Lucan · Conditions

Acute leukaemias

Australian guidance: Optimal Care Pathways for acute leukaemia (separate documents — adult AML incl. APL, adult ALL, and paediatric/CAYA acute leukaemia — Cancer Council Victoria/Australia and Leukaemia Foundation, hosted at optimalcarepathways.com.au and cancer.org.au) + eviQ (Cancer Institute NSW) AML/ALL/APML protocols + HealthPathways WA

1. Definition and epidemiology

Acute leukaemia is a clonal malignancy of the haematopoietic stem or progenitor cell in which a block in normal differentiation allows immature blast cells to accumulate in the bone marrow, peripheral blood, and, in some cases, extramedullary sites, at the expense of normal blood cell production. The two principal categories, acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), are distinguished by the lineage of the transformed blast (myeloid versus lymphoid) and differ substantially in epidemiology, biology, and treatment, so "acute leukaemia" functions as an umbrella term for a bedside emergency-first approach rather than a single disease. ALL is predominantly a disease of childhood: it is the most common cancer diagnosed in Australian children, with a sharp incidence peak between two and five years of age, though a smaller second peak occurs in older adults, in whom the disease behaves more aggressively and carries a substantially worse prognosis. AML shows the opposite age distribution, rising steadily with age and reaching a median age at diagnosis in the mid-to-late sixties; it is the most common acute leukaemia in Australian adults, and its incidence is projected to keep rising as the population ages. Acute promyelocytic leukaemia (APML) is a distinct, cytogenetically defined subtype of AML that accounts for only a small minority of AML cases overall but is disproportionately important clinically because of its unique presentation and its near-universal risk of early death from bleeding if it is not recognised promptly.

2. Pathophysiology

The unifying pathological event in acute leukaemia is the acquisition of somatic mutations in a haematopoietic stem or early progenitor cell that simultaneously block terminal differentiation and confer a proliferative or survival advantage, producing a clonal population of blasts that expands within the marrow, suppresses normal polyclonal haematopoiesis by physical crowding and cytokine-mediated inhibition, and eventually spills into the peripheral blood. The resulting failure of normal marrow output, rather than the leukaemic mass itself, drives most of the acute morbidity of the disease. Myeloid blasts retain enough lineage-specific machinery to be identifiable on a blood film or marrow smear by Auer rods, needle-shaped cytoplasmic inclusions formed from fused, crystallised primary (azurophilic) granules; Auer rods are pathognomonic of myeloid lineage and are never seen in ALL, making them a useful bedside discriminator while formal immunophenotyping is pending.

In APML specifically, the malignant promyelocytes are typically hypergranular and often contain bundles of multiple Auer rods, described as "faggot cells," and the diagnostic lesion is the t(15;17) translocation fusing the PML and RARA genes, which produces an abnormal fusion protein that arrests myeloid differentiation at the promyelocyte stage; because this fusion protein remains responsive to pharmacological, supraphysiological doses of retinoic acid, APML is the one acute leukaemia that can be driven into differentiation and remission with a targeted, largely non-cytotoxic agent rather than conventional chemotherapy (Robbins Ch 13). Other recurrent cytogenetic and molecular lesions carry major prognostic weight across AML and ALL and increasingly define the disease entity itself under the WHO Classification of Haematolymphoid Tumours (5th edition, 2022): core-binding factor rearrangements (t(8;21), inv(16)) and mutated NPM1 without FLT3-ITD in AML are favourable; TP53 mutation and complex karyotype are adverse, whereas FLT3-ITD itself — whether with wild-type NPM1 (and no other adverse lesion) or with mutated NPM1 — is classed as intermediate-risk under the current European LeukemiaNet (ELN 2022) criteria, which dropped the earlier allelic-ratio-based stratification of FLT3-ITD altogether and no longer treats FLT3-ITD-without-NPM1 as adverse in its own right.

In ALL, the Philadelphia chromosome, t(9;22) producing the BCR-ABL1 fusion, historically conferred a very poor prognosis in adults but is now a treatable, targetable lesion with tyrosine kinase inhibitors, while hyperdiploidy is a favourable finding typical of childhood B-lineage disease.

3. Clinical presentation and diagnostic criteria

Most patients present with the direct consequences of marrow failure: fatigue, pallor, and exertional dyspnoea from anaemia; easy bruising, petechiae, and mucosal bleeding from thrombocytopenia; and fever or recurrent infection from functional neutropenia, even when the total white cell count is elevated, because circulating leukaemic blasts do not provide normal innate immune function. This marrow-failure triad, occurring together and out of proportion to any single explanation, is the classic trigger for an urgent full blood count and blood film in general practice; acute leukaemia is the diagnosis that must not be missed when anaemia coexists with unexplained bruising, bleeding, or infection rather than occurring in isolation.

Additional features reflect leukaemic infiltration of tissue beyond the marrow: bone pain (particularly prominent in childhood ALL, sometimes causing a limp or refusal to weight-bear), lymphadenopathy and hepatosplenomegaly (more typical of ALL than AML), gum hypertrophy and skin infiltration, or leukaemia cutis (more typical of monocytic AML subtypes), and central nervous system involvement with headache or cranial nerve palsies, a recognised sanctuary-site complication of ALL that shapes its treatment protocol.

Two presentations constitute genuine haematological emergencies and must be actively sought at diagnosis. Leukostasis results from marked hyperleukocytosis (very high circulating blast counts, most often above roughly 100 x 10^9/L, though it can occur at lower counts in monocytic AML) causing hyperviscosity and impaired microcirculatory flow, presenting with visual disturbance, headache, dyspnoea and hypoxia, priapism, or altered consciousness, with retinal haemorrhages on fundoscopy; it demands urgent cytoreduction and is worsened, not helped, by red cell transfusion before the blast count is lowered.

APML presents with marrow failure plus disseminated intravascular coagulation (DIC), driven by procoagulant and fibrinolytic material released from the malignant promyelocyte granules, producing a life-threatening bleeding diathesis, including intracranial haemorrhage, that can kill within hours of presentation; any blood film suggestive of APML (hypergranular promyelocytes, bundled Auer rods) is treated as APML until proven otherwise, with all-trans retinoic acid started empirically before cytogenetic confirmation returns.

4. Investigations and AU-specific cutoffs

Initial work-up combines a full blood count and blood film, looking specifically for blasts, Auer rods, and the degree of anaemia and thrombocytopenia, a coagulation screen including fibrinogen and D-dimer (mandatory whenever APML is suspected, to characterise DIC), and biochemistry to establish baseline renal function, urate, potassium, phosphate, and calcium as a tumour lysis risk assessment, since spontaneous or treatment-induced tumour lysis syndrome is a recognised complication of high-burden, rapidly proliferating disease.

Diagnosis is confirmed by bone marrow aspirate and trephine biopsy, with the WHO classification generally requiring 20 per cent or more blasts in the marrow or blood for a diagnosis of acute leukaemia, though several genetically defined AML entities, including APML and core-binding factor AML, are diagnosed by the presence of the defining lesion regardless of blast percentage. Immunophenotyping by flow cytometry is essential to assign lineage and subtype in every case: myeloid blasts typically express CD13, CD33, CD117, and myeloperoxidase, while lymphoblasts express CD19, CD22, and cytoplasmic CD79a for B-lineage disease, or cytoplasmic and later surface CD3 with CD7 for T-lineage disease, and this panel is what formally distinguishes AML from ALL when morphology alone, including the presence or absence of Auer rods, is equivocal.

Cytogenetic analysis and targeted fluorescence in situ hybridisation for t(15;17) is requested as an urgent, same-day test whenever APML is clinically suspected, because the result changes immediate management; broader cytogenetics and a molecular panel, including FLT3, NPM1, and CEBPA in AML and BCR-ABL1 in ALL, are sent in parallel to guide risk stratification and targeted therapy once the emergency has been addressed. Lumbar puncture with cerebrospinal fluid cytology is performed as part of staging in ALL, reflecting the CNS as a pharmacological sanctuary site, but is not routine in AML unless there are neurological symptoms.

In Western Australia, any blood film reported as showing blast cells, or an unexplained pancytopenia, triggers same-day discussion with the on-call haematology service per HealthPathways WA referral criteria, given the risk of an unrecognised marrow-failure emergency; nationally, eviQ (Cancer Institute NSW) is the protocol source most Australian haematology units use to standardise AML, ALL, and APML chemotherapy regimens once the diagnosis and risk category are established.

5. Management

Management begins with stabilising the emergencies identified above, in parallel with, not after, diagnostic confirmation. Suspected APML is treated with all-trans retinoic acid (ATRA) as soon as the blood film raises suspicion, without waiting for cytogenetic confirmation of t(15;17), because delay materially increases the risk of fatal haemorrhage; aggressive correction of coagulopathy with fresh frozen plasma, cryoprecipitate (to maintain fibrinogen above 1 to 1.5 g/L), and platelet transfusion runs alongside ATRA until DIC resolves. For confirmed low-to-intermediate-risk APML, the current Australian standard is a largely chemotherapy-free combination of ATRA plus arsenic trioxide, which achieves cure in the great majority of patients; high-risk APML, defined by a presenting white cell count above roughly 10 x 10^9/L, adds anthracycline-based chemotherapy to the ATRA-arsenic trioxide backbone.

Suspected leukostasis is managed with urgent cytoreduction, typically hydroxyurea or leukapheresis, with red cell transfusion deferred where possible until the blast count has been lowered, and tumour lysis prophylaxis, with aggressive intravenous hydration plus allopurinol or rasburicase in high-risk disease, is instituted before definitive chemotherapy in any patient with a high blast burden.

Outside these emergencies, treatment principles diverge by leukaemia type. Fit adults with AML receive intensive induction chemotherapy, classically cytarabine combined with an anthracycline such as daunorubicin or idarubicin (the "7+3" regimen), to achieve morphological remission, followed by consolidation chemotherapy or allogeneic haematopoietic stem cell transplantation, with the choice driven by cytogenetic-molecular risk stratification under the European LeukemiaNet criteria; FLT3-mutated AML adds a FLT3 inhibitor to induction. Older or unfit patients are increasingly managed with lower-intensity regimens, particularly venetoclax combined with a hypomethylating agent (azacitidine) or low-dose cytarabine, which has meaningfully improved outcomes for patients previously offered only palliation.

ALL is treated with prolonged, multi-agent chemotherapy delivered over induction, consolidation, and maintenance phases spanning roughly two years, with mandatory CNS-directed therapy, intrathecal chemotherapy with cranial irradiation reserved for higher-risk disease, to eradicate sanctuary-site disease; Philadelphia-positive ALL adds a tyrosine kinase inhibitor to the chemotherapy backbone, and adolescents and young adults are increasingly treated on intensified paediatric-inspired protocols shown to outperform standard adult regimens in this age group. Allogeneic transplant and, for relapsed or refractory B-lineage ALL in children and young adults, CD19-directed CAR-T cell therapy are reserved for high-risk or relapsed disease across both leukaemia types.

6. Pharmacology and AU PBS notes

ATRA (Vesanoid) and arsenic trioxide are the backbone agents for APML and are supplied through hospital pharmacy for inpatient induction; ATRA is orally administered and arsenic trioxide intravenously, with both continued through consolidation according to eviQ APML protocols. Cytarabine and the anthracyclines used in standard AML induction are hospital-supplied cytotoxic agents rather than PBS community prescriptions. Midostaurin (Rydapt) is PBS-listed for newly diagnosed FLT3-mutated AML in combination with standard induction and consolidation chemotherapy. Venetoclax (Venclexta) is PBS-listed, with streamlined authority, in combination with azacitidine or low-dose cytarabine for adults with newly diagnosed AML who are ineligible for intensive induction chemotherapy because of age or comorbidity.

Imatinib and the second-generation tyrosine kinase inhibitors (dasatinib, nilotinib) are PBS-listed for Philadelphia-positive ALL in combination with chemotherapy. Tisagenlecleucel (Kymriah), a CD19-directed CAR-T cell therapy, is funded for relapsed or refractory B-cell ALL in patients up to 25 years of age via the National Health Reform Agreement as a Highly Specialised Therapy, jointly funded by the Commonwealth and states following Medical Services Advisory Committee approval — it is not a PBS listing. Rasburicase is not PBS-listed in Australia: it returns no result on the official PBS medicine search under either the generic name or the brand Fasturtec, and carries no PBS item code or program, so it is supplied through hospital pharmacy (e.g. individual patient/hospital drug fund approval) rather than as a community or authority-required PBS benefit; allopurinol, which is PBS-listed, remains the standard prophylactic agent for lower-risk patients. Prophylactic antimicrobials, growth factor support with filgrastim, and irradiated, cytomegalovirus-safe blood products for transplant candidates are routine supportive measures throughout intensive treatment.

7. Complications and monitoring

Febrile neutropenia during the aplastic phase after induction chemotherapy is expected and is managed as a medical emergency with immediate empirical broad-spectrum intravenous antibiotics, following local Australian febrile neutropenia protocols, pending culture results; invasive fungal infection is an important cause of mortality during prolonged neutropenia and is actively screened for and treated in high-risk patients.

Differentiation syndrome, formerly called retinoic acid syndrome, is a recognised complication of ATRA and arsenic trioxide therapy in APML, presenting with fever, dyspnoea, pulmonary infiltrates, pleural or pericardial effusions, and hypotension; onset is earlier and more variable than "one to three weeks" suggests — the classic reported window is day 2 to day 21 of starting therapy, and in contemporary ATRA-plus-arsenic-trioxide regimens (the current Australian standard for low-to-intermediate-risk APML) median onset is as early as day 4 from ATRA initiation and day 2 from arsenic trioxide initiation, so clinicians should suspect it from the first days of treatment, not only after a week or more has passed. it is managed with prompt intravenous dexamethasone and, unless life-threatening, does not usually require ATRA or arsenic trioxide to be stopped.

Relapse remains the principal long-term threat across all subtypes and is monitored using measurable residual disease testing, by multiparameter flow cytometry or molecular PCR for a known fusion transcript or mutation, which has become central to treatment decisions including the timing of allogeneic transplant. Late effects of successful treatment include infertility from alkylating chemotherapy, anthracycline-related cardiotoxicity requiring periodic echocardiographic surveillance, and an increased lifetime risk of secondary malignancy; recipients of allogeneic transplant carry the additional long-term burden of graft-versus-host disease and its associated organ and infective complications.

Prognosis differs sharply by subtype and risk category: childhood ALL now achieves cure rates above 90 per cent with modern protocols in Australia, while adult ALL, and particularly older adults, fares considerably worse, although outcomes in Philadelphia-positive disease have improved substantially with tyrosine kinase inhibitors; AML prognosis is dominated by cytogenetic-molecular risk, with favourable-risk disease, such as core-binding factor rearrangements or mutated NPM1 without FLT3-ITD, achieving long-term survival in the majority of patients, and adverse-risk disease, such as complex karyotype or TP53 mutation, remaining poor despite intensive therapy; and APML, once the most rapidly fatal acute leukaemia because of DIC, now carries a cure rate above 90 per cent with prompt ATRA-based treatment, making early recognition on the blood film the single intervention that most changes this disease's outcome.

Written for Australian practice and grounded in the guidance named above. Study material only — not medical advice. Always check against current guidelines.