S145: the Combination of Ibrutinib Plus Venetoclax Results in a High Rate of Mrd Negativity in Previously Untreated Cll: the Results of the Planned Interim Analysis of the Phase Iii Ncri Flair Trial
Year: 2022
Type: conference-abstract
Study design: Clinical Trial
Abstract: Background: Ibrutinib (I) and venetoclax (V) improve outcome in CLL. I rarely eradicates measurable residual disease (MRD), whereas V (alone or with anti-CD20) can eradicate MRD permitting time limited therapy. Small studies suggest synergy between I and V, as I+V results in MRD negativity in many patients (pts). Aims: The primary aim was to compare the MRD eradication rate between I and I+V. Key secondary aims were IWCLL overall (ORR), complete response (CR) and safety. Methods: FLAIR (ISRCTN01844152), a phase III, randomised, controlled trial for previously untreated CLL requiring therapy by IWCLL criteria. Pts >75 yrs or with >20% 17p del were excluded. FLAIR was adapted in July 2017 to add two arms, I monotherapy and I+V. I was given at 420mg/day. For I+V, V was added after two months of I with dose escalation to 400mg/day over 5 weeks. The duration of therapy (DOT) was defined by MRD with treatment for up to 6 years. MRD was assessed centrally by flow cytometry, MRD negativity was defined as <1 CLL cell in 10,000 leucocytes (IWCLL criteria), was assessed in peripheral blood (PB) and bone marrow (BM) at 9 months post-randomisation, in PB at 12 months and then 6 monthly. When PB was MRD negative, this was repeated after 3 months and then in both PB & BM 3 months later. If PB & BM were negative the time to MRD negativity was calculated (treatment start to first MRD negative PB) and DOT was twice this. The earliest therapy could stop was 2 years post-randomisation. A formal interim analysis was performed when 50% pts in I and I+V arms had reached 2 yrs post-randomisation and a p-value of <0.005 was statistically significant. Results: 523 pts were randomised to I or I+V. We report the interim analysis in the first 274 pts (I [n=138] and I+V [n=136]) reaching 2 yrs post-randomisation from 83 UK Centres from 13/07/17 to 15/03/19. 72.3% male, median age 63 yrs (34.3% >65yo) and 40.9% Binet C. IGHV were available for 256 (93.4%) pts - 48.2% IGHV unmutated (≥98% homology to germline), 45.3% IGHV mutated and 9.1% Subset 2. Hierarchical FISH testing revealed 16.1% 11q del, 19% trisomy 12, 21.9% normal and 36.9% 13q del with 6.2% failed. The arms were well-balanced for all variables. For I+V arm, MRD negativity was achieved within 24 months in BM in 89/136 (65.4%) and PB in 97/136 (71.3%) compared to no pts for I (p<0.0001). MRD negativity for I+V in BM within 24 months was 51/64 (79.7%) for IGHV unmutated and 31/55 (56.4%) for IGHV mutated. At 9 months post-randomisation 49/136 (36%) I+V pts were MRD negative in BM and 56/136 (41.2%) negative in PB compared to 0/138 with I (p<0.0001). ORR at 9 months in 120/136 (88.2%) I+V pts and 119/138 (86.2%) I pts (p=0.6157). At 9 months CR in 81/136 (59.6%) for I+V and 11/138 (8%) for I (p<0.0001). For I+V CR at any time was 93.4%. At 24 months, 54/136 (39.7%) stopped I+V due to meeting MRD stopping criteria. SAEs were reported in 41.5% I+V and 38.2% I pts. Infectious SAEs 14.8% vs 19.9% and cardiac SAEs 11.9% vs 8.1% of pts for I+V & I respectively. Laboratory TLS was reported in 6/136 (4.4%) of I+V pts and none with I. There were no cases of clinical TLS. Most frequent any grade AEs within 12 months of randomisation differing between I+V & I were diarrhoea (52.6% I+V pts, 29.4% I), anaemia (28.9% vs 16.9%), leucopenia (36.3% vs 8.8%), thrombocytopenia (23.7% vs 14%). Leucopenia was the only grade ≥3 SAE reported in >10% of pts (27.4% I+V and 5.1% I). Image:Summary/Conclusion: Ibrutinib plus venetoclax is an effective and well tolerated combination resulting in a high rate of MRD negativity in blood (71.9%) and marrow (65.4%) in the first 2 years of treatment.
Source: HemaSphere
Authors: P. Hillmen, A. Pitchford, A. Bloor, A. Pettitt, P. Patten, F. Forconi, A. Schuh, C. Fox, N. Elmusharaf, S. Gatto, B. Kennedy, J. Gribben, N. Pemberton, O. Sheehy, G. Preston, D. Howard, A. Hockaday, D. Cairns, S. Jackson, N. Greatorex, N. Webster, S. Dalal, J. Shingles, K. Cwynarski, S. Paneesha, D. Allsup, A. Rawstron, T. Munir
Institutions: St James's University Hospital, Cancer Research UK Clinical Trials Unit, University of Manchester, Clatterbridge Cancer Centre NHS Foundation Trust, King's College Hospital, University of Southampton, University of Oxford, Oxford University Hospitals NHS Trust, Nottingham University Hospitals NHS Trust, University Hospital of Wales, Leicester Royal Infirmary, St Bartholomew's Hospital, Worcestershire Acute Hospitals NHS Trust, Belfast City Hospital, Aberdeen Royal Infirmary, University College London, Heartlands Hospital, Castle Hill Hospital
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,480
OpenAlex ID: W4283385103