Disease progression, graft-versus-host disease (GVHD), and non-relapse mortality (NRM) are the main causes of failure after allogeneic hematopoietic cell transplantation (SCT) for myeloid neoplasms. T-cell epitope-based models classify HLA-DPB1 mismatches by permissiveness and have been associated with differential risks of GVHD, relapse, and NRM. However, most studies were conducted before the routine use of post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis for unrelated donor (UD) SCT. We retrospectively analyzed 541 adults undergoing 8/8 UD SCT with PTCy prophylaxis, categorized as DP-matched (DP-M, n = 176), permissive mismatch (DP-P, n = 219), non-permissive graft-versus-host (DP-NP-GVH, n = 82), or host-versus-graft (DP-NP-HVG, n = 64). Outcomes were compared across groups with stratification by disease risk and remission/MRD status. Two-year relapse incidence was lower with DP-P versus DP-M (18% vs 28%; HR 0.6, 95% CI 0.4-0.9, p = 0.03), most pronounced in high-risk AML/MDS, where relapse rates approached those of lower-risk disease. This effect persisted after adjustment for remission and MRD status. GVHD incidence was unaffected by DPB1 status. OS and PFS did not differ significantly; age and comorbidity were dominant predictors of NRM. In UD SCT with PTCy, DPB1-permissive mismatching reduces relapse in high-risk AML/MDS without increasing GVHD or NRM, supporting DP-P mismatching as an actionable donor-selection criterion.

We developed a novel, explainable artificial intelligence (AI)-driven prognostic model using a contemporary single-centre cohort of 668 patients undergoing haploidentical hematopoietic cell transplantation (HCT) with post-transplantation cyclophosphamide (PTCy) prophylaxis (2015-2024) to define the hierarchy of prognostic factors for overall survival. Employing a gradient boosting machine with explainable AI techniques, including partial dependence plots and surrogate decision trees, revealed a non-linear, U-shaped effect of donor age, with optimal outcomes for donors in their late 20 s to early 40 s. Recipient age was the dominant risk factor, modulated by donor age and HLA factors. HLA-DPB1 non-permissive mismatches were the most significant HLA factor (9.6% 3-year OS reduction), followed by HLA-B leader and HLA-DQB1 mismatches, with no independent effect of HLA-DRB1. The model accurately stratified patients into distinct risk quartiles, with 3-year survival ranging from 75% in the lowest-risk to below 20% in the highest-risk group. Critically, simulation analyses demonstrated that optimal donor selection (age 30, no key HLA mismatches) could shift a patient's risk profile by approximately one full quartile, significantly improving survival (e.g., Q3 patients from 20% to 50% 3-year OS). This study provides a practical, data-driven framework for personalized donor selection in the modern HCT era. Future multi-center validation studies are warranted.

BACKGROUND:While immune checkpoint inhibitors (ICIs) have shown significant efficacy, a common side effect is cutaneous immune-related adverse events (irAEs). This study focuses on exploring the association between specific human leukocyte antigen (HLA) alleles and the development of cutaneous irAEs in melanoma patients undergoing ICI monotherapy and combination therapy. As certain HLA types are indicative of susceptibility to autoimmune diseases, it was hypothesized that HLA typing could serve as a potential screening tool for identifying patients at increased risk for developing irAEs. METHODS:A retrospective chart review was performed of 515 patients with melanoma who underwent ICI therapy, either as monotherapy or in combination, and had HLA typing available. This analysis spans from 2003 to 2023 with a focus on cutaneous irAEs. Statistical analyses were conducted to assess the association between HLA alleles and irAEs. RESULTS:Our analysis revealed that the HLA-B*51:01 allele was associated with a higher risk of cutaneous irAEs after adjusting for ICI regimen (hazard ratio: 1.71 [95% CI, 1.12-2.61], p = .013.) CONCLUSION: This is the largest study to link an HLA allele with ICI-induced cutaneous irAEs. The findings may support the use of HLA typing as an initial screen for developing irAEs, providing a simple, straightforward metric that can be rapidly performed on patients prior to initiation of ICIs. However, further research is needed across different cancer and toxicity types.

Fungal colonization is a known carcinogenic accomplice in lung and colon cancer but has not been implicated in breast cancer. Here, we attempt to explore the mechanism behind fungal colonization and carcinogenesis by Malassezia globosa in breast cancer. To begin with, we found an increased abundance of the fungus in tumor tissues of breast cancer patients and the fungal inhibitor Amphotericin-B impeded tumor growth in patient-derived breast cancer xenograft models. On the other hand, Malassezia globosa enhanced the proliferative, migratory, and invasive abilities of breast cancer cells, and facilitated tumor growth in vivo. The positive effect of Malassezia globosa on tumor growth occurred via M2 macrophage polarization resulting in the activation of the pro-inflammatory MBL-C3a-C3aR signaling cascade which was reversed with the knockout of MBL expression. The proliferative, migratory, and invasive capacities of breast cancer cells were enhanced by culture medium from Malassezia globosa-treated THP-1 cells, which were rescued by a C3aR antagonist. In conclusion, Malassezia globosa activates MBL-C3a-C3aR signaling to trigger M2 macrophage polarization, promoting breast cancer progression and this study unravels a novel paradigm for breast cancer treatment.

This study explores the molecular mechanism by which sentrin/SUMO-specific protease 1 (SENP1) promotes cisplatin (Cis) resistance and tumor stem cell characteristics in colon adenocarcinoma (COAD) through deSUMOylation-mediated modification of octamer-binding transcription factor 4 (OCT4). By analyzing single-cell and transcriptome sequencing datasets, we identified key genes and regulatory pathways in both resistant and sensitive COAD cells. Malignant cells were isolated and evaluated for stemness using the infercnv package, and differential genes between Cis-resistant and -sensitive groups were identified. Machine learning algorithms highlighted essential genes, and databases predicted interaction sites between OCT4 and SENP1. In vitro experiments using enriched HCT116 stem cells revealed that SENP1 and OCT4 expression significantly elevated CD44 and CD133 levels, enhancing stemness. Functional assays showed that SENP1's deSUMOylation of OCT4 intensified Cis resistance, migration, and invasion in cisplatin-resistant cell line 116 (Cis-116) cells. In vivo, SENP1 knockdown reduced tumor growth and stem cell markers, whereas OCT4 overexpression escalated tumor metastasis and structural damage. These findings demonstrate that SENP1's modulation of OCT4 is central to COAD's resistance and stem cell properties, offering a novel target for COAD therapy.NEW & NOTEWORTHY This study uncovers the critical role of SENP1 in regulating OCT4 through deSUMOylation, driving Cis resistance and tumor stemness in COAD. Targeting this pathway may provide novel therapeutic strategies for COAD management.

BACKGROUND:Minor histocompatibility antigens play an important role in eliciting an alloimmune response in allogeneic hematopoietic stem cell transplantation (allo-HSCT). HY antigens, minor histocompatibility antigens originating from distinct regions of the Y chromosome, serve as immunogenic targets in female-to-male (FtoM) allo-HSCT, potentially increasing the risk of graft-versus-host disease (GVHD) and the development of allogeneic HY antibodies. Moreover, extensive HLA polymorphism and diverse peptide-binding specificities of HLA molecules can lead to varying alloimmunity and subsequent clinical risks/benefits among patients upon exposure to the HY antigen. OBJECTIVE:In the current study, we investigated the clinical implications of HY molecular disparity using the predicted indirectly recognizable HY epitopes (PIRCHyE) score (PS) in 712 patients undergoing allo-HSCT from an HLA-matched related donor, including 336 gender-mismatched HSCT. RESULTS:In FtoM (N = 194) allo-HSCT, higher PS-I, which theoretically reflects CD8+ T-cell alloreactivity triggered by HY antigens, was associated with a significantly higher rate of grade III-IV acute GVHD (P = .005) and an increased relapse rate (P = .01). In contrast, high PS-II correlated with reduced progression (P = .04) and a higher risk of chronic GVHD (P = .01). To further explore the interplay between CD4 T-helper cell responses (PS-II) and CD8 cytotoxic effects (PS-I), we simultaneously assessed the impact of PS-I and PS-II and found high PS-I/low PS-II was associated with a significantly higher relapse rate (P = .002) and lower progression-free survival (PFS) (P = .02). Conversely, a low PS-I/high PS-II was significantly associated with a higher chronic GVHD rate (P = .02) and a favorable trend in PFS (P = .2) in multivariate analysis. No such effects were observed in the male-to-female allo-HSCT group. CONCLUSION:These findings indicate that molecular assessment of HY antigens enables quantitative prediction of HY alloreactivity, which may enhance donor selection and help mitigate complications in allo-HSCT.

HLA-DPB1 mismatching is common in unrelated donor (URD) hematopoietic cell transplantation (HCT) and increases graft-versus-host disease (GVHD) when using methotrexate and tacrolimus (MTX/Tac)-based GVHD prophylaxis. Historically, national and international guidelines recommended prioritizing HLA-DPB1 matching in URD selection. The impact of HLA-DPB1 matching in URD HCT when using post-transplantation cyclophosphamide (PTCy) has been understudied. Our primary endpoint was the association of GVHD-prophylaxis strategy with overall survival (OS) after T cell-replete 12/12 HLA-matched or HLA-DPB1 permissive or non-permissive (NP) mismatch (MM) (defined by the T-cell-epitope groups model) URD HCT. GVHD-free, relapse-free survival (GRFS) was our key secondary endpoint. This was a retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) database. Recipients underwent a first HCT from 2015-2020 for acute leukemia or myelodysplastic syndrome using either HLA-DPB1 NP MM (n = 329), permissive MM (n = 992), or 12/12 HLA-matched (n = 300) URD with PTCy ± mycophenolate mofetil and/or a calcineurin inhibitor, or HLA-DPB1 NP MM (n = 709), permissive MM (n = 2,395), or 12/12 HLA-matched (n = 911) URD with MTX/Tac. HLA-DPB1 NP MM HCT with MTX/Tac was associated with higher treatment-related mortality (TRM) (hazard ratio [HR]: 1.64, 1.08-2.49, P = .019), lower relapse (HR: 0.73, 0.59-0.92, P = .0073), inferior OS (HR: 1.27, 1.03 -1.57, P = .023), and worse GRFS (HR: 1.61, 1.34-1.94, P < .0001) when compared with HLA-DPB1 NP MM HCT with PTCy. Adjusted 1-yr estimates for GRFS were 54% (95% confidence interval [CI]: 49-60%) for PTCy and 40% (CI: 37-44%) for MTX/Tac. For permissive MM URD HCT, MTX/Tac was associated with inferior GRFS (HR 1.54, CI: 1.36-1.76, P < .0001) when compared with PTCy. When using PTCy, there were no significant differences in the above outcomes for HLA-DPB1 NP MM, HLA-DPB1 permissive MM, or 12/12 HLA-matched URD HCT. PTCy should be the preferred GVHD prophylaxis strategy for HLA-DPB1 MM URD HCT. Furthermore, within PTCy platforms, survival is comparable across HLA-DPB1 match and thus NP mismatching at HLA-DPB1 should not be avoided in URD selection when using PTCy.

Umbilical cord blood (CB) transplantion is limited by slower engraftment and higher failure rates compared to other allografts. We hypothesized that ex vivo expansion of CB using mesenchymal progenitor cells (MPCs) and exofucosylation to enforce expression of osteotropism-mediating sLeX would shorten engraftment time. Six patients with hematologic malignancies underwent transplantation with two CB units (CBUs). Five received one unmanipulated CBU and one MPC-expanded, exofucosylated CBU. Median neutrophil engraftment, platelets >20,000/µL, and platelets >50,000/µL were 29, 45, and 55 days, respectively. A sixth received one exofucosylated CBU and one MPC-expanded CBU, achieving neutrophil engraftment, platelets >20,000/µL, and platelets >50,000/µL in 34, 53, and 57 days, respectively. Acute GVHD occurred in 4/6 patients, including one grade III/IV case. Three were alive without disease relapse at a median of 43.6 months post-transplant. Deaths in three patients were due to relapse, COVID, and GVHD. Thus, these approaches were safe, but did not improve engraftment.

BackgroundMicroRNAs (miRNAs) are critical regulators of cancer progression, prompting our investigation into the specific function of miR-630 in pancreatic cancer stem cells (PCSCs). Analysis of miRNA and mRNA expression data in PCSCs revealed downregulation of miR-630 and upregulation of PRKCI, implying a potential role for miR-630 in PCSC function and tumorigenicity.ResultsFunctional assays confirmed that miR-630 directly targets PRKCI, leading to the suppression of the Hedgehog signaling pathway and consequent inhibition of PCSC self-renewal and tumorigenicity in murine models. This study unveiled the modulation of the PRKCI-Hedgehog signaling axis by miR-630, highlighting its promising therapeutic potential for pancreatic cancer (PC) treatment.ConclusionsMiR-630 emerges as a pivotal regulator in PCSC biology, opening up new avenues for targeted interventions in PC. The inhibitory effect of miR-630 on PCSC behavior underscores its potential as a valuable therapeutic target, offering insights into innovative treatment strategies for this challenging disease.

Human leukocyte antigen (HLA) testing plays an important role in hematopoietic stem cell transplantation (HCT). This chapter provides an overview of an HLA laboratory in support of HCT highlighting several emerging areas with current practice. The chapter mainly covers the topics on HLA genes; HLA nomenclature; HLA testing including HLA typing, HLA antibody identification, and natural killer cell immunoglobulin receptor gene typing. In addition, this chapter briefly reviewed HLA disparity in donor selection; donor-specific anti-HLA antibody identification and desensitization strategies; and HLA molecular mismatch algorithms in the assessment of HLA alloimmune risk.

Donor-specific anti-HLA antibodies (DSA) are an important cause of engraftment failure and may negatively impact survival outcomes of patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) using an HLA-mismatched allograft. The incidence of DSA varies across studies, depending on individual factors, detection or identification methods and thresholds considered clinically relevant. Although DSA testing by multiplex bead arrays remains semiquantitative, it has been widely adopted as a standard test in most transplant centers. Additional testing to determine risk of allograft rejection may include assays with HLA antigens in natural conformation, such as flow cytometric crossmatch, and/or antibody binding assays, such as C1q testing. Patients with low level of DSA (<2,000 mean fluorescence intensity; MFI) may not require treatment, while others with very high level of DSA (>20,000 MFI) may be at very high-risk for engraftment failure despite current therapies. By contrast, in patients with moderate or high level of DSA, desensitization therapy can successfully mitigate DSA levels and improve donor cell engraftment rate, with comparable outcomes to patients without DSA. Treatment is largely empirical and multimodal, involving the removal, neutralization, and blocking of antibodies, as well as inhibition of antibody production to prevent activation of the complement cascade. Desensitization protocols are based on accumulated multicenter experience, while prospective multicenter studies remain lacking. Most patients require a full intensity protocol that includes plasma exchange, while protocols relying only on rituximab and intravenous immunoglobulin may be sufficient for patients with lower DSA levels and negative C1q and/or flow cytometric crossmatch. Monitoring DSA levels before and after HSCT could guide preemptive treatment when high levels persist after stem cell infusion. This paper aims to standardize current evidence-based practice and formulate future directions to improve upon current knowledge and advance treatment for this relatively rare, but potentially serious complication in allogeneic HSCT recipients.

BackgroundAn increased incidence of subsequent solid cancers (SSCs) has been reported in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT), and SSC is associated with inferior mortality and morbidity. Previous studies showed that the incidence of SSC is significantly higher in those who underwent allo-HSCT from HLA-mismatched donors, suggesting that persistent alloimmunity may predispose patients to SSCs. It was recently reported that, in a cohort of patients who received allo-HSCT from an unrelated donor matched at HLA-A, -B, -C, -DRB1/3/4/5, and -DQB1 loci, HLA-DPB1 alloimmunity determined by high mismatched eplets (MEs) and Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score (PS), was associated with relapse protection and increased risk of acute graft-versus-host disease (GVHD). MethodsIn the present study, the impact of HLA-DPB1 alloimmunity assessed by molecular mismatch algorithms on the development of SSCs in a cohort of 1514 patients who underwent allo-HSCT for hematologic malignancies was further investigated. ME load at the HLA-DPB1 locus was measured using the HLAMatchmaker module incorporated in HLA Fusion software, and the PS for mismatched HLA-DPB1 was calculated using the HSCT module from the PIRCHE online matching service. ResultsIn multivariable analysis after adjusting for baseline risk factors, higher ME, PS-I, and PS-II in the GVH direction, but not in the HVG direction, were associated with an increased risk of SSCs (ME: subdistribution hazard ratio [SHR] 1.58, p = .01; PS-I: SHR 1.59, p = .009; PS-II: SHR 1.71, p = .003). In contrast, nonpermissive HLA-DPB1 mismatches defined by the conventional T-cell epitope algorithm were not predictive of the risk of SSCs. Moreover, posttransplant cyclophosphamide-based GVHD prophylaxis was associated with a reduced risk of SSC (SHR 0.34, p = .021). ConclusionsThese results indicate for the first time that increased GVH alloreactivity could contribute to the development of SSCs in allo-HSCT survivors.

The rapid adoption of next-generation sequencing in clinical oncology has enabled detection of molecular biomarkers which are shared between multiple tumour types. Intra-tumour heterogeneity is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the tumour-related copy number variants (CNVs), as key regulators of cancer origination, development, and progression, across various types of cancers are poorly understood.We performed pan-cancer CNV analysis of cancer-related genes in 15 types of cancers including 1438 cancerous patients by next-generation sequencing using a commercially available pan-cancer panel (Onco PanScan™). Downstream bioinformatics analysis was performed in order to detect CNVs, cluster analysis of the found CNVs, and comparison of the frequency of gained CNVs between different types of cancers. LASSO analysis was used for identification of the most important CNVs.We also identified 523 CNVs among which 16 CNVs were common while 22 CNVs were caner-specific CNVs. Meanwhile, FAM58A was most commonly found in all studied cancers in this study and significant differences were found in FAM58A between female and male patients (p = .001). Common CNVs, such as FOXA1, NFKBIA, HEY1, MECOM, CHD7, AGO2, were mutated in 6.79%, 8.45%, 7.51%, 6.43%, 7.59%, 8.16% of tumours, while most of these mutations have proven roles in positive regulation of transcription from RNA polymerase II promoter. 11 features including sex, DIS3, EPHB1, ERBB2, FLT1, HCK, KEAP1, MYD88, PARP3, TBX3, and TOP2A were found as the key features for classification of cancers using CNVs.The 16 common CNVs between cancers can be used to identify the target of pan-cancer drug design and targeted therapies. Additionally, 22 caner-specific CNVs can be used as unique diagnostic markers for each cancer type.

OBJECTIVES:The M2 polarization of tumor-associated macrophages (TAMs) facilitates the growth, invasion and metastasis of tumor cells. Here, we investigated the role of miR-216b in the M2 polarization of TAMs in colorectal cancer (CRC).METHODS:The expression of genes were examined by quantitative real-time polymerase chain reaction, Western blot, enzyme-linked immunosorbent assay and immunohistochemistry. The relationship between miR-216b and CPEB4 was verified through dual luciferase reporter assays. The proliferation, migration and invasiveness of CRC and Raw264.7 cells were assessed through cell counting kit-8 and Transwell assays. Flow cytometry was used to quantify the percentage of F4/80+/CD206+RAW264.7 cells. The metastasis of tumor cells in liver and lung tissues was evaluated by establishing a mouse xenograft tumor model and hematoxylin-eosin staining.RESULTS:Downregulation of miR-216b enhanced the M2 polarization of TAMs. CPEB4 was identified as a target of miR-216b. CPEB4 knockdown suppressed CRC cell proliferation, migration and invasion, which were rescued by miR-216b inhibition. It was confirmed that M2 macrophage infiltration in CRC was positively correlated with the expression levels of CPEB4 and IL-10. CPEB4 knockdown impaired the M2 polarization of Raw264.7 cells and reduced IL-10 expression. miR-216b overexpression suppressed tumor growth, metastasis and expressions of CPEB4, CD206 and IL-10 in CRC xenograft models.CONCLUSIONS:miR-216b targets CPEB4 to impair the IL-10-mediated M2 polarization of TAMs, thereby inhibiting CRC development.

HLA-DPB1 mismatches between donor and recipient are commonly seen in allogeneic hematopoietic stem cell transplantation from an unrelated donor. HLA-DPB1 mismatch, conventionally determined by the similarity of the T-cell epitope (TCE), is associated with an increased risk of acute graft-versus-host disease (GVHD) and a decreased risk of disease relapse. We investigated the clinical impact of HLA-DPB1 molecular mismatch quantified by mismatched eplets (ME) and the Predicted Indirectly Recognizable HLA Epitopes Score (PS) in a cohort of 1,514 patients receiving hematopoietic stem cell transplants from unrelated donors matched at HLA-A, -B, -C, -DRB1/3/4/5, and - DQB1 loci. HLA-DPB1 alloimmunity in the graft-versus-host direction, determined by high graft-versus-host ME/PS, was associated with a reduced risk of relapse (hazard ratio [HR]=0.83, P=0.05 for ME) and increased risk of grade 2-4 acute GVHD (HR=1.44, P<0.001 for ME), whereas high host-versus-graft ME/PS was only associated with an increased risk of grade 2-4 acute GVHD (HR=1.26, P=0.004 for ME). Notably, in the permissive mismatch subgroup classified by TCE grouping, high host-versus-graft ME/PS was associated with an increased risk of relapse (HR=1.36, P=0.026 for ME) and grade 2-4 acute GVHD (HR=1.43, P=0.003 for PS-II). Decision curve analysis showed that graftversus- host ME outperformed other models and provided the best clinical net benefit for the modification of acute GVHD prophylaxis regimens in patients with a high risk of developing clinically significant acute GVHD. In conclusion, molecular assessment of HLA-DPB1 mismatch enables separate prediction of host-versus-graft or graft-versus-host alloresponse quantitatively and allows further refinement of HLA-DPB1 permissiveness as defined by conventional TCE grouping.

Immune checkpoint inhibitors are associated with immune-related adverse events (irAEs), including arthritis (arthritis-irAE). Management of arthritis-irAE is challenging because immunomodulatory therapy for arthritis should not impede antitumor immunity. Understanding of the mechanisms of arthritis-irAE is critical to overcome this challenge, but the pathophysiology remains unknown. Here, we comprehensively analyze peripheral blood and/or synovial fluid samples from 20 patients with arthritis-irAE, and unmask a prominent Th1-CD8+ T cell axis in both blood and inflamed joints. CX3CR1hi CD8+ T cells in blood and CXCR3hi CD8+ T cells in synovial fluid, the most clonally expanded T cells, significantly share TCR repertoires. The migration of blood CX3CR1hi CD8+ T cells into joints is possibly mediated by CXCL9/10/11/16 expressed by myeloid cells. Furthermore, arthritis after combined CTLA-4 and PD-1 inhibitor therapy preferentially has enhanced Th17 and transient Th1/Th17 cell signatures. Our data provide insights into the mechanisms, predictive biomarkers, and therapeutic targets for arthritis-irAE.

The number of haploidentical hematopoietic stem cell transplantations (haplo-HSCT) performed has increased substantially in recent years. Previous single-center studies using in silico algorithms to quantitively measure HLA disparity have shown an association of the number of HLA molecular mismatches with relapse protection and/or increased risk of acute graft-versus-host disease (GVHD) in haplo-HSCT. However, inconsistent results from small studies have made it difficult to understand the full clinical impact of molecular mismatch in haplo-HSCT. In this study, we investigated the potential of the HLA class I and II mismatched eplet (ME) score measured by HLA-Matchmaker, as well as ME load at a specific locus to predict outcomes in a registry-based cohort of haplo-HSCT recipients. We analyzed data from 1287 patients who underwent their first haplo-HSCT for acute lymphoblastic leukemia, acute myelogenous leukemia, or myelodysplastic syndrome between 2013 and 2017, as entered in the Center for International Blood and Marrow Transplant Research database. ME load at each HLA locus and total class I and II were scored using the HLAMatchmaker module incorporated in HLA Fusion software v4.3, which identifies predicted eplets based on the crystalized HLA molecule models and identifies ME by comparing donor and recipient eplets. In the study cohort, ME scores derived from total HLA class I or class II loci or individual HLA loci were not associated with overall survival, disease-free survival, nonrelapse mortality, relapse, acute GVHD, or chronic GVHD (P < .01). An unexpected strong association was identified between total class II ME load in the GVH direction and slower neutrophil engraftment (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.75 to 0.91; P < .0001) and platelet engraftment (HR, 0.80; 95% CI, 0.72 to 0.88; P <.0001). This was likely attributable to ME load at the HLA-DRB1 locus, which was similarly associated with slower neutrophil engraftment (HR, 0.82;95% CI, 0.73 to 0.92; P = .001) and slower platelet engraftment (HR, 0.76; 95% CI, 0.70 to 0.84; P < 0001). Additional analyses suggested that this effect is attributable to a match versus a mismatch in the graft-versus-host direction and not to ME load, as a dose effect was not identified. These findings contradict those of previous relatively small studies reporting an association between ME load, as quantified by HLAMatchmaker, and haplo-HSCT outcomes. This study failed to demonstrate the predictive value of ME from HLA molecules for major clinical outcomes, and other molecular mismatch algorithms in haplo-HSCT settings should be tested. (c) 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.