PMID- 31876911 OWN - NLM STAT- MEDLINE DCOM- 20201102 LR - 20210409 IS - 1528-0020 (Electronic) IS - 0006-4971 (Print) IS - 0006-4971 (Linking) VI - 135 IP - 15 DP - 2020 Apr 9 TI - Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results. PG - 1204-1213 LID - 10.1182/blood.2018884940 [doi] AB - Therapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13]) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade >/=3 AEs (occurring in >/=5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443. CI - (c) 2020 by The American Society of Hematology. FAU - Byrd, John C AU - Byrd JC AD - Comprehensive Cancer Center, The Ohio State University, Columbus, OH. FAU - Wierda, William G AU - Wierda WG AD - The University of Texas MD Anderson Cancer Center, Houston, TX. FAU - Schuh, Anna AU - Schuh A AD - Department of Oncology, University of Oxford, Oxford, United Kingdom. FAU - Devereux, Stephen AU - Devereux S AD - King's College Hospital, NHS Foundation Trust, London, United Kingdom. FAU - Chaves, Jorge M AU - Chaves JM AD - Northwest Medical Specialties, Tacoma, WA. FAU - Brown, Jennifer R AU - Brown JR AD - Dana-Farber Cancer Institute, Boston, MA. FAU - Hillmen, Peter AU - Hillmen P AD - St. James's University Hospital, Leeds, United Kingdom. FAU - Martin, Peter AU - Martin P AD - Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, NY. FAU - Awan, Farrukh T AU - Awan FT AD - Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX. FAU - Stephens, Deborah M AU - Stephens DM AD - Huntsman Cancer Institute, University of Utah, Salt Lake City, UT. FAU - Ghia, Paolo AU - Ghia P AD - Universita Vita-Salute San Raffaele, Milan, Italy. AD - Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy. FAU - Barrientos, Jacqueline AU - Barrientos J AD - School of Medicine, Hofstra/Northwell, Hempstead, NY. FAU - Pagel, John M AU - Pagel JM AD - Swedish Cancer Institute, Seattle, WA. FAU - Woyach, Jennifer A AU - Woyach JA AD - Comprehensive Cancer Center, The Ohio State University, Columbus, OH. FAU - Burke, Kathleen AU - Burke K AD - Oncology iMED, AstraZeneca, Boston, MA. FAU - Covey, Todd AU - Covey T AD - Acerta Pharma, a member of the AstraZeneca Group, South San Francisco, CA; and. FAU - Gulrajani, Michael AU - Gulrajani M AD - Acerta Pharma, a member of the AstraZeneca Group, South San Francisco, CA; and. FAU - Hamdy, Ahmed AU - Hamdy A AD - Acerta Pharma, a member of the AstraZeneca Group, South San Francisco, CA; and. FAU - Izumi, Raquel AU - Izumi R AD - Acerta Pharma, a member of the AstraZeneca Group, South San Francisco, CA; and. FAU - Frigault, Melanie M AU - Frigault MM AD - Acerta Pharma, a member of the AstraZeneca Group, South San Francisco, CA; and. FAU - Patel, Priti AU - Patel P AD - Acerta Pharma, a member of the AstraZeneca Group, South San Francisco, CA; and. FAU - Rothbaum, Wayne AU - Rothbaum W AD - Acerta Pharma, a member of the AstraZeneca Group, South San Francisco, CA; and. FAU - Wang, Min Hui AU - Wang MH AD - Acerta Pharma, a member of the AstraZeneca Group, South San Francisco, CA; and. FAU - O'Brien, Susan AU - O'Brien S AD - Chao Family Comprehensive Cancer Center, UC Irvine Health, University of California, Irvine, CA. FAU - Furman, Richard R AU - Furman RR AD - Weill Cornell Medicine, NewYork-Presbyterian Hospital, New York, NY. LA - eng SI - ClinicalTrials.gov/NCT02029443 GR - R35 CA197734/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase I PT - Clinical Trial, Phase II PT - Journal Article PT - Multicenter Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Blood JT - Blood JID - 7603509 RN - 0 (Antineoplastic Agents) RN - 0 (Benzamides) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazines) RN - EC 2.7.10.2 (Agammaglobulinaemia Tyrosine Kinase) RN - EC 2.7.10.2 (BTK protein, human) RN - I42748ELQW (acalabrutinib) SB - IM MH - Adult MH - Agammaglobulinaemia Tyrosine Kinase/*antagonists & inhibitors MH - Aged MH - Aged, 80 and over MH - Antineoplastic Agents/adverse effects/*therapeutic use MH - Benzamides/adverse effects/*therapeutic use MH - Female MH - Humans MH - Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy MH - Male MH - Middle Aged MH - Neoplasm Recurrence, Local/*drug therapy MH - Protein Kinase Inhibitors/adverse effects/*therapeutic use MH - Pyrazines/adverse effects/*therapeutic use MH - Treatment Outcome PMC - PMC7146022 COIS- Conflict-of-interest disclosure: J.C.B. has received research funding from Acerta Pharma, Genentech, Janssen, and Pharmacyclics, and is a consultant (<$5000) for Acerta Pharma, Pharmacyclics, and Jazz Pharmaceuticals. W.G.W. has been a consultant for, and has received honoraria from, AbbVie, Celgene, Emergent, Genentech/Roche, Genzyme, Gilead, GlaxoSmithKline/Novartis, Sanofi, Merck, and Pharmacyclics; and has received research funding from Acerta Pharma, AbbVie, Emergent, Genentech, Gilead, GlaxoSmithKline/Novartis, Janssen, Juno, Karyopharm, Kite, and Pharmacyclics. A.S. has been a consultant for and has received honoraria from AbbVie, Gilead, GlaxoSmithKline, Janssen, Novartis, and Roche. S.D. has been a consultant for AbbVie, Gilead, GlaxoSmithKline, Janssen, MSD, and Roche; has received honoraria from AbbVie, Gilead, Janssen, and MSD; has received travel expenses from Gilead, Janssen, and Roche; is a member of speakers' bureaus for Gilead and Janssen; and is on an advisory board for Servier. J.M.C. is an employee of Northwest Medical Specialties, PLLC. J.R.B. has been a consultant for AbbVie, Astellas Pharma, AstraZeneca, BeiGene, Loxo, Sunesis, Celgene, TG Therapeutics, Gilead, Verastem Pharmaceuticals, Janssen, Pfizer, Pharmacyclics, Redx, Roche/Genentech, and Sun BioPharma; has received research funding from Gilead, Verastem, Loxo, and Sun; and serves on a data safety monitoring board for Morphosys and Invacs. P.H. has been a consultant for and has received honoraria from AbbVie, Acerta Pharma, Alexion Pharmaceuticals, Gilead, and Janssen; and his institution has received research funding from AbbVie, Gilead, Janssen, GlaxoSmithKline, Pharmacyclics, and Roche. P.M. has been a consultant for Bayer, Genentech, Gilead, Janssen/Pharmacyclics, Novartis, and Verastem; and has received research funding from Celgene and Teva. F.T.A. has been a consultant for AbbVie, Janssen, Gilead, AstraZeneca, Sunesis, Genentech, Celgene, Blueprint Medicines, and Pharmacyclics; has received research funding from Innate Pharma and Pharmacyclics; and has served on speakers' bureaus for AbbVie and AstraZeneca. D.M.S. has received research funding from Acerta, Gilead, Karyopharm, and the Lymphoma Research Foundation. P.G. has been a consultant for AbbVie, Acerta Pharma, AstraZeneca, Adaptive, ArQule, BeiGene, Dynamo, Gilead, Janssen, and Sunesis; and has received research funding from AbbVie, Gilead, Janssen, Novartis, and Sunesis. J.B. has served as a board or advisory committee member for AbbVie/Pharmacyclics, Gilead, and Janssen; and has received research funding from AbbVie/Pharmacyclics, Acerta Pharma, and Gilead. J.M.P. has been a consultant for Gilead and Pharmacyclics, and has equity ownership in and has received research funding from Actinium Pharmaceuticals, Inc. J.A.W. has been a consultant for Janssen, and received research funding from Acerta, AbbVie, Karyopharm, and Morphosys. P.P. is a current employee of and has equity ownership in Acerta Pharma; and has equity ownership in AstraZeneca. A.H., R.I., T.C., and M.G. are employees of, have equity ownership in, and hold related patents with Acerta Pharma. M.M.F. is an employee of, patent holder with, and equity owner of AstraZeneca. K.B. is an employee and equity owner of AstraZeneca. W.R. has equity ownership in, holds related patents with, and serves on the board of directors of Quogue BioVentures II LLC. M.H.W. is an employee of and has equity ownership in Acerta Pharma; and has equity ownership in AstraZeneca. S.O. has been a consultant for Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc, Vaniam Group LLC, AbbVie, and Alexion; has received research support from Kite Pharma, Regeneron, and Acerta Pharma; and has been a consultant for and received research support from Gilead, Pharmacyclics, TG Therapeutics, Pfizer, and Sunesis. R.R.F. has been a consultant for AbbVie, Acerta Pharma, AstraZeneca, BeiGene, Celgene, Gilead, TG Therapeutics, Verastem Pharmaceuticals, Janssen, Pfizer, Pharmacyclics, Roche/Genentech, Sunesis, and Loxo Pharmaceuticals; has served on the data safety monitoring boards of Incyte; has received research funding from Acerta Pharma, TG Therapeutics, Verastem, and Celgene; and has received speaker fees from Janssen. EDAT- 2019/12/27 06:00 MHDA- 2020/11/03 06:00 PMCR- 2021/04/09 CRDT- 2019/12/27 06:00 PHST- 2018/11/07 00:00 [received] PHST- 2019/10/23 00:00 [accepted] PHST- 2019/12/27 06:00 [pubmed] PHST- 2020/11/03 06:00 [medline] PHST- 2019/12/27 06:00 [entrez] PHST- 2021/04/09 00:00 [pmc-release] AID - S0006-4971(20)62113-9 [pii] AID - 2020/884940 [pii] AID - 10.1182/blood.2018884940 [doi] PST - ppublish SO - Blood. 2020 Apr 9;135(15):1204-1213. doi: 10.1182/blood.2018884940.