Coutré, Steven

7500 Background: The Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib +/- anti-CD20 antibody obinutuzumab (IO) is a standard frontline regimen for older adults with CLL. BTKi alone do not often lead to complete response (CR) or undetectable minimal residual disease (uMRD), thus are given indefinitely. Smaller trials showed that IO plus venetoclax (IVO) can induce uMRD CRs which may allow successful discontinuation. Methods: Alliance for Clinical Trials in Oncology A041702 is a multicenter trial designed to evaluate if IVO with response-guided discontinuation of I improves progression free survival (PFS) versus IO with indefinite I in treatment-naïve, older CLL pts. IO is given in standard fashion, and in the IVO arm V is added at C3D1 and continued until C14D28. After 14 cycles, pts undergo response evaluation including CT scans and bone marrow biopsy with central MRD assessment by flow cytometry. Pts in IVO arm with uMRD CR discontinue I; all others continue I until progression or unacceptable toxicity. Eligible pts were age ≥70 years (amended to ≥65). Pts had CrCl ≥ 40 mL/min, bilirubin ≤ 1.5 x ULN, and no other life-limiting intercurrent illness. Pts were stratified based on Rai stage and +/- del17p13.1 by FISH, and randomized 1:1 to IO:IVO. With 431 evaluable pts, the trial had 90% power to detect significant improvement in PFS using a one-sided log-rank test with one-sided type 1 error rate of 2.5%. The Alliance DSMB approved release of data on Nov 4, 2022 after meeting the protocol defined futility threshold at the second planned event-driven interim analysis. Data were locked on December 15, 2022. Results: Between January 4, 2019 and July 15, 2022, 465 pts were registered (IO:232, IVO:233). Median age was 74; 67% of pts were men. Rai stage 3-4 was seen in 55% and del17p in 13%. With median follow-up of 14 months, PFS of IO was 87.5% compared to 85% on IVO. Events were observed in 29 pts on IO (4 progressions, 23 deaths, 2 pts started other therapy) and 35 on IVO (7 progressions, 28 deaths). The predefined futility boundary was crossed, with a hazard ratio (HR) of 1.20 (95% CI: 0.73-1.97) in favor of IO. COVID-19 was the leading cause of death in both arms, (11 COVID-19 deaths on IO, 19 on IVO), with 13 and 11 additional deaths from other causes, respectively. Censoring pts with COVID-19 related deaths, PFS HR is 0.82 (95% CI: 0.44-1.53) in favor of IVO. Grade 3+ toxicity and discontinuation in year 1 of therapy were similar between arms. Conclusions: This study demonstrates that PFS for IVO is not superior to IO for treatment-naive older CLL pts in the setting of the COVID-19 pandemic. Study treatment is ongoing, and long-term follow-up will determine if there are advantages to IVO, with special attention to MRD and therapy discontinuation. Support: U10CA180821, U10CA180882, U24 CA196171; https://acknowledgments.alliancefound.org . Clinical trial information: NCT03737981 .

The treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) has significantly evolved in recent years. Targeted therapy with Bruton’s tyrosine kinase (BTK) inhibitors and BCL-2 inhibitors has emerged as an effective chemotherapy-free option for patients with previously untreated or relapsed/refractory CLL/SLL. Undetectable minimal residual disease after the end of treatment is emerging as an important predictor of progression-free and overall survival for patients treated with fixed-duration BCL-2 inhibitor-based treatment. These NCCN Guidelines Insights discuss the updates to the NCCN Guidelines for CLL/SLL specific to the use of chemotherapy-free treatment options for patients with treatment-naïve and relapsed/refractory disease.

Abstract Herein, we present the long-term follow-up of the randomized E1912 trial comparing the long-term efficacy of ibrutinib–rituximab (IR) therapy to fludarabine, cyclophosphamide, and rituximab (FCR) and describe the tolerability of continuous ibrutinib. The E1912 trial enrolled 529 treatment-naïve patients aged ≤70 years with chronic lymphocytic leukemia (CLL). Patients were randomly assigned (2:1 ratio) to receive IR or 6 cycles of FCR. With a median follow-up of 5.8 years, median progression-free survival (PFS) is superior for IR (hazard ratio [HR], 0.37; P < .001). IR improved PFS relative to FCR in patients with both immunoglobulin heavy chain variable region (IGHV) gene mutated CLL (HR: 0.27; P < .001) and IGHV unmutated CLL (HR: 0.27; P < .001). Among the 354 patients randomized to IR, 214 (60.5%) currently remain on ibrutinib. Among the 138 IR-treated patients who discontinued treatment, 37 (10.5% of patients who started IR) discontinued therapy due to disease progression or death, 77 (21.9% of patients who started IR) discontinued therapy for adverse events (AEs)/complications, and 24 (6.8% of patients who started IR) withdrew for other reasons. Progression was uncommon among patients able to remain on ibrutinib. The median time from ibrutinib discontinuation to disease progression or death among those who discontinued treatment for a reason other than progression was 25 months. Sustained improvement in overall survival (OS) was observed for patients in the IR arm (HR, 0.47; P = .018). In conclusion, IR therapy offers superior PFS relative to FCR in patients with IGHV mutated or unmutated CLL, as well as superior OS. Continuous ibrutinib therapy is tolerated beyond 5 years in the majority of CLL patients. This trial was registered at www.clinicaltrials.gov as #NCT02048813.

Abstract Introduction: Alliance for Clinical Trials in Oncology A041202 is a NCI National Clinical Trials Network phase 3 study (NCT01886872) comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) to determine whether ibrutinib-containing regimens are superior to chemoimmunotherapy (CIT) in terms of progression-free survival (PFS), and whether rituximab adds benefit to ibrutinib therapy. Initial results showed that ibrutinib-containing regimens had superior PFS to CIT, and that rituximab added to ibrutinib did not improve PFS over ibrutinib alone. Pts and Methods: Eligible pts on A041202 were those age ≥ 65 years with previously untreated, symptomatic CLL. Pts had a CrCl > 40 mL/min, bilirubin < 1.5 x ULN, and no significant life-limiting intercurrent illness or need for warfarin treatment. Pts were stratified on Rai stage, Zap-70 methylation performed centrally, and del(17)(p13.1) or del(11)(q22.3) by local interphase cytogenetics and were randomized 1:1:1 to each arm. Pts on Arm 1 who progressed could cross over to Arm 2. Here we present an updated analysis after the third planned interim analysis of Arms 2 and 3 versus Arm 1, and at the second planned interim analysis for Arms 3 vs 2. PFS and OS were estimated using the Kaplan-Meier method and corresponding hazard ratios with p-values were estimated using Cox proportional hazards models. These data encompass patient visits through April 2020 and were locked 15 February 2021. Results: Between 12/9/2013 and 5/16/2016, 547 pts were randomized (Arms 1: 183, 2: 182, and 3: 182). Baseline characteristics have previously been reported; briefly, median age was 71 years, 53% had unmethylated Zap-70, 61% were IGHV unmutated (performed in 66% of patients), 6% had del(17p) and 20% del(11q) by central FISH. Stimulated karyotype was performed centrally and revealed ≥ 3 abnormalities in 27%, and ≥ 5 in 11% of patients. With median follow-up of 55 months (mo), median PFS was 44 mo (95% CI 38-54) in Arm 1 and has not been reached in Arms 2 or 3 [Arm 2 vs 1 hazard ratio (HR): 0.36, 95% CI 0.26-0.52, p<0.0001; Arm 3 vs 1 HR 0.36, 95% CI 0.25-0.51, p<0.0001; Arms 3 vs 2 HR 0.99, 95% CI 0.66-1.48, p=0.96]. 48-month PFS estimates were 47%, 76% and 76% in Arms 1, 2, and 3 respectively (Figure 1). At this time, there are no significant differences in overall survival (OS) among arms (p=0.49). 48-month OS estimates were 84%, 85%, and 86% in Arms 1, 2, and 3, respectively (Figure 2). The benefit of ibrutinib regimens over CIT, with no additional benefit of rituximab when combined with ibrutinib, was consistent for all subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and IGHV (Figure 3). No significant interaction effects were observed between treatment arm and del(11q), complex karyotype, or IGHV. However, greater benefit of ibrutinib regimens over CIT was observed among patients with TP53 abnormalities than without (p<0.001). Thus in Arm 1, PFS was significantly worse for those with TP53 abnormalities vs without (HR 5.32, 95% CI 3.05-9.27, p<0.0001), but in Arms 2 and 3 combined, there was no significant difference in PFS by presence/absence of TP53 abnormalities (HR 0.99, 95% CI 0.51-1.91, p=0.98). Notable adverse events with ibrutinib include atrial fibrillation or flutter (afib) and hypertension (HTN). All grade afib was seen in 11 pts on BR (6%) and 67 pts on ibrutinib (19%). All grade HTN was seen in 95 pts on BR (54%) and 263 pts on ibrutinib (73%). Conclusions: This update of the A041202 trial continues to show that ibrutinib regimens prolong PFS over BR for older patients with treatment-naïve CLL. With longer follow-up, these benefits continue to be seen across subgroups, including those associated with higher risk disease. Strikingly, within the ibrutinib arms, there does not appear to be inferior PFS for patients with abnormalities in TP53, the highest risk feature seen in CLL, and a predictor of inferior PFS with ibrutinib in relapsed CLL. This differentiates ibrutinib (and perhaps BTKi in general) from other targeted therapy paradigms for treatment-naïve CLL. Similar to prior studies, rates of afib and HTN continue to increase with time on therapy. These data support the use of ibrutinib as initial therapy in CLL, and strengthen the rationale for use of ibrutinib for high risk disease. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org, Pharmacyclics, Inc Figure 1 Figure 1. Disclosures Woyach: Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy. Ruppert: Telios Pharma: Consultancy. Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Bartlett: ADC Therapeutics: Consultancy, Research Funding; Roche/Genentech: Consultancy; Seagen: Consultancy, Research Funding; Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding. Brander: Pfizer: Consultancy, Other: Biosimilars outcomes research panel; Genentech: Consultancy, Research Funding; Verastem: Consultancy; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; LOXO: Research Funding; TG Therapeutics: Consultancy, Research Funding; MEI Pharma: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; DTRM: Research Funding; BeiGene: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; ArQule: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Novartis: Research Funding. Barr: Seattle Genetics: Consultancy; Bristol Meyers Squibb: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Genentech: Consultancy; Abbvie/Pharmacyclics: Consultancy; Gilead: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy. Rogers: Pharmacyclics LLC: Consultancy; Innate Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals, Inc: Research Funding; ovartis Pharmaceuticals Corporation: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Coutre: Acerta: Other: Data Safety Monitoring Committee, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Larson: Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Gilead: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Rafael Pharmaceuticals: Research Funding; Cellectis: Research Funding. Erba: AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Owen: Genentech: Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Servier: Honoraria; Incyte: Honoraria; Pharmacyclics: Research Funding. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding. Stone: Onconova: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Jazz: Consultancy; Arog: Consultancy, Research Funding; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Innate: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees.

Abstract E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (<1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4%, and 8.6% at 3, 12, 24, and 36 months for FCR, and significantly lower at 7.9%, 4.2%, and 3.7% at 12, 24, and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24, and 36 months was associated with longer progression-free survival (PFS) in the FCR arm, with hazard ratios (MRD detectable/MRD undetectable) of 4.29 (95% confidence interval [CI], 1.89-9.71), 3.91 (95% CI, 1.39-11.03), 14.12 (95% CI, 1.78-111.73), and not estimable (no events among those with undetectable MRD), respectively. In the IR arm, patients with detectable MRD did not have significantly worse PFS compared with those in whom MRD was undetectable; however, PFS was longer in those with MRD levels <10−1 than in those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate end point for PFS in patients receiving FCR. In patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, whereas those with MRD <10−1 tended to have longer PFS, although continuation of ibrutinib would very likely be necessary to maintain treatment efficacy.

e20004 Background: IB is a Bruton’s tyrosine kinase inhibitor that showed superior progression-free survival compared with BR in CLL patients (pts) 65 years or older in a randomized phase 3 trial (Woyach et al, NEJM 2018). Pts receiving IB had higher rates of atrial fibrillation (AFIB) and hypertension (HTN); BR pts had higher rates of hematologic toxicity. Differences in treatment duration for BR (6 cycles) and IB (until progression) complicated adverse event (AE) comparisons. Here we use an exploratory approach to compare toxicity burden between arms and provide assessment of AFIB, HTN and infections (INF). Methods: AEs were reported for each of cycles 1-6 and then every 3 cycles until progression or nonprotocol CLL therapy. Only grade (gr) 3-4 AEs were reported thereafter until death. A simple global AE score was calculated for each pt by summing grades of all gr 1-4 AEs and dividing by the number of cycles over which AEs were submitted. Results: 537 pts began therapy (176 BR, 361 IB). 68% on BR completed all 6 cycles. At a median follow-up of 38 months, 64% remained on IB. Treatment discontinuation for AE occurred in 10% and 14% of BR and IB pts. Overall, median AE score was 1.8 (interquartile range (IQR) 0.9-3.3) and 3.8 (IQR 2.3-5.9) in BR and IB arms (p < 0.01). For cycles 1-6, median AE score was 6.2 (IQR 3.8-9.0) and 4.8 (IQR 3.0-7.2) in BR and IB arms (p < 0.01). In the IB arm, median AE score post 6 cycles decreased significantly to 3.4 (IQR 1.9-5.6) (p < 0.01). Gr 3 or higher cumulative rates of AFIB, HTN, and INF over time appear in the table. 100 pts (26/176 BR, 74/361 IB) had 137 severe INF (39% respiratory: 16 BR, 37 IB; 25% skin: 3 BR, 31 IB; 12% GU: 3 BR, 13 IB; 25% other: 12 BR, 22 IB). There were 7 gr 5 INF (3 BR, 4 IB), none confirmed fungal. Conclusions: There was no difference in treatment discontinuation rates for AE. Overall toxicity burden was significantly higher for IB, although IB toxicity burden decreased after 6 cycles. Toxicity burden was significantly higher in cycles 1-6 for pts receiving BR. Risk of severe AFIB, HTN, and INF is highest in the first year of IB. A simple AE score provides valuable information, especially when evaluating regimens of varying length. Clinical trial information: NCT01886872 . Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org ; Pharmacyclics; ClinicalTrials.gov Identifier: NCT01886872. [Table: see text]

Abstract High-risk acute promyelocytic leukemia (APL) remains a therapeutic challenge, with higher associated rates of early mortality and relapse than standard-risk APL. All-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) is a well-established treatment for patients with standard-risk APL, but it is not well defined for those with high-risk APL. In a prior study of patients with high-risk APL, the addition of gemtuzumab ozogamicin (GO) to ATO plus ATRA suggested benefit. The SWOG Cancer Research Network conducted a phase 2 study to confirm the efficacy and safety of the combination of ATRA plus ATO plus GO in treating high-risk APL patients. The primary end points were 3-year event-free survival (EFS) and early (6-week) death rates associated with this combination. Seventy patients were treated. With a median follow-up of 3.4 years, the 3-year EFS and overall survival estimates were 78% (95% confidence interval [CI], 67%-86%) and 86% (95% CI, 75%-92%), respectively. Overall, 86% of patients achieved complete response. The 6-week mortality rate was 11%. The most common treatment-emergent toxicities during the induction phase included febrile neutropenia, aspartate aminotransferase/alanine aminotransferase elevation, hyperglycemia, hypoxia, headache, and prolonged QT interval corrected for heart rate. Retinoic acid syndrome occurred in 9% of patients. Approximately 37% of patients did not complete all planned courses of postremission therapy. The combination of ATRA plus ATO plus GO in high-risk APL patients was effective and generally well tolerated, suggesting an opportunity to offer a chemotherapy-free induction platform for patients with this disease. This trial was registered at www.clinicaltrials.gov as #NCT00551460.

BACKGROUND: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) has been the standard therapy for younger patients with CLL. FCR therapy is particularly effective in patients with immunoglobulin heavy chain variable region (IGHV) mutated CLL. Approximately half of IGHV mutated patients are progression free 8 years after FCR therapy. At the ASH 2018 meeting, we reported the initial results of the ECOG 1912 (E1912) trial, a phase 3 trial comparing the FCR regimen to the combination of ibrutinib and rituximab (IR) for previously untreated CLL patients age 70 or younger who required therapy. With median follow-up of approximately 34 months, the trial demonstrated both a progression-free survival (PFS) and an overall survival (OS) benefit relative to FCR. On sub-set analysis by IGHV mutation status, the difference in PFS was statistically significant for IGHV unmutated patients but, with current follow-up, not IGHV mutated patients. Here, we present updated results for PFS in the E1912 trial. METHODS: As previously reported, eligible patients were treatment-naive individuals with CLL age 70 or younger. Patients with deletion 17p- were excluded from participating in the E1912 trial given their known poor response to FCR therapy. Patients were randomly assigned in a two-to-one ratio to receive ibrutinib (420 mg/day until disease progression or unacceptable toxicity) and rituximab (50 mg/m2 on day 1 of cycle 2, 325 mg/m2 on day 2 of cycle 2, and then 500 mg/m2 on day 1 of cycles 3-7) or six courses of intravenous fludarabine (25 mg/m2 days 1-3), cyclophosphamide (250 mg/m2 days 1-3) and rituximab (50 mg/m2 on day 1 of cycle 1, 325 mg/m2 on day 2 of cycle 1, and then 500 mg/m2 on day 1 of cycles 2-6) every 28-days. Adverse events (AEs) were graded according to the NCI Common Toxicity Criteria (version 4). Dose adjustments for cytopenias were based on the IWCLL CLL Working Group grading scale. The primary endpoint of the trial was PFS with OS a secondary endpoint. Analysis was by intention to treat. RESULTS: With median follow-up of 45 months, 257 (73%) of 354 patients randomized to IR remain on ibrutinib. With extended follow-up, grade 3 and above treatment-related AEs were observed in 70% of IR and 80% of FCR treated patients (OR=0.56; 95% CI 0.34 - 0.90; p=0.013). Among IR-treated patients, the median time on treatment is currently 43 months (range=0.2-61). Among the 95 patients who have discontinued ibrutinib, the reason for discontinuation was progression or death in 23 (7% of patients who started IR; 24% of those who discontinued treatment), AE or complication in 48 (14% of patients who started IR; 51% of those who discontinued treatment), and withdrawal of consent or other reasons in 24 (7% of patients who started IR; 25% of those who discontinued treatment). On multivariable Cox regression adjusting for Timed Up and Go test score, Cumulative Illness Rating Scale (CIRS) score, age, gender, ECOG performance status, creatinine clearance, and baseline anemia/thrombocytopenia, only CIRS score (range 0 - 14) predicted discontinuation of ibrutinib for a reason other than progression or death (HR=1.13 per unit increase; 95% CI 1.03 - 1.23; p=0.009). Among the 72 patients who discontinued ibrutinib for a reason other than progression or death, the median time on ibrutinib was 15.1 months (range 0.2-58.2 months). The median time from ibrutinib discontinuation to disease progression or death was 23 months. With current follow-up, we observed 110 PFS events. The hazard ratio (HR) for PFS favored IR over FCR (HR=0.39; 95% CI 0.26-0.57; p&lt;0.0001). Updated analysis of OS will be presented. On sub-group analysis by IGHV mutation status, IR was superior to FCR for IGHV unmutated patients (HR=0.28; 95% CI 0.17-0.48; p&lt;0.0001). With current follow-up the difference is not significant in IGHV mutated patients (HR=0.42; 95% CI 0.16-1.16; p=0.086). Kaplan-Meier estimates for PFS are shown in Figure 1. CONCLUSIONS: Although less than 7% of ibrutinib treated patients progressed while on therapy, roughly 1 in 5 patients have discontinued ibrutinib for a reason other than progression or death. The only parameter significantly associated with discontinuation for a reason other than progression was increased baseline CIRS score. With extended follow-up, the combination of ibrutinib and rituximab continues to provide superior PFS compared to FCR for younger patients with previously untreated CLL. Disclosures Shanafelt: Pharmacyclics: Research Funding; Patent: Patents & Royalties: US14/292,075 on green tea extract epigallocatechin gallate in combination with chemotherapy for chronic lymphocytic leukemia; Polyphenon E International: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Genentech: Research Funding; Celgene: Research Funding; Glaxo-SmithKline: Research Funding; Hospira: Research Funding; Cephalon: Research Funding. Kay:MorphoSys: Other: Data Safety Monitoring Board; Infinity Pharmaceuticals: Other: DSMB; Celgene: Other: Data Safety Monitoring Board; Agios: Other: DSMB. O'Brien:Janssen: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; Acerta: Research Funding; Eisai: Consultancy; Gilead: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Verastem: Consultancy; Celgene: Consultancy; Sunesis: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Regeneron: Research Funding; Kite: Research Funding. Barrientos:AbbVie: Consultancy, Research Funding; AstraZeneca: Consultancy; Genentech: Consultancy; Bayer: Consultancy; Gilead: Consultancy; Janssen: Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Sandoz: Consultancy; Oncternal Therapeutics: Research Funding. Coutre:Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Gilead: Research Funding; BeiGene: Other: Travel, Accommodations, Expenses & Data Safety Monitoring Committee; Genentech: Consultancy. Barr:Pharmacyclics LLC, an AbbVie company: Consultancy, Research Funding; Gilead: Consultancy; Verastem: Consultancy; Genentech: Consultancy; Seattle Genetics: Consultancy; Merck: Consultancy; Celgene: Consultancy; Janssen: Consultancy; AbbVie: Consultancy; Astra Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding. Cashen:Celgene: Other: Speaker's Bureau; Seattle Genetics: Other: Speaker's Bureau; Novartis: Other: Speaker's Bureau. Mato:AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Johnson & Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB member , Research Funding; LOXO: Consultancy, Research Funding; DTRM Biopharma: Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Gilead: Research Funding; Acerta: Consultancy; Janssen: Consultancy. Erba:Amgen: Consultancy; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; MacroGenics: Consultancy, Other: Lecture fees, Research Funding; Novartis: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; Astellas Pharma: Consultancy; Astellas Pharma: Consultancy; Amgen: Consultancy; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; ImmunoGen: Consultancy, Research Funding; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; GlycoMimetics: Consultancy, Other: Chair, data and safety monitoring board, Research Funding; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; Covance: Other: Fees for serving as chair on an independent review board for AbbVie Phase III studies; AbbVie: Consultancy, Other: Chair, IRC for phase III studies, Research Funding; Celgene: Consultancy, Other: chair, AML Registry Scientific Steering Committee, Speakers Bureau; Pfizer: Consultancy; Pfizer: Consultancy; Seattle Genetics: Consultancy; Seattle Genetics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding. Stone:Arog Pharmaceuticals: Consultancy, Honoraria, Research Funding; Otsuka-Astex Pharmaceuticals: Consultancy; Fujifilm: Consultancy; AstraZeneca: Consultancy; Celator Pharmaceuticals: Consultancy; Abbvie: Consultancy, Research Funding; Ono Pharmaceutical-Theradex Oncology: Consultancy; Cornerstone Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Takeda: Other: Fees for serving on a data and safety monitoring board ; Orsenix: Consultancy; MacroGenics: Consultancy; Jazz Pharmaceuticals: Consultancy; Agios: Consultancy, Research Funding; Stemline Therapeutics: Consultancy; Pfizer: Consultancy; Celgene: Consultancy, Other: Fees for serving on a steering committee, and fees for serving on a data and safety monitoring board; Novartis: Consultancy, Research Funding; Actinium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas Pharma: Membership on an entity's Board of Directors or advisory committees; Argenx: Other: Fees for serving on a data and safety monitoring board ; Roche: Consultancy. Tallman:Jazz Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Oncolyze: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: The most effective initial therapy for older adults with CLL has not yet been established due to the lack of comparison of chemoimmunotherapy (CIT) and targeted therapy with the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib. CIT has been the gold standard since studies showing that addition of CD20 antibody to chemotherapy prolongs survival. Bendamustine plus rituximab (BR) is one standard, more aggressive CIT regimen for patients (pts) age 65 or older. While ibrutinib has been FDA approved for untreated CLL since 2016, it has only been compared to chlorambucil, which is relatively ineffective, and never before to aggressive CIT. Additionally, the benefit of the addition of rituximab to ibrutinib in this setting has not been prospectively studied in a phase 3 trial. As part of a randomized phase 3 trial, the Alliance sought to answer these important clinical questions. Pts and Methods: Alliance A041202 is a multicenter NCI National Clinical Trials Network phase 3 study comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) to determine whether ibrutinib-containing regimens are superior to CIT in terms of PFS. Additionally, this study sought to determine if adding rituximab to ibrutinib would prolong PFS over ibrutinib alone. At time of progression, pts on Arm 1 could cross over to Arm 2. Eligible pts were those age ≥ 65 years with previously untreated, symptomatic CLL. Pts had a CrCl ≥ 40 mL/min, bilirubin ≤ 1.5 x ULN, and no significant life-limiting intercurrent illness or need for warfarin treatment. Pts were stratified based upon Rai stage, Zap-70 methylation performed centrally, and del(17)(p13.1) or del(11)(q22.3) by local interphase cytogenetics and were randomized 1:1:1 to each arm. With 166 pts per arm, the trial was powered to detect an improvement in 2-year PFS from 61% in Arm 1 to 75% in Arms 2 or 3 (HR=0.586) using two one-sided log-rank tests with type I error rate of 2.5% and 90% power. The Alliance Data and Safety Monitoring Board approved the data release after meeting the protocol-defined efficacy threshold at a planned interim analysis with a one-sided critical value of 0.001538. These data were locked July 2, 2018; updated results will be presented at the meeting. Results: Between 12/9/2013 and 5/16/2016, 547 pts were registered and randomized (Arms 1: 183, 2: 182, and 3: 182). Median age was 71 years and 67% of pts were men. High-risk Rai stage (stage III/IV) was seen in 54%, unmethylated Zap-70 in 53%, and del(17p) or del(11q) by local FISH in 28%. Local vs centralized FISH was performed for del(11q) and del(17p) with agreement between local and central results in 94% (Kappa=0.80) and 97% (Kappa=0.76) of pts, respectively. 525 (96%) pts were eligible and included in the primary PFS analysis (Arms 1: 176, 2: 178, and 3: 171). With median follow-up of 32 months (mo), median PFS was 41 mo in Arm 1 and has not been reached in Arms 2 or 3 (HR comparing Arm 2 to 1 is 0.40 with one-sided p&lt;0.0001; HR comparing Arm 3 to 1 is 0.41 with one-sided p&lt;0.0001; HR comparing Arm 3 to 2 is 1.01 with one-sided p=0.48). 2-year PFS estimates were 74%, 87% in 2, and 88% in Arms 1, 2, and 3 respectively. At this time, there are no significant differences in overall survival (OS) among arms (p=0.87), median OS has not been reached for any arm, and 2-year OS estimates were 95%, 90%, and 94% in Arms 1, 2, and 3, respectively. Adverse events (AEs) were compared among arms using Fisher's exact tests. Grade 3+ treatment-emergent AEs were seen in 428 of 537 evaluable pts with 61%, 41%, and 38% of pts experiencing Grade 3+ heme AEs (p&lt;0.0001) and 60%, 72%, and 71% of pts experiencing Grade 3+ non-heme AEs (p=0.03) in Arms 1, 2, and 3 respectively. Grade 5 AEs were seen in 5 (2.8%), 14 (7.8%), and 14 (7.7%) pts (p=0.07). Unexplained or unwitnessed death over the entire observation period was seen in 2 (1.1%), 7 (3.9%), and 4 (2.2%) pts (p=0.24) in Arms 1, 2, and 3 respectively. Conclusions: This international phase 3 trial demonstrates that ibrutinib produces superior PFS to standard CIT in older pts with CLL and justifies it as a standard of care treatment for pts age 65 and older. The addition of rituximab does not prolong PFS with ibrutinib. While ibrutinib represents a major therapeutic advance, toxicities and also cost justify future efforts to reduce the need for long-term continuous treatment. Support: K23CA178183, R01CA183444, U10CA180821, U10CA180882, U24CA196171, Clinicaltrials.gov identifier: NCT01886872 Figure. Figure. Disclosures Ding: Merck: Research Funding. Bartlett:Astra Zeneca: Research Funding; ImaginAB: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Bristol-Meyers Squibb: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Affimed: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Merck & Co: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Immune Design: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Millennium: Research Funding. Brander:BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Barr:AbbVie, Gilead: Consultancy. Parikh:Gilead: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Coutre:Celgene: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Research Funding; Beigene: Consultancy; AbbVie: Consultancy, Research Funding. Lozanski:Novartis: Research Funding; BI: Research Funding; Genentech: Research Funding; Stem Line: Research Funding; Coulter: Research Funding; Beckman: Research Funding. Larson:Ariad/Takeda: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Erba:Amgen: Research Funding; Juno: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; MacroGenics: Consultancy; Juno: Research Funding; Janssen: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Juno: Research Funding; Agios: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Incyte: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Novartis: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Incyte: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Celgene: Consultancy, Speakers Bureau; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Astellas: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; MacroGenics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Juno: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Pfizer: Consultancy, Other: grant; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Pfizer: Consultancy, Other: grant; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee. Owen:Janssen: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; AbbVie: Research Funding; Merck: Honoraria; Teva: Honoraria. Abramson:Bayer: Consultancy; Novartis: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy; Humanigen: Consultancy; Juno Therapeutics: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Amgen: Consultancy.

Abstract Background: Patients (pts) with deletion 17p (del17p) CLL follow an aggressive clinical course and experience poor outcomes with chemoimmunotherapy. Ibrutinib, an oral inhibitor of Bruton's tyrosine kinase (BTK), is approved for pts with CLL with ≥1 prior therapy and for pts with del17p CLL (including first-line). In the phase 2 RESONATE-17 study (PCYC-1117), ibrutinib demonstrated high efficacy with a favorable risk-benefit profile in del17p CLL/SLL (O'Brien, ASH 2014). We evaluate the baseline genetic features and prognostic factors of these pts to determine their impact on outcome. Methods: Pts with del17p CLL or SLL defined by peripheral blood FISH who failed ≥1 therapy received 420 mg oral ibrutinib once daily until progression or unacceptable toxicity. Using the primary analysis data cut, the overall response rate (ORR; iwCLL 2008 criteria by investigators), progression-free survival (PFS), and overall survival (OS) were assessed by subgroup. Results: Among 144 treated pts (137 CLL, 7 SLL), the median age was 64 (range 36-89). At baseline, 63% of pts had Rai stage III or IV disease, and 39% had received ≥3 prior therapies. Baseline cytogenetics included del11q (16%), del13q (74%), and trisomy 12 (17%), in addition to del17p in all pts. Of 116 pts with valid baseline genomic samples, IGHV status was unmutated in 84%; genomic variants that included mutations, rearrangements, insertions, deletions, and copy number variants affecting coding regions were identified as follows: ATM (14%), BIRC3 (3%), BTK (1%), MYC (2%), MYD88 (2%), NOTCH1 (16%), PLCG2 (3%), SF3B1 (27%), and TP53 (92%), which were consistent with previously identified mutations in pts with CLL (Wang, NEJM 2011; Winkelmann, Haematologica 2015). At a median follow-up of 11.5 months, the investigator-assessed ORR including partial response with lymphocytosis (PR-L) for all treated pts was 83% (17% PR-L). Median PFS and OS were not reached, with 12-month PFS and OS rates of 79% and 84%. Any-grade adverse events (≥15%) included diarrhea (36%), fatigue (31%), cough (24%), arthralgia (22%), nausea (19%), hypertension (19%), anemia (19%), pyrexia (17%), decreased appetite (17%), muscle spasms (17%), neutropenia (17%), and peripheral edema (15%). Serious AEs occurred in 40% of pts (38% ≥ grade 3). ORR, 12-month PFS, and 12-month OS are presented by subgroup for baseline characteristics, cytogenetics, and genomic variants (Table). There were no substantial differences in response rates and survival outcomes in the subgroups with and without baseline cytogenetic aberrations or genomic variants (Table). Response rates were similar for pts with and without NOTCH1 or SF3B1 variants. Of 11 pts with del17p CLL who developed Richter transformation, baseline aberrations included ATM (n=2), SF3B1 (n=3), and/or NOTCH1 (n=3); none had BIRC3 variants. Overall at baseline, there were 3 pts with a PLCG2 mutation (L163F, H193Q, P236L), and 1 with a BTK mutation (R236Q); all achieved a best overall response of PR-L or better. None had received prior therapy with a BTK or PI3K inhibitor. Two pts had a baseline MYD88 mutation (L265P, L142F) with a best overall response of PR in 1 pt. Two pts had baseline MYC amplifications with 5 of 5 exons amplified to 6 and 7 copies, respectively; 1 pt achieved a best overall response of PR. Conclusions: These results provide further evidence of ibrutinib's robust clinical activity and encouraging survival outcomes in this high-risk population regardless of baseline cytogenetic aberrations or genomic variants. The prognostic role of these clinical characteristics and genetic anomalies will continue to be elucidated with longer term follow-up of this population. Figure 1. Investigator-assessed efficacy outcomes by subgroups Figure 1. Investigator-assessed efficacy outcomes by subgroups Disclosures Stilgenbauer: AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Jones:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Research Funding. Coutre:AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mato:Celgene: Consultancy, Other: Travel, Accommodations, Expenses, Research Funding; TA Therapeutics: Research Funding; Gilead: Consultancy, Other: Travel, Accommodations, Expenses; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: Travel, Accommodations, Expenses. Hillmen:AbbVie: Honoraria, Research Funding; Roche Pharmaceuticals: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Honoraria, Research Funding. Tam:Janssen: Consultancy, Honoraria, Research Funding. Osterborg:Gilead: Honoraria; Janssen: Honoraria, Research Funding; GSK: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Amgen: Research Funding. Siddiqi:Pharmacyclics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau. Thirman:Gilead: Research Funding; Merck: Research Funding; AbbVie: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding. Furman:Gilead: Consultancy; Acerta Pharma BV: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Speakers Bureau. Li:Pharmacyclics LLC, an AbbVie Company: Employment. Eckert:Pharmacyclics LLC, an AbbVie Company: Employment. Chang:Pharmacyclics LLC, an AbbVie Company: Employment. James:Pharmacyclics LLC, an AbbVie Company: Employment. Chu:Pharmacyclics LLC, an AbbVie Company: Employment. Hallek:Pharmacyclics LLC, an AbbVie Company: Consultancy, Speakers Bureau; Janssen: Speakers Bureau. O'Brien:Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.