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Table of Contents

Purpose of This PDQ Summary
General Information About Chronic Lymphocytic Leukemia
Statistics
Stage Information for Chronic Lymphocytic Leukemia
Rai Staging System
Binet Classification
Treatment Option Overview
Stage 0 Chronic Lymphocytic Leukemia
Current Clinical Trials
Stage I, II, III, and IV Chronic Lymphocytic Leukemia
Current Clinical Trials
Refractory Chronic Lymphocytic Leukemia
Current Clinical Trials
Get More Information From NCI
Changes to This Summary (03/05/2009)
More Information

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic lymphocytic leukemia. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board.

Information about the following is included in this summary:

  • Prognostic factors.
  • Cellular classification.
  • Staging.
  • Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version, written in less technical language, and in Spanish.

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General Information About Chronic Lymphocytic Leukemia



Statistics

Estimated new cases and deaths from chronic lymphocytic leukemia (CLL) in the United States in 2008:[1]

  • New cases: 15,110.
  • Deaths: 4,390.

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.[5] At the present time, the natural history or clinical significance of these findings is unknown. In a selected series of 185 patients followed prospectively for a median of 6.7 years, progressive lymphocytosis occurred in 28% of patients, progressive CLL occurred in 15% of patients, and chemotherapy was administered in 7% of patients.[4]

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.[6-10] Antileukemic therapy is frequently unnecessary in uncomplicated early disease.[11] The median survival for all patients ranges from 8 to 12 years in older trials with data from the 1970s through the 1990s.[11,12] 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.[13]

As found in one report, CLL occurs primarily in middle-aged and elderly adults, with increasing frequency in successive decades of life.[14] 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.[15] Immunological aberrations, including Coombs-positive hemolytic anemia, immune thrombocytopenia, and depressed immunoglobulin levels may all complicate the management of CLL.[16] Prognostic factors that may help predict clinical outcome include cytogenetic subgroup, immunoglobulin mutational status, ZAP-70, and CD38 (see Prognostic Factors).[2,17-25] Patients who develop an aggressive high-grade non-Hodgkin lymphoma, usually diffuse large B-cell lymphoma and termed a Richter transformation, have a poor prognosis.[26]

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.[27] 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).[11] 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 macroglobulinemia (refer to the PDQ summary on Adult Non-Hodgkin’s Lymphoma Treatment for more information). Waldenström macroglobulinemia has a natural history and therapeutic options similar to CLL, with the exception of hyperviscosity syndrome associated with macroglobulinemia as a result of elevated immunoglobulin M. Prolymphocytic leukemia (PLL) is a rare entity characterized by excessive prolymphocytes in the blood with a typical phenotype that is positive for CD19, CD20, and surface-membrane immunoglobulin and negative for CD5. These patients demonstrate splenomegaly and poor response to low-dose or high-dose chemotherapy.[11,28] Cladribine (2-chlorodeoxyadenosine) appears to be an active agent (60% complete remission rate) for patients with de novo B-cell prolymphocytic leukemia.[29][Level of evidence: 3iiiDiv] Alemtuzumab (campath-1H), an anti-CD52 humanized monoclonal antibody, has been used for 76 patients with T-cell prolymphocytic leukemia after failure of prior chemotherapy (usually pentostatin or cladribine) with a 51% response rate (95% confidence interval, 40%–63%) and median time to progression of 4.5 months (range, 0.1–45.4 months).[30][Level of evidence: 3iiiDiv] These response rates have been confirmed by other investigators.[31] 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).[32,33] These patients often have neutropenia and a history of rheumatoid arthritis. The natural history is indolent, often marked by anemia and splenomegaly. This condition appears to fit into the clinical spectrum of Felty syndrome.[34] Therapy includes steroids, low doses of oral cyclophosphamide or methotrexate, and treatment of the bacterial infections acquired during severe neutropenia.[32,35,36]

References

  1. American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. Last accessed October 1, 2008. 

  2. Dighiero G, Hamblin TJ: Chronic lymphocytic leukaemia. Lancet 371 (9617): 1017-29, 2008.  [PUBMED Abstract]

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

  4. Rawstron AC, Bennett FL, O'Connor SJ, et al.: Monoclonal B-cell lymphocytosis and chronic lymphocytic leukemia. N Engl J Med 359 (6): 575-83, 2008.  [PUBMED Abstract]

  5. Dighiero G: Monoclonal B-cell lymphocytosis--a frequent premalignant condition. N Engl J Med 359 (6): 638-40, 2008.  [PUBMED Abstract]

  6. 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.  [PUBMED Abstract]

  7. 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.  [PUBMED Abstract]

  8. 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.  [PUBMED Abstract]

  9. 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.  [PUBMED Abstract]

  10. 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.  [PUBMED Abstract]

  11. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333 (16): 1052-7, 1995.  [PUBMED Abstract]

  12. Wierda WG, O'Brien S, Wang X, et al.: Prognostic nomogram and index for overall survival in previously untreated patients with chronic lymphocytic leukemia. Blood 109 (11): 4679-85, 2007.  [PUBMED Abstract]

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

  14. 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.  [PUBMED Abstract]

  15. 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.  [PUBMED Abstract]

  16. 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.  [PUBMED Abstract]

  17. 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.  [PUBMED Abstract]

  18. 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.  [PUBMED Abstract]

  19. 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.  [PUBMED Abstract]

  20. 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.  [PUBMED Abstract]

  21. 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.  [PUBMED Abstract]

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

  23. 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.  [PUBMED Abstract]

  24. 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.  [PUBMED Abstract]

  25. 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.  [PUBMED Abstract]

  26. Tsimberidou AM, Keating MJ: Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 103 (2): 216-28, 2005.  [PUBMED Abstract]

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

  28. 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.  [PUBMED Abstract]

  29. 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.  [PUBMED Abstract]

  30. 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.  [PUBMED Abstract]

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

  32. Sokol L, Loughran TP Jr: Large granular lymphocyte leukemia. Oncologist 11 (3): 263-73, 2006.  [PUBMED Abstract]

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

  34. 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.  [PUBMED Abstract]

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

  36. 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.  [PUBMED Abstract]

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Stage Information for Chronic Lymphocytic Leukemia

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

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

Rai Staging System

Stage 0

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

Stage I

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

Stage II

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

Stage III

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

Stage IV

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

Binet Classification

Clinical stage A*

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

Clinical stage B*

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

Clinical stage C

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

* [Note: 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.[6,7] The use of these markers to stratify patients in clinical trials, to help assess the need for therapy, and to help select the type of therapy continues to evolve. Prospective trials to verify and establish the role of these prognostic markers are ongoing. No large multivariable analyses exist as yet to test the relative power of these individual prognostic variables.[8]

  • Immunoglobulin variable region heavy chain gene (IgVH) mutation.[9-13] The finding of significant numbers of mutations in this region is associated with a median survival in excess of 20 to 25 years. The absence of mutations is associated with a median survival of 8 to 10 years.


  • ZAP-70. ZAP-70 has been proposed as a surrogate for the mutational status.[14-17] ZAP-70 positivity for previously untreated and asymptomatic patients (>30%) is associated with a more unfavorable median survival (6–10 years), while a negative ZAP-70 is associated with a median survival of more than 15 years. A prospective evaluation of these markers in a randomized study of fludarabine-based chemotherapy (ECOG-2997) failed to show any difference in response rates, response duration, progression-free survival, or overall survival.[18]


  • Chromosomal abnormalities by fluorescent in situ hybridization (FISH). FISH chromosomal abnormalities were associated with prognosis in retrospective and prospective studies and clonal evolution has been seen over time.[19-22] 13q- is favorable (with a 17-year median overall survival [OS] in a prospective study).[22] Trisomy 12 and 11q- have less favorable prognoses (with a 9- to 11-year median OS in a prospective study).[22] In particular, 17p- is associated with mutated p53 and with poor response rates and short duration of response to the standard therapeutic options.[12] 17p- is associated with the most unfavorable prognosis (with a 7-year median OS in one prospective trial).[18,22] 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.[17] These findings emphasize the need for prospective studies of combinations of these prognostic markers.[8]


  • CD38 immunophenotype.[10,23] 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).[24]


  • Beta-2-microglobulin (higher levels imply a worse prognosis).[25]


References

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

  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.  [PUBMED Abstract]

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

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

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

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

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

  9. 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.  [PUBMED Abstract]

  10. 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.  [PUBMED Abstract]

  11. 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.  [PUBMED Abstract]

  12. 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.  [PUBMED Abstract]

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

  14. 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.  [PUBMED Abstract]

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

  16. 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.  [PUBMED Abstract]

  17. 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.  [PUBMED Abstract]

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

  19. 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.  [PUBMED Abstract]

  20. 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.  [PUBMED Abstract]

  21. 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.  [PUBMED Abstract]

  22. 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.  [PUBMED Abstract]

  23. 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.  [PUBMED Abstract]

  24. 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.  [PUBMED Abstract]

  25. 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.  [PUBMED Abstract]

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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.[8] Transformation of CLL to diffuse large cell lymphoma (Richter syndrome) carries a poor prognosis with a median survival of less than 1 year, though 20% of the patients may live more than 5 years after aggressive combination chemotherapy.[9] (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

Autoimmune hemolytic anemia and/or thrombocytopenia can occur in patients with any stage of CLL.[10] 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.[11] Tumor lysis syndrome is an uncommon complication (presenting in 1 out of 300 patients) of chemotherapy for patients with bulky disease.[12]

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

References

  1. Keating MJ: Chronic lymphocytic leukemia. Semin Oncol 26 (5 Suppl 14): 107-14, 1999.  [PUBMED Abstract]

  2. Faguet GB: Chronic lymphocytic leukemia: an updated review. J Clin Oncol 12 (9): 1974-90, 1994.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  4. Zwiebel JA, Cheson BD: Chronic lymphocytic leukemia: staging and prognostic factors. Semin Oncol 25 (1): 42-59, 1998.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

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

  9. 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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  11. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333 (16): 1052-7, 1995.  [PUBMED Abstract]

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

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

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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.

Current Clinical Trials

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

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

References

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

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

  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.  [PUBMED Abstract]

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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).[1] 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.[1] More intensive regimens carry the risk of more substantial toxic effects without a demonstrated survival benefit; their use is unproven.[2]

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

  1. Observation in asymptomatic or minimally affected patients.[3] 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.[4-7] 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.[8] 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.[9][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.[3][Level of evidence: 1iiA]


  4. Fludarabine, 2-chlorodeoxyadenosine, or pentostatin as seen in the CLB-9011 trial, for example.[10-15]

    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.[16-19] 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.[16-20][Level of evidence: 1iiDiii] All of the trials demonstrated higher toxic effects with the purine analogs, especially granulocytopenic infections, herpes infections, autoimmune hemolytic anemia, and persistent thrombocytopenia.[21] The increased risk of infection may persist for months or years after treatment with a purine analog.[20,22] 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.[22] Purine analogs cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines.[19]



  5. Combination chemotherapy.

    Among all of the large randomized prospective trials of untreated patients (such as GCLLSG-CLL4, ECOG-2997 and LRF-CLL4), for example, 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.[23-25] 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.[2]

    • Fludarabine plus rituximab as seen in the CALGB-9712 and CALGB-9011 trials.[26]
    • Fludarabine plus cyclophosphamide plus rituximab.[27,28]
    • Fludarabine plus cyclophosphamide versus fludarabine plus cyclophosphamide plus rituximab as seen in the NCT00090051 trial.
    • Pentostatin plus cyclophosphamide plus rituximab as seen in the MAYO-MC0183 trial, for example.[29,30]
    • CVP: cyclophosphamide plus vincristine plus prednisone.[31]
    • CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[32]
    • Fludarabine plus cyclophosphamide versus fludarabine as seen in the LRF-CLL4 trial, for example.[24,25]
    • Fludarabine plus chlorambucil as seen in the CALGB-9011 trial, for example.[33]

    A meta-analysis of ten trials comparing combination chemotherapy (before the availability of rituximab) to chlorambucil alone showed no difference in OS at 5 years.[3][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, has been used as first-line therapy and after relapse from prior chemotherapy.[34-37] A prospective randomized trial of 297 previously untreated patients compared alemtuzumab given three times a week with chlorambucil given monthly; after a median follow-up of 24 months, the progression-free survival favored alemtuzumab (hazard ratio [HR] = 0.58; 95% confidence interval [CI], 0.43–0.77; P = .0001).[34][Level of evidence: 1iiDii] However, this trial demonstrated no difference in the secondary endpoint of survival. Also, the choice of chlorambucil as the comparison arm is problematic because this drug is usually not a first-line choice today and because other standard drugs or combinations, often employing fludarabine, have a much better progression-free survival. This agent shows activity (>50% response rate in 91 previously treated patients) in the setting of chemotherapy-resistant disease.[38] 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.[39-44] 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.[45] Myeloablative and nonmyeloablative allogeneic peripheral stem cell transplantation are also under clinical evaluation.[39-44,46-51] 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.


Current Clinical Trials

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

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

References

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

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

  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.  [PUBMED Abstract]

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

  5. 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.  [PUBMED Abstract]

  6. 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.  [PUBMED Abstract]

  7. 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.  [PUBMED Abstract]

  8. 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.  [PUBMED Abstract]

  9. 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.  [PUBMED Abstract]

  10. 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.  [PUBMED Abstract]

  11. 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.  [PUBMED Abstract]

  12. 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.  [PUBMED Abstract]

  13. 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.  [PUBMED Abstract]

  14. 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.  [PUBMED Abstract]

  15. 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.  [PUBMED Abstract]

  16. 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.  [PUBMED Abstract]

  17. 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.  [PUBMED Abstract]

  18. 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.  [PUBMED Abstract]

  19. 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.  [PUBMED Abstract]

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

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

  22. 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.  [PUBMED Abstract]

  23. 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.  [PUBMED Abstract]

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

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

  26. 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.  [PUBMED Abstract]

  27. 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.  [PUBMED Abstract]

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

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

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

  31. 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.  [PUBMED Abstract]

  32. 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.  [PUBMED Abstract]

  33. 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.  [PUBMED Abstract]

  34. Hillmen P, Skotnicki AB, Robak T, et al.: Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia. J Clin Oncol 25 (35): 5616-23, 2007.  [PUBMED Abstract]

  35. 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.  [PUBMED Abstract]

  36. 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.  [PUBMED Abstract]

  37. Zent CS, Call TG, Shanafelt TD, et al.: Early treatment of high-risk chronic lymphocytic leukemia with alemtuzumab and rituximab. Cancer 113 (8): 2110-8, 2008.  [PUBMED Abstract]

  38. 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.  [PUBMED Abstract]

  39. 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.  [PUBMED Abstract]

  40. 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.  [PUBMED Abstract]

  41. 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.  [PUBMED Abstract]

  42. 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.  [PUBMED Abstract]

  43. 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.  [PUBMED Abstract]

  44. 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.  [PUBMED Abstract]

  45. 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.  [PUBMED Abstract]

  46. 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.  [PUBMED Abstract]

  47. 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.  [PUBMED Abstract]

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

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

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

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

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Refractory 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.)

Clinical trials are appropriate and should be considered when possible.[1] In small studies, response rates of more than 40% have been reported for lenalidomide [2] and flavopiridol.[3][Level of evidence: 3iiiDiv] Bone marrow and peripheral stem cell transplantations are under clinical evaluation.[4-10]

Current Clinical Trials

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

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

References

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

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

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

  4. 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.  [PUBMED Abstract]

  5. 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.  [PUBMED Abstract]

  6. 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.  [PUBMED Abstract]

  7. 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.  [PUBMED Abstract]

  8. 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.  [PUBMED Abstract]

  9. 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.  [PUBMED Abstract]

  10. 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.  [PUBMED Abstract]

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Changes to This Summary (03/05/2009)

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 About Chronic Lymphocytic Leukemia

Added Dighiero et al. as reference 2.

Stage Information for Chronic Lymphocytic Leukemia

Cited Dighiero et al. as reference 6.

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

Added Zent et al. as reference 37.

Added Sorror et al. as reference 49, Schetelig et al. as reference 50, and Malhotra et al. as reference 51.

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More Information

About PDQ

Additional PDQ Summaries

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).

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A Service of the National Cancer Institute
Department of Health and Human Services National Institutes of Health USA.gov