Page 1820 - Hematology_ Basic Principles and Practice ( PDFDrive )

1622 Part X Transplantation

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transplants from HLA-haploidentical donors. Finally, posttransplant this study was 39% (95% CI, 33% to 45%) in recipients with
pharmacologic immunosuppression is likely to decrease the risk of HLA-matched donors, 44% (95% CI, 30% to 57%) in those with
graft failure following mismatched SCT. Although this has not been one-locus-mismatched donors, and 50% (95% CI, 29% to 68%) in
studied intensively in the HLA-haploidentical setting, the risk of graft those with two- or three-loci-mismatched donors. In a multivariable
failure after HLA-matched sibling BMT was significantly lower analysis, patients who received a graft from a one-locus-mismatched
among patients receiving posttransplant prophylaxis with methotrex- donor and a two- or three-loci-mismatched donor had an HR for
ate (MTX), cyclosporine (CsA), or both than among patients receiv- acute GVHD of 1.83 (95% CI, 1.04–3.22; p = .035) or 2.44 (95%
ing no GVHD prophylaxis. 43 CI, 1.14–5.21; p = .021), respectively, compared with those from an
HLA-matched donor. There was no increased risk of chronic GVHD
among recipients of partially HLA-mismatched grafts after RIC as
GVHD compared with recipients of HLA-matched sibling SCTs.
Hyperacute GVHD is defined in the literature as GVHD occur-
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Severe acute GVHD was a major complication of early trials of TCR, ring within the first 14 days after allogeneic SCT. Hyperacute
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HLA-haploidentical SCT. These early studies examined the rela- GVHD may be accompanied by high fever (>40°C) and may involve
tionship of serologic HLA incompatibility to the incidence and a more extensive skin rash and lower response to therapy than GVHD
severity of GVHD. Among patients receiving MTX as sole post- diagnosed after transplant day 14. HLA mismatch is associated with
transplant prophylaxis, the cumulative incidence of acute GVHD by hyperacute GVHD: HLA-haploidentical donors carry a 4.1-fold
day 100 was 34% among recipients of phenotypically HLA-matched higher relative risk of developing the syndrome compared with
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grafts and 84% among recipients of three-loci-incompatible marrow. recipients of grafts from HLA-matched siblings.
The vector of incompatibility has been found to influence the risk of In the past decade, novel methods of preventing GVHD after HLA-
GVHD. In a study conducted at the Fred Hutchinson Cancer haploidentical SCT have been developed, and these methods appear
Research Center, recipients of grafts with one HLA antigen mismatch to have reduced or eliminated the detrimental impact of HLA mis-
were categorized according to the vector of incompatibility. The match on GVHD, NRM, and OS. These methods and their clinical
cumulative incidence of acute GVHD by day 100 was 18% when effects are discussed later in the Modern Approaches to HLA-
the incompatibility was solely in the HVG direction (homozygous Haploidentical SCT section.
recipient of a heterozygous graft [n = 17]), but it was greater than
50% when there was incompatibility in the GVH direction (hetero-
zygous recipients of a homozygous or heterozygous graft [n = 87]; Impaired Immune Reconstitution and Infection
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p = .03). There was no significant difference in the incidence of
acute GVHD between recipients of grafts mismatched for a single Rapid reconstitution of innate and adaptive immunity is critical for
HLA class I antigen versus a single HLA class II antigen. In a resistance to opportunistic infections after allogeneic SCT. Patients
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CIBMTR study, recipients of bone marrow mismatched for two or who undergo HLA-haploidentical SCT have had significantly
three HLA antigens had a three- to fivefold higher risk of GVHD impaired immune reconstitution as measured by delayed recovery of
+
compared with recipients of HLA-matched sibling grafts. TCD of CD4 T cells compared with recipients of HLA-matched sibling
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the graft significantly reduced the risk of GVHD after HLA- grafts. A number of factors contribute to impaired immune recon-
mismatched as well as HLA-matched sibling BMT. stitution after HLA-haploidentical SCT. Damage to lymphoid tissues
The adverse effect of HLA mismatch on the incidence of acute resulting from conditioning may interfere with T-cell homing and
5
GVHD was confirmed in a subsequent analysis by the CIBMTR. the generation of immunologic memory. The rigorous TCD neces-
The incidence of grades II–IV acute GVHD was 29% among 1176 sary to prevent GVHD in the haploidentical setting results in
recipients of HLA-matched sibling marrow, 44% among 223 recipi- profound posttransplant immunodeficiency. 74,75 Finally, acute and
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ents of one HLA antigen–mismatched related marrow (p < .001), chronic GVHD both interfere with immune reconstitution, in part
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and 56% among 86 recipients of 2 HLA antigen-mismatched marrow through inhibition of thymopoiesis. The result of delayed immune
(p < .001). The incidence of grades III–IV acute GVHD also differed reconstitution after T cell–depleted haploidentical SCT is an increased
significantly according to degree of incompatibility: 13% for HLA- incidence of morbidity and NRM secondary to opportunistic infec-
matched siblings, 27% for two antigen–mismatched donors (p < tion. For example, among 101 patients receiving intensive condition-
.001), and 36% for two antigen–mismatched relatives (p < .001). ing and megadoses of rigorously T cell–depleted grafts in Perugia,
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Among patients surviving at least 90 days with evidence of donor Italy, 27 died as a result of opportunistic infection. Infection was
engraftment, the incidence of chronic GVHD by 2 years was 42% the cause of death in 7 of 29 patients with hematologic malignancies
+
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for recipients of HLA-matched sibling marrow, 52% for recipients of receiving RIC and haploidentical grafts depleted of CD3 and CD19
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one HLA antigen–mismatched marrow (p < .001), and 60% for cells by magnetic cell sorting. Infectious complications remain high
recipients of two HLA antigen–mismatched marrow (p = .02). even in the context of strategies designed to selectively deplete allo-
An analysis of the outcomes of allogeneic SCTs performed in reactive T cells while sparing immunity to pathogens. In a study done
Japan between 1991 and 2000 identified serologic HLA mismatch, at the Dana-Farber Cancer Institute, haploidentical donor grafts were
higher age, and high-risk disease as independent risk factors for both exposed to recipient cells in the presence of T-costimulatory blockade,
2
short survival and the development of grades III–IV acute GVHD. either CTLA4-Ig (n = 19) or a combination of antibodies to B7-1
Importantly, the correlation between HLA mismatch and the risk of and B7-2 (n = 5), to induce selective tolerance in alloreactive T cells
acute GVHD was preserved when the data were analyzed according before their transplant into lethally conditioned recipients. Despite
to the degree of HLA allele mismatch, as determined by molecular this maneuver, 12 of the 24 patients died as a result of treatment-
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typing methods. There was no significant difference in the risk of related causes, 6 as a result of infection with or without GVHD.
acute GVHD between patients mismatched for a single HLA class I Conditioning agents that deplete host and donor T cells, such as
allele versus a single HLA class II allele. The risk of grades III–IV antithymocyte globulin (ATG) or alemtuzumab (a monoclonal
acute GVHD was significantly higher after one HLA antigen– antibody against CD52 expressed on both B and T cells), may also
mismatched SCT than after HLA-matched URD BMT (30% vs. increase the incidence of opportunistic infection after haploidentical
16%; p = .0013). These data demonstrate that recipients of one HLA SCT. Among 49 patients receiving haploidentical SCT after a non-
antigen–mismatched related grafts have a higher risk of severe acute myeloablative conditioning regimen containing alemtuzumab, the
GVHD than recipients of HLA-matched sibling or unrelated grafts. rate of CMV reactivation was 86%, and 11 patients (22%) died as a
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The increased risk of acute GVHD with increasing HLA mis- result of opportunistic infections. These results illustrate the general
match between donor and recipient has also been confirmed among observation that strategies employed to reduce graft rejection and/or
recipients of HLA-haploidentical stem cells after reduced-intensity GVHD tend to increase the incidence and severity of opportunistic
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conditioning (RIC). The cumulative incidence of acute GVHD in infections after haploidentical SCT.