Novel CLL Therapies Prompt New Treatment Considerations

Now that targeted agents have “decisively” displaced chemoimmunotherapy as the first-line standard of care in chronic lymphocytic leukemia (CLL), clinicians and patients have a new set of factors to consider when choosing a therapeutic regimen.

In a new review article in the Blood Cancer Journal, corresponding author Matthew S. Davids, MD, MMSc, of the Dana-Farber Cancer Institute, and colleagues outlined the latest evidence and its implications for CLL treatment in the first-line setting.¹

Updates to national guidelines over the past 3 years have consistently centered on the use of targeted therapies, the authors noted. The recommended treatment options include continuous therapy with the selective Bruton’s tyrosine kinase (BTK) inhibitors acalabrutinib (Calquence; AstraZeneca) or zanubrutinib (Brukinsa; BeOne), or fixed-duration therapy with the BCL2 inhibitor venetoclax (Venclexta; Abbvie and Genentech) plus the CD20-directed obinutuzumab (Gazyva; Genentech) or the first-generation BTK inhibitor ibrutinib (Imbruvica; Pharmacyclics and Johnson & Johnson), the authors said. In some regions, they noted, the recommendations now include fixed-duration venetoclax plus acalabrutinib with or without obinutuzumab.

As those therapies have begun to predominate CLL treatment, Davids and colleagues explained that previous generalized treatment algorithms have become less useful.

“Instead, selecting the optimal treatment for a patient requires evaluation and weighting of many factors,” they said. Key among those factors, they added, is patient preference

The authors noted that the benefits of first-line monotherapy with a BTK inhibitor are well-documented, producing durable results in both high- and low-risk patients. They added that ibrutinib and acalabrutinib can also be used in combination with obinutuzumab and rituximab (Rituxan; Genentech and Biogen), though they said it is not clear whether such combinations produce superior results to monotherapy with a BTK inhibitor.

In high-risk patients, continuous BTK inhibitor therapy is generally preferred, Davids and colleagues said. A 2021 study, for instance, found that ibrutinib-based regimens led to superior long-term results compared to bendamustine and rituximab chemoimmunotherapy.² Second-generation BTK inhibitors have similarly shown strong results in high-risk patients, they added.¹ The investigators said current treatment guidelines tend to favor those second-generation BTK inhibitors over ibrutinib, as their selectivity translates into improved safety profiles, particularly when it comes to the risk of cardiac adverse events.

The authors also discussed the combination of venetoclax and obinutuzumab (Ven-Obi). They said the fixed-duration therapeutic strategy has a manageable safety profile in both fit and unfit patients with previously untreated CLL. The investigators said the risk of tumor lysis syndrome warrants consideration in regimens that include venetoclax, but they said the existing data suggests TLS risk can be managed. They noted that an analysis of data from the CLL14 trial found that only 3 of 216 patients who received Ven-Obi developed TLS, and in all of the cases, TLS occurred after obinutuzumab administration and before venetoclax initiation.³

With all of the movement in targeted therapies, the investigators said there is not much of a role for chemoimmunotherapy regimens in contemporary CLL treatment, though they said some patients—such as those who are young and fit and lack certain genomic features—may experience durable remissions with chemoimmunotherapy.¹ The authors said the long-term risks associated with chemoimmunotherapy render it an inferior option in most cases.

Ultimately, most patients will have more than one viable treatment option for first-line therapy, meaning that clinicians will need to rely on careful, informed discussions with patients.

“With effective shared decision-making, there has never been a better opportunity for prescribers to provide patients with CLL with a therapy that meets their individual therapeutic goals,” the authors said.

References

1. Davids MS, Stilgenbauer S, Tam CS. First-line treatment for CLL in the era of targeted therapy. Blood Cancer J. Published online January 8, 2026. doi:10.1038/s41408-025-01434-2
2. Woyach JA, Ruppert AS, Heerema NA, et al. Long-term results of Alliance A041202 show continued advantage of ibrutinib-based regimens compared with bendamustine plus rituximab (BR) chemoimmunotherapy. Blood. 2021;138(suppl 1):639. doi:10.1182/blood-2021-153146
3. Al-Sawaf O, Fink AM, Robrecht S, et al. Prevention and management of tumor lysis syndrome in patients with CLL and coexisting conditions treated with venetoclax-obinutuzumab or chlorambucil-obinutuzumab: results from the randomized CLL14 trial. Blood. 2019;134(suppl 1):4315. doi:10.1182/blood-2019-126570