A dynamic time-to-event model for prediction of acute graft-versus-host disease in patients after allogeneic hematopoietic stem cell transplantation

Katharina Och; Amin T Turki; Katharina M Götz; Dominik Selzer; Christian Brossette; Stefan Theobald; Yvonne Braun; Norbert Graf; Jochen Rauch; Kerstin Rohm; Gabriele Weiler; Stephan Kiefer; Ulf Schwarz; Lisa Eisenberg; Nico Pfeifer; Matthias Ihle; Andrea Grandjean; Sonja Fix; Claudia Riede; Jürgen Rissland; Sigrun Smola; Dietrich W Beelen; Dominic Kaddu-Mulindwa; Jörg Bittenbring; Thorsten Lehr

doi:10.1002/cam4.6833

A dynamic time-to-event model for prediction of acute graft-versus-host disease in patients after allogeneic hematopoietic stem cell transplantation

Cancer Med. 2023 Dec 22;13(1):e6833. doi: 10.1002/cam4.6833. Online ahead of print.

Authors

Katharina Och¹, Amin T Turki², Katharina M Götz¹, Dominik Selzer¹, Christian Brossette³, Stefan Theobald³, Yvonne Braun³, Norbert Graf³, Jochen Rauch⁴, Kerstin Rohm⁴, Gabriele Weiler⁴, Stephan Kiefer⁴, Ulf Schwarz⁵, Lisa Eisenberg⁶, Nico Pfeifer⁶, Matthias Ihle⁷, Andrea Grandjean⁷, Sonja Fix⁷, Claudia Riede⁷, Jürgen Rissland⁸, Sigrun Smola^{8

9}, Dietrich W Beelen², Dominic Kaddu-Mulindwa¹⁰, Jörg Bittenbring¹⁰, Thorsten Lehr¹

Affiliations

¹ Department of Clinical Pharmacy, Saarland University, Saarbrücken, Germany.
² Department of Hematology and Stem Cell Transplantation, West-German Cancer Center, University Hospital Essen, Essen, Germany.
³ Department of Pediatric Oncology and Hematology, Saarland University, Homburg, Germany.
⁴ Department of Biomedical Data & Bioethics, Fraunhofer Institute for Biomedical Engineering (IBMT), Sulzbach, Germany.
⁵ Institute for Formal Ontology and Medical Information Science, Saarland University, Saarbrücken, Germany.
⁶ Department of Computer Science, University of Tübingen, Tübingen, Germany.
⁷ Averbis GmbH, Freiburg, Germany.
⁸ Institute of Virology, Saarland University Medical Centre, Homburg, Germany.
⁹ Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research (HZI), Saarland University Campus, Saarbrücken, Germany.
¹⁰ Department of Internal Medicine 1, University Hospital of the Saarland, Homburg, Germany.

Abstract

Background: Acute graft-versus-host disease (aGvHD) is a major cause of death for patients following allogeneic hematopoietic stem cell transplantation (HSCT). Effective management of moderate to severe aGvHD remains challenging despite recent advances in HSCT, emphasizing the importance of prophylaxis and risk factor identification.

Methods: In this study, we analyzed data from 1479 adults who underwent HSCT between 2005 and 2017 to investigate the effects of aGvHD prophylaxis and time-dependent risk factors on the development of grades II-IV aGvHD within 100 days post-HSCT.

Results: Using a dynamic longitudinal time-to-event model, we observed a non-monotonic baseline hazard overtime with a low hazard during the first few days and a maximum hazard at day 17, described by Bateman function with a mean transit time of approximately 11 days. Multivariable analysis revealed significant time-dependent effects of white blood cell counts and cyclosporine A exposure as well as static effects of female donors for male recipients, patients with matched related donors, conditioning regimen consisting of fludarabine plus total body irradiation, and patient age in recipients of grafts from related donors on the risk to develop grades II-IV aGvHD. Additionally, we found that higher cumulative hazard on day 7 after allo-HSCT are associated with an increased incidence of grades II-IV aGvHD within 100 days indicating that an individual assessment of the cumulative hazard on day 7 could potentially serve as valuable predictor for later grades II-IV aGvHD development. Using the final model, stochastic simulations were performed to explore covariate effects on the cumulative incidence over time and to estimate risk ratios.

Conclusion: Overall, the presented model showed good descriptive and predictive performance and provides valuable insights into the interplay of multiple static and time-dependent risk factors for the prediction of aGvHD.

Keywords: acute graft-versus-host disease; allogeneic hematopoietic stem cell transplantation; cyclosporine a; risk factors; time-to-event model.