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Haploidentical donor hematopoietic cell transplantation for myelodysplastic/myeloproliferative overlap neoplasms: results from a North American collaboration
Jain, T., Tsai, H. L., Elmariah, H., Vachhani, P., Karantanos, T., Wall, S. A., Gondek, L. P., Bashey, A., Keyzner, A., Tamari, R., et al
Haematologica. 2023
Abstract
Haploidentical donors offer a potentially readily available donor, especially for non-White patients, for hematopoietic cell transplantation (HCT). In this North American collaboration, we retrospectively analyzed outcomes of first HCT using haploidentical donor and posttransplantation cyclophosphamide (PTCy) in MDS/MPN-overlap neoplasms (MDS/MPN). We included 120 consecutive patients who underwent HCT using a haploidentical donor for MDS/MPN across 15 centers. Median age was 62.5 years and 38% were of non-White/Caucasian ethnicity. The median follow-up was 2.4 years. Graft failure was reported in 7/120 (6%) of patients. At 3 years, nonrelapse mortality (NRM) was 25% (95%CI 17-34%), relapse 27% (95%CI 18-36%), grade 3-4 acute graft versus host disease (GVHD) 12% (95%CI 6-18%), chronic GVHD requiring systemic immunosuppression 14% (95%CI 7-20%), progression-free survival (PFS) 48% (95%CI 39-59%), and overall survival (OS) 56% (95%CI 47-67%). On multivariable analysis, NRM was statistically significantly associated with advancing age at HCT (per decade increment, sdHR 3.28, 95%CI 1.30-8.25); relapse with the presence of mutation in EZH2/RUNX1/SETBP1 (sdHR 2.61, 95%CI 1.06-6.44); PFS with advancing age at HCT (per decade increment, HR 1.98, 95% 1.13-3.45); and OS with advancing age at HCT (per decade increment, HR 2.01, 95% CI 1.11-3.63) and splenomegaly at HCT/prior splenectomy (HR 2.20, 95%CI 1.04-4.65). Haploidentical donors are a viable option for HCT in MDS/MPN, especially for those disproportionately represented in the unrelated donor registry. Hence, donor mismatch should not preclude HCT for patients with MDS/MPN, an otherwise incurable malignancy. In addition to patient age, disease-related factors including splenomegaly and high-risk mutations dominate outcomes following HCT.
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Improved Access to HCT with Reduced Racial Disparities Through Integration with Leukemia Care and Haploidentical Donors
Bashey, A., Zhang, X., Morris, L. E., Holland, H. K., Bachier-Rodriguez, L., Solomon, S. R., Solh, M. M.
Blood advances. 2023
Abstract
Few patients with non-favorable risk (NFR) acute leukemia and MDS (AL/MDS) have historically accessed allogeneic transplantation (HCT). We assessed whether this can be improved by the integration of HCT/leukemia care and use of haploidentical donors (HID). Of 256 consecutive patients aged ≤75 who received initial therapy at our center for NFR AL/MDS from 2016 to 2021, 147 (57%) proceeded to planned HCT (70% for patients aged <60). On logistic regression analysis, age (OR 1.50 per 10-year increment, p<0.001), race- black vs white (OR 2.05, p=0.023), were significant factors for failure to receive HCT. Reasons for no HCT were: comorbidities (37%), poor KPS, lack of adequate caregiver support, refractory malignancy (19% each) and patient refusal (17%). Lack of donor or insurance were rarely cited (3% each). In older patients (≥60 years), comorbidities (49 vs. 15%, p<0.001) and KPS (25% vs. 10%, p=0.06) were more common reasons, and lack of caregiver support was less common (13% vs. 30%, p=0.031). In black vs. white patients, lack of caregivers (37% vs 11%, p=0.002) was more frequent. Median time from initial treatment to HCT was 118 days and was similar for black vs white patients (112 vs 122 days, p=0.80). On landmark analysis, HCT within 6 months of initial treatment resulted in better survival. On multivariable analysis, HCT resulted in a significant survival benefit (HR 0.60, p=0.020). With the above approach, the majority of currently treated patents aged ≤75 can access planned HCT. Black patients remain at higher risk for not receiving HCT.
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Allogeneic blood or marrow transplantation with haploidentical donor and post-transplantation cyclophosphamide in patients with myelofibrosis: a multicenter study
Kunte, S., Rybicki, L., Viswabandya, A., Tamari, R., Bashey, A., Keyzner, A., Iqbal, M., Grunwald, M. R., Dholaria, B., Elmariah, H., et al
Leukemia. 2022;36(3):856-864
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Abstract
We report the results from a multicenter retrospective study of 69 adult patients who underwent haploidentical blood or marrow transplantation (haplo-BMT) with post-transplantation cyclophosphamide (PTCy) for chronic phase myelofibrosis. The median age at BMT was 63 years (range, 41-74). Conditioning regimens were reduced intensity in 54% and nonmyeloablative in 39%. Peripheral blood grafts were used in 86%. The median follow-up was 23.1 months (range, 1.6-75.7). At 3 years, the overall survival, relapse-free survival (RFS), and graft-versus-host-disease (GVHD)-free-RFS were 72% (95% CI 59-81), 44% (95% CI 29-59), and 30% (95% CI 17-43). Cumulative incidences of non-relapse mortality and relapse were 23% (95% CI 14-34) and 31% (95% CI 17-47) at 3 years. Spleen size ≥22 cm or prior splenectomy (HR 6.37, 95% CI 2.02-20.1, P = 0.002), and bone marrow grafts (HR 4.92, 95% CI 1.68-14.4, P = 0.004) were associated with increased incidence of relapse. Cumulative incidence of acute GVHD grade 3-4 was 10% at 3 months and extensive chronic GVHD was 8%. Neutrophil engraftment was reported in 94% patients, at a median of 20 days (range, 14-70). In conclusion, haplo-BMT with PTCy is feasible in patients with myelofibrosis. Splenomegaly ≥22 cm and bone marrow grafts were associated with a higher incidence of relapse in this study.
Clinical Commentary
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NIHMS1867052
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4.
Lineage-Specific Relapse Prediction Following Haploidentical Transplant with Post-Transplant Cyclophosphamide Based on Recipient HLA-B-Leader Genotype and HLA-C-Group KIR Ligand
Solomon, S. R., Aubrey, M. T., Zhang, X., Jackson, K. C., Roark, C. L., Freed, B. M., Morris, L. E., Holland, H. K., Solh, M. M., Bashey, A.
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND The role of NK cell alloreactivity on outcomes following T cell-replete haploidentical donor transplantation (HIDT) remains uncertain. Post-transplant, newly formed NK cells are licensed through interactions of donor inhibitory KIR (iKIR) and NKG2A receptors with their cognate ligands on recipient cells. Donor NKG2A recognizes HLA-E bound by recipient HLA class I leader peptides, a process requiring methionine (M) at position -21 of the leader sequence. A rs1050458C/T dimorphism results in approximately 40% of individuals expressing at least on copy of -21M HLA-B (M/M or M/T [M+]), allowing ligand expression. OBJECTIVES We assessed the impact of recipient HLA-B-leader genotype (M+ vs M- [T/T]) and HLA-C-group iKIR missing ligand (ML, C1C1/C2C2 vs. C1C2) on relapse and disease-free survival (DFS) in recipients of post-transplant cyclophosphamide (PTCy)-based HIDT. Based on pre-clinical data, we hypothesized that the relative impact of each variable may depend on disease lineage (lymphoid vs. myeloid). STUDY DESIGN To this end, we analyzed outcomes of 322 consecutive PTCy-based HIDT recipients with hematologic malignancy transplanted at a single institution using standardized supportive care measures with mature follow-up (median 45 months). Primary endpoints were relapse and DFS of patients based on HLA-B-leader genotype and HLA-C-group iKIR ML. Planned subgroup analysis included patient with lymphoid vs. myeloid malignancy. RESULTS M+ HLA-B-leader genotype and HLA-C-group iKIR ML were seen in 42% and 49% of recipients, respectively. The presence of a recipient M+ B-leader (vs. M-) improved OS and DFS and lowered cumulative incidence of relapse (CIR), an effect primarily seen in lymphoid malignancies (80% vs. 51%, 72% vs. 41%, 16% vs. 42%, respectively). In contrast, myeloid malignancy patients benefited most from HLA-C-group iKIR ML with better OS, DFS and lower CIR (67% vs. 51%, 64% vs. 44%, 25% vs. 45%, respectively). Multivariate analysis confirmed the disease-specific associations of improved relapse/DFS with M+ HLA-B-leader in lymphoid malignancy (HR 0.20, p<0.001 / HR 0.34, p<0.001) and HLA-C-group iKIR ML in myeloid malignancy (HR 0.44, p=0.004 / HR 0.54, p=0.009). Neither HLA-B-leader nor iKIR ML were associated with the incidence of NRM, acute or chronic GVHD. CONCLUSION Two distinct NK cell education pathways predict relapse and DFS after HIDT-PTCy in a disease-specific manner: the presence of recipient M+ HLA-B-leader genotype improves outcome in patients with lymphoid malignancies, whereas HLA-C-group iKIR ML improves outcome in patients with myeloid malignancies.. These findings strengthen the essential role of NK cells for optimal GVL in the context of HIDT-PTCy and may suggest different approaches to improving transplant outcome depending on disease type.
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Alternative donor transplantation for myelodysplastic syndromes: haploidentical relative and matched unrelated donors
Grunwald, M. R., Zhang, M. J., Elmariah, H., Johnson, M. H., St Martin, A., Bashey, A., Battiwalla, M., Bredeson, C. N., Copelan, E., Cutler, C. S., et al
Blood advances. 2021;5(4):975-983
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Abstract
We compared outcomes in 603 patients with myelodysplastic syndrome (MDS) after HLA-haploidentical relative (n = 176) and HLA-matched unrelated (n = 427) donor hematopoietic cell transplantation (HCT) from 2012 to 2017, using the Center for International Blood and Marrow Transplant Research database. All transplantations used reduced-intensity conditioning regimens. Total-body irradiation plus cyclophosphamide and fludarabine was the predominant regimen for HLA-haploidentical relative donor HCT, and graft-versus-host disease (GVHD) prophylaxis was uniformly posttransplantation cyclophosphamide, calcineurin inhibitor, and mycophenolate. Fludarabine with busulfan or melphalan was the predominant regimen for HLA-matched unrelated donor HCT, and GVHD prophylaxis was calcineurin inhibitor with mycophenolate or methotrexate. Results of multivariate analysis revealed higher relapse (hazard ratio [HR], 1.56; P = .0055; 2-year relapse rate, 48% vs 33%) and lower disease-free survival (DFS) rates after HLA-haploidentical relative donor HCT (HR, 1.29; P = .042; 2-year DFS, 29% vs 36%). However, overall survival (OS) rates did not differ between donor type (HR, 0.94; P = .65; 2-year OS, 46% for HLA-haploidentical and 44% for HLA-matched unrelated donor HCT) because of mortality associated with chronic GVHD. Acute grade 2 to 4 GVHD (HR, 0.44; P < .0001) and chronic GVHD (HR, 0.36; P < .0001) were lower after HLA-haploidentical relative donor HCT. By 2 years, probability of death resulting from chronic GVHD was lower after HLA-haploidentical relative compared with HLA-matched unrelated donor HCT (6% vs 21%), negating any potential survival advantage from better relapse control. Both donor types extend access to transplantation for patients with MDS; strategies for better relapse control are desirable for HLA-haploidentical relative donor HCT, and effective GVHD prophylaxis regimens are needed for unrelated donor HCT.
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A Phase II Trial of Melphalan Based Reduced-Intensity Conditioning for Transplantation of T-Replete HLA-Haploidentical Peripheral Blood Stem Cells with Posttransplant Cyclophosphamide in Patients with Hematologic Malignancies
Solh, M. M., Hinojosa, G., Laporte, J., Solomon, S. R., Morris, L. E., Zhang, X., Holland, H. K., Bashey, A.
Advances in hematology. 2021;2021:8868142
Abstract
T-replete haploidentical donor transplants using posttransplant cyclophosphamide (haplo) have greatly expanded donor availability and are increasingly utilized. Haplo were originally performed using truly nonmyeloablative conditioning and a bone marrow graft. We have also developed myeloablative conditioning and peripheral blood stem cell (PBSC) grafts for use with haplo. However, some patients may not tolerate myeloablative conditioning but may still benefit from a more dose-intensified preparative regimen to control malignancy and diminish graft rejection. To this end, we enrolled 25 patients on a prospective phase II trial utilizing a regimen of fludarabine 30?mg/m(2)/day?×?5 days and Melphalan 140?mg/m(2) on day -1 (flu/Mel) followed by infusion of unmanipulated PBSC graft from a haploidentical donor. GVHD prophylaxis included cyclophosphamide 50?mg/kg/day on days 3 and 4, mycophenolate mofetil on day 35, and tacrolimus on day 180. Median age was 57 years (range from 35 to 68). Transplantation diagnosis included AML (n?=?11), ALL (n?=?4), MDS/MPD (n?=?6), NHL/CLL (n?=?3), and MM (n?=?1). Using the refined Disease Risk Index (DRI), patients were low (n?=?1), intermediate (n?=?13), and high/very high (n?=?11). 22 out of 25 patients engrafted with a median time to neutrophil and platelet engraftment of 18 days and 36 days, respectively. All engrafting patients achieved full peripheral blood T-lymphocyte and myeloid donor chimerism at day 30. The 180-day cumulative incidence for acute GVHD grades II-IV and III-IV was seen in 20% (95% CI 8%-37%) and 8% (95% CI 2%-22%), respectively. The 2-year cumulative incidence of chronic GVHD was 16% (95% CI 5%-33%) (moderate-severe 12% (95% CI 3%-27%)). After a median follow-up of 28.3 months, the estimated 2-year OS, DFS, NRM, and relapse were 56% (95%CI 33-74%), 44% (95%CI 23%-64%), 20% (95% CI 8%-37%), and 36% (95% CI 17%-55%), respectively. Among patients with high/very high risk DRI, 2-year OS was 53% compared to 69% for low/intermediate DRI. When compared with a contemporaneous cohort of patients at our center receiving haploidentical transplant with nonablative fludarabine, Cytoxan, and total body irradiation flu/Cy/TBI regimen, the outcomes were statistically similar to the 2-year OS at 56% vs. 63% p=0.75 and DFS at 44% vs. 46% p=0.65.
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7.
HLA Informs Risk Predictions after Haploidentical Stem Cell Transplantation with Post-transplantation Cyclophosphamide
Fuchs, E. J., McCurdy, S. R., Solomon, S. R., Wang, T., Herr, M. M., Modi, D., Grunwald, M. R., Nishihori, T., Kuxhausen, M., Fingerson, S., et al
Blood. 2021
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Editor's Choice
Abstract
Hematopoietic cell transplantation from HLA-haploidentical related donors is increasingly used to treat hematologic cancers; however, characteristics of the optimal haploidentical donor have not been established. We studied the role of donor HLA mismatching in graft-versus-host disease (GVHD), disease recurrence and survival after haploidentical donor transplantation with post-transplantation cyclophosphamide (PTCy) for 1434 acute leukemia or myelodysplastic syndrome patients reported to the Center for International Blood and Marrow Transplant Research. The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods. Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1-mismatching with HLA-DQB1-matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-non-permissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1 and -DPB1 predicted disease-free survival, as did patient and donor CMV serostatus, patient age and co-morbidity index. A web-based tool was developed to facilitate selection of the best haploidentical related donor by calculating disease-free survival based on these characteristics. In conclusion, HLA factors influence the success of haploidentical transplantation with PTCy. HLA-DRB1 and -DPB1 mismatching and HLA-C, -B leader, and -DQB1 matching are favorable. Consideration of HLA factors may help to optimize the selection of haploidentical related donors.
PICO Summary
Population
Patients undergoing transplant for acute leukaemia or myelodysplastic syndrome at centres reporting to the CIBMTR (n=1434)
Intervention
The impact of mismatching in the graft-versus-host vector for HLA-A, -B, -C, -DRB1, and -DQB1 alleles, the HLA-B leader, and HLA-DPB1 T-cell epitope (TCE) were studied using multivariable regression methods.
Comparison
None
Outcome
Outcome was associated with HLA (mis)matches at individual loci rather than the total number of HLA mismatches. HLA-DRB1 mismatches were associated with lower risk of disease recurrence. HLA-DRB1-mismatching with HLA-DQB1-matching correlated with improved disease-free survival. HLA-B leader matching and HLA-DPB1 TCE-non-permissive mismatching were each associated with improved overall survival. HLA-C matching lowered chronic GVHD risk, and the level of HLA-C expression correlated with transplant-related mortality. Matching status at the HLA-B leader and HLA-DRB1, -DQB1 and -DPB1 predicted disease-free survival, as did patient and donor CMV serostatus, patient age and co-morbidity index. A web-based tool was developed to facilitate selection of the best haploidentical related donor by calculating disease-free survival based on these characteristics.
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Incidence and impact of community respiratory viral infections in post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis and haploidentical stem cell transplantation
Mulroney, C. M., Bilal Abid, M., Bashey, A., Chemaly, R. F., Ciurea, S. O., Chen, M., Dandoy, C. E., Diaz Perez, M. A., Friend, B. D., Fuchs, E., et al
British journal of haematology. 2021
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Abstract
Community respiratory viral infections (CRVIs) are associated with pulmonary function impairment, alloimmune lung syndromes and inferior survival in human leucocyte antigen (HLA)-matched allogeneic haematopoietic stem cell transplant (HCT) recipients. Although the incidence of viral infections in HLA-haploidentical HCT recipients who receive post-transplant cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis is reportedly increased, there are insufficient data describing the incidence of CRVIs and the impact of donor source and PTCy on transplant outcomes. Analysing patients receiving their first HCT between 2012 and 2017 for acute myeloid leukaemia, acute lymphoblastic leukaemia and myelodysplastic syndromes, we describe comparative outcomes between matched sibling transplants receiving either calcineurin-based GVHD prophylaxis (SibCNI, N = 1605) or PTCy (SibCy, N = 403), and related haploidentical transplants receiving PTCy (HaploCy, N = 757). The incidence of CRVIs was higher for patients receiving PTCy, regardless of donor type. Patients in the HaploCy cohort who developed a CRVI by day +180 had both a higher risk of treatment-related mortality [hazard ratio (HR) 2·14, 99% confidence interval (CI) 1·13-4·07; P = 0·002] and inferior 2-year overall survival (HR 1·65, 99% CI 1·11-2·43; P = 0·001) compared to SibCNI with no CRVI. This finding justifies further research into long-term antiviral immune recovery, as well as development of preventive and treatment strategies to improve long-term outcomes in such patients.
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Differences in GVHD Characteristics Between Haploidentical Transplantation Using Post-Transplant Cyclophosphamide and Matched Unrelated Donor Transplantation Using Calcineurin Inhibitors
Solh, M. M., Baron, J., Zhang, X., Bashey, A., Morris, L. E., Holland, H. K., Solomon, S. R.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
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Editor's Choice
Abstract
We assessed differences in presentation and response to therapy in 394 consecutive patients who developed acute or chronic GVHD after receiving their first allogeneic transplantation (HSCT) from a 10/10 HLA allele matched-unrelated donor (MUD, n=179) using calcineurin inhibitors or a T-replete haploidentical donor (haplo, n=215) using post-transplant cyclophosphamide at our center between 2005 and 2017. Median follow up for survivors was 52.5 months. The cumulative incidences for grade II-IV and III-IV aGVHD at day 180 post HCT were similar at 39% and 14% for haplo compared to 50% and 16% for MUD (p=NS). Haplo patients had lower cumulative incidence of mod-severe cGVHD at 22% (severe 19%) versus 31% for MUD (severe 29%) (p=0.026). Time to onset of moderate-severe cGVHD was faster for haplo at 213 vs 280 days (p=0.011) for MUD. Among patients with grade II-IV acute GVHD, there was no significant difference in organ involvement between haplo and MUD with skin being most affected (75% haplo vs 70% MUD), gastro-intestinal tract (71% haplo vs 69% MUD) and liver (14% haplo vs 17% MUD). For cGVHD, haplo patients had less involvement of the eyes (46% vs 75% for MUD, p<0.001) and of the joints/fascia (12% vs 36%, p=0.001).Also for cGVHD patients, haplo recipients had similar all-cause mortality (22% vs 18%, p=0.89) but were more likely to be off immunosuppression at 2 years post HCT (63% vs 43% p=0.03) compared to MUD.
PICO Summary
Population
Consecutive patients who developed acute or chronic GVHD after receiving their first allogeneic transplantation (n=394)
Intervention
Allogeneic transplantation from a 10/10 HLA allele matched-unrelated donor using calcineurin inhibitors (MUD, n=179)
Comparison
T-replete haploidentical transplantation using post-transplant cyclophosphamide (haplo, n=215)
Outcome
Median follow up for survivors was 52.5 months. The cumulative incidences for grade II-IV and III-IV aGVHD at day 180 post HCT were similar at 39% and 14% for haplo compared to 50% and 16% for MUD. Haplo patients had lower cumulative incidence of mod-severe cGVHD at 22% (severe 19%) versus 31% for MUD (severe 29%). Time to onset of moderate-severe cGVHD was faster for haplo at 213 vs 280 days for MUD. Among patients with grade II-IV acute GVHD, there was no significant difference in organ involvement between haplo and MUD with skin being most affected (75% haplo vs 70% MUD), gastro-intestinal tract (71% haplo vs 69% MUD) and liver (14% haplo vs 17% MUD). For cGVHD, haplo patients had less involvement of the eyes (46% vs 75% for MUD) and of the joints/fascia (12% vs 36%).Also for cGVHD patients, haplo recipients had similar all-cause mortality (22% vs 18%) but were more likely to be off immunosuppression at 2 years post HCT (63% vs 43%) compared to MUD.
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Class II HLA mismatch improves outcomes following haploidentical transplantation with posttransplant cyclophosphamide
Solomon, S. R., Aubrey, M. T., Zhang, X., Jackson, K. C., Morris, L. E., Holland, H. K., Solh, M. M., Bashey, A.
Blood advances. 2020;4(20):5311-5321
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Abstract
HLA disparity is the major predictor of outcome following unrelated donor (UD) transplantation, where a single mismatch (mm) at the HLA-A, HLA-B, HLA-C, or HLA-DRB1 locus leads to increased mortality, and mismatching at multiple loci compounds this effect. In contrast, HLA disparity has not been shown to increase mortality in the context of haploidentical transplant using posttransplant cyclophosphamide (PTCy). To better define the consequences of loci-specific HLA mm, we analyzed 208 consecutive patients undergoing haploidentical transplantation for hematologic malignancy using PTCy at our institution (median age, 52 years [range, 19-75 years]; peripheral blood stem cell, 66%; reduced-intensity conditioning, 59%). Median follow-up was 65.4 months (range, 34.3-157.2 months). In univariate analysis, a single class II HLA mm at HLA-DR, HLA-DQ or a nonpermissive (np) HLA-DP mm had a protective effect on disease-free and overall survival (OS), primarily a result of reduced relapse risk. Furthermore, this survival effect was cumulative, so that patients with 3 class II mm (HLA-DR, HLA-DQ, and np HLA-DP) had the best OS. In multivariate analysis, HLA-DR mm and np HLA-DP mm were both independently associated with improved OS (hazard ratio [HR], 0.43; P =.001; and HR, 0.47; P =.011, respectively). In contrast, single or multiple mm at HLA-A, HLA-B, or HLA-C loci had no effect on acute graft-versus-host disease (GVHD), nonrelapse mortality (NRM), relapse, or survival, although the presence of an HLA-A mm was associated with increased chronic GVHD incidence. The association of class II mm with lower relapse occurred without a corresponding increase in NRM or acute or chronic GVHD. These findings will require validation in larger registry studies.