Association between anti-thymocyte globulin exposure and survival outcomes in adult unrelated haemopoietic cell transplantation: a multicentre, retrospective, pharmacodynamic cohort analysis.
BACKGROUND
Anti-thymocyte globulin (ATG) is used to prevent graft-versus-host disease (GvHD) after allogeneic haemopoietic cell transplantation (HCT). However, ATG can also cause delayed immune reconstitution of T cells, negatively affecting survival. We studied the relation between exposure to ATG and clinical outcomes in adult patients with acute leukaemia and myelodysplastic syndrome.


METHODS
We did a retrospective, pharmacokinetic-pharmacodynamic analysis of data from patients with acute lymphoid leukaemia, acute myeloid leukaemia, or myelodysplastic syndrome receiving their first T-cell repleted allogeneic peripheral blood stem cell HCT with ATG (thymoglobulin) as part of non-myeloablative conditioning from March 1, 2004, to June 1, 2015. Patients received a cumulative intravenous dose of 8 mg/kg divided over 4 days, starting on day -8 before HCT. Active ATG concentrations were measured using a validated bioassay and pharmacokinetic exposure measures (maximum concentration, concentration at time of infusion of the graft, time to reach a concentration of 1 arbitary unit [AU] per day/mL, area under the curve [AUC], and the AUC before and after HCT) were calculated with a validated population pharmacokinetic model. The main outcome of interest was 5-year overall survival, defined as days to death from any cause or last follow-up. Other outcomes were relapse-related mortality, non-relapse mortality, event-free survival, acute and chronic GvHD, and assessment of current and optimum dosing. We used Cox proportional hazard models and Fine-Gray competing risk models for the analyses.


RESULTS
146 patients were included. ATG exposure after HCT was shown to be the best predictor for 5-year overall survival. Optimum exposure after transplantation was determined to be 60-95 AU per day/mL. Estimated 5-year overall survival in the group who had optimum exposure (69%, 95% CI 55-86) was significantly higher than in the group who had below optimum exposure (32%, 20-51, p=0·00037; hazard ratio [HR] 2·41, 95% CI 1·15-5·06, p=0·020) and above optimum exposure (48%, 37-62, p=0·030; HR 2·11, 95% CI 1·04-4·27, p=0·038). Patients in the optimum exposure group had a greater chance of event-free survival than those in the below optimum exposure group (HR 2·54, 95% CI 1·29-5·00, p=0·007; HR for the above optimum group: 1·83, 0·97-3·47, p=0·063). Above-optimum exposure led to higher relapse-related mortality compared with optimum exposure (HR 2·66, 95% CI 1·12-6·31; p=0·027). Below optimum exposure increased non-relapse mortality compared with optimum exposure (HR 4·36, 95% CI 1·60-11·88; p=0·0040), grade 3-4 acute GvHD (3·09, 1·12-8·53; p=0·029), but not chronic GvHD (2·38, 0·93-6·08; p=0·070). Modelled dosing based on absolute lymphocyte counts led to higher optimum target attainment than did weight-based dosing.


CONCLUSIONS
Exposure to ATG affects survival after HCT in adults, stressing the importance of optimum ATG dosing. Individualised dosing of ATG, based on lymphocyte counts rather than bodyweight, might improve survival chances after HCT.


BACKGROUND
Netherlands Organization for Health Research and Development and Queen Wilhelma Fund for Cancer Research.
Paediatric Blood and Marrow Transplant Program, University Medical Centre Utrecht, Utrecht, Netherlands; Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands; Department of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, Netherlands.
Rick
R
Admiraal
Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands.
Stefan
S
Nierkens
Adult Blood and Marrow Transplant Program, University Medical Centre Utrecht, Utrecht, Netherlands; Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands.
Moniek A
MA
de Witte
Adult Blood and Marrow Transplant Program, University Medical Centre Utrecht, Utrecht, Netherlands.
Eefke J
EJ
Petersen
Adult Blood and Marrow Transplant Program, University Medical Centre Utrecht, Utrecht, Netherlands.
Ger-Jan
GJ
Fleurke
Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands.
Luka
L
Verrest
Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, Netherlands.
Svetlana V
SV
Belitser
Department of Paediatrics, Leiden University Medical Center, Leiden, Netherlands.
Robbert G M
RGM
Bredius
Adult Blood and Marrow Transplant Program, University Medical Centre Utrecht, Utrecht, Netherlands; Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands.
Reinier A P
RAP
Raymakers
Department of Pharmacology, Leiden Academic Centre for Drug Research, University of Leiden, Leiden, Netherlands.
Catherijne A J
CAJ
Knibbe
Adult Blood and Marrow Transplant Program, University Medical Centre Utrecht, Utrecht, Netherlands.
Monique C
MC
Minnema
Paediatric Blood and Marrow Transplant Program, University Medical Centre Utrecht, Utrecht, Netherlands; Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands.
Charlotte
C
van Kesteren
Adult Blood and Marrow Transplant Program, University Medical Centre Utrecht, Utrecht, Netherlands; Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands.
Jurgen
J
Kuball
Paediatric Blood and Marrow Transplant Program, University Medical Centre Utrecht, Utrecht, Netherlands; Laboratory of Translational Immunology, University Medical Centre Utrecht, Utrecht, Netherlands. Electronic address: j.j.boelens@umcutrecht.nl.
Jaap J
JJ
Boelens
D000328:Adult; D000961:Antilymphocyte Serum / Q000627:therapeutic use*; D005260:Female; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects / Q000379:methods*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000628:therapy*; D008297:Male; D009190:Myelodysplastic Syndromes / Q000628:therapy*; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult
D000961:Antilymphocyte Serum