Prospective, Randomized, Double-Blind, Phase III Clinical Trial of Anti–T-Lymphocyte Globulin to Assess Impact on Chronic Graft-Versus-Host Disease–Free Survival in Patients Undergoing HLA-Matched Unrelated Myeloablative Hematopoietic Cell Transplantation

Abstract

Purpose Several open-label randomized studies have suggested that in vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG; formerly antithymocyte globulin-Fresenius) reduces chronic graft-versus-host disease (cGVHD) without compromising survival. We report a prospective, double-blind phase III trial to investigate the effect of ATLG (Neovii Biotech, Lexington, MA) on cGVHD-free survival. Patients and Methods Two hundred fifty-four patients 18 to 65 years of age with acute leukemia or myelodysplastic syndrome who underwent myeloablative HLA-matched unrelated hematopoietic cell transplantation (HCT) were randomly assigned one to one to placebo (n =128 placebo) or ATLG (n = 126) treatment at 27 sites. Patients received either ATLG or placebo 20 mg/kg per day on days -3, -2, -1 in addition to tacrolimus and methotrexate as GVHD prophylaxis. The primary study end point was moderate-severe cGVHD-free survival. Results Despite a reduction in grade 2 to 4 acute GVHD (23% v 40%; P = .004) and moderate-severe cGVHD (12% v 33%; P < .001) in ATLG recipients, no difference in moderate-severe cGVHD-free survival between ATLG and placebo was found (2-year estimate: 48% v 44%, respectively; P = .47). Both progression-free survival (PFS) and overall survival (OS) were lower with ATLG (2-year estimate: 47% v 65% [ P = .04] and 59% v 74% [ P = .034], respectively). Multivariable analysis confirmed that ATLG was associated with inferior PFS (hazard ratio, 1.55; 95% CI, 1.05 to 2.28; P = .026) and OS (hazard ratio, 1.74; 95% CI, 1.12 to 2.71; P = .01). Conclusion In this prospective, randomized, double-blind trial of ATLG in unrelated myeloablative HCT, the incorporation of ATLG did not improve moderate-severe cGVHD-free survival. Moderate-severe cGVHD was significantly lower with ATLG, but PFS and OS also were lower. Additional analyses are needed to understand the appropriate role for ATLG in HCT.

ATG in allogeneic stem cell transplantation: standard of care in 2017? Point

“…Retrospective studies are always questionable because of a possible selection bias. The recent prospective randomized trial 23 confirms the protection of ATG on aGVHD and cGVHD but has failed to show a benefit, due to a dramatic survival difference in a subset of patients prepared with cyclophosphamide total body irradiation (a minority), whereas no survival difference was seen in patients receiving busulfan-based regimens. For these reasons, most transplants in the United States still perform UD transplants without ATG, and this will expose patients to a significant risk of aGVHD and especially cGVHD, with a decrease in the quality of life.…”

“…Based on the lack of effective measures to treat cGVHD, 21 the author strongly agrees with the current use of ATG in Europe for all UD transplants, as well as for SIB grafts when PB is the stem cells source. In addition, the author is aware that this is not the case in the United States, where based on a retrospective study 22 and now also on a recent prospective study, 23 ATG is thought to increase the risk of relapse. Retrospective studies are always questionable because of a possible selection bias.…”

Unrelated donor haemopoietic stem-cell transplantation: ATG or not?

“…Despite important differences in the setting of these five trials, all showed that ATG protected from severe chronic GVHD. Relapse and overall survival were not significantly affected by ATG in four of these trials, whereas preliminary data from the trial of Soiffer and colleagues 6 show worse 2-year survival in patients in the ATLG group due to higher relapse-related mortality. There are no obvious explanations for these discrepancies besides that immunosuppression after grafting consisted of tacrolimus plus methotrexate in the study by Soiffer and colleagues and ciclosporine plus methotrexate in the other four trials.…”

ATG in allogeneic stem cell transplantation: standard of care in 2017? Counterpoint

“…7,8 There is yet another rabbit ATG formulation called anti-T lymphocyte globulin, ATLG Grafalon (Neovii), previously referred to as ATG-Fresenius, which is derived from the Jurkat T-cell leukemia cell line. 9,10 These different formulations do not have obvious dose equivalencies, and there is substantial interpatient variability. For example, the recommended dose in allogeneic HSCT for ATLG Grafalon is about 10 times that of Thymoglobulin, but they have not been compared clinically in head-to-head studies.…”

“…Antithymocyte globulin clearly impairs immune reconstitution after HSCT and may also lead to delayed engraftment. 10,16 In the Canadian randomized phase 3 trial of rabbit ATG vs no ATG as part of HSCT conditioning, 33% of patients in the ATG arm had EBV reactivation compared with 3% who did not have ATG. 2 Patients with higher serum levels of ATG also have more EBV reactivation, but it is impossible to determine in advance what serum level to expect.…”