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]

SAQ 2 — Veno-occlusive disease in the early post-transplant phase (10 marks, 20 minutes)

Prompt: A 54-year-old man underwent myeloablative allogeneic transplantation from a matched sibling donor for acute myeloid leukaemia, conditioned with busulfan plus cyclophosphamide. On day 16 he develops right upper quadrant tenderness, a weight gain of 7 per cent over six days, and a bilirubin that has risen from 18 to 95 micromol per litre. Coagulation is normal. He is oliguric with a creatinine that has risen from 85 to 165. Outline your diagnosis, the criteria you would apply, the differential you would exclude, and your management plan with evidence. [1]

Model Answer

Step 1 — The diagnosis (2 marks): [1]

The combination of weight gain over 5 per cent, tender hepatomegaly (right upper quadrant tenderness) and hyperbilirubinaemia over 34 micromol per litre within 21 days of conditioning, with ascites and renal impairment, is classic for veno-occlusive disease (now termed sinusoidal obstruction syndrome, SOS). [1]

Step 2 — Apply the criteria (2 marks): [1]

The modified Seattle criteria require bilirubin over 34 micromol per litre plus two of hepatomegaly, ascites and weight gain of at least 5 per cent, occurring within 21 days of transplant. The Baltimore criteria require bilirubin over 34 plus at least two of hepatomegaly, ascites and weight gain of at least 5 per cent. This patient satisfies both: he has weight gain of 7 per cent, tender hepatomegaly, ascites and bilirubin of 95 micromol per litre by day 16. The renal impairment raises concern for progression to multiorgan failure, the severe form of SOS. [1]

Step 3 — Exclude the differential (2 marks): [1]

I would exclude:

• Sepsis-related cholestasis — blood cultures, sepsis workup.
• Acute GVHD of the liver — usually later (after engraftment) and usually with skin or gut involvement; his bilirubin is rising without rash or diarrhoea.
• Drug hepatotoxicity — review cyclosporine or tacrolimus level, antibiotics, antifungals, total parenteral nutrition.
• Biliary disease — abdominal ultrasound for stones, sludge, biliary dilatation.
• Viral hepatitis — hepatitis B and C reactivation, adenovirus, HSV; viral PCR. [1]

Step 4 — Management (3 marks): [1]

• Supportive care: fluid and sodium restriction, analgesia, correction of coagulopathy (cautiously, avoiding over-transfusion that worsens volume overload), renal and respiratory support, paracentesis for tense ascites, and early nephrology and critical care liaison.
• Defibrotide 6.25 mg/kg intravenously every six hours for at least 21 days — the only agent with proven benefit in severe SOS with multiorgan failure. The phase 3 trial (Richardson, Blood 2016, PMID 26825712) showed improved day 100 survival of 38 per cent versus 25 per cent against historical controls [3].
• Renal dose adjustment and close monitoring; haemofiltration if required.
• Continued transplant supportive care — antimicrobial prophylaxis, transfusion (irradiated products), nutrition.

The principle: early recognition by daily application of the modified Seattle or Baltimore criteria in the first three weeks of transplant changes outcome. A registrar who attributes jaundice and weight gain to "drug" or "sepsis" without applying the criteria will miss the window for defibrotide, which is most effective when started before multiorgan failure is established. [1]