TY  - JOUR
A1  - Isberner, Nora
A1  - Kraus, Sabrina
A1  - Grigoleit, Götz Ulrich
A1  - Aghai, Fatemeh
A1  - Kurlbaum, Max
A1  - Zimmermann, Sebastian
A1  - Klinker, Hartwig
A1  - Scherf-Clavel, Oliver
T1  - Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice-a prospective single-center trial
JF  - Cancer Chemotherapy and Pharmacology
N2  - Purpose
Knowledge on Ruxolitinib exposure in patients with graft versus host disease (GvHD) is scarce. The purpose of this prospective study was to analyze Ruxolitinib concentrations of GvHD patients and to investigate effects of CYP3A4 and CYP2C9 inhibitors and other covariates as well as concentration-dependent effects.
Methods
262 blood samples of 29 patients with acute or chronic GvHD who were administered Ruxolitinib during clinical routine were analyzed. A population pharmacokinetic model obtained from myelofibrosis patients was adapted to our population and was used to identify relevant pharmacokinetic properties and covariates on drug exposure. Relationships between Ruxolitinib exposure and adverse events were assessed.
Results
Median of individual mean trough serum concentrations was 39.9 ng/mL at 10 mg twice daily (IQR 27.1 ng/mL, range 5.6-99.8 ng/mL). Applying a population pharmacokinetic model revealed that concentrations in our cohort were significantly higher compared to myelofibrosis patients receiving the same daily dose (p < 0.001). Increased Ruxolitinib exposure was caused by a significant reduction in Ruxolitinib clearance by approximately 50%. Additional comedication with at least one strong CYP3A4 or CYP2C9 inhibitor led to a further reduction by 15% (p < 0.05). No other covariate affected pharmacokinetics significantly. Mean trough concentrations of patients requiring dose reduction related to adverse events were significantly elevated (p < 0.05).
Conclusion
Ruxolitinib exposure is increased in GvHD patients in comparison to myelofibrosis patients due to reduced clearance and comedication with CYP3A4 or CYP2C9 inhibitors. Elevated Ruxolitinib trough concentrations might be a surrogate for toxicity.
KW  - toxicity
KW  - Ruxolitinib
KW  - graft versus host disease
KW  - therapeutic drug monitoring
KW  - CYP3A4
KW  - CYP2C9
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-266476
SN  - 1432-0843
VL  - 88
IS  - 6
ER  - 
TY  - JOUR
A1  - Robin, Marie
A1  - de Wreede, Liesbeth C.
A1  - Wolschke, Christine
A1  - Schetelig, Johannes
A1  - Eikema, Diderik-Jan
A1  - Van Lint, Maria Teresa
A1  - Knelange, Nina Simone
A1  - Beelen, Dietrich
A1  - Brecht, Arne
A1  - Niederwieser, Dietger
A1  - Vitek, Antonin
A1  - Bethge, Wolfgang
A1  - Arnold, Renate
A1  - Finke, Jürgen
A1  - Volin, Liisa
A1  - Yakoub-Agha, Ibrahim
A1  - Nagler, Arnon
A1  - Poiré, Xavier
A1  - Einsele, Hermann
A1  - Chevallier, Patrice
A1  - Holler, Ernst
A1  - Ljungman, Per
A1  - Robinson, Stephen
A1  - Radujkovic, Alekxandar
A1  - McLornan, Donal
A1  - Chalandon, Yves
A1  - Kröger, Nicolaus
T1  - Long-term outcome after allogeneic hematopoietic cell transplantation for myelofibrosis
JF  - Haematologica
N2  - Allogeneic hematopoietic stem cell transplant remains the only curative treatment for myelofibrosis. Most post-transplantation events Aoccur during the first two years and hence we aimed to analyze the outcome of 2-year disease-free survivors. A total of 1055 patients with myelofibrosis transplanted between 1995 and 2014 and registered in the registry of the European Society for Blood and Marrow Transplantation were included. Survival was compared to the matched general population to determine excess mortality and the risk factors that are associated. In the 2-year survivors, disease-free survival was 64% (60-68%) and overall survival was 74% (71-78%) at ten years; results were better in younger individuals and in women. Excess mortality was 14% (8-21%) in patients aged <45 years and 33% (13-53%) in patients aged >= 65 years. The main cause of death was relapse of the primary disease. Graft-versus-host disease (GvHD) before two years decreased the risk of relapse. Multivariable analysis of excess mortality showed that age, male sex recipient, secondary myelofibrosis and no GvHD disease prior to the 2-year landmark increased the risk of excess mortality. This is the largest study to date analyzing long-term outcome in patients with myelofibrosis undergoing transplant. Overall it shows a good survival in patients alive and in remission at two years. However, the occurrence of late complications, including late relapses, infectious complications and secondary malignancies, highlights the importance of screening and monitoring of long-term survivors.
KW  - Prognostic scoring system
KW  - Societe Francaise
KW  - Gruppo-italiano
KW  - European group
KW  - Late mortality
KW  - Midollo-Osseo
KW  - LATE DEATHS
KW  - Survival
KW  - Blood
KW  - Ruxolitinib
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226386
VL  - 104
IS  - 9
ER  -