Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first-line immunochemotherapy

Jamois, Candice; Gibiansky, Ekaterina; Gibiansky, Leonid; Buchheit, Vincent; Sahin, Denis; Cartron, Guillaume; Marcus, Robert; Hiddemann, Wolfgang; Seymour, John F.; Strefford, Jonathan C.; Hargreaves, Chantal E.; Meneses-Lorente, Georgina; Frey, Nicolas und Fingerle-Rowson, Guenter (2019): Role of obinutuzumab exposure on clinical outcome of follicular lymphoma treated with first-line immunochemotherapy. In: British Journal of Clinical Pharmacology, Bd. 85, Nr. 7: S. 1495-1506

Abstract

Aims Obinutuzumab (G) is a humanized type II, Fc-glycoengineered anti-CD20 monoclonal antibody used in various indications, including patients with previously untreated front-line follicular lymphoma. We investigated sources of variability in G exposure and association of progression-free survival (PFS) with average concentration over induction (C-meanIND) in front-line follicular lymphoma patients treated with G plus chemotherapy (bendamustine, CHOP, or CVP) in the GALLIUM trial. Methods Individual exposures (C-meanIND) were obtained from a previously established population pharmacokinetic model updated with GALLIUM data. Multivariate Cox proportional hazard models and univariate Kaplan-Meier plots investigated relationships of PFS with exposure and other potential prognostic factors. Results Overall, G exposure was lower in high body-weight patients and in males, and slightly lower in patients with high baseline tumour burden. Analysis of clinical outcomes showed that variability in G exposure did not impact PFS in G-bendamustine-treated patients;PFS was inferior in males and patients with FCGR2a/2b T232 T low-affinity receptor variant, and superior in patients with FCGR2a/2b I232T variant. In G-CHOP/CVP arms, PFS improved with increasing C-meanIND (hazard ratio = 1.74 and 0.394 at 5(th) and 95(th) percentile compared to median C-meanIND) and was inferior in patients with high baseline tumour size and B symptoms. Conclusions It remains unclear whether for G-CHOP/CVP patients lower G exposure is a consequence of adverse disease biology and/or resistance to chemotherapy backbone (higher clearance in nonresponder patients, as demonstrated for rituximab) rather than being the cause of poorer clinical outcome. A study with >1 dose level of G could help resolve this uncertainty.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0306-5251
• Sprache: Englisch