Zanubrutinib is well tolerated and effective in patients with CLL/SLL intolerant of ibrutinib/acalabrutinib: updated results Open Access

Chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) is the most common leukemia in the Western world.^1,2 In recent years, Bruton tyrosine kinase (BTK) inhibitors have revolutionized the treatment of CLL/SLL.^1,3 The first and second BTK inhibitors approved in the United States for the treatment of CLL, ibrutinib⁴ and acalabrutinib,⁵ have proven to be effective; however, their use can be limited by treatment-related toxicities. For instance, some BTK inhibitors can increase the risk of cardiovascular toxicities (including atrial fibrillation/flutter)^2,6 and hematologic adverse effects (ie, decreased hemoglobin, platelet, and/or neutrophil levels).⁵ These toxicities are likely due to off-target inhibition of other kinases.³ 

In real-world analyses of patients with relapsed/refractory (R/R) CLL treated with ibrutinib, discontinuation rates of 35.4% to 43.1% have been reported, mostly due to toxicity, with atrial fibrillation being among the most common events leading to treatment discontinuation.^7-9 Early results from a study of acalabrutinib vs ibrutinib showed similar efficacy (progression-free survival [PFS] with acalabrutinib was noninferior to that with ibrutinib) and improved safety with acalabrutinib (9.4% vs 16.0% of patients reported atrial fibrillation/flutter); however, 14.7% of patients discontinued acalabrutinib treatment due to adverse events (AEs).¹⁰ 

Zanubrutinib is a potent and selective next-generation BTK inhibitor¹¹ that was approved for the treatment of CLL in the United States, European Union, and China, and for the treatment of SLL in the United States and China (the European Medicines Agency considers SLL to be included in CLL).^12-14 Zanubrutinib was designed to maximize BTK occupancy and minimize off-target kinase binding and associated AEs.¹¹ Kinome profiling in vitro demonstrated that zanubrutinib has higher selectivity against BTK vs ibrutinib and acalabrutinib.^11,15 In a randomized, phase 3 study in patients with R/R CLL/SLL treated with zanubrutinib or ibrutinib, the zanubrutinib group had superior PFS, fewer AEs leading to treatment discontinuation (15.4% vs 22.2%), and fewer cardiac AEs (21.3% vs 29.6%).¹⁶ Early results from the ongoing phase 2 study BGB-3111-215 showed that at a median follow-up of 12.0 months, zanubrutinib was well tolerated and responses were maintained or improved in patients with B-cell malignancies who were intolerant of prior ibrutinib and/or acalabrutinib treatment.¹⁵ Here, 3-year follow-up data in the subgroup of patients with CLL/SLL are presented.

BGB-3111-215 (ClinicalTrials.gov identifier: NCT04116437) is an ongoing phase 2, multicenter, single-arm trial conducted in the United States, in which zanubrutinib monotherapy is being assessed in patients with previously treated CLL/SLL, mantle cell lymphoma, marginal zone lymphoma, or Waldenström macroglobulinemia who were intolerant of prior BTK inhibitors. This analysis focuses on patients with CLL/SLL. The methodological details have been reported previously.¹⁵ Briefly, eligible patients were aged ≥18 years; received previous treatment with ibrutinib and/or acalabrutinib for ≥4 weeks prior to enrollment, which was discontinued due to toxicity, met disease criteria for CLL/SLL requiring treatment according to the diagnostic criteria of the International Workshop for CLL (iwCLL)¹⁷ prior to initiation of ibrutinib or acalabrutinib treatment, and had an Eastern Cooperative Oncology Group performance status of 0, 1, or 2.

Patients had ibrutinib and/or acalabrutinib intolerance, defined by ≥1 of the following, leading to discontinuation of treatment: grade ≥2 nonhematologic toxicities for >7 days; grade ≥3 nonhematologic toxicity of any duration; grade 3 neutropenia with infection or fever of any duration; grade 4 heme toxicity; grade ≥1 nonhematologic toxicities of any duration with ≥3 recurrent episodes (acalabrutinib only); grade ≥1 nonhematologic toxicities for >7 days (acalabrutinib only); or inability to use acid-reducing agents or anticoagulants (eg, proton pump inhibitors, warfarin) due to concurrent acalabrutinib use. Patients were excluded if they had progressive disease (PD) while on ibrutinib and/or acalabrutinib treatment, known prolymphocytic leukemia or a history of Richter transformation, clinically significant cardiovascular disease (myocardial infarction, unstable angina, New York Heart Association class 3 or 4 congestive heart failure, history of sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes, QT interval of >480 micro seconds, or second- or third-degree heart block without a pacemaker), ischemic stroke within 180 days of first zanubrutinib dose, central nervous system hemorrhage, prior malignancy within the last 3 years, prior exposure to zanubrutinib, or opportunistic infection. Any prior grade ≥2 ibrutinib- or acalabrutinib-intolerance AE must have resolved to grade ≤1 or baseline, and any grade 1 acalabrutinib-intolerance AE must have resolved to grade 0 or baseline prior to the beginning of the study.

Cohort 1 consisted of patients intolerant of ibrutinib only. Cohort 2 consisted of patients intolerant of acalabrutinib, with or without ibrutinib intolerance. Patients received zanubrutinib 160 mg twice daily or 320 mg once daily. Patients and investigators could select either dose regimen but could not switch dose regimen during the study.

The primary end point was to assess the safety of zanubrutinib compared with patients’ prior ibrutinib- or acalabrutinib-intolerance AEs. This was assessed by recurrence and change in severity of intolerance AEs that occurred with prior ibrutinib or acalabrutinib treatment. Intolerance events during ibrutinib or acalabrutinib treatment and AEs with zanubrutinib treatment were assessed and graded based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. In patients with CLL, the severity of cytopenias was graded based on iwCLL criteria.¹⁷ 

Secondary end points included the investigator-assessed efficacy of zanubrutinib treatment, including the overall response rate (ORR), disease control rate (DCR; defined as the proportion of patients achieving a best overall response (BOR) of stable disease or better before initiation of subsequent antineoplastic therapy), and PFS, as well as duration of response (DoR), time to first response, and time to BOR. Response assessments were completed using the 2008 iwCLL guidelines¹⁷ for CLL with modification for treatment-related lymphocytosis¹⁸ and the Lugano classification¹⁹ for SLL every three 28-day cycles for the first year, then every 6 cycles. Disease status was assessed via positron emission tomography, computed tomography, or magnetic resonance imaging; physical examination; bone marrow aspirate/biopsy; and laboratory tests (please see supplemental Methods: computed tomography and bone marrow assessments, for further information).

Safety was assessed in all patients who received any dose of study drug. Response was assessed in patients who were efficacy evaluable (had ≥1 postbaseline disease assessment or died or discontinued the study due to AEs prior to the first disease assessment). Baseline patient demographics and disease characteristics, safety (including recurrence and change in severity of ibrutinib- or acalabrutinib-intolerance AEs), and time to response were analyzed using descriptive statistics. Clopper-Pearson 2-sided 95% confidence intervals (CIs) were used to assess the precision of the estimated response rates, including DCR. PFS and DoR were analyzed using the Kaplan-Meier method. For the PFS and DoR analyses, data were censored at the date of the last disease assessment prior to initiation of new anticancer therapy or if ≥2 consecutive disease assessments were missed (supplemental Table 1A).

This study was conducted in accordance with the Declaration of Helsinki and the International Council on Harmonization Guidelines for Good Clinical Practice. Institutional review board approval was obtained at each study site.

As of 1 May 2024, a total of 71 patients with CLL/SLL were enrolled in the study (ibrutinib intolerance only, n = 44 [cohort 1]; acalabrutinib intolerance, n = 27 [cohort 2]) and had received ≥1 dose of zanubrutinib. Of the patients who were intolerant of acalabrutinib, 17 were intolerant of acalabrutinib only and 10 were intolerant of both acalabrutinib and ibrutinib. Forty-eight patients (68%) received zanubrutinib 160 mg twice daily, and 23 patients (32%) received 320 mg once daily. Twenty-five ibrutinib-intolerant patients (57%) and 18 acalabrutinib-intolerant patients (67%) were still receiving zanubrutinib at the cutoff date (Figure 1), with a median follow-up of 41.8 months (range, 1.0-51.1) in cohort 1 and 16.5 months (range, 0.1-43.0) in cohort 2 (median follow-up in the entire CLL/SLL population, 34.5 months [range, 0.1-51.1]).

The median age was 71 years, 51% of patients were male, and most patients (97%) had an Eastern Cooperative Oncology Group performance status of 0 or 1 (Table 1). A total of 43 patients (98%) in cohort 1 received ibrutinib as their most recent previous treatment, and 26 patients (96%) in cohort 2 received acalabrutinib as their most recent previous treatment. The median duration of prior ibrutinib treatment was 12.9 months (range, 1.2-64.8), and the median duration of prior acalabrutinib treatment was 5.7 months (range, 0.2-68.6). The median time from the last dose of prior BTK inhibitor therapy to the first dose of zanubrutinib was 1.4 months (range, 0.5-34.8) in cohort 1, and 1.5 months (range, 0.5-29.6) in cohort 2. The median duration of zanubrutinib treatment was 40.7 months (range, 0.6-51.1) in cohort 1 and 9.2 months (range, 0.1-43.0) in cohort 2. Please see supplemental Table 2A for a summary of intolerance events with prior BTK inhibitors.

Of the 54 patients (44 from cohort 1 and 10 from cohort 2) with prior ibrutinib exposure, 52 reported ≥1 ibrutinib-intolerance event; 91 ibrutinib-intolerance AEs were reported in total (grade 1, n = 1; grade 2, n = 54; grade 3, n = 33; grade 4, n = 3; Figure 2). The most common intolerance AEs associated with ibrutinib (>5 events) were fatigue (n = 11), atrial fibrillation (n = 10), rash (n = 9), arthralgia (n = 8), and stomatitis (n = 6).

Of the 52 patients who reported an ibrutinib-intolerance event, 28 (54%) did not experience recurrence when treated with zanubrutinib, accounting for 55 of 91 ibrutinib-intolerance AEs (60%) that did not recur. The most common recurring ibrutinib-intolerance AEs (incidence ≥4 events) were fatigue (7 of 11 events [64%]), rash (5 of 9 events [56%]), hemorrhage (4 of 5 events [80%]), and arthralgia (4 of 8 events [50%]). Twenty-three of the 36 ibrutinib-intolerance AEs (64%) that recurred did so at a lower severity, and no ibrutinib-intolerance AEs recurred at a higher severity. Only 1 of the 10 ibrutinib-intolerance AEs of atrial fibrillation recurred, and it did so at a lower severity (grade 3 to grade 2). Of 33 grade 3 ibrutinib-intolerance AEs, 13 (39%) recurred, 10 (77%) of which recurred at a lower severity. None of the grade 4 AEs recurred. Of the 24 patients who experienced a recurrent ibrutinib-intolerance AE, 13 discontinued zanubrutinib treatment (6 due to PD, 3 due to AEs [1 recurrent AE; 2 novel AEs], 2 due to physician decision [1 patient showed signs of not responding to zanubrutinib; 1 patient had an extensive history of atrial fibrillation], 1 was lost to follow-up [patient had treatment held for a procedure and did not restart treatment following the procedure], and 1 for other reasons [patient was receiving hospice care and the family decided to stop treatment]).

The 27 patients with prior acalabrutinib exposure reported 32 acalabrutinib-intolerance AEs (grade 1, n = 5; grade 2, n = 14; grade 3, n = 13; Figure 2). The most common acalabrutinib-intolerance AEs (incidence in >2 patients) were headache (n = 4), rash (n = 4), arthralgia (n = 3), diarrhea (n = 3), hemorrhage (n = 3), and myalgia (n = 3).

Of the 27 patients who received prior acalabrutinib, 19 (70%) did not have recurrence of acalabrutinib-intolerance AEs when treated with zanubrutinib, accounting for 23 of 32 acalabrutinib-intolerance AEs (72%) not recurring. Diarrhea was the most common recurring acalabrutinib-intolerance AE (3 of 3 events [100%]). Four of the 9 recurrent acalabrutinib-intolerance AEs (44%) occurred at a lower severity with zanubrutinib, and none occurred at a higher severity. There were 2 acalabrutinib-intolerance events of atrial fibrillation, neither of which recurred. Four of 13 grade 3 acalabrutinib-intolerance AEs (31%) recurred, 2 at a lower severity, and 2 at the same severity. No grade 4 AEs related to acalabrutinib intolerance were reported. Of the 8 patients who experienced recurrent acalabrutinib-intolerance AEs, 5 discontinued zanubrutinib treatment (3 due to AEs [2 recurrent AEs; 1 novel AE], 1 due to PD, and 1 due to patient withdrawal).

Of the 10 patients exposed to both ibrutinib and acalabrutinib, 2 experienced the same intolerance AE with both drugs; 1 did not have a recurrence of the event (atrial fibrillation) with zanubrutinib, and the other (diarrhea of grade 3 with ibrutinib and grade 2 with acalabrutinib) had a recurrence with zanubrutinib at a lower grade (grade 1).

A total of 68 patients (96%) reported ≥1 treatment-emergent AE (TEAE) while taking zanubrutinib (Table 2). The most common TEAEs (incidence >20%) were fatigue (32%), COVID-19 (28%), contusion (24%), diarrhea (24%), arthralgia (21%), and cough (21%). Grade ≥3 TEAEs were reported in 61% of patients, with the most common (incidence >5%) being neutropenia (13%), pneumonia (7%), COVID-19 (6%), and hypertension (6%). TEAEs leading to dose reductions occurred in 20 patients (28%), and TEAEs leading to dose interruptions occurred in 45 patients (63%). Eight patients (11%) discontinued zanubrutinib treatment due to TEAEs (autoimmune hemolytic anemia, COVID-19 pneumonia [fatal], cardiac arrest [fatal], diarrhea, penile hemorrhage, rash, skin toxicity, and stomatitis [n = 1 each]).

Atrial fibrillation of any grade occurred in 4 patients (6%); 2 patients (3%) had grade ≥3 atrial fibrillation. One patient reported atrial fibrillation as a recurrent ibrutinib-intolerance AE; none reported atrial fibrillation as a recurrent acalabrutinib-intolerance AE.

Thirty-one patients (44%) reported hemorrhage of any grade; 1 patient had grade ≥3 hemorrhage. Four patients reported hemorrhage as a recurrent ibrutinib-intolerance AE, and 1 patient reported hemorrhage as a recurrent acalabrutinib-intolerance AE.

Treatment-emergent hypertension of any grade occurred in 14 zanubrutinib-treated patients (20%), with grade ≥3 hypertension in 4 patients (6%); of the patients with grade ≥3 hypertension, none reported hypertension as an intolerance event during prior BTK inhibitor treatment. Two patients reported hypertension as a recurrent ibrutinib-intolerance AE and none as a recurrent acalabrutinib-intolerance AE. Furthermore, among the 12 patients with treatment-emergent hypertension that was not a recurrent ibrutinib- or acalabrutinib-intolerance AE, 5 had a reported history of hypertension.

Of 67 efficacy-evaluable patients with CLL/SLL, 63 (94%) experienced disease control and 43 (64%) had a response (Table 3). Not all patients had active disease at enrollment; those who did not were considered unable to achieve a response higher than stable disease on study. The median time to first response (partial response [PR] with lymphocytosis or better) was 2.9 months (range, 2.6-28.1). The median DoR and median PFS were not reached in either cohort. The 2-year DoR event-free rate was 79% (95% CI, 62-89), and the 2-year PFS event-free rate was 76% (95% CI, 62-85).

Of the 43 efficacy-evaluable patients in cohort 1, 34 reported their BOR to prior ibrutinib therapy (CR, n = 2; nodular PR, n = 1; PR, n = 19; SD, n = 11; not evaluable, n = 1; Figure 3). Among the patients who reported BOR to prior ibrutinib, 13 (38%) maintained the same BOR and 11 (32%) achieved a deeper response after switching to zanubrutinib. The median duration of treatment was 13.4 months (range, 1.1-64.8) and 40.8 months (range, 1.6-51.1) on ibrutinib and zanubrutinib, respectively.

Of the 24 efficacy-evaluable patients in cohort 2, 19 reported their BOR to prior acalabrutinib therapy (CR, n = 2; PR, n = 8; SD; n = 9; Figure 3). Among these patients, 7 (37%) maintained the same BOR and 5 (26%) achieved a deeper response after switching to zanubrutinib. The median duration of treatment was 6.1 months (range, 0.2-68.6) and 12.9 months (range, 0.5-43.0) on acalabrutinib and zanubrutinib, respectively.

In this phase 2 trial in patients with CLL/SLL and intolerance of ibrutinib and/or acalabrutinib, recurrence of intolerance AEs was low with zanubrutinib. These results were consistent with observations in the full population of the trial, which included patients with CLL, SLL, Waldenström macroglobulinemia, mantle cell lymphoma, or marginal zone lymphoma; baseline demographics and characteristics were similar between the CLL/SLL population and the full population.¹⁵ Together, these data support zanubrutinib as a treatment option for patients with CLL/SLL who are intolerant of ibrutinib or acalabrutinib.

The ibrutinib- and acalabrutinib-intolerance AEs experienced by patients with CLL/SLL were consistent with the known safety profiles of both treatments in such patients.^4,5 Early trials of ibrutinib monotherapy in patients with R/R CLL/SLL (RESONATE) and treatment-naive CLL/SLL (RESONATE-2) found that discontinuation due to toxicities occurred in 12% and 28% of patients at a median follow-up of 44 and 60 months, respectively.^20,21 The most common toxicities leading to discontinuation of ibrutinib were pneumonia, anemia, thrombocytopenia, diarrhea, and anal incontinence in RESONATE, and atrial fibrillation, palpitations, and pneumonia in RESONATE-2. Additionally, hypertension was reported in 20% and 26%, atrial fibrillation in 11% and 16%, and major hemorrhage in 6% and 11% in RESONATE and RESONATE-2, respectively.^20,21 In a trial comparing acalabrutinib and ibrutinib in patients with R/R CLL, treatment discontinuation due to AEs occurred in 15% of patients treated with acalabrutinib at a median follow-up of 40.9 months; infections, cytopenia, and second primary malignancies were the most common AEs leading to discontinuation.¹⁰ Atrial fibrillation/flutter and hypertension each occurred in 9% of patients treated with acalabrutinib. In the BGB-3111-215 study, the most common intolerance AEs associated with ibrutinib were fatigue, atrial fibrillation, rash, arthralgia, and stomatitis, and the most common acalabrutinib-intolerance AEs were headache, rash, diarrhea, hemorrhage, myalgia, and arthralgia.

The rate of treatment discontinuation due to TEAEs was low (11% at a median follow-up of 34.5 months) with zanubrutinib, regardless of whether patients were intolerant of ibrutinib or acalabrutinib. Treatment with zanubrutinib was previously shown to result in fewer cardiovascular AEs compared with ibrutinib. In the recently published ALPINE study, patients with R/R CLL who received zanubrutinib vs ibrutinib had fewer AEs leading to treatment discontinuation (15% vs 22%) and fewer occurrences of atrial fibrillation or flutter (5% vs 13%), although there was no notable difference in the rate of hypertension (24% vs 23%).¹⁶ In a study of acalabrutinib in patients with R/R CLL who were intolerant of ibrutinib, with a median follow-up of 35.6 months (range, 1.1-47.4), treatment with acalabrutinib resulted in recurrence of 27 ibrutinib-intolerance AEs across 24 of 60 patients (40%), including recurrence of atrial fibrillation (2 of 16 patients), diarrhea (5 of 7), rash (3 of 7), bleeding (5 of 6), and arthralgia (2 of 7).²² One event (increased liver function test) occurred at a higher grade with acalabrutinib vs ibrutinib. Here, intolerance AEs recurred in 46% and 30% of patients intolerant of ibrutinib or acalabrutinib, respectively, and no intolerance AEs recurred at a higher grade. Only 1 patient discontinued treatment due to a recurrent ibrutinib-intolerance AE, and 2 patients discontinued due to a recurrent acalabrutinib-intolerance AE. Zanubrutinib’s milder toxicity profile compared with ibrutinib may be attributable to its higher BTK selectivity and decreased binding to off-target kinases.¹⁶ When tested against a panel of 370 kinases, zanubrutinib inhibited only 7 off-target kinases, whereas ibrutinib inhibited 17, acalabrutinib inhibited 15, and M27, a metabolite of acalabrutinib, inhibited 23; and zanubrutinib was ≥33 times more potent than acalabrutinib in inhibiting BTK.¹⁵ 

During prior ibrutinib or acalabrutinib therapy, only 65% and 53% of efficacy-evaluable patients who had a BOR assessment, respectively, reported a response of PR or better, partly due to short duration of treatment due to toxicities. In this analysis, in efficacy-evaluable patients with R/R CLL/SLL treated with zanubrutinib, the ORR was 64% and the DCR was 94%. For comparison, the ORR was 84% in patients with R/R CLL treated with zanubrutinib (median follow-up, 29.6 months).²³ It is important to note that in several patients in this study, the disease burden at baseline was already very low or absent due to prior partial treatment; thus, these patients could not meet the criteria for partial remission defined by Hallek et al.¹⁷ However, the high DCR with zanubrutinib treatment suggests that patients still benefit from BTK inhibitor therapy after switching from ibrutinib or acalabrutinib to zanubrutinib due to intolerance. Additionally, even with low disease burden after prior treatment, 30% of patients (16 of 53) had deeper response on zanubrutinib compared with the BOR with previous BTK inhibitor therapy. Longer follow-up will be needed to determine the long-term efficacy of zanubrutinib in acalabrutinib-intolerant patients with CLL/SLL.

Several limitations should be considered when interpreting the results of this study. First, the median follow-up of 16.5 months in cohort 2 was shorter than that in previous longer-term studies of ibrutinib and acalabrutinib.^10,20,21 The difference in follow-up between cohort 2 (16.5 months) and cohort 1 (41.8 months) can be attributed to the later addition of cohort 2 to the protocol and ongoing enrollment in cohort 2. With longer follow-up, more ibrutinib- and/or acalabrutinib-intolerance AEs may recur with zanubrutinib. However, the median time on zanubrutinib was longer than that on previous ibrutinib or acalabrutinib in patients in this study, and most AEs tend to occur within the first 3 months of treatment with ibrutinib²⁴ and the first 6 months with acalabrutinib.²⁵ Therefore, the median follow-up of 16.5 months in cohort 2 is likely sufficient for previous intolerance AEs to recur. It is also possible that some ibrutinib- and acalabrutinib-intolerance AEs might not recur if patients were rechallenged with the same drug; conversely, patients might not have recovered from AEs if they chose to receive a lower dose of the same drug. However, because the patients in this study were considered intolerant of ibrutinib or acalabrutinib if either treatment had to be discontinued despite best efforts to manage toxicities, recurrence of intolerance AEs with rechallenge of the same treatment seems likely. Finally, ibrutinib- and acalabrutinib-intolerance data were collected retrospectively, which could result in incomplete data.

AEs that previously caused patients with CLL/SLL to discontinue ibrutinib or acalabrutinib treatment were unlikely to recur with zanubrutinib, and recurrences were mostly at a lower grade. Disease was controlled during zanubrutinib treatment, suggesting that patients with CLL/SLL who are intolerant of ibrutinib or acalabrutinib are likely to receive clinical benefit by switching to zanubrutinib. These data suggest that zanubrutinib may be an alternative treatment option for patients with CLL/SLL who are intolerant of ibrutinib or acalabrutinib.

The authors thank the patients and their families, investigators, coinvestigators, and the study teams at each of the participating centers. The authors acknowledge the past contributions of Rocco Crescenzo and Kunthel By to the conception, design, interpretation, and analysis of data in previous versions of this study. Medical writing and editorial assistance for this article were provided by Hayley White, PhD, Kendall Foote, PhD, Frank Biegun, MSc, and Shanen Perumal, PhD of Nucleus Global, an Inizio company, under the direction of the authors.

Funding for this support was provided by BeOne Medicines Ltd.

Contribution: M.S., C.M.F., I.W.F., and J.P.S. contributed to conception/design, acquisition of data, and interpretation of data; J.M.B., J.C., H.A.Y., S.F.Z., J.M., and S.S.R. contributed to acquisition of data and interpretation of data; A.C. contributed to conception/design and interpretation of data; H.Y. contributed to interpretation of data and drafting the manuscript; A.I. contributed to conception/design, analysis of data, and interpretation of data; and Q.A. contributed to analysis of data and interpretation of data.

Conflict-of-interest disclosure: M.S. reports a consulting role and/or participation on advisory boards, steering committees, or data safety monitoring committees for AbbVie, Genentech, AstraZeneca, Genmab, Janssen, BeOne, Bristol Myers Squibb, MorphoSys/Incyte, Kite Pharma, Eli Lilly, Mustang Bio, Fate Therapeutics, Nurix, and Merck; received institutional research funding from Mustang Bio, Genentech, AbbVie, BeOne, AstraZeneca, Genmab, MorphoSys/Incyte, and Vincerx; reports stock options in Koi Biotherapeutics; and reports employment with Bristol Myers Squibb (spouse). J.M.B. received consultancy fees from AbbVie, Adaptive Biotechnologies, AstraZeneca, BeOne, Bristol Myers Squibb, Constellation, Eli Lilly, Epizyme, Foresight, Genentech, Genmab, Kura, Kymera, MorphoSys, Novartis, Nurix, TG Therapeutics, and Verastem; reports speakers bureau participation with BeOne; and received research funding from MorphoSys. J.C. reports employment with Florida Cancer Specialists & Research Institute; is a current equity holder in publicly traded company, American Oncology Network; and received research funding from Incyte, Takeda, Bristol Myers Squibb, Celgene, Acerta, BeOne, TG Therapeutics, Merck, Daiichi Sankyo, Novartis, MacroGenics, Eli Lilly, and Genentech. H.A.Y. reports speakers bureau participation with AbbVie, Amgen, AstraZeneca, BeOne, GlaxoSmithKline, Janssen, Karyopharm, and Takeda. C.M.F. served on an advisory board for Genmab/AbbVie; and speakers bureau for BeOne, Genentech, Genmab/AbbVie, Gilead/Kite, Incyte/MorphoSys, and Seagen. A.C. is a consultant to and equity holder in BeOne. H.Y., A.I., and Q.A. are employed by BeOne Medicines Ltd and may hold company stock/stock options. I.W.F. reports research grants (all payments made to institution) from AbbVie, AstraZeneca, BeOne Medicines Ltd, Bristol Myers Squibb, Celgene, City of Hope National Medical Center, Epizyme, Fate Therapeutics, Genentech, Gilead Sciences, IGM Biosciences, InnoCare Pharma, Incyte, Janssen, Kite Pharma, Loxo, Marker Therapeutics, Merck, MorphoSys, Myeloid Therapeutics, Novartis, Nurix, Pfizer, Roche, Seagen, TG Therapeutics, Vincerx, and 2seventy bio; reports consultancy fees (all payments made to physician) from AbbVie, BeOne, Genentech, Genmab, Kite Pharma, and Vincerx; and reports a role on an advisory committee for Vincerx. J.P.S. reports a consulting or advisory role with AbbVie, AstraZeneca, BeOne, Bristol Myers Squibb, Genentech, Janssen, Eli Lilly, and Merck. The remaining authors declare no competing financial interests.

Correspondence: Mazyar Shadman, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Seattle, 98109 WA; email: mshadman@fredhutch.org.