Acute Leukaemia — Clinical Case

DCE Long Case

Patient profile

Mrs R is a 64-year-old retired teacher who presents to the emergency department with a four-week history of progressive fatigue, easy bruising over the lower limbs, and two episodes of fever with a sore throat in the past week. [1]

Presenting concern: For four weeks she has felt increasingly tired, sleeping 12 hours a day and breathless walking up a single flight of stairs. She has noticed bruising appearing on her shins and thighs with minimal trauma, and her gums have bled when brushing her teeth. In the past week she has had two episodes of fever to 38.5 with a sore throat, treated with paracetamol at home. Her husband brought her to the emergency department this morning after she felt dizzy on standing. [1]

Past medical history: Type 2 diabetes (diagnosed age 55, current HbA1c 8.2 per cent on metformin 1000 mg twice daily and gliclazide 80 mg daily), ischaemic heart disease (NSTEMI four years ago, drug-eluting stent to the LAD, current aspirin 100 mg daily and atorvastatin 40 mg nocte), hypertension (on perindopril 5 mg daily), cholecystectomy. No prior haematological disease. Menopause at age 52. [1]

Medications: metformin 1000 mg twice daily, gliclazide 80 mg daily, aspirin 100 mg daily, atorvastatin 40 mg nocte, perindopril 5 mg daily, multivitamin. No over-the-counter or herbal products. [1]

Family history: Father with type 2 diabetes and ischaemic heart disease (died age 78 of myocardial infarction); mother with hypertension (alive, age 86); one brother with type 2 diabetes; two adult daughters, both well. No family history of haematological malignancy. [1]

Social: Retired teacher, lives with her husband (a retired engineer) in their own home. Two adult children. Independent in all activities of daily living; walked 3 km daily until the past month. Never smoker; alcohol 4 standard drinks per week. No illicit drugs. Has private health insurance. [1]

Examination:

• Alert, pale, tired-looking. Temperature 37.8. Pulse 98 regular. Blood pressure 105/65 (postural drop to 92/58 on standing). Respiratory rate 18. SpO2 96 per cent room air.
• Marked conjunctival and palmar crease pallor.
• Widespread petechiae over the lower limbs and hard palate; several 5 to 10 cm ecchymoses over the forearms and shins.
• No gum hypertrophy; mild oral candidiasis.
• No significant lymphadenopathy.
• Apex beat not displaced; heart sounds dual, no murmurs; jugular venous pressure not elevated; chest clear.
• Abdomen: a spleen tip palpable; no hepatomegaly; no masses.
• No focal neurological signs; fundoscopy shows a few flame haemorrhages; no cranial nerve palsies.
• Perianal examination: no sepsis. [1]

Investigations:

• Haemoglobin 72 g/L; MCV 96 fL; platelets 22 (low); white cell count 28 with 60 per cent blasts on the film.
• Blood film: medium to large blasts with high nuclear-to-cytoplasmic ratio, prominent nucleoli, fine chromatin; a few Auer rods noted; no promyelocyte granulation.
• INR 1.1; APTT 32 seconds; fibrinogen 2.8 g/L; D-dimer mildly elevated. (Coagulation normal — this is NOT APL.)
• Urea 8.2; creatinine 95; eGFR 56; sodium 136; potassium 4.2; corrected calcium 2.30; phosphate 1.1.
• ALT 32; ALP 110; bilirubin 14; albumin 36; LDH 980 (elevated, marker of tumour burden).
• Urate 0.55 (upper limit of normal); hepatitis B and C, HIV serology negative; CMV IgG positive.
• Group and screen: A positive; no atypical antibodies.
• Bone marrow aspirate: 70 per cent myeloblasts; flow cytometry confirms myeloid lineage (CD13, CD33, MPO positive); conventional karyotyping in progress; molecular panel requested (FLT3-ITD, FLT3-TKD, NPM1, CEBPA, IDH1, IDH2, TP53).
• Echocardiogram: ejection fraction 48 per cent; mild LV impairment; no regional wall motion abnormality; no significant valvular disease.
• ECG: sinus rhythm, rate 96; Q waves in leads V1 to V3 (old); non-specific T wave changes.
• Chest X-ray: clear lung fields; no mediastinal mass; heart size at upper limit of normal. [1]

Candidate's opening statement (SASPOP)

"This is Mrs R, a 64-year-old retired teacher presenting with a four-week history of progressive marrow failure — fatigue from anaemia, bruising from thrombocytopenia, and two febrile episodes from neutropenia — found on marrow to have acute myeloid leukaemia with myeloid-lineage blasts, awaiting molecular risk stratification. The bleeding phenotype is consistent with thrombocytopenia rather than disseminated intravascular coagulation (her fibrinogen and INR are normal, and the film shows myeloblasts with occasional Auer rods rather than promyelocytes), so this is not APL. Her main problems are the leukaemia itself (the molecular profile will determine her risk group and whether midostaurin is added), the immediate risk of neutropenic sepsis given she has already had two febrile episodes, her coexisting ischaemic heart disease with a borderline ejection fraction of 48 per cent that limits the anthracycline dose, her type 2 diabetes that will worsen with steroids and infection, and the psychosocial shock of the diagnosis on her and her husband. My priorities are to control infection and transfuse to safe thresholds, complete the molecular workup, and engage the haematology multidisciplinary team and the patient in a shared decision on intensive induction versus lower-intensity venetoclax-based therapy, weighing her comorbidity and the leukaemia's biology." [1]

Structured problem list (numbered, prioritised)

1. Newly diagnosed acute myeloid leukaemia — molecular risk pending (FLT3, NPM1, CEBPA); the risk group will drive the consolidation and transplant decision and whether midostaurin is added.
2. Marrow failure — anaemia (Hb 72), thrombocytopenia (platelets 22), neutropenia (inevitable).
3. Suspected neutropenic sepsis — she has had two febrile episodes; she must be on the neutropenic sepsis pathway immediately on the next fever.
4. Ischaemic heart disease and reduced ejection fraction (48 per cent) — limits the cumulative anthracycline dose; may push toward venetoclax-based therapy or a liposomal anthracycline.
5. Type 2 diabetes (HbA1c 8.2 per cent) — will worsen with steroids and sepsis.
6. Psychosocial and family — shock of diagnosis; communication with her husband and adult daughters; her wishes regarding resuscitation and intensive care.
7. Long-term survivorship — secondary malignancy surveillance; late cardiac toxicity; bone health. [1]

Integrated management plan

Step 1 — Immediate stabilisation: [1]

She is febrile (37.8) and likely neutropenic. I would take blood cultures from each lumen of any central line and peripherally, plus urine and sputum cultures, and give empiric piperacillin-tazobactam 4.5 g IV within one hour — the door-to-antibiotic time is a measurable survival determinant in neutropenic sepsis. I would transfuse red cells to keep haemoglobin over 80 g/L (she is symptomatic with 72) and platelets over 20 (over 50 if bleeding or febrile). I would start tumour lysis prophylaxis with aggressive intravenous hydration and allopurinol 300 mg daily (rasburicase preferred if TLS develops or if her urate was very high — it is not, so allopurinol is appropriate), with frequent electrolyte monitoring. [1]

Step 2 — Complete the diagnostic workup: [1]

The marrow has confirmed AML with myeloid lineage. I would wait for the molecular panel — FLT3-ITD and FLT3-TKD, NPM1, CEBPA, and a broader NGS panel including IDH1, IDH2, TP53, RUNX1, ASXL1. The risk group will drive the post-remission strategy and whether midostaurin is added to induction [3]. I would arrange HLA typing of the patient and her siblings in case allogeneic HSCT becomes relevant.

Step 3 — Induction — the decision: [1]

The decision between intensive 7+3 and lower-intensity venetoclax plus azacitidine is not driven by age alone but by performance status, comorbidity, and the leukaemia's biology. She is 64, ECOG 1 to 2 (she worked until last month and walked 3 km daily), but has ischaemic heart disease with an ejection fraction of 48 per cent. Two reasonable pathways: [1]

• Intensive 7+3 with daunorubicin 60 mg/m2 (rather than 90, given her cardiac history) plus cytarabine, with midostaurin added if FLT3 mutated. The E1900 trial established the dose-intensification benefit in younger adults; in a 64-year-old with cardiac comorbidity, 60 mg/m2 is a reasonable compromise [6]. Complete remission in fit adults is 70 to 80 per cent.
• Lower-intensity venetoclax plus azacitidine if her cardiac comorbidity or her preference pushes away from intensive therapy. VIALE-A showed improved complete remission (36.7 per cent) and overall survival (median 14.7 months) compared with azacitidine alone [4].

My recommendation, in discussion with the haematology MDT and cardiology, is intensive 7+3 with daunorubicin 60 mg/m2, because she is functionally fit and the curative intent is achievable, with careful cardiac monitoring and a low threshold to switch to a liposomal anthracycline or to venetoclax if her ejection fraction falls. [1]

Step 4 — Post-remission, driven by ELN 2022 risk: [1]

Once in complete remission, the consolidation strategy depends on her risk group [1]:

• Favourable-risk (isolated NPM1, or biallelic CEBPA, or core binding factor disease) — high-dose cytarabine consolidation, no allogeneic HSCT in first remission.
• Adverse-risk (TP53, complex karyotype, monosomy 5 or 7, myelodysplasia-related gene mutations) — allogeneic HSCT in first remission if a donor is available.
• Intermediate-risk (FLT3-ITD, or other) — consider allogeneic HSCT, especially with MRD positivity. [1]

A major change in the 2022 ELN revision is that the FLT3-ITD allelic ratio is no longer used; all FLT3-ITD-mutated AML is intermediate-risk regardless of the ratio [1].

Step 5 — Comorbidity: [1]

For her diabetes, I would use sliding scale insulin during induction and expect hyperglycaemia from steroids and infection — the diabetes educator and endocrine liaison would be involved. For her ischaemic heart disease, I would continue aspirin and atorvastatin and seek cardiology input on the safe cumulative anthracycline dose; if her ejection fraction falls further, I would switch to a liposomal anthracycline or proceed with venetoclax. [1]

Step 6 — Supportive care and safety netting: [1]

• Transfusion thresholds: red cells over 80 g/L (higher if symptomatic or with ischaemic heart disease); platelets over 20 (over 50 if febrile or bleeding).
• Neutropenic precautions: counsel the patient to take temperature at home, present immediately with fever, avoid crowds and sick contacts.
• Antimicrobial prophylaxis per local protocol — aciclovir, fluconazole, PJP prophylaxis during the neutropenic phase.
• Fertility is not relevant (she is post-menopausal), but her daughters' family cancer risk is a question she may ask — for the vast majority of AML the answer is no, it is sporadic. [1]

Step 7 — Communication, follow-up and safety: [1]

I would break the news with the haematologist and a clinical nurse specialist, in plain language, framing the diagnosis as serious but treatable. I would set out the two pathways honestly and document her preference. I would give written information, a named contact, and arrange follow-up at the next clinic. I would explicitly discuss her wishes regarding intensive care and resuscitation in the event of induction complications — not because we expect the worst, but because honest advance care planning is part of good practice in a patient with a serious new diagnosis and significant comorbidity. [1]

Probing questions the examiner would ask

Q: Her molecular panel returns NPM1-mutated with a co-existing FLT3-ITD. What changes? [1]

A: "Two things change. First, by ELN 2022, the presence of a FLT3-ITD places her in the intermediate-risk category regardless of the allelic ratio and regardless of the co-existing NPM1 — the NPM1 mutation is favourable only when FLT3-ITD is absent [1]. Second, I would add midostaurin 50 mg twice daily on days 8 to 21 of induction and consolidation — the RATIFY trial showed that adding midostaurin to standard chemotherapy significantly improves overall survival in FLT3-mutated AML [3]. The post-remission strategy shifts: she is now intermediate-risk, and I would discuss allogeneic HSCT in first complete remission, especially if MRD testing shows persistent NPM1 transcripts at end of induction."

Q: On day 9 of induction she develops fever 39.0, hypotension 85/50, and confusion. How do you respond? [1]

A: "This is neutropenic sepsis with septic shock — a medical emergency. I would follow the ABCDE approach: airway and breathing with high-flow oxygen, two large-bore IV cannulae (or use her central line), take cultures from each lumen of the line and peripherally, and give empiric broad-spectrum antibiotics immediately — meropenem 1 g IV (more appropriate than piperacillin-tazobactam given haemodynamic instability) plus vancomycin for line infection cover. I would give a 30 mL/kg crystalloid bolus for the hypotension and reassess, with a low threshold for noradrenaline if she does not respond. I would involve ICU early — septic shock in a neutropenic patient has a high mortality. I would not delay antibiotics for imaging or for consultant review. The Surviving Sepsis bundle — cultures and antibiotics within one hour, lactate, fluid resuscitation, vasopressors — applies in full." [1]

Q: How would your induction differ if her marrow shows a complex karyotype with a TP53 mutation? [1]

A: "Her risk group shifts to adverse-risk. The post-remission strategy is allogeneic HSCT in first complete remission if a donor is available, because the relapse risk with chemotherapy alone is very high and the graft-versus-leukaemia effect offers the only realistic chance of cure. TP53-mutated AML is challenging — it tends to be chemoresistant, the complete remission rate is lower, and even after transplant the relapse rate is high. I would set realistic expectations with her and her family: the prognosis is guarded (5-year overall survival in TP53-mutated AML is under 10 per cent in most series), and the goals of care discussion becomes important. I would not de-escalate to supportive care without her explicit choice, but I would make sure she understands the trade-offs." [1]

Q: How would your management differ if she were 84 rather than 64, frail, and living in supported accommodation? [1]

A: "The decision would shift toward lower-intensity therapy with venetoclax plus azacitidine, or toward best supportive care with transfusion alone, depending on her wishes and her overall trajectory. VIALE-A included patients up to the mid-80s and showed benefit for the combination, but the toxicity (cytopenias, infections) is real in the very elderly. I would assess her with a Comprehensive Geriatric Assessment where available, discuss the options honestly with her and her family, and respect her choice. For some frail patients, supportive care with transfusion, antibiotics for infection, and palliative care input is the most appropriate plan — it is not a failure of medicine but an honest alignment of therapy with the patient's goals." [1]

Q: Six months later she is in complete remission after intensive induction and consolidation. She asks about her long-term outlook and follow-up. What do you tell her? [1]

A: "I would frame the prognosis honestly. For favourable-risk AML in a fit adult, 5-year overall survival is over 60 per cent with modern therapy; for intermediate-risk it is around 40 to 50 per cent; for adverse-risk it is under 10 per cent. Her individual prognosis depends on her molecular risk group, her MRD status at end of induction, and her tolerance of the consolidation. Long-term follow-up involves surveillance for relapse (regular blood counts), monitoring of cardiac function (echocardiogram, because of the anthracycline), bone health (DEXA if on steroids), secondary malignancy surveillance (treatment-related MDS and AML can occur years later), and attention to psychosocial recovery — a leukaemia diagnosis and treatment affect every domain of life. I would offer her the haematology late-effects service and a primary care plan for shared surveillance." [1]

Communication and shared decision-making

"I would sit with Mrs R and her husband in a quiet room, with the haematologist and a clinical nurse specialist. I would explain in plain language what leukaemia is — a cancer of the blood-forming cells of the marrow — and what the immediate plan is. I would acknowledge the shock explicitly and give them space. I would set out the two pathways honestly — intensive therapy with curative intent but with a 4 to 6 week hospital stay and a real risk of induction mortality (perhaps 10 to 15 per cent in a 64-year-old with comorbidity), versus lower-intensity therapy with venetoclax that is better tolerated but with a less certain cure. I would address her anxiety about her heart directly — that the anthracycline dose is adjusted, that cardiology is involved, and that we will monitor her heart function closely. I would discuss contraception (not relevant — she is post-menopausal), the impact on her and her husband's life, and the practicalities of a prolonged hospital admission. I would document the shared decision and review it as the molecular profile clarifies the prognosis. I would also, sensitively, ask about her wishes regarding intensive care in the event of induction complications — not because we expect the worst, but because honest advance care planning is part of good practice." [1]

DCE Short Case — General Systems Examination in Acute Leukaemia

Instruction

"Examine this patient's general systems." [1]

Systematic examination routine

1. End of bed — observe for pallor, bruising, body habitus, lethargy. Note any oxygen, lines, or monitoring.
2. Hands — pallor of the palmar creases and conjunctivae; bruising and petechiae (distribution, size); splinter haemorrhages; nail-bed infarcts; peripheral cyanosis.
3. Pulse and haemodynamics — tachycardia of anaemia or sepsis; irregularly irregular of atrial fibrillation.
4. Face and mouth — conjunctival pallor; gum hypertrophy (monocytic AML); oral candidiasis, herpetic ulceration, mucositis; petechiae on the hard palate; dental sepsis.
5. Skin — leukaemia cutis (violaceous nodules, monocytic AML); bruising and ecchymoses; line insertion sites; perianal examination for sepsis.
6. Lymph nodes — cervical, axillary, supraclavicular, epitrochlear, inguinal.
7. Chest — signs of pneumonia; signs of a mediastinal mass (SVC obstruction in T-ALL).
8. Abdomen — hepatosplenomegaly (more prominent in ALL, chronic leukaemia, lymphoma; mild in AML); masses; ascites.
9. Nervous system — cranial nerves (facial nerve palsy — CNS leukaemia); fundoscopy (retinal haemorrhages); meningism.
10. Testes — in male patients with ALL, examine the testes (a sanctuary site). [1]

Key physical signs the patient demonstrates (for this case)

• Marked conjunctival and palmar pallor
• Widespread petechiae on the lower limbs and hard palate, with several large ecchymoses on the arms
• A spleen tip palpable; no hepatomegaly
• No significant lymphadenopathy
• No gum hypertrophy (which would point to monocytic AML)
• Fundoscopy shows a few flame haemorrhages [1]

Presentation template

"I examined Mrs R, a 64-year-old woman who looks pale and tired at the end of the bed. She has widespread petechiae over the lower limbs and hard palate and several large ecchymoses on the arms. There is marked conjunctival and palmar crease pallor. The pulse is regular at 96, blood pressure 110/70. There is no lymphadenopathy. The mouth shows no gum hypertrophy but there is mild oral candidiasis. The chest is clear. The abdomen reveals a spleen tip palpable, no hepatomegaly. Fundoscopy shows a few flame haemorrhages. There are no focal neurological signs. These findings are consistent with marrow failure — anaemia, thrombocytopenia with mucosal and skin bleeding — and mild splenomegaly. In a patient with circulating blasts, this picture is consistent with acute myeloid leukaemia. I would specifically ask whether acute promyelocytic leukaemia has been excluded given the bleeding tendency, because APL requires immediate ATRA, and I would examine the blood film for promyelocytes with Auer rods — in this patient the film shows myeloblasts with occasional Auer rods and no promyelocyte granulation, and the coagulation profile is normal, so APL is excluded." [1]

Discussion questions

Q: What is the significance of gum hypertrophy in acute leukaemia? [1]

A: "Gum hypertrophy is a sign of monocytic differentiation in AML — the M4 (myelomonocytic) and M5 (monoblastic) subtypes. The gums are swollen, boggy and bleeding, and the leukaemic monocytic precursors infiltrate the gingival tissue. It is a high-yield bedside sign for monocytic AML and is essentially never seen in ALL or in non-monocytic AML. I would specifically look for it in any new leukaemia presentation because it points to the subtype and because monocytic AML is more commonly associated with extramedullary disease (skin, CNS, gums) and with specific cytogenetics such as 11q23 KMT2A rearrangements." [1]

Q: How would you distinguish AML from ALL at the bedside? [1]

A: "The bedside discriminators are limited — the diagnosis is made on marrow morphology, immunophenotyping and cytogenetics. But there are clues. AML is more common in adults (median age 65) and tends to present with marrow failure alone, sometimes with gum or skin infiltration in monocytic subtypes. ALL is more common in children and young adults and tends to present with more prominent lymphadenopathy, hepatosplenomegaly, a mediastinal mass (T-ALL), bone pain, and occasionally CNS disease. Auer rods on the blood film are pathognomonic for AML. The definitive discrimination is flow cytometry of the marrow — myeloid markers (CD13, CD33, MPO) for AML; lymphoid markers (CD19, CD22, CD79a, CD3) for ALL." [1]

Q: What signs would make you concerned about leucostasis in a patient with acute leukaemia? [1]

A: "Leucostasis occurs with very high white cell counts (typically over 100 in AML) when the blasts plug the microcirculation. The clinical features are confusion, visual disturbance (retinal vein distension, papilloedema, retinal haemorrhages on fundoscopy), dyspnoea and pulmonary infiltrates, chest pain from myocardial ischaemia, and priapism in males. This is an emergency — the treatment is urgent cytoreduction with hydroxyurea and/or leucapheresis, plus aggressive hydration and tumour lysis prophylaxis. Leucapheresis is most useful in AML with leucostasis because the myeloblasts are larger and more rigid than lymphoid cells." [1]

Q: How would you counsel a patient about the side effects of daunorubicin before induction? [1]

A: "I would explain the three main concerns. First, alopecia — universal and temporary, regrows after completion. Second, nausea and mucositis — managed with antiemetics and mouth care; the mucositis can be severe and is a portal for infection. Third, and most importantly, cardiotoxicity — daunorubicin is an anthracycline that causes cumulative dose-dependent cardiac damage, with a lifetime cumulative dose limit (around 400 to 550 mg/m2 for daunorubicin). I would explain that we measure her cardiac function before starting and after each cycle, that the risk is small at the doses used in standard induction (cumulative 180 mg/m2 for 7+3), and that we adjust the dose or switch agents if her ejection fraction falls. The risk is higher in patients with pre-existing heart disease — as in this patient — which is why cardiology review and echocardiography are part of her workup." [1]

Q: What is the role of irradiated blood products in acute leukaemia, and which patients need them? [1]

A: "Irradiated blood products prevent transfusion-associated graft-versus-host disease (TA-GVHD), a rare but almost universally fatal complication in which donor T-lymphocytes in the transfused product engraft in the recipient and attack host tissues. The patients who need irradiated products are those with profound immunosuppression — patients who will have, are having, or have had allogeneic stem cell transplant; patients treated with purine analogues (fludarabine, cladribine); patients with Hodgkin lymphoma; and patients on certain immunosuppressive biologics. For a patient receiving standard 7+3 induction without those indications, irradiated products are not strictly required, but many haematology units use them for all leukaemia patients as a precaution. CMV-negative products are given to CMV-negative patients who are candidates for allogeneic transplant, to prevent CMV transmission." [1]