8.2 Leukaemias, Lymphomas & Plasma Cell Disorders

8.2 Leukaemias, Lymphomas & Plasma Cell Disorders

Acute and Chronic Leukaemias

Leukaemias represent malignant neoplastic proliferations of haematopoietic stem cells originating within the bone marrow, leading to impaired normal haematopoiesis and peripheral blood cytopenias or leucocytosis. They are broadly categorized by cellular lineage (myeloid versus lymphoid) and clinical acuity (acute vs. chronic).

Acute Myeloid Leukaemia (AML) & Acute Promyelocytic Leukaemia (APL)

AML is characterized by clonal expansion of myeloid blasts (≥20% blasts on bone marrow aspirate/trephine). Clinical features include bone marrow failure (anaemia, neutropenic infections, thrombocytopenic bleeding) and tissue infiltration (gum hypertrophy in monocytic AML subtypes M4/M5).

• Cytogenetic Risk Stratification in AML:

  • Favourable Risk: t(8;21)(q22;q22) [RUNX1-RUNX1T1], inv(16)(p13.1q22) / t(16;16) [CBFB-MYH11], mutated NPM1 without FLT3-ITD.
  • Intermediate Risk: Normal cytogenetics, mutated FLT3-ITD with low allelic ratio, t(9;11)(p22;q23) [MLLT3-KMT2A].
  • Adverse Risk: Complex karyotype (≥3 cytogenetic abnormalities), monosomal karyotype, deletion 5q/7q, t(6;9), mutated TP53, ASXL1, RUNX1.

• Acute Promyelocytic Leukaemia (APL - FAB M3):

  • Cytogenetics: Pathognomonic reciprocal translocation t(15;17)(q22;q12), resulting in the fusion gene PML-RARA (promyelocytic leukaemia - retinoic acid receptor alpha).
  • Morphology: Promyelocytes with hypergranular cytoplasm, bilobed nuclei, and prominent bundles of Auer rods ("faggot cells").
  • Coagulopathy & Emergency Management: APL is an immediate haematological emergency due to severe disseminated intravascular coagulation (DIC) and primary hyperfibrinolysis driven by tissue factor and annexin II expression on malignant promyelocytes.
  • Targeted Therapy: Immediate administration of All-Trans Retinoic Acid (ATRA / tretinoin) combined with Arsenic Trioxide (ATO) is curative in >90% of patients without conventional intensive chemotherapy. ATRA must be started immediately upon clinical suspicion before cytogenetic confirmation.
  • Differentiation Syndrome: A life-threatening complication of ATRA/ATO treatment, characterized by fever, dyspnoea, pulmonary infiltrates, pleural/pericardial effusions, weight gain, and acute renal failure. Treatment requires immediate cessation or pause of ATRA/ATO and prompt initiation of high-dose intravenous Dexamethasone 10 mg BD.

Leukaemia Cytogenetics & Targeted Therapy Panel

MRCPI Exam Pearl: In APL, initiating ATRA must occur immediately upon clinical suspicion before cytogenetic confirmation. Delaying ATRA treatment risks catastrophic fatal haemorrhage from DIC. Watch for differentiation syndrome (fever, dyspnoea, pulmonary infiltrates, weight gain), managed promptly with IV dexamethasone 10 mg BD.

Chronic Myeloid Leukaemia (CML) & Myeloproliferative Neoplasms (MPNs)

CML is a myeloproliferative neoplasm originating from a pluripotent haematopoietic stem cell.

• Pathogenesis: Driven by the Philadelphia chromosome, resulting from a reciprocal translocation t(9;22)(q34;q11). This fuses the BCR gene on chromosome 22 with the ABL1 proto-oncogene on chromosome 9, producing the BCR-ABL1 p210 chimeric protein with constitutive tyrosine kinase activity.

• Clinical Presentation: Marked leucocytosis with a full spectrum of granulocytic precursors (promyelocytes, myelocytes, metamyelocytes, mature neutrophils), prominent basophilia and eosinophilia, massive splenomegaly, weight gain, fatigue, and night sweats. Neutrophil alkaline phosphatase (NAP) score is characteristically low or zero.

• Phases: Chronic phase (median 3–5 years if untreated) → Accelerated phase (increasing blasts 10–19%, basophils ≥20%, persistent thrombocytopenia/thrombocytosis) → Blast crisis (blasts ≥20% in marrow/blood; 70% myeloid, 30% lymphoid).

• Treatment: First-line Tyrosine Kinase Inhibitors (TKIs): Imatinib (first-generation), Dasatinib, or Nilotinib (second-generation). Molecular monitoring via quantitative RT-PCR for BCR-ABL1 transcripts achieves Major Molecular Response (MMR ≤0.1% IS) in over 80% of patients.

• Other Classic Myeloproliferative Neoplasms (JAK2 V617F Mutated):

  • Polycythaemia Vera (PV): Clonal red cell expansion (>95% JAK2 V617F positive). Features aquagenic pruritus, splenomegaly, erythromelalgia, gout, elevated haematocrit (>0.49 in men, >0.48 in women). Managed with venesection (target Hct <0.45), low-dose aspirin, and cytoreduction (hydroxycarbamide or ruxolitinib).
  • Essential Thrombocythaemia (ET): Persistent thrombocytosis (platelets >450 x 10^9/L), megakaryocytic hyperplasia, 50-60% JAK2 V617F or CALR/MPL mutated. High risk of arterial/venous thrombosis or haemorrhage (acquired von Willebrand syndrome at platelets >1000 x 10^9/L).
  • Primary Myelofibrosis (PMF): Progressive bone marrow fibrosis, extramedullary haematopoiesis, massive splenomegaly, severe constitutional symptoms, and peripheral blood film showing leukoerythroblastic picture with tear-drop poikilocytes (dacrocytes).

Chronic Lymphocytic Leukaemia (CLL)

CLL is the most prevalent leukaemia in Western adults, characterized by progressive accumulation of monoclonal, immunologically incompetent, mature B-lymphocytes (co-expressing CD5+, CD19+, CD23+, with weak surface immunoglobulin). Smear/smudge cells (Gumprecht shadows) are characteristic on peripheral blood film due to cellular fragility during slide preparation.

• Staging Systems:
  • Binet System: Stage A (<3 lymph node areas involved, Hb ≥100 g/L, Plt ≥100 x 10^9/L); Stage B (≥3 lymph node areas involved); Stage C (Anaemia Hb <100 g/L or Thrombocytopenia Plt <100 x 10^9/L).
  • Rai System: Stage 0 (lymphocytosis alone) to Stage IV (thrombocytopenia).
• Indications for Treatment: Asymptomatic early-stage CLL (Binet A/B) is managed with a "watch and wait" strategy. Treatment is indicated for: progressive marrow failure (Hb <100 g/L, Plt <100 x 10^9/L), massive/symptomatic lymphadenopathy or splenomegaly, refractory autoimmune cytopenias (AIHA or ITP), or severe systemic B-symptoms.
• Modern Targeted Therapy: Chemotherapy-free targeted regimens are standard of care:
  • Bruton Tyrosine Kinase (BTK) Inhibitors: Acalabrutinib, Zanubrutinib, or Ibrutinib.
  • BCL-2 Inhibitor: Venetoclax (requires tumor lysis syndrome prophylaxis and stepped dose ramp-up) combined with anti-CD20 monoclonal antibody (Obinutuzumab or Rituximab).
  • High-Risk Cytogenetics: Deletion 17p [del(17p)] or TP53 mutation confers resistance to traditional chemoimmunotherapy (FCR); targeted BTK or BCL-2 inhibitors are strictly required.
  • Richter Transformation: Development of high-grade Diffuse Large B-Cell Lymphoma (DLBCL) in a patient with CLL, presenting with sudden clinical deterioration, rapidly enlarging asymmetric lymph nodes, elevated LDH, and B-symptoms (prognosis is poor, requiring intensive chemoimmunotherapy ± allogeneic stem cell transplant).

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Lymphomas: Hodgkin vs. Non-Hodgkin Lymphoma

Lymphomas arise from malignant transformation of lymphocytes within lymphoid tissue (lymph nodes, spleen, MALT) and are categorized into Hodgkin Lymphoma (HL) and Non-Hodgkin Lymphoma (NHL).

Diagnostic & Immunophenotypic Comparison

Classical Hodgkin Lymphoma (cHL)

Classical Hodgkin Lymphoma is characterized histologically by the presence of giant binucleated Reed-Sternberg cells ("owl-eye" appearance) within an inflammatory background of non-neoplastic T-cells, eosinophils, macrophages, and plasma cells.

• Immunophenotype: Reed-Sternberg cells are derived from germinal centre B-cells but characteristically express CD15+ and CD30+, while losing typical B-cell markers (CD20-, CD79a-).
• Subtypes: Nodular sclerosis (most common, 70%, frequent mediastinal involvement in young females), Mixed cellularity (associated with EBV in 75%, older patients), Lymphocyte-rich (best prognosis), Lymphocyte-depleted (worst prognosis).
• Ann Arbor Staging System:
  • Stage I: Single lymph node region or extranodal site.
  • Stage II: ≥2 lymph node regions on the same side of the diaphragm.
  • Stage III: Lymph node regions on both sides of the diaphragm.
  • Stage IV: Disseminated involvement of extranodal organs (liver, bone marrow, lungs).
  • Suffixes: A (no systemic symptoms) vs. B (unexplained fever >38°C, drenching night sweats, weight loss >10% over 6 months); X (bulky disease >10 cm or mediastinal mass >1/3 thoracic ratio).
• First-Line Treatment: ABVD chemotherapy: Adriamycin (doxorubicin), Bleomycin (monitor for pulmonary toxicity/fibrosis), Vinblastine (neuropathy), Dacarbazine. PET-CT response-adapted therapy is standard (interim PET after 2 cycles allowing bleomycin omission if PET-negative).

Non-Hodgkin Lymphomas (NHL)

Non-Hodgkin Lymphomas comprise a diverse group of lymphoproliferative malignancies (>85% B-cell origin, <15% T-cell/NK-cell origin).

1. Diffuse Large B-Cell Lymphoma (DLBCL):

   • Most common aggressive B-cell NHL (CD20+).
   • Presents with rapidly enlarging painless lymphadenopathy or extranodal masses (gastrointestinal tract, testes, CNS).
   • Curative intent therapy: R-CHOP regimen (Rituximab, Cyclophosphamide, Hydroxydaunorubicin/doxorubicin, Oncovin/vincristine, Prednisolone) administered every 21 days for 6 cycles.
   • Double-Hit / Triple-Hit Lymphomas: Rearrangements of MYC alongside BCL2 and/or BCL6; highly aggressive, requiring intensive regimens (e.g. DA-EPOCH-R).

2. Follicular Lymphoma:

   • Most common indolent (low-grade) B-cell NHL.
   • Cytogenetics: t(14;18)(q32;q21) translocation placing the BCL2 anti-apoptotic gene under the control of the immunoglobulin heavy chain (IgH) enhancer, leading to constitutive BCL2 overexpression and inhibition of apoptosis.
   • Clinical course: Waxing and waning painless generalized lymphadenopathy. Asymptomatic stage I-III disease is managed with watch-and-wait; symptomatic or bulky disease treated with immunochemotherapy (Rituximab + Bendamustine or R-CHOP). Annual risk of transformation to aggressive DLBCL is ~2-3% per year.

3. Burkitt Lymphoma:

   • Extremely high-grade B-cell NHL characterized by 100% Ki-67 proliferation index and classic "starry-sky" histological appearance (sheet of malignant B-cells interspersed with tangible-body macrophages ingesting apoptotic debris).
   • Cytogenetics: Pathognomonic reciprocal translocation t(8;14)(q24;q32) placing the c-MYC proto-oncogene next to the IgH locus (or variants t(2;8), t(8;22)), driving uncontrolled cellular proliferation.
   • Clinical Variants: Endemic (African, jaw/facial bone expansion, >95% EBV-associated), Sporadic (abdominal mass, ileocecal involvement), Immunodeficiency-associated (HIV).
   • Management: Medical emergency requiring immediate intensive multi-agent chemoimmunotherapy (CODOX-M/IVAC or Hyper-CVAD), aggressive tumor lysis syndrome prophylaxis with rasburicase, and mandatory intrathecal chemotherapy prophylaxis against CNS relapse.

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Plasma Cell Disorders: Multiple Myeloma & MGUS

Plasma cell dyscrasias involve clonal proliferation of terminally differentiated B-cells (plasma cells) in the bone marrow, secreting a monoclonal immunoglobulin protein (M-protein, paraprotein, or monoclonal free light chains).

Diagnostic Criteria: MGUS vs. Smouldering vs. Multiple Myeloma

Myeloma Diagnostic Markers (CRAB & SLiM Criteria)

Diagnosis of symptomatic Multiple Myeloma requires ≥10% clonal bone marrow plasma cells (or biopsy-proven plasmacytoma) PLUS at least one feature of end-organ damage (CRAB criteria) OR at least one myeloma-defining biomarker (SLiM criteria):

• C – Hypercalcaemia: Adjusted serum calcium >2.75 mmol/L (>11.0 mg/dL) or >0.25 mmol/L above upper limit of normal.
• R – Renal insufficiency: Serum creatinine >177 µmol/L (>2.0 mg/dL) or estimated GFR <40 mL/min (commonly secondary to light-chain cast nephropathy / myeloma kidney).
• A – Anaemia: Haemoglobin <100 g/L (<10.0 g/dL) or >20 g/L below lower limit of normal.
• B – Bone lesions: ≥1 osteolytic lesion detected on plain radiograph, low-dose whole-body CT, MRI, or PET-CT.
• SLiM Biomarkers (Myeloma-Defining Events without CRAB):
  • S: Sixty percent (≥60%) clonal plasma cells on bone marrow aspirate/biopsy.
  • Li: Involved-to-uninvolved Light chain ratio ≥100 (with involved serum free light chain concentration ≥100 mg/L).
  • M: MRI showing >1 focal lesion (at least 5 mm in size) in the skeleton.

Diagnostic Workup & Staging

• Laboratory Panel: Full blood count (normocytic normochromic anaemia, rouleaux formation on blood film), U&Es, calcium, albumin, serum quantitative immunoglobulins, Serum Protein Electrophoresis (SPEP) with Immunofixation (identifies M-protein spike, e.g. IgG 60%, IgA 20%, Light chain only 15%), 24-hour urine protein electrophoresis (UPEP) for Bence Jones protein (free light chains), and Serum Free Light Chain (SFLC) assay.
• Revised International Staging System (R-ISS):
  • Stage I: Serum beta-2 microglobulin <3.5 mg/L, serum albumin ≥35 g/L, normal LDH, standard-risk cytogenetics.
  • Stage II: Neither Stage I nor Stage III.
  • Stage III: Serum beta-2 microglobulin ≥5.5 mg/L AND high-risk cytogenetics [del(17p), t(4;14), t(14;16)] OR elevated serum LDH.

Therapeutic Management

• Transplant-Eligible Patients (<70 years, fit, no severe comorbidities):
  • Induction: Quadruplet or triplet regimen: Daratumumab (anti-CD38 monoclonal antibody) + Bortezomib (proteasome inhibitor) + Lenalidomide (immunomodulatory drug) + Dexamethasone (Dara-VRd or VRd).
  • Consolidation: High-dose Melphalan (200 mg/m²) followed by Autologous Stem Cell Transplantation (ASCT).
  • Maintenance: Single-agent Lenalidomide maintenance until disease progression.
• Transplant-Ineligible Patients: Continuous oral Dara-Rd (Daratumumab + Lenalidomide + Dexamethasone) or VRd-lite.
• Supportive Care: Monthly IV Zoledronic Acid (4 mg) or subcutaneous Denosumab for bone protection and prevention of skeletal-related events (SREs); prophylactic trimethoprim-sulfamethoxazole (PCP) and acyclovir (herpes zoster prophylaxis for bortezomib); thromboprophylaxis with aspirin or LMWH for lenalidomide regimens.

Related Plasma Cell Disorders

• AL Amyloidosis: Deposition of insoluble fibrillar monoclonal light chains (most commonly lambda light chains) in tissues. Features nephrotic-range proteinuria, restrictive cardiomyopathy (low-voltage ECG with thickened ventricular walls on echo), hepatomegaly, macroglossia, autonomic neuropathy, and periorbital ecchymoses ("raccoon eyes").
• Waldenström Macroglobulinaemia (WM): Lymphoplasmacytic lymphoma with monoclonal IgM paraproteinemia (>90% carry MYD88 L265P mutation). Features hyperviscosity syndrome (headache, visual disturbances, mucosal bleeding, engorged retinal veins - "sausage-link" appearance), hepatosplenomegaly, lymphadenopathy, and peripheral neuropathy. Plasmapheresis is required for acute hyperviscosity crisis before starting targeted therapy (Ibrutinib ± Rituximab).

MRCPI Exam Pearl: First-line induction therapy for transplant-eligible multiple myeloma patients consists of a triplet/quadruplet regimen containing Bortezomib (proteasome inhibitor), Lenalidomide (IMiD), and Dexamethasone (VRd), followed by autologous stem cell transplantation (ASCT).