Acute Lymphoblastic Leukaemia (ALL)

Acute lymphoblastic leukaemia is a malignant neoplasm of the lymphocyte precursor cells. These leukaemic lymphoblasts have an exaggerated and uncontrolled growth leading to bone marrow failure. They also fail to mount an appropriate immune response.

ALL represents <1% of adult cancers and 25% of childhood cancers. It is the most common acute leukaemia in children ≤14 years (75%).

WHO classification of ALL (based on morphology, cytochemistry, immunophenotyping, and cytogenetics)
- Pre-B cell Leukemia or Lymphoma: 85%
  - CALLA (CD10+), CD19+, CD20+, TdT+
- Pre-T cell Leukemia or Lymphoma: 15%
  - Common in Teenagers with a Thymic mass. Do not express CALLA (CD10)
  - CD2+, CD3+, CD4+, CD5+, CD7+, CD8+, TdT+
FAB classification of ALL (based on blast morphology and cytochemistry)
- ALL-L1: Precursor lymphoblasts; more common in children than in adults (85% vs 30%)
- ALL-L2: Precursor lymphoblasts; more common in adults than in children (60% vs 15%). They are larger than the typical L1 blasts (Oval or irregular nuclear outline, less homogeneous chromatin, variable nuclei but frequently prominent, sometimes multiple, more abundant cytoplasm but still pale blue)
- ALL-L3: more mature subtypes of B-cells (Burkitt-L3 cells)
Risk factors for ALL
- Genetic factors
  - Down syndrome
  - Bloom syndrome
  - Neurofibromatosis type 1
  - Ataxia telangiectasia
  - Klinefelter’s syndrome
  - Fanconi anaemia
- Ionizing radiation
Signs and symptoms
- Symptoms of anaemia
- Fever and recurrent infections due to neutropenia
- Spontaneous bleeding and bruising due to thrombocytopenia
- Weight loss, fevers, and night sweats due to B-cell dysfunction
- Lymphadenopathy due to extramedullary spread to lymph nodes
- Hepatsplenomegaly due to extramedullary hematopoiesis and spread to the liver and spleen
- Painless, unilateral testicular mass due to extramedullary spread to the testes
- Raised ICP and focal neurologic deficits due to CNS involvement
- Bone pains and difficulty walking – especially in young children – due to bone marrow expansion)
Differentials
- Acute myeloid leukaemia
- Myelodysplastic syndrome
- Myelofibrosis
- Reactive lymphocytosis
- Aplastic anaemia
- Immune thrombocytopaenia
Investigations
- Complete blood count
  - Pancytopenia
- Peripheral blood film
  - Lymphoblasts present
- Bone marrow biopsy for diagnosis
  - Increased marrow cellularity due to infiltration by densely packed blastic elements with no particular pattern of involvement)
  - Hypocellular presentations are rare in ALL
  - Frank fibrosis may be present, but increased reticulin is more common
- Cytochemical stains
  - MPO negative
  - Sudan B Black negative
  - Non-specific esterase (NSE) negative
  - Periodic Acid-Schiff (PAS) block positive
  - Acid phosphatase is focally positive
- Flow cytometry to further subclassifications into precursor B-cell and T-cell lineages
  - Terminal Deoxynucleotidyl transferase (TdT): positive for both
  - B-precursor leukemia: CD10+(CALLA), CD19+, CD22+, TdT, Cytoplasmic CD79A, CD34, CD9a+, CD20+, lack of cytoplasmic (c) and surface immunoglobulin (sIg) expression
  - T-precursor leukemia: CD2+, CD3+, CD4+, CD5+, CD7+
- Cytogenetic analysis for prognosis
- Polymerase chain reaction
- Lumbar puncture and CSF analysis for CNS involvement
  - CNS involvement used by the Children’s Cancer Group: >5WBC/L of CSF with unequivocal blasts identified on the cytospin
    - CNS 1: <5 WBC/L of CSF no blasts
    - CNS 2: < WBC/L of CSF with blasts
    - CNS 3: >5 WBC/L of CSF and blasts or cranial nerve findings
- Serum biochemistries to evaluate for tumor lysis syndrome
Treatment
- Psychological support
- Nutritional support
- Reverse isolation during admission
- Tranfsusion
- Broad-spectrum antibiotics, if needed
- Chemotherapy
  - Standard induction with cyclophosphamide, vincristin, adriamycin, and dexamethasone (CVAD)
  - Intrathecal methotrexate or ARA-C for CNS prophylaxis
- Counsel and reassure the patient
Complications
- Chemotherapy-related adverse effects
  - Cyclophosphamide → hemorrhagic cystitis
  - Vincristine → peripheral neuropathy
  - Adriamycin → Dilated cardiomyopathy
  - Dexamethasone → Cushing syndrome, bone demineralization, avascular necrosis
- Tumor lysis syndrome
- Complications related to cytopenias

Reference Intervals ›

Biochemistry

ACTH	P: <80 ng/L
ALT	P: 5–35 U/L
Albumin	P: 35–50 g/L
Aldosterone	P: 100–500 pmol/L
Alk. phosphatase	P: 30–130 U/L
α-Amylase	P: 0–180 IU/dL
α-Fetoprotein	S: <10 kU/L
Angiotensin II	P: 5–35 pmol/L
ADH	P: 0.9–4.6 pmol/L
AST	P: 5–35 U/L
Bicarbonate	P: 24–30 mmol/L
Bilirubin	P: 3–17 μmol/L
BNP	P: <50 ng/L
CRP	P: <10 mg/L
Calcitonin	P: <0.1 mcg/L
Calcium (ionized)	P: 1.0–1.25 mmol/L
Calcium (total)	P: 2.12–2.60 mmol/L
Chloride	P: 95–105 mmol/L
Cholesterol	P: <5.0 mmol/L
VLDL	P: 0.128–0.645 mmol/L
LDL	P: <2.0 mmol/L
HDL	P: 0.9–1.93 mmol/L
Cortisol AM	P: 450–700 nmol/L
Cortisol Midnight	P: 80–280 nmol/L
CK ♂	P: 25–195 U/L
CK ♀	P: 25–170 U/L
Creatinine	P: 70–100 μmol/L
Ferritin	P: 12–200 mcg/L
Folate	S: 2.1 mcg/L
FSH	P: 2–8 U/L ♂; >25 menopause
GGT ♂	P: 11–51 U/L
GGT ♀	P: 7–33 U/L
Glucose (fasting)	P: 3.5–5.5 mmol/L
Growth hormone	P: <20 mu/L
HbA1C (DCCT)	B: 4–6%
HbA1C (IFCC)	B: 20–42 mmol/mol
Iron ♂	S: 14–31 μmol/L
Iron ♀	S: 11–30 μmol/L
Lactate (venous)	P: 0.6–2.4 mmol/L
Lactate (arterial)	P: 0.6–1.8 mmol/L
LDH	P: 70–250 U/L
LH	P: 3–16 U/L
Magnesium	P: 0.75–1.05 mmol/L
Osmolality	P: 278–305 mosmol/kg
PTH	P: 0.8–8.5 pmol/L
Potassium	P: 3.5–5.3 mmol/L
Prolactin ♂	P: <450 U/L
Prolactin ♀	P: <600 U/L
PSA	P: 0–4 mcg/mL
Protein (total)	P: 60–80 g/L
Red cell folate	B: 0.36–1.44 μmol/L
Renin (erect)	P: 2.8–4.5 pmol/mL/h
Renin (recumbent)	P: 1.1–2.7 pmol/mL/h
Sodium	P: 135–145 mmol/L
TBG	P: 7–17 mg/L
TSH	P: 0.5–4.2 mU/L
T4	P: 70–140 nmol/L
Free T4	P: 9–22 pmol/L
TIBC	S: 54–75 μmol/L
Triglycerides	P: 0.50–2.3 mmol/L
T3	P: 1.2–3.0 nmol/L
Troponin T	P: <0.1 mcg/L
Urate ♂	P: 210–480 μmol/L
Urate ♀	P: 150–390 μmol/L
Urea	P: 2.5–6.7 mmol/L
Vitamin B12	S: 0.13–0.68 nmol/L
Vitamin D	S: 50 nmol/L

Arterial Blood Gases

pH	7.35–7.45
PaCO₂	4.7–6.0 kPa
PaO₂	>10.6 kPa
Base excess	±2 mmol/L

Urine

Cortisol (free)	<280 nmol/24h
Hydroxyindole acetic acid	16–73 μmol/24h
Hydroxymethylmandelic acid	16–48 μmol/24h
Metanephrines	0.03–0.69 μmol/mmol cr.
Osmolality	350–1000 mosmol/kg
17-Oxogenic steroids ♂	28–30 μmol/24h
17-Oxogenic steroids ♀	21–66 μmol/24h
17-Oxosteroids ♂	17–76 μmol/24h
17-Oxosteroids ♀	14–59 μmol/24h
Phosphate (inorganic)	15–50 mmol/24h
Potassium	14–120 mmol/24h
Protein	<150 mg/24h
Protein/creatinine ratio	<3 mg/mmol
Sodium	100–250 mmol/24h

Haematology

WCC	4.0–11.0 ×10⁹/L
RBC ♂	4.5–6.5 ×10¹²/L
RBC ♀	3.9–5.6 ×10¹²/L
Hb ♂	130–180 g/L
Hb ♀	115–160 g/L
PCV ♂	0.4–0.54 L/L
PCV ♀	0.37–0.47 L/L
MCV	76–96 fL
MCH	27–32 pg
MCHC	300–360 g/L
RDW	11.6–14.6%
Neutrophils	2.0–7.5 ×10⁹/L (40–75%)
Lymphocytes	1.0–4.5 ×10⁹/L (20–45%)
Eosinophils	0.04–0.44 ×10⁹/L (1–6%)
Basophils	0–0.10 ×10⁹/L (0–1%)
Monocytes	0.2–0.8 ×10⁹/L (2–10%)
Platelets	150–400 ×10⁹/L
Reticulocytes	0.8–2.0% / 25–100 ×10⁹/L
Prothrombin time	10–14 s
APTT	35–45 s

Paediatric

Pulse Rate (bpm)
Neonate	140–160
Infant <1yr	120–140
1–5 years	110–130
5–12 years	80–120
>12 years	70–100
Respiratory Rate (tachypnoea)
0–2 months	≥60/min
2–12 months	≥50/min
1–5 years	≥40/min
>5 years	≥30/min
Blood Pressure (mmHg)
Term	65/45
1 year	75/50
4 years	85/60
8 years	95/65
10 years	100/70
Weight Formulas
3–12 months	(a + 9)/2 kg
1–6 years	2a + 8 kg
>6 years	(7a − 5)/2 kg
Haemoglobin (g/dL)
Term newborn	13–20
1 month	11–18
2 months	10–15
1–2 years	10–13
>2 years	11–14
MUAC (6 months–5 years)
Obese	>17.5 cm
Normal	13.5–17.4 cm
At risk	12.5–13.4 cm
Moderate malnutrition	11.5–12.4 cm
Severe malnutrition	<11.5 cm
Developmental Milestones
Social smile	1.5 months
Head control	4 months
Sits unsupported	7 months
Crawls	10 months
Stands unsupported	10–12 months
Walks	12–13 months
Talks	18 months
CSF WBC (/mm³)
Term newborn	0–25
>2 weeks	0–5

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