Breast cancer survivor offers wisdom at Faulkner satellite center
Call 877-422-3324 today to make an appointment
Make your appointment or second opinion with Dana-Farber today to meet with an onsite specialist.
Can’t get to Boston? Explore our Online Second Opinion service to get expert advice from Dana-Farber oncologists.
Toll-Free Number866-408-DFCI (3324)
Discover the ways to give and how to get involved to support Dana-Farber.
Poet Richard Fox gains insight – and material – through cancer treatment
A family faces cancer in an unfamiliar city – with help
Choosing mastectomy or not: Studying young women's surgical choices
Jeff's targeted therapy has kept his advanced lung cancer at bay.
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.
Your fight against chronic lymphocytic leukemia (CLL) calls for care that is both knowledgeable and compassionate. Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) offers a dedicated Center for Chronic Lymphocytic Leukemia, led by world experts in treating the disease — and in driving efforts to find a cure.
Exceptional Care for Patients with Chronic Lymphocytic Leukemia
World-class care from a full array of specialists — including medical and radiation oncologists, infectious disease specialists, nursing professionals, physician assistants, psychologists, and social workers — with years of expertise in treating patients with CLL.
A personalized CLL risk assessment that will give you detailed, specific information about your disease as soon as you're diagnosed — and help you and your care team build a customized treatment plan.
Access to specialized CLL clinical trials, offering the latest and most promising therapies.
Close collaboration with you and your family as key members of the treatment team.
Partnership with your referring physician at each stage of your treatment, including follow-up care that's closer to your home.
Comprehensive support services for you and your family, including patient and caregiver education and survivorship programs.
The full expertise of two renowned medical centers: Brigham and Women's Hospital and Dana-Farber Cancer Institute.
To schedule a consultation or request a second opinion from our multidisciplinary team, please contact us at 617-632-3245 or 617-632-5138 or fill out our secure online form.
Chronic lymphocytic leukemia (also called CLL) is a blood and bone marrow disease that usually gets worse slowly. CLL is one of the most common types 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:
A lymphoid stem cell becomes a lymphoblast cell and then one of three types of lymphocytes (white blood cells):
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:
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:
Usually CLL does not cause any signs or symptoms and is found during a routine blood test. Signs and symptoms may be caused by CLL or by other conditions. Check with your doctor if you have any of the following:
The following tests and procedures may be used:
Treatment options depend on:
The prognosis (chance of recovery) depends on:
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:
In stage 0 chronic lymphocytic leukemia, there are too many lymphocytes in the blood, but there are no other signs or symptoms of leukemia. Stage 0 chronic lymphocytic leukemia is indolent (slow-growing).
In stage I chronic lymphocytic leukemia, there are too many lymphocytes in the blood and the lymph nodes are larger than normal.
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.
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.
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.
Refractorychronic lymphocytic leukemia is cancer that does not get better with treatment.
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.
Watchful waiting is closely monitoring a patient’s condition without giving any treatment until signs or symptoms appear or change. This is also called observation. During this time, problems caused by the disease, such as infection, are treated.
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 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.
Splenectomy is surgery to remove the spleen.
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 and tyrosine kinase inhibitor therapy are types 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.
Tyrosine kinase inhibitor therapy is a cancer treatment that blocks signals needed for tumors to grow.
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 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 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.
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.
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.
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 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.
Treatment of stage I, stage II, stage III, and stage IV chronic lymphocytic leukemia may include the following:
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 of refractorychronic lymphocytic leukemia may include the following:
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.
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 June 9, 2014.
Estimated new cases and deaths from chronic lymphocytic leukemia (CLL) in the United States in 2014:
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.
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).
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. 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.
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. 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.
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. Antileukemic
therapy is frequently unnecessary in uncomplicated early disease. The median survival for all patients ranges from 8 to 12 years in older trials with data from the 1970s through the 1990s. 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.
As found in one report, CLL occurs primarily in middle-aged and elderly adults, with increasing
frequency in successive decades of life. 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. Immunological aberrations,
including Coombs-positive hemolytic anemia, immune thrombocytopenia, and
depressed immunoglobulin levels may all complicate the management of CLL.
Prognostic factors that may help predict clinical outcome include cytogenetic
subgroup, immunoglobulin mutational status, ZAP-70, and CD38. (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.
Patients with CLL are also at increased risk for other malignancies, even before therapy.
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. 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). 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.
(2-chlorodeoxyadenosine) appears to be an active agent (60% complete remission
rate) for patients with de novo B-cell prolymphocytic leukemia.[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).[Level of evidence: 3iiiDiv] These response rates have been confirmed by other investigators. Patients with CLL who show prolymphocytoid transformation
maintain the classic CLL phenotype and have a worse prognosis than PLL
Large granular lymphocyte (LGL) leukemia is characterized by
lymphocytosis with a natural killer cell immunophenotype (CD2, CD16, and CD56)
or a T-cell immunophenotype (CD2, CD3, and CD8). 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. A characteristic genetic finding in almost 50% of the patients with T-cell LGL involves mutations in the signal transducer and activator of the transcription 3 gene (STAT 3). Therapy includes
low doses of oral cyclophosphamide or methotrexate, cyclosporine, and treatment of
the bacterial infections acquired during severe neutropenia.
Other PDQ summaries containing information about CLL include the following:
American Cancer Society: Cancer Facts and Figures 2014. Atlanta, Ga: American Cancer Society, 2014. Available online. Last accessed May 21, 2014.
Dighiero G, Hamblin TJ: Chronic lymphocytic leukaemia. Lancet 371 (9617): 1017-29, 2008.
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.
Shanafelt TD, Kay NE, Jenkins G, et al.: B-cell count and survival: differentiating chronic lymphocytic leukemia from monoclonal B-cell lymphocytosis based on clinical outcome. Blood 113 (18): 4188-96, 2009.
Rawstron AC, Bennett FL, O'Connor SJ, et al.: Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med 359 (6): 575-83, 2008.
Dighiero G: Monoclonal B-cell lymphocytosis--a frequent premalignant condition. N Engl J Med 359 (6): 638-40, 2008.
Fazi C, Scarfò L, Pecciarini L, et al.: General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL. Blood 118 (25): 6618-25, 2011.
Shanafelt TD, Kay NE, Rabe KG, et al.: Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol 27 (24): 3959-63, 2009.
Landgren O, Albitar M, Ma W, et al.: B-cell clones as early markers for chronic lymphocytic leukemia. N Engl J Med 360 (7): 659-67, 2009.
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.
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.
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.
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.
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.
Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333 (16): 1052-7, 1995.
Wierda WG, O'Brien S, Wang X, et al.: Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood 109 (11): 4679-85, 2007.
Montserrat E: CLL therapy: progress at last! Blood 105 (1): 2-3, 2005.
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.
Anaissie EJ, Kontoyiannis DP, O'Brien S, et al.: Infections in patients with chronic lymphocytic leukemia treated with fludarabine. Ann Intern Med 129 (7): 559-66, 1998.
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.
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.
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.
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.
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.
Klein U, Tu Y, Stolovitzky GA, et al.: Gene expression profiling of B cell chronic lymphocytic leukemia reveals a homogeneous phenotype related to memory B cells. J Exp Med 194 (11): 1625-38, 2001.
Orchard JA, Ibbotson RE, Davis Z, et al.: ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363 (9403): 105-11, 2004.
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.
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.
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.
Tsimberidou AM, Keating MJ: Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 103 (2): 216-28, 2005.
Tsimberidou AM, Wen S, McLaughlin P, et al.: Other malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol 27 (6): 904-10, 2009.
DiGiuseppe JA, Borowitz MJ: Clinical utility of flow cytometry in the chronic lymphoid leukemias. Semin Oncol 25 (1): 6-10, 1998.
Melo JV, Catovsky D, Galton DA: The relationship between chronic lymphocytic leukaemia and prolymphocytic leukaemia. I. Clinical and laboratory features of 300 patients and characterization of an intermediate group. Br J Haematol 63 (2): 377-87, 1986.
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.
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.
Dearden CE, Matutes E, Catovsky D: Alemtuzumab in T-cell malignancies. Med Oncol 19 (Suppl): S27-32, 2002.
Sokol L, Loughran TP Jr: Large granular lymphocyte leukemia. Oncologist 11 (3): 263-73, 2006.
Semenzato G, Zambello R, Starkebaum G, et al.: The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis. Blood 89 (1): 256-60, 1997.
Lamy T, Loughran TP Jr: How I treat LGL leukemia. Blood 117 (10): 2764-74, 2011.
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.
Koskela HL, Eldfors S, Ellonen P, et al.: Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med 366 (20): 1905-13, 2012.
Loughran TP Jr, Kidd PG, Starkebaum G: Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate. Blood 84 (7): 2164-70, 1994.
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.
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. 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.
Stage 0 CLL is characterized by absolute lymphocytosis (>15,000/mm3) without adenopathy, hepatosplenomegaly, anemia, or
Stage I CLL is characterized by absolute lymphocytosis with
lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.
Stage II CLL is characterized by absolute lymphocytosis with either
hepatomegaly or splenomegaly with or without lymphadenopathy.
Stage III CLL is characterized by absolute lymphocytosis and anemia
(hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or
Stage IV CLL is characterized by absolute lymphocytosis and
thrombocytopenia (<100,000/mm3) with or without
lymphadenopathy, hepatomegaly, splenomegaly, or anemia.
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. 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). The NCI-sponsored working
group has published guidelines for the diagnosis and treatment of CLL in both
clinical trial and general practice settings. Use of these systems allows
comparison of clinical results and establishment of therapeutic guidelines.
New prognostic markers are now available to the clinician and investigator. 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. Prognostic indices are under evaluation and will require prospective validation.
Other prognostic factors include:
Rai KR, Sawitsky A, Cronkite EP, et al.: Clinical staging of chronic lymphocytic leukemia. Blood 46 (2): 219-34, 1975.
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.
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.
Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. International Workshop on Chronic Lymphocytic Leukemia. Ann Intern Med 110 (3): 236-8, 1989.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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. 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. 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.
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.[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
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.
There was, however, no effect on survival. Routine chronic administration of
intravenous immunoglobulin is expensive, and the long-term benefit (>1
year) is unproven.
Second malignancies and treatment-induced acute leukemias may also occur in a
small percentage of patients. 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. (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. 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. Tumor lysis syndrome is an uncommon complication (presenting
in 1 out of 300 patients) of chemotherapy for patients with bulky disease.
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.
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.
Gribben JG, O'Brien S: Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 29 (5): 544-50, 2011.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Because of the indolent nature of stage 0 chronic lymphocytic leukemia (CLL),
treatment is not indicated. 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.[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.[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.
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.
Casper JT: Prognostic features of early chronic lymphocytic leukaemia. International Workshop on CLL. Lancet 2 (8669): 968-9, 1989.
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.
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, but only two trials have shown statistically significant improvement in overall survival (OS).
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).[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.[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. The surrogate endpoint of such clearance of residual disease, while prognostic, 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.
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.
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.
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. 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.[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).[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.
The increased risk of infection may persist for months or years after treatment with a purine analog.
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. Purine analogs cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines.
Bendamustine is a cytotoxic agent with bifunctional properties of an alkylator and a purine analog. In previously treated and untreated patients, bendamustine with rituximab has shown response rates around 70% to 90%.[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.[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.
Lenalidomide is an oral immunomodulatory agent with response rates over 50%, with or without rituximab, for patients with previously treated and untreated disease.[Level of evidence: 3iiiDiv] Prolonged, lower-dose approaches and attention to prevention of tumor lysis syndrome are recommended with this agent. Combination therapy and long-term toxicities from using lenalidomide (such as increased myelodysplasia, as seen in myeloma patients) remain undefined for patients with CLL.
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).[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. 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.
Other combination chemotherapy regimens include the following:
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.[Level of evidence: 1iiA]
In a combination regimen, subcutaneous alemtuzumab plus fludarabine (with or without cyclophosphamide) or intravenous alemtuzumab plus alkylating agents have resulted in excess infectious toxicities and death, with no compensatory improvement in efficacy in phase II trials.[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).[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. Antibiotic prophylaxis includes trimethoprim and sulfamethoxazole, itraconazole, and acyclovir (or ganciclovir) for asymptomatic cytomegalovirus viremia.
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. 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.[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. 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.
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.
Montserrat E, Moreno C, Esteve J, et al.: How I treat refractory CLL. Blood 107 (4): 1276-83, 2006.
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.
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.
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.
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.
Mavromatis B, Cheson BD: Monoclonal antibody therapy of chronic lymphocytic leukemia. J Clin Oncol 21 (9): 1874-81, 2003.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Steurer M, Pall G, Richards S, et al.: Purine antagonists for chronic lymphocytic leukaemia. Cochrane Database Syst Rev 3: CD004270, 2006.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Wendtner CM, Hillmen P, Mahadevan D, et al.: Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia. Leuk Lymphoma 53 (3): 417-23, 2012.
Badoux XC, Keating MJ, Wen S, et al.: Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 31 (5): 584-91, 2013.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Pettitt AR, Jackson R, Carruthers S, et al.: Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial. J Clin Oncol 30 (14): 1647-55, 2012.
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.
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.
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.
Gritti G, Reda G, Maura F, et al.: Low dose alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia. Leuk Lymphoma 53 (3): 424-9, 2012.
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.
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.
Lepretre S, Aurran T, Mahé B, et al.: Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood 119 (22): 5104-10, 2012.
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.
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.
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.
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.
Dreger P, Döhner H, McClanahan F, et al.: Early autologous stem cell transplantation for chronic lymphocytic leukemia: long-term follow-up of the German CLL Study Group CLL3 trial. Blood 119 (21): 4851-9, 2012.
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.
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.
Toze CL, Dalal CB, Nevill TJ, et al.: Allogeneic haematopoietic stem cell transplantation for chronic lymphocytic leukaemia: outcome in a 20-year cohort. Br J Haematol 158 (2): 174-85, 2012.
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.
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.
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.
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.
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.
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.
Advani RH, Buggy JJ, Sharman JP, et al.: Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol 31 (1): 88-94, 2013.
Byrd JC, Furman RR, Coutre SE, et al.: Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369 (1): 32-42, 2013.
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.
Clinical trials are appropriate and should be considered when possible.
In small studies, response rates of more than 40% have been reported for lenalidomide  and flavopiridol.[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.[Level of evidence: 1iiDiv] Bone marrow and peripheral stem
cell transplantations are under clinical evaluation.
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.
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.
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.
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.
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.
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.
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.
This information was last updated on April 16, 2014.
Our licensed social workers are here to help adult patients and their loved ones face the many new concerns and anxieties following a cancer diagnosis, offering emotional support and assistance with obtaining needed resources.
Our support groups are geared to specific cancers and methods of treatment. They give patients the opportunity to meet and share information and moral support. Our experienced, compassionate staff facilitates and guides discussion.
If you are dealing with the death of a loved one, grief can be a lonely and isolating experience. The Bereavement Program provides support to bereaved family members and friends following the death of a patient.
Concierge Services is your one-stop place to learn about Dana-Farber programs, services and resources, as well as information on getting around Boston, finding lodging or restaurants, and activities in the area.
The Expressive Arts Therapy program, sponsored by the Leonard P. Zakim Center for Integrative Therapies, provides adult patients, family members, and caregivers with a variety of options to support well-being during cancer treatment. From live music meditation to painting technique workshops, the program offers a range of creative outlets to suit every interest.
Dana-Farber and Brigham and Women's Hospital, including parking facilities, are fully accessible to people with disabilities. There are wheelchairs at the main entrance, and security staff can provide personal assistance. We also have many educational materials available in large print and audiotape formats.
The Ethics Consultation Service is available for patients and families who may be facing difficult decisions and choices regarding care. Our goal is to bring together patients, families and health care providers to talk about ethical concerns and help everyone involved arrive at a resolution that is right for all.
This comprehensive resource offers guidance, information and resources to support the entire family, including how to talk to children about cancer, advice for the well partner, and creating a support network.
Find practical tips and suggestions for individuals caring for a family member or friend with cancer, including creating a caregiving plan, finding community resources, and looking after your own well-being.
Friends' Place provides personal consultations to help cancer patients of all ages cope with changes in physical appearance that result from cancer treatment. Our experienced, compassionate team provides fittings for compression garments or breast prostheses, helps with wigs and other head coverings, and offers make-up and skincare advice.
The Friends' Corner Gift Shop, located on the first floor of the Yawkey Center for Cancer Care, offers a wide selection of unique gifts and everyday items for patients, families and staff.
Dana-Farber offers several services to help you and your family manage the financial side of cancer treatment. From creating bill payment schedules and estate planning advice to debt management and resource assistance for patients in need, our team is here for you.
Every year, thousands of patients with cancer from around the world come to Dana-Farber for their care. We provide a wide array of logistical and other services for individuals who live outside the United States.
Dana-Farber provides interpreting services for patients whose first language is not English. Interpreters may be requested for any activity, including registration, booking appointments, attending treatments and exams, support groups, and meetings with doctors and other members of your health care team.
Our nutritionists are registered dietitians who can assist you in planning an optimal diet during any stage of your cancer journey, cope with any side effects you may experience, and answer your questions about the latest findings on cancer and nutrition.
One-to-One connects adult patients, family members and caregivers with individuals who have gone through cancer themselves, providing an experienced and reassuring perspective for those facing a cancer diagnosis, treatment and recovery.
The Eleanor and Maxwell Blum Patient and Family Resource Center and its satellite resource rooms are staffed by health care professionals and provide computer stations, books, brochures, videos, and CDs to help you find information and support on a variety of issues about cancer treatment and care.
Patients websites help friends and family members stay up-to-date on their loved ones' condition and write messages of support and encouragement.
The Dana-Farber pharmacy fills prescriptions for all pediatric and adult patients. Our pharmacists are an extension of the patient care team and work closely with your physicians to provide seamless, convenient, safe care.
More than 1,200 Dana-Farber patients and their families have enjoyed free trips to baseball games, theater shows, museums, and other attractions this year through the Recreational Resources program.
The Sexual Health Program provides education, consultation and personalized rehabilitation for patients and their partners who have experienced changes in sexual health during and after cancer treatment.
Through all stages of cancer treatment and survivorship, our Spiritual Care staff is available 24 hours a day to provide emotional and spiritual support for adults and pediatric patients and family members.
Young adults with cancer face very different challenges than patients who were diagnosed earlier in childhood or later in adulthood. The Young Adult Program can help you to find the resources and expertise available at Dana-Farber to help support your cancer experience.
Integrative therapies, also known as complementary therapies, range from acupuncture and massage to nutritional guidance and music therapy. Patients treated at the Zakim Center credit its services with easing nausea, improving circulation, and reducing pain, stress, and anxiety associated with cancer treatment.
In this video, Dr. Ann LaCasce talks about her work in the Hematologic Oncology Treatment Center at Dana-Farber/Brigham and Women's Cancer Center.