skip to Text-Only Versionskip banner navigation
National Cancer Institute National Cancer Institute
U.S. National Institutes of Health National Cancer Institute
Search
NCI Home Cancer Topics Clinical Trials Cancer Statistics Research & Funding News About NCI
Chronic Lymphocytic Leukemia (PDQ®): Treatment
Patient VersionHealth Professional VersionEn españolLast Modified: 07/17/2007
skip to content



General Information






Stage Information






Treatment Option Overview






Stage 0 Chronic Lymphocytic Leukemia







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






Refractory Chronic Lymphocytic Leukemia






Changes to This Summary (07/17/2007)






More Information



Page Options
Print This Page  Print This Page
Print This Document  Print Entire Document
View Entire Document  View Entire Document
E-Mail This Document  E-Mail This Document
Quick Links
Director's Corner

Dictionary of Cancer Terms

NCI Drug Dictionary

Funding Opportunities

NCI Publications

Advisory Boards and Groups

NIH Calendar of Events

Español
Questions about cancer?

1-800-4-CANCER

NCI Highlights
Report Finds Cancer Death Rate Decline Doubling

October Is National Breast Cancer Awareness Month

The Nation's Investment in Cancer Research FY 2008

Statement on Fiscal Year 2008 Budget Request

President's Cancer Panel Annual Report: 2006-2007

Cancer Trends Progress Report: 2005 Update

NCAB Working Group Report on Biomedical Technology

Past Highlights
You CAN Quit Smoking Now!
HPV Vaccines for Cervical Cancer
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.[3-6] 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.[9-14]

    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.[15-18] 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.[15-19][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.[19,20] 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.[20] 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.[21,22] 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.[23]
    • Fludarabine + cyclophosphamide + rituximab.[24,25]
    • Fludarabine + cyclophosphamide versus fludarabine + cyclophosphamide + rituximab.[Study 102-14]
    • Pentostatin + cyclophosphamide + rituximab.[26]
    • CVP: cyclophosphamide + vincristine + prednisone.[27]
    • CHOP: cyclophosphamide + doxorubicin + vincristine + prednisone.[28]
    • Fludarabine + cyclophosphamide versus fludarabine.[22]
    • Fludarabine + chlorambucil.[29]

    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.[30-32] This agent shows activity (>50% response rate in 91 previously treated patients) in the setting of chemotherapy-resistant disease.[33] 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.[34-39] 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.[40] Myeloablative and nonmyeloablative allogeneic peripheral stem cell transplantation are also under clinical evaluation.[34-39,41,42] 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.


References

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

  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.  [PUBMED Abstract]

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

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

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

  20. 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]

  21. 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]

  22. 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]

  23. 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]

  24. 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]

  25. 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.  [PUBMED Abstract]

  26. 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]

  27. 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]

  28. 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]

  29. 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]

  30. 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.  [PUBMED Abstract]

  31. 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]

  32. 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]

  33. 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]

  34. 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]

  35. 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]

  36. 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]

  37. 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]

  38. 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]

  39. 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]

  40. 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]

  41. 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]

  42. 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]

Back to TopBack to Top

< Previous Section  |  Next Section >

skip footer navigation

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