Second-Generation Bruton's Tyrosine Kinase Inhibitors: Simply the Best Treatments for Chronic Lymphocytic Leukemia?

Ibrutinib is the oral, covalently binding inhibitor of Bruton's tyrosine kinase (BTK) that revolutionized therapy for patients with chronic lymphocytic leukemia (CLL).2][3] For a period, ibrutinib was considered optimal therapy for many patients with CLL.As ibrutinib is intended to be taken continuously for an indefinite period, tolerability of the drug is quite important.With longer follow-up, notable toxicities were documented for patients with CLL, including atrial fibrillation (11%-16%) and hypertension (20%-26%). 1,2Toxicities were cited as the cause of ibrutinib discontinuation in up to 28% of patients in phase III studies. 1 With the goals of maintaining the efficacy seen with ibrutinib but reducing toxicity through more selective BTK inhibition, second-generation BTK inhibitors were developed.Acalabrutinib is an oral covalently binding BTK inhibitor that is approved by the US Food and Drug Administration (FDA) for marketing in the treatment of CLL.This approval was based on acalabrutinib's ability to prolong progression-free survival (PFS) when compared with standard chemoimmunotherapy regimens in phase III studies. 4,5Acalabrutinib discontinuations because of toxicity were only seen in up to 11% of patients in these studies. 4,5It was hypothesized that acalabrutinib would have similar efficacy and less toxicity to ibrutinib.Therefore, a direct head-to-head comparison was undertaken.In the article accompanying this editorial, ELEVATE RR study is a phase III, randomized, open-label, noninferiority study with a primary end point of independent review committee-assessed noninferiority of PFS between acalabrutinib and ibrutinib. 6The study enrolled 533 patients with previously treated CLL and prognostic factors of del(17p) (45%) and/or del(11q) (64%), which were both considered high-risk factors at the time of study design [Del(11q) has since been associated with favorable prognosis in the setting of ibrutinib therapy. 7] After a median follow-up 41 months, acalabrutinib was found to be noninferior to ibrutinib with median PFS of 38.4 months in both arms (hazard ratio, 1.00).As anticipated, toxicities were experienced less by patients receiving acalabrutinib, including diarrhea, arthralgia, bruising, muscle spasm, and dyspepsia.Especially notable, atrial fibrillation and hypertension occurred less frequently with acalabrutinib.