What Influences Treatment for CLL? Understanding Modern Care Approaches

Chronic Lymphocytic Leukemia or CLL is a type of blood cancer. It is characterized by clonal proliferation of abnormal B lymphocytes that accumulate in the blood, bone marrow, lymph nodes, spleen, and other tissues of the lymphatic system. The disease has a variable clinical course. In some individuals with CLL the disease may progress very slowly and often remain asymptomatic for many years. Others may develop active CLL that requires treatment.

Treatment of CLL is determined by several clinical, biological and personal factors and has extended far beyond the conventional chemotherapy given for many years and now includes a large number of targeted therapy drugs to treat this particularly variable disease.

When Does CLL Require Treatment?

But there are many patients with early-stage CLL who have no symptoms and do not require treatment. These patients are said to be on “watch and wait” or “active surveillance”. Patients on watch and wait have regular check-ups with their doctor. Sometimes they will have physical exams, but often not. Blood work may be checked from time to time to see if the CLL is getting worse. Also, lymph nodes, spleen, and wight may be monitored for enlargement.

Monitoring is often used in the initial stages of CLL to assess progression of symptoms or disease and to consider treatment at a later stage. Active surveillance of CLL includes regular check-ups by physicians with clinical examination, measurement of lymph nodes and spleen, blood tests and clinical assessment of symptoms. If symptoms become worse or there is evidence of CLL-related complications, then treatment can be started.

Disease Progression: Need for CLL Treatment – Symptoms & Complications

While an increase in the absolute lymphocyte count is part of the clinical assessment, an elevated and rising lymphocyte count in isolation is not an indication for treatment.

Disease Characteristics Influence Treatment Choices

When determining the course of treatment for CLL, there are several key features of the leukemia that are considered. How aggressive is the disease? How quickly is it progressing? How much do the lymph nodes and spleen need to be enlarged? The patient’s blood work and symptomatology are all taken into consideration.

Consideration of the rate of disease progression, degree of lymphadenopathy/splenomegaly, degree of cytopenia, and patient symptoms with assessment of the CLL in the context of all other clinical findings provides a complete clinical assessment that takes into account so much more than just the absolute lymphocyte count.

This assessment will indicate whether continued monitoring is required or whether treatment is needed.

Genetic and Molecular Factors

Another parameter now routinely assessed in CLL is the genetic make-up of the cancer cells. The results from tests such as the TP53 mutation testing, 17p deletion testing and IGHV mutation testing can give the healthcare team an insight to the behavior of leukemia and how it may respond to treatment.

Tests, including for example TP53 mutations, 17p deletion, and IGHV mutation status, provide the clinician with insight into the risk of the CLL and enable the clinician to plan treatment accordingly. Genetic testing is just one factor, the test results must be combined with symptoms, blood counts, rate of disease progression, previous treatments, other health problems, and other individual circumstances.

The Role of Targeted Therapies

Targeted therapies have become an important component of CLL management in recent years. These are molecules that specifically target one protein in cancer cells, and these proteins are essential for the cancer cells to survive and to grow. Many of these proteins are part of a signaling pathway that outside of cancer, helps B-cells develop and function.

This is in contrast to traditional chemotherapy which is used to kill rapidly dividing cells. By targeting specific proteins within CLL cells, patients have more treatment options and are less likely to require chemotherapy. There are two main categories of targeted therapy for CLL. Firstly, there are the BTK inhibitors, which include medicines such as ibrutinib, acalabrutinib and Zanubrutinib. These medicines inhibit Bruton’s tyrosine kinase, a protein that is involved in the B-cell receptor signaling pathway and is essential for the survival of CLL cells.

BTK inhibitors work by targeting Bruton’s tyrosine kinase (a protein) involved in B-cell receptor signal pathways. Drugs within this class of therapy include ibrutinib, acalabrutinib, and Zanubrutinib. These medicines target BTK signaling pathways involved in CLL cell survival and growth.

Another class of targeted therapies is BCL-2 inhibitors. These therapies interfere with the protein BCL-2 which protects cancer cells from undergoing programmed cell death, or apoptosis. CLL cells can become dependent on BCL-2 for their survival and the drug venetoclax targets the BCL-2 pathway and has demonstrated activity against CLL cells.

Previous Treatment Matters

Importance of previous treatment in determining CLL Therapy. Person who has not been previously treated for CLL has more therapy options available to them than someone whose CLL has been previously treated.

Previous treatments (chemotherapy, and/or other medicines) can influence the choice of treatment for relapsed CLL or if the previous treatment(s) were not effective. This includes how long the medicine lasted for and the characteristics of CLL at relapse.

CLL is typically managed over a long period of time as a number of treatments are required to provide the best outcome for patients with this disease.

Combination and Time-Limited Approaches

Many CLL therapies are prescribed as single treatments; some may be used in combination with the goal of improving treatment responses in selected patients. These treatments work via different mechanisms and can be very powerful.

An approach which can be given for a certain time period may be preferred over another approach which has to be continued on a long-term basis. For example, a venetoclax-based approach may be chosen for a certain period of time.

When deciding on which of the previously mentioned therapies to use, many factors must be considered to determine which will be the best choice for that specific CLL patient, such as their prior therapy and the potential side effects of the new proposed therapy, as well as any adverse effects, medication interactions, degree of monitoring required, and other factors.

Overall, Health and Potential Side Effects

People with significant co-morbidities may not be considered suitable for some of the new therapies and need to be treated within their clinical circumstances.

The side effects of treatments can be very different and in some cases it may be necessary to monitor the blood pressure, heart function, kidney function and liver function and also watch for signs of infection. However, the introduction of CLL treatment using venetoclax needs to be done carefully and monitored for the risk of developing tumor lysis syndrome (TLS) as CLL cells die at a rapid rate. Monitoring of venetoclax dose escalation is required.

This long term management is affected by the CLL itself which can impair immune function, so infection prevention and management is an important aspect of long-term management of CLL patients on any therapy.

Patient Preferences and Quality of Life

Of course, in addition to laboratory values and the characteristics of the disease, there are many other aspects a patient wishes to consider in choosing between the various possible treatments for CLL. Their preferences regarding their disease and treatment must be taken into account and a choice of treatment made with them based on individual circumstances.

A range of factors are considered, including the duration for which the patient will need to take the treatment, how often the patient will need to return to the clinic for check-ups, the size and type of pills or tablets the patient will need to take, the potential for side effects, any interactions with other medications the patient is currently taking and how the treatment is likely to affect the patient’s daily life.

When appropriate, some patients and their families even prefer a time-limited approach compared to long-term CLL treatment. However, this must be felt to be appropriate by both the patient and their treating physician.

An Individualized Approach to CLL Care

Each case of CLL treatment is different, and therefore no single strategy is best for every person with CLL. A discussion of the active biology of CLL (the disease in question) and the patient’s total medical picture, including prior treatment, potential toxicity, and other medical problems as well as other personal goals and priorities can lead to the appropriate treatment plan for that individual.

A strategy of active surveillance can remain appropriate for years and often is the best strategy for asymptomatic patients with CLL. Sometimes patients with CLL require targeted therapies to manage symptoms or slow CLL progression. Treatment strategies for CLL may change over time even in effectively treated patients, due to a relapse or lack of effectiveness by previously effective CLL treatment. For now, though, with CLL under constant research as a single disease, new targeted therapies as well as several treatment regimens are becoming available for management of CLL.

Every CLL patient is unique. The details of a person’s case should be discussed with a qualified hematologist or oncologist, and an individualized medical assessment will help determine the most appropriate treatment approach for everyone with CLL.

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.