NORD gratefully acknowledges Jennifer R. Brown, MD, PhD, Director, CLL Center, Dana-Farber Cancer Institute, Associate Professor of Medicine, Harvard Medical School, for the assistance in the preparation of this report.
Approximately 50-75% of patients with chronic lymphocytic leukemia have no symptoms when first diagnosed. The disease is discovered during a routine exam or blood test. Symptoms can be similar between the two subdivisions of CLL, Ig-mutated and Ig-unmutated, although when Ig-unmutated CLL progresses, typically sooner, more symptoms may ensue.
Symptoms of chronic lymphocytic leukemia may include 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. These mutations cause 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 rarer 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, namely parents, siblings or children, 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. This is usually not required to make an initial diagnosis of CLL, since flow cytometry can be done on the blood.
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 predict response to treatment and the likelihood of relapse but the decision to treat is still based on clinical parameters – how you feel, your blood counts, lymph nodes, etc.
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. 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.
All care of CLL patients, whether receiving specific therapy or not, includes what we call supportive care and 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. Vaccinations are important and should include yearly influenza as well as the pneumococcal vaccines, prevnar and pneumovax. However, live virus vaccines like that against shingles can be dangerous.
The FDA approved the anti-cancer drug Rituxan (rituximab) in 2010 to treat certain patients with chronic lymphocytic leukemia. Rituxan is intended together with chemotherapy for patients with CLL who are beginning first line therapy. Rituxan is administered with two other chemotherapy drugs, fludarabine and cyclophosphamide. Rituxan is manufactured by Genentech, Inc.
Recently two other antibodies with the same target as rituximab have been approved by the FDA for frontline therapy of CLL in combination with the oral chemotherapy pill chlorambucil. These include obinutuzumab (Gazyva), which is very potent even at clearing CLL cells from bone marrow. The FDA has also approved Arzerra (Ofatumumab) to combat CLL, initially for refractory patients but more recently for previously untreated patients together with chlorambucil and for patients who have had previous chemoimmunotherapy and are in remission. Arzerra is manufactured by GlaxoSmithKline.
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 last few years have seen an explosion of very effective small molecule inhibitors for CLL. These are pills and generally well tolerated. In 2014, Imbruvica (ibrutinib) was approved to treat chronic lymphocytic leukemia patients who have received at least one previous therapy as well as those with high risk del17p. In 2016 this label was broadened to include all CLL patients even those who are previously untreated. This medication was previously approved to treat patients with mantle cell lymphoma. Imbruvica is manufactured by Pharmacyclics. Idelalisib is another oral inhibitor approved for relapsed CLL patients with comorbid medical problems, also in 2014. In 2016, venetoclax was approved just for relapsed 17p deleted CLL patients. These are all excellent drugs which we are still learning how best to use.
In 2017, the combination drug rituximab and hyaluronidase human (Rituxan Hycela) was approved for adults with CLL. This medication is manufactured by Genentech, Inc.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All clinical trials 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
Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For more information about clinical trials conducted in Europe, contact:
Contact for additional information about chronic lymphocytic leukemia:
Jennifer R. Brown, MD, PhD
Mayo Clinic. Chronic Lymphocytic Leukemia. Last Update April 19, 2016. http://www.mayoclinic.org/diseases-conditions/chronic-lymphocytic-leukemia/home/ovc-20200671 Accessed June 22, 2016.
National Cancer Institute. Chronic Lymphocytic Leukemia. Last Update October 23, 2015. http://www.cancer.gov/cancertopics/pdq/treatment/CLL/Patient/page1 Accessed June 22, 2016.
American Cancer Society. Leukemia-Chronic Lymphocytic. http://www.cancer.org/cancer/leukemia-chroniclymphocyticcll/index . Accessed June 22, 2016.
Vachani, C. Oncolink.com. Chronic Lymphocytic Leukemia. Last Update May 16, 2016. http://www.oncolink.org/types/article.cfm?c=8&s=29&ss=763&id=9590&p=4 Accessed June 22, 2016.
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