Targeted Therapy Combinations Shine in Upfront CLL Treatment

Frontline therapy options for the treatment of chronic lymphocytic leukemia (CLL) have significantly evolved in recent years, driven by new targeted therapies and innovative combinations to help improve survival outcomes.

Time-limited versus indefinite approaches are becoming more widely used among clinicians to treat patients with CLL, according to Nitin Jain, MD, MD Anderson Cancer Center, Houston, Texas, who presented current, future, and soon-to-be phased out CLL therapies at the Pan Pacific Leukemia Conference held July 15-18, 2025, in Lahaina, Hawaii.

Alkylating agents and chemotherapy have been bypassed by first and second-generation Bruton’s tyrosine kinase (BTK) inhibitors, B-cell lymphoma 2 (BCL-2) inhibitors, anti-CD20 monoclonal antibodies, PI3K inhibitors, and chimeric antigen receptor (CAR) T-cell therapy.

“The good thing is that all the therapies, whether you talk about a BTK inhibitor alone, BTK plus BCL-2, or BTK/BCL-2 plus CD20 antibodies, all of these are very effective therapies for patients with CLL,” Jain said in an interview with Blood Cancers Today.

On Target

During his discussion, “Optimal Upfront Treatment in CLL: A Moving Target Older Patients,” Jain explained indefinite therapies, such as ibrutinib, acalabrutinib with or without obinutuzumab, and zanubrutinib, and time-limited options (1 year) like venetoclax plus obinutuzumab, venetoclax plus ibrutinib (approved outside of the United States), and venetoclax plus acalabrutinib with or without obinutuzumab (an approval is expected).

Many of the clinical trials that he highlighted, such as RESONATE-2, ELEVATE-TN, and GLOW, included patients who ranged in median age from 60 to 73 years old.

Data from these trials showed significant progression-free survival and overall survival outcomes with BTK inhibitors compared with chemoimmotherapy. However, Jain shared challenges with this class of drugs, such as indefinite therapy, low complete response rates, and rarely observing undetectable minimal residual disease (MRD).

“All these trials have really come to the conclusion that, certainly, we should move away from chemotherapy. We should be doing targeted therapy for our patients,” Jain said.

He anticipates that BTK inhibitor monotherapy will be done except in specific cases, for instance, for patients with del(17p)/TP53 mutations and in those who are older and frail.

Moreover, Jain expects that venetoclax plus acalabrutinib will replace venetoclax plus obinutuzumab.

Triplet therapies will remain at the forefront. With an awaited FDA approval, the new preferred treatment choice may be venetoclax plus acalabrutinib with or without obinutuzumab, according to Jain.

Future Focus

While lisocabtagene maraleucel (liso-cel) is the only FDA-approved CAR-T therapy for CLL, it is only approved for patients with relapsed or refractory disease. Jain posed the question: Will immunotherapies, such as CAR T and bispecific antibodies, be used in the first-line setting?

Furthermore, the duration of combination therapies (1-year, 2-year, and MRD-guided) and mutated versus unmutated immunoglobulin heavy chain variable region gene should be investigated.

Ongoing clinical trials further advance the treatment landscape. “We’re expecting some data in the next 1-2 years. I think the results from those trials will further help us streamline or identify the right mix of treatment regimen for our patients with CLL,” Jain said.