PMID- 31512258
OWN - NLM
STAT- MEDLINE
DCOM- 20200413
LR  - 20211204
IS  - 1096-8652 (Electronic)
IS  - 0361-8609 (Print)
IS  - 0361-8609 (Linking)
VI  - 94
IP  - 12
DP  - 2019 Dec
TI  - Final analysis from RESONATE: Up to six years of follow-up on ibrutinib in 
      patients with previously treated chronic lymphocytic leukemia or small 
      lymphocytic lymphoma.
PG  - 1353-1363
LID - 10.1002/ajh.25638 [doi]
AB  - Ibrutinib, a once-daily oral inhibitor of Bruton's tyrosine kinase, is approved 
      in the United States and Europe for treatment of patients with chronic 
      lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL). The phase 3 
      RESONATE study showed improved efficacy of single-agent ibrutinib over ofatumumab 
      in patients with relapsed/refractory CLL/SLL, including those with high-risk 
      features. Here we report the final analysis from RESONATE with median follow-up 
      on study of 65.3 months (range, 0.3-71.6) in the ibrutinib arm. Median 
      progression-free survival (PFS) remained significantly longer for patients 
      randomized to ibrutinib vs ofatumumab (44.1 vs 8.1 months; hazard ratio [HR]: 
      0.148; 95% confidence interval [CI]: 0.113-0.196; P<.001). The PFS benefit with 
      ibrutinib vs ofatumumab was preserved in the genomic high-risk population with 
      del(17p), TP53 mutation, del(11q), and/or unmutated IGHV status (median PFS 44.1 
      vs 8.0 months; HR: 0.110; 95% CI: 0.080-0.152), which represented 82% of 
      patients. Overall response rate with ibrutinib was 91% (complete 
      response/complete response with incomplete bone marrow recovery, 11%). Overall 
      survival, censored for crossover, was better with ibrutinib than ofatumumab (HR: 
      0.639; 95% CI: 0.418-0.975). With up to 71 months (median 41 months) of ibrutinib 
      therapy, the safety profile remained consistent with prior reports; cumulatively, 
      all-grade (grade >/=3) hypertension and atrial fibrillation occurred in 21% (9%) 
      and 12% (6%) of patients, respectively. Only 16% discontinued ibrutinib because 
      of adverse events (AEs). These long-term results confirm the robust efficacy of 
      ibrutinib in relapsed/refractory CLL/SLL irrespective of high-risk clinical or 
      genomic features, with no unexpected AEs. This trial is registered at 
      www.clinicaltrials.gov (NCT01578707).
CI  - (c) 2019 The Authors. American Journal of Hematology published by Wiley 
      Periodicals, Inc.
FAU - Munir, Talha
AU  - Munir T
AUID- ORCID: 0000-0002-2901-0769
AD  - Department of Haematology, St. James's University Hospital, Leeds, UK.
FAU - Brown, Jennifer R
AU  - Brown JR
AD  - CLL Center, Dana-Farber Cancer Institute, Boston, Massachusetts.
FAU - O'Brien, Susan
AU  - O'Brien S
AUID- ORCID: 0000-0002-2481-7504
AD  - UC Irvine, Chao Family Comprehensive Cancer Center, Irvine, California.
FAU - Barrientos, Jacqueline C
AU  - Barrientos JC
AD  - Division of Medical Oncology and Hematology Northwell Health Cancer Institute, 
      Lake Success, New York.
FAU - Barr, Paul M
AU  - Barr PM
AD  - Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New 
      York.
FAU - Reddy, Nishitha M
AU  - Reddy NM
AD  - Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
FAU - Coutre, Steven
AU  - Coutre S
AD  - Stanford Cancer Center, Stanford University School of Medicine, Stanford, 
      California.
FAU - Tam, Constantine S
AU  - Tam CS
AD  - Peter MacCallum Cancer Centre, St. Vincent's Hospital and University of 
      Melbourne, Melbourne, Australia.
FAU - Mulligan, Stephen P
AU  - Mulligan SP
AD  - Royal North Shore Hospital, Sydney, Australia.
FAU - Jaeger, Ulrich
AU  - Jaeger U
AD  - Division of Hematology and Hemostaseology, Medical University of Vienna, Wien, 
      Austria.
FAU - Kipps, Thomas J
AU  - Kipps TJ
AD  - UCSD Moores Cancer Center, San Diego, California.
FAU - Moreno, Carol
AU  - Moreno C
AUID- ORCID: 0000-0003-3275-0271
AD  - Hospital de la Santa Creu i Sant Pau, Autonomous University of Barcelona, 
      Barcelona, Spain.
FAU - Montillo, Marco
AU  - Montillo M
AD  - Niguarda Ca' Granda Hospital, Milan, Italy.
FAU - Burger, Jan A
AU  - Burger JA
AD  - Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, 
      Texas.
FAU - Byrd, John C
AU  - Byrd JC
AD  - The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
FAU - Hillmen, Peter
AU  - Hillmen P
AD  - The Leeds Teaching Hospitals, St. James Institute of Oncology, Leeds, UK.
FAU - Dai, Sandra
AU  - Dai S
AD  - Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California.
FAU - Szoke, Anita
AU  - Szoke A
AD  - Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California.
FAU - Dean, James P
AU  - Dean JP
AD  - Pharmacyclics LLC, an AbbVie Company, Sunnyvale, California.
FAU - Woyach, Jennifer A
AU  - Woyach JA
AD  - The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
LA  - eng
SI  - ClinicalTrials.gov/NCT01578707
GR  - R35 CA197734/CA/NCI NIH HHS/United States
GR  - Janssen Pharmaceuticals/International
GR  - Pharmacyclics LLC, an AbbVie Company/International
PT  - Clinical Trial, Phase III
PT  - Comparative Study
PT  - Journal Article
PT  - Multicenter Study
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20191013
PL  - United States
TA  - Am J Hematol
JT  - American journal of hematology
JID - 7610369
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents, Immunological)
RN  - 0 (Piperidines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - 0 (Pyrazoles)
RN  - 0 (Pyrimidines)
RN  - 1X70OSD4VX (ibrutinib)
RN  - JAC85A2161 (Adenine)
RN  - M95KG522R0 (ofatumumab)
SB  - IM
CIN - Am J Hematol. 2019 Dec;94(12):1303-1305. PMID: 31621103
MH  - Adenine/analogs & derivatives
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antibodies, Monoclonal, Humanized/therapeutic use
MH  - Antineoplastic Agents, Immunological/therapeutic use
MH  - Cardiovascular Diseases/chemically induced
MH  - Female
MH  - Follow-Up Studies
MH  - Hematologic Diseases/chemically induced
MH  - Humans
MH  - Infections/etiology
MH  - Kaplan-Meier Estimate
MH  - Leukemia, Lymphocytic, Chronic, B-Cell/*drug therapy/genetics
MH  - Male
MH  - Middle Aged
MH  - Piperidines
MH  - Progression-Free Survival
MH  - Protein Kinase Inhibitors/adverse effects/*therapeutic use
MH  - Pyrazoles/adverse effects/*therapeutic use
MH  - Pyrimidines/adverse effects/*therapeutic use
MH  - Remission Induction
MH  - Risk
MH  - *Salvage Therapy
MH  - Treatment Outcome
PMC - PMC6899718
COIS- T.M. has received honoraria from Janssen, AbbVie, Gilead, Alexion, Novartis, and 
      Roche; and has been in a consulting role for MorphoSys and Sunesis. J.R.B. has 
      received honoraria from Janssen and Teva; has been in a consulting role for 
      AbbVie, Acerta, Astellas, BeiGene, Genentech/Roche, Gilead, Juno/Celgene, Kite, 
      Loxo, Novartis, Pfizer, Pharmacyclics LLC, an AbbVie Company, Redx, Sun, Sunesis, 
      TG Therapeutics, and Verastem; has received research funding from Gilead, Loxo, 
      Sun, and Verastem; and has served on data safety monitoring committees for 
      MorphoSys and Invectys. S.O. has been in a consulting role for Amgen, Astellas, 
      Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences, Vaniam Group, 
      AbbVie, Alexion, Verastem, and Eisai; has received research funding from Kite, 
      Regeneron, and Acerta; and has been in a consulting role and received research 
      funding from Gilead, Pharmacyclics LLC, an AbbVie Company, TG Therapeutics, 
      Pfizer, and Sunesis. J.C.Ba. has received honoraria from Janssen; has been in a 
      consulting role for Genentech, Gilead, Bayer, Pharmacyclics LLC, an AbbVie 
      Company, AbbVie, AstraZeneca, and Sandoz; and has received research funding from 
      Pharmacyclics LLC, an AbbVie Company, Oncternal Therapeutics, and AbbVie. P.M.B. 
      has been in a consulting role for Pharmacyclics LLC, an AbbVie Company, and 
      AbbVie, and has received research funding from Pharmacyclics LLC, an AbbVie 
      Company. N.M.R. has received honoraria from and has been in a consulting role for 
      Bristol-Myers Squibb (BMS), Genentech, AbbVie, Gilead, AstraZeneca, and Celgene; 
      has received research funding from BMS and Merck; and has been a paid speaker for 
      Gilead and Celgene. S.C. has received honoraria from Pharmacyclics LLC, an AbbVie 
      Company, and Janssen; has been in a consulting role for AbbVie, Celgene, 
      Genentech, Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Astellas, and 
      AstraZeneca; has received research funding from AbbVie, Acerta, Celgene, Gilead, 
      Janssen, Pharmacyclics LLC, an AbbVie Company, and Takeda; has provided expert 
      testimony for Genentech; has received travel, accommodations and other expenses 
      from AbbVie, BeiGene, Celgene, Genentech, Janssen, and Pharmacyclics LLC, an 
      AbbVie Company; and has other relationships with BeiGene. C.S.T. has received 
      honoraria from Janssen and Pharmacyclics LLC, an AbbVie Company, and research 
      funding from Janssen. S.P.M. has received honoraria from and has been in a 
      consulting role for Roche, AbbVie, Janssen, Gilead, and GlaxoSmithKline; has 
      received research funding from Roche, AbbVie, and Janssen; and has been a paid 
      speaker for Roche, AbbVie, Janssen, and Gilead. U.J. has received honoraria and 
      research funding from Janssen, and has been in a consulting role for Janssen. 
      T.J.K. has been in a consulting role for AbbVie, Genentech-Roche, Gilead, 
      Pharmacyclics LLC, an AbbVie Company, and Celgene and has received research 
      funding from AbbVie, Genentech-Roche, Pharmacyclics LLC, an AbbVie Company, and 
      Oncternal. C.M. has been in a consulting role for Pharmacyclics LLC, an AbbVie 
      Company, Janssen, and AbbVie. M.M. has received honoraria from and has been in a 
      consulting role for AbbVie, Janssen, Gilead, Roche, and AstraZeneca; has been a 
      paid speaker for AbbVie, Janssen, and Gilead; has received research funding from 
      Roche; and has received travel, accommodations, and expenses reimbursement from 
      AbbVie, Janssen, and AstraZeneca. J.A.B. has received honoraria from Janssen; has 
      been in a consulting role for Janssen; has received research funding from Gilead, 
      TG Therapeutics, Pharmacyclics LLC, an AbbVie Company, and BeiGene; has been a 
      paid speaker for Gilead, TG Therapeutics, Pharmacyclics LLC, an AbbVie Company, 
      Novartis, and Janssen; and has received travel, accommodations, and expenses 
      reimbursement from Gilead, TG Therapeutics, Pharmacyclics LLC, an AbbVie Company, 
      Novartis, and Janssen. J.C.By. has been in consulting role for Janssen; has 
      reported research funding from Pharmacyclics LLC, an AbbVie Company, Gilead, TG 
      Therapeutics, and BeiGene; and has been a paid speaker for Pharmacyclics LLC, an 
      AbbVie Company, Gilead, TG Therapeutics, Novartis, and Janssen; and received 
      travel, accommodations, and expenses reimbursement from Pharmacyclics LLC, an 
      AbbVie Company, Janssen, Novartis, Gilead, and TG Therapeutics. P.H. has received 
      honoraria from, has been in a consulting role for and has received research 
      funding from Janssen, Pharmacyclics LLC, an AbbVie Company, and AbbVie; and has 
      received travel, accommodations, and expenses reimbursement from Janssen and 
      AbbVie. S.D. is an employee of Pharmacyclics LLC, an AbbVie Company, and owns 
      stock in AbbVie, Celgene, Gilead, GlaxoSmithKline, and Exelixis. A.S. is an 
      employee of Pharmacyclics LLC, an AbbVie Company, and owns stock in AbbVie. 
      J.P.D. is an employee of Pharmacyclics LLC, an AbbVie Company, and owns stock in 
      AbbVie and was formerly employed by and owned stock in CTI BioPharma. J.W. has 
      been in a consulting role for Pharmacyclics LLC, an AbbVie Company, and Janssen; 
      and has received research funding from Pharmacyclics LLC, an AbbVie Company, 
      Janssen, AbbVie, Morphosys, Karyopharm, and Loxo.
EDAT- 2019/09/13 06:00
MHDA- 2020/04/14 06:00
PMCR- 2019/12/08
CRDT- 2019/09/13 06:00
PHST- 2019/06/17 00:00 [received]
PHST- 2019/09/03 00:00 [revised]
PHST- 2019/09/09 00:00 [accepted]
PHST- 2019/09/13 06:00 [pubmed]
PHST- 2020/04/14 06:00 [medline]
PHST- 2019/09/13 06:00 [entrez]
PHST- 2019/12/08 00:00 [pmc-release]
AID - AJH25638 [pii]
AID - 10.1002/ajh.25638 [doi]
PST - ppublish
SO  - Am J Hematol. 2019 Dec;94(12):1353-1363. doi: 10.1002/ajh.25638. Epub 2019 Oct 
      13.