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Mixed allogeneic chimerism and graft-versus-leukemia effects in acute myeloid leukemia

Leukemia volume 16, pages 753–754 (2002)Cite this article

Conventional allogeneic hematopoietic stem cell transplantation (HSCT) strategies rely both on the high-dose combination chemotherapy or chemotherapy with high-dose total body irradiation conditioning and the allogeneic graft-versus-tumor effect to eradicate residual leukemia. Conventional HSCT are associated with significant regimen-related toxicities, limiting the application of most of these approaches to patients under the age of 55 years. In an attempt to extend allogeneic HSCT to elderly individuals, novel nonmyeloablative conditioning regimens have been developed in which the burden of tumor eradication has been shifted almost entirely toward the allogeneic graft-versus-leukemia effect.

The nonmyeloablative HSCT regimen developed in Seattle uses a limited course of novel postgrafting immunosuppression to both ensure allogeneic engraftment and prevent serious graft-versus-host disease (GVHD), while maintaining graft-versus-tumor effects. In our canine model and in human transplantation using HLA-identical sibling (DLA-identical littermate) grafts, both host-versus-graft and graft-versus-host reactions are mediated by T cells, suggesting that T cell-directed therapies might effectively modulate both effects. One T cell-specific agent used in this setting is mycophenolate mofetil (MMF), which blocks an important enzyme in the de novo purine salvage pathway. We found a synergistic immunosuppressive effect when we combined MMF with cyclosporin A (CsA), a T cell activation blocker. Using these two agents to induce postgrafting immunosuppression in a canine model, we demonstrated that in combination with a very low and sublethal dose of total body irradiation (2 Gy delivered at 0.07 Gy/min), consistent engraftment could be accomplished.1 The immunosuppressive effect of MMF/CsA on engraftment was comparable to that of an added single dose of 7.2 Gy total body irradiation (total dose 9.2 Gy) otherwise needed before HSCT. Administration of MMF and CsA for no more than 5 weeks after HSCT allowed the allograft to be maintained in 11 of 12 dogs studied. The granulocyte nadir was just below 1000/μl and the platelet nadir was 30 000/μl, demonstrating that this conditioning regimen was not myeloablative. In fact, 28 of 29 dogs given 2 Gy total body irradiation and no subsequent marrow grafts survived with spontaneous return of marrow function.2 Chimerism studies on peripheral blood, marrow and lymph node compartments demonstrated mixed donor/host hematopoietic chimerism for now more than 3 years after allogeneic HSCT. We also demonstrated that full donor chimerism in transplanted dogs could be induced by lymphocyte infusions from marrow donors sensitized to host minor histocompatibility antigens.3

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References

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Authors and Affiliations

  1. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    R Storb

  2. Department of Medicine, University of Washington, Seattle, WA, USA

    R Storb

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This paper is part of a series of keynote addresses to be published in Leukemia. They were presented at the Acute Leukemia Forum, San Francisco, 20 April 2001. Supported by an unrestricted educational grant from Immunex.

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Storb, R. Mixed allogeneic chimerism and graft-versus-leukemia effects in acute myeloid leukemia. Leukemia 16, 753–754 (2002). https://doi.org/10.1038/sj.leu.2402521

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