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 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 Class II HLA Epitope Level Mismatch Can Predict Chronic Graft-Versus-Host Disease and Survival Following Haploidentical Transplant Using Post-Transplant Cyclophosphamide

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 311-311
Author(s):  
Scott R Solomon ◽  
Michael T Aubrey ◽  
Cheri Anobile ◽  
Xu Zhang ◽  
Brian M Freed ◽  
...  
Keyword(s):  
Graft Versus Host Disease ◽  
Chronic Gvhd ◽  
Hla Class I ◽  
Class Ii ◽  
Class I ◽  
Transplant Outcome ◽  
Graft Versus Host ◽  
Hla Dr ◽  
Hla Dq ◽  
The Impact

Abstract Post-transplant cyclophosphamide (PTCy) has improved the outcomes and expanded the use of haploidentical hematopoietic cell transplantation (haplo-HCT). Unlike many other allogeneic HCT settings, the impact of HLA disparity on graft-versus-host disease (GVHD) and transplant outcome in this setting remains unclear. HLAMatchmaker is a computer algorithm that assesses HLA compatibility at the structural level by determining what and how many functional epitopes (eplets), defined as patches of polymorphic residues within a radius of 3.0-3.5 Ångstroms, are shared between donor and recipient. It has been useful in the identification of acceptable mismatches (mm) for alloimmunized kidney transplant candidates. In order to determine the effects of HLA class I (HLA-A, B, C) and II (HLA-DR, DQ, DP) epitope mm on transplant outcome, we retrospectively analyzed 208 consecutive donor-recipient pairs receiving haplo-HCT with PTCy for hematologic malignancy. The impact of epitope mm (GVH direction) on GVHD and survival endpoints was evaluated by Cox multivariate analysis (MVA), controlling for other significant patient, donor and transplant-related factors. Median (range) recipient and donor age was 52 (19-75) and 38 (15-73) years respectively. Patients were transplanted for AML (34%), MDS/MPS/CML (20%), ALL (17%), NHL/HD/CLL (25%). PBSC was used as the stem cell source in 66% of patients, and conditioning intensity was myeloablative in 41%. The donor was a child, sibling, or parent in 47%, 38%, and 14% respectively. Median (range) follow-up for surviving patients was 33 (7-130) months. HLA class I epitope mm had no effect on GVHD or survival. In contrast, increased HLA class II epitope mm (>16) was significantly correlated to an increased frequency of chronic GVHD (figure 1). In MVA, higher degree of class II epitope mm was associated with chronic GVHD, total (HR 1.91, p=0.012) and moderate-to-severe (HR 2.37, p=0.006). The positive effect of increased class II epitope mm on chronic GVHD was driven mostly by HLA-DQ epitope mm (HR 1.7 for >7 vs. ≤7, p=0.047) with a non-significant contribution from HLA-DP (HR 1.36 for >2 vs. ≤2, p=0.24). In contrast, increased HLA-DR epitope mm had a protective effect on chronic GVHD (HR 0.52 for >7 vs. ≤7, p=0.021). Epitope mm was not significantly associated with acute GVHD, grade 2-4 or 3-4. There was also no effect of allele-level mm at any HLA loci on acute or chronic GVHD. We next tested the impact of class I and II epitope mm on survival, including the individual impact of HLA-DR, -DQ and -DP epitope mm. Although class I epitope mm had no impact in univariate analysis, a higher number of class II epitope mm (>16) was correlated with better overall survival and the effect was primarily driven by HLA-DQ epitope mm (figure 2). To better assess the impact of class II epitope mm on survival, we analyzed this variable in the context of a previously published MVA (Solomon et al. Biol Blood Marrow Transplant. 2018;24:789-798). Controlling for other significant variables (age, race, CMV status, donor relationship, HLA-DR mm, nonpermissive HLA-DP mm, KIR receptor-ligand mm and KIR haplotype), only increased HLA-DQ epitope mm (>7) was independently associated with decreased non-relapse (HR 0.34, p=0.021) and overall mortality (HR 0.60, p=0.039). These results indicate a significant effect of class II epitope mm on chronic GVHD and survival following haplo-HCT with PTCy. Higher level of class II epitope mm and HLA-DQ epitope mm is associated with increased chronic GVHD incidence, whereas HLA-DR epitope mm is protective. Higher HLA-DQ epitope mm is independently associated with better survival, when controlling for the presence of HLA-DR allele-level mm or a nonpermissive HLA-DP mm, which have been shown previously to improve survival. Class II HLA epitope level matching provides important prognostic information in the setting of haplo-HCT and PTCy, which is not reflected by conventional allele-level matching. Disclosures Solh: Amgen: Speakers Bureau; Celgene: Speakers Bureau; ADC Therapeutics: Research Funding.

39-P: Establishment of HLA Class I and Class II cutoff values for the donor-specific solid-phase lysate crossmatch medthod (DSA)

2008 ◽  
Vol 69 ◽  
pp. S26
Author(s):  
Steven R. De Goey ◽  
Brittany A. Schneider ◽  
S. Breanndan Moore ◽  
Sarah M. Jenkins
Keyword(s):  
Solid Phase ◽  
Hla Class I ◽  
Class Ii ◽  
Class I ◽  
Cutoff Values

A Comparison of 1 Antigen-Mismatched Related and Matched Unrelated Transplants.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3051-3051
Author(s):  
Poliana Patah ◽  
Rima Saliba ◽  
Marcelo Fernandez-Vina ◽  
Pedro Cano ◽  
Susana Pesoa ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Resolution ◽  
Cumulative Incidence ◽  
Chronic Gvhd ◽  
Class Ii ◽  
Class I ◽  
Stem Cell Source ◽  
Cell Source ◽  
Grade Ii

Abstract It is unclear how related donor transplants in which the donor-recipient pair is mismatched in one locus (1AgMM) compare to transplants performed using a fully matched unrelated donor (MUD), matching at HLA-A, B, C, DRB1 and DQB1. Here, we performed such a comparison. Methods: We studied 83 consecutive patients (pts) with acute leukemias and myeloproliferative/myelodysplasia syndromes receiving grafts considered to be “1-antigen mismatched related” (1AgMM) and compared their outcomes to that of 134 MUD HSCT performed from 1992 to 2006. Among 83 1AgMM transplants, 40 had prospectively or retrospectively performed high-resolution HLA typing (Hires), of which 6 pts were 8/10 matched, and 43 had only low resolution (Lowres) typing. 8/10 Hires pts were excluded from this analysis. All MUD donor-recipient pairs were typed by Hires. Median age, gender, cytogenetic risk, disease status at transplant and stem cell source were similar. Diagnosis were ALL in 5% of the Hires group, 28% of the Lowres and 0 in the MUD group; AML/MDS cases were 76%, 60% and 87%, respectively; and CML cases were 19%, 12% and 13%, respectively(p< 0.001). Preparative regimens were of reduced intensity for 22% of Hires, 21% of Lowres patients and 40% of MUD patients (p=0.02). High-resolution typing was performed for HLA-A, B, DRB1, DQB1 and DPB1, and SBT/SSOP for HLA-C. Cumulative incidence of NRM, acute and chronic GVHD was estimated accounting for death in the absence of event as a competing risk. The Cox’s proportional hazards model was used to compare outcomes beteween groups. Results: With a median follow-up of 15 mo for MUD pts, 27 mo for Hires patients and 33 mo for Lowres pts, OS at 18 mo is 52%, 46% and 22% (p= 0.002 for the comparison of MUD vs Lowres; P=NS for the comparison of MUD vs Hires); NRM is 23%, 26% and 54%(p=0.001 for the comparison of MUD vs Lowres; P=NS for the comparison of MUD vs Hires). Primary graft failure occurred in 1% of MUD, 5% of MOL and 12% of SER (p=0.003). Cumulative incidence of grade II-IV aGVHD is 34% for MUD pts, 48% for Hires and 49% for Lowres(p= 0.07); cGVHD: 34%, 40% and 54%(p=0.01 for the comparison of MUD vs Lowres). We divided the Hires related group according to presence of Class I or Class II mismatches, and compared their outcomes to the MUD group (Table). 23 pts had Class I and 11 pts had Class II mismatches; median follow-up is 26 and 62 mo, respectively. Distribution of gender, diagnosis, cytogenetic risk, dis. status at transplant, ablative/RIC regimens and stem cell source was similar between the 2 groups. Pts with class I mismatches had the worse survival. Conclusion: Cumulative incidence of grade II-IV aGVHD and cGVHD, non-relapse mortality and overall survival of 1AgMM (allele level typing) patients was similar to that observed in a cohort of recipients of molecularly matched, HLA 10/10 MUD transplants. OS at 18 mo HR (95%CI) P C. Incid. gd II-IV aGVHD HR (95% CI) P C. Incid. chronic GVHD HR (95% CI) P C. Incid= cumulative incidence MUD n=134 52% Reference 34% Reference 34% Reference Class I n=23 34% 1.8 (1–3.1) P=0.05 40% 1.3 (0.6–2.9) P=0.4 35% 1.1 (0.5–2.5) P=0.7 Class II n=11 73% 0.6 (0.2–1.9) P=0.4 64% 2.8 (1.3–6.3) P=0.01 48% 2.3 (0.9–5.7) P=0.08

The Detection of Donor-Directed, HLA-Specific Alloantibodies in Recipients of Unrelated Hematopoietic Cell Transplantation Is Predictive of Graft Failure.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 475-475 ◽  
Author(s):  
Robert Bray ◽  
Sandy Rosen-Bronson ◽  
Michael Haagenson ◽  
John Klein ◽  
Susan Flesch ◽  
...  
Keyword(s):  
Graft Failure ◽  
Hla Class I ◽  
Class Ii ◽  
Hematopoietic Cell ◽  
Class I ◽  
Unrelated Donor ◽  
Specific Antibodies ◽  
Cell Dose ◽  
Increased Risk ◽  
Cmv Status

Abstract Animal studies point to a strong role for MHC-specific antibody as a cause for failed donor hematopoietic cell engraftment, but the role of donor-directed HLA-specific allo-antibodies in human transplants has been controversial. To investigate such a role, we used a retrospective case-control design and studied unrelated donor:recipient pairs whose transplants were facilitated through the NMDP. A total of 37 cases with graft failure and 78 matched control pairs were evaluated. The 37 graft failure cases were selected based on survival beyond 28 days of transplant with no sustained engraftment, and available cryopreserved recipient serum to test for HLA-specific alloantibodies. Up to 3 controls were selected for each case, and matched for disease, disease status, graft type, patient age and year of transplant. Patients had AML, ALL, CML or MDS, 98% received myeloablative conditioning regimens, 100% received T replete grafts, 97% received marrow, and 97% received calcineurin-based GVHD prophylaxis. Patients and donors were retrospectively typed for HLA-A,B,Cw,DRB1,DQB1,DQA1,DPB1,and DPA1 by sequencing or other high resolution typing methods. Stored pre-transplant serum samples (patients and controls) were retrieved from the NMDP Research Repository, and assayed for HLA antibodies by solid-phase FlowPRA (One Lambda, Inc). All positive samples were evaluated for HLA specificity by single-antigen microparticles (LabScreen, One Lambda, Inc). Among the 37 failed transplants, 11 (30%) recipients possessed alloantibodies specific for donor HLA Class I or Class II, compared to only 3 (4%) of 78 controls. HLA-DR or DQ specific antibodies were not detected; hence, all HLA Class II-specific antibodies were directed to DP. Recipients with anti-DP antibodies against the donor mismatched DP were at increased risk of graft failure, indicating the importance of recipient antibodies directed against mismatched donor DP antigens. Exact conditional logistic regression analysis for the presence of either Class I HLA-A,B,Cw or Class II HLA-DP antibodies showed similar findings (Class I alone: OR. 6.31: 95% CI 1.17–62.9; p=0.03, Class II alone: OR 12.00; 95% CI 1.46–551.97; p=0.01, Class I and II combined: OR 19.08; 95% CI 2.72–828.49; p=0.0003). Further analyses were conducted to evaluate a limited set of covariates not accounted for in the case:control study, i.e. patient CMV status, cell dose and HLA-C match. Cell dose and CMV status were independently predictive of engraftment, p=0.01 and 0.03, respectively. No effect was observed for HLA-Cw match (p=0.84). The presence of anti-donor HLA Class I or II antibodies was predictive of engraftment when adjustment was made for either cell dose (OR 15.49; 95% CI 2.06–697.83; p=0.002) or CMV status (OR 7.94; 95% CI 0.97–367.84; p=0.05). In summary, these results indicate that donor-specific HLA Class I or Class II antibodies in recipients of unrelated donor hematopoietic cell transplants are associated with failed engraftment. We recommend that, as a “Standard-of-Practice”, all potential recipients be screened for the presence of HLA class I and class II antibodies including HLA DP. Donors should be excluded if they carry mismatched HLA types against which the patient has specific antibodies.

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
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