Chronic Lymphocytic Leukemia (CLL) is a B-cell malignancy that is caused by the abnormal proliferation of B-cells, which are found in the blood, bone marrow, lymph nodes and other organs. Over the past few years, many CLL treatments have gone from being traditional chemotherapy to targeted therapy, with many patients now treated with BTK (Bruton’s Tyrosine Kinase) inhibitors. BTK inhibitors are one class of therapies used in the management of CLL.
Use of BTK Inhibitors for Treatment of CLL – a Patient-Centric View. There is more to CLL treatment than just the use of BTK Inhibitors to treat the CLL itself. The patient’s symptoms, age, co-morbidities, other medications, preference, potential toxicities, convenience and longer-term goals all need to be considered when choosing and managing a CLL treatment that includes a CLL BTK inhibitor for the treatment.
Understanding BTK Inhibition in CLL
BTK is a key component involved in the signaling pathway through the B-cell receptor for B-cells. The B-cell receptor signaling pathway controls B-cell development, activation, migration, proliferation and survival. In CLL cells, signaling via the B-cell receptor controls survival.
BTK inhibitors are medicines that inhibit the activity of Bruton’s tyrosine kinase (BTK) which is a crucial component in B-cell receptor signaling pathway. Inhibition of this pathway disrupts the signals that give cell survival processes to CLL cells.
With their introduction as treatment options in CLL into clinical practice several years ago, the BTK inhibitors have significantly broadened the spectrum of available treatments not only for previously untreated but also for relapsed and/or treatment refractory CLL patients.
When Treatment Is Needed
While most people with CLL start treatment within 6-12 months of diagnosis, many patients are first observed for slow growing disease for extended periods of time before symptoms or low blood counts develop. It is at this time of active disease that patients typically start consideration of treatment of their CLL.
When considering the timing of cancer treatment, not all patients with CLL should be placed on therapy immediately. Several factors need to be taken into consideration for the individual patient including their overall health, presence of other medical conditions, current medications, and other personal circumstances that may affect treatment.
Considering the Individual Patient
CLL is a disease of older adults, frequently presented in individuals with a variety of co-existing chronic medical conditions. When developing a treatment plan for a patient with CLL, it is essential to incorporate a list of the patient’s current medications as well as any existing medical problems (including bleeding and cardiovascular disease) as well as any previous clinical problems such as bleeding, infections, etc.
The patient’s current medication may also affect treatment decisions. The clinician must know if the patient is taking anticoagulants, antiplatelet agents, or any other medications that could have an adverse interaction with the cancer treatment chosen for the patient or could increase the risk of certain adverse events.
The patient’s ability to receive repeated measurements, to take oral medication daily for extended periods, and to report any adverse events in between clinic visits must all be considered.
Safety and Tolerability
As for adverse reactions BTK inhibitors can cause, there are many such events, with cardiovascular events, bleeding and infections being more common. Also gastrointestinal events, cytopenias and others related to treatment can occur.
For example, a patient with a prior history of heart disease may have a different risk profile with respect to cardiovascular events with a BTK inhibitor than the average patient. Similarly, a patient on aspirin or other agents that affect blood clotting may have increased risk of bleeding events with certain BTK inhibitors.
Shared decision-making between patients and healthcare providers allows them to consider evidence against their individual values. So, two people with the same clinical presentation of CLL will likely consider treatment differently given their different clinical histories and their different values and priorities.
Treatment Convenience and Quality of Life
Most of the BTK inhibitors are oral medications, meaning that instead of going to an infusion center for treatment, patients can have their BTK inhibitor prescribed and administered by them outside of a hospital or treatment center. However, since many of these are to be taken daily for a long period of time, patients need to remember to take their BTK inhibitors on time.
The side effects of oral cancer treatment, which patients take daily for long periods of time, can affect the quality of life of cancer patients. Their impact is not limited to the treatment itself but also extends to their daily routine.
These are the sorts of questions and concerns that the patient should discuss with their health care provider, and these would include the details of the treatment such as the frequency of blood tests and the potential side effects of the treatment as well as what to do if a dose is missed.
Continuous Treatment and Long-Term Planning
An important consideration of BTK inhibitors in CLL is the treatment durations as BTK inhibitors are therapy for chronic diseases like CLL until the disease progresses or becomes unacceptable to continue. Use of BTK inhibitors in fixed-duration strategies, either as single agents or in combination with other targeted therapies, is also currently under investigation.
Since CLL is typically a chronic disease and can be returned in the future, managing a patient on BTKi therapy for an extended period will require long-term planning and the possibility that the disease may return or become refractory to therapy and change to an alternate therapy.
BTK inhibitors are not devoid of resistance. Many cases of resistance to covalent inhibitors of BTK have been studied and acquired alterations in BTK or downstream signaling pathways have been identified as the principal mechanisms of resistance.
The Importance of Shared Decision-Making
In terms of Shared Decision Making between the physician and the patient, two patients with identical CLL characteristics can have entirely different treatment choices based on a variety of factors including their complete medical history, current medication list and associated drug interactions, lifestyle choices and personal preferences.
Examples of factors and questions for discussion with a patient that could be considered by a clinician when choosing between agents for a particular patient are shown in Box 1.
This can also include how treatment is going to affect patients in terms of work, travel and daily activities. The patient’s preferences and goals can be incorporated into the clinical evidence and form the basis of the treatment decision making process.
Monitoring During BTK Inhibitor Therapy
Blood counts, symptoms and disease-related changes, lymph node size, tolerance of treatment and signs of and potential treatment-related damage to health are all indicators that must be followed during treatment.
Identifying complications early on, before they become serious, is key to BTK inhibitor treatment. If for any reason, what or how a patient is treated needs to change, monitoring for complications and managing side effects is crucial. Patients must report any new or worsening symptoms to their doctor as soon as possible.
This monitoring is usually dictated by the specific treatment being taken by the patient as well as the stage of their disease.
Looking Ahead
Since the last update of this paper a great deal of new information has been reported about BTK-directed therapies, Several investigational BTK-targeted therapies are being evaluated in clinical research; their safety and effectiveness have not been established for routine clinical use as well as a number of new BTK-inhibitors that are designed to be reversible as well as combination regimens of BTK-inhibitors with other targeted therapies and/or conventional chemotherapy.
Future treatment strategies for CLL will likely include a molecular and sensitive biological profile of each patient, their prior therapy, concomitant diseases and their treatment, interactions with all of the patient’s current medications, potential toxicity and safety issues, convenience of administration and potential effects on patient’s quality of life and long-term outcome.
Conclusion
Palliative treatment of CLL with BTK inhibitors has to be tailored to the patients’ total medical care needs. The choice of the appropriate BTK inhibitor can be based on a variety of factors including the patient’s disease, prior therapy, co-morbidities, medications the patient is already on, potential toxicities, convenience, and impact on quality of life as well as planning for the long-term.
Ongoing research is evaluating approaches that may support more individualized treatment strategies in CLL. The clinician will take into consideration the molecular features of the patient’s CLL, the previous treatments and their side effects, as well as the patient’s co-morbidities, current medicines, and interactions between these and the BTK inhibitor. Moreover, the convenience of the treatment, the impact on the patient’s quality of life, and the long-term management of the treated patient will be major factors to be considered for making clinical decisions.
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.
