title: Anti-thymocyte globulin-induced hyperbilirubinemia in patients with myelofibrosis undergoing allogeneic hematopoietic cell transplantation.
abstract: Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment option for myelofibrosis (MF) despite the emergence of novel targeted therapies. To reduce graft rejection and graft-versus-host disease (GvHD), current allo-HCT protocols often include in vivo T lymphocyte depletion using polyclonal anti-thymocyte globulin (ATG). Shortly after ATG administration, an immediate inflammatory response with fever, chills, and laboratory alterations such as cytopenias, elevation of serum C-reactive protein, bilirubin, and transaminases can develop. Here, we explore whether MF patients, who commonly exhibit extramedullary hematopoiesis in the liver, might be particularly susceptible to ATG-induced liver toxicity. To test this hypothesis, we analyzed 130 control and 94 MF patients from three transplant centers treated with or without ATG during the allo-HCT conditioning regimen. Indeed, hyperbilirubinemia was found in nearly every MF patient treated with ATG (MF-ATG 54/60 = 90 %) as compared to non-ATG treated MF (MF-noATG 15/34 = 44.1 %, p < 0.001) and respectively ATG-treated non-MF patients of the control group (control-ATG, 43/77 = 56 %, p < 0.001). In contrast, transaminases were only inconsistently elevated. Hyperbilirubinemia was in most cases self-limiting and not predictive of increased incidence of non-relapse mortality, hepatic sinusoidal obstruction syndrome (SOS) or liver GvHD. In sum, awareness of this stereotypic bilirubin elevation in MF patients treated with ATG provides a relatively benign explanation for hyperbilirubinemia occurring in these patients during the early transplant. However, attention to drug levels of biliary excreted drugs is warranted, since altered bile flow may influence their clearance and enhance toxicity (e.g., busulfan, antifungal agents).
authors.affiliation: Division of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: Matyas
authors.initials: M
authors.lastname: Ecsedi
authors.affiliation: Department of Hematology and Oncology, Medical Center, University of Tuebingen, 72076, Tuebingen, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Schmohl
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, 79106, Freiburg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Zeiser
authors.affiliation: Division of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Drexler
authors.affiliation: Division of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Halter
authors.affiliation: Division of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Medinger
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, 79106, Freiburg, Germany.
authors.forename: Justus
authors.initials: J
authors.lastname: Duyster
authors.affiliation: Department of Hematology and Oncology, Medical Center, University of Tuebingen, 72076, Tuebingen, Germany.
authors.forename: Lothar
authors.initials: L
authors.lastname: Kanz
authors.affiliation: Division of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland.
authors.forename: Jakob
authors.initials: J
authors.lastname: Passweg
authors.affiliation: Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, 79106, Freiburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Finke
authors.affiliation: Department of Hematology and Oncology, Medical Center, University of Tuebingen, 72076, Tuebingen, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Bethge
authors.affiliation: Division of Hematology, University Hospital Basel, Petersgraben 4, 4031, Basel, Switzerland. claudia.lengerke@usb.ch.|Department for Biomedicine, University Hospital Basel, Hebelstr. 20, 4031, Basel, Switzerland. claudia.lengerke@usb.ch.
authors.forename: Claudia
authors.initials: C
authors.lastname: Lengerke
mesh_terms: D000328:Adult; D000368:Aged; D000961:Antilymphocyte Serum / Q000009:adverse effects* / Q000627:therapeutic use; D016022:Case-Control Studies; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006086:Graft vs Host Disease / Q000517:prevention & control; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D006932:Hyperbilirubinemia / Q000209:etiology* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D019190:Iron Overload / Q000097:blood / Q000209:etiology; D008099:Liver / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D055728:Primary Myelofibrosis / Q000097:blood / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology; D065227:Transfusion Reaction; D019172:Transplantation Conditioning / Q000379:methods; D014184:Transplantation, Homologous; D055815:Young Adult
chemical_list: D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents
keywords: Anti-thymocyte globulin; Bilirubin; Hematopoietic cell transplantation; Hepatic toxicity; Myelofibrosis