IGHV Unmutated Status, Low Tumor Lysis Risk Disease and BRAF Mutated Status Are Predictors for Early MRD Responders Treated with MRD Defined Ibrutinib with Venetoclax: Report of the UK NCRI FLAIR Study
Authors: Munir Talha , Varghese Abraham Mullasseril , Bloor Adrian , Allsup David , Cwynarski Kate , Pettitt Andrew , Paneesha Shankara , Fox Christopher P , Eyre Toby A. , Forconi Francesco , Elmusharaf Nagah , Kennedy Ben , Gribben Prof. John G. , Pemberton Nicholas , Sheehy Oonagh , Preston Gavin , Schuh Anna , Hockaday Anna , Cairns David A. , Jackson Sharon , Greatorex Natasha , Girvan Sean , Bell Sue , Stones David , McWhirter Nichola , Dalal Surita , Rawstron Andrew , Patten Piers , Hillmen Peter 
Published: December 2024

Introduction:
Ibrutinib (I), irreversible Btk inhibitor, and venetoclax (V), Bcl-2 inhibitor, have both improved outcomes in CLL in numerous clinical trials compared to chemoimmunotherapy. V has been approved for CLL alone or combined with I or CD20 antibodies. I and V target two key pathophysiological pathways in CLL and the combination results in synergistic mechanism of action. FLAIR reported improved PFS and OS with MRD defined I+V as compared to FCR. In this analysis, we ascertained the factors driving CLL patients achieving early vs late MRD negativity with I+V combination in FLAIR study.
Methods:
FLAIR (ISRCTN01844152) is an ongoing, phase III, multicentre, randomised, controlled, open, parallel group trial for untreated CLL. FLAIR was adapted in July 2017 to add two arms, I monotherapy and I+V compared to FCR. In I+V after 2 months of I, V was added with dose escalation to 400mg/day over the next month and then I+V for up to 6 years. TLS risk was assessed prior to introduction of venetoclax, and the duration of I+V was defined by MRD. PB and BM MRD was assessed at 9 months, PB MRD was assessed at 12 months and then every 6 months. If PB was MRD negative, then it was repeated after 3 months and at 6 months in PB and BM. If both were MRD negative, then the initial MRD negative PB was considered the time to MRD negativity, and duration of therapy was defined as twice that period. Therefore, the earliest a patient could stop therapy was at 2 years. Patients who attained early MRD negativity (within a year) were compared with patients who attained late response (beyond 1 years) or no response in terms or MRD attainment. Logistic regression for the achievement of early MRD response by clinical, laboratory and genetic factors were calculated using standard methods.
Results:
260 patients were randomised to I+V arm of FLAIR study. 71.5% male, median age 62 years (range (55-67), 31.2 % &gt;65 years, 41.9 % Binet Stage C and 69.6% with WHO performance status 0. TLS risk was established in all patients after ibrutinib debulking and just before venetoclax introduction. IGHV data was available for 216 patients with 47.3 % IGHV unmutated (≥98% homology to germline), 35.8% mutated and 5% with subset 2. Hierarchical FISH testing revealed 17.3 % 11q del, 21.9 % trisomy 12, 20.0 % normal and 33.5 % 13q del. DNA sequencing using an Illumina MiSeq platform showed mutation frequency ranging from 0.1-18.8% with mutations in SF3B1 (11.9%), ATM (15.7%), NOTCH1 (11.1%), MYD88 (2.6%), POT1 (4.2%), BRAF (5%) and RPS15 (4.6%) being the most frequent. One hundred and thirteen (43.4%) attained MRD negativity at the end of 1 year, another 21 (8.1%) attained by 18 months and 10 (3.8%) patients attained it at the end of 2 years. Multiple predictor variables to calculate logistic regression on early MRD attainment including age, sex, IGHV mutational status, 11q del, trisomy 12, 13q del, normal karyotype, tumor lysis syndrome (TLS) risk, spleen size , β2 macroglobulin, nodal size, WHO performance status, mutation in TP53, SF3B1, ATM, NOTCH1, MYD88, POT1, BRAF, RPS15, BIRC3, TRAF3, CREBBP, MED12, ARID1A, NOTCH2 and FBXW7 showed early attainment of MRD negativity in low TLS risk [low vs. medium/ high odds ratio (OR) 1.82 (95% confidence interval (CI) 1.00, 3.31), p=0.0484], unmutated IGHV [ mutated vs. unmutated OR 0.44 (95% CI 0.25, 0.75), p=0.0026] and BRAF mutated patients [mutation vs. no mutation [OR 5.76 (95% CI 1.20, 27.70), p=0.0289].
Conclusion:
FLAIR trial has shown that I+V is a highly effective combination in attaining early MRD negativity in certain CLL sub-group. Low TLS risk, unmutated IGHV status and BRAF mutation are predictors of early MRD attainment in CLL with this combination. Further in-depth analysis will be presented at ASH 2024.