Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)

Background

• CLL is a hematologic malignancy characterized by progressive accumulation of phenotypically mature malignant B-cell lymphocytes in peripheral blood, bone marrow, and lymph nodes.
• CLL is the most common leukemia in adults with a reported incidence of about 4-6 per 100,000 people per year in Western countries.
• CLL is more common in White individuals and men; with median age of diagnosis 72 years.
• Most patients are asymptomatic when diagnosed but 10% may present with night sweats, weight loss, fatigue, and fever (B symptoms). Enlarged lymph nodes is the most common finding.
• The cause of CLL is unclear, although it may be associated with exposure to some chemicals and toxins. Several genetic mutations, including in TP53, ATM, MYD88, NOTCH1, and SF3B1 have been identified in patients with CLL.
• Many biological markers have been identified and used in risk stratification for CLL; only the presence of del17p, TP53 mutations, and del(11q) with unmutated IgVH are considered to influence clinical management of patients with CLL.
• SLL is a different manifestation of the same disease as CLL, with the main difference being that abnormal lymphocytes mainly accumulate in lymph nodes and other tissues; bone marrow may be involved but usually with patchy disease and there are no circulating tumor cells or evidence of cytopenias.
• Monoclonal B-cell lymphocytosis (MBL) is described as a disease with a low burden of monoclonal B cells (< 5,000 per mm³) that are phenotypically identical to CLL cells, but without evidence of lymphadenopathy, cytopenias, or bone marrow involvement.

Evaluation

• Suspect CLL in patients who are found to have monoclonal B lymphocytes ≥ 5 × 10⁹/L (≥ 5,000 per mm³) by flow cytometry, and who have evidence of lymphadenopathy, organomegaly, and/or cytopenias and symptoms from these clinical findings.
• Suspect SLL in patients found to have monoclonal B lymphocytes ≤ 5 × 10⁹/L (≤ 5,000 per mm³) by flow cytometry with adenopathy and absence of cytopenias.
• Suspect Monoclonal B-cell lymphocytosis (MBL) in older patients found to have monoclonal B lymphocytes < 5 × 10⁹/L (< 5,000 per mm³) by flow cytometry without evidence of lymphadenopathy, organomegaly, and/or cytopenias.
• Perform the following workup to establish diagnosis:
  • complete blood count with immunophenotyping by flow cytometry (Strong recommendation).
  • peripheral blood smear, which typically shows
    • small mature lymphocytes with a narrow border of cytoplasm and a dense nucleus without discernible nucleoli and with partially aggregated chromatin
    • presence of "smudge cells" due to lymphocyte debris from preparation of the peripheral smear is characteristic of CLL
  • lymph node biopsy for diagnosis of SLL; histopathologic evaluation of the lymph node (whenever possible) showing lymph node architecture effacement(Strong recommendation).
• The routine work-up before treatment includes a complete blood count with differential, and a comprehensive metabolic panel (Strong recommendation).
• Additional testing may include:
  • fluorescence in situ hybridization (FISH) or stimulated cytogenetics to detect chromosomal abnormalities (Strong recommendation).
    • deletion of chromosomes 11 (del[11q]), 13 (del[13q]), or 17 (del[17p])
    • translocations of chromosome 11 - t(11;14)
    • additional chromosome 12 (trisomy 12)
  • molecular analysis for (Strong recommendation)
    • immunoglobulin heavy-chain variable (IGHV) mutation status
    • TP53 sequencing
  • unilateral bone marrow biopsy (with or without aspirate) at initiation of therapy not always needed, unless to help diagnose unclear cytopenias (Weak recommendation)
  • serology testing for hepatitis B and C, cytomegalovirus (CMV), and human immunodeficiency virus (HIV) if treatment with chemotherapy, alemtuzumab, CD20 monoclonal antibody or allogeneic stem cell transplantation is planned (Strong recommendation).
  • assessment of quantitative immunoglobulins, reticulocyte count, haptoglobin, direct Coombs test, beta-2 microglobulin (B2M), and/or uric acid (Weak recommendation).
  • pregnancy testing in patients of childbearing age if any therapy is planned (Weak recommendation).
  • imaging studies, such as:
    • chest/abdominal/pelvic computed tomography (CT) if peripheral adenopathy and symptoms suggest bulky lymph node disease or to distinguish SLL from monoclonal B-cell lymphocytosis (Weak recommendation).
    • positron emission tomography (PET) scan may assist in directing nodal biopsy if Richter's transformation suspected (Weak recommendation).
• Because leukemic clones may evolve, FISH and TP53 mutation analyses should be repeated before treatment in patients who are initially observed, or before treatment for relapse initiated (Strong recommendation).
• Staging can be done using Rai or Binet staging systems.

Management

• Treatment indication is based on the presence of symptomatic active disease, regardless of initial presentation, relapsed disease or presence of del(17p) or TP53 mutation.
• Other indications for treatment may include (Strong recommendation):
  • threatened end-organ function
  • complications from lymphadenopathy, splenomegaly, and/or hepatomegaly
  • presence of B-symptoms
  • progressive anemia and/or thrombocytopenia if not due to autoimmune hemolytic anemia or thrombocytopenia
• If there is no indication for treatment, offer observation and monitoring (with blood counts and clinical exam every 3-12 months) to assess for development of indications for treatment (Strong recommendation).
• Evaluate fitness (performance status, for example) and comorbidity burden of patients to guide treatment choices.
• Management decisions may be based on presence of del(17p)/TP53 mutation, along with age, comorbidities and disease status (initial or relapsed/refractory).
• Consider enrollment in a clinical trial for all patients with CLL (Weak recommendation).
• For initial management of CLL in patients with indications for treatment regardless of presence of del(17p)/TP53 mutation, offer one of:
  • acalabrutinib with or without obinutuzumab (Strong recommendation)
  • venetoclax plus obinutuzumab (Strong recommendation)
  • zanubrutinib (Strong recommendation for patients without del(17p)/TP53 mutation; Weak recommendation for patients with del(17p)/TP53 mutation)
  • ibrutinib monotherapy (Strong recommendation for patients without del(17p)/TP53 mutation; Weak recommendation for patients with del(17p)/TP53 mutation).
• For management of relapsed or refractory CLL in patients regardless of presence of del(17p)/TP53 mutation, offer one of:
  • acalabrutinib (Strong recommendation)
  • venetoclax plus rituximab (Strong recommendation)
  • ibrutinib (Strong recommendation), with evaluation of cardiac function prior to initiation
  • zanubrutinib (Strong recommendation)
  • venetoclax monotherapy (Weak recommendation).
• Perform a response assessment to determine quality and duration of response and plan next treatment (Strong recommendation).
• Provide supportive care for patients throughout treatment, including monitoring for and management of complications (Strong recommendation).