How Do Doctors Determine When to Treat Chronic Lymphocytic Leukemia (CLL)?

Blood cancers can affect any of these cell lines. Because of this diversity of their origins, there are many kinds of blood cancers, including polycythemia vera (affecting the RBCs), and essential thrombocythemia (an overproduction of platelets). When cancers rev up the production of WBC, they are called termed leukemias or lymphomas.

Leukemias and lymphomas signify the location of the involved cancer cells. In leukemia, the cancer cells occupy the bone marrow and the blood. In lymphoma, the errant cells take up residence within the lymph nodes and the lymphatic system. They can often form masses that can be seen or felt in lymphoma patients.

Chronic Lymphocytic Leukemia

RELATED: Chronic Lymphocytic Leukemia (CLL): Overview

CLL signals an abnormal number of WBCs or lymphocytes within the bone marrow and blood. Despite increased numbers, these leukemic WBCs are abnormal and lack the ability to fight off infections. Furthermore, as their number increases, they crowd out the bone marrow leaving little room to produce normal RBCs, WBCs, and platelets. This can lead to anemia (lack of RBCs), a vulnerability to infections (lack of WBCs), and an elevated risk of bleeding and bruising (lack of platelets), even after minor injuries.

CLL is the most common leukemia in older adults. An average patient is diagnosed around age 70. It is rare in people younger than 40 and even rarer in children. According to the American Cancer Society, around 59,610 new cases of leukemia will be diagnosed in the United States in 2023. One quarter or almost 18,000 of these will be CLL. This disease will also result in 4,490 deaths within the same year.

Symptoms Of CLL

Oftentimes, CLL does not cause any symptoms and is only diagnosed when a routine blood test detects an abnormal WBC count. In some patients, symptoms could be present and may include:

• Fever with a body temperature of 100(F) or more for more than 2 weeks without any infections
• Fatigue, which is often severe and impairs the ability to work
• Unintentional loss of 10% bodyweight over 6 months
• Drenching night sweats for more than 1 month
• Frequent infections
• Shortness of Breath
• Easy bleeding and bruising
• Feeling full after eating small amounts of food
• Enlarging spleen, which can often be felt below the rib cage
• Swollen glands in the groin, armpits, and/or neck

RELATED: Chronic Lymphocytic Leukemia (CLL): Symptoms & Diagnosis

Overall Outlook & Treatment for CLL Patients

CLL is rarely curable, hence the term chronic within its name. However, patients with this condition can live for years without any symptoms or needing treatment. In fact, a small number of CLL patients, those with del13q14 but no other genetic mutations, may enjoy the same life expectancy without any treatment as those without CLL.

Many patients, however, will require treatment at some point in time. This usually happens when patients become symptomatic or when their symptoms start to worsen significantly. There are many different types of treatments available for patients with CLL. These include:

• Watchful waiting: Using this approach, patients are carefully monitored by their doctors with regular follow-ups. The overarching aim is to only start treatment once symptoms appear or start worsening. Many patients whose disease is only incidentally diagnosed because of blood tests may be excellent candidates for this approach.
• Chemotherapy: It uses drugs that are toxic to all growing cells, including cancer cells. It is usually given through an injection into a muscle or vein. Chlorambucil and bendamustine are two chemotherapy medications used for CLL. Although they can be highly effective, these drugs carry bothersome toxicities, such as immense nausea, vomiting, diarrhea, hair loss, etc.
• Immunotherapy: This form of therapy uses a patient's own system to fight cancer. Lenalidomide is one such medication.
• Targeted therapy: These therapies exploit unique features of cancer cells and use drugs that target these features. Bruton’s Tyrosine kinase inhibitors (BTKs), such as ibrutinib and zanubrutinib, are drugs that block the tyrosine kinase enzyme, which plays an instrumental role in the development of CLL. BCL2 inhibitors, such as venetoclax, are another class of targeted therapies, which block the BCL2 proteins that can be found on some leukemic cells. Monoclonal antibodies are proteins that can target different proteins present on many cancer cells. Rituximab is one such monoclonal antibody, which is commonly used for CLL treatment.
• New treatments are being continuously tested in clinical trials. For some patients participating in a clinical trial may be the best option, especially if their cancer has unique features, which are being evaluated in new clinical trials.

When to Consider Active Surveillance

"We have a lot of data that has demonstrated that people live the same very long amount of time with this disease whether you treat them right away or you don't," says Dr. Ann LaCasce, Director of Hematology/Oncology at Dana-Farber Cancer Institute. Thus, active surveillance can be the most appropriate option for a lot of patients for a variety of reasons. These include:

• All treatments carry real risks. Chemotherapies have significant side effects, such as nausea, vomiting, diarrhea, weight loss, and hair loss, which can be devastating for patients. Targeted therapies have their own downsides, such as fatigue, rashes, muscle cramps, and muscle and bone pains. Immunotherapies carry many risks, from causing mild flu-like symptoms to a full-blown autoimmune inflammation of the lungs, kidneys, and heart. These risks must be carefully weighed against potential benefits while considering treatment.
• There has been no robust scientific evidence to date that early treatment for people with early, low-risk CLL holds any tangible benefit for or prolongs the lifespan of patients. It can be hard to justify a medical treatment that does not carry at least some amount of benefit especially when it entails real risks and side effects.
• If treated early, some CLL patients may develop resistance to the drugs they receive over time. "You don't want to treat too early because you may kill off the more easily-killed cells and spare those that are more resistant [to treatment] to predominate," explains Dr. LaCasce.
• "We have so many very, very effective therapies for this disease for patients [when they eventually do need] treatment," per Dr. LaCasce. "This disease is one of a couple over the past decade that has accelerated the fastest in terms of new agents and really tolerable treatments." Thus, when patients progress, they have a lot of quality treatment options available to them. This is unlike other cancers, where patients with progressive, advancing diseases tend to have only a limited set of options.

As CLL is still "cancer," patients are understandably wary of sitting back and waiting for their cancer to become aggressive enough to warrant treatment. "It's a lot of reassurance and education when we initially meet a patient with CLL. You have to balance the toxicity of treatment versus the benefit. It takes time [for patients to understand this]," per Dr. LaCasce. She continues, "We often involve our social worker or psychologist. We point patients to particular websites where they can get reliable information, maybe meet other patients who have the same diagnosis and are undergoing active surveillance."

When to Treat?

RELATED: Determining When CLL Treatment is Needed

Given the favorable outlook for the disease, CLL patients may be managed with active surveillance for years before they ever need treatment. There has not yet been a scientific study to discern the best time to initiate treatment. Therefore, physicians and subject matter experts have put together the most reasonable guidelines for treatment initiation based on their expertise. This includes a worsening of the symptoms outlined above. Most importantly, treatment should be considered for patients experiencing so-called B symptoms, such as:

• Fever with a body temperature 100(F) or more for more than 2 weeks without any infections
• Fatigue, which is often severe and impairs the ability to work
• Unintentional loss of 10% bodyweight over 6 months
• Drenching night sweats for more than 1 month
• Enlarging lymph nodes, especially in the neck, armpit, and groin regions, over a few follow-up examinations
• An enlarging spleen that causes uncomfortable fullness and bloating sensation in the abdomen
• When the disease spreads outside of lymph nodes, especially to organs such as the lungs, kidneys, and the spine
• Laboratory studies indicating worsening bone marrow function:
  • RBC count < 10g/dL
  • Platelet count < 100,000/ /uL
• Development of treatment-resistant autoimmune hemolytic anemia or thrombocytopenia, which are conditions where the patient's own immune system starts to attack their RBCs and platelets
• Increasing blood lymphocyte count, especially when counts double in less than 6 months or increase by more than 50% over 2 months. This indication for treatment is a point of debate among physicians, and not all agree that this should be used to initiate treatment in the absence of any other indications

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