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

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

This information is produced and provided by the National Cancer Institute (NCI). The information in this topic may have changed since it was written. For the most current information, contact the National Cancer Institute via the Internet web site at http://cancer.gov or call 1-800-4-CANCER.

General Information About Chronic Lymphocytic Leukemia (CLL)

Incidence and Mortality

Estimated new cases and deaths from CLL in the United States in 2022:[1]

  • New cases: 20,160.
  • Deaths: 4,410.

Anatomy

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]

Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell. A myeloid stem cell becomes a red blood cell, a platelet, or a myeloblast, which then becomes a granulocyte (the types of granulocytes are eosinophils, basophils, and neutrophils). A lymphoid stem cell becomes a lymphoblast and then becomes a B-lymphocyte, T-lymphocyte, or natural killer cell.
Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

Clinical Presentation

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.[3] Immunological aberrations, including Coombs-positive hemolytic anemia, immune thrombocytopenia, and depressed immunoglobulin levels may all complicate the management of CLL.[4]

Diagnostic Evaluation and Differential Diagnosis

Tests and procedures used to diagnose CLL include the following:[5]

  • History and physical examination (including bidimensional diameters of the largest palpable lymph nodes in the cervical, axillary, and inguinal nodal sites and dimensions of the liver and spleen below their respective costal margins as assessed by palpation).
  • Complete blood count with differential and chemistry panel (including creatinine, bilirubin, transaminases, and alkaline phosphatase). Other blood tests may include lactate dehydrogenase and beta-2-microglobulin. With suspicion of autoimmune hemolytic anemia, testing for reticulocyte count, indirect bilirubin, serum haptoglobin, antiglobulin (direct Coombs), and cold agglutinin may be helpful.
  • Flow cytometry (for immunophenotyping).
  • Fluorescence in situ hybridization (FISH) (for del(11q), del(13q), del(17p), trisomy 12, and t(11;14)).
  • TP53 mutation analysis.
  • IgVH mutation analysis.
  • Serum immunoglobulin levels.
  • Hepatitis B and C and HIV tests.
  • Computed tomography (CT) is usually not required in the absence of peripheral adenopathy; extensive adenopathy on examination should prompt investigation of retroperitoneal adenopathy.
  • Bone marrow aspiration and biopsy is usually not required.

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).[6,7] 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 in 6% of adults older than 60 years.[8] 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.[9,10]

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.[11] This coexpression occurs in only 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).[12] 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. In a database analysis, for up to 77 months before diagnosis, almost all patients with a CLL diagnosis had prediagnostic B-cell clones that were identified in peripheral blood (when available).[7,13]

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 and B-cell receptor inhibitors.[14]

The differential diagnosis must exclude the following:

  • Monoclonal B-cell lymphocytosis (MBL) is defined as a clonal B-cell population circulating in peripheral blood with fewer than 5 x 109 /L B cells and no signs of lymphadenopathy or splenomegaly.[15] Most cases have the immunophenotype of CLL. Low-count MBL (≤0.5 x 109 /L B cells) rarely progresses to overt CLL, but higher levels can progress to symptomatic CLL at a rate of less than 2% per year.[15] In two selected series of more than 900 patients followed up prospectively for a median of 5 to 7 years, overt CLL requiring chemotherapy occurred in 7% of patients.[8,16]
  • Hairy cell leukemia. (Refer to the PDQ summary on Hairy Cell Leukemia Treatment for more information.)
  • Waldenström macroglobulinemia. 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. (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)
  • Prolymphocytic leukemia (PLL) is a rare form of lymphocytic leukemia 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.[17] These patients demonstrate splenomegaly and poor response to low-dose or high-dose chemotherapy.[12,18]

    Cladribine (2-chlorodeoxyadenosine) appears to be an active agent (60% complete remission rate) for patients with de novo B-cell PLL.[19][Level of evidence: 3iiiDiv] Anecdotal responses have been seen with venetoclax.[20][Level of evidence: 3iiiDiv] Alemtuzumab, an anti-CD52 humanized monoclonal antibody, has been used for 76 patients with T-cell PLL after failure of previous 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).[21][Level of evidence: 3iiiDiv] These response rates have been confirmed by other investigators.[22] 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).[23,24,25] 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.[26] A characteristic genetic finding in almost 50% of the patients with T-cell LGL involves mutations in the STAT3 gene .[27] Therapy includes low doses of oral cyclophosphamide or methotrexate, cyclosporine, and treatment of the bacterial infections acquired during severe neutropenia.[23,25,28,29]

Prognostic Factors

Prognostic markers help stratify patients in clinical trials, assess the need for therapy, and select the type of therapy.[2,30,31] Prognostic factors that may help predict clinical outcome include cytogenetic subgroup, immunoglobulin mutational status, and CD38 immunophenotype.[2,32,33,34,35,36,37,38,39,40]

Prognostic markers include the following:

  • IgVH mutation.[33,34,35,40,41] 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.
  • FISH test results. FISH chromosomal abnormalities were associated with prognosis in retrospective and prospective studies and clonal evolution has been seen over time.[32,42,43,44] The following chromosomal abnormalities have been reported:
    • del(13q) is a favorable prognostic marker (with a 17-year median overall survival [OS] in a prospective study).[44]
    • Trisomy 12 and del(11) have a less favorable prognosis (with a 9- to 11-year median OS in a prospective study).[44]
    • del(17p) is associated with mutated TP53 and with poor response rates and short duration of response to the standard therapeutic options.[40] del(17p) is associated with the most unfavorable prognosis (with a 7-year median OS in one prospective trial).[44,45,46]
    • The combination of adverse cytogenetics, such as del(11q) or del(17p) deletion (suggesting a worse prognosis), with zeta-chain-associated protein 70 kDa negativity (suggesting a better prognosis) in the same patients resulted in a poor prognosis.[39]

    These findings emphasize the need for prospective studies of combinations of these prognostic markers.[47]

Other prognostic factors include the following:

  • Anemia and thrombocytopenia. These are important adverse prognostic variables, but only if due to extensive marrow involvement by CLL. Autoimmune hemolytic anemia and immune thrombocytopenic purpura do not confer a worse prognosis.
  • Age. CLL occurs primarily in middle-aged and elderly adults, with worse prognosis in successive decades of life.[43]
  • Stage.[48,49] (Refer to the Rai Staging System section and the Binet Classification section of this summary for more information.)
  • Positron emission tomography (PET)-CT scan results. This test should only be used in the context of recurrent fever, soaking night sweats, weight loss (>10% baseline weight in 6 months), or rapidly growing lymph nodes, because these findings might herald histologic transformation to a diffuse large B-cell lymphoma (so-called Richter transformation). Of 432 patients retrospectively reviewed, 209 patients had a maximum standardized uptake value (SUVmax) of 5 or higher.[50] Eighty percent of these patients had histologically aggressive CLL or Richter syndrome, and both of these entities had equally worse prognoses. When the SUVmax was 10 or higher, the 5-year OS rate was only 30%.[50]
  • Lymphocyte doubling time. Doubling of the white blood cell count in under 1 year implies a worse prognosis.[51]
  • Beta-2-microglobulin. Higher levels imply a worse prognosis.[52]
  • Richter transformation. Patients who develop an aggressive high-grade non-Hodgkin lymphoma, usually diffuse large B-cell lymphoma, have a poor prognosis.[53]
  • Clearance of minimal residual disease (MRD). The improvements in response rates from more intensive regimens have maximized the clearance of MRD. In one prospective trial of 493 patients, clearance of MRD was an independent predictor of OS by multivariate analysis.[54] The surrogate endpoint of clearance of residual disease, while prognostic,[54,55] 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.[30,56]
  • CD38 immunophenotype.[34,57] 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 malignancies. Patients with CLL are also at increased risk for other malignancies, even before therapy.[58] A population-based analysis of almost 2 million cancer patients in the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) database was performed. The findings suggested that cancer-specific survival for patients with pre-existing CLL who subsequently develop colorectal and breast cancer was 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 did not have antecedent CLL, after adjusting for age, sex, race, and disease stage, and excluding CLL-related deaths.[59]

An international prognostic index (IPI) for CLL (CLL-IPI) identified four prognostic subgroups on the basis of IgVH mutational status, clinical stage, age (≤65 years vs. >65 years), and TP53 status (no abnormalities vs. del(17p) or TP53 mutation or both).[60] A scoring system to predict time to first treatment for early-stage CLL identified three adverse risk factors: unmutated IgVH, absolute lymphocyte count higher than 15 × 109 /L, and palpable lymph nodes.[61]

Follow-up After Treatment

CT scans have a very limited role in monitoring patients after completion of treatment; the decision to treat for relapse was determined by CT scan or ultrasonography in only 2 of 176 patients in three prospective trials for the German CLL Study Group.[62]

References:

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  7. 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.
  8. 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.
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  10. 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.
  11. DiGiuseppe JA, Borowitz MJ: Clinical utility of flow cytometry in the chronic lymphoid leukemias. Semin Oncol 25 (1): 6-10, 1998.
  12. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333 (16): 1052-7, 1995.
  13. 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.
  14. 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.
  15. Strati P, Shanafelt TD: Monoclonal B-cell lymphocytosis and early-stage chronic lymphocytic leukemia: diagnosis, natural history, and risk stratification. Blood 126 (4): 454-62, 2015.
  16. 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.
  17. Staber PB, Herling M, Bellido M, et al.: Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia. Blood 134 (14): 1132-1143, 2019.
  18. 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.
  19. 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.
  20. Boidol B, Kornauth C, van der Kouwe E, et al.: First-in-human response of BCL-2 inhibitor venetoclax in T-cell prolymphocytic leukemia. Blood 130 (23): 2499-2503, 2017.
  21. 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.
  22. Dearden CE, Matutes E, Catovsky D: Alemtuzumab in T-cell malignancies. Med Oncol 19 (Suppl): S27-32, 2002.
  23. Sokol L, Loughran TP: Large granular lymphocyte leukemia. Oncologist 11 (3): 263-73, 2006.
  24. Semenzato G, Zambello R, Starkebaum G, et al.: The lymphoproliferative disease of granular lymphocytes: updated criteria for diagnosis. Blood 89 (1): 256-60, 1997.
  25. Lamy T, Loughran TP: How I treat LGL leukemia. Blood 117 (10): 2764-74, 2011.
  26. 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.
  27. 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.
  28. Loughran TP, Kidd PG, Starkebaum G: Treatment of large granular lymphocyte leukemia with oral low-dose methotrexate. Blood 84 (7): 2164-70, 1994.
  29. 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.
  30. 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.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. Orchard JA, Ibbotson RE, Davis Z, et al.: ZAP-70 expression and prognosis in chronic lymphocytic leukaemia. Lancet 363 (9403): 105-11, 2004.
  38. 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.
  39. 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.
  40. 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.
  41. 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.
  42. 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.
  43. 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.
  44. 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.
  45. 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.
  46. 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.
  47. 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.
  48. Rai KR, Sawitsky A, Cronkite EP, et al.: Clinical staging of chronic lymphocytic leukemia. Blood 46 (2): 219-34, 1975.
  49. 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.
  50. 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.
  51. 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.
  52. 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.
  53. Tsimberidou AM, Keating MJ: Richter syndrome: biology, incidence, and therapeutic strategies. Cancer 103 (2): 216-28, 2005.
  54. 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.
  55. 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.
  56. Montserrat E, Moreno C, Esteve J, et al.: How I treat refractory CLL. Blood 107 (4): 1276-83, 2006.
  57. 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.
  58. 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.
  59. 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.
  60. International CLL-IPI working group: An international prognostic index for patients with chronic lymphocytic leukaemia (CLL-IPI): a meta-analysis of individual patient data. Lancet Oncol 17 (6): 779-90, 2016.
  61. Condoluci A, Terzi di Bergamo L, Langerbeins P, et al.: International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia. Blood 135 (21): 1859-1869, 2020.
  62. 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 Information for CLL

Chronic lymphocytic leukemia (CLL) does not have a standard staging system. The Rai staging system (Table 1) and the Binet classification (Table 2) 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

Table 1. Rai Staging System
Stage Stage Criteria
Stage 0 Absolute lymphocytosis (>15,000/mm3) without adenopathy, hepatosplenomegaly, anemia, or thrombocytopenia.
Stage I Absolute lymphocytosis with lymphadenopathy without hepatosplenomegaly, anemia, or thrombocytopenia.
Stage II Absolute lymphocytosis with either hepatomegaly or splenomegaly with or without lymphadenopathy.
Stage III Absolute lymphocytosis and anemia (hemoglobin <11 g/dL) with or without lymphadenopathy, hepatomegaly, or splenomegaly.
Stage IV Absolute lymphocytosis and thrombocytopenia (<100,000/mm3) with or without lymphadenopathy, hepatomegaly, splenomegaly, or anemia.

Binet Classification

Table 2. Binet Classification System
Stage Stage Criteria
a Lymphoid areas include cervical, axillary, inguinal, and splenic.
Clinical stage Aa No anemia or thrombocytopenia and fewer than three areas of lymphoid involvement (Rai stages 0, I, and II).
Clinical stage Ba No anemia or thrombocytopenia with three or more areas of lymphoid involvement (Rai stages I and II).
Clinical stage C Anemia and/or thrombocytopenia regardless of the number of areas of lymphoid enlargement (Rai stages III and IV).

The Binet classification integrates the number of disease-involved nodal groups 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 was recognized in the Rai staging, and from the 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, 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.

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.

Selection of Therapy for CLL

Treatment of patients with chronic lymphocytic leukemia (CLL) must be individualized on the basis of the clinical behavior of the disease.[1] Because this disease is generally not curable, occurs in an elderly population, and often progresses slowly, it is most often treated in a conservative fashion.[2]

In older trials with data collected from the 1970s through the 1990s, the median survival for all patients ranged from 8 to 12 years.[3,4] However, with the introduction of the B-cell receptor inhibitors and targeting of BCL2, the median survival for all patients has not been reached with over 10 years of follow-up.

Treatment of patients with CLL ranges from observation with treatment of infectious, hemorrhagic, or immunologic complications to a variety of therapeutic options administered as single agents or combination therapy. In asymptomatic patients, treatment may be deferred until the disease progresses and symptoms occur.[3] 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.[5] Although even asymptomatic patients with del(17p) on fluorescence in situ hybridization (FISH) analysis (or TP53 mutation) may be followed with watchful waiting, frequent monitoring may be required to avert rapid progression. A meta-analysis of randomized trials showed no survival benefit for immediate versus delayed therapy for patients with early-stage disease.[6][Level of evidence: 1iiA] For patients with progressing CLL, treatment will not be curative in most cases. Selected patients treated with allogeneic stem cell transplantation have achieved prolonged disease-free survival (DFS); sometimes exceeding 20 years.[7,8,9,10,11] Prolonged DFS was also noted in young patients (<60 years) with IgVH hypermutation who received the FCR regimen (fludarabine, cyclophosphamide, and rituximab).[12,13,14]

The following clinical factors may be helpful in predicting progression of disease:[2]

  • IgVH gene mutation.
  • Chromosomal abnormalities by FISH analysis or cytogenetics.
  • Beta-2-microglobulin.
  • Lymphocyte doubling time.

Symptomatic or progressive CLL is defined as the following by the International Workshop on Chronic Lymphocytic Leukemia:[15]

  • Evidence of progressive marrow failure—the development or worsening of anemia and/or thrombocytopenia (in some patients, platelet counts <100 × 109 /L may remain stable over a long period; this does not automatically require therapeutic intervention). Cutoff levels of hemoglobin less than 10 g/dL or platelet counts less than 50 × 109 /L are generally regarded as an indication for treatment.
  • Massive (i.e., ≥6 cm below the left costal margin), progressive, or symptomatic splenomegaly.
  • Massive nodes (i.e., ≥10 cm in longest diameter), progressive, or symptomatic lymphadenopathy.
  • Progressive lymphocytosis with an increase of 50% or more over a 2-month period, or lymphocyte-doubling time (LDT) less than 6 months. LDT can be obtained by linear regression extrapolation of absolute lymphocyte counts obtained at intervals of 2 weeks over an observation period of 2 to 3 months; patients with initial blood lymphocyte counts less than 30 × 109 /L may require a longer observation period to determine the LDT. Factors contributing to lymphocytosis other than CLL (e.g., infections or steroid administration) should be excluded.
  • Autoimmune complications, including anemia or thrombocytopenia that respond poorly to corticosteroids.
  • Symptomatic or functional extranodal involvement (e.g., skin, kidney, lung, or spine). Disease-related symptoms defined as any of the following:
    • Unintentional weight loss of 10% or more within the previous 6 months.
    • Significant fatigue (i.e., Eastern Cooperative Oncology Group performance scale 2 or worse, cannot work, or unable to perform usual activities).
    • Fevers of 100.5°F or 38.0°C or higher for 2 or more weeks without evidence of infection.
    • Night sweats for at least 1 month without evidence of infection.

Considerations for the Selection of Therapy

The following general principles may provide a sequencing for available therapeutic options:

  • Despite many therapeutic options, asymptomatic or minimally affected patients with CLL are often offered observation outside the context of a clinical trial. Therapy often begins when patients develop profound cytopenias, or when symptoms, such as enlarging bulky lymphadenopathy or debilitating symptoms, substantially impact their quality of life.
  • Because nontransplant curative therapy has not been found, the initial goal of therapy is to maximize efficacy (with improvement of overall survival), while introducing the least overall short- and long-term toxicity.
  • Of the new biologic agents, ibrutinib, acalabrutinib, and venetoclax are approved by the U.S. Food and Drug Administration for first-line use in newly diagnosed patients with CLL who require therapy.[16] In patients with adverse prognostic factors (especially del(17p) or mutated TP53) ibrutinib, acalabrutinib, or venetoclax should be considered.
  • 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. Yet, prolonged DFS (over 10 years) can be seen with the use of the FCR regimen in younger patients (<60 years) with IgVH hypermutation.[12,13,14]
    • Avoiding alkylating agents and purine analogs 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.
  • Older patients with comorbidities may better tolerate the newer biologic agents (such as ibrutinib or venetoclax), monoclonal antibody therapy alone (such as high-dose rituximab), or dose modification of standard chemotherapeutic agents combined with rituximab. For older patients (>65 years), the combination of rituximab plus bendamustine (BR regimen) resulted in fewer adverse events and better outcomes than the FCR regimen.[17]

Adverse Sequelae of the Disease and Therapy

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.[18] There was, however, no effect on survival. Routine chronic administration of intravenous immunoglobulin is expensive, and the long-term benefit (>1 year) is unproven.[19,20]

Autoimmune hemolytic anemia and/or thrombocytopenia can occur in patients with any stage of CLL.[21] Initial therapy involves corticosteroids with or without alkylating agents (fludarabine can worsen the hemolytic anemia). It is often necessary to control the autoimmune destruction with corticosteroids, if possible, before administering marrow-suppressive chemotherapy because it may be difficult for a patient to successfully receive a red blood cell or platelet transfusion. Alternate therapies include high-dose immune globulin, rituximab, cyclosporine, azathioprine, splenectomy, and low-dose radiation therapy to the spleen.[3,22] Tumor lysis syndrome is an uncommon complication (presenting in 1 of 300 patients) of chemotherapy for patients with bulky disease.[23]

Second malignancies and treatment-induced acute leukemias may also occur in a small percentage of patients.[24] Transformation of CLL to diffuse large cell lymphoma (Richter syndrome) carries a poor prognosis with a median survival of less than 1 year, although 20% of the patients may live more than 5 years after aggressive combination chemotherapy.[25] (Refer to the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment for more information.)

References:

  1. Montserrat E: CLL therapy: progress at last! Blood 105 (1): 2-3, 2005.
  2. Gribben JG, O'Brien S: Update on therapy of chronic lymphocytic leukemia. J Clin Oncol 29 (5): 544-50, 2011.
  3. Rozman C, Montserrat E: Chronic lymphocytic leukemia. N Engl J Med 333 (16): 1052-7, 1995.
  4. 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.
  5. 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.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. Rossi D, Terzi-di-Bergamo L, De Paoli L, et al.: Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood 126 (16): 1921-4, 2015.
  15. Hallek M, Cheson BD, Catovsky D, et al.: iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood 131 (25): 2745-2760, 2018.
  16. 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.
  17. Eichhorst B, Fink AM, Bahlo J, et al.: First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 17 (7): 928-942, 2016.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.

Asymptomatic CLL Treatment

Observation

Because of its indolent nature, treatment for asymptomatic or minimally affected patients with chronic lymphocytic leukemia (CLL) with chemotherapy is not indicated, and observation is the generally accepted approach.[1] Because the rate of progression may vary, 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 IgVH mutational status, and the presence of del(11q) or del(17p) established by fluorescence in situ hybridization analysis.[2] Spontaneous regression, manifested by a sustained reduction of the malignant clone without therapy, occurs in less than 5% of patients. These patients almost exclusively have hypermutation of IgVH.[3]

Evidence (observation):

  1. The French Cooperative Group on Chronic Lymphocytic Leukemia randomly assigned 1,535 patients with previously untreated stage A disease to receive either chlorambucil or no immediate treatment.[4]
    • The results showed no survival advantage for immediate treatment with chlorambucil.[4][Level of evidence: 1iiA]
  2. A meta-analysis evaluated six trials of patients with early-stage CLL that involved immediate versus deferred therapy with chlorambucil (including the aforementioned trial by the French Cooperative Group).[5]
    • The results showed no difference in overall survival at 10 years.[5][Level of evidence: 1iiA]

Despite many therapeutic options, observation should be considered for asymptomatic or minimally affected patients, even in the context of adverse prognostic findings. Therapy begins when patients develop profound cytopenias or when symptoms adversely impact quality of life.

To date, there are no clinical trial results that confirm that immediate treatment of asymptomatic or minimally affected patients with the B-cell receptor inhibitors or BCL2 inhibitors is superior to observation.

Clinical trials will need to establish improved outcomes using the newer biologic therapies in asymptomatic patients before observation or watchful waiting is abandoned.

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. 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.
  3. Kwok M, Oldreive C, Rawstron AC, et al.: Integrative analysis of spontaneous CLL regression highlights genetic and microenvironmental interdependency in CLL. Blood 135 (6): 411-428, 2020.
  4. 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.
  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.

Symptomatic or Progressive CLL Treatment

The following regimens are considered first-line approaches for patients with chronic lymphocytic leukemia (CLL) who are experiencing symptomatic progression:

  • Ibrutinib with or without rituximab or obinutuzumab.
  • Venetoclax with or without rituximab or obinutuzumab.
  • Acalabrutinib with or without rituximab or obinutuzumab.
  • BR (bendamustine and rituximab).
  • FCR (fludarabine, cyclophosphamide, and rituximab).

Several large prospective clinical trials have compared these approaches. A chemotherapy-free approach for first-line therapy is usually preferred for most patients, but is mandatory for patients with del(17p) or TP53-positive disease.[1,2,3,4,5]

Anti-CD20 monoclonal antibodies are often combined with venetoclax, ibrutinib, acalabrutinib, or chemotherapy regimens. The three monoclonal antibodies typically used include rituximab, obinutuzumab, and ofatumumab.[6,7,8,9]

  1. ECOG-E1912 (NCT02048813) was a prospective randomized trial that compared ibrutinib and rituximab with FCR. A total of 529 patients previously untreated for CLL were randomly assigned in a 2:1 ratio to receive either ibrutinib and rituximab followed by ibrutinib maintenance (354 patients) or six cycles of FCR (175 patients).[10]

    Ibrutinib is a selective irreversible inhibitor of Bruton tyrosine kinase, a signaling molecule located upstream in the B-cell receptor-signaling cascade.

    • With a median follow-up of 33.6 months, the 3-year overall survival (OS) rate favored the ibrutinib arm (98.8% vs. 91.5%) (hazard ratio [HR], 0.17; 95% confidence interval [CI], 0.05–0.54; P < .001).[10][Level of evidence: 1iiA]
    • For the 281 patients with IgVH-unmutated disease, the 3-year progression-free survival (PFS) rate favored ibrutinib plus rituximab versus FCR (89% vs. 65%) (HR, 0.28; 95% CI, 0.17−0.48; P < .001). However, for the 114 patients with IgVH-mutated disease, the 3-year PFS rate was not significantly different at 88% for the ibrutinib arm and 82% for the FCR arm (HR, 0.42; 95% CI, 0.16−1.16; P = .086) in a trial reported in abstract form.[10,11]
  2. A prospective trial of 547 previously untreated patients aged 65 years or older randomly assigned patients to BR versus ibrutinib alone versus ibrutinib plus rituximab.[12]
    • With a median follow-up of 38 months, the 2-year PFS rate was 74% for patients who received BR. The rates were significantly higher for patients who received ibrutinib alone (87%; HR, 0.39; 95% CI, 0.25–0.58) or ibrutinib plus rituximab (88%; HR, 0.38; 95% CI, 0.25–0.59; P < .001).[12][Level of evidence: 1iiDiii]
    • There was no difference between the PFS of the two ibrutinib groups (HR, 1.00; 95% CI, 0.62–1.62; P = .49) and no difference in OS between each of the groups.
  3. A prospective randomized trial of 208 patients who were previously untreated or had relapsed disease also evaluated rituximab plus ibrutinib versus ibrutinib alone.[13]
    • With a median follow-up of 36 months, there was no difference in PFS (86%; HR, 1.04; 95% CI, 0.49−2.20; P = .91).[13][Level of evidence: 1iiDiii]
  4. In the prospective CLL14 trial (NCT02242942), 432 previously untreated patients with significant medical comorbidities (6 or higher on the Cumulative Illness Rating Scale; median age, 72 years) were randomly assigned to venetoclax (a highly selective inhibitor of BCL2) plus obinutuzumab (the human anti-CD20 monoclonal antibody) versus chlorambucil plus obinutuzumab.[14]
    • With a median follow-up of 28.1 months, the 2-year PFS rate was significantly higher for patients who received venetoclax plus obinutuzumab at 88.2% (95% CI, 83.7%–92.6%), compared with 64.1% for chlorambucil plus obinutuzumab (95% CI, 57.4%–70.8%) (HR, 0.35; 95% CI, 0.23–0.53; P < .001).[14][Level of evidence: 1iiDiii]
    • With a median follow-up of 39.6 months, the 3-year PFS rate for the venetoclax arm was 82% with 57% undetectable (<10 -4) minimal residual disease (MRD) in the bone marrow versus a 50% 3-year PFS rate and 17% MRD-negative marrow in the chlorambucil arm (HR, 0.31; 95% CI, 0.22−0.44; P < .0001).[15][Level of evidence: 1iiDiii]
  5. In the prospective MURANO trial (NCT02005471), 389 patients with relapsed or refractory CLL were randomly assigned to venetoclax (2 years) plus rituximab (first 6 months) versus BR for 6 months.
    • With a median follow-up of 24 months, the 2-year PFS rate was 84.9% for venetoclax plus rituximab versus 36.3% for BR (HR, 0.17; 95% CI, 0.11–0.25; P < .001).[16,17] An update with a 48-month median follow-up, reported in abstract form, showed a 4-year OS rate of 85.3% versus 66.8% (HR, 0.41; 95% CI, 0.26−0.65; P < .0001).[18][Level of evidence: 1iiA]
  6. A prospective trial, reported in abstract form, of 535 previously untreated patients aged 65 years or older with comorbidities (e.g., creatinine clearance <70 mL/min) randomly assigned patients to three arms: acalabrutinib plus obinutuzumab, acalabrutinib alone, or chlorambucil plus obinutuzumab.[19] Acalabrutinib is a highly selective covalent irreversible Bruton tyrosine kinase inhibitor, designed to minimize the gastrointestinal toxicities and risk of atrial fibrillation seen with ibrutinib.
    • With a median follow-up of 28 months, the 30-month PFS rates were 90% for acalabrutinib plus obinutuzumab (HR, 0.10; 95% CI, 0.06−0.17; P < .0001), 82% for acalabrutinib alone (HR, 0.20; 95% CI, 0.13−0.30; P < .0001), and 34% for chlorambucil plus obinutuzumab.[19][Level of evidence: 1iiDiii]
    • There was a small but significant difference between the PFS rates of the two acalabrutinib groups (93% vs. 87% at 24 months) favoring the combination (HR, 0.49; 95% CI, 0.26−0.95).[19][Level of evidence: 1iiDiii]
  7. The German CLL Study Group compared BR versus FCR as first-line therapy in patients with CLL who required therapy.[20]
    • With a 37.1-month median follow-up, the median PFS was better for patients who received FCR (55.2 months vs. 41.7 months) (HR, 1.64; 90% CI, 1.31–2.06; P = .001), but there was no difference in the OS rate at 3 years (91% vs. 92%, not significant).[20][Level of evidence: 1iiDiii]
    • In patients older than 65 years, there was no difference in PFS between the two arms, but more infections occurred with FCR than with BR (grade 3 to 5 infection, 47% vs. 27%).
  8. FCR is used for patients with IgVH hypermutation. Several trials used FCR for fit patients with mutated IgVH who required therapy. The PFS rate exceeded 60% at more than 10 years.[21,22,23][Level of evidence: 3iiiDiii] Nonetheless, late relapses were seen beyond 10 years.
  9. In a phase II trial, 80 previously untreated patients who were aged 65 or older or had high-risk disease were treated with ibrutinib for 3 months followed by combined ibrutinib plus venetoclax for a total of 24 months.[24]
    • The 1-year response rate was 88%, the PFS rate was 98% (95% CI, 94%–100%), and the OS rate was 99% (95% CI, 96%–100%).[24][Level of evidence: 3iiiDiv]
    • The toxicity of the combination is similar to either agent alone and avoids the tumor lysis syndrome seen when starting with venetoclax.
    • High rates of undetectable MRD (<10-4 by 8 color flow cytometry) in the peripheral blood (75%) and bone marrow (72%) is unprecedented. The clinical significance of this finding awaits prospective randomized trials to establish clinical outcomes versus either drug alone. This combination has also been tried in the relapsed/refractory setting.[25]

Summary: These trials establish the use of venetoclax with rituximab or obinutuzumab, or the use of ibrutinib or acalabrutinib (with or without rituximab or obinutuzumab) as first-line therapy in previously untreated patients with CLL. Unlike ibrutinib or acalabrutinib, which are given continuously until relapse, venetoclax may be stopped after 12 months, with durable maintenance of remission. Venetoclax can be readministered with success, if needed. The combination of venetoclax and ibrutinib needs to be evaluated in prospective randomized trials versus either agent alone. The considerable financial toxicity of this combination mandates verification of superior efficacy. These trials further establish the rationale for a chemotherapy-free approach for first-line therapy for CLL instead of the previous standard of BR and FCR (which proved more efficacious than chlorambucil regimens).

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. 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.
  2. O'Brien S, Furman RR, Coutre S, et al.: Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood 131 (17): 1910-1919, 2018.
  3. O'Brien S, Jones JA, Coutre SE, et al.: Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol 17 (10): 1409-1418, 2016.
  4. Stilgenbauer S, Eichhorst B, Schetelig J, et al.: Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol 17 (6): 768-78, 2016.
  5. Stilgenbauer S, Eichhorst B, Schetelig J, et al.: Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial. J Clin Oncol 36 (19): 1973-1980, 2018.
  6. 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.
  7. 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.
  8. Goede V, Fischer K, Busch R, et al.: Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med 370 (12): 1101-10, 2014.
  9. Flinn IW, Hillmen P, Montillo M, et al.: The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood 132 (23): 2446-2455, 2018.
  10. Shanafelt TD, Wang XV, Kay NE, et al.: Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med 381 (5): 432-443, 2019.
  11. Shanafelt TD, Wang V, Kay NE, et al.: Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 trial. [Abstract] Blood 134 (Suppl 1): A-33, 2019.
  12. Woyach JA, Ruppert AS, Heerema NA, et al.: Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med 379 (26): 2517-2528, 2018.
  13. Burger JA, Sivina M, Jain N, et al.: Randomized trial of ibrutinib vs ibrutinib plus rituximab in patients with chronic lymphocytic leukemia. Blood 133 (10): 1011-1019, 2019.
  14. Fischer K, Al-Sawaf O, Bahlo J, et al.: Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med 380 (23): 2225-2236, 2019.
  15. Fischer K, Ritgen M, Al-Sawaf O, et al.: Quantitative analysis of minimal residual disease (MRD) shows high rates of undetectable MRD after fixed-duration chemotherapy-free treatment and serves as surrogate marker for progression-free survival: a prospective analysis of the randomized CLL14 trial. [Abstract] Blood 134 (Suppl 1): A-36, 2019.
  16. Seymour JF, Kipps TJ, Eichhorst B, et al.: Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med 378 (12): 1107-1120, 2018.
  17. Kater AP, Seymour JF, Hillmen P, et al.: Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study. J Clin Oncol 37 (4): 269-277, 2019.
  18. Seymour JF, Kipps TJ, Eichhorst BF, et al.: Four-year analysis of Murano study confirms sustained benefit of time-limited venetoclax-rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). [Abstract] Blood 134 (Suppl 1): A-355, 2019.
  19. Sharman JP, Banerji V, Fogliatto LM, et al.: ELEVATE TN: Phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (Pts) with treatment-naive chronic lymphocytic leukemia (CLL). [Abstract] Blood 134 ( Suppl 1): A-31, 2019.
  20. Eichhorst B, Fink AM, Bahlo J, et al.: First-line chemoimmunotherapy with bendamustine and rituximab versus fludarabine, cyclophosphamide, and rituximab in patients with advanced chronic lymphocytic leukaemia (CLL10): an international, open-label, randomised, phase 3, non-inferiority trial. Lancet Oncol 17 (7): 928-942, 2016.
  21. 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.
  22. 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.
  23. Rossi D, Terzi-di-Bergamo L, De Paoli L, et al.: Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood 126 (16): 1921-4, 2015.
  24. Jain N, Keating M, Thompson P, et al.: Ibrutinib and Venetoclax for First-Line Treatment of CLL. N Engl J Med 380 (22): 2095-2103, 2019.
  25. Hillmen P, Rawstron AC, Brock K, et al.: Ibrutinib Plus Venetoclax in Relapsed/Refractory Chronic Lymphocytic Leukemia: The CLARITY Study. J Clin Oncol 37 (30): 2722-2729, 2019.

Recurrent or Refractory CLL Treatment

The same regimens considered for first-line therapy for patients with chronic lymphocytic leukemia (CLL) can be readministered in a sequential fashion. These regimens are described in more detail under first-line therapy. (Refer to the Symptomatic or Progressive CLL Treatment section of this summary for more information.)

  • Ibrutinib with or without rituximab or obinutuzumab.
  • Venetoclax with or without rituximab or obinutuzumab.
  • Acalabrutinib with or without rituximab or obinutuzumab.
  • BR (bendamustine plus rituximab).
  • FCR (fludarabine, cyclophosphamide, and rituximab).

In the relapsed setting, venetoclax showed similar efficacy and safety even after previous therapy with ibrutinib or idelalisib (the phosphatidylinositol 3-kinase [PI3K] delta inhibitor).[1,2]

Similarly, in a trial reported in abstract form, ibrutinib and acalabrutinib showed similar efficacy and safety after previous therapy with venetoclax.[3] Sequencing these novel agents showed efficacy in the relapsed/refractory setting.[4]

Chimeric Antigen Receptor (CAR) T-Cell Therapy

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.[5] A dramatic response lasting 6 months has prompted larger trials of this concept.[5][Level of evidence: 3iiiDiv] Ongoing clinical trials are testing the concept of T cells directed at CD19 with engineered CAR T cells.[6,7]

Idelalisib or Duvelisib

Idelalisib is an oral inhibitor of the delta isoform of PI3K, which is in the B-cell receptor-signaling cascade. Duvelisib is an oral dual inhibitor of the delta and gamma isoforms of PI3K.[8]

  1. 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.[9]
    • With a median follow-up of less than 1 year, the progression-free survival (PFS) rate at 24 weeks favored the rituximab and idelalisib arm (93%) versus the rituximab and placebo arm (46%) (hazard ratio [HR], 0.15; 95% confidence interval [CI], 0.08–0.28; P < .001).[9][Level of evidence: 1iA]
    • The overall survival (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).[9][Level of evidence: 1iA]
    • With a median follow-up of 18 months, this trial demonstrated significantly better median OS for rituximab and idelalisib at 40.6 months (95% CI, 28.5–57.3 months) versus 34.6 months (95% CI, 16.0–not reached) for rituximab and placebo.[10][Level of evidence: 1iA]
  2. In 64 previously untreated patients, the combination of idelalisib plus rituximab resulted in a PFS rate of 83% at 3 years.[11][Level of evidence: 3iiiDiii]
  3. In a prospective trial, 319 patients with relapsed and refractory CLL/small lymphocytic lymphoma were randomly assigned to receive duvelisib versus ofatumumab.[12]
    • With a median follow-up of 24 months, the median PFS was significantly higher for duvelisib at 13.3 months versus 9.9 months (HR, 0.52; P < .0001).
  4. In a prospective randomized trial, 261 patients with previously treated disease were randomly assigned to receive idelalisib plus ofatumumab versus ofatumumab alone.[13]
    • With a median follow-up of 16.1 months, the median PFS favored the idelalisib combination at 16.3 months (95% CI, 13.6−17.8) versus 8.0 months (range, 5.7−9.2) (HR, 0.27; 95% CI, 0.19−0.39; P < .0001).[13][Level of evidence: 1iiDiii]

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.[14,15,16,17,18,19][Level of evidence: 3iiiDiv] Prolonged, lower-dose approaches and attention to prevention of tumor lysis syndrome are suggested with this agent.[14,20] Combination therapy and long-term toxicities from using lenalidomide (such as increased myelodysplasia, as seen in myeloma patients) remain undefined for patients with CLL.

Bone Marrow or Peripheral Blood Stem Cell Transplantation

In a prospective randomized trial, 241 previously untreated patients younger than 66 years with advanced-stage disease received induction therapy with a CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone)-based regimen followed by fludarabine.[21] 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 cytarabine, and cisplatin reinduction followed by either ASCT or fludarabine plus cyclophosphamide (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.[21][Level of evidence: 1iiDi] Autologous bone marrow/stem cell transplantation is rarely employed for relapsing CLL.

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 blood stem cell transplantation.[22,23,24,25,26,27] Although most patients who attain complete remission after autologous transplantation eventually relapse, a survival plateau for allogeneic stem cell support suggests an additional graft-versus-leukemia effect.[27] A series (NCT00281983) of 90 patients with relapsed or refractory CLL who underwent allogeneic stem cell transplantation 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).[28][Level of evidence: 3iiiD]

Ofatumumab

Ofatumumab is a humanized anti-CD20 monoclonal antibody.

Evidence (ofatumumab alone and in combination with chlorambucil):

  1. 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.[29]
    • 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.[29][Level of evidence: 1iiDiii]
  2. A prospective randomized trial of 447 patients who were previously untreated compared ofatumumab plus chlorambucil with chlorambucil alone.[30]
    • With a median follow-up of 2 years, median PFS favored the ofatumumab plus chlorambucil 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.[30][Level of evidence: 1iiDiii]

Involved-Field Radiation Therapy

Relatively low doses of radiation therapy can be administered for lymphadenopathy that is causing problems due to size or encroachment on adjacent organs. Sometimes radiation therapy to one nodal area or the spleen will result in an abscopal effect (i.e., the shrinkage of lymph nodes in untreated sites).

Alemtuzumab

Alemtuzumab is no longer available commercially in the United States for neoplastic indications but can be obtained from the pharmaceutical company on a compassionate-use basis (Lemtrada REMS [Risk Evaluation and Mitigation Strategy] Program).

Alemtuzumab, the monoclonal antibody directed at CD52, shows activity in the setting of chemotherapy-resistant disease or high-risk untreated patients with del(17p) or TP53 mutation.[31,32,33] 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.[33,34,35,36,37]

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.[38,39,40][Level of evidence: 3iiiDiv]; [41][Level of evidence: 1iiDiii]

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. Jones JA, Mato AR, Wierda WG, et al.: Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol 19 (1): 65-75, 2018.
  2. Coutre S, Choi M, Furman RR, et al.: Venetoclax for patients with chronic lymphocytic leukemia who progressed during or after idelalisib therapy. Blood 131 (15): 1704-1711, 2018.
  3. Mato AR, Roeker LE, Eyre TA, et al.: Efficacy of therapies following venetoclax discontinuation in CLL: focus on B-cell receptor signal transduction inhibitors and cellular therapies. [Abstract] Blood 134 (Suppl 1): A-502, 2019.
  4. Mato AR, Hill BT, Lamanna N, et al.: Optimal sequencing of ibrutinib, idelalisib, and venetoclax in chronic lymphocytic leukemia: results from a multicenter study of 683 patients. Ann Oncol 28 (5): 1050-1056, 2017.
  5. 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.
  6. Turtle CJ, Hay KA, Hanafi LA, et al.: Durable Molecular Remissions in Chronic Lymphocytic Leukemia Treated With CD19-Specific Chimeric Antigen Receptor-Modified T Cells After Failure of Ibrutinib. J Clin Oncol 35 (26): 3010-3020, 2017.
  7. Siddiqi T, Soumerai JD, Dorritie KA: Rapid undetectable MRD (uMRD) responses in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) treated with lisocabtagene maraleucel (liso-cel), a CD19-directed CAR T cell product: updated results from Transcend CLL 004, a phase 1/2 study including patients with high-risk disease previously treated with ibrutinib. [Abstract] Blood 134 (Suppl 1): 503, 2019.
  8. Patel K, Danilov AV, Pagel JM: Duvelisib for CLL/SLL and follicular non-Hodgkin lymphoma. Blood 134 (19): 1573-1577, 2019.
  9. 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.
  10. Sharman JP, Coutre SE, Furman RR, et al.: Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia. J Clin Oncol 37 (16): 1391-1402, 2019.
  11. O'Brien SM, Lamanna N, Kipps TJ, et al.: A phase 2 study of idelalisib plus rituximab in treatment-naïve older patients with chronic lymphocytic leukemia. Blood 126 (25): 2686-94, 2015.
  12. Flinn IW, Hillmen P, Montillo M, et al.: The phase 3 DUO trial: duvelisib vs ofatumumab in relapsed and refractory CLL/SLL. Blood 132 (23): 2446-2455, 2018.
  13. Jones JA, Robak T, Brown JR, et al.: Efficacy and safety of idelalisib in combination with ofatumumab for previously treated chronic lymphocytic leukaemia: an open-label, randomised phase 3 trial. Lancet Haematol 4 (3): e114-e126, 2017.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. 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.
  19. 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.
  20. 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.
  21. 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.
  22. 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.
  23. 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.
  24. 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.
  25. 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.
  26. 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.
  27. 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.
  28. 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.
  29. van Oers MH, Kuliczkowski K, Smolej L, et al.: Ofatumumab maintenance versus observation in relapsed chronic lymphocytic leukaemia (PROLONG): an open-label, multicentre, randomised phase 3 study. Lancet Oncol 16 (13): 1370-9, 2015.
  30. Hillmen P, Robak T, Janssens A, et al.: Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet 385 (9980): 1873-83, 2015.
  31. 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.
  32. 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.
  33. 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.
  34. 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.
  35. 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.
  36. 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.
  37. 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.
  38. 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.
  39. 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.
  40. 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.
  41. 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.

Key References for CLL Treatment

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

  • Fischer K, Al-Sawaf O, Bahlo J, et al.: Venetoclax and Obinutuzumab in Patients with CLL and Coexisting Conditions. N Engl J Med 380 (23): 2225-2236, 2019. [PUBMED Abstract]

    Cited in:

    • Symptomatic or Progressive CLL Treatment
  • Seymour JF, Kipps TJ, Eichhorst BF, et al.: Four-year analysis of Murano study confirms sustained benefit of time-limited venetoclax-rituximab (VenR) in relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL). [Abstract] Blood 134 (Suppl 1): A-355, 2019.

    Cited in:

    • Symptomatic or Progressive CLL Treatment
  • Seymour JF, Kipps TJ, Eichhorst B, et al.: Venetoclax-Rituximab in Relapsed or Refractory Chronic Lymphocytic Leukemia. N Engl J Med 378 (12): 1107-1120, 2018. [PUBMED Abstract]

    Cited in:

    • Symptomatic or Progressive CLL Treatment
  • Shanafelt TD, Wang XV, Kay NE, et al.: Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med 381 (5): 432-443, 2019. [PUBMED Abstract]

    Cited in:

    • Symptomatic or Progressive CLL Treatment
  • Shanafelt TD, Wang V, Kay NE, et al.: Ibrutinib and rituximab provides superior clinical outcome compared to FCR in younger patients with chronic lymphocytic leukemia (CLL): extended follow-up from the E1912 trial. [Abstract] Blood 134 (Suppl 1): A-33, 2019.

    Cited in:

    • Symptomatic or Progressive CLL Treatment
  • Sharman JP, Banerji V, Fogliatto LM, et al.: ELEVATE TN: Phase 3 study of acalabrutinib combined with obinutuzumab (O) or alone vs O plus chlorambucil (Clb) in patients (Pts) with treatment-naive chronic lymphocytic leukemia (CLL). [Abstract] Blood 134 ( Suppl 1): A-31, 2019.

    Cited in:

    • Symptomatic or Progressive CLL Treatment
  • 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:

    • Selection of Therapy for CLL
    • Symptomatic or Progressive CLL Treatment

Changes to This Summary (02 / 25 / 2022)

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

Updated statistics with estimated new cases and deaths for 2022 (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 in the care of their 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 reviewer for Chronic Lymphocytic Leukemia Treatment is:

  • Eric J. Seifter, MD (Johns Hopkins University)

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]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

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Last Revised: 2022-02-25

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