📋 Key Information Summary
- Acute lymphoblastic leukaemia (ALL) is the most common cancer in children aged 1–14 years, with a peak incidence at 2–5 years; ~80% of cases are B-ALL and ~15% T-ALL.
- Adult ALL is rarer (median age ~35–40 years) with inferior outcomes compared to paediatric disease; Philadelphia chromosome-positive (Ph+) ALL increases with age.
- CNS involvement (CNS leukaemia) is present at diagnosis in 5–10% of paediatric and ~5% of adult cases; prophylactic intrathecal (IT) therapy is mandatory in all risk groups.
- Diagnosis requires ≥20% bone-marrow lymphoblasts (WHO 2022 threshold), confirmed by morphology, immunophenotyping (flow cytometry), cytogenetics and molecular studies including BCR::ABL1, KMT2A rearrangements and IKZF1 deletions.
- Induction therapy achieves morphological remission (M1, <5% blasts) in >95% of paediatric and ~85–90% of adult patients using multi-agent vincristine + corticosteroid + L-asparaginase ± anthracycline backbones.
- Minimal residual disease (MRD) by flow cytometry or qPCR at end of induction (Day 28–35) is the single strongest prognostic factor and drives risk-stratified post-remission therapy.
- Ph+ ALL requires a tyrosine-kinase inhibitor (TKI — dasatinib or ponatinib) from day 1 of induction combined with chemotherapy or blinatumomab.
- Paediatric-inspired protocols (e.g., COG/DFCI hybrids adapted for Australia) produce superior survival in adolescents and young adults (AYA, 15–39 years) compared with adult regimens.
- Blinatumomab (CD3/CD19 BiTE) is PBS-listed for relapsed/refractory B-ALL (≥18 years, prior ≥1 therapy) and now used in first-line Ph+ ALL and high-risk MRD-positive settings.
- Allogeneic haematopoietic stem-cell transplant (allo-HSCT) is indicated in high-risk groups — Ph+ ALL in first remission, persistent MRD positivity after consolidation, early T-precursor (ETP) ALL with adverse features, and all second or subsequent remissions.
- Mediastinal masses in T-ALL carry a risk of superior vena cava (SVC) syndrome and airway compromise — anaesthetic and procedural planning is mandatory before general anaesthesia.
- Tumour lysis syndrome (TLS) prophylaxis with rasburicase (PBS Authority) or allopurinol plus aggressive IV hydration is essential from the time of diagnosis in all high-burden patients.
- Aboriginal and Torres Strait Islander children experience higher ALL incidence but lower event-free survival, driven by later presentation, treatment toxicity, and remote-care barriers — culturally safe, centralised management is critical.
- L-asparaginase–associated thrombosis and pancreatitis require pre-emptive antithrombin monitoring and patient/family education regarding abdominal pain during treatment.
- Five-year overall survival exceeds 90% in standard-risk paediatric ALL but remains <50% in relapsed adult ALL; treatment at an accredited paediatric or adult haematology centre is mandatory.
Introduction & Australian Epidemiology
Acute lymphoblastic leukaemia (ALL) is a haematological malignancy characterised by clonal proliferation and accumulation of immature lymphoid cells (lymphoblasts) in the bone marrow, blood and extramedullary sites. It is the most common cancer diagnosed in children, accounting for approximately 25% of all paediatric malignancies, and is also recognised as a significant disease in adolescents, young adults and older adults.
In Australia, ALL accounts for approximately 300–350 new diagnoses per year. The age-specific incidence is highest in children aged 2–5 years (approximately 5 per 100,000 per year), declining through adolescence and adulthood to approximately 1–1.5 per 100,000 in adults over 50 years of age. There is a slight male preponderance (male:female ratio ~1.2:1), which is more pronounced in T-ALL.
Paediatric ALL represents one of the great success stories of modern oncology, with five-year overall survival exceeding 90% in contemporary Australian and international cooperative-group trials. This achievement reflects successive protocol refinements in risk stratification, central nervous system-directed therapy, treatment intensity modulation, and the use of minimal residual disease (MRD) monitoring to guide therapeutic decisions.
Outcomes in adult ALL remain less favourable, with five-year overall survival of approximately 40–50% in patients aged 25–60 years and <20% in those over 60 years. The adoption of paediatric-inspired regimens in adolescents and young adults (AYA, defined as 15–39 years in Australia) has narrowed this gap, with Australian centres increasingly using hybrid DFCI/COG-style protocols in this age group.
In Aboriginal and Torres Strait Islander populations, limited registry data suggest an equal or higher incidence of ALL in children, but significantly worse event-free and overall survival — a disparity driven by later presentation, greater treatment-related toxicity, and barriers to accessing tertiary paediatric oncology centres. National collaborative efforts through the Children's Oncology Group, ANZCHOG and state-based services aim to reduce this gap.
Centralised care: All patients with ALL — paediatric, AYA and adult — should be managed at an accredited haematology/oncology centre with access to a multidisciplinary team, clinical trials, flow-cytometry MRD testing, and allogeneic HSCT services. Regional or remote patients require urgent transfer arrangements.
Pathogenesis & Classification (B vs T)
Pathogenesis
ALL arises from the malignant transformation of lymphoid progenitor cells (lymphoblasts) within the bone marrow. The leukaemic transformation involves sequential acquisition of genetic abnormalities — including chromosomal translocations, gene fusions, aneuploidy, and cooperating somatic mutations — that arrest normal lymphoid differentiation, confer a survival and proliferative advantage, and permit immune evasion. Most ALL-initiating lesions arise in utero, as evidenced by the detection of leukaemia-associated fusion genes (e.g., TCF3::PBX1, ETV6::RUNX1) in neonatal Guthrie spots of children who later develop ALL.
The bone-marrow microenvironment plays a critical role: lymphoblasts disrupt normal haematopoiesis, leading to cytopenias (anaemia, thrombocytopenia, neutropenia), and can infiltrate extramedullary sanctuary sites — most importantly the central nervous system (CNS) and testes — where they may be shielded from systemic chemotherapy.
WHO 2022 / ICC 2022 Classification
The current World Health Organization (WHO) 2022 and International Consensus Classification (ICC) 2022 frameworks classify ALL primarily by lineage and defining genetic lesion rather than blast percentage alone. A bone-marrow blast count of ≥20% remains the standard threshold for diagnosis, though certain genetic subtypes (e.g., BCR::ABL1 ALL) are considered acute leukaemia regardless of blast count.
B-Lymphoblastic Leukaemia/Lymphoma (B-ALL) — ~80% of paediatric, ~75% of adult ALL
| Subtype | Genetic Alteration | Frequency (Paediatric) | Prognosis |
|---|---|---|---|
| Hyperdiploid (>50 chromosomes) | Trisomies of chromosomes 4, 10, 17 (favourable); +21 | ~25–30% | Favourable |
| ETV6::RUNX1 (t(12;21)) | ETV6–RUNX1 fusion | ~20–25% | Favourable |
| BCR::ABL1 (Ph+) (t(9;22)) | BCR::ABL1 p190 (usually) | ~3% paediatric; ~25% adult | Historically poor → improved with TKI |
| KMT2A-rearranged (t(v;11q23)) | KMT2A::AFF1 (t(4;11)) most common in infant ALL | ~2% overall; ~75% of infant ALL | Unfavourable (especially infant <6 months) |
| TCF3::PBX1 (t(1;19)) | TCF3–PBX1 fusion | ~5–6% | Intermediate (with modern therapy) |
| IKZF1 deletion / iAMP21 | IKZF1del, RUNX1 amplification | ~15% (IKZF1del); ~2% (iAMP21) | Unfavourable — intensified therapy |
| Ph-like ALL | ABL-class fusions, JAK-STAT, CRLF2 rearrangements | ~10–15% | Unfavourable — TKI / JAK inhibitor trials |
| B-ALL NOS (B-other) | No recurrent defining abnormality | ~10–15% | Heterogeneous — MRD-driven |
T-Lymphoblastic Leukaemia/Lymphoma (T-ALL) — ~15% of paediatric, ~25% of adult ALL
| Subtype | Genetic Alteration | Key Features |
|---|---|---|
| Early T-cell precursor (ETP) ALL | Mutations in FLT3, NRAS/KRAS, DNMT3A, IKZF1, RUNX1, IL7R, JAK1/3, BCL11B, GATA3 | Immunophenotype: CD1a⁻, CD8⁻, CD5 weak/neg, myeloid/stem-cell markers; historically poor prognosis, improved with intensified therapy |
| Near ETP / intermediate ETP | Overlapping features | Variable prognosis |
| TAL/LMO rearranged | TAL1, TAL2, LMO1, LMO2 deletions/duplications | More common in older children/adults; intermediate prognosis |
| TLX1/TLX3 rearranged | HOXA activation | Prothymocyte stage; variable outcomes |
| NKX2-1 / HOXA activated | NUP214::ABL1, SET::NUP214 | Potential TKI sensitivity |
Immunophenotyping Markers
| Lineage | Positive Markers | Negative Markers |
|---|---|---|
| B-ALL (common) | CD19, CD79a, CD22, CD10 (cALLa), TdT, HLA-DR | sIg⁻, cIg⁻ (usually), MPO⁻, CD3⁻ |
| Pro-B ALL | CD19, CD79a, CD22, TdT, HLA-DR | CD10⁻, sIg⁻ |
| Pre-B ALL | CD19, CD10, cIgμ+, TdT | sIg⁻ |
| T-ALL | cytoplasmic CD3 (cCD3), CD7, CD5, CD2, TdT | CD19⁻, CD10⁻/weak |
| ETP-ALL | cCD3+, CD7+, CD5 weak/neg, CD1a⁻, CD8⁻, myeloid markers (CD13, CD33, CD11b, CD65), CD34 | CD1a⁻, CD8⁻ |
A lineage switch from ALL to AML (or vice versa) at relapse is rare but well described, particularly in KMT2A-rearranged disease. Repeat immunophenotyping at relapse is mandatory.
Clinical Features & CNS Involvement
Presenting Features
The clinical presentation of ALL reflects the consequences of bone-marrow failure (replacement by blasts) and extramedullary infiltration. Onset is typically subacute over weeks, although fulminant presentations with severe pancytopenia, TLS or respiratory compromise from a mediastinal mass occur.
| System | Features | Mechanism |
|---|---|---|
| General | Fatigue, pallor, lethargy, fever (with or without infection), weight loss, night sweats | Anaemia, cytokine release, marrow infiltration |
| Haematological | Anaemia, thrombocytopenia (petechiae, purpura, epistaxis, gum bleeding), neutropenia (recurrent/severe infections) | Marrow failure — blast replacement of normal haematopoiesis |
| Musculoskeletal | Bone pain (especially lower limbs, back), joint pain, refusal to walk (young children), limp | Periosteal infiltration, marrow expansion, leukaemic arthritis |
| Lymphatic | Generalised lymphadenopathy, hepatomegaly, splenomegaly | Extramedullary infiltration |
| Mediastinal (T-ALL) | Dyspnoea, orthopnoea, cough, SVC syndrome (facial/upper-limb oedthora, plethora, venous distension), stridor | Anterior mediastinal mass — present in ~60–70% of T-ALL, rare in B-ALL |
| CNS | Headache, vomiting, cranial nerve palsies (especially CN VII), visual changes, seizures, altered consciousness | Leukaemic meningitis, intracranial mass, cranial nerve infiltration |
| Testicular | Painless testicular enlargement (unilateral or bilateral) | Leukaemic infiltration — sanctuary site |
| Renal | Renal enlargement, loin pain, hypertension, acute kidney injury | Leukaemic infiltration, TLS, urate nephropathy |
Mediastinal mass emergency in T-ALL: Anterior mediastinal masses carry a significant risk of airway and vascular compression. General anaesthesia or sedation may precipitate complete airway collapse. A chest CT must be performed before any sedation/anaesthesia, and management should involve an experienced anaesthetist. Awake procedures are preferred for bone-marrow aspiration where possible. Urgent radiotherapy or steroid pre-phase may be required before definitive tissue diagnosis.
CNS Involvement
The central nervous system is a major sanctuary site in ALL. CNS leukaemia is defined by the presence of lymphoblasts in the cerebrospinal fluid (CSF) and/or clinical signs of CNS infiltration.
CNS Status Classification (Children's Oncology Group)
| CNS Status | Criteria |
|---|---|
| CNS-1 | No blasts in CSF (regardless of WBC count) |
| CNS-2 | WBC <5/μL in CSF with blasts present on cytospin |
| CNS-3 | WBC ≥5/μL in CSF with blasts present — overt CNS leukaemia; OR cranial nerve palsy; OR intracranial mass on imaging |
| TLP+ | Traumatic lumbar puncture (≥10 RBC/μL) with blasts present — regarded as CNS-3 equivalent if ≥10 blasts, or CNS-2 equivalent if <10 blasts |
CNS involvement at diagnosis is present in approximately 5–10% of paediatric and ~3–5% of adult ALL. Traumatic lumbar puncture (TLP) at diagnosis — seen in ~10–15% of children — is associated with inferior outcomes, particularly when blasts are introduced into the CSF. Prophylactic intrathecal therapy (IT methotrexate ± hydrocortisone) is given at every lumbar puncture to prevent sanctuary-site relapse.
Tip: Use atraumatic LP technique (small-gauge atraumatic needle, lateral decubitus position in children, ultrasound guidance where available). A short sedation-free window or anaesthetist involvement may reduce TLP rates.
Testicular Involvement
Testicular infiltration occurs in ~2% of boys at diagnosis (more common in T-ALL and high-risk disease) and was historically a major site of relapse. With modern intensive therapy and maintenance, isolated testicular relapse is now rare. Testicular examination should be performed at every clinical review; ultrasound is indicated for any abnormality.
Investigations & Diagnosis
Initial Workup
Essential
Full blood count with differential & peripheral blood film
Anaemia, thrombocytopenia, neutropenia, circulating blasts (may be absent in hypocellular presentations). Blast percentage on film. MBS Item 65070.
Essential
Bone-marrow aspirate & trephine biopsy
Blast morphology (FAB L1/L2), blast percentage (≥20% threshold), trephine for cellularity and reticulin fibrosis. Two aspirate sites recommended. MBS Item 13705.
Essential
Multi-parameter flow cytometry (immunophenotyping)
Panel must include CD19, CD10, CD20, CD22, CD79a, CD7, CD5, CD2, cCD3, CD1a, CD34, TdT, MPO, CD13, CD33, CD11b, CD65, HLA-DR, sIg, cIg. Available at all tertiary centres with haematopathology — turnaround 24–48 h.
Essential
Conventional cytogenetics (G-banding)
Karyotype on bone-marrow aspirate; requires viable dividing cells — turnaround 5–10 days. Identifies hyperdiploidy, hypodiploidy, structural rearrangements. MBS Item 73296.
Essential
FISH panel — BCR::ABL1, KMT2A, ETV6::RUNX1, TCF3::PBX1, iAMP21, CRLF2, JAK2, ABL-class fusions
Rapid turnaround (24–72 h) — provides result before conventional karyotype. Reflex FISH for Ph-like genes (ABL1, ABL2, CSF1R, PDGFRA, PDGFRB, FGFR1, JAK2, EPOR) if BCR::ABL1-negative and high-risk features. MBS Item 73304/73312.
Essential
RT-PCR / qPCR for BCR::ABL1 (p190 & p210)
Quantitative BCR::ABL1 testing for TKI monitoring. Essential for all adults >25 years and any patient with t(9;22) or BCR::ABL1 by FISH.
Available
NGS-based targeted gene panel / whole-exome sequencing
Detects IKZF1 deletion, Ph-like gene fusions, PAX5 alterations, TP53 mutations, RAS pathway mutations, and other cooperating lesions. Available through specialised laboratories (e.g., VCGS, SA Pathology, PathWest) — turnaround 10–14 days. Increasingly standard of care.
Essential
Lumbar puncture with CSF cytology & cell count
CNS status assignment (CNS-1/2/3). CSF flow cytometry increases sensitivity. IT methotrexate (± hydrocortisone) given at first diagnostic LP where feasible. MBS Item 13700.
Available
Serum biochemistry — LDH, urate, creatinine, potassium, phosphate, calcium, LFTs, coagulation (PT/APTT/fibrinogen)
TLS markers (LDH, urate, phosphate, potassium, creatinine), hepatic/renal function for drug dosing, DIC screening. MBS Items 66500, 66503, 66507.
Available
Imaging — chest X-ray, chest CT (if T-ALL or mediastinal mass suspected), testicular ultrasound
CXR for all; CT chest with contrast for any anterior mediastinal mass concern (mandatory before GA in T-ALL). MRI brain with contrast if CNS symptoms.
Available
Minimal residual disease (MRD) — flow cytometry & qPCR
End of induction (Day 28–35) MRD is the strongest independent prognostic factor. Flow cytometry MRD (sensitivity 10⁻⁴) available at major centres; qPCR for clonal immunoglobulin/T-cell receptor gene rearrangements (sensitivity 10⁻⁵) via specialised lab. MRD ≥0.01% at end induction = high risk in most protocols.
Tumour lysis syndrome prophylaxis: Initiate IV hydration (≥3 L/m²/day or 200 mL/kg/day paediatric) and consider rasburicase (0.2 mg/kg IV — PBS Authority Required, authority number 2772) if urate >0.45 mmol/L or high tumour burden. Allopurinol (100–300 mg PO daily — PBS General Benefit) if rasburicase unavailable or for lower-risk patients. Monitor U&E, phosphate, calcium, urate, LDH 6–12 hourly.
Diagnostic Criteria Summary
- ≥20% bone-marrow lymphoblasts with a lymphoid immunophenotype (WHO 2022 threshold).
- Exceptions: BCR::ABL1, KMT2A rearrangements, hypodiploidy, iAMP21 — diagnosed as ALL regardless of blast count.
- Lineage assignment by flow cytometry: B-ALL (CD19+, CD79a+, CD22+); T-ALL (cCD3+, CD7+).
- Morphology: L1 (small, regular blasts — common in paediatric), L2 (larger, irregular — more common in adult), L3 (Burkitt — now classified separately).
Management (Induction, Consolidation, Maintenance)
Overview of Treatment Phases
ALL therapy follows a sequential, risk-stratified multi-phase approach. Australian paediatric centres participate in ANZCHOG-coordinated trials aligned with COG or BFM-style protocols. Adult centres increasingly adopt paediatric-inspired regimens (e.g., DFCI-adapted) for patients up to age 40–45 years, with modified hyper-CVAD or CALGB-type regimens for older adults.
Phase 1
Remission Induction (4–6 weeks)
Goal: achieve morphological complete remission (CR, <5% marrow blasts, M1 marrow). >95% CR in paediatric; 85–90% in adult.
Phase 2
Consolidation / Intensification (6–12 months)
Goal: eradicate residual disease, prevent CNS/testicular relapse, consolidate MRD remission. High-dose methotrexate, cyclophosphamide, cytarabine blocks.
Phase 3
Maintenance / Continuation Therapy (18–24 months from diagnosis total ~2.5–3 years)
Goal: sustain remission with lower-intensity continuous therapy. Daily oral 6-mercaptopurine + weekly oral methotrexate, with monthly vincristine/pulses.
Ongoing
CNS-Directed Therapy (throughout all phases)
Intrathecal methotrexate ± hydrocortisone at defined intervals. Cranial irradiation only for overt CNS-3 disease (dose-reduced to 12–18 Gy in modern protocols).
Phase 1: Remission Induction
The induction backbone differs by age group and protocol but generally comprises:
Vincristine
Vincristine® · Vinca alkaloid
Adult dose
1.4 mg/m² IV (max 2 mg) weekly × 4–6 doses during induction
Paediatric dose
1.5 mg/m² IV (max 2 mg) weekly × 4–6 doses
Route / Frequency
IV push weekly
Key toxicity
Peripheral neuropathy (dose-capped at 2 mg in adults), constipation, SIADH, jaw pain
PBS status
✔ PBS General Benefit
Dexamethasone
Dexamethasone · Corticosteroid
Adult dose
10–12 mg/m²/day PO or IV (divided BID) for 14–28 days, then taper over 7–14 days
Paediatric dose
6 mg/m²/day PO (max 10 mg) days 1–28 induction; pulses during consolidation/maintenance per protocol
Key notes
Superior CNS penetration vs prednisolone; associated with higher avascular necrosis (AVN) risk in adolescents. Pre-phase steroids for 5–7 days before full induction reduces TLS risk.
PBS status
✔ PBS General Benefit
Pegaspargase (PEG-Asparaginase)
Oncaspar® · Modified E. coli asparaginase
Adult dose
2000 IU/m² IM (max 3750 IU) — single dose during induction; repeated every 14 days in consolidation blocks
Paediatric dose
2500 IU/m² IM (max 3750 IU) day 4 of induction; repeated per protocol schedule
Key toxicity
Hypersensitivity/anaphylaxis (anti-drug antibodies — clinical allergy or silent inactivation), pancreatitis, thrombosis, hepatotoxicity, hyperglycaemia
Monitoring
Serum asparaginase activity level (ASAL) ≥0.1 IU/mL at 7 and 14 days post-dose; antithrombin III, fibrinogen, amylase/lipase, LFTs
PBS status
PBS Restricted Benefit
Daunorubicin
Daunorubicin · Anthracycline
Adult dose
45–60 mg/m² IV weekly × 2–4 doses (cumulative induction dose 200–300 mg/m²)
Paediatric dose
25–30 mg/m² IV weekly (standard-risk B-ALL may omit; high-risk and T-ALL include)
Key toxicity
Cardiotoxicity (cumulative — echocardiogram/MUGA monitoring required), myelosuppression, nausea, mucositis
PBS status
✔ PBS General Benefit
Cyclophosphamide
Cyclophosphamide · Alkylating agent
Dose
1000 mg/m² IV (induction day 1 in T-ALL protocols; consolidation blocks). Hydration + MESNA for haemorrhagic cystitis prophylaxis.
PBS status
✔ PBS General Benefit
Dasatinib
Sprycel® · BCR::ABL1 TKI (2nd generation)
Dose (Ph+ ALL)
100–140 mg PO daily (adults); paediatric: 60 mg/m²/day (max 100 mg). Started day 1 of induction alongside chemotherapy.
Key notes
Superior CNS penetration compared with imatinib; preferred TKI in Ph+ ALL. Monitor for pleural effusion, myelosuppression, QTc prolongation.
PBS status
PBS Restricted Benefit — Ph+ ALL
Phase 2: Consolidation / Intensification
Post-remission therapy consists of multiple consolidation blocks, typically given as inpatient cycles over 6–12 months. The composition is risk-stratified based on MRD at end of induction, cytogenetic/molecular risk group, and CNS status.
Key Consolidation Components
High-Dose Methotrexate
Methotrexate · Antimetabolite
Adult dose
3–5 g/m² IV over 24 hours (dose per protocol), with leucovorin rescue (15 mg PO/IV q6h starting 42 h post-start, minimum 3 doses until MTX <0.1 μmol/L)
Paediatric dose
5 g/m² IV over 24 hours (COG/BFM protocols); leucovorin rescue as above. Alkaline hydration (pH >7.0) and urine output monitoring essential.
Key notes
Therapeutic drug monitoring of serum methotrexate levels at 24, 42, 48 h. Prolonged excretion (>0.1 μmol/L at 42 h) requires escalated leucovorin rescue. Renal dose adjustment mandatory.
PBS status
✔ PBS General Benefit
Cytarabine (Ara-C)
Cytarabine · Antimetabolite
Dose
75 mg/m² SC/IV daily × 4 days per week × 4 weeks (interim maintenance blocks) or high-dose 1–3 g/m² IV q12h × 4–6 doses (intensification blocks in T-ALL/high-risk)
PBS status
✔ PBS General Benefit
Risk Stratification Driving Consolidation Intensity
Standard Risk
SR B-ALL
Age 1–9.99 years, WBC <50 × 10⁹/L, favourable genetics (hyperdiploidy or ETV6::RUNX1), CNS-1, no TLP, end-induction MRD <0.01%.
Therapy: Standard-intensity consolidation blocks; no cranial irradiation; no allo-HSCT in CR1.
Intermediate Risk
IR B-ALL
Does not meet SR or HR criteria. Includes age ≥10 years, WBC ≥50 × 10⁹/L, CNS-2, TLP+ (without blasts), MRD 0.01–0.1% at end induction.
Therapy: Augmented/intensified consolidation; additional IT therapy if CNS-2; allo-HSCT considered if MRD persistently ≥0.01%.
High Risk
HR B-ALL & T-ALL
Ph+ ALL, KMT2A-rearranged (>6 months age), hypodiploidy (<44 chromosomes), iAMP21, IKZF1 deletion, end-induction MRD ≥1%, CNS-3, induction failure (M2/M3 marrow day 28), ETP-ALL with adverse features.
Therapy: Intensified blocks; allo-HSCT in CR1 for most HR subgroups; blinatumomab for MRD-positive patients; TKI for Ph+/Ph-like ALL.
Phase 3: Maintenance Therapy
Maintenance is a defining feature of ALL treatment and distinguishes it from AML therapy. Continuous low-dose oral chemotherapy sustains long-term remission.
6-Mercaptopurine
Puri-Nethol® · Purine antimetabolite
Dose
50–75 mg/m²/day PO (continuous daily, adjusted to maintain ANC 1–3 × 10⁹/L). Take on empty stomach — avoid dairy within 1 hour (TPMT/NUDT15 pharmacogenomics).
Key toxicity
Myelosuppression (TPMT/NUDT15 poor metaboliser → severe neutropenia), hepatotoxicity, pancreatitis
Pharmacogenomics
TPMT and NUDT15 genotyping before first dose. ~10% heterozygous (reduce dose 50–70%); ~0.3% homozygous deficient (contraindicated — substitute with alternative).
PBS status
✔ PBS General Benefit
Methotrexate
Methotrexate oral · Antimetabolite
Dose
20 mg/m² PO once weekly (maintenance); concurrent with 6-MP daily. Folic acid 1 mg PO on non-MTX days.
Key toxicity
Hepatotoxicity, mucositis, myelosuppression, pneumonitis (rare)
PBS status
✔ PBS General Benefit
Maintenance includes monthly vincristine IV pulses and 5-day dexamethasone pulses every 4–8 weeks (protocol-dependent). Intrathecal methotrexate continues at defined intervals (typically every 8–12 weeks) during maintenance. Total treatment duration is approximately 2–2.5 years for girls and 3 years for boys (longer in boys due to historical excess of testicular relapses with shorter maintenance).
Targeted & Immunotherapy Agents
Blinatumomab
Blincyto® · CD3/CD19 bispecific T-cell engager (BiTE)
Dose
28 μg/day IV continuous infusion × 28 days per cycle (4-week off between cycles). Pre-phase dexamethasone for CRS prophylaxis.
Indications
Relapsed/refractory B-ALL (≥18 y, ≥1 prior therapy); Ph+ ALL in first-line (ECOG 1910); MRD-positive high-risk B-ALL
Key toxicity
Cytokine release syndrome (CRS), neurotoxicity (ICANS — confusion, seizures, aphasia), neutropenia
PBS status
PBS Authority Required — R/R B-ALL ≥18 years
Inotuzumab Ozogamicin
Besponsa® · Anti-CD22 antibody–drug conjugate
Dose
1.8 mg/m² IV per cycle (divided Day 1: 0.8 mg/m², Days 8 and 15: 0.5 mg/m²) × 3-week cycles. Dose-adjusted for hepatic function.
Indications
Relapsed/refractory CD22+ B-ALL (adults)
Key toxicity
Veno-occlusive disease / sinusoidal obstruction syndrome (VOD/SOS) — hepatotoxicity risk, especially pre-transplant. Myelosuppression, thrombocytopenia.
PBS status
PBS Authority Required
Ponatinib
Iclusig® · 3rd-generation BCR::ABL1 TKI
Dose
45 mg PO daily (starting dose); reduce to 15–30 mg daily once major molecular response achieved. Dose-reduce for hepatic impairment.
Indications
Ph+ ALL with T315I mutation; dasatinib-intolerant/resistant Ph+ ALL
Key toxicity
Arterial thrombotic events (stroke, MI, peripheral arterial disease) — vascular risk stratification mandatory before starting. Hepatotoxicity, pancreatitis.
PBS status
PBS Authority Required — T315I mutation or TKI failure
Nelarabine
Atriance® · Purine antimetabolite (T-cell specific)
Dose
1500 mg/m² IV on days 1, 3, 5 (adult); 650 mg/m²/day IV × 5 days (paediatric) — repeated every 21 days. Important role in relapsed T-ALL.
Key toxicity
Severe neurotoxicity (demyelination, peripheral neuropathy, somnolence, seizures) — cumulative; contraindicated if pre-existing grade ≥2 neuropathy.
PBS status
PBS Authority Required — R/R T-ALL
Rituximab
MabThera® · Anti-CD20 monoclonal antibody
Dose
375 mg/m² IV — given with chemotherapy blocks in CD20+ B-ALL (≥20% CD20 expression). Increasingly used in adult B-ALL induction/consolidation.
Key notes
Improves outcomes in CD20+ adult B-ALL when combined with chemotherapy (GRAALL-R trial). Infusion reactions — pre-medicate with paracetamol, antihistamine, corticosteroid.
PBS status
✔ PBS General Benefit (oncology indication)
Allogeneic Haematopoietic Stem-Cell Transplant (Allo-HSCT)
Allo-HSCT remains the most effective post-remission therapy for high-risk ALL, offering a graft-versus-leukaemia (GvL) effect that chemotherapy alone cannot replicate. Australian transplant centres (e.g., RCH Melbourne, SCH Sydney, RAH Adelaide, QCH Brisbane, PMH Perth, RHH Hobart via interstate arrangement) perform approximately 50–70 ALL-related transplants annually.
Allo-HSCT indications in first remission (CR1):
- Ph+ ALL (particularly in adults — increasingly replaced by TKI + blinatumomab chemo-free regimens, but HSCT still standard in many protocols)
- KMT2A-rearranged ALL in infants (<1 year at diagnosis)
- Hypodiploid ALL (<44 chromosomes)
- End-induction MRD ≥1% (or MRD ≥0.01% after consolidation in some protocols)
- Induction failure (M2/M3 marrow at end of induction)
- Early T-cell precursor (ETP) ALL with high MRD after consolidation
- All second or subsequent remissions
CNS-Directed Therapy — Intrathecal Protocol Summary
| Phase | IT Therapy | Frequency |
|---|---|---|
| Induction | IT methotrexate (age-based dose: <1 y: 8 mg; 1–2 y: 10 mg; 2–3 y: 12 mg; ≥3 y: 12–15 mg) + hydrocortisone 15 mg (triple IT with cytarabine in CNS-3) | Day 1 (or at diagnostic LP), Day 8, Day 15 (CNS-2/3: Day 22 also) |
| Consolidation | IT methotrexate ± hydrocortisone | Every 4–8 weeks per protocol; CNS-3: intensified schedule |
| Maintenance | IT methotrexate | Every 8–12 weeks throughout maintenance (total ~16–26 IT doses over treatment) |
| CNS-3 at diagnosis | Triple IT (MTX + Ara-C + hydrocortisone) twice weekly until clear, then intensified schedule. Cranial irradiation 12–18 Gy (after age 2–3 years) + IT therapy. | Intensified |
Relapsed / Refractory ALL
Relapse in ALL can occur in the bone marrow, CNS, testes, or extramedullary sites. Bone-marrow relapse carries the worst prognosis, particularly if occurring during maintenance or <18 months from diagnosis.
Relapse management principles:
- Re-induction chemotherapy with agents not used in frontline therapy or with novel agents (blinatumomab, inotuzumab, nelarabine).
- MRD assessment after re-induction to guide transplant decision.
- Allo-HSCT in second remission for all eligible patients — the only curative option after relapse.
- CAR-T cell therapy (tisagenlecleucel / brexucabtagene) — available through clinical trials and compassionate-access programmes at select Australian centres (Peter Mac, Westmead, RCH). PBS listing pending.
- Consider palliative care referral for patients not transplant-eligible with multiply-relapsed disease.
Monitoring
During Active Treatment
| Parameter | Frequency | Purpose |
|---|---|---|
| FBC with differential | Before each phase; weekly during maintenance (more often if myelosuppressive blocks) | Dose adjustment of 6-MP/MTX; infection risk; engraftment post-HSCT |
| MRD (flow cytometry / qPCR) | End of induction (Day 28–35); end of consolidation block 1; pre-transplant; any clinical concern | Risk stratification; early relapse detection; transplant decision |
| Serum asparaginase activity (ASAL) | 7 and 14 days after each PEG-asparaginase dose | Detect silent inactivation; ensure therapeutic levels (≥0.1 IU/mL) |
| LFTs, amylase, lipase | Before each PEG-asp dose; weekly during consolidation blocks | L-asparaginase hepatotoxicity and pancreatitis detection |
| Coagulation (fibrinogen, ATIII, PT/APTT) | Before each asparaginase dose; clinical suspicion of thrombosis | Thrombosis prophylaxis — cryoprecipitate for hypofibrinogenemia; ATIII concentrate if <60% |
| Serum methotrexate levels | 24, 42, 48 h post-start of HD-MTX infusion | Guide leucovorin rescue; detect delayed clearance (renal dose adjustment) |
| Echocardiogram / MUGA | Baseline; after cumulative anthracycline 150–200 mg/m²; annually if post-HSCT | Anthracycline cardiotoxicity surveillance — LVEF <50% requires cardiology review and possible anthracycline modification |
| TPMT / NUDT15 genotype | Before first 6-MP dose | Pharmacogenomics — dose reduction or alternative for poor metabolisers |
| Lumbar puncture / CNS imaging | Each IT therapy timepoint; new neurological symptoms | CNS status reassessment; early detection of CNS relapse |
| Infectious monitoring (blood cultures, CMV/EBV PCR post-HSCT) | As clinically indicated; post-HSCT: weekly viral PCRs | Febrile neutropenia management; post-HSCT viral reactivation |
Long-Term / Survivorship Follow-Up
ALL survivors require lifelong surveillance for late effects of treatment. Australian follow-up guidelines (adapted from COG LTFU and ANZCHOG recommendations) include:
- Cardiac function: echocardiogram every 1–5 years depending on cumulative anthracycline dose (lifelong if >250 mg/m²).
- Endocrine: thyroid function (especially post-cranial irradiation), growth hormone monitoring in paediatric patients, pubertal assessment.
- Neurocognitive: formal neuropsychological testing after CNS-directed therapy (IT chemotherapy, cranial irradiation), especially if learning difficulties emerge at school.
- Fertility: pre-treatment counselling for all post-pubertal patients; sperm/ovarian tissue cryopreservation where appropriate; gonadotropin monitoring post-therapy.
- Secondary malignancy: radiation-related solid tumours (thyroid, brain, breast — especially in childhood irradiation survivors); alkylator-related MDS/AML.
- Psychosocial: mental health screening, survivorship care plan, education/vocational support, transition from paediatric to adult services.
Special Populations
Pregnancy
Diagnosis
ALL diagnosed in pregnancy is rare (~1 in 75,000 pregnancies). Bone-marrow biopsy is safe. MRI (no radiation) preferred for staging. Avoid gadolinium in first trimester.
Treatment
First trimester: therapeutic termination should be discussed due to teratogenicity risk from multi-agent chemotherapy. Second/third trimester: induction therapy (vincristine, steroids, daunorubicin) can be given with careful foetal monitoring. Avoid methotrexate and 6-MP in first trimester (teratogenic). PEG-asparaginase preferred over native asparaginase. Avoid L-asparaginase in third trimester (coagulopathy risk).
Delivery
Delay chemotherapy 2–3 weeks before anticipated delivery to allow bone-marrow recovery and minimise neonatal cytopenias. Elective caesarean section for obstetric indications only — not required solely for ALL.
Paediatrics
Infants (<1 year)
KMT2A-rearranged infant ALL has the worst prognosis of any ALL subgroup (<50% EFS). Intensified chemotherapy + allo-HSCT in CR1 for most. Interfant protocols used internationally.
Children (1–9 years)
Best prognosis age group (>90% 5-year EFS for standard risk). COG/BFM-type protocols with MRD-guided risk stratification.
Adolescents (10–18 years)
Superior outcomes with paediatric-inspired vs adult-type regimens. Higher rates of T-ALL, obesity-related toxicity, and AVN (dexamethasone-associated). ANZCHOG coordinates enrolment to COG trials.
AYA (15–39 years)
Treated on paediatric-inspired protocols at most Australian centres. Higher treatment-related mortality than younger children. Fertility preservation discussion mandatory pre-treatment.
Elderly (≥60 years)
Prognosis
Significantly worse outcomes — 5-year OS <20%. Higher rate of Ph+ ALL (up to 50%), comorbidities, treatment-related mortality, and resistance.
Therapy
Reduced-intensity regimens (mini-hyper-CVD, inotuzumab-based). TKI + corticosteroids ± blinatumomab may be used as a lower-toxicity backbone for Ph+ ALL. Goal of achieving molecular remission before reduced-intensity allo-HSCT if fit.
Supportive care
Comprehensive geriatric assessment. Aggressive supportive care for TLS, infections, bleeding. Early palliative care integration for frail patients.
Renal Impairment
Methotrexate
HD-MTX contraindicated if eGFR <30 mL/min. Dose-reduce for eGFR 30–60. Extended leucovorin rescue and intensified hydration. Glucarpidase (carboxypeptidase G2) available for life-threatening MTX toxicity — not PBS-listed; compassionate access.
6-MP
Dose-reduce by 50% if eGFR <30 mL/min.
TLS prophylaxis
Rasburicase preferred over allopurinol in renal impairment with hyperuricaemia. Aggressive hydration with loop diuretics if oliguric.
Hepatic Impairment
PEG-Asparaginase
Contraindicated if severe hepatic dysfunction (bilirubin >3× ULN). Monitor LFTs closely — grade 3–4 transaminitis common but usually reversible.
Daunorubicin / Vincristine
Dose-reduce if bilirubin 3–5× ULN. Daunorubicin contraindicated if >5× ULN.
VOD risk
Pre-existing liver disease increases post-HSCT veno-occlusive disease risk. Defibrotide prophylaxis/treatment available at transplant centres.
Immunocompromised
Infection risk
ALL therapy is profoundly immunosuppressive. G-CSF (filgrastim) may be used to shorten neutropenic duration. Antimicrobial prophylaxis: co-trimoxazole (PJP), aciclovir (HSV/VZV), fluconazole (fungal — per local protocol).
Vaccination
All live vaccines contraindicated during and for 6 months after chemotherapy. Post-HSCT re-vaccination programme per ANZICS/ASID guidelines.
Post-HSCT
CMV and EBV viral monitoring (PCR weekly for 100 days). IVIg if IgG <4 g/L. PJP prophylaxis for 6–12 months post-HSCT. Donor-specific immune reconstitution monitoring.
Aboriginal and Torres Strait Islander Health Considerations
Aboriginal and Torres Strait Islander Health
Aboriginal and Torres Strait Islander children experience an equal or higher incidence of ALL compared with non-Indigenous Australian children, yet registry data consistently demonstrate significantly worse event-free and overall survival. These disparities are multifactorial and require targeted, culturally safe interventions at every stage of the patient journey.
Key resources: Cancer Australia — Optimal Care Pathway for Aboriginal and Torres Strait Islander people with cancer (2018, updated 2022). RHDAustralia clinical resources. AIHW cancer data reports with Indigenous stratification. All treating teams should have access to Aboriginal Liaison services from diagnosis.
📚 References
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