Makindo Medical Notes

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)

Chronic Lymphocytic Leukaemia (CLL) is commonly complicated by panhypogammaglobulinaemia. Although IV immunoglobulin can prevent recurrent infections, it does not prolong survival.

About

• CLL is a typically benign, slow-growing malignant clone of B lymphocytes.
• Smear cells may be seen on blood films.
• Lymphocytes - smear cells seen. CLL B cells have CD5 and CD23

Aetiology

• CLL is the most common form of leukaemia in adults.
• It primarily affects individuals over the age of 60.
• Often detected in older patients through routine blood tests showing raised WCC.
• Typically of B cell origin, and it is indolent and slow-growing.
• More common in farmers; possible links to insecticides and chemicals.

Clinical Features

• Often asymptomatic, diagnosed incidentally during routine FBC.
• Some patients may present with lymphadenopathy and hepatosplenomegaly.
• History of recent shingles infection.
• Haemolytic anaemia (warm antibody IgG) may occur, though not caused directly by the leukaemic cells.
• Recurrent infections due to hypogammaglobulinaemia.
• Thrombocytopenia and bone marrow failure may be present.
• Richter's syndrome in less than 10% of cases, where CLL transforms into high-grade Non-Hodgkin B cell lymphoma with poor prognosis.

Investigations

• Full Blood Count (FBC): Hb and platelets may be low, WCC high.
• WCC: > 15 x 10⁹/L with > 40% lymphocytes in the peripheral blood film.
• Smear cells: Seen on blood film as artefacts; CLL cells are fragile and burst easily.
• Immunotyping: Reveals a B cell clone expressing CD19 and CD23.
• Plasma protein electrophoresis: Shows kappa or lambda immunoglobulin light chains.
• Flow cytometry: Can detect monoclonal B lymphocytosis (less than 5 × 10⁹/L).
• Reticulocyte count and Coombs test: To detect autoimmune haemolytic anaemia.
• Monoclonal bands are rarely seen, though IgG, IgA, and IgM levels are usually low.
• Bone marrow biopsy: Not essential for diagnosis, but may provide additional information.
• Cytogenetics: Detection of chromosome 17p deletion or TP53 mutation provides prognostic insight.

Differential Diagnosis: Myelofibrosis vs CML

• Myelofibrosis: Abnormal megakaryocytes release factors that increase localized bone marrow fibrosis, leading to extramedullary haematopoiesis.
• Philadelphia chromosome: Absent in myelofibrosis, present in CML.
• Leucoerythroblastic blood film: Seen in myelofibrosis, with "teardrop" cells.
• Hepatosplenomegaly: Common in myelofibrosis.
• Blood Counts: High platelets and WCC in early myelofibrosis, later leading to anaemia and cytopenia.
• LAP Score: May be high in myelofibrosis, low in CML.

Staging (Rai Staging)

• Stage 0: Lymphocytosis only (WCC > 5x10⁹/L) – 15-year survival.
• Stage 1: Lymphocytosis and lymphadenopathy – 8-year survival.
• Stage 2: Lymphocytosis and splenomegaly – 6-year survival.
• Stage 3: Lymphocytosis and Hb < 11g/dL – 3-year survival.
• Stage 4: Lymphocytosis and thrombocytopenia (<100 x10⁹/L) – 2-year survival.
• Prognosis also depends on levels of Beta2-microglobulin, thymidine kinase, and soluble CD23.
• Low levels of ZAP-70 indicate a good prognosis (ZAP = zeta associated protein), measurable via flow cytometry.

Indications for Treatment

• Progressive marrow failure: worsening anaemia and/or thrombocytopenia.
• Massive or progressive lymphadenopathy (>10 cm).
• Massive or progressive splenomegaly (>6 cm).
• Progressive lymphocytosis: > 50% increase over 2 months or lymphocyte doubling time < 6 months.
• Systemic symptoms: weight loss > 10% in the past 6 months, fever > 38°C for > 2 weeks, night sweats, extreme fatigue.
• Autoimmune cytopenias such as immune thrombocytopenia (ITP).

Management

• Treat bacterial infections or shingles promptly.
• Many patients require no treatment and may have a normal life expectancy with regular follow-up.
• Treatment is required for bone marrow failure, massive lymphadenopathy, splenomegaly, weight loss, rising WCC, autoimmune haemolytic anaemia, or thrombocytopenia.
• Younger patients (under 70) without TP53 mutations: Fludarabine, cyclophosphamide, and Rituximab (FCR) is the standard treatment.
• Older or less fit patients: Rituximab with Bendamustine or oral chlorambucil is preferred.
• Obinutuzumab, a more potent anti-CD20 antibody, may be superior to Rituximab in some cases.
• Ibrutinib, a Bruton's tyrosine kinase inhibitor, is also useful in CLL management.
• Steroids are helpful for treating Coombs-positive haemolytic anaemia; splenectomy may be necessary if steroids fail.
• Radiotherapy may be used for massive lymphadenopathy or splenomegaly causing symptoms.
• Richter's transformation (CLL to aggressive high-grade lymphoma) is a possible complication.