Makindo Medical Notes.com

Related Subjects: |Leukaemias in General |Acute Promyelocytic Leukaemia |Acute Myeloblastic Leukaemia (AML) |Acute Lymphoblastic Leukaemia (ALL) |Chronic Lymphocytic leukaemia (CLL) |Chronic Myeloid Leukaemia (CML) |Hairy Cell Leukaemia |Differentiation syndrome |Tretinoin (All-trans-retinoic acid (ATRA) ) |Haemolytic anaemia |Immune(Idiopathic) Thrombocytopenic Purpura (ITP)

CLL is commonly complicated by panhypogammaglobulinaemia. Although IV immunoglobulin prevents recurrent infections it does not prolong survival.

About

• Usually a benign slow-growing malignant clone of B lymphocytes
• May see Smear cells

Aetiology

• CLL is the commonest leukaemia in adults
• It is commonest in those over 60 years of age
• Older patients in a blood film with raised WCC
• Usually B cell origin and Indolent and slow-growing
• Commoner in Farmers? insecticides? chemicals

Clinical

• Asymptomatic and diagnosed on a routine FBC
• Some may have Lymphadenopathy, Hepatosplenomegaly
• Recent shingles infection
• Haemolytic anaemia - usually a warm antibody IgG haemolytic anaemia may be seen but oddly not by the leukaemic cells! The mechanism is unknown
• Infections due to hypogammaglobulinemia
• Thrombocytopenia and marrow failure
• Richter's syndrome is seen in less than 10% where the CLL transforms to a high-grade Non-Hodgkin B cell lymphoma with a poor prognosis

Investigations

• Hb and platelets may be low and WCC high
• WCC > 15 x 10⁹/L with > 40% lymphocytes in the peripheral film.
• Excess lymphocytes are B lymphocytes (95%) the remaining 5% are T lymphocytes)
• 'Smear cells' are seen on blood film - artefact as cells damaged in process of making a film. CLL cells are fragile and burst.
• Immunotyping - shows a clone of B cells expressing CD19 and CD23
• Plasma protein electrophoresis: kappa or lambda immunoglobulin light chains
• Flow cytometry: CLL cells at a level less than 5 × 10⁹/L called monoclonal B lymphocytosis of uncertain significance
• Reticulocyte count and a direct Coombs test for autoimmune haemolytic anaemia
• Rarely a monoclonal band can be seen. More usually low IgG IgA IgM
• Bone marrow examination by aspirate and trephine not essential to make a diagnosis
• Cytogenetics: loss of chromosome 17p or mutation in the TP53 gene helps prognostically

Differential: Myelofibrosis vs CML

• Myelofibrosis - abnormal megakaryocyte precursors release a factor increasing localised fibrosis within the bone marrow. This leads to extramedullary haemopoiesis
• Myelofibrosis - absent Philadelphia chromosome but seen in CML
• Myelofibrosis - A leucoerythroblastic blood film with "teardrop" shaped cells
• Myelofibrosis - hepatosplenomegaly
• Myelofibrosis - high platelets and white cells which eventually falls and anaemia
• Myelofibrosis - possible high LAP score, Low in CML

Staging

• Stage 0 - lymphocytosis only (WCC > 5x10⁹) > 15 year survival
• Stage 1 - lymphocytosis (WCC > 5x10⁹) and lymphadenopathy- 8 year survival
• Stage 2 - lymphocytosis (WCC > 5x10⁹) and splenomegaly - 6 year survival
• Stage 3 - lymphocytosis (WCC > 5x10⁹) and Hb < 11g/dl - 3 year survival
• Stage 4 - lymphocytosis (WCC > 5x10⁹) and Thrombocytopenia (<100 x10⁹) - 2 year survival
• Prognosis is also related to the levels of Beta2-microglobulin, thymidine kinase and soluble CD23
• Low levels of ZAP-70 indicated a good prognosis ZAP = zeta associated protein. Measured using flow cytometry

Indication for Treatment

• Progressive marrow failure: worsening of anaemia and/or thrombocytopenia. This is importing and when assessing needs for therapy.
• Massive (>10 cm) or progressive lymphadenopathy
• Massive (>6 cm) or progressive splenomegaly
• Progressive lymphocytosis: > 50% increase over 2 months or lymphocyte doubling time < 6 months
• Systemic symptoms: weight loss > 10% in previous 6 months, fever >38°C for > 2 weeks, extreme fatigue, night sweats
• Autoimmune cytopaenias e.g. ITP

Management

• Acutely treat any bacterial infections or shingles.
• Many patients require no treatment but just regular follow up and life expectancy may be unaltered.
• Treatment needed for bone marrow failure, massive lymphadenopathy, weight loss, sweats, rise in WCC, autoimmune haemolytic anaemia or thrombocytopenia
• Younger pts (<70) and TP53 mutation-negative, fludarabine, cyclophosphamide and Rituximab (FCR) is standard care.
• Older, less fit patients, Rituximab with bendamustine or oral chlorambucil.
• A more potent type 2 anti-CD20 antibody, Obinutuzumab, has is superior to Rituximab
• Ibrutinib inhibits Bruton's tyrosine kinase and may also be useful
• Steroids are useful for those with a Coomb's positive haemolytic anaemia, Splenectomy if that fails
• Ultimately patients become immunoparesed, anaemic and vulnerable to infection with bone marrow failure
• Radiotherapy for massive lymphadenopathy or splenomegaly causing symptoms
• CLL can transform to aggressive high-grade lymphoma, called Richter's transformation.