title: Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study.
abstract: BACKGROUND
  Selective BCL2 inhibition with venetoclax has substantial activity in patients with relapsed or refractory chronic lymphocytic leukaemia. Combination therapy with rituximab enhanced activity in preclinical models. The aim of this study was to assess the safety, pharmacokinetics, and activity of venetoclax in combination with rituximab.
  
  
  METHODS
  Adult patients with relapsed or refractory chronic lymphocytic leukaemia (according to the 2008 Modified International Workshop on CLL guidelines) or small lymphocytic lymphoma were eligible for this phase 1b, dose-escalation trial. The primary outcomes were to assess the safety profile, to determine the maximum tolerated dose, and to establish the recommended phase 2 dose of venetoclax when given in combination with rituximab. Secondary outcomes were to assess the pharmacokinetic profile and analyse efficacy, including overall response, duration of response, and time to tumour progression. Minimal residual disease was a protocol-specified exploratory objective. Central review of the endpoints was not done. Venetoclax was dosed daily using a stepwise escalation to target doses (200-600 mg) and then monthly rituximab commenced (375 mg/m2in month 1 and 500 mg/m2in months 2-6). Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for adverse events version 4.0. Protocol-guided drug cessation was allowed for patients who achieved complete response (including complete response with incomplete marrow recovery) or negative bone marrow minimal residual disease. Analyses were done per protocol for all patients who commenced drug and included all patients who received at least one dose of venetoclax. Data were pooled across dose cohorts. Patients are still receiving therapy and follow-up is ongoing. The trial is registered at ClinicalTrials.gov, number NCT01682616.
  
  
  RESULTS
  Between Aug 6, 2012, and May 28, 2014, we enrolled 49 patients. Common grade 1-2 toxicities included upper respiratory tract infections (in 28 [57%] of 49 patients), diarrhoea (27 [55%]), and nausea (25 [51%]). Grade 3-4 adverse events occurred in 37 (76%) of 49 patients; most common were neutropenia (26 [53%]), thrombocytopenia (eight [16%]), anaemia (seven [14%]), febrile neutropenia (six [12%]), and leucopenia (six [12%]). The most common serious adverse events were pyrexia (six [12%]), febrile neutropenia (five [10%]), lower respiratory tract infection, and pneumonia (each three [6%]). Clinical tumour lysis syndrome occurred in two patients (resulting in one death) who initiated venetoclax at 50 mg. After enhancing tumour lysis syndrome prophylaxis measures and commencing venetoclax at 20 mg, clinical tumour lysis syndrome did not occur. The maximum tolerated dose was not identified; the recommended phase 2 dose of venetoclax in combination with rituximab was 400 mg. Overall, 42 (86%) of 49 patients achieved a response, including a complete response in 25 (51%) of 49 patients. 2 year estimates for progression-free survival and ongoing response were 82% (95% CI 66-91) and 89% (95% CI 72-96), respectively. Negative marrow minimal residual disease was attained in 20 (80%) of 25 complete responders and 28 (57%) of 49 patients overall. 13 responders ceased all therapy; among these all 11 minimal residual disease-negative responders remain progression-free off therapy. Two with minimal residual disease-positive complete response progressed after 24 months off therapy and re-attained response after re-initiation of venetoclax.
  
  
  CONCLUSIONS
  A substantial proportion of patients achieved an overall response with the combination of venetoclax and rituximab including 25 (51%) of 49 patients who achieved a complete response and 28 (57%) of 49 patients who achieved negative marrow minimal residual disease with acceptable safety. The depth and durability of responses observed with the combination offers an attractive potential treatment option for patients with relapsed or refractory chronic lymphocytic leukaemia and could allow some patients to maintain response after discontinuing therapy, a strategy that warrants further investigation in randomised studies.
  
  
  BACKGROUND
  AbbVie Inc and Genentech Inc.
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Victorian Comprehensive Cancer Centre, Parkville, Melbourne, VIC, Australia; Faculty of Medicine, University of Melbourne, Parkville, Melbourne, VIC, Australia. Electronic address: john.seymour@petermac.org.
authors.forename: John F
authors.initials: JF
authors.lastname: Seymour
authors.affiliation: Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Ma
authors.affiliation: Duke University Medical Center, Durham, NC, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Brander
authors.affiliation: University of California San Diego, San Diego, CA, USA.
authors.forename: Michael Y
authors.initials: MY
authors.lastname: Choi
authors.affiliation: Hofstra Northwell School of Medicine, Hempstead, NY, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Barrientos
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, USA.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Davids
authors.affiliation: Department of Clinical Haematology and BMT, The Royal Melbourne Hospital, Parkville, Melbourne, VIC, Australia; Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, VIC, Australia.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Anderson
authors.affiliation: Duke University Medical Center, Durham, NC, USA.
authors.forename: Anne W
authors.initials: AW
authors.lastname: Beaven
authors.affiliation: City of Hope National Medical Center, Duarte, CA, USA.
authors.forename: Steven T
authors.initials: ST
authors.lastname: Rosen
authors.affiliation: Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Victorian Comprehensive Cancer Centre, Parkville, Melbourne, VIC, Australia; Faculty of Medicine, University of Melbourne, Parkville, Melbourne, VIC, Australia.
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Tam
authors.affiliation: AbbVie, Inc, North Chicago, IL, USA.
authors.forename: Betty
authors.initials: B
authors.lastname: Prine
authors.affiliation: AbbVie, Inc, North Chicago, IL, USA.
authors.forename: Suresh K
authors.initials: SK
authors.lastname: Agarwal
authors.affiliation: AbbVie, Inc, North Chicago, IL, USA.
authors.forename: Wijith
authors.initials: W
authors.lastname: Munasinghe
authors.affiliation: AbbVie, Inc, North Chicago, IL, USA.
authors.forename: Ming
authors.initials: M
authors.lastname: Zhu
authors.affiliation: AbbVie, Inc, North Chicago, IL, USA.
authors.forename: L Leanne
authors.initials: LL
authors.lastname: Lash
authors.affiliation: AbbVie, Inc, North Chicago, IL, USA.
authors.forename: Monali
authors.initials: M
authors.lastname: Desai
authors.affiliation: AbbVie, Inc, North Chicago, IL, USA.
authors.forename: Elisa
authors.initials: E
authors.lastname: Cerri
authors.affiliation: AbbVie, Inc, North Chicago, IL, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Verdugo
authors.affiliation: AbbVie, Inc, North Chicago, IL, USA.
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: AbbVie, Inc, North Chicago, IL, USA.
authors.forename: Rod A
authors.initials: RA
authors.lastname: Humerickhouse
authors.affiliation: AbbVie, Inc, North Chicago, IL, USA.
authors.forename: Gary B
authors.initials: GB
authors.lastname: Gordon
authors.affiliation: University of California San Diego, San Diego, CA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kipps
authors.affiliation: Victorian Comprehensive Cancer Centre, Parkville, Melbourne, VIC, Australia; Faculty of Medicine, University of Melbourne, Parkville, Melbourne, VIC, Australia; Department of Clinical Haematology and BMT, The Royal Melbourne Hospital, Parkville, Melbourne, VIC, Australia; Division of Cancer and Haematology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Melbourne, VIC, Australia.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Roberts
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage; D015331:Cohort Studies; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000473:pathology; D011379:Prognosis; D012074:Remission Induction; D000069283:Rituximab / Q000008:administration & dosage; D016879:Salvage Therapy; D013449:Sulfonamides / Q000008:administration & dosage; D015996:Survival Rate
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D013449:Sulfonamides; D000069283:Rituximab; C579720:venetoclax