LAUSR

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