Posttransplantation cyclophosphamide facilitates engraftment of major histocompatibility complex-identical allogeneic marrow in mice conditioned with low-dose total body irradiation

Abstract

Cyclophosphamide (Cy) has been studied extensively for its immunosuppressive properties and is frequently combined with total body irradiation (TBI) as conditioning prior to HLA-identical allogeneic blood or marrow transplantation (alloBMT) in humans. Because Cy is most effective at suppressing host-versus-graft reactions when the drug is given after the transplantation (Mayumi H et al. Transplant Proc. 1986;18:363-369), we investigated whether posttransplantation Cy could prevent rejection of allogeneic marrow in mice conditioned with low-dose TBI. In a mouse model, posttransplantation Cy reduced the dose of TBI required from 500 cGy to < or = 200 cGy for the engraftment of 10 million major histocompatibility complex (MHC)-identical marrow cells in 100% of recipients. In animals conditioned with low-dose TBI and posttransplantation Cy, donor chimerism was proportional to the dose of TBI, was present in multiple hematopoietic lineages, and was associated with the indefinite survival of donor-strain skin grafts. In contrast, animals conditioned with either TBI alone or posttransplantation Cy alone failed to achieve engraftment after alloBMT and contained antidonor cytotoxic T-cells. Although <5% donor chimerism could be induced without TBI by transplanting > or = 50 million MHC-identical cells and administering posttransplantation Cy, the addition of low-dose TBI reduced the dose of donor cells required for alloengraftment and increased long-term donor chimerism to >50%. These data demonstrate that low-dose TBI and posttransplantation Cy cooperate to prevent graft rejection following the transplantation of standard doses of MHC-identical marrow cells.

Erratum: Modern approaches to HLA-haploidentical blood or marrow transplantation.

“…109 Subsequently, the PTCy approach was extended to alloBMT. In major histocompatibility complex (MHC)-mismatched mouse models, treatment with PTCy reduced the dose of radiation required to induce reliable engraftment [110][111][112] and also prevented GVHD and prolonged survival. 113 Graft failure could be further reduced by the use of antilymphocyte globulin, 114 and radiation in the conditioning regimen could be replaced entirely by fludarabine, although high levels of donor chimerism required at least 100 cGy of TBI.…”

New strategies for haploidentical transplantation

“…In these protocols, donor-derived lymphocytes are exposed to host antigens that induce proliferation of antigen-specific lymphocytes. It is hypothesized that by timely exposure to post-transplant CY, proliferating lymphocytes are killed whereas resting lymphocytes are spared (50,51). In a study of 68 patients with hematological malignancies, CY (50 mg/kg) was given on day 3 or days 3 and 4 after nonmyeloablative conditioning and transplantation of T-cellreplete haploidentical BM (52).…”

Preservation of Immune Repertoire by Selective Depletion of Haploidentical Grafts

“…In retrospect, cyclophosphamide may have been given at the wrong time or at a dose that was too low to be maximally effective at suppressing GVHD. Results of the more recent preclinical work, however, indicates that the primitive HSC is fairly resistant to high-dose cyclophosphamide, and provides the rationale to test this approach in the clinical setting [21].…”