• ALL is the most common cancer (~25%) in children ^[2][4] and the most common childhood malignancy overall when combined with AML (acute leukaemia accounts for ~30% of all childhood cancers, with ALL accounting for ~80% of childhood leukaemia) ^[5][6].
• Peak incidence: age 2–5 years (3/4 of cases occur before age 6) ^[2][4].
• There is a second, smaller peak in incidence > 60 years of age ^[4].
• ALL is much less common than AML in adults ^[2]; in adults, AML accounts for ~80% of acute leukaemia cases ^[5].

• Overall slight male predominance, particularly in T-ALL (which shows clear male predominance) ^[2][4].

^[2][4]

• In Hong Kong, childhood ALL follows the same age-peak pattern (2–5 years). Given the predominantly Chinese population, the genetic landscape may differ slightly (e.g., lower frequency of certain favourable cytogenetics like ETV6-RUNX1 compared with Caucasian populations, but higher frequency of some unfavourable subtypes). The Hong Kong Children's Hospital and Queen Mary Hospital are the main treatment centres.
• Adult ALL is uncommon but carries a significantly worse prognosis than childhood ALL.

^[5][6][7]

• Chemical exposure (e.g., benzene, pesticides) ^[5][6]
• Radiation exposure — ionizing radiation (e.g., atomic bomb survivors, therapeutic radiation) ^[5][6]
• Smoking — parental smoking may slightly increase risk in offspring ^[5][6]

• Alkylating agents (Cyclophosphamide / Ifosfamide) ^[5][6]
• Topoisomerase II inhibitors (e.g., etoposide, doxorubicin) — these cause DNA double-strand breaks at specific sites, leading to characteristic translocations (e.g., MLL rearrangements at 11q23) ^[5][6]

• Myelodysplastic syndrome (MDS) ^[5][6]
• Myeloproliferative neoplasm (MPN) ^[5][6]
• Aplastic anaemia ^[5][6]
• Paroxysmal nocturnal haemoglobinuria (PNH) ^[5][6]

Why would aplastic anaemia predispose to ALL? In aplastic anaemia, there is T-cell–mediated destruction of haematopoietic stem cells (HSCs). The remaining HSCs are under intense proliferative stress to repopulate the marrow. This chronic replicative stress increases the chance of acquiring somatic mutations, which can lead to clonal evolution → MDS or acute leukaemia.

• Advanced paternal age — possibly due to increased accumulation of de novo mutations in spermatogonial stem cells with age ^[2][4]
• Infections / immune dysregulation — Greaves' "delayed infection" hypothesis proposes that lack of early childhood infection exposure leads to an abnormal immune response to later infections, triggering leukaemogenesis in children with a pre-existing pre-leukaemic clone

• HSCs reside in the bone marrow and give rise to all blood cell lineages.
• The common lymphoid progenitor (CLP) commits to lymphoid differentiation.
• B-cell development occurs primarily in the bone marrow: pro-B → pre-B → immature B → mature naïve B cell (released into peripheral blood and lymphoid organs).
• T-cell development requires migration to the thymus where pro-T cells undergo positive/negative selection to become mature T cells.
• ALL arises from malignant transformation of precursor lymphocytes at various stages of differentiation. The stage at which the cell is "arrested" determines the immunophenotype.

Although the "two-hit hypothesis" is classically described for AML ^[4], a similar concept applies to ALL. Leukaemogenesis requires the accumulation of multiple cooperating genetic lesions:

1. Initiating mutations — often occur in utero (demonstrated by studies of identical twins where both carry the same pre-leukaemic clone, but only one develops ALL). These create a pre-leukaemic clone with a survival/self-renewal advantage.

   • Examples: ETV6-RUNX1 fusion [t(12;21)], hyperdiploidy

2. Cooperating / secondary mutations — occur post-natally and drive frank leukaemia by:

   • Blocking differentiation (e.g., PAX5, IKZF1 deletions)
   • Activating proliferative signalling (e.g., RAS pathway mutations, JAK mutations)
   • Disrupting tumour suppressors (e.g., CDKN2A/p16 deletion)

Mutations can occur in utero and post-natally (usually NOT inherited) ^[2][4]

Two anatomic sites are particularly important in ALL:

1. CNS — the blood–brain barrier prevents adequate penetration of most systemically administered chemotherapy drugs. Leukaemic blasts can "hide" in the CSF/meningeal compartment and serve as a source of relapse.
2. Testes — the blood–testis barrier similarly protects leukaemic cells from systemic chemotherapy.

This is why ALL treatment protocols include CNS-directed therapy (intrathecal chemotherapy ± cranial irradiation) and careful testicular surveillance.

The FAB classification is based purely on light microscopy morphology of the blasts. It is largely of historical interest and has been superseded by the WHO classification, but is still referenced:

^[7]

Flow cytometry is essential for lineage determination. Key markers:

TdT (Terminal deoxynucleotidyl Transferase) — a DNA polymerase that adds random nucleotides at V(D)J junctions during lymphocyte receptor gene rearrangement. It is expressed in precursor lymphocytes (lymphoblasts) but NOT in mature lymphocytes. Therefore, TdT positivity is a hallmark of precursor lymphoid neoplasms (ALL) and distinguishes them from mature lymphoid neoplasms (e.g., CLL, lymphoma).

T-ALL frequently presents with a mediastinal mass (50–75%) ^[2][4]. The thymic mass can cause:

• Superior vena cava obstruction (SVCO) → facial oedema, plethora, distended neck veins, upper body oedema
• Tracheal compression → stridor, dyspnoea, respiratory failure
• Pericardial effusion → cardiac tamponade

This can be a medical emergency requiring immediate treatment (often steroids) before definitive diagnosis, because anaesthesia/sedation in a patient with a large anterior mediastinal mass can cause fatal airway collapse.

• Defined as WBC > 100 × 10⁹/L
• Can cause leucostasis (microvascular occlusion) → neurological symptoms (headache, confusion, visual changes), pulmonary symptoms (dyspnoea, hypoxia), and rarely priapism
• More common in AML but can occur in T-ALL (T-ALL blasts tend to have higher counts)
• Management: urgent leukapheresis, hydroxyurea, and initiation of chemotherapy; avoid RBC transfusion (which increases viscosity)

• ALL blasts have a high proliferative rate and are very sensitive to chemotherapy → rapid cell death releases large amounts of intracellular contents:
  • Potassium → hyperkalaemia → cardiac arrhythmias
  • Phosphate → hyperphosphataemia → secondary hypocalcaemia → tetany, seizures
  • Uric acid (from purine catabolism) → hyperuricaemia → acute urate nephropathy / AKI
  • LDH ↑ (marker of cell turnover)
• ALL is one of the highest-risk malignancies for TLS (along with Burkitt lymphoma)

This is the single most important differential because both AML and ALL present with bone marrow failure (anaemia, infection, bleeding) and extramedullary infiltration ^[8][4]. On peripheral blood smear, it is often difficult to distinguish myeloblasts from lymphoblasts on morphology alone ^[2][4].

How to differentiate:

Why can this be confusing? ~20% of AML cases co-express lymphoid markers (e.g., CD7, CD19), and some ALL cases may co-express myeloid markers (e.g., CD13, CD33). These "cross-lineage" expressions do NOT change the diagnosis — the key is whether the predominant lineage is myeloid or lymphoid based on the full panel. In truly ambiguous cases, the diagnosis is mixed phenotype acute leukaemia (MPAL) ^[4].

Burkitt lymphoma can also be very aggressive, but usually can be distinguished by morphology, immunophenotyping and cytogenetic/molecular features ^[2][4].

Why does this distinction matter clinically? The treatment is completely different. Burkitt leukaemia requires a short, very intensive chemotherapy regimen with anti-CD20 (rituximab), whereas standard ALL protocols use prolonged maintenance therapy. Misclassifying Burkitt as ALL (or vice versa) can lead to treatment failure.

Other lymphoproliferative disorders are usually clinically less aggressive and have different immunophenotype/genetics ^[2][4]. These include:

• Chronic Lymphocytic Leukaemia (CLL) — disease of older adults (median age 70); characterised by mature-appearing small lymphocytes with smudge cells on PBS, CD5+/CD23+ on flow cytometry. Never occurs in childhood ^[5]. The cells are mature, NOT blasts.
• Mantle cell lymphoma (MCL) in leukaemic phase — CD5+/CD23−, cyclin D1 overexpression, t(11;14)
• Follicular lymphoma — indolent, CD10+, BCL2+, t(14;18)
• Hairy cell leukaemia — distinctive "hairy" cytoplasmic projections, CD103+/CD25+, tartrate-resistant acid phosphatase (TRAP) positive

The key differentiator: ALL cells are precursor/immature (TdT+, blasts) while chronic lymphoproliferative disorders comprise mature lymphocytes (TdT−, no blasts).

Chronic myeloid leukaemia (CML) can undergo blast crisis and transform into an acute leukaemia. Approximately one-third of CML blast crises are of lymphoid phenotype (resembling ALL). This is essential to identify because BCR-ABL TKIs still have a role ^[4].

How to differentiate from de novo ALL:

• History of prior CML (elevated WBC with mature granulocytes, basophilia, splenomegaly)
• BCR-ABL1 positivity [t(9;22)] is present in both Ph+ ALL and CML blast crisis, but CML blast crisis typically has a prior chronic phase with additional cytogenetic abnormalities
• Additional Philadelphia chromosome (double Ph), +8, i(17q) are more common in CML blast crisis

MDS can present with pancytopenia, raising the differential with ALL. However:

• MDS features dysplastic changes in ≥1 myeloid cell lines (dyserythropoiesis, dysgranulopoiesis, dysmegakaryopoiesis) ^[3][9]
• Blast count is < 20% (otherwise it would be classified as AML, not MDS)
• MDS is a disease of the elderly; extremely rare in children (when it does occur, consider inherited bone marrow failure syndromes)

Both ALL and aplastic anaemia can present with pancytopenia. This is a critical differential, especially in children ^[6].

Why does aplastic anaemia have NO hepatosplenomegaly or lymphadenopathy? Because the spleen's job is to filter abnormal RBCs — in aplastic anaemia, the marrow doesn't even produce cells, so the spleen has nothing to recognise as abnormal. For lymphadenopathy, you need cells infiltrating lymph nodes, but in aplastic anaemia, there is nothing being produced or proliferating to infiltrate ^[10].

ITP can mimic ALL when a child presents with isolated thrombocytopenia and bruising/petechiae ^[6]. However:

• In ITP, the other cell lines are normal (normal Hb, normal WBC/differential)
• In ALL, pancytopenia is usually present (though occasionally ALL can present with isolated cytopenia)
• A bone marrow examination is recommended before starting steroids for presumed ITP in children if there are atypical features (e.g., hepatosplenomegaly, lymphadenopathy, bone pain, abnormal cells on PBS), because giving steroids to a child with undiagnosed ALL can temporarily improve counts and delay diagnosis (or obscure blast morphology)

Reactive lymphocytosis, e.g., infectious mononucleosis, pertussis, HIV, TB, osteomyelitis can mimic ALL ^[2][4].

This is one of the most important practical differentials, especially in the context of a young patient with fever, lymphadenopathy, and lymphocytosis.

Why can atypical lymphocytes mimic blasts? Both are large cells that look "unusual" on a blood film. However, atypical lymphocytes (reactive) are mature activated lymphocytes with abundant pale blue cytoplasm that "hugs" adjacent red cells, whereas lymphoblasts are immature precursors with scant cytoplasm, fine/dispersed chromatin, and sometimes visible nucleoli. An experienced haematologist or pathologist can usually distinguish them, but the clinical context (recent sore throat, pharyngitis, positive Monospot) is crucial.

Severe B₁₂ or folate deficiency can present with pancytopenia and prominent erythroid precursors in the marrow — which may mimic erythroleukaemia ^[4]. Key distinguishing features:

• Macrocytic anaemia (MCV typically > 110 fL) with hypersegmented neutrophils
• Low serum B₁₂ or folate levels
• Megaloblastic changes in marrow (large erythroid precursors with immature nuclei but haemoglobinised cytoplasm)
• No blasts, no abnormal immunophenotype

Infectious mononucleosis (IM) is the classic infectious mimic ^[6]. EBV-driven IM presents with:

• Fever, pharyngitis, cervical lymphadenopathy
• Splenomegaly (50–60%)
• Atypical lymphocytosis on PBS (NOT blasts)
• Positive Monospot (heterophile antibody) test / EBV-specific serology

Other infections in the differential of generalised lymphadenopathy ^[11]:

• Viral: EBV, CMV, HIV, acute viral hepatitis
• Bacterial/Mycobacterial: disseminated TB
• Parasitic: Toxoplasma gondii
• Dimorphic fungi: Talaromyces marneffei (particularly relevant in Hong Kong / Southeast Asia in immunocompromised hosts)

Autoimmune causes (e.g., SLE) and drug reactions can also cause generalised lymphadenopathy ^[11].

Juvenile Idiopathic Arthritis (JIA) is a well-known mimic of ALL in children ^[6]. Both can present with:

• Fever
• Bone/joint pain with swelling
• Limp or refusal to walk
• Elevated inflammatory markers

Key distinguishing features:

• JIA: joint swelling/synovitis is the primary feature; cytopenias are NOT typical; PBS/bone marrow is normal
• ALL: bone pain is due to marrow infiltration/periosteal stretching; true arthritis is uncommon — pain is more often metaphyseal bone pain rather than true joint inflammation; cytopenias and blasts on PBS point to ALL

The full differential diagnosis of pancytopenia is broad, but the most important conditions to distinguish from ALL include ^[6]:

• Immune thrombocytopenia (ITP) — isolated thrombocytopenia, other lines normal
• Aplastic anaemia — hypocellular marrow, no blasts, no organomegaly
• MDS — dysplastic features, elderly patients
• Marrow infiltration by solid tumours (see Category 3)
• Megaloblastic anaemia (see 2D above)

Why is the anaemia NcNc? In ALL, the fundamental problem is crowding out of normal erythroid precursors by blasts. The remaining RBCs that were produced before the marrow became overwhelmed are of normal size (normocytic) and normal haemoglobin content (normochromic). This is "anaemia of underproduction." Contrast with iron deficiency (microcytic hypochromic — abnormal RBC production) or B₁₂/folate deficiency (macrocytic — defective DNA synthesis during erythropoiesis).

The PBS is examined by a haematologist under light microscopy. In ALL:

• Circulating lymphoblasts: scanty to abundant basophilic cytoplasm without granules, vacuolation, large and heterogeneous, NO Auer rods ^[2][4]
• Often difficult to be distinguished from myeloid blasts on morphology alone ^[2][4]

Key morphological clues on PBS:

How to distinguish lymphoblasts from atypical lymphocytes on PBS: Lymphoblasts have a high nuclear-to-cytoplasmic (N:C) ratio, fine/dispersed ("open") chromatin, visible nucleoli, and scant cytoplasm. Atypical lymphocytes (reactive) are larger, have abundant cytoplasm that appears to "hug" adjacent RBCs, condensed chromatin, and represent activated mature T cells. The clinical context (sore throat in a teenager → IM vs. a child with pancytopenia → ALL) is also critical.

This is the definitive investigation for ALL diagnosis. It is performed at the posterior iliac crest (typically), with alternatives including the anterior iliac crest and sternum (aspiration only) ^[3].

Two techniques are used, done simultaneously at adjacent sites 1–2 cm apart ^[3]:

Expected bone marrow findings in ALL:

• Hypercellular marrow with lymphoblasts ^[2][4]
• If organ or LN involvement is the initial presentation, look for lymphoblasts in tissue section ^[2][4]
• Blasts replace normal haematopoietic tissue → explains the pancytopenia

Contraindications to bone marrow biopsy:

• Severe bleeding disorders (severe haemophilia, DIC) are the only absolute C/I, excluding thrombocytopenia of any severity → just top up platelets to > 20 × 10⁹/L prior ^[3]

Cytochemistry refers to detection of dye or reaction product in the cells-of-interest using microscopy ^[3]:

Why is there no good cytochemical marker for lymphoid lineage? Lymphoid precursors do not contain the enzyme-rich azurophilic granules that characterise myeloid cells. No good markers exist for lymphoid lineage (previous use of acid phosphatase for T cells is now obsolete) ^[3]. The definitive assignment of lymphoid lineage requires immunophenotyping (flow cytometry), not cytochemistry.

In practice: Cytochemistry is used as a rapid initial screen — if MPO is strongly positive, you're dealing with AML. If MPO is negative, ALL is likely, but you MUST confirm with immunophenotyping.

This is the gold standard for lineage determination and sub-classification. Flow cytometry analyses the expression of cell surface and intracellular markers on individual cells.

Flow cytometry is used for sub-classification and lineage specification ^[1][12].

Key markers in ALL:

Why does TdT matter so much? TdT is a unique enzyme expressed almost exclusively in precursor lymphocytes (both B and T) during the V(D)J recombination stage. Its presence tells you: (1) the cells are lymphoid (not myeloid), and (2) the cells are immature precursors (not mature lymphocytes). TdT is negative in mature lymphoid neoplasms (CLL, lymphomas) and in myeloid neoplasms. Therefore, TdT positivity + lymphoid markers = ALL.

Cytogenetics (and FISH to detect specific chromosomal abnormalities) provide diagnostic and prognostic information ^[1][12].

Two techniques are used:

Key cytogenetic findings in ALL and their prognostic significance:

Cytogenetics in ALL are non-diagnostic (cf AML) but essential for prognosis and classification ^[2][4].

Molecular genetics by PCR or sequencing are non-diagnostic but essential for prognosis and classification ^[2][4].

Key molecular findings:

Goal: Destroy the bulk of leukaemic blasts and restore normal haematopoiesis. High-intensity chemotherapy to destroy the bulk of tumour ^[4].

The specific combination varies by protocol (e.g., UKALL, BFM, COG, HyperCVAD), but the core drugs are:

Why do we use so many drugs simultaneously? The principle is the same as anti-TB therapy or anti-HIV therapy — combining drugs with different mechanisms of action reduces the risk of resistance (a resistant clone that survives one drug may be killed by another) and allows synergistic cell kill across different phases of the cell cycle.

Expected outcomes during induction:

• Severe BM hypoplasia requiring intensive support and in-patient care ^[4]
• Peripheral pancytopenia lasting 2–4 weeks ("the nadir")
• Complete remission (CR) rate: ~95% in children, ~80–90% in adults

Definition of Complete Remission (CR):

• BM blast < 5%
• No circulating blasts
• No extramedullary disease
• Recovery of blood counts (ANC ≥ 1.0 × 10⁹/L, PLT ≥ 100 × 10⁹/L) ^[4]

Ph+ ALL — Addition of TKI

Especially note Philadelphia chromosome t(9;22) → BCR-ABL TKI can be used in Ph+ ALL ^[2][4].

Why does Ph+ ALL need a TKI? The BCR-ABL1 fusion protein is a constitutively active tyrosine kinase that drives uncontrolled proliferation. TKIs specifically block this kinase, converting what was historically the worst-prognosis ALL subtype into one with much improved outcomes. This is one of the great success stories of targeted therapy in haematology.

Goal: Eradicate residual leukaemia that survived induction. Multiple courses of chemotherapy to attack residual disease ^[4].

• Involves several blocks (typically 4–8 cycles) of intensive chemotherapy over ~6 months
• Uses agents similar to induction but in different combinations/doses:
  • High-dose methotrexate
  • High-dose cytarabine
  • Cyclophosphamide
  • Re-induction blocks (delayed intensification)
• Periods of BM hypoplasia requiring support, usually over 2–6 months and ~1 course per month ^[4]
• Continued CNS-directed therapy (intrathecal methotrexate/cytarabine/hydrocortisone)

This phase is unique to ALL among acute leukaemias and is one of the most important conceptual differences.

Prolonged cytotoxic treatment of a milder degree — usually oral drugs, for 2–3 years ^[8][4].

Usually in outpatient setting, usually low intensity, oral treatment for 2–3 years ^[4].

Why 2–3 years? Studies in the 1960s–70s showed that patients who received < 2 years of maintenance had significantly higher relapse rates. The current duration of ~2 years (girls) to ~3 years (boys) represents the optimal balance between relapse prevention and cumulative toxicity. Boys receive longer maintenance because testicular relapse risk is higher (testicular sanctuary site).

Concurrent CNS prophylaxis — intrathecal methotrexate → better penetration ^[8].

CNS prophylaxis: to prevent CNS infiltration — only in ALL ^[4].

Why intrathecal and not just IV? Most chemotherapy drugs cannot cross the blood–brain barrier (BBB) at standard doses. The BBB exists to protect the brain from circulating toxins, but it also protects leukaemic cells hiding in the CNS. By injecting drugs directly into the CSF (intrathecal = "intra" + "theca" = within the sheath/sac), we bypass the BBB entirely and achieve high local drug concentrations in the CSF where the blasts are lurking.

HBV Reactivation Prevention

HBsAg, anti-HBc, anti-HBs ± HBV DNA: risk of HBV reactivation during chemotherapy ^[4]. In Hong Kong, where HBV carriage is prevalent (~8% of the population), all patients must be screened. HBsAg-positive patients require entecavir or tenofovir prophylaxis during and after chemotherapy.

Tumour lysis syndrome — hydration and urate-lowering agents (allopurinol, febuxostat, rasburicase) ^[8].

Leukostasis — urgent leukapheresis ^[8]. Not for the long term, since they grow so fast that the moment you remove them they'll come back (so have adjunctive chemo as well) ^[8].

10 years ago, we were doing HSCT for all adult patients with ALL → nowadays, triage them with something called MRD (measurable residual disease) following chemo ^[8].

If very low MRD, then can be good with just monitoring, no need transplant ^[8].

What is MRD and why is it so important? Measurable residual disease (MRD) — previously called "minimal residual disease" — refers to the detection of leukaemic cells below the threshold of conventional morphology (< 5% blasts = "remission" by morphology). MRD is measured by flow cytometry (sensitivity ~10⁻⁴, i.e., 1 leukaemic cell per 10,000 normal cells) or RT-qPCR (sensitivity ~10⁻⁵ to 10⁻⁶). MRD status after induction is the single strongest predictor of relapse — it has largely replaced traditional risk factors (age, WBC at presentation) in determining who needs HSCT vs. chemotherapy alone.

Neutropenic Fever — A Haematological Emergency

Neutropenic fever occurs in 10–50% of solid tumours but risk is much higher in haematological malignancies ^[4].

Definitions ^[4]:

• Neutropenia: ANC ≤ 0.5 × 10⁹/L, or ≤ 1.0 × 10⁹/L with predictable decline to ≤ 0.5 × 10⁹/L in 24–48 hours
• Fever: pyrexia > 38.3°C or > 38°C for > 1 hour

Why does neutropenia cause such severe infection risk? Neutrophils are the first-line defence against bacterial and fungal pathogens. They perform phagocytosis, release bactericidal enzymes, and form neutrophil extracellular traps. When ANC falls below 0.5 × 10⁹/L, the body effectively loses its innate immune barrier. The lower the ANC and the longer the duration of neutropenia, the higher the infection risk. In ALL, neutropenia is doubly caused: (a) the disease itself crowds out normal granulopoiesis, and (b) chemotherapy further destroys both leukaemic and normal marrow cells.

Key organisms:

• Bacteria: Gram-positive (coagulase-negative staphylococci, Staph. aureus, Streptococcus spp. — often from indwelling catheters/mucositis) and Gram-negative (E. coli, Klebsiella, Pseudomonas aeruginosa)
• Fungi: Candida spp. (especially with prolonged neutropenia + broad-spectrum antibiotics), Aspergillus spp. (with prolonged/profound neutropenia > 7–10 days)
• Viruses: HSV reactivation, VZV, CMV (especially post-HSCT)
• Pneumocystis jirovecii — hence the need for PCP prophylaxis with co-trimoxazole

Management:

Febrile neutropenia is a medical emergency requiring blood cultures and broad-spectrum antibiotics within one hour. ANC below 0.5 × 10⁹/L combined with fever necessitates urgent empirical therapy, as delayed treatment significantly increases mortality in immunocompromised patients ^[14].

• Petechiae, purpura, mucosal bleeding (epistaxis, gingival bleeding, menorrhagia) — from impaired primary haemostasis due to low platelets
• Intracranial haemorrhage (ICH) — the most feared complication; can be fatal. Risk increases dramatically when platelets < 10 × 10⁹/L
• GI haemorrhage — can present as haematemesis or melaena

Note: DIC is characteristically associated with APL (AML-M3), NOT ALL ^[8]. However, severe sepsis complicating ALL can trigger secondary DIC.

Management: PLT transfusion if PLT ≤ 10, or ≤ 20 if fever/bleeding ^[4].

• Fatigue, exercise intolerance, high-output cardiac failure (in severe chronic anaemia)
• Management: RBC transfusion if symptomatic anaemia ^[4]

ALL is one of the highest-risk malignancies for TLS (alongside Burkitt lymphoma) because of high tumour burden and exquisite chemosensitivity — rapid blast death releases massive intracellular contents.

Prevention and management ^[8][4]:

• Hydration — aggressive IV fluids to maintain high urine output (dilute uric acid, prevent crystal precipitation)
• Allopurinol or febuxostat — xanthine oxidase inhibitors (prevent new uric acid formation). Must check HLA-B5801 before allopurinol* ^[8]
• Rasburicase — recombinant urate oxidase; rapidly converts uric acid to allantoin (highly soluble). Used in high-risk patients. Contraindicated in G6PD deficiency ^[4][1]
• Cardiac monitoring — for hyperkalaemia-related arrhythmias
• Dialysis — if severe AKI unresponsive to medical management

• Defined as WBC > 100 × 10⁹/L
• Blasts are large, "sticky" cells that can occlude the microvasculature
• Consequences: pulmonary leucostasis (dyspnoea, hypoxia, diffuse infiltrates on CXR) and cerebral leucostasis (headache, confusion, visual changes, stroke-like symptoms)
• Management: urgent leukapheresis + chemotherapy. Avoid RBC transfusion until WBC is lowered ^[4] (transfused RBCs increase viscosity → worsen microvascular occlusion)

• ALL blasts cross the blood–brain barrier and infiltrate the meninges
• Presents with headache, vomiting, papilloedema, cranial nerve palsies (especially CN VI, VII), meningism
• If untreated, virtually all ALL patients would eventually develop CNS relapse — this is why CNS prophylaxis is mandatory ^[4][8]
• Diagnosis: LP with CSF cytology showing blasts; elevated CSF protein; low CSF glucose

• Mediastinal mass in 50–75% of T-ALL ^[4] → can cause:
  • SVCO (superior vena cava obstruction) — facial plethora, distended neck veins, upper body oedema
  • Upper airway obstruction — stridor, dyspnoea
  • Pericardial effusion → tamponade
• Anaesthetic hazard: general anaesthesia in a patient with a large anterior mediastinal mass can cause fatal airway collapse (because positive-pressure ventilation and loss of muscle tone allow the mass to compress the trachea/bronchi)

• Testes are a sanctuary site (blood–testis barrier limits chemotherapy penetration)
• Presents as painless testicular enlargement
• Requires testicular biopsy for confirmation and testicular irradiation ± systemic reinduction

These are especially important in childhood ALL survivors because they survive for decades and must live with the consequences of treatment received during critical developmental periods.

Long-term complications related to type and intensity of chemotherapy including neurodevelopmental delay, growth retardation, cardiotoxicity, risk of secondary malignancy, endocrinopathies and infertility ^[5][6].

Intensive chemotherapy can incur substantial academic, developmental and psychosocial costs for children with ALL and considerable financial costs and stress to families ^[5][6].

For patients who undergo allogeneic HSCT, additional complications include ^[4]:

ALL patients should only receive inactivated vaccination during chemotherapy ^[5][6]. Live-virus vaccines such as MMR and oral poliovirus are contraindicated ^[5][6].

Why? ALL patients receiving chemotherapy are profoundly immunosuppressed. Live-attenuated vaccines contain weakened but replicating organisms. In an immunocompromised host, these "weakened" organisms can cause disseminated, life-threatening infection (e.g., vaccine-strain measles encephalitis, vaccine-strain polio paralysis). Only inactivated vaccines (e.g., inactivated influenza, pneumococcal polysaccharide/conjugate) are safe during active treatment. Live vaccines (MMR, varicella, oral polio, BCG) can typically be re-administered 6–12 months after completing ALL treatment when immune reconstitution has occurred.