A Closer Look at Treatment for CLL and How Therapeutic Approaches Are Evolving

Chronic lymphocytic leukemia (CLL) is a type of cancer of the blood and lymphatic system that originates from B lymphocytes (B cells), a subtype of white blood cells. Abnormal B lymphocytes or CLL cells tend to accumulate in the blood, bone marrow, lymph nodes, spleen and other organs, and in most cases progress slowly. Many people with CLL will have an indolent disease and may have no symptoms at the time of diagnosis.

While many CLL patients can be treated and go on to live for many years on their current therapy, for others the disease can progress rapidly. In addition to traditional chemotherapy treatments for CLL, targeted therapies have emerged. These therapies may be used alone or in combination with other treatments and target specific aspects of CLL biology.

Why CLL Management Can Differ Between Patients

There is great variation in the natural history of CLL, from patients with a stable disease of long duration without any symptoms at all to patients with an aggressive course. Therefore, when making treatment decisions for a given patient with CLL, a single diagnosis of CLL is not sufficient. Instead, other factors must also be taken into consideration by a patient’s health care team.

When deciding whether or not treatment is required for CLL there are a number of factors that are taken into account. These include the severity of symptoms, affected blood cell count, degree of lymph node enlargement and the degree of spleen enlargement. Also considered is the rate of disease progression, the patient’s genetic makeup and previous treatment for CLL as well as their overall health status.

Active surveillance, or watchful waiting, of CLL, such as is used for some early-stage cases of breast cancer and leukemias, is currently the treatment of choice for individuals without symptoms and with no active CLL.

Understanding Active Surveillance

Active surveillance, often called “watch and wait,” is A commonly used management strategy for selected patients with CLL who have early-stage disease. They are being watched, even though no treatment is being given and there are currently no symptoms associated with their leukemia. As with other patients with CLL, they have follow-up appointments with their treating doctor where the doctor performs a physical exam and orders blood work. He or she also asks the patient about symptoms.

Healthcare professionals may perform physical examinations, blood tests, and symptom assessments during follow-up visits. Monitoring may include evaluation of lymph node and spleen size, blood cell counts, and overall health status.

Active surveillance with treatment is indicated when CLL is active or producing symptoms, such as disease related anemia or thrombocytopenia, increase in size of lymph nodes or spleen, persistent fever, night sweats, unexplained weight loss, or disease related fatigue that worsens over time. Some stages of CLL will have an elevated lymphocyte count. However, an isolated elevation in the lymphocyte count is not in itself an indication for treatment.

The Shift Toward Targeted Treatment

Targeted CLL treatment includes new types of chemotherapy, as well as several other treatments that affect the CLL cells in different ways. They are used to treat the CLL by attacking the proteins and biological pathways that the cancer cells use to survive and to divide and grow.

Traditional chemotherapy works by killing cells that are rapidly dividing. Many normal cells also fall into this category and can be affected. In contrast, Targeted Therapies work by specifically targeting one or more of the key processes or proteins that the CLL cancer cells use to survive, grow and spread.

First, there are BTK inhibitors, which interfere with Bruton’s tyrosine kinase, a crucial protein in the B-cell receptor signaling pathway found in CLL cancer cells. Then, there are BCL-2 inhibitors such as venetoclax, which interfere with the BCL-2 protein and allows CLL cells to die naturally.

BTK Inhibitors

Bruton’s tyrosine kinase (BTK) is a key component in the B-cell receptor signaling pathway that is required for the activation and subsequent survival of B-cell malignancies, including CLL. BTK inhibitors are used to inhibit the B-cell receptor pathway. These are used in the treatment of CLL. Examples of BTK inhibitors are Zanubrutinib, ibrutinib, and acalabrutinib. Clinical studies have evaluated these therapies in various CLL treatment settings.

Treatment options using BTK inhibitors include Zanubrutinib, ibrutinib, and acalabrutinib. Since there are multiple BTK inhibitors available, there are various options that may be better for a specific patient based on the potential benefits and risks of treatment, as well as drug interactions and other clinical factors.

BCL-2 Inhibitors

The protein BCL-2 (B-cell lymphoma 2) is another important protein within the pathway of CLL. It prevents programmed cell death (apoptosis). CLL cells can become fully addicted to survival by BCL-2 in some cases. BCL-2 inhibitor used to treat CLL by promoting apoptosis of CLL cells. Apoptosis is programmed cell death. This agent is used as a single agent and in a number of regimens as part of combination treatment. It is typically given for a defined period of time in certain patients. These may be used as a single agent or in combination and in some cases provided for a fixed time period with a specific end point, which can be a distinct strategy from continuing on a treatment for life.

Combination and Time-Limited Strategies

Various medicines that interfere with different parts of the CLL cell can be used in combination, providing a variety of treatment options with different modes of action. Since they have different effects on the CLL cells and different side effects These approaches are being studied and used with the goal of improving treatment responses.

There are some strategies which are time-limited and others that are to be taken on an ongoing basis. The strategy depends on several factors including the patient’s disease and their prior treatment as well as their other medical comorbidities, potential drug interactions and side effects and their priorities.

Choosing the best treatment is not simply a case of picking the most therapy option. The key factors to be weighed up by health care professionals are disease control, safety, convenience, the amount of monitoring required and the patient’s treatment goals.

The Importance of Molecular Information

Molecular information plays a larger role in modern CLL management as genetic and molecular diagnostics and commercial tests are incorporated into diagnosis and into the management of patients with CLL.

Assessment for TP53 mutations, 17p deletion and IGHV mutation status provides the healthcare professional with information on the biological nature of the CLL and the patient’s risk of development of aggressive disease. However, it is important to realize that molecular testing alone is not enough to make appropriate decisions for the individual patient. Results from genetic tests must be correlated with clinical features, including the patient’s symptoms, blood counts, rate of disease progression, previous treatments, and concomitant diseases.

Monitoring Treatment and Supporting Overall Health

In addition to managing leukemia, treatment must consider the potential side effects of therapy with due consideration to the patient’s overall health with monitoring and support of therapy side effects as well as other comorbidities.

As each therapy has different safety profiles for adverse events (AEs), the monitoring parameters for patients on therapy will vary. In addition to routine blood counts, patients on certain therapies will require monitoring of blood pressure, cardiac function, renal function and liver function to name a few.

There is a risk of causing tumor lysis syndrome (a potentially life-threatening condition due to the rapid death of cancer cells) when using venetoclax, and this should be managed by a gradual introduction of the treatment with close monitoring. The treatments for CLL can also affect a patient’s immune system and so increase their risk of infection. Vaccination against and prevention of infections is an important part of the overall management of CLL and of the treatment itself. Monitoring for and treatment of any such infections or complications is also an important component of supportive care.

An Increasingly Individualized Approach

CLL has become a disease that can be treated on a case-by-case basis. Management of CLL is increasingly individualized based on patient and disease characteristics.  Many patients can be managed in an observational setting while others will need treatment for a symptomatic or progressive disease. Further, a patient who has been treated for his CLL may need different treatment for his relapse or even for a cancer cell that is resistant to prior therapy.

Some people are managed with a long term ‘watch and wait’ strategy. Others require treatment for symptom-producing CLL or active disease. Patients who have been on treatment in the past may require a very different approach upon relapse, especially if there is evidence of resistance to prior therapies.

Treatment for CLL is something that can be continuously discussed with the patient’s hematologist or oncologist. In many cases the patient will have to come back to the clinic for follow-up visits. Sometimes even between doses of CLL treatment the patient will have to return to the clinic for check-up.

Looking Ahead

Ongoing research to develop new targeted agents, novel combinations, and different sequences of treatment to control CLL for longer with less toxicity to treat.

As more is learned about the biology of CLL, the range of treatment approaches for CLL has expanded as research has advanced. What will be best for any individual with CLL will depend on their disease and their general health and how they bear the side effects of treatment.

There is increasing interest in novel therapies for CLL. Many of these are targeted in nature, are used as part of combination regimens, as alternative sequences or as therapies to prevent disease relapse. It is best that all decisions about management of CLL are made with a suitable hematology or oncology team, after discussion with the patient.

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.