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Deep responses in R/R CLL with venetoclax monotherapy

Prof. Arnon Kater, Amsterdam University Medical Center, the Netherlands
EHA 2020
Phase 3, VENICE 1
Venetoclax monotherapy can achieve deep responses and has a tolerable and manageable safety profile in patients with relapsed/refractory chronic lymphocytic leukaemia (R/R CLL), patients.

Prof. Arnon Kater (Amsterdam University Medical Center, the Netherlands) presented the outcomes of the open-label, single arm, phase 3b VENICE 1 trial. The purpose of this study was to evaluate the efficacy of venetoclax monotherapy in participants with R/R CLL, including those with the 17p deletion, TP53 mutation, or those who have received prior treatment with a BCRi.

The primary endpoint of the study was complete remission (CR) rate or CR with incomplete bone marrow recovery (CRi) in BCRi-naïve patients at week 48. Key secondary endpoints were overall response rate (ORR), progression-free survival (PFS), overall survival (OS), quality of life (QOL) assessed via Functional Assessment of Cancer Therapy – Leukemia Questionnaire (FACT-Leu), and safety. Minimal residual disease (MRD) levels were set as an exploratory endpoint.

Patients (n=258) underwent a 5-week ramp-up from 20 mg to 400 mg venetoclax daily, and then stayed on 400 mg for 2 years. Clinical response was assessed (iwCLL 2008) at weeks 24, 36, and 48. Most patients were BCRi-naïve (n=191), but 67 had had prior BCRi-treatment (BCRi-exposed). Site-reported genetics indicated that 17p-loss or TP53 mutation was present in 16.8% of BCRi-naïve patients versus 43.3% of BCRi-exposed patients.

The primary endpoint was met; at week 48, CR/CRi rates were 35.1% in the BCRi-naïve cohort as opposed to 25.4% in the BCRi-exposed group (see Table). ORR was 85.3% for BCRi-naïve patients compared with 64.2% in the BCRi-exposed group. Furthermore, MRD at week 48 was undetectable in 35.6% of the BCRi-naïve patients and 26.9% of the BCRi-exposed patients. PFS was 30.5 months (77.0%) overall, 28.6 months (67.1%) in patients with 17p/TP53 aberration, and 30.5 months (79.4%) versus 28.6 months (69.9%) for the BCRi-naïve and BCRi-exposed groups, respectively. Median PFS was not reached for patients who had either undetectable MRD or CR/CRi, suggestive of a deep and durable response. PFS with partial remission/nodular partial remission was 30.5 months. OS was 83.7% overall, 88.0% for BCRi-naïve patients, and 71.6% for BCRi-exposed patients. QOL showed clinically meaningful improvement at week 48 for all subgroups.

Table. Response rates with VEN treatment in BCRi-naïve and BCRi-experienced groups

BCRi, B-cell receptor pathway inhibitors; CI, confidence interval; CR, complete response; CRi, complete response with incomplete bone marrow recovery; MRD, minimal residual disease; nPR, nodular partial remission; ITT, intention to treat; PB, peripheral blood; PR, partial remission; uMRD, undetectable minimal residual disease; VEN, venetoclax.
*Median OS was not reached.

Toxicity was high, but manageable; 74.4% experienced grade ≥3 adverse events (AEs) (neutropenia 37.2%, infection 19.0%); 12.4% of patients reduced dose due to AEs, and 109 (42.2%) discontinued venetoclax (12.8% because of AEs, 10.9% because of disease progression). No new safety signals were observed.

In brief, venetoclax monotherapy can achieve deep responses (CR, undetectable MRD) and has a tolerable and manageable safety profile in patients with R/R CLL.

    1. Kater A, et al. Efficacy of venetoclax in patients with relapsed/refractory chronic lymphocytic leukemia: primary endpoint analysis of the international phase 3b trial (VENICE I). EHA25 Virtual, 11-21 June 2020, Abstract S156.

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