13.2 Haematological Malignancies: Leukaemias, Lymphomas & Myeloma

Haematological Malignancies: Leukaemias, Lymphomas & Myeloma

Haematological malignancies encompass a broad spectrum of neoplastic proliferations arising from hematopoietic stem cells, myeloid or lymphoid progenitors, and differentiated lymphoid or plasma cell lineages. Clinical investigation and urgent referral pathways follow NICE guidelines (NG12: Suspected cancer recognition and referral) and British Society for Haematology standards.

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1. Acute Leukaemias

Acute leukaemias are characterised by the rapid, clonal proliferation of immature, non-functional hematopoietic blast cells arrested in early differentiation. Blasts accumulate in the bone marrow (>20% marrow cellularity) and spill into the peripheral blood, displacing normal haematopoiesis and causing fulminant bone marrow failure:

• Anaemia: Severe lethargy, exertional dyspnoea, pallor, and cardiac ischaemia.
• Neutropenia: Recurrent, severe, or opportunistic bacterial and fungal infections; fever.
• Thrombocytopenia: Petechiae, spontaneous ecchymoses, epistaxis, and mucosal bleeding.

Acute Myeloid Leukaemia (AML)

• Epidemiology: Predominantly an illness of older adults (median age at diagnosis ~68 years).
• Diagnostic Hallmarks: Peripheral blood film and bone marrow aspirate show large, granular myeloblasts. The presence of Auer rods—clumped crystalline aggregates of lysosomal myeloperoxidase visible as pink/red linear needle-like cytoplasmic inclusions—is pathognomonic of AML.
• Acute Promyelocytic Leukaemia (APML / AML M3):
  • Cytogenetics: Pathognomonic reciprocal translocation t(15;17)(q24;q21), which fuses the promyelocytic leukaemia (PML) gene on chromosome 15 to the retinoic acid receptor alpha (RARA) gene on chromosome 17, blocking myeloid differentiation at the promyelocyte stage.
  • Medical Emergency: Promyelocytes contain abundant azurophilic granules rich in tissue factor and annexin II. Cell breakdown triggers fulminant, catastrophic Disseminated Intravascular Coagulation (DIC), with high risks of early intracranial or pulmonary haemorrhage.
  • Immediate Therapy: Immediately initiate All-Trans Retinoic Acid (ATRA / Tretinoin) alongside arsenic trioxide (ATO) the moment APML is clinically or morphologically suspected, without waiting for cytogenetic or PCR confirmation. ATRA forces malignant promyelocytes to differentiate into mature neutrophils, terminating the procoagulant crisis.

Acute Lymphoblastic Leukaemia (ALL)

• Epidemiology: The commonest childhood malignancy, with a peak incidence between 2 and 5 years of age; a second smaller incidence peak occurs in adults over 60 years.
• Clinical Presentation: Bone and joint pain (often presenting as a limp or refusal to bear weight due to leukaemic marrow expansion and periosteal infiltration), pallor, bruising, high fevers, generalized painless lymphadenopathy, and prominent hepatosplenomegaly.
• Sanctuary Sites: Leukaemic lymphoblasts characteristically infiltrate anatomical sanctuary sites shielded by biological barriers, namely the Central Nervous System (CNS) and the testes (manifesting as painless, stony-hard testicular enlargement).
• Management: Multi-agent systemic induction chemotherapy followed by prolonged maintenance therapy. Intrathecal chemotherapy (methotrexate and cytarabine) is mandatory for CNS prophylaxis and treatment. Childhood ALL achieves cure rates exceeding 90%.

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2. Chronic Leukaemias

Chronic Myeloid Leukaemia (CML)

• Pathophysiology: A clonal myeloproliferative neoplasm characterized by the unregulated proliferation of mature and maturing granulocytic lineages. Driven by the Philadelphia chromosome, an acquired reciprocal translocation t(9;22)(q34;q11).
• Molecular Genetics: Translocates the ABL1 proto-oncogene from chromosome 9 to the BCR locus on chromosome 22, generating the BCR-ABL1 fusion gene. This encodes a constitutively active p210 tyrosine kinase that drives autonomous cellular proliferation and suppresses apoptosis.
• Clinical Presentation: Often discovered incidentally on routine full blood count; symptomatic patients present with weight loss, nocturnal hyperhidrosis, fatigue, gout (hyperuricaemia from rapid purine turnover), and symptoms of massive splenomegaly (early satiety, dragging left upper quadrant fullness).
• Laboratory Profile: Profound leukocytosis (frequently 50–300 x 10^9/L) displaying the entire spectrum of granulocytic differentiation (myeloblasts <10%, promyelocytes, myelocytes, metamyelocytes, band forms, and mature neutrophils). Markedly elevated basophil and eosinophil counts.
• Targeted Therapy: First-line treatment revolutionized survival through oral Tyrosine Kinase Inhibitors (TKIs), primarily Imatinib (first-generation) or second-generation TKIs (Dasatinib, Nilotinib). TKIs competitively bind the ATP-binding pocket of the BCR-ABL1 kinase, restoring normal haematopoiesis and achieving near-normal life expectancy.

Chronic Lymphocytic Leukaemia (CLL)

• Pathophysiology: The most prevalent leukaemia in adults in Western countries; median age at diagnosis ~70 years. Arises from a clonal expansion of incompetent, mature-appearing B-lymphocytes co-expressing CD5, CD19, and CD23.
• Clinical Presentation: Over 70% of patients are entirely asymptomatic at presentation, identified via an incidental finding of marked absolute lymphocytosis (>5 x 10^9/L). Symptomatic patients manifest with painless, non-tender, symmetrical, rubbery generalized lymphadenopathy, hepatosplenomegaly, and fatigue.
• Blood Film: Packed with small, monomorphic mature lymphocytes alongside fragile, disrupted cellular remnants known as "smear cells" or "smudge cells".
• Immune Complications:
  • Hypogammaglobulinaemia: Progressive failure of normal antibody synthesis leads to recurrent severe encapsulating bacterial respiratory tract infections.
  • Autoimmune Cytopenias: Autoimmune haemolytic anaemia (warm AIHA, DAT positive) occurs in 10%–15%, as does immune thrombocytopenia (ITP).
  • Richter's Transformation: Acute transformation (~5%–10% of cases) into an aggressive, high-grade Diffuse Large B-Cell Lymphoma (DLBCL), heralded by rapid asymmetric lymph node enlargement, sudden onset B symptoms, and rising LDH.
• Management: Early, asymptomatic CLL is managed with a "watch and wait" surveillance strategy, as early cytotoxic intervention yields no survival benefit. Treatment is indicated only for active, symptomatic disease (B symptoms, progressive marrow failure, massive lymphadenopathy/splenomegaly), using targeted agents such as Bruton's tyrosine kinase inhibitors (Ibrutinib, Acalabrutinib) or BCL-2 antagonists (Venetoclax) in combination with anti-CD20 monoclonal antibodies (Obinutuzumab, Rituximab).

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3. Malignant Lymphomas

Lymphomas represent primary neoplastic proliferations of lymphoid tissue. Clinical presentation typically features painless, rubbery, discrete, non-tender lymphadenopathy (most commonly cervical >70%, followed by supraclavicular, axillary, and inguinal nodes). Systemic "B symptoms" are defined as:

1. Unexplained persistent fever (>38.0°C)
2. Drenching night sweats (requiring changing nightclothes/bedding)
3. Unintentional weight loss (>10% of baseline body weight over the preceding 6 months)

Hodgkin Lymphoma (HL)

• Pathology: Characterised by neoplastic giant multinucleated cells known as Reed-Sternberg cells (classically displaying a bilobed nucleus with prominent inclusion-like nucleoli resembling "owl's eyes", staining positive for CD15 and CD30, negative for CD45 and CD20), set against a reactive inflammatory background.
• Epidemiology: Distinct bimodal age distribution, with the primary peak in young adults (20–30 years) and a secondary peak in older adults (>60 years).
• Clinical Presentation: Orderly, contiguous anatomical spread along contiguous nodal chains; extranodal involvement is rare at presentation. A classic, specific symptom is alcohol-induced lymph node pain (immediate severe pain in involved nodes following alcohol ingestion). Pel-Ebstein fevers (cyclical fevers fluctuating over days) are occasionally observed.
• Prognosis & Therapy: Highly curable (>85% 5-year overall survival) using multi-agent chemotherapy, historically the ABVD regimen (Adriamycin [Doxorubicin], Bleomycin, Vinblastine, Dacarbazine) with or without involved-site radiotherapy. Long-term survivorship surveillance is critical due to treatment-related second malignancies (e.g. breast cancer in young women irradiated to the chest) and cardiopulmonary toxicity (bleomycin pulmonary fibrosis, anthracycline cardiomyopathy).

Non-Hodgkin Lymphoma (NHL)

• Overview: A diverse group of B-cell (~85%) and T-cell/NK-cell (~15%) malignancies. Characterised by non-contiguous, unpredictable nodal spread and a high propensity for early extranodal disease (gastrointestinal tract [most common extranodal site], bone marrow, liver, skin, CNS).
• Diffuse Large B-Cell Lymphoma (DLBCL): The most common NHL (~35%). High-grade, rapidly proliferating, aggressive malignancy. Rapidly enlarging symptomatic nodal mass or extranodal tumor. Curative intent treatment: R-CHOP chemoimmunotherapy (Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone).
• Follicular Lymphoma: The most common indolent low-grade NHL (~20%). Arises from germinal centre B cells carrying the pathognomonic chromosomal translocation t(14;18)(q32;q21), which juxtaposes the BCL2 oncogene to the immunoglobulin heavy chain (IGH) promoter, causing BCL2 overexpression and inhibiting apoptosis. Indolent, widely disseminated at presentation, typically incurable with conventional chemotherapy; managed with "watch and wait" until symptomatic, then rituximab-based regimens.

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4. Multiple Myeloma

Multiple myeloma is a malignant clonal proliferation of plasma cells originating in the bone marrow, accounting for ~10% of haematological cancers (median age at diagnosis ~70 years). The neoplastic plasma cells produce excess amounts of a single monoclonal immunoglobulin (paraprotein, or M-protein)—most commonly IgG (~60%) or IgA (~20%)—alongside monoclonal free light chains (kappa or lambda).

Diagnostic Hallmark: The CRAB Criteria

Symptomatic, end-organ damaging multiple myeloma is defined by bone marrow clonal plasma cells ≥10% (or biopsy-proven plasmacytoma) in the presence of one or more CRAB criteria:

• C — Hypercalcaemia (Serum Calcium >2.75 mmol/L or >0.25 mmol/L above normal): Driven by neoplastic plasma cell production of osteoclast-activating factors (RANKL, MIP-1 alpha) and suppression of osteoblasts (DKK-1), resulting in severe, uncoupled osteolysis. Manifests with polydipsia, polyuria, constipation, confusion, and shortened QT interval.
• R — Renal Impairment (Serum Creatinine >177 umol/L or CrCl <40 mL/min): Primarily caused by light chain cast nephropathy ("myeloma kidney"): excess circulating free light chains overwhelm proximal tubular endocytic capacity, precipitate with Tamm-Horsfall mucoprotein in distal tubules, and form obstructive, highly toxic tubular casts. Dehydration, hypercalcaemia, and concurrent NSAID use exacerbate acute kidney injury.
• A — Normocytic Normochromic Anaemia (Hb <100 g/L or >20 g/L below normal): Secondary to leukaemic plasma cell replacement of hematopoietic bone marrow niches, cytokine-mediated suppression of erythropoiesis, and relative erythropoietin deficiency from renal disease.
• B — Bone Lesions (≥1 Osteolytic Lesion): Punched-out, well-demarcated osteolytic lesions without surrounding reactive osteoblastic sclerosis visible on skeletal surveys, whole-body low-dose CT, or MRI. Causes severe, persistent bone pain (particularly in the lumbar spine, ribs, and pelvis), vertebral compression fractures, spinal cord compression, and pathological fractures.

Diagnostic Laboratory Workup

• Serum & Urine Protein Electrophoresis (SPEP & UPEP): Demonstrates a sharp, narrow monoclonal M-protein spike in the gamma globulin region. Urine electrophoresis detects Bence Jones proteinuria (monoclonal free light chains excreted into urine).
• Serum Free Light Chain (sFLC) Assay: Quantifies circulating free kappa and lambda chains, showing a pathologically skewed kappa/lambda ratio (>100 or <0.01).
• Peripheral Blood Film: Shows prominent rouleaux formation (erythrocytes stacked like coins, driven by high concentrations of positively charged paraprotein neutralizing the negative zeta potential of red cells). Background erythrocyte sedimentation rate (ESR) is markedly elevated (frequently >100 mm/h).
• Bone Marrow Aspirate & Trephine Biopsy: Confirms infiltration by ≥10% clonal, atypical plasma cells (clock-face chromatin, abundant basophilic cytoplasm, eccentric nucleus).

Treatment Principles

• Induction Triplet Regimen: Proteasome inhibitor (Bortezomib) + immunomodulatory drug (Lenalidomide) + high-dose corticosteroid (Dexamethasone) [the VRd regimen].
• Consolidation: Eligible, fit patients under 70 years undergo high-dose melphalan conditioning followed by Autologous Stem Cell Transplantation (ASCT).
• Supportive Skeletal & Renal Protection: All patients with active myeloma require monthly intravenous bisphosphonates (e.g. Zoledronic acid) to inhibit osteoclast resorption, reduce pathological fractures, and control hypercalcaemia. Vigorous hydration protects renal tubular function.