Chronic Lymphocytic Leukemia (CLL) Treatment

Chronic lymphocytic leukemia is a slow-growing cancer that occurs when lymphocytes—infection-fighting white blood cells found in the bone marrow—undergo harmful changes that cause them to grow uncontrollably. Abnormal lymphocytes then build up in the bloodstream, lymph nodes, spleen and other organs, gradually crowding out healthy cells and compromising the body’s immune system.

In the United States, chronic lymphocytic leukemia is the most frequently diagnosed adult leukemia, accounting for roughly one quarter of all new cases and affecting nearly 20,000 individuals each year. Although CLL can occur across a wide age range, its incidence is highest among older adults. The average age at diagnosis is 70, and the condition is rarely seen in people younger than 40.

Chronic lymphocytic leukemia often develops gradually over many years, although certain cases may progress more rapidly. Some patients can be safely monitored without immediate therapy, while others may require earlier intervention. To achieve the best possible outcome and quality of life, treatment must be tailored to the individual, taking into consideration the cancer’s stage, molecular and genetic features, symptom burden and the patient’s overall health.

Observation for chronic lymphocytic leukemia

Observation—also known as watchful waiting or active surveillance—is a common first step for many people diagnosed with CLL. Because this type of leukemia often grows very slowly and may not cause symptoms for a long time, immediate treatment is not always warranted. Initiating therapy too early can lead to unnecessary side effects without offering a clear clinical advantage, so the healthcare team may recommend careful monitoring instead.

When is watchful waiting recommended for chronic lymphocytic leukemia?

A wait-and-watch approach may be recommended if blood counts are stable, symptoms are minimal and there is no evidence of cancer progression. Many people learn they have CLL after a routine blood test and feel completely well at the time of diagnosis. In these situations, postponing treatment is unlikely to negatively affect the outcome and can spare the patient from therapies they may not need right away.

Most often people with CLL do not exhibit any symptoms and many diagnoses are discovered during blood work for another unrelated health issue. Typically, that’s when patients and physicians discover a high lymphocyte count.

Dr. Javier Pinilla

Malignant Hematology Department

What does active surveillance for chronic lymphocytic leukemia involve?

During observation, the patient will have regularly scheduled appointments with the healthcare team to help ensure that any signs of leukemia progression are identified early. Typically, these visits will include:

• A physical examination to check for enlarged lymph nodes or organs
• Blood testing to track lymphocyte counts and detect anemia or low platelets
• Imaging if needed to evaluate internal lymph nodes or the spleen
• A discussion about CLL symptoms, such as fatigue, fever, night sweats or weight loss

This structured monitoring approach can help ensure the patient begins treatment at the best possible time.

What are the benefits of watchful waiting for chronic lymphocytic leukemia?

Active surveillance can allow the patient to delay treatment—and the potential side effects that come with it—until it is truly necessary. In addition to maintaining the patient’s quality of life, this approach can also protect the effectiveness of future treatment options. Starting therapy too early can expose leukemia cells to medications before they are needed, increasing the chance that the cancer will adapt or become resistant over time. By reserving treatment for when the condition becomes active or symptomatic, the patient can begin therapy at a point when it is more likely to work well and provide meaningful benefits.

Chemotherapy for chronic lymphocytic leukemia

Chemotherapy uses powerful drugs that enter the bloodstream and circulate throughout the body to target and destroy fast-dividing cells. While this can help control cancer progression, relieve symptoms and improve blood counts, it can also affect healthy cells that naturally divide rapidly, leading to a range of side effects.

Although chemotherapy has long been a mainstay of CLL treatment, it is increasingly being combined with—or replaced by—targeted therapy, a more precise approach that can block the specific molecules and pathways that cancer cells rely on to grow and survive. Targeted medications often spare healthy cells, which may lead to fewer side effects and longer-lasting cancer control.

What is the role of chemotherapy in chronic lymphocytic leukemia treatment?

Despite recent advances in targeted therapy, chemotherapy continues to play an important role in many CLL cases. Some patients respond well to established chemotherapy regimens, while others may achieve better results when chemotherapy is combined with targeted therapy or immunotherapy. Treatment planning aims to balance effectiveness with tolerability, selecting the approach that offers the best possible leukemia control with the fewest side effects.

Common chemotherapy regimens for chronic lymphocytic leukemia

Chemotherapy for CLL may be given orally or through intravenous infusion, often on a cycle-based schedule. Each cycle includes a period of active treatment followed by a period of rest to allow the body time to recover.

For CLL, commonly used chemotherapy agents include fludarabine, cyclophosphamide, bendamustine and chlorambucil. These medications work by interfering with the cancer cells’ ability to replicate DNA or divide.

Some patients may receive a single chemotherapy drug, while others may benefit more from a combined approach tailored to the specifics of their cancer. For example, some regimens pair chemotherapy drugs with rituximab, a monoclonal antibody that binds to a specific protein found on the surface of CLL cells. By attaching to the cancer cells, rituximab can help the immune system recognize and destroy them, enhancing the impact of chemotherapy.

Frequently used drug combinations for chronic lymphocytic leukemia include:

• FC – Fludarabine and cyclophosphamide
• FCR – Fludarabine, cyclophosphamide and rituximab
• BR – Bendamustine and rituximab

When creating the treatment plan, the physician will consider several key factors, including the patient’s genetic test results, age, other medical conditions and response to any prior CLL treatments.

What are the potential risks and side effects of chemotherapy for chronic lymphocytic leukemia?

Like all cancer treatments, chemotherapy carries certain risks. The side effects can differ based on the drugs used and the patient’s response, but common experiences include:

• Fatigue
• Increased susceptibility to infections
• Nausea or vomiting
• Hair thinning or hair loss
• Easy bruising or bleeding
• Decreased appetite or changes in taste sensation

Supportive care strategies, such as medications to manage nausea or injections to boost blood cell counts, can help reduce any treatment-related discomfort.

Preparation and recovery from chemotherapy for chronic lymphocytic leukemia

Before beginning chemotherapy, the patient will have a medication review, imaging studies and a series of lab tests to ensure the treatment plan is safe and appropriate. In some cases, a central line or port may be placed to make repeated infusions easier and more comfortable.

Many chemotherapy side effects ease during the rest periods between cycles. The patient will be monitored closely throughout treatment to help ensure the regimen remains safe and effective. Adequate rest, proper hydration and balanced nutrition can further support recovery during and after each cycle.

Targeted therapy for chronic lymphocytic leukemia

Targeted therapy has significantly advanced the treatment of CLL. These specialized medications are designed to block key signals and pathways that leukemia cells depend on, allowing for a more focused approach than traditional chemotherapy. By acting on cancer-specific mechanisms, targeted therapy can provide effective disease control with greater precision.

How does targeted therapy work?

Targeted therapy interferes with the specific signaling pathways that allow leukemia cells to proliferate. Some drugs block the external signals that prompt CLL cells to multiply, while others act inside the cell to counteract the proteins that prevent normal cell death. By acting directly on these disease-driving processes, targeted therapies can achieve effective leukemia control and often produce fewer side effects than traditional chemotherapy.

When is targeted therapy considered for chronic lymphocytic leukemia?

Targeted therapy for CLL may be used:

• As a first-line treatment for a newly diagnosed patient
• If chemotherapy is not feasible
• After relapse or if previous treatments become ineffective
• As part of a long-term maintenance strategy

Many targeted therapies are oral medications that can be taken at home, offering greater convenience and flexibility for the patient.

What are the potential risks and side effects of targeted therapy for chronic lymphocytic leukemia?

Although targeted therapy is generally well tolerated, side effects can occur. Depending on the specific medication used, some patients experience:

• Diarrhea
• Fatigue
• Muscle or joint pain
• Headache
• Leg swelling
• Heart rhythm changes (rare)

During targeted therapy, the healthcare team will monitor the patient closely and adjust the dosing or medications as needed.

Preparation and recovery from targeted therapy for chronic lymphocytic leukemia

Before beginning targeted therapy, the patient will have blood work and, in some cases, heart function tests to confirm that the treatment strategy is appropriate. Most individuals tolerate targeted medications well and can continue their normal routines during treatment. Ongoing follow-up appointments will allow the healthcare team to track the patient’s response and address any issues that may arise, helping to ensure the therapy remains safe and effective over time.

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Immunotherapy for chronic lymphocytic leukemia

Immunotherapy works by strengthening the body’s own immune defenses so they can better recognize and eliminate cancer cells. A common form of immunotherapy for CLL uses monoclonal antibodies, which bind to specific markers on leukemia cells and help the immune system target them more effectively.

How does immunotherapy work?

Immunotherapy uses laboratory-engineered antibodies designed to attach to specific proteins found on the surface of CLL cells. Once bound, the antibodies signal the immune system to attack and eliminate the cancer cells. Immunotherapy may be used alone or in combination with chemotherapy or targeted therapy to promote a stronger, more effective treatment response.

How is immunotherapy administered?

Immunotherapy medications are usually delivered through intravenous infusions. Depending on the drug, each infusion can take up to several hours. Some immunotherapy drugs can also be administered as injections.

The timing and frequency of immunotherapy can vary based on the specific medication and whether it is being used alone or in combination with other therapies. The healthcare team will develop a schedule that aligns with the drug’s requirements and the patient’s overall treatment plan.

What are the potential risks and side effects of immunotherapy for chronic lymphocytic leukemia?

Because immunotherapy activates the immune system, side effects can occur, particularly early in treatment when the body is still adjusting to the medication. Common experiences include:

• Fever and chills
• Nausea
• Fatigue
• Low blood cell counts
• Mild skin reactions
• Increased risk of infections

Any infusion-related reactions will be carefully monitored by the healthcare team. Most side effects are temporary and can be managed with supportive medications.

Preparation and recovery from immunotherapy for chronic lymphocytic leukemia

Before starting immunotherapy, the patient will undergo blood work and may receive premedications to help reduce the risk of infusion-related reactions. Recovery is generally mild, with any side effects typically diminishing over time. Through close monitoring, the healthcare team will ensure the treatment remains safe and appropriate.

Bone marrow transplantation (BMT) for chronic lymphocytic leukemia

BMT is an intensive therapy reserved for select cases of CLL. While not commonly used as frontline treatment, it may be appropriate for a patient whose cancer behaves aggressively or no longer responds to standard therapies, such as targeted agents or immunotherapy. Because bone marrow transplantation involves replacing the body’s entire blood-forming system, it requires careful consideration and specialized expertise.

When is bone marrow transplantation considered for chronic lymphocytic leukemia?

BMT is recommended only when the potential benefits outweigh the risks. It is generally considered for younger, medically fit patients with high-risk CLL, particularly those whose leukemia progresses rapidly or returns despite multiple prior treatments. Genetic findings, such as certain chromosomal abnormalities or mutations associated with treatment resistance, may also influence eligibility. The healthcare team will perform a comprehensive evaluation to determine whether a bone marrow transplant offers a realistic chance of long-term cancer control.

What does bone marrow transplantation for chronic lymphocytic leukemia involve?

The BMT process occurs in several stages, beginning with preparation of the bone marrow and ending with the recovery of healthy blood cell production. Key steps typically include:

• Conditioning – High-dose chemotherapy (and sometimes radiation therapy) will be given to eliminate the diseased bone marrow and suppress the immune system enough to allow the new cells to engraft.
• Infusion – Healthy blood-forming cells, collected either from the patient (autologous transplant) or, more commonly in CLL, from a compatible donor (allogeneic transplant), will be infused into the patient’s bloodstream. Once there, the cells can travel to the bone marrow and begin restoring normal blood cell production.
• Intensive monitoring – The healthcare team will closely track the patient’s blood counts, infection risk and early signs of engraftment. Supportive care, such as transfusions, antibiotics and medications to reduce BMT complications, will be provided throughout this period.

Because bone marrow transplantation temporarily weakens the immune system, recovery often requires several weeks of hospitalization followed by close outpatient follow-up. While BMT is demanding, it may offer the possibility of long-term remission for an appropriately selected patient. A detailed pretransplant assessment will be essential to determine the patient’s readiness and optimize the outcome.

What are the potential benefits and risks of bone marrow transplantation for chronic lymphocytic leukemia?

The primary benefit of BMT is the potential for durable remission, especially in cases where the leukemia has stopped responding to other therapies. Donor cells can introduce a new immune system capable of recognizing and attacking residual CLL cells, a phenomenon known as the graft-versus-leukemia effect.

However, because BMT involves replacing the body’s immune system, it carries significant risks. Possible complications include:

• Severe infections due to prolonged immune suppression
• Graft-versus-host disease (GVHD), in which the donor cells attack healthy tissues
• Organ toxicity, which may affect the liver, lungs or other systems
• Delayed blood cell recovery, which may require ongoing transfusion and supportive care

Long-term monitoring and careful management of any side effects are essential to support recovery and maximize the benefits of the procedure.

Radiation therapy for chronic lymphocytic leukemia

Radiation therapy uses targeted, high-energy beams to shrink abnormal tissues and relieve symptoms in specific areas of the body. Unlike systemic treatments that circulate throughout the bloodstream, radiation is delivered only to the region being treated, allowing for focused symptom management with minimal impact on the rest of the body.

What is the role of radiation therapy for chronic lymphocytic leukemia?

Radiation therapy has a limited but meaningful role in CLL care. Because it targets only a specific area of the body, it is not used as a primary treatment for chronic lymphocytic leukemia, which involves the blood and lymphatic system on a widespread basis. Instead, radiation may be directed to a localized region where leukemia-related swelling or tissue involvement is causing discomfort or affecting daily function. This approach may be considered if:

• Enlarged lymph nodes are causing pain or restricting movement
• An enlarged spleen is contributing to abdominal fullness or discomfort
• Localized symptoms require prompt relief that systemic therapy may not provide

By delivering high-energy beams to the affected site, radiation therapy can reduce lymphoid tissue and ease symptoms. It may also be used as part of the preparation process for a bone marrow transplant in select cases.

What are the potential risks and side effects of radiation therapy for chronic lymphocytic leukemia?

The side effects of radiation therapy can vary depending on the treatment location, dose and individual response. Common issues include:

• Fatigue
• Skin irritation in the treated area
• Localized swelling or tenderness
• Nausea, particularly when the abdomen is targeted

These side effects are generally manageable and tend to improve after treatment ends. The radiation oncology team will offer guidance on what to expect and how to care for the treated area during recovery.

Clinical trials for chronic lymphocytic leukemia

Clinical trials allow carefully selected patients to access promising new therapies that are not yet widely available and may lead to a better treatment outcome. Through these important research studies, scientists and clinicians assess the effectiveness of innovative medications, immunotherapy combinations, cellular therapies and next-generation targeted approaches compared to the current standard of care.

For a patient with chronic lymphocytic leukemia, a clinical trial may be an option:

• At diagnosis
• As a first-line therapy
• After relapse
• If standard therapies lose effectiveness

Beyond offering access to groundbreaking therapies, clinical trials enable participants to play an active role in advancing the field of CLL treatment.

Benefit from world-class care at Moffitt Cancer Center

Effective treatment for chronic lymphocytic leukemia requires a tailored plan that reflects the specific features of the patient’s cancer. Moffitt’s integrated, multispecialty model brings together hematologic oncologists, pathologists, radiologists, transplant specialists and supportive care experts who collaborate closely to develop individualized treatment strategies. This coordinated approach incorporates advanced diagnostic tools, innovative therapies and comprehensive supportive care.

Our team meets regularly to review complex cases and refine treatment recommendations based on the latest evidence and the patient’s response. By working in unison, we provide care that not only targets the cancer effectively but also prioritizes the patient’s overall well-being throughout the treatment process.

If you would like to explore your treatment options for chronic lymphocytic leukemia with a specialist in the Malignant Hematology Program at Moffitt, you can request an appointment by calling 1-888-663-3488 or submitting a new patient registration form online. We do not require referrals.