Citations

Abstract Advancements in the understanding of chronic lymphocytic leukemia (CLL) have transformed patient care, leading to the development of novel targeted therapies. Traditionally, patient fitness for treatment was based on the tolerability of chemoimmunotherapy such as fludarabine–cyclophosphamide–rituximab. As the CLL patient population is predominantly older, age has historically been a major factor in how a physician selects a patient's treatment. However, as a patient's fitness goes beyond age, the definition of patient fitness should also evolve. Here, we provide suggestions for the current best practice on assessing fitness for treating CLL. Considerations for treatment include assessment of polypharmacy, history of infections, cardiovascular and renal comorbidities, functional status, cognitive and psychological status, nutritional status, and social support. The flow of assessments can start with a typical clinical evaluation followed by geriatric, cardiovascular, and renal reviews, if needed, and include collecting a patient's full history to evaluate their risk of complications with specific CLL treatments. The severity of a patient's cardiovascular profile can range from low to high risk; for those at high risk, collaboration with a cardiologist is recommended. Geriatric assessment is advised to determine baseline frailty and resilience to tolerate treatments, to avoid inappropriate treatment or undertreating patients based on chronological age, and to align the patient's fitness status with the most optimal treatment. Continuous monitoring and assessment, regardless of therapy, are recommended. Patient preferences are also integral to this decision‐making process. Looking beyond a patient's age and basing treatment selection on their fitness is key in the new era of treatment in CLL.

Abstract Introduction FD Ibr+Ven is approved as first-line (1L) treatment (tx) for CLL/SLL in 78 countries across Asia, Europe, the Middle East, and South America, plus Australia, Canada, and New Zealand. Clinical trials with up to 5.5 years (yrs) of follow-up have demonstrated progression-free and overall survival benefits of 1L FD Ibr+Ven in pts with CLL/SLL (Wierda WG, ASH 2024; Jacobs R, EHA 2024). Despite established clinical benefits, there is a lack of RW evidence on the effectiveness and tolerability of FD Ibr+Ven outside of clinical trial settings. Here we present pooled data from REALITY-WW and REALITY-2 to understand the usage, factors for therapy decision, clinical response, and safety of FD Ibr+Ven in routine clinical practice. Methods REALITY-WW and REALITY-2 are prospective observational cohort studies. REALITY-WW is an international study; REALITY-2 is conducted in Germany. Both included previously untreated pts with CLL/SLL from hospitals and medical institutions where Ibr+Ven was routinely used. The decision to start FD Ibr+Ven was made prior to and independent of pt enrollment. Pts aged ≥18 yrs with a confirmed diagnosis of CLL/SLL requiring 1L tx per iwCLL 2018 criteria received 3 cycles of Ibr, followed by 12 cycles of FD Ibr+Ven orally (Ibr, 420 mg/d; Ven, 5-week ramp-up to 400 mg/d). Primary end point was overall response rate (ORR) per iwCLL 2018 criteria. Secondary end points and outcomes of interest included tx-emergent adverse events (TEAEs), tumor lysis syndrome (TLS) risk, and factors associated with physician decision to initiate FD Ibr+Ven in routine clinical practice. Results At data cutoff (REALITY-WW: May 2025; REALITY-2: March 2025), 129 pts from both studies received FD Ibr+Ven (REALITY-WW, 81; REALITY-2, 48). The median (range) time on study was 6.4 (0.1-19.0) months (mo). Median (range) age was 65.0 (37.0-87.0) yrs, with 46.5% of pts aged <65 yrs and 53.5% of pts aged ≥65 yrs; 62.8% were male. Median (range) time from diagnosis to FD Ibr+Ven initiation was 38.1 mo (0.1-238.0) and median (range) duration of tx was 6.0 mo (0.1-15.9) for Ibr and 3.2 mo (0.1-8.4) for Ven. A Cumulative Illness Rating Scale score of >6 was observed in 12.6% of pts, with a higher score in pts aged ≥65 vs <65 yrs (18.0% vs 6.9%). TP53 mutations were seen in 7.4% of pts; 52.8% had an unmutated IGHV status. ORR was assessed in the 44 pts with ≥ 1 post-baseline assessment in REALITY-WW. Of these, 39 showed a response by the end of 6 tx cycles (3 cycles of Ibr + 3 cycles of FD Ibr+Ven) and 5 had stable disease. ORR at 6 mo per iwCLL 2018 criteria (partial response [PR] with lymphocytosis [PR-L] or better) was 88.6% (95% CI, 79.3-98.0), including complete responses in 29.5%, PR in 34.1%, and PR-L in 25.0% pts. Among 129 treated pts, TEAEs were reported in 61.2%; diarrhea was the most common TEAE (14.0%). Serious TEAEs and grade 3/4 TEAEs were reported in 12.4% and 8.5% of pts, respectively. The most common grade 3/4 TEAE was myocardial infarction (1.6%). Dose reduction was observed in 13.2% (Ibr) and 2.3% (Ven) of pts, mainly due to tx-associated TEAE/toxicity/TLS. Rates of TEAEs leading to discontinuation, dose reduction, and interruption of ≥1 study tx were 4.7%, 10.9%, and 20.9%, respectively. At baseline (n=129), 18.6%, 45.0%, and 14.7% of pts had high, intermediate, and low TLS risk, respectively, while 20.2% were not assessed and 1.6% had missing data. After the 3-cycle Ibr lead-in, the distribution shifted to 9.3%, 24.8%, and 24.0%, respectively, with 14.7% not assessed and 27.1% missing. There were no TEAEs of TLS and no hospitalizations due to TLS. Seven pts (6 aged ≥65 yrs and 1 <65 yrs) were hospitalized prophylactically for TLS. Prophylactic hospitalization was observed in 8.5% (11/129) of pts with high or medium TLS risk and impaired renal function for whom the Ven ramp-up was initiated; no pts were hospitalized due to laboratory/clinical TLS during the Ven ramp-up period. Physician questionnaire responses (n=126) indicated the most common factors associated with decision to initiate FD Ibr+Ven were administration route advantage (91.3%), overall health status (87.3%), anticipated superior efficacy of tx (84.1%), and general risk factors such as high tumor burden/genetic risk factors (81.0%). Conclusions Overall findings suggest that FD Ibr+Ven is an effective and safe tx for pts with CLL/SLL in a RW population, including those aged ≥65 yrs. Data with longer follow-up will be presented at the meeting.

Abstract Background: Covalent Bruton tyrosine kinase inhibitors (cBTKi) have dramatically changed the treatment (tx) landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), especially in the first-line setting. However, cBTKi resistance or intolerance eventually occurs. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits BTK with low nM potency throughout the daily dosing interval. Pirtobrutinib demonstrated safety and efficacy in the phase 1/2 BRUIN study among patients (pts) with R/R CLL/SLL, including pts previously treated with a BTKi. Pirtobrutinib is approved for treating CLL in adults in the EU after prior tx with a BTKi, and in the USA for adults with CLL/SLL who have received at least 2 prior lines of therapy, including a BTKi and a BCL-2i. Here, we report the final results from the phase 1/2 BRUIN study (NCT03740529) with more than 5 years (yrs) follow-up (f/u), focusing on efficacy and safety of pirtobrutinib in pts with CLL/SLL in the post-cBTKi setting. Methods: Pts with prior cBTKi-exposed CLL/SLL were eligible for tx with pirtobrutinib. Endpoints included overall response rate (ORR) per 2018 iwCLL criteria, ORR including partial response with lymphocytosis (PR-L), duration of response (DOR), and progression-free survival (PFS), assessed by independent review committee (IRC; presented herein) and investigator, overall survival (OS), and safety. Data cut was 27 January 2025, providing a median study f/u of 34.1 months (mos; range, 0.5-69.8). Results: Among the 282 pts with CLL/SLL who were cBTKi-exposed and treated with pirtobrutinib, of which 84.4% (238/282) received 200 mg as the starting dose, the median age was 69 yrs (range, 36-88). The median number of prior therapies was 4 (range, 1-11), with 45.4% of pts having received prior BCL2i, and 77.0% having discontinued prior cBTKi due to progressive disease (PD), 19.5% due to toxicity, and 3.5% due to other reasons/missing. High-risk features were frequent: unmutated IGHV in 85.8% (193/225), mutated TP53 in 40.4% (99/245), and del(17p) in 29.2% (59/202). The ORR was 72.3% (95% CI, 66.7-77.5). ORR including PR-L was 81.6% (95% CI, 76.5-85.9), which was consistent across subgroups including BCL2i-exposed (80.5%; 95% CI, 72.5-86.9), BCL2i-naive (82.5%; 95% CI, 75.5-88.1), unmutated IGHV (82.9%; 95% CI, 6.8-87.9), del(17p) (88.1%; 95% CI, 77.1-95.1), and prior cBTKi discontinuation due to PD (79.7%; 95% CI, 73.8, 84.9) or toxicity (87.5%; 95% CI, 76.8-94.4). The median DOR was 18.4 mos (95% CI, 14.82-20.27), with 36-mos DOR rate of 28.0% (21.6-34.7). The median PFS was 18.7 mos (95% CI, 16.6-21.8) among all pts and the 36-mos PFS rate was 25.0% (95% CI, 19.4-31.0) with 44 mos of f/u. Further, the median PFS was 22.3 mos (95% CI, 19.3-27.6) for BCL2i-naive pts, and 15.9 mos (95% CI, 13.6-17.5) for BCL2i-exposed pts; 16.6 mos (95% CI, 13.8-19.4) among those who discontinued prior cBTKi therapy due to PD, and not estimable (NE) (95% CI, 25.2-NE) in those who discontinued due to toxicity. Among all pts with CLL/SLL, with a median f/u of 46.5 mos, the median OS was NE (95% CI, 47.8-NE), with the 36-mos OS rate of 62.0% (95% CI, 55.8-67.7). Median time on pirtobrutinib was 20.0 mos (range, 0.2-69.8), and 43 (15.2%) pts were still on tx at data cutoff. The most frequent TEAEs, regardless of attribution, were fatigue (38.7%), neutropenia/neutrophil count decreased (35.8%), diarrhea (30.5%), cough (29.8%), COVID-19 (28.4%), and contusion (27.7%). The most frequent grade ≥3 TEAEs were infection (36.5%) and neutropenia/neutrophil count decreased (29.8%). Low rates of grade ≥3 TEAE of hypertension (5.3%), hemorrhage/hematoma (2.5%), and atrial fibrillation/flutter (2.1%) were observed. Grade 5 TEAEs, regardless of attribution, occurred in 35 (12.4%) pts. Overall, 11 (3.9%) pts had a TRAE leading to a dose reduction, and 9 (3.2%) pts had a TRAE leading to pirtobrutinib discontinuation. Conclusion: In heavily pretreated R/R post-cBTKi CLL/SLL pts, pirtobrutinib continues to show favorable and durable efficacy. Pirtobrutinib is well-tolerated, with low rates of hypertension, hemorrhage/hematoma, and atrial fibrillation/flutter, which can be frequently observed with cBTKi. Additionally, dose reductions/discontinuations due to pirtobrutinib TRAEs were low. No new pirtobrutinib safety signals were identified with more than 5 yrs of f/u.

Abstract Introduction: BTK inhibitors are effective treatments for CLL/SLL; however, treatment intolerance and resistance to BTK inhibitors are major clinical challenges for many patients. BGB-16673 is an orally available protein degrader that blocks BTK signaling by tagging BTK for degradation through the cell's proteasome pathway, leading to tumor regression. CaDAnCe-101 (BGB-16673-101; NCT05006716) is an ongoing open-label, phase 1/2 study evaluating BGB-16673 monotherapy in patients with B-cell malignancies. Here, updated phase 1 safety and efficacy data are reported for patients with relapsed/refractory (R/R) CLL/SLL. Methods: Eligible patients must have confirmed R/R CLL/SLL (≥2 prior therapies), an ECOG performance status of 0-2 (0-1 in the EU), and adequate organ function. In the US, EU, and Australia, patients must have previously received a covalent BTK inhibitor (cBTKi). Patients received BGB-16673 once daily orally. The primary phase 1 objectives were to assess safety/tolerability (NCI-CTCAE v5.0; iwCLL hematologic toxicity criteria) and to establish the maximum tolerated dose and recommended dose for expansion. A secondary objective was to assess overall response rate (ORR) per iwCLL 2018 criteria with partial response with lymphocytosis (PR-L) modification and per 2014 Lugano criteria for SLL, with the first response assessment after 12 weeks of treatment. Results: As of May 23, 2025, 67 patients with CLL/SLL were enrolled and treated (50 mg, n=1; 100 mg, n=22; 200 mg, n=17; 350 mg, n=15; 500 mg, n=12). Patients had a median age of 70 years (range, 47-91 years) and a median of 4 prior lines of therapy (range, 2-10), including cBTKis (n=63 [94.0%]), BCL2is (n=55 [82.1%]), and noncovalent BTK inhibitors (ncBTKis; n=14 [20.9%]). At study baseline, 65.7% (44/67) of patients had CLL/SLL with del(17p) and/or TP53 mutation, 77.6% (38/49) with unmutated IGHV, 38.1% (24/63) with BTK mutation, and 15.9% (10/63) with PLCG2 mutation. Median study follow-up was 18.0 months (range, 0.3-31.0 months); 39 patients (58.2%) remained on treatment at the data cutoff. Overall, 95.5% of patients had any-grade treatment-emergent adverse events (TEAEs); any-grade TEAEs in ≥25% of patients were fatigue (37.3%), contusion/bruising (31.3%), diarrhea (28.4%), and neutropenia (28.4%). Grade ≥3 TEAEs occurred in 62.7% of patients; grade ≥3 TEAEs in ≥5% of patients were neutropenia (23.9%), pneumonia (10.4%), and thrombocytopenia (6.0%). Eight patients (11.9%) had a TEAE leading to dose reduction. TEAEs led to treatment discontinuation in 12 patients (17.9%), three (4.5%) of whom had treatment-related TEAEs (subdural hemorrhage, maculopapular rash, and disseminated aspergillosis). Four patients (6.0%) had TEAEs that led to death (all due to infections, including 1 fungal infection); no deaths were deemed related to treatment. In 66 response-evaluable patients (1 patient on treatment did not reach the first assessment by the data cutoff), ORR (PR-L or better) was 86.4% (n=57), with a 4.5% (n=3) complete response (CR)/CR with incomplete marrow recovery rate. At 200 mg, ORR was 93.8% (15/16), including 1 CR. The median time to first response was 2.8 months (range, 2.0-19.4 months). Thirty-three patients (49.3%) remained on treatment for ≥12 months. Responses deepened over time: of 22 patients with initial PR-L, 15 transitioned to partial response (PR); of 16 patients with initial stable disease, 1 transitioned to PR-L and 10 to PR. Responses were seen in patients previously treated with a cBTKi (53/62 [85.5%]) or ncBTKi (10/14 [71.4%]), with double (cBTKi and BCL2i; 39/42 [92.9%]) and triple exposure (cBTKi, BCL2i, and ncBTKi; 9/12 [75.0%]), with (18/24 [75.0%]) and without (36/39 [92.3%]) BTK mutations, with del(17p) and/or TP53 mutation (35/43 [81.4%]), and with PLCG2 mutation (9/10 [90.0%]). The 12-month progression-free survival rate was 79.2%; 15 patients (22.4%) had progressive disease (2 associated with Richter transformation to diffuse large B-cell lymphoma), and 4 (6.0%) died. Further exploratory analyses will be presented at the meeting.Conclusions: Data from the ongoing CaDAnCe-101 study demonstrate that the novel BTK degrader BGB-16673 has a tolerable safety profile and shows robust and deepening responses in patients with heavily pretreated R/R CLL/SLL, including those with prior BTK inhibitor treatment and BTK mutations. The 200-mg dose of BGB-16673 is being evaluated in phase 2 and 3 studies in patients with R/R CLL/SLL.

PURPOSE The combination of the Bruton tyrosine kinase inhibitor ibrutinib with bendamustine-rituximab for first-line treatment of mantle cell lymphoma (MCL) prolonged progression-free survival (PFS), but without improvement in overall survival (OS), likely because of toxicity. Acalabrutinib was shown to be efficacious and less toxic than ibrutinib in a head-to-head trial in chronic lymphocytic leukemia and therefore might lead to better outcomes in MCL. METHODS Patients 65 years and older with previously untreated MCL received acalabrutinib (100 mg twice daily) or placebo (until disease progression or unacceptable toxicity), plus six cycles of bendamustine (90 mg/m 2 once daily; days 1 and 2) and rituximab (375 mg/m 2 as a single dose; day 1) followed by rituximab maintenance in responding patients for 2 years. Crossover to acalabrutinib at disease progression was permitted. The primary end point was PFS per the independent review committee; overall response rate and OS were secondary end points. RESULTS In total, 598 patients were randomly assigned, with 299 in each arm. At a median follow-up of 49.8 months using the reverse Kaplan-Meier method, the median PFS was 66.4 months in the acalabrutinib arm and 49.6 months in the placebo arm (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.94]; P = .0160). Benefit was seen across all subgroups, including those with high-risk features. Overall response/complete response rates were 91.0%/66.6% and 88.0%/53.5% in the acalabrutinib and placebo arms, respectively. OS was not significantly different (HR, 0.86 [95% CI, 0.65 to 1.13]; P = .27). Grade 3 or greater adverse events were reported in 88.9% and 88.2% in the acalabrutinib and placebo arms, respectively. CONCLUSION The combination of acalabrutinib with bendamustine-rituximab significantly improved PFS. Clinical benefit of acalabrutinib with bendamustine-rituximab was achieved with manageable toxicity.

Abstract Richter transformation (RT) is defined as an aggressive lymphoma emerging in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). Despite novel therapeutics developed in CLL, RT is associated with poor outcomes. In light of recent progress regarding the diagnostic procedures and therapeutic concepts of RT, an international group of experts, under the coordination of the European Research Initiative on CLL, has developed consensus recommendations for clinical procedures and future research on this disease. Patients with RT typically present with a rapid clinical decline, worsening B-symptoms, elevated lactate dehydrogenase, and/or rapidly enlarging lymphadenopathy. Workup should include a positron emission tomography–computed tomography scan for patients with suspected RT. An excisional biopsy should be taken from an accessible lesion, preferably with the highest fluorodeoxyglucose avidity, and analyzed for the presence of aggressive lymphoma. The molecular relationship to the original CLL clone(s) should be defined. Because no effective standard treatment for RT exists, patients should be treated in a clinical trial. Response of both RT and CLL should be assessed at an early time point, and survival end points should be prioritized in trial design. We hope that these recommendations can help to harmonize clinical and translational research and improve outcomes for patients with RT.

Abstract ZUMA-8 evaluated the safety of brexucabtagene autoleucel (brexu-cel), a CD19-directed autologous chimeric antigen receptor (CAR) T-cell immunotherapy, for patients with relapsed/refractory chronic lymphocytic leukemia (R/R CLL). Patients with ≥2 prior lines of therapy (including a Bruton tyrosine kinase inhibitor) underwent leukapheresis, optional bridging therapy, and conditioning chemotherapy (fludarabine/cyclophosphamide) before infusion of 1 × 106 (cohort 1) or 2 × 106 (cohort 2) anti-CD19 CAR T cells per kg. Patients in cohort 3 (low tumor burden), and cohort 4A (postibrutinib) received 1 × 106 cells per kg. Fifteen patients, median age of 63 years (range, 52-79), were treated in cohorts 1 (n = 6), 2 (n = 3), 3 (n = 3), and 4A (n = 3). Median follow-up was 24.3 months. One dose-limiting toxicity was observed in cohort 3 (grade 4 cytokine release syndrome). Grade ≥3 neurologic events occurred in 3 patients (20%). Seven of 15 patients responded (overall response rate, 47%; complete response [CR], 7%), including all 3 patients in cohort 3 (1 with CR). CAR T-cell expansion occurred in 4 patients (27%), with an apparent weak inverse correlation with absolute lymphocyte count before apheresis. Brexu-cel had no new safety signals in R/R CLL. CAR T-cell expansion and responses occurred in patients with low tumor burden. This trial was registered at www.clinicaltrials.gov as #NCT03624036.

Introduction: Ibrutinib, a Bruton tyrosine kinase inhibitor (BTKi), changed the treatment landscape by demonstrating improved overall survival (OS) compared with chemotherapy/chemoimmunotherapy across multiple phase 3 trials in patients (pts) with CLL, including those with high-risk genomic features. Recently, data were reported for pts treated with ibrutinib in the phase 3 RESONATE-2 trial with up to 10 years of follow-up, representing the longest follow-up of any BTKi used in first-line treatment of CLL. With the most robust long-term follow-up data among BTKis, ibrutinib therapy trials are uniquely positioned to assess the long-term OS benefit of first-line BTKi treatment in pts with CLL across pt subgroups. We previously demonstrated that first-line ibrutinib is associated with OS rates that are similar to those in the age-matched general population, with a median follow-up of 5.9 years since initial diagnosis (Ghia P et al. HemaSphere 2024), but it remains unclear whether this holds true for pts with high-risk genomic features. This updated analysis evaluated long-term OS outcomes with a median follow-up of 8 years since randomization and 10 years since initial diagnosis in a pooled population of pts with previously untreated CLL, including those with high-risk features, who received first-line ibrutinib treatment in 2 phase 3 trials with comparison of survival estimates to the US age-matched general population. Methods: Data were pooled for pts who received first-line treatment with single-agent ibrutinib or ibrutinib + rituximab in the RESONATE-2 (NCT01722487) and ECOG-ACRIN E1912 (NCT02048813) trials, respectively. OS probabilities from the time of randomization and from the time of initial diagnosis for ibrutinib-treated pts were compared with an age-matched general population using 2021 life tables for the total US population published by the Centers for Disease Control and Prevention using the Kaplan-Meier method. Subgroup analyses were performed for high-risk pts, defined as those with del(11q), del(17p), mutated TP53, and/or unmutated IGHV (uIGHV). Results: A total of490 pts were pooled across the 2 studies: 352 pts (71.8%) were treated with ibrutinib + rituximab, and 135 pts (27.6%) were treated with single-agent ibrutinib; 3 pts did not receive study treatment. The median age at time of randomization was 61 years; 36.5% (179/490) were aged ≥65 years, 21.8% had del(11q), 7.8% had del(17p) and/or mutated TP53, and 54.7% had uIGHV. The median time from initial CLL diagnosis to randomization was 20.9 months (range, 0.0-341.8); the median follow-up was 123.5 months (10.3 years) from initial diagnosis and 99.2 months (8.3 years) from the time of randomization. From the time of randomization, estimated 9-year OS rates were 81.2% (95% CI, 76.8-84.9) in all ibrutinib-treated pts versus 82.0% (95% CI, 78.3-85.2) in the age-matched population (hazard ratio [HR] 1.17; 95% CI, 0.86-1.58). In high-risk pts, estimated 9-year OS rates were 79.5% (95% CI, 73.5-84.3) for ibrutinib-treated pts versus 83.2% (95% CI, 78.5-86.9) in the age-matched general population (HR 1.24; 95% CI, 0.84-1.84). In pts aged ≥65 years, estimated 9-year OS rates were 68.7% (95% CI, 60.5-75.6) for ibrutinib-treated pts and 68.7% (95% CI, 61.4-75.0) in the age-matched general population (HR 1.12; 95% CI, 0.77-1.63). In pts aged <65 years, estimated 9-year OS rates were 89.3% (95% CI, 84.6-92.7) for ibrutinib-treated pts and 90.0% (95% CI, 86.1-92.9) in the age-matched general population (HR 1.15; 95% CI, 0.68-1.94). From the time of initial diagnosis, estimated 15-year OS rates were 78.4% (95% CI, 72.8-83.0) in all ibrutinib-treated pts versus 72.0% (95% CI, 67.8-75.7) in the age-matched general population (HR 0.83; 95% CI, 0.62-1.11). Study treatment had been discontinued in 59.8% (293/490) of pooled ibrutinib-treated pts; the most frequent reasons for discontinuation were adverse events (43.0%; 126/293) and progressive disease (20.5%; 60/293). Study treatment was ongoing in 31.8% of pooled pts (156/490). Conclusions: With the longest follow-up time for any commercially available targeted therapy, this pooled analysis demonstrates that, regardless of evaluation from randomization or initial diagnosis, and irrespective of age or high-risk features, first-line treatment with ibrutinib provides long-term OS benefit with survival estimates that appear similar to those of a US age-matched cohort.

Introduction: Bruton tyrosine kinase (BTK) inhibitors are effective therapies for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Their use can be limited by intolerance and/or acquired resistance, due to BTK mutations. BGB-16673 is a bivalent small molecule that induces BTK degradation by binding specifically to BTK and the E3 ligase. The E3 ligase catalyzes the transfer of ubiquitin molecules to BTK which marks BTK for destruction by the proteasome. In preclinical models, BGB-16673 degraded wild-type and mutant forms of BTK associated with resistance to covalent and noncovalent BTK inhibitors, leading to tumor suppression. CaDAnCe-101 (BGB-16673-101, NCT05006716) is an ongoing, open-label, first-in-human, phase 1/2 study designed to evaluate BGB-16673 monotherapy in patients with B-cell malignancies. Here, updated results in patients with relapsed or refractory (R/R) CLL/SLL enrolled in the phase 1 portion are presented. Methods: Eligiblepatients must have confirmed R/R CLL/SLL (≥2 prior therapies), an ECOG performance status of 0-2, and adequate organ function. In the US, EU, and Australia, patients must have previously received a covalent BTK inhibitor (cBTKi). BGB-16673 was dosed once daily orally in 28-day cycles. Dose escalation used a Bayesian optimal interval design (6 planned dose levels, 50-600 mg once daily). Primary objectives were to assess safety/tolerability (CTCAE v5.0 and iwCLL hematologic toxicity criteria), and to establish the maximum tolerated dose (MTD) and the recommended phase 2 dose. Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks (cycle 1). A secondary objective was to evaluate the overall response rate (ORR, iwCLL 2018 criteria or 2014 Lugano criteria for SLL), with the first assessment occurring after 12 weeks of treatment. Results: As of May 24, 2024, 49 patients with CLL were enrolled and treated (50 mg, n=1; 100 mg, n=5; 200 mg, n=16; 350 mg, n=15; 500 mg, n=12). The median age was 70 years (range, 50-91 years), and the median number of prior therapies was 4 (range, 2-10), including prior cBTKis (n=45 [92%]), BCL2 inhibitors (n=42 [86%]), and noncovalent BTK inhibitors (ncBTKis; n=12 [24%]). Of tested patients, 63% (31/49) had del(17p) and/or TP53 mutation and 82% (32/39) had unmutated IGHV. The median follow-up was 7.9 months (range, 0.3-23.1 months). Ninety-six percent of patients reported any-grade treatment-emergent adverse events (TEAEs; grade ≥3, 57%), of which the most common (≥25%) were fatigue (35%; grade ≥3, 2%), contusion (29%; no grade ≥3), and diarrhea (27%; grade ≥3, 2%). The most common grade ≥3 TEAEs (≥10%) were neutropenia/neutrophil count decreased (20%) and pneumonia (10%). One patient (2%) each experienced hypertension (grade 1), febrile neutropenia (in the context of COVID-19 pneumonia and norovirus diarrhea), and major hemorrhage. No atrial fibrillation was observed. Three patients (6%) experienced a TEAE that led to dose reduction. One DLT occurred in 1 patient at 200 mg (grade 3 maculopapular rash on day 27; decreased to grade 1 after 5-day hold; patient continues on treatment). The MTD was not reached. Three patients had TEAEs that led to death (septic shock, bronchopulmonary aspergillosis/cerebral aspergillosis, and pneumonia in the context of disease progression; n=1 each); none of the deaths were considered related to treatment. In 49 response-evaluable patients, the ORR (partial response with lymphocytosis or better) was 78% (38/49), and the CR/CR with incomplete hematologic recovery rate was 4% (n=2). At 200 mg, the ORR was 94% (15/16) including the 2 CRs. Median time to first response was 2.8 months (range, 2.6-8.3 months). Seventeen patients remained on treatment for ≥9 months and all 17 have ongoing responses. Responses were seen at the lowest dose, as well as in patients previously treated with a cBTKi, ncBTKi, double- (cBTKi and BCL2i) and triple- (cBTKi, BCL2i, ncBTKi) exposed patients, and in patients with and without BTK mutations. Conclusions: Emerging data from this ongoing, first-in-human study demonstrate that the novel BTK degrader BGB-16673 has a tolerable safety profile and shows promising and deep overall responses in heavily pretreated patients with R/R CLL/SLL, including those with prior BTK inhibitor treatment and BTK resistance mutations.