Chronic Lymphocytic Leukemia

CLL is characterized by a progressive accumulation of monoclonal, mature, non-functional B lymphocytes. CLL is usually discovered on routine blood tests as an isolated lymphocytosis. It is defined by a > 5000/uL B-lymphocytes in the peripheral blood that are marked CD5+ and CD23+. The aberrant expression of CD5+ (a T-cell marker) is very specific for CLL. Treatment is not required for asymptomatic patients as it does not improve survival. Rituximab is a very useful drug used for targeted immunotherapy in CLL.

CLL is the most common leukemia in adults in the Western world. Incidence rises with age. 90% of cases are older than 50 years. The median age of diagnosis is 70 years. It affects males > females.

Rai staging system of CLL

based on the fact that there is a gradual and progressive increase in the body burden of leukemic lymphocytes that progressively invade other tissue and compromise bone marrow function.

Binet staging of CLL

Classifies patients according to the 5 potential sites of involvement (cervical, axillary, inguinal, spleen, and liver) and presence of anemia and/or thrombocytopenia

• Risk factors for CLL
  • Chemical exposure
    • Farmers and agricultural workers
    • Rubber workers
    • Petroleum workers
  • Familial history (strongest risk factors)
    • History of CLL
    • History of Low-grade lymphoma
  • Mutations, trisomies, anddeletions
    • del17p13
• Clinical features Rarely presents with symptoms. Up to 70% of patients are asymptomatic on presentation.
  • Weight loss and night sweats (constitutional B-symptoms)
  • Peripheral lymphadenopathy
  • Hepatosplenomegaly (due to invasion and extramedullary hematopoiesis)
  • Fatigue, pallor, breathlessness (due to anemia)
  • Recurrent infection and fever (due to neutropenia)
  • Easy bruising (due to thrombocytopenia)
  • Leukemia cutis (due to skin involvement)
    • Macules, plaques, blisters, ulcers and nodules

• How does CLL cause cytopenia (anemia and thrombocytopenia)?
  • Leukemic infiltrate of the bone marrow
  • Autoimmune hemolysis and destruction of platelets
  • Hypersplenism
  • Chemotherapy
• What are the autoimmune complications seen in CLL? Occurs in 4% to 25% of CLL/SLL patients
  • Autoimmune Hemolytic Anaemia
  • Immune Thrombocytopenia
  • Autoimmune agranulocytosis
  • Pure red cell aplasia
• Investigations
  • Peripheral Blood evaluation
    • Complete Blood Count: absolute lymphocytosis of >5×10^9/L (patients can have counts as high as 100×10^9/L)
    • Peripheral Blood Film:
      • Lymphocytosis (cells are small, mature appearing lymphocytes with a dense nucleus, partially aggregated or clumped chromatin without discernable nucleoli, they have a scanty basophilic cytoplasm), “
      • Smudge” cells or “basket” cells (Lymphocytes that appear to have been flattened or smudged in the process of being spread on the glass slide.
  • Bone marrow evaluation ***BMA and trephine biopsy are not required for diagnosis of CLL
    • Bone Marrow Aspirate: normal to increased cellularity with lymphocytes accounting for more than 30% of nucleated cells
    • Trephine Biopsy: exhibits a range of infiltration patterns (focal, non-para trabecular nodules; interstitial infiltrates – CLL cells are admixed with hematopoietic elements and diffuse solid lesions) ***The pattern of Bone marrow infiltration is useful to distinguish CLL from other DDx considerations
  • Immunophenotyping (Flow cytometry) ***essential for establishing Dx and prognostication
    • B-cell markers: CD19+, CD20+, CD23+, CD5+ (Aberrant expression of CD5+ – a T-cell markers – is very specific for CLL) SmIg weak (Only a single IgL chain is expressed confirming the clonal nature of these cells)
    • T-cell markers: CD3+, CD4+, CD5+, CD8+
  • Cytogenetics ***Evaluation with FISH is routine for pretreatment evaluation of patients with CLL
    • Chromosomal abnormalities: del(13q), del(17p), del(11q), trisomy 12 in more than 80% of CLL cases *** These alterations are neither sensitive nor specific for CLL Dx.

• Non-favorable Prognostic markers
  • Clinical: Male, Age > 60y, ECOG status > 0 , Lymphocyte doubling time <12 months
  • Lab: CD38+, CD49d+, ZAP-70+, Elevated serum-free IgL chain, IgM peak, Elevated serum thymidine kinase, Elevated B2-microglobulin
  • Genetic: IGVH unmutated, IGHV3-23 usage, 17p13 del, TP53 mutation, t(14:19)(q32:q13), MYC translocation, Complex Karyotype, NOTCH1 mutation, SF381 mutation
• Favorable prognostic markers
  • Clinical: Female, Age <60y
  • Lab: CD38-, CD49d-, ZAP-70-
  • Genetic: IGHV hypermutated, Trisomy 12, 13q14 del
• What is the difference between CLL and SLL?
  • SLL is essentially the solid tissue (lymph node) component of CLL.
  • The diagnosis of SLL is reserved for:
    • Lymph node biopsy consistent with CLL/SLL: diffusely effaced architecture, naked germinal centers, infiltration of mature-appearing small lymphocytes
    • Absolute peripheral lymphocytosis < 5000/uL
• Treatment
  • Fludarabine + Cyclophosphamide + Rituximab for young, healthy patients
  • Chlorambucil + Rituximab for older patients, or patients with comorbidities
  • Prednisone or IVIG for autoimmune manifestations
  • Splenectomy for autoimmune cytopenia
• Complications
  • Chemotherapy related complications
    • CMV reactivation seen with Fludarabine, among other drugs
  • Hypogammaglobulinemia (5-10%)
  • Autoimmune hemolytic anemia (1-5%): Tx with Prednisone or IVIG
  • Immune thrombocytopenic purpura (1-5%): Tx with Prednisone
  • Pure red cell aplasia (1-6%): Tx with Prednisone
  • Richter transformation (5%): sudden onset of B-symptoms. Transformation of CLL to high-grade non-Hodgkin lymphoma.