Haematopoietic Stem Cell Transplantation — Written Clinical Reasoning

SAQ 1 — Acute graft-versus-host disease after haploidentical stem cell transplantation (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 graft-versus-host disease — the classic triad of skin (palms, soles, ears, 60 per cent body surface area), gut (watery diarrhoea 2 litres per day) and liver (bilirubin 88 micromol per litre) involvement, presenting on day 38 after allogeneic transplant. This is at least grade II to III by the Glucksberg-Przepiorka system ^[4].
2. Possible sepsis — the patient is febrile. Neutropenic or post-engraftment fever in an immunosuppressed transplant patient mandates an empirical sepsis workup alongside the GVHD assessment; the two are not mutually exclusive.
3. Risk of fluid, electrolyte and nutritional compromise — litre-volume diarrhoea depletes fluid, potassium and magnesium and prevents oral intake.
4. Risk of opportunistic infection — the patient is on immunosuppression; CMV reactivation (currently negative), Pneumocystis, invasive fungal disease, and viral respiratory infection must be considered.
5. Psychosocial — a 47-year-old man with refractory leukaemia who has now developed the dominant complication of his curative therapy; he and his family will need honest framing.

Step 1 — Grade the acute GVHD (3 marks): ^[1]

Using the Glucksberg-Przepiorka staging system ^[4], I stage each organ: skin stage 3 (over 50 per cent body surface area with maculopapular rash), liver stage 2 (bilirubin 51 to 102 micromol per litre, here 88), gut stage 2 (diarrhoea over 1 litre per day). The combined overall grade is at least III (severe). A grade III to IV designation triggers systemic corticosteroid and a low threshold for early ruxolitinib escalation if there is no response.

Step 2 — Investigations (4 marks): ^[1]

• Confirm GVHD and exclude mimics. Skin biopsy (epithelial apoptosis with lymphocytic infiltrate supports the diagnosis, though may be non-specific); rectal or sigmoid biopsy if diarrhoea persists (epithelial apoptosis, crypt cell dropout); liver biopsy only if the diagnosis is unclear or if drug toxicity is suspected.
• Exclude infectious diarrhoea. Stool culture, Clostridioides difficile toxin assay, multiplex stool PCR for norovirus, adenovirus, Campylobacter, Salmonella, Shigella, and CMV PCR on stool or biopsy.
• Sepsis workup. Blood cultures from each lumen of the central line and peripherally; urine culture; chest X-ray.
• CMV and EBV surveillance. Whole-blood CMV PCR (repeat weekly; currently negative); EBV viral load given haploidentical transplant and antithymocyte globulin-containing prophylaxis risk for PTLD.
• Daily blood count, electrolytes including magnesium, liver function, coagulation. Monitor for transfusion needs, electrolyte depletion from diarrhoea, and hepatic dysfunction.
• Baseline chest CT if respiratory symptoms develop or if invasive fungal infection is suspected (the patient is neutropenic-immunosuppressed and on broad-spectrum antibiotics). ^[1]

Step 3 — Immediate management (5 marks): ^[1]

• Empiric antibiotics for neutropenic or immunosuppressed fever — cultures then piperacillin-tazobactam 4.5 g intravenously within one hour, with vancomycin added for line infection or haemodynamic instability. The door-to-antibiotic time matters; do not wait for consultant review or imaging.
• Systemic corticosteroid — methylprednisolone 2 mg/kg per day intravenously for grade III acute GVHD. Taper on response (typically after seven to 14 days, then wean over weeks).
• Continue and optimise GVHD prophylaxis — tacrolimus with therapeutic trough monitoring; mycophenolate may be continued or adjusted per protocol.
• Skin care — emollients, topical corticosteroid for affected areas, strict skin hygiene, surveillance for desquamation and secondary infection; consider burn-unit principles if bullous transformation occurs.
• Gut rest and nutrition — bowel rest with parenteral nutrition until diarrhoea subsides; loperamide only after infectious causes excluded; octreotide for severe secretory diarrhoea.
• Fluid and electrolyte management — aggressive intravenous replacement of water, sodium, potassium and magnesium; daily weights and strict fluid balance.
• Transfusion — red cells to haemoglobin over 80 g/L (higher if symptomatic); platelets over 20 (over 50 if bleeding or requiring procedures); irradiated blood products to prevent transfusion-associated graft-versus-host disease. ^[1]

Step 4 — Anticipate steroid-refractory disease and escalate (2 marks): ^[1]

I would define steroid-refractory disease as progression after three days or no response by day seven to 14. If this occurs, I would escalate to ruxolitinib 5 to 10 mg twice daily based on the REACH1 phase 2 trial (Jagasia, Blood 2020) and the REACH2 phase 3 randomised trial (Zeiser, NEJM 2020, PMID 32320566), which demonstrated a higher overall response rate at day 28 (62 per cent versus 39 per cent against best available therapy) ^[1]. I would consider extracorporeal photopheresis as a steroid-sparing adjunct, particularly for skin and gut disease. I would continue weekly CMV PCR surveillance (valganciclovir preemptively if it rises) and mould-active antifungal prophylaxis with posaconazole while on corticosteroid ^[6].

Step 5 — Supportive care and safety netting (1 mark): ^[1]

• Continue PJP prophylaxis with co-trimoxazole (or pentamidine if cytopenic).
• Deep vein thrombosis prophylaxis unless contraindicated.
• Stress ulcer prophylaxis while on corticosteroid.
• Skin and line site care to prevent secondary infection.
• Monitor for hyperglycaemia, hypertension, neuropsychiatric effects of corticosteroid and tacrolimus.
• Patient-controlled analgesia if mucositis or skin pain is significant. ^[1]

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

I would sit with the patient, his family and the haematology and transplant nursing team, in plain language. I would frame the acute GVHD as a serious but treatable complication of the graft-versus-leukaemia effect that was always a possibility with a haploidentical transplant. I would explain the immediate plan (high-dose corticosteroid, supportive care, close monitoring) and the escalation pathway (ruxolitinib) if the disease does not respond within the first week. I would set honest expectations: grade III acute GVHD has a real mortality (approaching 50 per cent for grade IV, lower for grade III with modern therapy), and we will be honest about his progress at each step. I would document the shared decisions and review daily as the clinical picture evolves. ^[1]