Chronic Lymphocytic Leukemia Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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General Information About Chronic Lymphocytic Leukemia (CLL)

Incidence and Mortality

Estimated new cases and deaths from CLL in the United States in 2017:[1 ]

  • New cases: 20,110.
  • Deaths: 4,660.

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 ,4 ] As assays have become more sensitive for detecting monoclonal B-CLL-like cells in peripheral blood, researchers have detected a monoclonal B-cell lymphocytosis in 3% of adults older than 40 years and 6% in adults older than 60 years.[5 ] 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.[6 ,7 ]

In two selected series of more than 900 patients followed prospectively for a median of 5 to 7 years, overt CLL requiring chemotherapy occurred in 7% of patients.[5 ,8 ] In a database analysis and for up to 77 months before diagnosis, almost all patients with a diagnosis of CLL had prediagnostic B-cell clones that were identified in peripheral blood when available.[4 ,9 ]

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.[10 ,11 ,12 ,13 ,14 ] Antileukemic therapy is frequently unnecessary in uncomplicated early disease.[15 ] The median survival for all patients ranges from 8 to 12 years in older trials with data from the 1970s through the 1990s.[15 ,16 ] 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.[17 ]

As found in one report, CLL occurs primarily in middle-aged and elderly adults, with increasing frequency in successive decades of life.[18 ] 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.[19 ] Immunological aberrations, including Coombs-positive hemolytic anemia, immune thrombocytopenia, and depressed immunoglobulin levels may all complicate the management of CLL.[20 ] Prognostic factors that may help predict clinical outcome include cytogenetic subgroup, immunoglobulin mutational status, ZAP-70, and CD38.[2 ,21 ,22 ,23 ,24 ,25 ,26 ,27 ,28 ,29 ] (Refer to the Prognostic Factors section in the Stage Information for Chronic Lymphocytic Leukemia section of this summary for more information.) 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.[30 ] Patients with CLL are also at increased risk for other malignancies, even before therapy.[31 ] A population-based analysis of almost 2 million cancer patients in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database suggests that cancer-specific survival for patients with pre-existing CLL who subsequently develop colorectal and breast cancer is significantly lower (hazard ratio [HR], 1.46; P < .001 for colorectal cancer and HR, 1.41; P = .005 for breast cancer) than cancer-specific survival for patients with colorectal and breast cancer who do not have antecedent CLL, after adjusting for age, sex, race, and disease stage, and excluding CLL-related deaths.[32 ]

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.[33 ] 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).[15 ] 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 and Waldenström macroglobulinemia. (Refer to the PDQ summaries on Hairy Cell Leukemia and Adult Non-Hodgkin 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.[15 ,34 ]

Cladribine (2-chlorodeoxyadenosine) appears to be an active agent (60% complete remission rate) for patients with de novo B-cell prolymphocytic leukemia.[35 ][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).[36 ][Level of evidence: 3iiiDiv] These response rates have been confirmed by other investigators.[37 ] Patients with CLL who show prolymphocytoid transformation maintain the classic CLL phenotype and have a worse prognosis than PLL patients.

Large granular lymphocyte (LGL) leukemia is characterized by lymphocytosis with a natural killer cell immunophenotype (CD2, CD16, and CD56) or a T-cell immunophenotype (CD2, CD3, and CD8).[38 ,39 ,40 ] 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.[41 ] A characteristic genetic finding in almost 50% of the patients with T-cell LGL involves mutations in the signal transducer and activator of the transcription 3 gene (STAT 3).[42 ] Therapy includes low doses of oral cyclophosphamide or methotrexate, cyclosporine, and treatment of the bacterial infections acquired during severe neutropenia.[38 ,40 ,43 ,44 ]

Related Summaries

Other PDQ summaries containing information about CLL include the following:

  • Adult Non-Hodgkin Lymphoma Treatment
  • Hairy Cell Leukemia

References:

  1. American Cancer Society: Cancer Facts and Figures 2017. Atlanta, Ga: American Cancer Society, 2017. Available online. Last accessed October 13, 2017.
  2. Dighiero G, Hamblin TJ: Chronic lymphocytic leukaemia. Lancet 371 (9617): 1017-29, 2008.
  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.
  4. Shanafelt TD, Kay NE, Jenkins G, et al.: B-cell count and survival: differentiating chronic lymphocytic leukemia from monoclonal B-cell lymphocytosis based on clinical outcome. Blood 113 (18): 4188-96, 2009.
  5. 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.
  6. Dighiero G: Monoclonal B-cell lymphocytosis--a frequent premalignant condition. N Engl J Med 359 (6): 638-40, 2008.
  7. Fazi C, Scarfò L, Pecciarini L, et al.: General population low-count CLL-like MBL persists over time without clinical progression, although carrying the same cytogenetic abnormalities of CLL. Blood 118 (25): 6618-25, 2011.
  8. Shanafelt TD, Kay NE, Rabe KG, et al.: Brief report: natural history of individuals with clinically recognized monoclonal B-cell lymphocytosis compared with patients with Rai 0 chronic lymphocytic leukemia. J Clin Oncol 27 (24): 3959-63, 2009.
  9. Landgren O, Albitar M, Ma W, et al.: B-cell clones as early markers for chronic lymphocytic leukemia. N Engl J Med 360 (7): 659-67, 2009.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333 (16): 1052-7, 1995.
  16. 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.
  17. Montserrat E: CLL therapy: progress at last! Blood 105 (1): 2-3, 2005.
  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. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. Orchard JA, Ibbotson RE, Davis Z, et al.: ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363 (9403): 105-11, 2004.
  27. 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.
  28. 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.
  29. 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.
  30. Tsimberidou AM, Keating MJ: Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 103 (2): 216-28, 2005.
  31. Tsimberidou AM, Wen S, McLaughlin P, et al.: Other malignancies in chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol 27 (6): 904-10, 2009.
  32. Solomon BM, Rabe KG, Slager SL, et al.: Overall and cancer-specific survival of patients with breast, colon, kidney, and lung cancers with and without chronic lymphocytic leukemia: a SEER population-based study. J Clin Oncol 31 (7): 930-7, 2013.
  33. DiGiuseppe JA, Borowitz MJ: Clinical utility of flow cytometry in the chronic lymphoid leukemias. Semin Oncol 25 (1): 6-10, 1998.
  34. 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.
  35. 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.
  36. 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.
  37. Dearden CE, Matutes E, Catovsky D: Alemtuzumab in T-cell malignancies. Med Oncol 19 (Suppl): S27-32, 2002.
  38. Sokol L, Loughran TP Jr: Large granular lymphocyte leukemia. Oncologist 11 (3): 263-73, 2006.
  39. Semenzato G, Zambello R, Starkebaum G, et al.: The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis. Blood 89 (1): 256-60, 1997.
  40. Lamy T, Loughran TP Jr: How I treat LGL leukemia. Blood 117 (10): 2764-74, 2011.
  41. 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.
  42. Koskela HL, Eldfors S, Ellonen P, et al.: Somatic STAT3 mutations in large granular lymphocytic leukemia. N Engl J Med 366 (20): 1905-13, 2012.
  43. Loughran TP Jr, Kidd PG, Starkebaum G: Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate. Blood 84 (7): 2164-70, 1994.
  44. 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 for CLL

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).

*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 CLL 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 ,8 ] 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.[9 ] Prognostic indices are under evaluation and will require prospective validation.[8 ,10 ] The new prognostic markers include the following:

  • Immunoglobulin variable region heavy chain gene (IgVH) mutation.[11 ,12 ,13 ,14 ,15 ] 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.[16 ,17 ,18 ,19 ] 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 (E2997 [NCT00003764]) failed to show any difference in response rates, response duration, progression-free survival, or overall survival (OS).[20 ]
  • 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.[21 ,22 ,23 ,24 ] 13q- is favorable (with a 17-year median OS in a prospective study).[24 ] Trisomy 12 and 11q- have less favorable prognoses (with a 9- to 11-year median OS in a prospective study).[24 ] In particular, 17p- is associated with mutated TP53 and with poor response rates and short duration of response to the standard therapeutic options.[14 ] 17p- is associated with the most unfavorable prognosis (with a 7-year median OS in one prospective trial).[20 ,24 ,25 ] 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.[19 ] These findings emphasize the need for prospective studies of combinations of these prognostic markers.[9 ]
  • CD38 immunophenotype.[12 ,26 ] 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.[1 ,2 ] (Refer to the Rai staging system section and the Binet classification section of this summary for more information.)
  • Positron emission tomography-computed tomography (PET-CT) scan results. Of 432 patients retrospectively reviewed, 209 patients had a maximum standardized uptake value (SUVmax) of 5 or higher.[27 ] Eighty percent of these patients had histologically aggressive CLL or Richter syndrome, and both of these entities had equally worse prognoses. If the SUVmax was 10 or higher, the 5-year OS rate was only 30%.[27 ]
  • Lymphocyte doubling time (doubling of the white blood cell count in excess of 1 year implies a favorable prognosis).[28 ]
  • Beta-2-microglobulin (higher levels imply a worse prognosis).[29 ]

References:

  1. Rai KR, Sawitsky A, Cronkite EP, et al.: Clinical staging of chronic lymphocytic leukemia. Blood 46 (2): 219-34, 1975.
  2. Binet JL, Auquier A, Dighiero G, et al.: A new prognostic classification of chronic lymphocytic leukemia derived from a multivariate survival analysis. Cancer 48 (1): 198-206, 1981.
  3. 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.
  4. Moreno C, Hodgson K, Ferrer G, et al.: Autoimmune cytopenia in chronic lymphocytic leukemia: prevalence, clinical associations, and prognostic significance. Blood 116 (23): 4771-6, 2010.
  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. Dighiero G, Hamblin TJ: Chronic lymphocytic leukaemia. Lancet 371 (9617): 1017-29, 2008.
  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.
  8. Pflug N, Bahlo J, Shanafelt TD, et al.: Development of a comprehensive prognostic index for patients with chronic lymphocytic leukemia. Blood 124 (1): 49-62, 2014.
  9. 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.
  10. Shanafelt TD, Jenkins G, Call TG, et al.: Validation of a new prognostic index for patients with chronic lymphocytic leukemia. Cancer 115 (2): 363-72, 2009.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. Orchard JA, Ibbotson RE, Davis Z, et al.: ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363 (9403): 105-11, 2004.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  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.
  26. 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.
  27. Falchi L, Keating MJ, Marom EM, et al.: Correlation between FDG/PET, histology, characteristics, and survival in 332 patients with chronic lymphoid leukemia. Blood 123 (18): 2783-90, 2014.
  28. 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.
  29. 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 for CLL

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.[1 ] 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.[2 ]

A meta-analysis of randomized trials showed no survival benefit for immediate versus delayed therapy for patients with early-stage disease, nor for the use of combination regimens incorporating an anthracycline compared with a single-agent alkylator for advanced-stage disease.[3 ][Level of evidence: 1iiA] A variety of clinical factors, including the immunoglobulin variable region heavy chain (IgVH) gene mutation, chromosomal abnormalities by fluorescent in situ hybridization analysis or cytogenetics, beta-2-microglobulin, and lymphocyte doubling time may be helpful in predicting progression of disease.[1 ]

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.[4 ] There was, however, no effect on survival. Routine chronic administration of intravenous immunoglobulin is expensive, and the long-term benefit (>1 year) is unproven.[5 ,6 ]

Second malignancies and treatment-induced acute leukemias may also occur in a small percentage of patients.[7 ] 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.[8 ] (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.[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, before administering marrow-suppressive chemotherapy because the patients may be difficult to transfuse successfully with either red blood cells or platelets. Alternate therapies include high-dose immune globulin, rituximab, cyclosporine, azathioprine, splenectomy, and low-dose radiation therapy to the spleen.[10 ,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 ]

Computed tomographic (CT) scans have a very limited role in following patients after completion of treatment; the decision to treat for relapse was determined by CT scan or ultrasound in only 2 of 176 patients in three prospective trials for the German CLL Study Group.[14 ]

References:

  1. Gribben JG, O'Brien S: Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 29 (5): 544-50, 2011.
  2. Del Giudice I, Chiaretti S, Tavolaro S, et al.: Spontaneous regression of chronic lymphocytic leukemia: clinical and biologic features of 9 cases. Blood 114 (3): 638-46, 2009.
  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. 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.
  5. 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.
  6. 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.
  7. 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.
  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. Kaufman M, Limaye SA, Driscoll N, et al.: A combination of rituximab, cyclophosphamide and dexamethasone effectively treats immune cytopenias of chronic lymphocytic leukemia. Leuk Lymphoma 50 (6): 892-9, 2009.
  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.
  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.
  14. Eichhorst BF, Fischer K, Fink AM, et al.: Limited clinical relevance of imaging techniques in the follow-up of patients with advanced chronic lymphocytic leukemia: results of a meta-analysis. Blood 117 (6): 1817-21, 2011.

Stage 0 CLL

Because of the indolent nature of stage 0 chronic lymphocytic leukemia (CLL), treatment is not indicated.[1 ] The French Cooperative Group on CLL randomly assigned 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

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

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.
  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 CLL

Clearance of Minimal Residual Disease

The improvements in response rates from more intensive regimens have maximized the clearance of minimal residual disease (MRD). In one prospective trial of 493 patients, clearance of MRD was an independent predictor of overall survival (OS) by multivariate analysis.[1 ] The surrogate endpoint of clearance of residual disease, while prognostic,[1 ,2 ] did not show improved survival in a randomized prospective trial. The necessary study would include patients who fail to completely clear the marrow with induction therapy and randomly assign them to further alternative treatment versus the same treatment later at relapse, looking at OS as the primary endpoint.[3 ,4 ]

Choice of Treatment Options

In the absence of randomized trials comparing the new B-cell receptor inhibitors and bcl-2 inhibitors to the new monoclonal antibodies and to more conventional chemotherapeutic agents, the following general principles may provide a sequencing for available therapeutic options:

  • Despite many other options, asymptomatic or minimally affected patients with chronic lymphocytic leukemia (CLL) are often offered observation outside the context of a clinical trial. Therapy often begins when patients develop profound cytopenias, or when they become symptomatic enough that quality of life is substantially impacted, such as with enlarging bulky lymphadenopathy or debilitating symptoms.
  • Because no curative therapy has been found, a recommendation is that initial therapy maximize efficacy (with improvement of OS), while introducing the least overall toxicity, both short term and long term.
  • Standard chemotherapeutic agents, such as fludarabine, bendamustine, cyclophosphamide, and chlorambucil, induce mutational damage to the genome that can manifest as more aggressive and refractory phenotypes upon relapse and can induce second malignancies.
    • Avoiding alkylators and purine analogues also prevents prolonged cytopenias and the recurrent, long-lasting, and sometimes fatal infections seen after therapy with these agents.
    • Avoiding chemotherapeutic agents upfront, when possible, is a new paradigm of sequencing therapy for CLL.
  • Of the new biologic agents, only ibrutinib (the Bruton tyrosine kinase inhibitor) is U.S. Food and Drug Administration (FDA)-approved on its own for first-line use in all newly diagnosed patients with CLL, who require therapy.

Treatment options:

  1. Observation.[5 ]

    Outside of the context of a clinical trial, treatment for asymptomatic or minimally affected patients with CLL 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. One nomogram to predict time-to-first treatment relies on the number of lymph node sites, size of cervical lymph nodes, lactate-dehydrogenase level, the immunoglobulin variable region heavy chain (IgVH) mutational status, and the presence of 11q- or 17p- deletion established by fluorescence in situ hybridization (FISH) analysis.[6 ]

  2. Ibrutinib. Ibrutinib is a selective irreversible inhibitor of Bruton tyrosine kinase, a signaling molecule located upstream in the B-cell receptor-signaling cascade. Trials of previously untreated patients and of patients with relapsed or refractory CLL showed durable responses to the oral agent in phase I and II studies.[7 ,8 ][Level of evidence: 3iiiDiii]

    A phase Ib-II trial (NCT01105247) of 85 patients with relapsed or refractory CLL showed a 26-month progression-free survival (PFS) rate of 75% and included patients with 17p- or unmutated IgVH FISH testing.[9 ][Level of evidence: 3iiiDiii] Patients who discontinued ibrutinib early because of disease progression or drug intolerance had very poor outcomes, which were mainly attributable to very poor pre-existing prognostic factors.[10 ,11 ]

    A prospective, randomized trial of 391 patients with relapsed or refractory CLL or small lymphocytic lymphoma compared ibrutinib with ofatumumab. With a median follow-up of 9.4 months, the 12-month OS favored ibrutinib (90% vs. 81%) (hazard ratio [HR], 0.43; P = .005).[12 ][Level of evidence: 1iiA] Similar outcomes were seen for patients whose disease was resistant to purine analogues or who had a chromosome 17p deletion.

    A prospective, randomized trial of 269 previously untreated patients who were aged 65 years or older compared ibrutinib with chlorambucil. With a median follow-up of 18 months, the 2-year OS favored ibrutinib (98% vs. 85%) (HR, 0.16; 95% CI, 0.05-0.56; P = .001).[13 ][Level of evidence: 1iiA]

    A prospective, randomized trial of 578 previously treated patients compared ibrutinib plus bendamustine plus rituximab with bendamustine plus rituximab. With a median follow-up of 17 months, PFS favored the ibrutinib-combination arm at 18 months (79% vs. 24%) (HR, 0.20; 95% confidence interval [CI], 0.15-0.27; P = .0001).[14 ][Level of evidence: 1iDiii]

    These randomized trials establish the rationale for first-line use of ibrutinib in patients with CLL, especially for high-risk patients with 17p- disease. These trials also establish the use of ibrutinib for patients with relapsed disease.

  3. Rituximab. Rituximab is a murine anti-CD20 monoclonal antibody.[15 ,16 ,17 ,18 ,19 ] 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.
  4. Obinutuzumab. Obinutuzumab is a human anti-CD20 monoclonal antibody.

    In a randomized prospective trial (NCT01010061), 781 previously untreated patients with coexisting medical problems were randomly assigned to chlorambucil and obinutuzumab versus chlorambucil and rituximab versus chlorambucil alone.[20 ] The median PFS was best for the obinutuzumab arm (26.7 months) versus the rituximab arm (16.3 months) versus chlorambucil alone (11.1 months) (HR, 0.18; 95% CI, 0.13-0.24; P < .001) for obinutuzumab and chlorambucil versus chlorambucil alone; for rituximab and chlorambucil versus chlorambucil alone (HR, 0.44; 95% CI, 0.34-0.57; P < .001). The 2-year OS was significantly improved for the obinutuzumab arm (91%) versus chlorambucil alone (80%) (HR, 0.41; 95% CI, 0.23-0.74; P = .002). Patients who received obinutuzumab did not have improved survival compared with those who received rituximab alone.[20 ][Level of evidence: 1iiA]

  5. Ofatumumab. Ofatumumab is a human anti-CD20 monoclonal antibody.

    A prospective, randomized trial of 447 patients who were previously untreated compared ofatumumab plus chlorambucil with chlorambucil alone. With a median follow-up of 2 years, median PFS favored the ofatumumab arm at 22.4 months versus 13.1 months (HR, 0.57; 95% CI, 0.45-0.72; P = .0001) but with no difference in OS.[21 ][Level of evidence: 1iiDiii]

    A prospective trial of 474 previously treated patients who attained partial or complete remission to second- or third-line chemotherapy were randomly assigned to 2 years of maintenance therapy with ofatumumab versus observation. With a median follow-up of 19 months, median PFS favored the ofatumumab maintenance arm at 29.4 months versus 15.2 months (HR, 0.50; 95% CI, 0.38-0.66; P < .0001) but with no difference in OS.[22 ][Level of evidence: 1iiDiii]

  6. Venetoclax. Venetoclax is a highly selective inhibitor of BCL2.

    In a phase I dose escalation study, 56 previously treated patients received venetoclax, resulting in a 79% response rate, including patients with adverse prognosis resistant to fludarabine or with 17p deletion.[23 ][Level of evidence: 3iiiDiv] These data led to FDA approval for use in relapsed disease.

  7. Idelalisib. Idelalisib is an oral inhibitor of the delta isoform of the phosphatidylinositol 3-kinase, which is located in the B-cell receptor-signaling cascade.

    In a randomized, double-blind, prospective trial (NCT01539512), 220 patients treated mainly with fludarabine-based regimens and who had coexisting medical problems, such as renal dysfunction, received rituximab and idelalisib versus rituximab and placebo.[24 ] With a median follow-up of less than 1 year, the PFS rate at 24 weeks favored the rituximab and idelalisib arm (93%) versus the rituximab and placebo arm (46%) (HR, 0.15; 95% CI, 0.08-0.28; P < .001), and the OS rate at 1 year was significantly better for the rituximab and idelalisib arm (92%) versus the rituximab and placebo arm (80%) (HR, 0.28; 95% CI, 0.09-0.86; P = .02).[24 ][Level of evidence: 1iA] In 64 previously untreated patients, the combination of idelalisib plus rituximab resulted in a PFS rate of 83% at 3 years.[25 ][Level of evidence: 3iiiDiii]

  8. Oral alkylating agents with or without corticosteroids.[26 ]

    The French Cooperative Group on CLL randomly assigned 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment and found no survival advantage for chlorambucil.[27 ][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.[5 ][Level of evidence: 1iiA]

  9. Purine analogs.[28 ,29 ,30 ,31 ,32 ,33 ]

    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.[34 ,35 ,36 ,37 ,38 ] All of these trials showed higher or equivalent response rates for the purine analog, and most showed an improvement in PFS; one reached significance in OS favoring fludarabine.[34 ,36 ,37 ,38 ,39 ,40 ][Level of evidence: 1iiDiii]

    A comparison of chlorambucil versus fludarabine, after 15 years' median follow-up, showed patients with improved median OS with fludarabine at 63 versus 59 months (P = .04) and an improved percentage of patients alive at 8 years (31% vs. 19%, P = .04).[39 ][Level of evidence: 1iiA] All of the trials demonstrated higher toxic effects with the purine analogs, especially granulocytopenic infections, herpes infections, autoimmune hemolytic anemia, and persistent thrombocytopenia.[41 ] The increased risk of infection may persist for months or years after treatment with a purine analog.[40 ,42 ]

    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.[42 ] Purine analogs cause less hair loss or nausea than combination chemotherapy, including alkylators and anthracyclines.[37 ]

  10. Bendamustine. Bendamustine is a cytotoxic agent with bifunctional properties of an alkylator and a purine analog.[43 ] In previously treated and untreated patients, bendamustine with rituximab has shown response rates around 70% to 90%.[44 ,45 ][Level of evidence: 3iiiDiii]

    In a randomized comparison with chlorambucil in 319 previously treated patients, bendamustine showed a better response rate (68% vs. 31%, P < .0001) and PFS (21.6 months vs. 8 months) with a median follow-up of 35 months.[46 ][Level of evidence: 1iiDiii] The German CLL Study Group compared bendamustine plus rituximab versus fludarabine plus cyclophosphamide plus rituximab (FCR) as first-line therapy in patients with CLL who required therapy. With a 36-month median follow-up, the median PFS was better for FCR (53.7 months vs. 43.2 months) (HR, 1.58; 95% CI, 1.25-2.07; P = .001), but there was no difference in OS at 3 years (91% vs. 92%, not significant).[47 ][Level of evidence: 1iiDiii]

  11. Lenalidomide. Lenalidomide is an oral immunomodulatory agent with response rates of more than 50%, with or without rituximab, for patients with previously treated and untreated disease.[48 ,49 ,50 ,51 ,52 ,53 ][Level of evidence: 3iiiDiv] Prolonged, lower-dose approaches and attention to prevention of tumor lysis syndrome are suggested with this agent.[48 ,54 ] Combination therapy and long-term toxicities from using lenalidomide (such as increased myelodysplasia, as seen in myeloma patients) remain undefined for patients with CLL.
  12. Combination chemotherapy.

    Combination chemotherapy was used in a trial of 817 patients that compared FCR with fludarabine plus cyclophosphamide (FC) and at a median follow-up of 5.9 years showed improved OS at 6 years for the rituximab combination (69% vs. 62%) (HR, 0.68; 95% CI, 0.54-0.89; P = .001).[55 ][Level of evidence: 1iiA] FCR has never been compared with watchful waiting up front in asymptomatic or minimally affected patients. The improvements in response rates from more intensive regimens have maximized the clearance of MRD. However, the surrogate endpoint of MRD clearance has not been proven to be a valid surrogate for improved survival in a randomized, prospective trial; the necessary study would take patients who fail to completely clear the marrow with induction therapy and randomly assign them to further alternative treatment versus the same treatment later at relapse looking at OS as the primary endpoint.[3 ,4 ] A cumulative incidence of 6% to 8% for myelodysplasia is seen at 5 to 7 years in patients who received FC, with or without rituximab.[56 ,57 ]

    Other combination chemotherapy regimens include the following:

    • FCR.[55 ,58 ,59 ,60 ,61 ]
    • Fludarabine plus rituximab as seen in the CLB-9712 (NCT00003248) and CLB-9011 trials.[62 ]
    • FC versus FCR.[63 ,64 ]
    • Pentostatin plus cyclophosphamide plus rituximab as seen in the MAYO-MC0183 (NCT00201721) trial, for example.[65 ,66 ]
    • Ofatumumab plus FC.[67 ]
    • CVP: cyclophosphamide plus vincristine plus prednisone.[68 ]
    • CHOP: cyclophosphamide plus doxorubicin plus vincristine plus prednisone.[69 ]
    • FC versus fludarabine as seen in the E2997 (NCT00003764) trial and the LRF-CLL4 (NCT00004218) trial, for example.[70 ,71 ]
    • Fludarabine plus chlorambucil as seen in the CLB-9011 trial, for example.[72 ]

    A meta-analysis of ten trials compared combination chemotherapy (before the availability of rituximab) with chlorambucil alone and showed no difference in OS at 5 years.[5 ][Level of evidence: 1iiA]

  13. Involved-field radiation therapy. Relatively low doses of radiation therapy will affect 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).
  14. Alemtuzumab. Alemtuzumab, the monoclonal antibody directed at CD52, shows activity in the setting of chemotherapy-resistant disease or high-risk untreated patients with 17p deletion or p53 mutation.[73 ,74 ,75 ] As a single agent, the subcutaneous route of delivery for alemtuzumab is preferred to the intravenous route in patients because of the similar efficacy and decreased adverse effects, including less acute allergic reactions that were shown in some nonrandomized reports.[75 ,76 ,77 ,78 ,79 ]

    In a combination regimen, subcutaneous alemtuzumab plus fludarabine (with or without cyclophosphamide) or intravenous alemtuzumab plus alkylating agents have resulted in excess infectious toxicities and death, with no compensatory improvement in efficacy in three phase II trials and one randomized trial.[80 ,81 ,82 ][Level of evidence: 3iiiDiv]; [83 ][Level of evidence: 1iiDiii]

    In a randomized prospective study, 335 previously treated patients received intravenous alemtuzumab plus fludarabine versus fludarabine alone. With a median follow-up of 30 months, the combination of fludarabine plus intravenous alemtuzumab had better PFS, with a median of 23.7 months versus 16.5 months (HR, 0.61; 95% CI, 0.47-0.80; P = .0003); and better OS, with a median not reached, versus 52.9 months (HR, 0.65; 95% CI, 0.45-0.94; P = .021).[84 ][Level of evidence: 1iiA] Profound and long-lasting immunosuppression has been seen, which mandates monitoring for reactivation of cytomegalovirus and prophylaxis for pneumocystis and herpes virus infections.[85 ,86 ] Antibiotic prophylaxis includes trimethoprim and sulfamethoxazole, itraconazole, and acyclovir (or ganciclovir) for asymptomatic cytomegalovirus viremia.

  15. Bone marrow and peripheral stem cell transplantations. Bone marrow and peripheral stem cell transplantations are under clinical evaluation.[87 ,88 ,89 ,90 ,91 ,92 ,93 ]

    In a prospective randomized trial, 241 previously untreated patients younger than 66 years with advanced-stage disease received induction therapy with a CHOP-based regimen followed by fludarabine.[94 ] Complete responders (105 patients) were randomly assigned to undergo autologous stem cell transplantation (ASCT) or observation, while the other 136 patients were randomly assigned to receive dexamethasone, high-dose aracytin, and cisplatin reinduction followed by either ASCT or FC. Although the 3-year event-free survival (EFS) favored ASCT in complete responders, there was no difference in OS in any of the randomized comparisons.[94 ][Level of evidence: 1iiDi]

    Patients with adverse prognostic factors are very likely to die from CLL. These patients are candidates for clinical trials that employ high-dose chemotherapy and immunotherapy with myeloablative or nonmyeloablative allogeneic peripheral stem cell transplantation.[87 ,88 ,89 ,90 ,91 ,92 ,95 ,96 ,97 ,98 ,99 ,100 ,101 ,102 ] Although most patients who attain complete remission after ASCT eventually relapse,[93 ] a survival plateau for allogeneic stem cell support suggests an additional graft-versus-leukemia effect.[102 ] A series (NCT00281983) of 90 patients with relapsed or refractory CLL who underwent ASCT reported a 58% 6-year OS rate and a 38% 6-year EFS rate, which included those patients with the worst prognostic factors (such as TP53 gene mutation).[103 ][Level of evidence: 3iiiD] Patients who relapse after ASCT may respond well and durably to salvage regimens.[104 ]

  16. Autologous T cells directed at specific antigen targets. Autologous T cells were modified by a lentiviral vector to incorporate antigen receptor specificity for the B-cell antigen CD19 and then infused into a previously treated patient.[105 ] A dramatic response lasting 6 months has prompted larger trials of this concept.[105 ][Level of evidence: 3iiiDiv] Ongoing clinical trials are testing the concept of T cells directed at specific antigen targets with engineered chimeric-antigen receptors (termed CARs).[106 ]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

  1. Böttcher S, Ritgen M, Fischer K, et al.: Minimal residual disease quantification is an independent predictor of progression-free and overall survival in chronic lymphocytic leukemia: a multivariate analysis from the randomized GCLLSG CLL8 trial. J Clin Oncol 30 (9): 980-8, 2012.
  2. Strati P, Keating MJ, O'Brien SM, et al.: Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL. Blood 123 (24): 3727-32, 2014.
  3. 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.
  4. Montserrat E, Moreno C, Esteve J, et al.: How I treat refractory CLL. Blood 107 (4): 1276-83, 2006.
  5. 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.
  6. Molica S, Giannarelli D, Gentile M, et al.: External validation on a prospective basis of a nomogram for predicting the time to first treatment in patients with chronic lymphocytic leukemia. Cancer 119 (6): 1177-85, 2013.
  7. O'Brien S, Furman RR, Coutre SE, et al.: Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol 15 (1): 48-58, 2014.
  8. Byrd JC, Furman RR, Coutre SE, et al.: Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 125 (16): 2497-506, 2015.
  9. Byrd JC, Furman RR, Coutre SE, et al.: Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 369 (1): 32-42, 2013.
  10. Jain P, Keating M, Wierda W, et al.: Outcomes of patients with chronic lymphocytic leukemia after discontinuing ibrutinib. Blood 125 (13): 2062-7, 2015.
  11. Maddocks KJ, Ruppert AS, Lozanski G, et al.: Etiology of ibrutinib therapy discontinuation and outcomes in patients with chronic lymphocytic leukemia. JAMA Oncology 1 (1): 80-7, 2015.
  12. Byrd JC, Brown JR, O'Brien S, et al.: Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 371 (3): 213-23, 2014.
  13. Burger JA, Tedeschi A, Barr PM, et al.: Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med 373 (25): 2425-37, 2015.
  14. Chanan-Khan A, Cramer P, Demirkan F, et al.: Ibrutinib combined with bendamustine and rituximab compared with placebo, bendamustine, and rituximab for previously treated chronic lymphocytic leukaemia or small lymphocytic lymphoma (HELIOS): a randomised, double-blind, phase 3 study. Lancet Oncol 17 (2): 200-11, 2016.
  15. Mavromatis B, Cheson BD: Monoclonal antibody therapy of chronic lymphocytic leukemia. J Clin Oncol 21 (9): 1874-81, 2003.
  16. 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.
  17. 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.
  18. 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.
  19. Castro JE, Sandoval-Sus JD, Bole J, et al.: Rituximab in combination with high-dose methylprednisolone for the treatment of fludarabine refractory high-risk chronic lymphocytic leukemia. Leukemia 22 (11): 2048-53, 2008.
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  33. 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.
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  37. 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.
  38. Eichhorst BF, Busch R, Stilgenbauer S, et al.: First-line therapy with fludarabine compared with chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 114 (16): 3382-91, 2009.
  39. Rai KR, Peterson, Frederick R. Appelbaum BL, Appelbaum FR, et al.: Long-term survival analysis of the North American Intergroup Study C9011 comparing fludarabine (F) and chlorambucil (C) in previously untreated patients with chronic lymphocytic leukemia (CLL). [Abstract] Blood 114 (22): A-536, 2009.
  40. Steurer M, Pall G, Richards S, et al.: Purine antagonists for chronic lymphocytic leukaemia. Cochrane Database Syst Rev 3: CD004270, 2006.
  41. 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.
  42. 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.
  43. Leoni LM, Bailey B, Reifert J, et al.: Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res 14 (1): 309-17, 2008.
  44. Fischer K, Cramer P, Busch R, et al.: Bendamustine combined with rituximab in patients with relapsed and/or refractory chronic lymphocytic leukemia: a multicenter phase II trial of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 29 (26): 3559-66, 2011.
  45. Iannitto E, Morabito F, Mancuso S, et al.: Bendamustine with or without rituximab in the treatment of relapsed chronic lymphocytic leukaemia: an Italian retrospective study. Br J Haematol 153 (3): 351-7, 2011.
  46. Knauf WU, Lissichkov T, Aldaoud A, et al.: Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 27 (26): 4378-84, 2009.
  47. Eichhorst B, Fink AM, Busch R, et al.: Frontline chemoimmunotherapy with fludarabine (F), cyclophosphamide (C), and rituximab (R) (FCR) shows superior efficacy in comparison to bendamustine (B) and rituximab (BR) in previously untreated and physically fit patients (pts) with advanced chronic lymphocytic leukemia (CLL): final analysis of an international, randomized study of the German CLL Study Group (GCLLSG) (CLL10 study). [Abstract] Blood 124 (21): A-19, 2014.
  48. Chen CI, Bergsagel PL, Paul H, et al.: Single-agent lenalidomide in the treatment of previously untreated chronic lymphocytic leukemia. J Clin Oncol 29 (9): 1175-81, 2011.
  49. 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.
  50. Ferrajoli A, Lee BN, Schlette EJ, et al.: Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 111 (11): 5291-7, 2008.
  51. Strati P, Keating MJ, Wierda WG, et al.: Lenalidomide induces long-lasting responses in elderly patients with chronic lymphocytic leukemia. Blood 122 (5): 734-7, 2013.
  52. Wendtner CM, Hillmen P, Mahadevan D, et al.: Final results of a multicenter phase 1 study of lenalidomide in patients with relapsed or refractory chronic lymphocytic leukemia. Leuk Lymphoma 53 (3): 417-23, 2012.
  53. Badoux XC, Keating MJ, Wen S, et al.: Phase II study of lenalidomide and rituximab as salvage therapy for patients with relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol 31 (5): 584-91, 2013.
  54. Moutouh-de Parseval LA, Weiss L, DeLap RJ, et al.: Tumor lysis syndrome/tumor flare reaction in lenalidomide-treated chronic lymphocytic leukemia. J Clin Oncol 25 (31): 5047, 2007.
  55. Hallek M, Fischer K, Fingerle-Rowson G, et al.: Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial. Lancet 376 (9747): 1164-74, 2010.
  56. Smith MR, Neuberg D, Flinn IW, et al.: Incidence of therapy-related myeloid neoplasia after initial therapy for chronic lymphocytic leukemia with fludarabine-cyclophosphamide versus fludarabine: long-term follow-up of US Intergroup Study E2997. Blood 118 (13): 3525-7, 2011.
  57. Carney DA, Westerman DA, Tam CS, et al.: Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy. Leukemia 24 (12): 2056-62, 2010.
  58. Lamanna N, Jurcic JG, Noy A, et al.: Sequential therapy with fludarabine, high-dose cyclophosphamide, and rituximab in previously untreated patients with chronic lymphocytic leukemia produces high-quality responses: molecular remissions predict for durable complete responses. J Clin Oncol 27 (4): 491-7, 2009.
  59. Foon KA, Boyiadzis M, Land SR, et al.: Chemoimmunotherapy with low-dose fludarabine and cyclophosphamide and high dose rituximab in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 27 (4): 498-503, 2009.
  60. Thompson PA, Tam CS, O'Brien SM, et al.: Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 127 (3): 303-9, 2016.
  61. Badoux XC, Keating MJ, Wang X, et al.: Fludarabine, cyclophosphamide, and rituximab chemoimmunotherapy is highly effective treatment for relapsed patients with CLL. Blood 117 (11): 3016-24, 2011.
  62. Woyach JA, Ruppert AS, Heerema NA, et al.: Chemoimmunotherapy with fludarabine and rituximab produces extended overall survival and progression-free survival in chronic lymphocytic leukemia: long-term follow-up of CALGB study 9712. J Clin Oncol 29 (10): 1349-55, 2011.
  63. Fischer K, Bahlo J, Fink AM, et al.: Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 127 (2): 208-15, 2016.
  64. Robak T, Dmoszynska A, Solal-Céligny P, et al.: Rituximab plus fludarabine and cyclophosphamide prolongs progression-free survival compared with fludarabine and cyclophosphamide alone in previously treated chronic lymphocytic leukemia. J Clin Oncol 28 (10): 1756-65, 2010.
  65. 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.
  66. 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.
  67. Wierda WG, Kipps TJ, Dürig J, et al.: Chemoimmunotherapy with O-FC in previously untreated patients with chronic lymphocytic leukemia. Blood 117 (24): 6450-8, 2011.
  68. 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.
  69. 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.
  70. 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.
  71. 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.
  72. 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.
  73. 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.
  74. Parikh SA, Keating MJ, O'Brien S, et al.: Frontline chemoimmunotherapy with fludarabine, cyclophosphamide, alemtuzumab, and rituximab for high-risk chronic lymphocytic leukemia. Blood 118 (8): 2062-8, 2011.
  75. Pettitt AR, Jackson R, Carruthers S, et al.: Alemtuzumab in combination with methylprednisolone is a highly effective induction regimen for patients with chronic lymphocytic leukemia and deletion of TP53: final results of the national cancer research institute CLL206 trial. J Clin Oncol 30 (14): 1647-55, 2012.
  76. Stilgenbauer S, Zenz T, Winkler D, et al.: Subcutaneous alemtuzumab in fludarabine-refractory chronic lymphocytic leukemia: clinical results and prognostic marker analyses from the CLL2H study of the German Chronic Lymphocytic Leukemia Study Group. J Clin Oncol 27 (24): 3994-4001, 2009.
  77. Cortelezzi A, Pasquini MC, Gardellini A, et al.: Low-dose subcutaneous alemtuzumab in refractory chronic lymphocytic leukaemia (CLL): results of a prospective, single-arm multicentre study. Leukemia 23 (11): 2027-33, 2009.
  78. Osterborg A, Foà R, Bezares RF, et al.: Management guidelines for the use of alemtuzumab in chronic lymphocytic leukemia. Leukemia 23 (11): 1980-8, 2009.
  79. Gritti G, Reda G, Maura F, et al.: Low dose alemtuzumab in patients with fludarabine-refractory chronic lymphocytic leukemia. Leuk Lymphoma 53 (3): 424-9, 2012.
  80. Lin TS, Donohue KA, Byrd JC, et al.: Consolidation therapy with subcutaneous alemtuzumab after fludarabine and rituximab induction therapy for previously untreated chronic lymphocytic leukemia: final analysis of CALGB 10101. J Clin Oncol 28 (29): 4500-6, 2010.
  81. Badoux XC, Keating MJ, Wang X, et al.: Cyclophosphamide, fludarabine, alemtuzumab, and rituximab as salvage therapy for heavily pretreated patients with chronic lymphocytic leukemia. Blood 118 (8): 2085-93, 2011.
  82. Lepretre S, Aurran T, Mahé B, et al.: Excess mortality after treatment with fludarabine and cyclophosphamide in combination with alemtuzumab in previously untreated patients with chronic lymphocytic leukemia in a randomized phase 3 trial. Blood 119 (22): 5104-10, 2012.
  83. Geisler CH, van T' Veer MB, Jurlander J, et al.: Frontline low-dose alemtuzumab with fludarabine and cyclophosphamide prolongs progression-free survival in high-risk CLL. Blood 123 (21): 3255-62, 2014.
  84. Elter T, Gercheva-Kyuchukova L, Pylylpenko H, et al.: Fludarabine plus alemtuzumab versus fludarabine alone in patients with previously treated chronic lymphocytic leukaemia: a randomised phase 3 trial. Lancet Oncol 12 (13): 1204-13, 2011.
  85. Elter T, Vehreschild JJ, Gribben J, et al.: Management of infections in patients with chronic lymphocytic leukemia treated with alemtuzumab. Ann Hematol 88 (2): 121-32, 2009.
  86. Byrd JC, Peterson BL, Rai KR, et al.: Fludarabine followed by alemtuzumab consolidation for previously untreated chronic lymphocytic leukemia: final report of Cancer and Leukemia Group B study 19901. Leuk Lymphoma 50 (10): 1589-96, 2009.
  87. 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.
  88. 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.
  89. 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.
  90. 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.
  91. 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.
  92. 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.
  93. Dreger P, Döhner H, McClanahan F, et al.: Early autologous stem cell transplantation for chronic lymphocytic leukemia: long-term follow-up of the German CLL Study Group CLL3 trial. Blood 119 (21): 4851-9, 2012.
  94. Sutton L, Chevret S, Tournilhac O, et al.: Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood 117 (23): 6109-19, 2011.
  95. 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.
  96. Toze CL, Dalal CB, Nevill TJ, et al.: Allogeneic haematopoietic stem cell transplantation for chronic lymphocytic leukaemia: outcome in a 20-year cohort. Br J Haematol 158 (2): 174-85, 2012.
  97. 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.
  98. 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.
  99. 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.
  100. 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.
  101. 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.
  102. Dreger P, Döhner H, Ritgen M, et al.: Allogeneic stem cell transplantation provides durable disease control in poor-risk chronic lymphocytic leukemia: long-term clinical and MRD results of the German CLL Study Group CLL3X trial. Blood 116 (14): 2438-47, 2010.
  103. Dreger P, Schnaiter A, Zenz T, et al.: TP53, SF3B1, and NOTCH1 mutations and outcome of allotransplantation for chronic lymphocytic leukemia: six-year follow-up of the GCLLSG CLL3X trial. Blood 121 (16): 3284-8, 2013.
  104. Rozovski U, Benjamini O, Jain P, et al.: Outcomes of Patients With Chronic Lymphocytic Leukemia and Richter's Transformation After Transplantation Failure. J Clin Oncol 33 (14): 1557-63, 2015.
  105. Porter DL, Levine BL, Kalos M, et al.: Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 365 (8): 725-33, 2011.
  106. Maus MV, Grupp SA, Porter DL, et al.: Antibody-modified T cells: CARs take the front seat for hematologic malignancies. Blood 123 (17): 2625-35, 2014.

Recurrent or Refractory CLL

In a phase II trial of 300 patients, after previous therapy with rituximab and combination chemotherapy, duration of first remission of fewer than 3 years was a poor prognostic factor.[1 ] Repeat treatment with the same regimen was often successful when applied to patients with a first remission of more than 3 years.[1 ]

Clinical trials are appropriate and should be considered when possible.[2 ] In small studies, response rates of more than 40% have been reported for lenalidomide [3 ,4 ,5 ] and flavopiridol.[6 ,7 ][Level of evidence: 3iiiDiv] The addition of the BCL2 anti-sense oligonucleotide oblimersen to FC improved complete response rates in a randomized study of 241 patients with relapsed disease.[8 ][Level of evidence: 1iiDiv] Bone marrow and peripheral stem cell transplantations are under clinical evaluation.[9 ,10 ,11 ,12 ,13 ,14 ,15 ]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

  1. Tam CS, O'Brien S, Plunkett W, et al.: Long-term results of first salvage treatment in CLL patients treated initially with FCR (fludarabine, cyclophosphamide, rituximab). Blood 124 (20): 3059-64, 2014.
  2. 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.
  3. 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.
  4. Ferrajoli A, Lee BN, Schlette EJ, et al.: Lenalidomide induces complete and partial remissions in patients with relapsed and refractory chronic lymphocytic leukemia. Blood 111 (11): 5291-7, 2008.
  5. Andritsos LA, Johnson AJ, Lozanski G, et al.: Higher doses of lenalidomide are associated with unacceptable toxicity including life-threatening tumor flare in patients with chronic lymphocytic leukemia. J Clin Oncol 26 (15): 2519-25, 2008.
  6. 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.
  7. Lin TS, Ruppert AS, Johnson AJ, et al.: Phase II study of flavopiridol in relapsed chronic lymphocytic leukemia demonstrating high response rates in genetically high-risk disease. J Clin Oncol 27 (35): 6012-8, 2009.
  8. O'Brien S, Moore JO, Boyd TE, et al.: 5-year survival in patients with relapsed or refractory chronic lymphocytic leukemia in a randomized, phase III trial of fludarabine plus cyclophosphamide with or without oblimersen. J Clin Oncol 27 (31): 5208-12, 2009.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.

Key References for Chronic Lymphocytic Leukemia Treatment

These references have been identified by members of the PDQ Adult Treatment Editorial Board as significant in the field of chronic lymphocytic leukemia treatment. This list is provided to inform users of important studies that have helped shape the current understanding of and treatment options for chronic lymphocytic leukemia. Listed after each reference are the sections within this summary where the reference is cited.

  • Burger JA, Tedeschi A, Barr PM, et al.: Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med 373 (25): 2425-37, 2015.[PUBMED Abstract]

    Cited in:

    • Stage I, II, III, and IV CLL
  • Byrd JC, Furman RR, Coutre SE, et al.: Three-year follow-up of treatment-naïve and previously treated patients with CLL and SLL receiving single-agent ibrutinib. Blood 125 (16): 2497-506, 2015.[PUBMED Abstract]

    Cited in:

    • Stage I, II, III, and IV CLL
  • Fischer K, Bahlo J, Fink AM, et al.: Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood 127 (2): 208-15, 2016.[PUBMED Abstract]

    Cited in:

    • Stage I, II, III, and IV CLL
  • Furman RR, Sharman JP, Coutre SE, et al.: Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370 (11): 997-1007, 2014.[PUBMED Abstract]

    Cited in:

    • Stage I, II, III, and IV CLL
  • Roberts AW, Davids MS, Pagel JM, et al.: Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med 374 (4): 311-22, 2016.[PUBMED Abstract]

    Cited in:

    • Stage I, II, III, and IV CLL
  • Thompson PA, Tam CS, O'Brien SM, et al.: Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood 127 (3): 303-9, 2016.[PUBMED Abstract]

    Cited in:

    • Stage I, II, III, and IV CLL

Changes to This Summary (01 / 20 / 2017)

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 (CLL)

Updated statistics with estimated new cases and deaths for 2017 (cited American Cancer Society as reference 1).

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic lymphocytic leukemia. It 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.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

  • be discussed at a meeting,
  • be cited with text, or
  • replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Chronic Lymphocytic Leukemia Treatment are:

  • Eric J. Seifter, MD (Johns Hopkins University)
  • Mikkael A. Sekeres, MD, MS (Cleveland Clinic Taussig Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this 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.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Chronic Lymphocytic Leukemia Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/leukemia/hp/cll-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389470]

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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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Last Revised: 2017-01-20