• Most common acute leukemia in adults, accounting for ~80% of acute leukemia cases in adults ^[2][3][4]
• Incidence: 3–5 per 100,000 ^[4], and increases with age ^[2][3][4]
• Median age at diagnosis: ~65 years ^[2][3][4]
• Male-to-female ratio = 5:3 ^[2][3][4]
• Very rare in childhood ^[2][3] — in paediatric populations, ALL dominates (80% of childhood leukemia), while AML accounts for only ~15% of childhood leukemia ^[2][3]
• Overall, acute leukemia (AML + ALL) is the most common childhood malignancy, accounting for ~30% of paediatric cancers ^[2][3]

• AML is not a common disease in absolute numbers ^[5]
• Approximately 150–200 new cases of AML per year in the entire Hong Kong population (based on Hong Kong Cancer Registry data)
• Disease follows the same age-increasing pattern as global data, with the bulk of cases in elderly patients
• Given HK's ageing population, the incidence burden is expected to rise

Key points:

• The bone marrow is the primary site of haematopoiesis in adults
• The HSC sits at the apex: self-renewing, multipotent
• The CMP gives rise to all myeloid lineages (neutrophils, monocytes, eosinophils, basophils, RBCs, platelets)
• In AML, the malignant clone arises from the CMP or downstream progenitors, becoming arrested at the blast stage

• The leukemic blasts proliferate uncontrollably and physically crowd out normal haematopoietic precursors in the marrow space
• This leads to pancytopenia (reduced RBCs, neutrophils, and platelets) despite paradoxically high total WBC counts
• The blasts themselves are non-functional — they cannot perform phagocytosis, oxygen transport, or clotting

• The spleen acts as a filter for abnormal/old blood cells and a site of extramedullary haematopoiesis
• In AML, splenomegaly can occur due to infiltration by leukemic blasts or compensatory extramedullary haematopoiesis
• However, hepatosplenomegaly and lymphadenopathy are more common presenting features in ALL than AML ^[6]

Why do DNA repair defects predispose to AML? Because haematopoietic stem cells are among the most rapidly dividing cells in the body. Each cell division is an opportunity for replication errors. If DNA repair mechanisms are impaired, mutations accumulate faster, driving malignant transformation.

• Chemical exposure ^[2][3][4]: especially benzene (occupational exposure in petrochemical, rubber, shoe industries)
  • Benzene metabolites (hydroquinone, catechol) cause oxidative DNA damage and chromosomal aberrations in HSCs
• Radiation exposure ^[2][3]: ionising radiation causes double-strand DNA breaks
  • Historical evidence: atomic bomb survivors, therapeutic radiation
• Smoking ^[2][3]: tobacco smoke contains benzene and other carcinogens; ~1.2× increased risk

This is a critically important category and is poor prognosis ^[4]:

• Alkylating agents (e.g., cyclophosphamide, ifosfamide) ^[2][3]

  • Cause DNA cross-linking → chromosomal deletions (del(5q), del(7q))
  • Latency: 5–7 years after exposure
  • Often preceded by MDS phase

• Topoisomerase II inhibitors (e.g., etoposide, doxorubicin) ^[2][3]

  • Cause balanced translocations (e.g., 11q23/MLL rearrangements)
  • Latency: 1–3 years after exposure
  • Often present as overt AML without preceding MDS

• Myelodysplastic syndrome (MDS) ^[2][3][4] → the classic "pre-leukemic" state; ~30% transform to AML
• Myeloproliferative neoplasms (MPN) ^[2][3][4], particularly CML (blast crisis)
  • All forms of MPN share potential to progress to blastic transformation ^[5]
• Aplastic anaemia ^[2][3] → chronic stem cell stress + immunosuppressive therapy → clonal evolution
• Paroxysmal nocturnal haemoglobinuria (PNH) ^[2][3] → clonal haematopoietic disorder with overlap to MDS/AML

AML pathogenesis is classically explained by the "two-hit hypothesis" ^[4]:

• Class I mutations: confer proliferative advantage ^[4]

  • Examples: FLT3-ITD, c-Kit, RAS mutations
  • These activate signalling pathways (e.g., RAS/MAPK, PI3K/AKT) that promote cell survival and proliferation
  • Why? FLT3 (FMS-like tyrosine kinase 3) is a receptor tyrosine kinase normally expressed on haematopoietic progenitors. The ITD (internal tandem duplication) mutation causes constitutive (always-on) activation → uncontrolled proliferation

• Class II mutations: impair haematopoietic differentiation ^[4]

  • Examples: CEBPA mutations, PML-RARA (t(15;17)), AML1-ETO (t(8;21)), CBFB-MYH11 (inv(16))
  • These block the transcription factors needed for myeloid cells to mature
  • Why? C/EBPα is a transcription factor essential for granulocytic differentiation. Loss-of-function mutations arrest cells at the blast stage

The two-hit model states that BOTH types of mutation are needed for full leukemic transformation:

• Class I alone → proliferation without differentiation block → MPN-like picture
• Class II alone → differentiation block without proliferation → MDS-like picture
• Class I + Class II → proliferation AND differentiation block → AML

Once both hits occur, the consequences are:

1. Marrow replacement → normal haematopoietic precursors are crowded out → pancytopenia
2. Blast release into blood → circulating blasts → can infiltrate organs
3. Ineffective haematopoiesis → even non-leukemic progenitors are suppressed by the tumour microenvironment (cytokine dysregulation)

APL deserves special mention because of its unique pathophysiology and treatment:

• Caused by t(15;17)(q24;q21) creating the PML-RARA fusion gene
• RARα (retinoic acid receptor alpha) normally promotes granulocytic differentiation when bound by retinoic acid
• The PML-RARα fusion protein acts as a dominant negative — it recruits histone deacetylases and blocks transcription of differentiation genes → promyelocytes cannot mature
• APL cells express tissue factor (Factor III) on their surface and release procoagulant granules → triggers DIC ^[7]

DIC in APL: the APL cells express tissue factor (the initiator of the extrinsic pathway). This leads to excessive activation of the coagulation cascade → too much thrombin → too much fibrin formation → fibrin clots block blood vessels + excessive consumption of coagulation factors → bleeding tendency + fibrin clots trap platelets → thrombocytopenia ^[7]. The clotting profile classically shows PT elevated (Factor VII has shortest half-life, consumed first), APTT initially preserved (Factor VIII is an acute phase reactant, stays high), low fibrinogen, high D-dimer ^[7].

The FAB classification was the original morphological system. While largely superseded by the WHO classification, it remains referenced, especially in clinical practice and exams:

The WHO classification integrates morphology, immunophenotype, cytogenetics, and molecular genetics. The key categories ^[4][8]:

1. AML with recurrent genetic abnormalities ^[4]

   • t(15;17) — PML-RARA (APL) → good prognosis with ATRA
   • t(8;21) — RUNX1-RUNX1T1 → favourable
   • inv(16)/t(16;16) — CBFB-MYH11 → favourable
   • Mutated NPM1 → favourable (most common mutation in AML, ~30%)
   • FLT3-ITD → adverse prognosis
   • Biallelic CEBPA mutation → favourable
   • Note: Diagnosis can be made by blast cells even if < 20% when specific leukemia-associated cytogenetic/molecular genetic abnormalities are present ^[4]

2. AML with myelodysplasia-related changes ^[4]

   • Microscopic features of dysplasia in at least 50% cells in ≥2 lineages
   • Poor prognosis ^[4]

3. Therapy-related myeloid neoplasm (t-AML) ^[4]

   • AML arising after prior chemotherapy/radiotherapy
   • Poor prognosis ^[4]

4. AML, not otherwise specified (NOS) ^[4]

   • Absence of recurrent cytogenetic abnormalities
   • Comprises ~30% of all AML ^[4]
   • Mutations in NPM and FLT3 genes seen in ~50% and ~30% of all AML respectively, and are frequent in those with normal cytogenetics ^[4]

5. Myeloid sarcoma ^[4]

   • Resembles a solid tumour but composed of myeloid blast cells
   • Prominent extramedullary disease (e.g., cutaneous or gingival infiltration), occurs in < 1% ^[4]

6. Myeloid proliferation related to Down syndrome ^[4]

   • Transient abnormal myelopoiesis (in neonates)
   • Myeloid leukemia

This is crucial for prognosis and treatment decisions:

This is the single most important differential — because both are acute leukemias presenting with pancytopenia, blasts, and organ infiltration.

Why is this distinction critical? Treatment regimens are completely different. AML uses anthracycline-based induction ("7+3"), while ALL uses multi-agent protocols with CNS prophylaxis. Giving the wrong regimen is potentially fatal.

A subtle but important exam point: some ALL cells may co-express myeloid markers or even be mixed phenotype acute leukemia (MPAL) ^[4]. Conversely, ~20% of AML will co-express lymphoid markers, but these do not influence prognosis ^[4]. This is why immunophenotyping alone is not sufficient — you need the full MCICM workup.

MDS is the classic "pre-leukemic" state and sits on a spectrum with AML.

Why is this a key differential? The blast count may be marginal (i.e., approaching 20%), especially with BM regeneration after chemotherapy or G-CSF injection — this does not always imply AML transformation ^[4]. The 20% threshold is somewhat arbitrary, and serial monitoring is needed.

From first principles: MDS is a disorder of ineffective haematopoiesis — the marrow IS making cells, but they are dysplastic and die before release into the circulation (intramedullary apoptosis). This is why the marrow is hypercellular but the peripheral blood is cytopenic. In AML, the problem shifts to maturation arrest — blasts cannot differentiate at all.

CML in blast crisis is an essential differential — it is critical to identify the underlying condition because BCR-ABL TKIs (e.g., imatinib) may still have a role ^[4].

Why does this matter? If you treat CML blast crisis like de novo AML with standard chemotherapy alone, you miss the opportunity to use a TKI (tyrosine kinase inhibitor) targeting BCR-ABL. The TKI is the cornerstone of CML treatment and dramatically improves outcomes.

From first principles: CML starts as a chronic phase disorder driven by the BCR-ABL fusion oncoprotein (constitutive tyrosine kinase → proliferative advantage). Over time, additional mutations accumulate (similar to the two-hit model), and the disease transforms through an accelerated phase into blast crisis (≥20% blasts). This is why chronic leukemia transforms into acute leukemia if left untreated — leukemic cells acquire more and more mutations over time ^[1].

Aplastic anaemia presents with pancytopenia resulting from bone marrow hypoplasia or aplasia ^[13], which overlaps with the pancytopenia of AML.

Why no hepatosplenomegaly in aplastic anaemia? The spleen's job is to filter and destroy abnormal RBCs. In aplastic anaemia, there isn't even a functional bone marrow producing RBCs — the spleen has nothing to recognise as abnormal, so no splenomegaly. For lymphadenopathy — there is no malignant component producing cells that infiltrate lymph nodes ^[13].

The critical distinction is the bone marrow biopsy: hypercellular with blasts = AML; hypocellular "empty" marrow with fat = aplastic anaemia. However, remember that aplastic anaemia itself is a risk factor for developing AML ^[2][3].

Vitamin B12 and folate deficiency can cause pancytopenia with prominent erythroid elements — this may mimic erythroleukaemia (AML-M6) ^[4].

Why the confusion? In severe B12/folate deficiency, the bone marrow can be hypercellular with abundant erythroid precursors that look "immature" — because DNA synthesis is impaired (thymidine synthesis requires folate), so the nucleus lags behind the cytoplasm in maturation (nuclear-cytoplasmic dyssynchrony). This can superficially resemble the erythroid hyperplasia of AML-M6. The key is: there are no true blast cells, and hypersegmented neutrophils on the PBS are the giveaway for megaloblastic anaemia.

A leukemoid reaction is a marked reactive leukocytosis (WBC > 50 × 10⁹/L, sometimes > 100) that mimics CML or even AML clinically.

From first principles: Left shift means abundant immature forms of the granulocyte series (band cells, metamyelocytes, myelocytes) — this indicates severe infection/sepsis or CML ^[9][11]. A left shift is the marrow's attempt to rapidly mobilise neutrophils in response to infection. Crucially, it does NOT include blasts — blasts in the peripheral blood are always abnormal ^[9][11].

A leukoerythroblastic picture (left shift in granulocyte series + nucleated RBCs ± tear-drop RBCs) indicates marrow infiltration — by primary myelofibrosis or any metastatic cancer ^[9][11].

Metastatic carcinoma (breast, prostate, lung, neuroblastoma in children) can infiltrate the marrow, causing:

• Pancytopenia
• Leukoerythroblastic blood film
• Bone pain

The key distinction from AML: there are no myeloid blasts, and the infiltrating cells are non-haematopoietic (epithelial, neuronal, etc.), identifiable on trephine biopsy with appropriate immunohistochemistry.

Myeloma can cause pancytopenia (from marrow replacement by clonal plasma cells) with bone pain, mimicking AML. However:

• PBS shows rouleaux formation, not blasts
• Serum protein electrophoresis shows monoclonal M-spike ^[14]
• Bone marrow shows clonal plasma cells, not myeloblasts
• CRAB criteria (Calcium elevated, Renal insufficiency, Anaemia, Bone lesions) ^[14]

High-grade lymphomas (e.g., Burkitt lymphoma, DLBCL) can present with marrow involvement, cytopenias, and circulating abnormal cells. Distinguished by:

• Immunophenotype: lymphoid markers (CD20+, CD19+)
• Cytogenetics: lymphoma-specific translocations (e.g., t(8;14) for Burkitt)
• Clinical: prominent lymphadenopathy, extranodal masses

This threshold is somewhat arbitrary but clinically validated. It distinguishes AML from MDS (which also has blasts, but < 20%). Below 20%, the disease behaves more indolently (MDS pattern); above 20%, the biology shifts to aggressive blast proliferation requiring urgent chemotherapy. The count is performed on a 500-cell differential to ensure statistical reliability.

Because certain cytogenetic/molecular abnormalities are so specific to AML biology that their presence defines the disease regardless of blast percentage ^[2][3][4]:

These are sometimes called "AML-defining recurrent genetic abnormalities". Even if the blast count is 10%, finding t(15;17) means the patient has APL and needs immediate treatment.

Additionally, myeloid sarcoma (an extramedullary tumour composed of myeloid blasts) is diagnostic of AML regardless of blast count in blood or marrow ^[4].

This is always the first investigation — it tells you "something is wrong" before you know exactly what.

Why can WBC be LOW in AML? In some cases (especially APL), the blasts are "sticky" and remain in the marrow, with relatively few spilling into the peripheral blood. APL classically presents with pancytopenia rather than high WBC ^[1]. The automated counter sees low total WBC because not many blasts have escaped into circulation.

The PBS is where you first see the disease. It provides morphological clues before the bone marrow is done.

PBS findings in AML ^[4][10]:

• Circulating myeloblasts (present in 95% of cases) ^[2][3]: immature myeloid cells with large nuclei and prominent nucleoli with variable amount of pale blue cytoplasm with Wright-Giemsa stain ^[2][3]
• Granules present in the cytoplasm (distinguishing from ALL blasts which have NO granules) ^[10]
• Increased cytoplasm (relatively lower N:C ratio compared to ALL) due to concomitant increase in nuclear size ^[10]
• > 20% blasts, large cells ~3× the size of normal lymphocytes → open chromatin ^[10]
• Positive for cytochemical staining (MPO/SBB) ^[10]

PBS findings specifically in APL ^[10]:

• Bilobed (reniform/kidney-shaped) nucleus ^[10]
• Auer rods — pink or red rod-like granular structures in cytoplasm ^[2][3]; pathognomonic of myeloblasts ^[2][3]
• Faggot cells → once having 3 or more Auer rods ^[10][11] — abnormal promyelocytes with numerous Auer rods → indicates APML, a haematological emergency ^[9][11]
• Giant platelets + schistocytes (due to DIC) ^[10]
• Absolute thrombocytopenia ^[10]

PBS findings in ALL (for comparison) ^[10]:

• No granules ^[10]
• Decreased cytoplasm (high N:C ratio) ^[10]
• > 20% blasts, large cells ~3× the size of normal → open chromatin ^[10]
• Negative for cytochemical staining (MPO/SBB) ^[10]

Auer rods are normally difficult to distinguish between myelo-/lymphoblasts morphologically, but the presence of Auer rods confirms myeloblastic nature, i.e., a diagnosis of AML ^[9][11]. This is because Auer rods are crystallised azurophilic granules containing myeloperoxidase — a myeloid-specific enzyme. Lymphoblasts do not produce these granules.

This is the definitive diagnostic investigation and provides material for the entire MCICM workup.

Technique ^[11][16]:

• Site: typically posterior iliac crest; alternative sites include anterior iliac crest and sternum (sternum for aspiration only) ^[11][16]
• Two procedures done together 1–2 cm apart ^[11][16]:
  • Aspirate for smear: permits cytology examination, flow cytometry, and genetic studies ^[11][16]
  • Trephine biopsy: permits histological examination (marrow cellularity, architectural details, marrow fibrosis, bone structure) and immunohistochemistry ^[11][16]

Contraindications ^[11][16]:

• Only absolute contraindication: severe bleeding disorders (severe haemophilia, DIC) ^[11][16]
• Thrombocytopenia of any severity is NOT a contraindication — just top up platelets to > 20 × 10⁹/L prior ^[11][16]
• Complications are uncommon (0.05–0.07%): most commonly pain, infection, bleeding ^[11][16]

Key BM findings in AML ^[2][3][4]:

• Hypercellular bone marrow ^[2][3]
  • Partial or total replacement of normal cellular components of marrow by immature or undifferentiated cells ^[2][3]
• ≥20% of blasts ^[2][3][4]
  • Blasts include: pronormoblast, myeloblast, abnormal promyelocyte, promonocyte, megakaryoblast ^[2][3]
• Presence of Auer rods ^[2][3] — pathognomonic of myeloblasts, pink or red rod-like granular structure in cytoplasm ^[2][3]

General support: adequate nutrition, antiemetic, analgesia ^[4][6][9]

Five haematological emergencies that can arise during acute leukemia ^[1]:

Why avoid blood transfusion in leucostasis? Packed red cells increase blood viscosity. When the WBC is already > 100 × 10⁹/L and blasts are clogging microvessels, adding more viscosity with RBCs is like throwing fuel on a fire. Reduce the blast count first with leukapheresis or hydroxyurea, THEN transfuse as needed.

Why is leukapheresis only a temporary measure? Blasts grow so fast that the moment you remove them, they'll come back — so adjunctive chemotherapy is always needed ^[1]. Leukapheresis is a bridge to buy time.

Indicated in young adults with unfavourable risk AML or relapse cases after complete remission (CR) ^[2]:

• AML/ALL: CR1 but with high risk for relapse (post-induction), CR2 or beyond ^[4]
• Adverse-risk cytogenetics/molecular profile
• Refractory or relapsed disease

Two purposes ^[4][2]:

1. Myeloablative conditioning: high-dose chemo/radiation wipes out the diseased marrow completely
2. T-cells in donor graft induce a graft-versus-leukemia (GvL) effect against residual disease that has survived the conditioning ^[2]

The GvL effect is actually the most important therapeutic component — donor T-cells recognise leukemic cells as "foreign" (because they express recipient-specific alloantigens) and destroy them. This is why allogeneic (not autologous) HSCT reduces relapse rates.

HLA typing is required ^[2]:

• CANNOT accept HLA mismatch in bone marrow transplantation ^[2]
• Matching for HLA Class I and II genes at allelic level is crucial ^[2]
• Must include: HLA-A, HLA-B, HLA-C, HLA-DRB1 ^[2]
• HLA-DPA1/B1, HLA-DQA1/B1 extended in some centres ^[2]

ALWAYS ask for family members such as siblings for potential allogeneic HSCT candidates ^[2]

Arrange HLA typing for siblings if HSCT anticipated ^{[4][6][9][15]} CMV-negative blood only for potential HSCT recipients if patient is CMV-negative ^[4]

Reduced intensity conditioning (RIC) may be considered for older patients or those with comorbidities ^[4] — this uses lower-dose conditioning to reduce TRM while still allowing engraftment and GvL effect.

Induction therapy uses differentiating agents to induce terminal differentiation of arrested promyelocytes into mature neutrophils ^[4]:

How do ATRA and ATO work?

Hong Kong is leading in this regard — we have oral arsenic ^[1]. Oral ATO formulations have been developed and shown to be effective, offering a more convenient administration route.

If you tide them over the acute period with no ICH, then the prognosis is good — so you CANNOT miss APL ^[1]

Coagulopathy: controlled by platelet + FFP + cryoprecipitate transfusion ^[4]

• Maintain platelets > 30–50 × 10⁹/L (higher threshold than other AML)
• Maintain fibrinogen > 1.5 g/L

Differentiation syndrome ^[4]:

• Dexamethasone 10 mg IV Q12h × ≥3 days as prophylaxis ^[4]
• Pathogenesis: due to production of inflammatory cytokines by large burden of maturing myeloid cells ^[4]
• Why does this happen? ATRA and ATO work by forcing promyelocytes to differentiate. The massive wave of differentiating cells releases inflammatory cytokines (IL-1, IL-6, TNF-α), causing a systemic inflammatory response
• S/S: dyspnoea, fever, peripheral oedema, hypotension, pleuro-pericardial effusion, acute renal failure, jaundice ^[4]

Remission is achieved in ~90% of patients ^[4]:

• ATRA/ATO induction → post-remission with ATO + ATRA ^[4]
• ATRA/chemo induction → post-remission with anthracycline + ATRA ^[4]

APL is the most curable subtype of AML — with current protocols, long-term cure rates approach 90%.

• Mechanism: Leukemic blasts replace normal granulocytic precursors → functional neutropenia despite potentially high total WBC → impaired innate immunity → overwhelming susceptibility to infections
• Febrile neutropenia is a medical emergency requiring blood cultures and broad-spectrum antibiotics within one hour. ANC < 0.5 × 10⁹/L combined with fever necessitates urgent empirical therapy, as delayed treatment significantly increases mortality ^[17]

Why S. viridans? Prolonged bone marrow suppression is associated with very high incidence of infections, especially S. viridans sepsis and S. viridans shock syndrome ^[2]. S. viridans is part of the normal oral flora. Chemotherapy-induced mucositis (destruction of the oral mucosa barrier) allows these commensal bacteria to translocate into the bloodstream. In a neutropenic patient with no functional neutrophils to contain them, this becomes lethal bacteraemia.

Why Aspergillus? Aspergillus spores are ubiquitous in the environment (soil, water, air ducts). In immunocompetent individuals, alveolar macrophages and neutrophils destroy inhaled spores. In prolonged neutropenia, these spores germinate into hyphae that invade lung tissue → invasive pulmonary aspergillosis (IPA). This is why HEPA-filtered rooms and antifungal prophylaxis are standard of care during induction.

• Mechanism: Megakaryocytes are replaced by blasts → thrombocytopenia → impaired primary haemostasis → spontaneous bleeding
• Most common sites: mucocutaneous (gum bleeding, epistaxis, petechiae), GI, GU
• Life-threatening sites: CNS (intracranial haemorrhage), pulmonary

Bleeding in APL is particularly dangerous ^[1][6]:

• DIC (disseminated intravascular coagulation) — driven by tissue factor release and primary hyperfibrinolysis from APL cells ^[1][4]
• Bleeding symptoms are out of proportion to the platelet count ^[1] — because DIC consumes clotting factors AND platelets simultaneously
• ICH (intracranial haemorrhage) is the leading cause of early death in APL ^[4] — untreated APL has a median survival of < 1 month; the patient CAN die in front of you from ICH ^[4]

• Mechanism: Rapid spontaneous or chemotherapy-induced destruction of large numbers of blast cells → massive release of intracellular contents:

  • K⁺ → hyperkalaemia (cardiac arrhythmia risk)
  • Phosphate → hyperphosphataemia (calcium-phosphate complex precipitation → hypocalcaemia → tetany, seizures)
  • Nucleic acids → purine catabolism → hyperuricaemia (uric acid crystals deposit in renal tubules → acute uric acid nephropathy → AKI)
  • LDH → elevated as a marker of cell lysis

• Risk factors: high tumour burden (WBC > 100 × 10⁹/L), high LDH, pre-existing renal impairment, monocytic subtypes (M4/M5)

• Prevention: hydration + allopurinol or febuxostat or rasburicase ^[6][9]

• Check HLA-B5801 before starting allopurinol* ^[1]; check G6PD before rasburicase ^[6][9][15]

• Headache, vision change, SOB ^[8] — due to microvascular occlusion by large, adhesive myeloid blasts
• Typically when WBC > 100 × 10⁹/L (~20% of AML patients at presentation)
• More common in AML than ALL because myeloid blasts are larger and stickier
• Organ damage: pulmonary leucostasis (ARDS-like picture), cerebral leucostasis (stroke, altered consciousness), renal impairment
• Avoid blood transfusion until WBC is lowered ^[4][6] — adding RBCs increases viscosity
• Management: urgent leukapheresis + cytoreductive chemotherapy

• CNS infiltration: headache, cranial nerve palsies, meningism — more common in M5 (monocytic) and paediatric AML
• Gum infiltration: gum hypertrophy (AML-M5) ^[1][4][8] — monocytic blasts have tropism for gingival tissue
• Skin infiltration (leukemia cutis): violaceous nodules/papules
• Ocular: haemorrhage, Roth spots, cotton wool spots ^[8] — from thrombocytopenia + blast infiltration of retinal vessels
• Bone pain: periosteal stretching from expanding blast population within the medullary cavity

Already discussed extensively in prior sections — most characteristic of APL (AML-M3). The fundamental problem: release of procoagulants from leukemic blasts ^[1] → excessive coagulation cascade activation → simultaneous thrombosis AND bleeding.

• Severe BM hypoplasia requiring intensive support and in-patient care ^[4][6][9]
• Marked BM hypocellularity and peripheral pancytopenia are EXPECTED after induction ^[4]
• The "nadir" period (2–4 weeks post-induction) is when the patient is most vulnerable to infection and bleeding
• This is a planned complication — you EXPECT it and manage it supportively:
  • RBC transfusion if symptomatic anaemia ^[4][6][9]
  • PLT transfusion if PLT ≤10, or ≤20 if fever/bleeding ^[4][6][9]
  • Prophylactic antibiotics/antifungals ^[2]
  • Acyclovir for HSV-seropositive patients ^[4]

This deserves its own section because it is the leading cause of morbidity and mortality during AML treatment.

Prolonged bone marrow suppression is associated with very high incidence of infections, especially: ^[2]

• S. viridans sepsis and S. viridans shock syndrome
• Fungal infection such as Aspergillus infection

Treatment for suspected infections: antibiotics for fever and neutropenia; antifungals for prolonged fever and neutropenia ^[2]

• Mechanism: Cytotoxic chemotherapy destroys rapidly dividing mucosal epithelial cells → mucosal barrier breakdown
• Oral mucositis: painful ulceration of the oropharyngeal mucosa → impaired nutrition, portal of entry for oral flora (→ S. viridans bacteraemia)
• Non-oral mucositis: abdominal pain, nausea, diarrhoea (GI mucosal damage)
• Management: oral care protocols, ice cubes, analgesics, ± TPN if severe

• Mechanism: Anthracyclines (daunorubicin, idarubicin) generate free radicals via iron-dependent redox cycling → direct myocardial cell injury → myocyte apoptosis → progressive dilated cardiomyopathy
• Dose-dependent — cumulative lifetime dose must be tracked (e.g., daunorubicin > 550 mg/m²)
• ECG + echocardiogram (TTE) required before anthracycline use ^[2][3][15] — to establish baseline LVEF
• Can be acute (arrhythmias during infusion) or chronic (progressive HF months to years later)
• Cardioprotection: dexrazoxane (iron chelator that reduces free radical formation); dose monitoring; liposomal formulations

This is critically important in Hong Kong given the high HBV carrier prevalence (~7–8% in the general adult population).

• Mechanism: Immunosuppressive chemotherapy suppresses the immune surveillance that keeps HBV in check → viral replication surges → when immune reconstitution occurs post-chemotherapy, there is a massive immune flare against HBV-infected hepatocytes → severe hepatitis, potentially fulminant liver failure
• Hepatitis B serology (HBsAg, anti-HBc, anti-HBs ± HBV DNA) must be checked before chemotherapy ^{[4][6][9][15]} — risk of HBV reactivation during chemotherapy
• Potentially dangerous and fatal, especially in patients with decompensated liver disease or abnormal immune systems (lymphoma, leukemia) ^[18]
• Anti-CD20 (rituximab) and anti-CD52 (alemtuzumab) are also capable of reactivating occult hepatitis B ^[18] — can be FATAL ^[18]
• Reactivation can even occur in patients who are anti-HBs positive (i.e., previously cleared infection / "occult" HBV) ^[18]
• Prevention: Antiviral prophylaxis (entecavir or tenofovir) for all HBsAg+ patients before chemotherapy; monitor HBV DNA in anti-HBc+ patients

• Occurs in patients treated with ATRA or ATO for APL
• Pathogenesis: production of inflammatory cytokines by large burden of maturing myeloid cells ^[4]
• S/S: dyspnoea, fever, peripheral oedema, hypotension, pleuro-pericardial effusion, acute renal failure, jaundice ^[4]
• Timing: typically 2–21 days after starting ATRA, often with rising WBC
• Management: dexamethasone 10 mg IV Q12h × ≥3 days ^[4]; temporarily hold ATRA if severe

Why does VOD happen? The high-dose conditioning regimen (alkylating agents, total body irradiation) is directly toxic to the hepatic sinusoidal endothelium. The damaged endothelium swells, activates coagulation, and forms micro-thrombi. These block the hepatic venular outflow → congestion → hepatocyte necrosis → the classic triad of painful hepatomegaly, ascites, and jaundice.

Overall prognosis of HSCT ^[4]:

• Allogeneic HSCT: 75% long-term survival; 80% at 15 years for those who survived ≥2 years; 9.9× mortality compared to general population (highest years 2–5 post-HSCT); 29% relapse; 22% chronic GVHD ^[4]
• Autologous HSCT: 80% overall survival at 20 years for those who survived ≥5 years; 4–9× mortality compared to general population ^[4]