Most people diagnosed with CLL are interested in learning about the various medicines available for treatment of their disease. While traditional chemotherapy (using drugs to kill rapidly dividing cancer cells) is no longer the main stay of CLL treatment, several targeted therapies have been developed to interfere with specific pathways that allow CLL cancer cells to survive and proliferate.
People who are affected by CLL and their families often look for information about them. Newer treatment options for CLL. As mentioned previously, it is very important to remember that merely because a person has been diagnosed with CLL, that doesn’t necessarily mean that treatment must begin immediately. Several factors are taken into consideration including symptoms, blood counts, rate of disease progression, genetic features, prior treatment, age, overall health and potential treatment-related toxicity.
When Does CLL Treatment Begin?
Because most people with CLL have a generally slow disease process and do not have symptoms due to their leukemia, most people are initially managed with a ‘watchful waiting’ strategy. Treatment is not immediately started following a person’s CLL diagnosis.
Treatment is indicated in cases where CLL causes disturbing symptoms, requires rapid reduction of leukemia cells, reduction of blood cells (anemia, thrombocytopenia), increase in size of lymph glands and spleen, marked increase in number of CLL cells in the blood, and a variety of constitutional symptoms including persistent fever of unknown origin, night sweats, unexplained loss of weight and feeling of fatigue. Many people live for years after their diagnosis without requiring any treatment at all. Doctors prefer to keep an eye on them, until symptoms develop. Only then do they decide on the best treatment option.
Targeted Therapies in CLL Treatment
Unlike many other cancers where traditional chemotherapy is used to kill rapidly dividing cancer cells, for the last decade CLL treatment has focused on targeting specific cancer cells and the processes by which they survive.
BTK Inhibitors
These include ibrutinib, acalabrutinib, and zanubrutinib. Bruton tyrosine kinase (BTK) inhibitors interfere with the BTK signaling pathway within the CLL cells. Have demonstrated clinical activity in certain patients with CLL.
BTK inhibitors interfere with the BTK signaling pathway, important for the survival of B cells (cancer and normal) in the blood and lymph nodes. They block BTK, a critical enzyme in the signaling pathway of B-cell receptors on the surface of CLL B-cells and help to stop the proliferation and survival of the CLL cells. Factors that determine which BTK inhibitor to use include the patient’s specific CLL disease, the patient’s prior therapy, other medical problems the patient has, and potential side effects of the medication. As noted by NCI, acalabrutinib and Zanubrutinib have been associated with lower incidence of atrial fibrillation compared with ibrutinib in some clinical trials.
Venetoclax and BCL2 Inhibition
BCL2 (B-cell lymphoma 2) proteins are involved in apoptosis or cell death. Venetoclax targets BCL2, a protein involved in cell survival pathways. It is often given in combination with an antibody such as obinutuzumab or rituximab. Importantly, many of the venetoclax-containing regimens are of fixed duration.
Venetoclax may cause Tumor Lysis Syndrome in CLL patients. The risk for TLS can be assessed before starting therapy and TLS can be monitored with dose escalation.
Treatment Combinations Are an Important Area of Research
Can medicines be used in combination to treat CLL for set time periods and achieve better disease control than is currently possible with current single-agent treatments?
Combination studies of BTK inhibitors and venetoclax are being investigated in various tumor types including CLL and some are already being used in the clinic to treat patients with specific disease characteristics. Additionally, there are several clinical trials currently enrolling to study the combination of Zanubrutinib and venetoclax in previously untreated CLL patients.
The role of MRD in stratifying patients in terms of treatment duration is also an area of ongoing research, with studies looking to define optimum MRD-based strategies for the extension of initial therapy with fixed duration agents. Indeed, the definition of MRD as detected by flow cytometry is now a standard endpoint in clinical trials of CLL.
New Options for CLL That Has Returned
The CLL therapies, as mentioned earlier, can sometimes stop working. Researchers are developing alternative CLL treatment approaches, both for patients with CLL that has relapsed or is refractory to previous treatment.
Pirtobrutinib (BSJ08) is a novel, non-covalent BTK inhibitor, particularly intended for CLL patients who have been previously exposed to covalent BTK inhibitors, with pre-clinical data demonstrating Demonstrated BTK inhibition in preclinical studies.
After relapse of CLL, the treatment strategy depends on the previous treatment(s) with anti-cancer drugs, the presence of resistance or intolerance to certain drugs.
Cellular and Immune-Based Therapies
Additional studies in CLL also are examining use of the patient’s own immune system to target and kill CLL cancer cells.
In other studies, patients with CLL have received CAR T-cell therapy. In these studies, patients’ T-cells have been collected and then become modified in the laboratory to create T-cells that can recognize CLL cancer cells. These modified cells are then given back to the patient in the form of an infusion, and the patient’s immune system is stimulated to attack the CLL cancer cells.
Ongoing and new trials are evaluating several different immune-based approaches, alone or in combination with other therapies. Of particular interest in CLL are trials combining a CD20-targeting antibody with a BTK inhibitor (e.g. ibrutinib or Zanubrutinib) in patients with measurable residual disease.
What Are the Next Steps for Patients?
CLL latest drugs are constantly being evolved for the CLL treatment and there is no single drug that is right for every patient. Prior to initiation of therapy, patients often require a multitude of tests including complete blood counts, genetic and molecular studies, imaging studies, and more. Patients should ask their hematologist or oncologist what the goals of therapy are and what the expected benefits and side effects of treatment will be. In addition, there are often aspects of treatment such as duration of therapy, potential drug interactions, and clinical trials that patients should be aware of prior to starting treatment.
Patients newly diagnosed with CLL will have blood tests, genetic/molecular tests, and imaging studies to gain insight into their individual situation and to plan the appropriate treatment approach considering their disease and its potential modifications by prior therapy (so-called treatment history). Specifically, the presence of TP53 alterations and a chromosome 17p deletion, for example, can influence the choice of therapy.
It is very important for patients to review the goals of treatment and the potential benefits and harms (to include drug interactions) of all treatment options as well as the duration of treatment with their hematologist/oncologist and consider participation in clinical trials.
While newer targeted therapies, including some in combination with others as well as others used in an MRD-directed strategy, are emerging to treat CLL patients, their use will become more accepted as additional information emerges to guide their use in individual patients with this disease. In the meantime, it is best for those with CLL to obtain the latest medical advice from their hematologists and to follow closely for updates on this. Expanding range of treatment options.
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.