Impact of Anti- T Lymphocyte Globulin (ATLG) on Immune Reconstitution in Patients Undergoing HLA Matched Unrelated Myeloablative Hematopoietic Cell Transplantation (HCT): Results From a Prospective Randomized Double Blind Phase 3 Clinical Trial

Field: Medicine (Health Sciences)

Impact of Anti- T lymphocyte Globulin (ATLG) on Immune Reconstitution in Patients Undergoing HLA Matched Unrelated Myeloablative Hematopoietic Cell Transplantation (HCT): Results from a Prospective Randomized Double Blind Phase 3 Clinical Trial. Background: We recently conducted a prospective randomized double-blind study of ATLG (Neovii, formerly ATG-Fresenius) in which moderate/severe cGVHD, but not cGVHD free survival, was reduced in patients receiving ATLG. In a companion study, we performed immunophenotpyic analysis to determine the impact of ATLG on recovery of lymphocyte subsets and to correlate immune reconstitution with clinical outcomes. Patients and Methods: Study entry criteria included patients ages 18-65 years with a diagnosis of AML, ALL, or MDS. All patients received 8/8 HLA allele matched unrelated products (74% mobilized PB, 26% BM) after myeloablative conditioning. All patients received tacrolimus/mtx for GVHD prophylaxis. Patients received ATLG or placebo on Days -3, -2, -1 at an ATLG dose of 20 mg/kg per day (60 mg/kg total). This companion study included 91/254 patients (44 ATLG, 47 placebo) who had received blinded study drug on the parent protocol. Peripheral blood was obtained at 30, 100, 180, and 360 days after transplantation. Multi-parameter flow cytometry was performed in a blinded fashion. After unblinding, impact of treatment arm on immune recovery at each time point was determined (Wilcoxan Rank Sum test). Multivariable Cox regression models treating each phenotypic parameter as a time dependent variable were constructed to study impact of reconstitution on clinical outcomes. Results: Treatment arms were balanced with respect to age, gender, conditioning diagnosis, remission status, graft source, and CMV status. ATLG treatment was associated with lower absolute CD4 counts at Days 30, 100, 180 and 360 (Figure 1). Treg/Tcon ratios were higher at Day 30 in ATLG recipients though no differences were noted thereafter. Absolute CD8 counts were significantly lower in patients receiving ATLG only at Day 30. Detailed heat maps comparing the impact of ATLG on Treg, Tcon and CD8 subsets at Day 30 are displayed in Figure 2. No difference in B cell or NK cell reconstitution was evident at any time point between ATLG and placebo. Cox regression models suggested that delayed CD3, CD4, and CD8 count recovery was associated with OS, PFS, and NRM (Figure 3). Delayed CD3, CD4, or CD8 cell recovery did not impact disease relapse nor development of moderate/severe cGVHD. Treg/Tcon ratio < .1 was associated with the development of cGVHD (HR 3.80, 95% CI 1.27-14.94).Figure 2Heatmap.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Figure 3Multivariable cox regression models treating each phenotypic parameter as a time dependent variable.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Conclusion: Treatment with ATLG resulted in delayed CD4 count recovery for up to a year, whereas recovery of CD8 cells occurred sooner and was not significantly different than placebo by Day 100. Delayed CD3, CD4 and CD8 recovery was associated with inferior OS and PFS due to higher NRM.