Ibrutinib Plus Venetoclax with MRD-Directed Duration of Treatment Is Superior to FCR and Is a New Standard of Care for Previously Untreated CLL: Report of the Phase III UK NCRI FLAIR Study

• Published in: Blood 2023-11, Vol.142 (Supplement 1), p.631-631
• Main Authors: Hillmen, Peter, Cairns, David Allan, Bloor, Adrian John Clifton, Allsup, David, Cwynarski, Kate, Pettitt, Andrew, Paneesha, Shankaranarayana, Fox, Christopher P., Eyre, Toby A., Forconi, Francesco, Elmusharaf, Nagah, Kennedy, Ben, Gribben, John G., Pemberton, Nicholas, Sheehy, Oonagh, Preston, Gavin, Schuh, Anna, Howard, Dena, Hockaday, Anna, Jackson, Sharon, Greatorex, Natasha, Girvan, Sean, Bell, Sue, Brown, Julia, Webster, Nichola, Dalal, Surita, de Tute, Ruth M, Rawstron, Andrew, Patten, Piers EM, Munir, Talha
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2023-178298

Introduction: Ibrutinib (I), an irreversible Btk inhibitor, and venetoclax (V), a Bcl-2 inhibitor, improve CLL outcomes in trials compared to chemoimmunotherapy. I and V target two key pathophysiological pathways in CLL and should be synergistic. This is supported both by in vitro studies and Phase II trials in which I+V results in high proportions of measurable residual disease (MRD) negativity. A Phase III trial comparing I+V (15 months [mo]) with chlorambucil-obinutuzumab led to the approval of I+V. However, mathematical disease modelling and Phase II studies favor defining duration of I+V according to individual patient sensitivity. We hypothesized that I+V is more effective than FCR in CLL and that treatment duration personalised using MRD response would optimize outcome. Methods: FLAIR (ISRCTN01844152) is a phase III, multicentre, randomised, controlled, open, parallel group trial for untreated CLL. Patients (pts) with >20% 17p deleted cells were excluded. FLAIR was adapted in 2017 to add 2 arms, I alone and I+V compared to FCR. Here we report the planned analysis of I+V vs FCR. In I+V after 2 mo I, V was added with a 4-week dose escalation to 400mg/day and then I+V for up to 6 years with duration of I+V defined by MRD (65yo) and 40.9 % Binet Stage C. IGHV unmutated (≥98% homology to germline) in 56.9%, 37.6% IGHV mutated and 5.5% Subset 2. Hierarchical FISH: 20.6% 11q del, 20.1% trisomy 12, 27.8% normal and 31.4% 13q del. At 2 yrs 111/260 (42.7%) and 3 yrs 135/232 (58.1%) pts stopped I+V according to the MRD stopping rules. At a median 43.7 months there were 87 progressions - 75 FCR and 12 I+V. The hazard ratio (HR) for PFS for I+V vs FCR is 0.13 (95% CI: [0.07, 0.24]; p