Total Lymphoid Irradiation–Antithymocyte Globulin Conditioning and Allogeneic Transplantation for Patients with Myelodysplastic Syndromes and Myeloproliferative Neoplasms

Abstract

Allogeneic hematopoietic cell transplantation (allo HCT) is the only curative therapy for the myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but treatment toxicity has been a barrier to its more widespread use. The nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) permits the establishment of donor hematopoiesis necessary for the graft-versus-malignancy effect and is protective against acute graft-versus-host disease (aGVHD), but it has minimal direct cytotoxicity against myeloid diseases. We explored the use of TLI-ATG conditioning to treat 61 patients with allo HCT for MDS (n = 32), therapy-related myeloid neoplasms (n = 15), MPN (n = 9), and chronic myelomonocytic leukemia (n = 5). The median age of all patients was 63 years (range, 50 to 73). The cumulative incidence of aGVHD grades II to IV was 14% (95% confidence interval [CI], 4% to 23%) and for grades III to IV, 4% (95% CI, 0 to 9%), and it did not differ between patients who received allografts from related or unrelated donors. The cumulative incidence of nonrelapse mortality (NRM) at 100 days, 12 months, and 36 months was 0%, 7%, and 11%. Overall survival and progression-free survival were 41% (95% CI, 29% to 53%) and 35% (95% CI, 23% to 48%), respectively. The safety and tolerability of TLI-ATG, as exemplified by its low NRM, provides a foundation for further risk-adapted or prophylactic interventions to prevent disease progression.

Immune Recovery after Allogeneic Hematopoietic Stem Cell Transplantation Following Flu-TBI versus TLI-ATG Conditioning

“…In an effort at preventing GVHD, the Stanford group has developed another nonmyeloablative conditioning that combines total lymphoid irradiation (TLI, 8 Gy total dose) with anti-thymocyte globulin (ATG; 7.5 mg/kg thymoglobulin total dose; refs. [18][19][20][21][22][23]. This approach allowed sustained engraftment with a low incidence of GVHD.…”

“…In murine models of transplantation, this was achieved through Th2 polarization of donor T cells by recipient invariant NK/T cells (iNKT, still present at transplantation thanks to their relative resistance to ionizing radiation; refs. [18][19][20][21]24), and through expansion of donor regulatory T cells (Treg) by recipient iNKT (24).…”

Risks and benefits of sex-mismatched hematopoietic cell transplantation differ according to conditioning strategy

“…15 Non-myeloablative conditioning regimens such as total lymphoid irradiation and anti-thymocyte globulin (TLI-ATG) conditioning have shown promise as a method to reduce GVHD incidence and non-relapse mortality. [16][17][18][19] TLI-ATG has generally been adapted for older patients or those with comorbidity for the purpose of reducing severe acute GVHD without losing the benefit of allogeneic anti-tumor effects. 16,18 In our experience with the TLI-ATG protocol at Stanford University Hospital, grade II-IV acute GVHD occurred in 10% or less of cases and chronic GVHD in about 30%.…”

“…The TLI-ATG conditioning protocol (n=430) has already been reported. 16,18,19 RIC (n=266) mainly included fludarabine-based conditioning regimens. MAC (n=345) included total body irradiation (TBI)-based or busulfan-based conditioning regimens.…”

HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity

“…HCT-CI score 0 25 (35) 78 (40) HCT-CI score 1 16 (22) 44 (23) HCT-CI score 2 14 (19) 28 (15) HCT-CI score $3 17 (24) 43 (22) …”