As the first Bruton’s tyrosine kinase (BTK) inhibitor approved by the US Food and Drug Administration as a first-line therapy for chronic lymphocytic leukemia (CLL), ibrutinib has transformed the landscape of CLL treatment. However, patients may develop resistance to covalent BTK inhibitors, and a substantial number of patients have experienced adverse events (AEs) that contributed to high rates of treatment discontinuation (30%-60%) in ibrutinib studies.1

AEs linked to ibrutinib included hypertension, cardiac arrythmia, and hemorrhage, many of which are attributable to the drug’s off-target inhibition of other kinases such as epidermal growth factor receptor (EGFR), interleukin-2-inducible T-cell kinase (ITK), and tyrosine protein kinase Tec (TEC).1

Further developments in the realm of BTK inhibitors have led to an additional approved therapy and several emerging contenders that may overcome some of the challenges associated with ibrutinib.

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With greater selectivity for BTK compared to ibrutinib, the covalent BTK inhibitor acalabrutinib is an effective FDA-approved therapy for CLL treatment that is not associated with inhibition of EGFR, ITK, or TEC and related off-target toxicities that can occur with ibrutinib.

The phase 3 ASCEND and ELEVATE-TN trials demonstrated greater progression-free survival (PFS) with acalabrutinib compared to chemoimmunotherapy in both relapsed or refractory (R/R) and treatment-naïve CLL patients.2,3 In the phase 3 ELEVATE-RR trial, acalabrutinib showed greater efficacy vs ibrutinib in R/R CLL patients with 17p and/or 11q deletion, with an overall response rate (ORR) of 81% vs 77%, respectively, and a median PFS of 38.4 with both therapies.4

AEs affected 68.8% of patients in the acalabrutinib group compared to 74.9% of those in the ibrutinib group, leading to discontinuation of treatment in 14.7% and 21.3% of patients, respectively. Roughly 30% of each group experienced grade 3 infections.4

In treatment-naïve patients, indirect comparisons suggest a lower risk of progression with acalabrutinib plus obinutuzumab compared to ibrutinib monotherapy and ibrutinib plus obinutuzumab. Ongoing studies are also exploring the use of other doublet or triplet acalabrutinib-based combinations, including acalabrutinib plus venetoclax and acalabrutinib plus venetoclax plus obinutuzumab or rituximab.1

Cardiovascular AEs were observed less frequently in the acalabrutinib vs ibrutinib group, including any-grade atrial fibrillation or atrial flutter (9.4% vs 16%), hypertension (25% vs 61%), and bleeding events (38% vs 51.3%).1


The covalent BTK inhibitor zanubrutinib demonstrated superiority to chemoimmunotherapy in treatment-naïve CLL patients in the SEQUOIA trial and interim results of the phase 3 ALPINE trial showed a significantly higher ORR with zanubrutinib vs ibrutinib (78.3% vs 62.5%) in patients with R/R CLL.5,6 The ORR for patients with 17p deletion was 83.3% in those treated with zanubrutinib and 53.8% in those treated with ibrutinib. The 12-month PFS was 94.9% with zanubrutinib vs 84% with ibrutinib, and no difference in overall survival (OS) was noted between groups.6

Although the zanubrutinib arm showed lower rates of AEs such as atrial fibrillation or flutter (2.5% vs 10.1%), grade 3 infections (12.7% vs 17.9%), major bleeding (2.9% vs 3.9%), and death (3.9% vs 5.8%), higher rates of neutropenia were observed with zanubrutinib vs ibrutinib (28.4% vs 21.7%). Treatment discontinuation due to AEs was noted in 7.8% of zanubrutinib-treated patients compared to 13% of ibrutinib-treated patients.6

Various studies have produced promising preliminary results with combination strategies such as zanubrutinib plus venetoclax, which showed an ORR of 96.8% after a median follow-up of 11.2 months in treatment-naïve CLL patients with 17p deletion. Grade 3 AEs occurred in 37.1% of patients.1

In patients treated with a combination of zanubrutinib, obinutuzumab, and venetoclax (BOVen), 89% reached undetectable minimal residual disease (uMRD) and were able to discontinue treatment after 10 months. The uMRD persisted in 94% of patients at 15.8 months post-treatment.1

With both of these combination therapies, neutropenia was the most common grade 3 adverse event, affecting 11.4% and 18% of patients, respectively.1

Favorable results have also been observed in phase 1 and phase 2 studies of other covalent BTK inhibitor candidates in R/R CLL, including orelabrutinib (showing an ORR of 93.8% and an estimated 30-month duration of response of 70.6%) and tirabrutinib (showing ORR of 83%, estimated median PFS of 38.5 months, and OS of 44.9 months with a median follow-up 32.5 months). Both therapies were associated with encouraging safety data.1