Acute Leukaemia — Written Clinical Reasoning

SAQ 1 — Acute Promyelocytic Leukaemia presenting as a bleeding emergency (20 marks, 30 minutes)

Prompt: Outline your immediate assessment, the investigations you would order, your integrated management plan addressing each problem, and the shared decision-making framework. Justify each decision with reference to evidence. [1]

Model Answer

Problem list (4 marks): [1]

1. Acute promyelocytic leukaemia (APL) — the morphology (promyelocytes with heavy granulation and Auer rods) combined with the DIC picture (low fibrinogen, prolonged INR and APTT, elevated D-dimer) is diagnostic, pending PML-RARA confirmation.
2. Life-threatening coagulopathy — disseminated intravascular coagulation with hyperfibrinolysis; the dominant immediate risk is haemorrhagic death (cerebral or pulmonary).
3. Marrow failure — anaemia and thrombocytopenia contributing to bleeding; neutropenia not yet evident but inevitable with induction.
4. Tumour lysis risk — moderate, given the white cell count is not high, but rises with induction.
5. Psychosocial — a 35-year-old with a new leukaemia diagnosis; shock; fertility; family. [1]

Step 1 — Immediate actions on suspicion of APL (5 marks): [1]

The single most important action is to start all-trans retinoic acid (ATRA) immediately, without waiting for cytogenetic or molecular confirmation. The rationale is that APL's principal early danger is haemorrhagic death from DIC, and ATRA reverses the differentiation block and the coagulopathy. The Lo-Coco trial established ATRA plus arsenic trioxide as the curative, chemotherapy-free regimen for low-to-intermediate risk APL [2]. ATRA is dosed at 45 mg/m2 per day in divided doses.

In parallel I would: [1]

• Send urgent PML-RARA testing (FISH or RT-PCR) to confirm the diagnosis.
• Correct the coagulopathy aggressively: keep platelets over 30 to 50 (target over 50 given active bleeding), fibrinogen over 1.5 g/L using cryoprecipitate (each unit raises fibrinogen by about 0.5 g/L), and INR and APTT near normal with fresh frozen plasma. Transfuse red cells to haemoglobin over 80 g/L.
• Avoid invasive procedures — no intramuscular injections, no arterial lines unless essential, no lumbar puncture until the coagulopathy is corrected.
• Admit to a monitored bed (high-dependency or ICU depending on severity) and involve haematology, transfusion and intensive care as a single team.
• Counsel the patient in plain language that we are starting treatment for a specific, highly curable form of leukaemia while we confirm the diagnosis. [1]

Step 2 — Risk stratify and complete the workup (3 marks): [1]

Once the diagnosis is confirmed, I would risk-stratify using the Sanz classification, based on the initial white cell count and platelet count: [1]

• Low / intermediate risk (white cell count up to 10) — the patient here, given his white cell count is 2.8 — treated with ATRA plus arsenic trioxide, chemotherapy-free.
• High risk (white cell count over 10) — treated with ATRA plus arsenic plus an anthracycline-based chemotherapy (e.g. idarubicin). [1]

I would complete the workup with a bone marrow aspirate and trephine (morphology, flow cytometry, conventional karyotyping for t(15;17), FISH for PML-RARA, and a molecular panel for concurrent mutations such as FLT3), an echocardiogram (baseline before any anthracycline), viral serology (HIV, HBV, HCV, CMV), Group and Screen, and HLA typing of the patient and siblings (a precaution in case of relapse). [1]

Step 3 — Definitive therapy (3 marks): [1]

For this low-intermediate risk patient, I would proceed with ATRA plus arsenic trioxide as the induction, per the Lo-Coco protocol [2]. This achieves complete remission in essentially all evaluable patients with a 2-year event-free survival of 97 per cent, without the haematologic toxicity of chemotherapy. Consolidation and maintenance follow the protocol. The expected outcome is long-term cure in 80 to 90 per cent of patients — APL is now the most curable form of adult AML.

Step 4 — Anticipate and manage differentiation syndrome (2 marks): [1]

I would specifically watch for differentiation syndrome (formerly retinoic acid syndrome) over the first 3 weeks — fever, dyspnoea, pulmonary infiltrates, weight gain, pleural or pericardial effusion, hypotension and renal failure, caused by cytokine release as the leukaemic promyelocytes differentiate. The treatment is immediate dexamethasone 10 mg intravenously twice daily, started on clinical suspicion rather than waiting for confirmation [5]. ATRA or arsenic is held only if severe. Supportive care includes oxygen, diuresis and ventilatory support as needed.

Step 5 — Supportive care and safety netting (2 marks): [1]

• Tumour lysis prophylaxis — aggressive intravenous hydration and allopurinol, with frequent electrolyte monitoring (potassium, phosphate, calcium, creatinine, urate every 4 to 6 hours) for the first 48 hours.
• Transfusion thresholds — red cells over 80 g/L (higher if symptomatic or bleeding); platelets over 50 while bleeding and over 30 thereafter.
• Irradiated blood products are not required for APL-specific therapy but would be if allogeneic transplant or purine analogue therapy were used.
• Neutropenic precautions — counsel the patient to take temperature at home, present immediately with fever, avoid crowds and sick contacts. [1]

Step 6 — Communication, fertility and shared decision-making (1 mark): [1]

I would break the news with the haematologist and a clinical nurse specialist, in plain language, framing APL as a highly curable form of leukaemia but acknowledging the immediate bleeding risk. I would discuss fertility preservation before any chemotherapy (this patient is not receiving chemotherapy, but the discussion is relevant for future contingencies). I would document the shared decision, give written information and a named contact, and arrange follow-up at the next clinic. [1]

SAQ 2 — Risk-stratified management of newly diagnosed AML in a 55-year-old fit man (10 marks, 20 minutes)

Prompt: A 55-year-old man presents with fatigue and bruising. Marrow shows 50 per cent myeloblasts with a normal karyotype. Molecular testing shows an NPM1 mutation with no FLT3-ITD and no adverse cytogenetic or molecular abnormality (biallelic CEBPA not tested, but not relevant given the NPM1). He is fit with an ECOG performance status of 0. Outline your induction and post-remission strategy and justify with the ELN 2022 framework and the relevant trials. [1]

Model Answer

Step 1 — Confirm the risk group (2 marks): [1]

By the 2022 European LeukemiaNet recommendations, NPM1-mutated AML in the absence of FLT3-ITD and without adverse-risk cytogenetic or molecular abnormalities is classified as favourable risk [1]. A key change from the 2017 ELN classification is that the FLT3-ITD allelic ratio is no longer used; the co-existence of any FLT3-ITD with NPM1 would shift the patient to intermediate risk. With isolated NPM1 and normal karyotype, this patient is favourable-risk.

Step 2 — Induction (3 marks): [1]

Standard induction for a fit younger adult is 7+3 — cytarabine 100 mg/m2 per day by continuous infusion for 7 days plus daunorubicin 60 mg/m2 per day for 3 days (the E1900 trial established that daunorubicin 90 mg/m2 improves complete remission and overall survival versus 45 mg/m2 in younger adults; many units use 60 to 90 depending on protocol and age). The target is complete remission (marrow blasts below 5 per cent, neutrophils at least 1.0, platelets at least 100). Given his favourable-risk NPM1 disease, no targeted addition (midostaurin, gemtuzumab) is strictly required, though gemtuzumab ozogamicin (an anti-CD33 antibody-drug conjugate) is often added based on the ALFA-0701 trial. FLT3 status must be confirmed at diagnosis before induction because midostaurin improves survival in FLT3-mutated disease (RATIFY) [3].

Step 3 — Consolidation and the transplant decision (3 marks): [1]

For favourable-risk AML in first complete remission, the standard is high-dose cytarabine consolidation (typically 3 to 4 cycles), with no allogeneic stem cell transplant in first remission — the relapse risk is low enough and the transplant-related mortality high enough that consolidation chemotherapy is superior. Allogeneic HSCT is reserved for relapse. [1]

I would monitor with measurable residual disease (MRD) testing — molecular RT-PCR for NPM1 at the end of induction and at consolidation milestones. Persistent or rising NPM1 transcripts are an early warning of relapse and would prompt consideration of allogeneic HSCT, even in nominally favourable-risk disease. MRD kinetics now guide consolidation intensity in the ELN 2022 framework [1].

Step 4 — Prognosis and communication (2 marks): [1]

I would frame the prognosis honestly — 5-year overall survival for favourable-risk AML in a fit younger adult is over 60 per cent with modern therapy. I would discuss fertility preservation before induction if he has not completed his family. I would explain the induction course (4 to 6 weeks in hospital, with neutropenic sepsis as the principal risk), the consolidation phase, and the long-term survivorship plan including late cardiac toxicity (anthracycline cumulative dose) and secondary malignancy surveillance. [1]

Step 3 — The principle: the ELN 2022 framework converts molecular and cytogenetic data into a risk group that drives consolidation — favourable risk gets chemotherapy, adverse risk gets allogeneic transplant in first remission, intermediate risk is a balanced decision informed by MRD. The registrar's job is to ensure the molecular panel is complete and the risk group is correctly assigned. [1]