title: Impact of Venetoclax Exposure on Clinical Efficacy and Safety in Patients with Relapsed or Refractory Chronic Lymphocytic Leukemia.
abstract: Venetoclax is a selective, potent, first-in-class B-cell lymphoma-2 inhibitor that restores apoptosis in cancer cells and has demonstrated efficacy in a variety of hematological malignancies.
  
  
  
  The objective of this research was to characterize the relationship between venetoclax exposures and efficacy and safety in patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).
  
  
  
  A total of 272 and 338 patients from four clinical studies were pooled for the exposure-efficacy and exposure-safety analyses, respectively. Demographics, baseline disease characteristics, and select co-medications were evaluated for their impact on efficacy (lymphocytes, tumor size, objective response [OR]) and safety (neutropenia and infection).
  
  
  
  Higher venetoclax concentrations led to a more rapid decrease in lymphocyte counts and tumor size, which translated into patients more rapidly achieving OR. The 17p deletion somatic mutation was not identified, in any of the analyses, to affect the responsiveness of patients to venetoclax. Model-based simulations of lymphocyte counts and tumor size estimated an OR rate (ORR) of 84.8 % (95 % confidence interval 81.5-88.0 %) at a venetoclax dosage of 400 mg daily, with minimal increase in ORR at higher doses. The safety analyses of the adverse events (grade 3 or higher) of neutropenia and infection indicated that higher average venetoclax concentrations were not associated with an increase in adverse events.
  
  
  
  The exposure-response analyses indicated that a venetoclax dosage regimen of 400 mg daily results in a high (>80 %) probability of achieving OR in R/R CLL/SLL patients, with minimal probability of increasing neutropenia or infection with higher exposures.
authors.affiliation: Abbvie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA. kevin.freise@abbvie.com.
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Freise
authors.affiliation: Abbvie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Aksana K
authors.initials: AK
authors.lastname: Jones
authors.affiliation: Abbvie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Doerthe
authors.initials: D
authors.lastname: Eckert
authors.affiliation: Abbvie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Sven
authors.initials: S
authors.lastname: Mensing
authors.affiliation: Abbvie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Shekman L
authors.initials: SL
authors.lastname: Wong
authors.affiliation: Abbvie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Rod A
authors.initials: RA
authors.lastname: Humerickhouse
authors.affiliation: Abbvie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Walid M
authors.initials: WM
authors.lastname: Awni
authors.affiliation: Abbvie Inc., 1 North Waukegan Road, North Chicago, IL, 60064, USA.
authors.forename: Ahmed Hamed
authors.initials: AH
authors.lastname: Salem
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage* / Q000009:adverse effects; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis* / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009503:Neutropenia / Q000139:chemically induced; D012008:Recurrence; D013449:Sulfonamides / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D019086:Bridged Bicyclo Compounds, Heterocyclic; D013449:Sulfonamides; C579720:venetoclax