Elsevier

The Lancet Oncology

Volume 21, Issue 9, September 2020, Pages 1188-1200
The Lancet Oncology

Articles
Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial

https://doi.org/10.1016/S1470-2045(20)30443-5Get rights and content

Summary

Background

Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia.

Methods

CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30–69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942.

Findings

Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8–43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22–0·44; p<0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7–40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma).

Interpretation

2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia.

Funding

F Hoffmann-La Roche and AbbVie.

Introduction

Managing patients with chronic lymphocytic leukaemia and coexisting conditions can be a clinical challenge because these patients require effective, but tolerable treatment regimens. Chemoimmunotherapy with chlorambucil plus obinutuzumab is an established regimen to treat patients with chronic lymphocytic leukaemia who are elderly or unfit, as it has shown superior progression-free survival and overall survival compared with other chemotherapy and chemoimmunotherapy approaches.1, 2 Novel targeted drugs such as ibrutinib, the Bruton's tyrosine kinase inhibitor, has shown superiority over conventional chemoimmunotherapy. However, these drugs usually require continuous therapy until disease progression.3, 4 The prolonged drug exposure of continuous regimens could be associated with increased side-effects, interactions with concomitant medications, development of resistance, and high therapy costs.5, 6 The level of minimal residual disease (MRD) predicts progression-free survival.7, 8 Hence, establishment of fixed-duration treatments that achieve deep remissions with high rates of undetectable MRD is warranted. The kinetics of MRD levels during and after treatment might further provide information on how the disease course of chronic lymphocytic leukaemia develops over time, but long-term data on MRD after frontline treatment are sparse.

Previously, results from the CLL14 trial showed that a fixed-duration treatment regimen with the oral BH3-mimetic compound venetoclax in combination with obinutuzumab improved progression-free survival compared with chlorambucil plus obinutuzumab.9 After six 28-day cycles of venetoclax plus obinutuzumab and six 28-day cycles of venetoclax, patients showed deep remissions with undetectable MRD across all subgroups. During follow-up, levels of MRD were closely monitored to depict the kinetics of possible disease progressions.

Here, we report an extended follow-up of patients treated in the CLL14 trial,9 all of whom had been off treatment for at least 24 months. The aim of this analysis is to provide longitudinal observation of MRD kinetics and its relation with disease progression in patients with chronic lymphocytic leukaemia after treatment with venetoclax plus obinutuzumab.

Section snippets

Study design and participants

The CLL14 study is an ongoing global, phase 3, randomised, open-label, randomised, study done at 196 sites in 21 countries (appendix pp 36–38). Eligible patients were 18 years or older, had previously untreated, active chronic lymphocytic leukaemia requiring treatment per International Workshop on Chronic Lymphocytic Leukemia criteria,10 and were considered unfit due to coexisting conditions, as assessed by a cumulative illness rating scale greater than 6, a creatinine clearance of less than 70

Results

Between Aug 7, 2015, and Aug 4, 2016, 514 patients were screened for eligibility and 432 patients were randomly assigned to a treament group (216 patients to venetoclax plus obinutuzumab and 216 to chlorambucil plus obinutuzumab; figure 1). Baseline characteristics are in table 1, and MRD status at the end of treatment (3 months after treatment completion) according to baseline characteristics are in table 2 and the appendix (p 3). Four patients assigned to the venetoclax plus obinutuzumab

Discussion

This 3-year follow-up report of the randomised, phase 3 CLL14 trial shows that clinical benefit was maintained for previously untreated patients with chronic lymphocytic leukaemia and coexisting conditions after a fixed-duration treatment with venetoclax plus obinutuzumab, compared with a fixed-duration treatment with chlorambucil plus obinutuzumab. The aim of this report was to outline the efficacy and durability of a fixed-duration frontline treatment for chronic lymphocytic leukaemia with

Data sharing

The German CLL Study Group, Roche, and AbbVie will consider data sharing requests on a case-by-case basis. With publication, requests by academic study groups for de-identified patient data with the intent-to-achieve aims of the original proposal can be forwarded to the corresponding author and will be evaluated by the German CLL Study Group, Roche, and AbbVie. The study protocol will be provided in the appendix of this publication. The statistical analysis plan and informed consent form will

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