Chronic Lymphocytic Leukemia

Summary Type: Treatment
Summary Audience: Health professionals
Summary Language: English
Summary Description: Expert-reviewed information summary about the treatment of chronic lymphocytic leukemia.

Chronic Lymphocytic Leukemia

General Information

Note: Estimated new cases and deaths from chronic lymphocytic leukemia (CLL) in the United States in 2007:^1,

• New cases: 15,340.
• Deaths: 4,500.

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.)

CLL is a disorder of morphologically mature but immunologically less mature lymphocytes and is manifested by progressive accumulation of these cells in the blood, bone marrow, and lymphatic tissues.² In this disorder, lymphocyte counts in the blood are usually greater than or equal to 5,000/mm3 with a characteristic immunophenotype (CD5 and CD23 positive B cells).^3, 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) (i.e., MLUS in analogy to the monoclonal gammopathy of undetermined significance, MGUS) in 3% of adults older than 40 years and 6% in adults older than 60 years.⁴ 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. 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.^5,6,7,8,9 Antileukemic therapy is frequently unnecessary in uncomplicated early disease.¹⁰ The median survival for all patients ranges from 8 to 12 years in older trials with data from the 1970s and 1980s.¹⁰ 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.^11,

CLL occurs primarily in middle-aged and elderly adults, with increasing frequency in successive decades of life.¹² 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.¹³ Immunological aberrations, including Coombs-positive hemolytic anemia, immune thrombocytopenia, and depressed immunoglobulin levels may all complicate the management of CLL.¹⁴ Prognostic factors that may help predict clinical outcome include cytogenetic subgroup, immunoglobulin mutational status, ZAP-70, and CD38 (see Prognostic Factors).^{2,15,16,17,18,19,20,21,22,23} Patients who develop an aggressive high-grade non-Hodgkin's lymphoma, usually diffuse large B-cell lymphoma and termed a Richter's transformation, have a poor prognosis.^24,

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 CD5.²⁵ 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).¹⁰ 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 (refer to the PDQ summary on Hairy Cell Leukemia Treatment for more information), and Waldenström’s macroglobulinemia (refer to the PDQ summary on Adult Non-Hodgkin’s Lymphoma Treatment for more information). Waldenström’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.^10,26 Cladribine (2-chlorodeoxyadenosine) appears to be an active agent (60% complete remission rate) for patients with de novo B-cell prolymphocytic leukemia.^27,[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, 0.1-45.4 months).^28,[Level of evidence: 3iiiDiii] These response rates have been confirmed by other investigators.²⁹ 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).^30,31 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.³² Therapy includes steroids, low doses of oral cyclophosphamide or methotrexate, and treatment of the bacterial infections acquired during severe neutropenia.^30,33,34,

¹ American Cancer Society.: Cancer Facts and Figures 2007. Atlanta, Ga: American Cancer Society, 2007. Also available online. Last accessed March 5, 2007.

² Chiorazzi N, Rai KR, Ferrarini M: Chronic lymphocytic leukemia. N Engl J Med 352 (8): 804-15, 2005.

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 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.

⁵ 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.

⁶ 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.

⁷ 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.

⁸ 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.

⁹ 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.

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

¹¹ Montserrat E: CLL therapy: progress at last! Blood 105 (1): 2-3, 2005.

¹² 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.

¹³ 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.

¹⁴ 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.

¹⁵ 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.

¹⁶ 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.

¹⁷ 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.

¹⁸ 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.

¹⁹ 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.

²⁰ Orchard JA, Ibbotson RE, Davis Z, et al.: ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363 (9403): 105-11, 2004.

²¹ 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.

²² 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.

²³ 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.

²⁴ Tsimberidou AM, Keating MJ: Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 103 (2): 216-28, 2005.

²⁵ DiGiuseppe JA, Borowitz MJ: Clinical utility of flow cytometry in the chronic lymphoid leukemias. Semin Oncol 25 (1): 6-10, 1998.

²⁶ 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.

²⁷ 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.

²⁸ 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.

²⁹ Dearden CE, Matutes E, Catovsky D: Alemtuzumab in T-cell malignancies. Med Oncol 19 (Suppl): S27-32, 2002.

³⁰ Sokol L, Loughran TP Jr: Large granular lymphocyte leukemia. Oncologist 11 (3): 263-73, 2006.

³¹ Semenzato G, Zambello R, Starkebaum G, et al.: The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis. Blood 89 (1): 256-60, 1997.

³² 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.

³³ Loughran TP Jr, Kidd PG, Starkebaum G: Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate. Blood 84 (7): 2164-70, 1994.

³⁴ 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 comparisons for interpreting specific treatment results. Anemia and thrombocytopenia are the major adverse prognostic variables.

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

Rai staging system

Stage 0

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

Stage I

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

Stage II

Stage II CLL is characterized by absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy.

Stage III

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

Stage IV

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

Binet classification

Clinical stage A*

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

Clinical stage B*

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

Clinical stage C

Clinical stage C CLL is characterized by anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai stages III and IV).

*Lymphoid areas include cervical, axillary, inguinal, and spleen.

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

Prognostic factors

New prognostic markers are now available to the clinician and investigator.⁶ 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 just starting. No large multivariable analyses exist as yet to test the relative power of these individual prognostic variables.^7,

• Immunoglobulin variable region heavy chain gene (IgVH) mutation.^8,9,10,11 The finding of significant numbers of mutations in this region is associated with a median survival in excess of 20 to 25 years. The absence of mutations is associated with a median survival of 8 to 10 years. This test is very labor intensive and not available as yet for general clinical use. Prognostic marker surrogates are being evaluated.
• ZAP-70. This test, which is commercially available, but has not undergone national standardization, has been proposed as a surrogate for the mutational status.^12,13,14,15 ZAP-70 positivity (>30%) correlates with a more unfavorable median survival (6–10 years), while a negative ZAP-70 correlates with a median survival of more than15 years.
• Chromosomal abnormalities by fluorescent in situ hybridization.^16,17,18 13q- is favorable (with a 17-year median overall survival [OS] in a prospective study).¹⁹ Trisomy 12 and 11q- have less favorable prognoses (with a 9- to 11-year median OS in a prospective study).¹⁹ In particular, 17p- correlates with mutated p53 and with poor response rates and short duration of response to the standard therapeutic options.¹¹ 17p- is associated with the most unfavorable prognosis (with an 8-year median OS in a prospective trial).¹⁹ The combination of adverse cytogenetics such as 11q- or 17p- (suggesting a worse prognosis) with ZAP-70 negativity (suggesting a better prognosis) in the same patients resulted in a poor prognosis.¹⁵ These findings emphasize the need for prospective studies of combinations of these prognostic markers.^7,
• CD38 immunophenotype.^9,20 CD38 positivity (>30%) correlates with a worse prognosis, but there is a 30% false-positive rate and a 50% false-negative rate using IgVH mutational status as the gold standard for prognosis.

Other prognostic factors include:

• Stage (see Rai staging system and Binet classification above).^1,2,
• Lymphocyte doubling time (doubling of the white blood cell count in excess of 1 year implies a favorable prognosis).^21,
• Beta-2-microglobulin (higher levels imply a worse prognosis).^22,

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 Chiorazzi N, Rai KR, Ferrarini M: Chronic lymphocytic leukemia. N Engl J Med 352 (8): 804-15, 2005.

⁷ 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.

⁸ 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.

⁹ 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.

¹⁰ 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.

¹¹ 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.

¹² 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.

¹³ Orchard JA, Ibbotson RE, Davis Z, et al.: ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363 (9403): 105-11, 2004.

¹⁴ 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.

¹⁵ 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.

¹⁶ 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.

¹⁷ 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.

¹⁸ 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.

¹⁹ 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.

²⁰ 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.

²¹ 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.

²² Di Giovanni S, Valentini G, Carducci P, et al.: Beta-2-microglobulin is a reliable tumor marker in chronic lymphocytic leukemia. Acta Haematol 81 (4): 181-5, 1989.

Treatment Option Overview

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 analogs, combination chemotherapy, monoclonal antibodies, and transplant options.¹ Because this disease is generally not curable, occurs in an elderly population, and often progresses slowly, it is most often treated in a conservative fashion.² 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.^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 (>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, though 20% of the patients may live more than 5 years after aggressive combination chemotherapy.⁸ (Refer to the PDQ summary on Adult Non-Hodgkin’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 therapy to the spleen.¹⁰ Tumor lysis syndrome is an uncommon complication (presenting in 1 out of 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.

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

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

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

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

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

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 options:

Among all of the large randomized prospective trials of untreated patients, almost all have demonstrated statistically significant improvements in response rates, event-free survival, and progression-free survival, but no trial has shown patients with statistically significant improvement in overall survival (OS). Improvements in response rates that maximize the clearance of minimal residual disease have not translated into demonstrable survival benefits on the basis of any randomized study. More intensive regimens carry the risk of more substantial toxic effects without a demonstrated survival benefit; their use is unproven.^1,

Note: These options are ordered by level of toxic effects, starting with the least toxic options.

1. Observation in asymptomatic or minimally affected patients.² Outside of the context of a clinical trial, treatment for asymptomatic or minimally affected patients with chronic lymphocytic leukemia is observation. No data exist as yet to suggest any harm with a delay in therapy until the patient becomes symptomatic or develops serious cytopenias despite growth factor support. Because the rate of progression may vary from patient to patient, with long periods of stability and sometimes spontaneous regressions, frequent and careful observation is required to monitor the clinical course.
2. Rituximab, an anti-CD20 monoclonal antibody.^3,4,5,6 When used alone, higher doses of rituximab or increased frequency or duration of therapy is required for comparable responses to those seen for other indolent lymphomas.
3. Oral alkylating agents with or without corticosteroids.⁷ The French Cooperative Group on Chronic Lymphocytic Leukemia randomized 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment and found no survival advantage for chlorambucil.^8,[Level of evidence: 1iiA] A meta-analysis of six trials of immediate versus deferred therapy with chlorambucil (including the aforementioned trial by the French Cooperative Group) showed no difference in OS at 10 years.^2,[Level of evidence: 1iiA]
4. Fludarabine, 2-chlorodeoxyadenosine, or pentostatin.^{9,10,11,12, 13,14,}

   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.^15,16,17,18 All of these trials showed higher or equivalent response rates for the purine analog and most showed an improvement in progression-free survival, though none showed an advantage in OS.^15,16,17,18,[Level of evidence: 1iiDii] 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.¹⁹ 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.¹⁹ Purine analogs cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines.¹⁸

5. Combination chemotherapy.

   Among all of the large randomized prospective trials of untreated patients, almost all have demonstrated statistically significant improvements in response rates, event-free survival, and progression-free survival, but no trial has shown patients with statistically significant improvement in OS. Improvements in response rates that maximize the clearance of minimal residual disease have not translated into demonstrable survival benefits on the basis of any randomized study. More intensive regimens carry the risk of more substantial toxic effects without a demonstrated survival benefit; their use is unproven.^1,

   • Fludarabine + rituximab.^20,
   • Fludarabine + cyclophosphamide + rituximab.^21,22,
   • Fludarabine + cyclophosphamide versus fludarabine + cyclophosphamide + rituximab.[Study 102-14]
   • CVP: cyclophosphamide + vincristine + prednisone.^23,
   • CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone.^24,
   • Fludarabine + cyclophosphamide.^25,26,27,
   • Fludarabine + chlorambucil.^28,

   A meta-analysis of 10 trials comparing combination chemotherapy (before the availability of rituximab) to chlorambucil alone showed no difference in OS at 5 years.^2,[Level of evidence: 1iiA]

6. Involved-field radiation therapy. Relatively low doses of radiation therapy will effect an excellent response for months or years. Sometimes radiation therapy to one nodal area or the spleen will result in abscopal effect (i.e., the shrinkage of lymph node tumors in untreated sites).
7. Alemtuzumab (campath-1H), the monoclonal antibody directed at CD52, is under clinical evaluation for first-line use alone or in combination therapy.^29,30,31 This agent shows activity (>50% response rate in 91 previously treated patients) in the setting of chemotherapy-resistant disease.³² The subcutaneous route of delivery is preferred to the intravenous route to avoid acute allergic reactions. Profound and long-lasting immunosuppression has been seen, which mandates monitoring for reactivation of cytomegalovirus and prophylaxis for pneumocystis and herpes virus infections.
8. Bone marrow and peripheral stem cell transplantations are under clinical evaluation.^{33,34,35,36,37,38,} Patients younger than 60 years with adverse prognostic factors are very likely to die from chronic lymphocytic leukemia. These types of patients are candidates for clinical trials that employ high-dose chemotherapy and immunotherapy with autologous peripheral stem cell support.³⁹ Myeloablative and nonmyeloablative allogeneic peripheral stem cell transplantation are also under clinical evaluation.^{33,34,35,36,37,38,40,41} Although most patients who attain complete remission after autologous stem cell transplantation eventually relapse, a survival plateau for allogeneic stem cell support suggests an additional graft-versus-leukemia effect.

¹ Montserrat E, Moreno C, Esteve J, et al.: How I treat refractory CLL. Blood 107 (4): 1276-83, 2006.

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

⁴ 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.

⁵ 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.

⁶ 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.

⁷ 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.

⁸ 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.

⁹ 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.

¹⁰ 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.

¹¹ 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.

¹² 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.

¹³ 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.

¹⁴ 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.

¹⁵ 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.

¹⁶ 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.

¹⁷ 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.

¹⁸ 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.

¹⁹ 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.

²⁰ Byrd JC, Rai K, Peterson BL, et al.: Addition of rituximab to fludarabine may prolong progression-free survival and overall survival in patients with previously untreated chronic lymphocytic leukemia: an updated retrospective comparative analysis of CALGB 9712 and CALGB 9011. Blood 105 (1): 49-53, 2005.

²¹ Wierda W, O'Brien S, Wen S, et al.: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab for relapsed and refractory chronic lymphocytic leukemia. J Clin Oncol 23 (18): 4070-8, 2005.

²² Keating MJ, O'Brien S, Albitar M, et al.: Early results of a chemoimmunotherapy regimen of fludarabine, cyclophosphamide, and rituximab as initial therapy for chronic lymphocytic leukemia. J Clin Oncol 23 (18): 4079-88, 2005.

²³ 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.

²⁴ 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.

²⁵ O'Brien SM, Kantarjian HM, Cortes J, et al.: Results of the fludarabine and cyclophosphamide combination regimen in chronic lymphocytic leukemia. J Clin Oncol 19 (5): 1414-20, 2001.

²⁶ Schiavone EM, De Simone M, Palmieri S, et al.: Fludarabine plus cyclophosphamide for the treatment of advanced chronic lymphocytic leukemia. Eur J Haematol 71 (1): 23-8, 2003.

²⁷ Eichhorst BF, Busch R, Hopfinger G, et al.: Fludarabine plus cyclophosphamide versus fludarabine alone in first-line therapy of younger patients with chronic lymphocytic leukemia. Blood 107 (3): 885-91, 2006.

²⁸ 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.

²⁹ Lundin J, Kimby E, Björkholm 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.

³⁰ 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.

³¹ Lozanski G, Heerema NA, Flinn IW, et al.: Alemtuzumab is an effective therapy for chronic lymphocytic leukemia with p53 mutations and deletions. Blood 103 (9): 3278-81, 2004.

³² 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.

³³ 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.

³⁴ 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.

³⁵ 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.

³⁶ 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.

³⁷ 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.

³⁸ 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.

³⁹ 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.

⁴⁰ 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.

⁴¹ Toze CL, Galal A, Barnett MJ, et al.: Myeloablative allografting for chronic lymphocytic leukemia: evidence for a potent graft-versus-leukemia effect associated with graft-versus-host disease. Bone Marrow Transplant 36 (9): 825-30, 2005.

Refractory Chronic Lymphocytic Leukemia

Clinical trials are appropriate and should be considered when possible.¹ Information about ongoing clinical trials for patients with refractory chronic lymphocytic leukemia is available from the NCI Web site. Bone marrow and peripheral stem cell transplantations are under clinical evaluation.^{2,3,4,5,6,7,8,}

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

² 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.

³ 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.

⁴ 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.

⁵ 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.

⁶ 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.

⁷ 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.

⁸ 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.

Changes to This Summary (02/07/2007)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

General Information

Updated statistics with estimated new cases and deaths for 2007 (cited American Cancer Society).

Added Ritgen et al. as reference 5, Moreno et al. as reference 6, Khouri et al. as reference 7, Doney et al. as reference 8, and Pavletic et al. as reference 9.

Added text about the variation in survival among patients and the need for treatment to be based on the clinical behavior of the disease (cited Montserrat as reference 11).

Added Kröber et al. as reference 22 and Byrd et al. as reference 23.

Added Sokol et al. as reference 30.

Stage Information

Added Binet et al. as reference 7.

Added Byrd et al. as reference 11.

Added Kröber et al. as reference 15.

Added text about a 17-year median overall survival in a prospective study and that trisomy 12 and 11q- have less favorable prognoses (cited Shanafelt et al. as reference 19).

Added text about 17p- having the worst prognosis and that the combination of adverse cytogenetics with ZAP-70 negativity in the same patients resulted in a poor prognosis (cited Kröber et al. as reference 15). Also added text about the need for prospective studies of combinations of prognostic markers (cited Binet et al. as reference 7).

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

Added text about trials that have demonstrated statistically significant improvements in response rates, event-free survival, and progression-free survival but not in overall survival. Also added that improvements in response rates have not translated into demonstrable survival benefits in any randomized study and that more intensive regimens carry the risk of more toxic effects without a demonstrated survival benefit (cited Montserrat as reference 1).

Added Ritgen et al. as reference 35, Khouri et al. as reference 37, and Pavletic et al. as reference 38.

Refractory Chronic Lymphocytic Leukemia

Added Dreger et al. as reference 2, Ritgen et al. as reference 4, Moreno et al. as reference 5, Khouri et al. as reference 6, Doney et al. as reference 7, and Pavletic et al. as reference 8.

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