Hematopoietic SCT from partially HLA-mismatched (HLA-haploidentical) related donors

Abstract

Hematopoietic SCT from a partially HLA-mismatched (HLA-haploidentical) first-degree relative offers the benefits of rapid and near universal donor availability but also the risks that result from traversing the HLA barrier; namely, graft failure, severe GVHD and prolonged immunodeficiency. Improvements over the last 10 years in conditioning regimens, graft engineering and pharmacological immunoprophylaxis of GVHD have substantially reduced the morbidity and mortality of HLA-haploidentical SCT. Highly immunosuppressive but nonmyeloablative conditioning extends the availability of HLA-haploidentical SCT to elderly hematologic malignancy patients lacking HLA-matched donors and permits recovery of autologous hematopoiesis in the event of graft failure. Current regimens for HLA-haploidentical SCT are associated with a 2-year non-relapse mortality of 20+/-5%, relapse of 35+/-15% and overall survival of 50+/-20%. Major developmental areas include harnessing natural killer cell alloreactivity to reduce the risk of disease relapse and improving immune reconstitution by delayed infusions of lymphocytes selectively depleted of alloreactive cells. Hematologic malignancy patients who lack suitably matched related or unrelated donors can now be treated with HLA-haploidentical related donor or unrelated umbilical cord blood SCT. Future clinical trials will assess the relative risks and benefits of these two graft sources.

Figure 1

Interactions between inhibitory killer immunoglobulin-like receptors (iKIRs) and their HLA ligands of relevance to natural killer (NK) cell alloreactivity after allo-SCT. For convenience, a single NK cell expressing four distinct iKIRs is shown. Each NK cell need only express one molecular species of iKIR for functional maturation to occur. High resolution HLA typing is required to determine whether specific alleles of HLA-B and HLA-Cw are ligands of specific iKIRs. Group 2 HLA-C alleles (C2; for example, -Cw2, -Cw4, -Cw5 and -Cw6) are the ligands for KIR2DL1, whereas group 1 HLA-C alleles (C1; for example, -Cw1, -Cw3, -Cw7, -Cw8) are the ligands for KIR2DL2 and KIR2DL3. High resolution typing of HLA-B and -Cw loci are incorporated into the ligand incompatibility, receptor-ligand and missing ligand models of NK cell alloreactivity (Figure 2). Interactions between KIR3DL2 and HLA-A3 or -A11 are generally not considered in these models.

Figure 2

Models of natural killer (NK) cell alloreactivity after allo-SCT. Models of NK cell alloreactivity incorporate some or all of the following information: (1) high resolution HLA typing of donor and recipient; (2) genotyping of the killer immunoglobulin-like receptor (KIR) locus by PCR of genomic DNA using sequence-specific oligonucleotide probes (SSP) and (3) phenotyping of KIR expression by flow cytometry using commercially available antibodies. (a) The ligand incompatibility model predicts NK cell alloreactivity in the graft-vs-host direction (depicted) when the recipient lacks expression of an HLA ligand for inhibitory KIR, in this case a member of the HLA-C1 group, that is present in the donor. The presence of functional donor NK cells expressing KIR2DL2, the receptor for molecules of the HLA-C1 group, is assumed in this model. (b) The receptor-ligand model predicts NK cell alloreactivity in the graft-vs-host direction when the recipient lacks an HLA ligand for donor inhibitory KIR, whose presence is verified by KIR genotyping and flow cytometry of donor NK cells. The HLA type of donor cells is irrelevant to this model. (c) The missing ligand model predicts NK cell alloreactivity in the graft-vs-host direction when recipient cells lacks expression of at least one of the HLA ligands (C1, C2 or -Bw4) for inhibitory KIR. (d) The KIR gene–gene model predicts NK alloreactivity when the donor and recipient are mismatched for KIR gene content. Inhibitory KIR genes are shown as unshaded boxes, whereas black boxes represent activating KIR genes. In the example shown, the recipients KIR genotype is said to be ‘included’ in the donor’s KIR genotype.

Figure 3

Treatment schemata for Blood and Marrow Transplant Clinical Trials Network (BMT CTN) multicenter clinical trials of nonmyeloablative conditioning and transplantation of (a) partially HLA-mismatched (haploidentical) BM (BMT CTN 0603) or (b) double unit unrelated umbilical cord blood (UBC) (BMT CTN 0604) for adults with leukemia or lymphoma.