Page 1828 - Hematology_ Basic Principles and Practice ( PDFDrive )

1630 Part X Transplantation

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related donor allografting, respectively. The same study showed that
Case Study of Donor Selection for Human Leukocyte
BOX 106.2 Antigen–Haploidentical Stem Cell Transplant the presence of antidonor lymphocytotoxic antibodies on crossmatch
was associated with a 39% graft failure rate, compared with 10% in
A 58-year-old woman is found to have acute myeloid leukemia (AML) patients with a negative crossmatch. In haploBMT with PTCy,
harboring the FLT3 internal tandem duplication. She achieves complete Ciurea et al found that graft failure occurred in 75% of recipients
remission with induction chemotherapy. Human leukocyte antigen with DSA compared with 5% of recipients without DSA (p = .008)
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(HLA) typing reveals that her 65-year-old brother is an HLA-matched and that antibodies to HLA-DRB1 were most frequent. In subse-
sibling. On evaluation, he appears to be healthy but is found to have quent analyses by Ciurea et al, the overall incidence of DSA in
a white blood cell count of 3200/µL and a platelet count of 140,000/µl. haploBMT assessments was 18%, 86% of whom were women.
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The patient also has three children: a 32-year-old son and two daugh- Thirty-two percent of patients with DSA experienced graft rejection.
ters, ages 30 and 27 years. All three children are healthy and have The mean fluorescence intensity (MFI) of antidonor HLA antibody
normal blood counts. The patient is mismatched with the son bidirec-
tionally at HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1, whereas was 10,055 for patients who experienced rejection versus 2065 for
she is mismatched to the daughters, who are HLA matched to each those with engraftment. Graft failure was associated with a comple-
other, bidirectionally at HLA-A, and bidirectionally at HLA-DRB1. Solid- ment assay that detects C1q-binding DSA, with only one C1q-
phase immunoassays demonstrate antibodies against HLA-DRB1*1501, negative patient (who had an MFI of 6265) without engraftment.
present in the daughters, with a mean fluorescence intensity of 15,000, Patients with C1q-binding DSA also had a higher median MFI than
and a weaker antibody against HLA-DQB1*0501, present in the son, C1q-negative patients (15,279 vs. 2471). All male patients were C1q
with a mean fluorescence intensity of 1000. The patient and both negative, and their median MFI levels were much lower. Pregnancy
daughters are blood type A+ and cytomegalovirus (CMV) seropositive, was associated with a much higher risk of developing DSA than
but her son is blood type O− and CMV seropositive. transfusion of blood products.
This case presents a number of considerations for selection of the
appropriate donor. Remissions in patients with AML and the FLT3 tend DSA can be quantified by SPI using fluorescent beads coated
to be brief, so there may not be time to search, identify, and mobilize with a single phenotype and single HLA antigens. SPI results can
an unrelated donor. Ordinarily, an HLA-matched sibling would be the be correlated with crossmatching by flow cytometry or CDC assays
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first choice of donor, but the patient’s 65-year-old brother has abnormal to generate a “virtual crossmatch.” Gladstone et al found that
blood counts, raising the possibility of an underlying clonal hematopoi- HLA-directed DSA occurred in 14.5% of all patients and 42% of
etic disorder. Caution should be exercised in using this donor, even if women undergoing haplotransplant evaluation. In patients without
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examination of his bone marrow and an AML mutation panel are both alternative available donors, plasmapheresis combined with anti-CMV
normal. The strength of the antibody against HLA-DRB1, a high- intravenous immunoglobulin, tacrolimus, and MMF starting 1 to 2
expression HLA molecule, is consistent with a positive crossmatch weeks before conditioning, depending on the level of DSA, was associ-
result on a complement-dependent cytotoxicity (CDC) assay. Antidonor 19,167
HLA antibodies resulting in a positive CDC assay are an absolute ated with a 64.4% mean reduction in DSA levels. Fifteen patients
contraindication to donation, so the daughters are ruled out. In contrast, received this treatment, and the fourteen patients who achieved
the patient’s antibody against HLA-DQB1*0501 would not rule out her DSA reduction to negative or weak levels underwent transplant and
son as a donor. It is a weak antibody that would not result in a positive engrafted. Ciurea et al proposed an alternative desensitization method
flow cytometric or CDC assay. Low-level antibodies against the low- of plasma exchange, rituximab, and intravenous immunoglobulin,
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expression HLA molecules, such as HLA-DQB1 or HLA-DRB3, HLA- which they found to be only partially effective. However, combining
DRB4, or HLA-DRB5, are generally not a contraindication to the use that regimen with the infusion of donor HLA antigens via a buffy
of a donor. However, the bone marrow transplant physician should coat 24 hours before SCT was highly effective. They also reported
always consult closely with the immunogenetics laboratory in cases that clearing of DSA may be unnecessary, with reduction to non-
where antidonor antibodies are present.
Although the son has a minor ABO incompatibility and is heavily HLA complement-binding levels sufficient to achieve engraftment.
mismatched with the mother, neither is a contraindication to transplant, The management of a patient with antidonor HLA antibodies
and modern approaches to HLA-haploidentical stem cell transplant depends to a great extent upon the strength of the antibodies and upon
have reduced if not eliminated the detrimental impact of HLA mis- the availability of other donors. All other factors being equal, prefer-
matching on outcome. He is therefore an appropriate donor for ence should be given to donors against whom the patient does not
transplant for his mother. Umbilical cord blood is another potential have antibodies. Not all antibody specificities are equal. For example,
source of stem cells for this patient. At present, there are no clinical antibodies against low-expression HLA molecules such as HLA-DQB1
data that would mandate the choice of an HLA-haploidentical donor or HLA-DRB3, HLA-DRB4, or HLA-DRB5 may not carry as high
over umbilical cord blood, or vice versa.
a risk of graft rejection as antibodies against the high-expression HLA
molecules, HLA-A, HLA-B, HLA-Cw, and HLA-DRB1. We quantify
antibody strengths using SPI with single HLA antigen–coated beads.
is the preferred HLA-haploidentical donor for megadose, T cell– The SPI reports antibody strength as MFI. An antibody with an MFI
depleted HSCT. Wang et al studied outcomes of 1210 patients of 1000 to 3000 is considered a weak antibody, one with an MFI of
treated with the GIAC protocol. With this platform, younger donors 3000 to 15,000 is considered a moderate antibody, and one with an
and male donors were found to be associated with less NRM and MFI greater than 15,000 is considered a strong antibody. Antibod-
better survival. Less acute GVHD was seen when using the patient’s ies with an MFI greater than 10,000 are generally associated with a
child or an HLA-haploidentical relative who was mismatched for positive CDC crossmatch. It is critically important to consult with an
NIMA as the donor; however, use of either of these donor types was immunogeneticist with experience in the management of patients with
not associated with any significant improvement in patient survival DSA. As a general rule, we never use a donor if the MFI of antidonor
outcomes. By contrast, use of maternal donors was associated with HLA antibody is greater than 10,000. For patients with antibodies
higher acute and chronic GVHD and worse survival. Overall, the associated with a positive flow cytometric crossmatch but a negative
authors suggested that a NIMA-mismatched male child was the best CDC crossmatch (MFI 3000 to 10,000), strategies to reduce the risk
possible donor for haploBMT using the GIAC protocol, whereas use of graft rejection by lowering the concentration of antidonor HLA
of older mother donors and noninherited paternal antigen-mismatched antibody have been developed. One such method of desensitizing
donors should be avoided. 188 patients includes plasma exchange and intravenous immunoglobulin
every other day combined with tacrolimus and MMF, 19,168 which was
Management of the Patient With Antidonor followed by sustained engraftment of HLA-haploidentical stem cells
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in 14 of 15 treated patients. Other methods to desensitize patients
HLA Antibodies with antidonor HLA antibodies include treatment with bortezomib,
transfusion of platelets expressing the targeted HLA antigens, or the
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HLA-mismatch was also historically associated with graft failure, with combination of rituximab and plasma exchange, with or without
rates of 12% and 2% after HLA-mismatched and HLA-matched intravenous immunoglobulin.