PURPOSE Acalabrutinib, a highly selective, potent, Bruton tyrosine kinase inhibitor, was evaluated in this global, multicenter, randomized, open-label, phase III study in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). METHODS Eligible patients, aged ≥ 18 years with R/R CLL, were randomly assigned 1:1 centrally and stratified by del(17p) status, Eastern Cooperative Oncology Group performance status score, and number of prior lines of therapy. Patients received acalabrutinib monotherapy or investigator’s choice (idelalisib plus rituximab [I-R] or bendamustine plus rituximab [B-R]). The primary end point was progression-free survival (PFS) assessed by an independent review committee (IRC) in the intent-to-treat population. Key secondary end points included IRC-assessed overall response rate, overall survival, and safety. RESULTS From February 21, 2017, to January 17, 2018, a total of 398 patients were assessed for eligibility; 310 patients were randomly assigned to acalabrutinib monotherapy (n = 155) or investigator’s choice (n = 155; I-R, n = 119; B-R, n = 36). Patients had received a median of two prior therapies (range, 1-10). After a median follow-up of 16.1 months (range, 0.03-22.4 months), median PFS was significantly longer with acalabrutinib monotherapy (PFS not reached) compared with investigator’s choice (16.5 months [95% CI, 14.0 to 17.1 months]; hazard ratio, 0.31 [95% CI, 0.20 to 0.49]; P < .0001). Estimated 12-month PFS was 88% (95% CI, 81% to 92%) for acalabrutinib and 68% (95% CI, 59% to 75%) for investigator’s choice. Serious adverse events occurred in 29% of patients (n = 44 of 154) treated with acalabrutinib monotherapy, 56% (n = 66 of 118) with I-R, and 26% (n = 9 of 35) with B-R. Deaths occurred in 10% (n = 15 of 154), 11% (n = 13 of 118), and 14% (n = 5 of 35) of patients receiving acalabrutinib monotherapy, I-R, and B-R, respectively. CONCLUSION Acalabrutinib significantly improved PFS compared with I-R or B-R and has an acceptable safety profile in patients with R/R CLL.

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Acalabrutinib is a Bruton tyrosine kinase inhibitor approved for patients with chronic lymphocytic leukemia (CLL). ASCEND is the pivotal phase 3 study of acalabrutinib versus investigator’s choice of idelalisib plus rituximab (IdR) or bendamustine plus rituximab (BR) in patients with relapsed/refractory (R/R) CLL. In the primary ASCEND analysis (median 16.1-month follow-up), acalabrutinib showed superior efficacy with an acceptable tolerability profile versus IdR/BR; here, we report final ~4 year follow-up results. Patients with R/R CLL received oral acalabrutinib 100 mg twice daily until progression or unacceptable toxicity, or investigator’s choice of IdR or BR. A total of 310 patients (acalabrutinib, n = 155; IdR, n = 119; BR, n = 36) were enrolled. At median follow-up of 46.5 months (acalabrutinib) and 45.3 months (IdR/BR), acalabrutinib significantly prolonged investigator-assessed progression-free survival (PFS) versus IdR/BR (median, not reached [NR] vs 16.8 months; P < 0.001); 42-month PFS rates were 62% (acalabrutinib) versus 19% (IdR/BR). Median overall survival (OS) was NR (both arms); 42-month OS rates were 78% (acalabrutinib) versus 65% (IdR/BR). Adverse events led to drug discontinuation in 23%, 67%, and 17% of patients in the acalabrutinib, IdR, and BR arms, respectively. Events of clinical interest (acalabrutinib vs IdR/BR) included all-grade atrial fibrillation/flutter (8% vs 3%), all-grade hypertension (8% vs 5%), all-grade major hemorrhage (3% vs 3%), grade ≥3 infections (29% vs 29%), and second primary malignancies excluding nonmelanoma skin cancer (7% vs 2%). At ~4 years follow-up, acalabrutinib maintained favorable efficacy versus standard-of-care regimens and a consistent tolerability profile in patients with R/R CLL.