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Chronic Lymphocytic Leukaemia

CLINICAL FEATURES

• Peripheral blood and bone marrow involvement in all cases
• The number of B-cells in the peripheral blood must exceed 5 x 10⁹/l, unless there is evidence of nodal disease or >30% B-cells in the bone marrow
• Variable degrees of nodal and splenic involvement
• Hypogammaglobulinaemia
• Autoimmune phenomena, particularly haemolysis

LABORATORY DIAGNOSIS

A) Morphology

• Peripheral blood and bone marrow aspirates show a monomorphic population of small lymphocytes with minimal cytoplasm and dense heterochromatin.
• Trephine biopsies show a nodular or diffuse pattern of infiltration. Marrow replacement is common.
• Lymph nodes show a loss of normal architecture and infiltration with small lymphocytes. Proliferation centres consisting of prolymphocytes and immunoblasts are characteristic and may also be seen on trephine biopsies. Previously the term small lymphocytic lymphoma was used when the diagnosis was made on the basis of a lymph node biopsy. This is misleading and B-CLL is now the preferred term.

Small cells with thin rim of cytoplasm	Higher power magnification showing 'smear cell' (arrowed)	Bone marrow trephine biopsy showing extensive infiltration by CLL cells

B) Immunophenotype

• Weak expression of sIg is the characteristic feature of CLL. This is IgD and/or IgM in the majority of cases^[3,4].
• CLL cells also typically express CD20 and CD22 at a lower level than other B-cell lymphoproliferative disorders
• CD19⁺ CD20⁺ CD5⁺ CD23⁺ CD11a^- FMC7^- CD10^- CD38^-
• Immunoglobulin genes show evidence of somatic hypermutation in approximately 50% of cases^[5,6].
• Around 30% of cases have an atypical phenotype. These cases may have stronger sIg expression, the absence of CD23 and expression of CD11a, FMC7 and CD38. These cases often have atypical morphological features.

Four-colour flow cytometric analysis of peripheral blood from a case of chronic lymphocytic leukaemia. The CLL cells co-express CD19 and CD5, but at a lower density than the corresponding 'normal' B-cells and T-cells. There is light chain restriction with almost all the CD19-positive CLL cells expressing sIg-kappa.

CYTOGENETICS

• Trisomy 12 occurs almost exclusively in cases with atypical morphology and phenotype. In affected cases only a proportion of the cells show the abnormality.
• Deletion of 11q, 13q12 and 13q14 are relatively frequent.
• The pathogenic significance of these abnormalities is not known.

Atypical CLL cells showing trisomy 12, demonstrated by FISH (only visible in right-hand cells; out of focal plane in cell on left).

OUTCOME AND THERAPY

• Many patients do not require therapy.
• The median survival of all patients is approximately 9-10 years^[13].
• Chlorambucil is the gold standard treatment. Responses occur in ~60% of patients but complete remission is rare.
• Fludarabine is effective; response rates of up to 80% are seen and complete remission is not uncommon^[14].
• Autologous transplantation is an option in younger patients.
• Monoclonal antibody therapy with Campath 1H is an option in patients who progress following fludarabine^[15].
• Trisomy 12, atypical phenotype and the presence of non-mutated immunoglobulin genes have all been associated with a poorer prognosis although there is still some uncertainty as to the magnitude of this effect.
• Large cell transformation (Richter's syndrome) is a very rare terminal event in B-CLL.

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