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Clinical Trial
. 2019 Aug;25(8):1526-1535.
doi: 10.1016/j.bbmt.2019.02.021. Epub 2019 Mar 1.

Standard Antithymocyte Globulin Dosing Results in Poorer Outcomes in Overexposed Patients after Ex Vivo CD34+ Selected Allogeneic Hematopoietic Cell Transplantation

Michael Scordo  1 , Valkal Bhatt  2 , Patrick Hilden  3 , Melody Smith  4 , Katie Thoren  5 , Christina Cho  4 , Gunjan L Shah  4 , Molly A Maloy  6 , Esperanza B Papadopoulos  4 , Ann A Jakubowski  4 , Scott T Avecilla  5 , Richard J O'Reilly  7 , Hugo Castro-Malaspina  4 , Roni Tamari  4 , Brian C Shaffer  4 , Jaap J Boelens  7 , Miguel-Angel Perales  4 , Sergio A Giralt  4
Affiliations
Clinical Trial

Standard Antithymocyte Globulin Dosing Results in Poorer Outcomes in Overexposed Patients after Ex Vivo CD34+ Selected Allogeneic Hematopoietic Cell Transplantation

Michael Scordo et al. Biol Blood Marrow Transplant. 2019 Aug.

Abstract

Antithymocyte globulin (ATG) use mitigates the risk of graft rejection and graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (allo-HCT), but ATG overexposure in the setting of lymphopenia negatively affects immune recovery. We hypothesized that standard empiric weight-based dosing of ATG, used to prevent graft rejection in ex vivo CD34-selected allo-HCT, may lead to serious adverse consequences on outcomes in certain patients. We evaluated 304 patients undergoing myeloablative-conditioned ex vivo CD34-selected allo-HCT with HLA-matched donors for the treatment of hematologic malignancies. Patients received rabbit ATG at a dose of 2.5 mg/kg/day i.v. on days -3 and/or -2. An ATG dosing cutoff of 450 mg was used for statistical analyses to assess the relationship between ATG and overall survival (OS). Among all patients, median total ATG dose was 360 mg (range, 130 to 510 mg); 279 (92%) received a total dose of ATG ≤450 mg, and 25 (8%) received a total dose >450 mg. On the first day of ATG administration (day -3), the median absolute lymphocyte count was .0 K/µL. For patients who received a total dose of ATG >450 mg or ≤450 mg, the incidences of acute and late-acute GVHD grade II-IV were statistically similar. At 3 years post-HCT, for patients who received a total dose of ATG >450 mg or ≤450 mg, nonrelapse mortality (NRM) rates were 35% and 18%, respectively (P = .029), disease-free survival (DFS) rates were 37% and 61%, respectively (P = .003), and OS rates were 40% and 67%, respectively (P = .001). Among all patient and HCT characteristics in multivariable analyses, receipt of a total dose of ATG >450 mg was associated with an increased risk of NRM (hazard ratio [HR], 2.9; P = .01), shorter DFS (HR, 2.0; P = .03), and inferior OS (HR, 2.1; P = .01). In summary, the use of weight-based ATG at a time of relative lymphopenia before ex vivo CD34-selected allo-HCT results in overdosing in heavier patients, leading to higher NRM and lower DFS and OS. Further pharmacokinetic investigation in this setting is critical to determining the optimal dosing strategy for ATG.

Keywords: Allogeneic hematopoietic cell transplantation; Antithymocyte globulin; Ex vivo CD34 selection.

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Conflict of interest statement

Author disclosures: There are no conflicts of interest related to the subject matter of this article. Unless otherwise listed, authors have no disclosures to report. M.Sc. is an ad hoc consultant for McKinsey & Company and a consultant for Angiocrine Bioscience, Inc. V.B. is a consultant for Spectrum Pharmaceuticals, Inc. and Incyte Corporation. G.L.S. receives research funding from Janssen Pharmaceuticals, Inc. and Amgen, Inc. S.T.A received an honorarium in 2015 for Abbott Diagnostics. R.J.O. received royalties following licensure of the EBV-specific T-cell bank by Atara Biotherapeutics and has received research support and consultant fees from Atara Biotherapeutics. J.J.B. is a consultant for Avrobio, Inc., and a consulting member of the DSMB for Magenta Therapeutics, Chimerix, Inc., and Bluebird Bio, Inc. M.P. receives research funding from Incyte Corporation for a clinical trial and is a consultant for Merck. M.P. is on the ad hoc advisory boards of Incyte, Novartis, Nektar Therapeutics, Abbvie, and is on the scientific advisory board for MolMed and NexImmune. M.P. is a DSMB member for Servier and Medigene. S.A.G. receives research funding from Miltenyi Biotec, Takeda Pharmaceutical Co., Celgene Corp., Amgen Inc., Sanofi, Johnson and Johnson, Inc., Actinium Pharmaceuticals, Inc., and is on the Advisory Boards for: Kite Pharmaceuticals, Inc., Celgene Corp., Sanofi, Novartis, Johnson and Johnson, Inc., Amgen Inc., Takeda Pharmaceutical Co., Jazz Pharmaceuticals, Inc., Actinium Pharmaceuticals, Inc.

Figures

Figure 1.
Figure 1.
Cumulative Incidence of Acute GVHD by Total ATG Dose. ATG, anti-thymocyte globulin; GVHD, graft-versus-host disease; HCT, hematopoietic cell transplant;
Figure 2.
Figure 2.
Cumulative Incidence of NRM by Total ATG Dose. ATG, anti-thymocyte globulin; HCT, hematopoietic cell transplant; NRM, non-relapse mortality.
Figure 3.
Figure 3.
DFS by Total ATG Dose. ATG, anti-thymocyte globulin; HCT, hematopoietic cell transplant; DFS, disease-free survival.
Figure 4.
Figure 4.
Cumulative Incidence of Relapse by Total ATG Dose
Figure 5.
Figure 5.
OS by Total ATG Dose. ATG, anti-thymocyte globulin; HCT, hematopoietic cell transplant; OS, overall survival.
See this image and copyright information in PMC

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