The Evolving Landscape of First-Line CLL Therapy
For patients with chronic lymphocytic leukaemia (CLL), the shift from chemoimmunotherapy to targeted agents has fundamentally transformed the standard of care. Currently, combinations involving Bruton’s tyrosine kinase (BTK) inhibitors and B-cell lymphoma 2 (BCL2) inhibitors represent the vanguard of treatment. Triplet regimens—incorporating a BTK inhibitor, a BCL2 inhibitor, and an anti-CD20 monoclonal antibody—have demonstrated exceptional efficacy in achieving deep, durable remissions. However, the high potency of these triplets often comes at the cost of increased hematological toxicity and a higher incidence of infections.
The HOVON 158/NEXT STEP trial addresses a critical question in clinical oncology: Can we achieve the efficacy of a triplet regimen while minimizing toxicity through a tailored, response-adaptive approach? By using measurable residual disease (MRD) as a biological compass, the study explored whether intensification should be reserved only for those who fail to reach deep remission after an initial doublet therapy.
Study Design and Methodology: The NEXT STEP Protocol
HOVON 158/NEXT STEP was a multicentre, open-label, phase 2 trial conducted across 17 specialized hematology centers in the Netherlands and Denmark. The study enrolled 85 treatment-naive patients with CLL who required therapy according to the International Workshop on Chronic Lymphocytic Leukemia (iwCLL) criteria. Participants were required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
The treatment protocol was divided into two distinct phases. In the initial phase, all participants received 15 cycles (each 28 days) of oral ibrutinib (420 mg daily). Oral venetoclax was introduced at cycle 4 with a standard 5-week ramp-up to a maintenance dose of 400 mg daily. Following 15 cycles, patients underwent a comprehensive response assessment, including bone marrow biopsies to evaluate measurable residual disease at a sensitivity of 10^-4 (uMRD4).
Patients who achieved a complete remission (CR) or complete remission with incomplete count recovery (CRi) along with undetectable MRD in the bone marrow (BM uMRD4) were assigned to the observation group and discontinued treatment. All other participants—those with detectable MRD or who achieved only a partial remission—entered the intensification phase. This second phase consisted of six additional cycles of ibrutinib (420 mg daily) combined with intravenous obinutuzumab (1000 mg on a standard schedule). The primary endpoint was the proportion of patients in the intensification group who reached BM uMRD4 CR/CRi three months after completing the ibrutinib-obinutuzumab regimen.
Results: Deepening Responses via Tailored Intensification
Between December 2020 and August 2021, 84 eligible participants were analyzed. After the initial ibrutinib-venetoclax phase, only 17 patients (20%) met the stringent criteria for the observation group, highlighting the challenge of achieving bone marrow uMRD4 with a doublet alone within 15 cycles. The remaining 55 patients entered the intensification phase.
The primary analysis yielded positive results for the intensification strategy. Three months after completing the ibrutinib-obinutuzumab intensification, 33 out of 55 participants (60%; 90% CI 48-71) achieved the primary endpoint of BM uMRD4 CR or CRi. This represents a significant conversion rate, demonstrating that the addition of an anti-CD20 antibody can successfully deepen remissions in patients who remain MRD-positive after BTK and BCL2 inhibition.
Secondary analyses indicated that the strategy was effective across various genetic subgroups, although the trial was not powered for definitive subgroup comparisons. The ability to convert over half of the suboptimal responders to a deep uMRD state suggests that the sequential addition of agents based on response is a viable alternative to simultaneous triplet administration.
Safety and Tolerability: A Manageable Profile
The safety profile observed in HOVON 158 was consistent with the known toxicities of the individual agents, though the sequential nature of the trial allowed for a nuanced view of adverse event timing. During the initial ibrutinib-venetoclax phase, the most common grade 3-4 adverse events were neutropenia (43%) and infections (23%). Serious adverse events (SAEs) occurred in 33% of participants during this initial phase.
In contrast, the intensification phase with ibrutinib-obinutuzumab appeared relatively well-tolerated. Grade 3-4 neutropenia and thrombocytopenia occurred in 10% of the 52 participants who started this phase. Nervous system disorders were reported in 8% of the intensification group. SAEs during intensification were lower than in the initial phase, occurring in 13% of participants. Importantly, there were no treatment-related deaths reported throughout the study, suggesting that the intensification phase does not exponentially increase the cumulative risk of fatal complications.
Clinical Implications and Expert Commentary
The findings from the NEXT STEP trial suggest a paradigm shift toward personalized, time-limited therapy in CLL. Rather than a ‘one size fits all’ approach where every patient receives a triplet, clinicians might consider a ‘doublet first’ approach with the option to escalate.
Experts note that while upfront triplet therapy (such as the GAIA-CLL13 or GLOW regimens) provides high rates of uMRD, the HOVON 158 data shows that 20% of patients can achieve these results with a doublet alone, thereby avoiding the infusion reactions and logistical burdens associated with obinutuzumab. For the remaining 80%, the intensification phase effectively ‘rescues’ the response, bringing the majority to an undetectable MRD status. This ‘just-in-time’ intensification preserves the depth of response while potentially sparing a significant minority of patients from unnecessary drug exposure.
However, limitations must be acknowledged. This was a phase 2 study with a relatively small sample size. Long-term follow-up is essential to determine if the uMRD4 achieved through intensification translates into the same progression-free survival (PFS) benefits seen with upfront triplet therapy. Furthermore, the cost-effectiveness of monitoring MRD frequently to guide therapy must be balanced against the cost of the drugs themselves.
Conclusion
The HOVON 158/NEXT STEP trial provides robust evidence that an MRD-guided intensification strategy is both feasible and effective in first-line CLL. By tailoring the duration and intensity of treatment to the individual patient’s biological response, clinicians can maximize the depth of remission while potentially reducing the overall toxicity burden. This approach merits further investigation in randomized phase 3 trials to compare long-term outcomes against fixed-duration triplets and continuous BTK inhibitor monotherapy. As we move closer to the goal of ‘curing’ CLL or at least providing very long treatment-free intervals, response-adaptive strategies like those demonstrated in NEXT STEP will likely become a cornerstone of precision hematology.
Funding and Clinical Trial Information
This study was funded by Janssen. The trial is registered at ClinicalTrials.gov, identifier: NCT04639362.
References
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3. Al-Sawaf O, et al. Venetoclax-Obinutuzumab for Previously Untreated Chronic Lymphocytic Leukemia. N Engl J Med. 2019;380:2095-2107.