Partial response or better at six months is prognostic of superior progression-free survival in Waldenström macroglobulinaemia patients treated with ibrutinib

Abstract

Ibrutinib is associated with durable responses in patients with Waldenström macroglobulinaemia (WM). We hypothesized that response depth is predictive of progression-free survival (PFS) in WM patients treated with ibrutinib. Using landmark analyses, we evaluated response depth in two cohorts of WM patients treated with ibrutinib monotherapy. The learning cohort was composed of 93 participants from two clinical trials, and the validation cohort of 190 consecutive patients treated off clinical trial. Rates of partial response (PR) or better at six months in learning and validation cohorts were 64% and 71% respectively (P = 0·29). In the learning cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 81% and 57% respectively (P = 0·009). In the validation cohort, three-year PFS rates for patients who attained PR or better at six months versus not were 83% and 54% respectively (P = 0·008). In multivariate analyses, attaining PR or better at six months was associated with superior PFS in the learning [hazard ratio (HR) 0·38; P = 0·01] and validation cohorts (HR 0·18; P = 0·004). Attaining PR at six months on ibrutinib emerges as an intermediate outcome of interest and should be validated as surrogate for PFS in clinical trials evaluating Bruton tyrosine kinase inhibitors in WM.

Keywords: Ibrutinib; Waldenström macroglobulinaemia; response.

Conflict of interest statement

Disclosures

JJC received honoraria and/or research funding from Abbvie, Beigene, Janssen, Kymera, Millennium, Pharmacyclics and TG Therapeutics. RHA received research funding from Janssen and Pharmacyclics. MLP received honoraria and/or research funding from Celgene, Kite, Merck, Novartis and Pharmacyclics. SMA received research funding from Affimed, AI Therapeutics, Bristol Myers Squibb, Pfizer, Regeneron, Seattle Genetics and Trillium. MAG received honoraria and/or research funds from Abbvie, Alnylam, Amgen, Annexon, Appellis, Celgene, Ionis/Akcea, Janssen, Johnson & Johnson, Pharmacyclics, Prothena, Teva and Spectrum. PK received research funding from Amgen, Celgene and Takeda Pharmaceuticals. SPT received research funding and/or consulting fees from Bristol Myers Squibb, Janssen and Pharmacyclics. All other authors have no conflicts of interest to disclose.

© 2020 British Society for Haematology and John Wiley & Sons Ltd.

Figures

Figure 1.

Kaplan-Meier progression-free survival (PFS) curves starting at the 6-month mark in Waldenström macroglobulinemia patients. Learning cohort: (A) PFS, (B) PFS according to attaining partial response (PR) at 6 months or not, and (C) PFS according to attaining very good partial response (VGPR) at 6 months or not. Validation cohort: (D) PFS, (E) PFS according to attaining PR at 6 months or not, and (F) PFS according to attaining VGPR at 6 months or not.

Figure 2.

Kaplan-Meier progression-free survival (PFS) curves starting at the 12-month mark in Waldenström macroglobulinemia patients. Learning cohort: (A) PFS, (B) PFS according to attaining partial response (PR) at 12 months or not, and (C) PFS according to attaining very good partial response (VGPR) at 12 months or not. Validation cohort: (D) PFS, (E) PFS according to attaining PR at 12 months or not, (F) PFS according to attaining VGPR at 12 months or not.