In CLL, New Therapies Offer Potential for Personalized Approaches

The treatment of chronic lymphocytic leukemia (CLL) has evolved dramatically over the past decade, with the development of targeted oral therapies. A new review article says the treatment landscape will continue to evolve as newer therapies are developed that may bring scientists closer to an elusive cure.

The study authors explored the latest developments in the treatment of CLL in a review published last month in the Journal of Clinical Medicine.¹

They noted that the standard treatment for progressive and symptomatic CLL had long been chemoimmunotherapy with cytotoxic drugs and CD20 monoclonal antibodies. However, not all patients benefit equally from such regimens. One study found that the median progression-free survival (PFS) following treatment with the FCR regimen of fludarabine with cyclophosphamide and rituximab (Rituxan) was 14.6 years in patients with mutated IGHV but just 4.2 years for those with unmutated IGHV.² And even though FCR works well in a subset of patients, it also creates a small risk of developing myelodysplastic syndrome or acute myeloid leukemia.¹

For those and other reasons, targeted oral therapies like Bruton tyrosine kinase inhibitors (BTKis) and the BCL-2 inhibitor venetoclax (Venclexta; Abbvie and Genentech) have become the standard first-line therapies.

Yet, CLL remains incurable, leading scientists to develop a range of new therapies and treatment strategies.

Among them are next-generation BTKis. The authors noted that covalent BTKis have achieved superior results to CIT, but their use is limited by cardiovascular toxicity and other adverse events. Some second-generation BTKis, including acalabrutinib (Calquence; AstraZeneca) and zanubrutinib (Brukinsa; BeOne) have been found to have lower rates of certain cardiac adverse events compared to first-generation BTKis.

Non-covalent BTKis like pirtobrutinib (Jaypirca; Eli Lilly) and nemtabrutinib are among another wave of BTKis being evaluated for the treatment of CLL.

Unlike covalent BTKis, “they do not depend on binding to C481 residue, which allows them to maintain activity in patients who have developed resistance due to C481 mutations,” the authors wrote.

Meanwhile, next-generation BCL-2 inhibitors and BTK degraders have shown promise in early clinical trials, the authors said. Among the second-generation BCL-2 inhibitors under investigation is sonrotoclax, they noted.

“Sonrotoclax is a more sensitive and more pharmacologically potent inhibitor of BCL-2 than venetoclax,” the authors noted. “Moreover, it has a shorter half-life and does not accumulate in the body observed.

Bispecific T-cell engagers have been approved in other malignancies, and several bispecific antibodies targeting CD3 and CD20 are under investigation in CLL, with more than 10 investigational trials ongoing. However, the authors cautioned that these drugs’ use in CLL “remains experimental.”

Other immunotherapeutic approaches, such as chimeric antigen receptor T-cell therapies, also hold significant promise, the authors said.

The investigators also discussed the potential of phosphoinositide 3-kinases (PI3Ks) as a treatment for relapsed or CLL. However, they said their potential role remains in question, in part due to high toxicity.

The authors noted that an additional consequence of the development of so many new therapies is that it is now possible to extend survival using time-limited, minimal residual disease (MRD)-guided treatment strategies. However, they added that disease resistance—and double-refractory patients, in particular—are emerging clinical challenges.

They said future management of CLL will rely increasingly on personalized treatment regimens, taking into account genetic and molecular biomarkers, MRD status, and individual risk profiles.

“Although a cure remains out of reach, the rapid development of new agents moves the field closer to achieving durable, treatment-free remission in many patients,” they concluded.

References

1. Robak T, Iskierka-Jażdżewska E, Puła A, Robak P, Puła B. The development of novel therapies for chronic lymphocytic leukemia in the era of targeted drugs. J Clin Med. 2025;14(22):8247. Published 2025 Nov 20. doi:10.3390/jcm14228247

2. Thompson PA, Bazinet A, Wierda WG, et al. Sustained remissions in CLL after frontline FCR treatment with very long-term follow-up. Blood. 2023;142(21):1784-1788. doi:10.1182/blood.2023020158