Details

Autor(en) / Beteiligte

• Sun, Clare
• Nierman, Pia
• Kendall, Ellen K.
• Cheung, Jean
• Gulrajani, Michael
• Herman, Sarah E.M.
• Pleyer, Christopher
• Ahn, Inhye E.
• Stetler-Stevenson, Maryalice
• Yuan, Constance M.
• Maric, Irina
• Gaglione, Erika M.
• Harris, Hailey M.
• Pittaluga, Stefania
• Wang, Min Hui
• Patel, Priti
• Farooqui, Mohammed Z.H.
• Izumi, Raquel
• Hamdy, Ahmed
• Covey, Todd
• Wiestner, Adrian

Titel

Clinical and biological implications of target occupancy in CLL treated with the BTK inhibitor acalabrutinib

Ist Teil von

• Blood, 2020-07, Vol.136 (1), p.93-105

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors. However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remain undefined. This randomized phase 2 study investigated the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily (BID) or 200 mg once daily (QD) in 48 patients with relapsed/refractory or high-risk treatment-naïve CLL. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% confidence interval [CI], 78.9-99.9) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI, 70.0-97.8) with BID dosing and an ORR of 79.2% (95% CI, 57.9-92.9) and an estimated PFS rate at 24 months of 87.2% (95% CI, 57.2-96.7) with QD dosing. BTK resynthesis was faster in patients with CLL than in healthy volunteers. BID dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared with QD dosing. Small increments in occupancy attained by BID dosing relative to QD dosing compounded over time to augment downstream biological effects. The impact of BTK occupancy on long-term clinical outcomes remains to be determined. This trial was registered at www.clinicaltrials.gov as #NCT02337829. •Acalabrutinib is clinically effective in relapsed/refractory and high-risk treatment naïve chronic lymphocytic leukemia.•BID dosing maintains near complete occupancy of BTK in blood and tissues and more profoundly inhibits oncogenic signaling than QD dosing. [Display omitted]