Chronic Lymphocytic Leukemia

 

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Chronic Lymphocytic Leukemia

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.

Synonyms of Chronic Lymphocytic Leukemia

• chronic lymphoid leukemia
• CLL
• SLL (small lymphocytic lymphoma)

Subdivisions of Chronic Lymphocytic Leukemia

• IgHV-mutated CLL
• IgHV-unmutated CLL

General Discussion

Chronic lymphocytic leukemia (CLL) is a malignant blood disorder in which there are an increased number of white blood cells in the lymphoid tissue. In CLL, the abnormal lymphocytes, also called leukemic cells, are produced instead of healthy white blood cells, and then accumulate over time. As the number of unhealthy blood cells grows, there is less room for healthy cells. The combination of fewer healthy cells and the fact that the CLL lymphocytes are poor at fighting infections can lead to frequent infection, anemia, and easy bleeding. This disease progresses slowly, and the uncontrolled buildup and enlargement of lymphoid tissue can occur in various sites of the body such as the lymph nodes, spleen, bone marrow, and lungs. CLL is the most common type of leukemia in adults and very rarely occurs in children. In the majority of individuals, chronic lymphocytic leukemia is the result of a rapid production of B lymphocyte cells (a type of white blood cell that is responsible for the production of antibodies to help fight infection). What was previously called CLL derived from T lymphocytes has been renamed as another disorder, T cell prolymphocytic leukemia. The overgrowth of cells in this T-cell disease tends to be much faster. The ability to distinguish between cells that have unmutated IgVH (Ig-unmutated CLL) and mutated IgVH (Ig-mutated CLL) has become very important in predicting the course of the disease (prognosis). Patients who have Ig-unmutated CLL have a much shorter time to treatment and historically a shorter average survival period compared to Ig-mutated CLL patients, whose average survival period exceeded 25 years even before the advent of modern therapy. These survival times however are based on much older data and are certainly longer now, with improved therapies. The other major determinant of prognosis is the chromosome makeup of the CLL, with particular concern about two higher risk chromosome abnormalities, loss of the short arm of chromosome 17 or the long arm of chromosome 11Determining the subset of CLL based on IGVH status is important because it is very predictive of prognosis. Because CLL usually progresses so slowly, many patients do not need immediate treatment and some do not even require it in their lifetime. Treatment is still based primarily on symptoms or worsening blood counts, not on these prognostic factors.

Signs & Symptoms

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.

Causes

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.

Affected Populations

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.

Related Disorders

Symptoms of the following disorders can be similar to those of chronic lymphocytic leukemia. Comparisons may be useful for a differential diagnosis.

B cell prolymphocytic leukemia (PLL) is a rare, aggressive form of leukemia. Prolymphocytes are immature white blood cells whose primary function it is to secrete antibodies which fight bacteria and viruses. When fighting these toxins, cellular memories are usually developed, which is why humans do not usually contract chicken pox more than once, for example. A key feature of this disease is that this adaptive immunity is missing. This leukemia is characterized by overly large prolymphocytes, which can cause a swollen spleen, weight loss, tiredness, and high concentrations of prolymphocytes in the bone marrow and/or blood. Sometimes as CLL becomes more refractory, it shows evolution toward PLL.

Richter’s syndrome develops in 3-15% of patients who have CLL. Richter’s syndrome is a very aggressive form of lymphoma. Usual symptoms a patient may experience when their CLL develops into Richter’s syndrome is increased swelling of the lymph nodes, spleen, and liver, a high fever, abdominal pain and even more weight loss. Blood counts will also worsen. The prognosis for Richter’s syndrome is very poor, but can be diagnosed with a lymph node biopsy. Treatment includes chemotherapy followed by stem cell transplant if possible.

Hairy cell leukemia (HCL) is a rare type of blood cancer characterized by abnormal changes in white blood cells known as B lymphocytes. The bone marrow creates too many of these defective cells, known as “hairy cells” because of the thin hair-like projections found on their surface. Overproduction and accumulation of hairy cells causes a deficiency of normal blood cells (pancytopenia), including an abnormal decrease of certain white blood cells (neutrophils [neutropenia]), red blood cells (anemia) or platelets [thrombocytopenia]). Affected individuals usually exhibit fatigue and weakness due to anemia (abnormally low levels of red blood cells), fever, weight loss, and/or abdominal discomfort due to an abnormally enlarged spleen (splenomegaly). In addition, affected individuals may have a slightly enlarged liver (hepatomegaly) and may be unusually susceptible to bruising and/or severe infection. The exact cause of hairy cell leukemia is not known although almost all cases have a particular mutation in the B-raf gene. (For more information on this disorder, choose “leukemia, hairy cell” as your search term in the Rare Disease Database.)”

Non-Hodgkin’s lymphomas (NHLs) are a group of cancers of the lymphatic system. Functioning as part of the immune system, the lymphatic system helps to protect the body against infection and disease. NHLs may be broadly classified into lymphomas that arise from abnormal B-lymphocytes (B-cell lymphomas) and those derived from abnormal T-lymphocytes (T-cell lymphomas). Abnormal, uncontrolled growth and multiplication (proliferation) of malignant lymphocytes may lead to enlargement of a specific lymph node region or regions, involvement of other lymphatic tissues, such as the spleen and bone marrow; and spread to other bodily tissues and organs, potentially resulting in life-threatening complications. The specific symptoms and physical findings may vary from person to person, depending upon the extent and region(s) of involvement and other factors. Groups of lymph nodes are located throughout the body, including in the neck, under the arms (axillae), at the elbows, and in the chest, abdomen, and groin. Symptoms of non-Hodgkin’s lymphomas may be anemia (abnormally low levels of red blood cells), weight loss, fever, night sweats, and weakness.

Mantle cell lymphoma (MCL) belongs to the group of non-Hodgkin’s lymphomas. MCL is a B-cell lymphoma that develops from malignant B-lymphocytes within a region of the lymph node known as the mantle zone. According to various estimates, MCL represents approximately 2 to 7 percent of adult NHLs in the United States and Europe. It affects more men than women, and mostly over the age of 50 years. Many affected individuals have widespread disease at diagnosis, with involved regions often including multiple lymph nodes, the spleen, and, potentially, the bone marrow, the liver, and/or regions of the digestive (gastrointestinal) tract. (For more information on this disorder, choose “mantle cell lymphoma” as your search term in the Rare Disease Database.)

Chronic myelogenous leukemia is a rare myeloproliferative disorder characterized by the excessive development of white blood cells in the spongy tissue found inside large bones of the body (bone marrow), spleen, liver and blood. As the disease progresses, the leukemic cells invade other areas of the body including the intestinal tract, kidneys, lungs, gonads and lymph nodes. (For more information on this disorder, choose “chronic myelogenous leukemia” as your search term in the Rare Disease Database.)

Myelodysplastic syndromes (MDS) are a rare group of blood disorders that occur as a result of improper development of blood cells within the bone marrow. The three main types of blood cells (i.e., red blood cells, white blood cells and platelets) are affected. These improperly developed blood cells fail to develop normally and enter the bloodstream. As a result, individuals with MDS have abnormally low blood cell levels (low blood counts). General symptoms associated with MDS include fatigue, dizziness, weakness, bruising and bleeding, frequent infections, and headaches. In some patients, MDS may progress to life-threatening failure of the bone marrow or develop into an acute leukemia. (For more information on these disorders, choose “myelodysplastic syndromes” as your search term in the Rare Disease Database.)

Diagnosis

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.

Standard Therapies

Treatment

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 Food and Drug Administration (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, Fludara (fludarabine) and Cytoxan (cyclophosphamide).

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 Leukeran (chlorambucil): Gazyva (obinutuzumab) and Arzerra (ofatumumab) have been approved to combat CLL. Arzerra was initially approved to treat refractory patients, but more recently was approved for previously untreated patients in combination with Leukeran, and for patients who have had previous chemoimmunotherapy and are in remission.

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.

The last few years have seen an explosion of very effective small molecule inhibitors for CLL. These are tasken in pill form and generally well tolerated. Zydelig (idelalisib) was approved for relapsed CLL patients with comorbid medical problems in 2014. Also 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 Imbruvica’s label was broadened to include all CLL patients, including those previously untreated. Venclexta (venetoclax) was approved just for relapsed 17p deleted CLL patients in 2016.

In 2017, the combination drug Rituxan Hyecela (rituximab and hyaluronidase human) was approved for adults with CLL. Patients can only receive Rituxan Hyecela after they have received at least one intravenous treatment of Rituxan.

In 2019, Calquence (acalabrutinib), a drug previous approved to treat patients with mantle cell lymphoma, was approved by FDA to treat CLL in adult patients.

Investigational Therapies

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

Email: prpl@cc.nih.gov

Some current clinical trials also are posted on the following page on the NORD website:

https://rarediseases.org/for-patients-and-families/information-resources/news-patient-recruitment/

For information about clinical trials sponsored by private sources, contact:

www.centerwatch.com

For more information about clinical trials conducted in Europe, contact:

https://www.clinicaltrialsregister.eu/

Contact for additional information about chronic lymphocytic leukemia:

Jennifer R. Brown, MD, PhD
617-632-5847

Supporting Organizations

• American Cancer Society, Inc.
  • 250 Williams NW St
  • Ste 6000
  • Atlanta, GA 30303 USA
  • Phone: (404) 320-3333
  • Toll-free: (800) 227-2345
  • Website: http://www.cancer.org
• Cancer Research UK
  • Angel Building
  • 407 St John Street
  • London, EC1V 4AD United Kingdom
  • Phone: 02072420200
  • Email: cancerhelpuk@cancer.org.uk
  • Website: http://www.cancerresearchuk.org/cancer-help/
• Cancer Support Community
  • 1050 17th St NW Suite 500
  • Washington, DC 20036
  • Phone: (202) 659-9709
  • Toll-free: (888) 793-9355
  • Website: http://www.cancersupportcommunity.org/
• Cancer.Net
  • American Society of Clinical Oncology
  • 2318 Mill Road Suite 800
  • Alexandria, VA 22314
  • Phone: (571) 483-1780
  • Toll-free: (888) 651-3038
  • Email: contactus@cancer.net
  • Website: http://www.cancer.net/
• Children’s Leukemia Research Association
  • 585 Stewart Avenue, Suite 18
  • Garden City, NY 11530
  • Phone: (516) 222-1944
  • Email: info@childrensleukemia.org
  • Website: http://www.childrensleukemia.org
• Friends of Cancer Research
  • 1800 M Street NW
  • Suite 1050 South
  • Washington, DC 20036
  • Phone: (202) 944-6700
  • Email: info@focr.org
  • Website: http://www.focr.org
• Genetic and Rare Diseases (GARD) Information Center
  • PO Box 8126
  • Gaithersburg, MD 20898-8126
  • Phone: (301) 251-4925
  • Toll-free: (888) 205-2311
  • Website: http://rarediseases.info.nih.gov/GARD/
• Leukemia & Lymphoma Society
  • 3 International Drive
  • Suite 200
  • Rye Brook, NY 10573
  • Phone: (914) 949-5213
  • Toll-free: (800) 955-4572
  • Email: infocenter@LLS.org
  • Website: http://www.LLS.org
• Livestrong Foundation
  • 2201 E. Sixth Street
  • Austin, TX 78702
  • Phone: (512) 236-8820
  • Toll-free: (877) 236-8820
  • Email: media@livestrong.org
  • Website: http://www.livestrong.org
• Lymphoma Research Foundation
  • Wall Street Plaza
  • 88 Pine Street, Suite 2400
  • New York, NY 10005 USA
  • Phone: (212) 349-2910
  • Toll-free: (800) 500-9976
  • Email: LRF@lymphoma.org
  • Website: http://www.lymphoma.org
• National Cancer Institute
  • 6116 Executive Blvd Suite 300
  • Bethesda, MD 20892-8322 USA
  • Phone: (301) 435-3848
  • Toll-free: (800) 422-6237
  • Email: cancergovstaff@mail.nih.gov
  • Website: http://www.cancer.gov
• OncoLink: The University of Pennsylvania Cancer Center Resource
  • 3400 Civic Center Blvd
  • Suite 2338
  • Philadelphia, PA 19104 USA
  • Phone: (215) 349-8895
  • Email: hampshire@uphs.upenn.edu
  • Website: https://www.oncolink.org/
• Rare Cancer Alliance
  • 405 Holly Street
  • Goodrich, TX 77335 USA
  • Website: http://www.rare-cancer.org

References

INTERNET
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.

Years Published

1991, 1992, 1996, 1997, 1998, 2002, 2004, 2011, 2016

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