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HLA loss-mediated immune escape of acute leukemias in pediatric patients post haploidentical transplantation

Bone Marrow Transplantation volume 60, pages 1178–1180 (2025)Cite this article

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Human leukocyte antigen (HLA)-mismatched hematopoietic cell transplantation (HCT) provides the potential benefit of graft-versus-leukemia (GvL) effects, but immune pressure exerted by donor cells may lead to immune escape. Deletions of HLA genes in leukemic cells have emerged as a common mechanism of post-transplant immune escape after haploidentical (haplo)HCT in adults, having been documented in 25–50% of relapses of hematologic malignancies across diverse transplant protocols [1,2,3,4,5,6,7]. However, data for pediatric patients is limited and predictive factors remain elusive. Copy neutral loss of heterozygosity (cnLOH), often encompassing the entire recipient-specific mismatched HLA haplotype [1, 6, 8], renders leukemic cells unresponsive to donor lymphocyte infusions (DLI), making detection of HLA loss paramount in treatment decisions that carry risk of graft-versus-host disease (GvHD) with no benefit of GvL [9]. We describe retrospective data analysis of HLA loss in a single institution cohort of 53 pediatric patients with acute leukemias who relapsed after a total of 60 haploHCT.

Patients and transplant procedures, testing methods, and statistical analyses are detailed in Supplementary Methods, and recipient characteristics are shown in Supplementary Table 1. Of 53 patients, 35 had acute myeloid leukemia (AML), 16 had acute lymphoblastic leukemia (ALL), and 2 had other acute leukemias. Relapse samples were tested for HLA loss, with classical relapses defined by similar host chimerism on non-HLA and HLA chromosomal targets, whereas HLA loss relapses exhibited loss of HLA signal (Supplementary Fig. 1).

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Fig. 1: HLA loss relapse after haploidentical transplant.

Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to acknowledge the referring physicians, the staff of the clinical research office with assistance conducting the clinical studies, the staff of the Human Applications, HLA, Molecular Pathology, and Biorepository Laboratories, the staff of the Department of Bone Marrow Transplantation and Cellular Therapy for their excellent patient care, and the patients and families of St. Jude. This study was supported by the Biostatistics Shared Resource of St. Jude Children’s Research Hospital, the St. Jude Comprehensive Cancer Center (NIH P30CA021765) and the American Lebanese Syrian Associated Charities. AS is also supported by a grant (1U01HL163983) from the NIH/National Heart, Lung, and Blood Institute (NHLBI). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Paula Y. Arnold

  2. Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Subodh Selukar & Guangjin Luo

  3. Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Ying Li, Rebecca Epperly, Stephen Gottschalk, Renee M. Madden, Amr Qudeimat, Akshay Sharma, Ali Y. Suliman, Aimee C. Talleur, Brandon M. Triplett & Swati Naik

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Contributions

PYA, SN, and BMT conceived and designed the study; SS and GL performed statistical analysis; PYA performed correlative studies, HLA Typing and HLA Loss assays; SN, BMT, ACT, RMM, AQ, AS, AYS, RE, and SG recruited and cared for patients; SN, PYA, YL, and BMT analyzed and provided input on data interpretation; PYA wrote the manuscript; SN, SS, SG, and BMT edited the manuscript; SN and BMT contributed equally as co-senior authors, all authors reviewed and approved the final draft of the manuscript.

Corresponding authors

Correspondence to Paula Y. Arnold or Swati Naik.

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Competing interests

AS has received consultant fees from Spotlight Therapeutics, Medexus Inc, Vertex Pharmaceuticals, Sangamo Therapeutics, and Editas Medicine; is a medical monitor for a Conditioning SCID Infants Diagnosed Early clinical trial for which he receives financial compensation; has received research funding from CRISPR Therapeutics and honoraria from Vindico Medical Education and Blackwood CME; and is the St. Jude Children’s Research Hospital site principal investigator of clinical trials for genome editing of sickle cell disease sponsored by Vertex Pharmaceuticals/CRISPR Therapeutics (NCT03745287), Novartis Pharmaceuticals (NCT04443907), and Beam Therapeutics (NCT05456880). The industry sponsors provide funding for the clinical trial, which includes salary support paid to the institution. AS has no direct financial interest in these therapies. SG is a member of the Data Safety Monitoring Board (DSMB) of Immatics, serves on the Scientific Advisory Board of Be Biopharma, served as a consultant for CARGO Therapeutics within the last 12 months, and has patents and patent applications in the fields of T cell and/or gene therapy for cancer. These conflicts are managed through the compliance office at St. Jude Children’s Research Hospital in accordance with their conflict-of-interest policy. All other authors have nothing to disclose.

Ethics approval and consent to participate

All methods were performed in accordance with the relevant guidelines and regulations. This retrospective study was approved by the St. Jude Children’s Research Hospital Institutional Review Board (No. 20-0635).

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Arnold, P.Y., Selukar, S., Luo, G. et al. HLA loss-mediated immune escape of acute leukemias in pediatric patients post haploidentical transplantation. Bone Marrow Transplant 60, 1178–1180 (2025). https://doi.org/10.1038/s41409-025-02622-1

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