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A perfect mismatch: haploidentical hematopoietic stem cell transplantation overtakes a bend

Cellular & Molecular Immunology volume 20, pages 978–980 (2023)Cite this article

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Matching for the major histocompatibility complex (MHC)—and more specifically, the human leukocyte antigen (HLA) system—has been the gold standard in transplantation for decades. Selecting an HLA-matched donor is the preferred and straightforward choice for most immunologists, hematologists, and organ transplant specialists. Conversely, HLA-mismatched donors have been less accepted in hematopoietic stem cell transplantation (HSCT) due to unacceptable severe graft-versus-host disease (GvHD) and/or host-versus-graft (HvG) rejection. However, in the past three decades, a new approach has emerged: haploidentical HSCT (haplo-HSCT), which uses a related donor who is only partially matched to the recipient, such as parents and offspring. This new treatment has been shown to have similar or even better outcomes than classical HSCT of HLA-identical sibling donors (MSDs). Haploidentical donors have become a significant donor source for stem cell transplantation around the world in the past decade, and they now account for more than 60% of all donors in China and ~20% of donors in Europe and North America [1, 2]. This has led many to question whether mismatch could lead to better transplantation outcomes, and if so, for whom, how, and why?

In contrast to organ transplants, HSCT has a desired shadow power parallel to GvHD, known as the graft-versus-tumor (GvT) effect, which reduces the risk of relapse in various hematological malignancies after HSCT. It seems logical to maximize this effect by selecting donors with a significant HLA mismatch to the donor. Nevertheless, it has been considered too risky to use this power without controlling GvHD and graft rejection, which nearly resulted in the abandonment of haplo-HSCT three decades ago. The breakthrough of T-cell depletion (TCD) allografts, as well as two T-cell-replete (TCR) haplo-HSCT platforms—including the Beijing protocol (G-CSF-mobilized allografts and anti-thymocyte globulin based) and the Baltimore Protocol (posttransplant cyclophosphamide-based, PT-CY)—have resulted in promising outcomes in terms of acceptable GvHD and engraftment rates. The outcomes of patients following haplo-HSCT, especially by TCR protocols, have gradually become comparable to the outcomes of patients using either HLA-identical sibling donors or matched unrelated donors in the past two decades [2]. Although preliminary results from 2011 showed that the new haplo-HSCT protocol might exert more potent GvT effects in high-risk acute leukemia patients [3], this idea was not widely accepted, and registry studies reported downbeat results [4]. Since 2017, there has been increasing evidence to suggest that haplo-HSCT has overtaken HLA-matched HSCT in the treatment of high-risk patients. Chang et al. reported that AML patients with pre-HSCT measurable residual disease (MRD) receiving haploidentical HSCT following the Beijing protocol had a lower relapse rate (19% vs. 55%, P < 0.001) and longer disease-free survival (DFS, 74% vs. 33%, P < 0.001) than those receiving HLA-matched sibling HSCT [5]. In patients with high-risk ALL, haploidentical HSCT was associated with a lower 3-year relapse rate (23% vs. 47%, p = 0.006) and longer DFS (65% vs. 43%, p = 0.023) [6]. These results were further verified by haplo-HSCT following Baltimore protocols in high-risk AML and lymphoma [7, 8]. This has caused the question to evolve from “Is there a stronger GvT effect using HLA-haploidentical donors?” to “Why is haplo-HSCT taking the lead?” The report by Guo et al. opened up a new era of research to answer this exciting question [9].

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Acknowledgements

National Key Research and Development Program of China (No.2022YFA1103300, 2021YFA1100902); Major Program, Key Program and General Program of the National Natural Science Foundation of China (82293630, 81930004, 82070182); Beijing Nova Program of Science and Technology (No. Z191100001119120); Fund of China Scholarship Council (202106015007).

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  1. These authors contributed equally: Meng Lv, Hui-Dong Guo.

Authors and Affiliations

  1. Peking University People’s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Beijing, China

    Meng Lv, Hui-Dong Guo & Xiao-jun Huang

  2. Peking-Tsinghua Center for Life Sciences, Beijing, China

    Xiao-jun Huang

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  1. Meng Lv
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XJH designed the comment. ML and HDG drafted the manuscript and prepared the figures. All authors read and approved the final manuscript.

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Correspondence to Xiao-jun Huang.

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Lv, M., Guo, HD. & Huang, Xj. A perfect mismatch: haploidentical hematopoietic stem cell transplantation overtakes a bend. Cell Mol Immunol 20, 978–980 (2023). https://doi.org/10.1038/s41423-023-01007-y

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