Modern approaches to HLA-haploidentical blood or marrow transplantation

Abstract

Allogeneic blood or bone-marrow transplantation (alloBMT) is a potentially curative treatment for a variety of haematological malignancies and nonmalignant diseases. Historically, human leukocyte antigen (HLA)-matched siblings have been the preferred source of donor cells owing to superior outcomes compared with alloBMT using other donors. Although only approximately one-third of patients have an HLA-matched sibling, nearly all patients have HLA-haploidentical related donors. Early studies using HLA-haploidentical alloBMT resulted in unacceptably high rates of graft rejection and graft-versus-host disease (GVHD), leading to high nonrelapse mortality and consequently poor survival. Several novel approaches to HLA-haploidentical alloBMT have yielded encouraging results with high rates of successful engraftment, effective GVHD control and favourable outcomes. In fact, outcomes of several retrospective comparative studies seem similar to those seen using other allograft sources, including those of HLA-matched-sibling alloBMT. In this Review, we provide an overview of the three most-developed approaches to HLA-haploidentical alloBMT: T-cell depletion with 'megadose' CD34(+) cells; granulocyte colony-stimulating factor-primed allografts combined with intensive pharmacological immunosuppression, including antithymocyte globulin; and high-dose, post-transplantation cyclophosphamide. We review the preclinical and biological data supporting each approach, results from major clinical studies, and completed or ongoing clinical studies comparing these approaches with other alloBMT platforms.

Figure 1

HLA-haploidentical donors. a | Located on the short arm of chromosome 6, the HLA region contains the genes for class I and class II histocompatibility molecules, which are commonly tested as clinically relevant transplantation antigens. However, the HLA region is genetically complex and includes other class I and class II genes in addition to genes not involved in histocompatibility (not shown). b | An example pedigree is shown. The patient in this pedigree does not have an HLA-matched sibling, although she has four HLA-haploidentical family members. Each individual haplotype is denoted by a lower-case letter above it. Note that the term HLA-haploidentical simply denotes the presence of one shared haplotype and one unshared haplotype between the patient and her potential donors; a ‘haplo’ donor can be more than ‘half-matched’ if there are common alleles on the unshared haplotypes. HVG and GVH indicate the degree of matching in the host-versus-graft and graft-versus-host directions, respectively. Mismatching at non-inherited maternal or non-inherited paternal antigens, which also might affect the relative antigenicity of the donor:recipient pair, are indicated for the ‘haplo’ siblings. Abbreviations: GVH, graft-versus-host; HLA, human leukocyte antigen; HVG, host-versus-graft; NIMA, non-inherited maternal antigens; NIPA, non-inherited paternal antigens.

Figure 2

Components of each transplantation platform. Interventions on the donor or recipient that are required for each transplantation platform are shown at each stage of the transplantation procedure. Abbreviations: ATG, antithymocyte globulin; BM, bone-marrow; BMT, blood or bone-marrow transplantation; GCSF, granulocyte colony-stimulating factor; G-PBSCs, granulocyte colony-stimulating factor-mobilized peripheral-blood stem cells; MMF, mycophenolate mofetil; PBSCs, peripheral-blood stem cells; PTCy, post-transplantation cyclophosphamide; TCD, T-cell depletion; TCR, T-cell receptor.