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ARTICLE
HLA Matching Status Among Patients Requiring Hematopoietic Stem Cell Transplant: The Need for a National and Regional Stem Cell Bank

Objectives: Hematopoietic stem cell transplant is a strategic treatment for many malignant and nonmalignant blood diseases. Finding an HLA-matched donor is a requirement for a successful transplantation. The aim of the current study was to explore indications, demographics, and HLA patient-donor matching status among Bahraini patients requiring this transplant.

Materials and Methods: Records of 100 patients who required hematopoietic stem cell transplant at the Salmaniya Medical Complex, Ministry of Health tertiary hospital in Bahrain were retrospectively studied. Data were analyzed and compared with data from similar studies.

Results: For the 100 patients, 294 potential donors were HLA typed. Indications for transplant included malignant diseases (50%) and hereditary blood diseases (50%). For those in the 0- to 5-year age group, the main indication was acute lymphoblastic leukemia, whereas acute myeloid leukemia was the main indication for those who were >5 years old. Sex distribution showed that 55% of patients were males and 45% were females. With regard to age distribution, 22% of patients were less than 5 years old, 30% were 5 to 17 years old, and 48% were 18 years and older. Patient-donor HLA matching status was 50% HLA identical, 32% haploidentical, 15% more than haploidentical, and 3% less than haploidentical. The number of potential donors per patient ranged from 1 to 11 typed for each patient (average of 2.94 ± 1.86).

Conclusions: The rate of finding a family member as HLA-matched donor for hematopoietic stem cell transplant in our study on Bahraini patients was higher than reports in western countries yet close to other reports from countries with almost similar family sizes. We recommend forming a national Bahrain registry in addition to a regional Eastern Mediterranean stem cell bank to increase the success rate of finding an HLA-matched donor.


Key words : Bahrain, Hereditary blood disease, HLA-matched donor

Introduction

Hematopoietic stem cell transplantation (HSCT) plays a major role in the treatment of many diseases. The results of the HLA-matching process can decide the success of HSCT procedures. However, finding an HLA-matched donor can be a major challenge. The ideal donor is a fully HLA-matched sibling. The probability of finding an HLA identical donor among siblings depends on the number of siblings, with success rates of 25% if there is 1 sibling and up to 90% for patients who have 8 siblings.1 This fact predicts that a higher number of patients with matched donors can be found in regional Eastern Mediterranean countries compared with western societies because of the higher number of consanguineous marriages and the larger family size.

Malignancy is the major indication for HSCT.2 However, given differences in incidence of hereditary blood diseases in our region compared with western societies, we expect that a higher number of HSCT procedures are performed because of blood disease-related causes.

Research on HSCT and HLA has recently focussed on forming HLA registries and on cord blood stem cell transplant; however, HLA is highly variable among ethnicities and different cultures. Therefore, it is important to study the HLA status patterns in each country. In this study, our aim was to explore the different indications for HSCT, the demographics, and the HLA patient-donor matching status among Bahraini patients requiring this treatment, thus aiming to determine the rate of finding an HLA identical donor.

Materials and Methods

This study was conducted at Salmaniya Medical Complex, Ministry of Health, a tertiary hospital in Bahrain. Records of 100 patients who required HSCT and their 294 family members (potential donors) were retrospectively studied in the 3-year period from 2017 to 2019. HLA class I and II analyses were performed by polymerase chain reaction and/or microcytotoxicity methods for patients and donors. An HLA-matched donor was defined as matching in class IA, B, and C and class II DR and DQ.

Official ethical approval for this study was given by the Bahrain Ministry of Health, Secondary Healthcare Research Committee.

Statistical analyses
We used Microsoft Excel 2016 and the SPSS (Statistical Package for Social Sciences) program version 20 for statistical analyses. Quantitative variables are presented as mean ± standard deviation. Categorical data are shown as counts and percentages.

Results

One hundred patients were enrolled in our study. Of 294 potential donors, 197 were siblings, 76 were parents, 4 were daughters, 1 was a grandmother, 15 were sons, and 1 was an uncle. Sex distribution showed that was 55% were male patients and 45% were female patients. Among the patients, 22% were less than 5 years old, 30% were 5 to 17 years old, and 48% were 18 years and older. The minimum number of donors tested for each patient was 1 and the maximum number was 11. The overall average number of donors typed for each patient was 2.94 ± 1.86. Patient-donor HLA matching status was 50% HLA identical, 32% haploidentical, 15% more than haploidentical (more than 50% matching and less than 100%), and 3% less than haploidentical (less than 50% matching), as illustrated in Figure 1 .

Figure 2 shows that patients were more likely to find an HLA-matched donor if they were older; 68.70% of those who were above 18 years old had an HLA-matched identical donor compared with 43.3% of those who were >5 to 18 years old and 18.20% of those who were 0 to 5 years old.Table 1 shows the average number of donors tested per patient in each age group and the average number of matching donors for each patient.

Indications for HSCT were 50% because of malignant diseases (leukemia/lymphoma) and 50% because of benign hematological disorders (mainly sickle cell disease, thalassemia major, aplastic anemia, Fanconi anemia, hemophagocytic lymphohistiocytosis, and myelodysplastic syndrome). In the 0- to 5-year age group, the main indication was acute lymphoblastic leukemia, whereas acute myeloid leukemia was the predominant indication in those older than 5 years old. The most common indication with regard to benign hematological disorders was sickle cell disease followed by thalassemia major and aplastic anemia.

Discussion

The overall rate of finding a fully matched HLA identical donor (10 of 10) in our study was 50%, which is higher than the percentage reported in Turkey (44%)3 and lower than that reported in Saudi Arabia (60% in Riyadh4 and 59% in Damam5) as well as in Jordan (65.5%),6 as illustrated in Figure 3 . However, our rate was significantly greater than in western countries. The total number of HCSTs from 2013 to 2017 performed in the United States with an HLA-matched sibling or other related donor was 18%,7 and the percentage of HLA-matched related donors among HSCTs was 36% in Europe as reported in data survey study from 2014.2 The greater rate reported in our study can be explained by the larger family size and the higher rates of consanguineous marriage found in Middle Eastern societies. The total consanguineous marriages reported in Bahrain in 2008 was 10.9% and 11.4% in 2009.8 A study on Saudi Arabia families reported 57.7% of included families were consanguineous marriages.9 Among Jordanians, the rate of consanguineous marriage is 49%.10 In western countries, one-third of patients for HSCT have HLA identical siblings.11

The likelihood of finding an HLA identical donor increases significantly with age, with a rate of 68.70% in those >18 years old and only 18.20% in those between 0 and 5 years old. This may be attributed to older patients having larger families and greater numbers of siblings to screen and therefore having a higher chance of finding a matched donor, which agrees with findings from previous studies in Saudi Arabia4 and Jordan.6

Nonmalignant disease-related causes as an indication for transplant were found in 50% of our cases, with most related to hereditary blood diseases. This finding is in contrast to the European data survey study on HSCT from 2014,2 in which transplant because of nonmalignant indications was only 6%. This can be explained by the high prevalence of hereditary blood diseases in Bahrain. A study published in 1995 reported that 2% of newborns had sickle cell disease and 18% had sickle cell trait, whereas 24% were carriers of the thalassemia gene and 10.4% of non-neonates had sickle cell disease.12

Although the chance of finding an HLA-matched donor reported in our study and other studies in the region is high, there is still a large percentage of patients who are not able to find an HLA-matched donor. This places a need for constructing a national Bahrain donor registry, which is important for HSCT. A good example is Turkey, where a national registry has been in place since 2015 (“TURKOK”); this registry has had a key role in finding unrelated donors. National donor banks are important for both finding an unrelated donor within a shorter time than international donor searches and for their economic impact. In addition, there is a need for a regional stem cell bank for HSCT, which could provide great opportunities to study HLA haplotypes prevalent in our region in addition to providing higher chances of finding a suitable matched donor for patients. The common ethnic origin, higher rates of consanguinity, and larger family size present in our region are strong factors in favor of a successful bank. Cooperation between the Kingdom of Bahrain and Turkey in the field of oncology has already started.

Conclusions

The rate of finding HLA-matched family members as donors for HSCT in our study on Bahraini patients was higher than the rate reported in western countries yet close to other reports from countries with almost similar family sizes. We recommend forming a national Bahrain registry in addition to a regional stem cell bank to increase the success rate of finding an HLA-matched donor.

Hematopoietic stem cell transplantation (HSCT) plays a major role in the treatment of many diseases. The results of the HLA-matching process can decide the success of HSCT procedures. However, finding an HLA-matched donor can be a major challenge. The ideal donor is a fully HLA-matched sibling. The probability of finding an HLA identical donor among siblings depends on the number of siblings, with success rates of 25% if there is 1 sibling and up to 90% for patients who have 8 siblings.1 This fact predicts that a higher number of patients with matched donors can be found in regional Eastern Mediterranean countries compared with western societies because of the higher number of consanguineous marriages and the larger family size.

Malignancy is the major indication for HSCT.2 However, given differences in incidence of hereditary blood diseases in our region compared with western societies, we expect that a higher number of HSCT procedures are performed because of blood disease-related causes.

Research on HSCT and HLA has recently focussed on forming HLA registries and on cord blood stem cell transplant; however, HLA is highly variable among ethnicities and different cultures. Therefore, it is important to study the HLA status patterns in each country. In this study, our aim was to explore the different indications for HSCT, the demographics, and the HLA patient-donor matching status among Bahraini patients requiring this treatment, thus aiming to determine the rate of finding an HLA identical donor.

Materials and Methods

This study was conducted at Salmaniya Medical Complex, Ministry of Health, a tertiary hospital in Bahrain. Records of 100 patients who required HSCT and their 294 family members (potential donors) were retrospectively studied in the 3-year period from 2017 to 2019. HLA class I and II analyses were performed by polymerase chain reaction and/or microcytotoxicity methods for patients and donors. An HLA-matched donor was defined as matching in class IA, B, and C and class II DR and DQ.

Official ethical approval for this study was given by the Bahrain Ministry of Health, Secondary Healthcare Research Committee.

Statistical analyses
We used Microsoft Excel 2016 and the SPSS (Statistical Package for Social Sciences) program version 20 for statistical analyses. Quantitative variables are presented as mean ± standard deviation. Categorical data are shown as counts and percentages.

Results

One hundred patients were enrolled in our study. Of 294 potential donors, 197 were siblings, 76 were parents, 4 were daughters, 1 was a grandmother, 15 were sons, and 1 was an uncle. Sex distribution showed that was 55% were male patients and 45% were female patients. Among the patients, 22% were less than 5 years old, 30% were 5 to 17 years old, and 48% were 18 years and older. The minimum number of donors tested for each patient was 1 and the maximum number was 11. The overall average number of donors typed for each patient was 2.94 ± 1.86. Patient-donor HLA matching status was 50% HLA identical, 32% haploidentical, 15% more than haploidentical (more than 50% matching and less than 100%), and 3% less than haploidentical (less than 50% matching), as illustrated in Figure 1.

Figure 2 shows that patients were more likely to find an HLA-matched donor if they were older; 68.70% of those who were above 18 years old had an HLA-matched identical donor compared with 43.3% of those who were >5 to 18 years old and 18.20% of those who were 0 to 5 years old. Table 1 shows the average number of donors tested per patient in each age group and the average number of matching donors for each patient.

Indications for HSCT were 50% because of malignant diseases (leukemia/lymphoma) and 50% because of benign hematological disorders (mainly sickle cell disease, thalassemia major, aplastic anemia, Fanconi anemia, hemophagocytic lymphohistiocytosis, and myelodysplastic syndrome). In the 0- to 5-year age group, the main indication was acute lymphoblastic leukemia, whereas acute myeloid leukemia was the predominant indication in those older than 5 years old. The most common indication with regard to benign hematological disorders was sickle cell disease followed by thalassemia major and aplastic anemia.

Discussion

The overall rate of finding a fully matched HLA identical donor (10 of 10) in our study was 50%, which is higher than the percentage reported in Turkey (44%)3 and lower than that reported in Saudi Arabia (60% in Riyadh4 and 59% in Damam5) as well as in Jordan (65.5%),6 as illustrated in Figure 3. However, our rate was significantly greater than in western countries. The total number of HCSTs from 2013 to 2017 performed in the United States with an HLA-matched sibling or other related donor was 18%,7 and the percentage of HLA-matched related donors among HSCTs was 36% in Europe as reported in data survey study from 2014.2 The greater rate reported in our study can be explained by the larger family size and the higher rates of consanguineous marriage found in Middle Eastern societies. The total consanguineous marriages reported in Bahrain in 2008 was 10.9% and 11.4% in 2009.8 A study on Saudi Arabia families reported 57.7% of included families were consanguineous marriages.9 Among Jordanians, the rate of consanguineous marriage is 49%.10 In western countries, one-third of patients for HSCT have HLA identical siblings.11

The likelihood of finding an HLA identical donor increases significantly with age, with a rate of 68.70% in those >18 years old and only 18.20% in those between 0 and 5 years old. This may be attributed to older patients having larger families and greater numbers of siblings to screen and therefore having a higher chance of finding a matched donor, which agrees with findings from previous studies in Saudi Arabia4 and Jordan.6

Nonmalignant disease-related causes as an indication for transplant were found in 50% of our cases, with most related to hereditary blood diseases. This finding is in contrast to the European data survey study on HSCT from 2014,2 in which transplant because of nonmalignant indications was only 6%. This can be explained by the high prevalence of hereditary blood diseases in Bahrain. A study published in 1995 reported that 2% of newborns had sickle cell disease and 18% had sickle cell trait, whereas 24% were carriers of the thalassemia gene and 10.4% of non-neonates had sickle cell disease.12

Although the chance of finding an HLA-matched donor reported in our study and other studies in the region is high, there is still a large percentage of patients who are not able to find an HLA-matched donor. This places a need for constructing a national Bahrain donor registry, which is important for HSCT. A good example is Turkey, where a national registry has been in place since 2015 (“TURKOK”); this registry has had a key role in finding unrelated donors. National donor banks are important for both finding an unrelated donor within a shorter time than international donor searches and for their economic impact. In addition, there is a need for a regional stem cell bank for HSCT, which could provide great opportunities to study HLA haplotypes prevalent in our region in addition to providing higher chances of finding a suitable matched donor for patients. The common ethnic origin, higher rates of consanguinity, and larger family size present in our region are strong factors in favor of a successful bank. Cooperation between the Kingdom of Bahrain and Turkey in the field of oncology has already started.

Conclusions

The rate of finding HLA-matched family members as donors for HSCT in our study on Bahraini patients was higher than the rate reported in western countries yet close to other reports from countries with almost similar family sizes. We recommend forming a national Bahrain registry in addition to a regional stem cell bank to increase the success rate of finding an HLA-matched donor.


References:

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DOI : 10.6002/ect.2020.0354


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From the 1Department of Pathology, Immunology Section, Salmaniya Medical Complex, Ministry of Health, and the 2College of Medicine, Arabian Gulf University, Kingdom of Bahrain
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Eman Farid, Department of Pathology, Immunology Section, Salmaniya Medical Complex, Ministry of Health, P.O. Box 12, Kingdom of Bahrain
E-mail: emanfarid57@gmail.com; efareed@health.gov.bh