HLA-mismatched Unrelated Donors Research Articles

Abatacept for acute graft-versus-host disease prophylaxis after unrelated donor hematopoietic cell transplantation

AbstractAbatacept plus calcineurin inhibitors/methotrexate (CNI/MTX) is the first US Food and Drug Administration (FDA)-approved regimen for acute graft-versus-host disease (aGVHD) prophylaxis during unrelated-donor hematopoietic cell transplantation (URD-HCT). Using Center for International Blood and Marrow Transplant Research data, we investigated its impact in patients receiving 7/8 HLA-mismatched unrelated donor (MMUD) or 8/8 HLA-matched unrelated donor (MUD) URD-HCT between 2011 and 2018. Primary outcomes included day-180, 1-year, and 2-year overall survival (OS) and relapse-free survival (RFS) for abatacept + CNI/MTX vs CNI/MTX, CNI/MTX + antithymocyte globulin (ATG), and posttransplant cyclophosphamide-based prophylaxis (PT-Cy). For 7/8 MMUDs, day-180 OS (primary end point supporting FDA approval) was significantly higher for abatacept + CNI/MTX vs CNI/MTX (98% vs 75%; P = .0028). Two-year RFS was significantly higher for abatacept + CNI/MTX vs CNI/MTX (74% vs 49%; P = .0098) and CNI/MTX + ATG (77% vs 35%; P = .0002), and similar vs PT-Cy (72% vs 56%; P = .1058). For 8/8 MUDs, 2-year RFS for abatacept + CNI/MTX was numerically higher vs CNI/MTX (63% vs 52%; P = .1497), with an improved hazard ratio (HR) of 0.46 (0.25-0.86), and vs CNI/MTX + ATG (66% vs 55%; P = .1193; HR, 0.39 [0.21-0.73]), and was similar vs PT-Cy (68% vs 57%; P = .2356; HR, 0.54 [0.26-1.11]). For 7/8 MMUD and 8/8 MUD recipients, abatacept + CNI/MTX prophylaxis improved survival outcomes vs CNI/MTX and CNI/MTX + ATG; outcomes were similar to PT-Cy–based regimens. Abatacept + CNI/MTX may facilitate unrelated donor pool expansion for HCT.

Comparison of Cyclophosphamide-Based Graft Versus Host Disease Prophylaxis after "Allogeneic Stem Cell Transplantation from 9/10 HLA Matched Unrelated Donor'' with Standard Graft Versus Host Disease Prophylaxis after "10/10 HLA Matched Relative Donor'' Transplant.

Background: Graft Versus Host Disease (GvHD), which can be observed at a rate of 30-80% after allogeneicstem cell transplantation (ASCT) is an important complication that adversely affects the survival and quality of the life of patients.Posttransplant cyclophosphamide (PTCy) effectively prevents GvHD after HLA-haploidentical ASCT. In our study, the use of PTCy in 1-antigen HLA-mismatched unrelated donor (9/10MMUD) ASCT was compared with standard GvHD prophylaxis in HLA-identical related donor (MRD) ASCT. Materials and Methods: We conducted a retrospective study of the comparison of 42 patients with 9/10 MMUD ASCT receiving PTCy+Methotrexate (MTX)+Calcineurin Inhibitor (CNI) and 37 patients with HLA-identical MRD who received MTX+CNI in 3 bone marrow transplantation centers. Results: Cumulative incidences of grade I-II (64.6% vs 45.4%, p=0.187) or grade III to IV acute GvHD (35.4% vs54.6%,p=0.187)and chronic GvHD (11.9% vs 29.7%, p=0.096) were similar in the PTCy group and control group. No statistically significant differences were observed between PTCy and the control group in overall survival rate (52.4% vs 62.2%, p=0.381), progression-free survival (1483.97 vs 1200.70 days, p=0.502), relapsed-related mortality rate (21.4% vs 16.2%, p=0.556) and treatment-related mortality rate (16.7% vs 21.6%, p=0.575). Conclusion: With the addition of PTCy to standard GvHD prophylaxis in 9/10MMUD ASCT, the risk of GvHD due to incompatibility and unrelated transplantation is eliminated, and transplantation success is achieved with MRD ASCT. PTCy-based prophylaxis is an effective and safe strategy to prevent GvHD in 9/10 MMUD ASCT without increasing the risk of relapse and treatment-related mortality.

Haploidentical Versus Mismatched Unrelated Donor Hematopoietic Cell Transplantation: HLA Factors and Donor Age Considerations

HLA-mismatched unrelated donors and haploidentical related donors are suitable stem cell sources for hematopoietic cell transplantation (HCT) when patients lack HLA-matched donors. Clinical outcome after mismatched HCT is influenced by HLA factors including the similarity of peptide-binding motifs (PBMs) between the patient and unrelated donor, and of the HLA-B leader in unrelated and haploidentical donors. Whether these factors can aid in the selection between mismatched unrelated and haploidentical donors is not known. To address this question, we investigated outcomes between the two donor types defined by matching for the PBM and leader peptide. We compared PBM-matched (n = 614) and mismatched (n = 958) MMUDs with calcineurin-inhibitor-based prophylaxis to four haploidentical groups that received post-transplant cyclophosphamide (PTCy)-based prophylaxis. The haploidentical groups were B-leader matched/DRB1-mismatched (n = 722), B-leader matched/DRB1-matched (n = 154), B-leader mismatched/DRB1-mismatched (n = 493), and B-leader mismatched/DRB1-matched (n = 63). Multivariate analysis showed that the B-leader matched/DRB1-mismatched haploidentical group had the best overall survival (OS) compared to the PBM-matched MMUD, while other haploidentical groups had comparable OS. The PBM-mismatched MMUD showed the poorest outcomes, similar to the B-leader mismatched/DRB1-matched haploidentical group. Among non-HLA factors, donor age was the most significant predictor of OS. These results suggest that a B-leader matched/DRB1 mismatched haploidentical donor might be the preferred choice among donors of similar age. If such a donor is not available, the youngest donor from either PBM-matched unrelated or other haploidentical groups could be a beneficial choice. These findings need validation with both donor groups receiving PTCy-based graft-versus-host disease prophylaxis.

Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis following mismatched unrelated donor peripheral blood stem cell (PBSC) transplantation.

6503 Background: Our prior prospective multi-center clinical trial (15-MMUD; NCT02793544) estimated 79% overall survival (OS) at one year in adult patients with hematological malignancies undergoing reduced intensity conditioning (RIC), receiving bone marrow (BM) grafts from HLA-mismatched unrelated donors (MMUD), and post-transplant cyclophosphamide (PTCy)-based graft- versus-host disease (GVHD) prophylaxis (Shaw et al, J Clin Oncol 2021). We sought to determine whether OS in adults receiving mobilized PBSC from MMUD would be comparable. Methods: We conducted a prospective, multi-center Phase II study (ACCESS; NCT04904588) to assess the impact of PTCy-based GVHD prophylaxis on OS following MMUD transplantation in adults and children with advanced hematological malignancies. The study included three strata: two for adults based on conditioning regimen intensity [myeloablative (MAC) or RIC] using PBSC, and one pediatric cohort using MAC and BM. Eligible donors were matched at 4-7/8 HLA-loci (HLA -A, -B, -C, and -DRB1) and < 35 years. The primary endpoint was OS at one year following transplantation. We report the results of a planned interim analysis of the first 70 adult patients enrolled on the RIC PBSC stratum. Results: Thirteen sites enrolled 70 patients with the following demographics: median age of 65 years (range 24-77); 50% male; diagnoses: AML (53%), MDS (26%), ALL (7%), other heme malignancies (14%); and patient race/ethnicity: non-Hispanic white (48%). Donor characteristics included: median age 25y (range 18-35); male (44%); and HLA match level: 7/8: 67%; 6/8: 27%; 5/8: 6%. Conditioning regimens included fludarabine (flu) and melphalan (63%), flu/busulfan (20%), other (17%). OS at one year post HCT was 79% (95% confidence interval (CI): 68-87%). Secondary endpoints are provided in the table. Conclusions: Encouraging OS was observed at one year following MMUD PBSC in patients receiving RIC and PTCy. Notably, half of enrolled patients were people of color. OS was similar to our prior study using BM grafts. Rates of GVHD and other complications appear comparable to those in HLA-matched donor recipients, suggesting MMUD HCT could expand access to a potentially life-saving therapy. Accrual to both adult strata of ACCESS is complete, with over 200 patients in follow-up. Accrual to the pediatric stratum continues. Clinical trial information: NCT04904588 . [Table: see text]

Combined effect of unrelated donor age and HLA peptide-binding motif match status on HCT outcomes

AbstractAn HLA-mismatched unrelated donor who is class I peptide-binding motif (PBM)-matched is preferred over a PBM-mismatched donor. We hypothesized that using a younger donor (aged ≤35 years vs >35 years) could compensate for the inferior overall survival (OS) associated with PBM mismatches. We compared 6 groups: HLA-matched/younger donor (n = 10 531), HLA-matched/older donor (n = 3572), PBM-matched/younger donor (n = 357), PBM-matched/older donor (n = 257), PBM-mismatched/younger donor (n = 616), and PBM-mismatched/older donor (n = 339) in patients undergoing transplantation with conventional graft-versus-host disease prophylaxis. In multivariate analysis, HLA-matched/younger donors were associated with superior OS relative to any other group. Pairwise comparisons showed that donor age significantly impacted OS in both HLA-matched and HLA-mismatched groups. Moreover, younger donors appeared to negate the detrimental effect of PBM mismatching: the PBM-matched/younger donor group had similar OS as the HLA-matched/older donor group and the PBM-mismatched/younger donor group had similar OS as the PBM-matched/older donor group. Our study suggests that older unrelated donor age and PBM mismatching confer similarly adverse effects on OS and the impacts are additive, a finding which may widen the “acceptable” donor pool. The best OS is observed with HLA-matched/younger donors and the worst with PBM-mismatched/older donors. These findings should be validated with other data sets and with posttransplantation cyclophosphamide-based prophylaxis.

Flares of acute graft-versus-host disease: a Mount Sinai Acute GVHD International Consortium analysis

AbstractThe absence of a standardized definition for graft-versus-host disease (GVHD) flares and data on its clinical course are significant concerns. We retrospectively evaluated 968 patients across 23 Mount Sinai Acute GVHD International Consortium (MAGIC) transplant centers who achieved complete response (CR) or very good partial response (VGPR) within 4 weeks of treatment. The cumulative incidence of flares within 6 months was 22%, and flares were associated with a higher risk of nonrelapse mortality (NRM; adjusted hazard ratio [aHR], 4.84; 95% confidence interval [CI], 3.19-7.36; P < .001). Flares were more severe (grades 3/4, 41% vs 16%; P < .001) and had more frequent lower gastrointestinal (LGI) involvement (55% vs 32%; P < .001) than the initial GVHD. At CR/VGPR, elevated MAGIC biomarkers predicted the future occurrence of a flare, along with its severity and LGI involvement. In multivariate analyses, higher Ann Arbor (AA) biomarker scores at CR/VGPR were significant risk factors for flares (AA2 vs AA1: aHR, 1.81 [95% CI, 1.32-2.48; P = .001]; AA3 vs AA1: aHR, 3.14 [95% CI, 1.98-4.98; P < .001]), as were early response to initial treatment (aHR, 1.84; 95% CI, 1.21-2.80; P = .004) and HLA-mismatched unrelated donor (aHR, 1.74; 95% CI, 1.00-3.02; P = .049). MAGIC biomarkers also stratified the risk of NRM both at CR/VGPR and at the time of flare. We conclude that GVHD flares are common and carry a significant mortality risk. The occurrence of future flares can be predicted by serum biomarkers that may serve to guide adjustment and discontinuation of immunosuppression.

Comparison of long-term outcomes after first HLA-mismatched unrelated donor transplantation with single unrelated cord blood transplantation using reduced-intensity or reduced-toxicity conditioning

BackgroundNo comparative data have shown significant survival differences between HLA-mismatched unrelated donor (MMUD) transplantation and cord blood (CB) transplantation, each with reduced-intensity/reduced-toxicity conditioning (RIC/RTC). However, advances in graft-versus-host disease (GVHD) prophylaxis might help update current strategies. MethodsWe retrospectively compared the outcomes of first allogeneic hematopoietic cell transplantation from MMUDs (n = 15) or single unrelated CB (n = 35) after RIC/RTC. ResultsThe median age was 60 years. The MMUD group had a numerically lower 100-day incidence of grade III–IV acute GVHD (7% vs. 29%, P = 0.079) and non-relapse mortality (0% vs. 40%, P = 0.12). Eight MMUD recipients received anti-thymocyte globulin, bortezomib, or posttransplant cyclophosphamide for GVHD prophylaxis. They did not develop grade III–IV acute GVHD. The MMUD group had significantly better 5-year overall survival than the CB group (62% vs. 31%, P = 0.021), although relapse rates were similar. A multivariable analysis and sensitivity analysis also showed trends toward higher overall survival in the MMUD group. ConclusionMMUD with better GVHD prophylaxis might be preferred over CB in patients with older age and comorbidities.

Retrospective analysis of allogeneic hematopoietic stem cell transplantation for multiple myeloma after myeloablative conditioning with 8 Gy of total body irradiation

Allogeneic hematopoietic stem cell transplantation (allo-SCT) is a curative treatment option for multiple myeloma (MM), but few patients are eligible due to its high risk of treatment-related toxicity and relapse. Here, we report the feasibility and efficacy of allo-SCT after myeloablative conditioning with 8 Gy of total body irradiation (TBI) for reducing relapse of MM. We retrospectively analyzed data from 30 consecutive patients who received allo-SCT for MM after 8 Gy of TBI at Japanese Red Cross Medical Center between 2012 and 2021. Median age at allo-SCT was 47 (range 31-61) years. Stem-cell sources were peripheral blood from an HLA-matched related donor (MRD, n=5), bone marrow from an HLA-matched unrelated donor (MUD, n=5), bone marrow from an HLA-mismatched unrelated donor (MMUD, n=13), and cord blood (n=7). All patients received conditioning with 8 Gy of TBI combined with Flu/Mel (n=28) or others (n=2). Five-year PFS and 5-year OS were 36.7% and 46.2%, respectively. Sixteen patients died during the observation period (12 of primary disease and 4 of treatment-related toxicity). Patients with VGPR or better before allo-SCT had significantly better PFS (p=0.009) and OS (p=0.01) than others. Patients who received MMUD cells tended to have better PFS than those with other cell sources. Our report showed that allo-SCT for MM after 8 Gy of TBI is feasible, and the better PFS of MMUD suggests graft-versus-myeloma effects.

Geriatric Nutritional Risk Index Is an Important Predictor of Survival in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Introduction:The body mass index (BMI) and geriatric nutritional risk index (GNRI) are nutrition-related risk assessment tool and has been used in various clinical settings. The relationship between BMI and the associated risk of hematopoietic stem cell transplantation (HSCT), such as relapse and non-relapse mortality (NRM), have been reported (Fuji S et al. BMT. 2014;49:1505). However, the relationship between GNRI and HSCT outcome remains inconclusive. We aimed to evaluate the association between GNRI and overall survival (OS), relapse, and NRM of patients who received allogenic HSCT for hematological malignancies. Methods:We retrospectively analyzed aged 16 years or older patients who underwent first allogeneic HSCT from January 2010 to December 2022 at the Jikei university hospital. The primary endpoints of this study was OS at 5 years. Secondary endpoints were NRM, the incidences of relapse, all-grade acute GVHD and chronic GVHD. Nutritional risk was evaluated both BMI and GNRI. Patients were classified into three groups based on pre-transplant BMI (underweight; BMI &amp;lt;18.5, overweight; BMI ≥25, and others as standard), and also classified into three groups based on pre-transplant GNRI (low-risk; GNRI&amp;gt;98, intermediate-risk; 92≤GNR≤98, and high-risk; GNR&amp;lt;92). GNRI was calculated as follows: (1.519 x serum albumin) + (41.7 x current body weight/ ideal body weight). Data on serum albumin level and body weight were collected at the beginning of conditioning regimen. Results:Two hundred and three patients who received allogeneic HSCT for hematological malignancies (acute myeloid leukemia; n=98, acute lymphoblastic leukemia; n=51, myelodysplastic syndrome; n=27, myeloproliferative neoplasms; n=8, chronic myeloid leukemia; n=18, and other leukemias; n=2) were evaluated. The median age was 52 years old (range 16-69). The median follow-up period of survivors was 1394 days (range 51-4420) after allogeneic HSCT. The donor sources consisted of 39 (19.2%) HLA-matched related donor, 50(24.6%) HLA-mismatched related donor, 26(12.8%) HLA-matched unrelated donor and 88(43.4%) HLA-mismatched unrelated donor. One hundred and nine patients (53.7%) received myeloablative conditioning regimens. Based on the BMI, underweight, standard, overweight were included 33 (16.3%), 139 (68.4%), and 31 (15.3%) patients, respectively. While, based on the GNRI, the low-risk, intermediate-risk and high-risk were divided into 105 (51.7%), 46 (22.8%), and 51 (25.2%) patients, respectively . The 5-year OS rates of standard, underweight, and overweight were 52.6%, 39.5%, and 62.1%, respectively (p=0.07). On the other hand, the 5-year OS of low-risk, intermediate-risk, and high-risk were 62.6%, 50.4%, and 33.2%, respectively (p=0.01). In addition, multivariate analysis showed high-risk group showed significantly lower OS (p=0.03). Five-year cumulative incidences (CI) of relapse in the standard, underweight, and overweight, were 46.4%, 45.4%, and 25.0%, respectively (p=0.11). However, multivariate analysis showed that CI of relapse ratio was significantly lower in overweight group (p=0.02). While, 5-year CI of relapse rates in the low-risk, intermediate-risk, and high-risk were 36.5%, 47.2%, and 52.5%, respectively (p=0.03). However, multivariate analysis showed that there were no significant differences in relapse among three risk groups (p=0.06). There were no significant differences in CI of NRM, acute GVHD and chronic GVHD either BMI or GNRI. Subgroup analysis in the patients who underwent HSCT in complete remission revealed that there was no significant difference in OS among the three BMI groups (p=0.11), as well as the three GNRI groups (p=0.06). For the patients in non-remission at the time of allogeneic HSCT, there was no significant difference in OS between the three groups in BMI; however, OS was shorter in the high-risk group in GNRI (p=0.01). Conclusions:In our study, OS of high-risk group defined by GNRI showed significantly poor , especially in non-remission patients. Although overweight defined by BMI did predict low CI of relapse, overweight did not predict OS. These results suggest that nutrition-related risk assessed by GNRI could be prognostic marker for survival in patients who received allogeneic HSCT.

Combined Effect of Unrelated Donor Age and HLA Peptide-Binding Motifs (PBM) Match Status on HCT Outcomes

Background: HLA-mismatched unrelated donors (MMUDs) can be either matched or mismatched at protein binding motifs (PBM), while all HLA-matched donors are PBM-matched. A MMUD who is class I PBM-matched in the graft-vs-host (GVH) direction is preferred over a PBM-mismatched donor [ JCO.2023;41(13):2416]. As donor age is also an important prognostic factor, we hypothesized that using a younger donor could compensate for the inferior overall survival (OS) associated with PBM-mismatches. Specifically, we tested if OS after transplantation with HLA-mismatched/PBM-matched/younger donors is similar to that with HLA-matched/older donors, and if OS is similar with HLA-mismatched/PBM-mismatched/younger donors as with HLA-mismatched/PBM-matched/older donors. Methods: We analyzed the outcomes of patients with acute leukemia or myelodysplastic neoplasms who underwent HLA-matched or single class I MMUD HCT with a calcineurin inhibitor (CNI) for GVHD prophylaxis using a publicly available Center for International Blood and Marrow Transplant Research dataset. HLA class I MMUDs were categorized as “PBM-mismatched” if there was any GVH mismatch for the PBM, or “PBM-matched” if there was PBM-matching or only host-versus-graft mismatching. Donor age was dichotomized as “older” (&amp;gt; 35 years) or “younger” (&amp;lt; 35 years). Six groups were compared: HLA-matched/younger donor (n=10,531), HLA-matched/older donor (n=3572), PBM-matched/younger donor (n=357), PBM-matched/older donor (n=257), PBM-mismatched/younger donor (n=616), and PBM-mismatched/older donor (n=339). The primary outcome of interest was OS. Results: Median patient age was 50.3-56.2 years. Acute myeloid leukemia was the most common diagnosis in all groups (53-60%), most had early/intermediate disease (64-70%), most received myeloablative conditioning (60-69%) and peripheral blood (PB) graft (76-81%). A minority (18-23%) had T-cell epitope -DPB1 non-permissive GVH mismatched. All patients received CNI-based prophylaxis, without post-transplant cyclophosphamide (PTCy). Median follow-up among survivors was 48-61 months. In multivariate analysis, transplantation from HLA-matched/younger donors was associated with superior OS relative to any other group [ Figure]. The notable findings of pairwise comparisons were three-fold. First, donor age significantly impacts OS in both HLA-matched and HLA-mismatched groups, but the negative impact of older donors relative to younger donors increases with increased mismatching for the PBM (18%, 25% and 35% increased mortality in older compared to younger donors within HLA-matched, PBM-matched and PBM-mismatched groups, respectively) [ Table, pairwise comparison group 1]. Secondly, younger donors appear to negate the detrimental effect of PBM-mismatching [comparison group 2]. Specifically, the PBM-matched/younger donor group had similar OS as the HLA-matched/older donor group and the PBM-mismatched/younger donor group had similar OS as the PBM-matched/older donor group. Thirdly, HLA/PBM-matching is important within the younger and the older donor groups [comparison group 3]; however, the impact of PBM-mismatching was higher with older donors (25% and 62% increased risk of mortality with PBM-matched and PBM-mismatched, respectively than HLA-matched) than with younger donors (18% and 42% increased risk of mortality with PBM-matched and PBM-mismatched than HLA-matched). Conclusion: Older unrelated donor age and PBM-mismatching confer similarly adverse effects on OS after transplantation with CNI prophylaxis and the impacts are additive. The preferred donor is HLA-matched, followed by HLA-mismatched/PBM-matched, and HLA-mismatched/PBM-mismatched. Transplantation from younger donors with inferior matching led to comparable outcomes as the older donors with better matching - a finding which may widen the “acceptable” donor pool. The best OS is observed with HLA-matched/younger donors and the worst with PBM-mismatched/older donors. Whether the use of PTCy modifies the impact of donor age and/or HLA/PBM-mismatching needs investigation.

Mismatched Unrelated Donor Transplantation with Ptcy-Based Gvhd Prophylaxis Is Associated with Better Survival Than Double Unit Umbilical Cord Blood Transplantation in Patients with AML in First CR: A Study from the ALWP of the EBMT

Background: The best donor option for acute myeloid leukemia (AML) patients lacking an HLA-matched donor has remained unknown. The recently reported BNT CTN 1101 trial observed higher non-relapse mortality (NRM) and lower overall survival (OS) in patients randomized to double-unit unrelated umbilical cord blood transplantation (dCBT) in comparison to those randomized to HLA-haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis 1. In addition, recent registry studies observed at least as good transplantation outcomes in AML patients given grafts from 9/10 HLA-matched unrelated donor (UD 9/10) with PTCy-based GVHD prophylaxis as those given grafts from HLA-haploidentical donors 2,3. These observations prompted us to perform a retrospective registry study comparing hematopoietic cell transplantation (HCT) outcomes between UD 9/10 and dCBT. Methods: Inclusion criteria consisted of adult patient, AML in CR1 at transplantation, either peripheral blood stem cells (PBSC) from UD 9/10 with PTCy as GVHD prophylaxis or dCBT, transplantation between 2013 and 2021, and no in vivo T-cell depletion. Results: A total of 208 dCBT patients and 270 UD 9/10 allo-HCT were included. The 180-day cumulative incidence of grade II-IV acute GVHD was 29% in UD 9/10 versus 44% in dCBT recipients (P=0.001). The 2-year cumulative incidences of relapse and of NRM were 23.5% and 12.5%, respectively, in UD 9/10 recipients versus 27% (P=0.39) and 18% (P=0.07), respectively in dCBT recipients. Two-year OS and LFS were 70% and 64%, respectively, in UD 9/10 recipients versus 60% (P=0.016) and 55% (P=0.028), respectively in dCBT recipients. In multivariate analyses, in comparison with UD 9/10 recipients, dCBT patients had a higher non-relapse mortality (HR=2.35, 95% CI: 1.23-4.48; P=0.01), comparable relapse incidence (HR=1.12, 95% CI: 0.67-1.86; P=0.66), lower leukemia-free survival (HR=1.5, 95% CI: 1.01-2.23; P=0.047), and lower overall survival (HR=1.66, 95% CI: 1.08-2.55; P=0.02). Conclusions: In summary, our results suggest that transplantation outcomes are better with UD 9/10 with PTCy-based GVHD prophylaxis than with dCBT for AML patients in CR1. These data might support the use of UD 9/10 with PTCy-based GVHD prophylaxis in AML patients lacking an HLA-matched donor. References Fuchs, E. J. et al. Double unrelated umbilical cord blood vs HLA-haploidentical bone marrow transplantation: the BMT CTN 1101 trial. Blood 137, 420-428 (2021).Baron, F. et al. Comparison of HLA-mismatched unrelated donor transplantation with post-transplant cyclophosphamide versus HLA-haploidentical transplantation in patients with active acute myeloid leukemia. Bone Marrow Transplant. 57, 1657-1663 (2022).Battipaglia, G. et al. Post-transplant cyclophosphamide in one-antigen mismatched unrelated donor transplantation versus haploidentical transplantation in acute myeloid leukemia: a study from the Acute Leukemia Working Party of the EBMT. Bone Marrow Transplant. 57, 562-571 (2022).

Improving Outcomes of Peripheral Blood Stem Cell (PBSC) HLA-Mismatched Unrelated Donor (MMUD) Hematopoietic Cell Transplantation (HCT): Effect of Graft Versus Host Disease (GVHD) Prophylaxis

Human leukocyte antigen (HLA) well matched donor (related or unrelated) has remained the preferred donor source for patients undergoing HCT for hematological disease, but the probability of finding a suitable related or unrelated donor has varied based on ethnic groups. HLA-mismatch unrelated donor (MMUD) transplantation has improved access to HCT in underrepresented minority groups and patients of mixed race. Historically, MMUD HCT has been associated with inferior survival outcomes compared to matched unrelated donor HCT when using conventional platforms of GVHD prophylaxis. (PMID: 31449184, 20538804). Efforts to improve outcomes have investigated the addition of a third agent such as anti-thymocyte globulin (ATG), mini-methotrexate (MTX) or mycophenolate mofetil (MMF). More recently, a study by the National Marrow Donor Program (NMDP) demonstrated the feasibility of post-transplant cyclophosphamide (PTCy) based GVHD prophylaxis in MMUD HCT using bone marrow (BM) grafts (PMID: 33905264). Additionally, our group demonstrated promising overall survival (OS) and GVHD-free/relapse-free-survival (GRFS) rates in peripheral blood stem cell (PBSC) MMUD HCT using PTCy based GVHD prophylaxis (PMID: 34156440). Here, we compare outcomes of PBSC MMUD HCT among patients receiving GVHD prophylaxis with either: (1) tacrolimus plus sirolimus (T/S), (2) T/S plus mini-methotrexate (T/S/MTX), or (3) PTCy, MMF, and tacrolimus or sirolimus (PTCy). Patients with various hematologic malignancies that underwent PBSC MMUD HCT (≥5/8 HLA-matched donors) at City of Hope between January 2005 and December 2021 were included in this retrospective review. Of 390 subjects included, GVHD prophylaxis included T/S (n=114), T/S/MTX (n=160), and PTCy (n=116). The median age was 51 (range:15-79), 53.3% of patients belonged to a racial/ethnic minority, and 34.8% (n=136) patients had disease risk index high or very high. Degree of HLA mismatch was 7/8 (91.3%), 6/8 (8.5%), and 5/8 (0.3%). Hematologic diseases included AML (40.3%), ALL (20.3%), MDS/MPN (15.9%), Lymphoma (16.9%), and CML/CMMol (6.7%). Most common conditioning regimens were fTBI-based (34.4%) and melphalan-based (57.2%). HCT comorbidity index was ≥ 3 in 30.8% (n=120), which was most common in PTCy compared to T/S and T/S/MTX: 48.3% vs. 23.7% vs. 23.1%, P&amp;lt;.001. The rate of neutrophil engraftment (15 days vs. 15 days vs 16 days, P=0.002) and platelet engraftment (15 days vs. 16 days vs 27 days, P=0.004) were shorter in T/S compared to T/S/MTX and PTCy, respectively. With median follow-up of 5.4 years (range: 1.0-16.7) the 5-year OS was superior in PTCy (P=0.045) compared to T/S and T/S/MTX: 58.0% (95% CI: 46.6-67.8) vs. 41.1% (95% CI: 31.9-50.1) and 39.6% (95% CI: 32-47.2). The 5-year disease-free survival (DFS) was superior in PTCy (P=0.042) compared to T/S and T/S/MTX: 54.2% (95% CI: 43.3-63.9) vs. 37.1% (95% CI: 28.2-46.0) vs. 37.2% (95% CI: 29.7-44.6), respectively. There was no significant difference in 5-year cumulative incidence of relapse (CIR) in T/S vs. T/S/MTX vs. T/S vs. PTCy: 29.1% (95% CI: 21.0-37.6) vs. 29.5% (95% CI: 22.6-36.7) vs. 22.1% (95% CI: 14.3-31.0), respectively. Additionally, there was no significant difference in 2-year NRM between the cohorts (P=0.459): 24.6% (95% CI: 17.1-32.9) vs. 23.1% (95% CI: 16.9-29.9) vs. 20.4% (95% CI: 13.5-28.4), respectively. The rate of 100-day Grade III-IV acute GVHD were similar between in the cohorts (P=0.321): 19.3% (95% CI: 12.6-27.0) vs. 18.1% (95% CI: 12.6 -24.5) vs. 12.9% (95% CI: 7.6-19.7). When comparing T/S vs. T/S/MTX and PTCy, the incidence of chronic GVHD was less in the PTCy cohort at both 1-year and 2-years (P&amp;lt;.001) with 1-year incidence of 55.0% (95% CI: 45.1-63.7) vs. 61.9% (95% CI: 53.8-68.9) vs. 38.9% (95% CI: 30-47.8), respectively, and 2-year incidence of 58.9% (95% CI: 49.0-67.6) vs. 66.2% (95% CI: 58.3-73.1) vs. 42.7% (95% CI: 33.4-51.6), respectively. To our knowledge, this is the largest reported single center outcome of PBSC MMUD HCT. In this study, we demonstrate the superiority of PTCy based GVHD prophylaxis compared to T/S and T/S/MTX in outcomes of 5-year OS (P=0.045), 5-year DFS (P=0.042), and incidence of chronic GVHD (P&amp;lt;.001). Our experience further supports the superiority of PTCy as the preferred GVHD prophylaxis in the PBSC MMUD HCT setting achieved by lowering chronic GVHD and associated complications.

Interindividual HLA Evolutionary Divergence in Single HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation for Malignant Hematological Disorders: A Report on Behalf of the Cellular Therapy and Immunobiology Working Party of the EBMT

In allogeneic hematopoietic cell transplantation (allo-HCT), alloreactive T-cell responses (graft versus leukemia - GvL and graft versus host disease - GvHD) are mediated by the interaction between recipient antigens and donor lymphocytes via human leukocyte antigen (HLA) molecules. HLA evolutionary divergence (HED) is a metric recently implemented as a functional proxy for the structural variability between two homologous HLA alleles at their peptide binding sites, mirroring quantitative differences in pathogen and cancer-related immunopeptidomes ( A). 1 Here, we hypothesize that differences in and between donor and recipient HEDs at given loci may modulate the direction and the intensity of alloreactivity, informing on post-transplant outcomes. We tested this hypothesis in onco-hematologic patients undergoing allo-HCT from a single HLA-A, -B, -C, -DRB1, or -DQB1 (9/10) mismatched unrelated donor (MMUD) at EBMT centers. We included patients with selected hematological malignancies, receiving a thymoglobulin-based T cell depletion, for whom complete clinical and HLA information was available in the EBMT database. We deployed individual locus-specific recipient/donor HED (HED-R, HED-D) metrics as previously described 1, and conceptualized two novel interindividual HED scores accounting for functional differences at the mismatched HLA loci ( A). The latter were considered as: 1) DeltaHED, quantifying the relative directional difference between HED-D and HED-R and informing on differences in immunopeptidome sizes, potentially capturing the direction and the intensity of the alloreactive response (GvH or HvG); 2) HEDmismatch, describing the HED of the mismatched locus as a proxy for the qualitative differences in immunopeptidomes between donor and recipient ( B). Using multivariable Cox regression (cause-specific) models adjusted for relevant clinical variables, we investigated the associations of HED-R, DeltaHED and HEDmismatch, analyzed as continuous variables, with relapse free survival (RFS), overall survival (OS), non-relapse mortality (NRM), relapse and grade II-IV acute and chronic GvHD. For each outcome and in each mismatched subgroup, we built separate models for these immunogenetic parameters and checked for proportional hazards assumption (PHA). To account for multiple comparisons, only p-values &amp;lt;0.01 were considered significant. Overall, 4639 adult patients, with available HLA data, received a 9/10 MMUD allo-HCT between 2010 and 2019 for acute leukemia (N=3853, 83%), myelodysplastic syndromes or myeloproliferative neoplasms (N=786, 17%). Median recipient age was 53.5 (IQR 40.2-61.9) with a male/female ratio of 1.28, whilst median donor age was 33.1 (IQR 24.5-40). Majority of patients (90%) received peripheral blood stem cells and were mismatched with their donors for locus A (33%), followed by C (21%), B (15%), DQB1 (14%) and DRB1 (6%). When analyzing the impact of HED-related parameters in each model, we observed that most recurrent associations with outcomes occurred with DRB1-related metrics. In the DRB1-mismatched subgroup (N=276), a time-varying association was found for HEDmismatch of DRB1 locus with higher HEDmismatch leading to worse RFS [HR:1.25 at t=0, (95% CI 1.1-1.42), p&amp;lt;0.001] and lower OS [HR:1.23 at t=0, (95%CI 1.08-1.41), p=0.002]. The strength of this associations declined over time for both endpoints (respectively RFS: HR:0.91, 95% CI 0.86-0.97, p=0.005 and OS: HR:0.93, 95% CI 0.88-0.98, p=0.013). The (directional) DeltaHED DRB1 measure instead did not display any impact on outcomes. In the same subgroup, higher HED-R in the locus C showed also a time-varying association with NRM at transplant [HR:1.89, (95% CI 1.29-2.85), p=0.002], progressively declining over time (HR:0.77, 95% CI 0.65-0.92, p=0.003). Furthermore, DRB1 HED-R modulated the probability of survival in B-mismatched subgroup, being higher scores associated with reduced OS [HR:1.03, (95%CI 1.01-1.06), p=0.009]. Here, we provide an immunogenetic benchmark to explore donor-recipient interactions in MMUD allo-HCT, demonstrating how different HLA configurations within the mismatched loci, in particular for DRB1 genes, can influence post-transplant outcomes. Given the peculiar associations observed, HED may have a role in driving early GvL effects, informing on future donor selection strategies in high-risk patients.

Existence of HLA-Mismatched Unrelated Donors Closes the Gap in Donor Availability Regardless of Recipient Ancestry

In patients without a matched sibling donor (MSD) or well-matched unrelated donor (MUD), hematopoietic cell transplantation (HCT) can still be successful when using an HLA-mismatched unrelated donor (MMUD) in combination with post-transplantation cyclophosphamide (PTCy), abatacept, or other novel approaches. This may allow clinicians to choose a suitable donor from a wide range of donor options while optimizing other donor selection characteristics, including donor age. We hypothesized that allowing for a 5/8 HLA match level considering high-resolution matching at HLA-A, -B, -C and -DRB1, there is a potential to close the donor availability gap for all patients regardless of their race/ethnicity. In this work, we estimate the likelihood of matching for all racial/ethnic groups at different HLA match thresholds. Our study aimed to assess the potential for identifying an available MUD or MMUD in the National Marrow Donor Program (NMDP)/Be The Match (BTM) donor registry for 21 detailed and 5 broad racial/ethnic groups, using high-resolution HLA matching for HLA-A, -B, -C, and -DRB1 at various levels (8/8, 7/8, 6/8, and 5/8). We used donor registry population data from the NMDP/BTM in 2020 and redistributed the donor registry data according to existing population ratios, accounting for demonstrated donor availability. Finally, we used a genetic model at the population level to estimate the match likelihood for detailed and broad racial/ethnic groups. Likelihood of 8/8 HLA match ranging from 16% to 74% were obtained for various detailed racial/ethnic groups with available donors age ≤35 years. When considering more mismatches in the HLA loci, registry coverage became >99% with a 5/8 HLA match level for donors of all ages or those age ≤35 years, with HLA-DPB1 T cell epitope permissive matching, or when searching for donors outside of their racial/ethnic group. Our registry models demonstrate the potential for using MMUDs at various HLA match levels to study whether this will expand access to HCT across racial/ethnic groups. Expanded donor options may erase the donor availability gap for all patients while allowing for selection of MMUDs with favorable characteristics, such as younger age.

Allogeneic hematopoietic cell transplantation for patients with AML aged 70 years or older in first remission. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Accessibility to allogeneic hematopoietic cell transplantation (HCT) programs for older patients is growing constantly. We report on the clinical outcomes of a group of 701 adults aged ≥70 years, with acute myeloid leukemia (AML) in first complete remission (CR1), who received a first HCT, from HLA-matched sibling donors (MSD), 10/10 HLA-matched unrelated donors (UD), 9/10 HLA-mismatched unrelated donors (mUD) or haploidentical (Haplo) donors. The 2-year overall survival (OS) was 48.1%, leukemia-free survival (LFS) 45.3%, relapse incidence (RI) 25.2%, non-relapse mortality (NRM) 29.5% and GVHD-free, relapse-free survival (GRFS), 33.4%. Compared to MSD, patients transplanted from Haplo and UD presented lower RI (HR 0.46, 95% CI 0.25-0.8, p = 0.02 and HR 0.44, 95% CI: 0.28-0.69, p = 0.001, respectively); this translated into prolonged LFS for Haplo (HR 0.62, 95% CI: 0.39-0.99, p = 0.04). Patients transplanted from mUD exhibited the highest NRM incidence (HR 2.33, 95% CI: 1.26-4.31, p = 0.007). HCT in selected adult CR1 AML patients >70 years is feasible and could be associated with good clinical outcomes. Prospective clinical trials are warranted.

Outcomes of HLA-mismatched HSCT with TCRαβ/CD19 depletion or post-transplant cyclophosphamide in patients with inborn errors of immunity – an EBMT inborn errors working party analysis

HLA-mismatched donor HSCT is an increasingly utilized approach for patients with inborn errors of immunity (IEI) lacking a matched donor, thanks to the development of in-vivo T-cell depletion with post-transplant cyclophosphamide (PTCY) or in-vitro TCRαβ/CD19 depletion (TCRab). Our study analyzed the outcome with these approaches in patients with IEI. Pediatric patients who received a first HSCT between 2011 and 2019 from haploidentical related or ≤9/10 HLA-mismatched unrelated (MMUD) donors were included in this retrospective study.We included 296 patients, 139 with PTCY and 157 with TCRab, who received HSCT at a median age of 1.4 years (0.1–19.6) from haploidentical donors (n = 282) or MMUD (n = 14). There were significant differences in patient characteristics: PTCY recipients had a higher rate of pre-HSCT infections (p = 0.002), and organ damage (p < 0.001), had lower performance scores (0.008), and were transplanted more recently (p = 0.001). Owing to the approach, there was a higher proportion with busulfan-based conditioning and multi-drug GVHD prophylaxis, and a lower proportion with serotherapy in the PTCY group; and lower CD34+ but higher CD3+ numbers were infused to PTCY recipients (all p < 0.001). Neutrophil and platelet engraftment occurred significantly earlier after TCRab depletion (p < 0.001). Acute GVHD°III-IV occurred in 10.3% of patients, more frequently after PTCY (p = 0.022), while 14.3% of patients required secondary cellular therapy (boost, DLI, 2nd HSCT), more frequently after TCRab (p = 0.026). Adenoviremia was more frequent (p = 0.012) and veno-occlusive disease (p = 0.015), acute kidney injury (p = 0.028), autoimmune cytopenia (p = 0.032), and pulmonary complications (p = 0.011) less frequent after TCRab. Overall survival at 3 years was 81% (95%CI: 75–88%) and 70% (63–78%; p = 0.001) after TCRab and PTCY, respectively, while event free survival (graft failure, extensive chronic GVHD) was 69% (62–77%) and 63% (55–71%), respectively. In univariate analysis, use of PTCY, conditioning other than busulfan or treosulfan, pre HSCT organ damage, preHSCT infections and number of preHSCT morbidities correlated negatively with overall survival.This study of HLA-mismatched HSCT in IEI demonstrated better overall but not event-free survival after TCRab, but patients with PTCY had significantly higher rates of preHSCT risk factors. We conclude that both approaches are feasible and efficacious in patients with IEI lacking an HLA-matched donor.

308 - Access: A Multi-Center, Phase II Trial of HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide for Patients with Hematologic Malignancies

308 - Access: A Multi-Center, Phase II Trial of HLA-Mismatched Unrelated Donor Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide for Patients with Hematologic Malignancies

357 - Outcomes after HLA-Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide for Graft-Vs-Host Disease Prophylaxis: A Systematic Review and Meta-Analysis

357 - Outcomes after HLA-Mismatched Unrelated Donor Hematopoietic Stem Cell Transplantation with Post-Transplant Cyclophosphamide for Graft-Vs-Host Disease Prophylaxis: A Systematic Review and Meta-Analysis

A new beginning: can omidubicel emerge as the next, viable alternative donor source?

Umbilical cord blood (UCB) transplantation (CBT) has been an important alternative donor option for patients lacking matched related donor (MRD) or unrelated donor (URD) grafts. Only 30% of patients with high-risk hematologic malignancies have a human leukocyte antigen (HLA)-identical sibling; subjects without a MRD option are referred for HLA-matched URD selection, or utilize alternative donor sources such as HLA-mismatched URD, UCB, or haploidentical donor grafts. While CBT demonstrates an excellent graft-versus-leukemia (GVL) effect, use of UCB as a graft source is limited due to a lower cell dose that can result in delayed engraftment and an immature immune system with increased infectious risk as a consequence. Together, increased transplant related mortality (TRM) has been associated with UCB allografts. Omidubicel is an ex vivo expanded single cord blood product that has demonstrated rapid engraftment, improved immune reconstitution, and reduced infectious complications in clinical trials. Omidubicel has now been granted U.S. Food & Drug Administration approval to enhance neutrophil recovery and decrease infectious risk. This review will focus on CBT, benefits and barriers to using this alternative donor source, and finally the potential advancements with incorporation of omidubicel in the transplant setting for malignant and non-malignant diseases.

Abstract B121: HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies

Abstract Introduction: Racial and ethnic disparities exist in three areas related to hematopoietic cell transplantation (HCT): donor availability, access, and post-HCT outcomes. A significant barrier to access to HCT for patients (pts) of racial or ethnic minorities (REM) is the limited availability of fully matched donors (i.e., grafts matched at HLA-A, -B, -C, and -DRB1 loci) in volunteer registries. While mismatched unrelated donor (MMUD) grafts (i.e., &amp;lt;7/8 match) can be offered to pts without matched donors, MMUD HCT results in poor survival when traditional graft-versus-host disease (GVHD) prophylaxis (PPx) is used. GVHD PPx with post-transplantation cyclophosphamide (PTCy) is associated with favorable survival after haploidentical HCT, and promising outcomes have been reported in a prospective multicenter study utilizing PTCy in MMUD HCT. Herein, we analyzed the outcomes of an ethnically diverse cohort of pts who underwent MMUD HCT with PTCy at two large urban transplant centers. Objectives and Methods: Subjects receiving HCT from an MMUD from 2010-to 2020 at the University of Miami and Memorial Sloan-KetteringCancer Center were included. Pts were stratified by age, HCT indication, race/ethnicity, graft type, conditioning intensity, disease status, and degree of HLA mismatch. The primary study endpoint was one-year overall survival (OS). Secondary endpoints were event-free survival (EFS), non-relapse mortality (NRM), and cumulative incidence of acute and chronic GVHD. Results: A total of 82 pts were evaluated. The median age at HCT was 60 years (21-75), the most common indication for HCT was acute leukemia (51%), 41% of pts received an ablative conditioning regimen, and 50% received peripheral blood (PB) grafts. Forty-four percent identified as non-Hispanic white (NHW), and 56% identified as REM (Non-Hispanic Black: 30%; Hispanic: 64%; Asian/Pacific: 4.3%). The two groups (NHW vs. REM) were well-matched for leading HCT indication, disease-risk index, degree of mismatch, and disease status at HCT. REM pts were younger (median age at HCT 65 vs 56 years for NHW, p=0.001) and more likely to receive a PB graft (63% vs 40%, P = 0.04). One-year OS was 75%, EFS was 69%, and NRM was 16% for the entire cohort. Grade 3-4 acute GVHD at day 180 post-HCT was 15%, and one-year severe chronic GVHD was 9%. OS was comparable between 7/8-matched and highly-mismatched (&amp;lt;6/8) HCT recipients (75% vs. 76%, respectively; P &amp;gt;0.9). There were no differences in one-year OS (77% vs 74%, p = 0.9) and EFS (63% vs 72%, p = &amp;gt;0.9) between NHW and REM pts. Similarly, rates of acute (17% vs 13%, p = 0.5) and chronic GVHD (5.7% vs 11%, p = 0.5) were comparable between NHW and REM pts. Conclusion: PTCy resulted in encouraging clinical outcomes following MMUD HCT. Post-HCT OS, RFS, and GVHD rates were comparable between NHW and REM pts and those receiving 7/8 or highly mismatched grafts. Favorable post-HCT outcomes following MMUD with PTCy may increase HCT utilization and access for REM pts. Citation Format: Antonio M. Jimenez Jimenez, Sunil Iyer, Krishna Komanduri, Samantha Brown, Trent Wang, Stephanie Chinapen, Denise Pereira, Sean Devlin, Mark Goodman, Amer Beitinjaneh, Craig Sauter, Lazaros Lekakis, Miguel Angel Perales, Doris Ponce, Brian Shaffer. HLA-mismatched unrelated donor hematopoietic cell transplantation with post-transplant cyclophosphamide improves clinical outcomes for racial and ethnic minority patients with hematologic malignancies [abstract]. In: Proceedings of the 15th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2022 Sep 16-19; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr B121.