Outcomes of Therapies and Resistance Mutations Following Non-Covalent Bruton's Tyrosine Kinase Inhibitor Treatment for Patients with Chronic Lymphocytic Leukemia and Richter Transformation

Background: Non-covalent Bruton's Tyrosine Kinase inhibitors (ncBTKi) have shown excellent clinical activity for patients (pts) with relapsed and/or refractory chronic lymphocytic leukemia (CLL) and Richter Transformation (RT). However, some pts treated with ncBTKi develop progressive disease (PD). In addition, acquired BTK mutations (mut) at the time of PD on ncBTKi were recently described, although the frequency at which these mut occur has not been reported. Currently, data regarding treatment sequencing post ncBTKi are lacking but are critical to guide further treatment selection.

Methods: We conducted a retrospective, multicenter study of pts treated with any ncBTKi for CLL or RT who have discontinued ncBTKi for any reason. Using a standardized template we collected: pt and disease characteristics (including prior therapies, cytogenetic/molecular characteristics), demographics, clinical response to ncBTKi and subsequent therapies, and survival. Data on 2 lines of therapies (LOT) following ncBTKi were collected for each pt. Primary endpoint was overall response rate (ORR) for therapies following ncBTKi. Progression free survival (PFS) was estimated using the Kaplan Meier method. We also collected next generation sequencing (NGS) data for CLL pts who discontinued ncBTKi. Analyses were performed using STATA 17.0.

Results: We identified 63 pts (48 CLL, 15 RT) treated with who then discontinued ncBTKi. Baseline characteristics at ncBTKi start are presented in Table 1. Median number of prior therapies was 4 (1-10), and most pts received prior covalent BTKi (93.7%) and venetoclax (57.1%). At ncBTKi start, 84.8% of patients had unmutated IGHV, 48.8% had a TP53 mut and 37.0% had a complex karyotype.

ORR to ncBTKi was 58.8% for the CLL cohort (PR 54.4%, PR-L 4.4%) and 46.7% for the RT cohort (CR 6.7%, PR 40%). Median duration of ncBTKi exposure prior to discontinuation was 9 (1-27) and 4 (1-12) months for CLL and RT, respectively. Overall, 73.7% of the combined cohort progressed on ncBTKi. Specific reasons for ncBTKi discontinuation included: CLL PD (n=26, 41.2%), PD of existing RT (n=7), death not secondary to PD or toxicity (n=6), other reason (n=6), stem cell transplant (SCT, n=5), toxicity (n=4), PD of CLL to RT (n=4), MD/pt preference (n=2), CAR T (n=2), and sudden death on therapy (n=1).

Following ncBTKi, 76.2% of pts (n=48) received another LOT. Therapies and responses are presented in Table 1. Common treatment strategies were: chemo+/-immunotherapy (CIT) (n=16, ORR 18.8%), CD19-directed CAR T-cell therapy (n=7, ORR 85.7%), allogeneic SCT (n=6, ORR 83.3%), and venetoclax-based therapy (n=10, ORR 70.0%). 27.3% of therapies administered post ncBTKi were administered on a clinical trial.

For CLL pts, median PFS for first LOT following ncBTKi was 14 months (n=25 pts, Figure 1). For the RT cohort, the median PFS for the first LOT following ncBTKi discontinuation was 6 months (median follow-up 2.5 months). Importantly, median PFS for venetoclax following ncBTKi discontinuation for CLL pts was 14 months (8 pts, 87.5% venetoclax-naive, median follow-up 10.5 months). 49.2% of the overall cohort has died, with 58.6% of deaths due to CLL or RT (n=17 of 29 pts with available data).

15 CLL pts who discontinued ncBTKi for PD had end of treatment NGS data available. For these pts, at the start of ncBTKi, BTKC481 mut and PLCG2 mut were present in 38.5% and 33%, respectively. At end of ncBTKi treatment, novel (not C481) BTK mut were identified in 9 of 15 pts (60.0%). These included mut in BTKL528W (n=6), BTKV416L (n=2) and BTKT474I (n=2); 1 pt had mut in both BTKT474I and BTKL528W. Additionally, 4 pts had pre-existing mut in PLCG2 that persisted at PD. Overall, 11 of 15 (73.3%) of CLL pts had a novel BTK mut and/or a persistent PLCG2 mut at PD on ncBTKi.

Conclusions: We report results from the first series of CLL and RT pts following ncBTKi discontinuation. CIT for RT and CLL yielded poor outcomes, while CAR T-cell therapy and allogeneic SCT had high ORR warranting further investigation. Most importantly, venetoclax has clinical activity (high ORR, durable PFS) for CLL pts following ncBTKi discontinuation suggesting CLL pts can stay within the BTKi class prior to switching to venetoclax. In addition, at PD 73% of pts had a novel BTK mut and/or the persistence of a PLCG2 mut conferring resistance to ncBTKis. Overall, these results highlight an unmet need for novel therapeutic strategies for pts who require treatment following ncBTKi.

Thompson:Curio Science: Honoraria; VJHemOnc: Honoraria; Massachusetts Medical Society: Honoraria; Intellisphere, LLC: Honoraria; MJH Life Sciences: Honoraria; Brazilian Association of Hematology and Hemotherapy: Honoraria. Coombs:AbbVie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; CTI Biopharma: Current equity holder in publicly-traded company; Novartis: Honoraria; TG Therapeutics: Honoraria; MEI Pharma: Honoraria; Loxo/Lilly: Consultancy, Honoraria, Research Funding. Roeker:Qilu Puget Sound Biotherapeutics: Research Funding; Ascentage: Consultancy; Aptose Biosciences: Research Funding; Abbott Laboratories: Current equity holder in publicly-traded company; TG Therapeutics: Consultancy; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy; Loxo Oncology: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy; Beigene: Consultancy; AbbVie: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; AstraZeneca: Consultancy. Jensen:AbbVie: Current equity holder in private company. Shah:Epizyme: Consultancy; Novartis: Consultancy; Lilly Oncology: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria, Speakers Bureau; Miltenyi Biotec: Consultancy, Research Funding; Kite Pharma: Consultancy; Bristol Myers Squibb: Consultancy; TG therapeutics: Consultancy. Patel:MEI Pharma: Consultancy, Research Funding; Nurix: Research Funding; Kite pharma: Consultancy, Research Funding, Speakers Bureau; Epizyme: Consultancy, Research Funding; Curis, Inc: Research Funding; CRISPR Therapeutics: Research Funding; Celgene: Consultancy, Research Funding, Speakers Bureau; Sunesis Pharmaceuticals: Research Funding; Pharmacyclics/Janssen: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Speakers Bureau; Morphosys: Consultancy; Trillium Therapuetics/Pfizer: Consultancy, Research Funding; Genetech/Roche: Consultancy, Research Funding, Speakers Bureau; Loxo Oncology: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Fate Therapeutics: Research Funding; Caribou Biosciences: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; ADC Therapeutics: Consultancy; Aptevo Therapeutics: Research Funding; Velos Bio: Research Funding; Abbvie: Consultancy; Adaptive Biotechnologies: Research Funding. Fakhri:TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; CSL Behring: Consultancy; Lox/o Oncology/Eli Lilly and Company: Research Funding; BMC: Research Funding; Angiocrine: Research Funding; Adaptive: Research Funding; Seattle Genetics: Research Funding; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; University of California San Francisco: Current Employment. Eyre:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; KITE: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; LOXO Lilly: Membership on an entity's Board of Directors or advisory committees, Other, Speakers Bureau; PeerView: Speakers Bureau; Medscape: Speakers Bureau; Secura Bio: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ghione:Kyowa Hakko Kirin: Consultancy; Secura Bio: Consultancy; AstraZeneca Pharmaceuticals: Consultancy; Kite Pharma: Research Funding. Rhodes:SeaGen: Consultancy; Janssen: Consultancy, Research Funding; Morphosys: Consultancy; Genmab: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genentech: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Oncternal: Research Funding; Velosbios: Research Funding; Beigene: Consultancy; Abbive: Consultancy; Loxo Oncology: Research Funding; Epizyme: Research Funding. Zelenetz:BeiGene: Consultancy, Research Funding; AstraZeneca: Consultancy; MEI Pharma: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Gilead/Kite: Consultancy; BMS/Celgene/JUNO: Consultancy; Abbvie: Research Funding; Amgen: Consultancy; Jansen: Consultancy; Pharmacyclics/Abbvie: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Lymphoma Research Foundation: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Taylor:Karyopharm, Inc: Honoraria. Palomba:Notch Therapeutics: Current holder of stock options in a privately-held company, Honoraria; GSK: Honoraria; Da Volterra: Honoraria; Thymofox: Honoraria; Garuda: Honoraria; Ceramedix: Honoraria; Lygenesis: Honoraria; Pluto Therapeutics: Current holder of stock options in a privately-held company, Honoraria; Nektar Therapeutics: Honoraria; Frazier Healthcare Partners: Honoraria; Rheos: Honoraria; Vor Biopharma: Honoraria; Seres: Current holder of stock options in a privately-held company, Honoraria, Research Funding; MustangBio: Honoraria; Kite: Honoraria; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Synthekine: Honoraria; Novartis: Honoraria; BMS: Consultancy. Abdel-Wahab:H3B Biomedicine, Foundation Medicine Inc, Merck, Prelude Therapeutics, and Janssen: Consultancy; Envisagenics Inc., AIChemy, Harmonic Discovery Inc., and Pfizer Boulder: Membership on an entity's Board of Directors or advisory committees; H3B Biomedicine, LOXO Oncology, and Nurix Therapeutics: Research Funding. Mato:Nurix: Research Funding; LOXO: Honoraria, Research Funding; DTRM Biopharma: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Johnson & Johnson: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria; AstraZeneca: Honoraria, Research Funding; Pharmacyclics, LLC: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; TG Therapeutics, Inc: Honoraria, Research Funding; Octopharma: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Pfizer: Research Funding; Curio: Honoraria; Dava: Honoraria; BMS: Honoraria; Medscape: Honoraria; Acerta: Research Funding; PER: Honoraria; PerView: Honoraria.