A Non-Myeloablative Allogeneic Transplant Becomes the Ultimate ImmunoTherapy

While the graft-versus-cancer effect is highly desirable after allogeneic transplant, the toxicities associated with high dose chemotherapy/radiation during the conditioning regimen have been a barrier. In addition, the off-target attack by the donor immune cells (GVHD, graft-versus-host disease) is a major post transplant complication. To find a different conditioning regimen to facilitate the donor cell engraftment while decreasing the transplant associated side effects, Drs. Samuel Strober (Immunology and Rheumatology) and Richard Hoppe (Radiation Oncology) devised a novel regimen in pre-clinic mouse models. In this regimen, low dose total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG) were given to facilitate the donor cell engraftment without ablation of the marrow of the animals. With this novel approach, the acute GVHD was greatly reduced even with mismatched allograft while the anti-tumor effects were preserved. Given the successful pre-clinical data, Dr. Robert Lowsky applied this non-myeloablative conditioning regimen (TLI/ATG) to treat patients with leukemia and lymphoma in a clinical trial. The early experience was extremely encouraging, showing a very low incidence of acute GVHD, which was reported in a landmark paper in the New England Journal of Medicine (2005; 253:1321). A follow-up report (Blood, 2009: 114:1099) on a larger patient cohort confirmed low incidence of acute GVHD (grade II-IV, related donor: 2%, unrelated donor: 10%) and chronic GVHD (extensive, both related and related donor: 27%). One-year transplant-related mortality was 3.6%. This result demonstrated a superior toxicity profile compared to myeloablative or other reduced intensity conditioning regimen.    

Despite attenuation of GVHD, TLI/ATG preserved graft-versus-tumor effects. The 4-year disease free survival was estimated to be 40% in all patients (A). As predicted, patients who achieved full donor T-cell engraftment had a much lower incidence of disease relapse/progression (B). Given its safety profile, this non-myeloablative regimen can be administered safely without a defined upper age limit. Armed with this unique protocol, the Stanford BMT team now offers many patients the benefit of ultimate immunotherapy without the excess toxicity.

The highlights

  • Low transplant-related mortality
  • Low incidence of both acute and chronic GVHD
  • Preserved graft-versus-tumor effect

Despite attenuation of GVHD, TLI/ATG preserved graft-versus-tumor effects. The 4-year disease free survival was estimated to be 40% in all patients (A). As predicted, patients who achieved full donor T-cell engraftment had a much lower incidence of disease relapse/progression (B). Given its safety profile, this non-myeloablative regimen can be administered safely without a defined upper age limit. Armed with this unique protocol, the Stanford BMT team now offers many patients the benefit of ultimate immunotherapy without the excess toxicity.


Dr. Robert Lowsky leads the way translating the TLI/ATG regimen from a mouse model to a new viable option for many patients who were not even considered transplant candidates just a few years ago. His work has resulted in several sentinel publications in the field. Dr. Lowsky continues to work on fine-tuning this novel approach in order to make it safer and more effective in a variety of hematological malignancies.