Anti-thymocyte globulin overcomes the negative impact of HLA mismatching in transplantation from unrelated donors (original) (raw)
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Biology of Blood and Marrow Transplantation, 2009
patients with a median age of 41 years (range: 1-68 years) received stem cell transplantation (SCT) from unrelated donors after an antithymocyte-globulin (ATG)containing conditioning regimen. In 268 patients, complete molecular typing (4-digit) of HLA-A, -B, -C, -DRB1, and -DQB1 was available: 110 patients were completely matched for 10 alleles, 91 patients had 1 allele-mismatch (9/10), and 67 patients were mismatched for 2-4 alleles (6-8/10). The incidence of grade II-IV acute graft-versus-host disease (aGVHD) was 33% in the 10/10, 41% in the 9/10, and 40% in the 6-8/10 group, respectively (P 5 .1). The cumulative incidence of treatment-related mortality (TRM) and relapse among the groups were similar (27%, 31%, and 32%, P 5 .2; and 28%, 27%, and 26%, P 5 .9. After a median follow-up of 35 months (range: 3-120 months), the estimated 5-year disease-free survival (DFS) was 42% and did not differ among the 10/10, the 9/10, and the 6-8/10-mismatched groups (45% versus 42% versus 39%) (P 5 .5). In multivariate analysis, only age (hazard ratio [HR] 1.013) (P 5 .004) and badrisk disease (HR 1.975) (P \ .001) were independent risk factors for DFS. In conclusion, pretransplant ATG allows allogeneic SCT from unrelated donors with HLA disparities.
Biology of Blood and Marrow Transplantation, 2015
Over the past 2 decades, reduced-intensity conditioning allogeneic hematopoietic cell transplantation (RIC HCT) has increased substantially. Many patients do not have fully HLA-matched donors, and the impact of HLA mismatch on RIC HCT has not been examined in large cohorts. We analyzed 2588 recipients of 8/8 HLA-high resolution matched (n ¼ 2025) or single-locus mismatched (n ¼ 563) unrelated donor (URD) RIC HCT from 1999 to 2011. Overall survival (OS) was the primary outcome. Secondary endpoints included treatment-related mortality (TRM), relapse, disease-free survival (DFS), and acute/chronic graft-versus-host disease (GVHD). Adjusted 1-and 3-year OS was better in 8/8-versus 7/8-matched recipients (54.7% versus 48.8%, P ¼ .01, and 37.4% versus 30.9%, P ¼ .005, respectively). In multivariate models 7/8 URD RIC HCT recipients had more grades II to IV acute GVHD (RR ¼ 1.29, P ¼ .0034), higher TRM (RR ¼ 1.52, P < .0001), and lower DFS (RR ¼ 1.12, P ¼ .0015) and OS (RR ¼ 1.25, P ¼ .0001), with no difference in relapse or chronic GVHD. In subgroup analysis, inferior transplant outcomes were noted regardless of the HLA allele mismatched. Previously reported permissive mismatches at HLA-C (C*03:03/C*03:04) and HLA-DP1 (based on T celleepitope matching) were not associated with better outcomes. Although feasible, single-locus mismatch in RIC URD HCT is associated with inferior outcomes.
Transplantation, 1998
Methods. HLA-A-, HLA-B-, and HLA-DR-compatible unrelated bone marrow was given to 132 patients. The diagnoses included chronic myeloid leukemia (n,)34؍ acute lymphoblastic leukemia (n,)92؍ acute myeloid leukemia (n,)72؍ myelodysplastic syndrome (n,)4؍ lymphoma (n,)3؍ myeloma (n,)1؍ myelofibrosis (n,)1؍ severe aplastic anemia (n,)21؍ and metabolic disorders (n.)21؍ The median age was 25 years (range 1-55 years). HLA class I was typed serologically, and class II was typed by polymerase chain reaction using sequence-specific primer pairs. Immunosuppression consisted of antithymocyte globulin or OKT3 for 5 days before transplantation and methotrexate combined with cyclosporine.
Bone marrow transplantation, 2016
Graft failure remains a severe complication of hematopoietic stem cell transplantation (HSCT). Several risk factors have already been published. In this study, we re-evaluated them in a large cohort who had the benefit of the recent experience in HSCT (2006-2012). Data from 4684 unrelated donor HSCT from 2006 to 2012 were retrospectively collected from centers belonging to the French Society for Stem Cell Transplantation. Among the 2716 patients for whom HLA typing was available, 103 did not engraft leading to a low rate of no engraftment at 3.8%. In univariate analysis, only type of disease and status of disease at transplant for malignant diseases remained significant risk factors (P=0.04 and P<0.0001, respectively). In multivariate analysis, only status of disease was a significant risk factor (P<0.0001). Among the 61 patients who did not engraft and who were mismatched for 1 HLA class I and/or HLA-DP, 5 donor-specific antibodies (DSAs) were detected but only 1 was clearly ...
Biology of Blood and Marrow Transplantation, 2016
Background: Many patients (pts) especially those of non-European & mixed ancestries without matched siblings also have no 8/8 HLA-matched unrelated donors (URD). While unrelated CB & haplo donors offer alternative grafts their availability in all pt populations is not established. Methods: We are investigating the addition of haplo CD34+ cells to double unit CB grafts (haplo-dCBT) to provide a myeloid bridge prior to CB engraftment. Thus, we have prospectively evaluated CB & haplo graft availability 9/2012-7/2015 in pts with hematologic malignancies & without 8/8 HLA-matched URDs. CB units required a cryopreserved TNC dose > 1.5 x 10 7 /kg/unit & > 4/6 HLA-A,-B antigen,-DRB1 allele match. Results: 89 pts [median age 50 years (range 15-68)] were evaluated. Diagnoses included 58 acute leukemias, 10 MDS/ MPD, & 21 NHL/HD. Overall, 59 (66%) pts received haplo-dCBT (using 9 parents, 17 siblings, 27 children, 6 extended family) whereas 17 (19%) pts received dCBT only, & 13 (15%) pts did not have a CB graft. Detailed evaluation of the CB &/or haplo graft availability revealed 4 pt groups (Gp, Figure): Gp 1 (6/89, 7%) pts underwent dCBT only as they had no family members suitable to type or were adopted. Gp 2 (52/89, 58%) received a haplo-dCBT & the 1 st haplo chosen was cleared for donation. Of these pts, the minority [24/52 (46%)] were non-European. Gp 3 (18/89, 20%) had dCB grafts but required work-up of 2-5 haplo donors/pt. 41 haplos were evaluated but in only 7 pts was haplo-dCBT possible. Haplos failed clearance predominantly due to medical &/ or psychosocial reasons (eg inability of national or international donors to come to our center, donor refusal or withdrawal of consent, imprisonment, or patient refusal to approach the donor). Haplo workups creating unacceptable delay also played a role. The majority of Gp 3 pts were non-European (14/18, 78%). Gp 4 (13/89, 15%) pts had no dCB grafts. 3 also had no haplos identified, 2 underwent haplo only transplants, & 8 had no transplant due to loss to follow-up, alternative therapy, or rapid disease progression. The majority of Gp 4 pts were non-European (11/13, 85%). The median weight of Gp 4 pts was 93 kg (range 52-143) vs 78 kg (range 33-133) in the total 76 pts (Gps 1-3) who received dCB grafts. Conclusions: 15% of pts had no CB grafts & as expected the majority were non-European with a high weight. Importantly, while few pts had no haplos identified, the substantial difficulty in clearing haplos for donation was unexpected.
Transplantology, 2022
HSCT from an unrelated HLA-mismatched donor (MMUD) is one of the alternatives where an HLA-matched donor is not found. The aim of this study was to compare GvHD prophylaxis with anti-thymocyte globulin (ATG) vs. post-transplant cyclophosphamide (PT-Cy). Thirty-nine adult patients were uniformly treated with rabbit ATG-Cy-A-MTX and peripheral blood stem cell (PBSC) and 40 adult patients with PT-Cy-MMF-tacrolimus and PBSC. This retrospective study was registered at ClinicalTrials.gov NCT04598789. Three-year overall survival was 42% vs. 64% for ATG and PT-Cy (p < 0.0005), three-year treatment-related mortality (TRM) was 36% vs. 8% (p = 0.0033) and the three-year relapse incidence (RI) was 15% vs. 28% (p = NS), respectively. The incidences of day-100 GvHD graded II–IV and III–IV were 39% vs. 7% (p = 0.0006) and 11% vs. 0% (p = 0.04), respectively, whereas the three-year cGvHD incidences were 48% vs. 13% (p = 0.0005), respectively. We were able to show how PT-Cy can reduce the inciden...
Blood, 2011
To clarify which is preferable, a related donor with an HLA-1 Ag mismatch at the HLA-A, HLA-B, or HLA-DR loci in the graft-versus-host (GVH) direction (RD/1AG-MM-GVH) or an HLA 8/8-allele (HLA-A, HLA-B, HLA-C, and HLA-DRB1)–matched unrelated donor (8/8-MUD), we evaluated 779 patients with acute leukemia, chronic myelogenous leukemia, or myelodysplastic syndrome who received a T cell–replete graft from an RD/1AG-MM-GVH or 8/8-MUD. The use of an RD/1AG-MM-GVH donor was significantly associated with a higher overall mortality rate than the use of an 8/8-MUD in a multivariate analysis (hazard ratio, 1.49; P < .001), and this impact was statistically significant only in patients with standard-risk diseases (P = .001). Among patients with standard-risk diseases who received transplantation from an RD/1AG-MM-GVH donor, the presence of an HLA-B Ag mismatch was significantly associated with a lower overall survival rate than an HLA-DR Ag mismatch because of an increased risk of treatment-...
Bone Marrow Transplantation, 2020
Patients with acute myeloid leukaemia (AML) who lack a matched sibling or unrelated donor commonly undergo transplantation from a donor matched at 9/10 HLA-A,-B,-C,-DRB1,-DQB1 alleles, and it is unclear if a specific locus mismatch is preferable to any other. We therefore studied 937 patients with AML in complete remission transplanted using a reduced intensity conditioning regimen from an unrelated donor mismatched at a single allele. In a multivariate analysis, patient age, adverse karyotype and patient cytomegalovirus (CMV) seropositivity were correlated with decreased leukaemia free survival (LFS) and overall survival (OS). There was no significant difference in LFS or OS between patients transplanted from donors mismatched at HLA-A,-B,-C or-DRB1 in comparison to a HLA-DQB1 mismatched transplant. In a multivariate analysis, patients transplanted with a HLA-A mismatched donor had higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM) than patients transplanted with a HLA-DQB1 mismatched donor. Patient CMV seropositivity was associated with an increase in NRM and acute GVHD and reduced LFS and OS, regardless of donor CMV status. For CMV seropositive patients lacking a fully matched donor, alternative GVHD and CMV prophylaxis strategies should be considered.