Background: In CLL pts treated with the Bruton tyrosine kinase (BTK) inhibitor IBR, the most common reason for discontinuation was adverse events (AEs; 50%-63%; Mato et al, 2018). This Phase 2 trial evaluated acalabrutinib, a highly selective, potent, covalent BTK inhibitor, in IBR-intolerant pts with R/R CLL. Methods: Pts with R/R CLL (≥1 prior therapy) who discontinued IBR due to Gr 3/4 AEs or persistent/recurrent Gr 2 AEs and had progressive disease (PD) after IBR discontinuation were eligible. Acalabrutinib was given at 100 mg BID PO in 28-d cycles until PD or unacceptable toxicity. The primary endpoint was overall response rate (ORR). Results: 60 pts were treated (median age 70 y [range 43-88]). Pt characteristics included bulky disease ≥5 cm (33%), Rai stage III/IV (47%), del17p (28%), del11q (23%) and unmutated IGHV (79%). 52/55 (95%) pts with available baseline samples were wild type for BTK and PLCG2. Median number of prior therapies was 2 (range 1-10). Median duration of prior IBR therapy was 6 mo (range <1-55); common AEs that led to IBR discontinuation were atrial fibrillation/flutter (25%), diarrhea (12%), arthralgia (10%) and rash (12%). At a median follow-up of 19 mo (range 1-31), 67% of pts remain on acalabrutinib; discontinuations were mostly due to PD (13%) and AEs (10%; pneumonia [n=2], diarrhea, headache, ascites, arthralgia, subdural hematoma [all n=1]). Efficacy outcomes are in the Table. Common AEs (any grade) were diarrhea (48%), headache (40%), contusion (35%) and dizziness (32%). Serious AEs (≥2 pts) were pneumonia (10%), anemia (3%) and syncope (3%). Atrial fibrillation occurred in 3 pts (5%; all Gr 1/2) and major hemorrhage in 2 (3%; Gr 3 hematuria and Gr 2 subdural hematoma). Gr 5 AEs were pneumonia (n=2), bronchopulmonary aspergillosis (n=1) and ventricular fibrillation (n=1), all considered not related to treatment. Conclusions: Acalabrutinib is tolerable and effective in IBR-intolerant pts, providing a viable strategy for continuing BTK inhibitor therapy. Clinical trial information: NCT02717611

PR = partial response; PRL = PR with lymphocytosis.