ARTICLE - Chronic Lymphocytic Leukemia First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial Carol Moreno,1,2 Richard Greil,3 Fatih Demirkan,4 Alessandra Tedeschi,5 Bertrand Anz,6 Loree Correspondence: C. Moreno Larratt,7 Martin Simkovic,8 Jan Novak,9 Vladimir Strugov,10 Devinder Gill,11 John G. Gribben,12 cmorenoa@santpau.cat Kevin Kwei,13 Sandra Dai,13 Emily Hsu,13 James P. Dean13 and Ian W. Flinn14 Received: May 5, 2021. Accepted: November 4, 2021. 1 Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Prepublished: January 13, 2022. Spain; 2Josep Carreras Leukemia Research Institute, Barcelona, Spain; 33rd Medical Department, Paracelsus Medical University, Salzburg Cancer Research Institute-CCCIT, https://doi.org/10.3324/haematol.2021.279012 Salzburg, Austria; 4Dokuz Eylul University, Division of Hematology, Izmir, Turkey; 5Niguarda ©2022 Ferrata Storti Foundation Ca Granda Hospital, Milan, Italy; 6Tennessee Oncology, Chattanooga, TN, USA; 7University of Published under a CC BY-NC license Alberta Hospital, Edmonton, Alberta, Canada; 8Department of Internal Medicine, Haematology, University Hospital and Medical School Hradec, Králové, Czech Republic; 9 University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic; 10Almazov National Medical Research Centre, St. Petersburg, Russia; 11 Princess Alexandra Hospital, Brisbane, Queensland, Australia; 12Barts Cancer Institute, London, UK; 13Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, USA and 14Sarah Cannon Research Institute, Nashville, TN, USA Abstract iLLUMINATE is a randomized, open-label phase III study of ibrutinib plus obinutuzumab (n=113) versus chlorambucil plus obinutuzumab (n=116) as first-line therapy for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma. Eligible patients were aged ≥65 years, or <65 years with coexisting conditions. Patients received oral ibrutinib 420 mg once daily until disease progression or unacceptable toxicity or six cycles of oral chlorambucil, each in combination with six cycles of intravenous obinutuzumab. After a median follow-up of 45 months (range, 0.2-52), median progression-free survival continued to be significantly longer in the ibrutinib plus obinutuzumab arm than in the chlorambucil plus obinu- tuzumab arm (median not reached versus 22 months; hazard ratio=0.25; 95% confidence interval: 0.16-0.39; P<0.0001). The best overall rate of undetectable minimal residual disease (<0.01% by flow cytometry) remained higher with ibrutinib plus obinutuzumab (38%) than with chlorambucil plus obinutuzumab (25%). With a median treatment duration of 42 months, 13 months longer than the primary analysis, no new safety signals were identified for ibrutinib. As is typical for ibrutinib-based regimens, common grade ≥3 adverse events were most prevalent in the first 6 months of ibrutinib plus obinutuzumab treatment and generally decreased over time, except for hypertension. In this final analysis with up to 52 months of follow-up (median 45 months), ibrutinib plus obinutuzumab showed sustained clinical benefit, in terms of pro- gression-free survival, in first-line treatment of chronic lymphocytic leukemia, including in patients with high-risk features. ClinicalTrials.gov identifier: NCT02264574. Introduction tients with CLL, including in combination with the anti- CD20 monoclonal antibody obinutuzumab based on the primary results of the iLLUMINATE study.2,3 In two first- Over the past decade, the introduction of novel therapies line studies ibrutinib or ibrutinib-based combination ther- targeting B-cell receptor signaling has shifted the treat- apy was associated with superior progression-free survival ment landscape for patients with chronic lymphocytic (PFS) and overall survival (OS) compared with chlorambu- leukemia (CLL), including for patients with high-risk ge- cil4 or fludarabine, cyclophosphamide, and rituximab nomic features who previously had limited treatment op- (FCR)5 regimens in patients with CLL/small lymphocytic tions.1 Ibrutinib is an oral, once-daily inhibitor of Bruton lymphoma (SLL). Ibrutinib (with or without rituximab) was tyrosine kinase (BTK) approved for the treatment of pa- also associated with superior PFS compared to benda- Haematologica | 107 September 2022 2108 ARTICLE - iLLUMINATE: final analysis C. Moreno et al. mustine plus rituximab.6 With up to 7 years of follow-up score >6, creatinine clearance <70 mL/min, del(17p) con- (median: 74.9 months; range, 0.1‒86.8) in the phase III firmed by fluorescence in situ hybridization analysis, or RESONATE-2 study in patients with CLL aged ≥65 years, TP53 mutation confirmed by next-generation sequencing. single-agent ibrutinib provided sustained PFS with ex- Additional eligibility criteria included an Eastern Cooper- tended follow-up, with a PFS of 61% at 6.5 years.4,7 No- ative Oncology Group (ECOG) performance status 0-2, tably, in patients with high-risk genomic features such as measurable lymph node disease (longest diameter >1.5 del(17p)/TP53 mutation, del(11q), and unmutated immuno- globulin heavy-chain variable region gene (IGHV), which cm), adequate hematologic function (absolute neutrophil are known to be associated with inferior outcomes with count ≥1×109 cells/L; platelet count >50×109 cells/L), and chemoimmunotherapy,8 ibrutinib-based regimens have adequate hepatic and renal function. consistently achieved superior PFS versus established chemotherapy/chemoimmunotherapies and appear to Treatments confer comparable outcomes to those of ibrutinib-treated Patients were randomized 1:1 to receive ibrutinib plus obi- patients without these high-risk features.4,5,9,10 nutuzumab or chlorambucil plus obinutuzumab, as strat- The multicenter, randomized, phase III iLLUMINATE study ified by geographic region (North America vs. rest of was initiated to compare the efficacy of ibrutinib com- world), ECOG performance status (0-1 vs. 2), and cytogen- bined with obinutuzumab versus chlorambucil combined etic status (del[17p] vs. del[11q] without del[17p] vs. others with obinutuzumab as first-line therapy for patients with [neither del11q nor del[17p]). Patients received oral ibruti- CLL/SLL. Results from the primary analysis with a median follow-up of 31 months demonstrated that ibrutinib plus nib 420 mg once daily until disease progression or unac- obinutuzumab significantly prolonged PFS compared with ceptable toxicity or oral chlorambucil 0.5 mg/kg body chlorambucil plus obinutuzumab as assessed by an inde- weight on days 1 and 15 of each 28-day cycle for six pendent review committee (median not reached vs. 19 cycles. Intravenous obinutuzumab (100 mg on day 1 and months) as well as by the study investigators (median not 900 mg on day 2, and 1,000 mg on days 8 and 15 of cycle reached vs. 22 months) in both the intention-to-treat 1, followed by 1,000 mg on day 1 of each subsequent 28- population and in patients with high-risk genomic fea- day cycle) was administered for up to six cycles. tures.3 Here we report the final analysis of iLLUMINATE with a Outcomes median follow-up of 45 months. The primary endpoint for the final analysis was PFS by in- vestigator assessment based on iwCLL 2008 criteria with subsequent clarifications to account for treatment-related Methods lymphocytosis.11 Secondary endpoints included overall re- Study design sponse rate (ORR; defined as complete response [CR], CR iLLUMINATE was a multicenter, randomized, open-label, with incomplete bone marrow (BM) recovery [CRi], nodular phase III study that enrolled patients at 71 sites in Aus- partial response [nPR], or partial response [PR]), rate of un- tralia, New Zealand, Canada, Israel, Turkey, Russia, the detectable minimal residual disease (MRD) (<1 CLL cell per European Union, and the USA (ClinicalTrials.gov identifier: 10,000 leukocytes in peripheral blood (PB) and/or BM aspi- NCT02264574). The study was conducted in accordance rate, as measured by central laboratory flow cytometry), with the Declaration of Helsinki, the International Confer- ence on Harmonisation Guidelines for Good Clinical Prac- OS, sustained hematologic improvement (continuous ≥2 tice, and local regulations. The protocol was approved by g/dL increase in hemoglobin levels from baseline, or ≥50% the institutional review boards, research ethics boards, or increase in platelet counts from baseline for ≥56 days independent ethics committees of participating institu- without blood transfusion or growth factors), and safety. tions. All patients provided written informed consent. Full Responses were assessed by the investigator for the final details of the study methodology have been published analysis. Non-hematologic adverse events were graded previously3 and are briefly described below. using National Cancer Institute Common Terminology Crite- ria for Adverse Events, version 4.03; hematologic adverse Participants events were assessed using iwCLL criteria.11 Because the Eligible patients had previously untreated CLL/SLL requi- ring treatment according to International Workshop on additional follow-up since the primary analysis extends Chronic Lymphocytic Leukemia (iwCLL) criteria11 and were beyond the adverse event reporting period for the chlo- aged ≥65 years or <65 years with at least one of the fol- rambucil plus obinutuzumab arm, safety findings are pres- lowing co-existing conditions: a cumulative illness rating ented only for the ibrutinib plus obinutuzumab arm. Haematologica | 107 September 2022 2109 ARTICLE - iLLUMINATE: final analysis C. Moreno et al. 65 (58%) patients remained on ibrutinib until study com- Results pletion (Table 1) and 100 (88%) patients completed six Patient demographics and characteristics cycles of obinutuzumab (Online Supplementary Figure S1). Two hundred twenty-nine patients were randomized to In the chlorambucil plus obinutuzumab arm, 103 (89%) pa- receive ibrutinib plus obinutuzumab (n=113) or chloram- tients and 100 (86%) patients completed the planned six bucil plus obinutuzumab (n=116). Patient baseline demo- cycles of chlorambucil and obinutuzumab, respectively. graphics and disease characteristics were generally Of the 116 patients randomized to chlorambucil plus obi- comparable between treatment arms (Online Supplemen- nutuzumab, 50 (43%) patients subsequently received tary Table S1). The median age was 71 years (range, 40-87), ibrutinib with study crossover (n=45; 39%) or with com- with most patients (n=183; 80%) aged ≥65 years. Most pa- mercial ibrutinib (n=6; 5%); one patient received both tients (148 [65%]) had high-risk disease features of commercial and crossover ibrutinib. At study completion, del(17p), TP53 mutation, del(11q), or unmutated IGHV. 35 of the 45 crossover patients (78%) were still receiving single-agent ibrutinib. Patient disposition and treatment All patients received concomitant medications during study The final analysis was performed upon study completion. treatment; in the ibrutinib plus obinutuzumab arm, 63/113 The median time on study was 45 months (range, 0.2-52 (56%) patients received any anticoagulant or antiplatelet months) for the total study population, 45.5 months agent; of these, 36/113 (32%) patients received anticoagu- (range, 0.2-52 months) for the ibrutinib plus obinutuzu- lants and 48/113 (42%) received antiplatelet agents. Ninety- mab arm, and 43 months (range, 1-52 months) for the three of 113 patients (82%) received systemic antibacterial chlorambucil plus obinutuzumab arm. With study com- drugs. Of the 113 patients in the ibrutinib plus obinutuzu- pletion, discontinuations across both arms were due to mab arm, 78 (69%) received acid-reducing medications; sponsor termination of the study (74%; n=170), death (18%; 71/113 (63%) received proton pump inhibitors, 14/113 (12%) n=42), withdrawal of consent (6%; n=14), and other (1%; received H2-receptor antagonists, and 8/113 (7%) received n=1 each: high dose of steroids, obinutuzumab allergy, and other acid-reducing agents. infusion reaction). Of patients treated with ibrutinib and obinutuzumab, 26 (23%) and 10 (9%) patients, respectively, Progression-free survival discontinued these agents due to adverse events; notably, At the final analysis, with a median follow-up of 45 treatment duration in the ibrutinib plus obinutuzumab months, PFS remained significantly longer in the ibruti- arm was longer than that in the chlorambucil plus obinu- nib plus obinutuzumab arm (median not reached; 95% tuzumab arm (median: 42 vs. 5 months). In the ibrutinib confidence interval [95% CI], 49 months to not estimable plus obinutuzumab arm, discontinuation of ibrutinib ther- [NE]) than in the chlorambucil plus obinutuzumab arm apy due to disease progression was infrequent (n=5; 4%); (22 months; 95% CI: 18-27 months), resulting in a 75% Table 1. Summary of treatment disposition. Ibrutinib plus obinutuzumab Chlorambucil plus obinutuzumab (N=113) (N=116) Ibrutinib Obinutuzumab Chlorambucil Obinutuzumab Treatment status, N (%) Did not receive study drug 0 0 1 (1) 1 (1) Completed/ongoing at study closure 65 (58) 100 (88) 103 (89) 100 (86) Primary reason for discontinuation of study treatment, N (%) Disease progression 5 (4) 1 (1) 0 0 Adverse events 25 (22) 10 (9) 11 (9) 15 (13) Death 5 (4) 0 0 0 Withdrawal of consent 6 (5) 1 (1) 0 0 Investigator decision 3 (3) 0 1 (1) 0 Other 4 (4) 1 (1) 0 0 Haematologica | 107 September 2022 2110 ARTICLE - iLLUMINATE: final analysis C. Moreno et al. reduction in the risk of disease progression or death with PFS benefit for patients with high-risk features (del[17p], ibrutinib plus obinutuzumab (hazard ratio [HR]=0.25; del[17p]/TP53 mutation, del[11q] and/or unmutated IGHV) 95% CI: 0.16-0.39; P<0.0001) (Figure 1). The estimated treated with ibrutinib plus obinutuzumab versus chloram- PFS at 42 months was 74% in the ibrutinib plus obinu- bucil plus obinutuzumab (HR=0.17; 95% CI: 0.10-0.28; tuzumab arm and 33% in the chlorambucil plus obinu- P<0.0001). Within the high-risk population, PFS estimates tuzumab arm. at 42 months were significantly higher in the ibrutinib plus Similar to the overall population, there was a significant obinutuzumab arm than in the chlorambucil plus obinu- Figure 1. Progression-free survival per investigator assessment in the intention-to-treat population. CI: confidence interval; mo: months; NE, not estimable; PFS, progression-free survival. Figure 2. Progression-free survival per investigator assessment in the high-risk population of patients with del(17p), del(11q), TP53 mutations, and/or unmutated IGHV. CI: confidence interval; mo: months; NE: not estimable; PFS: progression-free survival. Haematologica | 107 September 2022 2111 ARTICLE - iLLUMINATE: final analysis C. Moreno et al. tuzumab arm (70% vs. 12%). At 48 months, the PFS benefit from ibrutinib plus obinutuzumab among both subgroups was maintained since the time of the primary analysis at of unmutated and mutated IGHV patients persisted after 30 months (70% vs. 77%, respectively) (Figure 2). The ex- excluding patients with del(17p) (unmutated: HR=0.17; clusion of patients with del(17p) did not affect 42-month 95% CI: 0.09-0.30; mutated: HR=0.25; 95% CI: 0.08-0.74) PFS estimates for the rest of the high-risk population, (Online Supplementary Figure S3). The hazard ratios of which were 71% and 14%, respectively, for the two treat- 0.20 and 0.17 observed in the mutated and unmutated ment arms (Online Supplementary Figure S2). IGHV subgroups of the ibrutinib plus obinutuzumab arm Likewise, a PFS benefit with ibrutinib plus obinutuzumab are consistent with the hazard ratio for the intention-to- was observed irrespective of IGHV mutation status (Fig- treat population (HR=0.25) which includes other non- ure 3). Among patients with unmutated IGHV, up to 48 high-risk subgroups (Figure 1). Online Supplementary months median PFS was not reached with ibrutinib plus Figure S4 depicts consistently superior PFS associated obinutuzumab versus 15 months with chlorambucil plus with ibrutinib plus obinutuzumab across various sub- obinutuzumab (HR=0.17; 95% CI: 0.10-0.29). Whereas the groups of patients defined by age, Rai stage, ECOG per- median PFS was not reached in either treatment arm for formance status, and bulky disease, in addition to patients with mutated IGHV, ibrutinib plus obinutuzumab specified genomic risk factors mentioned above. significantly reduced the risk of progression or death in In patients randomized to ibrutinib plus obinutuzumab, no this subgroup (HR=0.20; 95% CI: 0.07-0.59). Within the significant difference in PFS was shown between patients ibrutinib plus obinutuzumab arm, the estimated PFS at with or without del(17p)/TP53 mutation (HR=0.93; 95% CI: 48 months was 67% and 89% for patients with unmu- 0.32-2.69; P=0.895) (Figure 4). The median PFS was not tated and mutated IGHV, respectively. The PFS benefit reached in either subgroup, with estimated 48-month PFS Figure 3. Progression-free survival per investigator assessment according to IGHV mutation status. CI: confidence interval; mo: months; NE, not estimable; PFS, progression-free survival. Haematologica | 107 September 2022 2112 ARTICLE - iLLUMINATE: final analysis C. Moreno et al. Figure 4. Progression-free survival per investigator assessment according to TP53 aberration status (del[17p] or TP53 mutation) in the ibrutinib plus obinutuzumab arm. CI: confidence interval; mo: months; NE, not estimable; PFS, progression-free survival. rates of 77% and 74% in patients wih and without Minimal residual disease del(17p)/TP53 mutation, respectively. Initially MRD information was obtained from BM from all patients at cycle 9 and upon achieving CR, but subsequent Time to next treatment protocol amendments enabled data collection from both Over a median follow-up of 45 months, fewer patients re- BM and PB, and from all responders on a scheduled basis ceiving ibrutinib plus obinutuzumab initiated subsequent thereafter. Overall, MRD assessments were obtained from treatment for CLL/SLL compared with those receiving 101/113 patients on ibrutinib plus obinutuzumab (93 BM and chlorambucil plus obinutuzumab (3/113 [3%] vs. 55/116 90 PB) and from 92/116 patients in the chlorambucil plus [47%] patients, respectively). The median time to next obinutuzumab arm (84 BM and 60 PB). Most patients with treatment was not reached in the ibrutinib plus obinutu- undetectable MRD (<0.01%) were subsequently followed zumab arm compared with 33 months (95% CI: 24 with at least one repeat MRD assessment (91% for ibrutinib months-NE) in the chlorambucil plus obinutuzumab arm, plus obinutuzumab; 86% for chlorambucil plus obinutuzu- corresponding to a 96% reduction in the risk of needing mab), with a median follow-up of 23 and 30 months, re- next-line therapy (HR=0.04; 95% CI: 0.01-0.13; P<0.0001). spectively, following initial attainment of undetectable MRD. Overall, 38% (43/113) of patients in the ibrutinib plus obi- Response rates nutuzumab arm achieved undetectable MRD in BM or PB Consistent with the primary analysis, the ORR by investi- compared with 25% (29/116) in the chlorambucil plus obi- gator assessment was higher in the ibrutinib plus obinu- nutuzumab arm (P=0.033) (Online Supplementary Table tuzumab arm (n=103/113; 91%) than in the chlorambucil S2). Rates of undetectable MRD for the ibrutinib plus obi- plus obinutuzumab arm (n=94/116; 81%) (Figure 5). CR nutuzumab arm were 25% for BM (28/113) and 33% for PB rates, including CRi, in the ibrutinib plus obinutuzumab (37/113); rates for the chlorambucil plus obinutuzumab arm (47 [42%]) were slightly increased relative to rates re- arm were 17% (20/116) in BM and 20% (23/116) in PB. In ported at the primary analysis (46 [41%]); CR/CRi rates in these patients, the cumulative rate of undetectable MRD the chlorambucil plus obinutuzumab arm were unchanged (<0.01%) increased over the first 3 years with continuous compared to those reported at the primary analysis (n=20 ibrutinib therapy and then remained stable through final [17%]; P<0.0001 for the difference between arms). The analysis (Figure 6). As expected, given the differences in median duration of response was not reached in the PFS for the two arms following initial attainment of unde- ibrutinib plus obinutuzumab arm (95% CI: NE-NE) and was tectable MRD, 60% of patients receiving ibrutinib plus obi- 19 months (95% CI: 16-31) in the chlorambucil plus obinu- nutuzumab maintained undetectable MRD status through tuzumab arm. last PB or BM testing compared to 31% of patients receiv- Haematologica | 107 September 2022 2113 ARTICLE - iLLUMINATE: final analysis C. Moreno et al. Figure 5. Best overall response per investigator assessment with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab. CR: complete response; CRi, complete response with incomplete bone marrow recovery; nPR, nodular partial response; PR, partial response. ing chlorambucil plus obinutuzumab (Online Supplemen- chlorambucil plus obinutuzumab group ([n=15/23]; 65% tary Figure S5A). The cumulative MRD relapse rate (defined vs. [n=3/11]; 27%). In high-risk patients with >24 months as MRD ≥1% after previously achieving undetectable MRD) of MRD follow-up, five of six patients (83%) in the ibruti- was lower in the ibrutinib plus obinutuzumab group than nib plus obinutuzumab arm remain MRD negative com- in the chlorambucil plus obinutuzumab group (12% vs. pared with two of five patients (40%) in the chlorambucil 24%) and the median time to MRD relapse was not esti- plus obinutuzumab arm. As in the overall population, the mable (range, 0.03-44.2 months) in the ibrutinib plus obi- cumulative MRD relapse rate in the high-risk population nutuzumab arm versus 37.5 months (range, 0.03-44.2 after achieving undetectable MRD was lower in the months) in the chlorambucil plus obinutuzumab arm. ibrutinib plus obinutuzumab group than in the chloram- Examined among patients who achieved a best response bucil plus obinutuzumab group (0%; [n=0/23] vs. 27%; of CR/CRi with ibrutinib plus obinutuzumab, 28/47 pa- [n=3/11]). The median time to MRD relapse was not esti- tients (60%) had undetectable MRD while among those mable in either the ibrutinib plus obinutuzumab arm in the chlorambucil plus obinutuzumab arm achieving (range, 0.03-38.6 months) or the chlorambucil plus obi- CR, 15/20 patients (75%) had undetectable MRD in PB or nutuzumab arm (range, 0.03-33.4 months). BM. By contrast, among patients who achieved a best re- sponse of PR/nPR, 14/56 patients had undetectable MRD Overall survival levels in PB or BM in the ibrutinib plus obinutuzumab arm At the time of final analysis, the median OS was not (25%) and 14/74 (19%) in the chlorambucil plus obinutu- reached in either treatment arm (HR=1.08; 95% CI: 0.60- zumab arms. Although limited by the small number of 1.97; P=0.793) (Online Supplementary Figure S6). Among the evaluable patients, the median PFS was similar in pa- 45 patients who crossed-over to single-agent ibrutinib, the tients with CR/CRi, regardless of MRD status (Online Sup- 24-month OS was 88% (95% CI: 74.0-94.9) and six deaths plementary Figure S5B, C); undetectable MRD trended to were reported (13%). Overall, 22 (19%) patients in the ibruti- correlate positively with longer PFS in patients with nib plus obinutuzumab arm and 21 (18%) patients in the PR/nPR, especially in the chlorambucil plus obinutuzu- chlorambucil plus obinutuzumab died during the study. mab arm. Likewise, in the high-risk population, more than double Adverse events in the ibrutinib plus obinutuzumab arm the percentage of patients in the ibrutinib plus obinutu- At final analysis, the median duration of exposure to zumab arm maintained undetectable MRD than in the ibrutinib was 42 months (range, 0.1-52) in the ibrutinib Haematologica | 107 September 2022 2114 ARTICLE - iLLUMINATE: final analysis C. Moreno et al. Figure 6. Cumulative rates of minimal residual disease over time (in bone marrow or peripheral blood). Clb: chlorambucil; Ibr: ibrutinib; MRD: minimal residual disease; Ob: obinutuzumab. plus obinutuzumab group, which was 13 months longer arm, the most common adverse events (occurring in ≥10% than ibrutinib exposure at the primary analysis (median 29 of patients in either arm) were neutropenia (44%), throm- months3); 73 patients (65%) received ≥3 years of ibrutinib bocytopenia (35%), diarrhea (35%), cough (29%), infusion- and 18 (16%) received ≥4 years of ibrutinib therapy. All pa- related reaction (25%), and arthralgia (24%) (Online tients had completed or discontinued obinutuzumab (on Supplementary Table S3). The most common grade ≥3 ad- both arms) and chlorambucil before the primary analysis, verse events in the ibrutinib plus obinutuzumab arm were thus the median durations of treatment for obinutuzumab neutropenia (36%), thrombocytopenia (19%), pneumonia did not change since the primary analysis (4.6 months (9%), atrial fibrillation (6%), and febrile neutropenia (5%). [range, 4.6-4.9] for the chlorambucil plus obinutuzumab The prevalence of these grade ≥3 adverse events was group; 4.6 months [range, 4.6-4.7] for the ibrutinib plus highest during the first 6 months of treatment with ibruti- obinutuzumab group).3 The median duration of treatment nib plus obinutuzumab and generally decreased over time, with chlorambucil was 5.1 months (range, 5.1-5.3) in the with the exception of hypertension (Figure 7). The preva- chlorambucil plus obinutuzumab group.3 lence of grade ≥3 hypertension was 2% (n=2/113), 3% With ongoing treatment in the ibrutinib plus obinutuzu- (n=3/98), 4% (n=3/84), and 3% (n=2/74) in years 0-1, 1-2, mab arm, no new safety signals were noted in this analysis 2-3, and 3-4, respectively. No patient discontinued ibruti- relative to the primary analysis.3 With a median treatment nib therapy due to hypertension of any grade. The preva- exposure of 42 months in the ibrutinib plus obinutuzumab lence of any grade atrial fibrillation decreased, being 10% Haematologica | 107 September 2022 2115 ARTICLE - iLLUMINATE: final analysis C. Moreno et al. Figure 7. Prevalence of most common adverse events of any grade (≥20%) and grade ≥3 adverse events (≥3%) over time in patients treated with ibrutinib plus obinutuzumab. Haematologica | 107 September 2022 2116 ARTICLE - iLLUMINATE: final analysis C. Moreno et al. (n=11/113), 10% (n=10/98), 8% (n=7/84), and 9% (n=7/74) in one patient had stable disease; seven patients had no op- years 0-1, 1-2, 2-3, and 3-4, respectively; the prevalence portunity for response assessment. With a median follow- of grade ≥3 atrial fibrillation was 4% (n=5/113), 2% up of 17 months (range, 0.03-42) after ibrutinib (n=2/98), 0%, and 1% (n=1/74), in years 0-1, 1-2, 2-3, and discontinuation, 18-month PFS in these 38 patients who 3-4, respectively. Among 17 patients with atrial fibrillation discontinued for reasons other than progression or death of any grade, atrial fibrillation led to discontinuation of was 73.8% (95% CI: 55.4-85.5). ibrutinib in one patient (a grade 3 event). Seven major hemorrhagic adverse events (grade 1/2 for 2 events, grade 3 for 5 events, and no grade 4/5 events) oc- curred in five (4%) patients in the ibrutinib plus obinutu- Discussion zumab arm: catheter site hematoma, ecchymosis, Results from the final analysis of the iLLUMINATE study hematemesis, hemoptysis, post-procedural hematoma, with up to 52 months of follow-up (median: 45 months) subdural hematoma, and traumatic hematoma. Major confirmed the durable efficacy of ibrutinib plus obinutu- hemorrhage led to discontinuation of ibrutinib in one pa- zumab in previously untreated patients with CLL. Ibrutinib tient (grade 2 hemoptysis). plus obinutuzumab resulted in sustained PFS compared Over a median duration of 42 months of ibrutinib therapy, to chlorambucil plus obinutuzumab, with median PFS not the only adverse event leading to discontinuation of ibruti- reached after a median follow-up of 45 months and the nib in more than one patient was thrombocytopenia (n=2); risk of disease progression or death reduced by 75%. No- all other adverse events leading to discontinuation of tably, durable PFS was also seen in the high-risk patient ibrutinib occurred in only one patient each. Of these, population (i.e., with del[17p], TP53 mutation, del[11q], or seven and six patients discontinued during the first 6 and unmutated IGHV) treated with ibrutinib plus obinutuzu- 12 months of treatment, respectively. Four patients each mab, confirming earlier observations from the primary discontinued at time intervals of >12‒≤24 months, >24‒≤36 analysis of iLLUMINATE.3 At 42 months, the PFS estimates months, and >36‒≤48 months. among patients with del(17p), TP53, unmutated IGHV or In the ibrutinib plus obinutuzumab arm, 17 (15%) patients del(11q) mutations were significantly higher in the ibrutinib experienced a total of 32 adverse events (including 18 plus obinutuzumab arm than in the chlorambucil plus obi- grade ≥3 events) that led to ibrutinib dose reduction, most nutuzumab arm. Importantly, the benefit in PFS was ob- commonly due to neutropenia (6 [5%] patients) (Online served regardless of high-risk features.3 A similar benefit Supplementary Figure S7). Most (28/32 [88%]) of these ad- was observed in the CLL14 trial for the venetoclax plus verse events resolved or recovered with dose reduction, obinutuzumab regimen in patients with unmutated and including 94% (17/18) of grade ≥3 events. mutated IGHV.12 These results support current global con- At the time of final analysis, 14 and three patients had died sensus guidelines,13,14 noting ibrutinib as a preferred thera- from treatment-emergent adverse events in the ibrutinib peutic regimen for older patients and/or those with plus obinutuzumab and chlorambucil plus obinutuzumab comorbidities regardless of the presence of del(17p)/TP53 arms, respectively (Online Supplementary Table S4). Of the mutations and unmutated CLL. The follow-up for other, five deaths that occurred in the ibrutinib plus obinutuzu- similarly recommended novel treatment options is more mab arm with the additional follow-up, four were due to limited. adverse events (1 each due to respiratory tract infection, With this extended follow-up, as has been observed con- pneumonia, septic shock and one death was due to an un- sistently across several large, randomized phase III studies known cause after the adverse event reporting period). In of ibrutinib in previously untreated15 and relapsed/refrac- the chlorambucil plus obinutuzumab arm, an additional tory patients with CLL/SLL,16,17 highly durable PFS and OS two deaths occurred since the primary analysis, after have been confirmed even in patients with high-risk dis- crossover to the ibrutinib plus obinutuzumab arm. One ease characteristics. was due to sepsis, the other was due to progressive dis- In line with the results of the iLLUMINATE trial, other ease. phase III studies have also reported the superiority of ibrutinib-based regimens over chemoimmunotherapy in Outcomes after discontinuation of ibrutinib the first-line treatment of CLL. Concurrently, in the phase Thirty-eight patients discontinued ibrutinib after a median III ALLIANCE 041202 study in patients with CLL aged ≥65 of 15.5 months (range, 0.1-43.7) of treatment for reasons years (median follow-up: 38 months), first-line single- other than progression or death at any time on study, 25 agent ibrutinib or ibrutinib plus rituximab significantly patients discontinued due to adverse events (Table 1). prolonged PFS compared with bendamustine plus rituxi- Among patients who discontinued ibrutinib for reasons mab; estimated 2-year PFS rates were 87% and 88% ver- other than progressive disease or death, eight patients sus 74%, respectively.6 In patients aged ≤70 years, the had achieved a CR or CRi, 22 patients had PR or nPR, and phase III ECOG1912 study (median follow-up: 34 months) Haematologica | 107 September 2022 2117 ARTICLE - iLLUMINATE: final analysis C. Moreno et al. demonstrated that first-line treatment with ibrutinib plus nificantly improved over the impressive results with rituximab resulted in significantly longer PFS (3-year rate single-agent ibrutinib.6,24,25 The lack of data showing quality 89% vs. 73%) and OS (3-year rate 99% vs. 92%) compared of life or survival outcome benefits notwithstanding, the with FCR.5 With additional follow-up (median: 45 months), addition of an anti-CD20 agent may nonetheless provide PFS favored ibrutinib plus rituximab over FCR (HR=0.39; reassurance for patients concerned with increased abso- 95% CI: 0.26-0.57; P<0.0001).18 lute lymphocyte count. In a cross-trial comparison of With additional follow-up since the primary analysis of iL- RESONATE-2 and iLLUMINATE, patients treated with LUMINATE, the percentage of patients treated with ibruti- ibrutinib plus obinutuzumab combination therapy had nib plus obinutuzumab achieving undetectable MRD higher CR/CRi rates (44% vs. 27%; P=0.006) and shorter increased (from 34.5% at primary analysis to 38.1% at final time to absolute lymphocyte count normalization (8 vs. analysis), demonstrating deepening of remission with con- 55 weeks) than patients treated with single-agent ibruti- tinued ibrutinib treatment. Furthermore, fewer patients in nib.25 Compared to single-agent ibrutinib, the combination the ibrutinib arm experienced MRD relapse, with approxi- of ibrutinib plus rituximab was demonstrated by Burger et mately 60% of patients maintaining undetectable MRD at al. to improve CR/CRi rates (particularly in the first-line a median follow-up of 2 years after first attaining unde- setting: 50% vs. 20%) and shortened time to absolute lym- tectable MRD status. Due to the small numbers of pa- phocyte count normalization (24 vs. 48 weeks) in a phase tients in the subgroups, the association between MRD II study with a median follow-up of 36 months.24 In the status and PFS was not further studied. phase III ALLIANCE 041202 study, the CR rates (12% and Few patients discontinued treatment during the additional 7%) and rates of undetectable MRD (4% and 1%) were 13 months of follow-up after the primary analysis (n=14), slightly higher with ibrutinib plus rituximab than with and no new safety signals were reported with ongoing single-agent ibrutinib.6 The difference in response rates ibrutinib treatment. This is consistent with prior reports tended to be greater in patients with high-risk disease, that rates of most adverse events are highest during the suggesting that combination therapy may be most useful first year of ibrutinib-based treatment and decrease in for patients with high-risk or bulky disease.24 In the re- frequency thereafter.4,9,19,20 Most patients had improvement lapsed/refractory high-risk setting, the GENUINE study or resolution of adverse events following dose reduction, demonstrated significantly higher ORR with ublituximab suggesting that many such events are managed effectively plus ibrutinib compared to single-agent ibrutinib after a by dose modification, allowing patients to stay on therapy median follow-up of 41.6 months (83% vs. 65%; P=0.02).26 and continue to maintain disease control. The discontinu- In the setting of other BTK inhibitors, the ELEVATE-TN ation rate due to adverse events (22%) is comparable to study reported investigator-assessed CR/CRi rates of 24% that for first-line, single-agent ibrutinib after 4 years of with acalabrutinib plus obinutuzumab compared to 8% for follow-up in the RESONATE-2 study (19%)4 and is sup- acalabrutinib monotherapy and 13% for obinutuzumab ported by real-world studies showing that treatment dis- plus chlorambucil.27 continuation is similar in patients with CLL/SLL receiving In terms of PFS, 48-month estimates between RESONATE- single-agent ibrutinib or ibrutinib-based combination 2 and the current study were similar across ibrutinib- therapy.21 based treatment arms (76% vs. 74%), although it is worth Overall, first-line ibrutinib plus obinutuzumab was well noting that the current study included patients with high- tolerated, which is important given that the median age risk genomic features whereas RESONATE-2 excluded at diagnosis of CLL is over 70 years,22 a demographic that those with del17p.4,10 Regardless, these broad clinical data often presents with comorbidities that preclude the use clearly refute preclinical hypotheses of ibrutinib negating of chemotherapy-containing regimens. In patients receiv- anti-CD20 efficacy, although anti-CD20 use may be im- ing concomitant medications, ibrutinib was well tolerated. portant to optimize efficacy of other BTK inhibitors.27 Notably, ibrutinib can be co-administered with acid-re- In conclusion, ibrutinib plus obinutuzumab remains an ef- ducing medications, offering an advantage over other ki- fective chemotherapy-free regimen for patients with nase inhibitors known to have drug‒drug interactions with CLL/SLL that provides sustained efficacy and significantly acid-reducing agents.23 Overall, these results strengthen reduces the risk of disease progression or death compared and build upon the broad experience with ibrutinib. with chlorambucil plus obinutuzumab, including in pa- Several studies have assessed whether adding anti-CD20 tients with high-risk genomic features. With ongoing therapy to ibrutinib results in a clinically relevant improve- once-daily dosing, long-term ibrutinib therapy was well ment in efficacy in CLL.5,6,24 Evidence suggests that addi- tolerated with no new safety signals observed. tion of anti-CD20 therapy to ibrutinib may increase depth of response and decrease the time to absolute lympho- Disclosures cyte count normalization relative to single-agent ibrutinib CM has provided consulting/advisory services for Janssen, therapy, although survival outcomes have not been sig- AbbVie, AstraZeneca, and BeiGene; has received research Haematologica | 107 September 2022 2118 ARTICLE - iLLUMINATE: final analysis C. Moreno et al. funding from AbbVie and Janssen; and participated in and Myovant Science. EH and JPD are employed by Phar- speakers bureaus for AbbVie and Janssen. RG has received macyclics LLC, an AbbVie Company; and own stock in Abb- honoraria from Celgene, Roche, Merck, AstraZeneca, No- Vie. IWF has provided consulting/advisory services for vartis, Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, AbbVie, AstraZeneca, BeiGene, Genentech, Gilead, Great Sandoz, AbbVie, Gilead, and Daiichi Sankyo; has provided Point Partners, Iksuda Therapeutics, Janssen, Juno Thera- consulting/advisory services for Celgene, Novartis, Roche, peutics, Kite Pharma, MorphoSys, Nurix Therapeutics, Bristol Myers Squibb, Takeda, AbbVie, AstraZeneca, Jan- Pharmacyclics LLC, an AbbVie Company, Roche, Seattle ssen, Merck Sharp & Dohme, Merck, Gilead, and Daiichi Genetics, Takeda, TG Therapeutics, Unum Therapeutics, Sankyo; has received research funding from Celgene, Verastem, and Yingli Pharma; and has received research Merck, Takeda, AstraZeneca, Novartis, Amgen, Bristol Myers funding from AbbVie, Acerta Pharma, Agios, ArQule, Astra- Squibb, Merck Sharp & Dohme, Sandoz, Gilead, and Roche; Zeneca, BeiGene, Calithera Biosciences, Celgene, Constel- has received travel or accommodation funds from Roche, lation Pharmaceuticals, Curis, Forma Therapeutics, Forty Amgen, Janssen, AstraZeneca, Novartis, Merck Sharp & Seven, Genentech, Gilead, IGM Biosciences, Incyte, Infinity Dohme, Celgene, Gilead, Bristol Myers Squibb, and AbbVie. Pharmaceuticals, Janssen, Juno Therapeutics, Karyopharm FD has had a consulting/advisory role for AbbVie, AstraZe- Therapeutics, Kite Pharma, Loxo, Merck, MorphoSys, No- neca, Roche, and Amgen; has received research funding vartis, Pfizer, Pharmacyclics LLC, an AbbVie Company, Por- from AbbVie, Janssen, Pharmacyclics LLC, an AbbVie com- tola Pharmaceuticals, Rhizen Pharmaceuticals, Roche, pany, and AstraZeneca; has participated in speakers bu- Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium reaus for Janssen, AbbVie, and Amgen; and has received Therapeutics, Triphase Pharma, Unum Therapeutics, and travel or accommodation expenses from Amgen, Janssen, Verastem. AbbVie, and Pfizer. AT has received honoraria from Jan- ssen, AbbVie, AstraZeneca, and BeiGene; and has partici- Contributions pated in speakers bureaus for Janssen, BeiGene, As members of the Steering Committee, CM, DG, JGG, and AstraZeneca, and AbbVie. BA has nothing to disclose. LL IWF collaborated with the study sponsors to design the has provided consulting/advisory services for AbbVie and study and protocol; CM, RG, RD, AT, BA, LL, MS, JN, VS, DG, Janssen. MS has received honoraria from AbbVie, Roche, JGG, and IWF collected the study data; SD analyzed the Janssen-Cilag, Gilead, and Acerta Pharma; has played a data; KK collected and tested the high-risk genomic factor consulting/advisory role for AbbVie; has participated in data for the study; SD, EH, and JD confirmed the accuracy speakers bureaus for AbbVie, Roche, Janssen-Cilag, and of the data and compiled it for analysis. All authors had Gilead; and has received travel or accommodation expen- access to the data and were involved in the interpretation ses from AbbVie, Roche, Janssen-Cilag, and Gilead. JN has of data, contributed to the manuscript review and revi- played a consulting/advisory role for Amgen, Takeda, sions, and approved the final version for submission. Roche, Celgene, Pfizer, and Novartis; and has received tra- vel or accommodation expenses from Amgen and Janssen. Acknowledgments VS is employed by Eco-Safety Medical Center; has stock The authors thank the patients who participated in this ownership in Portola Pharmaceuticals, Gilead, Moderna, trial and their families. The authors also thank Cindi A. and Clovis Oncology; has received research funding from Hoover, PhD, for medical writing, which was supported by Janssen; and has received travel or accommodation ex- Pharmacyclics LLC, an AbbVie Company. penses from AbbVie and Janssen. DG has received hono- raria from Janssen-Cilag; and has played a Funding consulting/advisory role for Janssen-Cilag. JGG has recei- Pharmacyclics LLC, an AbbVie Company, sponsored and ved honoraria from AbbVie, Roche, Bristol Myers Squibb, designed the study. Study investigators and their research Janssen, and AstraZeneca; has provided consulting/advi- teams collected the data. The sponsor confirmed data ac- sory services for AbbVie, Janssen, and Gilead; and received curacy and analyzed the data. Medical writing was funded research funding from Janssen, AstraZeneca, and Celgene. by the sponsor. KK is employed by Pharmacyclics LLC, an AbbVie Company; and owns stock in Pharmacyclics LLC, an AbbVie Company, Data-sharing statement and Gilead. SD has been employed by Pharmacyclics LLC, Requests for access to individual participant data from cli- an AbbVie Company. and Horizon Therapeutics; and has nical studies conducted by Pharmacyclics LLC, an AbbVie stock ownership in AbbVie, Bristol Myers Squibb, Gilead, Company, can be submitted through Yale Open Data Ac- GlaxoSmithKline, Exelixis, Revance, Horizon Therapeutics, cess (YODA) Project site at http://yoda.yale.edu. Haematologica | 107 September 2022 2119 ARTICLE - iLLUMINATE: final analysis C. Moreno et al. References 1. Burger JA, O'Brien S. Evolution of CLL treatment - from 14. 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