Trotman, Judith

Introduction: BTK inhibitors (BTKis) are approved for chronic lymphocytic leukemia (CLL), Waldenström macroglobulinemia (WM), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). Disease that progresses on BTKis often has BTK mutations that lead to treatment (tx) resistance; novel BTK-targeting agents that overcome BTKi resistance are needed. BGB-16673 is a heterobifunctional small molecule that binds to BTK and E3 ligase, resulting in BTK degradation via ubiquitination. In preclinical models, BGB-16673 degraded wild-type (WT) BTK and known covalent and noncovalent BTKi-resistant mutant proteins, leading to tumor suppression. Methods: Pts with R/R CLL, WM, MCL, MZL, non-germinal center B-cell diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), or Richter transformation (RT) were eligible for this open-label, first-in-human, phase 1 trial (BGB-16673-101; NCT05006716). Pts must have received ≥2 prior therapies (≥1 for RT) and have an ECOG performance status of 0-2 and adequate end-organ function. In the US and Australia, pts must have received a covalent BTKi (cBTKi) if approved for their disease. BGB-16673 was dosed daily by mouth in 28-day cycles. Escalation using a Bayesian optimal interval design with 6 dose levels (50-600 mg once daily) is planned. Primary objectives are to assess safety/tolerability and establish the maximum tolerated dose (MTD) and recommended phase 2 dose. Key secondary objectives are to assess pharmacokinetics, pharmacodynamics (PD), and preliminary antitumor activity. Safety was assessed according to CTCAE v5.0 (all pts) and iwCLL hematologic toxicity criteria (pts with CLL). Dose-limiting toxicities (DLTs) were assessed in the first 4 weeks. Response was assessed per Lugano criteria for all except CLL (iwCLL 2018 criteria) and WM (iwWM-6 criteria). Results: As of May 26, 2023, 26 pts (10 CLL, 4 MCL, 2 MZL, 4 WM, 4 FL, 1 DLBCL, 1 RT) were enrolled at 5 dose levels (50 mg, 4; 100 mg, 9; 200 mg, 9; 350 mg, 3; 500 mg, 1). Median age was 70.5 y (range, 25-83). Median number of prior therapies was 3.5 (range, 2-9), including cBTKis (n=21; 10 CLL, 4 WM, 4 MCL, 1 MZL, 1 RT, 1 DLBCL), BCL2 inhibitors (n=12; 9 CLL, 2 WM, 1 RT), and noncovalent BTKis (ncBTKis; n=4; 2 CLL, 1 WM, 1 FL). In CLL, del17p/ TP53 mutation (n=8) and unmutated IGHV (n=7) were frequent. Median follow-up was 3.5 mo (range, 0.2-13.9). MTD was not reached. Treatment-emergent AEs (TEAEs) were reported by 88.5% of pts (grade [gr] ≥3, 46.2%; serious, 38.5%). The most common TEAEs were contusion (30.8%; no gr ≥3), pyrexia (23.1%; no gr ≥3), neutropenia/neutrophil count decreased (23.1%; gr ≥3, 15.4%), and lipase increased (23.1%; gr ≥3, 3.8%; all transient and asymptomatic). No hypertension or atrial fibrillation was observed. One pt died from sepsis with possible disease progression. No discontinuations due to AEs occurred. Two pts had dose reductions due to TEAEs (gr 3 hematuria with urinary tract infection and recurrent urothelial carcinoma and gr 2 arthralgia). One DLT occurred in 1 pt at 200 mg (gr 3 maculopapular rash on day 27; after 5-day dose hold, assigned dose was recommenced with persistent gr 1 rash). BGB-16673 exposure increased in a dose-dependent manner. At steady state with doses ≥50 mg daily, BGB-16673 exposure exceeded the calculated half maximal degradation concentration for WT and cysteine 481-mutated BTK for the dosing interval. Preliminary PD data showed deep, sustained reductions in BTK protein levels in peripheral blood and tumor tissue, even at the lowest dose. Most CLL pts experienced lymphocytosis during the first 3 cycles of tx. Twenty of 26 pts (77%) remain on therapy (discontinuation: 4 progressive disease, 2 withdrawal). Of 18 response-evaluable pts, 12 (67%) responded (5/6 CLL, 1/3 MCL, 2/2 MZL, 3/4 WM, 1/2 FL, 0/1 DLBCL; 1 CR in MCL, all others had PR; Figure), including pts who received a cBTKi (n=10) and an ncBTKi (n=2). Responses started at the lowest dose level. All responders remain in response, the longest responder remaining on tx for 60 weeks. Conclusions: Preliminary data from this ongoing, first-in-human study of the novel BTK degrader BGB-16673 demonstrate a tolerable safety profile and clinical responses in heavily pretreated pts with B-cell malignancies, including those with BTKi-resistant disease. Substantial reductions in BTK protein levels in peripheral blood and tumor tissue were also observed, demonstrating proof-of-concept of a strong, on-target effect.

Abstract With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. Although the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet, the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification, and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses, and epigenetic profiling will be discussed because these will likely become important future tools for implementing precision medicine approaches in clinical decision making for patients with lymphoid malignancies.

Purpose: In RE-MIND2 (NCT04697160), patient-level outcomes from the L-MIND study (NCT02399085) of tafasitamab plus lenalidomide were retrospectively compared with patient-level matched observational cohorts treated with National Cancer Care Network (NCCN)/European Society for Medical Oncology (ESMO)-listed systemic therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Patients and Methods: Data were collected from health records of eligible patients aged ≥18 years with histologically confirmed DLBCL who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy). Patients from L-MIND were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest-neighbor matching, balanced for nine covariates. The primary analysis compared tafasitamab plus lenalidomide with patients who received any systemic therapy for R/R DLBCL (pooled in one cohort) or bendamustine plus rituximab (BR) or rituximab plus gemcitabine and oxaliplatin (R-GemOx; as two distinct cohorts). The primary endpoint was overall survival (OS). Secondary endpoints included treatment response and time-to-event outcomes. Results: In RE-MIND2, 3,454 patients were enrolled from 200 sites in North America, Europe, and Asia-Pacific. Strictly matched pairs of patients consisted of tafasitamab plus lenalidomide versus systemic therapies pooled (n = 76 pairs), versus BR (n = 75 pairs), and versus R­GemOx (n = 74 pairs). Significantly prolonged OS was reported with tafasitamab plus lenalidomide versus systemic pooled therapies [hazard ratios (HR): 0.55; P = 0.0068], BR (HR: 0.42; P < 0.0001), and R-GemOx (HR: 0.47; P = 0.0003). Conclusions: RE-MIND2, a retrospective observational study, met its primary endpoint, demonstrating prolonged OS with tafasitamab plus lenalidomide versus BR and R-GemOx. See related commentary by Cherng and Westin, p. 3908

Abstract Outcomes for marginal zone lymphoma (MZL) and follicular lymphoma (FL) remain suboptimal, owing to the limited number of approved agents and the incurable nature of the diseases. BGB-3111-AU-003 was a phase 1/2, open-label, multicenter, single-agent study of the selective Bruton’s tyrosine kinase inhibitor zanubrutinib in 385 patients with B-cell malignancies. Here, we present safety and efficacy outcomes for the 53 enrolled patients with relapsed/refractory MZL (n = 20) and relapsed/refractory FL (n = 33), all of whom were enrolled during the part 2 dose expansion, and therefore received zanubrutinib at the recommended phase 2 dose. Treatment with zanubrutinib was generally well tolerated, with most adverse events being ≤ grade 2. Atrial fibrillation/flutter was not reported. Two patients required dose reduction, and 4 patients discontinued treatment because of adverse events. Response was assessed by an independent review committee for MZL and the investigators for FL, per Lugano 2014 classification for non-Hodgkin lymphoma. In patients with MZL, the overall response rate (ORR) was 80%, and the complete response (CR) rate was 20%. With median follow-up of 33.8 months, median progression-free survival (PFS) was not reached. In patients with FL, the ORR was 36.4%, and the CR rate was 18.2%. After a median follow-up of 33.9 months, median PFS was 10.4 months. In conclusion, the results of this study suggest a favorable benefit–risk profile and support zanubrutinib as a potentially meaningful addition to available therapies for patients with relapsed/refractory MZL and FL. This trial was registered at www.clinicaltrials.gov as #NCT02343120.

SummaryThe phase I/II AU‐003 study in patients with treatment‐naïve (TN) or relapsed/refractory (R/R) chronic lymphocytic leukaemia/small lymphocytic lymphoma demonstrated that zanubrutinib therapy results in clinically meaningful and durable responses with acceptable safety and tolerability. We report updated safety and efficacy data for 123 patients with a median follow‐up of 47·2 months. Patients received zanubrutinib 160 mg twice daily (81 patients), 320 mg once daily (40), or 160 mg once daily (two). Discontinuations due to adverse events or disease progression were uncommon. The overall response rate (ORR) was 95·9% (TN, 100%; R/R, 95%) with 18·7% achieving complete response (CR). Ongoing response at 3 years was reported in 85·7%. The ORR in patients with del(17p)/tumour protein p53 mutation was 87·5% (CR 16·7%). The 2‐ and 3‐year progression‐free survival estimates were 90% (TN, 90%; R/R, 91%) and 83% (TN, 81%; R/R, 83%) respectively. The most reported Grade ≥3 adverse events were neutropenia (15·4%), pneumonia (9·8%), hypertension (8·9%) and anaemia (6·5%). The annual incidence of atrial fibrillation, major haemorrhage, Grade ≥3 neutropenia and Grade ≥3 infection decreased over time. With a median follow‐up of ~4 years, responses remain clinically meaningful and durable and long‐term tolerability to zanubrutinib therapy continues.

Abstract Background Several therapies are recommended by NCCN/ESMO guidelines for autologous stem cell transplant (ASCT)-ineligible patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). In the single-arm, Phase II L-MIND study (NCT02399085), the chemotherapy-free regimen tafasitamab + lenalidomide (LEN) demonstrated efficacy for this patient population. In the absence of randomized clinical trial data, RE-MIND2 (NCT04697160), an observational, retrospective cohort study, compared patient outcomes from L-MIND with matched patient populations treated with NCCN/ESMO recommended therapies for ASCT-ineligible patients with R/R DLBCL. Methods Data were retrospectively collected between 1 April and 13 November 2020 from academic and public hospitals, as well as private practices in North America, Europe and Asia Pacific. To ensure consistency with L-MIND I/E criteria, patients aged ≥18 years with histologically confirmed DLBCL and who had received ≥2 systemic therapies for DLBCL (including ≥1 anti-CD20 therapy) were enrolled. For the main analysis, patients from the L-MIND tafasitamab + LEN cohort were matched with patients from the RE-MIND2 observational cohort using estimated propensity score-based 1:1 nearest neighbor matching, balanced for six baseline characteristics: age (<70 vs ≥70 years), refractoriness to last line of therapy (yes vs no), number of prior lines of therapy (1 vs 2/3), history of primary refractoriness (yes vs no), prior ASCT (yes vs no), and Eastern Cooperative Oncology Group performance status (0-1 vs ≥2). A sensitivity analysis was performed using an inverse probability of treatment weighting method calculating the average effect of the treatment on the treated, to generate balanced cohorts based on nine baseline characteristics: age, refractoriness to last line of therapy, number of previous lines of therapy, history of primary refractoriness, prior ASCT, Ann Arbor Stage (I/II vs III/IV), elevated LDH (yes vs no), neutropenia (yes vs no), and anemia (yes vs no). Additional sensitivity analyses accounting for missing baseline characteristics using multiple imputation technique were performed. Data are presented for tafasitamab + LEN versus polatuzumab vedotin + bendamustine + rituximab (pola-BR), rituximab + LEN (R2), and CD19 CAR-T therapies (CAR-T). The primary endpoint was overall survival (OS). Secondary endpoints included objective response rate (ORR), complete response rate, progression-free survival and duration of response. Results Of 3,454 patients enrolled from 200 sites, 106, 106, and 149 patients were treated with pola-BR, R2, and CAR-T, respectively. For the comparative analysis, matched patient pairs were created using 1:1 nearest neighbor matching with a caliper. Matched pairs consisted of: tafasitamab + LEN vs pola-BR, n=24 pairs; vs R2, n=33 pairs; and vs CAR-T, n=37 pairs. A significant OS benefit was associated with tafasitamab + LEN compared to pola-BR (HR: 0.44, 95% confidence interval [CI]: 0.20-0.96; p=0.038) and R2 (HR=0.44, 95% CI: 0.22-0.84; p=0.014) (Figure 1A-B). There was no significant difference in OS benefit between tafasitamab + LEN and CAR-T (HR=0.95, 95% CI: 0.47-1.91; p=0.891) (Figure 1C). ORR was 62.5% (15/24) for tafasitamab + LEN vs 58.3% (14/24) for pola-BR (p=1.000), 63.6% (21/33) vs 30.3% (10/33) for R2 (p=0.013), and 59.5% (22/37) vs 75.7% (28/37) for CAR-T (p=0.214). Improved outcomes were also observed with tafasitamab + LEN for other secondary endpoints (Table 1). Results are consistent with those obtained in the sensitivity analyses. Conclusions The results of this retrospective cohort analysis suggest that the novel tafasitamab + LEN combination may significantly improve health outcomes, with a prolonged survival benefit for ASCT-ineligible R/R DLBCL patients, relative to NCCN/ESMO recommended therapies. Tafasitamab + LEN improved survival outcomes compared with pola-BR and R2 in closely matched patient populations. Comparable outcomes were observed for tafasitamab + LEN vs CAR-T. Although based on limited patient numbers, these data may be clinically relevant in the context of emerging therapies for R/R DLBCL. While this study design does not replace randomized data, it remains more rigorous than inter-trial comparison. The limitations of comparing clinical trial and matched retrospective real-world data will be discussed. Funding: MorphoSys AG. Figure 1 Figure 1. Disclosures Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding. Joffe: AstraZeneca. Epizyme: Consultancy. Fleury: Abbvie, Astrazeneca, BMS, Celgene, Janssen, Kite-Gilead, Merck, Novartis, Roche, Seattle Genetics: Other: conference and advisory role. Peters: AbbVie, Incyte: Consultancy, Honoraria. Greil: Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Sandoz: Honoraria, Research Funding. Ku: Roche: Consultancy; Antegene: Consultancy; Genor Biopharma: Consultancy. Marks: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; AbbVie: Other: Meeting attendance; Kite/Gilead: Honoraria; Merck: Consultancy. Kim: AstraZeneca: Research Funding. Zinzani: BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, 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. Trotman: Beigene: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding; Roche: Research Funding; Janssen: Research Funding; PCYC Pharmacyclics: Research Funding. Sabatelli: Incyte: Current Employment, Current equity holder in publicly-traded company. Huang: MorphoSys: Current Employment. Waltl: MorphoSys: Current Employment. Winderlich: MorphoSys: Current Employment, Current equity holder in publicly-traded company. Ambarkhane: MorphoSys: Current Employment, Other: Support for attending meetings/travel. Kurukulasuriya: MorphoSys: Current Employment, Current equity holder in publicly-traded company, Other: Support for attending meetings/travel. Cordoba: Pfizer: Research Funding; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADCTherapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: 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; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: 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. Hess: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead/Kite: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genmab: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; EUSA: Honoraria, Membership on an entity's Board of Directors or advisory committees. Salles: Miltneiy: Consultancy; Novartis: Consultancy; Morphosys: Consultancy, Honoraria; Janssen: Consultancy; Genentech/Roche: Consultancy; Kite/Gilead: Consultancy; Regeneron: Consultancy, Honoraria; Velosbio: Consultancy; Takeda: Consultancy; Allogene: Consultancy; Ipsen: Consultancy; Loxo: Consultancy; Rapt: Consultancy; Genmab: Consultancy; Incyte: Consultancy; Epizyme: Consultancy, Honoraria; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria.

Abstract Zanubrutinib is a potent and highly selective inhibitor of Bruton tyrosine kinase (BTK). In this first-in-human, open-label, multicenter, phase 1 study, patients in part 1 (3 + 3 dose escalation) had relapsed/refractory B-cell malignancies and received zanubrutinib 40, 80, 160, or 320 mg once daily or 160 mg twice daily. Part 2 (expansion) consisted of disease-specific cohorts, including treatment-naive or relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). The primary end points were safety and tolerability, and definition of the maximum tolerated dose (part 1). Additional end points included pharmacokinetics/pharmacodynamics and preliminary efficacy. Reported herein are results from 144 patients enrolled in the dose-finding and CLL/SLL cohorts. No dose-limiting toxicities occurred in dose escalation. Median BTK occupancy in peripheral blood mononuclear cells was >95% at all doses. Sustained complete (>95%) BTK occupancy in lymph node biopsy specimens was more frequent with 160 mg twice daily than 320 mg once daily (89% vs 50%; P = .0342). Consequently, 160 mg twice daily was selected for further investigation. With median follow-up of 13.7 months (range, 0.4-30.5 months), 89 CLL/SLL patients (94.7%) remain on study. Most toxicities were grade 1/2; neutropenia was the only grade 3/4 toxicity observed in >2 patients. One patient experienced a grade 3 subcutaneous hemorrhage. Among 78 efficacy-evaluable CLL/SLL patients, the overall response rate was 96.2% (95% confidence interval, 89.2-99.2). Estimated progression-free survival at 12 months was 100%. Zanubrutinib demonstrated encouraging activity in CLL/SLL patients, with a low incidence of major toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02343120.