Acute Leukaemia — Viva Defence

Long Case Viva Defence

The scenario

A 64-year-old retired teacher 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. She has a background of type 2 diabetes (HbA1c 8.2 per cent on metformin and gliclazide) and ischaemic heart disease (NSTEMI 4 years ago, drug-eluting stent to the LAD, current aspirin and atorvastatin). She lives with her husband, has two adult children, and worked as a teacher until last week. Full blood count on arrival: haemoglobin 72 g/L, platelets 22, white cell count 28 with 60 per cent blasts on the film. Bone marrow aspirate shows 70 per cent myeloblasts; conventional karyotyping is in progress; a molecular panel has been requested (including FLT3, NPM1, CEBPA). Her echocardiogram shows an ejection fraction of 48 per cent. ^[1]

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 to have acute myeloid leukaemia on bone marrow. Her main problems are the leukaemia itself (the molecular profile is pending but will determine her risk group and whether midostaurin is added to induction), the immediate risk of neutropenic sepsis, her coexisting ischaemic heart disease with a borderline ejection fraction 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 family. My priorities are to control infection and transfuse to safe thresholds while completing the molecular workup, then engage the haematology multidisciplinary team and the patient in a shared decision on intensive induction versus lower-intensity therapy with venetoclax and azacitidine, weighing her comorbidity and the leukaemia's biology." ^[1]

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.
2. Marrow failure — anaemia (Hb 72), thrombocytopenia (platelets 22), neutropenia (inevitable); transfuse and treat infection.
3. Suspected neutropenic sepsis — 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 — will worsen with steroids and sepsis; sliding scale insulin during induction.
6. Psychosocial and family — shock of diagnosis; communication with husband and adult children; fertility (she is 64, post-menopausal — not relevant, but her daughters' family cancer risk and her wishes regarding resuscitation and intensive care matter).
7. Long-term — survivorship; secondary malignancy surveillance; late cardiac toxicity. ^[1]

Integrated management plan

Pillar 1 — Immediate stabilisation: "She is febrile and 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 matters. I would transfuse red cells to keep haemoglobin over 80 and platelets over 20 (over 50 if bleeding or febrile). I would assess her haemodynamic status and escalate to ICU if she is septic." ^[1]

Pillar 2 — Complete the diagnostic workup: "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. I would arrange an echocardiogram (already done — ejection fraction 48 per cent), HLA typing of the patient and any siblings in case allogeneic HSCT becomes relevant, viral serology, Group and Screen, and a baseline ECG." ^[1]

Pillar 3 — Induction — the decision: "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 probably 1 to 2 (she worked until last week), 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. E1900 established the dose-intensification benefit in younger adults; in a 64-year-old with cardiac comorbidity, 60 mg/m2 is a reasonable compromise ^[6]. The complete remission rate 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, would be intensive 7+3 with daunorubicin 60 mg/m2 if her cardiology review and exercise tolerance support it, because she is functionally fit and the curative intent is achievable. If her ejection fraction is the deciding factor or she prefers to avoid prolonged hospitalisation, venetoclax plus azacitidine is an excellent alternative." ^[1]

Pillar 4 — Post-remission, driven by ELN 2022 risk: "Once in complete remission, the consolidation strategy depends on her risk group. 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) — allogeneic HSCT in first remission if a donor is available. Intermediate-risk (FLT3-ITD, or other) — consider allogeneic HSCT, especially with MRD positivity. A major change in the 2022 ELN revision is that the FLT3-ITD allelic ratio is no longer used ^[1]."

Pillar 5 — Comorbidity: "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]

Pillar 6 — Communication and shared decision: "I would sit with her and her husband, the haematologist and a clinical nurse specialist, and explain in plain language what leukaemia is and what the immediate plan is. 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 document her preference and review as the molecular profile clarifies the prognosis." ^[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: She asks whether her daughters are at increased risk of leukaemia. How do you answer? ^[1]

A: "For the vast majority of acute myeloid leukaemia cases the answer is no — AML is sporadic, driven by acquired somatic mutations in a haematopoietic stem cell, not inherited. There are rare exceptions — a family history of a known predisposition syndrome such as familial AML with mutant CEBPA, or germline mutations in genes such as RUNX1 (familial platelet disorder with propensity to AML), GATA2, or DDX41 — but these account for only a small minority. I would take a careful family history (any haematological malignancy in first-degree relatives, especially at a young age) and, if there is a suspicious pattern, refer for genetic counselling and germline testing. For most patients the reassurance is straightforward, and I would give it clearly." ^[1]

Q: How does your management 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. If she proceeds to transplant and relapses, the discussion shifts toward clinical trials (such as TP53-directed agents) and palliative care." ^[1]

Q: How would your induction 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]

Communication and shared decision-making

"I would frame Mrs R's leukaemia as a serious but treatable diagnosis, with a clear immediate plan and a shared decision on the intensity of therapy. I would explain the two pathways in plain language, the trade-offs (curative intent with intensive therapy versus better tolerance with venetoclax), and the role of the molecular profile in refining prognosis. 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 if relevant, 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 clinical picture evolves." ^[1]