Leukemia, Chronic Lymphocytic (CLL)

  • Dana-Farber/Brigham and Women's Cancer Care

    Chronic lymphocytic leukemia (CLL) is a slowly progressing disease in which too many lymphoblasts (immature white blood cells) are found in the blood and bone marrow. Learn about chronic lymphocytic leukemia and find information on how we support and care for people with CLL before, during, and after treatment.

Treatment 

The Hematologic Oncology Center provides specialized care for all types of cancers of the blood, including leukemia, lymphoma, multiple myeloma and Waldenström’s macroglobulinemia.

The center also includes the hematopoietic stem cell transplantation program, which is one of the largest and most experienced in the world.

To make sure your care is as seamless as possible, a dedicated team of clinicians, who are highly specialized experts in your type of blood cancer, will care for you throughout the treatment process, from diagnosis though long-term follow-up.

Your care team will include oncologists, surgeons, hematologists, physician assistants, nurses, and clinical social workers who are committed to delivering safe, high-quality patient care.  

We develop personalized, comprehensive treatment plans for all our patients, offering the latest therapies and supportive resources and taking your individual needs into account.

In addition to conventional treatment approaches, you may have the opportunity to participate in clinical trials that offer access to new, innovative treatments for your type of cancer.

A variety of services and programs also support your care, including nutrition services, emotional support and counseling, pain management, donor services for stem cell transplantation, and support for cancer survivors.

Learn more about treatment and care in the Hematologic Oncology Center 

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Information for: Patients | Healthcare Professionals

General Information About Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia is a type of cancer in which the bone marrow makes too many lymphocytes (a type of white blood cell).

Chronic lymphocytic leukemia (also called CLL) is a blood and bone marrow disease that usually gets worse slowly. CLL is the second most common type of leukemia in adults. It often occurs during or after middle age; it rarely occurs in children.

Normally, the body makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell.

A myeloid stem cell becomes one of three types of mature blood cells:

  • Red blood cells that carry oxygen and other substances to all tissues of the body.
  • White blood cells that fight infection and disease.
  • Platelets that form blood clots to stop bleeding.

A lymphoid stem cell becomes a lymphoblast cell and then one of three types of lymphocytes (white blood cells):

  • B lymphocytes that make antibodies to help fight infection.
  • T lymphocytes that help B lymphocytes make antibodies to fight infection.
  • Natural killer cells that attack cancer cells and viruses.
Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.
Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

In CLL, too many blood stem cells become abnormal lymphocytes and do not become healthy white blood cells. The abnormal lymphocytes may also be called leukemia cells. The lymphocytes are not able to fight infection very well. Also, as the number of lymphocytes increases in the blood and bone marrow, there is less room for healthy white blood cells, red blood cells, and platelets. This may cause infection, anemia, and easy bleeding.

This summary is about chronic lymphocytic leukemia. See the following PDQ summaries for more information about leukemia:

  • Adult Acute Lymphoblastic Leukemia Treatment.
  • Childhood Acute Lymphoblastic Leukemia Treatment.
  • Adult Acute Myeloid Leukemia Treatment.
  • Childhood Acute Myeloid Leukemia/Other Myeloid Malignancies Treatment.
  • Chronic Myelogenous Leukemia Treatment.
  • Hairy Cell Leukemia Treatment
  • Adult Non-Hodgkin Lymphoma Treatment

Older age can affect the risk of developing chronic lymphocytic leukemia.

Anything that increases your risk of getting a disease is called a risk factor. Having a risk factor does not mean that you will get cancer; not having risk factors doesn’t mean that you will not get cancer. Talk with your doctor if you think you may be at risk. Risk factors for CLL include the following:

  • Being middle-aged or older, male, or white.
  • A family history of CLL or cancer of the lymph system.
  • Having relatives who are Russian Jews or Eastern European Jews.

Possible signs of chronic lymphocytic leukemia include swollen lymph nodes and tiredness.

Usually CLL does not cause any symptoms and is found during a routine blood test. Sometimes symptoms occur that may be caused by CLL or by other conditions. Check with your doctor if you have any of the following problems:

  • Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin.
  • Feeling very tired.
  • Pain or fullness below the ribs.
  • Fever and infection.
  • Weight loss for no known reason.

Tests that examine the blood, bone marrow, and lymph nodes are used to detect (find) and diagnose chronic lymphocytic leukemia.

The following tests and procedures may be used:

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease, such as lumps or anything else that seems unusual. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Complete blood count (CBC) with differential: A procedure in which a sample of blood is drawn and checked for the following:
    • The number of red blood cells and platelets.
    • The number and type of white blood cells.
    • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
    • The portion of the blood sample made up of red blood cells.
    Complete blood count (CBC); left panel shows blood being drawn from a vein on the inside of the elbow using a tube attached to a syringe; right panel shows a laboratory test tube with blood cells separated into layers: plasma, white blood cells, platelets, and red blood cells.
    Complete blood count (CBC). Blood is collected by inserting a needle into a vein and allowing the blood to flow into a tube. The blood sample is sent to the laboratory and the red blood cells, white blood cells, and platelets are counted. The CBC is used to test for, diagnose, and monitor many different conditions.
  • Immunophenotyping: A laboratory test in which the antigens or markers on the surface of a blood or bone marrow cell are checked to see if they are lymphocytes or myeloid cells. If the cells are malignant lymphocytes (cancer), they are checked to see if they are B lymphocytes or T lymphocytes.
  • FISH (fluorescence in situ hybridization): A laboratory technique used to look at genes or chromosomes in cells and tissues. Pieces of DNA that contain a fluorescent dye are made in the laboratory and added to cells or tissues on a glass slide. When these pieces of DNA bind to specific genes or areas of chromosomes on the slide, they light up when viewed under a microscope with a special light.
  • Flow cytometry: A laboratory test that measures the number of cells in a sample, the percentage of live cells in a sample, and certain characteristics of cells, such as size, shape, and the presence of tumor markers on the cell surface. The cells are stained with a light-sensitive dye, placed in a fluid, and passed in a stream before a laser or other type of light. The measurements are based on how the light-sensitive dye reacts to the light.
  • IgVH gene mutation test: A laboratory test done on a bone marrow or blood sample to check for an IgVH gene mutation. Patients with an IgVH gene mutation have a better prognosis.
  • Bone marrow aspiration and biopsy: The removal of bone marrow, blood, and a small piece of bone by inserting a hollow needle into the hipbone or breastbone. A pathologist views the bone marrow, blood, and bone under a microscope to look for abnormal cells.
    Bone marrow aspiration and biopsy; drawing shows a patient lying face down on a table and a Jamshidi needle (a long, hollow needle) being inserted into the hip bone. Inset shows the Jamshidi needle being inserted through the skin into the bone marrow of the hip bone.
    Bone marrow aspiration and biopsy. After a small area of skin is numbed, a Jamshidi needle (a long, hollow needle) is inserted into the patient’s hip bone. Samples of blood, bone, and bone marrow are removed for examination under a microscope.

Certain factors affect treatment options and prognosis (chance of recovery).

Treatment options depend on:

  • The stage of the disease.
  • Red blood cell, white blood cell, and platelet blood counts.
  • Whether there are symptoms, such as fever, chills, or weight loss.
  • Whether the liver, spleen, or lymph nodes are larger than normal.
  • The response to initial treatment.
  • Whether the CLL has recurred (come back).

The prognosis (chance of recovery) depends on:

  • Whether there is a change in the DNA and the type of change, if there is one.
  • Whether lymphocytes are spread throughout the bone marrow.
  • The stage of the disease.
  • Whether the CLL gets better with treatment or has recurred (come back).
  • Whether the CLL progresses to lymphoma or prolymphocytic leukemia.
  • The patient's general health.

Stages of Chronic Lymphocytic Leukemia

After chronic lymphocytic leukemia has been diagnosed, tests are done to find out how far the cancer has spread in the blood and bone marrow.

Staging is the process used to find out how far the cancer has spread. It is important to know the stage of the disease in order to plan the best treatment. The following tests may be used in the staging process:

  • Chest x-ray: An x-ray of the organs and bones inside the chest. An x-ray is a type of energy beam that can go through the body and onto film, making a picture of areas inside the body, such as the lymph nodes.
  • MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of areas inside the body, such as the brain and spinal cord. This procedure is also called nuclear magnetic resonance imaging (NMRI).
  • CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that makes it.
  • Antiglobulin test: A test in which a sample of blood is looked at under a microscope to find out if there are any antibodies on the surface of red blood cells or platelets. These antibodies may react with and destroy the red blood cells and platelets. This test is also called a Coomb's test.

The following stages are used for chronic lymphocytic leukemia:

Stage 0

In stage 0 chronic lymphocytic leukemia, there are too many lymphocytes in the blood, but there are no other symptoms of leukemia. Stage 0 chronic lymphocytic leukemia is indolent (slow-growing).

Stage I

In stage I chronic lymphocytic leukemia, there are too many lymphocytes in the blood and the lymph nodes are larger than normal.

Stage II

In stage II chronic lymphocytic leukemia, there are too many lymphocytes in the blood, the liver or spleen is larger than normal, and the lymph nodes may be larger than normal.

Stage III

In stage III chronic lymphocytic leukemia, there are too many lymphocytes in the blood and there are too few red blood cells. The lymph nodes, liver, or spleen may be larger than normal.

Stage IV

In stage IV chronic lymphocytic leukemia, there are too many lymphocytes in the blood and too few platelets. The lymph nodes, liver, or spleen may be larger than normal and there may be too few red blood cells.

Refractory Chronic Lymphocytic Leukemia

Refractorychronic lymphocytic leukemia is cancer that does not get better with treatment.

Treatment Option Overview

There are different types of treatment for patients with chronic lymphocytic leukemia.

Different types of treatment are available for patients with chronic lymphocytic leukemia. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Five types of standard treatment are used:

Watchful waiting

Watchful waiting is closely monitoring a patient’s condition without giving any treatment until symptoms appear or change. This is also called observation. During this time, problems caused by the disease, such as infection, are treated.

Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells or keep them from growing. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, or the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated.

See Drugs Approved for Chronic Lymphocytic Leukemia for more information.

Surgery

Splenectomy is surgery to remove the spleen.

Targeted therapy

Targeted therapy is a type of treatment that uses drugs or other substances to identify and attack specific cancer cells without harming normal cells. Monoclonal antibodytherapy is a type of targeted therapy used in the treatment of chronic lymphocytic leukemia.

Monoclonal antibody therapy is a cancer treatment that uses antibodies made in the laboratory from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances in the body that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells.

See Drugs Approved for Chronic Lymphocytic Leukemia for more information.

New types of treatment are being tested in clinical trials.

This summary section describes treatments that are being studied in clinical trials. It may not mention every new treatment being studied. Information about clinical trials is available from the NCI Web site.

Chemotherapy with stem cell transplant

Chemotherapy with stem cell transplant is a method of giving chemotherapy and replacing blood-forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body’s blood cells.

Biologic therapy

Biologic therapy is a treatment that uses the patient's immune system to fight cancer. Substances made by the body or made in a laboratory are used to boost, direct, or restore the body's natural defenses against cancer. This type of cancer treatment is also called biotherapy or immunotherapy.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.

Treatment Options by Stage

Stage 0 Chronic Lymphocytic Leukemia

Treatment of stage 0 chronic lymphocytic leukemia is usually watchful waiting.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 chronic lymphocytic leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Stage I, Stage II, Stage III, and Stage IV Chronic Lymphocytic Leukemia

Treatment of stage I, stage II, stage III, and stage IV chronic lymphocytic leukemia may include the following:

  • Watchful waiting when there are few or no symptoms.
  • Monoclonal antibody therapy.
  • Chemotherapy with 1 or more drugs, with or without steroids or monoclonal antibody therapy.
  • Low-doseexternal radiation therapy to areas of the body where cancer is found, such as the spleen or lymph nodes.
  • A clinical trial of chemotherapy and biologic therapy with stem cell transplant.
  • A clinical trial of biologic therapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia and stage IV chronic lymphocytic leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Treatment Options for Refractory Chronic Lymphocytic Leukemia

Treatment of refractorychronic lymphocytic leukemia may include the following:

  • A clinical trial of chemotherapy with stem cell transplant.
  • A clinical trial of a new treatment.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with refractory chronic lymphocytic leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

To Learn More About Chronic Lymphocytic Leukemia

For more information from the National Cancer Institute about chronic lymphocytic leukemia, see the following:

For general cancer information and other resources from the National Cancer Institute, see the following:


This information is provided by the National Cancer Institute.

This information was last updated on October 28, 2013.


General Information About Chronic Lymphocytic Leukemia

Incidence and Mortality

Estimated new cases and deaths from chronic lymphocytic leukemia (CLL) in the United States in 2013:[1]

  • New cases: 15,680.
  • Deaths: 4,580.

CLL is a disorder of morphologically mature but immunologically less mature lymphocytes and is manifested by progressive accumulation of these cells in the blood, bone marrow, and lymphatic tissues.[2] In this disorder, lymphocyte counts in the blood are usually greater than or equal to 5,000/mm3 with a characteristic immunophenotype (CD5- and CD23-positive B cells).[3][4] As assays have become more sensitive for detecting monoclonal B-CLL–like cells in peripheral blood, researchers have detected a monoclonal B-cell lymphocytosis (MBL) in 3% of adults older than 40 years and 6% in adults older than 60 years.[5] Such early detection and diagnosis may falsely suggest improved survival for the group and may unnecessarily worry or result in therapy for some patients who would have remained undiagnosed in their lifetime, a circumstance known in the literature as overdiagnosis or pseudodisease.[6][7]

In two selected series of more than 900 patients followed prospectively for a median of 5 to 7 years, overt CLL requiring chemotherapy occurred in 7% of patients.[5][8] In a database analysis and for up to 77 months before diagnosis, almost all patients with a diagnosis of CLL had prediagnostic B-cell clones that were identified in peripheral blood when available.[4][9]

For patients with progressing CLL, treatment with conventional doses of chemotherapy is not curative; selected patients treated with allogeneic stem cell transplantation have achieved prolonged disease-free survival.[10][11][12][13][14] Antileukemic therapy is frequently unnecessary in uncomplicated early disease.[15] The median survival for all patients ranges from 8 to 12 years in older trials with data from the 1970s through the 1990s.[15][16] There is, however, a large variation in survival among individual patients, ranging from several months to a normal life expectancy. Treatment must be individualized based on the clinical behavior of the disease.[17]

As found in one report, CLL occurs primarily in middle-aged and elderly adults, with increasing frequency in successive decades of life.[18] The clinical course of this disease progresses from an indolent lymphocytosis without other evident disease to one of generalized lymphatic enlargement with concomitant pancytopenia. Complications of pancytopenia, including hemorrhage and infection, represent a major cause of death in these patients.[19] Immunological aberrations, including Coombs-positive hemolytic anemia, immune thrombocytopenia, and depressed immunoglobulin levels may all complicate the management of CLL.[20] Prognostic factors that may help predict clinical outcome include cytogenetic subgroup, immunoglobulin mutational status, ZAP-70, and CD38.[2][21][22][23][24][25][26][27][28][29] (Refer to the Prognostic Factors section in the Stage Information for Chronic Lymphocytic Leukemia section of this summary for more information.) Patients who develop an aggressive high-grade non-Hodgkin lymphoma, usually diffuse large B-cell lymphoma and termed a Richter transformation, have a poor prognosis.[30] Patients with CLL are also at increased risk for other malignancies, even before therapy.[31]

Confusion with other diseases may be avoided by determination of cell surface markers. CLL lymphocytes coexpress the B-cell antigens CD19 and CD20 along with the T-cell antigen CD5.[32] This coexpression only occurs in one other disease entity, mantle cell lymphoma. CLL B cells express relatively low levels of surface-membrane immunoglobulin (compared with normal peripheral blood B cells) and a single light chain (kappa or lambda).[15] CLL is diagnosed by an absolute increase in lymphocytosis and/or bone marrow infiltration coupled with the characteristic features of morphology and immunophenotype, which confirm the characteristic clonal population.

The differential diagnosis must exclude hairy cell leukemia and Waldenström macroglobulinemia. (Refer to the PDQ summaries on Hairy Cell Leukemia and Adult Non-Hodgkin Lymphoma Treatment for more information.) Waldenström macroglobulinemia has a natural history and therapeutic options similar to CLL, with the exception of hyperviscosity syndrome associated with macroglobulinemia as a result of elevated immunoglobulin M. Prolymphocytic leukemia (PLL) is a rare entity characterized by excessive prolymphocytes in the blood with a typical phenotype that is positive for CD19, CD20, and surface-membrane immunoglobulin and negative for CD5. These patients demonstrate splenomegaly and poor response to low-dose or high-dose chemotherapy.[15][33]

Cladribine (2-chlorodeoxyadenosine) appears to be an active agent (60% complete remission rate) for patients with de novo B-cell prolymphocytic leukemia.[34][Level of evidence: 3iiiDiv] Alemtuzumab (campath-1H), an anti-CD52 humanized monoclonal antibody, has been used for 76 patients with T-cell prolymphocytic leukemia after failure of prior chemotherapy (usually pentostatin or cladribine) with a 51% response rate (95% confidence interval, 40%–63%) and median time to progression of 4.5 months (range, 0.1–45.4 months).[35][Level of evidence: 3iiiDiv] These response rates have been confirmed by other investigators.[36] Patients with CLL who show prolymphocytoid transformation maintain the classic CLL phenotype and have a worse prognosis than PLL patients.

Large granular lymphocytic leukemia is characterized by lymphocytosis with a natural killer cell immunophenotype (CD2, CD16, and CD56) or a T-cell immunophenotype (CD2, CD3, and CD8).[37][38][39] These patients often have neutropenia and a history of rheumatoid arthritis. The natural history is indolent, often marked by anemia and splenomegaly. This condition appears to fit into the clinical spectrum of Felty syndrome.[40] Therapy includes low doses of oral cyclophosphamide or methotrexate, cyclosporine, and treatment of the bacterial infections acquired during severe neutropenia.[37][39][41][42]

Related Summaries

Other PDQ summaries containing information about CLL include the following:

  • Adult Non-Hodgkin Lymphoma Treatment
  • Hairy Cell Leukemia

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  34. Saven A, Lee T, Schlutz M, et al.: Major activity of cladribine in patients with de novo B-cell prolymphocytic leukemia. J Clin Oncol 15 (1): 37-43, 1997.

  35. Keating MJ, Cazin B, Coutré S, et al.: Campath-1H treatment of T-cell prolymphocytic leukemia in patients for whom at least one prior chemotherapy regimen has failed. J Clin Oncol 20 (1): 205-13, 2002.

  36. Dearden CE, Matutes E, Catovsky D: Alemtuzumab in T-cell malignancies. Med Oncol 19 (Suppl): S27-32, 2002.

  37. Sokol L, Loughran TP Jr: Large granular lymphocyte leukemia. Oncologist 11 (3): 263-73, 2006.

  38. Semenzato G, Zambello R, Starkebaum G, et al.: The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis. Blood 89 (1): 256-60, 1997.

  39. Lamy T, Loughran TP Jr: How I treat LGL leukemia. Blood 117 (10): 2764-74, 2011.

  40. Bowman SJ, Sivakumaran M, Snowden N, et al.: The large granular lymphocyte syndrome with rheumatoid arthritis. Immunogenetic evidence for a broader definition of Felty's syndrome. Arthritis Rheum 37 (9): 1326-30, 1994.

  41. Loughran TP Jr, Kidd PG, Starkebaum G: Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate. Blood 84 (7): 2164-70, 1994.

  42. Dhodapkar MV, Li CY, Lust JA, et al.: Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance? Blood 84 (5): 1620-7, 1994.

Stage Information for Chronic Lymphocytic Leukemia

Staging is useful in chronic lymphocytic leukemia (CLL) to predict prognosis and also to stratify patients to achieve comparisons for interpreting specific treatment results. Anemia and thrombocytopenia are the major adverse prognostic variables.

CLL has no standard staging system. The Rai staging system and the Binet classification are presented below.[1][2] A National Cancer Institute (NCI)-sponsored working group has formulated standardized guidelines for criteria related to eligibility, response, and toxic effects to be used in future clinical trials in CLL.[3]

Rai Staging System

Stage 0

Stage 0 CLL is characterized by absolute lymphocytosis (>15,000/mm3) without adenopathy, hepatosplenomegaly, anemia, or thrombocytopenia.

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.

Binet Classification

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, axillary, inguinal, and spleen.

The Binet classification integrates the number of nodal groups involved with the disease with bone marrow failure. Its major benefit derives from the recognition of a predominantly splenic form of the disease, which may have a better prognosis than in the Rai staging, and from recognition that the presence of anemia or thrombocytopenia has a similar prognosis and does not merit a separate stage. Neither system separates immune from nonimmune causes of cytopenia. Patients with thrombocytopenia or anemia or both, which is caused by extensive marrow infiltration and impaired production (Rai III/IV, Binet C) have a poorer prognosis than patients with immune cytopenias.[4] The International Workshop on CLL has recommended integrating the Rai and Binet systems as follows: A(0), A(I), A(II); B(I), B(II); and C(III), C(IV).[5] The NCI-sponsored working group has published guidelines for the diagnosis and treatment of CLL in both clinical trial and general practice settings.[3] Use of these systems allows comparison of clinical results and establishment of therapeutic guidelines.

Prognostic factors

New prognostic markers are now available to the clinician and investigator.[6][7] The use of these markers to stratify patients in clinical trials, to help assess the need for therapy, and to help select the type of therapy continues to evolve. Prospective trials to verify and establish the role of these prognostic markers are ongoing. No large multivariable analyses exist as yet to test the relative power of these individual prognostic variables.[8] Prognostic indices are under evaluation and will require prospective validation.[9]

  • Immunoglobulin variable region heavy chain gene (IgVH) mutation.[10][11][12][13][14] The finding of significant numbers of mutations in this region is associated with a median survival in excess of 20 to 25 years. The absence of mutations is associated with a median survival of 8 to 10 years.
  • ZAP-70. ZAP-70 has been proposed as a surrogate for the mutational status.[15][16][17][18] ZAP-70 positivity for previously untreated and asymptomatic patients (>30%) is associated with a more unfavorable median survival (6–10 years), while a negative ZAP-70 is associated with a median survival of more than 15 years. A prospective evaluation of these markers in a randomized study of fludarabine-based chemotherapy (E2997 [NCT00003764]) failed to show any difference in response rates, response duration, progression-free survival, or overall survival (OS).[19]
  • Chromosomal abnormalities by fluorescent in situ hybridization (FISH). FISH chromosomal abnormalities were associated with prognosis in retrospective and prospective studies and clonal evolution has been seen over time.[20][21][22][23] 13q- is favorable (with a 17-year median OS in a prospective study).[23] Trisomy 12 and 11q- have less favorable prognoses (with a 9- to 11-year median OS in a prospective study).[23] In particular, 17p- is associated with mutated TP53 and with poor response rates and short duration of response to the standard therapeutic options.[13] 17p- is associated with the most unfavorable prognosis (with a 7-year median OS in one prospective trial).[19][23][24] The combination of adverse cytogenetics such as 11q- or 17p- (suggesting a worse prognosis) with ZAP-70 negativity (suggesting a better prognosis) in the same patients resulted in a poor prognosis.[18] These findings emphasize the need for prospective studies of combinations of these prognostic markers.[8]
  • CD38 immunophenotype.[11][25] CD38 positivity (>30%) correlates with a worse prognosis, but there is a 30% false-positive rate and a 50% false-negative rate using IgVH mutational status as the gold standard for prognosis.

Other prognostic factors include:

  • Stage.[1][2] (Refer to the Rai staging system section and the Binet classification section of this summary for more information.)
  • Lymphocyte doubling time (doubling of the white blood cell count in excess of 1 year implies a favorable prognosis).[26]
  • Beta-2-microglobulin (higher levels imply a worse prognosis).[27]

References:

  1. Rai KR, Sawitsky A, Cronkite EP, et al.: Clinical staging of chronic lymphocytic leukemia. Blood 46 (2): 219-34, 1975.

  2. Binet JL, Auquier A, Dighiero G, et al.: A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48 (1): 198-206, 1981.

  3. Hallek M, Cheson BD, Catovsky D, et al.: Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia updating the National Cancer Institute-Working Group 1996 guidelines. Blood 111 (12): 5446-56, 2008.

  4. Moreno C, Hodgson K, Ferrer G, et al.: Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance. Blood 116 (23): 4771-6, 2010.

  5. Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. International Workshop on Chronic Lymphocytic Leukemia. Ann Intern Med 110 (3): 236-8, 1989.

  6. Dighiero G, Hamblin TJ: Chronic lymphocytic leukaemia. Lancet 371 (9617): 1017-29, 2008.

  7. Developments in the treatment of lymphoproliferative disorders: rising to the new challenges of CLL therapy. A report of a symposium presented during the 48th American Society of Hematology Annual Meeting and Exposition, December 8, 2006, Orlando, Florida. Clin Adv Hematol Oncol 5 (3 Suppl 5): 1-14; quiz 15-6, 2007.

  8. Binet JL, Caligaris-Cappio F, Catovsky D, et al.: Perspectives on the use of new diagnostic tools in the treatment of chronic lymphocytic leukemia. Blood 107 (3): 859-61, 2006.

  9. Shanafelt TD, Jenkins G, Call TG, et al.: Validation of a new prognostic index for patients with chronic lymphocytic leukemia. Cancer 115 (2): 363-72, 2009.

  10. Hamblin TJ, Davis Z, Gardiner A, et al.: Unmutated Ig V(H) genes are associated with a more aggressive form of chronic lymphocytic leukemia. Blood 94 (6): 1848-54, 1999.

  11. Damle RN, Wasil T, Fais F, et al.: Ig V gene mutation status and CD38 expression as novel prognostic indicators in chronic lymphocytic leukemia. Blood 94 (6): 1840-7, 1999.

  12. Rosenwald A, Alizadeh AA, Widhopf G, et al.: Relation of gene expression phenotype to immunoglobulin mutation genotype in B cell chronic lymphocytic leukemia. J Exp Med 194 (11): 1639-47, 2001.

  13. Byrd JC, Gribben JG, Peterson BL, et al.: Select high-risk genetic features predict earlier progression following chemoimmunotherapy with fludarabine and rituximab in chronic lymphocytic leukemia: justification for risk-adapted therapy. J Clin Oncol 24 (3): 437-43, 2006.

  14. Kharfan-Dabaja MA, Chavez JC, Khorfan KA, et al.: Clinical and therapeutic implications of the mutational status of IgVH in patients with chronic lymphocytic leukemia. Cancer 113 (5): 897-906, 2008.

  15. Crespo M, Bosch F, Villamor N, et al.: ZAP-70 expression as a surrogate for immunoglobulin-variable-region mutations in chronic lymphocytic leukemia. N Engl J Med 348 (18): 1764-75, 2003.

  16. Orchard JA, Ibbotson RE, Davis Z, et al.: ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363 (9403): 105-11, 2004.

  17. 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. N Engl J Med 351 (9): 893-901, 2004.

  18. Kröber A, Bloehdorn J, Hafner S, et al.: Additional genetic high-risk features such as 11q deletion, 17p deletion, and V3-21 usage characterize discordance of ZAP-70 and VH mutation status in chronic lymphocytic leukemia. J Clin Oncol 24 (6): 969-75, 2006.

  19. Grever MR, Lucas DM, Dewald GW, et al.: Comprehensive assessment of genetic and molecular features predicting outcome in patients with chronic lymphocytic leukemia: results from the US Intergroup Phase III Trial E2997. J Clin Oncol 25 (7): 799-804, 2007.

  20. Döhner H, Stilgenbauer S, Benner A, et al.: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343 (26): 1910-6, 2000.

  21. Kröber A, Seiler T, Benner A, et al.: V(H) mutation status, CD38 expression level, genomic aberrations, and survival in chronic lymphocytic leukemia. Blood 100 (4): 1410-6, 2002.

  22. Catovsky D, Fooks J, Richards S: Prognostic factors in chronic lymphocytic leukaemia: the importance of age, sex and response to treatment in survival. A report from the MRC CLL 1 trial. MRC Working Party on Leukaemia in Adults. Br J Haematol 72 (2): 141-9, 1989.

  23. Shanafelt TD, Witzig TE, Fink SR, et al.: Prospective evaluation of clonal evolution during long-term follow-up of patients with untreated early-stage chronic lymphocytic leukemia. J Clin Oncol 24 (28): 4634-41, 2006.

  24. Catovsky D, Richards S, Matutes E, et al.: Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 370 (9583): 230-9, 2007.

  25. Ghia P, Guida G, Stella S, et al.: The pattern of CD38 expression defines a distinct subset of chronic lymphocytic leukemia (CLL) patients at risk of disease progression. Blood 101 (4): 1262-9, 2003.

  26. Montserrat E, Sanchez-Bisono J, Viñolas N, et al.: Lymphocyte doubling time in chronic lymphocytic leukaemia: analysis of its prognostic significance. Br J Haematol 62 (3): 567-75, 1986.

  27. Di Giovanni S, Valentini G, Carducci P, et al.: Beta-2-microglobulin is a reliable tumor marker in chronic lymphocytic leukemia. Acta Haematol 81 (4): 181-5, 1989.

Treatment Option Overview

Treatment of chronic lymphocytic leukemia (CLL) ranges from periodic observation with treatment of infectious, hemorrhagic, or immunologic complications to a variety of therapeutic options, including steroids, alkylating agents, purine analogs, combination chemotherapy, monoclonal antibodies, and transplant options.[1] Because this disease is generally not curable, occurs in an elderly population, and often progresses slowly, it is most often treated in a conservative fashion.[1] In asymptomatic patients, treatment may be deferred until the patient becomes symptomatic as the disease progresses. Since the rate of progression may vary from patient to patient, with long periods of stability and sometimes spontaneous regressions, frequent and careful observation is required to monitor the clinical course.[2]

A meta-analysis of randomized trials showed no survival benefit for immediate versus delayed therapy for patients with early stage disease, nor for the use of combination regimens incorporating an anthracycline compared with a single-agent alkylator for advanced stage disease.[3][Level of evidence: 1iiA] A variety of clinical factors, including IgVH mutation, chromosomal abnormalities by fluorescent in situ hybridization analysis or cytogenetics, beta-2-microglobulin, and lymphocyte doubling time may be helpful in predicting progression of disease.[1]

Infectious complications in advanced disease are in part a consequence of the hypogammaglobulinemia and the inability to mount a humoral defense against bacterial or viral agents. Herpes zoster represents a frequent viral infection in these patients, but infections with Pneumocystis carinii and Candida albicans may also occur. The early recognition of infections and the institution of appropriate therapy are critical to the long-term survival of these patients. A randomized study of intravenous immunoglobulin (400 mg/kg every 3 weeks for 1 year) in patients with CLL and hypogammaglobulinemia produced significantly fewer bacterial infections and a significant delay in onset of first infection during the study period.[4] There was, however, no effect on survival. Routine chronic administration of intravenous immunoglobulin is expensive, and the long-term benefit (>1 year) is unproven.[5][6]

Second malignancies and treatment-induced acute leukemias may also occur in a small percentage of patients.[7] Transformation of CLL to diffuse large cell lymphoma (Richter syndrome) carries a poor prognosis with a median survival of less than 1 year, though 20% of the patients may live more than 5 years after aggressive combination chemotherapy.[8] (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

Autoimmune hemolytic anemia and/or thrombocytopenia can occur in patients with any stage of CLL.[9] Initial therapy involves corticosteroids with or without alkylating agents (fludarabine can worsen the hemolytic anemia). It is frequently advisable to control the autoimmune destruction with corticosteroids, if possible, prior to administering marrow-suppressive chemotherapy because such patients may be difficult to transfuse successfully with either red blood cells or platelets. Alternate therapies include high-dose immune globulin, rituximab, cyclosporine, azathioprine, splenectomy, and low-dose radiation therapy to the spleen.[10][11] Tumor lysis syndrome is an uncommon complication (presenting in 1 out of 300 patients) of chemotherapy for patients with bulky disease.[12]

About 1% of morphologic CLL cases express T-cell markers (CD4 and CD7) and have clonal rearrangements of their T-cell receptor genes. These patients have a higher frequency of skin lesions, more variable lymphocyte shape, and shorter median survival (13 months) with minimal responses to chemotherapy.[13]

Computed tomographic (CT) scans have a very limited role in following patients after completion of treatment; the decision to treat for relapse was determined by CT scan or ultrasound in only 2 of 176 patients in three prospective trials for the German CLL Study Group.[14]

References:

  1. Gribben JG, O'Brien S: Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 29 (5): 544-50, 2011.

  2. Del Giudice I, Chiaretti S, Tavolaro S, et al.: Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood 114 (3): 638-46, 2009.

  3. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst 91 (10): 861-8, 1999.

  4. 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. N Engl J Med 319 (14): 902-7, 1988.

  5. Griffiths H, Brennan V, Lea J, et al.: Crossover study of immunoglobulin replacement therapy in patients with low-grade B-cell tumors. Blood 73 (2): 366-8, 1989.

  6. Weeks JC, Tierney MR, Weinstein MC: Cost effectiveness of prophylactic intravenous immune globulin in chronic lymphocytic leukemia. N Engl J Med 325 (2): 81-6, 1991.

  7. Maddocks-Christianson K, Slager SL, Zent CS, et al.: Risk factors for development of a second lymphoid malignancy in patients with chronic lymphocytic leukaemia. Br J Haematol 139 (3): 398-404, 2007.

  8. Robertson LE, Pugh W, O'Brien S, et al.: Richter's syndrome: a report on 39 patients. J Clin Oncol 11 (10): 1985-9, 1993.

  9. Mauro FR, Foa R, Cerretti R, et al.: Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 95 (9): 2786-92, 2000.

  10. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333 (16): 1052-7, 1995.

  11. Kaufman M, Limaye SA, Driscoll N, et al.: A combination of rituximab, cyclophosphamide and dexamethasone effectively treats immune cytopenias of chronic lymphocytic leukemia. Leuk Lymphoma 50 (6): 892-9, 2009.

  12. Cheson BD, Frame JN, Vena D, et al.: Tumor lysis syndrome: an uncommon complication of fludarabine therapy of chronic lymphocytic leukemia. J Clin Oncol 16 (7): 2313-20, 1998.

  13. Hoyer JD, Ross CW, Li CY, et al.: True T-cell chronic lymphocytic leukemia: a morphologic and immunophenotypic study of 25 cases. Blood 86 (3): 1163-9, 1995.

  14. Eichhorst BF, Fischer K, Fink AM, et al.: Limited clinical relevance of imaging techniques in the follow-up of patients with advanced chronic lymphocytic leukemia: results of a meta-analysis. Blood 117 (6): 1817-21, 2011.

Stage 0 Chronic Lymphocytic Leukemia

Because of the indolent nature of stage 0 chronic lymphocytic leukemia (CLL), treatment is not indicated.[1] The French Cooperative Group on CLL randomly assigned 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment and found no survival advantage for immediate treatment with chlorambucil.[2][Level of evidence: 1iiA] A meta-analysis of six trials of immediate versus deferred therapy with chlorambucil (including the aforementioned trial by the French Cooperative Group) showed no difference in overall survival at 10 years.[3][Level of evidence: 1iiA] Whether immediate therapy with the nucleoside analogs or other newer strategies will be superior to a watchful waiting approach is uncertain.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage 0 chronic lymphocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Casper JT: Prognostic features of early chronic lymphocytic leukaemia. International Workshop on CLL. Lancet 2 (8669): 968-9, 1989.

  2. Dighiero G, Maloum K, Desablens B, et al.: Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med 338 (21): 1506-14, 1998.

  3. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst 91 (10): 861-8, 1999.

Stage I, II, III, and IV Chronic Lymphocytic Leukemia

Several decades of large, randomized, prospective trials of previously untreated patients have demonstrated statistically significant improvements in response rates, event-free survival (EFS), and progression-free survival (PFS) with comparison of combinations of drugs versus single-agent alkylators,[1][2] but only two trials have shown statistically significant improvement in overall survival (OS).[3][4]

The first trial, a comparison of chlorambucil versus fludarabine, after 15 years of median follow-up, showed improved median OS for patients on the fludarabine regimen at 63 months versus 59 months (P = .04), and an improved percentage of patients were alive at 8 years (31% vs. 19%, P = .04).[3][5][Level of evidence: 1iiA]

The second trial, which had 817 patients, compared FCR (fludarabine + cyclophosphamide + rituximab) versus FC (fludarabine + cyclophosphamide) with a median follow-up of 38 months and showed improved OS at 3 years for the rituximab combination (i.e., 87% vs. 83%, P = .01.[4][Level of evidence: 1iiA] Yet neither fludarabine nor FCR has been compared in a randomized study against watchful waiting in asymptomatic or minimally affected patients.

The improvements in response rates from more intensive regimens have maximized the clearance of minimal residual disease (MRD). In one prospective trial of 493 patients, clearance of MRD was an independent predictor of OS by multivariate analysis.[6] The surrogate endpoint of such clearance of residual disease, while prognostic,[6] has not been shown to improve survival in a randomized prospective trial; the necessary study would take patients who fail to completely clear the marrow with induction therapy and randomly assign them to further alternative treatment versus the same treatment later at relapse, looking at OS as the primary endpoint.[1][2]

The sequencing of the following treatment options cannot be determined from the current set of completed clinical trials. When patients become symptomatic or require treatment, FCR has become the most frequently chosen option outside of a clinical trial, mostly on the basis of the previously described prospective study.[4]

Treatment options:

Note: Standard options are roughly ordered by level of toxic effects, starting with the least toxic options. More recently discovered options are mentioned at the end of the list.

  1. Observation in asymptomatic or minimally affected patients.[7] Outside of the context of a clinical trial, treatment for asymptomatic or minimally affected patients with chronic lymphocytic leukemia (CLL) is observation. No data exist as yet to suggest any harm with a delay in therapy until the patient becomes symptomatic or develops serious cytopenias despite growth factor support. Because the rate of progression may vary from patient to patient, with long periods of stability and sometimes spontaneous regressions, frequent and careful observation is required to monitor the clinical course.
  2. Rituximab, a murine anti-CD20 monoclonal antibody.[8][9][10][11][12] When used alone, higher doses of rituximab or increased frequency or duration of therapy is required for comparable responses to those seen for other indolent lymphomas.
  3. Ofatumomab is a human anti-CD20 monoclonal antibody.[13] A trial of 138 patients, who were previously treated with fludarabine and alemtuzumab, showed overall response rates around 50% in patients refractory to fludarabine and with prior exposure to rituximab.[13][14][Level of evidence: 3iiiDiv]
  4. Oral alkylating agents with or without corticosteroids.[15] The French Cooperative Group on CLL randomly assigned 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment and found no survival advantage for chlorambucil.[16][Level of evidence: 1iiA] A meta-analysis of six trials of immediate versus deferred therapy with chlorambucil (including the aforementioned trial by the French Cooperative Group) showed no difference in OS at 10 years.[7][Level of evidence: 1iiA]
  5. Fludarabine, 2-chlorodeoxyadenosine, or pentostatin as seen in the CLB-9011 trial, for example.[17][18][19][20][21][22]

    Several randomized trials have compared the purine analogs with chlorambucil; with cyclophosphamide, doxorubicin, and prednisone; or with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in previously untreated patients.[5][23][24][25][26] All of these trials showed higher or equivalent response rates for the purine analog and most showed an improvement in PFS, with one reaching significance in OS favoring fludarabine.[3][23][24][25][26][27][Level of evidence: 1iiDiii]

    A comparison of chlorambucil versus fludarabine, after 15 years' median follow-up, showed patients with improved median OS with fludarabine at 63 versus 59 months (P = .04) and an improved percentage of patients alive at 8 years (31% vs. 19%, P = .04).[3][Level of evidence: 1iiA] All of the trials demonstrated higher toxic effects with the purine analogs, especially granulocytopenic infections, herpes infections, autoimmune hemolytic anemia, and persistent thrombocytopenia.[28] The increased risk of infection may persist for months or years after treatment with a purine analog.[27][29]

    Although empiric evidence is lacking, some investigators recommend prophylaxis with trimethoprim-sulfa during therapy and for 6 to 12 months afterwards to prevent pneumocystis infection. In a similar way, other investigators employ prophylaxis (e.g., acyclovir) for the herpes viruses.[29] Purine analogs cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines.[25]

  6. Bendamustine.

    Bendamustine is a cytotoxic agent with bifunctional properties of an alkylator and a purine analog.[30] In previously treated and untreated patients, bendamustine with rituximab has shown response rates around 70% to 90%.[31][32][Level of evidence: 3iiiDiii]

    In a randomized comparison with chlorambucil in 319 previously treated patients, bendamustine showed a better response rate (68% vs. 31%, P < .0001) and PFS (21.6 months vs. 8 months) with a median follow-up of 35 months.[33][Level of evidence: 1iiDiii] The German CLL Study Group is comparing bendamustine plus rituximab versus FCR as first-line therapy in patients with CLL who require therapy.[31]

  7. Lenalidomide.

    Lenalidomide is an oral immunomodulatory agent with response rates over 50% for patients with previously treated and untreated disease.[34][35][36][37][Level of evidence: 3iiiDiv] Prolonged, lower-dose approaches and attention to prevention of tumor lysis syndrome are recommended with this agent.[34][38] Combination therapy and long-term toxicities from using lenalidomide (such as increased myelodysplasia, as seen in myeloma patients) remain undefined for patients with CLL.

  8. Combination chemotherapy.

    A trial of 817 patients comparing FCR versus FC with a median follow-up of 38 months showed improved OS at 3 years for the rituximab combination (87% vs. 83%, P = .01).[4][Level of evidence: 1iiA] FCR has never been compared with watchful waiting up front in asymptomatic or minimally affected patients. The improvements in response rates from more intensive regimens have maximized the clearance of MRD. However, the surrogate endpoint of MRD clearance has not been proven to be a valid surrogate for improved survival in a randomized prospective trial; the necessary study would take patients who fail to completely clear the marrow with induction therapy and randomly assign them to further alternative treatment versus the same treatment later at relapse looking at OS as the primary endpoint.[1][2] A cumulative incidence of 6% to 8 % for myelodysplasia is seen at 5 to 7 years in patients who received fludarabine plus cyclophosphamide, with or without rituximab.[39][40]

    Other combination chemotherapy regimens include the following:

    • Fludarabine plus cyclophosphamide plus rituximab.[4][41][42][43][44]
    • Fludarabine plus rituximab as seen in the CLB-9712 and CLB-9011 trials.[45]
    • Fludarabine plus cyclophosphamide versus fludarabine plus cyclophosphamide plus rituximab.[4][46]
    • Pentostatin plus cyclophosphamide plus rituximab as seen in the MAYO-MC0183 trial, for example.[47][48]
    • Ofatumumab plus fludarabine plus cyclophosphamide.[49]
    • CVP: cyclophosphamide plus vincristine plus prednisone.[50]
    • CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[51]
    • Fludarabine plus cyclophosphamide versus fludarabine as seen in the E2997 trial [NCT00003764] and the LRF-CLL4 trial, for example.[52][53]
    • Fludarabine plus chlorambucil as seen in the CLB-9011 trial, for example.[54]

    A meta-analysis of ten trials comparing combination chemotherapy (before the availability of rituximab) with chlorambucil alone showed no difference in OS at 5 years.[7][Level of evidence: 1iiA]

  9. Involved-field radiation therapy. Relatively low doses of radiation therapy will affect an excellent response for months or years. Sometimes radiation therapy to one nodal area or the spleen will result in abscopal effect (i.e., the shrinkage of lymph node tumors in untreated sites).
  10. Alemtuzumab, the monoclonal antibody directed at CD52, shows activity in the setting of chemotherapy-resistant disease or high-risk untreated patients with 17p deletion or p53 mutation.[55][56] As a single agent, the subcutaneous route of delivery for alemtuzumab is preferred to the intravenous route in patients because of the similar efficacy and decreased adverse effects, including less acute allergic reactions that were shown in some nonrandomized reports.[57][58][59]

    In a combination regimen, subcutaneous alemtuzumab plus fludarabine or intravenous alemtuzumab plus alkylating agents have resulted in excess infectious toxicities and death, with no compensatory improvement in efficacy in phase II trials.[60][61][Level of evidence: 3iiiDiv] In a randomized prospective study, 335 previously treated patients received intravenous alemtuzumab plus fludarabine versus fludarabine alone; with a median follow-up of 30 months, the combination of fludarabine plus intravenous alemtuzumab had better PFS, with a median of 23.7 months versus 16.5 months (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.47–0.80; P = .0003); and better OS, with a median not reached versus 52.9 months (HR, 0.65; 95% CI, 0.45–0.94; P = .021).[62][Level of evidence: 1iiA] Profound and long-lasting immunosuppression has been seen, which mandates monitoring for reactivation of cytomegalovirus and prophylaxis for pneumocystis and herpes virus infections.[63][64]

  11. Bone marrow and peripheral stem cell transplantations are under clinical evaluation.[65][66][67][68][69][70]

    In a prospective randomized trial, 241 previously untreated patients younger than 66 years with advanced-stage disease received induction therapy with a CHOP-based regimen followed by fludarabine.[71] Complete responders (105 patients) were randomly assigned to undergo autologous stem cell transplantation (ASCT) or observation, while the other 136 patients were randomly assigned to receive dexamethasone, high-dose aracytin, and cisplatin reinduction followed by either ASCT or fludarabine plus cyclophosphamide. Although the 3-year EFS favored ASCT in complete responders, there was no difference in OS in any of the randomized comparisons.[71][Level of evidence: 1iiDi]

    Patients with adverse prognostic factors are very likely to die from CLL. These patients are candidates for clinical trials that employ high-dose chemotherapy and immunotherapy with myeloablative or nonmyeloablative allogeneic peripheral stem cell transplantation.[65][66][67][68][69][70][72][73][74][75][76][77][78][79] Although most patients who attain complete remission after ASCT eventually relapse, a survival plateau for allogeneic stem cell support suggests an additional graft-versus-leukemia effect.[79]

  12. Autologous T-cells were modified by a lentiviral vector to incorporate antigen receptor specificity for the B-cell antigen CD19 and then infused into a previously treated patient.[80] A dramatic response lasting 6 months has prompted larger trials of this concept.[80][Level of evidence: 3iiiDiv] Ongoing clinical trials are testing this concept.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with stage I chronic lymphocytic leukemia, stage II chronic lymphocytic leukemia, stage III chronic lymphocytic leukemia and stage IV chronic lymphocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Developments in the treatment of lymphoproliferative disorders: rising to the new challenges of CLL therapy. A report of a symposium presented during the 48th American Society of Hematology Annual Meeting and Exposition, December 8, 2006, Orlando, Florida. Clin Adv Hematol Oncol 5 (3 Suppl 5): 1-14; quiz 15-6, 2007.

  2. Montserrat E, Moreno C, Esteve J, et al.: How I treat refractory CLL. Blood 107 (4): 1276-83, 2006.

  3. Rai KR, Peterson, Frederick R. Appelbaum BL, Appelbaum FR, et al.: Long-term survival analysis of the North American Intergroup Study C9011 comparing fludarabine (F) and chlorambucil (C) in previously untreated patients with chronic lymphocytic leukemia (CLL). [Abstract] Blood 114 (22): A-536, 2009.

  4. Hallek M, Fischer K, Fingerle-Rowson G, et al.: Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376 (9747): 1164-74, 2010.

  5. Rai KR, Peterson BL, Appelbaum FR, et al.: Fludarabine compared with chlorambucil as primary therapy for chronic lymphocytic leukemia. N Engl J Med 343 (24): 1750-7, 2000.

  6. Böttcher S, Ritgen M, Fischer K, et al.: Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol 30 (9): 980-8, 2012.

  7. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst 91 (10): 861-8, 1999.

  8. Mavromatis B, Cheson BD: Monoclonal antibody therapy of chronic lymphocytic leukemia. J Clin Oncol 21 (9): 1874-81, 2003.

  9. O'Brien SM, Kantarjian H, Thomas DA, et al.: Rituximab dose-escalation trial in chronic lymphocytic leukemia. J Clin Oncol 19 (8): 2165-70, 2001.

  10. Byrd JC, Murphy T, Howard RS, et al.: Rituximab using a thrice weekly dosing schedule in B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma demonstrates clinical activity and acceptable toxicity. J Clin Oncol 19 (8): 2153-64, 2001.

  11. Hainsworth JD, Litchy S, Barton JH, et al.: Single-agent rituximab as first-line and maintenance treatment for patients with chronic lymphocytic leukemia or small lymphocytic lymphoma: a phase II trial of the Minnie Pearl Cancer Research Network. J Clin Oncol 21 (9): 1746-51, 2003.

  12. Castro JE, Sandoval-Sus JD, Bole J, et al.: Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia 22 (11): 2048-53, 2008.

  13. Wierda WG, Kipps TJ, Mayer J, et al.: Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 28 (10): 1749-55, 2010.

  14. Wierda WG, Padmanabhan S, Chan GW, et al.: Ofatumumab is active in patients with fludarabine-refractory CLL irrespective of prior rituximab: results from the phase 2 international study. Blood 118 (19): 5126-9, 2011.

  15. A randomized clinical trial of chlorambucil versus COP in stage B chronic lymphocytic leukemia. The French Cooperative Group on Chronic Lymphocytic Leukemia. Blood 75 (7): 1422-5, 1990.

  16. Dighiero G, Maloum K, Desablens B, et al.: Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med 338 (21): 1506-14, 1998.

  17. O'Brien S, Kantarjian H, Beran M, et al.: Results of fludarabine and prednisone therapy in 264 patients with chronic lymphocytic leukemia with multivariate analysis-derived prognostic model for response to treatment. Blood 82 (6): 1695-700, 1993.

  18. Tallman MS, Hakimian D, Zanzig C, et al.: Cladribine in the treatment of relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 13 (4): 983-8, 1995.

  19. Saven A, Lemon RH, Kosty M, et al.: 2-Chlorodeoxyadenosine activity in patients with untreated chronic lymphocytic leukemia. J Clin Oncol 13 (3): 570-4, 1995.

  20. Dillman RO, Mick R, McIntyre OR: Pentostatin in chronic lymphocytic leukemia: a phase II trial of Cancer and Leukemia group B. J Clin Oncol 7 (4): 433-8, 1989.

  21. Morrison VA, Rai KR, Peterson BL, et al.: Impact of therapy with chlorambucil, fludarabine, or fludarabine plus chlorambucil on infections in patients with chronic lymphocytic leukemia: Intergroup Study Cancer and Leukemia Group B 9011. J Clin Oncol 19 (16): 3611-21, 2001.

  22. Robak T, Blonski JZ, Gora-Tybor J, et al.: Cladribine alone and in combination with cyclophosphamide or cyclophosphamide plus mitoxantrone in the treatment of progressive chronic lymphocytic leukemia: report of a prospective, multicenter, randomized trial of the Polish Adult Leukemia Group (PALG CLL2). Blood 108 (2): 473-9, 2006.

  23. Robak T, Bloński JZ, Kasznicki M, et al.: Cladribine with prednisone versus chlorambucil with prednisone as first-line therapy in chronic lymphocytic leukemia: report of a prospective, randomized, multicenter trial. Blood 96 (8): 2723-9, 2000.

  24. Johnson S, Smith AG, Löffler H, et al.: Multicentre prospective randomised trial of fludarabine versus cyclophosphamide, doxorubicin, and prednisone (CAP) for treatment of advanced-stage chronic lymphocytic leukaemia. The French Cooperative Group on CLL. Lancet 347 (9013): 1432-8, 1996.

  25. Leporrier M, Chevret S, Cazin B, et al.: Randomized comparison of fludarabine, CAP, and ChOP in 938 previously untreated stage B and C chronic lymphocytic leukemia patients. Blood 98 (8): 2319-25, 2001.

  26. Eichhorst BF, Busch R, Stilgenbauer S, et al.: First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 114 (16): 3382-91, 2009.

  27. Steurer M, Pall G, Richards S, et al.: Purine antagonists for chronic lymphocytic leukaemia. Cochrane Database Syst Rev 3: CD004270, 2006.

  28. Dearden C, Wade R, Else M, et al.: The prognostic significance of a positive direct antiglobulin test in chronic lymphocytic leukemia: a beneficial effect of the combination of fludarabine and cyclophosphamide on the incidence of hemolytic anemia. Blood 111 (4): 1820-6, 2008.

  29. Perkins JG, Flynn JM, Howard RS, et al.: Frequency and type of serious infections in fludarabine-refractory B-cell chronic lymphocytic leukemia and small lymphocytic lymphoma: implications for clinical trials in this patient population. Cancer 94 (7): 2033-9, 2002.

  30. Leoni LM, Bailey B, Reifert J, et al.: Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res 14 (1): 309-17, 2008.

  31. Fischer K, Cramer P, Busch R, et al.: Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 29 (26): 3559-66, 2011.

  32. Iannitto E, Morabito F, Mancuso S, et al.: Bendamustine with or without rituximab in the treatment of relapsed chronic lymphocytic leukaemia: an Italian retrospective study. Br J Haematol 153 (3): 351-7, 2011.

  33. Knauf WU, Lissichkov T, Aldaoud A, et al.: Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 27 (26): 4378-84, 2009.

  34. Chen CI, Bergsagel PL, Paul H, et al.: Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol 29 (9): 1175-81, 2011.

  35. Chanan-Khan A, Miller KC, Musial L, et al.: Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol 24 (34): 5343-9, 2006.

  36. Ferrajoli A, Lee BN, Schlette EJ, et al.: Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 111 (11): 5291-7, 2008.

  37. Badoux XC, Keating MJ, Wen S, et al.: Lenalidomide as initial therapy of elderly patients with chronic lymphocytic leukemia. Blood 118 (13): 3489-98, 2011.

  38. Moutouh-de Parseval LA, Weiss L, DeLap RJ, et al.: Tumor lysis syndrome/tumor flare reaction in lenalidomide-treated chronic lymphocytic leukemia. J Clin Oncol 25 (31): 5047, 2007.

  39. Smith MR, Neuberg D, Flinn IW, et al.: Incidence of therapy-related myeloid neoplasia after initial therapy for chronic lymphocytic leukemia with fludarabine-cyclophosphamide versus fludarabine: long-term follow-up of US Intergroup Study E2997. Blood 118 (13): 3525-7, 2011.

  40. Carney DA, Westerman DA, Tam CS, et al.: Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy. Leukemia 24 (12): 2056-62, 2010.

  41. Lamanna N, Jurcic JG, Noy A, et al.: Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: molecular remissions predict for durable complete responses. J Clin Oncol 27 (4): 491-7, 2009.

  42. Foon KA, Boyiadzis M, Land SR, et al.: Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 27 (4): 498-503, 2009.

  43. Tam CS, O'Brien S, Wierda W, et al.: Long-term results of the fludarabine, cyclophosphamide, and rituximab regimen as initial therapy of chronic lymphocytic leukemia. Blood 112 (4): 975-80, 2008.

  44. Badoux XC, Keating MJ, Wang X, et al.: Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood 117 (11): 3016-24, 2011.

  45. Woyach JA, Ruppert AS, Heerema NA, et al.: Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol 29 (10): 1349-55, 2011.

  46. Robak T, Dmoszynska A, Solal-Céligny P, et al.: Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 28 (10): 1756-65, 2010.

  47. Kay NE, Geyer SM, Call TG, et al.: Combination chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab shows significant clinical activity with low accompanying toxicity in previously untreated B chronic lymphocytic leukemia. Blood 109 (2): 405-11, 2007.

  48. Shanafelt TD, Lin T, Geyer SM, et al.: Pentostatin, cyclophosphamide, and rituximab regimen in older patients with chronic lymphocytic leukemia. Cancer 109 (11): 2291-8, 2007.

  49. Wierda WG, Kipps TJ, Dürig J, et al.: Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood 117 (24): 6450-8, 2011.

  50. Raphael B, Andersen JW, Silber R, et al.: Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial. J Clin Oncol 9 (5): 770-6, 1991.

  51. Is the CHOP regimen a good treatment for advanced CLL? Results from two randomized clinical trials. French Cooperative Group on Chronic Lymphocytic Leukemia. Leuk Lymphoma 13 (5-6): 449-56, 1994.

  52. Flinn IW, Neuberg DS, Grever MR, et al.: Phase III trial of fludarabine plus cyclophosphamide compared with fludarabine for patients with previously untreated chronic lymphocytic leukemia: US Intergroup Trial E2997. J Clin Oncol 25 (7): 793-8, 2007.

  53. Catovsky D, Richards S, Matutes E, et al.: Assessment of fludarabine plus cyclophosphamide for patients with chronic lymphocytic leukaemia (the LRF CLL4 Trial): a randomised controlled trial. Lancet 370 (9583): 230-9, 2007.

  54. Morrison VA, Rai KR, Peterson BL, et al.: Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011. J Clin Oncol 20 (18): 3878-84, 2002.

  55. Moreton P, Kennedy B, Lucas G, et al.: Eradication of minimal residual disease in B-cell chronic lymphocytic leukemia after alemtuzumab therapy is associated with prolonged survival. J Clin Oncol 23 (13): 2971-9, 2005.

  56. Parikh SA, Keating MJ, O'Brien S, et al.: Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood 118 (8): 2062-8, 2011.

  57. Stilgenbauer S, Zenz T, Winkler D, et al.: Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 27 (24): 3994-4001, 2009.

  58. Cortelezzi A, Pasquini MC, Gardellini A, et al.: Low-dose subcutaneous alemtuzumab in refractory chronic lymphocytic leukaemia (CLL): results of a prospective, single-arm multicentre study. Leukemia 23 (11): 2027-33, 2009.

  59. Osterborg A, Foà R, Bezares RF, et al.: Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia. Leukemia 23 (11): 1980-8, 2009.

  60. Lin TS, Donohue KA, Byrd JC, et al.: Consolidation therapy with subcutaneous alemtuzumab after fludarabine and rituximab induction therapy for previously untreated chronic lymphocytic leukemia: final analysis of CALGB 10101. J Clin Oncol 28 (29): 4500-6, 2010.

  61. Badoux XC, Keating MJ, Wang X, et al.: Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood 118 (8): 2085-93, 2011.

  62. Elter T, Gercheva-Kyuchukova L, Pylylpenko H, et al.: Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol 12 (13): 1204-13, 2011.

  63. Elter T, Vehreschild JJ, Gribben J, et al.: Management of infections in patients with chronic lymphocytic leukemia treated with alemtuzumab. Ann Hematol 88 (2): 121-32, 2009.

  64. Byrd JC, Peterson BL, Rai KR, et al.: Fludarabine followed by alemtuzumab consolidation for previously untreated chronic lymphocytic leukemia: final report of Cancer and Leukemia Group B study 19901. Leuk Lymphoma 50 (10): 1589-96, 2009.

  65. Doney KC, Chauncey T, Appelbaum FR, et al.: Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplant 29 (10): 817-23, 2002.

  66. Schetelig J, Thiede C, Bornhauser M, et al.: Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol 21 (14): 2747-53, 2003.

  67. Ritgen M, Stilgenbauer S, von Neuhoff N, et al.: Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood 104 (8): 2600-2, 2004.

  68. Moreno C, Villamor N, Colomer D, et al.: Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol 23 (15): 3433-8, 2005.

  69. Khouri IF, Keating MJ, Saliba RM, et al.: Long-term follow-up of patients with CLL treated with allogeneic hematopoietic transplantation. Cytotherapy 4 (3): 217-21, 2002.

  70. Pavletic SZ, Khouri IF, Haagenson M, et al.: Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research. J Clin Oncol 23 (24): 5788-94, 2005.

  71. Sutton L, Chevret S, Tournilhac O, et al.: Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood 117 (23): 6109-19, 2011.

  72. Sorror ML, Maris MB, Sandmaier BM, et al.: Hematopoietic cell transplantation after nonmyeloablative conditioning for advanced chronic lymphocytic leukemia. J Clin Oncol 23 (16): 3819-29, 2005.

  73. Toze CL, Galal A, Barnett MJ, et al.: Myeloablative allografting for chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemia effect associated with graft-versus-host disease. Bone Marrow Transplant 36 (9): 825-30, 2005.

  74. Milligan DW, Fernandes S, Dasgupta R, et al.: Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses. Blood 105 (1): 397-404, 2005.

  75. Khouri IF, Saliba RM, Admirand J, et al.: Graft-versus-leukaemia effect after non-myeloablative haematopoietic transplantation can overcome the unfavourable expression of ZAP-70 in refractory chronic lymphocytic leukaemia. Br J Haematol 137 (4): 355-63, 2007.

  76. Sorror ML, Storer BE, Sandmaier BM, et al.: Five-year follow-up of patients with advanced chronic lymphocytic leukemia treated with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning. J Clin Oncol 26 (30): 4912-20, 2008.

  77. Schetelig J, van Biezen A, Brand R, et al.: Allogeneic hematopoietic stem-cell transplantation for chronic lymphocytic leukemia with 17p deletion: a retrospective European Group for Blood and Marrow Transplantation analysis. J Clin Oncol 26 (31): 5094-100, 2008.

  78. Malhotra P, Hogan WJ, Litzow MR, et al.: Long-term outcome of allogeneic stem cell transplantation in chronic lymphocytic leukemia: analysis after a minimum follow-up of 5 years. Leuk Lymphoma 49 (9): 1724-30, 2008.

  79. Dreger P, Döhner H, Ritgen M, et al.: Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood 116 (14): 2438-47, 2010.

  80. Porter DL, Levine BL, Kalos M, et al.: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365 (8): 725-33, 2011.

Recurrent or Refractory Chronic Lymphocytic Leukemia

Clinical trials are appropriate and should be considered when possible.[1] In small studies, response rates of more than 40% have been reported for lenalidomide [2][3][4] and flavopiridol.[5][6][Level of evidence: 3iiiDiv] The addition of the Bcl-2 anti-sense oligonucleotide oblimersen to fludarabine/cyclophosphamide improved complete response rates in a randomized study of 241 patients with relapsed disease.[7][Level of evidence: 1iiDiv] Bone marrow and peripheral stem cell transplantations are under clinical evaluation.[8][9][10][11][12][13][14]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with refractory chronic lymphocytic leukemia. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

  1. Byrd JC, Rai KR, Sausville EA, et al.: Old and new therapies in chronic lymphocytic leukemia: now is the time for a reassessment of therapeutic goals. Semin Oncol 25 (1): 65-74, 1998.

  2. Chanan-Khan A, Miller KC, Musial L, et al.: Clinical efficacy of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia: results of a phase II study. J Clin Oncol 24 (34): 5343-9, 2006.

  3. Ferrajoli A, Lee BN, Schlette EJ, et al.: Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 111 (11): 5291-7, 2008.

  4. Andritsos LA, Johnson AJ, Lozanski G, et al.: Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. J Clin Oncol 26 (15): 2519-25, 2008.

  5. Byrd JC, Lin TS, Dalton JT, et al.: Flavopiridol administered using a pharmacologically derived schedule is associated with marked clinical efficacy in refractory, genetically high-risk chronic lymphocytic leukemia. Blood 109 (2): 399-404, 2007.

  6. Lin TS, Ruppert AS, Johnson AJ, et al.: Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol 27 (35): 6012-8, 2009.

  7. O'Brien S, Moore JO, Boyd TE, et al.: 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol 27 (31): 5208-12, 2009.

  8. Dreger P, Brand R, Milligan D, et al.: Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia 19 (6): 1029-33, 2005.

  9. Schetelig J, Thiede C, Bornhauser M, et al.: Evidence of a graft-versus-leukemia effect in chronic lymphocytic leukemia after reduced-intensity conditioning and allogeneic stem-cell transplantation: the Cooperative German Transplant Study Group. J Clin Oncol 21 (14): 2747-53, 2003.

  10. Ritgen M, Stilgenbauer S, von Neuhoff N, et al.: Graft-versus-leukemia activity may overcome therapeutic resistance of chronic lymphocytic leukemia with unmutated immunoglobulin variable heavy-chain gene status: implications of minimal residual disease measurement with quantitative PCR. Blood 104 (8): 2600-2, 2004.

  11. Moreno C, Villamor N, Colomer D, et al.: Allogeneic stem-cell transplantation may overcome the adverse prognosis of unmutated VH gene in patients with chronic lymphocytic leukemia. J Clin Oncol 23 (15): 3433-8, 2005.

  12. Khouri IF, Keating MJ, Saliba RM, et al.: Long-term follow-up of patients with CLL treated with allogeneic hematopoietic transplantation. Cytotherapy 4 (3): 217-21, 2002.

  13. Doney KC, Chauncey T, Appelbaum FR, et al.: Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplant 29 (10): 817-23, 2002.

  14. Pavletic SZ, Khouri IF, Haagenson M, et al.: Unrelated donor marrow transplantation for B-cell chronic lymphocytic leukemia after using myeloablative conditioning: results from the Center for International Blood and Marrow Transplant research. J Clin Oncol 23 (24): 5788-94, 2005.


This information is provided by the National Cancer Institute.

This information was last updated on April 19, 2013.

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