regions of the major histocompatibility complex (MHC).

Recently, in the United States, for certain oncological diseases, the analysis of the distribution of nucleotide variants (SNPs, single nucleotide polymorphisms) localized in the HLA-DRB1 gene allowed to show associations between certain genotypes and the risk of morbidity and mortality (13).

The analysis of these SNPs allowed identifying associations predictive of unfavorable transplant outcomes. Petersdorf et al demonstrated that the presence of the HLA-DRB1 alleles of the patient with a FEY motif at residues 26/28/30 in the HLA-DRB1 antigen presentation pocket, was associated with an increased risk of mortality after non-HLA identical unrelated donor transplantations (13).

The analysis of the ethno-geographic distribution of the FEY motif showed that its frequency was higher among African-Americans and Hispanics compared to Caucasian populations; this means that patients’ HLA germline can be responsible for differences in survival in these populations. Ethnic differences in survival have been identified for some cancers, with African Americans having shorter overall survival compared to whites in many solid tumors. The reasons are yet to be defined, but they include socio-economic and cultural factors, cancer biology, difference in intensity of treatment, pharmacogenetics and co-morbidities (14). However, the effect of ethnicity on HSCT outcomes remains controversial and merits further evaluations (14-16).

This retrospective study aims to categorize the HLA-DRB1 alleles of sickle cell patients transplanted in Europe according to the FEY motif (residues 26/28/30 of the HLA-DRB1 peptide binding region) in order to (i) analyze the prevalence of this motif, (ii) assess its potential impact on transplantation related mortality in comparison with the other antigenic motifs present at the same position (FDY or FDH).

HLA data from approximately 500 sickle cell patients transplanted in an EBMT center from an HLA-identical sibling donor will be collected, along with patient clinical characteristics, donor characteristics, details of the transplantation protocol and HSCT outcome. Concerning the outcomes, we will focus more specifically on mortality, but also on rejection, acute and chronic GVHD, chimerism and post-HSCT infections.

HLA data from approximately 70 patients, transplanted from an unrelated donor, will be collected, along with patient clinical characteristics and transplantation outcomes. The patient / donor HLA discrepancies will be characterized and in particular, in-depth studies on the variations of HLA-DRB1 in the germline will be carried out.

The main objective of this study will be to analyze the risk of mortality linked to the FEY motif in sickle cell patients who have undergone a HSCT.

The secondary objectives of the study will be to demonstrate whether the FEY motif is also linked to the risk of rejection, acute or chronic GvHD, chimerism and infections.

The incidence of this pattern will be analyzed to demonstrate its prevalence in patients of African descent.

Furthermore, the study will assess whether other motifs in the same position (in the peptide-binding region) are linked to an increased risk of transplantation related mortality.

The results of our study could predict the outcomes of HSCT for SCD patients and, thus, guide doctors on the choice of indications and transplantation methods, adapted to the risk, in order to increase the monitoring of post-transplant complications in patients with higher risk of mortality.

Paediatric Diseases Working Party (PDWP)
Study number:
8417030_4
Type of transplant:
 
Diseases:
 
Short title:
 
Study status:
Preparation of the study
Deadline for data collection:
 
Study design:
 
Primary objective:
The objectives of this study on a European cohort of sickle cell patients are:
1. to assess whether a major risk of transplantation related mortality is linked to the presence of the FEY motif;
2. to demonstrate whether the FEY motif is also linked to an increased risk of rejection, acute or chronic GvHD, chimerism and infections;
3. to evaluate the frequency of the FEY motif on residues 26/28/30 of HLA-DRB1 in sickle cell patients;
4. to assess whether other motifs in the same position (in the peptide-binding region) are linked to an increased risk of transplantation related mortality.
Key inclusion criteria:
INCLUSION CRITERIA
• SCD patients transplanted from an HLA identical sibling or an unrelated donor before December 31st 2019
• Available HLA data for patients and donors in intermediate/ high resolution typing.
Country:
 
Principal investigator:
Eliane Gluckman
Principal investigator email:
 
EBMT Study coordinator:
Arnaud Dalissier