Fixed-duration ibrutinib–venetoclax with MRD-guided ibrutinib–obinutuzumab intensification in first-line chronic lymphocytic leukaemia (HOVON 158/NEXT STEP): primary analysis of a multicentre, open-label, phase 2 trial

Background:

Triplet regimens combining a Bruton's tyrosine kinase inhibitor, B-cell lymphoma 2 inhibitor, and anti-CD20 antibody are among the most effective first-line treatments for chronic lymphocytic leukaemia, but come with substantial toxicity. We investigated whether fixed-duration ibrutinib plus venetoclax, followed by ibrutinib plus obinutuzumab intensification for individuals with residual disease only, could offer a more tailored and less toxic alternative. 

Methods:

HOVON158/NEXT STEP was an open-label, phase 2 study at 17 hospitals in the Netherlands and Denmark. Eligible participants were aged 18 years or older with previously untreated chronic lymphocytic leukaemia, requiring treatment according to the International Workshop on Chronic Lymphocytic Leukemia, with an Eastern Cooperative Oncology Group performance status of 0, 1, or 2. Participants with complete remission or complete remission with incomplete count recovery and undetectable measurable residual disease (<10⁻⁴ uMRD4) in bone marrow after 15 28-day cycles of oral ibrutinib (420 mg once daily) plus oral venetoclax (5-weekly ramp-up from cycle 4 up to 400 mg once daily) discontinued treatment; all other participants received an additional six cycles of ibrutinib plus obinutuzumab intravenously (1000 mg on days 1, 2, 8, and 15 of cycle 1 and day 1 of cycles 2–6). The primary endpoint was bone marrow uMRD4 complete remission or complete remission with incomplete count recovery 3 months after the end of intensification with ibrutinib plus obinutuzumab in participants who were not in complete remission or who had detectable measurable residual disease (MRD) on ibrutinib plus venetoclax, and analysed according to the modified intention-to-treat principle excluding participants retrospectively deemed ineligible. All participants who received at least one dose of the study drug were included in the safety assessment. This report is the primary endpoint analysis of this trial, which is registered at ClinicalTrials.gov , NCT04639362 , and is ongoing. 

Findings:

Between Dec 29, 2020, and Aug 20, 2021, 85 participants were enrolled, 84 of whom were eligible (56 male and 28 female). The intensification group consisted of 55 participants (37 male and 18 female) and the observation group consisted of 17 participants (11 male and six female). 3 months after the end of ibrutinib plus obinutuzumab treatment, 33 (60%; 90% CI 48–71) of 55 participants had bone marrow uMRD4 complete remission or complete remission with incomplete count recovery. The most common grade 3–4 adverse events during ibrutinib plus venetoclax treatment were neutropenia (36 [43%] of 84 participants) and infections (19 [23%] participants), and the most common during ibrutinib plus obinutuzumab treatment were neutropenia and thrombocytopenia (five [10%] of 52 participants) and nervous system disorders (4 [8%] participants). Serious adverse events occurred in 28 (33%) participants receiving ibrutinib plus venetoclax and seven (13%) participants receiving ibrutinib plus obinutuzumab. There were no treatment-related deaths. 

Interpretation:

An intensification strategy guided by response and MRD deepened remissions in individuals with residual disease and spared early responders further treatment. This approach merits further study as an alternative to fixed-duration triplet therapy.