Bruton’s tyrosine kinase (BTK) is involved in B-cell receptor signaling and is a critical therapeutic target in chronic lymphocytic leukemia (CLL). Acalabrutinib, an irreversible selective BTK inhibitor, has demonstrated clinical efficacy in relapsed CLL. Researchers presented preliminary results from an ongoing phase 1/2 study of acalabrutinib monotherapy in patients with previously untreated CLL.1 Patients with previously untreated CLL who met International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for treatment were eligible, irrespective of cytopenias. Patients received acalabrutinib, either 100 mg twice daily (n = 37) or 200 mg once daily (n = 37). Patients had a median age of 64 years (range, 48-85 years), bulky lymph nodes ≥5 cm (47%) and unmutated IGHV gene (57%). Responses were assessed per modified IWCLL criteria. Among 72 patients evaluable for response to acalabrutinib after median time on study of 11 months (range, 1-15 months), the overall response rate (ORR) was 96%. There were no complete responses. Partial response (PR) rate was 86%; PR + lymphocytosis (L), 10%; stable disease, 4%; progressive disease, 0%. Median time to PRL or better was 2 months (range, 2-8 months). Neither CLL progression nor Richter’s transformation has occurred. Median progression-free survival has not yet been reached. Although clinical activity was observed with both dose schedules of acalabrutinib, BTK occupancy was highest with twice-daily dosing (98% vs 93% predose at day 28). All patients had a rapid reduction in lymphadenopathy. Treatment-related lymphocytosis occurred in 53% of patients and resolved in 97% of these patients. In general, lymphocytosis peaked at a median of 1 week after starting acalabrutinib and resolved by a median of 7 weeks (range, 3-15 weeks). Acalabrutinib was well-tolerated; 97% of patients continue on the study drug. Most adverse events (AEs) were grade 1 or 2. The most common grade 1/2 AEs were headache (42%), diarrhea (35%), arthralgia (22%), contusion (18%), nausea (18%), and increased weight (18%). Grade 3/4 AEs that occurred in more than 2 patients were syncope (n = 2, both grade 3) and hypertension (n = 2, both grade 3). Severe events included 1 grade 5 event (pneumonia) and 1 grade 3 upper gastrointestinal bleed due to a gastric ulcer and aspirin use. Atrial fibrillation was not observed. Based on this phase 1/2 study in treatment-naïve patients with CLL, acalabrutinib therapy offers a favorable safety profile and high response rates that appear durable. A phase 3 trial comparing acalabrutinib, acalabrutinib + obinutuzumab, and obinutuzumab + chlorambucil in treatment-naïve CLL is now underway. 1. Wierda W, et al. EHA 2016. Abstract S431.