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]

Case vignette: A 35-year-old man presents with mucosal bleeding and widespread bruising. White cell count 2.8, platelets 45, fibrinogen 0.9 g/L, INR 1.8, APTT 42 seconds, D-dimer markedly elevated. Blood film shows promyelocytes with heavy granulation and Auer rods. ^[2]

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]