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Chronic Lymphocytic Leukemia (CLL)

  • Heterogeneous group of diseases
  • Characterised by an increased number of small, mature-appearing lymphocytes in the blood
  • The distinction between CLL and non-Hodgkin lymphoma (NHL) depends on presence or absence of peripheral blood involvement, respectively
  • Most common type of CLL is the proliferation of small B cells that express CD5 (T-cell associated Ag)
    • Other types

B-cell diffuse small lymphocytic lymphoma (SLL has no lymphocytosis)

      • Hairy cell leukaemia (HCL)
      • B-cell prolymphocytic leukaemia (B-PLL)

1. B-CELL CLL/SLL

Epidemiology

  • MC in adults
  • United States and W. Europe
  • MC in 55-65 year olds

Pathophysiology

  • Characterised by slow but persistent accumulation of small lymphocytes
    • They are arrested at a functionally immature level
  • CLL  and SLL cannot be distinguished on examination alone. They are distinguished by presence of lymphocytosis
    • CLL if there is lymphocytosis in the blood – >5000 lymphocytes/μL
    • SLL if there is no lymphocytosis
  • Complications of CLL are considered in relation to 4 factors
    • Immunosuppression
    • Autoimmune phenomena
    • Mass effects
    • Transformation to large cell lymphoma
  • Hypogammaglobulinemia is common – so pts are exposed to infections e.g. S.pneumoniae
  • There are also abnormalities in T-cell number and function – e.g decrease ratio of CD4/CD8 and impaired cell-mediated immunity

Clinical features

  • Most pts are asymptomatic at dx – lymphocytosis is detected incidentally at routine CBC
  • Symptoms due to anaemia – fatigue, dizziness, dyspnoea
  • Nonspecific symptoms – fever, night sweats, weight loss
  • Physical exam can be normal
    • MC abnormality is lymphadenopathy
    • Mild/moderate hepatomegaly

Diagnosis

  • Must be >5000 ly/μL
  • Mild anemia or thrombocytopenia
  • Hypogammaglobulinemia
  • Blood smear – very characteristic
    • ↑number of small mature-appearing lymphocytes
    • Nuclear chromatin looks condensed, looks like dense chunks of chromatic surrounded by white spaces (“Soccer ball nucleus”)
    • Many disintegrated cells on the smear (smudge cells)
    • may be occasional prolymphocytes (larger cells, with less condensed nuclear chromatin)
  • Bone marrow
    • >30% small lymphocytes
    • Infiltration can be nodular, interstitial or diffuse (worst prognosis)
  • Immunophenotype
    • Expression of CD19, 20, 23, 34 (B-cell markers)
    • CD5 (T-cell marker)
    • Weak (dim) expression of surface Ig with light chain restriction
      • This distinguishes CLL/SLL from mantle cell lymphoma (MCL) which has bright expression of Ig
  • Cytogenetics
    • Chromosomal deletions on – 11, 13, 17
      • Deletion on C13 – good prognosis

Differential diagnosis

  • Reactive lymphocytosis – MC in younger people. Lymphocytes have more variable appearance
  • Leukemic phase of NHL
    • SLL – lymphocytes <5000/μL
    • MCL – smudge cells are absent. Immunophenotyping by flowcytometry shows difference in surface markers (bright CD20; FMC-7, bright surface Ig, absence of CD23)
    • Follicular lymphoma – lys have prominent nuclear folds/clefts
  • Prolymphocytic leukemias – larger cell size, less condensed chromatin, different Immunophenotype (CD5 negative)

Staging

  • The stage in both systems depends on presence of lymphadenopathy and BM compromise

Disease course

  • Most pts have indolent disease with long survival
  • Complications
    • Infections – S.pneumoniae, S.aureus, H.influenza, E.coli, P.aeruginosa
    • Autoimmune phenomena – antibodies against blood cells
      • Autoimmune HA – warm type. Abs are produced by residual normal B-cells; directed against Rh blood group
      • Immune thrombocytopenia
      • Evan’s syndrome – simultaneous AIHA and AI thrombocytopenia
    • Progression to large cell lymphoma ( Richter syndrome )
      • Unresponsive to therapy

Treatment

  • Incurable with conventional therapy. Main goal of tx is to control symptoms and maximise quality of life
  • Indications for treatment
  • To remember tx – RFC
    • Rituximab, Fludarabine, Cyclophosphamide
    • Progressive systemic symptoms – fever, night sweats, WL
    • Progressively worsening anaemia or thrombocytopenia
    • AIHA or thrombocytopenia
    • Bulky lymphadenopathy that compresses vital structures
    • Marked splenomegaly
    • Marked lymphocytosis – >150,000/μL
  • Treatments
    • Alkylating agents – cylcophosphamide, chlorambucil
    • CTST – prednisolone (for autoimmune phenomena)
    • Purine analogues – fludarabine
    • Monoclonal Ab – rituximab (directed against CD20)
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