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  - Garitano-Trojaola, Andoni
A1  - Sancho, Ana
A1  - Götz, Ralph
A1  - Eiring, Patrick
A1  - Walz, Susanne
A1  - Jetani, Hardikkumar
A1  - Gil-Pulido, Jesus
A1  - Da Via, Matteo Claudio
A1  - Teufel, Eva
A1  - Rhodes, Nadine
A1  - Haertle, Larissa
A1  - Arellano-Viera, Estibaliz
A1  - Tibes, Raoul
A1  - Rosenwald, Andreas
A1  - Rasche, Leo
A1  - Hudecek, Michael
A1  - Sauer, Markus
A1  - Groll, Jürgen
A1  - Einsele, Hermann
A1  - Kraus, Sabrina
A1  - Kortüm, Martin K.
T1  - Actin cytoskeleton deregulation confers midostaurin resistance in FLT3-mutant acute myeloid leukemia
JF  - Communications Biology
N2  - The presence of FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) is one of the most frequent mutations in acute myeloid leukemia (AML) and is associated with an unfavorable prognosis. FLT3 inhibitors, such as midostaurin, are used clinically but fail to entirely eradicate FLT3-ITD+AML. This study introduces a new perspective and highlights the impact of RAC1-dependent actin cytoskeleton remodeling on resistance to midostaurin in AML. RAC1 hyperactivation leads resistance via hyperphosphorylation of the positive regulator of actin polymerization N-WASP and antiapoptotic BCL-2. RAC1/N-WASP, through ARP2/3 complex activation, increases the number of actin filaments, cell stiffness and adhesion forces to mesenchymal stromal cells (MSCs) being identified as a biomarker of resistance. Midostaurin resistance can be overcome by a combination of midostaruin, the BCL-2 inhibitor venetoclax and the RAC1 inhibitor Eht1864 in midostaurin-resistant AML cell lines and primary samples, providing the first evidence of a potential new treatment approach to eradicate FLT3-ITD+AML. Garitano-Trojaola et al. used a combination of human acute myeloid leukemia (AML) cell lines and primary samples to show that RAC1-dependent actin cytoskeleton remodeling through BCL2 family plays a key role in resistance to the FLT3 inhibitor, Midostaurin in AML. They showed that by targeting RAC1 and BCL2, Midostaurin resistance was diminished, which potentially paves the way for an innovate treatment approach for FLT3 mutant AML.
KW  - actin
KW  - acute myeloid leukaemia
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-260709
VL  - 4
IS  - 1
ER  -