Introduction

BTK inhibition has reshaped the treatment of CLL/SLL. Covalent BTK inhibitors such as ibrutinib, acalabrutinib, and zanubrutinib have moved the field away from routine chemoimmunotherapy for many patients and have provided effective oral therapy across multiple clinical and biologic risk groups. Second-generation covalent inhibitors generally offer improved tolerability relative to ibrutinib, although bleeding, infections, cytopenias, cardiovascular events, drug interactions, and treatment discontinuation remain clinically relevant considerations (Brown et al., 2023; Byrd et al., 2021; Sharman et al., 2020; Tam et al., 2022).

Pirtobrutinib, a noncovalent BTK inhibitor, received traditional FDA approval in December 2025 for adults with relapsed or refractory CLL/SLL previously treated with a covalent BTK inhibitor. In BRUIN CLL-321, pirtobrutinib improved progression-free survival compared with investigator’s choice of idelalisib plus rituximab or bendamustine plus rituximab in patients previously treated with a covalent BTK inhibitor. Patients with prior noncovalent BTK-inhibitor exposure were excluded, so the trial does not define treatment after pirtobrutinib progression (Sharman et al., 2025).

These advances have created a new sequencing problem. A growing population has received a covalent BTK inhibitor and a BCL-2 inhibitor, and some patients have also received pirtobrutinib, cellular therapy, PI3K inhibitors, anti-CD20 antibodies, or investigational agents. Treatment decisions in this setting must account for the reason each therapy was discontinued, prior response duration, molecular risk, transformation risk, cumulative toxicities, comorbidities, and patient goals.

BTK degraders are emerging as one possible investigational strategy. These agents recruit BTK to an E3 ubiquitin ligase, leading to ubiquitination and proteasomal degradation of the BTK protein. The approach is mechanistically attractive because it can reduce wild-type and selected mutant forms of BTK rather than relying solely on sustained occupancy of the kinase domain.

A compelling mechanism is not equivalent to established clinical benefit. BTK degraders remain investigational, and their efficacy, durability, comparative value, and long-term safety have not been established.

Why BTK Degradation Matters Now

Current CLL/SLL management includes covalent BTK inhibitors, venetoclax-based fixed-duration therapy, selected anti-CD20 combinations, pirtobrutinib after covalent BTK-inhibitor exposure, and lisocabtagene maraleucel for eligible patients after prior BTK-inhibitor and BCL-2-inhibitor therapy. Current NCCN and EHA guidance emphasizes matching treatment to prior exposure, prior response, disease biology, comorbidities, and patient preferences rather than applying a single uniform sequence (Eichhorst et al., 2026; Wierda et al., 2026).

This broader range of treatments has improved outcomes for many patients. However, it has also created a challenging population with diseases that have escaped multiple targeted therapies. These patients may have high-risk molecular features, cumulative marrow toxicity, immune dysfunction, recurrent infections, treatment-related cardiovascular or bleeding risks, and limited tolerance for additional therapy.

Acquired alterations involving BTK, PLCG2, BCL2, or other pathways may contribute to progression, but resistance biology varies among patients and can evolve over time. CLL/SLL that progresses after multiple targeted therapies may no longer be driven primarily by a single pathway.

BTK degraders are being studied in this therapeutic gap. Their potential role is particularly relevant after progression on established targeted options, but current development programs also include earlier-line and BTK-inhibitor-naive cohorts. Therefore, BTK degraders should not be characterized exclusively as post-pirtobrutinib rescue therapy.

At this stage of disease, clinicians should simultaneously consider approved therapies, cellular-therapy eligibility, clinical trial referral, transformation assessment, infection prevention, supportive care, and treatment goals.

Current Treatment Context: Not All BTK-Inhibitor Exposure Is the Same

The phrase “BTK inhibitor exposed” is too imprecise for modern CLL/SLL care. Treatment history should distinguish intolerance from progression, covalent from noncovalent BTK inhibition, and previous exposure from biologically resistant disease.

Some patients discontinue a covalent BTK inhibitor because of toxicity rather than progression. Depending on the adverse event, comorbidities, prior response, and remaining options, switching to a different covalent BTK inhibitor, using venetoclax-based therapy, or pursuing another approved strategy may be appropriate. In contrast, disease progression during covalent BTK inhibition generally calls for a therapy with a different binding approach or mechanism.

Pirtobrutinib is FDA-approved for adults with relapsed or refractory CLL/SLL previously treated with a covalent BTK inhibitor. Its indication no longer requires prior BCL-2-inhibitor exposure. However, the evidence supporting this approval does not establish efficacy after prior noncovalent BTK inhibition, and post-pirtobrutinib disease remains a separate, less well-defined problem (Mato et al., 2023; Sharman et al., 2025).

Lisocabtagene maraleucel is approved for adults with relapsed or refractory CLL/SLL who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. Its use requires specialized infrastructure and careful management of cytokine release syndrome, neurologic toxicity, prolonged cytopenias, serious infections, hypogammaglobulinemia, and secondary malignancy risk. BTK-degrader trials may enroll some of the same patients, but cellular therapy and targeted protein degradation should not be treated as interchangeable strategies (Siddiqi et al., 2023).

Table 1. Current Therapeutic Context After Prior BTK-Inhibitor Exposure

Strategy	Current role	Key safety considerations	Important limitation
Switch to another covalent BTK inhibitor	May be considered after intolerance in selected patients	Hemorrhage, infection, cytopenias, cardiac arrhythmias, hypertension, hepatotoxicity, and drug interactions vary by agent	Generally less appropriate for disease progressing through covalent BTK inhibition
Pirtobrutinib	FDA approved for relapsed or refractory CLL/SLL after prior covalent BTK-inhibitor treatment	Infections, hemorrhage, cytopenias, cardiac arrhythmias, second primary malignancies, hepatotoxicity, and embryo-fetal toxicity	Efficacy after prior noncovalent BTK inhibition is not established
Venetoclax-based therapy	Important option when not previously used; retreatment may be considered selectively	Tumor lysis syndrome, neutropenia, infections, and CYP3A or P-glycoprotein interactions	Requires risk-stratified ramp-up, prophylaxis, and monitoring
Lisocabtagene maraleucel	Approved for selected adults after at least two prior lines including a BTK inhibitor and BCL-2 inhibitor	Boxed warnings for cytokine release syndrome, neurologic toxicities, and secondary hematologic malignancies; prolonged cytopenias and infections also require attention	Requires cellular-therapy eligibility, manufacturing, monitoring, and specialized infrastructure
BTK-degrader trial	Investigational option across several protocol-defined treatment populations	Cytopenias, bruising or bleeding, infections, gastrointestinal effects, rash, and other toxicities remain under study	No FDA-approved BTK degrader for CLL/SLL as of July 23, 2026

Mechanistic Rationale for BTK Degraders

Covalent BTK inhibitors bind irreversibly to the C481 residue of BTK. Acquired substitutions involving C481 can reduce covalent drug binding and permit renewed B-cell receptor signaling. PLCG2 alterations and other mechanisms can also contribute to progression.

Noncovalent BTK inhibitors such as pirtobrutinib do not rely on C481 binding and can retain activity against some C481-mutant disease. Nevertheless, resistance to noncovalent BTK inhibition can emerge through additional BTK kinase-domain mutations, PLCG2 alterations, clonal evolution, or potentially BTK-independent mechanisms (Naeem et al., 2023; Wang et al., 2022).

BTK degraders use a different pharmacologic strategy. A degrader contains a BTK-binding component and an E3-ligase-recruiting component. Formation of the resulting complex promotes BTK ubiquitination and proteasomal degradation.

In principle, degradation may address selected resistance mechanisms that preserve BTK signaling despite previous inhibitor exposure. It may also reduce nonenzymatic or scaffold functions of BTK. The clinical importance of eliminating those scaffold functions remains under investigation and should not be presented as established human benefit (Salvaris et al., 2025).

The difference between degradation and inhibition matters in clinical settings, but it shouldn’t be exaggerated. Clinical benefit requires adequate drug exposure, sustained intracellular target degradation, acceptable tolerability, and durable disease control in a disease that remains meaningfully dependent on BTK biology.

No validated biomarker or clinical model can currently identify which patients will benefit most from a BTK degrader. Performance status, organ function, comorbidities, and prior toxicities are important for trial eligibility and safety, but they are not established predictors of degrader efficacy.

Early clinical findings support continued development. They do not establish superiority or a clear clinical advantage over approved therapies.

Emerging Evidence for Investigational BTK Degraders

Two oral agents have generated particular interest in CLL/SLL: bexobrutideg, previously designated NX-5948, and BGB-16673, also referred to as tacabrutideg. Both remain investigational.

Bexobrutideg

Bexobrutideg is an oral, cereblon-recruiting degrader designed to reduce wild-type and selected mutant forms of BTK. The ongoing first-in-human phase 1 study includes multiple CLL/SLL cohorts defined by prior BTK-inhibitor exposure, BCL-2-inhibitor exposure, molecular features, central nervous system involvement, and line of therapy.

A 2025 phase 1 conference report included 97 patients with CLL/SLL, most of whom had received a covalent BTK inhibitor and approximately three-quarters of whom had received a BCL-2 inhibitor. The reported overall response rate among response-evaluable patients was 78.6%. Purpura or contusion, neutropenia, fatigue, diarrhea, headache, petechiae, and thrombocytopenia were among the most frequently reported treatment-emergent events. Follow-up and cohort sizes remained limited (Omer et al., 2025).

A 2026 EHA update described 142 patients enrolled across dose-escalation and selected dose-expansion cohorts, including heavily pretreated, BTK-inhibitor-exposed but BCL-2-inhibitor-naive, and BTK-inhibitor-naive populations. Response rates were reported in the low-to-mid 80% range across the presented cohorts. These findings broaden the developmental context beyond patients who have exhausted every approved targeted therapy. However, the results remain early-phase, nonrandomized, and conference-reported (Munir et al., 2026).

A phase 2 study is evaluating bexobrutideg after prior BTK- and BCL-2-inhibitor treatment, and a randomized phase 3 study has been registered to compare bexobrutideg with pirtobrutinib after prior covalent BTK-inhibitor treatment. The phase 3 record should not be interpreted as evidence that the degrader is superior or equivalent to pirtobrutinib because comparative results are not yet available.

BGB-16673

BGB-16673 is another oral, cereblon-recruiting BTK degrader. The ongoing CaDAnCe-101 phase 1/2 study includes several B-cell malignancies and multiple CLL/SLL cohorts.

A 2025 conference update described 67 patients with CLL/SLL who had received a median of four prior treatment lines. Most had received a covalent BTK inhibitor, 82.1% had received a BCL-2 inhibitor, and 20.9% had received a noncovalent BTK inhibitor. The reported overall response rate among response-evaluable patients was 86.4%. Fatigue, contusion or bruising, diarrhea, and neutropenia were among the most common treatment-emergent events. Grade 3 or higher neutropenia, pneumonia, and thrombocytopenia were reported. Four deaths associated with treatment-emergent infections were reported, although investigators did not attribute those deaths to treatment. These results remain preliminary and require mature follow-up and independent confirmation (Ahn et al., 2025).

The BGB-16673 development program now includes several randomized phase 3 studies. One compares BGB-16673 with investigator’s choice in patients previously exposed to both a BTK inhibitor and a BCL-2 inhibitor. Another compares BGB-16673 with pirtobrutinib after prior covalent BTK-inhibitor treatment and excludes previous noncovalent BTK-inhibitor exposure. These differences show why prior pirtobrutinib treatment cannot be presented as a universal requirement for degrader enrollment.

Interpreting the Evidence

The early response signals are clinically encouraging, particularly because the initial studies enrolled patients with extensive prior treatment and high-risk disease. However, response rate alone does not establish durable disease control, survival benefit, superiority, or an improved therapeutic index.

Differences in eligibility, previous treatment exposure, molecular risk, dose selection, follow-up duration, response definitions, supportive care, and patient complexity preclude reliable cross-trial comparisons with pirtobrutinib, venetoclax, lisocabtagene maraleucel, or other therapies.

Apparent differences in response rates or adverse-event frequencies across separate studies should not be interpreted as direct comparative evidence. Randomized trials and longer follow-up are required.

Table 2. Evidence Snapshot for Investigational BTK Degraders in CLL/SLL

Agent	Current evidence	Reported clinical signal	Principal limitations
Bexobrutideg, NX-5948	Phase 1 dose-escalation and expansion data; phase 2 underway; phase 3 comparison with pirtobrutinib registered	Responses reported in heavily pretreated, BTK-inhibitor-exposed, and selected earlier-line cohorts	Nonrandomized evidence, conference reporting, heterogeneous cohorts, and limited mature durability data
BGB-16673, tacabrutideg	Phase 1/2 data; multiple randomized phase 3 trials recruiting	Responses reported after covalent BTK-, BCL-2-, and, in some patients, noncovalent BTK-inhibitor exposure	No mature randomized efficacy or comparative safety results
BTK-degrader class	Investigational in CLL/SLL	Biologically plausible strategy for selected BTK-dependent resistance mechanisms	No approved agent, validated predictive biomarker, established sequence, or confirmed class-wide safety profile

Safety Considerations

Safety assessment for BTK degraders must remain cautious. Clinicians should not assume that degraders reproduce the exact adverse-event profile of approved BTK inhibitors. They also should not assume that degradation eliminates BTK-associated bleeding, infection, cytopenia, or cardiovascular risks.

Patients enrolled in early degrader studies often have baseline cytopenias, immune dysfunction, previous serious infections, cardiovascular comorbidity, and exposure to anticoagulants or antiplatelet therapy. Attribution is therefore difficult, particularly in small, nonrandomized studies.

Approved BTK-inhibitor labeling provides a relevant but imperfect safety backdrop. Current pirtobrutinib labeling includes warnings for infections, hemorrhage, cytopenias, cardiac arrhythmias, second primary malignancies, hepatotoxicity, and embryo-fetal toxicity. Acalabrutinib and zanubrutinib labeling includes clinically important warnings for serious or opportunistic infections, hemorrhage, cytopenias, second primary malignancies, cardiac arrhythmias, and hepatotoxicity. Zanubrutinib labeling also includes embryo-fetal toxicity. Agent-specific labeling and interactions should be reviewed rather than assuming a uniform class profile.

Venetoclax safety remains important in sequencing discussions. CLL/SLL treatment requires a structured dose ramp-up, tumor lysis syndrome risk assessment, prophylaxis, and laboratory monitoring. Concomitant use with strong CYP3A inhibitors is contraindicated during initiation and ramp-up in CLL/SLL. Neutropenia and serious infections are additional monitoring concerns.

Early BTK-degrader studies have reported neutropenia, thrombocytopenia, bruising, purpura, petechiae, fatigue, diarrhea, rash, infections, pneumonia, and occasional bleeding or cardiac events. The frequency, causality, dose relationship, and class relevance of these findings remain uncertain.

The absence of a particular event in a small early-phase cohort does not establish that the risk is absent. Long-term safety, infection-related mortality, bleeding risk during anticoagulant or antiplatelet use, perioperative management, reproductive toxicity, drug interactions, dose optimization, and late treatment discontinuation patterns remain incompletely characterized.

Patient Selection and Trial Referral

There is no universally established “ideal candidate” for a BTK degrader. Trial referral should be based on the patient’s treatment history, remaining approved options, disease characteristics, comorbidities, goals, and the eligibility requirements of a specific protocol.

BTK-degrader trials may be particularly relevant for patients with relapsed or refractory CLL/SLL after covalent BTK-inhibitor exposure when standard options are limited or unsuitable. Prior venetoclax or pirtobrutinib exposure may define important investigational subgroups, but neither is a universal prerequisite.

Current trials enroll different populations. Some require previous treatment with both a BTK inhibitor and a BCL-2 inhibitor. Others compare a degrader directly with pirtobrutinib after covalent BTK-inhibitor treatment and exclude prior noncovalent BTK inhibition. Phase 1 programs may include BTK-inhibitor-naive, earlier-line, central nervous system, or transformation-specific cohorts. Eligibility must therefore be assessed against the actual protocol rather than a generalized treatment sequence.

Before referral, clinicians should clarify why each previous therapy was stopped. Intolerance, elective completion of a fixed-duration regimen, inadequate response, and progression during therapy have different implications.

The treatment record should document:

• Exact prior agents and combinations
• Best response and response duration
• Reason for discontinuation
• Prior covalent and noncovalent BTK-inhibitor exposure
• Prior venetoclax and anti-CD20 exposure
• Previous cellular-therapy evaluation
• Relevant toxicities, infections, and drug interactions
• Available resistance testing

Performance status, organ function, blood counts, infection history, cardiovascular disease, bleeding risk, and concomitant medications determine whether participation can be undertaken safely. These factors should be presented as safety and eligibility considerations, not as validated predictors of degrader efficacy.

Transformation Assessment

Clinicians should assess for Richter transformation when the clinical pattern is atypical. Rapid clinical deterioration, worsening B symptoms, rapidly enlarging or discordant lymphadenopathy, elevated lactate dehydrogenase, extranodal disease, or an unexpectedly aggressive progression pattern should prompt further evaluation.

Current ERIC recommendations support PET/CT when Richter transformation is suspected and tissue biopsy from an accessible lesion, preferably one with the greatest fluorodeoxyglucose avidity. BTK-degrader treatment should not substitute for appropriate transformation evaluation (Kittai et al., 2025).

Table 3. Practical Checklist Before BTK-Degrader Trial Referral

Clinical domain	Information to document	Clinical relevance
Previous BTK-inhibitor treatment	Agent, covalent or noncovalent mechanism, duration, response, progression versus intolerance	Determines whether approved sequencing options remain and whether protocol requirements are met
Previous BCL-2-inhibitor treatment	Regimen, tumor lysis risk, response, duration, completion or discontinuation reason	Helps define double-exposed disease and whether future BCL-2 use or retreatment is reasonable
Previous pirtobrutinib treatment	Response, duration, progression pattern, toxicities, and available resistance findings	Distinguishes the post-noncovalent BTK-inhibitor setting
Transformation risk	B symptoms, lactate dehydrogenase, nodal pattern, PET/CT findings, and biopsy when indicated	Richter transformation requires a distinct diagnostic and treatment approach
Safety baseline	CBC, renal and hepatic function, infection history, immune status, bleeding history, anticoagulants, antiplatelets, and cardiovascular history	Informs protocol eligibility and toxicity risk
Patient priorities	Treatment goals, logistics, travel, monitoring burden, and willingness to accept investigational uncertainty	Supports appropriate shared decision-making

Molecular and Diagnostic Considerations

Baseline molecular risk assessment remains useful in relapsed CLL/SLL. TP53 disruption, del(17p), complex karyotype, unmutated IGHV, short previous remissions, and patterns of clonal evolution may inform prognosis and treatment urgency.

BTK and PLCG2 mutation testing may help characterize resistance after BTK-inhibitor exposure. However, availability, assay sensitivity, specimen selection, variant allele frequency, timing, and clinical interpretation vary.

Molecular testing should not be used to overpromise benefit from degradation. A detected BTK mutation may support a BTK-dependent resistance mechanism, but it does not guarantee sensitivity to a degrader. Different mutations may affect inhibitor binding, kinase activity, protein structure, signaling, or degradability in different ways.

Conversely, the absence of a detected BTK mutation does not exclude continued dependence on BTK signaling. No molecular alteration is currently validated as a degrader-specific predictive biomarker.

Response assessment should follow established CLL/SLL principles. Lymphocyte count, nodal disease, spleen size, marrow function, constitutional symptoms, and transformation risk require contextual interpretation. Trial protocols may include pharmacodynamic measurements of BTK degradation, measurable residual disease testing, and serial molecular monitoring, but these remain research tools rather than routine degrader-selection tests (Hallek et al., 2018).

Practical Approach for Clinicians

A practical approach begins with a precise treatment history. The first question is whether a prior covalent BTK inhibitor was discontinued because of intolerance, planned treatment completion, or disease progression.

If a patient has relapsed or refractory CLL/SLL after a covalent BTK inhibitor and has not received pirtobrutinib, pirtobrutinib is an FDA-approved option. Choice should still account for previous therapies, comorbidities, infection history, bleeding risk, cardiovascular status, renal function, hepatic function, interacting medications, and patient preference.

If venetoclax has not been used, a venetoclax-based regimen may be appropriate depending on disease burden, tumor lysis risk, renal function, previous therapy, comorbidities, drug interactions, monitoring capacity, and treatment goals.

For patients previously treated with both a BTK inhibitor and a BCL-2 inhibitor, clinicians should review pirtobrutinib eligibility, lisocabtagene maraleucel eligibility, the potential role of selected retreatment strategies, transformation risk, and available clinical trials. There is no single sequence that applies to every patient (Shadman & Davids, 2025).

For disease progression after covalent BTK inhibition, venetoclax, and pirtobrutinib, timely referral to a CLL-focused center or clinical trial program is especially important. Referral should not imply that a BTK-degrader study is automatically preferable to every remaining standard or investigational option.

Trial screening should include protocol-specific review of performance status, organ function, blood counts, infection history, bleeding risk, cardiovascular conditions, previous malignancies, central nervous system involvement, prior therapies, and washout periods.

Patients should be told clearly that BTK degraders are investigational. Discussions should distinguish mechanistic rationale and preliminary response signals from proven clinical benefit. Uncertainty regarding durability, survival, long-term safety, interactions, and comparative effectiveness should be explicit.

Limitations of the Evidence

The evidence base for BTK degraders in CLL/SLL remains limited in several important ways.

First, most clinical findings come from early-phase, nonrandomized studies. Response rates in this context are preliminary and hypothesis-generating.

Second, several important datasets are available primarily through conference abstracts, presentations, clinical trial registries, or sponsor communications rather than mature peer-reviewed manuscripts. These sources can inform clinical awareness but should not be treated as equivalent to completed randomized trials.

Third, follow-up remains limited. Median progression-free survival, duration of response, overall survival, late infections, secondary malignancies, cumulative cytopenias, treatment discontinuation, and long-term cardiovascular or bleeding outcomes require further observation.

Fourth, cross-trial comparisons are unreliable. Studies of pirtobrutinib, bexobrutideg, BGB-16673, venetoclax, and cellular therapies differ in prior treatment exposure, eligibility, molecular risk, patient fitness, response criteria, follow-up, and supportive care.

Fifth, predictive biomarkers remain unsettled. BTK degradation may address some BTK-dependent resistance mechanisms, but multiply treated CLL/SLL may become biologically heterogeneous or less dependent on BTK signaling.

Sixth, randomized phase 3 trials are ongoing or registered, but no mature comparative results are available. Trial registration confirms development strategy, not clinical superiority.

Future Directions

The next phase of research should address four practical questions.

The first is whether BTK degraders can produce durable disease control after covalent and noncovalent BTK-inhibitor exposure. Activity after pirtobrutinib progression remains a particularly important unmet need.

The second is whether molecular or pharmacodynamic biomarkers can identify patients most likely to benefit. BTK, PLCG2, BCL2, TP53, complex karyotype, clonal evolution, and direct measurements of target degradation may help refine selection, but none is currently validated as a degrader-specific clinical decision tool.

The third is whether degraders can be combined safely with venetoclax, anti-CD20 antibodies, or other targeted agents. Combination studies are underway, but potential gains in depth of response must be balanced against overlapping cytopenias, infections, bleeding, drug interactions, and treatment burden.

The fourth is where degraders should fit relative to pirtobrutinib, lisocabtagene maraleucel, venetoclax retreatment, other emerging targeted therapies, and supportive or palliative approaches. Randomized trials, longer follow-up, and patient-reported outcomes will be needed before confident sequencing recommendations can be made.

References

Ahn, I. E., et al. (2025). Updated efficacy and safety results of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the ongoing phase 1 CaDAnCe-101 study. Blood, 146(Supplement 1), 85. https://doi.org/10.1182/blood-2025-85 https://ashpublications.org/blood/article/146/Supplement%201/85/548770/Updated-Efficacy-and-Safety-Results-of-the-Bruton

Brown, J. R., Eichhorst, B., Hillmen, P., Jurczak, W., Kazmierczak, M., Lamanna, N., et al. (2023). Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. New England Journal of Medicine, 388(4), 319-332. https://doi.org/10.1056/NEJMoa2211582. PMID: 36511784.

Byrd, J. C., Hillmen, P., Ghia, P., Kater, A. P., Chanan-Khan, A., Furman, R. R., et al. (2021). Acalabrutinib versus ibrutinib in previously treated chronic lymphocytic leukemia: Results of the first randomized phase III trial. Journal of Clinical Oncology, 39(31), 3441-3452. https://doi.org/10.1200/JCO.21.01210. PMID: 34310172.

ClinicalTrials.gov. (2026). A dose-escalation and expansion study of BGB-16673 in participants with B-cell malignancies: CaDAnCe-101 (NCT05006716). Retrieved July 23, 2026, from https://clinicaltrials.gov/study/NCT05006716

ClinicalTrials.gov. (2026). A study of NX-5948 in adults with relapsed or refractory B-cell malignancies (NCT05131022). Retrieved July 23, 2026, from https://clinicaltrials.gov/study/NCT05131022

ClinicalTrials.gov. (2026). BGB-16673 compared with investigator’s choice in CLL/SLL previously exposed to both BTK and BCL-2 inhibitors: CaDAnCe-302 (NCT06846671). Retrieved July 23, 2026, from https://clinicaltrials.gov/study/NCT06846671

ClinicalTrials.gov. (2026). BGB-16673 compared with pirtobrutinib in participants with relapsed or refractory CLL/SLL (NCT06973187). Retrieved July 23, 2026, from https://clinicaltrials.gov/study/NCT06973187

ClinicalTrials.gov. (2026). A study of NX-5948 in adults with CLL/SLL previously treated with a BTK inhibitor and BCL-2 inhibitor: DAYBreak CLL-201 (NCT07221500). Retrieved July 23, 2026, from https://clinicaltrials.gov/study/NCT07221500

ClinicalTrials.gov. (2026). Study of NX-5948 versus pirtobrutinib in relapsed or refractory CLL/SLL (NCT07516093). Retrieved July 23, 2026, from https://clinicaltrials.gov/study/NCT07516093

DailyMed. (2026). BREYANZI (lisocabtagene maraleucel) prescribing information. Retrieved July 23, 2026, from https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=lisocabtagene%20maraleucel

DailyMed. (2026). BRUKINSA (zanubrutinib) prescribing information. Retrieved July 23, 2026, from https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=zanubrutinib

DailyMed. (2026). CALQUENCE (acalabrutinib) prescribing information. Retrieved July 23, 2026, from https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=acalabrutinib

DailyMed. (2026). JAYPIRCA (pirtobrutinib) prescribing information. Retrieved July 23, 2026, from https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=pirtobrutinib

DailyMed. (2026). VENCLEXTA (venetoclax) prescribing information. Retrieved July 23, 2026, from https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=venetoclax

Eichhorst, B., Ghia, P., Bosch, F., Clifford, R., Gregor, M., Guieze, R., et al. (2026). EHA guidelines on management of chronic lymphocytic leukemia and Richter transformation. HemaSphere, 10(6), e70403. https://doi.org/10.1002/hem3.70403. PMID: 42293463.

Eichhorst, B., Ghia, P., Niemann, C. U., Kater, A. P., Gregor, M., Cymbalista, F., et al. (2024). ESMO Clinical Practice Guideline interim update on new targeted therapies in the first-line and relapsed chronic lymphocytic leukemia. Annals of Oncology, 35, 762-768. https://doi.org/10.1016/j.annonc.2024.06.016. PMID: 38969011.

Hallek, M., Cheson, B. D., Catovsky, D., Caligaris-Cappio, F., Dighiero, G., Dohner, H., et al. (2018). iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of chronic lymphocytic leukemia. Blood, 131(25), 2745-2760. https://doi.org/10.1182/blood-2017-09-806398. PMID: 29540348.

Kittai, A. S., Marchetti, M., Al-Sawaf, O., Benjamini, O., Danilov, A. V., Davids, M. S., et al. (2025). International consensus statement on diagnosis, evaluation, and research of Richter transformation: The ERIC recommendations. Blood, 146(3), 291-303. https://doi.org/10.1182/blood.2024028064. PMID: 40239121.

Mato, A. R., Woyach, J. A., Brown, J. R., et al. (2023). Pirtobrutinib after a covalent BTK inhibitor in chronic lymphocytic leukemia. New England Journal of Medicine, 389(1), 33-44. https://doi.org/10.1056/NEJMoa2300696. PMID: 37407001.

Munir, T., Omer, Z., Grosicki, S., Kwiatek, M., Danilov, A., Shah, N. N., et al. (2026). Updated efficacy and safety data from an ongoing phase 1a/b trial of the BTK degrader bexobrutideg (NX-5948) in patients with CLL across lines of therapy. EHA 2026 Oral Presentation S150. https://library.ehaweb.org/eha/2026/eha-2026/4206704/talha.munir.updated.efficacy.and.safety.data.
from.an.ongoing.phase.1a.b.trial.html

Naeem, A., Utro, F., Wang, Q., Cha, J., Vihinen, M., Martensson, A., et al. (2023). Pirtobrutinib targets BTK C481S in ibrutinib-resistant CLL, but second-site BTK mutations lead to resistance. Blood Advances, 7(9), 1929-1943. https://doi.org/10.1182/bloodadvances.2022008447. PMID: 36287227.

Omer, Z., et al. (2025). Bexobrutideg (NX-5948), a novel Bruton’s tyrosine kinase degrader, demonstrates rapid and durable clinical responses in relapsed or refractory chronic lymphocytic leukemia: New and updated findings from an ongoing phase 1a/b trial. Blood, 146(Supplement 1), 86. https://doi.org/10.1182/blood-2025-86. https://ashpublications.org/blood/article/146/Supplement%201/86/549702/Bexobrutideg-a-Novel-Bruton-s-Tyrosine-Kinase

Salvaris, R. T., Brennan, J., & Lewis, K. L. (2025). BTK is the target that keeps on giving: A review of BTK-degrader drug development, clinical data, and future directions in CLL. Cancers, 17(3), 557. https://doi.org/10.3390/cancers17030557. PMID: 39941922. https://pubmed.ncbi.nlm.nih.gov/39941922/

Shadman, M., & Davids, M. S. (2025). How I treat patients with CLL after prior treatment with a covalent BTK inhibitor and a BCL-2 inhibitor. Blood, 146(17), 2029-2036. https://doi.org/10.1182/blood.2024025482. PMID: 40729699.

Sharman, J. P., Egyed, M., Jurczak, W., Skarbnik, A., Pagel, J. M., Flinn, I. W., et al. (2020). Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukemia: A randomized, controlled, phase 3 trial. The Lancet, 395(10232), 1278-1291. https://doi.org/10.1016/S0140-6736(20)30262-2. PMID: 32305093.

Sharman, J. P., Munir, T., Grosicki, S., et al. (2025). Phase III trial of pirtobrutinib versus idelalisib/rituximab or bendamustine/rituximab in covalent Bruton tyrosine kinase inhibitor-pretreated chronic lymphocytic leukemia/small lymphocytic lymphoma: BRUIN CLL-321. Journal of Clinical Oncology, 43(22), 2538-2549. https://doi.org/10.1200/JCO-25-00166. PMID: 40479620.

Siddiqi, T., Maloney, D. G., Kenderian, S. S., Brander, D. M., Dorritie, K., Soumerai, J. D., et al. (2023). Lisocabtagene maraleucel in chronic lymphocytic leukemia and small lymphocytic lymphoma: TRANSCEND CLL 004. The Lancet, 402(10402), 641-654. https://doi.org/10.1016/S0140-6736(23)01052-8. PMID: 37295445.

Tam, C. S., Brown, J. R., Kahl, B. S., Ghia, P., Giannopoulos, K., Jurczak, W., et al. (2022). Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukemia and small lymphocytic lymphoma: The SEQUOIA trial. The Lancet Oncology, 23(8), 1031-1043. https://doi.org/10.1016/S1470-2045(22)00293-5. PMID: 35810754.

U.S. Food and Drug Administration. (2025, December 3). FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. Retrieved July 23, 2026, from https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic

Wang, E., Mi, X., Thompson, M. C., et al. (2022). Mechanisms of resistance to noncovalent Bruton’s tyrosine kinase inhibitors. New England Journal of Medicine, 386(8), 735-743. https://doi.org/10.1056/NEJMoa2114110. PMID: 35196427. https://pubmed.ncbi.nlm.nih.gov/35196427/

Wierda, W. G., Brown, J. R., Abramson, J. S., et al. (2026). NCCN Guidelines Insights: Chronic lymphocytic leukemia/small lymphocytic lymphoma, Version 2.2026. Journal of the National Comprehensive Cancer Network, 24(3), 68-80. https://doi.org/10.6004/jnccn.2026.0012. PMID: 41825137.