Citations

Abstract Novel treatment strategies are needed for the treatment of Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) in older patients. This trial evaluated the feasibility and outcomes with the anti-CD19 bispecific T-cell–engaging antibody, blinatumomab, in combination with dasatinib and steroids. Patients 65 years of age or older with Ph+ or Ph-like ALL (with dasatinib-sensitive fusions/mutations) were eligible and could be newly diagnosed or relapsed/refractory. Induction therapy consisted of dasatinib/prednisone. Patients not achieving response by day 56 proceeded to blinatumomab reinduction therapy. Patients achieving response with induction or reinduction therapy proceeded to blinatumomab/dasatinib postremission therapy for 3 cycles followed by dasatinib/prednisone maintenance. All patients received central nervous system prophylaxis with intrathecal methotrexate for a total of 8 doses. Response was assessed at days 28, 56, and 84 and at additional time points based on response parameters. Measurable residual disease was assessed centrally by 8-color flow cytometry at day 28. A total of 24 eligible patients with newly diagnosed Ph+ ALL were enrolled with a median age of 73 years (range, 65-87 years). This combination was safe and feasible. With a median of 2.7 years of follow-up, 3-year overall survival and disease-free survival were 87% (95% confidence interval [CI], 64-96) and 77% (95% CI, 54-90), respectively. Although longer follow-up is needed, these results are encouraging, and future trials are building on this backbone regimen. This trial was registered at www.clinicaltrials.gov as #NCT02143414.

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 Tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Many older patients (pts) are not good candidates for intensive chemotherapy and are treated with TKIs plus corticosteroids or low intensity chemotherapy. Although the remission rates with this approach have been high, the median disease-free survival (DFS) has been short. Therefore, novel treatment strategies are needed. This trial evaluated the feasibility of combining the TKI dasatinib with prednisone and blinatumomab in older pts with Ph+ ALL. Methods: This trial was activated through the NCTN in January 2015 and closed to accrual in April 2021. Pt eligibility included: age ≥ 65 years; Ph+ or Ph-like ALL (with dasatinib-sensitive fusions or mutations); newly diagnosed or relapsed/ refractory; no evidence of central nervous system (CNS) disease; and adequate organ function. Treatment: For induction, pts received dasatinib 140 mg/d orally (PO) Days 1-56 along with prednisone 60 mg/m 2/d PO Days 1-24. Pts achieving complete remission (CR) or CR with incomplete count recovery (CRi) (Day 28 or Day 56) continued dasatinib until Day 84 followed by 3 cycles of post-remission therapy (PRT) with blinatumomab/ dasatinib. Pts not achieving CR or CRi by Day 56 received re-induction with blinatumomab. Response was assessed at Day 35 of blinatumomab. Pts not achieving CR/ CRi could receive a second cycle of blinatumomab. This was followed by 3 cycles of PRT with blinatumomab/ dasatinib. Maintenance therapy consisted of prednisone 60 mg/m 2/d x 5 days every 28 days for a total of 18 cycles along with dasatinib 140 mg po qd indefinitely. CNS prophylaxis included intrathecal (IT) methotrexate every 4-6 weeks x 8 doses. IT methotrexate was given at least 2 days apart from blinatumomab. Response was assessed at Days 28, 56, 84 and additional time points were dependent on response. Minimal residual disease (MRD) was assessed centrally by multi-color flow cytometry at Day 28. Statistics: 9 eligible/ evaluable pts receiving PRT were to be evaluated before enrolling additional pts. Dose-limiting toxicities (DLTs) were defined as: > Grade 3 non-hematologic toxicities with the exception of nausea, vomiting, or diarrhea (if manageable with supportive care measures) or Grade 4 neutropenia lasting > 42 days with possible relationship to dasatinib or blinatumomab. If due to unexpected accrual, 12 pts were evaluable for DLT, the following rules would apply. If > 4 of the 12 pts experienced a DLT, the study would be temporarily closed pending review. Upon re-opening, 8 additional eligible and evaluable pts would be enrolled for a total of 20 pts receiving blinatumomab. Results: Due to rapid accrual, 16 pts enrolled before accrual was paused to assess feasibility and safety. Twelve pts were evaluable for DLT and 4 experienced a DLT: Grade 3 dyspnea and gastrointestinal pain (n=1), Grade 3 hypertension (n=1), Grade 3 dyspnea (n=1), Grade 3 hyperglycemia (n=1). These adverse events were deemed acceptable by the NCI and FDA and the study re-opened. A total of 25 eligible pts were accrued. The median age was 73 years (range 62-87). All pts were newly diagnosed. One pt was Ph-like, with the remainder being Ph+; 89% of Ph+ pts had additional cytogenetic abnormalities. During induction, 2 pts experienced treatment-related non-hematologic Grade 4 toxicities. No Grade 4 or higher treatment-related non-hematologic toxicities occurred during post-remission therapy or maintenance. Twenty-three out of 25 pts (92%) achieved a CR during dasatinib-based and prednisone induction therapy. Four did not receive PRT (2 due to adverse events, 1 to receive transplant, 1 because of insurance issues). Sixteen pts who achieved CR had MRD data. Five out of 16 pts (31%) were MRD negative at Day 28. One pt remains on PRT and 10 are on maintenance. The median follow up for pts who are alive is 1.7 years. The median overall survival (OS) and DFS have not been reached as of July 8, 2021. Kaplan-Meier 3-year estimates of OS and DFS are 85% (95% CI 58%-95%) and 80% (95% CI 55%-92%), respectively (Figure). Conclusions: This trial demonstrates the feasibility of combining dasatinib and blinatumomab in Ph+ ALL. In addition, with 1.7 years of follow up, outcomes are encouraging with high estimated 3-year DFS and OS. Longer follow up will be needed to determine the durability of these results. Figure 1 Figure 1. Disclosures Advani: Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunogen: Research Funding; OBI: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Moseley: BioSight Ltd: Consultancy. Wood: Pfizer, Amgen, Seattle Genetics: Honoraria; Juno, Pfizer, Amgen, Seattle Genetics: Other: Laboratory Services Agreement. Park: Intellia: Consultancy; Kura Oncology: Consultancy; BMS: Consultancy; Affyimmune: Consultancy; Curocel: Consultancy; Novartis: Consultancy; Artiva: Consultancy; PrecisionBio: Consultancy; Servier: Consultancy; Kite Pharma: Consultancy; Innate Pharma: Consultancy; Minerva: Consultancy; Autolus: Consultancy; Amgen: Consultancy. Wieduwilt: Gilead: Membership on an entity's Board of Directors or advisory committees; Reata: Current holder of stock options in a privately-held company. Jeyakumar: Jazz: Research Funding; Pfizer: Research Funding. Atallah: Abbvie: Consultancy, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy. Gerds: PharmaEssentia Corporation: Consultancy; CTI BioPharma: Research Funding; Sierra Oncology: Consultancy; AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Constellation: Consultancy; Novartis: Consultancy. O'Brien: Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy; Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding. Othus: Celgene: Other: Data safety monitoring board; Merck: Consultancy; Biosight: Consultancy; Glycomimetics: Other: Data safety monitoring board; Daiichi Sankyo: Consultancy. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Omeros: Other: Advisory Board; Astellas: Research Funding; AbbVie: Research Funding; Biosight: Other: Data monitoring committee. Stone: Actinium: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Arog: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Innate: Consultancy; Janssen: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Onconova: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Erba: 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: Other: Independent review committee; 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.

Abstract Background: The phase 3 head-to-head trial of acalabrutinib (acala) vs ibrutinib (ibr) (NCT02477696) demonstrated noninferior efficacy and improved tolerability with acala in previously treated CLL (Byrd J Clin Oncol 2021). We now report additional data to further characterize BTKi-related adverse events (AEs) and the safety profile of acala and ibr, including measures of AE burden that account for frequency, duration, and drug exposure, which are not captured by incidence alone. Methods: Patients (pts) received oral acala 100 mg BID or ibr 420 mg QD until disease progression or unacceptable toxicity. Overall incidence, exposure-adjusted (exp-adj) incidence, and exp-adj time with event (sum of event durations [all grades]*100/sum of treatment-emergent period [for all pts in each arm]) were assessed for the most common BTKi-related AEs. Atrial fibrillation (afib)/flutter, hypertension (htn), and bleeding events were further characterized by time to onset, cumulative incidence by Kaplan-Meier method, pt subgroup, and AE management. Results: A total of 533 pts (acala, n=268; ibr, n=265) were randomized; median treatment exposures were 38.3 and 35.5 mo, respectively. Incidence and exp-adj incidence and time with event are reported for the most common AEs and events of clinical interest (ECIs) (Table). Among cardiovascular (CV) ECIs, incidences of any-grade afib/flutter, htn, and bleeding were statistically higher with ibr, with higher exp-adj incidence (2.0-, 2.8-, and 1.6-fold, respectively) and exp-adj time with event (2.8-, 3.7-, and 1.8-fold). Ventricular arrhythmias were reported in 3 ibr-treated pts vs 0 pts in the acala arm. Among other BTKi-related AEs, incidences of any-grade diarrhea, arthralgia, contusion, urinary tract infection (UTI), back pain, muscle spasms and dyspepsia were statistically higher with ibr, with a 1.5- to 4.1-fold higher exp-adj incidence, and a 1.4- to 13.1-fold higher exp-adj time with event (except for UTI, which had a 1.4-fold lower exp-adj time with event for ibr). Incidences of headache and cough were statistically higher with acala, with a 1.6- and 1.2-fold higher exp-adj incidence, respectively, and a 1.4- and 1.1-fold higher exp-adj time with event. The total exp-adj time with event for all any-grade AEs was 37% higher with ibr (234 [acala] vs 320 [ibr] mo/100 person-mo). For any-grade afib/flutter, median time to onset was longer for acala vs ibr (28.8 vs 16.0 mo), and cumulative incidence was lower for acala at 6 mo (2% vs 6%), 12 mo (3% vs 8%), 18 mo (4% vs 10%), and 24 mo (5% vs 12%). Afib/flutter also occurred less frequently with acala vs ibr in subgroups of age (<65 y: 3% vs 7%; ≥65 y: 15% vs 23%), prior line of therapy (1-3: 10% vs 16%; ≥4: 7% vs 19%), and among pts without prior history (6% vs 15%). Cox proportional-hazards (PH) analysis of new-onset afib/flutter showed a 63% rate reduction favoring acala (Figure 1). Among all pts, concomitant medication use for afib/flutter was less common for acala (8%) vs ibr (14%), with antithrombotic use reported in 5% vs 9% of pts, respectively. For any-grade htn, median time to onset was similar for acala and ibr (8.1 vs 7.0 mo), but cumulative incidence was lower for acala at 6 mo (5% vs 12%), 12 mo (6% vs 16%), 18 mo (8% vs 20%), and 24 mo (8% vs 23%). Htn also occurred less frequently with acala vs ibr in subgroups of age (<65 y: 9% vs 23%; ≥65 y: 10% vs 23%), prior line of therapy (1-3: 10% vs 25%; ≥4: 4% vs 11%), and among pts without prior history (7% vs 23%). Cox PH analysis of new-onset htn showed a 77% rate reduction favoring acala (Figure 2). No dose reductions or treatment discontinuations due to htn occurred in either arm. Concomitant medication use for htn was less common for acala (5%) vs ibr (19%). For any-grade bleeding events, the median time to onset was similar for acala vs ibr (1.2 vs 1.2 mo), and cumulative incidence was lower for acala at 6 mo (29% vs 42%), 12 mo (32% vs 45%), 18 mo (34% vs 49%), and 24 mo (38% vs 51%). Bleeding events also occurred less frequently with acala vs ibr in most subgroups of age (<65 y: 26% vs 47%; ≥65 y: 49% vs 55%) and prior line of therapy (1-3: 39% vs 54%; ≥4: 32% vs 30%). Bleeding events were associated with dose reduction in 3 vs 2 pts in the acala vs ibr arms, respectively, and led to treatment discontinuation in 2 vs 4 pts. Conclusions: In this head-to-head trial of BTKis in CLL, event-based analyses demonstrated a higher BTKi-related toxicity burden with ibr, with a lower impact of CV-related toxicity with acala across subgroups. Figure 1 Figure 1. Disclosures Seymour: AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mei Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sunesis: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Newave: Membership on an entity's Board of Directors or advisory committees; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. Hillmen: Janssen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Pharmacyclics: Honoraria, Research Funding; Roche: Research Funding; Gilead: Research Funding; AstraZeneca: Honoraria; SOBI: Honoraria; BeiGene: Honoraria. Ghia: Acerta/AstraZeneca: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Sunesis: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Celgene/Juno/BMS: Consultancy, Honoraria; ArQule/MSD: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Research Funding. Kater: Genmab, LAVA: Other: Ad Board, Steering Committee; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; BMS, Roche/Genentech: Other: Ad Board, , Research Funding. Chanan-Khan: Ascentage: Research Funding; Alpha2 Pharmaceuticals, NonoDev, Starton: Current holder of stock options in a privately-held company; Cellectar: Current equity holder in publicly-traded company; Alpha2 Pharmaceuticals: Patents & Royalties: Tabi; BeiGene, Jansen, Ascentage: Honoraria; Ascentage, Starton, Cellectar, NonoDev, Alpha2 Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BieGene, Jansen, Ascentage: Consultancy. Furman: Genentech: Consultancy; Sanofi: Consultancy; Morphosys: Consultancy; Incyte: Consultancy; Beigene: Consultancy; Loxo Oncology: Consultancy; TG Therapeutics: Consultancy; X4 Pharmaceuticals: Consultancy; Sunesis: Consultancy; Acerta/AstraZeneca: Consultancy; Abbvie: Consultancy, Honoraria, Other: Expert testimony; Pharmacyclics: Consultancy; Oncotracker: Consultancy; Janssen: Consultancy, Honoraria; Verastem: Consultancy; AstraZeneca: Honoraria. O'Brien: Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy; Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding. Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; 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. Mato: Genmab: Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Nurix: Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; MSKCC: Current Employment; Acerta/AstraZeneca: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding. Stilgenbauer: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Honoraria; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Other: Research Support; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Consultancy; AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK, Hoffmann-La Roche, Janssen, Novartis, Sunesis: Research Funding. Kuptsova-Clarkson: AstraZeneca: Current Employment, Current equity holder in publicly-traded company; AbbVie: Current holder of individual stocks in a privately-held company. Miranda: ASTRAZENECA: Current Employment; ASTRAZENECA: Current equity holder in publicly-traded company. Wagner: AstraZeneca: Current Employment. Higgins: AstraZeneca: Current Employment; PROMETRIKA, LLC: Ended employment in the past 24 months. Sohoni: AstraZeneca: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Revolution Medicines: Current Employment, Current equity holder in publicly-traded company; Theravance: Current equity holder in publicly-traded company. Jurczak: AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; Jagiellonian University: Ended employment in the past 24 months; European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy.

Abstract Background: The ECOG-ACRIN randomized phase 3 clinical trial E1912 established ibrutinib-rituximab (IR) as the standard of care for CLL patients <= 70 years in the frontline setting by improving the progression free (PFS) and overall survival (OS) compared to previous standard chemo-immunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) (Shanafelt et al. NEJM 2019). Quality of life (QOL) was an important secondary endpoint on this trial comparing continuous (IR) vs time-limited (FCR) therapy due to the differing profile of treatment-related toxicities over the short and long-term. E1912 patient-reported outcomes (PROs) results are presented here. Methods: Patients enrolled on E1912 completed the Functional Assessment of Cancer Therapy-General (FACT-G) and Leukemia subscale at randomization (baseline), 3, 6, and 12 months post-randomization, and every 6 months for 2 years regardless of disease status. The primary outcome was the 31-item FACT-Leukemia Trial Outcome Index (FACT-Leu TOI), calculated by summing items from the FACT-G physical wellbeing (PWB), functional well-being (FWB), and leukemia subscales (score range: 0-124). The primary endpoint was defined as the difference in FACT-Leu TOI change scores from randomization to 12 months (at response evaluation) between patients treated with continuous therapy Arm A (IR) vs time-limited therapy Arm B (FCR). Mean change scores from baseline to each time point were calculated using all cases with data at baseline and the corresponding time point. Comparisons between treatment arms were performed using two-sample t tests. Linear mixed effects models were used to estimate the trajectories of PRO scores. Results: PRO data was extracted on 3/8/2021. PRO data was provided at baseline and 12 months for 233/354 (65.8%) patients on the IR arm and 118/175 (67.4%) patients on the FCR arm. At enrollment, there were no significant differences in the baseline FACT-Leu TOI scores (mean ± SE) between the two arms: IR (93.27 ± 1.03) vs FCR (92.68 ± 1.38; p=0.73). The FACT-Leu TOI score improved from baseline to 12 months in both arms (Table 1 and Figure 1). The change scores from baseline to 12 months, the primary outcome, were not significantly different between IR (7.59 ± 1.09) vs FCR (8.22 ± 1.44; p=0.73). Change in FACT-Leu TOI from baseline to 3 months was 5.77 ± 0.77 and 4.06 ± 1.18 (p=0.22); and from baseline to 6 months was 6.87 ± 0.87 and 8.01 ± 1.44 (p=0.50) in the IR and FCR arms, respectively. After the first 6 months of treatment, the improvement in FACT-Leu TOI scores was maintained in both treatment arms. There was no significant difference in total FACT-Leu TOI score in the continuous therapy (IR) vs time-limited therapy (FCR) arms over the first 36 months post registration. Analysis of FACT subscales showed PWB improved in the IR arm (0.37 ± 0.22) and declined in the FCR arm (-0.92 ± 0.39) from baseline to 3 months (p=0.004 for difference in PWB change between arms) but there was no significant difference between the two arms for change in PWB scores from baseline to 6 and 12 months. There were no significant differences between the two arms for change in FWB and FACT-Leu subscales from baseline to 3, 6 and 12 months. Conclusions: QOL improves in CLL patients age 70 and younger when treated in the frontline setting with IR or FCR. The improvement in QOL is maintained during continuous therapy with ibrutinib and there is no significant decline in QOL over time. Given the improvement in PFS and OS with IR over FCR seen in E1912, the results of this QOL analysis support the use of frontline ibrutinib in previously untreated younger CLL patients. Acknowledgement: This study was conducted by the ECOG-ACRIN Cancer Research Group (Peter J. O'Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and supported by the National Cancer Institute of the National Institutes of Health under award numbers: U10CA180794, U10CA180820, UG1CA189863, UG1CA190140, UG1CA232760, UG1CA233180, UG1CA233230, UG1CA233253, UG1CA233277, UG1CA233290, UG1CA233339, UG1CA189859, UG1CA233332. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Figure 1 Figure 1. Disclosures Kay: Oncotracker: Membership on an entity's Board of Directors or advisory committees; CytomX Therapeutics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tolero Pharmaceuticals: Research Funding; Acerta Pharma: Research Funding; Behring: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Targeted Oncology: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Research Funding; Sunesis: Research Funding; Genentech: Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding. O'Brien: Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy; Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding. Coutre: Janssen: Consultancy, Honoraria, 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; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: 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; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Other: Data Safety Monitoring Committee, Research Funding. Barr: AstraZeneca: Consultancy; Gilead: Consultancy; Janssen: Consultancy; Genentech: Consultancy; Beigene: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Abbvie/Pharmacyclics: Consultancy. Cashen: Secura Bio, ADC Therapeutics: Consultancy. Mato: Adaptive Biotechnologies: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; MSKCC: Current Employment; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; Janssen: Consultancy, Research Funding; Genmab: Research Funding. Erba: 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; 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. Stone: Onconova: Consultancy; AbbVie: Consultancy; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Research Funding; Takeda: 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; Innate: Consultancy; Janssen: Consultancy; GlaxoSmithKline: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Research Funding; Actinium: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Celgene: Consultancy; Macrogenics: Consultancy. Litzow: Actinium: Research Funding; Amgen: Research Funding; AbbVie: Research Funding; Pluristem: Research Funding; Jazz: Other: Advisory Board; Omeros: Other: Advisory Board; Astellas: Research Funding; Biosight: Other: Data monitoring committee. Tallman: NYU Grand Rounds: Honoraria; Kura: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Biosight: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Oncolyze: Membership on an entity's Board of Directors or advisory committees; KAHR: Membership on an entity's Board of Directors or advisory committees; Orsenix: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Rafael Pharmaceuticals: Research Funding; Glycomimetics: Research Funding; Biosight: Research Funding; Orsenix: Research Funding; Abbvie: Research Funding; Mayo Clinic: Honoraria; UC DAVIS: Honoraria; Northwell Grand Rounds: Honoraria; NYU Grand Rounds: Honoraria; Danbury Hospital Tumor Board: Honoraria; Acute Leukemia Forum: Honoraria; Miami Leukemia Symposium: Honoraria; New Orleans Cancer Symposium: Honoraria; ASH: Honoraria; NCCN: Honoraria. Shanafelt: Genentech, Pharmacyclics: Research Funding. Wagner: Eli Lilly, Johnson & Johnson: Other: Spouse, previously held individual stocks;; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Athenex Inc: Consultancy.

Abstract The management of chronic lymphocytic leukemia (CLL) has undergone unprecedented changes over the last decade. Modern targeted therapies are incorporated into clinical practice. Unfortunately, patients have begun to develop resistance or intolerance to multiple classes. Symptomatic patients previously treated with a BTK inhibitor (BTKi) and venetoclax represent a new and rapidly growing unmet need in CLL. Here, we define unmet needs in a modern treatment context. We also critically review the literature for PI3K inhibitors and chemoimmunotherapy and lack of data to support their utility following BTKis and venetoclax. Finally, we suggest opportunities to ensure the continued innovation for patients with CLL.

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.

PURPOSE Among Bruton's tyrosine kinase inhibitors, acalabrutinib has greater selectivity than ibrutinib, which we hypothesized would improve continuous therapy tolerability. We conducted an open-label, randomized, noninferiority, phase III trial comparing acalabrutinib and ibrutinib in patients with chronic lymphocytic leukemia (CLL). METHODS Patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) were randomly assigned to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity. The primary end point was independent review committee–assessed noninferiority of progression-free survival (PFS). RESULTS Overall, 533 patients (acalabrutinib, n = 268; ibrutinib, n = 265) were randomly assigned. At the data cutoff, 124 (46.3%) acalabrutinib patients and 109 (41.1%) ibrutinib patients remained on treatment. After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% CI acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio: 1.00; 95% CI, 0.79 to 1.27). All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; P = .02); among other selected secondary end points, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups and median overall survival was not reached in either arm (hazard ratio, 0.82; 95% CI, 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib. Treatment discontinuations because of adverse events occurred in 14.7% of acalabrutinib-treated patients and 21.3% of ibrutinib-treated patients. CONCLUSION In this first direct comparison of less versus more selective Bruton's tyrosine kinase inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.

7500 Background: Increased selectivity of the Bruton tyrosine kinase inhibitor (BTKi) acalabrutinib (Aca) vs ibrutinib (Ib) may improve tolerability. We conducted an open-label, randomized, noninferiority, phase 3 trial to compare Aca vs Ib in patients (pts) with chronic lymphocytic leukemia (CLL). Methods: Previously treated CLL pts with del(17p) or del(11q) by central lab were randomized to receive oral Aca 100 mg BID or Ib 420 mg QD (stratified by del(17p) status, ECOG PS [2 vs ≤1], and number of prior therapies [1–3 vs ≥4]) until progression or unacceptable toxicity. Primary endpoint was progression-free survival (PFS) as assessed by IRC; secondary endpoints of all grade atrial fibrillation (AF), grade ≥3 infection, Richter transformation, and overall survival (OS) were assessed in hierarchical order. Results: 533 pts (Aca, n=268; Ib, n=265) were randomized (median age 66 y; median 2 prior therapies; del(17p) 45.2%; del(11q) 64.2%). At a median follow-up of 40.9 mo (range 0.0–59.1), Aca was noninferior to Ib with a median PFS of 38.4 mo in both arms (HR 1.00; 95% CI 0.79–1.27). Aca was statistically superior to Ib in all-grade AF incidence (9.4% vs 16.0%; P=0.023). Among the other secondary endpoints, incidences of grade ≥3 infection (Aca: 30.8%, Ib: 30.0%) and Richter transformation (Aca: 3.8%, Ib: 4.9%) were comparable between arms. Median OS was not reached in either arm (HR 0.82 [95% CI 0.59–1.15]), with 63 (23.5%) deaths in the Aca arm and 73 (27.5%) in the Ib arm. Among any-grade AEs in ≥20% of pts in either arm, Aca was associated with a lower incidence of hypertension (9.4%, 23.2%), arthralgia (15.8%, 22.8%), and diarrhea (34.6%, 46.0%) but a higher incidence of headache (34.6%, 20.2%) and cough (28.9%, 21.3%). AEs led to treatment discontinuation in 14.7% of Aca- vs 21.3% of Ib-treated pts. Among any-grade events of clinical interest, cardiac, hypertension, and bleeding events were less frequent with Aca (Table). Conclusions: In this first head-to-head trial of BTKis in CLL, Aca demonstrated non-inferior PFS with less cardiotoxicity and fewer discontinuations due to AEs vs Ib. Clinical trial information: NCT02477696. [Table: see text]