A Targeted Approach to Treatment: The Last Decade in CLL Care

Back then, chemoimmunotherapy was still a major part of CLL treatment. Rituximab, an antibody that targets B cells, had already changed treatment for many B-cell cancers.

“When I finished medical school in 2011, rituximab had been on the market for 10 or 15 years and had really started changing our management of patients with B-cell malignancies. But basically, the treatment of CLL was rituximab plus chemotherapy,” Dr. Kline explains.

In the years that followed, an expanding number of targeted therapies changed that approach. The incredible advances mean more patients can live wth CLL without major disruptions to their quality of life.

The Evolution of Targeted Therapy

There are a range of targeted treatment options available for patients living with CLL.

“Over the subsequent decade and a half, we’ve had BTK inhibitors starting with ibrutinib and then acalabrutinib and zanubrutinib, the BCL-2 inhibitor venetoclax, another CD20 antibody, obinutuzumab, which has been a really good option for CLL treatment, taking the place of rituximab in some situations,” Dr. Kline explains.

Today, targeted therapy options for CLL include:

• BTK inhibitors, including ibrutinib, acalabrutinib, and zanubrutinib, block Bruton tyrosine kinase, an important signaling protein that helps CLL cells survive.
• Venetoclax, a BCL-2 inhibitor, targets another pathway that CLL cells depend on.
• Obinutuzumab, another more potent anti-CD20-directed antibody, has also become an important treatment option.

Some modern treatment approaches combine these targeted therapies, allowing many patients to receive effective treatment without traditional chemotherapy. For example, the FDA approved the BTK inhibitor acalabrutinib in combination with venetoclax for previously untreated CLL/SLL.

Pirtobrutinib (Jaypirca) is a newer type of BTK inhibitor known as a non-covalent or reversible BTK inhibitor. It can be particularly useful when CLL has progressed after treatment with a covalent BTK inhibitor such as ibrutinib, acalabrutinib, or zanubrutinib.

The FDA granted approval for pirtobrutinib for relapsed or refractory CLL/SLL after prior treatment with a covalent BTK inhibitor in December 2025.

The Emergence of CAR T-cell Therapy

Another major development has been the emergence of CAR T-cell therapy, a personalized treatment that modifies a patient’s own immune cells to recognize and attack cancer cells. CAR T-cell therapy is being used for selected patients with difficult-to-treat CLL, while additional cellular therapies and targeted treatments continue to be studied.

“More recently, [with] CAR T becoming an option, pirtobrutinib as a non-covalent BTK inhibitor … just multiple types of targeted agents that have really supplanted chemotherapy and improved outcomes for patients with CLL,” Dr. Kline explains.

For patients, this transformation means that a CLL diagnosis today is very different from what it was just 10 years ago. There are now multiple targeted treatment options, and physicians can consider the biology of the leukemia, previous treatments, other health conditions, and individual patient preferences when selecting therapy.

The progress is continuing. Some of these approaches will eventually provide additional options for patients whose CLL becomes resistant to current therapies.

Questions To Ask Your Doctor

• Are there any new targeted treatment options or drug combinations I should consider?
• What side effects should I be aware of with targeted therapy?
• What are my options if my disease does not respond to targeted therapy?
• Should I consider CAR T-cell therapy? Is it possible in my case?

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