Donor Search Research Articles

HLA profile of the donors in the Macedonian Bone Marrow Donor Registry.

The importance of HLA alleles in the process of haematopoietic stem cell transplantation, especially the process of unrelated donor search, is enormous. Macedonian Bone Marrow Donor Registry was established in 2010 and has registered volunteer donors from different nationalities that live in the Republic of Macedonia. The aim of this study was to determine the HLA allele and haplotype frequencies of the volunteer donors from the Macedonian Bone Marrow Donor Registry and to compare this results with the Macedonians from a family study. We analyzed 1,541 donors, with different nationalities, Macedonian, Albanian and Macedonian Muslims that were most numerous in MBMDR, and typed them for HLA-A, -B, -C, -DRB1, whereas Macedonian also for HLA-DQA1 and HLA-DQB1 by SSO method (One Lambda, CA, USA). The most frequent alleles in Macedonians were HLA-A*02, 01, 24; HLA-B*35, 18, 51; HLA-C*07, 04, 12; HLA-DRB1*11, 16, 13; HLA-DQA1*01, 05 and HLA-DQB1*05, 03, 06; in Albanians they were HLA-A*02, 24,01; HLA-B*51, 18, 35; HLA-C*07, 04, 12, HLA-DRB1*11, 13,16; and in Macedonian Muslims they were HLA-A*02, 01, 24; HLA-B*18, 51, 35, HLA-C*07, 04, 02 and HLA-DRB1*11, 16, 14. The most common haplotype in Macedonian was HLA-A*01-B*08-C*07-DRB1*03, whilst in Albanian and Macedonian Muslims HLA-A*02-B*18-C*07-DRB1*11. The comparison of the HLA allele groups between Macedonian from MBMDR and family study showed similar distribution. This study confirmed the close relationship between the populations that live in the Balkan Peninsula.

Probability of success in the search for a related bone marrow donor in Cologne, Germany using HLA-A, -B and -DRB1 haplotype frequencies.

Between 2004 and 2013, 603 patients and their relatives (n = 1297) were typed as part of the search for a suitable HLA‐matched donor in their nuclear and extended families at the central service provider for transfusion medicine at the University Hospital of Cologne. The high success rate in finding donors over the years at our center (38.1%) led us to examine our database retrospectively in order to evaluate the donor search and haplotype frequencies (HFs) in the sample. Our goal was to identify the factors contributing to this high success rate and also to compare the HFs we observed with other reported haplotype frequency estimations (HFE) for the Cologne area. Probability estimations for a successful donor search were constructed based on the HFEs for the sample.

The role of allogeneic stem cell transplantation in T-cell lymphoma.

T - and natural killer (NK) cell neoplasms are a heterogeneous group of rare diseases with often inferior outcome. Only few studies exist, clarifying the role of allogeneic transplantation in different clinical scenarios. Larger prospective randomized studies are largely missing even for the more frequent entities. Mostly retrospective analysis and anecdotal reports of patients with advanced disease are available, hampering direct conclusions on the significance of allogeneic stem cell transplantation (alloSCT). Looking at recent data for T and NK cell neoplasm, it becomes evident that advances in donor search and availability of alternative stem cell sources as haploidentical or mismatched donors in addition to substantial improvements in graft-versus-host-disease prophylaxis reduce treatment-related mortality in alloSCT. The time point of transplantation has been described in a number of studies to be critically impacting outcome results as patients with advanced, chemorefractory disease often profit much less from alloSCT. Allogeneic transplantation offers a treatment option that can induce long-term remissions even in the relapsed setting. Many patients do not reach transplantation though because of chemorefractory disease and efforts should be made to bring more patients to transplantation earlier in the course of disease.

OR48 Haploidentical hematopoietic cell transplantation in a highly sensitized patient with donor-specific antibodies – A success story

A nine-year-old female with refractory Acute Myelomonocytic Leukemia (AML) was referred to our institute for Hematopoietic Cell Transplant (HCT) in 2015. While preparing for transplant, this patient became severely refractory to platelet transfusion. HLA antibody identification using single antigen bead technology revealed that she was highly sensitized to both HLA class I and class II antigens and had donor specific antibodies (DSA) to both parents (antibodies against HLA-B35 specific for her father; antibodies against A36 and DQ2 specific for her mother). Flow cytometric T cell allo-crossmatch of patient serum was positive with both parents. Unfortunately, this patient had no full siblings and an unfavorable matched unrelated donor search. The patient had few options other than haploidentical HCT from one of her parents and was therefore given a desensitization regimen of rituximab and plasmapheresis. Following two cycles of desensitization, overall class I PRA remained high (91%), but the patient’s DSA against her father (B35) became negative. The patient’s maternal DSA to DQ2 persisted. Patient/father T cell crossmatch after the desensitization treatment was diminished to borderline. The patient proceeded to HCT using her father as the donor, and was supported with HLA compatible platelets in the post-transplant period. She had neutrophil and platelet engraftment by days +13 and +19 respectively, following HCT. HLA antibody testing on the patient’s serum nine months post-transplant revealed greatly reduced antibody positivity with only two positive class I specificities and no antibodies to class II. This patient continues to remain in remission nearly three years post-transplant. This case study highlights the value of desensitization regimens for patients with donor specific antibodies and few donor options for HCT.

OR5 Donor specific antibody (DSA) assessments using HLA P groups: The devil is in the details

Aim Use of HLA P groups for reporting purposes and DSA assessments for potential donors has been steadily increasing. P groups for HLA class II encompass exon2 sequences and capture the polymorphic rich peptide binding domain that serves as the primary target for alloantibody. Nevertheless, we have observed multiple sera exhibiting HLA-DQA1 or HLA-DPB1 reactivity to polymorphic sites outside of exon 2 and confirmed this reactivity using cell adsorptions. Methods HLA antibodies were assessed using Lifecodes single antigen; Immucor and LabScreen Single Antigen; One Lambda. Sera were pretreated to remove interference using Melon Columns™ (ThermoFisher). HLA typing was performed using rSSO LabType, One Lambda and confirmed using NGS TruSight HLA, Illumina. 10th international workshop B cell lines were used for adsorptions. Results We present a representative example in Fig. 1. Patient #1 typed as a DQA1∗05:05/DQB1∗03:19 yet her sera reacted with the DQA1∗05:03/DQB1∗03:01 bead with a median fluorescence intensity of 11,000. Sequence alignments illustrate an amino acid difference between DQA1∗05:03 and DQA1∗05:05 at position 159. There is also one amino acid difference between DQB1∗03:01 and DQB1∗03:19 but the DQA1∗05:05/DQB∗03:01 bead reactivity was negative, negating the possibility that the antibody was directed at HLA-DQB1. Serum adsorptions using a DQA1∗05:03/DQB1∗03:01 cell line showed an 84% reduction in the DQA1∗05:03/DQB1∗03:01 bead reactivity and a concomitant 3% reduction in reactivity with the DQA1∗03:01/DQB1∗03:01 bead. These data show that the serum reactivity with the DQA1∗05:03/DQB1∗03:01 bead was directed toward the HLA-DQA1 protein, which differed from the recipient by a single polymorphic difference outside of exon 2. Conclusions We show evidence of sensitization to a polymorphism outside of exon 2 implying the potential danger of using P group designations when performing virtual crossmatch assessments or unrelated stem cell donor searches for patients with complex HLA sensitization. A.M. Jackson: 3. Speaker’s Bureau; Company/Organization; Thermo Fisher. M. Bettinotti: 3. Speaker’s Bureau; Company/Organization; ThermoFisher.

OR28 Haploidentical donors for Hematopoietic Cell Transplantation (HCT): Changing demographics and the economics of typing this population

Aim HLA-mismatched allogeneic donors allow HCT of patients lacking an HLA identical sibling or matched unrelated donor. Most patients find a haploidentical or a partially-HLA mismatched donor among their first- and second-degree relatives or unrelated donors. We examined process improvements to reduce donor search time and cost in the new era of alternative donors and the less costly Next Generation Sequencing (NGS) technology for high resolution typing. Methods HLA class I typing was performed using reverse sequence specific oligonucleotide probe (rSSO) hybridization (One Lambda, Inc) to identify potential haploidentical donors. Select donors were typed at high resolution using Sanger sequence base typing during 2015 and 2016 (local and commercial kits) or NGS in 2017 (lllumina). Specimen (blood) collection kits were sent to donors using a third party vendor (Path-Tec). Results We performed a retrospective cost analysis of 2017 data. Currently, rSSO class I typing is performed on non-parent or child family members to rule out HLA disparate donors. Of 444 individuals, 188 appeared to be haploidentical and were reflexed to HRT. Only 3.9% of donors reflexed to NGS were disparate. If all 444 individuals had been initially typed by NGS, the cost for the program would have been 63.2% higher. As show in Table 1, the number of 2nd degree relatives has increased. As the donor pool expands beyond the patient’s nuclear family, the incidence of incorrectly reported donor relationships has increased, causing inappropriate testing and delays in reporting results. Furthermore, the donors’ geographical locations have expanded coast to coast, and even globally with increase of shipping costs. Of 413 kits sent in 2017, 20.1% were not returned. Download : Download high-res image (116KB) Download : Download full-size image Conclusions With the steady increase in the use of alternative HCT donors, the staggered class I typing schema remains cost effective even with the advent of NGS. Areas for cost reduction include obtaining correct relationships prior to testing and improving the return rate of collection kits. A.M. Jackson: 3. Speaker’s Bureau; Company/Organization; One Lambda/Thermo Fisher Scientific. M. Bettinotti: 3. Speaker’s Bureau; Company/Organization; One Lambda/Thermo Fisher Scientific.

The role of collateral related donors in haploidentical hematopoietic stem cell transplantation

A key issue in the haploiedntical hematopoietic stem cell transplantation (haplo-HSCT) setting is the search for the best donor, because donor selection can significantly impact the clinical outcomes. We aimed to identify the role of collateral related donors (CRDs) in donor selection for haplo-HSCT through comparing the clinical outcomes between CRDs (n = 60) and maternal donors (MDs, n = 296), which were the last choice of donor selection in immediate related donors (IRDs). The cumulative incidence of graft-versus-host disease was comparable between CRDs and MDs. The 5-year cumulative incidence of relapse and non-relapse mortality was 22.0% (95% CI, 11.3%–32.7%) versus 17.4% (95% CI, 13.0%–21.8%) (P = 0.455) and 25.0% (95% CI, 13.9%–36.1%) versus 23.1% (95% CI, 18.2%–28.0%) (P = 0.721) for the CRDs and MDs, respectively. The 5-year probabilities of disease-free survival and overall survival was 53.2% (95% CI, 40.4%–66.0%) versus 59.5% (95% CI, 53.8%–65.2%) (P = 0.406) and 56.5% (95% CI, 43.8%–69.2%) versus 61.8% (95% CI, 56.1%–67.5%) (P = 0.458) for the CRDs and MDs, respectively. Female donor/male recipient (FDMR) CRDs were associated with the poorest clinical outcomes, and the clinical outcomes of non-FDMR CRDs were comparable to those of MDs. In summary, our results showed that CRDs did not showed superiority over MDs. Thus, IRDs should be the first choice of donor selection, and CRDs could only be the donors for those without IRDs.

Outcomes Following Allogeneic Stem Cell Transplantation Using Non-sibling Family Donors.

For patients requiring allogeneic stem cell transplant, in the absence of a HLA-matched sibling, an extended donor search within the family may yield a suitable donor especially in societies with a high prevalence of consanguinity. We describe outcomes in transplants with non-sibling family donors, and compare outcomes with controls having a sibling donor transplant. Retrospective analysis of all matched related (non-sibling) donor transplants between 1995 and 2015. For comparison, appropriate age, sex and disease-matched patients were chosen from the sibling transplants (MSD) performed during the same time period (± 2years). Comparison between the fully matched non-sibling donor cohort and age, sex and disease-matched sibling donor transplants showed a significant increase in complications in the family donor group (viral infections, acute GVHD and rejection). Event-free survival and overall survival were significantly lower in the non-sibling donor cohort, and HLA disparity (1-2 antigen) further worsened the adverse impact. Though there was a significantly lower event-free and overall survival at 3years in the family donor cohort, this did not retain significance in the multivariate analysis. This data on allogeneic transplants using family donors showed higher complication rates and poorer outcomes. However in situations where financial constraints prevent access to matched unrelated donor sources, extended family searches may be fruitful in yielding a donor, and modifications in conditioning regimens and improvement in supportive care may help in improving the outcomes in family donor transplants.

Vzácné anémie ze skupiny vrozených syndromů selhání kostní dřeně

This review summarizes the pathophysiology, genetic background and clinical symptoms of anemias belonging to the group of inherited bone marrow failure syndromes with unilineage failure of erythropoiesis. It sums up the current knowledge of three diseases: Diamond-Blackfan anemia, congenital dyserythropoietic anemia and Fanconi anemia whose pathophysiology was elucidated in detail during the last decade, owing to the rapid development of new molecular-genetic techniques, especially next-generation sequencing. Fanconi anemia is included in this overview because of macrocytosis and/or anemia detected in the majority of the patients before they develop bone marrow failure. The paper also aims at pointing out typical associated anomalies in these diseases which might be overlooked and which can lead to early diagnosis. Unfortunately, the correct diagnosis is often established later in adulthood and, in some cases, as late as at the time of manifestation of malignant disease. Accurate and timely diagnosis of these conditions is extremely important for the determination of appropriate treatment approach, diagnosis of affected family members (especially in the process of bone marrow donor search), and genetic counselling, which can substantially influence the prognosis of these diseases. Key words: congenital dyserythropoietic anemia - Diamond-Blackfan anemia - DNA repair - dyserythropoiesis - Fanconi anemia - inherited bone marrow failure - ribosomopathies.

The distribution of HLA haplotypes in the ethnic groups that make up the Brazilian Bone Marrow Volunteer Donor Registry (REDOME).

The Registries of Bone Marrow Donors around the world include more than 30 million volunteer donors from 57 different countries, and were responsible for over 17,000 hematopoietic stem cell transplants in 2016. The Brazilian Bone Marrow Volunteer Donor Registry (REDOME) was established in 1993 and is the third largest registry in the world with more than 4.3 million donors. We characterized HLA allele and haplotypes frequencies from REDOME comparing them with the donor self-reported race group classification. Five-locus haplotype frequencies (A~C~B~DRB1~DQB1) were estimated for each of the six race groups, resolving phase and allelic ambiguity using the expectation-maximization (EM) algorithm. The top 100 haplotypes in the race groups were separated into eight clusters of haplotypes, based on haplotype similarity, using CLUTO. We present HLA allele and haplotype frequency data from six race groups from 2,938,259 individuals from REDOME. The most frequent haplotype was the same for all groups: A*01:01g~C*07:01g~B*08:01g~DRB1*03:01g~DQB1*02:01g. Some frequent haplotypes such as A*02:01g~C*16:01g~B*44:03~DRB1*07:01g~DQB1*02:01g was not found in people with Preta (Sub-Saharan African descent). A cluster including Branca (European) and Parda or non-informed (admixed) could be distinguished from both Preta (SubSaharan) and Indígena (Amerindian) groups, and from the Amarela (Asian) ones, which clustered with their original population. These results have implications on cross-population matching and can help in donor searches and population-based recruitment strategies.

Luminex® xMAP® technology is an effective strategy for high-definition human leukocyte antigen typing of cord blood units prior to listing.

Allele-level donor-recipient match at HLA-A, HLA-B, HLA-C and HLA-DRB1 loci impacts the outcome after cord blood transplantation for hematologic malignancies and modifies the strategy of donor selection. High definition of both class I and II HLA loci at time of listing is a way to improve the attractiveness of cord blood bank inventories, reducing the time for donor search and procurement and simplifying donor choice, in particular, for patients of non-European heritage. In 2014, Luminex® xMAP® technology was introduced in our laboratory practice and was applied to cord blood units typing. In this study, we evaluated the impact of this strategy in comparison with the platform in use until 2013, relying on LiPA reverse polymerase chain reaction-sequence-specific oligonucleotide (revPCR-SSO) plus polymerase chain reaction-sequence-specific primer (PCR-SSP). In 2014, the time for testing was shorter (141 vs 181 days on average), the number of test repetitions was lower (in particular for HLA-A locus, p = 0.026), and the cost reduced (240.7 vs 395.6 euros per unit on average) compared to 2013, demonstrating that Luminex xMAP technology is superior to the previous approach. Luminex xMAP platform has useful application in cord blood banking programs, to achieve high-definition HLA typing of cord blood units at the time of banking in a quick, accurate, and cost-effective manner.

The impact of donor liver allograft fibrosis on patients undergoing liver transplantation.

The utilization of extended criteria liver allografts (ECD) shortens time to transplantation. To characterize the effect of liver allograft fibrosis on graft and patient survival after liver transplantation (LT), with particular attention to fibrosis progression. Retrospective database search of donor and recipient liver allograft histology of liver transplants performed between 2007 and 2011. Donor and patient characteristics were analyzed. One hundred and one patients underwent LT with donor liver allografts with early-stage fibrosis (stage 1 fibrosis and stage 2 fibrosis). The level of liver fibrosis did not progress in 40% of the patients tested, and there was a regression of fibrosis in 30%. At a median follow-up of 71months, of 101 patients transplanted with fibrotic livers, 63 patients (63%) were alive with functioning initial grafts, six patients (6%) were retransplanted, and 35 patients expired. The graft survival rates were 82% and 69% at 1 and 5years, respectively. Graft survival differences were not found to be statistically significant between the degrees of liver allograft fibrosis: 5-year graft survival (73% for stage 1 fibrosis and 62% for stage 2 fibrosis, P=.24). The entire fibrosis group was further compared with a control group of 208 consecutive primary liver transplant patients with allografts having no fibrosis. The 5-year graft survival was not significantly different between the groups (69% for the fibrosis group vs 75% for the nonfibrosis group, P=.19). Survival was also not statistically different between the groups (5-year survival of 73% for the fibrosis group vs 79% for the nonfibrosis group, P=.2). In patients with HCV, graft survival differences were not found to be statistically significant with the use of early-stage fibrotic livers: 5-year graft survival of 60% for fibrosis group vs 70% for the nonfibrosis group, P=.22). This study demonstrates that allografts with early-stage fibrosis achieve acceptable long-term survival after liver transplantation. Given these preliminary results, the use of organs with early-stage fibrosis warrants further studies at a larger scale to validate these results.

Analysis of the Spanish CCR5-∆32 inventory of cord blood units: lower cell counts in homozygous donors.

The possibility to use CCR5-∆32 umbilical cord blood to cure HIV infection in patients in need of a hematopoietic transplant has been suggested. The less stringent HLA compatibility needed in this type of transplant facilitates the search of a suitable donor having the CCR5-∆32 mutation. To achieve an inventory of CCR5-∆32 cord blood units, the 20,236 best cell quality units of the Spanish Registry were genotyped. Furthermore, their CD34+ and total nucleated cells counts, blood type, gender, HLA and donor's geographical and ancestral origin were analyzed. The results showed 130 (0.64%) units homozygous for the deletion, 2,646 (13.08%) heterozygous and 17,460 (86.28%) did not present the mutation. Interestingly, a significant lower amount of CD34+ cells was found in the CCR5-∆32 homozygous units. In addition, a significant association was found among donor's ancestral origin and the mutation, with a higher percentage of CCR5-∆32 units with a European ancestry. In summary, identification of a relatively high number of CCR5-∆32 units is feasible and will facilitate the development of clinical trials for HIV cure in patients requiring hematopoietic transplantation. Further studies are required to understand the significance of lower cell counts within the CCR5-∆32 homozygous group and its clinical impact.

Outcomes of strategic alternative donor selection or suspending donor search based on Japan Marrow Donor Program coordination status.

In allogeneic hematopoietic stem cell transplantation (allo-HSCT) from unrelated donors, delays in donor search are adversely associated with patient outcome. However, the optimal duration for either waiting for an unrelated donor or selecting alternative sources remains undetermined. Using data from the Japan Marrow Donor Program (JMDP) registry, we retrospectively analyzed 349 adult patients who had searched for unrelated donors. Two hundred and three patients received allo-HSCT from JMDP donors (Group A) with a median of 140days required to identify a donor, 60 received allo-HSCT from alternative sources (Group B) after a median of 111.5days at which point either all donor candidates had failed or the patient achieved a second or subsequent complete remission, and 77 suspended allo-HSCT (Group C) after a median of 310days. The 5-year overall survival (OS) rate in Group A was superior to that of Group C (48.6 vs 38.5%, P=0.001). Although Group B included more patients with high or very high disease risk index (DRI) at the time of allo-HSCT compared with Group A, the 5-year OS was not significantly different between Groups A and B (48.6 vs 40.9%, P=0.07), indicating that switching to alternative donors may benefit patients with high DRI.

The Japan Marrow Donor Program, 25 years of experience in achieving 20,000 bone marrow transplantations: organization structure, activity, and financial basis.

The Japan Marrow Donor Program (JMDP), established in 1991, has continued to grow in its capacity to facilitate unrelated bone marrow (BMT) and peripheral blood stem cell transplantation (PBSCT) for the past 25 years in Japan. The current donor pool is 463,465 (as of 31 December 2016) and 20,237 transplants were performed with the help of the Japanese Red Cross, government, and supporters. As JMDP introduced PBSCT in 2010, the vast majority of transplants are BMT. All donors are fully typed for HLA-A, B, C, and DR. The peak age of registered donors is around 40 years. The 8/8 HLA-matched donors are found in our registry for 96% of the patients and 54% of the patients receive a transplant. The median time between the initiation of donor search and the transplantation is approximately 122 days. The median interval between the initiation of donor search and identification of the first potential donor is 40 days. The most common diseases for which unrelated BMT/PBSCT is indicated are acute myelogenous leukemia (AML), acute lymphocytic leukemia (ALL), myelodysplastic syndrome (MDS), and malignant lymphoma. In recent years we have seen a marked increase in elderly patients who received BMT.

Assessing the effect of a partly unobserved, exogenous, binary time-dependent covariate on survival probabilities using generalised pseudo-values

BackgroundInvestigating the impact of a time-dependent intervention on the probability of long-term survival is statistically challenging. A typical example is stem-cell transplantation performed after successful donor identification from registered donors. Here, a suggested simple analysis based on the exogenous donor availability status according to registered donors would allow the estimation and comparison of survival probabilities. As donor search is usually ceased after a patient’s event, donor availability status is incompletely observed, so that this simple comparison is not possible and the waiting time to donor identification needs to be addressed in the analysis to avoid bias. It is methodologically unclear, how to directly address cumulative long-term treatment effects without relying on proportional hazards while avoiding waiting time bias.MethodsThe pseudo-value regression technique is able to handle the first two issues; a novel generalisation of this technique also avoids waiting time bias. Inverse-probability-of-censoring weighting is used to account for the partly unobserved exogenous covariate donor availability.ResultsSimulation studies demonstrate unbiasedness and satisfying coverage probabilities of the new method. A real data example demonstrates that study results based on generalised pseudo-values have a clear medical interpretation which supports the clinical decision making process.ConclusionsThe proposed generalisation of the pseudo-value regression technique enables to compare survival probabilities between two independent groups where group membership becomes known over time and remains partly unknown. Hence, cumulative long-term treatment effects are directly addressed without relying on proportional hazards while avoiding waiting time bias.

An efficient, robust and automatic overlapping grid assembly approach for partitioned multi-block structured grids

An efficient, robust and fully automatic grid assembly method on multi-block cell-centered structured grids for massively parallel computation is proposed in this paper. Compared with the traditional serial algorithm, the new approach eliminates the complex irregular boundaries created during the grid partition and avoids the large load imbalance caused by the large variation of grid-block overlapping. The main task of the overlapping grid assembly is to categorize all grid points into field points, fringe points and hole points. As to the main processes of the overlapping grid assembly, for hole cutting, an improved hole map method is applied to accurately identify the hole points located on the wall boundary with less memory cost. For donor search which is the most complex process on account of the irregular distribution of the partitioned multi-block structured grids in a parallel computation environment, the Alternating Digital Tree (ADT) is utilized to find out the potential donor cells quickly for query points. Besides, to achieve better overlapping quality, the wall distance criterion is implemented for overlapping optimization. In addition, two load balance algorithms are designed to solve the imbalance problem of overlapping grid assembly. Two test cases are applied to test the new overlapping grid assembly algorithm and the results show that the new overlapping grid assembly algorithm can deal with large-scale simulation of vehicles. The comparison of total time and speed-up among three algorithms manifests that the initial load balance algorithm using query point number as load criterion is not reliable while the improved load balance algorithm achieves good speed-up and least runtime. Meanwhile, the maximum proportion the improved load balance algorithm takes in one physical unsteady step in wing-pylon-store separation test case is less than 6.1%.

Access to alternative donor hematopoietic search and transplantation for acute leukemia in different macro-regions of Italy. A GITMO/IBMDR study.

Hematopoietic Stem Cell Transplantation activity levels vary across European countries. No data are available on the homogeneity of access to the transplant procedure for patient with leukaemia, within any European country. We measured homogeneity of the rate of alternative donor search in patients affected by acute leukaemia resident in each Italian region and macro-region during years 2010-2013. A total of 2747 alternative donor searches were studied. Twenty-one percent of all donor searches were made through extra-regional migration. Rate of alternative donor searches varied among the country's regions and macro-regions. The rate of donor searches was 38% lower in South Italy than in North Italy, and the rate of alternative donor transplantations performed was 45% lower. A reduced rate of alternative donor search in South macro-region was observed in all age cohorts. Despite the overall allogeneic transplant rate in Italy is relatively high, there are wide regional differences in access to transplant from alternative donor. Extra-regional migration cannot completely compensate for the lower access to transplant of acute leukaemia patients living in those regions where transplant activity is low.

HLA-A, -B, -C and -DRB1 allele and haplotype frequencies in the Macedonian population based on a family study

AimThe aim of this study was to determine HLA allele and 2-, 3- and 4-loci haplotype frequencies in a sample from Macedonian population with defined haplotypes based on family history. Material and MethodsWe analysed 286 unrelated individuals with Macedonian origin, parents of patients who needed stem cell transplantation, in the period of 01.01.2003 till 31.12.2016. Allele and haplotype frequencies, as well as Hardy-Weinberg equilibrium were calculated using the Arlequin3.5 software. Population comparison was calculated using the PHYLIP software. ResultsWe identified 18 HLA-A, 26 HLA-B, 13 HLA-C and 13 HLA-DRB1 allele group families. The most frequent allele groups in our population were HLA-A*02 (29.0%), HLA-A*24 (13.8%), HLA-B*35 (16.1%), HLA-B*51 (14.7%), HLA-B*18 (14.7%), HLA-C*07 (27.9%), HLA-DRB1*11 (25.5%) and HLA-DRB1*16 (14.8%). The most frequent four loci haplotype was HLA-A*01-B*08-C*07-DRB1*03 (2.7%). Our comparison showed that the Macedonian population is closely related to the neighbouring countries in the Balkan Peninsula. ConclusionThis study provides data about the HLA diversity in the Macedonian population, which can be very important in the process of unrelated donor search, and in addition yields control group for future disease association studies in our population.

DNA-hypomethylating agents as epigenetic therapy before and after allogeneic hematopoietic stem cell transplantation in myelodysplastic syndromes and juvenile myelomonocytic leukemia.

Myelodysplastic syndrome (MDS) is a clonal bone marrow disorder, typically of older adults, which is characterized by ineffective hematopoiesis, peripheral blood cytopenias and risk of progression to acute myeloid leukemia. Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasm occurring in young children. The common denominator of these malignant myeloid disorders is the limited benefit of conventional chemotherapy and a particular responsiveness to epigenetic therapy with the DNA-hypomethylating agents 5-azacytidine (azacitidine) or decitabine. However, hypomethylating therapy does not eradicate the malignant clone in MDS or JMML and allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment option. An emerging concept with intriguing potential is the combination of hypomethylating therapy and HSCT. Possible advantages include disease control with good tolerability during donor search and HSCT preparation, improved antitumoral alloimmunity, and reduced risk of relapse even with non-myeloablative regimens. Herein we review the current role of pre- and post-transplant therapy with hypomethylating agents in MDS and JMML.