On the road to optimized BTK inhibition in CLL

In this issue of Blood, Byrd et al present the results of a pilot phase 1/2 trial assessing acalabrutinib in previously untreated patients with chronic lymphocytic leukemia (CLL).¹ 

Introduction of targeted, orally available small-molecule inhibitors ibrutinib, idelalisib, and venetoclax has radically changed the treatment landscape of CLL. The Bruton tyrosine kinase (BTK) inhibitor ibrutinib was the first of these agents to demonstrate hitherto unprecedented activity in patients with relapsed/refractory^2,3  and, subsequently, untreated CLL.^4,5  However, ibrutinib therapy may cause significant toxicity, such as atrial fibrillation, bleeding, or arterial hypertension, explained in part by off-target effects on kinases, such as epidermal growth factor receptor and interleukin-2–inducible T-cell kinase among others. These side effects can lead to discontinuation of ibrutinib in up to 21% patients.⁶  Acalabrutinib is a second-generation covalent BTK inhibitor designed to have more specific action against BTK with fewer off-target effects. Based on the randomized phase 3 trials ASCEND⁷  and ELEVATE-TN,⁸  which showed better efficacy than chemoimmunotherapy in significantly longer progression-free survival (PFS), acalabrutinib has been approved in the United States and European Union for treatment-naive as well as relapsed/refractory CLL (see table). Importantly, in indirect comparison with ibrutinib, acalabrutinib appears to have comparable efficacy but lower incidence of typical side effects associated with ibrutinib.

In the present study, Byrd et al report the long-term results of acalabrutinib monotherapy in 99 patients with previously untreated CLL (median age, 64 years; unmutated IGHV gene, 62%; and TP53 aberration, 18%.). The starting dose of acalabrutinib was 200 mg once daily (n = 37) or 100 mg twice daily (n = 62), and therapy continued until progression or unacceptable toxicity; twice daily dosing resulted in better trough BTK occupancy and was therefore selected for long-term therapy in all patients. Overall response rate was 97% (complete remissions, 7%); at the median of 53 months, 86% of patients continued to receive therapy, and the 4-year PFS rate was 96%. Acalabrutinib was generally well tolerated. The occurrence of grade ≥3 side effects of interest appears to be similar to the acalabrutinib arm in the ELEVATE-TN randomized trial: atrial fibrillation developed in 2%, bleeding in 3%, and infections in 15%.

This study is important for several reasons: first, 100 mg twice daily has been identified as the optimal acalabrutinib dosage for subsequent trials. Second, the results show excellent long-term efficacy of acalabrutinib in untreated CLL, with median follow-up almost twice that reported in the randomized ELEVATE-TN study. Third, it provides crucial data on the safety profile of acalabrutinib, which seems to be favorable compared with that of ibrutinib with regard to the typical off-target side effects (eg, atrial fibrillation or bleeding). Of note, the occurrence of second primary malignancies (SPMs) in this study was relatively high at 26%, compared with 9% in the ELEVATE-TN trial. However, 58% of the malignancies were nonmelanoma skin cancers, which are usually easily cured by surgery; grade ≥3 SPMs were reported in 5% of patients. Nevertheless, this finding certainly merits further exploration in larger trials, with longer follow-up and vigilance in routine practice. The only additional caveat of the study by Byrd et al appears to be a relatively vague indication of ineligibility for chemoimmunotherapy (CIT). This was defined as a patient’s refusal to undergo CIT or the patient’s comorbidity profile assessed by an investigator; however, comorbidities and creatinine clearance were not recorded, which makes the fitness and organ function of the study population less clearly defined for the purpose of comparison with other trials. Basic demographic data, efficacy, and safety of acalabrutinib vs ibrutinib in the first-line treatment of CLL are summarized in the table. It needs to be emphasized that, although the overall safety profile of acalabrutinib looks better than that of ibrutinib, it is the result of indirect cross-trial comparison with all of the well-known limitations, such as different trial populations, length of follow-up, and other factors. Therefore, it is essential to wait for the results of the randomized phase 3 ELEVATE-RR trial directly comparing acalabrutinib vs ibrutinib in previously treated CLL.¹⁰  In summary, Byrd et al have provided important data on the long-term efficacy and safety of acalabrutinib in the first-line therapy of CLL.