Leukemia (2020) 34:787–798 https://doi.org/10.1038/s41375-019-0602-x ARTICLE Chronic lymphocytic leukemia Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of follow-up from the phase 3 RESONATE-2 study Jan A. Burger1 Paul M. Barr2 Tadeusz Robak3 Carolyn Owen4 Paolo Ghia 5 Alessandra Tedeschi6 ● ● ● ● ● ● Osnat Bairey7 Peter Hillmen8 Steven E. Coutre9 Stephen Devereux10 Sebastian Grosicki11 Helen McCarthy12 ● ● ● ● ● ● David Simpson13 Fritz Offner14 Carol Moreno15 Sandra Dai16 Indu Lal16 James P. Dean16 Thomas J. Kipps17 ● ● ● ● ● ● Received: 11 April 2019 / Revised: 8 August 2019 / Accepted: 22 August 2019 / Published online: 18 October 2019 © The Author(s) 2019. This article is published with open access Abstract RESONATE-2 is a phase 3 study of first-line ibrutinib versus chlorambucil in chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Patients aged ≥65 years (n = 269) were randomized 1:1 to once-daily ibrutinib 420 mg 1234567890();,: continuously or chlorambucil 0.5–0.8 mg/kg for ≤12 cycles. With a median (range) follow-up of 60 months (0.1–66), 1234567890();,: progression-free survival (PFS) and overall survival (OS) benefits for ibrutinib versus chlorambucil were sustained (PFS estimates at 5 years: 70% vs 12%; HR [95% CI]: 0.146 [0.098–0.218]; OS estimates at 5 years: 83% vs 68%; HR [95% CI]: 0.450 [0.266–0.761]). Ibrutinib benefit was also consistent in patients with high prognostic risk (TP53 mutation, 11q deletion, and/or unmutated IGHV) (PFS: HR [95% CI]: 0.083 [0.047–0.145]; OS: HR [95% CI]: 0.366 [0.181–0.736]). Investigator-assessed overall response rate was 92% with ibrutinib (complete response, 30%; 11% at primary analysis). Common grade ≥3 adverse events (AEs) included neutropenia (13%), pneumonia (12%), hypertension (8%), anemia (7%), and hyponatremia (6%); occurrence of most events as well as discontinuations due to AEs decreased over time. Fifty-eight percent of patients continue to receive ibrutinib. Single-agent ibrutinib demonstrated sustained PFS and OS benefit versus chlorambucil and increased depth of response over time. Introduction Supplementary information The online version of this article (https:// Chronic lymphocytic leukemia (CLL) predominantly doi.org/10.1038/s41375-019-0602-x) contains supplementary affects older individuals who frequently have comorbidities material, which is available to authorized users. * Jan A. Burger 8 The Leeds Teaching Hospitals, St. James Institute of Oncology, jaburger@mdanderson.org University of Leeds, Leeds, UK 9 1 Stanford Cancer Center, Stanford University School of Medicine, Department of Leukemia, University of Texas MD Anderson Stanford, CA, USA Cancer Center, Houston, TX, USA 10 2 Kings College Hospital, NHS Foundation Trust, London, UK Wilmot Cancer Institute, University of Rochester Medical Center, 11 Rochester, NY, USA Department of Hematology and Cancer Prevention, Silesiam 3 Medical University, Katowice, Poland Medical University of Lodz, Copernicus Memorial Hospital, 12 Lodz, Poland Royal Bournemouth General Hospital, Bournemouth, UK 4 13 Tom Baker Cancer Centre, University of Calgary, Calgary, AB, North Shore Hospital, Auckland, New Zealand Canada 14 Universitair Ziekenhuis Gent, Gent, Belgium 5 Università Vita-Salute San Raffaele and IRCCS Ospedale San 15 Hospital de la Santa Creu i Sant Pau, Autonomous University of Raffaele, Milan, Italy Barcelona, Barcelona, Spain 6 ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy 16 Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA, USA 7 Rabin Medical Center, Petah Tikva, Israel and Sackler Faculty of 17 UCSD Moores Cancer Center, San Diego, CA, USA Medicine, Tel Aviv University, Tel Aviv, Israel 788 J. A. Burger et al. that may preclude the use of intensive chemoimmunother- confirmation of PD, patients randomized to chlorambucil apy regimens, such as fludarabine, cyclophosphamide, and were eligible to cross over to second-line treatment with rituximab (FCR) [1–3]. Before establishment of the ibrutinib. chlorambucil-based CD20 combinations, single-agent This study was conducted according to principles of the chlorambucil was considered a standard of care in older Declaration of Helsinki and the International Conference on patients with CLL [4, 5]. Harmonisation Guidelines for Good Clinical Practice and Ibrutinib is a first-in-class, oral, once-daily inhibitor of was approved by the institutional review boards of partici- Bruton’s tyrosine kinase (BTK), which as a single agent has pating institutions. All patients provided written informed led to prolonged progression-free survival (PFS) and overall consent. This study was registered with ClinicalTrials.gov, survival (OS) in patients with previously treated CLL [6, 7]. numbers NCT01722487 and NCT01724346. RESONATE-2 is an international phase 3 study evaluating the efficacy and safety of first-line ibrutinib compared with Endpoints and assessments chlorambucil in older patients with CLL or small lympho- cytic lymphoma (SLL) [8]. The primary analysis (median Endpoints included PFS, OS, overall response rate (ORR), follow-up of 18.4 months) demonstrated an 84% reduction improvement in hematologic parameters, patient-reported in the risk of disease progression (PD) or death (as assessed outcomes, and safety. Long-term PD and response were by an independent review committee) and significant assessed by the investigator per 2008 International Work- improvement in OS for ibrutinib compared with chlor- shop on CLL (iwCLL) criteria [12]. Long-term safety data ambucil, supporting the initial approval of first-line ibrutinib are reported for patients who were initially randomized to for CLL/SLL in the United States and for CLL in the ibrutinib. Nonhematologic adverse events (AEs) were gra- European Union, with ibrutinib now approved for CLL in ded using Common Terminology Criteria for Adverse over 90 countries [8–10]. Data previously reported from this Events, v4.03 [13]. Hematologic AEs were graded using study after a median follow-up of 28.5 months demon- iwCLL criteria [12]. strated a sustained PFS benefit for ibrutinib and improved depth of response over time, with no new unexpected safety Statistical analysis concerns [11]. Continued long-term study follow-up is important to provide quantitative assessments of response PFS and OS were analyzed according to the Kaplan–Meier durability, dimensions of patients’ well-being, and safety method. To adjust for the impact of crossover on OS, sen- with continuous single-agent ibrutinib treatment to inform sitivity analyses were performed as previously described clinical practice. [14]. Herein, we present the efficacy and safety outcomes for first-line ibrutinib treatment after a median follow-up of Data sharing statement 5 years from the RESONATE-2 study. This represents the longest follow-up to date from a phase 3 trial of BTK- Requests for access to individual participant data from directed therapy in the first-line setting for CLL. clinical studies conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted through Yale Open Data Access Project site at http://yoda.yale.edu. Subjects and methods Study design and population Results RESONATE-2 collectively includes the phase 3, open- Patients label, international, randomized study PCYC-1115 and extension study (PCYC-1116) comparing the efficacy and A total of 269 patients were randomized to ibrutinib (n = safety of ibrutinib versus chlorambucil in first-line CLL/ 136) or chlorambucil (n = 133; Supplementary Fig. 1). As SLL. Detailed methods have been previously reported [8]. previously reported, baseline characteristics were well Briefly, previously untreated patients without chromosome balanced across treatment arms (Table 1) [8]. Treatment 17p deletion [del(17p)] aged ≥65 years with CLL/SLL with first-line ibrutinib was ongoing in 79 (58%) patients requiring therapy per published criteria [12] were rando- after a median follow-up of 60 months (range, mized in a 1:1 ratio to oral ibrutinib (420 mg once daily) 0.1–66 months), while 56 (41%) discontinued treatment until PD or unacceptable toxicity, or 12 cycles of chlor- (Table 2). Of 133 patients randomized to chlorambucil, 96 ambucil (0.5 mg/kg, increased up to 0.8 mg/kg as tolerated, experienced PD (75 crossed over to ibrutinib and 21 did not on days 1 and 15 of each 28-day cycle). Following cross over after PD), one crossed over to receive ibrutinib Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of. . . 789 Table 1 Baseline characteristics Table 2 Duration of treatment with first-line ibrutinib Ibrutinib Chlorambucil Ibrutinib n = 136 n = 133 n = 136 Median age (range), years 73 (65–89) 72 (65–90) Median (range) duration of ibrutinib treatment, 57.1 (0.7–66.0) ≥70 years, n (%) 96 (71) 93 (70) monthsa Male, n (%) 88 (65) 81 (61) Treatment duration, n (%) ECOG performance status, n (%) >3 years 99 (73) 0 60 (44) 54 (41) >4 years 88 (65) 1–2 76 (56) 79 (59) >5 years 37 (27) Rai stage III or IV, n (%) 60 (44) 62 (47) Continuing ibrutinib on study, n (%) 79 (58) CIRS score >6, n (%) 42 (31) 44 (33) Continuing on commercial ibrutinib, n (%) 0 (0) Creatinine clearance <60 mL/min, 60 (44) 67 (50) Discontinued ibrutinib, n (%) 56 (41) n (%) Adverse event 29 (21) Bulky disease ≥5 cm, n (%) 54 (40) 40 (30) Progressive disease 8 (6) β2-microglobulin >3.5 mg/L, n (%) 85 (63) 89 (67) Death 8 (6) Hemoglobin ≤11 g/dL, n (%) 51 (38) 55 (41) Withdrawal by patient 7 (5) Platelet count ≤100 × 109/L, n (%) 35 (26) 28 (21) Investigator decision 4 (3) del(11q), n/N (%) 29/130 (22) 25/121 (21) a One patient did not receive any doses of ibrutinib Unmutated IGHV, n/N (%) 58/101 (57) 60/103 (58) TP53 mutation n/N (%) 12/124 (10) 3/94 (3) High prognostic risk features,a n (%) 74 (54) 69 (52) CIRS Cumulative Illness Rating Scale, ECOG Eastern Cooperative PFS in ibrutinib-treated patients compared with Oncology Group, IGHV immunoglobulin heavy chain variable region chlorambucil-treated patients. Ibrutinib dramatically a TP53 mutation, del(11q), and/or unmutated IGHV reduced the risk of PD or death by 97% compared with chlorambucil in patients with del(11q) (Fig. 3a). Ibrutinib reduced the risk of PD or death by 90% and 85% compared without documented PD, and 36 patients remained on the with chlorambucil for patients with either unmutated and chlorambucil arm without PD. Of 21 patients who did not mutated IGHV, respectively (Fig. 3b). PFS was not sig- cross over after PD (cross over to ibrutinib was not man- nificantly different for ibrutinib-treated patients with datory), six died, six were still on study without crossing unmutated and mutated IGHV. In patients treated with over, and six discontinued the study. Of the 36 patients ibrutinib, 79% of patients with del(11q) and 67% of patients remaining on the chlorambucil arm without PD, 16 were with unmutated IGHV were estimated alive and still on study, 11 discontinued the study, and nine died. progression-free at 5 years. Though patients with del(17p) CLL were excluded from the study, 12 ibrutinib-treated Progression-free survival and overall survival patients had TP53 mutation; median PFS was not reached for ibrutinib-treated patients with TP53 mutation or TP53 Ibrutinib significantly prolonged PFS compared with wild type (HR [95% CI: 0.866 [0.264–2.846]) and the chlorambucil (median not reached vs 15.0 months [95% 5-year estimates were 56% and 73%, respectively. Only confidence interval (CI): 10.2–19.4]), with an 85% reduc- three patients randomized to chlorambucil had TP53 tion in the risk of PD or death (hazard ratio, 0.146 [95% CI: mutation so no comparison could be made between 0.098–0.218]; Fig. 1). At 5 years, 70% of patients treated treatments. with ibrutinib and 12% with chlorambucil were estimated to Median OS was not reached for either the ibrutinib or be progression-free and alive. Eight (6%) of 136 patients chlorambucil arms (HR [95% CI], 0.450 [0.266–0.761]). discontinued ibrutinib due to PD. OS estimates at 5 years were 83% for ibrutinib and 68% for A PFS benefit for ibrutinib over chlorambucil was chlorambucil without censoring for crossover from chlor- observed across all patient subgroups examined, including ambucil to ibrutinib and were 80% for chlorambucil after those with the high-risk prognostic features of TP53 censoring for crossover to ibrutinib treatment after PD mutation, chromosome 11q deletion (del[11q]), and/or (Supplementary Table 1). In patients with high prognostic unmutated immunoglobulin heavy chain variable region risk CLL (TP53 mutation, del[11q], and/or unmutated (IGHV) (PFS: HR 0.083 [95% CI: 0.047–0.145]) (Fig. 2). IGHV), OS at 5 years without censoring for crossover to When examined individually, the presence of del(11q) and ibrutinib was 84% for ibrutinib and 62% for chlorambucil unmutated IGHV were each also associated with increased (HR 0.376 [95% CI: 0.180–0.786]). 790 J. A. Burger et al. Fig. 1 Progression-free survival with single-agent ibrutinib versus chlorambucil in first-line treatment for CLL/SLL. Survival analyses are from randomization until event or censored at last evidence of non- PD; vertical tick marks indicate censored patients. CI confidence interval, CLL chronic lymphocytic leukemia, NE not estimable, PD progressive disease, SLL small lymphocytic lymphoma Fig. 2 Progression-free survival according to baseline factor subgroups ECOG Eastern Cooperative Oncology Group, HR hazard ratio, IGHV of interest. CI confidence interval, del(11q) chromosome 11q deletion, immunoglobulin heavy chain variable region Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of. . . 791 Fig. 3 Progression-free survival by a del(11q) status and b IGHV patients. CI confidence interval, del(11q) chromosome 11q deletion, mutational status. Survival analyses are from randomization until event IGHV immunoglobulin heavy chain variable region, NE not estimable, or censored at last follow-up; vertical tick marks indicate censored NR not reached, PFS progression-free survival Overall response for patients treated with chlorambucil. The proportion of patients with a best response of CR or CR with incomplete With a median follow-up of 5 years (up to 66 months), the marrow recovery (CRi) increased over time (Fig. 4). In the ORR including partial response with lymphocytosis was ibrutinib arm, investigator-assessed CR/CRi rates increased 92% for patients treated with ibrutinib compared with 37% from 11% at the primary analysis (median follow-up, 792 J. A. Burger et al. Fig. 4 Overall response rate per investigator assessment with first-line ibrutinib. Cumulative best response over time in all patients. Percentages of patients in each category of response may not total the overall proportion with a response because of rounding. CR complete response, CRi complete response with incomplete marrow recovery, nPR nodular partial response, ORR overall response rate, PR partial response, PR-L partial response with lymphocytosis, SD stable disease 18 months) to 30% after a median follow-up of 5 years. In difference between ibrutinib- and chlorambucil-treated the ibrutinib arm, ORR and CR rates for patients with high- patients was observed for the proportion of patients who risk features (i.e., del[11q] or unmutated IGHV) were had clinically meaningful improvement in FACIT-F (63% consistent with the rates seen for all patients treated with vs 53%). By repeated measure analysis, ibrutinib resulted in ibrutinib. significantly greater score improvements over time in EQ- 5D-5L UIS (P = 0.0079), EQ-5D-5L VAS (P = 0.0003), Sustained hematologic improvement and FACIT-F (P = 0.0018) (Supplementary Fig. 2). There were no differences in EQ-5D-5L UIS, EQ-5D-5L VAS, or Among patients with baseline cytopenias treated with FACIT-F after chlorambucil-treated patients crossed over to ibrutinib, the proportion of patients with sustained hema- ibrutinib following PD compared with before chlorambucil- tologic improvement increased over time. Significantly treated patients crossed over (Supplementary Fig. 3). more ibrutinib-treated patients with baseline anemia Consistent with patient-reported outcomes, when com- (hemoglobin ≤11 g/dL) had sustained improvement in pared with chlorambucil, ibrutinib resulted in higher rates of hemoglobin levels compared with chlorambucil (90% improvements in disease-related symptoms of weight loss, [46 of 51] vs 45% [25 of 55]; P < 0.0001). Similarly, sig- fatigue, fever, night sweats, anorexia, and abdominal dis- nificantly more patients with baseline thrombocytopenia comfort due to splenomegaly (Supplementary Fig. 4). (platelets ≤100 × 109/L) had sustained improvement in pla- telet counts after ibrutinib treatment compared with chlor- Safety ambucil (89% [31 of 35] vs 46% [13 of 28]; P = 0.0007). For patients treated with ibrutinib, median hemoglobin level At data cutoff, the median duration of ibrutinib treatment was 11.6 g/dL at treatment initiation, 13.2 g/dL at year 1, was 57 months (range, 0.7–66 months) (Table 2) and and 13.7 g/dL at year 5 (Fig. 5). Median platelet counts for median relative dose intensity was 98%. The most frequent patients treated with ibrutinib were 143 × 109/L at treatment AEs of any grade with ibrutinib were diarrhea (50%), cough initiation, 155 × 109/L at year 1, and 147 × 109/L at year 5 (36%), and fatigue (36%) (Table 3), and the prevalence of (Fig. 5). many AEs decreased with time on treatment. Among AEs of particular interest, including those iden- Patient-reported outcomes and disease-related tified during early ibrutinib clinical development, hyper- symptoms tension of any grade occurred in 35 (26%) patients, including 13%, 6%, 6%, 5%, and 7% of patients in years Patient-reported outcomes as assessed with the EQ-5D-5L 0–1, 1–2, 2–3, 3–4, and 4–5, respectively (Supplementary and FACIT-F were improved with ibrutinib versus chlor- Fig. 5). Grade 3 hypertension occurred in 12 (9%) patients, ambucil. Clinically meaningful improvement in the EQ-5D- with no grade 4 or 5 events. Atrial fibrillation of any grade 5L UIS (≥0.084) [15] and in EQ-5D-5L VAS were observed occurred at any time in 22 (16%) patients, including 6%, significantly more frequently with ibrutinib than with 1%, 6%, 3%, and 4% of patients in years 0–1, 1–2, 2–3, chlorambucil (60% vs 44% of patients, P = 0.0089; 65% vs 3–4, and 4–5, respectively (Supplementary Fig. 5). Grade 3 52%, P = 0.0329, respectively), though no significant atrial fibrillation occurred in 7 (5%) patients, with no grade Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of. . . 793 Fig. 5 Hemoglobin levels and platelet counts over time in ibrutinib-treated patients. The horizontal line represents the lower limit of normal for platelet counts. CI confidence interval 4 or 5 events. Major hemorrhage (grouped terms) events patient were thrombocytopenia (n = 3), and anemia, occurred in 15 (11%) patients, including 4%, 3%, 1%, 3%, arthralgia, diarrhea, fatigue, and palpitations (n = 2 each). and 2% of patients in years 0–1, 1–2, 2–3, 3–4, and 4–5, After AE-related dose reductions, ibrutinib dose was suc- respectively (Supplementary Fig. 5). Grade 3 major cessfully re-escalated back to previous dose for ≥2 treatment hemorrhage occurred in 8 (6%) patients, grade 4 in 1 (1%) cycles in six (22%) patients, and re-escalated treatment patient, and no grade 5 events occurred. Of the patients who lasted a median of 589 days (preceding dose reductions experienced grade ≥3 major hemorrhage, 6 (67%) were lasting a median of 103 days). taking concomitant anticoagulation therapy. Ibrutinib dosing was held for ≥7 consecutive days Treatment discontinuations decreased over time on because of any grade AEs in 70 patients and 60 patients had ibrutinib, with 7% of patients discontinuing because of AEs complete resolution of the AE following dose hold. At the in years 0–1, 6% in years 1–2, 5% in years 2–3, 6% in years time of data cutoff, 36/70 of these patients remained on 3–4, and 1% in years 4–5 (Supplementary Fig. 6). Thirty- ibrutinib and 34/70 had discontinued ibrutinib at any time eight patients experienced AEs leading to discontinuation of during follow-up after the dose hold. Reasons for sub- ibrutinib; those reported in ≥2 patients were atrial fibrillation sequent discontinuation at any time during follow-up (n = 4), and palpitations, pneumonia, and worsening CLL included any further AE (n = 20), withdrawal from (n = 2 each), in addition to 2 deaths with unknown cause. study (n = 6), PD (n = 5), death (n = 2), or physician The rates of dose reductions due to AEs were similar decision (n = 1). Of note, only six patients discontinued due over time (Supplementary Fig. 6), with rates of 9% for to the same AE after the dose hold (atrial fibrillation, cer- patients in years 0–1, 8% in years 1–2, 6% in years 2–3, 5% ebral hemorrhage, cognitive disorder, myelodysplastic in years 3–4, and 7% in years 4–5. Dose reductions due to syndrome, non–small cell lung cancer, and staphylococcal any-grade AEs occurred in 27 patients; 25 (93%) had sepsis). For these 70 patients, the median duration between improvement or resolution of the AE following dose first dose hold of ibrutinib to study treatment discontinua- reduction. At the time of data cutoff, 12/27 remained on tion or last known date alive for those still on treatment was ibrutinib and 15/27 had discontinued ibrutinib at any time 48 months (maximum 64+ months). Following dose hold, during follow-up after the dose reduction. Reasons for ibrutinib was restarted at the same dose in 42 patients and at subsequent discontinuation at any time during follow-up a reduced dose in 22 patients. were for any AE (n = 9; two patients had dose reduction At the time of data cutoff, 23 patients randomized to and then discontinued because of the same AE), withdrawal ibrutinib died (8 while on treatment); 4 due to PD (all were from the study (n = 3), PD (n = 2), and physician decision aged ≥70 years). One AE of pneumonia was considered (n = 1). AEs leading to dose reduction reported in >1 possibly related to ibrutinib. There were six patients for 794 J. A. Burger et al. Table 3 Most frequent adverse Adverse events, n (%) Ibrutinib events over time in patients n = 135a treated with first-line ibrutinib 0–1 year 1–2 years 2–3 years 3–4 years 4–5 years Totald,e n = 135 n = 123 n = 111 n = 100 n = 89 n = 135 Any gradeb 133 (99) 118 (96) 104 (94) 97 (97) 87 (98) 135 (100) Diarrhea 57 (42) 11 (9) 13 (12) 8 (8) 8 (9) 67 (50) Fatigue 38 (28) 27 (22) 21 (19) 19 (19) 18 (20) 48 (36) Cough 26 (19) 13 (11) 12 (11) 10 (10) 11 (12) 49 (36) Peripheral edema 23 (17) 17 (14) 13 (12) 12 (12) 11 (12) 37 (27) Anemia 22 (16) 12 (10) 9 (8) 9 (9) 6 (7) 35 (26) Nausea 27 (20) 9 (7) 5 (5) 3 (3) 3 (3) 35 (26) Pyrexia 20 (15) 8 (7) 7 (6) 6 (6) 6 (7) 36 (27) Arthralgia 19 (14) 13 (11) 10 (9) 6 (6) 13 (15) 35 (26) Upper respiratory tract infection 17 (13) 8 (7) 10 (9) 10 (10) 7 (8) 35 (26) Hypertension 16 (12) 12 (10) 15 (14) 16 (16) 17 (19) 31 (23) Constipation 16 (12) 14 (11) 11 (10) 6 (6) 7 (8) 28 (21) Vomiting 16 (12) 5 (4) 7 (6) 3 (3) 1 (1) 27 (20) Grade ≥3c 78 (58) 48 (39) 30 (27) 39 (39) 32 (36) 112 (83) Neutropenia 11 (8) 4 (3) 1 (1) 1 (1) 0 (0) 17 (13) Pneumonia 7 (5) 3 (2) 3 (3) 4 (4) 2 (2) 16 (12) Hypertension 6 (4) 2 (2) 0 3 (3) 4 (4) 11 (8) Anemia 8 (6) 1 (1) 1 (1) 0 0 (0) 10 (7) Hyponatremia 3 (2) 4 (3) 0 0 1 (1) 8 (6) Atrial fibrillation 2 (1) 0 4 (4) 1 (1) 0 (0) 7 (5) Cataract 1 (1) 1 (1) 1 (1) 1 (1) 3 (3) 7 (5) Diarrhea 5 (4) 0 1 (1) 0 0 (0) 6 (4) a One patient did not receive any doses of ibrutinib b Occurring in ≥20% of patients c Occurring in ≥4% of patients d Median 5 years follow-up e Includes 5–6 year data whom cause of death was unknown, and of the remaining, was 56 months (95% CI: 44, NE) compared with 33 months there were two infections, three second malignancies, and (95% CI: 26, 46) for patients who were not CR/CRi at one each reported as multiorgan failure, heart attack, sudden ibrutinib discontinuation (HR [95% CI]: 0.390 [0.118, death, heart failure, sepsis, pulmonary fibrosis, and septic 1.285]). shock (Supplementary Fig. 7). Of patients with available follow-up data after ibrutinib discontinuation, 14 patients received subsequent therapy for Outcomes following ibrutinib discontinuation CLL, including standard chemoimmunotherapy (FCR, BR, or GC) (n = 8), chemotherapy (n = 3), and novel Outcomes following discontinuation of first-line ibrutinib agents (n = 3). Of nine patients with best overall response to treatment are shown in Supplementary Table 2. Median OS subsequent therapy reported, seven responded, one had following discontinuation was not reached (range, 0–64+ stable disease, and one had PD. Eleven of the 14 patients months) in patients who discontinued ibrutinib because of remained alive at last follow-up, two patients withdrew AEs (n = 29). Only eight patients discontinued ibrutinib consent, and one patient died. because of PD (including two patients due to Richter’s transformation); of these patients, 50% are still alive or had exited study with no known death at the data cut. The Discussion median OS following ibrutinib discontinuation due to PD was 20 months (range, 1+ to 28 months). Median PFS for With long-term follow-up of the RESONATE-2 study, patients who were in CR/CRi at ibrutinib discontinuation single-agent ibrutinib continues to demonstrate significant Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of. . . 795 and durable clinical benefit in older patients, including those more than 5 years follow-up. Real-world studies of patients with high-risk prognostic features (TP53 mutation, receiving first-line treatment, including patients who would del(11q), and/or unmutated IGHV). No new safety signals have been excluded from RESONATE-2 due to age <65 emerged over the extended treatment duration, and many years or the presence of del(17p), demonstrate similar events decreased over time. This is the longest follow-up response rates (71–82% vs 92%) and proportion of dis- report of patients receiving first-line treatment with a BTK continuations due to AEs (51–63% vs 52% of patients who inhibitor in a phase 3 study to date. discontinued) as the present study [21–24]. With up to 66 months of follow-up, the median Additional randomized trials have found that adding investigator-assessed PFS per iwCLL criteria was not rituximab to ibrutinib does not increase PFS compared with reached in the ibrutinib arm and was 15 months (95% CI single-agent ibrutinib in the first-line setting [25] and in [10–19]) in the chlorambucil arm. The rate of PD during relapsed/refractory patients or high-risk patients with ibrutinib treatment was low; only 8/136 (6%) patients pro- del(17p) or TP53 mutations receiving first-line treatment gressed while receiving ibrutinib, implying a low rate of [26]. In the iLLUMINATE study of ibrutinib plus obinu- developing the BCR pathway mutations associated with tuzumab, median PFS was also not reached for patients with PD. Improvement in PFS with first-line ibrutinib compared del(11q) nor for patients with unmutated IGHV, similar to with chlorambucil remains durable, as evidenced by an 85% what we report here for single-agent ibrutinib (Fig. 3). reduction in the risk of progression or death. Accordingly, These results with del(11q) and IGHV mutational status are when comparing similar timepoints between studies, the 3- also consistent across two other phase 3 studies of ibrutinib year PFS rate with ibrutinib (82%) was higher than that with in different patient populations and as a single agent or in chlorambucil (25%) and appears higher than rates pre- combination regimens [6, 18, 27]. A pooled analysis of viously reported for first-line chemoimmunotherapy with three phase 3 randomized studies (RESONATE, RESO- FCR (70%) or BR (55%) in an older patient population than NATE-2, and HELIOS) further showed that the prognostic in the CLL10 study, although the proportion of patients risk factors of del(11q) and unmutated IGHV traditionally with unmutated IGHV was higher in CLL10 than in the associated with worse outcomes in patients with CLL have current study [16, 17]. Three-year PFS rates for ibrutinib less prognostic significance with ibrutinib therapy in also appeared favorable compared with chlorambucil in patients without del(17p) [28]. combination with obinutuzumab (<40%) in older, less fit Our results also demonstrate an improved depth of patients in the CLL11 study [5]. response over time with first-line ibrutinib. Investigator- In addition, ibrutinib substantially improved PFS in high- assessed CR/CRi rates in ibrutinib-treated patients risk patients with del(11q) or unmutated IGHV compared improved from 11% at the primary analysis (median follow- with chlorambucil. Whereas the presence of del(11q) [18] up 18.4 months) [8] to 30% after a median of 5 years or unmutated IGHV [16, 19] confers poor outcomes in the follow-up. In addition, we continue to observe sustained chemoimmunotherapy setting, we observed prolonged PFS improvement in anemia and thrombocytopenia with ibruti- with ibrutinib compared with chlorambucil in patients with nib, which are important and frequent reasons patients with del(11q) or with unmutated IGHV. Patients with the com- CLL initiate treatment. These improvements may help posite high prognostic risk genomics of del(11q), unmutated alleviate the fatigue that is a major component of symptom IGHV, or TP53 mutation experienced markedly improved burden and reduced quality of life in patients with CLL PFS with ibrutinib, with a 92% reduction in risk of PD or [29], especially those with advanced age and multiple death versus chlorambucil. However, there were no mean- comorbidities [29]. Given that patients with CLL may ingful differences in PFS for ibrutinib-treated patients when remain on ibrutinib for many years, durable improvement in these high-risk factors were evaluated individually quality of life during treatment is an important goal. In this (del[11q], unmutated IGHV, or TP53 mutation). The study, ibrutinib treatment improved patient-reported out- exclusion of patients with del(17p) is an important limita- comes and disease-related symptoms that were sustained tion of this analysis given its prognostic significance and through extended follow-up, in contrast to the worsened frequent overlap with TP53 mutations [20]. Taken together, quality of life outcomes reported by patients treated with our results suggest that these high-risk prognostic features chlorambucil, as PD occurred earlier and more frequently. may not have meaningful prognostic value with ibrutinib- As the majority of patients with CLL (including those in mediated inhibition of the BCR pathway, unlike with this study) are elderly and may be less tolerant of toxicities, chemoimmunotherapy. treatments with a tolerable safety profile in long-term use Cross-study analyses suggest that the clinical benefit is are essential. Late high-grade toxicities have been observed highest when ibrutinib is used as initial therapy versus as a with other CLL therapies [30]. In this study, no unexpected later line of therapy [7], and the present study demonstrates AEs were identified after extended follow-up of ibrutinib- the durability of those outcomes in the first-line setting with treated patients. Patients continued to experience new AEs 796 J. A. Burger et al. throughout extended treatment, with some AEs appearing as efficacy, but results of randomized comparative studies are late events, such as cataracts, fall, and herpes zoster, not yet available and these agents lack long-term safety and although the impact of aging in this patient population with efficacy data [37, 38]. Here, we demonstrated that with a extended follow-up cannot be fully accounted for. In the median of 5 years of follow-up, over half of patients with primary analysis of RESONATE-2 (median follow-up, CLL/SLL were able to receive long-term continuous first- 18 months), the three most common AEs were diarrhea line treatment with single-agent ibrutinib and had sustained (42%), fatigue (30%), and cough (22%) [8], while in the efficacy benefits (70% of ibrutinib-treated patients estimated current analysis at median of 5 years of follow-up (~3.3- progression-free), including—importantly—in patients with fold longer exposure to ibrutinib) these AEs continue to be high-risk prognostic features, such as del(11q) or the most common events in 50%, 36%, and 36% of patients, unmutated IGHV. respectively. Compared with a younger enrolled patient population treated with ibrutinib plus rituximab for a shorter Acknowledgments We thank the patients who participated in the study and their supportive families, as well as the investigators and median follow-up of 33 months in the phase 3 clinical research staff from the study centers. This study was sponsored ECOG1912 study, more ibrutinib-treated patients in by Pharmacyclics LLC, an AbbVie Company. Medical writing support RESONATE-2 (~1.8-fold longer exposure to ibrutinib) was provided by Valerie Hilliard, PhD, and funded by Pharmacyclics experienced grade ≥3 AEs (83% vs 58%) overall, although LLC, an AbbVie Company. there was a lower frequency of grade ≥3 AEs in the ibrutinib Author contributions JAB, JPD, and TK designed the study or current plus rituximab cohort compared with the FCR cohort in analysis. JAB, PMB, TR, CO, PG, AT, OB, PH, SEC, SD, SG, HM, ECOG1912 (58% vs 72%) [31]. Compared with a similar DS, FO, and CM contributed to collecting the data with the other patient population in the ALLIANCE study, fewer RESONATE-2 investigators and their research teams. All authors had ibrutinib-treated patients in RESONATE-2 experienced full access to the data, were involved in data interpretation, and vouch for the accuracy of the data. JAB, SD, IL, and JPD collaboratively grade ≥3 hypertension than ibrutinib-treated patients in wrote the first draft of the manuscript. All authors reviewed and the ALLIANCE study (8% vs 29%), despite the difference revised the manuscript, provided final approval, and made the decision in follow-up (median: 60 months vs 38 months, respec- to submit the manuscript for publication. Medical writing support was tively) [25]. provided by a professional medical writer and funded by the sponsor. Overall, many AEs decreased over time in this study, with some exceptions, such as hypertension (the prevalence Compliance with ethical standards of grade ≥3 hypertension remained stable over time). The Conflict of interest JAB reported honoraria and a consulting/advisory incidence of major hemorrhage was generally highest in the role with Janssen; speakers’ bureau and travel expenses from Gilead, first 2 years of treatment and decreased thereafter. Based on Janssen, Novartis, Pharmacyclics LLC, an AbbVie Company, and TG prior reports, the risk for bleeding with ibrutinib is most Therapeutics; and research funding from BeiGene, Gilead, Pharma- often observed within the first 12 months of treatment and cyclics LLC, an AbbVie Company, and TG Therapeutics. PMB reported a consultancy/advisory role for AbbVie and Pharmacyclics then decreases over time [27, 32, 33]. Similarly, atrial LLC, an AbbVie Company; and research funding from Pharmacyclics fibrillation typically occurs early after ibrutinib initiation LLC, an AbbVie Company. TR reported research funding from and remains constant or declines over time [7, 34–36]. In Pharmacyclics LLC, an AbbVie company. CO reported honoraria this study after a median follow-up of 5 years, the cumu- from Gilead, Janssen, AbbVie, Roche, Merck, Teva, and AstraZeneca. PG reported honoraria from AbbVie, Acerta, BeiGene, Gilead, Roche, lative rate of major hemorrhage increased from 4% at the Sunesis, Celgene, and Janssen; a consultancy/advisory role from primary analysis to 11%, and for atrial fibrillation increased AbbVie, Acerta, BeiGene, Gilead, Janssen, Pharmacyclics LLC, an from 6% to 16%; however, few patients required dose AbbVie Company, Celgene, and Sunesis; speakers’ bureau for Gilead; reduction or discontinued because of these AEs. Overall, and research funding from AbbVie, Gilead, Janssen, and Novartis. AT reported a consultancy/advisory role for Janssen spa, Gilead, Sunesis, dose reductions and discontinuations due to AEs were and AbbVie; and speakers’ bureau for Janssen. OB reported a con- infrequent and discontinuations due to AEs decreased over sultancy/advisory role for AbbVie and research funding from Janssen. time with continued treatment, with 73% of patients PH reported honoraria, a consultancy/advisory role, and research receiving ibrutinib for >3 years. The ongoing incidence of funding from Janssen, Pharmacyclics LLC, an AbbVie Company, and AbbVie; and travel expenses from Janssen and AbbVie. SEC reported new AEs and increasing prevalence of hypertension high- honoraria from Pharmacyclics LLC, an AbbVie Company, and Jans- lights the importance of ongoing follow-up and monitoring sen; a consultancy/advisory role for AbbVie, Astellas, AstraZeneca, during treatment to maximize optimal management of AEs Celgene, Genentech, Pharmacyclics LLC, an AbbVie Company, with dose modifications (dose holds and reductions) and Novartis, and Janssen; travel, accommodations, expenses from Abb- Vie, BeiGene, Celgene, Genentech, Janssen, Pharmacyclics LLC, an thus mitigate the impact of AEs and enable patients to AbbVie Company; expert testimony for Genentech; other relationship continue to benefit from ongoing first-line ibrutinib. with BeiGene; and research funding from Celgene, Gilead, Janssen, As novel agents continue to be developed for CLL, long- Pharmacyclics LLC, an AbbVie Company, AbbVie, Takeda, and term data are crucial to inform practice. Additional BTK Acerta. SD reported a consultancy/advisory role for AbbVie, Janssen, GlaxoSmithKline, and Bristol-Myers Squibb; and speakers’ bureau inhibitors in development for CLL have shown encouraging Long-term efficacy and safety of first-line ibrutinib treatment for patients with CLL/SLL: 5 years of. . . 797 and travel expenses for Janssen and Gilead. HM reported honoraria 7. O'Brien S, Furman RR, Coutre S, Flinn IW, Burger JA, Blum K, and travel expenses from AbbVie, Janssen, Novartis, and Roche; and a et al. Single-agent ibrutinib in treatment-naive and relapsed/ consultancy/advisory role with Janssen. DS reported honoraria from refractory chronic lymphocytic leukemia: a 5-year experience. Celgene, Roche, MSD, and Janssen; travel expenses from Celgene, Blood. 2018;131:1910–9. Bristol-Myers Squibb, Janssen, and Novartis; and research funding 8. Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, et al. from Amgen, MSD, Pharmacyclics LLC, an AbbVie Company, Ibrutinib as initial therapy for patients with chronic lymphocytic AbbVie, Sanofi, Roche, BeiGene, and Acerta. CM reported a con- leukemia. N Engl J Med. 2015;373:2425–37. sulting/advisory role with Pharmacyclics LLC, an AbbVie Company, 9. Pharmacyclics LLC. IMBRUVICA (ibrutinib) prescribing infor- Janssen, and AbbVie. SD reported employment with Pharmacyclics mation. Sunnyvale, CA; 2019. LLC, an AbbVie Company; and stock ownership with AbbVie, Cel- 10. European Medicines Agency. IMBRUVICA 140 mg hard cap- gene, Gilead, GSK, and Exelixis. IL reported employment with sules. London, UK: European Medicines Agency; 2014. Pharmacyclics, an AbbVie Company, and spouse employment with 11. Barr PM, Robak T, Owen C, Tedeschi A, Bairey O, Bartlett NL, The Permanente Medical Group; and stock ownership with AbbVie, et al. Sustained efficacy and detailed clinical follow-up of first-line Gilead Sciences, Clovis, Infinity, The Permanente Medical Group, and ibrutinib treatment in older patients with chronic lymphocytic Reviva Pharmaceuticals. JPD reported employment with Pharma- leukemia: extended phase 3 results from RESONATE-2. Hae- cyclics LLC, an AbbVie Company, and CTI BioPharma Corp; and matologica. 2018;103:1502–10. stock ownership with AbbVie and CTI BioPharma Corp. TJK reported 12. Hallek M, Cheson BD, Catovsky D, Caligaris-Cappio F, Dighiero a consultancy/advisory role for AbbVie, Genentech-Roche, Gilead, G, Dohner H, et al. Guidelines for the diagnosis and treatment of Pharmacyclics LLC, an AbbVie Company, and Celgene; and research chronic lymphocytic leukemia: a report from the International funding from AbbVie, Genentech-Roche, Pharmacyclics LLC, an Workshop on Chronic lymphocytic leukemia updating the AbbVie Company, and Oncternal. SG and FO reported no relevant National Cancer Institute-Working Group 1996 guidelines. Blood. financial disclosures. 2008;111:5446–56. 13. National Cancer Insitute. Common Terminology Criteria for Publisher’s note Springer Nature remains neutral with regard to Adverse Events (CTCAE), version 4.03. Report No.: version 30. jurisdictional claims in published maps and institutional affiliations. Bethesda, MD: National Cancer Insitute; 2009. 14. Coutre S, Tedeschi A, Robak T, Barr PM, Owen C, Bairey O, et al. Survival adjusting for crossover: phase 3 study of ibrutinib Open Access This article is licensed under a Creative Commons vs chlorambucil in older patients with untreated chronic lym- Attribution 4.0 International License, which permits use, sharing, phocytic leukemia/small lymphocytic lymphoma. Haematologica. adaptation, distribution and reproduction in any medium or format, as 2018;103:e249–e251. long as you give appropriate credit to the original author(s) and the 15. Pickard AS, Neary MP, Cella D. Estimation of minimally source, provide a link to the Creative Commons license, and indicate if important differences in EQ-5D utility and VAS scores in cancer. changes were made. The images or other third party material in this Health Qual Life Outcomes. 2007;5:70. article are included in the article’s Creative Commons license, unless 16. Eichhorst B, Fink AM, Bahlo J, Busch R, Kovacs G, Maurer C, indicated otherwise in a credit line to the material. If material is not et al. First-line chemoimmunotherapy with bendamustine and included in the article’s Creative Commons license and your intended rituximab versus fludarabine, cyclophosphamide, and rituximab in use is not permitted by statutory regulation or exceeds the permitted patients with advanced chronic lymphocytic leukaemia (CLL10): use, you will need to obtain permission directly from the copyright an international, open-label, randomised, phase 3, non-inferiority holder. To view a copy of this license, visit http://creativecommons. trial. Lancet Oncol. 2016;17:928–42. org/licenses/by/4.0/. 17. Robak T, Burger JA, Tedeschi A, Barr PM, Owen C, Bairey O, et al. Single-agent ibrutinib versus chemoimmunotherapy regi- References mens for treatment-naive patients with chronic lymphocytic leu- kemia: a cross-trial comparison of phase 3 studies. Am J Hematol. 1. National Cancer Institute. Surveillance, Epidemiology, and End 2018;93:1402–10. Results Program. SEER cancer statistics review 1975–2015. 18. Moreno C, Greil R, Demirkan F, Tedeschi A, Anz B, Larratt L, https://seer.cancer.gov/archive/csr/1975_2015/. Updated Septem- et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obi- ber 10, 2018. Accessed October 11, 2019. nutuzumab in first-line treatment of chronic lymphocytic leukae- 2. Eichhorst B, Hallek M, Goede V. New treatment approaches in mia (iLLUMINATE): a multicentre, randomised, open-label, CLL: challenges and opportunities in the elderly. J Geriatr Oncol. phase 3 trial. Lancet Oncol. 2019;20:43–56. 2016;7:375–82. 19. Thompson PA, Tam CS, O'Brien SM, Wierda WG, Stingo F, 3. Burger JA, O'Brien S. Evolution of CLL treatment - from che- Plunkett W, et al. Fludarabine, cyclophosphamide, and rituximab moimmunotherapy to targeted and individualized therapy. Nat treatment achieves long-term disease-free survival in IGHV- Rev Clin Oncol. 2018;15:510–27. mutated chronic lymphocytic leukemia. Blood. 2016;127:303–9. 4. Eichhorst BF, Busch R, Stilgenbauer S, Stauch M, Bergmann 20. Buccheri V, Barreto WG, Fogliatto LM, Capra M, Marchiani M, MA, Ritgen M, et al. First-line therapy with fludarabine compared Rocha V. Prognostic and therapeutic stratification in CLL: focus on with chlorambucil does not result in a major benefit for elderly 17p deletion and p53 mutation. Ann Hematol. 2018;97:2269–78. patients with advanced chronic lymphocytic leukemia. Blood. 21. Mato AR, Hill BT, Lamanna N, Barr PM, Ujjani CS, Brander 2009;114:3382–91. DM, et al. Optimal sequencing of ibrutinib, idelalisib, and vene- 5. Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner toclax in chronic lymphocytic leukemia: results from a multicenter CM, et al. Obinutuzumab plus chlorambucil in patients with CLL study of 683 patients. Ann Oncol. 2017;28:1050–6. and coexisting conditions. N Engl J Med. 2014;370:1101–10. 22. Mato AR, Roeker LE, Allan JN, Pagel JM, Brander DM, Hill BT, 6. Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy et al. Outcomes of front-line ibrutinib treated CLL patients NM, et al. Ibrutinib versus ofatumumab in previously treated excluded from landmark clinical trial. Am J Hematol. chronic lymphoid leukemia. N Engl J Med. 2014;371:213–23. 2018;93:1394–401. 798 J. A. Burger et al. 23. Jain P, Thompson PA, Keating M, Estrov Z, Ferrajoli A, Jain N, 31. Shanafelt TD, Wang V, Kay NE, Hanson CA, O'Brien SM, et al. Long-term outcomes for patients with chronic lymphocytic Barrientos JC, et al. A randomized phase III study of ibrutinib leukemia who discontinue ibrutinib. Cancer. 2017;123:2268–73. (PCI-32765)-based therapy vs. standard fludarabine, cyclopho- 24. Mato AR, Nabhan C, Thompson MC, Lamanna N, Brander DM, sphamide, and rituximab (FCR) chemoimmunotherapy in Hill B, et al. Toxicities and outcomes of 616 ibrutinib-treated untreated younger patients with chronic lymphocytic leukemia patients in the United States: a real-world analysis. Haematolo- (CLL): a trial of the ECOG-ACRIN cancer research group. Blood. gica. 2018;103:874–9. 2018:LBA-4. 25. Woyach JA, Ruppert AS, Heerema NA, Zhao W, Booth AM, 32. Wang ML, Blum KA, Martin P, Goy A, Auer R, Kahl BS, et al. Ding W, et al. Ibrutinib regimens versus chemoimmunotherapy Long-term follow-up of MCL patients treated with single-agent in older patients with untreated CLL. N Engl J Med. 2018; ibrutinib: updated safety and efficacy results. Blood. 2015;126: 379:2517–28. 739–45. 26. Burger JA, Sivina M, Ferrajoli A, Jain N, Kim E, Kadia T, et al. 33. Jones JA, Hillmen P, Coutre S, Tam C, Furman RR, Barr PM, Randomized trial of ibrutinib versus ibrutinib plus rituximab (Ib et al. Use of anticoagulants and antiplatelet in patients with + R) in patients with chronic lymphocytic leukemia (CLL). chronic lymphocytic leukaemia treated with single-agent ibrutinib. Blood. 2017;130:427. Br J Haematol. 2017;178:286–91. 27. Fraser G, Cramer P, Demirkan F, Silva RS, Grosicki S, Pristupa 34. Byrd JC, Furman RR, Coutre SE, Burger JA, Blum KA, Coleman A, et al. Updated results from the phase 3 HELIOS study of M, et al. Three-year follow-up of treatment-naive and previously ibrutinib, bendamustine, and rituximab in relapsed chronic lym- treated patients with CLL and SLL receiving single-agent ibruti- phocytic leukemia/small lymphocytic lymphoma. Leukemia. nib. Blood 2015;125:2497–506. 2019;33:969–80. 35. Brown JR, Hillmen P, O'Brien S, Barrientos JC, Reddy NM, 28. Kipps TJ, Hillmen P, Demirkan F, Grosicki S, Coutre SE, Bar- Coutre SE, et al. Extended follow-up and impact of high-risk rientos JC, et al. 11q deletion (del11q) is not a prognostic factor prognostic factors from the phase 3 RESONATE study in patients for adverse outcomes for patients with chronic lymphocytic leu- with previously treated CLL/SLL. Leukemia. 2018;32:83–91. kemia/small lymphocytic lymphoma (CLL/SLL) treated with 36. Brown JR, Moslehi J, O'Brien S, Ghia P, Hillmen P, Cymbalista Ibrutinib: pooled data from 3 randomized phase 3 studies. Blood. F, et al. Characterization of atrial fibrillation adverse events 2016;128:2042. reported in ibrutinib randomized controlled registration trials. 29. Shanafelt TD, Bowen D, Venkat C, Slager SL, Zent CS, Kay NE, Haematologica. 2017;102:1796–805. et al. Quality of life in chronic lymphocytic leukemia: an 37. Byrd JC, Harrington B, O'Brien S, Jones JA, Schuh A, Devereux international survey of 1482 patients. Br J Haematol. 2007;139: S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic 255–64. leukemia. N Engl J Med. 2016;374:323–32. 30. Coutre SE, Barrientos JC, Brown JR, de Vos S, Furman RR, 38. Walter HS, Jayne S, Rule SA, Cartron G, Morschhauser F, Macip Keating MJ, et al. Management of adverse events associated with S, et al. Long-term follow-up of patients with CLL treated with the idelalisib treatment: expert panel opinion. Leuk Lymphoma. selective Bruton's tyrosine kinase inhibitor ONO/GS-4059. Blood. 2015;56:2779–86. 2017;129:2808–10.