22.2 Chronic Leukaemias & Myeloproliferative Neoplasms

2. Chronic Leukaemias & Myeloproliferative Neoplasms (MPNs)

Chronic Myeloid Leukaemia (CML)

• Cytogenetic Hallmark: Reciprocal translocation between the long arms of chromosomes 9 and 22: t(9;22)(q34;q11). This translocates the ABL1 proto-oncogene from chromosome 9 to the breakpoint cluster region (BCR) on chromosome 22, generating a shortened derivative chromosome 22 known as the Philadelphia chromosome. The resultant BCR-ABL1 fusion gene encodes a constitutively active, deregulated tyrosine kinase (p210 oncoprotein) that drives autonomous granulocyte proliferation and inhibits apoptosis.
• Clinical Presentation: Often asymptomatic (~40%) or presents with fatigue, weight loss, night sweats, and dragging left upper quadrant abdominal discomfort due to massive splenomegaly.
• Peripheral Blood Film: Striking, dramatic leukocytosis (often >100 x 10^9/L) displaying the entire spectrum of granulocytic maturation in a smooth, continuous cascade: myeloblasts (<2%), promyelocytes, myelocytes, metamyelocytes, band forms, and mature segmented neutrophils. Absolute basophilia and eosinophilia are universal.
• Discriminator: The Leukocyte Alkaline Phosphatase (LAP / NAP) score is characteristically low or zero in CML (granulocytes are functionally immature and deficient in LAP), which definitively distinguishes CML from a reactive leukaemoid reaction (severe leukocytosis secondary to sepsis or tissue necrosis, where the LAP score is markedly elevated).
• Targeted Pharmacotherapy: First-line treatment with oral BCR-ABL Tyrosine Kinase Inhibitors (TKIs): Imatinib (first-generation), or second-generation TKIs (dasatinib, nilotinib, bosutinib). Disease response is monitored every 3 months using quantitative RT-PCR on peripheral blood to measure BCR-ABL1 transcript levels on the International Scale (major molecular response: BCR-ABL1 <=0.1%).

Chronic Lymphocytic Leukaemia (CLL)

• Epidemiology: The most prevalent leukaemia in the Western world, primarily affecting elderly adults (median age 70 years, male:female ratio 2:1).
• Pathophysiology: Clonal accumulation of immunologically incompetent, mature-appearing CD5+ B lymphocytes in peripheral blood, bone marrow, spleen, and lymph nodes.
• Diagnostic Criteria: Sustained absolute monoclonal B-cell lymphocytosis >=5 x 10^9/L in peripheral blood for >=3 months.
• Blood Film & Immunophenotype:
  • Blood film shows small, uniform, mature lymphocytes with round nuclei, dense clumped ("soccer-ball") chromatin, and scant cytoplasm, alongside characteristic fragile cells damaged during slide preparation, termed "smudge cells" or "smear cells" (Gumprecht shadows).
  • Flow cytometry confirms a pathognomonic co-expression profile: CD5+ (aberrant T-cell marker), CD19+, CD20+ (weak), CD23+, with weak monoclonal surface immunoglobulin.
• Staging Systems (Binet Classification):
  • Stage A: <3 lymph node regions involved; Hb >=100 g/L, platelets >=100 x 10^9/L (median survival >10 years; managed with watchful waiting).
  • Stage B: >=3 lymph node regions involved; Hb >=100 g/L, platelets >=100 x 10^9/L.
  • Stage C: Anaemia (Hb <100 g/L) and/or thrombocytopenia (platelets <100 x 10^9/L), regardless of the number of affected lymph node areas.
• Crucial Clinical Complications:
  1. Hypogammaglobulinaemia: Occurs in up to 60% of patients due to progressive failure of normal polyclonal B-cell function, precipitating recurrent pyogenic bacterial respiratory tract infections (Streptococcus pneumoniae, Haemophilus influenzae). Treated with monthly prophylactic intravenous immunoglobulin (IVIG) if recurrent serious infections occur.
  2. Autoimmune Cytopenias: 10–15% develop Warm Autoimmune Haemolytic Anaemia (AIHA) (DAT positive) or Immune Thrombocytopenia (ITP). Exam pearl: Manage with systemic corticosteroids (oral prednisolone), NOT cytotoxic chemotherapy!
  3. Richter's Transformation: Catastrophic transformation of indolent CLL (in 5–10% of patients) into an aggressive, high-grade Diffuse Large B-cell Lymphoma (DLBCL). Characterized by sudden, rapid enlargement of a localized nodal mass, severe systemic B-symptoms (drenching night sweats, fever, weight loss), and a dramatic spike in serum LDH.

Classical BCR-ABL-Negative Myeloproliferative Neoplasms (MPNs)

Driven by somatic gain-of-function driver mutations that constitutively activate the intracellular JAK-STAT (Janus kinase / signal transducer and activator of transcription) signaling pathway:

• JAK2 V617F Mutation: A point mutation substituting valine for phenylalanine at codon 617 in the auto-inhibitory pseudokinase domain of JAK2 on chromosome 9p. Present in >95% of Polycythaemia Vera (PV), and 50–60% of Essential Thrombocythaemia (ET) and Primary Myelofibrosis (PMF). The remaining ET and PMF cases carry mutations in calreticulin (CALR) (20–30%) or the thrombopoietin receptor (MPL) (5–10%).

1. Polycythaemia Vera (PV):

   • Autonomous, erythropoietin-independent proliferation of erythroid precursors, producing a true absolute expansion of red cell mass.
   • Laboratory Profile: Elevated haematocrit (men >0.49, women >0.48) or haemoglobin (>165 g/L in men, >160 g/L in women). Serum erythropoietin (EPO) is characteristically subnormal or undetectable (in stark contrast to secondary polycythaemia caused by chronic hypoxia, cyanotic heart disease, smoking, or EPO-secreting tumours [renal cell carcinoma, cerebellar haemangioblastoma, hepatocellular carcinoma], where serum EPO is elevated).
   • Clinical Manifestations: Hyperviscosity symptoms (headache, dizziness, tinnitus, blurred vision), aquagenic pruritus (severe, stinging generalized itching without rash occurring within minutes of stepping out of a warm bath or shower, mediated by basophil degranulation and histamine release), gout (from high purine turnover), and atypical venous and arterial thromboses (specifically hepatic vein thrombosis / Budd-Chiari syndrome, mesenteric thrombosis, and stroke).
   • Management: First-line therapy is therapeutic venesection to maintain haematocrit <0.45 (proven by the CYTO-PV trial to significantly reduce cardiovascular death and major thrombotic events), low-dose aspirin (75 mg daily), and cytoreductive therapy with hydroxycarbamide (or pegylated interferon-alfa) in high-risk patients (age >=60 years or prior thrombosis).

2. Primary Myelofibrosis (PMF):

   • Clonal proliferation of atypical megakaryocytes that release massive amounts of fibrogenic cytokines (TGF-beta and PDGF) into the bone marrow stroma, stimulating polyclonal fibroblasts to deposit dense collagen and reticulin fibers.
   • Clinical Hallmarks: Progressive bone marrow obliteration leading to a "dry tap" on bone marrow aspiration (mandating a trephine biopsy), severe extramedullary haematopoiesis (resulting in massive, symptomatic splenomegaly extending into the right iliac fossa), constitutional B-symptoms, and cachexia.
   • Blood Film Signature: Leucoerythroblastic blood film (simultaneous presence of immature nucleated red blood cells and immature granulocytes / myelocytes) alongside pathognomonic "tear-drop" poikilocytes (dacrocytes), which are mechanically deformed as they squeeze out of the fibrotic bone marrow sinuses into the circulation.
   • Treatment: Supportive (transfusions, erythropoietin), JAK1/JAK2 inhibitor ruxolitinib (markedly shrinks splenomegaly and ameliorates debilitating constitutional symptoms), and allogeneic stem cell transplantation in young, fit patients.

3. Comparative Table: Acute vs. Chronic Leukaemias