CLL is a malignancy of mature B cells, accounting for approximately 30% of all leukemia cases in the United States. Traditional therapies for CLL include external beam radiation therapy (RT) and chemotherapy; however, within the last decade, targeted therapy for the treatment of cancer has emerged, paving the road for specific approaches in managing CLL. These therapies target specific proteins that are involved in cancer cell growth and survival.
Targeted therapy for CLL is becoming increasingly individualized and determined by various parameters, including the patient’s and the leukemia’s characteristics, previous treatments, genetic changes, comorbidities, potential toxicity, and above all, treatment duration as well as the patient’s preference.
Understanding the Molecular Basis of CLL
CLL tumors need several signaling pathways to survive and to grow in the bone marrow. Many CLL cells are dependent on activation of the B-cell receptor (BCR) pathway and on blockade of programmed cell death.
The BTK pathway is activated by engagement of the B cell receptor. In CLL cells, this results in B cell proliferation, migration, adhesion, and survival. Thus, targeted inhibition of BTK with inhibitors like Zanubrutinib represents a treatment approach to block these critical signals that are essential for the B cell malignancy.
Inhibitors of another important target in CLL, BCL-2 (anti-apoptotic protein), in particular, venetoclax, cause CLL cells to undergo apoptosis.
BTK Inhibitors in CLL
BTK inhibitors are used as single agents or in combination with other therapies to treat patients with CLL and associated disease. Acalabrutinib, zanubrutinib, and ibrutinib are examples of this class of targeted therapy.
There are differences between the various BTK inhibitors and their use in appropriate patients. The covalent inhibitors of BTK bind to BTK irreversibly. In contrast, the non-covalent BTK inhibitors, including pirtobrutinib, are reversible binders.
While resistance to covalent BTK inhibitors often results from specific molecular alterations affecting the BTK protein itself, alternative BTK inhibition strategies are needed. Pirtobrutinib, a non-covalent, irreversible BTK inhibitor, was approved by the FDA in December 2025 for the treatment of adults with relapsed or refractory CLL/SLL previously treated with one or more covalent BTK inhibitors.
BCL-2 Inhibition
Targeted treatment for CLL using BCL-2 inhibition involves blocking the BCL-2 protein to inhibit CLL cells’ survival by blocking their ability to prevent programmed cell death (apoptosis).
Unlike most of the BTK inhibitors that are administered on a continuous basis until disease progression, therapeutic strategies that incorporate venetoclax into their fixed-duration regimens have established their roles in the treatment of CLL, including previously untreated CLL (venetoclax/Obinutuzumab) and previously treated CLL (venetoclax/Rituximab).
BTK and BCL-2 targeting constitute two separate biological mechanisms on distinct CLL survival pathways, making the study of therapeutic combinations a rapidly evolving area of cancer therapeutics.
Combination and Fixed-Duration Strategies
With the new classes of targeted therapies, treatment is often given in combination. With the B-cell receptor pathway blocked by BTK inhibitors, other survival pathways within CLL cells can be targeted by agents with different mechanisms of action.
For instance, irreversible inhibitors of BTK such as Zanubrutinib can inhibit BCR signaling; meanwhile, a BCL-2 inhibitor can induce apoptosis of malignant cells. The strategy for the use of these molecules in the clinic is being explored, and potential combinations are under investigation.
These therapies can be given on a continuing basis, but most are designed to be given for a certain period of time (fixed duration). The treatment regimen containing venetoclax is a fixed-duration treatment for certain patients with CLL, but BTK inhibitors are typically continued until disease progression or untenable toxicity.
Treatment Selection Based on Disease Biology
The modern management of CLL is increasingly determined by the biological characteristics of the individual patient’s disease. Significantly, deletions of 17p and inactivation of TP53 are of particular concern and generally viewed as poor prognostic features.
Patients with CLL and high-risk molecular features may have different outcomes to patients with normal genetics and thus need to be treated with targeted therapies different from those used for chemotherapy. Both BTK inhibitors and BCL-2 inhibitors are considered for the treatment of patients with previously untreated and/or previously treated CLL that requires therapy.
Therefore, treatment with targeted agents in patients with CLL needs to be selected on the basis of the individual patient’s disease and clinical situation, and not only because the drug is available.
Targeted Therapy in Relapsed or Refractory CLL
Additionally, treatment planning for CLL that has relapsed or is refractory to prior therapies can be challenging given the prior patient exposure to BTK inhibitors, BCL-2 inhibitors, and other therapies.
Pirtobrutinib is a non-covalent BTK inhibitor being used as a treatment for patients with CLL/SLL that are previously treated with other BTK inhibitors. In clinical studies, it has been evaluated in patients with CLL/SLL previously treated with a covalent BTK inhibitor. Patients included in the approval of Pirtobrutinib for previously treated patients with CLL/SLL were those from the BRUIN-CLL-321 study.
In clinical trials, pirtobrutinib is being studied in combination with venetoclax to treat CLL or SLL that is resistant to covalent BTK inhibitors.
Monitoring and Patient-Specific Considerations
There are side effects that can occur with targeted therapy. This is why, when choosing a treatment, consideration should be made for a patient’s cardiovascular risk, risk of bleeding, possibility of serious infections, impact on blood counts, potential for drug interactions, and clinical effects on organs and tissues.
The importance of adherence to oral treatments must not be underestimated. Patients need to be informed about the medicinal products, their use, possible adverse effects, the monitoring required and the duration of treatment with the specific medicinal product or treatment option.
Incorporation of considerations related to the patient’s treatment goals for oncology issues affecting Quality of Life (QoL) and issues that can influence a patient’s treatment burden into selection decision-making.
The Future of CLL Treatment
Targeted therapies are continually being studied to find new ways to treat CLL. These include the use of BTK inhibitors, given in combination with BCL-2 inhibitors or other novel BTK inhibitors (e.g. reversible inhibitors). Strategies to obtain improved treatment responses and to keep patients on therapy for shorter durations of time are also being evaluated.
Furthermore, clinical trials with novel kinase inhibitors and BTK-directed treatment regimens including combinations as well as fixed-dose duration strategies are ongoing. These trials will also help to determine optimal sequences of currently available as well as novel targeted treatments for CLL/SLL.
Conclusion
Targeted therapies have become a significant treatment option for the treatment of CLL. BTK inhibitors like Zanubrutinib act by blocking the B-cell receptor signaling pathway and BCL-2 inhibitors, such as venetoclax, induce apoptosis by another mechanism. These cancer treatments may be used as single agents or in sequence or in combination in specific patient populations.
As the treatment landscape for CLL continues to advance, tailoring therapy using emerging agents and combination regimens under investigation is expected to remain a key component of disease management.
Disclaimer: The information provided in this article is intended for educational purposes only and should not be interpreted as medical advice, a clinical guideline, or a recommendation for any specific treatment.
Written by Saurabh Sharma (saurabh.sharmadigital@gmail.com)
