Acute lymphoid leukaemia is a malignant clonal proliferation of lymphoid precursor cells (lymphoblasts) in the bone marrow, leading to impaired normal haematopoiesis and infiltration of various organs.

Acute Lymphoid Leukaemia (ALL)

Acute Lymphoblastic Leukaemia (ALL) — also known as Acute Lymphoid Leukaemia — is a clonal malignant disease of the haematopoietic system ^[1] arising from precursor lymphocytes (lymphoblasts) of the B-cell, T-cell, or (rarely) NK-cell lineage ^[2]. The malignant lymphoblasts undergo uncontrolled proliferation with impaired maturation and impaired apoptosis ^[1], leading to their accumulation in the bone marrow, peripheral blood, and extramedullary tissues.

Let's break down the name:

"Acute" — in haematological oncology, this does NOT mean "sudden onset" as in other disciplines. Instead, the distinguishing factor between chronic and acute leukaemia is based on the pathological definition: in acute leukaemia, ≥ 20% of cells in the peripheral blood or bone marrow are blasts ^[1]. Because maturation is arrested, immature blasts accumulate rapidly → rapidly fatal if untreated ^[1].
"Lymphoblastic" — the malignant clone arises from lymphoid precursor cells (lymphoblasts), as opposed to myeloid precursors in AML.
"Leukaemia" — literally "white blood" (Greek: leukos = white, haima = blood); lymphoid neoplasms that present with bone marrow and peripheral blood involvement ^[3].

Leukaemia vs Lymphoma — Same Disease, Different Presentation

When the same precursor lymphoblastic neoplasm presents primarily as a mass (e.g., mediastinal mass in T-ALL), it is termed lymphoblastic lymphoma (LBL). When it presents with bone marrow/peripheral blood involvement, it is termed ALL. They are grouped under the same diagnostic entity in the WHO classification ^[2]^[3].

High Yield — Chronic vs Acute Leukaemia Distinction

Unlike many other chronic/acute diseases, the distinction is NOT based on time. ^[1] It is based on the blast percentage:

≥ 20% blasts in peripheral blood or bone marrow → acute leukaemia
< 20% blasts → chronic leukaemia

In chronic leukaemia, maturation is not impaired (cells can still differentiate to more mature forms), but there is uncontrolled proliferation + impaired apoptosis. In acute leukaemia, maturation IS impaired + uncontrolled proliferation + impaired apoptosis → blast arrest ^[1].

Chronic leukaemia can transform into acute leukaemia if left untreated, since leukaemic cells acquire more mutations over time (e.g., CML → blast crisis) ^[1].

2. Epidemiology

Subtype	Proportion	Key Features
B-ALL (precursor B-cell)	~85%	Most common; peak age 2–5 years
T-ALL	~10–15%	Male predominance; often presents with mediastinal mass
NK-ALL	< 1%	Extremely rare

3. Risk Factors

Key Concept

The etiology is unknown in virtually all cases of ALL. The majority of ALL cases are NOT associated with genetic or environmental risk factors. ^[5]^[6] Childhood ALL is NOT considered to be a familial disease and is thought to be caused by post-conception somatic mutations in lymphoid cells ^[5]^[6]. However, certain associations exist:

Genetic Syndrome	Mechanism	Risk
Down syndrome (Trisomy 21)	15–20× increased risk of ALL (and AML); likely due to extra copy of chromosome 21 genes affecting lymphoid/myeloid differentiation (e.g., DYRK1A, ERG genes on chr21)	Highest known genetic risk factor
Bloom's syndrome	Autosomal recessive; defective DNA helicase (BLM gene) → increased chromosomal breakage and genomic instability	Increased risk of ALL and other cancers
Fanconi anaemia	Autosomal recessive; defective DNA repair pathway → genomic instability, bone marrow failure	Increased risk of ALL/AML, aplastic anaemia

^[5]^[6]^[7]

4. Anatomy and Function of the Haematopoietic and Lymphoid Systems (Relevant to ALL)

Understanding ALL requires a firm grasp of normal lymphoid development and the organs involved.

Organ	Relevance to ALL
Bone marrow	Primary site of leukaemogenesis and blast accumulation; normal haematopoiesis is crowded out
Lymph nodes	Lymphadenopathy from blast infiltration (up to 50% of ALL)
Spleen	Splenomegaly from blast infiltration and extramedullary haematopoiesis
Liver	Hepatomegaly from blast infiltration (Kupffer cell/sinusoidal infiltration)
Thymus/Mediastinum	T-ALL blasts have thymic homing; mediastinal mass in 50–75% of T-ALL ^[2]^[4]
CNS (meninges, CSF)	Leukaemic meningitis — blasts can cross the blood–brain barrier; this is a sanctuary site where systemically administered chemotherapy has poor penetration
Testes	Another sanctuary site behind the blood–testis barrier; painless testicular enlargement

5. Etiology and Pathophysiology

Pathway	Examples	Consequence
Transcription factor alterations	PAX5 deletion/mutation, IKZF1 (Ikaros) deletion, ETV6-RUNX1 fusion	Block B-cell differentiation at precursor stage
Proliferative signalling	Philadelphia chromosome t(9;22) → BCR-ABL1; JAK2 mutations; RAS mutations	Constitutive kinase activity → uncontrolled proliferation
Cell cycle / tumour suppressor	CDKN2A (p16/ARF) deletion; TP53 mutation	Loss of cell cycle checkpoints, impaired apoptosis
Epigenetic	CREBBP mutations; histone modifications	Altered gene expression programs
NOTCH pathway (T-ALL)	Activating NOTCH1 mutations (~50% of T-ALL)	NOTCH1 is a critical regulator of T-cell development; constitutive activation drives T-cell proliferation

5.3 Pathophysiology: From Molecular to Clinical

The pathophysiology of ALL can be understood as two parallel processes:

The malignant lymphoblast clone undergoes uncontrolled proliferation within the bone marrow. As blasts accumulate, they physically crowd out normal haematopoietic cells and disrupt the bone marrow microenvironment (niche). This leads to failure of normal haematopoiesis:

Normal Cell Line Suppressed	Clinical Consequence
Red blood cells (erythropoiesis ↓)	Anaemia → fatigue, pallor, dyspnoea on exertion
Neutrophils (granulopoiesis ↓)	Neutropenia → recurrent / severe infections (despite WBC count being high — the elevated WBC comprises non-functional blasts, not mature neutrophils)
Platelets (megakaryopoiesis ↓)	Thrombocytopenia → bleeding tendency (petechiae, bruising, mucosal bleeding)

Why Can WBC Be High But the Patient Still Gets Infections?

This is a critical concept. In ALL, the total WBC count can be normal, low, or paradoxically very high (sometimes > 100 × 10⁹/L). However, the elevated WBC consists of non-functional leukaemic blasts that cannot perform immune functions (phagocytosis, killing of pathogens). The functional mature neutrophil count (ANC) is low → "functional neutropenia" → infection susceptibility. This is why you must always look at the differential count, not just the total WBC.

6. Classification

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:

FAB Subtype	Description
L1	Small homogeneous blasts — small cells with scant cytoplasm, regular nuclei; most common in children
L2	Large heterogeneous blasts — larger cells with variable size, more cytoplasm, irregular nuclei; more common in adults
L3	"Burkitt-like" B cells with vacuoles — large cells with deeply basophilic cytoplasm containing prominent vacuoles; corresponds to mature B-cell (Burkitt) leukaemia

^[7]

High Yield Exam Point

FAB L3 is now classified separately as Burkitt lymphoma/leukaemia in the WHO classification, NOT as ALL. This is because Burkitt leukaemia arises from mature B cells (with surface immunoglobulin), not precursor B cells. Treatment differs significantly (requires aggressive short-duration intensive chemotherapy like R-CODOX-M/IVAC, not the prolonged ALL-type protocols).

6.2 WHO Classification (Current, 5th Edition 2022)

The WHO classification incorporates immunophenotype, cytogenetics, and molecular genetics to define biologically and clinically distinct entities. ALL is classified under "Precursor Lymphoid Neoplasms":

Subcategory	Cytogenetic/Molecular Feature	Prognosis
B-ALL/LBL, not otherwise specified (NOS)	No defining genetic abnormality	Variable
B-ALL/LBL with recurrent genetic abnormalities:
— with t(9;22)(q34.1;q11.2); BCR::ABL1 (Philadelphia chromosome, Ph+)	Constitutive tyrosine kinase activity → uncontrolled proliferation	Poor (but improved dramatically with TKI therapy)
— with t(v;11q23.3); KMT2A (MLL)-rearranged	Common in infant ALL	Poor
— with t(12;21)(p13.2;q22.1); ETV6::RUNX1	Most common cytogenetic abnormality in childhood B-ALL (~25%)	Excellent
— with high hyperdiploidy (51–65 chromosomes)	Accumulation of extra chromosomes	Favourable
— with hypodiploidy ( < 44 chromosomes)	Loss of chromosomes	Very poor
— with t(1;19)(q23;p13.3); TCF3::PBX1		Intermediate
— with t(5;14)(q31.1;q32.3); IGH::IL3	Eosinophilia	Variable
— BCR::ABL1-like (Ph-like)	Gene expression profile similar to Ph+ ALL but without BCR-ABL1; often has kinase-activating fusions (e.g., ABL-class, JAK-STAT, CRLF2)	Poor (may respond to targeted TKI/JAK inhibitors)
— with iAMP21 (intrachromosomal amplification of chr 21)		Poor (improved with intensive therapy)

Feature	Details
Genetic hallmarks	Activating NOTCH1 mutations (~50%); TAL1, LMO1/2, TLX1/3 overexpression; CDKN2A deletion
Early T-cell precursor (ETP)-ALL	A distinct subtype with immature immunophenotype and myeloid/stem cell features; initially thought to have poor prognosis, now improved with intensive therapy

Flow cytometry is essential for lineage determination. Key markers:

Lineage	Key Markers
B-ALL	CD19, CD22, CD79a (cytoplasmic), CD10 (CALLA — common ALL antigen), TdT, PAX5
T-ALL	Cytoplasmic CD3 (most specific), CD7, CD2, CD5, CD1a, TdT
Common ALL (c-ALL)	B-ALL with CD10 positivity — the most common immunophenotype in childhood ALL

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).

7. Clinical Features

Clinical features are often non-specific → difficult to be distinguished from ordinary self-limited diseases of childhood ^[2]^[4]

The clinical presentation of ALL is driven entirely by the two pathophysiological processes described above: (1) bone marrow failure and (2) extramedullary infiltration. ^[1]

7.1 Symptoms

Symptom	Pathophysiological Basis
Fever	(1) Neutropenia → infection → fever; (2) Tumour-associated cytokine release (IL-1, IL-6, TNF-α) → "tumour fever"
Weight loss	Cytokine-mediated catabolism (TNF-α = "cachectin"); reduced oral intake
Night sweats	Cytokine-mediated hypothalamic thermoregulatory dysfunction

Constitutional symptoms are usually mild in severity in ALL ^[2]^[4] — this contrasts with lymphomas (especially Hodgkin lymphoma) where B-symptoms are more prominent.

Symptom	Cell Line Affected	Mechanism
Fatigue, lethargy, dyspnoea on exertion	Anaemia (↓ RBC)	Reduced oxygen-carrying capacity
Recurrent or severe infections (pneumonia, oral thrush, skin infections)	Neutropenia (↓ functional WBC)	Loss of innate immune defence despite potentially high total WBC count (blasts are non-functional)
Easy bruising, petechiae, mucosal bleeding (epistaxis, gingival bleeding), menorrhagia	Thrombocytopenia (↓ platelets)	Inadequate primary haemostasis

Symptom	Site	Mechanism
Bone pain (especially limbs, back)	Bone marrow / periosteum	Marrow expansion by blasts stretches periosteum (richly innervated with nociceptors); direct periosteal infiltration. In children, may present as limping or refusal to walk — often mistaken for growing pains or JIA
Headache, nausea/vomiting	CNS	Leukaemic meningitis → raised intracranial pressure
Abdominal fullness/discomfort	Liver/spleen	Hepatosplenomegaly causing capsular stretching
Painless testicular swelling	Testis	Blast infiltration behind the blood–testis barrier
Dyspnoea, stridor, facial swelling, distended neck veins	Mediastinum (T-ALL)	Anterior mediastinal mass → SVC obstruction / upper airway compression
Lymph node swelling	Lymph nodes	Blast infiltration and proliferation within lymphoid tissue

Symptom	Mechanism
Headache, visual changes, confusion	Cerebral leucostasis → microvascular occlusion → ischaemia
Dyspnoea	Pulmonary leucostasis → impaired gas exchange

Leucostasis is more common in AML (where blasts are larger and "stickier") than ALL, but can still occur in ALL with very high blast counts.

7.2 Signs

Sign	Pathophysiological Basis
Pallor (conjunctivae, palms)	Anaemia from marrow failure
Petechiae, purpura, ecchymoses	Thrombocytopenia → impaired primary haemostasis
Fever	Infection (neutropenia) or tumour-related cytokines

High Yield — GC Lecture Slide Point

ALL clinical features include: hepatosplenomegaly, lymphadenopathy, mediastinal mass (T-ALL), CNS and testicular involvement ^[1]^[8].

All lymphoid organs must be examined in physical examination, including cervical, axillary, epitrochlear, inguinal, popliteal lymph nodes + tonsils + testes ^[2].

Sign	Prevalence	Pathophysiological Basis
Hepatosplenomegaly (moderate)	Up to 50%	Blast infiltration of liver sinusoids/Kupffer cells and splenic red pulp; may also have extramedullary haematopoiesis
Generalised lymphadenopathy	Up to 50%	Blast infiltration and proliferation in lymph node paracortex/sinuses

Sign	Site	Pathophysiological Basis
Bone tenderness	Bone marrow	Periosteal stretching/infiltration by expanding blast population. Sternal tenderness is a classic examination finding in acute leukaemia
Meningism (neck stiffness, positive Kernig/Brudzinski signs), cranial nerve palsies	CNS	Leukaemic infiltration of meninges → meningeal irritation; infiltration of cranial nerves (especially CN VI, VII)
Papilloedema, retinal haemorrhages	Eye/CNS	Raised ICP from meningeal leukaemia; thrombocytopenia-related retinal haemorrhage
Painless testicular enlargement ( < 1%)	Testis	Blast infiltration — must examine bilaterally. Testes are a sanctuary site
Anterior mediastinal mass → SVCO signs (facial plethora, distended neck veins, upper limb oedema, dyspnoea, stridor)	Mediastinum (50–75% in T-ALL)	T-cell lymphoblasts home to the thymus → thymic enlargement → compression of SVC and trachea
Gum hypertrophy	Gums	Uncommon in ALL; characteristic of AML-M5 (acute monoblastic leukaemia) ^[1] — those monocytic cells have a preponderance for tissue infiltration

High Yield — ALL vs AML Extramedullary Features

Features MORE characteristic of ALL (uncommon in AML) ^[1]^[2]^[4]:

Hepatosplenomegaly and lymphadenopathy (prominent)
Mediastinal mass (T-ALL)
CNS involvement
Testicular involvement

Features MORE characteristic of AML (uncommon in ALL):

Gum hypertrophy (AML-M5, acute monoblastic leukaemia)
DIC (APL / APML — a haematological emergency)
Skin infiltration (leukaemia cutis)

Sign	Pathophysiological Basis
Roth spots (retinal haemorrhages with white centres)	Septic emboli (if infective endocarditis complicates neutropenia) or leukaemic infiltration of retina + thrombocytopenia
Cotton wool spots	Retinal ischaemia from anaemia/leucostasis
Fundal haemorrhages	Thrombocytopenia

Feature	Symptom	Sign	Mechanism
Anaemia	Fatigue, SOB, dizziness	Pallor	↓ RBC production (marrow crowding)
Neutropenia	Recurrent infections, fever	Fever, infective focus	↓ Functional neutrophils (blasts are non-functional)
Thrombocytopenia	Easy bruising, epistaxis	Petechiae, purpura	↓ Platelet production
Organ infiltration	Bone pain, headache, testicular swelling	Hepatosplenomegaly, lymphadenopathy, meningism, mediastinal mass	Blast homing to lymphoid tissues and sanctuary sites
Constitutional	Fever, weight loss, night sweats	Cachexia, fever	Cytokine release (IL-1, IL-6, TNF-α)

8. Special Clinical Scenarios

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)

High Yield Summary

Definition: ALL is a clonal malignancy of precursor lymphocytes (lymphoblasts) with ≥ 20% blasts in BM/blood; impaired maturation + uncontrolled proliferation + impaired apoptosis.
Epidemiology: Most common childhood cancer; peak age 2–5 years; 85% B-ALL, 10–15% T-ALL; much less common than AML in adults.
Risk factors: Mostly unknown/sporadic; Down syndrome (15–20× risk), Fanconi anaemia, Bloom syndrome; chemical/radiation exposure; prior chemotherapy (alkylating agents, topoisomerase II inhibitors); acquired haematopoietic conditions (MDS, MPN, aplastic anaemia, PNH).
Pathophysiology: (1) BM failure (crowding out → anaemia, neutropenia, thrombocytopenia); (2) Extramedullary infiltration (lymphoid organs, CNS, testes, mediastinum).
Clinical features: Non-specific; constitutional symptoms (mild); marrow failure symptoms; hepatosplenomegaly + lymphadenopathy (up to 50%); bone pain; CNS symptoms; testicular enlargement; mediastinal mass in T-ALL (50–75%).
Key distinguishing features from AML: ALL has MORE hepatosplenomegaly, lymphadenopathy, mediastinal mass (T-ALL), CNS/testicular involvement. AML has MORE gum hypertrophy (M5), DIC (APL), skin involvement.
Classification: FAB (L1/L2/L3 — historical); WHO (B-ALL with/without recurrent genetic abnormalities, T-ALL, ambiguous lineage); Immunophenotype (TdT+, CD19/CD10 for B-ALL, cytoplasmic CD3 for T-ALL).
Sanctuary sites: CNS and testes — require specific prophylactic treatment.

Active Recall - Acute Lymphoid Leukaemia (Definition to Clinical Features)

Differential Diagnosis of Acute Lymphoblastic Leukaemia (ALL)

The differential diagnosis of ALL is framed by the presenting clinical syndrome. A child or adult presenting with features of marrow failure (pancytopenia), extramedullary infiltration (hepatosplenomegaly, lymphadenopathy, bone pain), or an incidental abnormal blood count can have a wide differential. The key to narrowing the differential is understanding which diseases can mimic each component of the ALL presentation.

The differential diagnosis is best organised by the dominant clinical presentation:

Category 1: Haematological Malignancies Mimicking ALL

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:

Feature	ALL	AML
Age	Peak 2–5 years (children)	Peak ~65 years (adults)
Auer rods on PBS	Absent	Present → confirms myeloblastic nature, i.e. diagnosis of AML ^[3]^[9]
Cytochemistry	Myeloperoxidase (MPO) NEGATIVE	MPO POSITIVE (dark staining); Sudan Black B positive ^[2]^[4]^[9]
Immunophenotype	TdT+, CD19/CD10 (B-ALL) or cytoCD3/CD7 (T-ALL)	CD34, CD117, CD13, CD33, HLA-DR ^[4]
Extramedullary	HSM, LAD, mediastinal mass, CNS, testis	Gum hypertrophy (M5), skin, DIC (APL) ^[1]^[8]

High Yield — GC Lecture Slide: Distinguishing ALL from AML

AML is differentiated from ALL by demonstration of myeloid markers by cytochemistry and immunophenotyping ^[2]^[4]. The approach uses MCICM: Morphology, Cytochemistry, Immunophenotype, Cytogenetics, Molecular genetics ^[3]^[9].

Cytochemistry is lineage-defining: MPO/Sudan Black B for myeloid; no specific cytochemical marker for lymphoid ^[3]^[9].

Auer rods are normally difficult to differentiate between myelo-/lymphoblasts, but presence of Auer rods confirms myeloblastic nature, i.e. a diagnosis of AML ^[3]^[9].

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].

Feature	ALL (precursor B-ALL)	Burkitt Lymphoma/Leukaemia
Cell of origin	Precursor (immature) B-cell	Mature B-cell (germinal centre origin)
TdT	Positive (precursor marker)	Negative (mature cell)
Surface Ig	Negative (not yet rearranged/expressed)	Positive (mature B-cell with surface IgM)
Key cytogenetics	Various (see classification)	t(8;14) — c-MYC/IGH translocation
Morphology	L1/L2 (small/large heterogeneous blasts)	L3: "Burkitt-like" B cells with prominent cytoplasmic vacuoles ("starry sky" pattern on biopsy) ^[7]
Treatment	Prolonged multi-phase ALL protocol	Short intensive R-CODOX-M/IVAC–type regimen
Ki-67 index	Variable	Nearly 100% (extremely high proliferation)

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.

Category 2: Non-Malignant Haematological Conditions Mimicking ALL

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

Feature	ALL	Aplastic Anaemia
Bone marrow	Hypercellular with blast replacement	Hypocellular / aplastic (fat-filled marrow) ^[10]
Blasts	≥ 20% in BM or blood	No blasts; no malignant cells — just absence of normal cells ^[10]
Hepatosplenomegaly	Present (up to 50%)	Absent ^[10]
Lymphadenopathy	Present (up to 50%)	Absent ^[10]

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].

Clinical Pearl

A hypocellular bone marrow with pancytopenia but no blasts, no dysplasia, and no infiltrate = aplastic anaemia. A hypercellular marrow packed with blasts = acute leukaemia. The bone marrow biopsy (trephine) is essential to make this distinction.

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.

Feature	Reactive Lymphocytosis (e.g., IM)	ALL
Cell morphology	Atypical lymphocytes — large, with abundant cytoplasm, irregular nuclei (activated T cells reacting to EBV-infected B cells). NOT neoplastic → not to be mistaken as blasts or lymphoma cells ^[3]^[9]	Lymphoblasts — immature, high N:C ratio, fine chromatin, scant cytoplasm
TdT	Negative (mature activated lymphocytes)	Positive (precursor cells)
Heterogeneity	Heterogeneous population (polyclonal)	Monomorphic / monoclonal
Monospot / EBV serology	Positive (in IM)	Negative
Bone marrow	Normal or reactive	Blast-replaced, hypercellular

High Yield — GC Lecture Slide Point

Atypical lymphocytosis results from lymphocyte activation due to IM (prototypical), other viral infections, or autoimmune disease. These are NOT neoplastic → not to be mistaken as blasts or lymphoma cells ^[3]^[9].

Blasts on PBS are ALWAYS abnormal → if ≥ 20%, diagnostic of acute leukaemia ^[3]^[9].

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.

In children, several solid tumours can metastasise to the bone marrow and present with pancytopenia, bone pain, and sometimes hepatosplenomegaly — mimicking ALL ^[6]:

Tumour	Key Distinguishing Features
Neuroblastoma	Arises from neural crest cells; adrenal or paravertebral mass; elevated urinary catecholamines (VMA, HVA); rosette formation on marrow biopsy; age usually < 5 years
Retinoblastoma	Presents with leukocoria (white pupillary reflex) or strabismus; retinal mass on fundoscopy; usually < 3 years
Rhabdomyosarcoma	Soft tissue mass (head/neck, genitourinary); desmin/myogenin positive on IHC
Ewing sarcoma	Bone tumour in adolescents; t(11;22) EWS-FLI1 translocation; CD99+; "onion-skin" periosteal reaction on XR

Why do these solid tumours mimic ALL? They can infiltrate the bone marrow (stage IV disease) and cause pancytopenia through marrow replacement — identical to the mechanism in ALL. The key difference is that the infiltrating cells are non-haematopoietic tumour cells, not lymphoblasts. Immunophenotyping and tissue markers on bone marrow biopsy will reveal the correct diagnosis.

Category 4: Differential Diagnosis by Specific Clinical Presentation

Investigation	What It Distinguishes
PBS + manual differential	Blasts (ALL/AML) vs atypical lymphocytes (reactive) vs dysplastic cells (MDS) vs smudge cells (CLL) ^[3]^[9]
Cytochemistry (MPO)	MPO+: myeloid (AML). MPO−: lymphoid (ALL) ^[2]^[3]^[4]^[9]
Flow cytometry (immunophenotype)	B-ALL (CD19+, TdT+, CD10+) vs T-ALL (cytoCD3+, TdT+) vs AML (CD34+, CD117+, CD13/33+) vs mature lymphoid neoplasm (TdT−) ^[2]^[4]
Bone marrow biopsy (trephine)	Hypercellular + blasts (ALL) vs hypocellular (aplastic anaemia) vs dysplastic (MDS) vs non-haematopoietic tumour cells (metastatic solid tumour)
Cytogenetics + molecular genetics	Specific translocations defining subtypes: t(9;22) BCR-ABL (Ph+ ALL/CML), t(8;14) c-MYC (Burkitt), t(12;21) ETV6-RUNX1 (favourable B-ALL), t(15;17) PML-RARA (APL, NOT ALL)
EBV serology / Monospot	Confirms infectious mononucleosis (reactive lymphocytosis) vs ALL

High Yield — MCICM Approach

The 5-step approach to diagnosis of haematological malignancy (MCICM) ^[3]^[9]:

Morphology — PBS, BM aspirate and trephine
Cytochemistry — MPO/Sudan Black B for myeloid; no specific marker for lymphoid
Immunophenotyping — flow cytometry for lineage determination
Cytogenetics — karyotyping, FISH
Molecular genetics — PCR, sequencing, NGS

This systematic approach ensures you correctly classify the type of leukaemia and differentiate ALL from its mimics.

High Yield Summary — Differential Diagnosis of ALL

Must-know differentials:

AML — distinguished by Auer rods, MPO positivity, myeloid immunophenotype
Burkitt lymphoma/leukaemia — mature B-cell (TdT−, surface Ig+), t(8;14), L3 morphology with vacuoles
Aplastic anaemia — pancytopenia but hypocellular marrow with NO blasts, NO organomegaly
ITP — isolated thrombocytopenia, other lines normal
Infectious mononucleosis — atypical lymphocytes (NOT blasts), Monospot+, EBV serology+
JIA — bone/joint pain in children but no cytopenias, no blasts
Solid tumour BM metastasis (neuroblastoma, rhabdomyosarcoma, Ewing sarcoma) — non-haematopoietic cells on marrow biopsy
CML lymphoid blast crisis — prior history of CML, BCR-ABL1+, treat with TKI

Key principles: Never give steroids for presumed ITP or JIA without first excluding ALL (CBC + PBS ± BM). Atypical lymphocytes are reactive and NOT blasts. Use MCICM to systematically classify.

Active Recall - Differential Diagnosis of ALL

References

^[1] Lecture slides: GC 060. High white cell count.pdf (p5) ^[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (p418, p421) ^[3] Senior notes: Ryan Ho Fundamentals.pdf (p390) ^[4] Senior notes: Ryan Ho Haemtology.pdf (p51, p53, p54, p60, p61) ^[5] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1380, p1409) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p624, p731, p741, p742) ^[7] Senior notes: Maksim Medicine Notes.pdf (p173) ^[8] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p3) ^[9] Senior notes: Ryan Ho Haemtology.pdf (p47) ^[10] Senior notes: Block A - Family history of anaemia_ inherited causes of anaemia; haemolytic anaemia; aplastic anaemia.pdf (p7, p8) ^[11] Senior notes: Block A - Generalised Lymphadenopathy_ Differential diagnosis and principle of management.pdf (p2, p3)

Diagnostic Criteria, Diagnostic Algorithm, and Investigation Modalities for ALL

The diagnosis of ALL requires two simultaneous elements ^[2]^[4]:

Presence of lymphoblasts in the peripheral blood, bone marrow, or involved tissue with a diagnostic cut-off usually set at > 20% blasts ^[2]^[4]
Demonstration of lymphoid lineage in those blasts — through diagnostic morphology and immunophenotype demonstrating lymphoid lineage ^[2]^[4]

Put simply: you need to show (a) that the cells are blasts (immature, not mature) and (b) that those blasts are lymphoid (not myeloid).

High Yield — Key Diagnostic Finding

Key diagnostic finding: > 20% blasts in bone marrow or peripheral blood samples ^[2]^[9]. This applies to both ALL and AML.

The 20% threshold distinguishes acute from chronic leukaemia. In acute leukaemia, ≥ 20% of the cells in peripheral blood or bone marrow are blasts ^[8]. Below 20% blasts with a myeloid lineage might be MDS; below 20% with a lymphoid expansion might be a chronic lymphoproliferative disorder.

Important exception for AML (not ALL): In AML, certain AML-defining genetic abnormalities (e.g., t(15;17), t(8;21), inv(16)) are diagnostic even if the blast count is < 20% ^[4]. There is no equivalent exception for ALL — the 20% threshold generally applies.

How Do We "Demonstrate Lymphoid Lineage"?

This is where the MCICM approach becomes essential. You can't just look at a blast under the microscope and say "it's lymphoid" — it is often difficult to distinguish lymphoblasts from myeloblasts on morphology alone ^[2]^[4]^[3]. You need:

Step	What It Shows for ALL
Morphology	Blasts present (but cannot definitively distinguish lineage)
Cytochemistry	MPO NEGATIVE (rules out myeloid) — this is lineage-defining ^[2]^[4]
Immunophenotyping	Flow cytometry shows lymphoid markers (TdT+, CD19/CD10 for B-ALL; cytoCD3 for T-ALL) — confirms lineage
Cytogenetics	Karyotyping/FISH for chromosomal abnormalities — non-diagnostic but essential for prognosis and classification ^[2]^[4]
Molecular genetics	PCR/sequencing/NGS — non-diagnostic but essential for prognosis and classification ^[2]^[4]

Why is cytogenetics "non-diagnostic" in ALL but can be diagnostic in AML? In AML, certain cytogenetic findings (e.g., t(15;17) PML-RARA) are so specific that they alone define the diagnosis even with < 20% blasts. In ALL, no single cytogenetic finding is absolutely pathognomonic — the diagnosis still rests on morphology + immunophenotype confirming lymphoid blasts ≥ 20%. However, cytogenetics are still essential because they determine the subtype, prognosis, and treatment (e.g., Ph+ ALL with t(9;22) requires TKI therapy).

3. Investigation Modalities — Detailed Breakdown

Parameter	Expected Findings in ALL	Interpretation
Haemoglobin	Normochromic normocytic (NcNc) anaemia of variable severity ^[2]^[4]	Marrow crowding out → ↓ erythropoiesis. NcNc because the remaining RBCs are normal in size and colour — the problem is underproduction, not defective maturation (unlike B₁₂/folate deficiency which is macrocytic)
Platelet count	Thrombocytopenia ^[2]^[4]	Marrow crowding out → ↓ megakaryopoiesis
WBC	Can be low, normal, or high with circulating lymphoblasts ^[2]^[4]	The total WBC is misleading. It can be high (blasts spilling into blood), normal (blasts confined to marrow), or low (severe marrow failure). The differential count is what matters — look for the blast percentage and the absolute neutrophil count
WBC differential	Absolute neutropenia; increased blast percentage	Even with high total WBC, functional neutrophils are low → infection risk

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).

High Yield — WBC in Acute Leukaemia

CBC: pancytopenia but WBC may be high ( > 100 in 20% of cases) or low ( < 5 in 25–40%) ^[2]^[9]. Never assume "high WBC = infection" — in a patient with pancytopenia of the other lines, a high WBC with blasts points to acute leukaemia.

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:

Finding	Significance
Blasts present	Always abnormal → if ≥ 20%, diagnostic of acute leukaemia ^[3]^[9]
No Auer rods	Favours ALL over AML (Auer rods confirm myeloblastic nature, i.e. AML) ^[3]^[9]
No granules	Lymphoblasts lack the azurophilic granules seen in myeloblasts
Faggot cells (abnormal promyelocytes with numerous Auer rods)	→ APML (haematological emergency) — NOT ALL ^[3]^[9]
Atypical lymphocytes	NOT neoplastic; from lymphocyte activation (IM, viral infections) → not to be mistaken as blasts ^[3]^[9]
Smudge cells	Fragile CLL lymphocytes that lyse on smearing ^[8] — NOT ALL
Leukoerythroblastic picture	Left shift + nucleated RBCs ± tear drop cells → indicates marrow infiltration ^[3]^[9]

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]:

Technique	What It Provides
Aspirate	Permits cytology (morphology of individual cells), flow cytometry (immunophenotyping), and genetic studies (cytogenetics, molecular) ^[3]
Trephine biopsy	Permits histological examination: marrow cellularity, architectural details, marrow fibrosis, bone structure and immunohistochemistry (IHC) for immunophenotyping ^[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]

Clinical Pearl

Consult Haematology for cytogenetic and molecular studies BEFORE performing BM ^[2]^[9]. This ensures the correct tubes/containers are prepared at the time of the procedure. Cytogenetic studies require fresh, heparinised samples for cell culture (karyotyping) or unstained slides for FISH. Molecular studies need EDTA-anticoagulated samples. Missing these at the time of the first marrow may mean an unnecessary repeat procedure.

High Yield — GC Lecture Slide: Bone Marrow Examination Components

Bone Marrow Examination ^[1]^[12]:

Morphology (APL, AML, ALL) on PB and BM
Cytochemistry (MPO and SBB) — AML vs ALL
Flow cytometry — for sub-classification and lineage specification
Cytogenetics (and FISH to detect specific chromosomal abnormalities) — diagnostic and prognostic information
Molecular genetics — diagnostic and prognostic information

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

Stain	Result in ALL	Result in AML	Interpretation
Myeloperoxidase (MPO)	NEGATIVE	POSITIVE (dark staining)	Lineage-defining ^[2]^[4] — MPO is an enzyme stored in azurophilic granules of myeloid cells. Its presence confirms myeloid origin
Sudan Black B (SBB)	Variable (can show weak positivity)	POSITIVE	Stains lipids in granules; MPO is more specific

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:

Marker	B-ALL	T-ALL	What It Means
TdT	POSITIVE	POSITIVE	Terminal deoxynucleotidyl transferase expression is important as a marker for diagnosis and prognostication ^[2]^[4]. TdT is a DNA polymerase active during V(D)J recombination in precursor lymphocytes — its presence confirms the cells are precursor (immature) lymphoid cells
CD19	Positive	Negative	Pan-B-cell marker
CD22	Positive	Negative	B-cell marker (cytoplasmic CD22 is one of the earliest B-lineage markers)
CD79a	Positive (cytoplasmic)	Negative	B-cell receptor signalling component
CD10 (CALLA)	Positive (in common ALL)	Variable	Common ALL antigen — present in the most common childhood B-ALL subtype ("common ALL")
PAX5	Positive	Negative	B-cell-specific transcription factor
Cytoplasmic CD3	Negative	POSITIVE	Most specific T-cell marker; must be cytoplasmic (surface CD3 may be absent in immature T cells)
CD7	Negative	Positive	Earliest T-cell surface marker
CD1a	Negative	Positive (cortical thymocyte stage)	T-cell differentiation marker
CD34	Often positive	Often positive	Stem/progenitor cell marker (not lineage-specific)
Surface Ig	Negative (precursor B)	N/A	If positive → mature B-cell neoplasm (Burkitt), NOT precursor B-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:

Technique	What It Detects	Advantages	Limitations
Conventional karyotyping	Gross chromosomal abnormalities: translocations, deletions, inversions, ploidy changes	Provides a genome-wide view; detects unexpected abnormalities	Requires dividing cells (culture needed); takes 1–2 weeks; resolution limited (~5 Mb)
FISH (Fluorescence In Situ Hybridisation)	Targeted detection of specific known abnormalities using fluorescent probes	Rapid (24–48 hours); can be done on non-dividing cells; high sensitivity	Only detects what you probe for — cannot find unexpected abnormalities

Key cytogenetic findings in ALL and their prognostic significance:

Cytogenetic Abnormality	Subtype	Prognosis	Clinical Significance
t(12;21) ETV6::RUNX1	B-ALL	Favourable	Most common translocation in childhood B-ALL (~25%); detected by FISH (cryptic on karyotype)
High hyperdiploidy (51–65 chromosomes)	B-ALL	Favourable	~25% of childhood B-ALL; extra chromosomes lead to increased drug sensitivity
t(9;22) BCR::ABL1 (Philadelphia chromosome)	B-ALL	Poor (historically); improved with TKI	Especially note Philadelphia chromosome t(9;22) → BCR-ABL TKI can be used in Ph+ ALL ^[2]^[4]. ~3–5% of childhood ALL, ~25% of adult ALL
t(v;11q23.3) KMT2A (MLL)-rearranged	B-ALL	Poor	Common in infant ALL ( < 1 year); poor response to standard therapy
Hypodiploidy ( < 44 chromosomes)	B-ALL	Very poor	Associated with TP53 mutations
t(1;19) TCF3::PBX1	B-ALL	Intermediate	~5% of childhood B-ALL
iAMP21	B-ALL	Poor (improved with intensive Rx)	Intrachromosomal amplification of chromosome 21
14q11, 7q34 rearrangements	T-ALL	Variable	Involve TCR gene loci; reflect T-cell origin

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].

Technique	What It Detects
RT-PCR	Fusion transcripts (e.g., BCR-ABL1, ETV6-RUNX1); also used for measurable residual disease (MRD) monitoring
Next-generation sequencing (NGS)	Panel of mutations (e.g., IKZF1, CDKN2A, JAK2, NOTCH1, TP53); identifies Ph-like ALL, ETP-ALL
Gene expression profiling	Classifies B-ALL into molecular subtypes; identifies Ph-like (BCR-ABL1-like) ALL

Key molecular findings:

Molecular Finding	Significance
BCR::ABL1 fusion	Defines Ph+ ALL → add TKI (imatinib/dasatinib) to chemotherapy backbone
IKZF1 deletion	Poor prognosis in B-ALL; associated with Ph-like ALL
NOTCH1 activating mutation	~50% of T-ALL; potential therapeutic target; may confer favourable prognosis in T-ALL
Ph-like gene expression profile	Poor prognosis; may respond to TKIs or JAK inhibitors depending on the specific fusion/mutation
CDKN2A/p16 deletion	Loss of tumour suppressor; common in ALL

3.8 Emergency / Pre-Treatment Investigations

These are done simultaneously with the diagnostic workup, not sequentially ^[1]^[8].

Investigation	Purpose	Expected in ALL
Clotting profile (PT, APTT)	Screen for DIC	Usually normal in ALL (DIC is characteristic of APL, not ALL) ^[1]
D-dimer	DIC screen
Fibrinogen	DIC screen (low fibrinogen = consumptive coagulopathy)

Biochemistry — renal function, potassium, calcium, phosphate, urate, LDH (features of tumour lysis syndrome) ^[1]

Analyte	Expected in TLS	Mechanism
Potassium ↑	Hyperkalaemia	Intracellular K+ released from lysed blast cells
Phosphate ↑	Hyperphosphataemia	Intracellular PO₄ released from blast cell nucleic acids
Calcium ↓	Hypocalcaemia (secondary)	Ca²⁺ binds to excess PO₄ → calcium phosphate precipitation
Uric acid ↑	Hyperuricaemia	Purine bases from DNA/RNA → xanthine → uric acid (via xanthine oxidase)
LDH ↑	Markedly elevated	Released from lysed cells; also a marker of tumour burden/cell turnover
Creatinine ↑	AKI	Uric acid / calcium phosphate crystals deposit in renal tubules → obstructive nephropathy

Investigation	Rationale
CXR	Disease-related complications (mediastinal mass in T-ALL, pleural effusions) and infections ^[1]
Contrast CT thorax	For all T-ALL: evaluation of mediastinal mass ^[2]
ECG + echocardiogram	Before anthracycline chemotherapy — anthracyclines (daunorubicin, doxorubicin) are cardiotoxic (cause dose-dependent cardiomyopathy). Need baseline cardiac function (LVEF) ^[1]
Hepatitis serology (HBV, HCV), HIV	Risk of reactivation during immunosuppressive chemotherapy; guides prophylactic antiviral therapy ^[1]
G6PD status	Risk of oxidative haemolysis with co-trimoxazole ^[1] — co-trimoxazole is used for Pneumocystis prophylaxis during ALL treatment. G6PD-deficient patients need alternative prophylaxis (e.g., dapsone, atovaquone)
Lumbar puncture (LP) with CSF analysis	For CSF analysis for leukaemic involvement (determines schedule of CNS prophylaxis) ^[2]^[4]. Should be done together with first intrathecal chemotherapy to prevent promotion of spread of tumour within CNS ^[2]
HLA typing	For patients with high-risk disease and candidates for HSCT ^[1]
Central venous catheter insertion	For reliable IV access for chemotherapy, blood products, and monitoring ^[1]
Baseline biochemistry/haematology	Renal function, liver function, electrolytes, coagulation — baseline before cytotoxic therapy ^[2]^[4]
Viral carrier status	In Hong Kong: HBV carrier status particularly important (high prevalence); EBV/CMV serology if HSCT is being considered ^[2]

High Yield — LP Timing in ALL

The LP should be done together with the first intrathecal chemotherapy to prevent promotion of spread of tumour within CNS ^[2]. Performing a "diagnostic" LP without intrathecal treatment is risky because the procedure itself can introduce circulating blasts from the blood into the CSF (traumatic tap → iatrogenic CNS contamination). By giving intrathecal methotrexate at the same time, you kill any blasts that might enter the CSF during the procedure.

High Yield — MCICM Systematic Approach

5 steps to diagnosis of haematological malignancy (MCICM) ^[3]^[9]:

Step	Technique	ALL-Specific Findings
M — Morphology	PBS: number, morphology, blasts. BM aspirate + trephine	Lymphoblasts (basophilic, no granules, no Auer rods); hypercellular marrow
C — Cytochemistry	MPO/Sudan Black B for myeloid; no marker for lymphoid	MPO NEGATIVE (lineage-defining)
I — Immunophenotyping	Flow cytometry (PB, marrow aspirate); IHC (trephine only)	TdT+, CD19/CD10 (B-ALL) or cytoCD3 (T-ALL)
C — Cytogenetics	Karyotyping, FISH	t(9;22), t(12;21), hyperdiploidy, hypodiploidy, KMT2A rearrangement
M — Molecular genetics	PCR, sequencing, NGS	BCR-ABL1, IKZF1, NOTCH1, Ph-like profile

Pitfall	Why It Matters	How to Avoid
Mistaking atypical lymphocytes for blasts	Reactive lymphocytosis (IM) → panic → unnecessary BM biopsy	Atypical lymphocytes are NOT neoplastic; look at clinical context + TdT ^[3]^[9]
Normal or low WBC does not exclude ALL	25–40% of ALL have WBC < 5 × 10⁹/L — "aleukemic leukaemia"	Always examine the differential count and PBS for blasts, even with low WBC ^[2]^[9]
Giving steroids before BM	Steroids are lympholytic → can temporarily clear blasts → obscure diagnosis	Perform BM and PBS before any steroid administration
Traumatic LP introducing blasts into CSF	Iatrogenic CNS contamination worsens staging and prognosis	LP should be done with first intrathecal chemotherapy ^[2]
Missing G6PD deficiency	Co-trimoxazole causes oxidative haemolysis in G6PD deficiency → acute haemolytic crisis during PCP prophylaxis	Check G6PD status before starting treatment ^[1]

High Yield Summary — Diagnosis of ALL

Diagnostic criteria: ≥ 20% lymphoblasts in BM/PB + lymphoid immunophenotype
MCICM approach: Morphology → Cytochemistry (MPO−) → Immunophenotype (TdT+, lineage markers) → Cytogenetics (karyotype + FISH) → Molecular (PCR/NGS)
Three goals of workup: (1) Make diagnosis, (2) Screen for emergencies (DIC, TLS, hyperleukocytosis), (3) Prepare for treatment (cardiac assessment, viral serology, G6PD, LP with intrathecal chemo, HLA typing, CVC insertion)
CBC: NcNc anaemia + thrombocytopenia; WBC can be high, normal, or low
PBS: Lymphoblasts — no granules, no Auer rods, basophilic cytoplasm; hard to distinguish from myeloblasts morphologically
Cytochemistry is lineage-defining: MPO positive = myeloid (AML); MPO negative = lymphoid (ALL)
TdT confirms precursor lymphoid origin; negative in mature lymphoid neoplasms
Cytogenetics/molecular are non-diagnostic but essential for prognosis and classification — especially t(9;22) Ph+ ALL for TKI therapy
LP with first intrathecal chemo — never do a "naked" diagnostic LP

Active Recall - Diagnosis and Investigation of ALL

References

^[1] Lecture slides: GC 060. High white cell count.pdf (p6, p7) ^[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (p418, p421) ^[3] Senior notes: Ryan Ho Fundamentals.pdf (p390, p391) ^[4] Senior notes: Ryan Ho Haemtology.pdf (p47, p51, p54, p61) ^[8] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p2, p3, p4, p5, p19) ^[9] Senior notes: Ryan Ho Haemtology.pdf (p47) ^[12] Lecture slides: GC 060. High white cell count.pdf (p7)

Management of Acute Lymphoblastic Leukaemia (ALL)

3. Phase-by-Phase Treatment

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

High Yield — GC Lecture / Senior Notes: ALL Induction Regimen

Multi-agent chemotherapy for ALL induction ^[8]:

Cyclophosphamide
Daunorubicin
Vincristine
Prednisolone
L-asparaginase
Methotrexate
Cytarabine

Very toxic regimen, so many drugs → paediatric protocol. In adults, Ph+ ALL is more common. ^[8]

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

Drug	Class	Mechanism of Action	Key Toxicities	Rationale in ALL
Vincristine	Vinca alkaloid	Binds tubulin → inhibits mitotic spindle formation → arrests cells in M phase	Peripheral neuropathy (dose-limiting), constipation (autonomic neuropathy), jaw pain	Cell-cycle specific; highly active against lymphoblasts
Prednisolone/Dexamethasone	Corticosteroid	Binds glucocorticoid receptor → induces apoptosis in lymphoid cells; also anti-inflammatory/immunosuppressive	Hyperglycaemia, osteoporosis, osteonecrosis (especially in adolescents), mood disturbance, weight gain, infection risk	Lymphoblasts are exquisitely sensitive to corticosteroid-induced apoptosis (unlike myeloid cells) — this is why steroids are a cornerstone of ALL, not AML
Daunorubicin	Anthracycline	Intercalates DNA → inhibits topoisomerase II → causes DNA double-strand breaks → apoptosis	Cardiotoxicity (cumulative, dose-dependent cardiomyopathy — hence need ECG + echocardiogram before anthracycline ^[1]), myelosuppression, mucositis	Potent cytotoxic agent active against dividing cells
L-asparaginase	Enzyme	Hydrolyses asparagine → depletes serum asparagine. Normal cells can synthesise their own asparagine (via asparagine synthetase), but lymphoblasts cannot → they are dependent on exogenous asparagine → cell death	Allergic reactions/anaphylaxis, pancreatitis, hepatotoxicity, thrombosis (↓ antithrombin III, fibrinogen), hyperglycaemia	Unique to ALL treatment — exploits a metabolic vulnerability specific to lymphoblasts
Cyclophosphamide	Alkylating agent	Cross-links DNA → prevents DNA replication → cell death	Myelosuppression, haemorrhagic cystitis (prevented with MESNA), infertility	Effective against both cycling and non-cycling cells
Methotrexate	Antifolate	Inhibits dihydrofolate reductase (DHFR) → ↓ tetrahydrofolate → ↓ thymidylate and purine synthesis → ↓ DNA synthesis	Mucositis, myelosuppression, hepatotoxicity, renal toxicity (crystallisation in tubules at high doses — needs alkaline hydration), neurotoxicity (intrathecal)	Used both systemically (high dose in consolidation) and intrathecally (CNS prophylaxis)
Cytarabine (Ara-C)	Nucleoside analogue	Incorporates into DNA → chain termination; also inhibits DNA polymerase	Myelosuppression, cerebellar toxicity (high dose), conjunctivitis (high dose — prevent with steroid eye drops)	Also used intrathecally for CNS prophylaxis

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].

TKI	Generation	Notes
Imatinib	1st generation	First TKI used in Ph+ ALL; added to chemotherapy backbone
Dasatinib	2nd generation	Preferred in Ph+ ALL because it has CNS penetration (unlike imatinib) — important given ALL's tropism for the CNS

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.

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].

Drug	Dose/Schedule	Mechanism
6-Mercaptopurine (6-MP)	Daily oral	Purine analogue → incorporates into DNA → inhibits purine synthesis → kills dividing lymphoblasts. Metabolised by TPMT (thiopurine methyltransferase) — check TPMT genotype before starting; deficient patients accumulate toxic metabolites → severe myelosuppression
Methotrexate	Weekly oral	Antifolate → inhibits DNA synthesis
± Vincristine + steroid pulses	Monthly	Intermittent re-induction to catch escaping clones

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).

Key Concept — Maintenance is ONLY in ALL, NOT AML

± Maintenance (of remission): low-intensity chemotherapy to maintain remission — only in ALL ^[4]. AML does NOT use maintenance therapy (with the exception of FLT3-mutant AML using midostaurin and some protocols using azacitidine maintenance). The reason: AML cells proliferate faster and are either killed during induction/consolidation or not — prolonged low-dose oral chemotherapy is ineffective against residual AML clones, but it IS effective against the slower-cycling ALL clones.

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

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

Modality	Details
Intrathecal chemotherapy	Intrathecal can only give methotrexate, cytarabine, and steroid → medicolegal implications, nothing else ^[8]. Triple intrathecal therapy (methotrexate + cytarabine + hydrocortisone) is standard
High-dose systemic methotrexate	Achieves therapeutic CSF levels when given IV at doses ≥ 1 g/m² (crosses blood–brain barrier at high doses)
Cranial irradiation	Historically used; now largely replaced by intensified intrathecal + systemic therapy due to long-term neurocognitive toxicity, growth hormone deficiency, and secondary CNS tumours. Still used in select high-risk CNS+ patients

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.

4. Supportive Care

Supportive care is critical — "if the patient dies, you have no one to treat" ^[8].

Product	Indication	Threshold
RBC transfusion	Symptomatic anaemia ^[4]	Hb < 70–80 g/L (or symptomatic at any level)
Platelet transfusion	PLT ≤ 10, or ≤ 20 if fever/bleeding ^[4]	Prophylactic if PLT < 10 × 10⁹/L; therapeutic if actively bleeding
FFP	Bleeding due to DIC ^[4]	Prolonged PT/APTT with active bleeding
Cryoprecipitate	Low fibrinogen in DIC	Fibrinogen < 1.0 g/L

Irradiated Blood Products

ALL patients receiving intensive chemotherapy are immunocompromised and at risk of transfusion-associated graft-versus-host disease (TA-GVHD) — where donor T-lymphocytes in the transfused blood attack the immunosuppressed recipient's tissues. This is prevented by gamma-irradiating all cellular blood products (RBC, platelets), which kills donor lymphocytes while preserving RBC/platelet function ^[13].

In an emergency where irradiated products are not available, ask the blood bank for the oldest bag of blood — once blood is stored for more than 14 days, the lymphocytes should have died ^[13].

Measure	Details	Rationale
Reverse isolation	Single room, HEPA filters, restricted visitors	Minimise exposure to environmental pathogens during neutropenic period
Face mask, hand hygiene	Standard precautions ^[8]
Low bacteria diet	Avoid raw foods, unpasteurised dairy	Reduce enteric infection risk
PCP prophylaxis	Co-trimoxazole (TMP-SMX) — check G6PD first ^[1]^[8]	Pneumocystis jirovecii pneumonia prophylaxis during immunosuppression
Antifungal prophylaxis	Fluconazole or posaconazole — in patients with prolonged and profound neutropenia ^[8]	Invasive fungal infections (Aspergillus, Candida) are a major cause of death during chemotherapy
Antiviral prophylaxis	Acyclovir for HSV-seropositive patients ^[4]	Prevent HSV reactivation during immunosuppression
Neutropenic fever	Immediate empirical broad-spectrum antibiotics ^[8] — e.g., piperacillin-tazobactam or meropenem	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 ^[14]

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].

Agent	Mechanism	Notes
Allopurinol	Xanthine oxidase inhibitor → ↓ uric acid production from purines	Must check HLA-B5801 before starting → risk of SJS/TEN* ^[8]. More common in Han Chinese population (Hong Kong relevance!)
Febuxostat	Non-purine xanthine oxidase inhibitor	Alternative to allopurinol; no HLA-B*5801 association
Rasburicase	Recombinant urate oxidase → converts uric acid to allantoin (highly soluble, easily excreted)	Rapid reduction of uric acid; used in high-risk TLS. Contraindicated in G6PD deficiency (generates H₂O₂ during uric acid metabolism → oxidative haemolysis in G6PD-deficient patients) ^[4]^[1]
IV hydration	Dilutes electrolytes, maintains renal blood flow	Mainstay of TLS prevention

High Yield — HLA-B*5801 and G6PD

Two pharmacogenomic checks that are must-know before starting ALL treatment:

Check HLA-B5801 before starting allopurinol* → risk of severe cutaneous adverse reactions (SJS/TEN) ^[8]. Particularly relevant in Hong Kong Chinese patients (allele frequency ~6–8%).
Check G6PD before starting co-trimoxazole (PCP prophylaxis) and before rasburicase ^[1]. G6PD deficiency → oxidative haemolysis.

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].

Intervention	Details
Leukapheresis	Mechanical removal of WBCs via apheresis machine; temporary debulking
Hydroxyurea	Rapid cytoreduction (ribonucleotide reductase inhibitor → ↓ DNA synthesis)
Urgent induction chemotherapy	Definitive treatment
Avoid RBC transfusion until WBC is lowered ^[4]	Transfused RBCs increase blood viscosity → worsen leucostasis

5. Haematopoietic Stem Cell Transplantation (HSCT)

Allogeneic HSCT → generally not needed, ALL is very responsive to drugs. For high-risk cases or relapse ^[8].

± HSCT: for selected patients with poor prognosis only → eliminate leukaemia cells + graft-versus-leukaemia effect by allograft cells ^[4].

Indication	Rationale
High-risk cytogenetics/molecular features	e.g., Ph+ ALL (if poor response to TKI + chemo), Ph-like ALL, KMT2A-rearranged, hypodiploidy
Poor response to induction (persistent MRD)	High risk of relapse with chemotherapy alone
Relapsed ALL	Salvage + HSCT offers the best chance of long-term remission
Adult ALL (selected cases)	Adults have worse prognosis than children with chemotherapy alone

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.

Component	Details
Conditioning regimen	Myeloablative (total body irradiation + cyclophosphamide) or reduced-intensity — destroys the recipient's marrow to make space for donor cells and provides anti-leukaemia effect
Donor source	HLA-matched sibling (best), matched unrelated donor (MUD), haploidentical (half-matched family member), cord blood
Graft-versus-leukaemia (GvL) effect	Donor T cells recognise and attack residual host leukaemia cells — this is the major therapeutic advantage of allogeneic (not autologous) HSCT
Major complication	Graft-versus-host disease (GVHD) — donor T cells also attack normal host tissues (skin, liver, gut). Acute GVHD (within 100 days) and chronic GVHD ( > 100 days)

For relapsed/refractory ALL, several transformative immunotherapies are now available:

Agent	Type	Mechanism	Indication
Blinatumomab	Bispecific T-cell engager (BiTE)	Bi-specific antibody linking CD3 (on T cells) to CD19 (on B-ALL blasts) → redirects patient's T cells to kill leukaemic cells	Relapsed/refractory B-ALL; MRD-positive B-ALL
Inotuzumab ozogamicin	Antibody-drug conjugate (ADC)	Anti-CD22 antibody conjugated to calicheamicin (cytotoxic) → delivers toxin directly to CD22+ B-ALL blasts	Relapsed/refractory B-ALL
CAR-T cell therapy (Tisagenlecleucel)	Chimeric antigen receptor T cells	Patient's T cells are genetically engineered to express a receptor targeting CD19 → infused back to kill CD19+ B-ALL cells	Relapsed/refractory B-ALL in children and young adults (up to age 25)
Nelarabine	Purine analogue (deoxyguanosine analogue)	Preferentially accumulated in T cells → inhibits DNA synthesis	Relapsed/refractory T-ALL

Why target CD19? CD19 is expressed on virtually all B-ALL blasts (and normal B cells) but not on haematopoietic stem cells or non-B-cell tissues. This makes it an excellent therapeutic target — you kill the B-ALL blasts (and normal B cells as a side effect → B-cell aplasia → can be managed with IV immunoglobulin replacement), but spare the stem cells so the bone marrow can eventually recover.

Prognostic stratification is essential for deciding on treatment, based on clinical + genetic features ^[2]^[4].

Factor	Favourable	Unfavourable
Age	1–9 years	< 1 year (infant), > 10 years (children), adult
WBC at presentation	< 50 × 10⁹/L	> 50 × 10⁹/L (especially > 100)
Cytogenetics	t(12;21) ETV6-RUNX1, high hyperdiploidy	t(9;22) BCR-ABL1, KMT2A-rearranged, hypodiploidy
Response to treatment	Early CR, MRD-negative by day 29–33	Slow response, MRD-positive
Immunophenotype	Common B-ALL (CD10+)	T-ALL (historically worse, now improved), pro-B ALL
CNS involvement	Absent (CNS-1)	Present at diagnosis (CNS-3)

Overall survival:

Childhood ALL: ~90% 5-year OS with modern protocols — childhood ALL is the first disseminated cancer shown to be curable ^[6]
Adult ALL: ~40–50% 5-year OS (much worse due to higher frequency of adverse genetics, e.g., Ph+ ALL, and worse tolerance of intensive chemotherapy)

Feature	ALL	AML
Induction	Multi-agent (vincristine, steroid, anthracycline, L-asparaginase, cyclophosphamide, methotrexate, cytarabine)	7+3 regimen (7d cytarabine + 3d anthracycline)
Maintenance	Yes — oral 6-MP + weekly MTX for 2–3 years	No (with few exceptions)
CNS prophylaxis	Mandatory — intrathecal chemo throughout treatment	Not routine (only in specific subtypes with CNS risk)
HSCT	Only for high-risk/relapsed; triaged by MRD	More commonly indicated (for intermediate/poor-risk disease)
Steroids	Core component (lymphoblasts are steroid-sensitive)	Not part of induction (myeloid cells are not steroid-sensitive)
L-asparaginase	Core component (lymphoblasts lack asparagine synthetase)	Not used
TKI	For Ph+ ALL (dasatinib preferred for CNS penetration)	For FLT3-mutant AML (midostaurin, gilteritinib)

High Yield Summary — Management of ALL

Three simultaneous management goals: Make diagnosis, manage haematological emergencies, prepare for treatment.
Induction: Multi-agent chemotherapy (vincristine, prednisolone, daunorubicin, L-asparaginase, cyclophosphamide, methotrexate, cytarabine). CR rate ~95% children, ~85% adults.
Consolidation: Intensification blocks over 6 months with high-dose methotrexate, cytarabine, cyclophosphamide.
Maintenance: Unique to ALL — oral 6-MP daily + methotrexate weekly for 2–3 years. Outpatient, low intensity.
CNS prophylaxis: Mandatory throughout — intrathecal methotrexate/cytarabine/steroid. Only MTX, Ara-C, and steroid can be given intrathecally.
Ph+ ALL: Add TKI (dasatinib preferred) to chemotherapy backbone.
HSCT: Reserved for high-risk or relapsed ALL; triaged by MRD. Not needed for most patients.
Supportive care: Blood products (irradiated for immunocompromised), infection prophylaxis (co-trimoxazole — check G6PD; antifungal; acyclovir), TLS prevention (allopurinol — check HLA-B*5801; rasburicase — CI in G6PD deficiency).
Novel therapies: Blinatumomab (BiTE, anti-CD3/CD19), inotuzumab ozogamicin (ADC, anti-CD22), CAR-T cells (anti-CD19), nelarabine (T-ALL).
Prognosis: Childhood ALL ~90% 5-year OS; adult ALL ~40–50%.

Active Recall - Management of ALL

References

^[1] Lecture slides: GC 060. High white cell count.pdf (p6) ^[2] Senior notes: Adrian Lui Pediatrics Notes.pdf (p421) ^[4] Senior notes: Ryan Ho Haemtology.pdf (p52, p56, p57, p59, p60, p61) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p741) ^[8] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p4, p9, p20) ^[13] Senior notes: Block A - Fever after a blood transfusion_ transfusion and related problems.pdf (p22) ^[14] Senior notes: Learning_Points_All_Lectures.txt

Complications of Acute Lymphoblastic Leukaemia (ALL)

The complications of ALL can be divided into two broad categories: (1) complications of the disease itself and (2) complications of treatment. Understanding each complication from first principles — why it happens, how it presents, and how to manage it — is essential for clinical practice.

1. Complications of the Disease

These arise from the two fundamental pathological processes of ALL: bone marrow failure and extramedullary infiltration.

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].

Step	Action	Rationale
1	Blood cultures (peripheral + from each lumen of CVC) before antibiotics	Identify causative organism, but never delay antibiotics waiting for cultures
2	Immediate empirical broad-spectrum antibiotics ^[8]	Cover the most likely lethal pathogens (Gram-negatives including Pseudomonas). Options: piperacillin-tazobactam, cefepime, or meropenem
3	Assess for focal source	Oral mucositis, perianal infection, CVC tunnel/exit site infection, pneumonia, UTI
4	Add vancomycin if indicated	Suspected CVC-related infection, severe mucositis, MRSA risk, haemodynamic instability
5	Add antifungal if persistent fever after 72–96h	Empirical antifungal (caspofungin, liposomal amphotericin B, voriconazole) for suspected invasive fungal infection

High Yield — GC Lecture Slide: Infections in Immunocompromised Hosts

Neutropenic sepsis → immediate empirical broad-spectrum antibiotics ^[8]. The principles are:

Do NOT wait for culture results
Cover Gram-negatives (including Pseudomonas) empirically
Escalate to antifungals if febrile > 72–96 hours on adequate antibiotics

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.

High Yield — GC Lecture Slide: TLS Screen

Biochemistry — renal function, potassium, calcium, phosphate, urate, LDH (features of tumour lysis syndrome) ^[1].

Metabolic Derangement	Mechanism	Clinical Consequence
Hyperkalaemia	K⁺ released from lysed cells (intracellular K⁺ concentration ~140 mmol/L)	Cardiac arrhythmias (peaked T waves → wide QRS → VF), muscle weakness
Hyperphosphataemia	PO₄ released from nucleic acid degradation	Calcium-phosphate precipitation in tissues
Hypocalcaemia (secondary)	Ca²⁺ binds to excess PO₄ → insoluble calcium phosphate crystals	Tetany, seizures, QT prolongation, cardiac arrest
Hyperuricaemia	Purine bases (adenine, guanine) from DNA/RNA catabolised → xanthine → uric acid (via xanthine oxidase)	Acute urate nephropathy → uric acid crystals precipitate in renal tubules → AKI
LDH ↑↑↑	Intracellular enzyme released	Marker of cell turnover; not directly toxic
AKI	Uric acid + calcium phosphate crystal deposition in tubules → tubular obstruction	Oliguric renal failure; may require haemodialysis

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

2. Complications of Treatment

Drug	Key Toxicity	Mechanism	Prevention/Management
Anthracyclines (daunorubicin)	Cardiotoxicity — dose-dependent dilated cardiomyopathy	Generation of free radicals → myocyte damage → irreversible myocardial fibrosis. Cumulative dose-dependent	ECG + echocardiogram before anthracycline ^[1]. Monitor cumulative dose (lifetime max ~450–550 mg/m² for doxorubicin). Dexrazoxane as cardioprotectant in select cases
Vincristine	Peripheral neuropathy — glove-and-stocking sensory + motor neuropathy; constipation (autonomic neuropathy); jaw pain	Disrupts microtubule assembly → axonal transport disruption in peripheral nerves	Dose reduction/cap. NEVER give vincristine intrathecally — universally fatal (ascending myeloencephalopathy)
Methotrexate	Mucositis, myelosuppression, hepatotoxicity; high-dose: renal toxicity (crystal nephropathy), neurotoxicity (leukoencephalopathy — especially intrathecal/high-dose)	Antifolate → affects rapidly dividing cells (GI mucosa, bone marrow). Crystals in renal tubules at high doses	Folinic acid (leucovorin) rescue after high-dose MTX; alkaline hydration to prevent renal crystal precipitation; monitor MTX levels
L-asparaginase	Pancreatitis, allergic reactions/anaphylaxis, thrombosis (↓ antithrombin III, fibrinogen), hyperglycaemia	Asparagine depletion → protein synthesis disruption in pancreas; immune-mediated allergy; decreased hepatic synthesis of coagulation inhibitors	Monitor lipase/amylase; pre-medicate for allergy; switch to PEG-asparaginase or Erwinia asparaginase if allergic reaction
Cyclophosphamide	Haemorrhagic cystitis; infertility	Hepatic metabolism produces acrolein → toxic to bladder urothelium; gonadotoxicity	MESNA (2-mercaptoethane sulfonate) → binds acrolein in urine, preventing urothelial damage. Fertility preservation counselling (sperm banking, oocyte/ovarian tissue cryopreservation)
Corticosteroids	Hyperglycaemia, osteonecrosis (AVN) (especially in adolescents), osteoporosis, immunosuppression, mood disturbance, weight gain, Cushingoid habitus, adrenal suppression	Glucocorticoid receptor-mediated effects: gluconeogenesis ↑, protein catabolism ↑, bone resorption ↑, immune suppression	Monitor BSL; gradual tapering; bisphosphonates if osteoporotic
6-Mercaptopurine (maintenance)	Myelosuppression, hepatotoxicity (veno-occlusive disease)	TPMT-deficient patients accumulate toxic thioguanine nucleotides → severe myelosuppression	Check TPMT genotype/activity before starting. Dose-reduce in TPMT-deficient/intermediate patients. Also avoid allopurinol co-administration (allopurinol inhibits xanthine oxidase, which metabolises 6-MP → accumulation → severe toxicity; if allopurinol needed, reduce 6-MP dose by 75%)
Intrathecal chemotherapy	Chemical arachnoiditis (headache, back pain, vomiting), leukoencephalopathy (especially with cranial irradiation)	Direct irritation of meninges; demyelination from chronic CNS drug exposure	Only give approved IT drugs (MTX, cytarabine, steroid)

Clinical Pearl — Vincristine Intrathecal is Universally Fatal

Accidental intrathecal administration of vincristine causes ascending radiculomyeloencephalopathy and death. This is such a feared error that modern safety protocols mandate vincristine to be dispensed in a small syringe (not an IV bag) and labelled "FOR IV USE ONLY — FATAL IF GIVEN INTRATHECALLY." In many centres, vincristine and intrathecal drugs are never prepared or administered at the same time.

Beyond neutropenic fever (discussed above), ALL patients are susceptible to specific infections at different phases of treatment:

Phase	Immune Defect	Organisms
Induction (profound neutropenia)	Neutropenia, mucosal barrier disruption	Bacteria (Gram +/−), Candida, Aspergillus
Consolidation	Neutropenia (repeated cycles)	Same as induction but cumulative risk of invasive fungal infection increases
Maintenance	Lymphopenia (6-MP, MTX → lymphocytotoxic)	Pneumocystis jirovecii (hence PCP prophylaxis), VZV reactivation, opportunistic infections
Post-HSCT	Profound immune reconstitution delay	CMV reactivation, EBV-related PTLD, Aspergillus, encapsulated bacteria (late)

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].

Late Complication	Cause	Mechanism	Monitoring/Prevention
Neurodevelopmental delay	Cranial irradiation (if used), intrathecal MTX, high-dose systemic MTX	White matter damage (leukoencephalopathy), impaired myelination in developing brain → ↓ IQ, learning difficulties, ↓ processing speed	Neurocognitive assessment; educational support. Modern protocols minimise cranial irradiation
Growth retardation	Cranial irradiation → hypothalamic-pituitary damage → ↓ GH secretion; corticosteroids → impaired bone growth	Radiation damages somatotrophs in anterior pituitary → GH deficiency; steroids inhibit linear growth	Monitor height velocity; GH stimulation test; GH replacement if deficient
Cardiotoxicity	Anthracyclines (cumulative)	Free radical-mediated myocyte damage → dilated cardiomyopathy → heart failure. Can present years to decades after treatment	Echocardiogram monitoring lifelong. LVEF deterioration is dose-dependent and cumulative
Secondary malignancies	Alkylating agents, topoisomerase II inhibitors, radiation	DNA damage from treatment → acquisition of new oncogenic mutations in surviving cells	t-MDS/t-AML (5–10 years post-treatment); solid tumours (breast, thyroid, brain — 10–30 years post-cranial irradiation); skin cancers
Endocrinopathies	Cranial irradiation (pituitary damage), corticosteroids, alkylating agents	Pituitary hormone deficiencies (GH, TSH, ACTH, gonadotropins); thyroid damage from radiation	Regular endocrine screening: TFTs, growth, pubertal development, glucose tolerance
Infertility	Alkylating agents (cyclophosphamide), total body irradiation (if HSCT)	Gonadotoxicity → destruction of oocytes/spermatogonia → premature ovarian insufficiency/azoospermia	Fertility preservation counselling BEFORE treatment: sperm banking (adolescent boys), oocyte/ovarian tissue cryopreservation (post-pubertal girls)
Osteonecrosis (AVN)	Corticosteroids (especially dexamethasone in adolescents)	Disruption of intraosseous blood supply → bone infarction, typically affecting femoral head, knee	MRI if symptomatic; joint replacement if severe
Obesity and metabolic syndrome	Corticosteroids, cranial irradiation (hypothalamic damage → leptin resistance)	Altered appetite regulation, insulin resistance	Lifestyle counselling, metabolic monitoring
Psychosocial	Prolonged hospitalisation, isolation from peers, school absence, family stress	Missed education → academic delays; PTSD, anxiety, depression in survivors	Psychosocial support, school liaison, counselling

The Paradox of Childhood Cancer Survivorship

70% of children will survive, but have a lot of long-term complications ^[15]. The very treatments that cure childhood ALL (chemotherapy, radiation, HSCT) cause cumulative damage to developing organs. Childhood ALL survivors are essentially trading one disease for a lifetime of surveillance for late effects. This is why modern protocols increasingly aim to de-escalate therapy for low-risk patients (reducing anthracycline dose, eliminating cranial irradiation) while intensifying only for those who truly need it — guided by MRD.

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

Complication	Timing	Mechanism
Graft-versus-host disease (GVHD) — Acute	< 100 days post-HSCT	Donor T cells recognise host tissues as foreign → attack skin (rash), liver (jaundice, ↑bilirubin), GI tract (diarrhoea)
Graft-versus-host disease — Chronic	> 100 days	Scleroderma-like skin changes, sicca syndrome (dry eyes/mouth), bronchiolitis obliterans (lung), hepatic dysfunction
Graft rejection (host-vs-graft)	Early	Residual host immune cells reject donor graft → graft failure
Veno-occlusive disease (VOD) / Sinusoidal obstruction syndrome	Early (first 3 weeks)	Conditioning regimen damages hepatic sinusoidal endothelium → occlusion → painful hepatomegaly, ascites, jaundice ± fulminant hepatic failure
Infections	Throughout	Early: bacteria, Candida, Aspergillus. Intermediate: CMV, adenovirus. Late: encapsulated bacteria, VZV
Post-transplant lymphoproliferative disease (PTLD)	Months to years	EBV-driven B-cell proliferation in the immunosuppressed post-HSCT setting → can range from polyclonal hyperplasia to frank lymphoma
Secondary malignancy	Years	Conditioning (TBI + chemo) → DNA damage → t-MDS/t-AML, solid tumours
Endocrine dysfunction	Late	TBI → pituitary, thyroid, gonadal damage; steroids for GVHD → T2DM, osteoporosis, AVN

Relapse is the most important disease complication determining long-term survival.

Relapse Site	Frequency	Presentation	Management
Bone marrow (isolated)	Most common	Recurrence of cytopenias, blasts on PBS/BM	Reinduction chemotherapy → HSCT in CR2
CNS relapse	~5%	Headache, vomiting, cranial nerve palsy, CSF shows blasts	Intensified intrathecal therapy + systemic reinduction ± cranial irradiation → HSCT
Testicular relapse	~2%	Painless testicular swelling	Testicular biopsy → testicular irradiation + systemic reinduction → HSCT
Combined (marrow + extramedullary)			Worst prognosis; requires HSCT

Timing of relapse matters: Early relapse ( < 18 months from diagnosis or < 6 months from end of therapy) carries a much worse prognosis than late relapse ( > 6 months from end of therapy)
Novel salvage options: Blinatumomab, inotuzumab ozogamicin, CAR-T cell therapy (tisagenlecleucel) — as discussed in management section

Category	Complication	Key Mechanism
Disease — Marrow failure	Infection (neutropenic fever)	Functional neutropenia
	Bleeding (ICH, GI, mucosal)	Thrombocytopenia
	Anaemia	Erythropoiesis failure
Disease — Extramedullary	CNS leukaemia	Blast infiltration of meninges (sanctuary site)
	Testicular relapse	Blast infiltration behind blood–testis barrier
	SVCO / airway obstruction	Mediastinal mass (T-ALL)
Disease — Metabolic	Tumour lysis syndrome	Rapid blast death → K⁺, PO₄, urate release
	Leucostasis	Hyperleukocytosis → microvascular occlusion
Treatment — Acute	Neutropenic sepsis	Chemo-induced marrow suppression
	Cardiotoxicity	Anthracycline free radical myocyte damage
	Neuropathy	Vincristine microtubule disruption
	Pancreatitis, thrombosis	L-asparaginase
	Haemorrhagic cystitis	Cyclophosphamide → acrolein
	HBV reactivation	Loss of immune control during chemotherapy
Treatment — Late	Secondary malignancy	DNA damage from alkylators/radiation
	Neurodevelopmental delay	Cranial irradiation / IT MTX
	Growth retardation	GH deficiency from pituitary irradiation
	Infertility	Gonadotoxic chemotherapy / TBI
	Cardiotoxicity	Cumulative anthracycline exposure
HSCT-specific	GVHD (acute and chronic)	Donor T cells vs host tissues
	VOD/SOS	Conditioning damages hepatic endothelium
	PTLD	EBV-driven lymphoproliferation in immunosuppression
Vaccination	Live vaccine contraindicated	Risk of disseminated vaccine-strain infection

High Yield Summary — Complications of ALL

Neutropenic fever is the most immediate life-threatening complication — requires blood cultures and empirical broad-spectrum antibiotics within 1 hour (ANC < 0.5 × 10⁹/L + fever > 38.3°C).
TLS is one of the highest-risk complications in ALL — monitor K⁺, PO₄, Ca²⁺, urate, LDH, Cr. Prevent with hydration + allopurinol (check HLA-B*5801) or rasburicase (check G6PD).
CNS relapse and testicular relapse occur at sanctuary sites — mandates CNS prophylaxis (IT chemo) throughout treatment.
Anthracycline cardiotoxicity is cumulative and irreversible — baseline and periodic echocardiograms are essential.
Long-term complications in childhood ALL survivors include neurodevelopmental delay, growth retardation, secondary malignancies, endocrinopathies, infertility, and cardiotoxicity.
Live vaccines are contraindicated during chemotherapy — only inactivated vaccines are safe.
HSCT complications include GVHD, VOD, infections, PTLD, and endocrine dysfunction.
Pharmacogenomic safety checks: HLA-B*5801 before allopurinol; G6PD before co-trimoxazole and rasburicase; TPMT before 6-mercaptopurine.

Active Recall - Complications of ALL

References

^[1] Lecture slides: GC 060. High white cell count.pdf (p6) ^[4] Senior notes: Ryan Ho Haemtology.pdf (p52, p57, p60, p70, p156) ^[5] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p1399) ^[6] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p750) ^[7] Senior notes: Maksim Medicine Notes.pdf (p173) ^[8] Senior notes: Block A - High white cell count_ acute and chronic leukaemia; bone marrow transplantation; immunogenetics.pdf (p3, p9, p20) ^[14] Senior notes: Learning_Points_All_Lectures.txt ^[15] Paediatrics lecture slides: Block C - A child with cancer_ paediatric cancers.pdf (p2)

High Yield Summary

Definition: ALL is a clonal malignancy of precursor lymphocytes (lymphoblasts) with ≥ 20% blasts in BM/blood; impaired maturation + uncontrolled proliferation + impaired apoptosis.
Epidemiology: Most common childhood cancer; peak age 2–5 years; 85% B-ALL, 10–15% T-ALL; much less common than AML in adults.
Risk factors: Mostly unknown/sporadic; Down syndrome (15–20× risk), Fanconi anaemia, Bloom syndrome; chemical/radiation exposure; prior chemotherapy (alkylating agents, topoisomerase II inhibitors); acquired haematopoietic conditions (MDS, MPN, aplastic anaemia, PNH).
Pathophysiology: (1) BM failure (crowding out → anaemia, neutropenia, thrombocytopenia); (2) Extramedullary infiltration (lymphoid organs, CNS, testes, mediastinum).
Clinical features: Non-specific; constitutional symptoms (mild); marrow failure symptoms; hepatosplenomegaly + lymphadenopathy (up to 50%); bone pain; CNS symptoms; testicular enlargement; mediastinal mass in T-ALL (50–75%).
Key distinguishing features from AML: ALL has MORE hepatosplenomegaly, lymphadenopathy, mediastinal mass (T-ALL), CNS/testicular involvement. AML has MORE gum hypertrophy (M5), DIC (APL), skin involvement.
Classification: FAB (L1/L2/L3 — historical); WHO (B-ALL with/without recurrent genetic abnormalities, T-ALL, ambiguous lineage); Immunophenotype (TdT+, CD19/CD10 for B-ALL, cytoplasmic CD3 for T-ALL).
Sanctuary sites: CNS and testes — require specific prophylactic treatment.

High Yield Summary — Differential Diagnosis of ALL

Must-know differentials:

AML — distinguished by Auer rods, MPO positivity, myeloid immunophenotype
Burkitt lymphoma/leukaemia — mature B-cell (TdT−, surface Ig+), t(8;14), L3 morphology with vacuoles
Aplastic anaemia — pancytopenia but hypocellular marrow with NO blasts, NO organomegaly
ITP — isolated thrombocytopenia, other lines normal
Infectious mononucleosis — atypical lymphocytes (NOT blasts), Monospot+, EBV serology+
JIA — bone/joint pain in children but no cytopenias, no blasts
Solid tumour BM metastasis (neuroblastoma, rhabdomyosarcoma, Ewing sarcoma) — non-haematopoietic cells on marrow biopsy
CML lymphoid blast crisis — prior history of CML, BCR-ABL1+, treat with TKI

Key principles: Never give steroids for presumed ITP or JIA without first excluding ALL (CBC + PBS ± BM). Atypical lymphocytes are reactive and NOT blasts. Use MCICM to systematically classify.

High Yield Summary — Diagnosis of ALL

Diagnostic criteria: ≥ 20% lymphoblasts in BM/PB + lymphoid immunophenotype
MCICM approach: Morphology → Cytochemistry (MPO−) → Immunophenotype (TdT+, lineage markers) → Cytogenetics (karyotype + FISH) → Molecular (PCR/NGS)
Three goals of workup: (1) Make diagnosis, (2) Screen for emergencies (DIC, TLS, hyperleukocytosis), (3) Prepare for treatment (cardiac assessment, viral serology, G6PD, LP with intrathecal chemo, HLA typing, CVC insertion)
CBC: NcNc anaemia + thrombocytopenia; WBC can be high, normal, or low
PBS: Lymphoblasts — no granules, no Auer rods, basophilic cytoplasm; hard to distinguish from myeloblasts morphologically
Cytochemistry is lineage-defining: MPO positive = myeloid (AML); MPO negative = lymphoid (ALL)
TdT confirms precursor lymphoid origin; negative in mature lymphoid neoplasms
Cytogenetics/molecular are non-diagnostic but essential for prognosis and classification — especially t(9;22) Ph+ ALL for TKI therapy
LP with first intrathecal chemo — never do a "naked" diagnostic LP

High Yield Summary — Management of ALL

Three simultaneous management goals: Make diagnosis, manage haematological emergencies, prepare for treatment.
Induction: Multi-agent chemotherapy (vincristine, prednisolone, daunorubicin, L-asparaginase, cyclophosphamide, methotrexate, cytarabine). CR rate ~95% children, ~85% adults.
Consolidation: Intensification blocks over 6 months with high-dose methotrexate, cytarabine, cyclophosphamide.
Maintenance: Unique to ALL — oral 6-MP daily + methotrexate weekly for 2–3 years. Outpatient, low intensity.
CNS prophylaxis: Mandatory throughout — intrathecal methotrexate/cytarabine/steroid. Only MTX, Ara-C, and steroid can be given intrathecally.
Ph+ ALL: Add TKI (dasatinib preferred) to chemotherapy backbone.
HSCT: Reserved for high-risk or relapsed ALL; triaged by MRD. Not needed for most patients.
Supportive care: Blood products (irradiated for immunocompromised), infection prophylaxis (co-trimoxazole — check G6PD; antifungal; acyclovir), TLS prevention (allopurinol — check HLA-B*5801; rasburicase — CI in G6PD deficiency).
Novel therapies: Blinatumomab (BiTE, anti-CD3/CD19), inotuzumab ozogamicin (ADC, anti-CD22), CAR-T cells (anti-CD19), nelarabine (T-ALL).
Prognosis: Childhood ALL ~90% 5-year OS; adult ALL ~40–50%.

High Yield Summary — Complications of ALL

Neutropenic fever is the most immediate life-threatening complication — requires blood cultures and empirical broad-spectrum antibiotics within 1 hour (ANC < 0.5 × 10⁹/L + fever > 38.3°C).
TLS is one of the highest-risk complications in ALL — monitor K⁺, PO₄, Ca²⁺, urate, LDH, Cr. Prevent with hydration + allopurinol (check HLA-B*5801) or rasburicase (check G6PD).
CNS relapse and testicular relapse occur at sanctuary sites — mandates CNS prophylaxis (IT chemo) throughout treatment.
Anthracycline cardiotoxicity is cumulative and irreversible — baseline and periodic echocardiograms are essential.
Long-term complications in childhood ALL survivors include neurodevelopmental delay, growth retardation, secondary malignancies, endocrinopathies, infertility, and cardiotoxicity.
Live vaccines are contraindicated during chemotherapy — only inactivated vaccines are safe.
HSCT complications include GVHD, VOD, infections, PTLD, and endocrine dysfunction.
Pharmacogenomic safety checks: HLA-B*5801 before allopurinol; G6PD before co-trimoxazole and rasburicase; TPMT before 6-mercaptopurine.

Acute Lymphoid Leukaemia

1. Definition

2. Epidemiology

2.1 Incidence and Age Distribution

2.2 Sex Distribution

2.3 Subtype Distribution

2.4 Hong Kong Context

3. Risk Factors

3.1 Genetic Predisposition / Chromosomal Abnormalities

3.2 Environmental / Chemical Exposure

3.3 Prior Chemotherapy (Therapy-Related)

3.4 Acquired Haematopoietic Conditions

3.5 Other Proposed Factors

4. Anatomy and Function of the Haematopoietic and Lymphoid Systems (Relevant to ALL)

4.1 Normal Lymphopoiesis

4.2 Relevant Lymphoid Organs

5. Etiology and Pathophysiology

5.1 The "Two-Hit" (Multi-Hit) Model of Leukaemogenesis

5.2 Key Molecular Pathways in ALL

5.3 Pathophysiology: From Molecular to Clinical

Process 1: Bone Marrow Failure (Crowding Out)

Process 2: Extramedullary Infiltration

5.4 Sanctuary Sites

6. Classification

6.1 French-American-British (FAB) Morphological Classification (Historical)

6.2 WHO Classification (Current, 5th Edition 2022)

B-lymphoblastic leukaemia/lymphoma (B-ALL/LBL) (~85%)

T-lymphoblastic leukaemia/lymphoma (T-ALL/LBL) (~10–15%)

ALL of ambiguous lineage

6.3 Immunophenotypic Classification

7. Clinical Features

7.1 Symptoms

A. Constitutional Symptoms

B. Symptoms of Bone Marrow Failure

C. Symptoms of Extramedullary Infiltration

D. Hyperviscosity / Leucostasis Symptoms (in hyperleukocytosis: WBC > 100 × 10⁹/L)

7.2 Signs

A. General Examination

B. Lymphoid System Examination

C. Signs of Organ Infiltration

D. Other Signs

7.3 Summary Table: Symptom–Sign–Mechanism

8. Special Clinical Scenarios

8.1 T-ALL Presenting as Mediastinal Emergency

8.2 Hyperleukocytosis and Leucostasis

8.3 Tumour Lysis Syndrome (TLS)

Active Recall - Acute Lymphoid Leukaemia (Definition to Clinical Features)

References

Category 1: Haematological Malignancies Mimicking ALL

1A. Acute Myeloid Leukaemia (AML)

1B. Burkitt Lymphoma / Leukaemia

1C. Other Lymphoproliferative Disorders

1D. CML in Lymphoid Blast Crisis

1E. Myelodysplastic Syndrome (MDS)

Category 2: Non-Malignant Haematological Conditions Mimicking ALL

2A. Aplastic Anaemia

2B. Immune Thrombocytopenia (ITP)

2C. Reactive Lymphocytosis / Atypical Lymphocytosis

2D. Megaloblastic Anaemia (Vitamin B₁₂ / Folate Deficiency)

Category 3: Other Malignancies with Bone Marrow Involvement (Especially in Children)

Category 4: Differential Diagnosis by Specific Clinical Presentation

4A. Fever + Lymphadenopathy

4B. Fever + Bone Pain + Joint Swelling

4C. Pancytopenia / Single Cytopenia

Summary: Key Differentiating Investigations

Active Recall - Differential Diagnosis of ALL

1. Diagnostic Criteria

2. Diagnostic Algorithm

3. Investigation Modalities — Detailed Breakdown

3.1 Complete Blood Picture (CBC) with Differential

3.2 Peripheral Blood Smear (PBS)

3.3 Bone Marrow Examination

3.4 Cytochemistry

3.5 Immunophenotyping (Flow Cytometry)

3.6 Cytogenetics

3.7 Molecular Genetics

3.8 Emergency / Pre-Treatment Investigations

A. Haematological Emergency Screen

B. Tumour Lysis Syndrome (TLS) Screen

C. Pre-Treatment Assessment