Importance:Frequent prophylactic intravitreal anti-vascular endothelial growth factor injections can reduce risk of progression to vision-threatening complications in nonproliferative diabetic retinopathy (NPDR). A refillable drug delivery system for continuous intraocular ranibizumab release could offer less frequent treatment regimens. Objective:To evaluate the Port Delivery System (PDS) with ranibizumab, 100 mg/mL, with refill-exchange procedures every 36 weeks (PDS Q36W), vs no PDS (control) in moderately severe to severe NPDR without center-involved diabetic macular edema (CI-DME), monitoring both groups every 4 weeks. Design, Setting, and Participants:This was a randomized clinical trial at 50 US investigational sites. Participants aged 18 years or older with moderately severe or severe NPDR (Diabetic Retinopathy Severity Scale [DRSS] level 47 or 53) secondary to type 1 or 2 diabetes were eligible. Data analysis was performed from August 10, 2020, to October 3, 2022. Intervention:Participants were randomized (unmasked) 5:3 to PDS Q36W vs control. Both groups could receive intravitreal ranibizumab injections if CI-DME, proliferative diabetic retinopathy (PDR), or anterior segment neovascularization (ASNV) developed. Main Outcomes and Measures:Proportion of participants with an improvement of at least 2 levels in Early Treatment Diabetic Retinopathy Study DRSS from baseline at week 52. Results:A total of 174 participants (mean [SD] age, 53.9 [11.7] years; 74 [42.5%] female) were randomized to PDS Q36W (n = 106) or control (n = 68). At week 52, 80.1% of those receiving PDS Q36W vs 9.0% of control participants had at least a 2-step DRSS improvement from baseline (difference, 71.1% [95% CI, 61.0% to 81.2%]; P < .001). Secondary outcomes included rate of development of CI-DME, PDR, or ASNV through week 52 (PDS Q36W, 7.1%; control, 47.0%; hazard ratio, 0.12 [95% CI, 0.05 to 0.28]; P < .001) and best-corrected visual acuity (BCVA) change from baseline to week 52 (+1.4 letters [95% CI, -0.5 to 3.3 letters] for those receiving PDS Q36W vs -2.6 letters [95% CI, -5.0 to -0.1 letters] for control participants; difference, 4.0 letters [95% CI, 0.9 to 7.1 letters]; P = .01). The PDS Q36W group had a transient BCVA decrease of 7.4 letters (95% CI, -10.3 to -4.5 letters) at 4 weeks after implantation, resolving 8 weeks later. Ocular adverse events of special interest occurred in 17 of 105 participants (16.2%) receiving PDS Q36W (cataract, 7 participants [6.7%]; vitreous hemorrhage, 6 participants [5.7%]; conjunctival bleb, conjunctival retraction, and hyphema, each 2 participants [1.9%]; conjunctival erosion and retinal detachment, each 1 participant [1.0%]), with no endophthalmitis reported through week 52. Conclusions and Relevance:At 1 year, PDS Q36W resulted in substantially more participants achieving at least a 2-step DRSS improvement and a reduced risk of developing CI-DME, PDR, or ASNV compared with control participants, with safety outcomes consistent with previous reports. These findings should be balanced with the transient, postoperative decrease in BCVA 4 through 12 weeks after implantation and the need for longer-term BCVA and safety outcomes. Trial Registration:ClinicalTrials.gov Identifier: NCT04503551.

BACKGROUND:An interim analysis of progression-free survival in this trial showed that ibrutinib-venetoclax was superior to fludarabine-cyclophosphamide-rituximab (FCR) among patients with chronic lymphocytic leukemia (CLL). Whether ibrutinib-venetoclax is more effective than ibrutinib alone is unclear. METHODS:In this phase 3, multicenter, open-label trial, we randomly assigned patients with CLL to receive ibrutinib-venetoclax, ibrutinib alone, or FCR. The primary end points were undetectable measurable residual disease (MRD) in bone marrow within 2 years in the ibrutinib-venetoclax group as compared with the ibrutinib-alone group and progression-free survival in the ibrutinib-venetoclax group as compared with the FCR group. A powered secondary end point was progression-free survival in the ibrutinib-venetoclax group as compared with the ibrutinib-alone group. Other secondary end points included overall survival. RESULTS:A total of 172 of the 260 participants (66.2%) in the ibrutinib-venetoclax group had undetectable MRD in bone marrow within 2 years, as compared with none of the 263 participants in the ibrutinib-alone group (P<0.001) and 127 of the 263 participants (48.3%) in the FCR group. With a median follow-up of 62.2 months, disease progression or death occurred in 18 participants (6.9%) in the ibrutinib-venetoclax group, as compared with 59 (22.4%) in the ibrutinib-alone group (hazard ratio, 0.29; 95% confidence interval [CI], 0.17 to 0.49; P<0.001) and 112 (42.6%) in the FCR group (hazard ratio, 0.13; 95% CI, 0.08 to 0.21; P<0.001). Progression-free survival at 5 years was 93.9% with ibrutinib-venetoclax, 79.0% with ibrutinib alone, and 58.1% with FCR. Death occurred in 11 participants (4.2%) in the ibrutinib-venetoclax group, as compared with 26 (9.9%) in the ibrutinib-alone group (hazard ratio, 0.41; 95% CI, 0.20 to 0.83) and 39 (14.8%) in the FCR group (hazard ratio, 0.26; 95% CI, 0.13 to 0.50). Sudden death occurred in 3, 8, and 4 participants in the ibrutinib-venetoclax, ibrutinib-alone, and FCR groups, respectively. CONCLUSIONS:With extended follow-up and increased enrollment, our trial showed that undetectable MRD and extended progression-free survival were more common with ibrutinib-venetoclax than with ibrutinib alone or FCR. The results for overall survival were also consistent with a benefit of ibrutinib-venetoclax. (Funded by Cancer Research UK and others; FLAIR ISRCTN Registry number, ISRCTN01844152; EudraCT number, 2013-001944-76.).

Introduction: The most effective chemoimmunotherapy (CIT) in previously untreated CLL is the combination of fludarabine, cyclophosphamide and rituximab (FCR). Ibrutinib (I), the first irreversible inhibitor of Bruton's tyrosine kinase approved for CLL, has improved outcomes in numerous clinical trials compared to different CIT regimens. Methods: FLAIR (ISRCTN01844152) is an ongoing, phase III, multicentre, randomised, controlled, open, parallel group trial for previously untreated CLL requiring therapy according to the IWCLL 2008 guidelines. Patients over 75 years or with >20% 17p-deleted cells were excluded. Participants were randomised on a 1:1 basis to receive 6 cycles of FCR (oral fludarabine 24mg/m 2/day for 5 days, oral cyclophosphamide 150mg/m 2/day for 5 days with IV rituximab [375 mg/m 2 on day 1/2 of cycle 1; 500 mg/m 2 on day 1 of cycles 2-6]) every 28-days, or IR (Ibrutinib [420mg/day] plus rituximab [6 doses as for FCR]) given for up to 6 years, with stratification by disease stage, age, gender and centre. The primary endpoint was to assess whether IR was superior to FCR in terms of investigator-assessed PFS. Secondary endpoints included overall survival (OS); attainment of undetectable MRD; response to therapy; safety and toxicity; health-related quality of life and cost-effectiveness. A formal interim analysis of this part of FLAIR was presented at ASH 2021 and published in Lancet Oncology. Here we report the final updated results of IR vs FCR. Results: A total of 771 patients were randomised (385 to FCR and 386 to IR) from 113 UK centres between 9/19/2014 and 7/19/2018. The data was locked on 06/23/2025; 73.3% were male, median age was 63 years (33.3% >65yo) and 43.6% were Binet Stage C. IGHV data was available for 725 (94.0%) patients with 50.2% IGHV unmutated (uIGHV), 38.0% IGHV mutated (mIGHV) and 5.8% Subset 2. Hierarchical FISH testing revealed 0.4% 17p del, 15.4% ATM deletion, 12.3% trisomy 12, 29.7% normal and 35.0% 13q del. The arms were well-balanced for disease variables. With a median follow-up of 97 (IQR: 86,108) months, IR had a superior PFS compared to FCR (median PFS is 112 months for IR versus 80 months for FCR; HR: 0.53; p<0.001). The PFS was significantly better for IR in patients with uIGHV CLL (HR: 0.45; p<0.001), but not for patients with mIGHV CLL at this follow-up (HR: 0.74; p=0.130). There was a significant difference in OS between the two arms with IR proving superior (HR: 0.66; p=0.014) with a total of 86 deaths in FCR arm (including 7 from CLL, 9 Richter transformation [RT], 8 AML/MDS, 8 COVID-19 and 5 cardiac/sudden) and 60 in the IR arm (including 7 CLL, 4 RT, 1 AML/MDS, 7 COVID-19 and 11 cardiac/sudden). The OS was significantly better for IR in patients with uIGHV CLL (HR: 0.58; p=0.0132), but not for patients with mIGHV CLL at this follow-up (HR: 0.78; p=0.4102). 7-year OS estimates are FCR: 81.1% and IR: 87.5%, uIGHV: FCR 76.1% - IR 85.2%, mIGHV: FCR 87.3% - IR 89.5%. Second line treatment was initiated for 149 patients after FCR (including 87 BTKi, 41 venetoclax+R [Ven-R], 3 Bendamustine -R [BR] and 5 CHOP-R []) and 99 after IR (including 8 FCR, 68 Ven-R, 3 BR, 3 CHOP-R [RT], 1 ABVD [Hodgkin's]). 243 patients completed 6 years of treatment of IR. 70/243 patients have finished six years of I on FLAIR and have been enrolled on STATIC (ISRCTN51675454) where patients are randomised to continuous vs intermittent therapy with ibrutinib. Overall, 80.1% of patients have received targeted therapies for CLL progression after . SAEs were reported in 54% of patients on FCR and 60.7% on IR. Notable differences for SAEs by organ class for FCR vs IR: infections in 33.6% of patients vs 33.1%; blood and lymphatic in 20.4% vs 12%; and cardiac in 1.1% vs 10.7%. With current follow-up, there were 16 sudden or cardiac deaths: 11 IR and 5 FCR. A history of hypertension or cardiac disease was observed in 7 of the 11 cardiac/sudden deaths in the IR arm. There were 24 cases of secondary MDS/AML: 22 in the FCR arm and 2 in the IR arm. Conclusion:Ibrutinib plus rituximab resulted in a superior PFS and OS compared to FCR, despite use of modern targeted agents as salvage therapy for patients progressing on FCR. With longer follow-up, continuous IR leads to improved outcomes especially in uIGHV patients whilst no new safety signals emerge with longer follow-up on ibrutinib. This data re-affirms the use of targeted agents in treatment-naive CLL.

Frequent prophylactic intravitreal anti–vascular endothelial growth factor injections can reduce risk of progression to vision-threatening complications in nonproliferative diabetic retinopathy (NPDR). A refillable drug delivery system for continuous intraocular ranibizumab release could offer less frequent treatment regimens. To evaluate the Port Delivery System (PDS) with ranibizumab, 100 mg/mL, with refill-exchange procedures every 36 weeks (PDS Q36W), vs no PDS (control) in moderately severe to severe NPDR without center-involved diabetic macular edema (CI-DME), monitoring both groups every 4 weeks. This was a randomized clinical trial at 50 US investigational sites. Participants aged 18 years or older with moderately severe or severe NPDR (Diabetic Retinopathy Severity Scale [DRSS] level 47 or 53) secondary to type 1 or 2 diabetes were eligible. Data analysis was performed from August 10, 2020, to October 3, 2022. Participants were randomized (unmasked) 5:3 to PDS Q36W vs control. Both groups could receive intravitreal ranibizumab injections if CI-DME, proliferative diabetic retinopathy (PDR), or anterior segment neovascularization (ASNV) developed. Proportion of participants with an improvement of at least 2 levels in Early Treatment Diabetic Retinopathy Study DRSS from baseline at week 52. A total of 174 participants (mean [SD] age, 53.9 [11.7] years; 74 [42.5%] female) were randomized to PDS Q36W (n = 106) or control (n = 68). At week 52, 80.1% of those receiving PDS Q36W vs 9.0% of control participants had at least a 2-step DRSS improvement from baseline (difference, 71.1% [95% CI, 61.0% to 81.2%]; P < .001). Secondary outcomes included rate of development of CI-DME, PDR, or ASNV through week 52 (PDS Q36W, 7.1%; control, 47.0%; hazard ratio, 0.12 [95% CI, 0.05 to 0.28]; P < .001) and best-corrected visual acuity (BCVA) change from baseline to week 52 (+1.4 letters [95% CI, –0.5 to 3.3 letters] for those receiving PDS Q36W vs –2.6 letters [95% CI, –5.0 to –0.1 letters] for control participants; difference, 4.0 letters [95% CI, 0.9 to 7.1 letters]; P = .01). The PDS Q36W group had a transient BCVA decrease of 7.4 letters (95% CI, –10.3 to –4.5 letters) at 4 weeks after implantation, resolving 8 weeks later. Ocular adverse events of special interest occurred in 17 of 105 participants (16.2%) receiving PDS Q36W (cataract, 7 participants [6.7%]; vitreous hemorrhage, 6 participants [5.7%]; conjunctival bleb, conjunctival retraction, and hyphema, each 2 participants [1.9%]; conjunctival erosion and retinal detachment, each 1 participant [1.0%]), with no endophthalmitis reported through week 52. At 1 year, PDS Q36W resulted in substantially more participants achieving at least a 2-step DRSS improvement and a reduced risk of developing CI-DME, PDR, or ASNV compared with control participants, with safety outcomes consistent with previous reports. These findings should be balanced with the transient, postoperative decrease in BCVA 4 through 12 weeks after implantation and the need for longer-term BCVA and safety outcomes. ClinicalTrials.gov Identifier: NCT04503551

Background The approval of Bruton tyrosine kinase (BTK) inhibitors in patients with previously untreated chronic lymphocytic leukaemia (CLL) was based on trials which compared ibrutinib with alkylating agents in patients considered unfit for fludarabine, cyclophosphamide, and rituximab, the most effective chemoimmunotherapy in CLL. We aimed to assess whether ibrutinib and rituximab is superior to fludarabine, cyclophosphamide, and rituximab in terms of progression-free survival.Methods This study is an interim analysis of FLAIR, which is an open-label, randomised, controlled, phase 3 trial in patients with previously untreated CLL done at 101 UK National Health Service hospitals. Eligible patients were between 18 and 75 years of age with a WHO performance status of 2 or less and disease status requiring treatment according to International Workshop on CLL criteria. Patients with greater than 20% of their CLL cells having the chromosome 17p deletion were excluded. Patients were randomly assigned (1:1) by means of minimisation (Binet stage, age, sex, and centre) with a random element in a web-based system to ibrutinib and rituximab (ibrutinib administered orally at 420 mg/day for up to 6 years; rituximab administered intravenously at 375 mg/m(2) on day 1 of cycle 1 and at 500 mg/m(2) on day 1 of cycles 2-6 of a 28-day cycle) or fludarabine, cyclophosphamide, and rituximab (fludarabine 24 mg/m(2) per day orally on day 1-5, cyclophosphamide 150 mg/m(2) per day orally on days 1-5; rituximab as above for up to 6 cycles). The primary endpoint was progression-free survival, analysed by intention to treat. Safety analysis was per protocol. This study is registered with ISRCTN, ISRCTN01844152, and EudraCT, 2013-001944-76, and recruiting is complete.Findings Between Sept 19, 2014, and July 19, 2018, of 1924 patients assessed for eligibility, 771 were randomly assigned with median age 62 years (IQR 56-67), 565 (73%) were male, 206 (27%) were female and 507 (66%) had a WHO performance status of 0. 385 patients were assigned to fludarabine, cyclophosphamide, and rituximab and 386 patients to ibrutinib and rituximab. After a median follow-up of 53 months (IQR 41-61) and at prespecified interim analysis, median progression-free survival was not reached (NR) with ibrutinib and rituximab and was 67 months (95% CI 63-NR) with fludarabine, cyclophosphamide, and rituximab (hazard ratio 0.44 [95% CI 0.32-0.60]; p<0.0001). The most common grade 3 or 4 adverse event was leukopenia (203 [54%] patients in the fludarabine, cyclophosphamide, and rituximab group and 55 [14%] patients in the ibrutinib and rituximab group. Serious adverse events were reported in 205 (53%) of 384 patients receiving ibrutinib and rituximab compared with 203 (54%) of 378 patients receiving fludarabine, cyclophosphamide, and rituximab. Two deaths in the fludarabine, cyclophosphamide, and rituximab group and three deaths in the ibrutinib and rituximab group were deemed to be probably related to treatment. There were eight sudden unexplained or cardiac deaths in the ibrutinib and rituximab group and two in the fludarabine, cyclophosphamide, and rituximab group.Interpretation Front line treatment with ibrutinib and rituximab significantly improved progression-free survival compared with fludarabine, cyclophosphamide, and rituximab but did not improve overall survival. A small number of sudden unexplained or cardiac deaths in the ibrutinib and rituximab group were observed largely among patients with existing hypertension or history of cardiac disorder.

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 (<1 CLL cell in 10,000 [flow cytometry]). PB MRD was assessed at 12 mo and then 6 monthly and if negative, was repeated at 3 mo and 6 mo in PB and BM. If all were MRD neg, then the duration of I+V was double the time between start of I+V and the initial MRD neg PB (I+V duration: 2 to 6 years). The primary endpoint for I+V vs FCR was investigator-assessed PFS. Key secondary endpoints presented were OS, IWCLL response, MRD and safety. Appropriate endpoints were analysed by CLL prognostic sub-groups. Results: 523 pts were randomised to FCR (n=263) and I+V (n=260) at 96 UK Centers from 07/20/2017 to 03/24/2021. Data-lock on 05/23/2023. 71.3% male, median age 62 yrs (31.2% >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<0.0001; Fig). This result was consistent for gender, age or stage. At 3 yrs 2.8% had progressed on I+V compared to 23.2% on FCR. There have been 34 deaths (25 FCR and 9 I+V) resulting in improved overall survival for I+V vs FCR: HR 0.31 (95% CI: [0.15, 0.67]; p=0.0029; Fig). At 3 years 2.0% of I+V pts had died compared to 7.0% for FCR. At 9 months (3 mo post-FCR) 48.3% FCR pts became MRD neg in BM compared to 41.5% for I+V. However, with continued I+V more pts became MRD neg: the odds of MRD negativity at any time for I+V vs FCR were 2.03 (95% CI: [1.43, 2.89]; P<0.001) in BM and 3.91 (95% CI: [2.55, 6.00]; P<0.001) in PB. 90.6% pts achieved PB MRD negativity at up to 5 yrs I+V and 88% of these were BM MRD negative 6 mo after their first PB MRD neg result. At 9 months a higher proportion achieved CR and overall response for I+V; CR - FCR 49.0% (95% CI: [42.9%, 55.3%]), I+V 59.2% (53%, 65.3%); ORR - FCR 76.4% (70.8%, 81.4%); I+V 86.5% (81.8%, 90.4%). This difference was greater for best response at any time: ORR 83.7% (78.6%, 87.9%) for FCR vs 95.4% (92.1%, 97.6%) for I+V; CR 71.5% (65.6%, 76.9%) for FCR vs 92.3% (88.4%, 95.2%) for I+V. The odds ratios estimate to achieve CR with I+V vs FCR is 1.51 (95% CI: [1.07, 2.14]; p<0.05). Responses and outcomes by FISH and IGHV will be presented. SAEs were reported in 252 (51.3%) pts (129 FCR vs 123 I+V). Notable SAEs by organ class for FCR vs I+V were: infections 18.8% of FCR pts vs 22.2% for I+V; blood and lymphatic 31% vs 5%; and cardiac in 0.4% vs 10.7%. 4 pts had sudden or cardiac deaths - 2 FCR and 2 I+V. 69 other cancers were diagnosed (45 in FCR, 24 in I+V) in 51 pts (34 FCR, 17 I+V). The incidence of other cancers per 100 pt-years was greater for FCR than I+V; 5.4 (95% CI: [5.11, 5.68]) vs. 2.6 (2.40, 2.79). There were 7 cases of MDS/AML with FCR and 1 with I+V. Conclusion: Ibrutinib plus venetoclax significantly improved progression-free and overall survival compared to FCR in untreated CLL. Using MRD to direct the duration of I+V maximizes outcome with 97.2% progression free survival at 3 years The efficacy seen in FLAIR is superior to previous Phase III CLL trials indicating that I+V with duration guided by MRD is a new gold standard for CLL treatment.

Summary The GA101 (obinutuzumab) monocLonal Antibody as Consolidation Therapy In chronic lymphocytic leukaemia (CLL) (GALACTIC) was a seamless phase II/III trial designed to test whether consolidation with obinutuzumab is safe and eradicates minimal residual disease (MRD) and, subsequently, whether this leads to prolonged progression‐free survival (PFS) in patients with CLL who have recently responded to chemo‐immunotherapy. Patients with a response 3–24 months after chemotherapy were assessed for MRD. MRD‐positive patients were randomised to receive consolidation therapy with obinutuzumab or no consolidation. The trial closed after the phase II part due to slow recruitment. In all, 48 patients enrolled of whom 19 were MRD negative and were monitored. Of the 29 MRD‐positive patients, 14 were randomised to receive consolidation and 15 to no consolidation. At 6 months after randomisation, 10 and 13 consolidated patients achieved MRD negativity by flow cytometry (sensitivity 10 −4 ) in bone marrow and peripheral blood respectively. PFS was significantly better in consolidated patients compared to non‐consolidated patients ( p = 0.001). No difference was observed in PFS, overall survival or duration of MRD negativity when comparing the 10 MRD‐negative patients after consolidation with the 19 MRD‐negative patients in the monitoring group. Common adverse events in the consolidation arm were thrombocytopenia, infection, and cough. Only 1% of events were infusion‐related reactions. This observation provides further evidence that consolidation to achieve MRD negativity improves outcomes in CLL and that obinutuzumab is well tolerated in patients with low levels of disease.

American Journal of HematologyVolume 97, Issue 5 p. E168-E171 CORRESPONDENCEFree Access Long-term follow-up of 415 patients with chronic lymphocytic leukemia treated with fludarabine and cyclophosphamide-based chemoimmunotherapy in the frontline ADMIRE and ARCTIC trials: A comprehensive assessment of prognostic factors David John Allsup, Corresponding Author David John Allsup [email protected] orcid.org/0000-0001-6159-6109 Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK Correspondence David John Allsup, Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK. Email: [email protected]Search for more papers by this authorZoe Craig, Zoe Craig Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorDavid Cairns, David Cairns Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorDena Howard, Dena Howard Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorAnna Hockaday, Anna Hockaday Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorAdrian Bloor, Adrian Bloor The Christie NHS Foundation Trust, Manchester, UKSearch for more papers by this authorZarni Soe, Zarni Soe St James Institute of Oncology, Leeds, UKSearch for more papers by this authorChristopher Pepper, Christopher Pepper Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, UKSearch for more papers by this authorValter Gattei, Valter Gattei Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano (PN), ItalySearch for more papers by this authorAntonella Zucchetto, Antonella Zucchetto orcid.org/0000-0003-3678-5957 Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano (PN), ItalySearch for more papers by this authorPauline Robbe, Pauline Robbe Laboratory for Transcriptome Technology, RIKEN Centre for Integrative Medical Sciences, Yokohama, JapanSearch for more papers by this authorRuth Clifford, Ruth Clifford Department of Haematology, University Hospital Limerick, Limerick, IrelandSearch for more papers by this authorAnna Schuh, Anna Schuh Department of Oncology, University of Oxford, Oxford, UKSearch for more papers by this authorTalha Munir, Talha Munir St James Institute of Oncology, Leeds, UKSearch for more papers by this authorAndrew Rawstron, Andrew Rawstron Haematological Malignancy Diagnostic Service, St James Hospital, Leeds, UKSearch for more papers by this authorPeter Hillmen, Peter Hillmen St James Institute of Oncology, Leeds, UK Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UKSearch for more papers by this author David John Allsup, Corresponding Author David John Allsup [email protected] orcid.org/0000-0001-6159-6109 Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK Correspondence David John Allsup, Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK. Email: [email protected]Search for more papers by this authorZoe Craig, Zoe Craig Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorDavid Cairns, David Cairns Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorDena Howard, Dena Howard Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorAnna Hockaday, Anna Hockaday Clinical Trials Research Unit, University of Leeds, Leeds, UKSearch for more papers by this authorAdrian Bloor, Adrian Bloor The Christie NHS Foundation Trust, Manchester, UKSearch for more papers by this authorZarni Soe, Zarni Soe St James Institute of Oncology, Leeds, UKSearch for more papers by this authorChristopher Pepper, Christopher Pepper Clinical and Experimental Medicine, Brighton and Sussex Medical School, Brighton, UKSearch for more papers by this authorValter Gattei, Valter Gattei Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano (PN), ItalySearch for more papers by this authorAntonella Zucchetto, Antonella Zucchetto orcid.org/0000-0003-3678-5957 Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano (PN), ItalySearch for more papers by this authorPauline Robbe, Pauline Robbe Laboratory for Transcriptome Technology, RIKEN Centre for Integrative Medical Sciences, Yokohama, JapanSearch for more papers by this authorRuth Clifford, Ruth Clifford Department of Haematology, University Hospital Limerick, Limerick, IrelandSearch for more papers by this authorAnna Schuh, Anna Schuh Department of Oncology, University of Oxford, Oxford, UKSearch for more papers by this authorTalha Munir, Talha Munir St James Institute of Oncology, Leeds, UKSearch for more papers by this authorAndrew Rawstron, Andrew Rawstron Haematological Malignancy Diagnostic Service, St James Hospital, Leeds, UKSearch for more papers by this authorPeter Hillmen, Peter Hillmen St James Institute of Oncology, Leeds, UK Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UKSearch for more papers by this author First published: 02 February 2022 https://doi.org/10.1002/ajh.26483Citations: 1 David John Allsup and Zoe Craig co-first authors. Funding information: Health Technology Assessment Programme; Associazione Italiana Ricerca Cancro, Grant/Award Number: IG-21687; Progetto Ricerca Finalizzata, Grant/Award Numbers: RF-2018-12365790, PE-2016-02362756; Core Clinical Trials Unit Infrastructure, Grant/Award Number: C7852/A25447; Roche Products Ltd AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL To the Editor: Chemoimmunotherapy (CIT) with fludarabine, cyclophosphamide, and rituximab (FCR) has been the mainstay treatment of previously untreated chronic lymphocytic leukemia (CLL) for many years.1 A minority of FCR-treated patients are identified as a favorable risk group by the presence of mutated immunoglobulin heavy chain variable genes (M-IGHV), weak CD49d expression, long telomeres and post-therapy assessment of minimal residual disease (MRD).2-4 Most patients treated with FCR relapse, and this has driven the development of efficacious therapies targeting the B-cell receptor (BCRi) but exposes patients to risks such as hypertension and other cardiovascular toxicities.5 Therefore, there may remain a case for CIT in untreated patients with CLL with favorable features. We report the outcomes of previously untreated patients with CLL after prolonged follow-up following fludarabine and cyclophosphamide-based CIT in two phase II randomized controlled trials, ADMIRE and ARCTIC. ADMIRE compared FCR with fludarabine, cyclophosphamide, mitoxantrone, and rituximab (FCMR), while ARCTIC compared FCR with fludarabine, cyclophosphamide mitoxantrone, and reduced dose rituximab (FCM-minR). In addition to reporting long-term outcomes, we assessed a range of factors reported to be prognostic to identify robust markers associated with favorable outcomes. Treatment-related toxicities and premature discontinuation of therapy may be associated with inferior outcomes, so we assessed how these events impact patient outcomes. Methods including trial design and assessment of prognostic factors are presented as Supporting information Appendix S1. ADMIRE/ARCTIC provided outcome data on 415 previously untreated patients with CLL recruited between July 2009 and September 2012 (Supporting information Tables 1 and 2). Median follow-up is 84 months (interquartile range [IQR]: 72–94 months), median progression-free survival (PFS) is 66 months (95% confidence interval [CI] 56–72 months), and median overall survival (OS) is 108 months (95% CI 101 months-not reached) (Supporting information Figure 1A and B). There is no difference in PFS or OS between FCR and FCM-R (PFS adjusted hazard ratio [aHR] 1.09, 95% CI 0.80–1.49; OS aHR 0.95, 95% CI 0.62–1.47). For FCR and FCM-miniR, a small difference was observed for PFS but not OS (PFS aHR 1.35, 95% CI 1.00–1.84; OS aHR 1.01, 95% CI 0.65–1.57) (Supporting information Figures 2A and B). Five years postrandomization, 68.9% (95% CI 60.6%–75.9%) of patients with M-IGHV CLL were progression-free and 83.0% were alive (95% CI 75.8%–88.3%). Unadjusted Cox regression analysis found unmutated IGHV (UM-IGHV) is associated with shortened PFS and OS (PFS HR 2.62, 95% CI 1.92–3.57; OS HR 1.65, 95% CI 1.09–2.48) (Supporting information Figure 3A and B). Three months posttreatment, 169 patients (40.7%) were bone marrow (BM) MRD positive, 84.0% had a PFS event and 40.2% had an OS event during follow-up, compared to 36.6% and 21.0% who were MRD negative (n = 186). Unadjusted Cox regression analysis of MRD found that MRD positivity is associated with shortened PFS and OS (PFS HR 4.49, 95% CI 3.33–6.04; OS HR 2.35, 95% CI 1.59–3.47) (Supplementary Figure 4A and B). The combination of MRD positivity and UM-IGHV resulted in highly shortened PFS and OS compared to M-IGHV and MRD negativity (PFS HR 11.1, 95% CI 6.76–18.22; OS HR 3.45, 95% CI 1.94–6.13) (Supporting information Figure 5A and B). Univariable Cox regression analysis of PFS revealed UM-IGHV, 17p/11q deletion, TP53 mutations (mutTP53), and increasing international prognostic index for CLL (CLL-IPI) are associated with shortened PFS (Supporting information Table 3A). Increasing CD38 (% positive cells), CD49d (% positive cells), and decreasing CD20 (mean fluorescence intensity [MFI]), CCR6 (MFI and % positive cells) and LAIR1 (MFI) are also associated with shortened PFS (Supporting information Table 3B). Multivariable penalized Cox regression found IGHV, MRD, standardized CD49d (% positive cells) and deletion 17p (d17p) and/or mutTP53 are, in combination, most prognostic of PFS (Supporting information Table 3C). Univariable Cox regression analysis of OS found age greater than 65 years, positive direct coombes' test (DCT), UM-IGHV, d17p, mutTP53, and increasing CLL-IPI are associated with shortened OS (Supporting information Table 4A). Increasing CD49d (% positive cells), decreasing CCR6 (MFI), and LAIR1 (MFI) are associated with shortened OS (Supporting information Table 4B). Mutations in ATM, BIRC3, NOTCH1, and SF3B1 are not independently associated with PFS or OS. Multivariable penalized Cox regression found MRD, age, CD49d (% positive cells), DCT and d17p, and/or mutTP53 are, in combination, most prognostics of OS (Table 1). TABLE 1. Multivariable penalized Cox regression analysis of OS Parameter estimate Standard error Hazard ratio and 95% CI Number of times variable selected out of the 42 imputed data sets 3-month posttreatment BM MRD status Positive vs. negative 0.39 0.18 1.48 (1.04 to 2.1) 42 Age at randomization >65 vs. ≤65 years 0.129 0.15 1.14 (0.847 to 1.53) 42 Standardized CD49d (% of positive cells) 0.0737 0.0686 1.08 (0.941 to 1.23) 36 Direct Coombs test Positive vs. negative 0.0496 0.147 1.05 (0.788 to 1.4) 24 Deletion 17p and/or mutated TP53 Yes vs. no 0.098 0.146 1.1 (0.828 to 1.47) 24 Standardized LAIR1 −0.000638 0.0407 0.999 (0.923 to 1.08) 5 Mutated BIRC3 Yes vs. no 0.00785 0.0725 1.01 (0.874 to 1.16) 3 Mutated ATM Yes vs. no 0.00426 0.0316 1 (0.944 to 1.07) 1 Mutated NOTCH1 Yes vs. no 0.000673 0.0477 1 (0.911 to 1.1) 1 Note: Variables frequently selected from the imputed data sets by the penalized Cox model are more predictive of the outcome than those not selected or selected infrequently. Each selected variable contributes to predicting the outcome in combination with the other selected variables, even if it is not significantly associated with the outcome itself. Abbreviations: BM, bone marrow; MRD, minimal residual disease; OS, overall survival. The proportion of PFS and OS events is higher in those who experienced any grade 3 or 4 adverse event (AE), a hematological-related grade 3 or 4 AE, or an infection-related grade 3 or 4 AE (Supporting information Table 5), but the presence of any grade 3 or 4 AE or hematological-related grade 3 or 4 AEs are not associated with shortened PFS or OS (Supporting information Table 6A and B). However, the presence of infection-related grade 3 or 4 AEs are associated with both shortened PFS and OS (PFS aHR 1.52, 95% CI 1.07–2.27: OS HR 1.64, 95% CI 1.02–2.63) (Supporting information Figure 6A and B). Baseline IgA and IgG levels are not associated with grade 3 or 4 AEs, a hematological or an infection grade 3 or 4 AE (Supporting information Table 7A–C). One hundred twenty-two second cancers were diagnosed in 102 of the 415 patients and comprised Richter's transformations 12 (2.9%), acute myeloid leukemia/myelodysplasia (AML/MDS) 19 (4.6%), skin (nonmelanoma) 37 (8.9%), skin (melanoma) 9 (2.2%), and solid tumors 35 (8.4%). In those diagnosed with a second cancer, the median time to diagnosis from randomization was 34.5 months (IQR: 22, 60 months). For patients developing Richter's, there was no preponderance of poor prognostic features (Supporting information Table 8). In patients who developed AML/MDS, this was not associated with trial therapy and occurred at a median of 34.9 months (IQR: 23, 46 months) post-therapy. Of patients who developed AML/MDS three had received more than one line of therapy (Supporting information Table 9). Patients who receive three or less treatment cycles tend to be older, more likely to have d17p and more likely to be MRD positive (Supporting information Table 10). Receiving three or less treatment cycles is associated with shorter PFS, and OS (PFS aHR 2.66, 95% CI 1.73–4.07; OS aHR 2.62, 95% CI 1.65–4.17) (Supporting information Figure 7A and B). For PFS, only patients who prematurely discontinued therapy due to toxicity, without progression, were included in the analysis. Of 192 patients who experienced disease progression, 79 (41.1%) received further treatment with 70 (88.6%) receiving one line, 8 (10.1%) receiving two lines, and 1 (1.3%) receiving three lines of subsequent treatment. Of these, 46.3% received CIT, 37.5% received BCRi, 5% received BCRi with a BCL2 inhibitor, 13.8% received a monoclonal antibody and 3.8% received steroids. The proportion of patients treated with novel agents at relapse increased over the duration of follow-up with a corresponding decrease in CIT (Supporting information Figure 8). We report excellent long-term outcomes in patients with CLL treated with FC-based CIT in two UK clinical trials. With a median follow-up of 84 months, the PFS and OS are 65 and 108 months. Patients with favorable factors such as M-IGHV and nondisrupted TP53 have prolonged survival outcomes following FC-based CIT and the incorporation of BM-MRD following therapy further refines the identification of a cohort with prolonged survival. We assessed all available parameters previously described as prognostic in similar patient populations and identified multiple factors predictive of PFS and OS in univariable analysis. However, the parameters most predictive of PFS on multivariable analysis were CD49d, d17p, and mutTP53 combined with posttreatment BM-MRD. Likewise, multivariable analysis revealed age, DCT, and d17P/mutTP53 combined with posttreatment BM-MRD were most predictive for OS. Thus, a relatively simple combination of prognostic factors and MRD can identify a cohort with prolonged survival. Our results complement those of others who demonstrate that IGHV, d17p, mutTP53, and posttreatment MRD are prognostic following CIT and facilitate the identification of patients with prolonged survival.2, 4 In addition to assessing the prognostic power of established biomarkers we sought to assess the role of patient specific factors in responses to FC-based CIT. Our finding that infection-related AEs were associated with shortened survival could reflect the impact of infectious events in an immunosuppressed patient population or could be a surrogate for other comorbidities not captured within our data collection. It is likely that a combination of reduced dose intensity due to premature discontinuation of therapy with associated suboptimal disease control and the consequences of grade 3/4 infections could contribute to inferior outcomes for a subset of patients. CLL is associated with an increased risk of second malignancies, a risk exacerbated by treatment with regimens such as FC. After prolonged follow-up of around 10 years 25% of patients were diagnosed with at least one new malignancy. Our results confirm that second malignancies remain a significant concern in FC-treated patients and support the role of health promotion interventions known to reduce cancer. In conclusion, we find that treatment of CLL with FC-based CIT is associated with excellent long-term outcomes. We show that the main markers for long-term progression-free and overall survival are MRD, age, IGHV, CD49d, DCT, d17p, and mutTP53. The results presented in this paper further aid in the consideration of which patients with CLL may benefit from initial treatment with FCR as opposed to targeted therapy and who may need less intensive follow-up following completion of therapy. ACKNOWLEDGMENTS ADMIRE was a National Institute for Health Research (NIHR) Portfolio Study developed in association with the NCRI CLL Subgroup and funded by Roche Products Ltd. ARCTIC was funded by the NIHR Health Technology Assessment program. This work was also supported by Core Clinical Trials Unit Infrastructure from Cancer Research UK (C7852/A25447). We also acknowledge funding from Progetto Ricerca Finalizzata PE-2016-02362756 (to Valter Gattei), and RF-2018-12365790 (to Antonella Zucchetto), Italian Ministry of Health, Rome, Italy; Associazione Italiana Ricerca Cancro, Investigator Grant IG-21687 (to Valter Gattei). CONFLICT OF INTERESTS David John Allsup reports personal fees and research funding from Roche Pharmaceuticals. Peter Hillmen received research funding and speakers' fees from Roche Pharmaceuticals. Andrew Rawstron reports personal fees from Roche Pharmaceuticals. Dr. Munir reports personal fees from Roche Pharmaceuticals. Adrian Bloor reports personal fees, consultancy/advisory fees and speakers' fees from Roche Pharmaceuticals. Dena Howard is an employee of Roche Pharmaceuticals. ETHICS STATEMENT Both trials were approved by relevant institutional ethical committees and regulatory review bodies and were conducted in accordance with the Declaration of Helsinki and Good Clinical Practice. TRIAL REGISTRATION ADMIRE was registered as an International Standard Randomized Controlled Trial (ISRCTN42165735) and on the European Clinical Trials Database (EudraCT: 2008-006342-122-25). ARCTIC was registered as an International Standard Randomized Controlled Trial (ISRCTN16544962) and on the European Clinical Trials Database (EudraCT: 2009-010998-20). Supporting Information Filename Description ajh26483-sup-0001-Supinfo.docxWord 2007 document , 1.3 MB Appendix S1: Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. REFERENCES 1Thompson PA, Tam CS, O'Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. 2016; 127(3): 303- 309. 2Böttcher S, Ritgen M, Fischer K, et al. Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol. 2012; 30(9): 980- 988. 3Pepper AGS, Zucchetto A, Norris K, et al. Combined analysis of IGHV mutations, telomere length and CD49d identifies long-term progression-free survivors in TP53 wild-type CLL treated with FCR-based therapies. Leukemia. 2022; 36(1): 271- 274. 4Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. 2016; 127(2): 208- 215. 5Caldeira D, Alves D, Costa J, Ferreira JJ, Pinto FJ. Ibrutinib increases the risk of hypertension and atrial fibrillation: systematic review and meta-analysis. PloS One. 2019; 14(2):e0211228. Citing Literature Volume97, Issue5May 2022Pages E168-E171 ReferencesRelatedInformation

Introduction: Ibrutinib (I), the first irreversible inhibitor of Bruton's tyrosine kinase, and venetoclax (V), the first approved Bcl-2 inhibitor, have both improved outcomes in CLL in numerous clinical trials compared to CIT. Theoretically ibrutinib could be more effective in IGHV unmutated CLL as these cases appear to be more dependent on B-cell receptor signalling. Phase II and phase III randomised trials suggested that using I+V in combination could result in high proportions of MRD negativity, particularly in IGHV unmutated CLL. We therefore hypothesize that I+V may be more effective in IGHV unmutated CLL. Methods: FLAIR is an ongoing, phase III, multicentre, randomised, controlled, open, parallel group trial for previously untreated CLL requiring therapy according to IWCLL. TP53 deleted patients were excluded from recruitment. FLAIR was adapted in July 2017 to add two arms, I monotherapy and I+V. I was given at 420mg/day for up to 6 years. In the I+V arm after the first 2 months of I, V was added with dose escalation to 400mg/day over the next month and then the combination was also given for up to a total of 6 years. In both arms the duration of therapy was defined by MRD status. PB and BM MRD was assessed at 9 months post-randomisation, PB MRD was then assessed at 12 months and every 6 months thereafter. When PB is MRD negative, it is repeated after 3 months and, if negative, PB and BM MRD are performed 3 months later. If both are MRD negative, then the initial MRD negative PB was considered the time to MRD negativity, and the planned duration of therapy will be twice that period. Therefore, the earliest a patient could stop therapy was 2 years post-randomisation. The primary endpoint for I vs I+V in FLAIR was to assess the rate of MRD eradication between I and I+V within 2 months post-randomisation. Key secondary endpoints presented here are IWCLL response and safety. MRD was assessed in a central laboratory by multiparameter flow cytometry and MRD negativity was defined as less than 1 CLL cell in 10,000 leucocytes. A formal interim analysis for MRD was performed once 50% of participants in the I and I+V arms had reached 2 years post-randomisation. For the interim analysis, if the p-value is less than 0.005, the result is statistically significant. Here we present the analysis of MRD negativity in peripheral blood and bone marrow within 2 years of continuous I + V combination analysed by CLL prognostic sub-groups. Results: 523 patients were randomised on a 1:1 basis between I and I+V. Here we report the interim analysis of the eradication of MRD in the first 274 patients randomized between I (n=138) and I+V (n=136) reaching 2 years post-randomisation from 83 UK Centres between 13/07/2017 and 15/03/2019. The data was locked on 2/8/2022. 72.1% were male, median age was 63 years (34.3% >65yo) and 40.9% were Binet Stage C. IGHV data was available for 256 (93.4%) patients with 48.2% IGHV unmutated, 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 disease variables with no significance differences. In the I+V arm, 51/64 (79.7%) IGHV unmutated were MRD-negative in the BM within 24 months compared with 31/55 (56.4%) IGHV mutated and 3/8 (37.5%) subset 2. At 9 months post-randomisation, 34/64 (53.1%) of IGHV unmutated patients were MRD-negative in the BM as compared to 19/55(34.5%) IGHV mutated and 3/8 (37.5%) subset 2. In the PB, the MRD-negative rates in IGHV unmutated patients were 35/64 (54.7%) at 9 month and 53/64 (82.8%) at 24 months post-randomisation respectively. The MRD-negative rates in the PB for IGHV mutated patients improved from 18/55 (32.7%) at 9 months post-randomisation to 35/55 (63.6%) at 24 months. The probability of achieving MRD-negativity within 24 months of I + V was higher in IGHV unmutated CLL with an odds ratio of 3.60 [95% CI: 1.59, 8.15] in favour of unmutated vs mutated CLL (p-value 0.0022). 26/31 (83.9%) of patients with 11q (ATM) deletion achieved MRD negativity at 2 years but 22/31 (71%) of these patients were IGHV unmutated compared to only 41/103 (39.8%) of those without ATM deletion. Conclusion: Ibrutinib plus venetoclax leads to high MRD-negative rates in BM with 2 years of continuous therapy in both IGHV mutated and unmutated CLL. Patients with IGHV unmutated CLL are statistically more likely to achieve MRD negativity in the PB and BM with this combination as compared to IGHV mutated CLL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Abstract Introduction: Ibrutinib (Ibr) is the first approved irreversible BTK inhibitor. Cardiovascular (CV) adverse events, include hypertension (HT) and atrial fibrillation (AF). Ventricular tachyarrhythmias and sudden death have been reported possibly due to off target kinase inhibition. Several randomised Phase III trials have reported low numbers of cardiac deaths, sudden/unexplained deaths, and/or ventricular arrhythmias with Ibr including 9 deaths in RESONATE-2 Trial, 11 unexplained or unwitnessed deaths in Alliance Trial A041202 (med age 71; Ibr (n=7 [4%]), Ibr+ritux (IR; 4 [2%]), one death in the IR arm of ECOG1912 Trial (mean age 56.7) and 3 unexplained plus 5 cardiac deaths with BR + Ibr in the HELIOS trial (med age 64). Methods: FLAIR, a phase III, multicentre, randomised, controlled, open, trial recruiting 771 pts with untreated CLL requiring therapy. Pts were ≤75 years, considered fit for FCR and were randomized to IR or FCR. Pts with inadequately controlled symptomatic cardiac failure or unstable angina were excluded. We conducted ad hoc evaluations of the potential association of sudden or cardiac deaths with prior medical history or therapies for cardiac disorders (AF, Ischaemic heart disease, MI or angina) and HT via univariate analyses. We used Fisher's Exact test and estimated relative risk (RR) and associated confidence intervals under a normal approximation. Results: In FLAIR, 384 and 378 pts were treated with IR and FCR, respectively, median 52.7 months FU and treatment durations of 47.2 and 4.7 months. Median age 62. 84/384 (22%) IR pts had pre-existing HT and 17/384 (4%) a prior history of a cardiac disorder. 74/378 (20%) FCR pts had HT and 18/378 (5%) a cardiac disorder. To date 10 pts had a sudden or cardiac death: 2 (0.5%) FCR and 8 (2%) IR - median 33 mo (range: 13-48) from initiating IR to death. 9/10 pts were male aged 54 to 73 years at randomisation. 7/ 8 IR pts experiencing a sudden or cardiac death, had a prior history of HT and/or cardiac disorder (RR 23.6 vs pts with no HT/CV history, 95%CI [2.9-195]; Fisher's Exact P=0.0003; Table 1). Hypertensive cardiomyopathy and/or coronary artery disease was found at post mortem of all 3 IR pts having a PM. The risk of sudden or cardiac death with IR was 0.3% (1/291) in pts without pre-existing risk. The number of pts taking anti-hypertensives at trial entry (some taking more than one class) was: ACE inhibitors (ACEi) 47 IR, 37 FCR; Angiotensin II receptor blockers (ARB's) 15 IR, 17 FCR; Ca channel blockers 30 IR, 34 FCR; B-blockers 24 IR, 20 FCR; Diuretics 13 IR, 16 FCR; and alpha blockers 7 IR, 5 FCR. Overall, 291/384 (76%) IR and 296/378 (78%) FCR were taking no HT or cardiac medications at trial entry. The use of ACEi at study entry was associated with an increased risk of sudden or cardiac death with IR: 7/47 (15%) pts on ACEi at trial entry had a sudden or cardiac death compared to 1/336 (0.3%) not taking ACEi (RR 50.2, 95%CI [6.3-399]; P < 0.0001; Table 1). 2/7 pts had discontinued ACEi and switched to ARB's due to cough sometime prior to death. In contrast 0/37 FCR pts with a history of HTN/CV taking ACEi experienced a sudden or cardiac death. In the IR arm, none of the 46 pts receiving cardiac medication but not ACEi had a sudden or cardiac death suggesting that the risk was not simply a prior history of HT or cardiac disorder. 3/11 (27%) IR pts taking an ACEi plus a beta blocker at study entry had a sudden or cardiac death vs 4/32 (12.5%) pts on ACEi without a beta blocker. Factors potentially confounding the interpretation: 1) analyses did not take into account severity of underlying HT/CV risk, as it is possible that pts on ACEi had more severe underlying CV disease than others; and 2) analyses did not adjust for changes in HT/CV medications during the course of the study. However, the lack of any such signal in pts with a prior cardiovascular/HT history on therapies other than ACEi suggests a potential association with the medication itself. Conclusion: Sudden or cardiac deaths seen on IR in FLAIR were observed predominantly among male pts with a prior history of HT or cardiac disease. The prior use of ACEi was correlated with the risk of sudden or cardiac death in IR pts. In contrast, pts treated with IR who were not on ACEi (regardless of medical history) had a very low rate of cardiac or sudden death. Whilst these findings need confirming in other Ibr trials we believe that caution should be taken when concurrently administering ibrutinib and ACE inhibitors in pts with a medical history of HT or CV disease. Figure 1 Figure 1. Disclosures Munir: F. Hoffmann-La Roche: Consultancy; Alexion: Honoraria. Bloor: Novartis: Honoraria; Kite, a Gilead Company: Honoraria. Broom: AbbVie: Honoraria; AstraZeneca: Honoraria; Janssen-Cilag Ltd: Honoraria; Takeda UK Ltd: Honoraria; Celgene Ltd: Honoraria; Gilead: Honoraria. Furtado: Abbvie: Other: Conference support. Morley: Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference support; AbbVie; Takeda: Other: Conference support; Janssen: Honoraria; Kite: Honoraria. Cwynarski: Atara: Consultancy; BMS/Celgene: Other; Celgene: Consultancy; Gilead: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Other; Kite, a Gilead Company: Consultancy, Speakers Bureau; Roche: Consultancy, Other, Speakers Bureau; Takeda: Consultancy, Other, Speakers Bureau. Gatto: Roche: Consultancy. Paneesha: AbbVie: Honoraria; Bristol Myers Squibb: Honoraria; Gilead: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria. Fox: F. Hoffmann-La Roche Ltd: Consultancy, Membership on an entity's Board of Directors or advisory committees. Howard: Roche: Current Employment. Cairns: Takeda: Research Funding; Amgen: Research Funding; Merck Sharpe and Dohme: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Patten: NOVARTIS: Honoraria; ASTRA ZENECA: Honoraria; ABBVIE: Honoraria; JANSSEN: Honoraria; GILEAD SCIENCES: Honoraria, Research Funding; ROCHE: Research Funding. Hillmen: BeiGene: Honoraria; SOBI: Honoraria; AstraZeneca: Honoraria; Gilead: Research Funding; Roche: Research Funding; Pharmacyclics: Honoraria, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding.

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Abstract Introduction: The most effective chemoimmunotherapy (CIT) in previously untreated CLL is the combination of fludarabine, cyclophosphamide and rituximab (FCR). Ibrutinib (I), the first irreversible inhibitor of Bruton's tyrosine kinase approved for CLL, has improved outcomes in numerous clinical trials compared to different CIT. Methods: FLAIR (ISRCTN01844152) is an ongoing, phase III, multicentre, randomised, controlled, open, parallel group trial for previously untreated CLL requiring therapy according to the IWCLL 2008 guidelines. Patients over 75 years or with >20% 17p-deleted cells were excluded. Participants were randomised on a 1:1 basis to receive 6 cycles of FCR (oral fludarabine 24mg/m 2/day for 5 days, oral cyclophosphamide 150mg/m 2/day for 5 days with IV rituximab [375 mg/m 2 on day 1/2 of cycle 1; 500 mg/m 2 on day 1 of cycles 2-6]) every 28-days or IR (Ibrutinib [420mg/day] plus rituximab [6 doses as for FCR]) given for up to 6 years with stratification by disease stage, age, gender and centre. The primary endpoint was to assess whether IR was superior to FCR in terms of investigator-assessed PFS. Secondary endpoints included overall survival,; attainment of undetectable MRD; response to therapy; safety and toxicity; health-related quality of life and cost-effectiveness. A formal interim analysis was planned when 191 events were observed in both arms or 109 events in the FCR arm alone with a p-value of 0.005 leading to reporting of the trial. Here we report the results of this planned interim analysis. Results: A total of 771 patients were randomised (385 to FCR and 386 to IR) from 113 UK Centres between 9/19/2014 and 7/19/2018. The data was locked on 5/24/2021. 73.3% were male, median age was 62 years (33.6% >65yo) and 45.1% were Binet Stage C. IGHV data was available for 728 (94.4%) patients with 53.2% IGHV unmutated (≥98% homology to germline), 40.5% IGHV mutated and 6.3% Subset 2. Hierarchical FISH testing revealed 0.4% 17p del, 15.4% 11q del, 12.3% trisomy 12, 29.7% normal and 35% 13q del; with 7.1% failed. The arms were well-balanced for disease variables with no significance differences. Median follow-up was 52.7 months. IR had a superior PFS compared to FCR (Median PFS not reached for IR versus 67 months for FCR; HR: 0.44; p<0.001; see Figure). The PFS was significantly better for IR in patients with IGHV unmutated CLL (HR: 0.41; p<0.001), but not for patients with IGHV mutated CLL at this follow-up (HR: 0.66; p=0.179). There was no difference in overall survival between the two arms (HR: 1.01; p=0.956) with a total of 29 deaths in FCR arm (including 4 from CLL, 3 Richter's [RT], 3 AML/MDS, 3 COVID-19 and 2 cardiac/sudden) and 30 in the IR arm (including 3 CLL, 1 RT, 0 AML/MDS, 3 COVID-19 and 8 cardiac/sudden). Second line treatment was initiated for 59 patients after FCR (including 38 BTKi, 7 venetoclax+R [venR], 4 BendamustineR [BR] and 3 CHOP-R [RT]) and 21 after IR (including 7 FCR, 5 venR, 1 BR, 1 CHOP-R [RT], 1 ABVD [Hodgkin's]). Overall, 88.1% of patients have received targeted therapies for CLL progression after FCR. The overall survival with FCR in FLAIR is significantly improved compared to FCR in previous NCRI trials (ADMIRE and ARCTIC) which had the same inclusion criteria, the same Centres and an identical FCR schedule, but were conducted prior to widespread availability of targeted therapies in the relapse (recruited between 2009 and 2012). The 4 year overall survival for FCR in FLAIR was 94.5% compared to 84.2% for FCR between 2009 and 2012. SAEs were reported in 53.7% of patients on FCR and 53.4% on IR. Notable differences for SAEs by organ class for FCR vs IR: infections in 33.6% of patients vs 27.1%; blood and lymphatic in 19.8% vs 10.7%; and cardiac in 1.1% vs 8.3%. With current follow-up, there were 10 sudden or cardiac deaths: 8 IR and 2 FCR. Further analysis indicated that 7 of the 8 cardiac or sudden deaths in the IR arm had a history of hypertension or cardiac disease (further detailed in additional abstract; Munir et al.). Neither of the sudden deaths in the FCR arm had a prior cardiac or hypertensive history or were on cardiac or anti-hypertensive treatment. There were 6 cases of secondary MDS/AML in the FCR arm and 1 in the IR arm. Conclusion: Ibrutinib plus rituximab resulted in a superior PFS compared to FCR. There was no difference in overall survival, most likely due to effective second-line targeted therapy in patients progressing after FCR. Figure 1 Figure 1. Disclosures Hillmen: Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; SOBI: Honoraria; BeiGene: Honoraria; AstraZeneca: Honoraria. Bloor: Novartis: Honoraria; Kite, a Gilead Company: Honoraria. Broom: AbbVie: Honoraria; AstraZeneca: Honoraria; Janssen-Cilag Ltd: Honoraria; Takeda UK Ltd: Honoraria; Celgene Ltd: Honoraria; Gilead: Honoraria. Furtado: Abbvie: Other: Conference support. Morley: Kite: Honoraria; Janssen: Honoraria; AbbVie; Takeda: Other: Conference support; Roche: Membership on an entity's Board of Directors or advisory committees, Other: Conference support. Cwynarski: Adienne, Takeda, Roche, Autolus, KITE, Gilead, Celgene, Atara, Janssenen: Other. Paneesha: Celgene: Honoraria; Roche: Honoraria; Janssen: Honoraria; Gilead: Honoraria; Bristol Myers Squibb: Honoraria; AbbVie: Honoraria. Howard: Roche: Current Employment. Cairns: Merck Sharpe and Dohme: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Celgene / BMS: Other: travel support, Research Funding. Patten: NOVARTIS: Honoraria; ROCHE: Research Funding; JANSSEN: Honoraria; ASTRA ZENECA: Honoraria; ABBVIE: Honoraria; GILEAD SCIENCES: Honoraria, Research Funding. Munir: F. Hoffmann-La Roche: Consultancy; Alexion: Honoraria.

Background The FLAIR trial in chronic lymphocytic leukaemia has a randomised, controlled, open-label, confirmatory, platform design. FLAIR was successfully amended to include an emerging promising experimental therapy to expedite its assessment, greatly reducing the time to reach the primary outcome compared to running a separate trial and without compromising the validity of the research or the ability to recruit to the trial and report the outcomes. The methodological and practical issues are presented, describing how they were addressed to ensure the amendment was a success. Methods FLAIR was designed as a two-arm trial requiring 754 patients. In stage 2, two new arms were added: a new experimental arm and a second control arm to protect the trial in case of a change in practice. In stage 3, the original experimental arm was closed as its planned recruitment target was reached. In total, 1516 participants will be randomised to the trial. Results The changes to the protocol and randomisation to add and stop arms were made seamlessly without pausing recruitment. The statistical considerations to ensure the results for the original and new hypotheses are unbiased were approved following peer review by oversight committees, Cancer Research UK, ethical and regulatory committees and pharmaceutical partners. These included the use of concurrent comparators in case of any stage effect, appropriate control of the type I error rate and consideration of analysis methods across trial stages. The operational aspects of successfully implementing the amendments are described, including gaining approvals and additional funding, data management requirements and implementation at centres. Conclusions FLAIR is an exemplar of how an emerging experimental therapy can be assessed within an existing trial structure without compromising the conduct, reporting or validity of the trial. This strategy offered considerable resource savings and allowed the new experimental therapy to be assessed within a confirmatory trial in the UK years earlier than would have otherwise been possible. Despite the clear efficiencies, treatment arms are rarely added to ongoing trials in practice. This paper demonstrates how this strategy is acceptable, feasible and beneficial to patients and the wider research community. Trial registration ISRCTN Registry ISRCTN01844152 . Registered on August 08, 2014

Introduction: In CLL achieving minimal residual disease (MRD) negativity has a survival advantage compared to MRD positive patients regardless of the approach used to achieve MRD negativity. The UK CLL207 phase II trial assessed consolidation with alemtuzumab following chemotherapy and showed that 38% of patients attained MRD negativity at 6 months post-consolidation. These patients had a significantly improved progression-free survival (PFS) compared to MRD positive patients. However, significant toxicity was associated with alemtuzumab. Obinutuzumab, a type II monoclonal antibody targeting the CD20 antigen has shown greater efficacy in CLL than previous anti-CD20 antibodies with respect to MRD, and appears to be less immune suppressive than alemtuzumab. Methods: The GALACTIC trial was a seamless phase II/III trial, with an overall planned sample size of 188 patients which was designed to test whether consolidation with obinutuzumab is safe and eradicates MRD (phase II) which subsequently leads to prolonged PFS (phase III), in patients with B-CLL who have recently responded to chemotherapy. Patients achieving a complete or partial response (CR/PR) 3-24 months after chemotherapy were eligible. Patients with lymph node >1.5cm were excluded. Eligible patients assessed as MRD positive were randomised to receive either consolidation therapy with obinutuzumab or no consolidation therapy. Obinutuzumab was given 1000mg weekly for first 4 doses (split over two days for first dose) and then 4 further doses fortnightly. Prophylaxis was given to reduce the risk of infusion-related reactions. Simon's 2-stage design was used to define stopping rules in phase II with 80% power, 1-sided sig. level of 10% and minimum efficacy rate of 15%. If 2/9 (stage I) and 6/23 (stage II) participants randomised to obinutuzumab achieved MRD negativity, the trial would continue to phase III. If fewer than 23 MRD assessments were recorded, 6 MRD negative results were still required. Results: GALACTIC opened in March 2015 and passed the stage I stopping rule in April 2016. The trial closed early in February 2017 due to poor recruitment likely due to the advent of novel targeted therapy, such as ibrutinib and venetoclax, for relapsed CLL. A total of 48 patients were enrolled of whom 19 were MRD negative and not entered into the randomisation. The remaining 29 MRD positive participants were randomised to consolidation therapy (n=14; 7 CR, 7 PR) or no consolidation therapy (n=15; 5 CR, 9 PR, 1 N/K). The median age was 69 (46, 82) with 55.2% >65 and 72.4% were male. Overall, 93.1% had received previous rituximab, 41.4% had received 2 or 3 lines of prior therapy and 55.2% had MRD level >0.3% at the time of trial entry. Overall 12 (85.7%) participants randomised to consolidation received all 8 infusions, two participants received 7 doses due to dose limiting toxicity, neutropenia and thrombocytopenia. At 6 months post-randomisation, 10 (71.4%) (80%CI: 50.8, 86.9) consolidation participants achieved MRD negativity by flow cytometry (sensitivity 10-4) in bone marrow passing the stage II stopping rule. 13 (92.6%) achieved MRD negativity in the peripheral blood. In the consolidation arm, response rates were 13 (92.9%) CR and 1 (7.1%) PR, compared to 6 (40.0%) CR and 1 (6.7%) PR with no consolidation therapy. Two consolidated participants experienced 3 severe adverse reactions (serious infection (n=2), neutropenic sepsis (n=1)) which resolved. The most common adverse events in consolidation arm were thrombocytopenia (22.2%), infection (8.9%) and cough (8.4%), only 1% of events were infusion-related reactions. Conclusion: Consolidation therapy with obinutuzumab is highly effective at eradicating MRD by 6 months post-randomisation with 71.4% achieving an MRD negative bone marrow. Obinutuzumab is extremely well-tolerated with minimal infusion reactions and toxicity. Improvement in MRD was demonstrated and it can be postulated that consolidation may result in improvement of PFS and time to next treatment. However, long-term data is needed to establish this hypothesis. Disclosures Munir: Roche: Honoraria; AbbVie: Honoraria; Alexion Pharmaceuticals, Inc.: Honoraria; Janssen: Honoraria; Gilled: Honoraria. Hillmen: Celgene: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria. Rawstron: AbbVie: Consultancy, Honoraria; BD biosciences: Patents & Royalties; Gilead: Research Funding; Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria.

Chronic lymphocytic leukemia patients with mutated immunoglobulin heavy-chain genes (IGHV-M), particularly those lacking poor-risk genomic lesions, often respond well to chemoimmunotherapy (CIT). DNA methylation profiling can subdivide early-stage patients into naive B-cell-like CLL (n-CLL), memory B-cell-like CLL (m-CLL), and intermediate CLL (i-CLL), with differing times to first treatment and overall survival. However, whether DNA methylation can identify patients destined to respond favorably to CIT has not been ascertained. We classified treatment-naive patients (n = 605) from 3 UK chemo and CIT clinical trials into the 3 epigenetic subgroups, using pyrosequencing and microarray analysis, and performed expansive survival analysis. The n-CLL, i-CLL, and m-CLL signatures were found in 80% (n = 245/305), 17% (53/305), and 2% (7/305) of IGHV-unmutated (IGHV-U) cases, respectively, and in 9%, (19/216), 50% (108/216), and 41% (89/216) of IGHV-M cases, respectively. Multivariate Cox proportional analysis identified m-CLL as an independent prognostic factor for overall survival (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.87; P = .018) in CLL4, and for progression-free survival (HR, 0.25; 95% CI, 0.10-0.57; P = .002) in ARCTIC and ADMIRE patients. The analysis of epigenetic subgroups in patients entered into 3 first-line UK CLL trials identifies m-CLL as an independent marker of prolonged survival and may aid in the identification of patients destined to demonstrate prolonged survival after CIT.

Multi-arm clinical trials assessing multiple experimental treatments against a shared control group can offer efficiency advantages over independent trials through assessing an increased number of hypotheses. Published opinion is divided on the requirement for multiple testing adjustment to control the family-wise type-I error rate (FWER). The probability of a false positive error in multi-arm trials compared to equivalent independent trials is affected by the correlation between comparisons due to sharing control data. We demonstrate that this correlation in fact leads to a reduction in the FWER, therefore FWER adjustment is not recommended solely due to sharing control data. In contrast, the correlation increases the probability of multiple false positive outcomes across the hypotheses, although standard FWER adjustment methods do not control for this. A stringent critical value adjustment is proposed to maintain equivalent evidence of superiority in two correlated comparisons to that obtained within independent trials. FWER adjustment is only required if there is an increased chance of making a single claim of effectiveness by testing multiple hypotheses, not due to sharing control data. For competing experimental therapies, the correlation between comparisons can be advantageous as it eliminates bias due to the experimental therapies being compared to different control populations.