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Fixed 12 cycles and MRD-guided venetoclax consolidation effective in CLL

Presented By
Dr Mark-David Levin, Albert Schweitzer Hospital, the Netherlands
EHA 2021
Phase 2, HOVON 139/GiVe

Primary endpoint results of the phase 2 HOVON 139/GiVe trial demonstrated high efficacy and good tolerability after fixed 12 cycles of venetoclax or minimal residual disease (MRD)-guided treatment with venetoclax after pre-induction with obinutuzumab. These results warrant further research on both these treatment options for patients with naïve chronic lymphocytic leukaemia (CLL) who are unfit for first-line fludarabine, cyclophosphamide, and rituximab (FCR).

Fixed-duration treatment of CLL patients with venetoclax combined with anti-CD20 antibody, both in first-line (12 cycles) and in relapsed/refractory (r/r) disease (24 cycles) results in high rates of undetectable MRD and prolonged progression-free survival (PFS) [1]. The randomised, phase 2 HOVON 139/GiVe trial enrolled CLL patients who were unfit for first-line FCR. The trial evaluated the impact of a standard or MRD-based addition of venetoclax for 12 cycles after induction treatment with obinutuzumab + venetoclax. Dr Mark-David Levin (Albert Schweitzer Hospital, the Netherlands) presented the primary endpoint analysis after a maximum of 24 cycles [2].

The participants (n=67) first received 2 cycles of obinutuzumab for pre-induction, followed by induction with 6 cycles of obinutuzumab + venetoclax, and 6 cycles of venetoclax monotherapy. They were randomised to receive maintenance therapy with venetoclax for 12 additional cycles in arm A or MRD-guided venetoclax arm B (i.e. venetoclax maintenance stopped or not started if patients reached blood MRD-negativity at any time point following randomisation).

After obinutuzumab pre-induction treatment, the risk of tumour lysis syndrome (TLS) was downgraded in most patients. There was no clinical TLS and 2 cases of laboratory TLS (1 in pre-induction, 1 with obinutuzumab + venetoclax treatment). At randomisation, undetectable MRD was 79–88% and overall response rate (ORR) was 97% (32% in complete remission [CR] and 65% in partial remission [PR]).

The primary endpoint was the proportion of patients who have MRD-negative bone marrow after a maximum of 24 cycles of venetoclax and no progression at any earlier time point after randomisation. In arm A (n=32), 28 patients received 12 cycles of venetoclax; 19 patients showed undetectable MRD and no progression, with an ORR of 88% (CR 16 patients; PR 12 patients; disease progression 3 patients). In arm B (n=30), 1 patient received 3 cycles of venetoclax; 17 patients showed undetectable MRD and no progression, with an ORR of 97% (CR 19 patients; PR 10 patients; disease progression 1 patient). In arm B, patients who were MRD-negative at randomisation did not start venetoclax treatment. The safety profile of arms A and B were similar. Adverse events were mostly pulmonary infections.

In summary, 2 cycles of obinutuzumab pre-induction led to a lower TLS risk in most patients receiving obinutuzumab + venetoclax, which was shown to be a highly effective treatment regimen in first-line, for FCR-unfit patients. Venetoclax consolidation treatment (arm A) and MRD-based venetoclax consolidation (arm B) were well tolerated and led to high efficacy outcomes 2 years after starting treatment.

    1. Kater AP, et al. J Clin Oncol 2020;38(34):4042–54.

    2. Levin MD, et al. MRD-guided or fixed 12 cycles of venetoclax consolidation after venetoclax plus obinutuzumab treatment in first-line FCR-unfit patients with CLL: primary endpoint analysis of the HOVON 139/GiVe trial. P409-5, EHA 2021 Virtual Congress, 9–17 June.


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