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

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

Fixed duration treatment of chronic lymphocytic leukaemia (CLL) patients with venetoclax combined with an anti-CD20 antibody results in high rates of undetectable minimal residual disease (uMRD) and prolonged progression-free survival (PFS) [1]. The next step in CLL treatment may be a tailored approach based on remission status.

The randomised, phase 2 HOVON 139/GiVe trial included naïve CLL patients that were unfit for first-line fludarabine, cyclophosphamide, and rituximab and studied the impact of a standard or MRD-based addition of venetoclax for 12 cycles after induction treatment with obinutuzumab plus venetoclax. Dr Mark-David Levin (Albert Schweitzer Hospital, the Netherlands) presented the primary endpoint analysis after a maximum of 24 cycles [2].

Patients (n=70) received 2 cycles of obinutuzumab for pre-induction followed by induction with 6 cycles of obinutuzumab plus venetoclax, subsequently followed by 6 cycles of venetoclax monotherapy. Patients were thereafter randomised 1:1 to maintenance therapy in 2 arms. Arm A received venetoclax for 12 additional cycles irrespective of MRD status and arm B received MRD-guided venetoclax. After obinutuzumab pre-induction treatment, the risk of tumour lysis syndrome (TLS) was downgraded in a majority of patients. At randomisation, uMRD was 79% to 88%.

After obinutuzumab pre-induction overall response rate (ORR) was 43%, which increased after the venetoclax monotherapy to 97%. The primary endpoint was the proportion of patients who had 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 uMRD and no progression. In arm B, patients who were MRD-negative at randomisation did not start venetoclax treatment. In arm B (n=30), only 1 patient received 3 cycles of venetoclax; 17 patients showed uMRD and no progression.  The safety profile of arms A and B were similar with some advantages in arm B. Adverse events were mostly pulmonary infections.

In summary, 2 cycles of obinutuzumab pre-induction abrogated TLS risk in a large majority of patients receiving obinutuzumab plus venetoclax. Venetoclax consolidation treatment, both at fixed cycles and MRD-based, was highly effective and well tolerated.

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 Congress, 09–17 June.

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Posted on 16 June 20215 August 2021