BTK Inhibitors in CLL : Second Generation Drugs and Beyond

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Dr. Constantine Tam provides an overview of the current and emerging treatment landscape for chronic lymphocytic leukemia (CLL), with a focus on Bruton's tyrosine kinase (BTK) inhibitors like ibrutinib and the next generation of BTK inhibitors under development.

BTK Inhibitors in CLL: Second Generation Drugs and Beyond

Constantine S. Tam, MD, MBBS, presents the biomarker subgroup analysis from the phase 3 SEQUOIA study investigating zanubrutinib in treatment-naïve CLL/SLL.

Broad Superiority of Zanubrutinib Over Bendamustine + Rituximab Across Multiple High-Risk Factors: Biomarker Subgroup Analysis in the Phase 3 SEQUOIA Study in Patients With Treatment-Naive Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma Without del(17p)

Zanu is a Bruton tyrosine kinase (BTK) inhibitor with high potency, selectivity, and efficacy and a favorable toxicity profile.

In the phase 3 SEQUOIA study (NCT03336333; Tam et al. Lancet Oncol. 2022), zanu treatment demonstrated superior progression-free survival (PFS) in TN patients (pts) with CLL/SLL and without del(17p) (cohort 1) compared with BR treatment (hazard ratio [HR], 0.42; 95% CI, 0.28-0.63; 2-sided P<.0001).

We evaluated PFS in both treatment arms in pt subgroups based on various biomarkers, including several known negative prognostic factors for CLL.

A total of 479 pts in cohort 1 were randomized to either zanu (n=241) or BR (n=238).

Blood (CLL) or bone marrow (SLL) samples collected at screening were used for fluorescence in situ hybridization for chromosome abnormalities, cytogenetic analysis for complex karyotype (CK), next-generation sequencing (NGS) per the European Research Initiative on CLL (ERIC) for immunoglobulin heavy chain variable (IGHV) gene mutations and expressed clones, and ultrasensitive targeted NGS for mutation analysis of 106 genes.

For NGS, all pathogenic mutations with variant allele frequency ≥1% were analyzed. The association between biomarkers and PFS was quantified using the log-rank test and HR and summarized by the Kaplan-Meier method. Data cutoff was October 31, 2022.

Overall, the CLL features analyzed were similarly distributed between both treatment arms (Table).

In pts with cytogenetic abnormalities, zanu demonstrated significantly better PFS than BR in those with del(11q) (P<.001), del(13q) (P<.001), trisomy 12 (P<.01), or CKT ≥3 (P<.01) (Table). Furthermore, zanu treatment conferred a similar PFS benefit to pts with the negative prognostic factor, del(11q) (P=.05) or intermediate prognostic factor, trisomy 12 (P=.40), compared to those without these abnormalities (Table). Notably, in the zanu arm, CKT ≥3 was not associated with worse PFS (P=.18; Table).

Pts with either mutated IGHV (mIGHV) or unmutated IGHV (uIGHV) in the zanu arm had significantly better PFS than pts in the BR arm (uIGHV: P<.0001; mIGHV: P<.01; Table); analysis was confirmed by an ERIC-certified provider. Furthermore, PFS was unaffected by IGHV mutational status in pts treated with zanu (P=.12). In pts with uIGHV, IGHV1-69 was the most prevalent expressed clone in both arms (zanu: 24.6% [31/126]; BR: 30.7% [39/127]). In the present study, pts with uIGHV harboring IGHV1-69 clones showed significantly better PFS with zanu vs BR (P<.0001).

Across all pts, the most frequently mutated genes were ATM (zanu: 11%; BR: 16%), SF3B1 (zanu: 17%; BR: 21%), NOTCH1 (zanu: 20%; BR: 20%), and BRAF (zanu: 11%; BR: 7%; Table). Pts with mutations associated with poor prognosis in CLL had significantly better PFS with zanu than with BR (eg, ATM [P=.02], BRAF [P=.01], NOTCH1 [P<.001], SF3B1 [P<.001]; Table). Furthermore, zanu-treated pts with or without mutations in ATM (P=.58), NOTCH1 (P=.38), and SF3B1 (P=.39) had similar PFS.

TN del(17p)-negative pts with CLL/SLL were evenly distributed between zanu and BR arms in SEQUOIA cohort 1 based on the biomarkers analyzed.

PFS in zanu-treated pts was superior to that of BR-treated pts in all biomarker subgroups analyzed, including some known negative prognostic markers in CLL such as del11q, CKT≥3, and uIGHV.

Importantly, within the zanu-treatment arm, pts with negative prognostic biomarkers showed comparable PFS benefit to pts without those markers.

Like with other BTK inhibitors, ibrutinib and acalabrutinib, IGHV mutational status did not affect PFS outcome (Bartosz et al. Hematology in Clinical Practice 2022). However, contrary to what has been reported for TN or relapsed/refractory pts treated with ibrutinib-based regimens, CKT ≥3 was not associated with worse PFS in zanubrutinib-treated patients (Rigolin et al. Blood. 2021; Thompson et al. Cancer. 2015). This study provides further evidence that zanu is a valuable first-line treatment option for pts with CLL/SLL.

Constantine S. Tam, MD, MBBS, presents the biomarker subgroup analysis from the phase 3 SEQUOIA study investigating zanubrutinib in patients with treatment-naïve chronic lymphocytic leukemia/small lymphocytic lymphoma without del(17p).

Treatment of B-cell malignancies has been improved by effective inhibitors of B-cell receptor signaling, such as the first-generation BTK inhibitor, ibrutinib

Although ibrutinib has demonstrated efficacy, it has been associated with an increased risk of cardiovascular toxicities such as atrial fibrillation/flutter (Afib)2-5 and ventricular arrhythmias (VA)

Zanubrutinib is an irreversible, potent, next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition-related toxicities

Zanubrutinib has been generally well tolerated, with an established efficacy reported in clinical trials in patients with B-cell malignancies

Here, we report the occurrence of Afib and symptomatic idiopathic VA (IVA; defined as a VA occurring in structurally normal hearts in the absence of myocardial scarring and active infections) in the 2 head-to-head trials of zanubrutinib vs ibrutinib, ASPEN (NCT03053440) and ALPINE (NCT03734016), and a larger pooled analysis of zanubrutinib studies

Safety data reported by investigators from clinical studies of zanubrutinib were pooled and descriptively analyzed

Event rates and exposure-adjusted incidence rates (EAIR) of Afib and IVA with zanubrutinib vs ibrutinib were calculated in a post hoc analysis of the phase 3 clinical studies ASPEN(cohort 1) and ALPINEand in a pooled analysis of 10 clinical studies of zanubrutinib in patients with B-cell malignancies

The primary analysis was to compare EAIR between ibrutinib and zanubrutinib, with P values of the comparison calculated based on asymptotic normal distribution

Medical history of Afib and cardiovascular disorders (i.e. VA or HTN) was assessed at the time of enrollment and before treatment with zanubrutinib or ibrutinib using MedDRA v24.0

Afib included atrial fibrillation and atrial flutter events; VA included any event in SMQs of ventricular tachyarrhythmias (narrow) and MedDRA HLT of ventricular arrhythmias and cardiac arrest; cases were adjudicated to include IVA

Afib and VA events that occurred during treatment were graded by CTCAE (v5.0 in the LTE1 study and v4.03 in all other studies); symptomatic VAs were grade ≥2 VA events per CTCAE

In the pooled analyses, 1550 patients received zanubrutinib as monotherapy for the treatment of B-cell malignancies, with the largest subgroup being individuals with CLL/SLL (61%; 938/1550 patients)

Median age was 67 years, with 61% of patients aged at least 65 years

Most patients were men (66%), White (67%), and had an ECOG performance status of 0 or 1 (44.5% and 49.4%, respectively)

Despite the similar proportion of patients with a medical history of Afib in the zanubrutinib arm compared with the ibrutinib arm in ASPEN (cohort 1) or ALPINE, respectively, the rate of treatment-emergent Afib events was approximately 4-fold lower with zanubrutinib than ibrutinib

In cohort 1 of ASPEN, the rate of Afib events was lower with zanubrutinib (5.9%; 6/101) than ibrutinib (22.4%; 22/98)

In ALPINE, Afib rates during the study were lower with zanubrutinib (1.9%; 6/324) compared with ibrutinib (8.0%; 26/324)

The EAIR of Afib was significantly lower with zanubrutinib than ibrutinib in both studies (

< 0.05); zanubrutinib Afib EAIR in the pooled analysis were comparable to those observed in ASPEN and ALPINE

Symptomatic IVA was reported in 0.3% (5/1550) of patients treated with zanubrutinib vs 1.4% (6/422) with ibrutinib

In the ALPINE study, 0.6% (2/324) vs 1.5% (5/324) of patients reported AEs of symptomatic IVA with zanubrutinib vs ibrutinib, respectively

No events of symptomatic IVA were reported in the zanubrutinib arm of the ASPEN study; one event was observed in the ibrutinib arm

The EAIR of symptomatic IVA was lower with zanubrutinib (0.43 per 100 person-years) vs ibrutinib (1.19 per 100 person-years) in the ALPINE study (P = 0.2270) and in the pooled analysis for zanubrutinib (0.14 per 100 person-years) vs ibrutinib (0.87 per 100 person-years; P = 0.0028) in the pooled analysis.

Across the pooled populations, symptomatic IVA led to discontinuation in 0.06% (1/1550) of patients treated with zanubrutinib and 0.5% (2/422) of patients treated with ibrutinib

No deaths due to symptomatic IVA occurred with zanubrutinib, and one death occurred with ibrutinib

The EAIR of Afib in the ASPEN cohort 1 (P = 0.0010) and ALPINE (P = 0.0003) studies were significantly lower for zanubrutinib than ibrutinib, and consistent with the rates in the pooled analysis of patients with B-cell malignancies treated with zanubrutinib

EAIR of symptomatic IVA was significantly lower with zanubrutinib than ibrutinib in the pooled populations (P = 0.0028) and numerically lower in the ALPINE study (P = 0.2270)

The EAIR of symptomatic IVA with zanubrutinib in ALPINE was low (0.4 per 100 person-years), but the EAIR with ibrutinib was consistent with that of previous reports (1.2 per 100 person-years)

The data from the 2 head-to-head studies comparing zanubrutinib with ibrutinib in patients with CLL or WM, as well as pooled data presented here, demonstrate that the rates of Afib and symptomatic IVA with zanubrutinib are overall low and occur less frequently compared with ibrutinib therapy.

Our findings support the use of zanubrutinib as a treatment option for patients with B-cell malignancies.


Tam CS, Wallis N, Zhang M et al. Rate of Atrial Fibrillation in Patients With B-Cell Malignancies Who Undergo Treatment with Zanubrutinib Poster presented at: 2022 Lymphoma, Leukemia, Myeloma, October 18-21, 2022; Abstract 1324736.

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Dr Tam reviews the risk of atrial fibrillation along with other cardiovascular events in patients who either receive ibrutinib or zanubrutinib for b-cell malignancies.

Rate of Atrial Fibrillation in Patients With B-Cell Malignancies Who Undergo Treatment With Zanubrutinib

Constantine S. Tam, MD, MBBS, associate professor, Peter MacCallum Cancer Centre, discusses the 3 FDA approved BTK inhibitors in hematologic malignancies: ibrutinib (Imbruvica), acalabrutinib (Calquence), and zanubrutinib (Brukinsa).

Ibrutinib, acalabrutinib, and zanubrutinib all target BTK in the same place and bond and disable BTK irreversibly, but the drugs differ in the specificity of targeting, explains Tam. Ibrutinib targets related enzymes including BTK, ITK, TAG, and EGFR, which may explain many of the adverse events (AEs) associated with ibrutinib, says Tam.

In comparison, acalabrutinib and zanubrutinib also do not solely target BTK. Comparatively across clinical trials, none of them head-to-head, it appears acalabrutinib and zanubrutinib are associated with reductions in select AEs, including bleeding, atrial fibrillation, myalgias, and arthralgias, suggesting that these targeted drugs may have more activity, according to Tam.

Another major difference between the 3 BTK inhibitors is drug penetration. With zanubrutinib, high drug levels are achieved with the current levels of dosing, which are around 6 to 10 times higher in drug exposure compared with acalabrutinib or ibrutinib, says Tam. The hope is higher drug levels will mean better clinical responses for patients, concludes Tam.

Constantine S. Tam, MD, MBBS, discusses the 3 FDA approved BTK inhibitors in hematologic malignancies: ibrutinib, acalabrutinib, and zanubrutinib.

Dr. Tam on FDA Approved BTK Inhibitors in Hematologic Malignancies

Constantine S. Tam, MD, MBBS, associate professor, Peter MacCallum Cancer Centre, discusses the FDA approval of zanubrutinib (Brukinsa) in mantle cell lymphoma (MCL).

In November 2019, the FDA granted an accelerated approval to zanubrutinib capsules for the treatment of adult patients with MCL who have received ≥1 prior therapy, explains Tam.

The approval is based on 2 single-arm studies that showed high response rates with the BTK inhibitor. In the open-label, multicenter, phase II BGB-3111-206 trial (NCT03206970) conducted in China, the complete response rate was 59%, which was substantially higher than reports for ibrutinib, Tam concludes.

Constantine S. Tam, MD, MBBS, discusses the FDA approval of zanubrutinib in mantle cell lymphoma.

Dr. Tam on Zanubrutinib Approval in MCL

Constantine S. Tam, MD, MBBS, associate professor, Peter MacCallum Cancer Centre, compares BTK inhibitors in mantle cell lymphoma (MCL).

For example, zanubrutinib in clinical use appears to have better tolerability compared with other BTK inhibitors, such as ibrutinib, explains Tam. Ongoing studies in other hematologic malignancies will further showcase the efficacy and safety of zanubrutinib in comparison to other BTK inhibitors.

The complete remission rates for zanubrutinib are encouraging, according to Tam, but since outcomes of zanubrutinib are being reported in 2 separate studies, it is difficult to compare definitively. Tam looks forward to seeing the long-term follow-up of zanubrutinib.

Constantine S. Tam, MD, MBBS, discusses a comparison of BTK inhibitors in mantle cell lymphoma.

Dr. Tam on Varying BTK Inhibitors in Mantle Cell Lymphoma

Constantine S. Tam, MD, MBBS, associate professor, Peter MacCallum Cancer Centre, discusses the results of the phase II CAPTIVATE study in chronic lymphocytic leukemia (CLL).

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Constantine S. Tam, MD, MBBS

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