Abstract: Ibrutinib has transformed the management of chronic lymphocytic leukemia (CLL), though its use is limited by toxicity and resistance. In this study, we utilized an “add on” approach for patients who had been treated with ibrutinib in the front-line or relapsed/refractory settings with detectable MRD. Umbralisib and ublituximab (U2) were added on to ibrutinib, patients were treated until achieving undetectable-MRD (U-MRD), and then they entered a period of treatment-free observation (TFO). Patients and Methods: Patients were eligible if they received ibrutinib in any line of therapy for at least 6 months and had detectable MRD (flow cytometry, & lt;1 cell in 10–4 cutoff for U-MRD). U2 was added to ibrutinib, and patients were monitored serially for MRD. Once U-MRD was achieved or a total of 24 cycles were administered, patients entered a period of TFO. The primary study objective was rate of U-MRD. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation. Results: Twenty-eight patients were enrolled of whom 27 were evaluable for efficacy. Patients received ibrutinib for a median of 21 months (range 7–67) prior to study enrollment. Fourteen patients (52%) have achieved U-MRD per protocol whereas 78% had at least one U-MRD evaluation. Seventeen patients (63%) have entered TFO after a median of 6.4 months on triplet therapy. Progression-free survival at 12 months was estimated at 95%. Grade ≥3 adverse events were hypertension 7%, diarrhea 4%, and increased ALT/AST 4%. Conclusions: This triplet approach utilizes the addition of U2 to ibrutinib as an MRD-driven time-limited therapy. This therapy was well tolerated and effective. TFO following this therapy appears durable in ongoing follow-up.

Abstract: Background: While time-limited novel agent combinations have demonstrated high overall response rates and durable responses for patients with chronic lymphocytic leukemia (CLL), they also have high rates of adverse events and possibly overtreat many favorable risk patients. Meanwhile, patients receiving indefinite ibrutinib monotherapy are at risk for cumulative toxicity and acquired resistance with continuous exposure. To address these challenges, we utilized an "add-on" approach to combination therapy after a period of ibrutinib monotherapy exposure. We examined the addition of umbralisib (a selective PI3Kδ and casein kinase-1epsilon [CK1ε] inhibitor) and ublituximab (a novel anti-CD20 monoclonal antibody glycoengineered for enhanced antibody-dependent cellular cytotoxicity; U2) to ibrutinib in CLL patients with detectable minimal residual disease (MRD) after an initial period of treatment with ibrutinib monotherapy. With this strategy, we aimed to induce undetectable MRD (uMRD), minimize the risk of developing BTKi resistance mutations, stop all CLL-directed therapy, and achieve a durable treatment-free observation (TFO) period in CLL patients who would most benefit from combination therapy. Methods: This is a phase II, multicenter, open label clinical trial (NCT04016805). Eligible patients were receiving ongoing ibrutinib, in any line of therapy, for a minimum duration of 6 months and had detectable residual CLL in the peripheral blood via MRD assay (flow cytometry with a cutoff of 10^-4 for uMRD). Umbralisib (administered daily at 800mg) and ublituximab (administered intravenously at 900 mg on Days 1/2 [split 150/750 mg], 8, and 15 of Cycle 1, Day 1 of Cycles 2-6, and on Day 1 every 3 cycles after Cycle 6) were added to ibrutinib, and patients were monitored serially for MRD starting on Cycle 3 Day 1. Once uMRD was achieved and confirmed 4 weeks later, patients entered a period of TFO. Patients who did not attain uMRD continued treatment for up to 24 cycles followed by TFO. The primary objective of the study was rate of uMRD, with a prespecified MRD conversion rate of 25% defined as promising. Secondary endpoints included safety and durability of clinical benefit after treatment discontinuation. Results: In this fully accrued study, U2 was added to ibrutinib in 26 patients. Median age was 63 years (range, 48-81) and 77% were male. Disease characteristics included del(17p) in 8%, del(11q) in 12%, and unmutated IGHV in 31%. Median duration of ibrutinib treatment prior to addition of U2 was 22 months (range 7-66 months). The swimmer plot in Figure 1 depicts time on ibrutinib prior to enrolling in this study, the duration of treatment with triplet therapy, achievement of uMRD, and TFO. MRD has been assessed in 24 patients; 71% (17/24) had uMRD in at least 1 assessment. Median time to first uMRD result was 5 months (range 2 - 12). A total of 16 patients (67%) entered TFO; 15 had 2 consecutive uMRD assessments and 1 completed 24 cycles with detectable MRD. TFO appears durable, with a median of 242 days off therapy (range 5-538 days) as of the data cutoff. 73% remain uMRD at last follow up. No patient has progressed or required re-treatment per iwCLL criteria. U2 plus ibrutinib was well tolerated. All-causality grade 3/4 adverse events of special interest included ALT/AST increase (4%), diarrhea (4%), and hypertension (8%). Two patients discontinued all therapy due to rash; both were uMRD at the time of treatment discontinuation and remain uMRD. One patient died due to complications of COVID-19. Conclusions: This is the first MRD-driven approach utilizing the combination of BTKi, PI3Ki, and anti-CD20 monoclonal antibody. This novel agent combination therapy was well tolerated and effective, with achievement of uMRD in 71% of evaluable patients. This "add-on" approach for patients on continuous ibrutinib resulted in deep remissions that allowed for a tailored, time-limited therapy and sustained treatment-free observation. Figure 1 Figure 1. Disclosures Roeker: Pharmacyclics: Consultancy; TG Therapeutics: Consultancy; Pfizer: Consultancy, Research Funding; AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company; Loxo Oncology: Consultancy. Leslie: Karyopharm Therapeutics: Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Merck: Consultancy; Janssen: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; BeiGene: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Soumerai: Abbvie: Consultancy; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy, Research Funding; BMS: Consultancy; BostonGene: Research Funding; GlaxoSmithKline: Research Funding; Seattle Genetics: Consultancy; TG Therapeutics: Consultancy, Research Funding. Zelenetz: MorphoSys: Honoraria; AstraZeneca: Honoraria; Gilead: Honoraria, Research Funding; Verastem: Honoraria; BMS/Celgene/JUNO: Honoraria, Other; NCCN: Other; Gilead: Honoraria; LFR: Other; MEI Pharma: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Janssen: Honoraria; Beigene: Honoraria, Other, Research Funding; SecuraBio: Honoraria; Amgen: Honoraria; Pharmacyclics: Honoraria; MethylGene: Research Funding; Genentech/Roche: Honoraria, Research Funding; Novartis: Honoraria. Falchi: Abbvie: Consultancy, Research Funding; Roche: Research Funding; Genetech: Research Funding; Genmab: Consultancy, Research Funding. Park: Curocel: Consultancy; PrecisionBio: Consultancy; BMS: Consultancy; Minerva: Consultancy; Novartis: Consultancy; Affyimmune: Consultancy; Innate Pharma: Consultancy; Kite Pharma: Consultancy; Autolus: Consultancy; Kura Oncology: Consultancy; Servier: Consultancy; Amgen: Consultancy; Artiva: Consultancy; Intellia: Consultancy. Battiato: Janssen Pharmaceutical: Other: Advisory Board July 2020; Abbvie Pharmaceuticals: Other: CLL Steering Committee November 2020-present. Thompson: VJHemOnc: Honoraria; Curio Science: Honoraria; MJH Life Sciences: Honoraria. Miskin: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Sportelli: TG Therapeutics, Inc.: Current Employment, Current equity holder in publicly-traded company. Mato: Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; MSKCC: Current Employment; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Nurix: Research Funding; AstraZeneca: Consultancy; Acerta/AstraZeneca: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Genmab: Research Funding; AbbVie: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding.

Abstract: Background: Non-covalent Bruton's Tyrosine Kinase inhibitors (ncBTKi) are in clinical development for the treatment of chronic lymphocytic leukemia (CLL) and Richter Transformation (RT). These agents (pirtobrutinib, ARQ-531, SNS-062) reversibly bind BTK and overcome acquired resistance to covalent BTKis (cBTKi). In the phase I/II trial of pirtobrutinib, clinical activity was observed in a heavily pre-treated patient (pt) population including CLL pts with acquired mutations in BTK and pts with RT. Given the efficacy of ncBTKis, these agents hold promise to address an unmet need for pts with CLL. As an increasing number of pts are treated with ncBTKis, data on the sequential use of each therapy are critical to guide clinical decision-making following their discontinuation and where ncBTKi may ultimately fit into the CLL sequencing paradigm. Currently, there are no available data on treatment of CLL or RT following discontinuation of ncBTKis. Therefore, we sought to report outcomes for CLL and RT pts following discontinuation of ncBTKis. Methods: We conducted a retrospective, multicenter, international study of pts treated with any ncBTKi for a diagnosis CLL or RT who have discontinued ncBTKi. Data was collected using a standardized data template which included pt and disease characteristics, prior therapies, demographics, response to ncBTKi and subsequent therapies and outcomes. Data on up to two lines of therapies following ncBTKi were collected. The primary study endpoint was investigator-assessed overall response rate (ORR) for therapies following ncBTKi discontinuation. Analyses were descriptive and were performed using STATA 17.0. Results: 42 pts with CLL (n=33) or RT (n=9) were identified who were treated with and subsequently discontinued a ncBTKi. Baseline characteristics at start of ncBTKi are presented in Table 1. Pts were treated with a median of 3.5 (range 1-10) prior therapies including: cBTKi (95%), chemo+/-immunotherapy (CIT, 76%), venetoclax (50%), phosphatidylinositol 3-kinase inhibitors (PI3Ki, 33%) and cellular therapies (14%). Baseline disease characteristics included unmutated IGHV (74%), del17p (49%) and TP53 mutation (45%). Best ORR to ncBTKi was 48.5% in CLL pts and 44.4% in RT pts. Median duration of treatment exposure was 5.5 months (range 1-18). The six most common reasons for discontinuation were progressive CLL 38.1%, progression of existing RT 14.3%, CLL progression to RT 9.5%, allogeneic stem cell transplant (allo SCT) 9.5%, death not secondary to progression or toxicity 7.1%, and adverse events 7.1%. Presently, 32 pts (76.2%) received another line of therapy following discontinuation of ncBTKi. Therapies and ORR following ncBTKi discontinuation are presented in Table 2. The 3 most common treatment strategies included: cellular therapy (11 pts), venetoclax-based therapy (10 pts) and CIT for RT (9 pts). ORR to any first line of therapy post ncBTKi was 46.7% (n=30 pts with response data). ORR to any second line of therapy following ncBTKi was 45.4% (n=11 pts with response data). Focusing on specific treatment strategies, ORR to cellular therapy (allo SCT or chimeric antigen receptor (CAR) T-cell therapy) for RT or CLL was 81.8% (complete response (CR): 6, partial response (PR): 3, stable disease (SD): 1, progression of disease (PD):1, n=11) with an ORR of 80.0% (n=5) after CAR T-cell therapy and an of ORR 75.0% after allo SCT (n=4). ORR to venetoclax-based therapy was 60.0% (CR: 0, PR: 6, SD: 3, PD: 1, n=10, all CLL pts, 9 venetoclax naïve pts). Additionally, two pts received alternative ncBTKis (PR: 1, SD: 1). CIT was ineffective for either RT or CLL (ORR: 12.5% and 33.3%, respectively). At the time of data cut, 15 of 42 (35.7%) pts had died with 9 deaths due to CLL or RT. Conclusion: In this first study to report outcomes of CLL and RT pts who have discontinued a ncBTKi, several important themes have emerged. For venetoclax naive CLL pts, venetoclax appears to be a promising strategy following ncBTKi discontinuation supporting the ability to stay within the BTKi class prior to switching to venetoclax. Cellular therapies including CAR T-cell therapy and allo SCT had a high ORR and warrant further investigation (80% of pts had prior cBTKi, ncBTKi and venetoclax and 100% had prior cBTKi and ncBTKi). CIT was associated with very low response rates and poor outcomes for both RT and CLL. Data to be updated with additional pts and survival outcomes. Figure 1 Figure 1. Disclosures Thompson: MJH Life Sciences: Honoraria; Curio Science: Honoraria; VJHemOnc: Honoraria. Coombs: LOXO: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria; Genentech: Honoraria; MEI Pharma: Honoraria. Roeker: Pfizer: Consultancy, Research Funding; TG Therapeutics: Consultancy; Pharmacyclics: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company; AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Loxo Oncology: Consultancy. Pagel: Gilead: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; Pharmacyclics/AbbVie: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy; Actinium Pharmaceuticals: Consultancy; Incyte/MorphoSys: Consultancy; BeiGene: Consultancy. Battiato: Janssen: Honoraria; Abbvie: Honoraria. Rhodes: Conquer Cancer Foundation Young Investigator Award: Other: Grant/Research Support; AbbVie, Genentech, Pharmacyclics, TG Therapeutics: Other: Consultant. Fakhri: Loxo/Lilly: Research Funding. Eyre: Secura Bio: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Janssen: Honoraria; Incyte: Consultancy; AstraZeneca: Honoraria, Research Funding; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau. Mato: TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Janssen: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; DTRM BioPharma: Consultancy, Research Funding; Genmab: Research Funding; Nurix: Research Funding; MSKCC: Current Employment; AstraZeneca: Consultancy; Sunesis: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding.