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.

Cases — Chronic Lymphocytic Leukaemia (CLL)

• Case 1 — Incidental Lymphocytosis: A 72-year-old man has routine bloods for hypertension follow-up. FBC shows WCC 22 ×10⁹/L with predominant lymphocytosis, Hb 13.4 g/dL, platelets normal. He is well with no B symptoms. Flow cytometry demonstrates a clonal population of CD5+, CD23+ B cells. Diagnosis: Early-stage asymptomatic CLL (Rai stage 0).
• Case 2 — Symptomatic Progression: A 65-year-old woman presents with fatigue, drenching night sweats, and 5 kg weight loss. Examination reveals generalised lymphadenopathy and splenomegaly. Bloods: Hb 9.8 g/dL, WCC 65 ×10⁹/L, platelets 85 ×10⁹/L. Diagnosis: Symptomatic CLL with cytopenias requiring treatment.
• Case 3 — Complication (Autoimmune Haemolysis): A 70-year-old man with known CLL presents with jaundice and dark urine. Hb 7.2 g/dL, reticulocytes high, LDH raised, direct Coombs test positive. LFTs show unconjugated hyperbilirubinaemia. Diagnosis: Autoimmune haemolytic anaemia secondary to CLL.

Teaching Commentary 🧬

CLL is the most common adult leukaemia in the UK, usually affecting older men. It arises from a monoclonal proliferation of mature but dysfunctional B lymphocytes. Many patients are diagnosed incidentally, but progression can lead to anaemia, thrombocytopenia, bulky lymphadenopathy, and systemic symptoms. Autoimmune cytopenias (especially haemolytic anaemia and ITP) are important complications. Management depends on stage and symptoms: watchful waiting is safe in early disease, whereas progressive/symptomatic cases may require targeted agents such as ibrutinib, venetoclax, or chemo-immunotherapy. Prognosis is variable and influenced by genetic markers (e.g., del(17p)).