Nonmyeloablative Allogeneic Transplantation Using TLI-ATG Conditioning for Lymphoid and Myeloid Malignancies: Mature Follow-up from a Large, Single Institution Cohort
Authors: Spinner Michael A , Kennedy Vanessa E , Tamaresis John S , Lavori Philip W , Elder Linda V , Arai Sally , Johnston Laura J , Meyer Everett H , Miklos David B. , Muffly Lori S , Negrin Robert S. , Rezvani Andrew R , Shizuru Judith A , Weng Wen-Kai , Hoppe Richard T , Strober Samuel , Lowsky Robert 
Published: October 2019

Abstract
Background:
Nonmyeloablative total lymphoid irradiation and antithymocyte globulin (TLI-ATG) conditioning is associated with a low risk of graft-versus-host disease (GVHD) and non-relapse mortality (NRM) while retaining graft-versus-tumor activity across a range of lymphoid and myeloid malignancies. Prior studies of TLI-ATG conditioning have been limited by the relatively small sample size and short duration of follow up. Herein we report mature data from a large, single-institution cohort of patients with lymphoid and myeloid malignancies who underwent allogeneic transplantation using TLI-ATG conditioning.
Methods:
Patients: We included all consecutively transplanted patients at Stanford University Hospital from December 2001 through December 2016 who underwent allogeneic hematopoietic cell transplantation (HCT) using TLI-ATG conditioning for lymphoid or myeloid malignancies. All patients received G-CSF-mobilized peripheral blood hematopoietic cells and cyclosporine and mycophenolate mofetil for GVHD prophylaxis.
Statistical analysis: The data were analyzed as of December 31, 2017, allowing for a minimum follow up of 1 year for all patients. For time-to-event analyses, the Kaplan-Meier method was used to estimate overall survival (OS), progression-free survival (PFS), and the cumulative incidence of acute and chronic GVHD and NRM. An exploratory analysis was done to identify factors associated with mortality and relapse. Log-rank tests were used to calculate differences between groups.
Results:
Patient characteristics: 613 patients underwent allogeneic HCT with TLI-ATG conditioning at a median age of 60 years (range 21-78 years) with a median follow up of 5.1 years (range 1.0-15.3 years). Diagnoses included acute myeloid leukemia (AML, N=194), myelodysplastic syndrome (MDS, N=93), myelofibrosis (N=10), chronic myeloid leukemia (N=12), acute lymphoblastic leukemia (N=11), chronic lymphocytic leukemia (CLL, N=83), non-Hodgkin lymphoma (NHL, N=175), and Hodgkin lymphoma (HL, N=35). 44% of patients had HLA-matched related, 41% had HLA-matched unrelated, and 15% had HLA-mismatched unrelated donors. 34% of patients had a comorbidity index ≥3, and 34% of patients had a disease risk index (DRI) of high or very high. 55% of lymphoma patients had failure of prior autologous HCT.
Safety and tolerability: Patient outcomes are shown in Figure 1. Among all 613 patients, the cumulative incidences of acute GVHD grade 2-4 and grade 3-4 at day +100 were 11% and 4%, respectively, and the cumulative incidence of extensive chronic GVHD was 21% at 1 year. NRM was 7% at 1 year, and was consistently low across high-risk subgroups including older adults ≥65 years old (9% at 1 year), patients with a comorbidity index ≥3 (9% at 1 year), and patients lacking an HLA-matched related donor (10% at 1 year). 49% of patients remained outpatient without hospitalization during the first 100 days post-transplant.
Long-term outcomes: For the five most common diagnoses, the 4-year OS and PFS estimates were 41% and 32% for AML, 31% and 23% for MDS, 66% and 42% for CLL, 67% and 46% for NHL, and 79% and 46% for HL, respectively. Factors associated with mortality included a high or very high DRI (HR 2.11, 95% CI 1.65-2.69, p<0.0001), age ≥65 years (HR 1.81, 95% CI 1.38-2.38, p<0.0001), comorbidity index ≥3 (HR 1.47, 95% CI 1.15-1.87, p=0.002), and lack of an HLA-matched related donor (HR 1.27, 95% CI 1.02-1.57, p=0.034). Factors associated with disease relapse included a high or very high DRI (HR 1.75, 95% CI 1.38-2.23, p<0.0001) and mixed chimerism, defined as <95% donor CD3+ cells by day +90 (HR 1.50, 95% CI 1.20-1.89, p=0.0004). A reduced risk of relapse was observed in patients who developed chronic GVHD (HR 0.52, 95% CI 0.41-0.66, p<0.0001) or acute GVHD (HR 0.66, 95% CI 0.47-0.92, p=0.034).
Conclusions:
TLI-ATG conditioning was well tolerated with a low risk of GVHD and NRM even among high-risk subgroups, including septuagenarians, patients with multiple comorbidities, and patients lacking an HLA-matched related donor. Nearly half of all patients remained outpatient during the first 100 days post-transplant. Long-term OS and PFS were seen across a range of hematologic malignancies, with particularly favorable outcomes for lymphoma patients, most of whom had failure of prior autologous HCT. Mixed chimerism correlates with the risk of relapse, and efforts are underway to augment donor chimerism and reduce relapse rates.
Figure 1. Figure 1.

Disclosures
Miklos: Kite - Gilead: Consultancy, Research Funding; Pharmacyclics - Abbot: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Genentech: Research Funding. Muffly:Adaptive Biotechnologies: Research Funding; Shire Pharmaceuticals: Research Funding.