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Chronic lymphocytic leukemia (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. Lymphocyte counts in the blood are usually equal to or higher than 10,000 per cubic millimeter.[1] Treatment with conventional doses of chemotherapy is not curative; selected patients treated with allogeneic stem cell transplantation have achieved prolonged disease-free survival.[2-5] The overall 5-year survival is approximately 60%, but depends on stage of disease. Antileukemic therapy is frequently unnecessary in uncomplicated early disease.[6]
CLL occurs primarily in middle-aged and elderly individuals, with increasing frequency in successive decades of life.[7] 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.[8] Immunological aberrations, including Coombs-positive hemolytic anemia, immune thrombocytopenia, and depressed immunoglobulin levels may all complicate the management of CLL.[9] Prognostic factors that may help predict clinical outcome include cytogenetic subgroup [10] and CD38 expression.[11,12]
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.[13] 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).[6] CLL is diagnosed by an absolute increase in lymphocytosis and/or bone marrow infiltration coupled with the characteristic features of morphology and immunophenotype.
The differential diagnosis must exclude hairy cell leukemia (refer to the PDQ summary on Hairy Cell Leukemia Treatment for more information), and Waldenstrom's macroglobulinemia (refer to the PDQ summary on Multiple Myeloma and Other Plasma Cell Neoplasms Treatment for more information). Waldenstrom's 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.[6,14] Cladribine (2-chlorodeoxyadenosine) appears to be an active agent (60% complete remission rate) for patients with de novo B-cell prolymphocytic leukemia.[15][Level of evidence: 3iiiDiii] 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).[16,17] 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's syndrome.[18] Therapy includes steroids, low doses of oral cyclophosphamide or methotrexate, and treatment of the bacterial infections acquired during severe neutropenia.[16,19,20]
Chronic lymphocytic leukemia (CLL) has no standard staging system. The Rai staging system and the Binet classification are presented below.[1,2] An NCI-sponsored working group has formulated standardized guidelines for eligibility, response, and toxic effects criteria to be used in future clinical trials in CLL.[3]
Clinical stage B: no anemia or thrombocytopenia with three or more areas of
lymphoid involvement (Rai stages I and II)*
Clinical stage C: 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 due to 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 Chronic Lymphocytic Leukemia 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 National Cancer Institute-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.
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 analogues, 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 generally treated in a conservative fashion.[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 to a single agent alkylator for advanced stage disease.[3][Level of evidence: 1iiA] A variety of clinical factors, including beta-2-microglobulin, lymphocyte doubling-time, and cytogenetic abnormalities, may be helpful in predicting progression of disease.[4]
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 milligrams per kilogram 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.[5] However, there was no effect on survival, routine chronic administration of intravenous immunoglobulin is expensive, and the long-term benefit (more than 1 year) is unproven.[6,7]
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's syndrome) carries a poor prognosis with a median survival of less than 1 year, although 20% of the patients may live more than 5 years after aggressive combination chemotherapy.[8] (Refer to the PDQ summary on Adult Non-Hodgkin's 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, cyclosporine, splenectomy, and low-dose radiation to the spleen.[10] Tumor lysis syndrome is an uncommon complication (presenting in 1 in 300 patients) of chemotherapy for patients with bulky disease.[11]
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.[12]
The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.
Because of the indolent nature of stage 0 chronic lymphocytic leukemia (CLL), treatment is not indicated.[1] The French Cooperative Group on Chronic Lymphocytic Leukemia randomized 1535 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 6 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.
Observation in asymptomatic or minimally affected patients. The French Cooperative Group on Chronic Lymphocytic Leukemia randomized 1535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment and found no survival advantage for chlorambucil.[1][Level of evidence: 1iiA] A meta-analysis of 6 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.[2][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.
Standard treatment options:
Note: Prophylactic use of hydration and allopurinol should be considered when treating patients with large lymph node masses.
2. Chemotherapy with oral alkylating agents (for example, chlorambucil or
cyclophosphamide in standard doses) with or without corticosteroids (for
example, prednisone or prednisolone).[2]
3. Fludarabine, 2-chlorodeoxyadenosine, or pentostatin.[3-7]
Several randomized trials have compared the purine analogues with chlorambucil or with cyclophosphamide, doxorubicin, and prednisone in previously untreated patients.[8-10][Levels of evidence: 1iiA] Although all of these trials showed higher response rates for the purine analogue and most showed an improvement in progression-free survival, none showed an advantage in overall survival. All of the trials demonstrated higher toxic effects with the purine analogues, especially granulocytopenic infections, herpes infections, and autoimmune hemolytic anemia.
4. Involved-field radiation therapy. Relatively low doses of radiation will
effect an excellent response for months or years. Sometimes radiation of 1
nodal area or the spleen will result in abscopal effect (shrinkage of lymph
node tumors in untreated sites).
5. Combination chemotherapy.
6. CAMPATH-1H and rituximab (monoclonal antibodies) are under clinical
evaluation.[14,15] Higher doses of rituximab than those used for other non-
Hodgkin lymphomas are required.[16,17]
7. Bone marrow and peripheral stem cell transplantations are under clinical
evaluation.[18-20]
Standard treatment options:
Note: Prophylactic use of hydration and allopurinol should be considered when treating patients with large lymph node masses.
1. Observation in asymptomatic or minimally affected patients.[1]
2. Oral alkylating agents with or without corticosteroids.[2] The French
Cooperative Group on Chronic Lymphocytic Leukemia randomized 1535 patients with
previously untreated stage A disease to receive either chlorambucil or no
immediate treatment and found no survival advantage for chlorambucil.[3][Level
of evidence: 1iiA] A meta-analysis of 6 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.[1][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.
3. Fludarabine, 2-chlorodeoxyadenosine, or pentostatin.[4-8] Several
randomized trials have compared the purine analogues with chlorambucil or with
cyclophosphamide, doxorubicin, and prednisone in previously untreated
patients.[9-11][Levels of evidence: 1iiA] Although all of these trials showed
higher response rates for the purine analogue and most showed an improvement in
progression-free survival, none showed an advantage in overall survival. All
of the trials demonstrated higher toxic effects with the purine analogues,
especially granulocytopenic infections, herpes infections, and autoimmune
hemolytic anemia.
4. Combination chemotherapy. CVP: cyclophosphamide + vincristine +
prednisone.[12] CHOP: cyclophosphamide + doxorubicin + vincristine +
prednisone.[13] Fludarabine + cyclophosphamide.[14]
5. Involved-field radiation therapy. Relatively low doses of radiation will
effect an excellent response for months or years. Sometimes radiation of 1
nodal area or the spleen will results in abscopal effect (shrinkage of lymph
node tumors in untreated sites).
8. Bone marrow and peripheral stem cell transplantations are under clinical
evaluation.[20-22]
Treatment options:
Note: Prophylactic use of hydration and allopurinol should be considered when treating patients with large lymph node masses.
1. Observation in asymptomatic or minimally affected patients.[1]
2. Oral alkylating agents with or without corticosteroids.[2]
3. Fludarabine, 2-chlorodeoxyadenosine, or pentostatin.[3-7] Several
randomized trials have compared the purine analogues with chlorambucil or with
cyclophosphamide, doxorubicin, and prednisone in previously untreated
patients.[8-10][Levels of evidence: 1iiA] Although all of these trials showed
higher response rates for the purine analogue and most showed an improvement in
progression-free survival, none showed an advantage in overall survival. All
of the trials demonstrated higher toxic effects with the purine analogues,
especially granulocytopenic infections, herpes infections, and autoimmune
hemolytic anemia.
4. Combination chemotherapy.
5. Splenectomy or splenic irradiation may be helpful in patients with
hypersplenism or for patients with the complications of immune mediated
thrombocytopenia or hemolytic anemia who fail to respond to alkylating agents
and prednisone.[14,15]
6. CAMPATH-1H and rituximab (monoclonal antibodies) are under clinical
evaluation.[16,17] Higher doses of rituximab than those used for other non-
Hodgkin lymphomas are required.[18,19]
7. Bone marrow and peripheral stem transplantations are under clinical
evaluation.[20-23]
Standard treatment options:
Note: Prophylactic use of hydration and allopurinol should be considered when treating patients with large lymph node masses.
1. Observation in asymptomatic or minimally affected patients.[1]
2. Oral alkylating agents with or without corticosteroids.[2]
3. Fludarabine, 2-chlorodeoxyadenosine, or pentostatin.[3-7] Several
randomized trials have compared the purine analogues with chlorambucil or with
cyclophosphamide, doxorubicin, and prednisone in previously untreated
patients.[8-10][Levels of evidence: 1iiA] Although all of these trials showed
higher response rates for the purine analogue and most showed an improvement in
progression-free survival, none showed an advantage in overall survival. All
of the trials demonstrated higher toxic effects with the purine analogues,
especially granulocytopenic infections, herpes infections, and autoimmune
hemolytic anemia.
4. Combination chemotherapy and new single agents.
5. Splenectomy or splenic irradiation may be helpful in patients with
hypersplenism or for patients with the complications of immune mediated
thrombocytopenia or hemolytic anemia who fail to respond to alkylating agents
and prednisone.[14,15]
6. CAMPATH-1H and rituximab (monoclonal antibodies) are under clinical
evaluation.[16,17] Higher doses of rituximab than those used for other non-
Hodgkin lymphomas are required.[18,19]
7. Bone marrow and peripheral stem transplantations are under clinical
evaluation.[20-22]
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