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by Dr. C.D. Buckner M.D. Medically reviewed by Dr. C.H. Weaver M.D. 2/2022

Chronic lymphocytic leukemia (CLL) is a disease characterized by high numbers of circulating abnormal lymphocytes (B-Cells) in the peripheral blood. The disease often involves enlargement of lymph nodes in various parts of the body as well as enlargement of the spleen. In CLL the marked elevation of lymphocytes in the blood is partially due to a prolonged survival of abnormal lymphocytes compared to normal lymphocytes.

  • Signs & Symptoms of Chronic Lymphocytic Leukemia
  • Risk Factors for Chronic Lymphocytic Leukemia
  • Diagnosis & Tests
  • Staging of Chronic Lymphocytic Leukemia
  • Treatment of Chronic Lymphocytic Leukemia
Leukemia CancerConnect 490

CLL typically occurs in individuals between 65 and 70 years of age. Historically, it has been diagnosed at an advanced stage that typically involves the lymph nodes and bone marrow. More recently, however, the disease has frequently been detected in routine blood tests, allowing for earlier diagnosis. As a result, more patients are presenting with early-stage asymptomatic disease.

CLL is the most common adult leukemia with over 18,000 Individuals diagnosed per year in the United States. CLL is not a rapidly growing cancer, but the abnormal cells accumulate in blood, bone marrow, lymph nodes and spleen, resulting in enlargement of these organs and decreased bone marrow and immune function. This disease interferes with the normal production of antibodies and immunoglobulins, so the body cannot properly fight infections.

Chronic lymphocytic leukemia has unique features that are not present in other kinds of leukemia, such as immune-mediated destruction of red blood cells and platelets. These are referred to as autoimmune-mediated cytopenias. Patients with CLL may also experience repeated infections from low levels of normal immunoglobulin production.1

Monoclonal B-Cell Lymphocytosis

Some individuals will have all the characteristics of CLL in a blood test but have a lymphocyte count of less than 5,000. This is known as monoclonal B-cell lymphocytosis. Such low levels of CLL cells are detected in approximately 3% of the general population. Chromosomal abnormalities are frequently detected in this group of apparently normal patients. It is estimated that 1-2% of patients per year with monoclonal B-cell lymphocytosis will progress to CLL and require treatment. Monoclonal B-cell lymphocytosis occurs predominantly in elderly individuals and requires periodic monitoring but not necessarily treatment.2

Symptoms & Signs of CLL

One of the most important factors that affects the decision to treat or not to treat CLL is whether or not patients with CLL have symptoms of their disease.1 Some of the symptoms of CLL include:

  • fever
  • frequent infections
  • night sweats
  • swollen and painful lymph nodes
  • significant weight loss.

Risk Factors for CLL

A risk factor is anything that increases a person’s chance of developing cancer. Risk factors can influence the development of cancer, but most do not directly cause cancer. Many individuals with risk factors will never develop cancer and others with no known risk factors will. Most leukemias develop sporadically, which means for no known reason. Risk factors for CLL include the following1:

  • Being exposed to certain chemicals, pesticides, fertilizers and solvents such as benzene.
  • Older age is also a risk factor for most cancers. The chance of getting cancer increases as you get older.

Cause of CLL

The cause of CLL in most patients is not known. CLL begins when healthy cells acquire a genetic change (mutation) that causes them to turn into abnormal cells.

Diagnosis & Tests for CLL

Doctors use many tests to diagnose and evaluate CLL. They also do tests to learn where leukemia has spread in the body. The doctor may recommend some or all of these tests to help make a diagnosis and develop a treatment plan.1

  • Bone Marrow Aspirate & Biopsy
  • Genomic or Biomarker Testing - By testing CLL for specific unique biomarkers doctors can offer the most personalized treatment approach utilizing precision medicines. 
    •  FISH: The FISH test can detect abnormal chromosomes and genes in either blood or bone marrow cells. It is very common for CLL cells to have abnormal chromosomes. 
    • Karyotype: A karyotype is a picture of chromosomes. It shows if there is a defect in the size, shape, and number of chromosomes. A “complex karyotype” is linked to a poorer outcome. A complex karyotype is 3 or more unrelated defects in chromosomes that occur in more than one cell. 
    • Quantitative Immunoglobulins: Immunoglobulins (Ig) are protein antibodies made by immune cells to help the body detect germs and other threats. Quantitative Ig measures the amount of three distinct antibodies; IgG, IgA, and IgM in the blood. Some people with CLL have low levels of antibodies before cancer treatment and levels can decrease during cancer treatment increasing the risk of infection. 
    • DNA Sequencing tests for mutations in genes in a blood or bone marrow sample. IGHV mutation: Normal antibodies are made of two heavy chain proteins and two light chain proteins. IGHV region genes contain instructions for making the heavy chain protein. These genes may or may not be mutated in people with CLL. The outlook is good if IGHV is mutated. Surface proteins CD38, CD49d, and ZAP-70 are markers for the IGHV mutation. If IGHV testing can’t be done, testing for these markers is an option. But, IGHV testing is preferred. TP53 Mutation: The TP53 gene is for a protein that signals whether damaged cells should be repaired or destroyed. It helps to prevent tumors from forming.
  • Computed Tomography (CT) Scan: A CT scan is a technique for imaging body tissues and organs, during which X-ray transmissions are converted to detailed images, using a computer to synthesize X-ray data. A CT scan is conducted with a large machine positioned outside the body that can rotate to capture detailed images of the organs and tissues inside the body.
  • Magnetic Resonance Imaging (MRI): MRI uses a magnetic field rather than X-rays, and can often distinguish more accurately between healthy and diseased tissue than a CT. An MRI gives a better picture of cancer located near bone than does CT, does not use radiation, and provides pictures from various angles that enable doctors to construct a three-dimensional image of the cancer.
  • Positron emission tomography (PET): Positron emission tomography scanning is an advanced technique for imaging body tissues and organs. One characteristic of living tissue is the metabolism of sugar. Prior to a PET scan, a substance containing a type of sugar attached to a radioactive isotope (a molecule that emits radiation) is injected into the patient’s vein. The cancer cells “take up” the sugar and attached isotope, which emits positively charged, low energy radiation (positrons) that create the production of gamma rays that can be detected by the PET machine to produce a picture. If no gamma rays are detected in the scanned area, it is unlikely that the mass in question contains living cancer cells.

Staging of CLL

There are two staging systems in use: Rai and Binet.

The Rai system has five stages:

  • Stage 0: Stage 0 CLL is characterized by absolute lymphocytosis (high lymphocyte count) without lymphadenopathy (enlarged lymph nodes), hepatosplenomegaly (enlarged liver and spleen), anemia (low red blood cell count), or thrombocytopenia (low platelet count).
  • Stage I: Stage I CLL is characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.
  • Stage II: Stage II CLL is characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy.
  • Stage III: Stage III CLL is characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly.
  • Stage IV: Stage IV CLL is characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.

The Binet staging system has three stages:

  • Clinical Stage A: Clinical Stage A CLL is characterized by no anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai Stages 0, I, and II).
  • Clinical stage B: Clinical Stage B CLL is characterized by no anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai Stages I and II).
  • Clinical Stage C: Clinical Stage C CLL is characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai Stages III and IV).
  • *Lymphoid areas include cervical, inguinal and spleen.

Although all patients should be accurately staged with one of the above staging systems, for treatment purposes patients are divided into two groups: asymptomatic patients with early-stage disease (usually Binet Stage A and RAI Stage 0, I, and II) and symptomatic patients who usually have advanced-stage disease (Binet Stage B and C and RAI Stage III and IV). The goal of staging is to determine which patients have early and which have advanced-stage CLL.

Treatment of Chronic Lymphocytic Leukemia

There have been tremendous advances in the treatment of CLL over the past decade. Complete molecular remissions and long-term disease-free survival can be achieved. It has therefore become important to determine when patients should be treated and how aggressively.

When to Initiate Treatment?

Approximately 30-50% of newly diagnosed individuals with CLL will develop progressive disease within a short period of time, while the remainder may live for decades and not require therapy. In general, patients with asymptomatic early-stage CLL should not be treated unless they are participating in a clinical trial evaluating the effects of therapy on patients with adverse prognostic features.1,3-5

Indications for Beginning Treatment of CLL:

  • Anemia (hemoglobin level less than 11.0 g/dL)
  • Thrombocytopenia (platelet count less than 100,000/mm3)
  • Massive or progressive enlargement of lymph nodes
  • A lymphocyte doubling time of less than 6 months
  • Fever, weight loss, night sweats or profound fatigue

​Treatment of Symptomatic Advanced CLL

Chronic lymphocytic leukemia is treated with systemic therapy using chemotherapy, immunotherapy or precision cancer medicines. Systemic therapy is any treatment directed at destroying leukemia cells throughout the body. Historically CLL was mainly treated with chemotherapy however advances in the development of newer precision cancer medicines and immunology have allowed doctors to more specifically target and treat the leukemia cells and avoid harming normal cells resulting in fewer side effects of treatment in some patients.

The specific treatment for CLL is personalized and is based on the age and condition of the individual, the extent of the cancer, and its genomic profile. Individuals with a defect in chromosome 17 called “del(17p)” which is linked with loss of the TP53 gene are treated differently than individuals with CLL who don't have this defect. These individuals tend to respond better to treatment with precision cancer medicines and do poorly with chemotherapy.1

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  • Chemotherapy uses medications that can be taken orally as a pill or are injected into a vein to kill cancer cells. In some situations, chemotherapy is combined with precision cancer medicines or radiation therapy to achieve the best results.
  • Precision Cancer Medicines use targeted drugs and immunotherapies engineered to directly attack leukemia cells with specific abnormalities, leaving normal cells largely unharmed.
  • Kinase Inhibitors: Within cells, kinases are part of many chemical pathways, some of which increase cell growth. Kinase inhibitors block the growth signals and decreases the number of new cells being made. Imbruvica (Ibrutinib) and Calquence (acalabrutinib) Within CLL cells, BTK (Bruton’s tyrosine kinase) is a protein/carbohydrate complex that is involved in maintaining cellular survival and replication. Inhibiting the activity of BTK reduces the growth of cancer and causes cellular death.6,7 Zydelig (idelalisib) targets one form of PI3K (phosphoinositide 3-kinase) called delta.8 Copiktra (duvelisib) targets two forms of PI3K— delta and gamma.9
  • BCL-2 Inhibitors: BCL-2 is a protein inside of B cells that helps prevent cell death. Over expression of the BCL-2 protein in lymphoma cells is associated with increased survival time of the cancer cells as well as resistance to standard chemotherapy. Ventoclax (veneclexta) is a BCL-2 inhibitor that allows the cancer cells to self-destruct.10
  • Monoclonal Antibodies: Antibodies are proteins of the immune system that help your body detect and destroy foreign substances. Monoclonal antibodies can be made in a lab to target specific abnormalities on cancer cells. CLL cells may have surface proteins called CD20 and CD52. Monoclonal antibodies that attach to CD20 and CD52 have been developed and directly kill cells or mark them for destruction by your immune system.5,11,12
    •  Gazyva (obinutuzumab) is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain types of B-cells. It is thought to work by attacking targeted cells both directly and together with the body’s immune system. 
    • Arzerra (ofatumumab) is a fully human monoclonal antibody that binds specifically to the small and large extracellular loops of the CD20 molecule proximal to the cell membrane. 
    • Campath (alemtuzumab) is a fully human monoclonal antibody that selectively targets the CD52 antigen, which is expressed more prominently on malignant lymphocytes than other cells. The binding of Campath stimulates destruction of the malignant lymphocytes and reduction or elimination of cancerous cells throughout the bone marrow, blood and lymph system.
    • Rituxan (rituximab) is an engineered monoclonal antibody designed to attach to CD20, a protein found on certain types of B-cells. It is thought to work by attacking targeted cells both directly and together with the body’s immune system.
  • Immunomodulators are drugs that modify some parts of the immune system. Revlimid (lenalidomide) is an immunomodulator that is often used to treat a cancer called multiple myeloma. For CLL, it is sometimes used as maintenance treatment.2
  • Cellular Immunotherapy: The goal of cellular immunotherapy is to activate an individual’s immunologic cells to recognize and destroy the leukemia cells. Currently there are two approaches that have been demonstrated to produce long term remissions and potentially cure recurrent CLL. 
    •  Allogenic stem cell transplant has been used to treat recurrent CLL in younger patients for many years. During an alloSCT the CLL is first treated with high dose therapy and then stem cells previously collected from a donor are infused into the patient to restore the immune system and normal blood cell production.
    • CAR T Cell Therapy utilizes T-cells (CART T), a patient’s own immune cells that are re-programmed to recognize and kill cancer cells throughout the body. The process involves the removal of some T cells from a patient, and through laboratory processes these T cells are re-programmed to identify a patient’s cancer cells and destroy them.20

Initial Treatment of Del(17p) and TP53 Positive CLL

Initial Treatment of Del(17p) and TP53 Mutation Negative CLL

  • Imbruvica
  • Imbruvica + Gazyva
  • Gazyva + Venclexta
  • Treanda (bendamustine) chemotherapy has been shown to improve response to treatment and delay cancer recurrence compared to Chlorambucil.13
  • Fludara, Cytoxan, and Rituxan (FCR) is very active in the treatment of CLL. In a study in 224 previously untreated patients the overall response rate was 95%. At two years, over 90% of patients were alive and over 80% had not progressed; all complete responders were alive. Infectious episodes occurred in a third of all patients.14-18

Maintenance Therapy:

After immunochemotherapy, your doctor may recommend Revlimid for maintenance treatment. It is sometimes given if the cancer is likely to relapse. Relapse is more likely if very small amounts of cancer cells remain in your blood after treatment. This small amount is called MRD (minimal residual disease).

Recurrent or Refractory CLL

Individuals with recurrent CLL are typically treated with chemotherapy and precision cancer medicines that are different than their initial treatment. Those listed below are "recommended" by the NCCN but any of the classes of CLL treatment described above may be used. Individuals should consider a second opinion at a cancer center with expertise in alloSCT and CAR T-cell therapy. These therapies appear curative and are rapidly improving.19,20

In July 2010, the first two patients with advanced CLL received autologous CD19 chimeric antigen receptor (CAR) T-cell (CAR-T) therapy (tisagenlecleucel): their disease went into complete remission and has remained there for over 8 years.1 As of 6/2019 both patients remain in deep molecular remission with CAR-T cells still present.20

Recurrent Del(17p) and TP53 Positive CLL

Recurrent Del(17p) and TP53 Mutation Negative CLL

Other Medications

Aliqopa(copanlisib) Aliqopa is a precision cancer medicine that inhibits several key cell-signaling pathways in lymphoma cell lines resulting in cancer cell death by apoptosis and inhibition of the growth of primary malignant B cell lymphoma cell lines.

Keytruda® (pembrolizumab) belongs to a new class of medicines called PD-1 inhibitors that help the immune system recognize and attack cancer. PD-1 is a protein that inhibits certain types of immune responses. Drugs that block PD-1 may enhance the ability of the immune system to fight cancer. Keytruda® works by blocking PD-1.

Revlimid® (lenalidomide) This oral immunomodulatory therapy is being used in combination with Rituxan.2

CML Newsletter 490

Supportive Care

Infections remain a major cause of morbidity and mortality in patients with CLL. These infections are related to immune defects inherent to CLL as well as to therapy-related immunosuppression. Infectious complications are increased with the use of Fludara and monoclonal antibodies such as Rituxan and Campath compared to treatment with chemotherapy alone. Although bacterial infections are the most common; fungal and herpesvirus infections are also seen with use of these agents. Infections such as Pneumocystis carinii and cytomegalovirus pneumonias are due to reactivation of these organisms already present in the body.

Several steps can be taken to improve the survival and well being of patients with CLL:

Intravenous Immunoglobulin: Intravenous immunoglobulin should be administered to patients with low levels of gamma globulin for infection prevention.19

Pneumocystis carinii: Pneumocystis carinii (now called jiroveci) is a common lung infection in immunosuppressed patients caused by a fungus. Pneumonia due to this infection can be prevented by the prophylactic administration of cotrimoxazole or another appropriate drug.

Cytomegalovirus: Cytomegalovirus causes pneumonia in immunosuppressed patients and can be prevented by the prophylactic administration of gancyclovir or another appropriate drug.20

Bacterial Infections: The prophylactic administration of a systemic broad-spectrum antibiotic is indicated for CLL patients receiving combination therapy. Patients should also be vaccinated with pneumococcal vaccine.21

Fungal Infections: Anti-fungal agents are used to prevent or treat fungal infections which are common in CLL.

Neutropenia: Neulasta® (pegfilgrastim) or Neupogen® (filgrastim) are frequently administered prophylactically to patients receiving combination chemotherapy and antibody therapy for CLL to hasten recovery of granulocytes in the blood.

Anemia: Anemia due to chemotherapy can be prevented or treated with Aranesp® (darbepoetin alfa) or Epogen® (epoetin alfa).


  2. Rawston AC, Bennet FL, O’Connor SJM, et al. Monoclonal B-cell lymphocytosis (MBL) is a precursor state for chronic lymphocytic leukemia (CLL) with 1% progression per year. Blood. 2007;110:230a, abstract number 749
  3. Rassenti LZ, Huynh L, Toy TL, et al. ZAP-70 compared with immunoglobulin heavy-chain gene mutation status as a predictor of disease progression in chronic lymphocytic leukemia. New EnglandJournal of Medicine. 2004; 351: 893-901.
  4. Bergmann MA, Eichhorst BF, Busch R, et al. Prospective evaluation of prognostic parameters in early stage chronic lymphocytic leukemia (CLL): Results of the CLL1-protocol of the German CLL Study Group (CCLLSG). Blood 2007;193a, abstract 625.
  5. Narrative review: Initial management of newly diagnosed, early-stage chronic lymphocytic leukemia. Annals of Internal Medicine 2006;145:435-447.
  6. Burger J, Ketaing M, Wierda W, et al. Safety and activity of ibrutinib plus rituximab for patients with high-risk chronic lymphocytic leukaemia: a single-arm, phase 2 study. The Lancet Oncology, 15;1090 – 1099, September 2014.
  7. Patel V, Balakrishnan K, Bibikova E, et al. Comparison of acalabrutinib, a selective Bruton tyrosine kinase inhibitor, with ibrutinib in chronic lymphocytic leukemia cells.Clin Cancer Res. 2017;23:3734-3743
  8. Zelenetz A, Robak T, Coiffier B, et al. LBA-5 Idelalisib plus bendamustine and rituxumab (BR) is superior to BR alone in patients with relapsed/refractory chronic lymphocytic leukemia: results of a phase 3 randomized double-blind placebo-controlled study.[Abstract] ASH 57th Annual Meeting & Exposition, Orlando FL, December 5-8, 2015.
  9. Winkler et al. PI3K-delta and PI3K-gamma inhibition by IPI-145 abrogates immune responses and suppresses activity in autoimmune and inflammatory disease models. Chem Biol 2013; 20:1-11.
  10. Phase III Data Showed That Venclexta Plus Gazyva Reduced The Risk Of Disease Worsening Or Death In People With Previously Untreated Chronic Lymphocytic Leukemia With Co-Morbidities
  11. Hillmen P, Skotnicki A, Tobak T, et al. Preliminary Phase III Efficacy and Safety of Alemtuzumab vs Chlorambucil as Front-Line Therapy for Patients with Progressive B-Cell Chronic Lymphocytic Leukemia (BCLL). Proceedings from the 42nd annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2006. Abstract # 6511.
  12. Dmoszynska A, Fetni R, Wang Y, et al. Cytogenetic Correlation with Efficacy on Alemtuzumab (Campath®, Mabcampath®) (CAM) vs Chlorambucil (CHLO) as Front-Line therapy for Patents with Progressive B-Cell Chronic Lymphocytic Leukemia (BCLL). Proceedings from the 42 annual meeting of the American Society of Clinical Oncology. Atlanta, Ga. June 2006. Abstract # 6601.
  13. Cephalon Receives FDA Approval for TREANDA, a Novel Chemotherapy for Chronic Lymphocytic Leukemia. Available at: Accessed April 2008.
  14. Keating MJ, O’Brien S, Albitar M, et al. Early results of a chemoimmunotherapy regimen of Fludara, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. Journal of Clinical Oncology. 2005;23:4079-4088.
  15. Wierda W, O’Brien S, Wen S, et al. Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. *Journal of Clinical Oncology.*2005;23:4070-4078.
  16. Tarhini AA, Land S, Pietragallo A, et al. Final results of lower dose fludarabine (F) and cyclophosphamide (C), and high dose rituximab (R), (FCR-lite) for patients with untreated chronic lymphocytic leukemia (CLL). Blood 2007;110:606a, abstract 2037.
  17. Egle A, Weiss L, Russ G, et al. Planned first efficacy and safety analysis of de-intensified induction with fludarabine, cyclophosphamide plus rituximab (FCR) followed by fludarabine plus rituximab (FR) and remission maintenance with rituximab in previously untreated B-cell chronic lymphocytic leukemia (B-CLL). Blood 2007;110:609a, abstract number 2045.
  18. Hillman P, Popcock C, Cohen D, et al. NCRI CLL201 Trial: A randomized phase II trial of fludarabine, cyclophosphamide and mitoxantrone (FCM) with or without rituximab in previously treated CLL. Blood2007;231a, abstract number 762.
  19. Porter DL, Levine BL, Kalos M, Bagg A, and June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365(8):725-733.
  20. Melenhorst JJ, Porter DL, Nobles CL, et al. Long-term remission of CLL sustained by oligoclonal CD19-specific chimeric antigen receptor T cell clones. Presented at: 2019 American Society of Gene and Cell Therapy (ASGCT) Annual Meeting; Washington, D.C.; April 29-May 2, 2019. Abstract 358
  21. Intravenous immunoglobulin for the prevention of infection in chronic lymphocytic leukemia. A randomized controlled clinical trial. Cooperative Group for the Study of Immunoglobulin in Chronic Lymphocytic Leukemia. New EnglandJournal of Medicine 1988;319:902-907.
  22. O’Brien S, Ravandi F, Riehl T, et al. Valganciclovir prevents CMV reactivation in patients receiving alemtuzumab based therapy. Blood 2007; e-pub ahead of print November 2007.
  23. Sinisalo M, Vilpo J, Itala M, et al. Antibody response to 7-valent conjugated pneumococcal vaccine in patients with chronic lymphocytic leukemia. Vaccine 2007;26:82-87.1