Ibrutinib Plus Venetoclax for First-Line original reports Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study William G. Wierda, MD, PhD1; John N. Allan, MD2; Tanya Siddiqi, MD3; Thomas J. Kipps, MD, PhD4; Stephen Opat, MBBS5; Alessandra Tedeschi, MD6; Xavier C. Badoux, MBBS7; Bryone J. Kuss, MBBS, PhD8; Sharon Jackson, MD9; Carol Moreno, MD, PhD10; Ryan Jacobs, MD11; John M. Pagel, MD, PhD12; Ian Flinn, MD, PhD13; Yvonne Pak, PhD14; Cathy Zhou, MS14; Edith Szafer-Glusman, PhD14; Joi Ninomoto, PharmD14; James P. Dean, MD, PhD14; Danelle F. James, MD, MAS14; Paolo Ghia, MD, PhD15; and Constantine S. Tam, MBBS, MD16 abstract PURPOSE CAPTIVATE (NCT02910583), a randomized phase II study, evaluates minimal residual disease (MRD)-guided treatment discontinuation following completion of first-line ibrutinib plus venetoclax treatment in patients with chronic lymphocytic leukemia (CLL). METHODS Previously untreated CLL patients age , 70 years received three cycles of ibrutinib and then 12 cycles of combined ibrutinib plus venetoclax. Patients in the MRD cohort who met the stringent random assignment criteria for confirmed undetectable MRD (Confirmed uMRD) were randomly assigned 1:1 to double-blind placebo or ibrutinib; patients without Confirmed uMRD (uMRD Not Confirmed) were randomly assigned 1:1 to open-label ibrutinib or ibrutinib plus venetoclax. Primary end point was 1-year disease-free survival (DFS) rate with placebo versus ibrutinib in the Confirmed uMRD population. Secondary end points included response rates, uMRD, and safety. RESULTS One hundred sixty-four patients initiated three cycles of ibrutinib lead-in. After 12 cycles of ibrutinib plus venetoclax, best uMRD response rates were 75% (peripheral blood) and 68% (bone marrow). Patients with Confirmed uMRD were randomly assigned to receive placebo (n 5 43) or ibrutinib (n 5 43); patients with uMRD Not Confirmed were randomly assigned to ibrutinib (n 5 31) or ibrutinib plus venetoclax (n 5 32). Median follow- up was 31.3 months. One-year DFS rate was not significantly different between placebo (95%) and ibrutinib (100%; arm difference: 4.7% [95% CI, –1.6 to 10.9]; P 5 .15) in the Confirmed uMRD population. After ibrutinib lead-in tumor debulking, 36 of 40 patients (90%) with high tumor lysis syndrome risk at baseline shifted to medium or low tumor lysis syndrome risk categories. Adverse events were most frequent during the first 6 months of ibrutinib plus venetoclax and generally decreased over time. CONCLUSION The 1-year DFS rate of 95% in placebo-randomly assigned patients with Confirmed uMRD ASSOCIATED suggests the potential for fixed-duration treatment with this all-oral, once-daily, chemotherapy-free regimen in CONTENT first-line CLL. Data Supplement J Clin Oncol 39:3853-3865. © 2021 by American Society of Clinical Oncology Protocol Creative Commons Attribution Non-Commercial No Derivatives 4.0 License Author affiliations and support information (if INTRODUCTION chemotherapy and/or chemoimmunotherapy regimens applicable) appear in randomized phase III studies in previously untreated at the end of this Targeted therapies that antagonize B-cell receptor CLL or small lymphocytic lymphoma (SLL; RESONATE- article. signaling by inhibiting the Bruton tyrosine kinase (BTK) pathway and restore apoptosis by inhibiting the anti- 2; ECOG1912).2,3 Venetoclax is an oral BCL-2 inhibitor Accepted on August 30, 2021 and apoptotic protein B-cell lymphoma 2 (BCL-2) have approved for the treatment of CLL and SLL as a single published at remarkably improved outcomes for patients with agent or combined with anti-CD20 monoclonal anti- ascopubs.org/journal/ chronic lymphocytic leukemia (CLL).1 Ibrutinib, a once- bodies (rituximab or obinutuzumab).4 Venetoclax pro- jco on October 7, daily BTK inhibitor, is the only targeted therapy to vides deep responses with undetectable minimal 2021: DOI https://doi. org/10.1200/JCO.21. demonstrate both improved progression-free survival residual disease (uMRD) rates in bone marrow (BM) of 00807 (PFS) and overall survival (OS) over standard 16% with single-agent venetoclax in relapsed or Volume 39, Issue 34 3853 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Wierda et al CONTEXT Key Objective Continuous single-agent ibrutinib affords survival benefit in the first-line treatment of chronic lymphocytic leukemia (CLL), but there is increasing desire for convenient, all-oral, time-limited treatment options that may be safely administered in the outpatient setting. This randomized phase II study evaluated minimal residual disease (MRD)-guided treatment discontinuation following combination treatment with ibrutinib plus venetoclax in patients with previously untreated CLL. Knowledge Generated One-year disease-free survival rates after random assignment were not significantly different between placebo- and ibrutinib-randomly assigned patients with confirmed undetectable MRD following 12 cycles of combined ibrutinib plus venetoclax. Progression-free survival rates were $ 95% across all MRD-guided randomized treatment arms. Relevance (J.W. Friedberg) These results show the potential for fixed-duration treatment with ibrutinib plus venetoclax, using MRD guidance. Ongoing randomized trials are comparing fixed-duration therapy to continuous Bruton tyrosine kinase inhibitor therapy in patients with CLL.* *Relevance section written by JCO Editor-in-Chief Jonathan W. Friedberg, MD. refractory CLL5-8 and 57% with venetoclax plus obinutuzu- evaluating disease-free survival (DFS) and treatment-free mab in previously untreated CLL.9 Continuous ibrutinib af- remission. fords survival benefit, but there is increasing desire for convenient, all-oral, time-limited treatment options that may METHODS be safely administered in the outpatient setting. Study Design and Patients Ibrutinib plus venetoclax provides synergistic and com- CAPTIVATE is a multicenter, international, randomized, phase plementary antitumor activity beyond peripheral blood (PB) II study conducted at 35 sites (Data Supplement, online only). and BM compartments.10-14 In preclinical CLL models, The study comprised two cohorts: the MRD cohort and a combined ibrutinib plus venetoclax resulted in greater separate fixed-duration (FD) cohort (enrolled after the MRD antitumor activity than either agent alone.10,11,14 Ibrutinib cohort and to be reported subsequently). The study was and venetoclax have complementary mechanisms of ac- conducted in accordance with International Conference on tion: ibrutinib inhibition of BTK enhances dependence Harmonisation guidelines for Good Clinical Practice and of CLL cells on BCL-2 through reductions in MCL-1 and principles of the Declaration of Helsinki. The Protocol (online BCL-XL.10,11 In addition to inhibiting CLL cell proliferation only) was approved by institutional review boards or inde- and survival, ibrutinib mobilizes CLL cells from protective pendent ethics committees of all participating institutions. All microenvironment niches and disease compartments into patients provided written informed consent. This study is circulation by blocking retention signals, rendering cells registered with ClinicalTrials.gov (NCT02910583). more susceptible to apoptosis, which is notably accelerated by addition of venetoclax.10,12,14,15 Recent clinical studies Eligible patients were age $ 18 to , 70 years with previ- with ibrutinib plus venetoclax demonstrated high uMRD ously untreated CLL or SLL requiring treatment per iwCLL rates in both PB and BM in patients with CLL or SLL.16-20 criteria25 and had measurable nodal disease by computed tomography; Eastern Cooperative Oncology Group perfor- With time-limited therapies, uMRD is an important end mance status 0-1; and adequate hepatic, renal, and he- point that appears predictive of durable efficacy outcomes. matologic function. Patients with known allergy to xanthine In patients treated with chemoimmunotherapy, such as oxidase inhibitors and/or rasburicase were excluded be- fludarabine, cyclophosphamide, and rituximab (FCR), cause of requirement for tumor lysis syndrome (TLS) uMRD status correlated with longer PFS and OS, regardless prophylaxis per venetoclax prescribing information.4 of depth of clinical response per International Workshop on CLL (iwCLL) criteria.21-23 uMRD at the end of combination Treatment and Random Assignment venetoclax and rituximab in relapsed or refractory CLL was Patients in the MRD cohort received treatment during two also predictive of longer PFS.24 Increasing MRD clearance phases: a prerandomization phase followed by an MRD- with targeted combinations is anticipated to lead to longer guided randomization phase (Data Supplement). During PFS and potentially OS. the prerandomization phase, patients received single-agent In CAPTIVATE, we investigated combined ibrutinib plus oral ibrutinib (420 mg once daily) lead-in for three cycles venetoclax in first-line treatment of CLL or SLL. We report followed by ibrutinib plus oral venetoclax (target dose 400 mg primary analysis results from the CAPTIVATE MRD cohort once daily after standard 5-week ramp-up, with TLS 3854 © 2021 by American Society of Clinical Oncology Volume 39, Issue 34 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Ibrutinib Plus Venetoclax for First-Line CLL Therapy prophylaxis and monitoring per venetoclax prescribing in- ensure random assignment of 60 patients with Confirmed formation)4 for 12 cycles. Each cycle was 28 days. TLS risk uMRD. This would provide approximately 80% power to categories were based on tumor burden (Data Supplement).4 detect a 30% difference for continued ibrutinib versus Patients in the high-risk category for TLS ($ 1 lymph node placebo at a two-sided significance level of 0.05. lesion $ 10 cm in longest diameter, or $ 1 lesion $ 5 cm Efficacy and safety were evaluated in all patients who plus circulating lymphocytes . 25 3 109/L) were hospitalized received $ 1 dose of study treatment. Time-to-event end during the first 24-48 hours of venetoclax treatment for more points, including 1-year DFS rates, were estimated using the rigorous TLS monitoring and prophylaxis.4 Hospitalization Kaplan-Meier method. Between-arm difference in 1-year was also recommended for patients with medium TLS risk DFS rates was tested by Z test with standard error of and creatinine clearance , 80 mL/min.4 each arm computed based on Greenwood’s formula. Patients who completed the three-cycle ibrutinib lead-in and Pharmacokinetics were evaluated using noncompartmental then 12 cycles of ibrutinib plus venetoclax continued one analysis. Other efficacy end points and adverse events (AEs) additional cycle of ibrutinib plus venetoclax, during which were summarized descriptively. 95% CIs for response rates MRD status was confirmed and tumor response was were estimated based on the exact binomial distribution. assessed; eligible patients were then randomly assigned to subsequent treatment according to MRD status (stratified by RESULTS immunoglobulin heavy variable [IGHV] gene mutation status). Patients with Confirmed uMRD (defined as , 1 CLL cell per Patient Characteristics 10,000 leukocytes, serially over $ 2 assessments $ 3 months Among 164 enrolled patients, median age was 58 years apart, and in both PB and BM) (Data Supplement) were (range, 28-69 years). Most patients had high-risk disease randomly assigned 1:1 to double-blinded treatment with features, including del(17p) (16%), del(11q) (17%), del(17p) placebo or ibrutinib until confirmed MRD relapse (increase or TP53 mutation (20%), complex karyotype (19%), TP53 to $ 1 CLL cell per 100 leukocytes, confirmed on two separate mutation (12%), and unmutated IGHV gene (60%; Table 1). occasions) or disease progression. Patients who did not meet Baseline characteristics by MRD-guided randomized treat- the strict Confirmed uMRD definition (ie, uMRD Not Con- ment arm are shown in the Data Supplement. firmed population) were randomly assigned 1:1 to open-label Prerandomization Phase: Disposition and Efficacy treatment with single-agent ibrutinib or continued ibrutinib plus venetoclax (maximum 2 years overall duration for ven- All patients initiated ibrutinib lead-in and 159 received etoclax) until disease progression or unacceptable toxicity. ibrutinib plus venetoclax (Fig 1). Overall, 148 of 164 pa- tients (90%) completed planned prerandomization treat- Outcomes and Assessments ment (Fig 1); see the Data Supplement for all progressive The primary end point was 1-year DFS rate in the Con- disease events. Fifteen patients were ineligible for random firmed uMRD population. One-year DFS was defined as assignment because of discontinuation of one or both study absence of MRD relapse, progression, or death at least 1 drugs (Fig 1). year after random assignment. Secondary end points were uMRD rates in PB and BM, overall response rate per in- During the prerandomization phase, 75% (123 of 164) and vestigator assessment using 2008 iwCLL criteria,25,26 68% (112 of 164) of all-treated patients achieved a best complete response (CR) rate (including CR with incom- MRD response of uMRD in PB and BM, respectively (75% plete BM recovery [CRi]), duration of response, TLS risk [123 of 163] and 72% [112 of 156] of evaluable patients, category reduction (proportion of patients at high risk for respectively) (Fig 2A). Among patients with uMRD in PB TLS after ibrutinib lead-in v baseline), PFS, OS, pharma- prerandomization with matched BM sample, 94% had cokinetics of ibrutinib and venetoclax in combination, and uMRD in both compartments. High uMRD rates in BM safety and tolerability (Data Supplement). ranging from 56% to 79% were observed across patient subgroups based on clinical and biologic features, in- Assessments included MRD status by flow cytometry and cluding those with high-risk disease features (Fig 2B). clinical response using physical examination, laboratory Response was achieved in 159 of 164 patients (overall evaluations, and radiographic evaluation (Data Supplement). response rate, 97%; 95% CI, 93 to 99) with CR including Safety was evaluated at every visit. TLS risk per US pre- CRi in 76 of 164 (46%; 95% CI, 39 to 54). In patients with scribing information for venetoclax4 was assessed at baseline best response of CR including CRi, 83% (63 of 76) and before venetoclax initiation, and limited pharmacokinetic achieved PB uMRD and 80% (61 of 76) achieved BM sampling was performed (Data Supplement). uMRD; in patients with a best response of partial response Statistical Analysis (PR) or nodular PR, corresponding rates were 72% (60 of Sample size was calculated based on the primary end point 83) and 61% (51 of 83), respectively. (1-year DFS rate) with placebo versus ibrutinib in patients Among 149 patients eligible for random assignment, 86 with Confirmed uMRD. Assuming a 40% uMRD rate at patients met Confirmed uMRD criteria for random as- random assignment, enrollment of 150 patients would signment (best uMRD rates of 100% in both PB and BM Journal of Clinical Oncology 3855 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Wierda et al TABLE 1. Patient Demographics and Disease Characteristics at Baseline prerandomization) (Fig 2C). The remaining 63 patients not Characteristic All Patients (N 5 164) meeting strict criteria of Confirmed uMRD for random Age assignment (Data Supplement) still achieved best uMRD Median, years (range) 58 (28-69) rates of 48% (30 of 63) in PB and 32% (20 of 63) in BM $ 65 years, No. (%) 41 (25) prerandomization (Fig 2C). Male, No. (%) 103 (63) Tumor debulking with three cycles of ibrutinib27 (reductions ECOG PS, No. (%) in lymph node diameter and absolute lymphocyte count) 0 105 (64) (Data Supplement) led to substantial reduction in TLS risk 1 59 (36) category. Together, 36 of 40 patients (90%) with high TLS Histology, No. (%) risk at baseline shifted to medium or low TLS risk categories CLL 157 (96) after ibrutinib lead-in and 4 of 164 (2%) remained at high SLL 7 (4) TLS risk (Fig 3); no patients with medium or low TLS risk Rai stage, No. (%) shifted to high-risk category. The proportion of patients with hospitalization indicated for TLS monitoring decreased 0 or I or II 111 (68) from 47% (77 of 164) at baseline to 18% (30 of 164) after III or IV 53 (32) ibrutinib lead-in. Overall, 131 of 159 patients (82%) initi- Bulky disease, No. (%) ated venetoclax without hospitalization. Rasburicase was $ 5 cm 53 (32) used per investigator discretion for treatment of hyperuri- $ 10 cm 5 (3) cemia in 1 of 164 (1%) patients and as TLS prophylaxis in Cytopenia at baseline, No. (%) 10 of 164 (6%) patients. Any cytopenia 59 (36) Hemoglobin # 11 g/dL 35 (21) Prerandomization Phase: Safety and Pharmacokinetics Platelet count # 100 3 10 /L9 30 (18) Median treatment duration in the prerandomization phase ANC # 1.5 3 109/L 14 (9) was 14.7 months (range, 0.5-22.7 months) (Data Supple- Hierarchical cytogenetics classification, No. (%)a ment). The most common treatment-emergent AEs among Del(17p) 26 (16) 164 patients treated during the prerandomization phase were diarrhea (71%, n 5 116), nausea (45%, n 5 74), and Del(11q) 28 (17) neutropenia (43%, n 5 70) (Data Supplement). Most di- Trisomy 12 22 (13) arrhea events and all nausea events were grade 1 or 2. The Normal 25 (15) most common grade 3 or 4 AEs were neutropenia (35%, Del(13q) 63 (38) n 5 58), hypertension (8%, n 5 13), thrombocytopenia Unknown 0 (5%, n 5 9), and diarrhea (5%, n 5 8) (Data Supplement). TP53 mutation, No. (%) No fatal AEs occurred. Serious AEs of any grade occurred in Yes 19 (12) 35 patients (21%) (Data Supplement). Atrial fibrillation of No 132 (80) any grade occurred in 12 patients (7%) and was grade $ 3 Unknown 13 (8) in three (2%). Major hemorrhage occurred in two patients Del(17p) or TP53 mutation, No. (%) (1%). Grade $ 3 infections occurred in 14 patients (9%) and Yes 32 (20) febrile neutropenia occurred in three (2%). No clinical TLS occurred. Laboratory TLS per Howard criteria28 occurred in No 120 (73) one patient categorized as low risk for TLS who did not Unknown 12 (7) receive Protocol-specified oral hydration and allopurinol; IGHV gene mutation status, No. (%) abnormalities spontaneously resolved without dose modifi- Unmutated 99 (60) cation, clinical sequelae, or hospitalization. Mutated 63 (38) AEs led to dose reductions of ibrutinib in 24 patients (15%) Unknown 2 (1) and venetoclax in 16 patients (10%) before random as- Complex karyotype, No. (%)b signment. AEs led to discontinuation of ibrutinib in 10 Yes 31 (19) patients (6%) and venetoclax in six patients (4%). Two No 106 (65) patients with grade 3 or 4 cardiac arrest discontinued both Unknown 27 (16) ibrutinib and venetoclax; no other AEs led to discontinu- ation of either study drug in . 1 patient, and no patients Abbreviations: ANC, absolute neutrophil count; CLL, chronic lymphocytic leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; discontinued because of infections. Diarrhea, neutropenia, IGHV, immunoglobulin heavy variable; MRD, minimal residual disease; SLL, small and thrombocytopenia were rarely associated with dose lymphocytic lymphoma. reductions (1%-4% of patients) or discontinuations. Forty- a Per Dohner hierarchy. eight patients (29%) received neutrophil growth factor at b Defined as $ 3 abnormalities by conventional CpG-stimulated cytogenetics. investigator discretion per local standards of care. 3856 © 2021 by American Society of Clinical Oncology Volume 39, Issue 34 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Ibrutinib Plus Venetoclax for First-Line CLL Therapy There was no change in ibrutinib mean plasma area under Randomized Phase: Efficacy and Safety in Confirmed the curve (n 5 112) when coadministered with venetoclax uMRD Population (660 ng$h/mL) versus that observed during single-agent The primary end point of DFS rate 1 year after random ibrutinib lead-in (677 ng$h/mL). Venetoclax mean plasma assignment was not significantly different for patients with area under the curve (n 5 151) was higher when coad- Confirmed uMRD randomly assigned to placebo (95%) ministered with ibrutinib (58.6 mg$h/mL) than that previ- versus ibrutinib (100%; arm difference: 4.7% [95% CI, ously reported for single-agent venetoclax 400 mg/d –1.6 to 10.9]; P 5 .15) (Fig 4). With a median follow-up of (32.8 mg$h/mL), but was within the range observed in 31.3 months (16.6 months after random assignment), doses previously studied (150-800 mg/d).4 Pharmacokinetic- there were three (7%) DFS events (disease progression, safety analyses revealed no association between exposure n 5 2; MRD relapse, n 5 1) in the placebo arm and no and AEs (data not shown). events in the ibrutinib arm. No additional DFS events were Enrolled (N = 164) Started ibrutinib lead-in (n = 164) Discontinued during ibrutinib lead-in (n = 5) AEs (n = 4) Richter’s transformation (n = 1) Completed ibrutinib lead-in and started ibrutinib plus venetoclax combination (n = 159) Discontinued during ibrutinib plus venetoclax combination (n = 10) Discontinued both ibrutinib and venetoclax (n = 7) AEs (n = 4) One patient who discontinued Richter’s transformation (n = 1) venetoclax because of AE (and Patient withdrawal (n = 1) continued ibrutinib) remained Investigator decision (n = 1) eligible for random assignment Discontinued ibrutinib only (n = 2) AE (n = 2) Discontinued venetoclax only (n = 1) AE (n = 1) Eligible for random assignment (n = 149) Confirmed uMRD uMRD Not Confirmed (n = 86) (n = 63) Placebo Ibrutinib Ibrutinib Ibrutinib plus venetoclax (n = 43) (n = 43) (n = 31) (n = 32) Discontinued ibrutinib plus Discontinued placebo (n = 5) Discontinued ibrutinib (n = 3) venetoclax (n = 6) Consent withdrawal (n = 3) Discontinued ibrutinib (n = 2) AE (n = 1) Investigator decision (n = 3) PD (n = 1) Consent withdrawal (n = 2) Death (n = 1) AE (n = 2) MRD relapse (n = 1) Consent withdrawal (n = 1) Consent withdrawal (n = 1) Completed 2-year venetoclax (n = 3) Ongoing placebo Ongoing ibrutinib Ongoing ibrutinib Ongoing ibrutinib (n = 26) (n = 38) (n = 41) (n = 28) Ongoing venetoclax (n = 23) FIG 1. Patient flow and disposition. AEs, adverse events; MRD, minimal residual disease; PD, progressive disease; uMRD, undetectable minimal residual disease. Journal of Clinical Oncology 3857 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Wierda et al A PB MRD BM MRDa 100 100 1 90 2 90 80 2 80 MRD level 52 < 10–4 70 62 70 Patients (%) Patients (%) 70 68 10–4 to < 10–3 60 75 60 10–3 to < 10–2 83 10–2 to < 10–1 50 50 10–1 40 16 40 Not evaluable or missing 30 16 30 12 13 15 20 12 2 20 9 1 10 4 9 10 1 3 10 9 4 8 1 12 9 10 5 1 5 0 0 Baseline After After After Best MRD Best MRD 6 Cycles 9 Cycles 12 Cycles Response Response Combination Combination Combination B No. uMRD Rate in BM (95% CI) All patients 164 68 (61 to 75) Age, years < 65 123 67 (58 to 75) 65 41 73 (57 to 86) Sex Male 103 67 (57 to 76) Female 61 70 (57 to 81) Race White 147 67 (59 to 75) Non-White 17 76 (50 to 93) Rai stage 0 or I or II 111 72 (63 to 80) III or IV 53 60 (46 to 74) ECOG PS 0 105 70 (61 to 79) 1-2 59 64 (51 to 76) Bulky disease < 5 cm 111 67 (57 to 75)  5 cm 53 72 (58 to 83) Del(17p) Yes 26 69 (48 to 86) No 137 68 (59 to 76) Del(17p) or TP53 mutation Yes 32 66 (47 to 81) No 120 72 (63 to 80) FISH cytogenetics categoryb Del(17p) 26 69 (48 to 86) Del(11q) 28 79 (59 to 92) Other 110 65 (56 to 74) IGHV Mutated 63 56 (42 to 68) Unmutated 99 77 (67 to 85) 40 60 80 100 Patients (%) FIG 2. MRD response during the prerandomization phase. (A) MRD levels serially over time in PB and best MRD response in PB and BM. (B) Forest plot of undetectable MRD in BM across patient subgroups by baseline characteristics. (C) Best MRD response of the prerandomization (continued on following page) 3858 © 2021 by American Society of Clinical Oncology Volume 39, Issue 34 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Ibrutinib Plus Venetoclax for First-Line CLL Therapy C Overall Best MRD response (uMRD definition: < 1 CLL cell per 10,000 leukocytes at any assessment) uMRD All patients (N = 164) Detectable MRD 25%c 32%c (n = 41) (n = 52) 75% 68% (n = 123) (n = 112) PB BM By random assignment population Confirmed uMRD definition: < 1 CLL cell per 10,000 leukocytes over  2 assessments  3 months apart in PB, and in BM at cycle 16 Confirmed uMRD: 86/149 (58%) uMRD Not Confirmed: 63/149 (42%) 32% 52% 48% (n = 20) 68% (n = 33) (n = 30) (n = 43) 100% 100% (n = 86) (n = 86) PB BM PB BM FIG 2. (Continued). phase in all-treated patients and according to Confirmed uMRD status in patients eligible for random assignment. aBM MRD assessment was scheduled after completion of 12 cycles of combination treatment (cycle 16). bPer Dohner hierarchy. cPatients without available samples (PB, n 5 1; BM, n 5 8) were counted as having detectable MRD. BM, bone marrow; CLL, chronic lymphocytic leukemia; ECOG PS, Eastern Cooperative Oncology Group performance status; FISH, fluorescence in situ hybridization; IGHV, immunoglobulin heavy variable; MRD, minimal residual disease; PB, peripheral blood; uMRD, undetectable minimal residual disease. observed with additional follow-up (Data Supplement). Es- before and after random assignment and decreased over timated 30-month PFS rates (from first dose of study time in both arms (Figs 5A and 5B). treatment) were 95% (95% CI, 83 to 99) with placebo and 100% (95% CI, 100 to 100) with ibrutinib (Data Supple- Randomized Phase: Efficacy and Safety in uMRD Not ment). Modest CR including CRi rate improvements (5%- Confirmed Population 9%) were observed postrandomization in both arms (Data Estimated 30-month PFS rates in the uMRD Not Confirmed Supplement). At random assignment, uMRD in PB and BM population were 95% (95% CI, 71 to 99) with ibrutinib and was 100%; at 12 cycles postrandomization, uMRD was 84% 97% (95% CI, 79 to 100) with ibrutinib plus venetoclax (Data (36 of 43) in PB and 81% (35 of 43) in BM with placebo, and Supplement). Approximately half of the patients who achieved 77% (33 of 43) in both PB and BM with ibrutinib. a best response of PR prerandomization converted to CR Median treatment duration across the overall study period including CRi with further ibrutinib (8 of 15) or ibrutinib plus was 31.3 months (range, 19.4-37.0 months) in the placebo venetoclax (10 of 24) (Data Supplement). With randomized arm and 31.3 months (range, 20.3-39.8 months) in the treatment, the proportion of patients with best response of ibrutinib arm (Data Supplement). AEs of any grade generally uMRD remained relatively unchanged at 45% in PB but decreased in prevalence over time after random assignment improved from 32% to 42% in BM with ibrutinib, and from (Fig 5A). Prevalence of grade $ 3 AEs also decreased 50% to 69% in PB and from 31% to 66% in BM with ibrutinib before and after random assignment, with a greater re- plus venetoclax (Fig 6). duction in the placebo arm (Fig 5B). Diarrhea and neu- Median treatment duration across the overall study period tropenia were less prevalent with placebo versus ibrutinib was 31.2 months (range, 17.8-36.6 months) in the ibrutinib Journal of Clinical Oncology 3859 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Wierda et al venetoclax provided deep remissions, as evidenced by 100 2 24 (n = 4) attainment of uMRD in over two-thirds of patients with CLL 90 (n = 40) or SLL, including high BM uMRD rates in those with high- 80 High risk disease features, such as del(17p) or TP53 mutation, Patients (%) 70 65 Medium (n = 107) del(11q), and unmutated IGHV gene. Overall, best uMRD 60 Low rates were high in both BM (68%) and PB (75%), and 50 Missing 62 (n = 102) compartmental concordance was 94%. These findings are 40 consistent with preclinical synergistic antitumor activity 30 between ibrutinib and venetoclax.10,11,14 20 30 (n = 49) 10 13 2 Given the lack of information on PFS outcomes after FD (n = 22) (n = 4) 0 treatment with ibrutinib or venetoclax at the time of study Baseline After lbrutinib Lead-In design, a strict definition of Confirmed uMRD was used to Timepoint ensure equipoise for placebo-randomly assigned patients. For patients who achieved Confirmed uMRD in PB and BM FIG 3. Impact of single-agent ibrutinib lead-in on TLS risk category. with ibrutinib plus venetoclax prerandomization, rates of Shown are TLS risk categories at baseline and after ibrutinib lead-in DFS 1 year after random assignment to placebo or ibrutinib in the prerandomization phase. TLS, tumor lysis syndrome. were comparable at 95% and 100%, respectively, sug- gesting that ibrutinib can be discontinued in the setting of a arm and 29.2 months (range, 15.4-36.9 months) in the deep response with minimal risk of early relapse during the ibrutinib plus venetoclax arm (Data Supplement). In the first year after discontinuation. The proportion of patients uMRD Not Confirmed population, the prevalence of with uMRD in PB at 12 cycles postrandomization was grade $ 3 AEs was higher with ibrutinib plus venetoclax than comparable with placebo or ibrutinib; the majority (84%) of with ibrutinib during months 7-12 postrandomization (Fig 5B). placebo patients still had uMRD through the first year after The prevalence of infections increased postrandomization in discontinuing active CLL treatment, supporting the po- both arms (Fig 5A). One grade 5 AE (sudden cardiac death) tential for durable, treatment-free remissions with FD occurred in the ibrutinib arm during cycle 32. ibrutinib plus venetoclax. PFS rates at 30 months were $ 95% across all four DISCUSSION treatment arms in this population of young, fit patients. First-line treatment with three cycles of single-agent ibru- Taking patient population differences into account, and tinib followed by 12 cycles of combined ibrutinib plus pending confirmation in the phase III setting, these rates 100 90 80 70 12 cycles after random assignment DFS (%) 60 50 a 40 DFS Placebo Ibrutinib 1-year DFS rate (%)b 95.3 100.0 30 Arm difference, % 4.7 (–1.6 to 10.9) 20 Placebo (95% CI) 10 Ibrutinib P value .15 0 3 6 9 12 15 18 21 24 Time Since Random Assignment (months) (patients randomly assigned after 12 cycles of combined ibrutinib plus venetoclax) No. at risk: Placebo 43 42 41 41 22 21 3 3 0 Ibrutinib 43 43 42 42 25 23 5 5 0 FIG 4. Disease-free survival. Kaplan-Meier estimates of DFS by randomized treatment arm in the Confirmed uMRD population. Tick marks indicate patients with censored data. Patients who did not experience a DFS event were censored by the last MRD sample date with a valid result or the date of last adequate disease assessment after random assignment, whichever occurred earlier. aThe three DFS events in the placebo arm were disease progression in two patients and MRD relapse in one patient; of the two patients with disease progression, after primary analysis one was confirmed to have partial response (not progression), for a total of two DFS events. bAt 12 cycles after random assignment. DFS, disease-free survival; MRD, minimal residual disease; uMRD, undetectable minimal residual disease. 3860 © 2021 by American Society of Clinical Oncology Volume 39, Issue 34 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Ibrutinib Plus Venetoclax for First-Line CLL Therapy A Prevalence (ongoing burden of each AE) by Time Interval Overall Incidence (%) Confirmed uMRD uMRD Not Confirmed Ibrutinib plus Placebo (n = 43) Ibrutinib (n = 43) Ibrutinib (n = 31) venetoclax (n = 32) Diarrhea (%) 100 67 68 69 Placebo 63 56 58 58 59 59 42 42 45 Ibrutinib (Confirmed uMRD) 77 50 35 28 35 32 27 34 19 14 21 Ibrutinib (uMRD Not Confirmed) 77 Ibrutinib plus venetoclax 88 0 100 Arthralgia (%) Placebo 37 50 Ibrutinib (Confirmed uMRD) 37 26 21 23 26 23 23 28 28 21 16 19 19 14 14 17 14 12 13 16 14 Ibrutinib (uMRD Not Confirmed) 39 Ibrutinib plus venetoclax 44 0 Hypertension (%) 100 Placebo 21 50 Ibrutinib (Confirmed uMRD) 26 16 12 19 14 19 19 13 13 16 13 Ibrutinib (uMRD Not Confirmed) 26 7 9 12 5 6 10 13 13 10 0 Ibrutinib plus venetoclax 22 0 Fibrillation (%) 100 Atrial Placebo 9 50 Ibrutinib (Confirmed uMRD) 7 9 10 Ibrutinib (uMRD Not Confirmed) 13 2 2 2 2 5 5 5 5 5 0 3 6 3 0 0 0 3 7 Ibrutinib plus venetoclax 6 0 100 Bleeding (%) 68 56 Placebo 56 49 53 44 45 45 47 44 50 35 40 33 40 36 39 38 34 28 Ibrutinib (Confirmed uMRD) 72 28 14 Ibrutinib (uMRD Not Confirmed) 77 Ibrutinib plus venetoclax 72 0 Neutropenia (%) 100 56 Placebo 37 50 30 37 29 34 Ibrutinib (Confirmed uMRD) 56 14 14 19 16 13 16 16 10 Ibrutinib (uMRD Not Confirmed) 42 7 3 9 2 2 2 0 Ibrutinib plus venetoclax 44 0 Infections (%) 100 53 58 58 53 Placebo 84 42 45 45 50 41 48 50 35 35 33 30 35 33 35 31 Ibrutinib (Confirmed uMRD) 84 24 19 Ibrutinib (uMRD Not Confirmed) 87 Ibrutinib plus venetoclax 88 0 Treatment Period Ibrutinib lead-in, 1-3 months Ibrutinib plus venetoclax, before random assignment 4-9 months Ibrutinib plus venetoclax, before random assignment 10-15 months After random assignment 1-6 months After random assignment 7-12 monthsa FIG 5. Rates over time of AEs of clinical interest. (A) Prevalence of AEs of clinical interest over time by randomized treatment arm for any-grade AEs and (B) grade $ 3 AEs. aAt postrandomization 7-12 months, Confirmed uMRD population: placebo (n 5 42), ibrutinib (n 5 42); uMRD Not Confirmed population: ibrutinib (n 5 30), ibrutinib plus venetoclax (n 5 29). bGrade 3 menorrhagia in one patient. cGrade 3 retroperitoneal hemorrhage in one patient. AEs, adverse events; uMRD, undetectable minimal residual disease. (continued on following page) Journal of Clinical Oncology 3861 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Wierda et al B Prevalence (ongoing burden of each AE) by Time Interval Overall Incidence (%) Confirmed uMRD uMRD Not Confirmed Ibrutinib plus Placebo (n = 43) Ibrutinib (n = 43) Ibrutinib (n = 31) venetoclax (n = 32) Diarrhea (%) 100 Placebo 7 Ibrutinib (Confirmed uMRD) 2 50 Ibrutinib (uMRD Not Confirmed) 6 0 2 5 0 0 0 2 0 0 0 3 3 0 0 0 0 6 0 0 3 Ibrutinib plus venetoclax 9 0 100 Arthralgia (%) Placebo 5 50 Ibrutinib (Confirmed uMRD) 2 Ibrutinib (uMRD Not Confirmed) 0 2 2 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 0 Ibrutinib plus venetoclax 0 0 Hypertension (%) 100 Placebo 16 50 Ibrutinib (Confirmed uMRD) 14 9 Ibrutinib (uMRD Not Confirmed) 10 2 5 2 5 7 2 5 5 3 6 3 6 3 0 0 0 0 0 0 Ibrutinib plus venetoclax 6 0 Fibrillation (%) 100 Atrial Placebo 0 50 Ibrutinib (Confirmed uMRD) 2 Ibrutinib (uMRD Not Confirmed) 3 0 0 0 0 0 2 0 0 0 0 0 3 3 0 0 0 0 0 0 3 Ibrutinib plus venetoclax 3 0 100 Bleeding (%) Placebo 0 50 Ibrutinib (Confirmed uMRD) 2 c Ibrutinib (uMRD Not Confirmed) 0 b 0 0 0 0 0 0 2 0 0 0 0 0 0 0 0 0 0 0 0 3 Ibrutinib plus venetoclax 3 0 Neutropenia (%) 100 Placebo 26 47 50 Ibrutinib (Confirmed uMRD) 49 28 25 19 19 16 Ibrutinib (uMRD Not Confirmed) 35 5 9 5 3 6 9 9 6 2 2 0 0 0 0 Ibrutinib plus venetoclax 31 0 Infections (%) 100 Placebo 7 50 Ibrutinib (Confirmed uMRD) 14 10 Ibrutinib (uMRD Not Confirmed) 19 2 0 0 0 2 2 2 0 5 5 3 6 0 0 3 0 3 3 3 Ibrutinib plus venetoclax 16 0 100 Any Grade ≥ 3 AE (%) 63 Placebo 65 48 44 50 35 33 35 29 32 Ibrutinib (Confirmed uMRD) 79 25 25 16 16 14 12 16 16 21 Ibrutinib (uMRD Not Confirmed) 68 9 10 7 Ibrutinib plus venetoclax 75 0 Treatment Period Ibrutinib lead-in, 1-3 months Ibrutinib plus venetoclax, before random assignment 4-9 months Ibrutinib plus venetoclax, before random assignment 10-15 months After random assignment 1-6 months After random assignment 7-12 monthsa FIG 5. (Continued). 3862 © 2021 by American Society of Clinical Oncology Volume 39, Issue 34 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Ibrutinib Plus Venetoclax for First-Line CLL Therapy 100 BM PB Additional randomized treatment 12 cycles of combined 80 ibrutinib plus venetoclax uMRD (%) 19 60 (n = 6) 10 34 (n = 3) (n = 11) 40 69 66 n = 22 n = 21 50 42 45 45 (n = 16) 20 32 n = 13 31 (n = 14) n = 14 (n = 10) (n = 10) 0 Ibrutinib Ibrutinib Plus Ibrutinib Ibrutinib Plus (n = 31) Venetoclax (n = 31) Venetoclax (n = 32) (n = 32) Treatment Arm FIG 6. Best overall uMRD rates by randomized treatment arm in the uMRD Not Confirmed population. BM, bone marrow; PB, peripheral blood; uMRD, undetectable minimal residual disease. appear to compare favorably with 3-year PFS rates reported Reductions in TLS risk category through effective debulking with FCR (73%), continuous ibrutinib combined with rit- before venetoclax initiation have the potential to improve uximab (89%), and FD venetoclax plus obinutuzumab convenience for patients, caregivers, and health care (82%).3,9 Longer follow-up and results from the CAPTIVATE providers and increase the ease of venetoclax administra- FD cohort and ongoing randomized phase III study com- tion. In the CLL14 study, no TLS was noted during venetoclax paring FD ibrutinib plus venetoclax to chlorambucil plus initiation after initial treatment with obinutuzumab; however, obinutuzumab (GLOW, NCT03462719) will help answer TLS occurred during obinutuzumab lead-in.34 Three cycles important remaining questions regarding time-limited of single-agent ibrutinib reduced TLS risk category in 90% of treatment with this promising combination, including du- patients with high baseline TLS risk and only 2% remained rability, efficacy in patients with high-risk genomic features, categorized with high risk before initiation of venetoclax ramp- and characteristics of patients most suitable to receive up. TLS risk category reduction was primarily attributable to time-limited versus continuous treatment with ibrutinib. rapid reductions in lymph node bulk with single-agent ibru- Observed high CR and uMRD rates may translate into even tinib as predicted by earlier studies.27,29 Consequently, the longer-term PFS.21 frequency with which hospitalization was indicated for TLS monitoring decreased by more than half (from 47% to 18%) uMRD rates are consistent with those previously reported after ibrutinib lead-in. Moreover, rasburicase use for TLS with ibrutinib plus venetoclax (61% in BM after 12 cycles) in prophylaxis (6%) was lower than that reported with single- first-line CLL,29 and higher than those reported with single- agent venetoclax (27%-45%).35,36 agent ibrutinib (# 10% in both PB and BM)30,31 or single- agent venetoclax (PB, 27%; BM, 16% in relapsed or The safety profile of ibrutinib plus venetoclax was con- refractory patients).5-8 uMRD rates also compare favorably sistent with known AEs for each agent alone, with no new with first-line CLL treatments, such as ibrutinib plus safety signals observed. Diarrhea and neutropenia infre- obinutuzumab (PB, 30%; BM, 20%),32 FCR (PB, 59%- quently led to dose modifications or treatment discon- 63%; BM, 43%),3,21-23 venetoclax plus obinutuzumab (PB, tinuation. Rates of grade $ 3 diarrhea were somewhat 76%; BM, 57%),9 and ibrutinib plus venetoclax plus obi- higher than expected with ibrutinib alone but were sim- nutuzumab (67% in both PB and BM),33 particularly for ilarly low (# 5%) as with continuous ibrutinib plus rit- MRD eradication in BM. The results from the post- uximab or FCR,3 venetoclax plus obinutuzumab,9 or randomization phase add to the body of evidence correlating ibrutinib plus venetoclax plus obinutuzumab.33 Rates of depth of response (uMRD and CR) with survival outcomes, grade $ 3 neutropenia (35%) were higher than contin- with similar changes in uMRD and CR status in patients uous ibrutinib plus rituximab (26%)3 but lower than FCR receiving further treatment with placebo or ibrutinib after 12 (45%),3 venetoclax plus obinutuzumab (53%),9 or ibru- cycles of ibrutinib plus venetoclax. Greater improvements in tinib plus venetoclax plus obinutuzumab (56%).33 AEs led uMRD rates are seen in patients with uMRD Not Confirmed to discontinuation of ibrutinib and/or venetoclax in 7% of status receiving further treatment with ibrutinib plus ven- patients prerandomization, compared with 11% and 24% etoclax. Additional follow-up will elucidate the impact of with ibrutinib plus rituximab and FCR, respectively, in further treatment with ibrutinib or ibrutinib plus venetoclax ECOG19123 and 16% with venetoclax plus obinutuzumab on long-term outcomes, such as PFS. in CLL14.9 Journal of Clinical Oncology 3863 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Wierda et al Frequencies of new or ongoing AEs were generally highest In conclusion, the ibrutinib plus venetoclax combination for during the first 6 months of prerandomization treatment first-line treatment of patients with CLL or SLL represents an all- with ibrutinib plus venetoclax and then decreased over time oral, once-daily, chemotherapy-free regimen that provides high irrespective of randomized arms. A slightly higher preva- rates of uMRD in both BM and PB. The 1-year DFS rate of lence of infections was observed postrandomization in the 95% in patients with Confirmed uMRD randomly assigned to uMRD Not Confirmed population than in the Confirmed placebo following 12 cycles of combined ibrutinib plus ven- uMRD population, suggesting that prevalence of infections etoclax and 30-month PFS rates of $ 95% across MRD- may be influenced by disease status. Postrandomization guided randomized treatment arms suggest the potential for treatment with ibrutinib plus venetoclax was associated FD treatment with this combination, which may provide with higher prevalence of grade $ 3 AEs, any-grade physicians with the ability to continue to select ibrutinib-based neutropenia, and any-grade diarrhea than placebo or therapy (continuous or fixed) in the outpatient setting while continued ibrutinib. Thus, the benefit of improved uMRD considering patient preferences and treatment goals. Fixed and CR rates with continued ibrutinib plus venetoclax duration is being evaluated in the younger population of pa- needs to be weighed against the risk of increased or on- tients in the CAPTIVATE FD cohort and in a complementary going toxicities. elderly or unfit population in the ongoing phase III GLOW study. AFFILIATIONS CLINICAL TRIAL INFORMATION 1 Department of Leukemia, University of Texas MD Anderson Cancer NCT02910583 Center, Houston, TX 2 Weill Cornell Medicine, New York, NY 3 AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF City of Hope National Medical Center, Duarte, CA 4 UCSD Moores Cancer Center, San Diego, CA INTEREST 5 Monash University, Clayton, VIC, Australia Disclosures provided by the authors are available with this article at DOI 6 ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy https://doi.org/10.1200/JCO.21.00807. 7 Ministry of Health, Kogarah, NSW, Australia 8 Flinders University and Medical Centre, Bedford Park, SA, Australia DATA SHARING STATEMENT 9 Middlemore Hospital, Auckland, New Zealand Requests for access to individual participant data from clinical studies 10 Hospital de la Santa Creu I Sant Pau, Autonomous University of conducted by Pharmacyclics LLC, an AbbVie Company, can be submitted Barcelona, Barcelona, Spain through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. 11 Levine Cancer Institute, Charlotte, NC 12 Swedish Cancer Institute Center for Blood Disorders and Stem Cell Transplantation, Seattle, WA AUTHOR CONTRIBUTIONS 13 Sarah Cannon Research Institute/Tennessee Oncology, Nashville, TN Conception and design: William G. Wierda, Thomas J. Kipps, Cathy Zhou, 14 Pharmacyclics LLC, an AbbVie Company, Sunnyvale, CA Joi Ninomoto, Danelle F. James, Paolo Ghia 15 Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Provision of study material or patients: Tanya Siddiqi, Thomas J. Kipps, Milan, Italy Stephen Opat, Alessandra Tedeschi, Sharon Jackson, John M. Pagel 16 Peter MacCallum Cancer Center and St Vincent’s Hospital and the Collection and assembly of data: William G. Wierda, John N. Allan, Tanya University of Melbourne, Melbourne, VIC, Australia Siddiqi, Thomas J. Kipps, Alessandra Tedeschi, Xavier C. Badoux, Bryone J. Kuss, Sharon Jackson, Carol Moreno, Ryan Jacobs, John M. Pagel, Ian Flinn, Cathy Zhou, Edith Szafer-Glusman, Joi Ninomoto, James P. Dean, CORRESPONDING AUTHOR Paolo Ghia, Constantine S. Tam William G. Wierda, MD, PhD, Department of Leukemia, University of Data analysis and interpretation: William G. Wierda, John N. Allan, Tanya Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Siddiqi, Thomas J. Kipps, Stephen Opat, Xavier C. Badoux, Bryone J. Kuss, Houston, TX 77030; e-mail: wwierda@mdanderson.org. Sharon Jackson, Carol Moreno, John M. Pagel, Ian Flinn, Yvonne Pak, Cathy Zhou, Joi Ninomoto, James P. Dean, Danelle F. James, Paolo Ghia EQUAL CONTRIBUTION Manuscript writing: All authors P.G. and C.S.T. contributed equally to the study and are cosenior Final approval of manuscript: All authors authors. Accountable for all aspects of the work: All authors PRIOR PRESENTATION ACKNOWLEDGMENT Presented at the All-Virtual 62nd American Society of Hematology (ASH) The authors thank all the patients who participated in this study and their Annual Meeting & Exposition, December 5-8, 2020. supportive families, as well as the investigators and clinical research staff from the study centers; Kristin Russell, BS, of Pharmacyclics LLC, an AbbVie Company, for her contributions to clinical trial management; and SUPPORT Melanie Sweetlove, MSc, for medical writing support, which was funded Supported by Pharmacyclics LLC, an AbbVie Company. by Pharmacyclics LLC, an AbbVie Company. REFERENCES 1. Burger JA: Treatment of chronic lymphocytic leukemia. N Engl J Med 383:460-473, 2020 3864 © 2021 by American Society of Clinical Oncology Volume 39, Issue 34 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. 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Wierda et al AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Ibrutinib Plus Venetoclax for First-Line Treatment of Chronic Lymphocytic Leukemia: Primary Analysis Results From the Minimal Residual Disease Cohort of the Randomized Phase II CAPTIVATE Study The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I 5 Immediate Family Member, Inst 5 My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center. Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments). William G. Wierda Sharon Jackson Consulting or Advisory Role: Sanofi Honoraria: AbbVie NZ Ltd Research Funding: GlaxoSmithKline/Novartis, AbbVie, Genentech, Consulting/Advisory Role: AbbVie NZ Pharmacyclics, Acerta Pharma, Gilead Sciences, Janssen, Juno Therapeutics, Speakers Bureau: AbbVie NZ Kite, a Gilead Company, Oncternal Therapeutics, Loxo, Xencor, miRagen, Sunesis Travel, Accommodations, Expenses: Roche NZ Pharmaceuticals, Cyclacel Carol Moreno John N. Allan Consulting/Advisory Role: Janssen Oncology, Abbott/AbbVie, AstraZeneca, Honoraria: AstraZeneca, AbbVie, Pharmacyclics/Janssen, BeiGene BieGene Consulting/Advisory Role: AbbVie/Genentech, Pharmacyclics, Ascentage Pharma, Speakers Bureau: Janssen Oncology BeiGene, Janssen Oncology, Epizyme, AstraZeneca, TG Therapeutics, ADC Therapeutics Research Funding: AbbVie Research Funding: Genentech, Janssen, Celgene, TG Therapeutics Ryan Jacobs Tanya Siddiqi Consulting/Advisory Role: AstraZeneca, Janssen Oncology, Secura Bio, Consulting/Advisory Role: Juno Therapeutics, AstraZeneca, BeiGene, Celgene, Genentech, Adaptive Biotechnologies, ADC Therapeutics, TG Therapeutics Pharmacyclics, Bristol Myers Squibb/Celgene, Pharmacyclics/Janssen Speakers Bureau: Pharmacyclics, Janssen Oncology, AbbVie, TG Therapeutics, Speakers Bureau: Pharmacyclics/Janssen, AstraZeneca, BeiGene, Bristol AstraZeneca Myers Squibb/Celgene Research Funding: TeneoBio (Inst), Pharmacyclics (Inst), TG Therapeutics Research Funding: Juno Therapeutics (Inst), Kite, a Gilead Company (Inst), (Inst), MEI Pharma (Inst) Acerta Pharma (Inst), TG Therapeutics (Inst), BeiGene (Inst), Pharmacyclics John M. Pagel (Inst), Celgene (Inst), Oncternal Therapeutics (Inst) Consulting/Advisory Role: Gilead Sciences, AstraZeneca, Actinium Pharmaceuticals, Thomas J. Kipps BeiGene, Loxo, MEI Pharma, TG Therapeutics, MorphoSys, Epizyme Employment: Moores Cancer Center Ian Flinn Stock and Other Ownership Interests: Oncternal Therapeutics Consulting/advisory role: AbbVie (Inst), Seattle Genetics (Inst), TG Therapeutics Honoraria: Pharmacyclics, AbbVie, Janssen, Genentech, Gilead Sciences, (Inst), Verastem (Inst), Roche (Inst), Gilead Sciences (Inst), Kite, a Gilead Company DAVAOncology, AstraZeneca (Inst), Janssen (Inst), BeiGene (Inst), Takeda (Inst), AstraZeneca (Inst), Juno Consulting/Advisory Role: AbbVie, Pharmacyclics, Genentech, Janssen, Therapeutics (Inst), Unum Therapeutics (Inst), MorphoSys (Inst), Nurix (Inst), DAVAOncology Shanghai Yingli Pharmaceuticals (Inst), Genentech (Inst), Great Point Partners Speakers Bureau: Verastem/Pharmacyclics, Pharmacyclics/Janssen, AbbVie/ (Inst), Iksuda Therapeutics (Inst), Novartis (Inst), Pharmacyclics (Inst), Century Genentech, Gilead Sciences, DAVA Pharmaceuticals Therapeutics (Inst), Hutchison MediPharma (Inst), Servier (Inst), Vincerx (Inst) Research Funding: Pharmacyclics/Janssen (Inst), Breast Cancer Research Research Funding: Acerta Pharma (Inst), Agios (Inst), Calithera Biosciences Foundation (Inst), Oncternal Therapeutics (Inst), Leukemia and Lymphoma (Inst), Celgene (Inst), Constellation Pharmaceuticals (Inst), Genentech (Inst), Society (Inst), California Institute for Regenerative Medicine (CIRM) (Inst), Gilead Sciences (Inst), Incyte (Inst), Infinity Pharmaceuticals (Inst), Janssen National Cancer Institute (Inst), NIH (Inst) (Inst), Karyopharm Therapeutics (Inst), Kite, a Gilead Company (Inst), Novartis Patents, Royalties, Other Intellectual Property: Cirmtuzumab was developed by (Inst), Pharmacyclics (Inst), Portola Pharmaceuticals (Inst), Roche (Inst), TG Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the Therapeutics (Inst), Trillium Therapeutics (Inst), AbbVie (Inst), ArQule (Inst), University of California to Oncternal Therapeutics, Inc, which provided stock BeiGene (Inst), Curis (Inst), Forma Therapeutics (Inst), Forty Seven (Inst), Merck options and research funding to the Thomas J. Kipps laboratory. (Inst) (Inst), Pfizer (Inst), Takeda (Inst), Teva (Inst), Verastem (Inst), AstraZeneca Travel, Accommodations, Expenses: AbbVie/Pharmacyclics, Genentech/ (Inst), Juno Therapeutics (Inst), Unum Therapeutics (Inst), MorphoSys (Inst), Roche, Janssen, Gilead Sciences, Celgene, DAVAOncology, Breast Cancer Seattle Genetics (Inst), IGM Biosciences (Inst), Loxo (Inst), Rhizen Research Foundation, TG Therapeutics, Verastem, AstraZeneca Pharmaceuticals (Inst), Triact Therapeutics (Inst) Stephen Opat Yvonne Pak Honoraria: AbbVie, AstraZeneca, Janssen, Roche, Gilead Sciences, Employment: BridgeBio Pharma, AbbVie Mundipharma, Takeda, Merck, and CSL Behring Stock and Other Ownership Interests: BridgeBio Pharma, AbbVie Consulting/Advisory Role: AbbVie, AstraZeneca, Janssen, Celgene, Novartis, Gilead Sciences, Takeda, Merck, Mundipharma, CSL Behring Cathy Zhou Research Funding: AstraZeneca (Inst), BeiGene (Inst), Roche (Inst), AbbVie Employment: Abbvie/Pharmacyclics (Inst), Gilead Sciences (Inst), Takeda (Inst), Pharmacyclics (Inst), Janssen (Inst), Stock and Other Ownership Interests: Abbvie/Pharmacyclics Celgene (Inst), Merck (Inst), Epizyme (Inst) Edith Szafer-Glusman Travel, Accommodations, Expenses: Roche Stock and Other Ownership Interests: AbbVie Alessandra Tedeschi Joi Ninomoto Consulting/Advisory Role: Janssen, BeiGene, AstraZeneca, AbbVie Employment: AbbVie Speakers Bureau: AbbVie, AstraZeneca, Janssen, BeiGene Stock and Other Ownership Interests: AbbVie Xavier C. Badoux James P. Dean Honoraria: Janssen/Pharmacyclics, AbbVie Employment: Pharmacyclics Bryone J. Kuss Stock and Other Ownership Interests: AbbVie Stock and Other Ownership Interests: Commonwealth Serum Laboratories (CSL) Danelle F. James Honoraria: Roche, Janssen Oncology, AstraZeneca, AbbVie, Merck, Employment: Abbvie/Pharmacyclics Mundipharma, Takeda, Sandoz Leadership: Abbvie/Pharmacyclics Consulting/Advisory Role: AbbVie, Janssen Oncology, Kyowa Kirin International, Stock and Other Ownership Interests: AbbVie/Pharmacyclics AstraZeneca Patents, Royalties, Other Intellectual Property: AbbVie/Pharmacyclics Speakers Bureau: AstraZeneca, Janssen-Ortho Travel, Accommodations, Expenses: Abbvie/Pharmacyclics Paolo Ghia Honoraria: AbbVie, BeiGene, Janssen Oncology, Gilead Sciences, Juno Therapeutics, Sunesis Pharmaceuticals, ArQule, Adaptive Biotechnologies, © 2021 by American Society of Clinical Oncology Volume 39, Issue 34 Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved. Ibrutinib Plus Venetoclax for First-Line CLL Therapy Dynamo Therapeutics, MEI Pharma, Acerta Pharma/AstraZeneca, Juno/ Constantine S. Tam Celgene/Bristol Myers Squibb, MSD, Lilly, Roche Honoraria: Janssen-Cilag, AbbVie, Novartis, BeiGene, Pharmacyclics Consulting/Advisory Role: AbbVie, BieGene, Janssen, Gilead Sciences, Sunesis Consulting/Advisory Role: Janssen, Loxo, Roche, BeiGene, AbbVie Pharmaceuticals, Juno Therapeutics, ArQule, Adaptive Biotechnologies, Dynamo Research Funding: Janssen-Cilag, AbbVie Therapeutics, MEI Pharma, Acerta Pharma/AstraZeneca, MSD, Lilly, Roche No other potential conflicts of interest were reported. Research Funding: AbbVie, Janssen Oncology, Gilead Sciences, Sunesis Pharmaceuticals, Novartis, AstraZeneca Journal of Clinical Oncology Downloaded from ascopubs.org by 158.109.91.150 on October 26, 2022 from 158.109.091.150 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.