title: Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.
abstract: BACKGROUND
  New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells.
  
  
  METHODS
  We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.
  
  
  RESULTS
  The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%.
  
  
  CONCLUSIONS
  Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.).
authors.affiliation: From the Department of Clinical Haematology and the Bone Marrow Transplantation Unit, Royal Melbourne Hospital (A.W.R., M.A.A.), the Division of Cancer and Haematology, Walter and Eliza Hall Institute of Medical Research (A.W.R., M.A.A.), and the Victorian Comprehensive Cancer Centre (A.W.R., J.F.S.), Parkville, VIC, and the University of Melbourne (A.W.R., J.F.S.) and Peter MacCallum Cancer Centre (J.F.S.), Melbourne, VIC - all in Australia; Dana-Farber Cancer Institute, Boston (M.S.D., J.R.B.); the Swedish Medical Center, Seattle (J.M.P.); Washington University, St. Louis (B.S.K.); University of Arizona, Tucson (S.D.P.); Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York (J.F.G.); University of California, San Diego, San Diego (T.J.K.); AbbVie, North Chicago, IL (L.G., S.W., M.D., M.Z., M.B.D., E.C., S.H.E., R.A.H.); and University of Texas M.D. Anderson Cancer Center, Houston (W.G.W.).
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Davids
authors.forename: John M
authors.initials: JM
authors.lastname: Pagel
authors.forename: Brad S
authors.initials: BS
authors.lastname: Kahl
authors.forename: Soham D
authors.initials: SD
authors.lastname: Puvvada
authors.forename: John F
authors.initials: JF
authors.lastname: Gerecitano
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Anderson
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Brown
authors.forename: Lori
authors.initials: L
authors.lastname: Gressick
authors.forename: Shekman
authors.initials: S
authors.lastname: Wong
authors.forename: Martin
authors.initials: M
authors.lastname: Dunbar
authors.forename: Ming
authors.initials: M
authors.lastname: Zhu
authors.forename: Monali B
authors.initials: MB
authors.lastname: Desai
authors.forename: Elisa
authors.initials: E
authors.lastname: Cerri
authors.forename: Sari
authors.initials: S
authors.lastname: Heitner Enschede
authors.forename: Rod A
authors.initials: RA
authors.lastname: Humerickhouse
authors.forename: William G
authors.initials: WG
authors.lastname: Wierda
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors*; D012008:Recurrence; D012074:Remission Induction; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D015275:Tumor Lysis Syndrome / Q000209:etiology
chemical_list: D000970:Antineoplastic Agents; C000595707:BCL2 protein, human; D019086:Bridged Bicyclo Compounds, Heterocyclic; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; C579720:venetoclax