HOVON 158/NEXT STEP: MRD-guided ibrutinib + obinutuzumab intensification in CLL

Results from the open-label, phase II HOVON 158/NEXT STEP trial (NCT04639362), investigating fixed-duration ibrutinib + venetoclax followed by measurable residual disease (MRD)-guided ibrutinib + obinutuzumab intensification in 84 adults with treatment-naïve (TN) chronic lymphocytic leukemia (CLL), were recently published in The Lancet Haematology by Kater et al. Patients with a complete response (CR) or CR with incomplete count recovery (CRi) and undetectable MRD (<10⁻⁴; uMRD4) in the bone marrow 3 months after fifteen 28-day cycles of ibrutinib + venetoclax discontinued treatment; all other patients received an additional 6 cycles of ibrutinib + obinutuzumab. The primary endpoint was CR/CRi rate with uMRD4 in the bone marrow 3 months after the end of intensification with ibrutinib + obinutuzumab. 

 Key data: Among 55 participants assigned to intensification, 60% (90% confidence interval [CI], 48–71) had a CR/CRi with bone marrow uMRD4 3 months after ibrutinib + obinutuzumab. Overall, 55% of the modified intention-to-treat (ITT) cohort (n = 84) that initiated ibrutinib + venetoclax therapy achieved CR/CRi with bone marrow uMRD4 at 9 months post-completion, irrespective of subsequent intensification or observation. Progression-free survival (PFS) was 94% (95% CI, 86–97) at 24 months and 92% (95% CI, 83–96) at 36 months. The most common Grade 3/4 adverse events (AEs) during ibrutinib + venetoclax were neutropenia and infections, and during ibrutinib + obinutuzumab were neutropenia, thrombocytopenia, infections, and nervous system disorders. There were no treatment-related deaths.  

Key learning: MRD-guided intensification with ibrutinib + obinutuzumab deepened responses in individuals with MRD after ibrutinib + venetoclax while sparing early responders from additional treatment, supporting further investigation of this tailored approach as an alternative to fixed-duration triplet therapy.