Chronic Lymphocytic Leukemia (CLL) is a type of blood cancer which starts in B lymphocytes, a type of white blood cell, which makes up part of the body’s immune system. Although CLL is generally a slow growing cancer it can sometimes develop very quickly and require treatment. Recently there have been many advances in cancer research leading to the development of new medicines to treat disease as well as new ways of using existing treatments.
Recent advancements in cancer research have developed new treatments for CLL patients. These newly developed medicines have expanded available treatment options for some patients with CLL. Patients and their families should know about these new advancements to better understand current treatment options and discuss their options with their health care team.
Understanding Recent Advances in CLL Treatment
Increasing numbers of leukemia treatments are now targeted at specific proteins within cancer cells and are often used in combination with each other. Most of these treatments are not traditional chemotherapies but rather aim to specifically kill the leukemic B cells.
Conventional chemotherapy is in contrast aimed at all rapidly dividing cells and does therefore not make a distinction between malignant and normal cells. New targeted therapies in contrast are designed to specifically and selectively act on certain biological structures. These therapies may be considered for certain patients based on disease characteristics and prior treatment history.
These newer medicines are often determined by factors relating to the patient (their general health, for example) and their CLL (symptoms, for instance), previous treatment(s), and whether they are newly diagnosed with CLL or not.
BTK Inhibitors: Important Developments in CLL Care
BTK (Bruton’s tyrosine kinase) inhibitors are drugs that have been introduced as novel treatments for patients with CLL. BTK is involved in B cell signaling pathways and supports the survival of cancerous B cells. By irreversibly inhibiting BTK, BTK inhibitors stop these B cells from continuing to multiply and may promote apoptosis of malignant B cells.
Newer BTK Inhibitors
There are several different treatments available for CLL including the BTK inhibitors, Zanubrutinib, ibrutinib, and acalabrutinib. All these works by inhibiting the activity of BTK (a tyrosine kinase) which is necessary for the cancer B cells to survive by passing on signals through the B cells’ membrane.
Recently several new BTK inhibitors are in development for CLL and have shown activity in patients whose disease has progressed on earlier treatment. Pirtobrutinib, a non-covalent BTK inhibitor is under investigation for the treatment of patients with CLL who have received prior therapy with BTK inhibitors for their CLL.
Why These Developments Matter
There are many newer BTK inhibitors currently in research to treat CLL patients that have become resistant to previous BTK inhibitors. Some of these are currently being evaluated in clinical trials alone and in combination with other treatments to evaluate response outcomes in CLL patients.
The choice of a BTK inhibitor for treatment depends on clinical circumstances of the patient and on the available treatment options.
BCL-2 Inhibitors and Combination Treatments
A new class of CLL treatments are the BCL-2 inhibitors which are used to treat CLL by inhibiting the BCL-2 protein that helps the patient’s abnormal B cells to survive by preventing apoptosis or programmed cell death.
BCL-2 Inhibitors in CLL Treatment
CLL has been treated with a new type of therapy that takes advantage of cancer cells’ relatively high levels of BCL-2 by targeting CLL cells. This is often used as a single agent but can also be used in combination with other treatments, for example with certain antibodies or with BTK inhibitors to evaluate treatment outcomes.
Exploring New Combinations
In preclinical models, BCL-2 inhibitors are being evaluated in combination with targeted therapies to determine improved strategies for treating CLL patients. In addition, strategies involving longer treatment duration and reversed treatment order are also being evaluated to evaluate clinical outcomes and quality-of-life measures.
The aim of therapy is to control the disease and to preserve quality of life while treatment is being administered for as long a period as necessary.
Fixed-Duration Treatment and Deeper Responses
Some treatments for CLL are given for a fixed duration of time and then patients are taken off the treatment for a period. Clinical studies have evaluated fixed-duration venetoclax-based combinations and their impact on remission outcomes. Most studies to date have assessed the Venetoclax plus BTK inhibitor (or other kinases) and BCL-2 inhibitor combinations (in addition to antibody therapies), to seek synergy and clinical benefit.
The Role of Minimal Residual Disease
Minimal residual disease (MRD) assessment in CLL patients after treatment has been stopped measures the amount of cancer cells remaining in the body. The results from MRD testing can give an indication of the degree of response of a patient to treatment. Much of the research into the role of MRD in CLL patient management is aimed at deciding how long to continue treatment as well as to assess whether patients who achieve certain MRD levels require additional treatment.
Personalized Treatment Through Genetic Testing
Genetic and molecular tests have been developed to establish a precise diagnosis of CLL and to assess its different forms and behavior, thus enabling individualized therapy to be chosen.
Important Molecular Tests
These tests include analysis of the TP53 mutation, FISH tests and IGHV testing. Of importance to the CLL treatment decision is the clinician’s understanding of the disease’s molecular profile and its correlation with clinical presentation and potential response to therapy.
For instance, knowing whether a patient is a TP53 mutated individual can guide the clinician as to whether not a particular treatment might be efficacious in that individual, and/or lead to specific toxicities that might need to be avoided. Some of these new markers will predict treatment outcomes and others will be used to predict disease progression on existing therapies. Personalized treatment does not mean every single CLL patient gets a different drug for their leukemia. Rather, the treatment decision takes all clinical information, molecular data from tumor samples, previous treatments and the general health status of a patient into account.
New Options for Relapsed or Treatment-Resistant CLL
As the number of drugs for the treatment of CLL increases, some patients experience relapse or resistance to single drugs. This can happen early during treatment with BTK inhibitors or BCL-2 inhibitors, or after a period of several months.
Research is continually looking for new methods to treat CLL that have relapsed or have not responded to previous treatments, including BCL-2, BTK and other therapies.
Emerging Therapies
These include non-covalent BTK inhibitors, BTK degraders and other novel agents targeting CLL cancer cells by different mechanisms of action. In addition to non-covalent BTK inhibitors such as tyrosine kinase inhibitors with novel mechanisms of action as well as BTK degraders other forms of immunotherapy and/or cellular therapies like bispecific antibodies and CAR T-cell therapy are under investigation for patients with CLL that is difficult to treat and/or has relapsed or is refractory to previous treatments.
Be aware that even the CLL latest drugs have unknown long-term effects and have not yet been proven to be safe or effective in comparison to other treatments for CLL. Discuss the pros and cons of participating in a clinical trial and other emerging treatments with doctor.
Improving Safety and Long-Term Care
To control CLL but also reduce the harm that CLL treatment can cause, CLL research is not just aimed at treating the disease but also at preventing the complications caused by the treatment.
Side effects from CLL treatments can cause infections, bleeding and even cardiac problems. Researchers are studying CLL treatments to develop combination treatments and to find the optimal treatment duration and dose to minimize side effects. Long-term care is important even if treatment has had a positive effect in the short term. Follow-up of CLL and treatment side effects are often needed for a long time.
The Importance of Clinical Trials
A clinical trial to test a new CLL treatment is a research study to evaluate a new treatment, such as a medicine. These studies measure whether a new treatment is effective and compare it with the current treatment options for CLL.
There are clinical trials available for patients with newly diagnosed CLL as well as patients with CLL that have relapsed. When considering a clinical trial for CLL, as with any research study, the good and the not-so-good should be clearly discussed with healthcare team, including the potential benefit to you as well as the potential risks and requirements of the study.
Conclusion
Our CLL latest drugs information includes the latest CLL treatment developments. Many new CLL treatments including BTK inhibitors and BCL-2 inhibitors have been established as approved CLL therapies. Fixed-duration treatment approaches are increasingly used in appropriate clinical settings.
There are many investigation targeted therapies in development for patients with treatment-resistant CLL, including additional BTK inhibitors, as well as BCL-2, PI3K, and other targeted therapies, as well as immunotherapies and cellular therapies including bispecific antibodies and CAR T-cell therapies. However, there is no evidence that many of these investigational therapies will benefit all patients.
To treat CLL patients based on clinical evidence, evidence-based decisions have to be made based on individual disease parameters in conjunction with sufficient medical expert knowledge. Ongoing research and continued treatment of CLL patients in the long-term are required to improve their therapy.
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.
