Immune rejection: the immune biology of allogeneic hematopoietic stem cell transplantation (from mice to humans) - Immune Biology of Allogeneic Hematopoietic Stem Cell Transplantation - page 92

Clinical studies

Treatment with high-dose cyclophosphamide was sufficient to prevent
rejection after HCT with HLA-matched sibling donors for treatment of
aplastic anemia in untransfused patients but not in patients who had
previously received transfusions. The use of more intensive immuno-
suppressive conditioning regimens was explored as a way of preventing
rejection in transfused patients. In the absence of anti-donor antibod-
ies in the recipient, the increased risk of rejection in transfused patients
can be attributed to memory T cells that have been sensitized to alloanti-
gens shared by transfusion donors and the marrow donor. Regimens that
employ cyclophosphamide and TBI appeared to reduce the incidence
of rejection, but survival was often not improved because of increased
mortality from GVHD and interstitial pneumonia [82] . As an alternative,
regimens of cyclophosphamide and total lymphoid irradiation (TLI) or
thoracoabdominal irradiation with lung shielding decreased the risk of
rejection with improved survival compared to TBI regimens [83] . Enthusi-
asm for regimens that include radiation together with chemotherapy, how-
ever, has been tempered by increased cancer risk, sterility, and effects on
growth and development.

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Regimens of antithymocyte globulin (ATG) and cyclophosphamide were
used successfully to establish engraftment in 15 of 19 patients after second
HCT in patients with aplastic anemia who rejected an initial graft from an
HLA-identical sibling after conditioning with cyclophosphamide alone [84] .
Based on these results, ATG and cyclophosphamide regimen was tested as
the initial conditioning regimen before HCT for patients with aplastic ane-
mia. Only 2 of 39 patients (5%) treated with this regimen had graft rejection,
considerably lower than the 30-60% rate observed with cyclophosphamide
alone in studies before 1975 [84] . These results suggested that ATG had an
immunosuppressive effect that decreased the risk of rejection, but the two
groups differed in one additional respect. Cyclosporin (plus methotrex-
ate) was included in the post-transplant immunosuppressive regimen for
patients who received ATG but not for those who were treated with cyclo-
phosphamide alone. In a subsequent randomized trial where all patients
received both cyclosporin and methotrexate after HCT for treatment of
aplastic anemia, the rejection rate was 18% among patients who received
cyclophosphamide alone and 16% among those who received both cyclo-
phosphamide and ATG [85] .

In patients with aplastic anemia, the regimen of ATG and cyclophosphamide
was sufficient to prevent rejection after HCT with HLA-identical related
donors but not with HLA-matched unrelated donors. A dose de-escalation
study indicated that 200 cGy TBI added to ATG and cyclophosphamide was
sufficient to prevent rejection in most patients with HLA-matched unre-
lated donors [86] . With this conditioning regimen, rejection was observed
in only 1 of 35 patients (3%).

Non-myeloablative pretransplant conditioning regimens have been used
to treat malignant diseases in older patients and in younger patients who
could not tolerate a myeloablative conditioning regimen because of comor-
bid medical problems. Preclinical studies showed that TBI exposures as low
as 2 Gy were sufficient to prevent rejection after HCT with marrow from