Current NCCN Recommendations for CLL/SLL Diagnosis – Version 1.2023

Introduction

Both CLL and SLL are characterized by the progressive accumulation of leukemic cells in peripheral blood, bone marrow, and lymphatic tissues. Morphologically, these cells can be described as small, mature lymphocytes, occasionally mixed with larger or atypical cells or prolymphocytes. CLL and SLL essentially represent different manifestations of one disease. While SLL predominantly involves abnormally lymphocytes in lymph nodes, bone marrow, and other lymphatic tissues, CLL also features significant circulating abnormal lymphocytes in the bloodstream.

Diagnostic Procedure

Essential Tests for Diagnosis

• Evaluation of peripheral blood count and bone marrow aspirate or histopathological evaluation of a bone marrow or lymph node sample.
• Flow cytometry blood testing is adequate for diagnosing CLL/SLL – thus, a biopsy is generally not required.
  • For diagnosing CLL, the presence of monoclonic B lymphocytes ≥ 5 × 10⁹/l in peripheral blood is required.
  • B-cell clonality should be confirmed by flow cytometry.
  • Adequate immunophenotyping for diagnosis by flow cytometry using cellular surface markers includes: kappa/lambda, CD19, CD20, CD5, CD23, CD10, CD200. If flow cytometry is used for diagnosis, a cytospin for cyclin D1 or fluorescence in situ hybridization (FISH) for t(11;14), t(11q;v) should be included.
  • For SLL, the presence of lymphadenopathy and/or splenomegaly with monoclonal B lymphocytosis ≤ 5 × 10⁹/l in peripheral blood is essential.
  • The diagnosis of SLL should be confirmed by histopathological examination of a biopsied lymph node.
• If the diagnosis is not established using flow cytometry, a lymph node biopsy is essential. Bone marrow aspiration with biopsy is important when other material is non-yielding. Fine needle aspiration biopsy (FNAB) is not recommended.
  • Adequate immunophenotyping determined via immunohistochemistry uses: CD3, CD5, CD10, CD20, CD23, cyclin D1, LEF1, and SOX11.
• Absolute monoclonal B-lymphocyte count.

Tests Informative for Prognosis and/or Treatment Establishment

• FISH for detecting +12; del(11q); del(13q); del(17p).
• TP53 sequencing.
• Karyotyping from CpG-stimulated metaphase for determining complex karyotype (CK).
• Molecular analysis to detect mutational status of IGHV (variable regions of the immunoglobulin heavy chain gene).

In monoclonal B-cell lymphocytosis (MBL) with an absolute B-lymphocyte count < 5 × 10⁹/l and all lymph nodes up to 1.5 cm in size, without anemia, thrombocytopenia, organomegaly, and without B symptoms, the patient can be merely monitored.

Summary of Other Recommended Examinations in Case of CLL/SLL Diagnosis

Basic Examinations

• Medical history and physical examination including measurement of enlarged lymph nodes, liver, and spleen.
• Performance status.
• B symptom.
• Blood count with differential count.
• Complete biochemical examination including lactate dehydrogenase (LDH).

Meaningful Examinations Depending on Circumstances

• Quantitative determination of immunoglobulins.
• Determination of reticulocyte count, haptoglobin, direct antiglobulin test (Coombs).
• CT examination of chest/abdomen/pelvis with contrast, if clinically indicated.
• Beta-2-microglobulin.
• Uric acid.
• Bone marrow aspiration and biopsy from one site.
• Determination of hepatitis B and C serology.
• ECHO of the heart if a regimen with anthracyclines is indicated.
• Pregnancy test in women of childbearing age.
• Discussion about fertility preservation options.
• PET/CT examination to determine suitable lymph node biopsy if there is a suspicion for histological transformation.

Conclusion

The diagnosis of CLL requires the presence of at least 5 × 10⁹/l monoclonal B lymphocytes in peripheral blood, and lymphocyte clonality should be confirmed by flow cytometry.

In SLL, lymphadenopathy or splenomegaly is present with peripheral blood B lymphocyte levels < 5 × 10⁹/l. The diagnosis of SLL ideally should be confirmed by lymph node biopsy.

Additional examinations after diagnosis are similar to those for other lymphoid neoplasms.

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Source: Wierda W. G., Brown J., Abramson J. S. et al. NCCN guidelines: Chronic lymphocytic leukemia/small lymphocytic lymphoma. Version 1.2023. National Comprehensive Cancer Network, 2022 Aug 30. Available at: www.nccn.org/professionals/physician_gls/pdf/cll.pdf