Nonmyeloablative TLI-ATG conditioning for allogeneic transplantation: mature follow-up from a large single-center cohort

Abstract

Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is protective against graft-versus-host disease (GVHD), while retaining graft-versus-tumor activity across various hematologic malignancies. We report our comprehensive experience using TLI-ATG conditioning in 612 patients with hematologic malignancies who underwent allogeneic transplantation at Stanford University from 2001 to 2016. All patients received granulocyte colony-stimulating factor–mobilized peripheral blood grafts and cyclosporine and mycophenolate mofetil for GVHD prophylaxis. The median age was 60 years (range, 21-78), with a median follow-up of 6.0 years (range, 1.0-16.4). Common diagnoses included acute myeloid leukemia (AML; n = 193), myelodysplastic syndrome (MDS; n = 94), chronic lymphocytic leukemia (CLL; n = 80), non-Hodgkin lymphoma (NHL; n = 175), and Hodgkin lymphoma (HL; n = 35). Thirty-four percent of patients had a comorbidity index ≥3, 30% had a high to very high disease risk index, and 56% received unrelated donor grafts, including 15% with HLA-mismatched donors. Ninety-eight percent underwent transplant in the outpatient setting, and 57% were never hospitalized from days 0 through 100. The 1-year rates of nonrelapse mortality (NRM), grade II-IV acute GVHD, and extensive chronic GVHD were 9%, 14%, and 22%, respectively. The 4-year estimates for overall and progression-free survival were 42% and 32% for AML, 30% and 21% for MDS, 67% and 43% for CLL, 68% and 45% for NHL, and 78% and 49% for HL. Mixed chimerism correlated with the risk of relapse. TLI-ATG conditioning was well tolerated, with low rates of GVHD and NRM. Durable remissions were observed across hematologic malignancies, with particularly favorable outcomes for heavily pretreated lymphomas. Several efforts are underway to augment donor chimerism and reduce relapse rates while maintaining the favorable safety and tolerability profile of this regimen.

Safety and efficacy of a nonmyeloablative pretransplant conditioning regimen using total lymphoid irradiation with volumetric modulated arc therapy in healthy dogs: A pilot study

“…In this study, targeted irradiation for the lymphoid tissues involving dose reduction to OAR was achieved using the VMAT technique. Nonmyeloablative conditioning, such as 2 Gy TBI or 8 Gy TLI, for allogeneic HCT or organ transplantation affords stable mixed donor/host chimerism or engraftment in human medicine (Lange et al., 2009; McKay et al., 2014; Spinner et al., 2019). In addition, dose escalation regimen of pretransplant conditioning has been attempted in human patients based on advances in radiation therapy equipment and prevailing IMRT techniques (Patel et al., 2014; Somlo et al., 2011; Wong et al., 2013).…”

“…For this reason, these treatments have limited their adaptation to non‐comorbid and relatively young patients in human medicine (Baron & Storb, 2006). To expand the application range of allogeneic HCT to elderly patients or comorbid conditions, nonmyeloablative conditioning regimens have been extensively studied in both clinical and experimental settings (Baron & Sandmaier, 2006; Spinner et al., 2019; Storb et al., 1997, 1999). Previous research using dogs demonstrated that 2 Gy TBI combined with immunosuppressive drugs provided a stable allograft with a reduction in transplant‐related toxicities compared with myeloablative conditioning (Storb et al., 1997, 1999).…”

“…These conditioning treatments are used according to disease, stage or patient conditions (Lebeer et al., 2020; Schultheiss et al., 2007). TLI is one of the nonmyeloablative conditioning techniques in allogeneic hematopoietic cell or organ transplantation in human patients (McKay et al., 2014; Spinner et al., 2019). The main objective of TLI is to induce sufficient immunosuppression to prevent graft rejection.…”

“…With TLI and TMLI, there is concern about the lack of direct antitumor effect outside the radiation fields. However, Baron et al reported the 5‐year overall survival rate using fludarabine plus 2 Gy TBI or 8 Gy TLI plus ATG was identical in human patients with haematological disorders who were treated with allogeneic HCT (Baron et al., 2015; Spinner et al., 2019). In this study, the radiation fields of TLI included major lymph nodes and spleen, but not the bone marrow to avoid severe myelosuppression.…”

Dynamical Systems Modeling of Early-Term Immune Reconstitution with Different Anti-Thymocyte Globulin (ATG) Administration Schedules in Allogeneic Stem Cell Transplantation

“…This risk reduction is associated with increased risk of opportunistic infections, particularly Epstein-Barr Virus associated lymphoproliferative disorder 10 . The effect of ATG on transplant outcomes is dependent on both dose given and schedule of administration 11, 12, 13, 14 . The differential effects observed with ATG dose and schedule variation will logically be dependent on the rate of T cell reconstitution that follows such regimens.…”