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ACUTE MYELOID LEUKEMIA (AML)

15-Mark Long Answer | Based on Archith Boloor / Standard Medicine Textbooks

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CASE SUMMARY

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NORMAL BLOOD VALUES (Reference)

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(a) DIAGNOSIS [2 Marks]

• Bone marrow shows >20% myeloblasts - the WHO diagnostic criterion for AML is ≥20% blasts in bone marrow or peripheral blood. This patient has >25%, confirming the diagnosis.
• Peripheral smear showing blasts, many of which may show Auer rods - pathognomonic of AML (Auer rods are absent in ALL).
• Pancytopenia picture: Anaemia (Hb 7 g/dL), thrombocytopenia (platelets 18,000/mm³), and high WBC (48,000/mm³ - leukocytosis with circulating blasts).
• Clinical features: fever, gingival bleeding, petechiae, fatigue, and recurrent infections - classic triad of bleeding + infection + anaemia from bone marrow failure.

Note: WHO 2022 has revised the blast threshold to ≥20%; the older FAB classification used ≥30%. Some core-binding factor AMLs [t(8;21), inv(16), t(15;17)] are diagnosed as AML irrespective of blast count.

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(b) DIFFERENTIAL DIAGNOSIS [2 Marks]

• Also presents with fever, anaemia, bleeding, recurrent infections, and blasts on smear.
• Distinguished by: lymphoblasts (NOT myeloblasts), absence of Auer rods, positive TdT (terminal deoxynucleotidyl transferase), CD19/CD10 positivity, and negative MPO on flow cytometry.
• More common in children; AML is more common in adults.

• Can present with high WBC and blasts.
• Distinguished by: presence of Philadelphia chromosome [t(9;22)] and BCR-ABL fusion gene, preceded by a chronic phase with basophilia and left shift, presence of intermediate forms (metamyelocytes, myelocytes) on smear.

• Aplastic anaemia - pancytopenia but NO blasts; hypocellular marrow.
• Myelodysplastic Syndrome (MDS) - dysplastic cells, <20% blasts.
• Infectious mononucleosis / viral pancytopenia - atypical lymphocytes, not true blasts.

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(c) INVESTIGATIONS [4 Marks]

1. Confirmatory / Morphological

• Bone Marrow Aspiration and Trephine Biopsy - gold standard; confirms >20% myeloblasts, assesses cellularity and morphology.
• Peripheral Smear - look for blasts, Auer rods (pathognomonic of AML), toxic granules.

2. Immunophenotyping (Flow Cytometry)

• AML markers: MPO (Myeloperoxidase), CD13, CD33, CD34, CD117 (c-Kit), HLA-DR
• Distinguishes AML from ALL; identifies specific subtypes (M5 monocytic has CD14/CD64; APL/M3 has CD9, HLA-DR negative).

3. Cytogenetics (Karyotyping) and FISH

• Standard karyotype / FISH - identifies recurrent chromosomal abnormalities:
  • t(8;21) - good prognosis (RUNX1-RUNX1T1)
  • inv(16) or t(16;16) - good prognosis (CBFB-MYH11)
  • t(15;17) - APL, good prognosis, ATRA-responsive (PML-RARA)
  • -5, -7, complex karyotype - poor prognosis
• These guide both risk stratification and treatment selection.

4. Molecular / Gene Mutation Testing

• FLT3-ITD mutation - adverse prognosis; eligible for midostaurin/gilteritinib.
• NPM1 mutation - favorable prognosis.
• IDH1/IDH2 mutations - targeted therapy with ivosidenib/enasidenib.
• CEBPA biallelic mutation - favorable prognosis.
• TP53 mutation - very poor prognosis.

5. Baseline Organ Function (Pre-treatment Workup)

• CBC with differential, RBC indices - assess degree of anaemia and cytopenias.
• Coagulation profile (PT, aPTT, fibrinogen, D-dimer) - screen for DIC (especially if APL suspected).
• LFT, RFT, serum uric acid, electrolytes - baseline organ function and tumour lysis risk.
• LDH - marker of tumour burden and cell turnover.
• Echocardiogram / LVEF - essential before anthracycline use (cardiotoxicity risk).
• HLA typing - for potential allogeneic stem cell transplantation (SCT).
• Lumbar puncture (CSF examination) - if CNS symptoms present (headache, cranial nerve palsy).
• Serum beta-2 microglobulin, serum ferritin.
• Viral markers: HIV, HBsAg, HCV, CMV - prior to immunosuppression/SCT.
• Chest X-ray / CT scan - identify infection, mediastinal mass, chloroma.

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(d) TREATMENT PROTOCOL [5 Marks]

Phase 1: Induction Chemotherapy

• Mechanism: Cytarabine = S-phase specific antimetabolite (inhibits DNA synthesis); Anthracyclines = topoisomerase II inhibitors (DNA breaks).
• 60-80% of younger adults achieve Complete Remission (CR) with this regimen.
• CR is defined as: <5% blasts in bone marrow, peripheral blood count recovery, no Auer rods.

• ATRA (All-Trans Retinoic Acid) 45 mg/m²/day + Arsenic Trioxide (ATO) 0.15 mg/kg/day IV - this is the standard regimen; no cytarabine required in low-risk APL.
• ATRA induces differentiation of promyelocytes; ATO induces apoptosis and differentiation.
• Monitor for ATRA Differentiation Syndrome (respiratory distress, fever, weight gain).

• Midostaurin 50 mg orally BD (multikinase/FLT3 inhibitor) - added to 7+3 in FLT3-mutated AML (improves OS).
• Gemtuzumab ozogamicin (GO) - anti-CD33 antibody-drug conjugate - added in favorable-risk AML (CBF-AML).

• Venetoclax (BCL-2 inhibitor) 400 mg/day + Azacitidine (75 mg/m² SC, days 1-7) or Decitabine (hypomethylating agent).
• Response rate ~60%.

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Phase 2: Consolidation Chemotherapy

• Favorable risk (t(8;21), inv(16), NPM1 mutant/FLT3 wild-type): HiDAC alone; allo-SCT reserved for relapse.
• Intermediate/Adverse risk: Proceed to allo-SCT in CR1 if suitable donor available.

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Phase 3: Maintenance

• APL: ATRA ± 6-mercaptopurine + methotrexate maintenance for 2 years.
• FLT3-mutated AML: Midostaurin as maintenance post-transplant; or Gilteritinib for relapsed/refractory FLT3-AML.
• Non-APL AML: No established maintenance (clinical trial).

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Supportive Care

• Tumour Lysis Syndrome prophylaxis: IV fluids + Allopurinol 300 mg/day (or Rasburicase for high risk).
• Platelet transfusion: Keep platelets >10,000/mm³ (or >20,000 if active bleeding).
• Packed RBC transfusion: For Hb <8 g/dL.
• Broad-spectrum antibiotics (febrile neutropenia: Piperacillin-Tazobactam 4.5 g IV 6-hourly).
• Antifungals: Fluconazole/Voriconazole prophylaxis during neutropenia.
• G-CSF (Granulocyte Colony Stimulating Factor): Post-consolidation to shorten neutropenia.
• Heparin/FFP in APL with DIC.

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(e) PROGNOSTIC FACTORS [2 Marks]

Favorable Prognostic Factors (Good prognosis)

Unfavorable Prognostic Factors (Poor prognosis)

The ELN 2022 (European LeukemiaNet) risk classification stratifies AML into Favorable, Intermediate, and Adverse risk based on these cytogenetic and molecular features, guiding consolidation strategy (HiDAC vs. allo-SCT).

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SUMMARY TABLE

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• Harrison's Principles of Internal Medicine 22E - Chapter 109: AML
• Washington Manual of Medical Therapeutics - Hematology section
• Tietz Textbook of Laboratory Medicine, 7th Edition - AML cytogenetics table
• Goldman-Cecil Medicine - Postremission and Induction Therapy

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MULTIPLE MYELOMA

15-Mark Long Answer | Based on Standard Medicine Textbooks (Archith Boloor / Harrison's / Robbins / Goldman-Cecil)

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CASE SUMMARY

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NORMAL REFERENCE VALUES

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(a) DIAGNOSIS [2 Marks]

1. Multiple Myeloma (MM)

The clinicopathologic diagnosis relies on identification of clonal plasma cells in the marrow plus the presence of CRAB criteria (Robbins Pathologic Basis of Disease).

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(b) CRAB CRITERIA [3 Marks]

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C - hyperCalcaemia

• Serum calcium > 11 mg/dL (or > 1 mg/dL above upper normal limit)
• Mechanism: Malignant plasma cells secrete osteoclast-activating factors and increase RANKL (receptor activator of nuclear factor κB ligand) in the bone marrow. RANKL induces osteoclast differentiation and activation, leading to massive bone resorption and release of calcium into the blood. Simultaneously, myeloma cells inhibit osteoblast differentiation.
• Clinical features: Confusion, weakness, lethargy, constipation, polyuria, polydipsia, nausea, vomiting ("bones, moans, groans, psychic overtones").
• This patient: Serum calcium elevated - C criterion met.

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R - Renal insufficiency

• Serum creatinine > 2 mg/dL (or eGFR < 40 mL/min)
• Mechanism: The most important cause is light chain cast nephropathy (myeloma kidney) - excess monoclonal free light chains (Bence Jones proteins) are filtered, precipitate in distal tubules with Tamm-Horsfall protein, and form obstructing casts that are toxic to renal tubular epithelial cells. Other causes include:
  • Hypercalcaemia-induced nephrocalcinosis
  • AL amyloidosis depositing in glomeruli
  • Hyperuricaemia and urate nephropathy
  • Direct plasma cell infiltration of kidney (rare)
• This patient: Creatinine elevated - R criterion met.

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A - Anaemia

• Haemoglobin < 10 g/dL or > 2 g/dL below lower normal limit
• Mechanism:
  1. Replacement of normal marrow by neoplastic plasma cells - reduces erythropoiesis
  2. Suppression of erythropoietin production (from renal failure)
  3. Chronic disease (inflammatory cytokines like IL-6 suppress iron utilisation)
  4. Haemolysis (accelerated RBC destruction)
• Anaemia is normocytic normochromic in most patients; peripheral smear may show rouleaux formation due to elevated M protein causing RBCs to stack like coins.
• This patient: Hb 8.2 g/dL - A criterion met.

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B - Bone lesions

• Lytic bone lesions, osteoporosis, or pathological fractures on imaging
• Mechanism: Plasma cells secrete cytokines (IL-1β, TNF-α, IL-6, MIP-1α) that activate osteoclasts via RANKL pathway while simultaneously suppressing osteoblast activity. This results in net bone destruction without new bone formation - hence bone scans are often NEGATIVE (no new bone formation; unlike metastatic cancer).
• Classic radiological finding: "Punched-out" (raindrop) lytic lesions - sharply defined, without a sclerotic rim - most prominent in skull calvaria, vertebrae, ribs, pelvis, and proximal long bones.
• This patient: Punched-out skull lesions - B criterion met.

This patient satisfies all 4 CRAB criteria, confirming symptomatic multiple myeloma requiring treatment.

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(c) INVESTIGATIONS [4 Marks]

1. Blood Investigations

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2. Protein Studies (M Protein Detection) - KEY INVESTIGATION

• Serum Protein Electrophoresis (SPEP): Shows a tall, narrow M spike (monoclonal spike) in the gamma globulin region (80% of patients). M protein is IgG in 52%, IgA in 21%, light chain only in 16%, IgD in 2%.
• Serum Immunofixation Electrophoresis (IFE): More sensitive (detects M protein in 93% of patients); characterises the heavy and light chain type. Gold standard for M protein identification.
• Urine protein electrophoresis + immunofixation: Detects Bence Jones protein (free light chains - κ or λ) in urine; combined with serum studies detects M protein in 97% of myeloma patients.
• Serum Free Light Chain (FLC) assay: Measures free κ and λ light chains; useful for non-secretory myeloma, monitoring, and prognosis. Abnormal κ:λ ratio (>4:1 or <1:2) indicates clonality.

Threshold: Most myelomas have > 3 g/dL of serum M protein and/or > 6 mg/dL of urine Bence Jones protein.

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3. Bone Marrow Examination (Diagnostic Standard)

• Bone Marrow Aspiration + Trephine Biopsy
  • Clonal plasma cells ≥ 10% of nucleated cells (in 96% of patients)
  • Plasma cells show eccentric nucleus, perinuclear clearing (clockface/cartwheel chromatin), prominent nucleolus
  • Special variants: Flame cells (fiery red cytoplasm), Mott cells (grape-like cytoplasmic Ig droplets), Russell bodies (cytoplasmic Ig globules), Dutcher bodies (nuclear Ig inclusions)
  • Immunophenotype: CD138+, CD38+, CD56+, CD45-, CD19-, cytoplasmic Ig κ or λ (clonal)
  • Abnormal κ:λ ratio confirms clonality

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4. Imaging Studies

Note: Bone scan (technetium) is typically NEGATIVE in myeloma because there is bone destruction without new bone formation (unlike metastatic carcinoma).

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5. Additional / Staging Investigations

• Cytogenetics / FISH on bone marrow: t(4;14), t(14;16), del(17p) = poor prognosis; t(11;14) = intermediate; hyperdiploidy = good prognosis
• Beta-2 microglobulin (β2M) + Serum albumin: For ISS (International Staging System) staging
• Renal ultrasound: Rule out obstruction
• Echocardiogram: Screen for AL amyloidosis (cardiac involvement)

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(d) TREATMENT [4 Marks]

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Phase 1: Induction Therapy

• Daratumumab (anti-CD38 monoclonal antibody) 16 mg/kg IV weekly × 8 weeks, then every 2 weeks × 4 months, then monthly

• VCd (Bortezomib + Cyclophosphamide + Dexamethasone):
  • Cyclophosphamide 300 mg/m² orally on days 1, 8, 15, 22
  • Bortezomib 1.3 mg/m² IV on days 1, 8, 15, 22
  • Dexamethasone 40 mg orally on days 1, 8, 15, 22 - repeated every 4 weeks
• Daratumumab + Lenalidomide + Dexamethasone (DRd) - increasingly preferred

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Phase 2: Autologous Stem Cell Transplantation (ASCT)

• For transplant-eligible patients after induction achieving response
• High-dose Melphalan (200 mg/m²) as conditioning regimen followed by autologous stem cell rescue
• Significantly prolongs progression-free survival (PFS)
• Standard of care for fit patients aged <70 years

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Phase 3: Maintenance Therapy

• Lenalidomide 10-15 mg/day orally - standard maintenance post-ASCT; prolongs PFS and OS
• Bortezomib ± Lenalidomide - in high-risk cytogenetics [t(4;14), del(17p)]
• Continue until progression or intolerance

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Special Subtype: APL-like - t(11;14) Myeloma

• Venetoclax (BCL-2 inhibitor) has specific activity; not recommended for other cytogenetic subtypes.

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Management of Complications

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Relapsed/Refractory Myeloma (RRMM)

• Carfilzomib (next-gen proteasome inhibitor), Pomalidomide (3rd gen IMiD), Isatuximab (anti-CD38)
• CAR-T cell therapy: Idecabtagene vicleucel (ide-cel), Ciltacabtagene autoleucel (cilta-cel) - target BCMA (B-cell maturation antigen)
• Bispecific antibodies: Teclistamab (BCMA × CD3)

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(e) COMPLICATIONS [2 Marks]

Major Complications of Multiple Myeloma:

• Occurs in up to 50% of patients
• Mechanism: Light chain cast nephropathy (Bence Jones proteins precipitate in renal tubules), hypercalcaemia-induced nephrocalcinosis, AL amyloidosis (λ light chains of the λ6 and λ3 families prone to amyloid formation), hyperuricaemia, NSAIDs/contrast nephropathy.
• Myeloma kidney = obstructing casts → tubular atrophy → interstitial fibrosis → progressive renal failure

• Mechanism: Suppression of normal immunoglobulin synthesis → acquired hypogammaglobulinaemia → poor humoral immunity → recurrent bacterial infections (especially encapsulated organisms: Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, gram-negative bacilli).
• Cellular immunity (T-cell) is relatively unaffected.
• Neutropenia from chemotherapy further compounds infection risk.

• Pathological fractures (vertebral compression fractures most common - patient loses height)
• Spinal cord/nerve root compression - radiculopathy, paraplegia
• Bone pain (back/chest) - present in >2/3 of patients at diagnosis

• CNS effects: confusion, weakness, coma
• Cardiac arrhythmias, constipation, renal stones

• Symptoms: Headache, visual disturbances, confusion, mucosal bleeding
• Treatment: Urgent plasmapheresis

• λ light chains deposit as amyloid fibrils in heart, kidneys, nerves, tongue
• Cardiomyopathy (restrictive), nephrotic syndrome, macroglossia, peripheral neuropathy

• Due to amyloid deposits in nerves, or bortezomib/thalidomide toxicity

• Rare; tumour cells flood peripheral blood (>20% circulating plasma cells)

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SUMMARY FLOW CHART

Old age male + Bone pain + Anaemia + Recurrent infections
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ESR very high + Hypercalcaemia + Renal failure + Lytic bone lesions
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CRAB CRITERIA → Symptomatic Multiple Myeloma
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Bone Marrow Biopsy (≥10% clonal plasma cells) + M spike on SPEP/IFE
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DIAGNOSIS CONFIRMED: Multiple Myeloma
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Staging (ISS/R-ISS) + Cytogenetics (FISH)
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Transplant Eligible?
   YES → Induction (VRd/D-VRd) → ASCT → Maintenance (Lenalidomide)
   NO  → VCd / DRd + Supportive care

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• Robbins, Cotran & Kumar Pathologic Basis of Disease - Chapter 13: Multiple Myeloma, pp. 569-571
• Goldman-Cecil Medicine International Edition - Chapter 173: Multiple Myeloma, diagnosis, treatment dosing tables
• Harrison's Principles of Internal Medicine 22E (2025) - Chapter: Plasma Cell Disorders
• Washington Manual of Medical Therapeutics - Hematology section