title: Three newly approved drugs for chronic lymphocytic leukemia: incorporating ibrutinib, idelalisib, and obinutuzumab into clinical practice.
abstract: Three agents have received Food and Drug Administration (FDA) approval for treatment of chronic lymphocytic leukemia (CLL) within the past year. Ibrutinib and idelalisib block B-cell receptor signaling through inhibition of Bruton tyrosine kinase and phosphatidylinositol 3-kinase δ molecules respectively, interfering with several pathways required for leukemia cell survival. Idelalisib has shown efficacy in the relapsed setting and is currently approved by the FDA for use in combination with rituximab. Ibrutinib has been studied in patients with relapsed CLL and as frontline therapy. In the relapsed setting, these agents produce durable remissions, and might be preferable to re-treatment with chemoimmunotherapy for many patients. Ibrutinib is also effective treatment for patients with deletion 17p and is approved by the FDA as frontline therapy in this patient group, although it does not appear to completely abrogate this adverse prognostic factor. These agents have a unique side effect profile and longer follow-up is required to further understand tolerability and rare adverse effects. Obinutuzumab is a type-2 monoclonal anti-CD20 antibody which results in direct and antibody-dependent cell-mediated cytotoxicity of leukemia cells. It is approved by the FDA for use in combination with chlorambucil, and has shown efficacy in the frontline setting in patients unfit for more intensive chemoimmunotherapy. It produces increased response rates and minimal residual disease negativity compared with chlorambucil/rituximab and is associated with an advantage in progression-free survival but not yet overall survival. These agents underscore our advancement in the understanding of the biology of CLL and will improve outcomes for many patients with CLL.
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: David S
authors.initials: DS
authors.lastname: Sanford
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Department of Leukemia, University of Texas M.D. Anderson Cancer Center, Houston, TX. Electronic address: obrien@uci.edu.
authors.forename: Susan M
authors.initials: SM
authors.lastname: O'Brien
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D010880:Piperidines; D011687:Purines / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D052999:Quinazolinones / Q000627:therapeutic use*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D010880:Piperidines; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; C551803:ibrutinib; D000225:Adenine; C543332:obinutuzumab; C552946:idelalisib
keywords: Anti-CD20 antibody; BTK inhibitor; Lymphoid malignancy; Novel agents; PI3K inhibitor
references.citation: Blood. 2008 Aug 15;112(4):975-80
references.pmid: 18411418
references.citation: Nature. 2011 Jun 05;475(7354):101-5
references.pmid: 21642962
references.citation: Blood. 2002 Nov 15;100(10):3741-8
references.pmid: 12393602
references.citation: Future Oncol. 2015;11(1):51-9
references.pmid: 24901734
references.citation: N Engl J Med. 2012 May 24;366(21):2008-16
references.pmid: 22621628
references.citation: Leukemia. 2015 Apr;29(4):783-7
references.pmid: 25138588
references.citation: Adv Immunol. 2014;123:1-49
references.pmid: 24840946
references.citation: Blood. 2013 Oct 3;122(14):2412-24
references.pmid: 23940282
references.citation: N Engl J Med. 2011 Dec 29;365(26):2497-506
references.pmid: 22150006
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 20;107(29):13075-80
references.pmid: 20615965
references.citation: N Engl J Med. 2013 Jul 4;369(1):32-42
references.pmid: 23782158
references.citation: Blood. 2008 Jun 15;111(12):5446-56
references.pmid: 18216293
references.citation: Blood. 2011 Sep 29;118(13):3603-12
references.pmid: 21803855
references.citation: Blood. 2010 Oct 7;116(14):2438-47
references.pmid: 20595516
references.citation: J Clin Oncol. 2010 Apr 1;28(10):1756-65
references.pmid: 20194844
references.citation: J Clin Oncol. 2010 Apr 1;28(10 ):1749-55
references.pmid: 20194866
references.citation: J Clin Invest. 2010 Jan;120(1):214-22
references.pmid: 20038800
references.citation: Leukemia. 2007 Jan;21(1):12-7
references.pmid: 17109028
references.citation: J Clin Oncol. 2013 Jan 1;31(1):88-94
references.pmid: 23045577
references.citation: Leuk Lymphoma. 2013 Jun;54(6):1159-64
references.pmid: 23013295
references.citation: Lancet Oncol. 2014 Jan;15(1):48-58
references.pmid: 24332241
references.citation: N Engl J Med. 2014 Mar 20;370(12):1101-10
references.pmid: 24401022
references.citation: Leuk Lymphoma. 2015 Mar;56(3):711-5
references.pmid: 24913509
references.citation: J Clin Oncol. 2005 Jun 20;23(18):4070-8
references.pmid: 15767647
references.citation: Blood. 2012 May 31;119(22):5118-25
references.pmid: 22438256
references.citation: Blood. 2010 Jun 3;115(22):4393-402
references.pmid: 20194898
references.citation: Nature. 2012 Sep 13;489(7415):309-12
references.pmid: 22885698
references.citation: Leukemia. 2013 Sep;27(9):1949-52
references.pmid: 23787395
references.citation: Lancet. 2010 Oct 2;376(9747):1164-74
references.pmid: 20888994
references.citation: Semin Hematol. 2010 Apr;47(2):107-14
references.pmid: 20350657
references.citation: Blood. 2014 May 29;123(22):3390-7
references.pmid: 24615777
references.citation: Blood. 2012 May 31;119(22):5126-32
references.pmid: 22431570
references.citation: Leukemia. 2014 Mar;28(3):649-57
references.pmid: 24270740
references.citation: Curr Hematol Malig Rep. 2013 Mar;8(1):81-90
references.pmid: 23188619
references.citation: Nat Rev Cancer. 2006 Mar;6(3):184-92
references.pmid: 16453012
references.citation: N Engl J Med. 2014 Mar 13;370(11):997-1007
references.pmid: 24450857
references.citation: N Engl J Med. 2014 Jul 17;371(3):213-23
references.pmid: 24881631
references.citation: Blood. 2011 Jan 13;117(2):591-4
references.pmid: 20959606
references.citation: Blood. 2011 Jun 9;117(23):6287-96
references.pmid: 21422473
references.citation: J Exp Med. 2002 Sep 16;196(6):753-63
references.pmid: 12235209
references.citation: J Clin Oncol. 2011 Sep 10;29(26):3559-66
references.pmid: 21844497
references.citation: Science. 2002 Aug 9;297(5583):1031-4
references.pmid: 12130661
references.citation: N Engl J Med. 2014 Jun 12;370(24):2286-94
references.pmid: 24869598
references.citation: Mol Cell Biol. 2002 Dec;22(24):8580-91
references.pmid: 12446777
references.citation: Blood. 2011 Apr 28;117(17):4519-29
references.pmid: 21378274
references.citation: Blood. 2002 Apr 15;99(8):2969-76
references.pmid: 11929788
references.citation: Blood. 2014 Oct 2;124(14):2196-202
references.pmid: 25143487
references.citation: Hum Mutat. 2006 Dec;27(12):1209-17
references.pmid: 16969761