Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial

Abstract

Background: Therapy targeting Bruton's tyrosine kinase (BTK) with ibrutinib has transformed the treatment of chronic lymphocytic leukaemia. However, patients who are refractory to or relapse after ibrutinib therapy have poor outcomes. Venetoclax is a selective, orally bioavailable inhibitor of BCL-2 active in previously treated patients with relapsed or refractory chronic lymphocytic leukaemia. In this study, we assessed the activity and safety of venetoclax in patients with chronic lymphocytic leukaemia who are refractory to or relapse during or after ibrutinib therapy.

Methods: In this interim analysis of a multicentre, open-label, non-randomised, phase 2 trial, we enrolled patients aged 18 years or older with a documented diagnosis of chronic lymphocytic leukaemia according to the 2008 International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria and an Eastern Cooperative Oncology Group performance score of 2 or lower. All patients had relapsed or refractory disease after previous treatment with a BCR signalling pathway inhibitor. All patients were screened for Richter's transformation and cases confirmed by biopsy were excluded. Eligible patients received oral venetoclax, starting at 20 mg per day with stepwise dose ramp-up over 5 weeks to 400 mg per day. Patients with rapidly progressing disease received an accelerated dosing schedule (to 400 mg per day by week 3). The primary endpoint was overall response, defined as the proportion of patients with an overall response per investigator's assessment according to IWCLL criteria. All patients who received at least one dose of venetoclax were included in the activity and safety analyses. This study is ongoing; data for this interim analysis were collected per regulatory agencies' request as of June 30, 2017. This trial is registered with ClinicalTrials.gov, number NCT02141282.

Findings: Between September, 2014, and November, 2016, 127 previously treated patients with relapsed or refractory chronic lymphocytic leukaemia were enrolled from 15 sites across the USA. 91 patients had received ibrutinib as the last BCR inhibitor therapy before enrolment, 43 of whom were enrolled in the main cohort and 48 in the expansion cohort recruited later after a protocol amendment. At the time of analysis, the median follow-up was 14 months (IQR 8-18) for all 91 patients, 19 months (9-27) for the main cohort, and 12 months (8-15) for the expansion cohort. 59 (65%, 95% CI 53-74) of 91 patients had an overall response, including 30 (70%, 54-83) of 43 patients in the main cohort and 29 (60%, 43-72) of 48 patients in the expansion cohort. The most common treatment-emergent grade 3 or 4 adverse events were neutropenia (46 [51%] of 91 patients), thrombocytopenia (26 [29%]), anaemia (26 [29%]), decreased white blood cell count (17 [19%]), and decreased lymphocyte count (14 [15%]). 17 (19%) of 91 patients died, including seven because of disease progression. No treatment-related deaths occurred.

Interpretation: The results of this interim analysis show that venetoclax has durable clinical activity and favourable tolerability in patients with relapsed or refractory chronic lymphocytic leukaemia whose disease progressed during or after discontinutation of ibrutinib therapy. The durability of response to venetoclax will be assessed in the final analysis in 2019.

Funding: AbbVie, Genentech.

Figure 1. Study Flow Diagram

Data reported in this publication are for patients who had received ibrutinib as the last B-cell receptor pathway inhibitor (BCRi) therapy prior to enrollment (43 from the main cohort and 48 from the expansion cohort). *Data from patients who received idelalisib as their last BCRi prior to enrollment (n=36) will be reported in a separate publication and are indicated by the grey boxes in the diagram.

Figure 2. Kaplan-Meier curves

For all 91 patients, shown are the (A) time to progression (26 patients had an event), (B) progression-free survival (33 patients had an event), (C) overall survival (17 patients had an event) assessed by the investigator. (D) Duration of overall response is shown for 59 patients with a response (15 patients had an event), as assessed by the investigator. Below each curve is the number of patients at risk for the event at each time point. Tick marks represent censored data.

Figure 2. Kaplan-Meier curves

For all 91 patients, shown are the (A) time to progression (26 patients had an event), (B) progression-free survival (33 patients had an event), (C) overall survival (17 patients had an event) assessed by the investigator. (D) Duration of overall response is shown for 59 patients with a response (15 patients had an event), as assessed by the investigator. Below each curve is the number of patients at risk for the event at each time point. Tick marks represent censored data.

Figure 3. (A) Percentage of chronic lymphocytic leukaemia (CLL) cells in peripheral blood by minimal residual disease (MRD) status

Plot depicts the lowest percentage of MRD as assessed by six-color immunophenotyping (standardized ERIC protocol) during venetoclax treatment weeks 24 to 48. The percentage was calculated as the number of CLL cells divided by the total number of cells measured (with a minimum of 500,000 cells measured per assay). MRD-negativity (blue) was defined as <0·01% CLL cells (dashed line). Data from 45 of the 57 patients assessed for MRD are shown here as 12 patients had an atypical phenotype and the level of residual disease may be under-valued by the ERIC scoring algorithm. Orange indicates MRD positivity; Blue indicates MRD-negativity; triangle, complete response or complete response with incomplete bone marrow recovery (CR/CRi); square, partial response (PR) or nodular partial response (nPR); and circle, stable disease (SD); * indicates patients with subsequent assessments indicating MRD-negativity in bone marrow. (B) Progression-free survival (PFS) by MRD status. Shown are Kaplan-Meier curves for investigator-assessed PFS by peripheral blood MRD status. Data are shown for all 57 patients assessed for MRD, including 12 patients with an aberrant phenotype who had detectable disease and were considered MRD positive. There was a significant difference in PFS between 24 patients with MRD-negativity in blood (three patients had an event) vs 33 patients who were MRD-positive (14 patients had an event) (p=0·0093 by log-rank test). Below each curve is the number of patients at risk for the event at each time point. Tick marks represent censored data. For MRD analyses, patients with aberrant phenotype did have detectable disease present and were considered MRD positive per our assessments. These patients were excluded from Figure 3A as an actual level of % CLL cells could not be assessed due to scoring algorithm bias but were retained for the analysis shown in Figure 3B as they do have detectable disease and are MRD positive.