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First Direct Comparison of Ibrutinib versus Acalabrutinib in Patients with Previously Treated CLL

Phase III study results point to noninferiority of acalabrutinib, while it provides improved safety in patients with previously treated chronic lymphocytic leukaemia
03 Aug 2021
Targeted Therapy

In an open-label, randomised, prospective phase III study a next-generation, irreversible Bruton's tyrosine kinase (BTK) inhibitor, acalabrutinib demonstrated similar efficacy and improved safety with fewer atrial fibrillation events and discontinuations because of adverse events than ibrutinib in patients with previously treated chronic lymphocytic leukaemia (CLL). The findings from the first direct comparative phase III study of ibrutinib with acalabrutinib in CLL were published by Prof. John Byrd of The Ohio State University Comprehensive Cancer Center in Columbus, OH, US and colleagues on 26 July 2021 in the Journal of Clinical Oncology.

BTK plays a significant role in survival, proliferation, and adhesion of malignant B lymphocytes in CLL. BTK inhibitors have transformed CLL management. However, a systematic review and meta-analysis of randomised studies with ibrutinib demonstrated an increased risk of atrial fibrillation and hypertension. 

Although the cause of cardiac events with ibrutinib is not completely understood, rodent studies have suggested that off-target inhibition of the PI3K-Akt signalling pathway or C-terminal Src kinase may contribute. In addition, ibrutinib inhibits human epidermal growth factor receptor 2, which is involved in cardiac myocyte homeostasis. Ibrutinib binds irreversibly to Src kinase and to several non-BTK kinases with analogous cysteine residues at low nanomolar concentrations, which is not seen with acalabrutinib, likely contributing to alternative target adverse events with ibrutinib.

Among BTK inhibitors, acalabrutinib has greater selectivity than ibrutinib, which the study investigators hypothesized would improve continuous therapy tolerability. They randomly assigned patients with previously treated CLL with centrally confirmed del(17)(p13.1) or del(11)(q22.3) to oral acalabrutinib 100 mg twice daily or ibrutinib 420 mg once daily until progression or unacceptable toxicity.

The primary endpoint of the study was noninferiority of progression-free survival (PFS) assessed by independent review committee.

In total, 533 patients were randomly assigned to either acalabrutinib (n = 268) or ibrutinib (n = 265). At the data cut-off, 124 (46.3%) patients treated with acalabrutinib and 109 (41.1%) patients treated with ibrutinib remained on treatment.

After a median follow-up of 40.9 months, acalabrutinib was determined to be noninferior to ibrutinib with a median PFS of 38.4 months in both arms (95% confidence interval [CI] acalabrutinib, 33.0 to 38.6 and ibrutinib, 33.0 to 41.6; hazard ratio 1.00; 95% CI 0.79 to 1.27).

All-grade atrial fibrillation/atrial flutter incidence was significantly lower with acalabrutinib versus ibrutinib (9.4% v 16.0%; p = 0.02). Among other selected secondary endpoints, grade 3 or higher infections (30.8% v 30.0%) and Richter transformations (3.8% v 4.9%) were comparable between groups.

Median overall survival was not reached in either arm (hazard ratio 0.82; 95% CI 0.59 to 1.15), with 63 (23.5%) deaths with acalabrutinib and 73 (27.5%) with ibrutinib.

Treatment discontinuations because of adverse events occurred in 14.7% of patients treated with acalabrutinib and 21.3% of patients treated with ibrutinib.

The authors concluded that in this first direct comparison of less versus more selective BTK inhibitors in CLL, acalabrutinib demonstrated noninferior PFS with fewer cardiovascular adverse events.

Dr. Deborah M. Stephens, DO of the Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute at the University of Utah in Salt Lake City, UT, US wrote in an accompanied editorial that management of atrial fibrillation not only involves rate control, but also prophylactic anticoagulation. Ibrutinib has been associated with bleeding of any grade in approximately 40% of patients. It is strongly recommended not to use warfarin in combination with ibrutinib. 

In the ELEVATE RR study, all-grade bleeding events were experienced less frequently in patients receiving acalabrutinib compared with ibrutinib. Warfarin use was an exclusion criterion for this study, but the reduced risk of bleeding seen with acalabrutinib makes this a slightly safer choice for patients who need other anticoagulants secondary to atrial fibrillation or other causes.

The incidence of hypertension was lower in patients receiving acalabrutinib versus ibrutinib. Hypertension is a particularly important toxicity to avoid as ibrutinib-related hypertension has been associated with increased rates of morbidity and mortality.

Dr. Stephens commented that the list of efficacious and tolerable drugs for the treatment of CLL continues to grow. The ongoing ALPINE study is a similar comparison of zanubrutinib and ibrutinib in patients with relapsed or refractory CLL.

The study was supported by the US National Cancer Institute, Four Winds Foundation, Sullivan CLL Foundation, and the D. Warren Brown Foundation.


Byrd JC, Hillmen P, Ghia P, et al. Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. JCO; Published online 26 July 2021. DOI: 10.1200/JCO.21.01210

Stephens DM. Second-Generation Bruton's Tyrosine Kinase Inhibitors: Simply the Best Treatments for Chronic Lymphocytic Leukemia? JCO; Published online 26 July 2021. DOI: 10.1200/JCO.21.01414

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