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NCI/PDQ^® Health professionals: Chronic Lymphocytic Leukemia

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National Cancer Institute
Last Modified: June 6, 2003

TABLE OF CONTENTS

• General Information
• Stage Information
• Rai Staging System
• Binet classification
• Treatment Option Overview
• Stage 0 Chronic Lymphocytic Leukemia
• Stage I Chronic Lymphocytic Leukemia
• Stage II Chronic Lymphocytic Leukemia
• Stage III Chronic Lymphocytic Leukemia
• Stage IV Chronic Lymphocytic Leukemia
• Refractory Chronic Lymphocytic Leukemia
• Changes to This Summary (06/06/2003)
• Important

General Information

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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. In this disorder, lymphocyte counts in the blood are usually equal to or higher than 5,000 per cubic millimeter with a characteristic immunophenotype (CD5 and CD23 positive B cells). 1 As assays have become more sensitive for detecting monoclonal B-CLL-like cells in peripheral blood, researchers have detected a monoclonal lymphocytosis of undetermined significance (MLUS, in analogy to the monoclonal gammopathy of undetermined significance, MGUS) in 3% of individuals over 40 years of age and 6% in those over 60 years of age. 2 Such earlier diagnosis and recognition of cases that would have never crossed the threshold of diagnosis previously 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. At the present time, the natural history or clinical significance of these findings is unknown.

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. 3 4 5 6 The overall 5-year survival is approximately 60%, but depends on stage of disease. Antileukemic therapy is frequently unnecessary in uncomplicated early disease. 7

CLL occurs primarily in middle-aged and elderly individuals, with increasing frequency in successive decades of life. 8 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. 9 Immunological aberrations, including Coombs-positive hemolytic anemia, immune thrombocytopenia, and depressed immunoglobulin levels may all complicate the management of CLL. 10 Prognostic factors that may help predict clinical outcome include cytogenetic subgroup 11 and immunoglobulin mutational status. 12 13 14 15

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. 16 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). 7 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 Waldenstrm's macroglobulinemia (refer to the PDQ summary on Adult Non-Hodgkin's Lymphoma Treatment for more information). Waldenstrm'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. 7 17 Cladribine (2-chlorodeoxyadenosine) appears to be an active agent (60% complete remission rate) for patients with de novo B-cell prolymphocytic leukemia. 18 [Level of evidence: 3iiiDiii] 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 to 45.4 months). 19 [Level of evidence: 3iiiDiii] These response rates have been confirmed by other investigators. 20 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). 21 22 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. 23 Therapy includes steroids, low doses of oral cyclophosphamide or methotrexate, and treatment of the bacterial infections acquired during severe neutropenia. 21 24 25

References:

1. Cheson BD, Bennett JM, Grever M, et al.: National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 87 (12): 4990-7, 1996.
2. Rawstron AC, Green MJ, Kuzmicki A, et al.: Monoclonal B lymphocytes with the characteristics of "indolent" chronic lymphocytic leukemia are present in 3.5% of adults with normal blood counts. Blood 100 (2): 635-9, 2002.
3. van Besien K, Keralavarma B, Devine S, et al.: Allogeneic and autologous transplantation for chronic lymphocytic leukemia. Leukemia 15 (9): 1317-25, 2001.
4. Esteve J, Villamor N, Colomer D, et al.: Stem cell transplantation for chronic lymphocytic leukemia: different outcome after autologous and allogeneic transplantation and correlation with minimal residual disease status. Leukemia 15 (3): 445-51, 2001.
5. Toze CL, Shepherd JD, Connors JM, et al.: Allogeneic bone marrow transplantation for low-grade lymphoma and chronic lymphocytic leukemia. Bone Marrow Transplant 25 (6): 605-12, 2000.
6. Pavletic ZS, Arrowsmith ER, Bierman PJ, et al.: Outcome of allogeneic stem cell transplantation for B cell chronic lymphocytic leukemia. Bone Marrow Transplant 25 (7): 717-22, 2000.
7. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333 (16): 1052-7, 1995.
8. 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.
9. 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.
10. 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.
11. Dhner H, Stilgenbauer S, Benner A, et al.: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343 (26): 1910-6, 2000.
12. 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.
13. 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.
14. 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.
15. 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.
16. DiGiuseppe JA, Borowitz MJ: Clinical utility of flow cytometry in the chronic lymphoid leukemias. Semin Oncol 25 (1): 6-10, 1998.
17. 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.
18. 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.
19. 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.
20. Dearden CE, Matutes E, Catovsky D: Alemtuzumab in T-cell malignancies. Med Oncol 19 Suppl:S27-32, 2002.
21. Loughran TP: Clonal diseases of large granular lymphocytes. Blood 82 (1): 1-14, 1993.
22. Semenzato G, Zambello R, Starkebaum G, et al.: The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis. Blood 89 (1): 256-60, 1997.
23. 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.
24. Loughran TP, Kidd PG, Starkebaum G: Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate. Blood 84 (7): 2164-70, 1994.
25. Dhodapkar MV, Li CY, Lust JA, et al.: Clinical spectrum of clonal proliferations of T-large granular lymphocytes: a T-cell clonopathy of undetermined significance? Blood 84 (5): 1620-7, 1994.

Stage Information

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

CLL has no standard staging system. The Rai staging system and the Binet classification are presented below. 1 2 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

Rai Staging System

Stage 0

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

Stage I

Stage I chronic lymphocytic leukemia is characterized by absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.

Stage II

Stage II chronic lymphocytic leukemia is characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly, with or without lymphadenopathy.

Stage III

Stage III chronic lymphocytic leukemia is characterized by absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly.

Stage IV

Stage IV chronic lymphocytic leukemia is characterized by absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.

Binet classification

Clinical stage A*

Clinical stage A chronic lymphocytic leukemia is characterized by no anemia or thrombocytopenia and fewer than 3 areas of lymphoid involvement (Rai stages 0, I, and II).

Clinical stage B*

Clinical stage B chronic lymphocytic leukemia is characterized by no anemia or thrombocytopenia with 3 or more areas of lymphoid involvement (Rai stages I and II).

Clinical stage C

Clinical stage C chronic lymphocytic leukemia 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 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.

Prognostic factors under clinical evaluation for incorporation into clinical trials include cytogenetics 6 and immunoglobulin mutational status. 7 8 9 10 Patients with early-stage disease without somatic mutations of the immunoglobulin heavy chain variable region have a median survival of 8 years; those with somatic mutations have a median survival of 25 years. 7 8 9 10 More easily measured clinical surrogates are being sought. 11

References:

1. Rai KR, Sawitsky A, Cronkite EP, et al.: Clinical staging of chronic lymphocytic leukemia. Blood 46 (2): 219-34, 1975.
2. Binet JL, Auquier A, Dighiero G, et al.: A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48 (1): 198-206, 1981.
3. Cheson BD, Bennett JM, Grever M, et al.: National Cancer Institute-sponsored Working Group guidelines for chronic lymphocytic leukemia: revised guidelines for diagnosis and treatment. Blood 87 (12): 4990-7, 1996.
4. Mandelli F, De Rossi G, Mancini P, et al.: Prognosis in chronic lymphocytic leukemia: a retrospective multicentric study from the GIMEMA group. J Clin Oncol 5 (3): 398-406, 1987.
5. Chronic lymphocytic leukemia: recommendations for diagnosis, staging, and response criteria. International Workshop on Chronic Lymphocytic Leukemia. Ann Intern Med 110 (3): 236-8, 1989.
6. Dhner H, Stilgenbauer S, Benner A, et al.: Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med 343 (26): 1910-6, 2000.
7. 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.
8. 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.
9. 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.
10. 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.
11. 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.

Treatment Option Overview

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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 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. 5 There was, however, 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.

References:

1. Keating MJ: Chronic lymphocytic leukemia. Semin Oncol 26 (5 Suppl 14): 107-14, 1999.
2. Faguet GB: Chronic lymphocytic leukemia: an updated review. J Clin Oncol 12 (9): 1974-90, 1994.
3. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst 91 (10): 861-8, 1999.
4. Zwiebel JA, Cheson BD: Chronic lymphocytic leukemia: staging and prognostic factors. Semin Oncol 25 (1): 42-59, 1998.
5. 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.
6. 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.
7. 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.
8. Robertson LE, Pugh W, O'Brien S, et al.: Richter's syndrome: a report on 39 patients. J Clin Oncol 11 (10): 1985-9, 1993.
9. Mauro FR, Foa R, Cerretti R, et al.: Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood 95 (9): 2786-92, 2000.
10. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333 (16): 1052-7, 1995.
11. 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.
12. 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.

Stage 0 Chronic Lymphocytic Leukemia

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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.

References:

1. Casper James T.: Prognostic features of early chronic lymphocytic leukaemia. International Workshop on CLL. Lancet 2(8669): 968-969, 1989.
2. Dighiero G, Maloum K, Desablens B, et al.: Chlorambucil in indolent chronic lymphocytic leukemia. French Cooperative Group on Chronic Lymphocytic Leukemia. N Engl J Med 338 (21): 1506-14, 1998.
3. Chemotherapeutic options in chronic lymphocytic leukemia: a meta-analysis of the randomized trials. CLL Trialists' Collaborative Group. J Natl Cancer Inst 91 (10): 861-8, 1999.

Stage I Chronic Lymphocytic Leukemia

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Treatment for stage I chronic lymphocytic leukemia is 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.

1. Observation alone. 1 2
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 4 5 6 7

   Several randomized trials have compared the purine analogues with chlorambucil; with cyclophosphamide, doxorubicin, and prednisone; or with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in previously untreated patients. 8 9 10 11 Although all of these trials showed Although all of these trials showed higher or equivalent response rates for the purine analogue and most showed an improvement in higher or equivalent response rates for the purine analogue and most showed an improvement in progression-free survival, none showed an advantage in overall survival.progression-free survival, none showed an advantage in overall survival. 8 9 10 11 [Level of evidence: 1iiDii] All [Level of evidence: 1iiDii] All of the trials demonstrated higher toxic effects with the purine analogues, of the trials demonstrated higher toxic effects with the purine analogues, especially granulocytopenic infections, herpes infections, autoimmune especially granulocytopenic infections, herpes infections, autoimmune hemolytic anemia, and persistent thrombocytopenia. hemolytic anemia, and persistent thrombocytopenia. The increased risk of infection may persist for months or years after treatment with a purine analogue.The increased risk of infection may persist for months or years after treatment with a purine analogue. 12 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. 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. 12 Purine analogues cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines. Purine analogues cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines. 11

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.
   • CVP: cyclophosphamide + vincristine + prednisone. 13
   • CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone. 14
   • Fludarabine + cyclophosphamide. 15
   • Fludarabine + chlorambucil. 16
   • Fludarabine + rituximab. 17

   A meta-analysis of 10 trials comparing combination chemotherapy to chlorambucil alone showed no difference in overall survival at 5 years. 2 [Level of evidence: 1iiA]

6. Alemtuzumab (campath-1H) and rituximab (monoclonal antibodies) are under clinical evaluation. 18 19 20 21 Higher doses of rituximab than those used for other non-Hodgkin lymphomas are required. 20 21
7. Bone marrow and peripheral stem cell transplantations are under clinical evaluation. 22 23 24 25

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Robak T, Bloski 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.
9. 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.
10. Johnson S, Smith AG, Lffler 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.
11. Leporrier M, Chevret S, Cazin B, et al.: French Cooperative Group on Chronic Lymphocytic Leukemia: 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.
12. 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.
13. 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.
14. 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.
15. Flinn I, Eastern Cooperative Oncology Group: Phase III Randomized Study of Fludarabine With or Without Cyclophosphamide in Patients With Previously Untreated Chronic Lymphocytic Leukemia , E-2997, Clinical trial, Active.
16. 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.
17. Byrd JC, Peterson BL, Morrison VA, et al.: Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 101 (1): 6-14, 2003.
18. Lundin J, Kimby E, Bjrkholm M, et al.: Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 100 (3): 768-73, 2002.
19. Keating MJ, Flinn I, Jain V, et al.: Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 99 (10): 3554-61, 2002.
20. 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.
21. 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.
22. Khouri IF, Keating MJ, Vriesendorp HM, et al.: Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results. J Clin Oncol 12 (4): 748-58, 1994.
23. Michallet M, Archimbaud E, Bandini G, et al.: HLA-identical sibling bone marrow transplantation in younger patients with chronic lymphocytic leukemia. European Group for Blood and Marrow Transplantation and the International Bone Marrow Transplant Registry. Ann Intern Med 124 (3): 311-5, 1996.
24. Boussiotis VA, Freedman AS, Nadler LM: Bone marrow transplantation for low-grade lymphoma and chronic lymphocytic leukemia. Semin Hematol 36 (2): 209-16, 1999.
25. Doney KC, Chauncey T, Appelbaum FR, Seattle Bone Marrow Transplant Team: Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplant 29 (10): 817-23, 2002.

Stage II Chronic Lymphocytic Leukemia

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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 5 6 7 8

   Several randomized trials have compared the purine analogues with chlorambucil; with cyclophosphamide, doxorubicin, and prednisone; or with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in previously untreated patients. 9 10 11 12 Although all of these trials showed Although all of these trials showed higher or equivalent response rates for the purine analogue and most showed an improvement in higher or equivalent response rates for the purine analogue and most showed an improvement in progression-free survival, none showed an advantage in overall survival.progression-free survival, none showed an advantage in overall survival. 9 10 11 12 [Level of evidence: 1iiDii] All [Level of evidence: 1iiDii] All of the trials demonstrated higher toxic effects with the purine analogues, of the trials demonstrated higher toxic effects with the purine analogues, especially granulocytopenic infections, herpes infections, autoimmune especially granulocytopenic infections, herpes infections, autoimmune hemolytic anemia, and persistent thrombocytopenia. hemolytic anemia, and persistent thrombocytopenia. The increased risk of infection may persist for months or years after treatment with a purine analogue.The increased risk of infection may persist for months or years after treatment with a purine analogue. 13 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. 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. 13 Purine analogues cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines. Purine analogues cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines. 12

4. Combination chemotherapy.
   • CVP: cyclophosphamide + vincristine + prednisone. 14
   • CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone. 15
   • Fludarabine + cyclophosphamide. 16
   • Fludarabine + chlorambucil. 17
   • Fludarabine + rituximab. 18

   A meta-analysis of 10 trials comparing combination chemotherapy to chlorambucil alone showed no difference in overall survival at 5 years. 1 [Level of evidence: 1iiA]

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).
6. Splenic irradiation alone for palliation of hypersplenism. 19
7. Alemtuzumab (campath-1H) and rituximab (monoclonal antibodies) are under clinical evaluation. 20 21 22 23 Higher doses of rituximab than those used for other non-Hodgkin lymphomas are required. 22 23
8. Bone marrow and peripheral stem cell transplantations are under clinical evaluation. 24 25 26 27

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. 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.
9. Robak T, Bloski 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.
10. 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.
11. Johnson S, Smith AG, Lffler 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.
12. Leporrier M, Chevret S, Cazin B, et al.: French Cooperative Group on Chronic Lymphocytic Leukemia: 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.
13. 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.
14. 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.
15. 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.
16. Flinn I, Eastern Cooperative Oncology Group: Phase III Randomized Study of Fludarabine With or Without Cyclophosphamide in Patients With Previously Untreated Chronic Lymphocytic Leukemia , E-2997, Clinical trial, Active.
17. 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.
18. Byrd JC, Peterson BL, Morrison VA, et al.: Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 101 (1): 6-14, 2003.
19. Guiney MJ, Liew KH, Quong GG, et al.: A study of splenic irradiation in chronic lymphocytic leukemia. Int J Radiat Oncol Biol Phys 16 (1): 225-9, 1989.
20. Lundin J, Kimby E, Bjrkholm M, et al.: Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL). Blood 100 (3): 768-73, 2002.
21. Keating MJ, Flinn I, Jain V, et al.: Therapeutic role of alemtuzumab (Campath-1H) in patients who have failed fludarabine: results of a large international study. Blood 99 (10): 3554-61, 2002.
22. 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.
23. 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.
24. Khouri IF, Keating MJ, Vriesendorp HM, et al.: Autologous and allogeneic bone marrow transplantation for chronic lymphocytic leukemia: preliminary results. J Clin Oncol 12 (4): 748-58, 1994.
25. Michallet M, Archimbaud E, Bandini G, et al.: HLA-identical sibling bone marrow transplantation in younger patients with chronic lymphocytic leukemia. European Group for Blood and Marrow Transplantation and the International Bone Marrow Transplant Registry. Ann Intern Med 124 (3): 311-5, 1996.
26. Boussiotis VA, Freedman AS, Nadler LM: Bone marrow transplantation for low-grade lymphoma and chronic lymphocytic leukemia. Semin Hematol 36 (2): 209-16, 1999.
27. Doney KC, Chauncey T, Appelbaum FR, Seattle Bone Marrow Transplant Team: Allogeneic related donor hematopoietic stem cell transplantation for treatment of chronic lymphocytic leukemia. Bone Marrow Transplant 29 (10): 817-23, 2002.

Stage III Chronic Lymphocytic Leukemia

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

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 4 5 6 7

   Several randomized trials have compared the purine analogues with chlorambucil; with cyclophosphamide, doxorubicin, and prednisone; or with cyclophosphamide, doxorubicin, vincristine, and prednisone, in previously untreated patients. 8 9 10 11 Although all of these trials showed Although all of these trials showed higher or equivalent response rates for the purine analogue and most showed an improvement in higher or equivalent response rates for the purine analogue and most showed an improvement in progression-free survival, none showed an advantage in overall survival.progression-free survival, none showed an advantage in overall survival. 8 9 10 11 [Level of evidence: 1iiDii] All [Level of evidence: 1iiDii] All of the trials demonstrated higher toxic effects with the purine analogues, of the trials demonstrated higher toxic effects with the purine analogues, especially granulocytopenic infections, herpes infections, autoimmune 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 analogue.hemolytic anemia, and persistent thrombocytopenia. The increased risk of infection may persist for months or years after treatment with a purine analogue. 12 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. 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. 12 Purine analogues cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines. Purine analogues cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines. 11

4. Combination chemotherapy.
   • CVP: cyclophosphamide + vincristine + prednisone. 13
   • CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone. 14
   • Fludarabine + cyclophosphamide. 15
   • Fludarabine + chlorambucil. 16
   • Fludarabine + rituximab. 17

   A meta-analysis of 10 trials comparing combination chemotherapy to chlorambucil alone showed no difference in overall survival at 5 years. 1 [Level of evidence: 1iiA]

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. 18 19
6. Alemtuzumab (campath-1H) and rituximab (monoclonal antibodies) are under clinical evaluation. 20 21 22 23 Higher doses of rituximab than those used for other non-Hodgkin lymphomas are required. 22 23
7. Bone marrow and peripheral stem transplantations are under clinical evaluation. 24 25 26 27 28

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Robak T, Bloski 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.
9. 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.
10. Johnson S, Smith AG, Lffler 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.
11. Leporrier M, Chevret S, Cazin B, et al.: French Cooperative Group on Chronic Lymphocytic Leukemia: 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.
12. 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.
13. 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.
14. 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.
15. Flinn I, Eastern Cooperative Oncology Group: Phase III Randomized Study of Fludarabine With or Without Cyclophosphamide in Patients With Previously Untreated Chronic Lymphocytic Leukemia , E-2997, Clinical trial, Active.
16. 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.