CLL: Hematologists Face Off on Best Long-Term Strategy

Medscape

09-07-2025

In the age of targeted therapy, what's the best long-term strategy to treat chronic lymphocytic leukemia (CLL), the most common leukemia in Western countries? Should treatment be continuous to achieve deep remissions or time-limited to allow patients to take breaks?
At the 18th International Conference on Malignant Lymphoma (ICML) 2025 in Lugano, Switzerland, a pair of hematologists set aside their friendship for a few moments and took opposite sides in a debate over off-and-on BCL2 targeting vs continuous treatment with Bruton's tyrosine kinaseinhibitors (BTKis).
Here's a summary of their discussion — and insight from another specialist who provided perspective to Medscape Medical News.
Team Venetoclax: It's the 'Most Potent' Therapy
Hematologist John F. Seymour, MBBS, PhD, of the Royal Melbourne Hospital, Parkville, and the Peter MacCallum Cancer Center, Melbourne, both in Australia, supported on-and-off BLC2 targeting via therapy with venetoclax, which he called 'the most potent known anti-CLL therapy.'
He highlighted its early record of rapid improvement in patients and asked, 'Why would we not want to use a drug that potent?'
He cited data from the 2023 CLL13 study, which he said showed that venetoclax combinations have 'an astonishing and unprecedented ability to achieve incredibly deep remissions, as measured by undetectable MRD [measurable or minimal residual disease] rates in the peripheral blood above 90% with short term time-limited treatment.'
The study authors reported that 'venetoclax-obinutuzumab [VO] with or without ibrutinib was superior to chemoimmunotherapy as first-line treatment in fit patients with CLL.'
Seymour also noted phase 3 data from several studies demonstrating that time-limited therapy of 12-14 months achieved 4-year progression-free survival (PFS) rates between 75% and 85%, similar to continuous BTKi therapy outcomes. 'So in terms of PFS, both are equivalent,' he said.
Team BTKi: The Evidence Is in
Hematologist Stephan Stilgenbauer, MD, of Ulm University, Ulm, Germany, countered by emphasizing the extensive evidence base supporting continuous BTKi therapy, noting data from 'almost 2000 patients on nine clinical trials' with nearly 5 years of aggregate follow-up.
He added that 'we have a median follow-up time that is close to 50 years in aggregate, and even more importantly, seven of these nine trial arms involved the relevant CLL patient population — namely, patients of a median age of about 70 years.'
He contrasted this with more limited data for venetoclax combinations, stating that VO had evidence from only two trials, the CLL13 and CLL14 trials, with 'only a single arm' addressing the relevant older patient population. And the aggregated median follow-up time, he said, is just over 10 years.
Regarding efficacy, Stilgenbauer presented cross-trial comparisons showing 48-month PFS rates in older patients, with aggregate data showing 72% for BCL-2 inhibitors and 79% for '79% BTKis.'
'It is quite clear efficacy is better with [BTKis],' he said.
Team Venetoclax: Listen to Guidelines and Patients
Seymour highlighted European Society For Medical Oncology (ESMO) recommendations regarding therapy. ESMO's 2024 interim guideline update says that in front-line therapy, 'first-line treatment in patients with CLL regardless of IGHV [immunoglobulin heavy chain variable region status] but without a TP53 mutation or del(17p), preference should be given to time-limited therapies and to therapies and/or combinations with longer follow-up data, if efficacy is similar.'
However, the 2021 ESMO guidelines offer these cautions about time-limited therapies: 'side-effect profile (renal impairment and risk of TLS [tumor lysis syndrome] vs atrial fibrillation and bleeding risk), application mode (intravenous [IV] application with combination therapy due to the antibody infusion vs oral medication only), intensity of controls (5-week ramp-up period with the combination), and shorter follow-up have to be taken into consideration.'
Seymour also noted patient preference data showing that 'the most dominant factor for patients' preference with given equivalent efficacy was shorter duration of treatment.'
As for adverse effects, Seymour argued that current protocols have minimized this risk for TLS. 'Interventions are very uncommonly needed. When analyzing aggregate data, TLS is in less than 1 in 200 patients,' he said.
He contrasted this with the risks of continuous therapy, noting that 'continuous accumulation of risk of adverse events is seen, and some of those, and the most troublesome among those are cardiovascular. That can be atrial fibrillation or flutter. While second-generation drugs have a lower rate, they still occur, and they still increase with time.'
Most devastatingly, 'the risk of sudden cardiac death is increased with ibrutinib across a number of these studies. And that risk continues to accumulate with time.'
Team BTKi: Safety Matters
Stilgenbauer challenged safety perceptions about BTKis, highlighting the CLL12 placebo-controlled trial. 'When you look at the adverse event table from this trial, you see that all of these so-called treatment-emergent adverse events that occurred with ibrutinib also occurred with placebo,' he said. 'These adverse events occur due to the disease and not due to the treatment.'
He also noted safety data showing higher rates of severe neutropenia in venetoclax combinations. 'You have a high-grade neutropenia in more than 55% of patients. You have thrombocytopenia, anemia, you have febrile neutropenia and pneumonia,' Stilgenbauer said, comparing this to single-digit percentages with BTKis.
The Outside Expert: Focus on Patient Characteristics
Medscape Medical News contacted Hematologist Seema Ali Bhat, MD, of The Ohio State University in Columbus, Ohio, and asked her for her perspective. Here are excerpts from our conversation:
What do you think regarding time-limited venetoclax-based therapy vs continuous BTKi therapy?
Both regimens are highly effective options for CLL, and the choice between them should be individualized. Time-limited venetoclax combinations (with obinutuzumab or acalabrutinib +/- obinutuzumab) offer the advantage of finite therapy, with potential for deep remissions, MRD negativity, and treatment-free intervals.
On the other hand, BTKis have shown sustained efficacy with long-term data, even in high-risk groups. In fact, a pooled analysis of three trials showed that first-line treatment with ibrutinib provides long-term overall survival benefits, with estimates similar to those of an age-matched adult population.
What should hematologists be thinking about when they make decisions regarding treatment in these patients?
Several factors should guide treatment selection:
•Patient-specific factors: age, fitness, cardiovascular comorbidities (atrial fibrillation, hypertension, congestive heart failure, etc.), renal function, medication adherence, and treatment goals.
BTKis are known to have cardiac adverse effects, so patients with underlying uncontrolled cardiac condition like atrial fibrillation or hypertension may not be suitable for this kind of therapy.
On the other hand, patients with renal dysfunction may be prone to worsening renal function due to risk for TLS with venetoclax.
•Patient preferences: If a patient does not want to come in for frequent laboratory monitoring during venetoclax ramp-up, a BTKi is preferred. Similarly, if coming for IV infusions for 6 months is burdensome, it is better to avoid a VO regimen.
If there is a patient who wants fixed duration therapy but prefers not to have IV treatments, the acalabrutinib plus venetoclax (AV) regimen will be ideal in this case.
The consideration of patient preferences is important. Some patients value time off treatment and the concept of deep remissions while others may prioritize fewer visits or simpler oral treatments.
•Disease characteristics: We take disease biology into consideration, especially IGHV mutation status and TP53 disruption. In the CLL14 study, it was very clear that in patients with TP53 disruptions, the responses were not as durable as in patients without these abnormalities. Studies with BTKis have consistently shown similar outcomes in patients with or without TP53 disruption.
•Drug interactions: Due to an increased risk for bleeding, it is advised to be cautious when combining BTKis with blood thinners. In a patient who is at an increased risk for bleeding, venetoclax-based therapy may be preferred.
•Access and cost: Time-limited therapy may be more cost-effective, but access to obinutuzumab and logistical complexity of venetoclax ramp-up can be barriers.
Shared decision-making is essential, especially as both options — time-limited or continuous offer excellent outcomes in many patients.
Is there anything else you'd like to add about this topic?
Head-to-head comparisons between these different types of treatments are ongoing — for example, trials like FLAIR and CLL17— so we are eagerly awaiting those results which may help further refine this field.
Also, the oral doublets have so far been compared with chemoimmunotherapy, it will be important to see how AV compares to VO in the MAJIC trial or how zanubrutinib plus sonrotoclax, a new BCL2 inhibitor, compares to VO in the CELESTIAL trial.
Until we have definitive long-term comparative data, clinicians should avoid rigid treatment algorithms.