scholarly journals Implications of HLA linkage disequilibrium phenomenon in finding unrelated volunteer bone marrow donors

2007 ◽  
Vol 60 (3-4) ◽  
pp. 178-182
Author(s):  
Svetlana Vojvodic ◽  
Stevan Popovic ◽  
Lana Macukanovic-Golubovic
Keyword(s):  
Bone Marrow ◽  
Linkage Disequilibrium ◽  
Normal Population ◽  
Unrelated Donor ◽  
Strong Linkage Disequilibrium ◽  
Genetic Studies ◽  
Haplotype Frequencies ◽  
Unrelated Donors ◽  
Hla Phenotype ◽  
Hla Haplotypes

Introduction. The distribution of HLA genes and haplotypes in the normal population is of considerable importance in disease susceptability studies, population and genetic studies and tissue and organ transplantation. The HLA phenotype frequencies can be used for the estimation of the probability of finding phenotypically identical unrelated volunteer bone marrow donors. It has been presumed that patients with HLA haplotypes in strong linkage disequilibrium, a have higher probability of finding HLA identical unrelated donors than others. Material and methods. HLA gene and haplotype frequencies were calculated, as well as delta values and their significance. The implications of HLA disequilibrium phenomenon in unrelated donor search, was investigated by calculating the correlation coefficient between frequencies of haplotypes showing significant delta values and the linkage disequilibrium coefficient, as well as between the average number of donors necessary for research. Results. Haplotypes showing the highest delta values are at the same time the most frequent haplotypes (A1B8:0,1188 and 0,145; A3B35:0,0722 and 0,1;A2B12:0,055 and 0,105). In patients who have both haplotypes showing significant delta values (e.g. A2B5/A3B35), the number of donors necessary for research is clearly lower than in patients who have only one given haplotype, or have no such haplotypes. Conclusion. Our results showed that patients with HLA haplotypes showing significant delta values have a higher probability of finding HLA identical unrelated donors. .

Comparison of Outcomes of Bone Marrow and Umbilical Cord Blood Transplants from Unrelated Donors in Adult Patients with Acute Myeloid Leukemia/Myelodysplastic Syndrome.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2010-2010
Author(s):  
Kazuhiro Masuoka ◽  
Shigesaburo Miyakoshi ◽  
Kazuya Ishiwata ◽  
Masanori Tsuji ◽  
Shinsuke Takagi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cord Blood ◽  
Myeloid Leukemia ◽  
Adult Patients ◽  
Refractory Anemia ◽  
Unrelated Donor ◽  
Graft Versus Host ◽  
Unrelated Donors ◽  
Acute Myeloid

Abstract <Objectives> Promising results of cord blood transplants from unrelated donors have been reported in adults. To compare of outcomes of bone marrow transplants (BMT, n = 51), and umbilical cord blood transplants (UCBT, n = 110) from unrelated donors in adult patients with acute myeloid leukemia (AML) / myelodysplastic syndrome (MDS), we analyzed retrospectively the results of 161 adult patients with AML and MDS in our hospital. <Patients and Methods> We reviewed medical records of 161 patients with AML/MDS who had received a hematopoietic stem cell transplant from an unrelated donor between August 2000 and April 2007 at Toranomon Hospital, Tokyo, Japan. <Results> Patient’s median age was 55 years (17–71). Diagnoses include de novo AML (n =85), MDS overt AML (n=48), refractory anemia (RA) (n=13), and refractory anemia with excess of blasts (RAEB) (n=15). Disease status consisted of standard (CR1 of AML and RA, n=30) and advanced (other status, n=131). Recipients of UCBT had more advanced disease than recipients of BMT at the time of transplantation (89 percent vs. 65 percent, P<0.001). The median number of nucleated cells that were infused was 0.26×108 per kilogram of the recipient’s body weight for cord blood and 2.5×108 per kilogram for bone marrow (P<0.001). The major difference were higher number in the UCBT group of HLA mismatches (defined by serology for class 1 and molecular typing for DRB1).The donor was HLA mismatched in 96% of UCBT recipients, and in 41% of BMT recipients (P<0.001). Other significant differences were observed in preparative regimens, and graft-versus-host disease (GVHD) prophylaxis. Nonadjusted estimates of 2-year OS and DFS rates were 53% and 48% in the BMT group, and 33% and 25% in the UCBT group (P<0.001). However, 2-year OS and DFS rates in the standard group were not significantly different in the two groups (63% and 63% in the BMT group, and 75% and 58% in the UCBT group; p=0.98 and 0.32). Compared with BMT recipients, UCBT recipients had delayed hematopoietic recovery (Hazard ratio [HR]= 0.52; 95% confidence interval [95CI]: 0.36–0.75; p<0.001), increased 100 day TRM (HR=3.07; 95CI 1.45–6.51; p<0.01) and decreased grade II–IV acute graft-versus-host disease (aGVHD) (HR=0.58; 95CI 0.35–0.96; p=0.03). Two-year relapse rate was not significantly different in the two groups. <Conclusion> We conclude that UCBT from an unrelated donor is a therapeutic option for adult AML/MDS patients who lack an HLA-identical donors. Higher mortality, especially from non-relapse causes, is the biggest problem to be solved to increase the feasibility of this approach.

Comparative Study of French Unrelated Registered Stem Cell Donors and Cryopreserved Cord Blood Units.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5068-5068
Author(s):  
Marie-Lorraine M.L. Balere ◽  
Valerie V. Lapierre ◽  
Federico F. Garnier ◽  
Evelyne E. Marry
Keyword(s):  
Cord Blood ◽  
Equivalent Rate ◽  
The Em Algorithm ◽  
Significant Difference ◽  
Blood Banks ◽  
Haplotype Frequencies ◽  
National Patient ◽  
Unrelated Donors ◽  
Hla Haplotypes ◽  
Cord Blood Banks

Abstract The question of the HLA complementarity between unrelated Donors Registries and Cord Blood banks is often raised. On december 31th 2006, three methods were used to qualify and quantify the genetic diversity and complementarity between French marrow unrelated donors (FMUD) and French cryopreserved cord blood units (FCBU). The first one is based on HLA haplotype frequencies performed according to the EM algorithm method, the second on the contribution in new phenotypes (CinNP), the third on the presence of no, one or two frequent haplotypes within MUD/CBU phenotypes. Preliminary operations on HLA typings were necessary to homogenize data: split level, exclusion of only typed at class I level donors. HLA haplotype frequencies comparison does not lead to a global significant difference between FMUD and FCBU. The 5 most frequent haplotypes are identical in both populations: 01-08-17, 29-44-07, 03-07-15, 02-44-04, 02-07-15. Then some haplotypes, characteristic of either Nord or South of Europe, were more frequent among the FMUD than among the FCBU: 02-44-07, 02-51-13, 11-35-01, 02-60-13. On the contrary, some haplotypes of Middle East and Eastern Europe were more frequent among the FCBU than among the FMUD: 30-18-17, 24-35-11, 02-13-07, 33-65-01. In 2006 CinNP does not differ significantly between FMUD and FCBU. 49% of new MUD/CBU bring new HLA-ABDR low resolution split level phenotypes to the FMUD and FCBU populations present the year before, with differences between regions: Martinique and Reunion islands have the largest CinNP, Britanny the smallest. Effectiveness in term of CinNP have been studied for France during the past 6 years, by 2 year sections: 2001–2002, 2003–2004, 2005–2006. As expected, in order to reach an equivalent rate of CinNP, a growing number of donors must be registered every year. The 25 most frequent haplotypes among the FMUD and FCBU were calculated, and called “frequent haplotypes” (FH) among the French population. We could then categorize individuals according to the number of FH they had: none, one or two. 85% of harvested FMUD for a national patient between 2000 and 2006 had one or two FH versus 54% of infused FCBU. 50% of harvested FMUD/ infused FCBU for an international patient had no FH, versus 26% for a national patient. FMUD registry and FCBU banks are complementary: they answer to various HLA haplotypes needs for national and international patients. Incontestably, international patients benefit from French MUD/CBU, which present HLA characteristics not or under-represented in their Registry of origin.

Gemtuzumab Ozogamicin (GO) and Continuous Infusion Cytarabine (ARA-C) for Relapsed/Refractory Acute Myeloid Leukemia (AML) Prior to Allogeneic Stem Cell Transplantation (SCT).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 952-952
Author(s):  
Amer Zeidan ◽  
Wei Tan ◽  
Gregory Wilding ◽  
LaurieAnn Ford ◽  
Theresa Hahn ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Continuous Infusion ◽  
Chronic Gvhd ◽  
Disease Free Survival ◽  
Bone Marrow Aspiration ◽  
Infectious Complications ◽  
Unrelated Donor ◽  
Increased Risk ◽  
Unrelated Donors ◽  
Refractory Aml

Abstract The question whether to re-induce AML patients (pts) in first or subsequent relapse to reduce leukemia disease burden prior to SCT is not well studied. Several groups reported a 28–30% disease-free survival rate at five years for matched related donor SCT in first relapse without re-induction. Finally, re-induction regimen choices prior to SCT are relatively limited. Specifically, GO-containing regimens have been suspected to be associated with increased incidence of liver sinusoidal occlusive syndrome (SOS) when used prior to SCT. We evaluated our institutional experience of using GO and ARA-C for relapsed/refractory CD33-positive AML pts prior to allogeneic SCT. A total of 18 pts (median age 45.4 years; range 28–66) with relapsed/refractory AML were treated with GO/ARA-C. The median initial complete remission duration was 4.4 (range 0.5–14.5) months. The median time from relapse to GO/ ARA-C was 57 (range 6–142) days. Pts received GO (6 mg/m2 on day 1, 4 mg/m2 on day 8) and continuous infusion ARA-C (100 mg/m2) daily for 7 days. Bone marrow aspiration and biopsy were performed at a median of 15 (range 11–39) days post induction (one pt had >20% peripheral blasts on day 14 and therefore did not undergo bone marrow aspiration and biopsy). Three (17%) pts developed infectious complications following re-induction and one pt had disease progression that prevented them from undergoing bone marrow aspiration and biopsy and continuing on to SCT. Marrow aplasia (defined as <5% blasts and <20% cellularity) was reached in six of 14 (43%) evaluable pts. Three pts (all without achieving marrow aplasia) developed infectious complications that precluded SCT. A total of 11 pts proceeded onto SCT at a median of 30 (range 21–73) days after re-induction, including six pts who achieved marrow aplasia and five who did not. Six pts underwent matched unrelated donor SCT (two were mismatched at one allele) and five received matched sibling SCT. Reduced intensity preparatory regimens (fludarabine/melphalan) were used in all but one pt who received a fully myeloablative regimen (busulfan/cyclophosphamide). Engraftment to absolute neutrophil count ≥0.5x109/L for three days was achieved in all 11 pts at a median of 15 (range 9–21) days. During SCT, all pts were treated with prophylactic enoxaparin 40 mg subcutaneously once daily to prevent SOS of the liver. The two pts with mismatched unrelated donor SCT died three and nine days after achieving count recovery from pulmonary infiltrates and severe graft versus host disease (GVHD), respectively. Acute GVHD grade II-IV developed in six of the pts with matched donors (three related and three unrelated donors). Chronic GVHD developed in four (one related and three unrelated donors) of the pts. None developed liver SOS. Four pts are alive from starting GO/ARA-C at a median of 7.2 (range 1.2–52.7) months; two of them with and two of them without GVHD. Marrow aplasia prior to SCT was achieved in two of them. In summary, the question of whether to re-induce pts with relapsed/refractory AML to reduce leukemia burden prior to allogeneic SCT remains controversial. However, if one chooses to proceed with re-induction, then the combination of GO/ARA-C represents a feasible re-induction strategy with acceptable toxicity, achievement of marrow aplasia in approximately half of evaluable pts, and no increased risk of liver SOS in the setting of enoxaparin prophylaxis and low intensity conditioning regimens.

scholarly journals HLA Haplotype Mismatch Transplants and Posttransplant Cyclophosphamide

2016 ◽  
Vol 2016 ◽  
pp. 1-5 ◽  
Author(s):  
Andrea Bacigalupo ◽  
Simona Sica
Keyword(s):  
Bone Marrow ◽  
Randomized Trial ◽  
Peripheral Blood ◽  
Prospective Randomized Trial ◽  
High Dose ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Unrelated Donors ◽  
Conditioning Regimens

The use of high dose posttransplant cyclophosphamide (PT-CY) introduced by the Baltimore group approximately 10 years ago has been rapidly adopted worldwide and is becoming a standard for patients undergoing unmanipulated haploidentical (HAPLO) transplants. PT-CY has been used following nonmyeloablative as well as myeloablative conditioning regimens, for bone marrow or peripheral blood grafts, for patients with malignant and nonmalignant disorders. Retrospective comparisons of HAPLO grafts with conventional sibling and unrelated donor grafts have been published and suggest comparable outcome. The current questions to be answered include the use of PT-CY for sibling and unrelated donors transplant, possibly in the context of prospective randomized trial.

The Polymorphism of HLA-A,-B,-C,-DRB1,-DQB1,-DRB3/4/5 loci in Zhejiang Han Population,China Using NGS Technology

2020 ◽  
Author(s):  
Fang Wang ◽  
Lina Dong ◽  
Wei Wang ◽  
Nanying Chen ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Linkage Disequilibrium ◽  
Strong Linkage Disequilibrium ◽  
Chinese Han ◽  
Haplotype Estimation ◽  
Hla Alleles ◽  
Han Population ◽  
Haplotype Frequencies ◽  
Resolution Level ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing

Abstract Background The allele and haplotype frequencies of HLA loci are various in the populations. Most of the data for HLA alleles and haplotypes were at low resolution or two fields resolution. Here, the data for HLA alleles and haplotypes at three fields resolution was reported in Chinese Han population. Methods All samples were come from the Zhejiang Cord Blood Bank, China after information consent. HLA-A, -B, -C, -DRB1, -DQB1, -DRB3/4/5 loci was genotyped using next generation sequencing (NGS) method. The allele frequencies of HLA loci were analyzed at three fields resolution. The haplotype estimation and linkage disequilibrium analysis was used Arlequin software 3.5.2.2. Result The top three frequent alleles of HLA-A, -B, -C, -DRB1, -DQB1 loci were A*11:01:01 (25.81%), A*24:02:01 (16.70%), A*02:01:01 (10.61%); B*40:01:02 (15.97%), B*46:01:01 (11.48%), B*58:01:01 (7.96%); C*07:02:01 (19.03%), C*01:02:01 (17.65%), C*03:04:01 (10.41%); DRB1*09:01:02 (17.96%), DRB1*12:02:01 (9.57%), DRB1*08:03:02 (9.54%); DQB1*03:01:01(21.05%), DQB1*03:03:02 (19.15%), DQB1*06:01:01 (12.08%); DRB4*01:03:01(25.72%), DRB3*02:02:01(20.27%), DRB5*01:01:01(10.96%) respectively. A total of 1542 distinct A-B-C-DRB1-DQB1-DRB3/4/5 haplotypes were identified. The alleles of HLA loci were showed strong linkage disequilibrium. Conclusion The data of allele and haplotype of HLA-A, -B, -C, -DRB1, -DQB1 and -DRB3/4/5 loci at three fields resolution level was obtained, which will help to analyze the HLA ploymorphism in the populations.

scholarly journals IPEX syndrome caused by a novel mutation in FOXP3 gene can be cured by bone marrow transplantation from an unrelated donor after myeloablative conditioning

2015 ◽  
Vol 2 (1) ◽  
pp. 31-38 ◽  
Author(s):  
Luis Murguia-Favela ◽  
Vy Hong-Diep Kim ◽  
Julia Upton ◽  
Paul Thorner ◽  
Brenda Reid ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Novel Mutation ◽  
Marrow Transplant ◽  
Favourable Outcome ◽  
Unrelated Donor ◽  
Myeloablative Conditioning ◽  
Hematopoietic Stem ◽  
Foxp3 Gene ◽  
Immune Mediated ◽  
Unrelated Donors

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare primary immunodeficiency caused by inherited defects in the FOXP3 gene that impair regulatory T cells. IPEX syndrome can be cured by hematopoietic stem cell transplantation (HSCT) from HLA-matched unrelated donors (MUD); however, the best conditioning prior to HSCT for IPEX syndrome is not known. Here we report on a patient suffering from IPEX syndrome, including immune-mediated colitis and membranous nephropathy, without polyendocrinopathy, caused by a novel mutation in the Forkhead domain of the FOXP3 gene. The patient's symptoms resolved following MUD HSCT after myeloablative conditioning performed at 16 months of age. The patient is clinically well, 3 years after HSCT, with robust immune reconstitution and fully engrafted. The lack of extensive autoimmune damage might have contributed to the patient's favourable outcome following MUD HSCT with myeloablative conditioning. Statement of novelty: We describe a novel mutation in the FOXP3 gene causing IPEX syndrome and the correction of IPEX syndrome with bone marrow transplant from a HLA-matched unrelated donor following myeloablative conditioning.

Amelioration of Late Complications Following Unrelated Donor Bone Marrow Transplantation When Anti-Thymocyte Globulin Is Used as a Part of Conditioning.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5319-5319
Author(s):  
Matthew E. Adess ◽  
Patrick Stiff ◽  
Tulio Rodriguez ◽  
John Norton ◽  
Mala Parthasarthy ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Graft Rejection ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Donor Bone Marrow ◽  
Number Of Patients ◽  
Significant Difference ◽  
Unrelated Donors ◽  
The Impact

Abstract Polyclonal anti-thymocyte globulin (ATG) reduces the risk for primary graft rejection as well as acute graft-versus-host disease (GVHD) by depleting T cells in both the host and the infused allograft. However, the impact of ATG on late outcomes is less certain. We report the results of a retrospective landmark analysis of consecutive patients who underwent an unrelated donor bone marrow transplant at our center between January 2001 and October 2005 (n=45) and survived at least 90 days following transplant. We compared late outcomes in patients who either recieved ATG (n=25) or did not (n=20) as a part of their conditioning regimen. Conditioning was with either busulfan and cyclophosphamide (n= 28; 17 without ATG) or BCNU, etoposide, cytarabine, and melphalan (n=18; 3 without ATG). Most patients (20) received rabbit ATG at a median dose of 3 mg/kg (range: 1.5–9 mg/kg) on day -4 and -3. Others were given equine ATG. GVHD prophylaxis consisted of tacrolimus + methotrexate in both groups. Median age was 42 years (range 18–65; 14 female). Bone marrow from unrelated donors matched at HLA-A, B, C, and DRB1 (7/8 and 8/8 matches) was used as the stem cell source. Diseases treated were CML (11), HD (9), AML (8), MDS (6), NHL (3), MM (3), and other (5). A median of 3 prior therapies had been given before transplant (range 1–5). There was no significant difference (Pearson χ2) in the number of patients beyond CR1/CP1 (n=25) and those having failed a prior autograft (n=17) between the two groups. The median overall survival in the recipients of ATG was 1382 days (95% CI: 373– 2391 days) as opposed to 364 days (95% CI: 0–851) in those not receiving ATG (P=0.125 by Log-Rank test); with a 1-year overall survival of 76% (59%–93%) vs. 50% (28–72) in the ATG vs. no ATG cohorts respectively, and 69% (49–89) vs. 44% (22–66) at 2-years. The 1-year progression free survival was 84% (69–98) vs.90% (77–100) in the ATG vs. no ATG cohorts, and 84% (69–98) vs. 67% (37–97) at 2 years. Chronic GVHD developed in 15/20 (75%) patients not receiving ATG (45% extensive), and in 12/25 (48%) in those recieving ATG (16% extensive) (P=0.06 Pearson χ2). Graft rejection was seen in 2/20 patients in the non-ATG arm and 1/25 patients in the ATG arm. Despite a lower incidence of chronic GVHD, the relapse rate was similar in the two groups (16% in the ATG group vs. 20% in the non-ATG group; P=0.73). Lymphoid recovery was similar in the two groups. The absolute lymphocyte counts at day-90 and day-180 post transplant were 680 vs 800/microL and 1100 vs. 1500/microL in the no ATG vs. ATG cohorts (P=0.275 repeated measures ANOVA). Serious late infections requiring parenteral antimicrobial treatment occured in 8 patients (32%) receiving ATG, and in 9 patients (45%) in the non-ATG arm ((P=0.248). CMV reactivation was seen in 8 patients (32%) receiving ATG, and 7 (35%) in the non-ATG arm. Eleven patients (55%) have died in the no ATG cohort from either relapse (2), GVHD (4) or infection (5); whereas in the ATG cohort 9 (36%) have died of either relapse (4), GVHD (3) or infection (2). In conclusion, ATG appears to reduce delayed transplant related complications, such as chronic GVHD and infections, in patients receiving bone marrow from unrelated donors. This may lead to a favorable trend towards improved survival in patients recieving ATG as a part of non-total body irradiation based conditioning.

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