Elsevier

The Lancet Oncology

Volume 18, Issue 2, February 2017, Pages 230-240
The Lancet Oncology

Articles
Venetoclax plus rituximab in relapsed or refractory chronic lymphocytic leukaemia: a phase 1b study

https://doi.org/10.1016/S1470-2045(17)30012-8Get rights and content

Summary

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 ClinicalTrials.gov, 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.

Funding

AbbVie Inc and Genentech Inc.

Introduction

Members of the BCL2 protein family are important regulators of intrinsic apoptosis and contribute to tumour survival and therapy resistance in many cancers.1, 2 BH3-mimetic BCL2 inhibitors, which bind BCL2 via the molecular site used by physiological pro-apoptotic molecules, are active against chronic lymphocytic leukaemia as single agents.3, 4, 5, 6 Venetoclax is the first selective, potent BCL2 inhibitor.7 Monotherapy induces rapid reduction in the disease burden of chronic lymphocytic leukaemia and a high overall response of about 80% and complete response of 6–20% in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including disease harbouring chromosome 17p deletions (del[17p]).3, 5

Research in context

Evidence before this study

Based on preclinical data, combination therapies have the potential to enhance the activity of novel agents in the treatment of patients with relapsed or refractory chronic lymphocytic leukaemia. We searched PubMed for clinical trial reports published up to Aug 15, 2016, to identify new agents used to treat relapsed or refractory chronic lymphocytic leukaemia, using the terms “chronic lymphocytic leukemia” and “CLL”, as well as the following terms together with “CLL”: “relapsed” and “refractory”. Nearly 1450 articles were identified using these search parameters, with 279 reporting results of clinical trials. Based on recent data published within the past 5 years, several novel agents, including the B-cell receptor signalling inhibitors ibrutinib and idelalisib, and the BCL-2 inhibitor venetoclax, emerged as effective treatment options in this patient population.

Most patients treated with ibrutinib as a single agent and idelalisib in combination with rituximab (anti-CD20 antibody) achieve disease response; however, the number of complete remissions achieved is low. In addition, some patients are unable to tolerate these agents due to adverse events such as nausea, diarrhoea, colitis, elevated alanine transaminase, and elevated aspartate transaminase enzymes. Outcomes are poor for patients who must discontinue treatment due to toxicity or who progress on therapy; median overall survival after ibrutinib discontinuation ranges from 3 months for patients who have Richter's progression to 18 months for chronic lymphocytic leukaemia progression. To date, phase 2 studies of B-cell receptor signalling inhibitors in combination with other agents have not reported clearly higher complete remission rates than ibrutinib alone and indefinite therapy is still required.

BCL-2 inhibition with venetoclax monotherapy has been shown to result in a high proportion of patients with overall responses and complete remission in two recently published studies: a first-in-human study of patients with relapsed or refractory chronic lymphocytic leukaemia (79% of patients had an overall response with 20% complete remission as determined by investigators) and a phase 2 study of patients with chronic lymphocytic leukaemia that harbours chromosome 17p deletion (79% of patients had an overall response with 8% complete remission, as determined by an independent review committee). In preclinical models of B-cell malignancy, synergy was observed when venetoclax was combined with rituximab.

Added value of the study

This phase 1b study was the first to evaluate venetoclax in any combination for the treatment of patients with relapsed or refractory chronic lymphocytic leukaemia. We hypothesised that venetoclax plus rituximab would be tolerable and increase depth of response. Our results show that venetoclax plus rituximab is highly active with an acceptable safety profile in patients with relapsed or refractory chronic lymphocytic leukaemia. A high proportion of patients achieved an overall response, with 51% of patients achieving a complete remission. Systematic evaluations of serial bone marrow biopsies revealed that 57% of all patients were negative for minimal residual disease. Patients achieving such deep responses can maintain responses without ongoing therapy for periods up to 2 years, and respond to retreatment with venetoclax at progression.

Implications of all available evidence

Venetoclax administration in combination with rituximab is a tolerable and active combination for difficult-to-treat patients with relapsed or refractory chronic lymphocytic leukaemia. The data indicate that minimal residual disease-negative complete remissions are now readily achievable in patients with relapsed chronic lymphocytic leukaemia, and that patients achieving such deep responses need not continue therapy indefinitely. Abbreviated courses of treatment with venetoclax-containing combination regimens should be explored as alternatives to long-term therapy with B-cell receptor signalling inhibitors or venetoclax monotherapy in randomised trials.

Based on preclinical synergy,7 combination therapy might have substantially enhanced clinical activity. Although rituximab has modest single-agent activity in chronic lymphocytic leukaemia and small lymphocytic lymphoma,8, 9 when combined with chemotherapy, it improves the proportion of patients who achieve an overall response, progression-free survival, and overall survival.10, 11 Combining rituximab with an earlier BCL2 inhibitor, navitoclax, proved tolerable and highly active in patients with relapsed or refractory lymphoid malignancies,12 including chronic lymphocytic leukaemia,13 establishing the proof-of-principle and safety of this approach.

We hypothesised that combining venetoclax and rituximab would be well tolerated and increase depth and durability of response in patients with relapsed or refractory chronic lymphocytic leukaemia and small lymphocytic lymphoma.

Section snippets

Study design and participants

The M13-365 study was a phase 1b study of the combination of venetoclax plus rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. Patients were enrolled sequentially into five dose-escalation cohorts and an expansion cohort. Adult patients (aged 18 years or older) with chronic lymphocytic leukaemia and small lymphocytic lymphoma were eligible if they had relapsed or refractory disease that required therapy by standard International

Results

Between Aug 6, 2012, and May 28, 2014, 49 patients were enrolled (41 in the dose-escalation cohorts; eight in the safety expansion cohort) and comprised the per-protocol population for analysis. Baseline characteristics are shown in table 1. Three patients discontinued the study before rituximab commencement (one each due to adverse event of tumour lysis syndrome, consent withdrawal, and disease progression [Richter's transformation]).

31 (63%) of 49 patients remain active on study (appendix p 16

Discussion

Preclinical data strongly suggested synergistic cyototoxic activity of venetoclax in combination with anti-CD20 monoclonal antibodies, such as rituximab.7, 20 However, the addition of rituximab to myelosuppressive chemotherapy regimens increases cytopenias and infections.21 In the current study, venetoclax plus rituximab did not appear to substantially alter the pharmacokinetics or the adverse event profile observed in other studies with monotherapy in chronic lymphocytic leukaemia. Grade 3–4

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