Chronic Lymphocytic Leukemia (CLL) Guidelines

Updated: May 22, 2020
  • Author: Muhammad A Mir, MD, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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Guidelines Summary

Guidelines Contributor: Karen Seiter, MD Professor, Department of Internal Medicine, Division of Oncology/Hematology, New York Medical College

Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia (CLL) have been issued by the following organizations:

  • National Comprehensive Cancer Network (NCCN) [19]

  • International Workshop on Chronic Lymphocytic Leukemia (IWCLL) [17]

  • European Society of Medical Oncology (ESMO) [78]

Diagnosis and Staging

All three guidelines are in agreement that the diagnosis of CLL requires the presence of ≥5 × 109/L B lymphocytes in the peripheral blood and the clonality of the circulating B lymphocytes should be confirmed by flow cytometry. The IWCLL guidelines also require persistence of lymphocytosis for longer than 3 months, while NCCN and ESMO do not. [19, 17, 78]

For adequate immunophenotyping to establish diagnosis by flow cytometry, the NCCN recommends using the cell surface markers kappa/lambda, CD19, CD20, CD5, CD23, and CD10. If flow is used to establish the diagnosis, cytospin for cyclin D1, or fluorescence in situ hybridization (FISH) for t(11;14); t(11q;v) should also be included. [19]

The NCCN recommends proceeding with lymph node biopsy if diagnosis is not established by flow cytometry. Diagnosis on lymph node biopsy requires immunophenotyping of CD3, CD5, CD10, CD20, CD23, and cyclin D1. [19]

ESMO guidelines note that leukaemia cells are characteristically small, mature-appearing lymphocytes with a narrow border of cytoplasm and a dense nucleus lacking discernible nucleoli, and having partially aggregated chromatin. Larger, atypical lymphocytes or prolymphocytes cannot exceed 55%. [78]

The IWCLL guidelines also allow for the diagnosis of CLL in the presence of a cytopenia caused by clonal bone marrow involvement regardless of the peripheral B-lymphocyte count. [17]

Additional tests recommended prior to initiation of treatment include:

  • FISH to detect cytogenetic abnormalities, in particular a deletion of chromosome 17 [del(17p)], 13[del(13q)] and 11 [del(11q)] and trisomy of chromosome12 [19, 17, 78]

  • Molecular analysis to detect IGHV mutation status [17, 19]

  • Determination of CD38 and ZAP-70 expression by flow cytometry or immunohistochemistry [19]

  • TP53 sequencing  [19]

  • Prior to chemoimmunotherapy, alemtuzumab or allogeneic stem cell transplantation, testing for hepatitis B and C viruses, cytomegalovirus (CMV), and human immunodeficiency virus(HIV) [17, 78]

  • Unilateral bone marrow aspirate and biopsy [17, 78] ; however, most oncologists in the United States do not consider bone marrow analysis to be required

The NCCN considers the following essential in the workup of patients diagnosed with CLL [19] :

  • Physical exam with attention to node-bearing areas, including Waldeyer ring, and measurement of size of liver and spleen

  • Performance status determination

  • B symptoms assessment

  • Complete blood count and comprehensive metabolic panel

For staging, all three guidelines recommend use of either the Rai system or the Binet system. [19, 17, 78]


The guidelines are in agreement that patients with early-stage CLL should not be treated with chemotherapy until they become symptomatic or display evidence of rapid progression of disease. [19, 17, 78]

Patients at low risk and intermediate risk (ie, Rai stages 0-II) who have no indications for treatment should be observed. Blood cell counts and clinical examinations should be performed every 3–12 months. Indications for treatment include the following:

  • Significant disease-related symptoms (eg, fatigue, night sweats, weight loss, fever without infection)

  • Threatened end-organ function

  • Progressive bulky disease

  • Progressive anemia

  • Progressive thrombocytopenia

Therapy recommendations for patients at high risk (ie, Rai stages III-IV) and progressive cytopenia are based on the following:

  • Patient age
  • Patient comorbidities
  • Presence or absence of del(17p)
  • Presence or absence of TP53 mutations

For first-line treatment of CLL without del(17p) or TP53 mutations, NCCN category 1 recommendations (based on high-level evidence, with uniform NCCN consensus that the intervention is appropriate) are as follows [19] :

  • Patients < 65 years, without significant comorbidities: FCR (fludarabine, cyclophosphamide, rituximab)

  • Patients ≥65 years, and younger patients with significant comorbidities: Chlorambucil plus obinutuzumab or ibrutinib

For treatment of CLL with del(17p) or TP53 mutations, the NCCN recommends the following [19] :

  • First-line therapy: Ibrutinib (preferred)

  • Post–first-line maintenance therapy: Consider lenalidomide for high-risk patients

  • Relapsed/refractory disease therapy: Ibrutinib (category 1), venetoclax plus rituximab (category 1); other preferred regimens are idelalisib plus rituximab and monotherapy with venetoclax

  • Post–second-line therapy (ie, for patients with complete or partial response to relapsed/refractory therapy): Lenalidomide, ofatumumab

The ESMO guidelines note that patients with del(17p) have a poor response to fludarabine and short survival and instead recommend initial treatment with alemtuzumab or allogeneic stem cell transplantation. ESMO guidelines also recommend allogeneic stem cell transplantation in patients with very-high-risk p53 mutation and/or refractory disease. [78]