When a patient receives a diagnosis of CLL (Chronic Lymphocytic Leukemia), there are many questions that they have about the diagnosis and their treatment. The key questions are what does the diagnosis of CLL mean? Should I start treatment right away? What tests should I have to find out the best approach for me? In this article we discuss the latest in CLL treatment and how these are changing the way in which we manage CLL.
CLL or Chronic Lymphocytic Leukemia is a form of blood cancer. CLL develops in the lymphocytes or white blood cells. As with any cancer, it is best to seek the advice of your doctor. If you are diagnosed with CLL it does not mean you will need to start treatment immediately. There are cases where no treatment is needed for long periods of time, until symptoms occur or the disease starts to progress.
More importantly, a growing number of treatments are available for patients with CLL that can be used in a variety of different clinical circumstances. The latest CLL treatments are targeted at specific biological pathways and provide different treatment options to consider based on multiple factors.
What Is CLL?
Chronic Lymphocytic Leukemia (CLL) is a type of cancer. It is a blood cancer caused by the accumulation of abnormal B lymphocytes in the blood, bone marrow and sometimes in the lymph nodes and the spleen.
Though CLL can be considered a chronic form of cancer, it may behave differently. Some patients can stay in the same phase of the disease for years, whereas others can develop symptoms or changes in blood counts within a short period of time.
After a blood test has shown an abnormally high number of lymphocytes, a diagnosis can be confirmed by flow cytometry. Fluorescence in situ hybridization (FISH) as well as tests for TP53 mutations and for the IGH gene rearrangement are also used to characterize CLL cells in more detail.
Does Every Patient with CLL Need Treatment?
Some CLL patients are healthy and there are no symptoms. In these situations, monitoring the patient and their disease during regular clinic visits may be all that is required during the initial phase of their diagnosis. The healthcare team may use this time to check blood counts, lymph nodes, spleen, and monitor for symptoms of CLL.
For some patients with CLL, however, treatment may become necessary when the disease causes problems, for example by causing significant anemia or low platelet counts, by a rapidly increasing number of lymphocytes, by enlarged lymph nodes and/or spleen, or by symptoms, for example unexplained loss of weight, persistent or recurring fever and/or night sweats.
Newly diagnosed patients might find it difficult to understand the delay in starting treatment. However, in some cases monitoring may be appropriate, helping to avoid treatment-related side effects till treatment becomes necessary.
Why CLL Treatment Is Becoming More Individualized
There is no single treatment for CLL. Doctors consider several factors before recommending therapy, including:
- Age and overall health
- Blood cell counts
- Symptoms
- Lymph node and spleen involvement
- Previous treatments
- How quickly the disease is progressing
- TP53 abnormalities or chromosome changes
- IGH mutational status
- Other medical conditions
- The potential benefits and risks of available treatments
Genetic and molecular testing have become important diagnostic tools. For example, TP53 abnormalities and 17p chromosomal changes can affect the treatment of a patient with CLL as well as the overall behavior of the disease.
This is why two patients with the same type of CLL may receive different treatments when their diagnosis is seemingly the same.
How Latest CLL Treatments Are Changing Care
CLL treatment is changing and moving away from traditional chemotherapy. The majority of CLL treatment today is focused on using targeted therapies to treat the disease. BTK Inhibitors and BCL-2 Inhibitors are the two major classes of medicines currently used to treat patients with CLL. These medicines work through different biological pathways to inhibit the growth and survival of CLL cells.
BTK Inhibitors
BTK is a protein that is part of the signaling pathway used by B cells, including CLL-cells.
These have become important treatment options for CLL and may be used in different treatment settings depending on a patient’s individual circumstances:
- Zanubrutinib
- Acalabrutinib
- Ibrutinib
It is also very important to establish the potential side effects of any cancer treatment, as these need to be weighed up against the potential benefits of the treatment. As noted above, there are several treatments that can be used for BTK inhibition. Each treatment has its own profile of potential side effects and these need to be considered on an individual basis. This can include assessment of the patient’s cardiovascular status, potential for bleeding, review of current medications and previous treatment with BTK inhibitors.
BCL-2 Inhibitors
In addition to the other approaches to treatment of CLL that are mentioned above, in recent years the approach of targeting BCL-2 for inhibition by small molecule drugs has become an important approach to the treatment of this disease.
Venetoclax, a BCL-2 inhibitor, is used in the treatment of patients with CLL. Venetoclax can be used in combination with other therapies, for example with the antibody obinutuzumab and with other targeted therapies in different strategies.
Venetoclax may cause rapid deterioration of CLL cells leading to tumor lysis syndrome (TLS). Initiation of venetoclax requires gradual escalation of dose with close monitoring of patients for development of TLS. Monitoring patients’ blood work during initiation of treatment is critical.
Combination Treatment Is Expanding Options
These approaches to treatment of CLL using targeted single drugs are rapidly evolving and are increasingly being considered in combination.
There is increasing interest in the use of combination targeted therapies and one such combination, of acalabrutinib with venetoclax has recently been approved by the U.S. Food and Drug Administration for adults with CLL or SLL. Approval of this combination of acalabrutinib and venetoclax for use in previously untreated CLL patients without del(17p) or TP53 mutations was based on clinical evidence from the AMPLIFY trial.
However, it does not mean that the treatment is suitable for everyone. Many of the clinical trials for combination therapies have been conducted on specific populations of patients.
This growing number of treatments does not mean that the latest treatment is always appropriate for a given patient. The main factor in choosing between different therapies is the individual patient’s clinical and genetic profile.
What Happens When CLL Comes Back?
Relapsed CLL is when the disease returns after a period of response to treatment, while refractory CLL refers to disease that does not respond to treatment.
Treatment after relapse depends on prior treatment. In this way, patients who have previously been on a BTK inhibitor can be given different options than patients who have not received any prior therapy. Also, the length of time that a patient responded to a prior therapy and/or the presence of any disease related mutations are also very important considerations.
These approved targeted drugs can provide new therapeutic options to a patient with relapsed CLL.
Pirtobrutinib and the Expanding Treatment Landscape
Pirtobrutinib is a noncovalent BTK inhibitor that was granted traditional approval by the FDA on December 7, 2025, for the treatment of adults with CLL or SLL who have received prior treatment with a covalent BTK inhibitor, as determined by a clinical trial in patients with relapsed or refractory CLL/SLL, BRUIN-CLL-321.
Pirtobrutinib had been granted accelerated approval in August 2023 for adult patients with CLL/SLL who had received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor.
Treatment selection for relapsed CLL considers prior therapies and specific clinical and genetic features.
Are Traditional Chemotherapy Treatments Still Used?
Targeted therapies have changed the CLL treatment landscape and the way that chemotherapy is used as part of a treatment strategy for CLL patients. The use of chemotherapy is still in place but as part of a targeted approach and will depend on the individual case. The landscape of how chemotherapy is used has broadened in such a way that it is not viewed as the default option for the treatment of CLL.
What Tests Can Help Guide Treatment?
It is important to discuss with the healthcare team about the various tests to determine CLL treatment approach.
Complete Blood Count
A Complete Blood Count (CBC) measures the levels of all types of blood cells, including CLL cells. The levels of red blood cells and platelets are also important to monitor as CLL can affect their production.
Flow Cytometry
This test shows what proteins are on the surface of the cells. This is used to identify the immunophenotype of the CLL cells.
FISH Testing
FISH testing for CLL Chromosomes 11, 13, and 17 and their implications.
TP53 Testing
The role of TP53 abnormalities in the treatment of CLL patients. Patients with CLL may have TP53 variants in their CLL cells and corresponding chromosome changes.
IGH Testing
IGH testing for the mutational status of IGH gene in CLL cases can also provide the physician with insight into the biological nature of CLL in individual cases and may even help the physician assess the patient’s prognosis.
What Should Patients Ask Their CLL Specialist?
Having a list of questions to ask, the CLL Specialist will help in making treatment decisions.
Useful questions may include:
- treatment required now, or is monitoring appropriate?
- Are there special features of the disease which affect the selection of treatment options?
- Have TP53 and chromosome results been evaluated?
- What does IGH test show, if it has been performed?
- What are the goals of the recommended treatment?
- How will treatment be monitored?
- What side effects should be reported immediately?
- Are there interactions with existing medicines?
- How long is treatment expected to continue?
- What options are there if the CLL comes back?
- Are there relevant clinical trials?
Patients may also wish to consider asking for a second opinion from a hematologist or CLL specialist, as treatment decisions can be complex.
Managing Life During CLL Treatment
Treatment is only one part of living with CLL. Monitoring of the patient during treatment for CLL is key to patient management. Patients with CLL may have compromised immune systems and therefore need to take precautions to avoid infection and need to report any symptoms of possible infection promptly.
It is important for patients to seek advice from their healthcare team in relation to issues around vaccination, and infection, and around any other medicines that they are taking, in order to get proper advice.
In addition to the treatment of CLL, patients and their families also need support in coping with the effects that a chronic blood cancer can have on them. This can be in the form of emotional support and may be required by patients and their families at various stages of the treatment of their disease. Patients and their families can get support from family, from other patients and their families who are going through similar situations, from patient organizations and from a variety of other sources, including counseling.
The Future of CLL Treatment
There are ongoing clinical trials exploring the potential of various targeted therapies to treat CLL, to use different combinations of therapies and to better manage disease that has recurred.
Research into CLL is very active and new BTK inhibitors as well as other treatment combinations are under investigation. Additionally, there is a lot of interest in how molecular testing can help in choosing the right treatment for each individual’s unique disease profile.
It is also important to remember that ‘latest’ does not always mean ‘best’. Trials report on the results of patients with very specific disease profiles and who have not had previous treatments or other medical conditions. Treatment decisions are made on an individual basis.
The most appropriate treatment for CLL today is an individualized medical decision.
What a CLL Diagnosis Means Today
A CLL diagnosis can be overwhelming for patients and their families, but there are a number of different treatments available today for people with this disease.
Careful observation without treatment is appropriate for some patients. Targeted treatments, using BTK inhibitors such as ibrutinib and BCL-2 inhibitors such as venetoclax, can be the mainstay of treatment for others. There are also more treatments for relapsed CLL than ever before.
But most importantly, a patient with CLL needs to understand why a particular treatment is recommended. Because of the many characteristics of CLL, the various genetic changes, previous treatments, and a patient’s overall health and circumstances, the latest treatment is not always appropriate. Increasing number of latest CLL treatments provides multiple options for clinicians to consider for developing individualized treatment approaches.
Medical Disclaimer
This article is for information purposes only. Any decision about treatment for CLL needs to be based on the individual’s full clinical history and taken with a qualified Hematologist/Oncologist. Also note that availability of treatments and their regulatory status will vary by country.
