Received: 17 June 2019 Revised: 3 September 2019 Accepted: 9 September 2019 DOI: 10.1002/ajh.25638 RESEARCH ARTICLE Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma Talha Munir1 | Jennifer R. Brown2 | Susan O'Brien3 | Jacqueline C. Barrientos4 | Paul M. Barr5 | Nishitha M. Reddy6 | Steven Coutre7 | Constantine S. Tam8 | Stephen P. Mulligan9 | Ulrich Jaeger10 | Thomas J. Kipps11 | Carol Moreno12 | Marco Montillo13 | Jan A. Burger14 | John C. Byrd15 | Peter Hillmen16 | Sandra Dai17 | Anita Szoke17 | James P. Dean17 | Jennifer A. Woyach15 1 Department of Haematology, St. James's University Hospital, Leeds, UK 2 CLL Center, Dana-Farber Cancer Institute, Boston, Massachusetts 3 UC Irvine, Chao Family Comprehensive Cancer Center, Irvine, California 4 Division of Medical Oncology and Hematology Northwell Health Cancer Institute, Lake Success, New York 5 Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York 6 Vanderbilt-Ingram Cancer Center, Nashville, Tennessee 7 Stanford Cancer Center, Stanford University School of Medicine, Stanford, California 8 Peter MacCallum Cancer Centre, St. Vincent's Hospital and University of Melbourne, Melbourne, Australia 9 Royal North Shore Hospital, Sydney, Australia 10 Division of Hematology and Hemostaseology, Medical University of Vienna, Wien, Austria 11 UCSD Moores Cancer Center, San Diego, California 12 Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, Barcelona, Spain 13 Niguarda Ca' Granda Hospital, Milan, Italy 14 Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, Texas 15 The Ohio State University Comprehensive Cancer Center, Columbus, Ohio 16 The Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds, UK 17 Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California Correspondence Talha Munir, Department of Haematology, Abstract St. James's Hospital, Beckett St, Leeds, UK LS9 Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved in the United 7TF. Email: tmunir@nhs.net States and Europe for treatment of patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 RESONATE study showed improved Funding information Janssen Pharmaceuticals; Pharmacyclics LLC, efficacy of single-agent ibrutinib over ofatumumab in patients with relapsed/refractory an AbbVie Company CLL/SLL, including those with high-risk features. Here we report the final analysis from RESONATE with median follow-up on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median progression-free survival (PFS) remained significantly longer for Trial Registration: clinicaltrials.gov identifier: NCT01578707. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. © 2019 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc. Am J Hematol. 2019;94:1353–1363. wileyonlinelibrary.com/journal/ajh 1353 1354 MUNIR ET AL. patients randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 0.148; 95% confidence interval [CI]: 0.113-0.196; P˂.001). The PFS benefit with ibrutinib vs ofatumumab was preserved in the genomic high-risk population with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of patients. Overall response rate with ibrutinib was 91% (complete response/complete response with incomplete bone marrow recovery, 11%). Overall survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib therapy, the safety profile remained consistent with prior reports; cumulatively, all-grade (grade ≥3) hypertension and atrial fibrillation occurred in 21% (9%) and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because of adverse events (AEs). These long-term results confirm the robust efficacy of ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or genomic features, with no unexpected AEs. This trial is registered at www.clinicaltrials.gov (NCT01578707). 1 | I N T RO D UC T I O N improved PFS, OS, and overall response rates (ORR) compared with ofatumumab and was generally well tolerated.16 RESONATE was also Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma the first randomized trial that identified adverse events (AEs) associated (SLL) are heterogenous diseases with outcomes that are affected with ibrutinib, such as atrial fibrillation and bruising, that have been 1 by clinical status and genetic aberrations. Patients with relapsed followed long-term with BTK inhibitors. Herein, we report the final long- CLL/SLL and known high-risk factors, such as 17p deletion (del[17p]), term follow-up efficacy and safety results of this landmark study, includ- TP53 aberrations (deletion/mutation), 11q deletion (del[11q]), or ing analyses of subgroups with high-risk genomic features. unmutated immunoglobulin heavy chain variable region (IGHV) gene, have a poor prognosis, and recent International Workshop on Chronic 2 | METHODS Lymphocytic Leukemia (IWCLL) guideline updates recommend testing for these high-risk factors to aid in treatment decisions.2-6 Chemo- 2.1 | Patients immunotherapy has been at the forefront of treatment of CLL/SLL in the past decade, resulting in improved progression-free survival (PFS) Detailed eligibility criteria have been previously published.16 Briefly, and overall survival (OS) outcomes for untreated patients requiring patients with active relapsed/refractory CLL or SLL with measurable therapy.7-11 Additionally, treatment of relapsed CLL/SLL with combi- nodal disease by computed tomography (CT) who failed ≥1 prior line of nation chemoimmunotherapy resulted in modest improvements in therapy and met the International Workshop on Chronic Lymphocytic PFS and, in some cases, OS.12-14 In the past, however, once patients Leukemia (IWCLL) 200817 guidelines for requiring therapy, but were not became refractory to chemoimmunotherapy, especially those with candidates for purine analog therapy (see Supplementary Methods), were early relapse or high-risk genomic features, treatment options were eligible for inclusion in the study. All patients provided written informed limited and survival time was short. consent. The study was approved by the institutional review board or The introduction of targeted therapy to the armamentarium of independent ethics committee at each participating institution and was CLL/SLL therapy has dramatically improved treatment outcomes in conducted in accordance with the Declaration of Helsinki and Interna- patients refractory to chemoimmunotherapy. Ibrutinib, a first-in-class, tional Conference on Harmonisation Guideline for Good Clinical Practice. once-daily, covalent inhibitor of Bruton's tyrosine kinase (BTK; a B-cell The study was sponsored by Pharmacyclics LLC, an AbbVie Company, receptor signaling kinase expressed by various hematopoietic cells, and Janssen Research and Development LLC. B-cell lymphomas, and leukemias), was one such therapy introduced in this relapsed and refractory CLL/SLL population that has since 2.2 | Study Design revolutionized therapy.15 RESONATE was the first multicenter, open-label, randomized phase 3 study that compared ibrutinib to RESONATE was a randomized, multicenter, open-label, phase 3 study ofatumumab treatment outcomes in previously treated patients with that evaluated the efficacy and safety of ibrutinib compared with CLL/SLL, leading to full FDA approval of ibrutinib (after prior acceler- ofatumumab in previously treated patients with relapsed or refractory ated approval), including in patients with del(17p). The analysis from CLL/SLL (clinicaltrials.gov number NCT01578707). Enrollment was the first report of this trial demonstrated that ibrutinib significantly from June 2012 to April 2013. Patients were randomly assigned 1:1 MUNIR ET AL. 1355 to receive either oral ibrutinib 420 mg once daily (until disease pro- 3 | RESULTS gression or unacceptable toxicity) or intravenous ofatumumab for up to 24 weeks at an initial dose of 300 mg at week one, followed by a 3.1 | Patient features dose of 2000 mg weekly for seven weeks and then every four weeks Baseline characteristics of patients randomized to ibrutinib (n = 195) for 16 weeks. Stratification was by purine analog refractory status or ofatumumab (n = 196) are shown in Table S1.19 Similar proportions (defined as no response to or relapse within 12 months of last dose of of patients in the ibrutinib and ofatumumab arms had high-risk fea- purine analog) and presence or absence of del(17p). Based on durable tures, including del(17p) (32% and 33%, respectively), mutated TP53 responses in the ongoing pivotal phase 2 study PCYC-1102,18 a pro- (51% and 46%, respectively), del(11q) (33% and 31%, respectively), tocol amendment was instituted in August 2013 to allow patients on unmutated IGHV (73% and 63%, respectively), and complex karyotype the ofatumumab arm to cross over to receive ibrutinib. Following (25% and 22%, respectively) (Table S1). The majority of patients in study closure, eligible patients could continue to receive ibrutinib both the ibrutinib and ofatumumab arms (86% and 79%, respectively) treatment in a long-term extension study (PCYC-1145-LT; comprised the high-risk population, defined as having any of the fol- clinicaltrials.gov number NCT03229200). lowing: del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status. 2.3 | Assessments The final analysis was performed upon study closure. Median follow- PFS per investigator assessment was based on IWCLL 2008 criteria,17 with up on the study of patients initially assigned to ibrutinib was 65.3 months the 2012 clarification that treatment-related lymphocytosis was not consid- (range: 0.3−71.6), and median duration of ibrutinib therapy was ered progressive disease (PD) if in the setting of improvement in other dis- ease parameters. Other endpoints were ORR per investigator assessment T A B L E 1 Patient disposition and treatment exposure during (defined as the proportion of patients who achieved complete response study treatment [CR], CR with incomplete bone marrow recovery [CRi], nodular partial Ibrutinib Ofatumumab response, partial response, or partial response with lymphocytosis),17 OS, Parameter, n (%) (n = 195) (n = 196) and safety. Functional Assessment of Chronic Illness Therapy-Fatigue Duration of treatment, months, 41.0 (0.2-71.1) 5.3 (0.0-9.0) (FACIT-F) was a secondary endpoint; other patient-reported outcomes median (range) were exploratory endpoints. Methods for monitoring patients during Disposition of study treatment follow-up have been described and were continued through long-term Did not receive study drug 0 5 (2.6) follow-up. Details of assessments, including patient-reported outcomes and Completed treatment N/A 120 (61.2) cytogenetics, are provided in the Supplementary Methods. (ofatumumab arm only) Discontinued 195 (100.0) 71 (36.2) Progressive disease 72 (36.9) 36 (18.4) 2.4 | Statistical methods Study terminated by 43 (22.1) 0 Long-term efficacy, including PFS, OS, and ORR, were assessed in the sponsor intent-to-treat population. PFS and ORR were based on investigator Adverse event 32 (16.4) 7 (3.6) assessment (independent review committee assessments were per- Patient withdrawal 15 (7.7) 6 (3.1) formed only for the primary analysis).16 PFS and OS (with and without Deatha 13 (6.7) 9 (4.6) censoring at crossover for ofatumumab patients) were analyzed using Investigator decision 20 (10.3) 13 (6.6) Kaplan-Meier methodology and hazard ratio (HR) was estimated using Duration of treatment, years Cox regression model. In addition, the rank-preserving structural (randomized therapy)b failure time (RPSFT) randomization-based model was employed to ˃0 to 1 36 (18.5) 191 (97.4) estimate the OS HR using counterfactual survival times that would >1 to 2 25 (12.8) 0 have been observed in the absence of the extensive crossover. >2 to 3 31 (15.9) 0 Ofatumumab treatment was completed at the time of the primary >3 to 4 24 (12.3) 0 analysis and reported in the previous report. Long-term safety was >4 to 5 22 (11.3) 0 summarized by yearly interval for ibrutinib patients. >5 to 6 57 (29.2) 0 a These cases of death included the following: ibrutinib arm, pneumonia (n = 3), 2.5 | Data sharing statement sepsis (n = 2), unknown cause (sudden death, n = 2), neutropenic sepsis, terminal bowel cancer, lung infection, cardiac arrest, subdural hematoma, and Requests for access to individual participant data from clinical studies burns and ensuing complications in one patient each; ofatumumab arm, pneumonia (n = 2), upper respiratory tract infection, squamous cell carcinoma conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted of the neck, influenza A, aggressive squamous cell carcinoma of the scalp, through Yale Open Data Access (YODA) Project site at http://yoda. nocardiosis, fever of unknown origin, and bacteremia in one patient each. b yale.edu. Planned duration of treatment with ofatumumab was up to 24 weeks. 1356 MUNIR ET AL. 41 months (range: 0.2-71.1), with 41% of patients receiving more than 3.2 | Progression-free survival four years of therapy (Table 1). Among patients initially assigned to With an overall follow-up of 74 months, the median investigator ibrutinib, 43/195 (22%) remained on therapy until study closure (Table 1 assessed PFS per IWCLL criteria was 44.1 months (95% confidence and Figure S1). The most common reasons for ibrutinib discontinuation interval [CI]: 38.5-56.2) in the ibrutinib arm and 8.1 months (95% CI: prior to study closure were PD (72/195, 37%) and AEs (32/195, 16%). Pro- 7.8-8.3) in the ofatumumab arm. Similar to the prior analyses, PFS gressive disease was evidenced as Richter's transformation in 20 patients was significantly longer for patients assigned to ibrutinib than for (10%) in the ibrutinib arm, occurring in eight, four, six, zero, and two patients assigned to ofatumumab (HR: 0.148; 95% CI: 0.113-0.196; patients in years zero to one, one to two, two to three, three to four, and P˂.0001; Figure 1A). At the time of this analysis, 92% (180/196) of for to five, respectively. patients initially assigned to ofatumumab had a PFS event. At the Median follow-up of the 196 patients initially assigned to the 60-month landmark, the estimated PFS rates were 40% in the ofatumumab arm was 65.6 months (range: 0.1-73.9) and median dura- ibrutinib arm and 3% in the ofatumumab arm. Median PFS in patients tion of ofatumumab treatment was 5.3 months (range: 0-9.0). In total, in the high-risk population (with del[17p], TP53 mutation, del[11q], 133 of 196 patients (68%) crossed over to receive ibrutinib; 36% of and/or unmutated IGHV status) was 44.1 months (95% CI: 38.5-56.9) these patients (48/133) had received more than 4 years of next-line with ibrutinib and 8.0 months (95% CI: 6.4-8.2) with ofatumumab ibrutinib therapy, and 35% (47/133) were still receiving ibrutinib at the (HR: 0.110; 95% CI: 0.080-0.152) (Figure 1B). The PFS benefit of time of study closure. In addition, 15 of 196 patients (8%) had PD but ibrutinib vs ofatumumab was consistent across subgroups defined by exited the study on or before the protocol amendment allowing for patient baseline clinical and genomic risk factors; HRs ranged from crossover to receive ibrutinib. 0.042 to 0.306 (Figure 1C). (A) 100 Ibrutinib Ofatumumab (C) No. of Patients Hazard Ratio (95% CI) All patients 391 0.156 (0.119-0.204) 90 Ibrutinib Ofatumumab Age (n = 195) (n = 196) <70 233 0.120 (0.084-0.172) 80 Median PFS, mo 44.1 8.1 ≥70 158 0.219 (0.146-0.328) (95% CI) (38.5-56.2) (7.8-8.3) Gender Progression-free Survival (%) 70 Hazard ratio (95% CI) 0.148 (0.113-0.196) Male 266 0.176 (0.128-0.240) Female 125 0.119 (0.070-0.201) 60 Rai stage at baseline Stage 0–II 169 0.098 (0.062-0.154) 50 Stage III–IV 222 0.208 (0.149-0.290) 40 ECOG at baseline 0 159 0.168 (0.110-0.256) 30 1-2 232 0.150 (0.107-0.212) Bulky disease 20 <5 cm 165 0.168 (0.111-0.255) ≥5 cm 222 0.101 (0.068-0.152) 10 Cytopenias at baseline Yes 247 0.178 (0.129-0.246) 0 No 141 0.115 (0.070-0.189) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 High risk* Months Yes 322 0.110 (0.080-0.152) Patients at Risk Ibrutinib 195189 179 171 161 154149146138123 115110 105 99 92 84 82 80 77 70 65 56 33 5 No 69 0.306 (0.163-0.575) Ofatumumab 196 159 120 67 34 22 19 14 10 9 6 5 5 4 4 4 4 4 3 3 3 3 Del(11q) Yes 95 0.042 (0.018-0.098) No 164 0.229 (0.155-0.339) (B) 100 ||| Ibrutinib Ofatumumab Del(17p) Yes 127 0.123 (0.073-0.208) 90 Ibrutinib Ofatumumab No 264 0.162 (0.117-0.223) | | (n = 168) (n = 154) IGHV 80 | | Median PFS, mo 44.1 8.0 (95% CI) Mutated 85 0.200 (0.113-0.353) || (38.5-56.9) (6.4-8.2) Unmutated 181 0.103 (0.067-0.159) Progression-free Survival (%) 70 Hazard ratio (95% CI) 0.110 (0.080-0.152) ß2-microglobulin at baseline | ≤3.5 mg/L 58 0.077 (0.032-0.184) 60 || | | >3.5 mg/L 298 0.174 (0.130-0.234) 50 Prior lines of therapy | || 1 88 0.120 (0.064-0.225) 40 | 2 110 0.158 (0.093-0.268) | | | 3 70 0.113 (0.056-0.226) 30 4 48 0.176 (0.082-0.375) ≥5 75 0.109 (0.054-0.220) 20 Complex karyotype Yes 72 0.112 (0.054-0.233) 10 | No 228 0.159 (0.112-0.225) TP53 0 Mutated 147 0.176 (0.115-0.268) 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 Unmutated 156 0.147 (0.096-0.226) Months Patients at Risk 0.00 0.25 0.50 0.75 1.00 1.25 Ibrutinib 168164 156 148 140 134130127119107 100 96 93 87 80 73 71 70 67 62 58 50 29 3 Ibrutinib Better Ofatumumab Better Ofatumumab 154 123 89 44 20 13 11 8 5 4 2 1 1 1 1 1 1 1 0 F I G U R E 1 Progression-free survival (A) in the ITT population and (B) in the high-risk population (patients with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status). (C) Forest plot of HRs for progression-free survival by baseline subgroups (ITT population). CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; IGHV, immunoglobulin heavy-chain variable region gene; ITT, intention-to-treat; PFS, progression-free survival. *Patients with del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status MUNIR ET AL. 1357 (A) 100 1 2 (B) 100 | Del(17p) Del(11q) | 3 Neither | | | 4 90 | ≥5 90 | | | 80 80 | | | | | | || 70 70 Progression-free Survival (%) Progression-free Survival (%) | | | | | | 60 | 60 | | | | | | | | | ||| | ||| || | || 50 50 ||||| |||| | | | || | | || | || | 40 40 | | || | || | | | | ||| | | | | | | || | | | | | | | | | | | | 30 30 ||| | | || 20 20 Del(17p)* Del(11q)* Neither Lines of therapy 1 (n=35) 2 (n=57) 3 (n=32) 4 (n=27) ≥5 (n=44) (n=63) (n=50) (n=81) | 10 Median PFS, NR 67.3 44.1 33.0 27.3 || | 10 Median PFS, 40.6 60.7 42.5 mo (95% CI) (44.4-NE) (36.0-NE) (25.4-NE) (13.6-NE) (22.0-40.8) mo (95% CI) (25.4-44.6) (36.4-NE) (31.7-56.2) 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 Months Months Patients at Risk Patients at Risk 1: 35 35 34 33 32 31 30 30 30 29 26 26 26 24 21 19 19 19 19 17 16 14 7 2 Del(17p) 63 59 53 52 49 47 46 45 42 37 35 32 31 29 24 20 19 19 18 16 16 13 6 1 2: 57 54 53 51 47 46 45 44 42 40 37 36 34 33 32 29 29 29 29 28 26 24 18 3 Del(11q) 50 50 49 47 46 45 44 42 39 35 34 34 33 30 30 30 29 29 29 26 23 20 14 1 3: 32 31 29 28 26 25 25 24 22 18 17 17 16 15 15 14 13 12 10 9 9 8 4 Neither 81 79 76 71 65 61 58 58 56 50 45 43 40 39 37 33 33 31 29 27 25 22 12 3 4: 27 26 24 21 21 19 18 18 17 16 16 12 12 11 11 10 10 10 10 9 8 7 4 ≥5: 44 43 39 38 35 33 31 30 27 20 19 19 17 16 13 12 11 10 9 7 6 3 (C) 100 Complex karyotype No complex karyotype (D) 100 Mutated IGHV Unmutated IGHV | | 90 90 | | | 80 | 80 | | | | | | 70 | 70 Progression-free Survival (%) Progression-free Survival (%) | | | | 60 | 60 | | | 50 50 | | | | | | | ||| |||||| ||| | 40 | | || |||| |||| | 40 | | | | || ||| | | || || | | 30 30 | || | | | Complex karyotype No complex Mutated IGHV Unmutated IGHV (n=39) karyotype (n=114) (n=36) (n=98) 20 20 Median PFS, mo | Median PFS, mo 40.8 (24.4-67.7) 44.6 (37.9-61.0) 48.4 (35.6-60.8) 49.7 (40.2-NE) (95% CI) (95% CI) 10 10 Hazard ratio (95% CI) 1.279 (0.801-2.044) Hazard ratio (95% CI) 1.208 (0.741-1.971) 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 Months Months Patients at Risk Patients at Risk Complex karyotype 39 37 34 30 28 28 27 27 25 21 21 19 17 16 14 13 13 12 12 12 11 9 7 1 Mutated IGHV 36 34 33 32 31 29 28 28 26 24 24 23 22 21 20 17 17 16 14 11 8 6 3 No complex karyotype 114 112 106 104 96 92 89 87 82 74 69 66 64 60 55 51 49 48 46 44 41 36 22 3 Unmutated IGHV 98 95 90 88 82 79 77 76 74 66 60 59 58 55 51 46 45 44 43 42 40 36 19 2 Both del(17p) and TP53 mutation (E) 100 TP53 mutated No TP53 mutation (F) 100 Neither del(17p) nor TP53 mutation Either del(17p) or TP53 mutation 90 90 || 80 80 | | 70 70 Progression-free Survival (%) Progression-free Survival (%) | 60 60 | | 50 50 || | ||| ||| ||| | | || || 40 40 | | 30 | 30 TP53 mutated No TP53 mutation | || || | | (n=79) (n=75) Both del(17p) and Neither del(17p) nor Either del(17p) or 20 20 TP53 mutation TP53 mutation TP53 mutation Median PFS, mo 40.7 (25.4-44.6) 56.9 (36.4-NE) (n=38) (n=68) (n=48) (95% CI) || 10 10 Median PFS, 40.6 56.9 40.7 Hazard ratio (95% CI) 1.731 (1.156-2.593) mo (95% CI) (17.6-56.2) (36.4-NE) (25.4-57.3) 0 0 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 Months Months Patients at Risk Patients at Risk Both del(17p) and TP53 mutated 79 75 71 65 61 58 55 55 51 46 42 40 39 38 34 29 28 27 25 23 21 15 6 1 TP53 mutation: 38 34 30 29 27 26 25 25 23 21 20 19 18 18 16 13 12 12 11 9 9 7 2 0 No TP53 mutation 75 75 72 70 68 64 63 62 58 52 48 47 45 42 42 41 40 39 38 34 31 28 18 2 Neither del(17p) nor 68 68 65 63 61 58 57 56 53 48 45 44 42 39 39 38 37 36 35 31 28 26 17 2 TP53 mutation: Either del(17p) or 48 48 48 43 41 38 36 36 33 29 25 24 24 23 21 19 19 18 17 17 15 10 5 1 TP53 mutation: F I G U R E 2 Progression-free survival by lines of therapy and genomic subgroups in the ibrutinib arm (ITT population). (A) Analysis by number of prior lines of therapy. (B) Analysis by del(17p) and del(11q)*. (C) Analysis by CK. (D) Analysis by IGHV mutation status. (E) Analysis by TP53 mutation status. (F) Analysis by del(17p) and/or TP53 mutation status. CI, confidence interval; CK, complex karyotype; FISH, fluorescence in situ hybridization; IGHV, immunoglobulin heavy-chain variable region gene; NE, not estimable; NR, not reached; PFS, progression-free survival. *Genomic abnormalities by FISH cytogenetics were categorized according to Döhner hierarchical classification Within the ibrutinib arm, median PFS by line of therapy was not (n = 32; 95% CI: 25.4-NE), 33.0 (n = 27; 95% CI: 13.6-NE), and reached in patients who received 1 prior line of therapy (n = 35; 95% CI: 27.3 months (n = 44; 95% CI: 22.0-40.8) for patients who received two, 44.4-not estimable [NE]) and was 67.3 (n = 57; 95% CI: 36.0-NE), 44.1 three, four, or five or more prior lines of therapy, respectively (Figure 2A). 1358 MUNIR ET AL. Purine analog refractoriness had no impact on PFS, with median PFS of was 13.5 months (95% CI: 6.7-26.6). Median OS in patients with PD dur- 44.6 (n = 87; 95% CI: 31.7-57.4) and 44.0 months (n = 108; 95% CI: ing the first two years (n = 33) was 26.0 months (95% CI: 13.6-32.4), and 35.1-60.7) in patients who were and were not refractory at study enroll- in patients with PD at any time in the first four years (n = 72) was ment, respectively (HR: 0.983; 95% CI: 0.685-1.413). 39.3 months (95% CI: 34.2-50.8). Median PFS was 40.6 months (95% CI: 25.4-44.6) in the del(17p) subgroup (n = 63) and 60.7 months (95% CI: 36.4-NE) in the 3.5 | Patient-reported outcomes del(11q) subgroup (n = 50; Figure 2B). Median PFS was 42.5 months (95% CI: 31.7-56.2) in patients with neither del(11q) nor del(17p) Patient-reported outcomes during long-term follow-up were evalu- (n = 81). In an exploratory analysis that combined data from patients ated using FACIT-F and the EuroQol 5-Dimensions 5-Level (EQ-5D- with del(17p) and those with TP53 mutation, median PFS was 5L; © EuroQol Research Foundation. EQ-5D™ is a trade mark of the 40.6 months (95% CI: 27.5-44.1) in the subgroup with del(17p) EuroQol Research Foundation) questionnaires (Supplementary and/or TP53 mutation (n = 104) and 56.9 months (95% CI: 27.5-NE) Methods). The mean (standard deviation [SD]) FACIT-F score at baseline in the del(11q) subgroup (n = 33) (Figure S2). Median PFS was not was 36.2 (12.3) for the ibrutinib arm and 35.6 (11.9) for the ofatumumab reached (95% CI: 42.5-NE) in patients with neither del(11q) nor arm. A greater proportion of patients achieved clinically meaningful del(17p)/TP53 mutation (n = 58). Patients with complex karyotype improvement in FACIT-F score with ibrutinib (65%) than with (n = 39) had a median PFS of 40.8 months (95% CI: 24.4-67.7) and ofatumumab (49%; Figure S5A). At baseline, mean (SD) EQ-5D-5L visual patients without a complex karyotype (n = 114) had a median PFS of analog scale (VAS) scores were 66.5 (21.4) for ibrutinib and 67.6 (19.7) 44.6 months (95% CI: 37.9-61.0) (HR: 1.279; 95% CI: 0.801-2.044) for ofatumumab. Similarly, a greater proportion of patients achieved clini- (Figure 2C). Patients with mutated (n = 36) and unmutated (n = 98) cally meaningful improvement in their EQ-5D-5L VAS Scores with IGHV had similar PFS (median 48.4 [95% CI: 35.6-60.8] vs 49.7 [95% ibrutinib (66%), than with ofatumumab (45%). Improvements in the CI: 40.2-NE] months; HR: 1.208; 95% CI: 0.741-1.971) (Figure 2D). FACIT-F score and the EQ-5D-5L VAS were largely maintained over Patients without TP53 mutation (n = 75) had a median PFS of time with ibrutinib (Figures S5B, S5C). 56.9 months (95% CI: 36.4-NE), longer than the median PFS of 40.7 months (95% CI: 25.4-44.6) for patients with TP53 mutations 3.6 | Adverse events (n = 79) (HR: 1.731; 95% CI: 1.156-2.593) (Figure 2E). Median PFS was 40.6 months (95% CI: 17.6-56.2) for patients with both del(17p) At final analysis, the most commonly reported treatment-emergent AEs and TP53 mutation (n = 38), 40.7 months (95% CI: 25.4-57.3) for of any grade (occurring in ≥20% of the population) remained consistent those with either del(17p) or TP53 mutation (n = 48), and with previous reports of patients treated with ibrutinib (Figure S6) and 56.9 months (95% CI: 36.4-NE) for those with neither del(17p) nor generally decreased over time for patients remaining on ibrutinib ther- TP53 mutation (n = 68; Figure 2F). apy, with few exceptions (hypertension and bruising). Over up to 71 months of treatment, commonly reported grade ≥3 hematologic AEs included neutropenia (25%), thrombocytopenia (10%), and anemia (9%). 3.3 | Overall response Commonly reported grade ≥3 nonhematologic AEs included pneumonia At extended follow-up, the cumulative ORR was 91% for ibrutinib. (21%), hypertension (9%), urinary tract infection (7%), diarrhea (7%), and The proportion of patients with a best response of CR/CRi increased atrial fibrillation (6%). Overall, 19 patients (10%) in the ibrutinib arm over time to 11% with current follow-up (Figure S3). experienced major hemorrhage. The prevalence of any grade ≥3 AEs with ibrutinib decreased after the first year and remained stable thereaf- ter, with rates of 62%, 48%, 46%, 46%, 48%, and 32% during years zero 3.4 | Overall survival to one, one to two, two to three, three to four, four to five, and five to With up to 6 years of post-randomization follow-up, median OS was six, respectively. 67.7 months (95% CI: 61.0-NE) in the ibrutinib arm and 65.1 months In line with the overall prevalence, the prevalence of most (95% CI: 50.6-NE) in the ofatumumab arm, irrespective of the extensive grade ≥3 AEs of clinical interest with ibrutinib decreased over time (68%) crossover to ibrutinib (HR: 0.810; 95% CI: 0.602-1.091) (Figure 3). With up to 6 years of follow-up, grade ≥3 infections (Figure S4A). To compare OS outcomes between treatment arms occurred in 87 patients (45%) in the ibrutinib arm (Figure S7), occur- accounting for the extensive crossover from ofatumumab to ibrutinib ring at a median time of onset of 7.0 months (range: 0.0 to 63.0). The treatment, OS was analyzed with censoring at time of crossover and was most frequent categories/types of grade ≥3 infections included pneu- better among patients initially assigned to ibrutinib than to ofatumumab monia (21%), urinary tract infection (7%), cellulitis (4%), sepsis (4%), (HR: 0.639; 95% CI: 0.418-0.975) (Figure S4B). A sensitivity analysis of and lung infection (4%). The prevalence of grade ≥3 atrial fibrillation OS adjusting for crossover based on the RPSFT method also showed was 4%, 0%, 2%, 2%, 1%, and 0% over years zero to one, one to two, continued OS benefit with ibrutinib compared with ofatumumab (HR: two to three, three to four, four to five, and five to six, respectively 0.240; 95% CI: 0.105-0.550). In patients with del(17p), median OS was (Figure 3). The prevalence of all-grade atrial fibrillation was 6%, 5%, 61.8 months (95% CI: 38.7-NE) in the ibrutinib arm. Among patients in 8%, 8%, 6%, and 4% over years zero to one, one to two, two to three, the ibrutinib arm with PD in the first year of study (n = 19), median OS three to four, four to five, and five to six, respectively. Overall, MUNIR ET AL. 1359 patients who experienced hypertension were treated with concomi- >0-1 year (n = 195) Neutropenia >1-2 years (n = 160) tant antihypertensive medication during the treatment-emergent >2-3 years (n = 137) Anemia >3-4 years (n = 103) period (26/41, 63%). Other AEs of clinical interest with ibrutinib Thrombocytopenia >4-5 years (n = 79) included peripheral neuropathy (all grade: n = 26 [13%]; grade ≥3: >5 years (n = 57) n = 1 [0.5%]), congestive heart failure (all grade: n = 9 [5%]; grade ≥3: Pneumonia n = 5 [3%]), and ventricular arrhythmia (all grade: n = 2 [1%]; no Diarrhea grade ≥3 events). Hypertension Among patients in the ibrutinib arm, 17% (34/195) and 65% Atrial fibrillation (126/195) of patients required dose reductions and dose holds, respectively, to manage AEs. Among the 34 patients with dose reduc- Fatigue tions due to AEs, eight (24%) ultimately discontinued because of an Arthralgia AE, of which 4 discontinuations (12%) were due to the same AE that Congestive heart failure (combined terms) led to dose reduction. Of the 126 patients with a dose held because Peripheral neuropathy (combined terms) of AEs, 20 patients (16%) ultimately discontinued ibrutinib because of an AE, of which 13 discontinuations (10%) were due to the same AE Major hemorrhage (combined terms) that led to the dose hold. The frequency of AEs that led to ibrutinib Infections (combined terms) discontinuation remained consistent over time, and occurred in 6%, 0 10 20 30 40 50 60 70 80 90 100 3%, 4%, 4%, 6%, and 4% of patients during years zero to one, one to Patients (%) two, two to three, three to four, four to five, and five to six, respec- F I G U R E 3 Prevalence of grade ≥3 AEs of clinical interest over tively. Over the course of follow-up with a median treatment duration time for ibrutinib arm (ITT population). Prevalence was determined by of 41 months, 32 of 195 patients (16%) discontinued ibrutinib due to the proportion of patients with a given AE (existing event or new AEs, including 11 grade 5 events of sepsis (n = 3), pneumonia (n = 2), onset of an event) during each yearly interval. Multiple onsets of the unknown cause (sudden death, n = 2), lower respiratory tract infection same AE term within a specific yearly interval were counted once, and the same AE term continuing across several yearly intervals was (n = 1), lung infection (n = 1), cardiac arrest (n = 1), terminal bowel can- counted in each of the intervals. Congestive heart failure and cer (n = 1), subdural hematoma (n = 1), and serious burn and ensuing peripheral neuropathy were defined per terms included in the SMQ complications (n = 1). (narrow). Major hemorrhage (combined terms) was defined as any hemorrhagic event grade ≥3 in severity, or that results in one of the following: intraocular bleeding causing vision loss, need for a 3.7 | Response to next-line treatment following transfusion of ≥2 units of RBC or equivalent, hospitalization, or ibrutinib discontinuation prolongation of hospitalization. Infections (combined terms) include AEs reported under “infections and infestations” system organ class Best response to next-line CLL therapy was reported for 27 patients category. AE, adverse event; ITT, intention-to-treat; RBC, red after discontinuation of ibrutinib randomized therapy. Reasons for dis- blood cells continuation in these patients included PD (n = 22), AE (n = 3), and investigator decision (n = 2). Responses were observed in 10 of these 24 patients (12%) experienced atrial fibrillation of any grade, with a 27 patients upon next-line treatment, including patients who had dis- median duration of 10.0 days (range: 1-1323) for the events continued ibrutinib due to PD (eight of 22), AE (one of three), and (Table S2). Most patients who experienced atrial fibrillation had one physician decision (one of two). Next-line treatment regimens with or more relevant risk factors (22/24, 92%), such as a history of cardio- responders were venetoclax single agent (five responders of seven vascular disease (10/24, 42%), hypertension (9/24, 38%), and/or base- treated), idelalisib + rituximab (two of six), high-dose methylpredniso- line body mass index ˃25 kg/m 2 (11/24, 46%). Most received lone + monoclonal antibody (one of one, alemtuzumab), and investiga- concomitant medications (19/24, 79%), including antithrombotic med- tional agent(s) (two of three). ications in eight of 24 patients (33%). The prevalence of grade ≥3 hypertension was 4%, 8%, 7%, 7%, 8%, and 11% over years zero to 4 | DISCUSSION one, one to two, two to three, three to four, four to five, and five to six, respectively (Figure 3). A total of 41 patients (21%) experienced Targeted therapy with ibrutinib for relapsed CLL has changed the nat- hypertension of any grade (Figure S8), occurring at a median time of ural history of this disease, as first demonstrated in the trial described onset of 13.8 months (range: 1.0-54.0) and a median duration of herein. This 6-year update of the RESONATE study confirmed the 16.6 months (range: 0.1-64.5) for the events (Table S3). Most patients robust efficacy of ibrutinib in patients with relapsed or refractory CLL. who experienced hypertension had relevant risk factors (28/41, 68%) The median PFS of 44.1 months in the ibrutinib arm is substantially of either a history of hypertension or related disorders (21/41, 51%) superior to the median PFS in the comparator arm of ofatumumab or a history of other risk factors, such as diabetes mellitus, hyperlipid- (8.1 months) and to that of other treatments available at the time of emia, renal disease, smoking, or thyroid disease (19/41, 46%). Most study initiation. The efficacy of ibrutinib is confirmed in patients with 1360 MUNIR ET AL. high-risk clinical and genomic features, including TP53 alteration (dele- retrospective genetic/molecular analysis defining many of the sub- tion/mutation), unmutated IGHV status, complex karyotype, and ATM groups may be potential limitations in the interpretation of these aberrations (as shown by del[11q]). Analysis of OS is confounded by results. Development of acquired mutations in the B-cell receptor the high number of patients (n = 133) who crossed over to receive signaling pathway has been observed in patients relapsing during ibrutinib, with nonprogressing ofatumumab arm patients having the ibrutinib treatment and together with other as yet undefined mech- most indolent disease, and with ibrutinib use prolonging survival of anisms contributing to relapse may be associated with unstable the patients who crossed over. Despite this, when censored for cross- genomes. Answers to these questions are being actively pursued in over, OS was significantly improved in patients treated with ibrutinib ongoing studies. although the difference in the median OS for ibrutinib vs ofatumumab Unmutated IGHV and del(11q) have an adverse prognostic impact was small (2.6 months). While a larger difference was observed using on patients with CLL.2-5 The negative impact from these markers has the RPSFT method, the analysis was confounded by the design of the been substantially abrogated in the context of ibrutinib therapy, as study, which permitted early and extensive crossover, and the under- shown in this study and other studies.28,33 This is confirmed by the lying assumption of this method that there is a constant risk of death current results from RESONATE in which patients with del(11q) CLL throughout the study for both treatment arms. As expected, analysis appeared to have no decrement in benefit from continuous ibrutinib of OS outcomes by timing of relapse suggests that patients who expe- therapy. This is reflected in the median PFS for this group (n = 50), rienced PD earlier in the course of ibrutinib treatment (within the first which was 60.7 months and appeared to be longer than the median one or two years) had shorter OS, as compared to those who experi- PFS of the overall ibrutinib cohort. In addition, median PFS with enced PD at any time in the first four years. Ibrutinib was well toler- ibrutinib treatment was similar between patients with mutated and ated; the main reason for treatment discontinuation in this extended unmutated IGHV. Thus, our follow-up data suggest that IGHV muta- follow-up was PD rather than drug-related toxicity. The frequency tional status and del(11q) have no impact on the long-term outcomes and timing of Richter's transformation in ibrutinib-treated patients in with ibrutinib treatment. the RESONATE study are consistent with emerging data from clinical The ORR with ibrutinib remains high with longer follow-up (91%) studies with novel agents and historical data with chemotherapy- and was similar to rates reported with a median follow-up of based regimens.20-27 Notably, the patient population in the RESO- 44 months (91%).19 The CR/CRi rates have increased over time with NATE study was characterized by a high prevalence of factors previ- ibrutinib treatment, approaching a plateau beyond 3.5 years (9% and ously identified as associated with increased risk of Richter's 11% with median 44 and 64 months of follow-up, respectively). This transformation, including genomic risk factors and heavy prior treat- is consistent with deepening of response with continuous ibrutinib ment burden. Most cases of Richter's transformation were identified therapy for responding patients and is similar to the improved early in the course of ibrutinib treatment, with almost half of cases responses observed over time with longer follow-up in patients with occurring in the first year and all but two of the remaining cases relapsed/refractory CLL in the HELIOS study and in the phase occurring during years 2 and 3. 2 PCYC-1102/1103 study.31,34 Notably, the proportion of patients Studies have shown that patients with del(17p) CLL treated who reported clinically meaningful improvement in FACIT-F score with standard chemoimmunotherapy regimens have poor out- was greater with ibrutinib than ofatumumab, and the improvement 7,12,28-30 comes. The 5-year follow-up data from the relapsed/ was maintained over time. refractory cohort of the phase 2 PCYC-1102/1103 study with Assessment of long-term safety data is an important factor with single-agent ibrutinib showed a lower PFS rate in patients with continuous therapy, especially given the extended progression-free del(17p) than in patients without del(17p). 31 The 3-year follow-up efficacy conferred by ibrutinib treatment. This update confirms that of the RESONATE study reported the effectiveness of ibrutinib in ibrutinib is well tolerated, and the prevalence of most grade ≥3 AEs of patients regardless of del(17p).19 In this final analysis of RESO- clinical interest decreased with each subsequent year of treatment, NATE with 6 years of follow-up, we confirm no significant differ- apart from hypertension, in which prevalence remained relatively con- ence in PFS for ibrutinib-treated patients with or without del(17p). sistent from year to year. During prolonged follow-up, the overall However, when data from patients with TP53 mutation were prevalence of treatment-emergent atrial fibrillation and hypertension pooled with those with del(17p) in an exploratory analysis, we of any grade were 12% and 21%, respectively. These rates were simi- observed a lower PFS rate in the subgroup of patients with del(17p) lar to those reported earlier in RESONATE with a median 44-month and/or TP53 mutation than in patients without either of these follow-up (11% and 20%, respectively). In addition, most of the abnormalities. Consistent with findings reported with earlier RESO- patients who developed atrial fibrillation or hypertension had relevant NATE follow-up,32 the subset of ibrutinib-treated patients with risk factors for developing these complications.35-37 It is important to both del(17p) and TP53 mutation trended to have shorter PFS rela- note that the incidence of major hemorrhage with continued treat- tive to patients without either of these high-risk features. In con- ment was consistently low over the extended follow-up period. In trast to the earlier report from RESONATE, PFS outcomes in addition, substantial proportions of ibrutinib-treated patients who patients with either del(17p) or TP53 mutation (but not both) were experienced dose reductions or dose holds due to AEs were able to similar to that of patients with both del(17p) and TP53 mutation. restart or remain on ibrutinib treatment (15% and 25% of these The small number of patients in these subgroups and the patients, respectively, remained on ibrutinib until study closure). There MUNIR ET AL. 1361 were no new or concerning AE trends or unexpected events noted paid speaker for Gilead and Celgene. S.C. has received honoraria from with extended follow-up, and the safety profile appears consistent Pharmacyclics LLC, an AbbVie Company, and Janssen; has been in a with earlier reports. consulting role for AbbVie, Celgene, Genentech, Pharmacyclics LLC, To conclude, these 6-year follow-up results from the RESONATE an AbbVie Company, Janssen, Novartis, Astellas, and AstraZeneca; study confirm the robust and durable efficacy of ibrutinib with has received research funding from AbbVie, Acerta, Celgene, Gilead, extended treatment in patients with relapsed or refractory CLL. The Janssen, Pharmacyclics LLC, an AbbVie Company, and Takeda; has improvement in outcomes is evident in all risk groups, including provided expert testimony for Genentech; has received travel, accom- patients with high-risk clinical and genomic features, and the safety modations and other expenses from AbbVie, BeiGene, Celgene, Gen- analyses established that continuous treatment with ibrutinib can be entech, Janssen, and Pharmacyclics LLC, an AbbVie Company; and delivered long-term to provide benefit to patients with CLL. has other relationships with BeiGene. C.S.T. has received honoraria from Janssen and Pharmacyclics LLC, an AbbVie Company, and ACKNOWLEDGMENTS research funding from Janssen. S.P.M. has received honoraria from and has been in a consulting role for Roche, AbbVie, Janssen, Gilead, The authors thank the patients who participated in this study and and GlaxoSmithKline; has received research funding from Roche, their supportive families, as well as the investigators, subinvestigators, AbbVie, and Janssen; and has been a paid speaker for Roche, AbbVie, and coordinators at each of the study sites. The authors thank Jerry Janssen, and Gilead. U.J. has received honoraria and research funding Ping of Pharmacyclics LLC, an AbbVie Company, for his contributions from Janssen, and has been in a consulting role for Janssen. T.J.K. has to the statistical analyses and Joris Diels of Janssen and Suzy Van been in a consulting role for AbbVie, Genentech-Roche, Gilead, Sanden of Janssen-Cilag Ltd for their contributions to the crossover- Pharmacyclics LLC, an AbbVie Company, and Celgene and has adjusted overall survival analysis using the rank-preserving structural failure time method. John C. Byrd is supported by the Four Winds received research funding from AbbVie, Genentech-Roche, Foundation, D. Warren Brown Foundation, Mr. and Mrs. Michael Pharmacyclics LLC, an AbbVie Company, and Oncternal. C.M. has Thomas, Sullivan CLL Research Foundation, and R35 CA197734. Edi- been in a consulting role for Pharmacyclics LLC, an AbbVie Company, torial support was provided by Melanie Sweetlove, MSc, and was Janssen, and AbbVie. M.M. has received honoraria from and has been funded by Pharmacyclics LLC, an AbbVie Company. in a consulting role for AbbVie, Janssen, Gilead, Roche, and AstraZeneca; has been a paid speaker for AbbVie, Janssen, and Gilead; has received research funding from Roche; and has received travel, accommodations, CONF LICT OF IN TE RE ST and expenses reimbursement from AbbVie, Janssen, and AstraZeneca. T.M. has received honoraria from Janssen, AbbVie, Gilead, Alexion, J.A.B. has received honoraria from Janssen; has been in a consulting role Novartis, and Roche; and has been in a consulting role for MorphoSys for Janssen; has received research funding from Gilead, TG Therapeutics, and Sunesis. J.R.B. has received honoraria from Janssen and Teva; has Pharmacyclics LLC, an AbbVie Company, and BeiGene; has been a paid been in a consulting role for AbbVie, Acerta, Astellas, BeiGene, speaker for Gilead, TG Therapeutics, Pharmacyclics LLC, an AbbVie Com- Genentech/Roche, Gilead, Juno/Celgene, Kite, Loxo, Novartis, Pfizer, pany, Novartis, and Janssen; and has received travel, accommodations, Pharmacyclics LLC, an AbbVie Company, Redx, Sun, Sunesis, TG and expenses reimbursement from Gilead, TG Therapeutics, Therapeutics, and Verastem; has received research funding from Pharmacyclics LLC, an AbbVie Company, Novartis, and Janssen. J.C.By. Gilead, Loxo, Sun, and Verastem; and has served on data safety moni- has been in consulting role for Janssen; has reported research funding toring committees for MorphoSys and Invectys. S.O. has been in from Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, a consulting role for Amgen, Astellas, Celgene, GlaxoSmithKline, and BeiGene; and has been a paid speaker for Pharmacyclics LLC, an Janssen Oncology, Aptose Biosciences, Vaniam Group, AbbVie, AbbVie Company, Gilead, TG Therapeutics, Novartis, and Janssen; and Alexion, Verastem, and Eisai; has received research funding from received travel, accommodations, and expenses reimbursement from Kite, Regeneron, and Acerta; and has been in a consulting role and Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, and received research funding from Gilead, Pharmacyclics LLC, an AbbVie TG Therapeutics. P.H. has received honoraria from, has been in a con- Company, TG Therapeutics, Pfizer, and Sunesis. J.C.Ba. has received sulting role for and has received research funding from Janssen, honoraria from Janssen; has been in a consulting role for Genentech, Pharmacyclics LLC, an AbbVie Company, and AbbVie; and has received Gilead, Bayer, Pharmacyclics LLC, an AbbVie Company, AbbVie, travel, accommodations, and expenses reimbursement from Janssen and AstraZeneca, and Sandoz; and has received research funding from Pharmacyclics LLC, an AbbVie Company, Oncternal Therapeutics, and AbbVie. S.D. is an employee of Pharmacyclics LLC, an AbbVie Company, AbbVie. P.M.B. has been in a consulting role for Pharmacyclics LLC, and owns stock in AbbVie, Celgene, Gilead, GlaxoSmithKline, and an AbbVie Company, and AbbVie, and has received research funding Exelixis. A.S. is an employee of Pharmacyclics LLC, an AbbVie Company, from Pharmacyclics LLC, an AbbVie Company. N.M.R. has received and owns stock in AbbVie. J.P.D. is an employee of Pharmacyclics LLC, honoraria from and has been in a consulting role for Bristol-Myers an AbbVie Company, and owns stock in AbbVie and was formerly Squibb (BMS), Genentech, AbbVie, Gilead, AstraZeneca, and Celgene; employed by and owned stock in CTI BioPharma. J.W. has been in a con- has received research funding from BMS and Merck; and has been a sulting role for Pharmacyclics LLC, an AbbVie Company, and Janssen; 1362 MUNIR ET AL. and has received research funding from Pharmacyclics LLC, an AbbVie 11. Keating MJ, O'Brien S, Albitar M, et al. Early results of a chemo- Company, Janssen, AbbVie, Morphosys, Karyopharm, and Loxo. immunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. 2005;23(18):4079-4088. 12. Fischer K, Cramer P, Busch R, et al. 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