Page 1829 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 106 Haploidentical Hematopoietic Cell Transplantation 1631

In summary, the presence of antidonor HLA antibodies that HLA-haploidentical SCT are associated with loss of the mismatched
produces a positive result on a CDC assay, or an MFI greater than HLA locus via acquired uniparental disomy, a process in which the
10,000 determined by SPI, is an absolute contraindication to the unshared HLA haplotype on chromosome 6 is replaced by the shared
use of a donor who expresses the targeted HLA molecule. Anti- HLA haplotype. 197,198 HLA-alloreactive T cells must be providing
bodies of intermediate strength, corresponding to a positive flow the selective pressure that results in the emergence of these variants,
cytometric crossmatch test or an antibody against a high-expression because relapse is never associated with loss of the shared HLA hap-
HLA molecule with MFI of 3000 to 10,000, may be reduced by a lotype, and HLA loss by uniparental disomy has not been described
desensitization protocol to allow the use of a donor expressing the after HLA-matched SCT. Clinically, relapses of AML associated
targeted HLA molecules. Antidonor HLA antibodies with an MFI with loss of mismatched HLA tend to occur later than relapses
199
less than 3000 measured by SPI may not require desensitization. with preserved HLA expression (307 days vs. 88 days; p < .001),
Management of the patient with antidonor HLA antibodies must but they tend to carry a similar poor prognosis. Donor lymphocyte
involve a close collaboration of the transplant physician and the infusion (DLI) may not be effective in light of the loss of the major
immunogenetics laboratory. targets of alloreactive T cells. OS at 6 months after relapse was 28.5%
for patients with HLA loss and 27.4% for patients with “classical”
relapse. Survival may be improved by performing a second transplant,
Management of Suspected Graft Failure especially from a different donor, though NRM is high (7 of 17
patients).
Graft failure occurs when donor HSCs are unable to support long- DLIs have been administered to patients with relapsed hematologic
term hematopoiesis in the recipient, resulting in loss of donor malignancy after HLA-haploidentical SCT plus PTCy. In one study,
hematopoietic chimerism. Potential causes of graft failure include a DLI was administered as a series of escalating infusions (ranging from
+
7
3
poor-quality graft containing a low number of CD34 cells; viral 10 to 10 T cells/kg), with or without preceding chemotherapy, to
infection in the recipient (such as CMV, human herpesvirus 6, adeno- patients with acute leukemia in molecular (n = 20) or hematologic
200
virus, or parvovirus); or immunologic rejection by antidonor HLA (n = 12) relapse, or to patients with Hodgkin lymphoma (n = 10).
antibodies, alloreactive recipient T cells, or both. Immunologic rejec- The incidence rates of acute GVHD after DLI in these groups were
tion of the donor graft almost certainly accounts for the higher 15%, 17%, and 10%, respectively, and the response rates were 45%,
incidence of graft failure after HLA-haploidentical as compared with 33%, and 70%. Two-year actuarial survival rates were 43%, 19%,
HLA-matched SCTs. and 80%, respectively. In a second report, 40 patients, including 16
The definition of graft failure depends upon the intensity of the with AML and 11 with lymphoma, received DLI starting at a dose
+
201
5
conditioning regimen employed. Chimerism studies are required to of 10 CD3 T cells/kg with subsequent dose escalation. The most
+
6
make a diagnosis of graft failure. Management of graft failure depends commonly used first dose was 10 CD3 T cells/kg. Acute GVHD
to some extent on the perceived risk of irreversible pancytopenia developed in 10 patients, 6 patients had grades III–IV, and 3 devel-
and upon the risk of disease relapse. Graft failure after myeloablative oped chronic GVHD. Twelve patients (30%) achieved a complete
conditioning is likely to be fatal unless the patient is effectively sal- response with a median duration of 11.8 months. Eight patients were
vaged by a second stem cell graft, whereas autologous hematopoiesis alive in complete response at the time of reporting, six for more than
often returns in the event of graft failure after nonmyeloablative 1 year.
conditioning. The Beijing group developed a modified DLI approach in which
PBSCs from HLA-haploidentical donors have been used success- patients with relapsed leukemia after haploBMT received chemother-
fully to salvage graft failure after myeloablative conditioning and apy and peripheral blood leukocytes from filgrastim-treated donors
HCT from partially HLA-mismatched URDs, from URD umbilical followed by an immunosuppressive drug (CsA or MTX) for 2 to 8
202
cord blood, 190,191 or from HLA-haploidentical donors. 192,193 When weeks after DLI. One hundred twenty-four patients in relapse after
salvaging graft failure after HLA-haploidentical SCT, the question haploBMT received chemotherapy followed by modified DLI con-
+
7
arises whether to use the same donor or switch to a different donor taining a median of 4 × 10 CD3 T cells/kg of recipient weight. The
for the second transplant. It is important to test the patient for the cumulative incidence of DLI-associated acute GVHD was 53.2% for
presence of antibodies against the mismatched HLA molecules of the grades II–IV and 28.4% for grades III–IV. The duration of GVHD
original donor because a positive test would demonstrate immunity prophylaxis after DLI was the only risk factor for DLI-associated
against this donor’s cells and a strong risk of rejection if the same grades III–IV acute GVHD (p < .05). The 2-year OS, NRM, and
donor is used. Preclinical studies demonstrate that graft rejection cumulative incidence of relapse after DLI were 47.2%, 34.1%, and
after nonmyeloablative conditioning can induce cellular immunity 34.6%, respectively. A subsequent study compared the antileukemic
194
against donor cells without detectable antidonor antibody. Thus effects of chemotherapy alone (n = 32) versus chemotherapy followed
lack of antidonor antibody does not mean lack of sensitization against by modified DLI (n = 50), with immunosuppression given for 4 to
a failed HLA-haploidentical allograft. If it is possible to switch to 8 weeks after DLI, in patients with relapsed acute leukemia after
203
an HLA-haploidentical donor who does not share the same mis- haploBMT. In patients receiving chemotherapy followed by modi-
matched HLA haplotype as the original donor, then a new donor is fied DLI, the CR rate was significantly higher (64.0% vs. 12.5%; p
preferred. = .000), the incidence of relapse was significantly lower (50.0% vs.
100.0%; p = .000) and DFS was significantly improved (36.0% vs.
Treatment of Relapsed Hematologic Malignancy After 0.0%; p = .000) compared with patients receiving chemotherapy
alone. Multivariate analysis demonstrated that patients with chronic
HLA-Haploidentical SCT GVHD after intervention (p = .000) and patients receiving chemo-
therapy followed by modified DLI (p = .037) were associated with
Relapse remains a significant complication of allogeneic SCT, a lower relapse rate.
including HLA-haploidentical SCT. There is substantial con- In summary, hematologic malignancies in relapse after HLA-
troversy regarding whether HLA disparity between donor and haploidentical SCT can be treated with DLIs. Patients with relapse of
recipient reduces relapse through a more intense GVH reaction. acute leukemia in the first 6 months after transplant generally have a
Most studies have not shown decreased relapse rates after HLA- poor prognosis. For patients with relapse of leukemia after 6 months,
haploidentical as compared with HLA-matched SCT, 180,187,195 though HLA typing of the leukemia blasts is recommended. If mismatched
such studies may be confounded by significant differences between HLA expression is preserved, DLI with or without preceding che-
donor types in the GVHD prophylaxis regimens employed. Other motherapy may be used. For patients in overt hematologic relapse,
+
6
studies have shown a decreased risk of relapse associated with HLA a starting dose of 10 CD3 T cells/kg may be used. If mismatched
196
mismatching, especially for patients with poor-risk hematologic HLA alleles have been lost, a second transplant procedure from a
2
malignancies. Approximately one-third of leukemic relapses after different donor may provide the best outcome.