Hematopoietic Stem Cell Transplantation From Alternative Sources and Donors

Unrelated Donor Transplants

One of the most widely used strategies for children who need an allograft and do not have an available HLA-identical sibling is to identify an unrelated HLA-matched donor in a registry ( Fig. 162.1 ). Worldwide international registries include almost 27 million HLA-typed volunteer donors. HLA-A, -B, -C class I loci, and the DRB1 class II locus are the HLA loci most influencing outcome after HSCT from an unrelated volunteer. Other class II loci (namely, DQB1 and DP1 loci), as well as KIR haplotypes, are also being increasingly considered when choosing a donor, although their impact on outcome is less well studied.

Although in the past serologic (low-resolution) typing was used for HLA-A and HLA-B loci, currently the unrelated donors are selected using high-resolution (allelic) molecular typing of loci HLA-A, -B, -C, and -DRB1. Less stringent HLA typing is required for cord blood units, where only HLA-A, -B, and -DRB1 are used. The chance of finding an HLA-matched unrelated donor depends on the frequency of the HLA phenotype, which is closely linked to the ethnic origin of the registry donors. Data from the National Marrow Donor Program (NMDP) donor registry and banked cord blood units estimated that essentially every patient in need of a transplant would be able to find a donor in a timely fashion, despite the recipient's race/ethnic group, donor availability, and cell dose. However, many of those patients may not have access to an “ideal” graft, defined as HLA matching of 8/8 for bone marrow and 6/6 for cord blood. It is also estimated that an additional 5.5 million donors will be added to the registry by 2017, making it even more likely for a potential, and more ideal, donor to be identified.

Initially, HLA polymorphism and the intrinsic limitations of conventional (i.e., serologic) HLA-typing techniques unfavorably affected the accuracy of matching, thus increasing rejection rates and the incidence of acute and chronic graft-versus-host disease (GVHD). The advent of both high-resolution molecular HLA classes I and II loci typing coupled with progress in the prophylaxis and treatment of GVHD has resulted in a reduction of transplantation-related mortality and improvement in outcome. Indeed, outcomes from a fully matched unrelated volunteer donor are now similar to those of HSCT from an HLA-identical sibling. The outcomes of haploidentical transplantation are similarly reaching that of matched unrelated donors as well as matched sibling donors.

Although a single locus disparity in patients with leukemia may be seen as beneficial by a reduction in the relapse rate caused by the graft-versus-leukemia (GVL) effect, in patients with nonmalignant disorders in whom GVL is not beneficial, optimal results are obtained only when a donor matched at the allelic level with the recipient is selected. In general, a single HLA disparity in the donor-recipient pair, irrespective of whether antigenic or allelic in nature, predicts a greater risk of nonleukemia mortality; multiple allelic disparities at different HLA loci have an additive detrimental effect and are associated with an even worse outcome. To reduce the risk of acute GVHD, ex vivo T-cell depletion of the graft has been employed, with variable efficacy. Studies are looking at selectively depleting donor α/β T cells, which are the T cells that drive GVHD, while preserving the T cells and natural killer (NK) cells, which may be responsible for GVL and protection from infection.

Although the majority of patients who have required a matched unrelated donor transplant have received a bone marrow or peripheral stem cell graft, for patients who urgently need a transplant, the time required to identify a suitable donor from a potential panel, establish eligibility, and harvest the cells may lead to relapse and failure to transplant. For this subset of patients who urgently need a transplant, attention has focused on unrelated cord blood and HLA-haploidentical, mismatched family donors.