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C H A P T E R 106

HAPLOIDENTICAL HEMATOPOIETIC CELL TRANSPLANTATION

Ephraim Fuchs

Allogeneic hematopoietic stem cell transplant (alloHSCT) is a recipient and differs by a number of HLA genes on the unshared
potentially effective treatment for a wide range of hematologic HLA haplotype. When typing is performed for three HLA class I
malignancies and nonmalignant hematologic or immunologic disor- genes, HLA-A, HLA-B, and HLA-C, and three class II genes, HLA-
ders. Sources of donor stem cells for alloHSCT include human leu- DRB1, HLA-DQB1, and HLA-DPB1, HLA disparity between the
kocyte antigen (HLA)-matched siblings, suitably HLA-matched HLA-haploidentical donor and recipient ranges from 0 to 6 alleles
unrelated adult donors, partially HLA-mismatched unrelated donors, or antigens. By definition, a parent and a child are HLA haploidenti-
related or unrelated donor umbilical cord blood, or partially HLA- cal to each other, and each biological sibling or half-sibling of a
mismatched related (HLA-haploidentical [“haplo”]) donors. Histori- patient has a 50% chance of being HLA haploidentical to each other.
cally, the paramount consideration in choosing between graft sources Other potential haplo donors include aunts, uncles, nieces, and
has been the degree of HLA match between donor and recipient. A nephews, who each have a 50% chance of being HLA haploidentical,
fully HLA-matched sibling has been the preferred donor for alloHSCT and cousins, who have a 25% chance of being HLA haploidentical.
because transplants from HLA-matched siblings have been associated Mismatching of HLA alleles or antigens can occur in the graft-
with the lowest incidence of graft failure, graft-versus-host disease versus-host (GVH) direction only, the host-versus-graft (HVG)
(GVHD), and nonrelapse mortality (NRM), as well as with the direction only, or bidirectionally. When the donor is homozygous for
highest overall survival (OS) and event-free survival. Unfortunately, an HLA allele but the recipient is heterozygous at the same genetic
only 30% of patients referred for alloHSCT have an HLA-matched locus, there is a mismatch in the GVH direction only. Conversely,
sibling, and the availability of closely matched unrelated donors varies when the recipient is homozygous for an HLA allele but the donor
significantly by patient ethnicity, being as low as 19% for African is heterozygous, there is a mismatch in the HVG direction only. HLA
Americans or as high as 80% for white people of Northern European mismatches in the GVH direction stimulate GVHD, whereas HLA
1
origin. HLA mismatching between donor and recipient is associated mismatches in the HVG direction stimulate rejection of the hema-
with increased alloreactivity of donor and recipient T cells, leading topoietic stem cell (HSC) graft by host T cells. The number of HLA
to higher risks of GVHD and NRM, as well as to worse outcomes. mismatches between an HLA-haploidentical donor and recipient
In the past two decades, techniques have been developed to mitigate should be expressed as the number of mismatches in the GVH
alloreactivity to the point that outcomes of HLA-haploidentical stem direction as well as the number of mismatches in the HVG direction.
cell transplant (SCT) rival those of umbilical cord blood and unre- For example, the patient in Fig. 106.1 differs from sibling 2 by four
lated donor (URD) transplants. This chapter starts by defining what antigens (and alleles) in the GVH direction and by five antigens (and
is an HLA-haploidentical donor and presents the immunobiology of alleles) in the HVG direction, and from sibling 3 by three antigens
the immune response to allogeneic HLA molecules. A history of (versus four alleles) in the GVH direction and by three antigens
HLA-haploidentical hematopoietic cell transplantation (HCT) is (versus five alleles) in the HVG direction.
provided, culminating in a presentation of modern approaches and
results. Finally, considerations that are unique to or enabled by HLA-
haploidentical HCT are discussed. WHY HLA-HAPLOIDENTICAL BONE MARROW
TRANSPLANT? (see Box 106.1)
DEFINITIONS: WHAT IS AN HLA HAPLOTYPE, AND WHO Advantages and Limitations of Haploidentical Donors
IS AN HLA-HAPLOIDENTICAL DONOR?
The major advantages of the HLA-haploidentical donor option over
A haplotype is a set of genes that are arranged closely together on a the other donor types include:
chromosome and are inherited as a biologic unit. The HLA locus on
chromosome 6p13.2 comprises a set of tightly linked genes encoding 1. Near-universal availability of highly motivated donors: Patients have
molecules that present peptide antigens to T cells. The HLA locus an average of 2.7 potential HLA-haploidentical donors among
contains three regions: first-degree relatives. By comparison, only approximately 30% of
patients have an HLA-matched sibling, and availability of a URD
1. The class I region encodes the “classical” class I genes HLA-A, genotypically matched at eight of eight alleles (HLA-A, HLA-B,
+
HLA-B, and HLA-C, which present antigens to CD8 T cells, as HLA-C, and HLA-DRB1) ranges from 19% to 80%, depending
well as nonclassical HLA-E, HLA-F, and HLA-G molecules. on the recipient’s ethnic background. 1
2. The class II region encodes HLA-DRB1, HLA-DQB1, and HLA- 2. Rapid availability: The time to identify and mobilize an adult
+
DPB1, which present antigens to CD4 T cells, as well as nonclas- URD can be longer than 3 months for up to 25% of patients. An
sical class II molecules HLA-DM and HLA-DO. HLA-haploidentical donor can be identified and mobilized within
3. The class III region encodes molecules not known to be involved 2 weeks to 1 month.
in histocompatibility reactions. 3. Adequate doses of HSCs: HLA-haploidentical grafts have sufficient
doses of HSCs for transplant of adult recipients and of memory
An HLA haplotype is defined as the set of histocompatibility genes T cells for immune reconstitution. In contrast, the total dose of
that are on the same chromosome 6 and so are inherited together. nucleated cells in a single umbilical cord blood unit may be
Each individual has two HLA haplotypes, one on the chromosome suboptimal for engraftment in larger adults, leading to delayed
6 inherited from the individual’s mother and the other on the chro- immune reconstitution.
mosome 6 inherited from the individual’s father. 4. Low cost of graft acquisition: The costs of acquiring grafts from
An HLA-haploidentical donor is a related donor who shares, by adult URDs and especially from umbilical cord blood banks can
common inheritance, exactly one HLA haplotype with the transplant be substantially higher than acquiring them from related donors.

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