NORD gratefully acknowledges Jennifer R. Brown, MD, PhD, Director, CLL Center, Dana-Farber Cancer Institute, Assistant Professor of Medicine, Harvard Medical School, for the assistance in the preparation of this report.
Approximately 50-75% of the patients with chronic lymphocytic leukemia have no symptoms when first diagnosed. The disease is discovered during a routine exam or blood test. Symptoms between the two subdivisions of CLL, Ig-mutated and Ig-unmutated, will experience the same symptoms, however, Ig-unmutated CLL progresses much faster.
Early signs of chronic lymphocytic leukemia may be fatigue, weight loss, loss of appetite (anorexia), labored breathing, low-grade fever, a feeling of fullness in the abdomen due to an enlarged spleen, and night sweats. Bacterial infections such as skin infections, fluid and inflammation of the lungs (pneumonia), and inflammation of the sinuses (sinusitis) often occur. As the disorder advances, the patient loses the ability to fight off infections. Viral infections become an increasing concern.
In the later stages of the disorder, the liver, spleen, and lymph nodes may steadily increase in size. Chronic lymphocytic leukemia may also invade other tissues such as the skin, eye socket (orbit), mucous membrane that lines the inside of the eyelids (conjunctivae), lungs, sacs that line the chest (pleura), heart, and gastrointestinal tract. Swelling and a yellow pigment of the skin (jaundice) may also occur.
The National Cancer Institute has published a six-step description of the staging of this disorder. The staging determines the treatment and management plan.
Stage 0: An abundance of lymphocytes in blood but no other sign of leukemia; lymph nodes, spleen, liver, red blood cells and platelets are normal.
Stage I: Too many lymphocytes; lymph nodes swollen; spleen and liver are normal as are erythrocytes and platelets.
Stage II: Too many lymphocytes; lymph nodes, spleen and/or liver swollen.
Stage III: Too many lymphocytes; too few red blood cells (anemia); lymph nodes swollen; spleen and/or liver may be swollen.
Stage IV: Too many lymphocytes; too few platelets (difficult blood clotting); lymph nodes, spleen and liver may be swollen; too few red blood cells (anemia).
Refractory: CLL does not respond to standard treatments.
The exact cause of chronic lymphocytic leukemia is not known. Multiple genetic mutations occur in the DNA of blood-producing cells. This mutation causes the blood cells to produce abnormal lymphocytes, which are not effective at fighting infection.
Usually, an abnormal chromosome is present in a patient with CLL. Most often this abnormality is a deletion, or the loss of part of a chromosome. The loss of part of chromosome 13 is the most common deletion, as well as chromosome 11 and 17 deletions. Sometimes there is an extra chromosome 12 (trisomy 12). Other rare chromosome abnormalities have also been reported. Scientists know these abnormalities are important in the causation of CLL, but it’s not yet clear which genes are involved in the development of CLL. The common chromosomal abnormalities are important prognostically, however, with deletions of chromosomes 11 and 17 predicting rapid disease progression.
First-degree relatives of someone who has been diagnosed with CLL have a 5-7 times greater chance of developing CLL.
Chronic lymphocytic leukemia is the most common type of leukemia found in multiple family members. It is twice as common in males as in females and the average age of onset in patients is 72. It is also more common in people that are white, or of Russian and Eastern European Jewish heritage. The rate of incidence of the disorder increases with age. CLL almost never affects children and is rare under the age of thirty. In the United States, it is thought that three out of every 100,000 people will develop CLL, but this may be an underestimate.
CLL is most commonly discovered when an abnormally high white blood cell count is noticed in routine blood work. A diagnosis can be made with one of the following tests:
1. Complete blood cell count-This test will measure the count of every type of blood cell, white blood cells, red blood cells, and platelets. A high number of B-cells, a certain type of white blood cell, may indicate CLL.
2. Flow cytometry-In this test, blood cells are examined with antibodies to determine if they are malignant (cancerous). This test establishes the diagnosis of CLL vs other related diseases.
3. Bone marrow biopsy-This test is conducted by removing a sample of bone marrow and examining it to determine what time of leukemia is present.
4. Lymph node biopsy-A biopsy of the lymph nodes can determine whether cancer has spread to the lymphatic system.
To predict the likely course of CLL, your doctor may also recommend more specialized tests. Specialized tests can determine the need for treatment vs. observation, and predict response to treatment and the likelihood of relapse.
Clinical Testing and Work-Up
Regular blood tests and physical exams are used to carefully watch for signs of progression because early-stage CLL may take years to progress,. It is also important to know the stage the CLL to know what treatment is appropriate. Generally just blood tests and physical exams are all that is required for routine disease monitoring, along with blood chemistries and antibody tests.
Treatment for CLL is based on the stage of the disease, symptoms, and prognosis. Patients with CLL may show no symptoms for years, and don’t require special care. However, in later stages of the disease, chemotherapy is a common choice of treatment. Another treatment option is monoclonal antibody therapy, which binds proteins to cancer cells, activating a mechanism that destroys them. Using both of these therapies together usually produces the highest treatment response.
In especially aggressive or recurrent cases of CLL, a blood and marrow stem cell transplant has shown promise.
Treatment of chronic lymphocytic leukemia includes platelet transfusions which are used for bleeding associated with a persistent decrease in the number blood platelets (thrombocytopenia). When anemia is present, transfusions of packed red blood cells are usually given. Antibiotics are used to combat bacterial infections usually related to a decrease in the number of leukocytes (lymphopenia) and a low level of gammaglobulin in the blood.
The FDA approved the anti-cancer drug Rituxan (rituximab) in 2010 to treat certain patients with chronic lymphocytic leukemia. Rituxan is intended for patients with CLL who are beginning chemotherapy for the first time and for those who have not responded to other cancer drugs for chronic lymphocytic leukemia. Rituxan is administered with two other chemotherapy drugs, fludarabine and cyclophosphamide. Rituxan is manufactured by Genentech, Inc.
Treanda (Bendamustine hydrochloride) has been approved by the FDA for treating CLL. It has been shown that Treanda can be effective when administered once every four weeks, similar to other chemotherapies for CLL. Treanda is manufactured by Cephalon, Inc.
The monoclonal antibody CAMPATH (alemtuzumab) has been approved by the FDA for the treatment of chronic lymphocytic leukemia. CAMPATH is manufactured by Genzyme, a Sanofi Company.
The FDA has also approved Arzerra (Ofatumumab) to combat CLL. This drug is usually only used when other treatments have not been successful because it can cause serious viral infections in the brain. To be sure that this medication is not causing harm, blood cell, kidney, and liver function need to be testing even after administration has stopped. Arzerra is manufactured by GlaxoSmithKline.
In 2014, Imbruvica (ibrutinib) was approved to treat chronic lymphocytic leukemia patients who have received at least one previous therapy. This medication was previously approved to treat patients with mantle cell lymphoma. Imbruvica is manufactured by Pharmacyclics.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Contact for additional information about chronic lymphocytic leukemia:
Jennifer R. Brown, MD, PhD
Rai KR, Stephenson J, Waldman H. Campath-1H: Emerging Frontline Therapy in Chronic Lymphocytic Leukemia. CRC Press – Parthenon Publishing. 2001;128.
Beers MH, Berkow R., eds. The Merck Manual, 17th ed. Whitehouse Station, NJ: Merck Research Laboratories; 1999:949-51.
Berkow R., ed. The Merck Manual-Home Edition. Whitehouse Station, NJ: Merck Research Laboratories; 1997:765-67.
Larson DE. ed. Mayo Clinic Family Health Book. New York, NY: William Morrow and Company, Inc; 1996:966-67.
Wiestner A, Rosenwald A, Barry TS, et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood. 2003: 15;101(12):4944-51. http://www.ncbi.nlm.nih.gov/pubmed/12595313
Kipps TJ. Advances in classification and therapy of indolent B-cell malignancies. Semin Oncol. 2002;29(1 Suppl 2):98-104.
Nabhan C, Rosen ST. Conceptual aspects of combining rituximab and Campath-1H in the treatment of chronic lymphocytic leukemia. 2002;29(1 Suppl 2):75-80.
Van BeslenK, Keralavarma B, Devine S, et al. Allogenic and autologous transplantation for chronic lymphocytic leukemia. Leukemia. 2001;15:1317-25.
Syrigos KN, Pliarchopoulou K, Harrington KJ. The development of monoclonal antibody therapy in leukemias. Hybridoma. 2001;20:145-48.
Monni O, Knuutila S. 11q deletions in hematological malignancies. Leuk Lymphoma. 2001;40:259-66.
Robak T. Cladribine in the treatment of chronic lymphocytic leukemia. Leuk Lymphoma. 2001;40:551-64.
Caligaris-Cappio F. Biology of chronic lymphocytic leukemia. Rev Clin Exp Hematal. 2000;4:5-21.
Stilgenbauer S, Lichter P, Dohner H. Genetic features of B-cell chronic lymphocytic leukemia. Rev Clin Exp Hematal. 2000;4:48-72.
FROM THE INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; http://omim.org/entry/151400 ; Last Update: 6/3/11.
Mayo Clinic. Chronic Lymphocytic Leukemia. http://www.mayoclinic.com/health/chronic-lymphocytic-leukemia/DS00565 Accessed 7/26/11.
National Cancer Institute. Chronic Lymphocytic Leukemia. http://www.cancer.gov/cancertopics/pdq/treatment/CLL/Patient/page1
Drugs.com. Ofatumumab. http://www.drugs.com/mtm/ofatumumab.html. Revision Date: 12/15/2010 Accessed 7/27/2011.
American Cancer Society. Leukemia-Chronic Lymphocytic. http://www.cancer.org/Cancer/Leukemia-ChronicLymphocyticCLL/DetailedGuide/leukemia-chronic-lymphocytic-what-causes Last Revised: 06/23/2011. Accessed 7/26/2011.
Vachani, C. Oncolink.com. Chronic Lymphocytic Leukemia. http://www.oncolink.org/types/article.cfm?c=8&s=29&ss=763&id=9590&p=4 Last Modified: August 22, 2007. Accessed 7/28/2011.
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