Page 1819 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 106 Haploidentical Hematopoietic Cell Transplantation 1621

provided by the ability to generate donor alloreactive NK clones in of graft failure is immunologic rejection mediated by radioresistant
all 51 ligand incompatible donor–recipient pairs but in none of the host T and/or NK cells. 50,51 Among patients receiving myeloablative
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61 donors who were KIR ligand matched with their recipients. NK conditioning, the incidence of either primary or secondary (late)
alloreactivity in the GVH direction was predicted to have three graft failure was 2.0% in recipients of HLA-matched sibling marrow,
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functional consequences : (1) a GVL effect arising from donor NK but it was 12.3% in recipients of marrow from HLA-haploidentical
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cytotoxicity against leukemia cells; (2) a decreased rate of graft rejec- related donors (p < .0001). The incidence of graft failure correlated
tion arising from donor NK cell killing of host T cells; and (3) a with the degree of HLA incompatibility, occurring in 3 (7%) of
decreased rate of GVHD arising from donor NK cell elimination of 43 patients receiving haploidentical grafts mismatched for 0 HLA
host antigen-presenting cells such as dendritic cells, which are antigens (HLA phenotypically matched grafts from a parent or child),
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required to initiate GVH reactions. Clinical trials performed by 11 (9%) of 121 recipients of 1 HLA antigen-mismatched graft,
Ruggeri et al (hereinafter the Perugia group) have consistently dem- 18 (21%) of 86 recipients of 2 HLA antigen-mismatched grafts,
onstrated a strong antitumor effect of KIR ligand incompatibility in and 1 of 19 recipients of 3 HLA antigen-mismatched grafts (p =
acute myeloid leukemia (AML) but not in acute lymphoblastic leu- .028). The effect of increasing HLA disparity on the risk of graft
kemia (ALL). rejection after myeloablative SCT was also confirmed in an analysis
The missing ligand model predicts NK-mediated GVH reactions performed by the Center for International Blood and Marrow
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when the transplant recipient is missing at least one of the three major Transplant Research (CIBMTR) consortium. In this study, the risk
classes of HLA ligands for iKIR. The missing ligand model differs of graft rejection among recipients of grafts mismatched for two or
from the ligand incompatibility model only in that it does not require three HLA antigens was approximately six to eight times greater than
the presence on donor cells of the HLA ligand that is missing in the among recipients of grafts from HLA-matched siblings. TCD of the
recipient. Consequently, donors who are predicted by the ligand donor graft increased the risk of graft failure after HLA-mismatched
incompatibility model to contain alloreactive NK cells against their as well as HLA-matched SCT. In another study, the risk of graft
recipients are a subset of the donors who are predicted by the missing failure was increased in patients mismatched with the donor for both
ligand model to contain antirecipient alloreactive NK cells. HLA-B and HLA-DR antigens, as well as in patients with a positive
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The KIR ligand incompatibility and missing KIR ligand models lymphocytotoxic crossmatch against donor cells. The presence of a
were compared for their ability to predict relapse after T cell–replete positive crossmatch predicts both graft failure 52–54 and poor OS for
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(TCR), URD SCT for hematologic malignancies. Among recipients patients receiving HLA-mismatched grafts. Crossmatching, either
of HLA-mismatched transplants, recipient homozygosity for HLA-B by lymphocytotoxic or by solid-phase immunoassay (SPI) (the “virtual
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or HLA-C KIR epitopes was used to define “missing” KIR ligands crossmatch”), is strongly recommended as a step in determining
and was associated with a decreased hazard of relapse (hazard ratio donor eligibility before HLA-mismatched SCT. If the crossmatch is
[HR], 0.61; 95% confidence interval [CI], 0.43–0.85; p = .004). The positive, further testing is recommended to assess for the presence
effect was observed in patients with AML, chronic myeloid leukemia, in the patient of antidonor HLA antibodies. In cases where the
or ALL. The same effect was not observed in HLA-identical unrelated flow cytometric crossmatch is positive but the cytotoxic crossmatch
transplants. KIR ligand incompatibility was not associated with a is negative or predicted to be negative by virtual crossmatching,
decreased risk of relapse in recipients of either HLA-mismatched or plasmapheresis or immunoadsorption can be used to clear antidonor
HLA-matched grafts. HLA antibodies and permit engraftment after HLA-haploidentical
SCT. 19,57 If the cytotoxic crossmatch is or is predicted to be positive,
then a search for a different donor is recommended.
COMPLICATIONS OF HLA-HAPLOIDENTICAL SCT In addition to the degree of HLA disparity between donor and
recipient, several other factors influence the risk of graft rejection after
Regardless of the immunologic disparity between donor and recipi- HLA-haploidentical bone marrow transplant (BMT), including
ent, all patients undergoing allogeneic SCT are at risk for the same characteristics of the patient, the graft, the conditioning regimen, and
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complications, namely conditioning regimen toxicity, graft failure, posttransplant immunoprophylaxis. A competent host immune
GVHD, infection, and relapse. Intense bidirectional alloreactivity system is clearly required for allogeneic graft rejection, because the
after HLA-haploidentical SCT results in higher risks of both graft barrier to engraftment is lower in patients with severe combined
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failure and acute GVHD than HLA-matched sibling SCT. Strategies immunodeficiency than in patients with hematologic malignancies.
employed to reduce the risk of one complication of haploidentical Conversely, sensitization of immunocompetent recipients, for
SCT have, to much frustration, resulted in an increased incidence of instance by blood transfusions, increases the risk of graft rejection
another serious complication. For example, TCD of the donor graft following allogeneic SCT. The dose of donor T cells and stem cells
reduces the risk of GVHD but increases the risk of fatal graft also has a powerful influence on donor cell engraftment after haploi-
failure. 6,43 Consequently, in early studies, TCD did not improve the dentical SCT. Early studies clearly established that depletion of T cells
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outcome of HLA-haploidentical SCT. Increased conditioning from the graft significantly increases the risk of graft failure following
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regimen intensity reduces the risk of graft failure but increases the HLA-haploidentical SCT. In some series, the risk of graft failure
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risk of regimen-related toxicity and also may increase the risk of following TCD approached 50%. However, the detrimental effects
GVHD. 45,46 Finally, low rates of graft rejection and GVHD can be of TCD on donor cell engraftment can be overcome by augmenting
achieved by giving rigorously T cell–depleted grafts to intensively recipient immunosuppression and escalating the dose of transplanted
conditioned recipients, but immune reconstitution is significantly stem cells. 60,61 These studies ultimately led to the concept and practice
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delayed, and NRM approaches or exceeds 40%, 39,40,47,48 much of it of using “megadoses” of haploidentical CD34 stem cells (>10 /kg of
due to infection. The following section describes transplant complica- recipient body weight) obtained from granulocyte colony-stimulating
tions whose incidence and/or severity may be affected by the immu- factor (G-CSF)–mobilized peripheral blood collections. 62,63 Studies
nologic disparity between donor and recipient. in mice suggest that megadoses of mismatched stem cells induce
tolerance by the “veto” mechanism, 64–66 in which the cytotoxicity of
alloreactive donor cells is inhibited by recipient cells expressing the
Graft Failure alloantigen. 67,68 Transplant of megadoses of stem cells into intensively
conditioned recipients enables TCD of haploidentical grafts to
Graft failure is a serious complication of allogeneic SCT and is nearly decrease the risk of acute GVHD without increasing the risk of fatal
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always fatal after myeloablative conditioning. Graft failure may graft failure. 39,40
be primary, marked by the lack of initial engraftment (neutrophils Increasing the intensity of transplant conditioning also lowers the risk
>500/µL) and absence of donor hematopoietic chimerism, or it may of graft failure after HLA-haploidentical SCT. For example, increased
be secondary, manifested as initial hematologic recovery followed intensity of total body irradiation (TBI) was inversely correlated with
by neutropenia and loss of donor chimerism. The primary cause the rate of graft failure among patients with leukemia receiving