Standardized monitoring of cytomegalovirus-specific immunity can improve risk stratification of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation
Eva Wagner-Drouet,
Daniel Teschner,
Christine Wolschke,
Dietlinde Janson,
Kerstin Schäfer-Eckart,
Johannes Gärtner,
Stephan Mielke,
Martin Schreder,
Guido Kobbe,
Mustafa Kondakci,
Inken Hilgendorf,
Marie von Lilienfeld-Toal,
Stefan Klein,
Daniela Heidenreich,
Sebastian Kreil,
Mareike Verbeek,
Sandra Grass,
Markus Ditschkowski,
Tanja Gromke,
Martina Koch,
Monika Lindemann,
Thomas Hünig,
Traudel Schmidt,
Anne Rascle,
Harald Guldan,
Sascha Barabas,
Ludwig Deml,
Ralf Wagner,
Daniel Wolff
Affiliations
Eva Wagner-Drouet
Dpt of Hematology, Medical Oncology, and Pneumology, University Medical Center, Mainz, Germany;
Daniel Teschner
Dpt of Hematology, Medical Oncology, and Pneumology, University Medical Center, Mainz, Germany;
Christine Wolschke
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany;
Dietlinde Janson
Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Germany;
Kerstin Schäfer-Eckart
Oncology, Hematology and Bone Marrow Transplantation Unit, Klinikum Nord, Nürnberg, Germany;
Johannes Gärtner
Oncology, Hematology and Bone Marrow Transplantation Unit, Klinikum Nord, Nürnberg, Germany;
Stephan Mielke
Department of Laboratory Medicine, Karolinska Institutet and University Hospital, Stockholm, Sweden;
Martin Schreder
First Department of Medicine, Center for Oncology and Hematology, Wilhelminenspital, Vienna, Austria;
Guido Kobbe
Department of Hematology, University Hospital, Heinrich Heine University Düsseldorf, Germany;
Mustafa Kondakci
Department of Hematology, University Hospital, Heinrich Heine University Düsseldorf, Germany;
Inken Hilgendorf
Klinik f. Innere Medizin II, Abt. Haematol. und Internist. Onkologie, Univ.-Klinikum Jena, Germany;
Marie von Lilienfeld-Toal
Klinik f. Innere Medizin II, Abt. Haemmatol. und Internist. Onkologie, Univ.-Klinikum Jena, Germany;
Stefan Klein
Dpt of Hematology and Oncology, Univ. Medical Center Mannheim, Univ. of Heidelberg, Mannheim,Germany;
Daniela Heidenreich
Dpt of Hematology and Oncology, Univ. Medical Center Mannheim, Univ. of Heidelberg, Mannheim,Germany;
Sebastian Kreil
Dpt of Hematology and Oncology, Univ. Medical Center Mannheim, Univ. of Heidelberg, Mannheim,Germany;
Mareike Verbeek
III. Medical Department, Hematology and Oncology, Klinikum rechts der Isar, TUM, Munich, Germany;
Sandra Grass
III. Medical Department, Hematology and Oncology, Klinikum rechts der Isar, TUM, Munich, Germany;
Markus Ditschkowski
Innere Klinik, Tumorforschung, University Hospital Essen, Germany;
Tanja Gromke
Innere Klinik, Tumorforschung, University Hospital Essen, Germany;
Martina Koch
Dpt of Transplantation Surgery, University Medical Center of the JGU, Mainz, Germany;
Monika Lindemann
Institute for Transfusion Medicine, University Hospital Essen, Germany;
Thomas Hünig
Institute of Virology and Immunobiology, University Medical Center Würzburg, Germany;
Traudel Schmidt
Lophius Biosciences, Regensburg, Germany;
Anne Rascle
Lophius Biosciences, Regensburg, Germany;
Harald Guldan
Lophius Biosciences, Regensburg, Germany;
Sascha Barabas
Lophius Biosciences, Regensburg, Germany;
Ludwig Deml
Lophius Biosciences, Regensburg, Germany;
Ralf Wagner
Institute of Clinical Microbiology and Hygiene, University Medical Center Regensburg, Germany;
Daniel Wolff
Dpt of Internal Medicine III, Hematology and Oncology, University Medical Center Regensburg, Germany
Recurrence of cytomegalovirus reactivation remains a major cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation. Monitoring cytomegalovirus-specific cellular immunity using a standardized assay might improve the risk stratification of patients. A prospective multicenter study was conducted in 175 intermediate- and high-risk allogeneic hematopoietic stem cell transplant recipients under preemptive antiviral therapy. Cytomegalovirus-specific cellular immunity was measured using a standardized IFN-γ ELISpot assay (T-Track® CMV). Primary aim was to evaluate the suitability of measuring cytomegalovirus-specific immunity after end of treatment for a first cytomegalovirus reactivation to predict recurrent reactivation. 40/101 (39.6%) patients with a first cytomegalovirus reactivation experienced recurrent reactivations, mainly in the high-risk group (cytomegalovirus-seronegative donor/cytomegalovirus-seropositive recipient). The positive predictive value of T-Track® CMV (patients with a negative test after the first reactivation experienced at least one recurrent reactivation) was 84.2% in high-risk patients. Kaplan-Meier analysis revealed a higher probability of recurrent cytomegalovirus reactivation in high-risk patients with a negative test after the first reactivation (hazard ratio 2.73; p=0.007). Interestingly, a post-hoc analysis considering T-Track® CMV measurements at day 100 post-transplantation, a time point highly relevant for outpatient care, showed a positive predictive value of 90.0% in high-risk patients. Our results indicate that standardized cytomegalovirus-specific cellular immunity monitoring may allow improved risk stratification and management of recurrent cytomegalovirus reactivation after hematopoietic stem cell transplantation. This study was registered at www.clinicaltrials.gov as #NCT02156479.
