Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice—a prospective single-center trial

Isberner, Nora; Kraus, Sabrina; Grigoleit, Götz Ulrich; Aghai, Fatemeh; Kurlbaum, Max; Zimmermann, Sebastian; Klinker, Hartwig; Oliver, Susan

doi:10.1007/s00280-021-04351-w

Cited by 8 publications

(7 citation statements)

References 36 publications

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“…Isberner et al suggested that ruxolitinib exposure is increased in GVHD patients in comparison to myelofibrosis patients due to a significant reduction in ruxolitinib clearance. 30 In agreement with our results, no significant differences in the mean ruxolitinib concentrations in GVHD patients after dose reduction were observed. So far, no guidelines exist for the optimal dose of ruxolitinib for clinical use.…”

Section: Discussionsupporting

confidence: 92%

Ruxolitinib for Treatment of Steroid-Refractory Graft-versus-Host Disease: Real-World Data from Chinese Patients

Zhang¹,

Liang²,

Yang³

et al. 2021

DDDT

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Background: Graft-versus-host disease (GVHD) is a main complication following allogeneic hematopoietic stem cell transplantation and is a leading cause of non-relapse-related death. Unsatisfactory response to standard first-line therapy with glucocorticoids is a predictor of a poor prognosis in patients with GVHD. Ruxolitinib is a selective Janus kinases 1/2 inhibitor which has been shown to control acute (a) and chronic (c) GVHD while maintaining graft-versus-tumor effects.Objective: This study aims to evaluate the efficacy and safety of ruxolitinib in the treatment of steroid-refractory GVHD (SR-GVHD) in a population of Chinese patients. Methods: We report the results of 55 patients, including 23 patients with aGVHD and 32 patients with cGVHD, who were treated with ruxolitinib as salvage therapy between August, 2017 and December, 2020. Results: In patients with aGVHD, the overall response rate (ORR) was 86.9%, and the 1-year overall survival (OS) was 82.6% (95% CI, 67.1-98.1%). The 1-year OS was significantly improved in responders than in non-responders (90.0% vs 33.3%, P=0.004). In patients with cGVHD, the ORR was 78.1%, and the 1-year OS was 81.3% (95% CI, 67.8-94.8%). There was no significant difference in the 1-year OS between responders and nonresponders (84.0% vs 71.4%, P=0.327). Cytopenia, cytomegalovirus-reactivation and infections were common adverse events, particularly in patients with aGVHD. Conclusion: Our real-world data from Chinese patients further confirm that ruxolitinib is a safe and effective treatment for SR-GVHD.

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Section: Discussionsupporting

confidence: 92%

Ruxolitinib for Treatment of Steroid-Refractory Graft-versus-Host Disease: Real-World Data from Chinese Patients

Zhang¹,

Liang²,

Yang³

et al. 2021

DDDT

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“…Isberner et al studied ruxolitinib exposure in patients with GVHD, of whom 31% had involvement of the gut, and found that ruxolitinib exposure was actually increased in GVHD patients in comparison with myelofibrosis patients. Since this difference was related to reduced ruxolitinib clearance, it is unlikely that ruxolitinib absorption is hampered in patients with GVHD of the gut [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

“…The underlying disease might have played a role. Isberner et al studied ruxolitinib in patients with GVHD and found a CL/F of 9.74 L/h, whereas Chen et al studied healthy volunteers and found a CL/F ranging from 18.6 to 23.5 L/h [ 34 , 37 ]. The authors did not find an explanation for why their findings differ from other studies [ 37 ].…”

Section: Resultsmentioning

confidence: 99%

“…Isberner et al studied ruxolitinib in patients with GVHD and found a CL/F of 9.74 L/h, whereas Chen et al studied healthy volunteers and found a CL/F ranging from 18.6 to 23.5 L/h [ 34 , 37 ]. The authors did not find an explanation for why their findings differ from other studies [ 37 ]. In patients with PV, CL/F was 13.7–20.7 L/h, further indicating that the underlying disease might play a role [ 35 ].…”

Section: Resultsmentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review

et al. 2023

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Background and Objective Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to treat myelofibrosis, polycythemia vera and steroid-refractory graft-versus-host disease in the setting of allogeneic stem-cell transplantation. This review describes the pharmacokinetics and pharmacodynamics of ruxolitinib. Methods Pubmed, EMBASE, Cochrane Library and web of Science were searched from the time of database inception to march 15, 2021 and was repeated on November 16, 2021. Articles not written in English, animal or in vitro studies, letters to the editor, case reports, where ruxolitinib was not used for hematological diseases or not available as full text were excluded. Results Ruxolitinib is well absorbed, has 95% bio-availability, and is bound to albumin for 97%. Ruxolitinib pharmacokinetics can be described with a two-compartment model and linear elimination. Volume of distribution differs between men and women, likely related to bodyweight differences. Metabolism is mainly hepatic via CYP3A4 and can be altered by CYP3A4 inducers and inhibitors. The major metabolites of ruxolitinib are pharmacologically active. The main route of elimination of ruxolitinib metabolites is renal. Liver and renal dysfunction affect some of the pharmacokinetic variables and require dose reductions. Model-informed precision dosing might be a way to further optimize and individualize ruxolitinib treatment, but is not yet advised for routine care due to lack of information on target concentrations. Conclusion Further research is needed to explain the interindividual variability of the ruxolitinib pharmacokinetic variables and to optimize individual treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s40262-023-01225-7.

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“…Ruxolitinib (5 × 10 −7 , 10 -6 , 5 × 10 −6 , 10 -5 M) or budesonide (10 -11 , 10 -10 , 10 -9 , and 10 -8 M) was added to the culture medium 1 h before exposure to LPS or poly (I:C). The ruxolitinib concentrations used in vitro were initially chosen by reference to those measured in the plasma of treated patients; these have been shown to be effective in vitro on monocytes (Lescoat et al, 2020;Isberner et al, 2021). After a 24-hour incubation, the remaining cells were counted in each plate and the supernatants were collected and stored at −20 °C for subsequent analysis.…”

Section: Treatment Of Lmsmentioning

confidence: 99%

Ruxolitinib inhibits cytokine production by human lung macrophages without impairing phagocytic ability

et al. 2022

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Background: The Janus kinase (JAK) 1/2 inhibitor ruxolitinib has been approved in an indication of myelofibrosis and is a candidate for the treatment of a number of inflammatory or autoimmune diseases. We assessed the effects of ruxolitinib on lipopolysaccharide (LPS)- and poly (I:C)-induced cytokine production by human lung macrophages (LMs) and on the LMs’ phagocytic activity.Methods: Human LMs were isolated from patients operated on for lung carcinoma. The LMs were cultured with ruxolitinib (0.5 × 10−7 M to 10–5 M) or budesonide (10–11 to 10–8 M) and then stimulated with LPS (10 ng·ml−1) or poly (I:C) (10 μg·ml−1) for 24 h. Cytokines released by the LMs into the supernatants were measured using ELISAs. The phagocytosis of labelled bioparticles was assessed using flow cytometry.Results: Ruxolitinib inhibited both the LPS- and poly (I:C)-stimulated production of tumor necrosis factor alpha, interleukin (IL)-6, IL-10, chemokines CCL2, and CXCL10 in a concentration-dependent manner. Ruxolitinib also inhibited the poly (I:C)- induced (but not the LPS-induced) production of IL-1ß. Budesonide inhibited cytokine production more strongly than ruxolitinib but failed to mitigate the production of CXCL10. The LMs’ phagocytic activity was not impaired by the highest tested concentration (10–5 M) of ruxolitinib.Conclusion: Clinically relevant concentrations of ruxolitinib inhibited the LPS- and poly (I:C)-stimulated production of cytokines by human LMs but did not impair their phagocytic activity. Overall, ruxolitinib’s anti-inflammatory activities are less intense than (but somewhat different from) those of budesonide—particularly with regard to the production of the corticosteroid-resistant chemokine CXCL-10. Our results indicate that treatment with a JAK inhibitor might be a valuable anti-inflammatory strategy in chronic obstructive pulmonary disease, Th1-high asthma, and both viral and non-viral acute respiratory distress syndromes (including coronavirus disease 2019).

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Ruxolitinib exposure in patients with acute and chronic graft versus host disease in routine clinical practice—a prospective single-center trial

Cited by 8 publications

References 36 publications

Ruxolitinib for Treatment of Steroid-Refractory Graft-versus-Host Disease: Real-World Data from Chinese Patients

Ruxolitinib for Treatment of Steroid-Refractory Graft-versus-Host Disease: Real-World Data from Chinese Patients

Pharmacokinetics and Pharmacodynamics of Ruxolitinib: A Review

Ruxolitinib inhibits cytokine production by human lung macrophages without impairing phagocytic ability

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