scholarly journals Management of Donor-Specific Antibodies in Haploidentical Transplant: Multicenter Experience From the Madrid Group of Hematopoietic Transplant

2021 ◽  
Vol 12 ◽  
Author(s):  
Rebeca Bailén ◽  
José Luis Vicario ◽  
Laura Solán ◽  
Irene Sánchez-Vadillo ◽  
Pilar Herrera ◽  
...  
Keyword(s):  
Solid Phase ◽  
Hla Class I ◽  
Progressive Increase ◽  
Buffy Coat ◽  
Class I ◽  
Hematopoietic Stem ◽  
Specific Antibodies ◽  
Single Antigen ◽  
Donor Specific Antibodies ◽  
Neutrophil Engraftment

BackgroundDonor specific antibodies (DSAs) can be responsible for graft failure (GF) in the setting of mismatched hematopoietic stem cell transplantation (HSCT). The aim of our study is to report the experience of the Madrid Group of Hematopoietic Transplant (GMTH) in patients with DSAs undergoing haplo-HSCT.MethodsPatients undergoing haplo-HSCT in centers from the GMTH from 2012 to 2020 were included in the study. DSAs were analyzed with a solid-phase single-antigen immunoassay; monitoring was performed during desensitization on days -14, -7, 0 and in a weekly basis until neutrophil engraftment. Desensitization strategies varied depending on center experience, immunofluorescence intensity, complement fixation and type of antibodies.ResultsWe identified a total of 20 haplo-HSCT in 19 patients performed with DSAs in 5 centers. 10 (53%) patients presented anti-HLA class I DSAs (6 of them with > 5000 mean fluorescence intensity (MFI)), 4 (21%) presented anti-HLA class II (1 with > 5000 MFI) and 5 (26%) presented both anti-HLA class I and II (5 with > 5000 MFI). 90% of patients received at least two treatments as desensitization strategy and all experienced a decrease of MFI after desensitization (mean reduction 74%). Only one patient who developed progressive increase of MFI after infusion developed GF. Desensitization treatments used included rituximab, immunoglobulins, therapeutic plasma exchange, incompatible platelets, buffy coat and immunosuppressors. Seventeen (90%) patients achieved neutrophil engraftment; one patient died before engraftment because of infection and one patient with class I DSAs developed primary GF despite an intensive desensitization. After a median follow-up of 10 months, OS and EFS were 60% and 58%, respectively, cumulative incidence of relapse was 5% and NRM was 32%.ConclusionsDespite the optimal strategy of DSAs desensitization remains unclear, the use of desensitization treatment guided by DSAs intensity kinetics constitute an effective approach with high rates of engraftment for patients with DSAs in need for an haplo-HSCT lacking an alternative suitable donor.

scholarly journals Management of Donor-Specific Antibodies in Haploidentical Transplant: Multicenter Experience from the Spanish Group of Hematopoietic Transplant (GETH-TC)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1798-1798
Author(s):  
Rebeca Bailen ◽  
Jose Luis Vicario ◽  
Beatriz Herruzo ◽  
Luisa Maria Guerra ◽  
Ana Vallés ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Solid Phase ◽  
Chronic Gvhd ◽  
Hla Class I ◽  
Class Ii ◽  
Buffy Coat ◽  
Class I ◽  
Suitable Alternative ◽  
Specific Antibodies ◽  
Donor Specific Antibodies

Abstract Background. Donor specific antibodies (DSAs) are preformed IgG antibodies with specificity against HLA molecules not shared with the donor that can lead to graft failure (GF) in the setting of mismatched HSCT. The aim of this study is to report the experience of the Spanish Group of Hematopoietic Transplant (GETH-TC) in patients with DSAs undergoing haplo-HSCT. Methods. Patients undergoing haplo-HSCT in centers from the GETH-TC from 2013 to 2021 were included in the study. DSAs were analyzed with a solid-phase single-antigen immunoassay (Luminex®); monitoring was performed prior to desensitization, prior to infusion and after infusion. Desensitization strategies used depended on center experience, immunofluorescence intensity, complement fixation and type of antibodies. Results. 59 haplo-HSCT with DSAs were performed in 57 patients in 13 centers. Characteristics of the population are shown in Table 1. 53 (93%) patients were female (91% with prior pregnancies). All patients lacked a suitable alternative donor. 51 (89%) received peripheral blood as stem cell source. Conditioning was myeloablative in 58% and all patients received post-transplant cyclophosphamide based GVHD prophylaxis; 3 (5%) patients received also ATG. 28 (49%) patients presented anti-HLA class I DSAs 22 of them with >5000MFI), 14 (25%) presented anti-HLA class II (6 with >5000MFI) and 15 (26%) presented both anti-HLA class I and II DSAs (13 with >5000MFI). Five patients did not receive desensitization treatment, 4 of them with <5000MFI. Of 52 patients receiving desensitization treatment, 49 received at least two treatments as desensitization strategy and all but 3 (6%) experienced a decrease of MFI after desensitization (mean reduction 80%); 2 out of those 3 patients developed GF. Desensitization treatments used included RTX in 83% of patients, IVIG (65%), therapeutic plasma exchange (TPE) (60%), incompatible platelets (16%), MMF (42%), buffy coat (only in patients with class II DSAs, 23%), tacrolimus (21%), bortezomib (4%) and steroids (2%). Cumulative incidence of neutrophil engraftment at day 30 was 74% (Figure 1), in a median of 18 days (IQR, 15-20); five patients died before engraftment due to toxicity and 7 patients experienced primary GF despite desensitization in 6 of them. 4 of them received a 2 nd transplant, one was alive after day 100. 30 (53%) patients died during the study period: 6 due to GF, 7 due to relapse, 7 due to infection, 6 due to endothelial complications (SOS, TA-TMA and diffuse alveolar hemorrhage) and 4 because of GVHD. After a median follow-up of 24 months, 2-year OS and EFS were 52% and 42%, respectively. 2-year cumulative incidence of relapse at was 14% and NRM was 41%. Cumulative incidence of grade II-IV aGVHD at day 180 was 13% and chronic GVHD was 25%. Conclusions. The use of desensitization treatment guided by DSAs intensity kinetics constitute an effective approach with high rates of engraftment for patients with DSAs in need for an haplo-HSCT lacking an alternative suitable donor, including non-malignant disorders. Figure 1 Figure 1. Disclosures Bailen: Pfizer, Kite-Gilead, Gilead: Honoraria. Oarbeascoa: Gilead: Honoraria, Speakers Bureau. Kwon: Novartis, Celgene, Gilead, Pfizer: Consultancy, Honoraria.

scholarly journals HLA donor-specific antibodies in allogeneic hematopoietic stem cell transplantation: challenges and opportunities

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 645-650 ◽  
Author(s):  
Douglas E. Gladstone ◽  
Maria P. Bettinotti
Keyword(s):  
Stem Cell ◽  
Hematopoietic Stem Cell ◽  
Solid Phase ◽  
Hla Antigens ◽  
Relative Strength ◽  
Hematopoietic Stem ◽  
Strength Assessment ◽  
Specific Antibodies ◽  
Challenges And Opportunities ◽  
Donor Specific Antibodies

Abstract Allogenic hematopoietic stem cell recipients may have preformed antibodies directed against foreign HLA antigens. The use of partially HLA-mismatched allogeneic hematopoietic stem cell donors allows for the possibility of the presence of circulating HLA donor-specific antibodies (DSAs) in the recipient. The presence of DSAs at the time of stem cell infusion increases the risk of primary graft failure. More recently developed technology using solid phase immunoassays (SPIs) with fluorochrome-conjugated beads has greatly improved the ability to detect and classify DSAs. When used in combination with the classic lymphocytotoxic complement-dependent and flow cytometric crossmatch tests, SPIs help provide DSA strength assessment. Parous females frequently harbor DSAs. DSAs tend to be of higher intensity when directed against haploidentical first-degree relatives. DSA assessment requires frequent monitoring as their relative strength can change over time. Although the criteria that constitutes a prohibitive DSA is unknown, desensitization techniques can result in engraftment rates as experienced in fully HLA-matched allogeneic blood or marrow transplantation recipients.

scholarly journals Impact of HLA Molecular Mismatch on Haploidentical Hematopoietic Stem Cell Transplantation: A Center for International Blood and Marrow Transplant Research Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3917-3917
Author(s):  
Jun Zou ◽  
Tao Wang ◽  
Yung-Tsi Bolon ◽  
Shahinaz M. Gadalla ◽  
Steven G.E. Marsh ◽  
...  
Keyword(s):  
Stem Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Hla Class I ◽  
Marrow Transplant ◽  
Class I ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Blood And Marrow Transplant ◽  
Neutrophil Engraftment

Abstract ABSTRACT BACKGROUND The number of haploidentical hematopoietic stem cell transplantations (haplo-HSCT) being performed has substantially increased in recent years. Single-center studies have previously used in silico algorithms to quantitively measure HLA disparity and shown an association of the number of HLA molecular mismatches with relapse protection and/or increased risk of acute graft-versus-host disease (GVHD) in haplo-HSCT. However, inconsistent results from small studies have made it difficult to understand the full clinical impact of molecular mismatch in haplo-HSCT. OBJECTIVE In the current study, we investigated the potential of the HLA class I and II mismatched eplet (ME) score measured by HLAMatchmaker, as well as ME load at a specific locus to predict outcomes in a registry-based cohort of haplo-HSCT recipients. STUDY DESIGN We analyzed data from patients (n= 1,287) who underwent their first haplo-HSCT for acute lymphoblastic leukemia, acute myeloid leukemia, or myelodysplastic syndrome between 2013 and 2017, as reported to the Center for International Blood and Marrow Transplant Research database. ME load at each HLA locus and total Class-I and -II were scored using the HLAMatchmaker module incorporated in HLA Fusion software v4.3, which identifies predicted eplets based on the crystalized HLA molecule models and identifies ME by comparing donor and recipient eplets. RESULTS In the cohort studied, ME scores derived from total HLA Class I or Class II loci or individual HLA loci were not associated with overall survival, disease-free survival, non-relapse mortality, relapse, acute or chronic GVHD (P< .01). An unexpected strong association was identified between total class II ME load in the GVH direction and slower neutrophil engraftment (HR 0.82; 95% CI, 0.75 - 0.91; P < .0001) and platelet engraftment (HR 0.80; 95% CI, 0.72 - 0.88; P < .0001). This was likely attributable to ME load at the HLA-DRB1 locus, which was similarly associated with slower neutrophil engraftment (HR 0.82; 95% CI, 0.73 - 0.92; P = .001) and slower platelet engraftment (HR 0.76; 95% CI, 0.70 - 0.84; P < .0001). Additional analyses suggested that this effect is attributable to matched vs. mismatched in the GVH direction and not to ME load, as there was no dose effect identified. CONCLUSION These findings contradict those of prior relatively small studies reporting that ME load, as quantified by HLAMatchmaker, was associated with haplo-HSCT outcomes. As the study failed to demonstrate the predictive value of ME from HLA molecules for major clinical outcomes, other molecular mismatch algorithms in haplo-HSCT settings should be tested. Disclosures Lee: Pfizer: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Janssen: Other; Takeda: Research Funding; Syndax: Research Funding; AstraZeneca: Research Funding; Kadmon: Research Funding; Amgen: Research Funding.

scholarly journals Long-term survival of the transplanted kidney and the clinical relevance of donor-specific antibodies

2020 ◽  
Vol 3 (1) ◽  
pp. 17-22
Author(s):  
Eva Svobodova ◽  
Sarka Valhova ◽  
Ondrej Viklicky ◽  
Ilja Striz ◽  
Jelena Skibova ◽  
...  
Keyword(s):  
Graft Survival ◽  
Solid Phase ◽  
Kidney Graft ◽  
Term Survival ◽  
Specific Antibodies ◽  
Antibody Mediated Rejection ◽  
Number Of Patients ◽  
Single Antigen ◽  
Donor Specific Antibodies

The aim of our study was to evaluate the relevance of donor-specific antibodies (DSA) as defined by solid-phase single-antigen (SA) assays for predicting long-term graft survival after kidney transplantation. Sera from 132 kidney transplant recipients were retrospectively tested before, 3, 6 and 12 months after transplantation. The incidence of rejection and graft survival was followed up for 7 years. We found 29 episodes of acute cellular rejection (CR), 21 cases of antibody-mediated rejection (AMR) and 18 graft failures due to immunological reasons. Pre-transplant DSA and DSA three months after transplantation correlated with an increased rate of AMR and impaired graft function. After the fourth year, recipients with persistent DSA were at a higher risk of graft failure (p = 0.0317). Antibody specificity was prevailingly to HLA class I antigens (66.6% DSA, 75% non-DSA). During the first year after transplantation, the number of patients with non-DSA decreased (30.3% to 10.7%), while, due to de novo production of antibodies, the number of DSA positive patients remained constant. Conclusion: Detection of antibodies to HLA antigens using solid-phase assays, especially single-antigen bead technology before and three months after transplantation is predictive for increased incidence of antibody-mediated rejection and impaired long-term kidney graft survival.

EPITOPE ANALYSIS OF HLA CLASS I DONOR SPECIFIC ANTIBODIES IN SENSITIZED RENAL TRANSPLANT RECIPIENTS

2000 ◽  
Vol 70 (2) ◽  
pp. 323-327 ◽  
Author(s):  
Andreas C. Papassavas ◽  
Aliki Iniotaki-Theodoraki ◽  
John Boletis ◽  
Alkiviadis Kostakis ◽  
Catherine Stavropoulos-Giokas
Keyword(s):  
Renal Transplant ◽  
Hla Class I ◽  
Class I ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Specific Antibodies ◽  
Epitope Analysis ◽  
Donor Specific Antibodies

scholarly journals Case report - pre-transplant testing and post-transplant monitoring for an HLA-immunized recipient in heart transplantation

2020 ◽  
Vol 3 (1) ◽  
pp. 52-56
Author(s):  
Lucija Jukic ◽  
Biserka Palfi ◽  
Bosko Skoric ◽  
Marija Burek Kamenaric
Keyword(s):  
Heart Transplantation ◽  
Solid Phase ◽  
Screening Method ◽  
Hla Class I ◽  
Specific Antibodies ◽  
Post Transplant ◽  
Complement Dependent Cytotoxicity ◽  
Human Leucocyte Antigens ◽  
Donor Specific Antibodies ◽  
Leucocyte Antigens

We report the workflow of immunogenetic pre-transplant testing and post-transplant monitoring in the case of a recipient immunized to human leucocyte antigens (HLA) who was waitlisted for heart transplantation. The recipient underwent heart transplantation across preformed HLA class I Donor Specific Antibodies (DSAs) detected by solid phase Luminex screening method but not by complement dependent cytotoxicity (CDC) screening method. The CDC lymphocyte crossmatch, which was performed retrospectively, was a weak positive. Post-transplant DSA monitoring by Luminex method revealed the decrease of HLA-A1, A25 and B57 DSAs with, at the same time, an increase of HLA-B8 DSA, as well as weak transient non-DSA HLA-DP antibodies. This case presents the importance of extensive immunogenetic testing and monitoring for identifying recipients with increased immunological risk for successful heart transplantation.

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