Cancer treatment is moving away from traditional chemotherapy, although in specific circumstances it can still be the best option to treat B-cell malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and other types of B-cell cancers. Several targeted therapies have been developed and evaluated in recent years.
When it comes to treating B-cell cancers, such as non-Hodgkin’s lymphoma and chronic leukemia, like CLL (Chronic Lymphocytic Leukemia), many of the new B-cell malignancy medicines are targeted therapy and specifically are BTK inhibitor drugs. The class of targeted BTK inhibitor drugs interfere with the enzyme Bruton tyrosine kinase (BTK), involved in B-cell receptor signaling. These drugs inhibit signaling pathways involved in the survival and growth of certain malignant B cells.
Understanding the Role of BTK in B-Cell Cancers
B cells communicate in two main ways: by releasing chemicals from their surface and by responding to chemicals in the environment by growing, splitting and dying in an ordered fashion. Much of the signaling for these processes occurs through the B cell receptor (BCR), a complex of proteins on the surface of B cells that recognizes and binds to specific chemicals (such as proteins).
B cells from patients with B-cell malignancies also utilize these pathways for growth, survival and malignant transformation. Thus, by inhibiting BTK, these drugs can interfere with signaling crucial for the survival of malignant B cells.
In contrast to conventional chemotherapy drugs that primarily kill rapidly dividing cancer cells, targeted cancer therapies work by attacking specific cancer-causing molecular abnormalities. Like conventional cancer drugs, however, targeted cancer therapies can have several adverse effects, affecting not only cancer cells but also normal cells.
From Ibrutinib to Newer BTK Inhibitors
Developed by Washington University School of Medicine and developed by several pharmaceutical companies, ibrutinib (PCI-32741) was the first in its class of a family of very potent BTK inhibitors (as described above) to be approved for use in treating several types of B-cell malignancies and also several B-cell related lymphoproliferative disorders.
Other BTK inhibitors also have been studied, such as acalabrutinib and zanubrutinib. These are considered to be as covalent inhibitors of BTK as ibrutinib and, thus, have similar mechanisms of action but vary in their potential for inhibition of BTK and for reactions that could result in adverse effects.
Pirtobrutinib is a non-covalent BTK inhibitor that binds to BTK through a different mechanism than covalent BTK inhibitors (eg, ibrutinib, acalabrutinib). For patients whose disease has relapsed on prior treatment with a covalent BTK inhibitor, Pirtobrutinib may provide an alternative option.
The approval status of the above molecules and their usage as single agents or in combination within different clinical settings vary from country to country and require specific approval from respective regulatory bodies.
Expanding Treatment Options for CLL
The most notable disease to be treated with BTK inhibitors, to date, is CLL (Chronic Lymphoid Leukemia). Given the variability in presentation and in the complexity of the disease in terms of driver mutations and other genetic abnormalities, the strategy for treatment of CLL is highly individualized.
The use of BTK inhibitors in the treatment of CLL can be as part of initial treatment and / or for the treatment of relapsed or refractory disease.
While these new agents hold promise in therapy for some cancer patients, there are no plans to remove chemotherapy from cancer treatment. Different cancers require individualized treatment and chemotherapy still remains a mainstay in cancer treatment for many patients.
Moving Toward Combination Treatment
Ongoing research is also examining the combination of BTK inhibitors with other single agent targeted therapies, including those that are already approved by regulatory authorities and those that are in development.
Some examples of combination research include the BTK inhibitor plus venetoclax, a BCL2 inhibitor used in patients with CLL to kill malignant B cells. There are also studies evaluating the use of BTK inhibitors with other targeted agents to treat other types of B-cell malignancies.
Researchers are evaluating whether combination approaches may influence treatment outcomes. To identify the most promising combinations and the patients who may be appropriate candidates for these treatment approaches studies are being conducted to evaluate the benefits of different combinations of such treatments.
The Importance of Molecular and Genetic Testing
For increasingly targeted treatment it is important to know the individual patient’s disease in more detail.
TP53 alterations and chromosome 17p deletions are well-established markers in CLL that affect treatment choices. The similar use of molecular, and other, genetic markers to inform the choice of individual and / or combination of drugs in leukaemia and lymphoma is an active area of research and therapeutic development. Other factors that have to be considered are: Prior treatments; Tumor resistance; Co-morbidities; Drug-drug interactions.
This means that two patients with a similar type of cancer (e.g. CLL) may be treated differently for a number of reasons including the presence of genetic alterations, previous treatment with specific types of therapies, concomitant medical problems and the potential for drug-drug interactions with medications that the patient is currently on.
Managing Safety and Side Effects
Like all medicines, the BTK inhibitors have side effects which can vary between individual medicines, and between individual patients.
Adverse events (AEs) for some of the BTK inhibitors being studied include Fatigue, Diarrhea, Nausea, Headache, Muscle pain, Joint pain, Infections and others. Some of the BTK inhibitors can cause: Bleeding and/or Increased risk of bleeding, Cardiovascular effects (e.g. atrial fibrillation).
As with all medications, some adverse reactions can occur; therefore, it is crucial to reveal any present illnesses and all current medications, including those available over the counter and any supplements, to her physician. Also, patients should be informed of any side effects.
Monitoring for adverse events and making treatment changes as necessary to treat any adverse events that occur is also important for these drugs.
What Happens When Resistance Develops?
The problem of treatment resistance in the long-term care of B-cell malignancy patients is significant. Reasons for resistance to treatment of B-cell malignancies as well as ways to adapt treatment are studied by researchers.
In cancer therapy resistance can often be observed as cancer cells adapt to the presence of drugs and develop a resistance to them. This is also true for BTK-inhibitors, and we are currently trying to find out why this resistance develops and how can change or add other treatments to overcome it.
These can be compared with others having different binding profiles. There are also BCL2 inhibitors, an increasing number of antibody-based therapeutics, as well as many more schemes involving combinations of therapies, and lastly, also a growing number of approaches using cell-based therapies.
The non-covalent BTK inhibitors are becoming more and more the object of preclinical and clinical research, not least because of their potential use in patients who have already been exposed to covalent BTK inhibitors.
The Future of B-Cell Malignancy Care
As move into the future of treatment for B-cell malignancies, it is likely to be given on an individual basis and often in combination. Will consider the specific disease, prior treatment and its response, as well as potential resistance.
Research is also being carried out into the concept of measurable residual disease (MRD) to determine the amount of cancer left in the body after treatment and the length of time for which patients should receive further therapy.
In the future, new treatments for B-cell malignancy will be evaluated in clinical trials and researchers will continue to search for new treatments to add to current therapies.
What Patients Should Discuss with Their Doctor
Hematologist/Oncologist
- Why is BTK inhibitor being recommended?
- Which BTK inhibitor is appropriate for my condition?
- How long might treatment continue?
- What side effects should I watch for?
- Could my current medicines interact with the treatment?
- Will I require regular blood or heart monitoring?
- Are combination treatments appropriate for my disease?
- Are there relevant clinical trials?
More medicines, in combination or alone, are being investigated for use in the treatment of B-cell malignancies. A choice of treatment is being developed for use in individual patients with specific diagnoses and different treatment histories.
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.
