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HLA-haplotype loss after TCRαβ/CD19-depleted haploidentical HSCT

Bone Marrow Transplantation volume 56, pages 733–737 (2021)Cite this article

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Genomic loss of the mismatched HLA haplotype (i.e. HLA loss) was first described nearly 10 years ago in adult patients with myeloid malignancies undergoing haploidentical hematopoietic stem cell transplantation (haplo-HSCT) [1]. A follow-up study examined patients with myeloid malignancies undergoing HLA-mismatched HSCT from either related or unrelated donors found that HLA loss accounted for 33% of disease recurrence in patients receiving haplo-HSCT, demonstrating a recurring mechanism of post mismatched HSCT relapse [2]. Other smaller case reports in adults affected by lymphoid malignancies receiving mismatched HSCT showed a similar incidence of HLA. Notably, HLA loss relapses have been recently reported to occur with similar frequency also after haplo-HSCT employing posttransplant cyclophosphamide (PT-Cy) [3], further demonstrating that HLA loss is an intrinsic relapse mechanism after HSCT [4] and especially when using mismatched donors [5, 6]. This finding also suggests that even though PT-Cy can dramatically decrease the risk of severe GvHD after haplo-HSCT, it does not eliminate T-cell alloreactivity against the partially HLA-mismatched leukemia.

A deeper examination of the HLA loss phenomenon by whole-genome single-nucleotide polymorphism arrays demonstrated loss of heterozygosity (LOH) of chromosome 6p in the absence of copy number variations, which is consistent with acquired somatic uniparental disomy (aUPD) [2]. This genomic alteration consists of the loss of a chromosomal region that is subsequently replaced by the homologous copy, resulting in acquired homozygosity of that region. As a consequence, the loss of the genes encoding the HLA molecules not shared between donor and recipient (which represented the most immunodominant targets for donor T-cell alloreactivity) renders the mutated blasts invisible to donor-derived alloreactive T cells. Here, we report the first two cases of leukemia relapse due to HLA loss after TCRαβ/CD19-depleted haploidentical HSCT (αβhaplo-HSCT).

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Fig. 1: Loss of mismatched HLA haplotype at genomic DNA level detected in post-HSCT leukemic cells.

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Author notes

  1. These authors contributed equally: David C. Shyr, Bing M. Zhang

  2. These authors jointly supervised this work: Marcelo Fernandez-Vina, Alice Bertaina

Authors and Affiliations

  1. Department of Pediatrics, Division of Stem Cell Transplant and Regenerative Medicine, Stanford University, Stanford, CA, USA

    David C. Shyr, Gopin Saini, Karen Kristovich & Alice Bertaina

  2. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA

    Bing M. Zhang, Nahid D. Madani & Marcelo Fernandez-Vina

  3. Department of Pediatrics, Division of Hematology and Oncology, Stanford University, Stanford, CA, USA

    Liora M. Schultz

  4. Department of Medicine, Cancer Institute, Stanford University, Stanford, CA, USA

    Shabnum Patel

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  1. David C. Shyr
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Contributions

DCS and BMZ wrote the paper; BMZ and NDM performed the experiment and analysis; LMS and KK contributed to patient clinical care; DCS, GS, SP, and KK contributed to data collection; AB and MFV designed the study and provided scientific advice and supervision; AB provided major revision of the paper. All authors read and approved the final version of the manuscript.

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Correspondence to Alice Bertaina.

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Shyr, D.C., Zhang, B.M., Saini, G. et al. HLA-haplotype loss after TCRαβ/CD19-depleted haploidentical HSCT. Bone Marrow Transplant 56, 733–737 (2021). https://doi.org/10.1038/s41409-020-01081-0

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