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Background: Bruton tyrosine kinase (BTK) is a critical component of B-cell receptor signaling pathway and a validated therapeutic target for CLL. Acalabrutinib is a highly selective, potent, covalent BTK inhibitor with minimal off-target activity that has been shown to have an overall response rate (ORR) of 95% (85% partial response [PR]; 10% PR with lymphocytosis [PRL]) after a median follow-up of 14.3 months in the relapsed CLL cohort of the Phase 1/2 ACE-CL-001 study. We present an updated analysis of the safety and efficacy results from the TN cohort of CLL patients from ACE-CL-001. Methods: Patients with TN CLL/small lymphocytic lymphoma (SLL) were eligible if they met International Workshop on Chronic Lymphocytic Leukemia (IWCLL) 2008 criteria for treatment, had an ECOG performance status of ≤2, and declined or were not appropriate candidates for chemotherapy. Patients received oral acalabrutinib 100 mg twice daily (BID) or 200 mg daily (patients were started on 200 mg QD and then switched to 100 mg BID) until progressive disease or unacceptable toxicity. Safety was the primary endpoint. Secondary endpoints were investigator-assessed overall response rate (ORR) by IWCLL 2008 criteria with modification for lymphocytosis, duration of response (DOR) and progression-free survival (PFS). Time to response (TTR; ≥ PR) and event-free survival (EFS) were exploratory endpoints. Results: A total of 99 patients (100 mg BID, n=62; 200 mg QD, n=37) were treated. The median age was 64 years (range 33-85), 46% of patients had bulky lymph nodes ≥5 cm, 47% had Rai stage III-IV disease at baseline, 10% (9/91) of patients had del(17p), and 62% (57/92) of patients had unmutated IGHV. As of December 1, 2017, the median time on study was 33 (1-39) months, with 91% of patients remaining on study treatment. Nine patients discontinued therapy: adverse events (n=5; 5%), pregnancy, disease progression, patient withdrawal, and initiation of subsequent therapy (n=1 each; 1%). The most common AEs (all grades; >20% of patients) were diarrhea (47%), headache (44%), contusion (34%), upper respiratory tract infection (33%), weight increase (30%), arthralgia (29%), nausea (26%), and cough (23%); the majority of these most common AEs were Grade 1/2. Grade 3/4 AEs occurred in 49% (49/99) of patients, most commonly (>2% of patients) neutropenia (7%), diarrhea (5%), headache (5%), nausea (4%), pneumonia (4%), hypertension (3%), and syncope (3%). Atrial fibrillation and hypertension (all grades vs grade 3/4) occurred in 6% vs 1% of patients and 14% vs 3% of patients, respectively. The most common bleeding events (>15%) were contusion (34%), petechiae (18%), and ecchymosis (16%); all bleeding events (60%) were Grade 1/2 except for 2 Grade 3 events (hematuria, upper gastrointestinal hemorrhage). Approximately 34% (34/99) of patients reported serious AEs (all grades), most commonly (≥5 patients) infection (pneumonia [4 patients], influenza [2 patients], and sinusitis [2 patients]). One grade 5 event (multiorgan failure due to neutropenic sepsis/pneumonia) was reported, which was considered unrelated to acalabrutinib. AEs leading to treatment discontinuation (5%) were secondary malignancies (angiosarcoma, glioblastoma multiforme, small cell lung cancer), neutropenic sepsis (Grade 2), rash (Grade 3), and urinary tract infection (Grade 3). ORR was high (97%) for this patient cohort (Table). Median DOR for the 96 responders (≥ PR) and median PFS for the 99 treated patients were not reached (NR) (95% CI: NR, NR; Figure 1). The 36-month DOR and PFS rate was 99% (95% CI: 91%, 100%) and 98% (95% CI: 92%, 100%), respectively. The EFS (with events defined as progression, death, discontinuation due to AE, or start of new anticancer therapy) was estimated to be 94.9% (95% CI: 88.2%, 97.9%) at 24 months (Figure 2). Median TTR was 3.7 months (range 2-22). For the 5 patients who achieved complete response (CR), the median time to CR was 28 months. One CLL progression was reported. No Richter's transformation occurred. Conclusion: Acalabrutinib monotherapy produced high response rates and demonstrated an acceptable safety profile in patients with TN CLL. Disclosures Furman: Gilead: Consultancy; Loxo Oncology: Consultancy; Acerta: Consultancy, Research Funding; Genentech: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy; Incyte: Consultancy, Other: DSMB; Janssen: Consultancy; AbbVie: Consultancy. Martin:Gilead: Consultancy; Janssen: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy; AstraZeneca: Consultancy; Kite: Consultancy. O'Brien:Janssen: Consultancy; GlaxoSmithKline: Consultancy; Acerta: Research Funding; Pfizer: Consultancy, Research Funding; Alexion: Consultancy; Pharmacyclics: Consultancy, Research Funding; Amgen: Consultancy; Sunesis: Consultancy, Research Funding; Celgene: Consultancy; Vaniam Group LLC: Consultancy; Astellas: Consultancy; Abbvie: Consultancy; Aptose Biosciences Inc.: Consultancy; Gilead: Consultancy, Research Funding; Kite Pharma: Research Funding; Regeneron: Research Funding; TG Therapeutics: Consultancy, Research Funding. Brown:Celgene: Consultancy; Verastem: Consultancy, Research Funding; Janssen: Consultancy; Genentech: Consultancy; Sunesis: Consultancy; Boehringer: Consultancy; Sun Pharmaceutical Industries: Research Funding; Gilead: Consultancy, Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees; Acerta / Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; TG Therapeutics: Consultancy; Roche/Genentech: Consultancy; Invectys: Membership on an entity's Board of Directors or advisory committees; Loxo: Consultancy. Barrientos:Pharmacyclics/Abbive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Devereux:Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Other: Personal fees. Hillmen:Novartis: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Alexion Pharmaceuticals, Inc: Consultancy, Honoraria; Acerta: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Research Funding; Gilead Sciences, Inc.: Honoraria, Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Pagel:Gilead: Consultancy; Pharmacyclics, an AbbVie Company: Consultancy. Chen:Acerta Pharma: Employment. Hamdy:Acerta Pharma: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: various patents for ACP-196. Izumi:Acerta Pharma: Employment, Equity Ownership, Patents & Royalties: Acerta Pharma, various patents for ACP-196. Patel:Acerta Pharma: Employment, Equity Ownership. Wang:Acerta Pharma: Employment. Jain:Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Research Funding; Pfizer: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Research Funding; Incyte: Research Funding; BMS: Research Funding; ADC Therapeutics: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Research Funding; BMS: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Infinity: Research Funding; Pfizer: Research Funding; Celgene: Research Funding; ADC Therapeutics: Research Funding; Astra Zeneca: Research Funding; Seattle Genetics: Research Funding; Servier: Research Funding; Verastem: Research Funding; Incyte: Research Funding; Cellectis: Research Funding; Celgene: Research Funding; Adaptive Biotechnologioes: Research Funding; Astra Zeneca: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Research Funding; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Research Funding; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologioes: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novimmune: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wierda:AbbVie, Inc: Research Funding; Genentech: Research Funding.