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: 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 safety and efficacy results of BGB-16673 are presented in patients with WM in the phase 1 portion of the study. Methods Eligible patients had confirmed relapsed/refractory (R/R) WM (≥2 prior therapies), an ECOG performance status of 0-2 (0-1 in the EU), and previous treatment with an anti-CD20 antibody and, in the US, Japan, and EU, a covalent BTK inhibitor. BGB-16673 was dosed once daily orally. The primary objectives of this phase 1 study were to evaluate safety and tolerability (NCI-CTCAE v5.0) and establish the maximum tolerated dose and recommended dose for expansion. A secondary objective was to evaluate the overall response rate (ORR; modified IWWM-6 consensus criteria), with the first assessment after 4 weeks of treatment. Results As of May 23, 2025, 42 patients with WM were enrolled and treated (100 mg, n=15; 200 mg, n=14; 350 mg, n=13). Median age was 72.0 years (range, 46-81 years), and the median number of prior therapies was 3 (range, 2-11), including prior covalent BTK inhibitors (n=42 [100%]), BCL2 inhibitors (n=10 [23.8%]), noncovalent BTK inhibitors (n=7 [16.7%]), anti-CD20 monoclonal antibodies (n=42 [100%]), and chemotherapy (n=39 [92.9%]). In total, 33.3% of patients (12/36) had WM with BTK mutations, 85.7% (36/42) with MYD88 mutations, 51.3% (20/39) with CXCR4 mutations, 52.8% (19/36) with TP53 mutations, and 5.6% (2/36) with PLCG2 mutations. Median follow-up was 8.8 months (range, 0.8-31.0 months). Overall, 97.6% of patients experienced treatment-emergent adverse events (TEAEs) of any grade (grade ≥3, 59.5%; serious TEAEs, 35.7%). The most common (≥20% incidence) TEAEs (any grade; grade ≥3) were neutropenia (38.1%; grade ≥3, 33.3%, most common grade ≥3 TEAE), diarrhea (26.2%; no grade ≥3), contusion/bruising (26.2%; no grade ≥3), and thrombocytopenia (21.4%; grade ≥3, 7.1%). No atrial fibrillation was observed. Grade 3 febrile neutropenia and major hemorrhage (grade 3 hematemesis caused by concurrent gastritis/duodenitis unrelated to treatment) occurred in 1 patient (2.4%) each. Seven patients (16.7%) had a grade ≥3 infection, including 2 patients with fungal infections. Three patients (7.1%) had TEAEs that led to treatment discontinuation (anemia, cerebral aspergillosis, pericardial effusion/pleural effusion; n=1 each), and 2 patients (4.8%) had a TEAE that led to dose reduction. Two patients (4.8%) died due to TEAEs (septic shock in the context of progressive disease [PD] and cerebral aspergillosis; n=1 each). All 42 patients were response-evaluable and the ORR (minor response [MR] or better) was 83.3% (n=35), the major response rate (partial response [PR] or better) was 64.3% (n=27), and the very good partial response (VGPR) rate was 26.2% (n=11). Median time to first overall response was 1.0 months (range, 0.9-3.8 months) and to best overall response was 1.9 months (range, 0.9-7.4 months). Responses deepened over time: of 9 patients with stable disease at first disease assessment, 3 transitioned to MR and 2 to PR; of 20 patients with initial MR, 10 transitioned to PR and 2 to VGPR; and of 13 patients with initial PR, 7 transitioned to VGPR. Thirty patients (71.4%) remain on treatment. Two deaths were due to PD. Responses were seen in patients previously treated with a covalent BTK inhibitor (35/42 [83.3%]) and a noncovalent BTK inhibitor (7/7 [100%]) and in patients who discontinued a prior BTK inhibitor due to PD (28/35 [80%]). Responses were independent of mutations in BTK (with, 12/12; without, 17/24), MYD88 (with, 30/36; without, 5/6), CXCR4 (with, 18/20; without, 14/19), TP53 (with, 16/19; without, 13/17), and PLCG2 (with, 1/2; without, 28/34). The 9-month duration of response rate was 84.1% (95% CI, 63.1%-93.7%). Conclusions Data from this ongoing phase 1 study demonstrate that the novel BTK degrader BGB-16673 was well tolerated and continued to show substantial antitumor activity in patients with heavily pretreated BTK inhibitor–exposed R/R WM, including those with BTK, MYD88, CXCR4, and TP53 mutations. Enrollment is ongoing in the phase 2 portion of the study.

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.

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.

Abstract ELEVATE-RR demonstrated noninferior progression-free survival and lower incidence of key adverse events (AEs) with acalabrutinib vs ibrutinib in previously treated chronic lymphocytic leukemia. We further characterize AEs of acalabrutinib and ibrutinib via post hoc analysis. Overall and exposure-adjusted incidence rate was assessed for common Bruton tyrosine kinase inhibitor–associated AEs and for selected events of clinical interest (ECIs). AE burden scores based on previously published methodology were calculated for AEs overall and selected ECIs. Safety analyses included 529 patients (acalabrutinib, n = 266; ibrutinib, n = 263). Among common AEs, incidences of any-grade diarrhea, arthralgia, urinary tract infection, back pain, muscle spasms, and dyspepsia were higher with ibrutinib, with 1.5- to 4.1-fold higher exposure-adjusted incidence rates. Incidences of headache and cough were higher with acalabrutinib, with 1.6- and 1.2-fold higher exposure-adjusted incidence rate, respectively. Among ECIs, incidences of any-grade atrial fibrillation/flutter, hypertension, and bleeding were higher with ibrutinib, as were exposure-adjusted incidence rates (2.0-, 2.8-, and 1.6-fold, respectively); incidences of cardiac events overall (the Medical Dictionary for Regulatory Activities system organ class) and infections were similar between arms. Rate of discontinuation because of AEs was lower for acalabrutinib (hazard ratio, 0.62; 95% confidence interval, 0.41-0.93). AE burden score was higher for ibrutinib vs acalabrutinib overall and for the ECIs atrial fibrillation/flutter, hypertension, and bleeding. A limitation of this analysis is its open-label study design, which may influence the reporting of more subjective AEs. Overall, event-based analyses and AE burden scores demonstrated higher AE burden overall and specifically for atrial fibrillation, hypertension, and hemorrhage with ibrutinib vs acalabrutinib. This trial was registered at www.clinicaltrials.gov as #NCT02477696.

Abstract Richter syndrome (RS), an aggressive lymphoma that develops in patients with chronic lymphocytic leukemia (CLL), is a striking example of histologic transformation. While recent therapeutic advances have transformed the treatment landscape of CLL and lymphoma, RS remains associated with dismal overall survival. Despite an advanced genomic and molecular characterization of CLL over the past decade, the current understanding of the genetic factors driving evolution of CLL to RS is limited. To decipher the genetics underlying this transformation, we have performed an integrative analysis of exome, genome and transcriptome data generated from matched RS and CLL samples from a discovery cohort of 53 patients with newly diagnosed RS of DLBCL histology. Through computational deconvolution of CLL and RS clones, we constructed phylogenetic relationships and traced evolution of CLL to RS, confirming both clonal related (87%) and unrelated cases (13%). In addition to identifying recognized RS-risk genetic lesions, we discovered novel RS-specific alterations, including 5 putative somatic driver genes (IRF2BP2, SRSF1, B2M, DNMT3A and EZH2), frequent copy number alterations beyond del(9p21)(CDKN2A/B), (including amp(7q21.2) (CDK6), amp(9p24) (PDL1/L2), and amp(1q23)(MCL1)), and recurrent whole genome duplication and chromothripsis. Integration of exome and genome sequencing data led to the identification of distinct molecular subtypes of RS with prognostic importance. To confirm these molecular subtypes, a validation cohort of 47 RS cases has been assembled with paired exome and transcriptome data. To further investigate the stepwise clonal evolution of CLL to RS, we performed single-cell RNA-sequencing on biopsy samples obtained at diagnosis from 5 individuals with clonally related transformation. Using a novel tool, CNVSingle, we inferred allele specific single-cell copy number alterations that enabled identification of the single-cell clusters representing distinct CLL and RS genetic subclones as well as intermediate, or transitional, evolutionary states. RS cells displayed gene expression enriched in pathways of MYC targets and cell cycle, in line with similar analysis on bulk transcriptomes. Finally, by ultra-low pass (ULP)-WGS sequencing of plasma samples from RS patients, we demonstrate detection of RS tumor DNA in plasma months prior to initial clinical diagnosis (n=3 of 6) or post-allogeneic stem cell transplant relapse (n=2 of 2). cfDNA is thus a promising tool for early detection of emerging RS and RS relapse as well as for non-invasive detection surrounding diagnosis. Altogether, our study defines RS-specific alterations and provides a molecular definition of RS, identifies distinct genetic subtypes of RS with prognostic significance, traces the evolutionary path to RS and suggests future strategies for improved detection. Citation Format: Erin M Parry, Ignaty Leshchiner, Romain Guieze, Connor Johnson, Eugen Tausch, Sameer A Parikh, Camilla K Lemvigh, Conor Messer, Filippo Utro, Chaya Levovitz, Kahn Rhrissorrakrai, Matthew S Davids, Julien Broseus, Shuqiang Li, Ziao Lin, Binyamin A Knisbacher, Christof Schneider, Laura Z Rassenti, Thomas J Kipps, Nitin Jain, William Wierda, Florence Cymbalista, Neil E Kay, Kenneth J Livak, Brian P Danysh, Chip Stewart, Donna Neuberg, Jennifer R Brown, Laxmi Paridi, Stephan Stilgenbauer, Gaddy Getz, Catherine Wu. Evolutionary history of transformation from chronic lymphocytic leukemia to Richter syndrome [abstract]. In: Proceedings of the Third AACR International Meeting: Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2022 Jun 23-26; Boston, MA. Philadelphia (PA): AACR; Blood Cancer Discov 2022;3(5_Suppl):Abstract nr A13.