Phase Ib trial results using combination of venetoclax and rituximab in R/R CLL

This month in The Lancet Oncology, John F. Seymour from the Peter MacCallum Cancer Centre, Melbourne, Australia, and colleagues reported the results of a phase Ib dose-escalation study using venetoclax in combination with rituximab in the treatment of relapsed or refractory CLL. The study’s goal was to understand the pharmacokinetics, safety, and efficacy of this combination therapy approach. They recruited 49 patients with R/R CLL between August 2012 and May 2014.

Key Highlights:

  • Treatment:
    • Cohort 1 and 2 given 50mg venetoclax, five patients had tumor lysis syndrome after first dose, subsequent initial dose lowered to 20mg venetoclax cohort 3–5
    • Venetoclax dose increased weekly to target of 200mg–600mg
    • Rituximab initiated one week after target venetoclax dose reached
    • Cohort 3–4 received 375mg/m2 week 1, and 500mg/m2 the first days of each subsequent month, max six infusions
    • Dose reduction in 41% pts, mostly due to AEs (cytopenias and gastrointestinal AEs)
    • Mean T-max: venetoclax = 6 hours at mean maximum concentration 1.93μg/ml unaffected by rituximab
  • ORR = 86%, CR = 51%
  • Two-year PFS estimate = 82% (95% CI, 66–91)
  • Two-year ongoing response estimate = 89% (95% CI, 72–96)
  • Bone marrow MRD: 42 pts evaluated, 57% MRD-negative
  • 80% with CR were MRD-negative (20/25), 47% with PR were MRD-negative (8/17)
  • Adverse Events
    • Grade 3–4 AEs in 76% pts: neutropenia (53%), thrombocytopenia (16%), and anemia (14%)
    • Anti-infection prophylaxis received by 53% pts (13pts grade 3 infections, no grade 4, no opportunistic infection)
    • Study discontinued by 18 pts (disease progression = 11pts, toxicity = 3 pts, withdrew consent = 3 pts, lost = 1 pt)
    • One death due to tumor lysis syndrome following initial cohort initial dose of 50mg venetoclax

The authors concluded by stating that combination therapy of rituximab and venetoclax is an attractive potential treatment for R/R CLL, with “acceptable safety”, pharmacokinetics, and activity of the therapy yielding responses which continued after treatment cessation. The authors recommended that a randomized phase II trial occurs with an upper dose defined as 400mg venetoclax, with 20mg initial induction with escalation however, a longer follow-up time is needed to support the authors’ conclusions.

  1. Seymour J.F. et al. Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study. The Lancet Oncology. 2017 Jan 17. DOI:


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/m2 in month 1 and 500 mg/m2 in 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, number NCT01682616. Findings. 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. Interpretation. 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.