Haematopoietic Stem Cell Transplantation — Clinical Case

DCE Long Case

Patient profile

Mr D is a 52-year-old schoolteacher who underwent haploidentical stem cell transplantation from his daughter two years ago for acute myeloid leukaemia in second complete remission. He is reviewed in the late-effects clinic with three months of progressive exertional dyspnoea, fatigue and dry cough. [1]

Presenting concern: Over the past three months Mr D has noticed increasing breathlessness walking up a single flight of stairs (previously he could manage three flights), a persistent dry cough worse on exertion, and fatigue. He has not had fevers, night sweats, haemoptysis, chest pain or orthopnoea. He also reports worsening of his long-standing dry eyes and dry mouth, oral discomfort on eating spicy food, tightening of the skin over his forearms and shins that has reduced his elbow extension, and erectile dysfunction that has emerged over the past six months. His wife mentions he has become withdrawn and has stopped socialising with friends. [1]

Past medical history: Acute myeloid leukaemia, diagnosed three years ago, treated with 7+3 induction then reinduction for a first relapse, followed by haploidentical stem cell transplantation from his daughter two years ago. Chronic graft-versus-host disease diagnosed at eight months post-transplant (sclerotic and lichenoid subtype, affecting skin, oral mucosa, eyes, oesophagus). Steroid-refractory at 12 months; ruxolitinib added. Hypothyroidism (one year post-transplant). Two episodes of CMV reactivation, treated with valganciclovir. Diet-controlled type 2 diabetes (BMI 31). Appendicectomy at age 20. [1]

Transplant details: Reduced-intensity conditioning with fludarabine plus melphalan (given his BMI and diabetes), GVHD prophylaxis with post-transplant cyclophosphamide 50 mg/kg on days 3 and 4, tacrolimus and mycophenolate. Engrafted on day 18. Full donor chimerism at day 28. Grade II acute skin GVHD at day 35, resolved with topical steroid and short oral prednisolone course. [1]

Medications: Prednisolone 10 mg daily, ruxolitinib 10 mg twice daily, tacrolimus 1 mg twice daily, aciclovir 400 mg twice daily, co-trimoxazole 480 mg daily, posaconazole 300 mg daily (delayed release), penicillin V 500 mg twice daily, thyroxine 100 micrograms daily, topical tacrolimus 0.1 per cent ointment to forearms, clobetasol oral rinse, artificial tears hourly, sildenafil 50 mg as required (unsuccessful). No over-the-counter or herbal products. [1]

Family history: Father with type 2 diabetes (died age 75 of myocardial infarction); mother alive and well at age 78; one daughter (the stem cell donor, age 28, well); one son age 26. No family history of haematological malignancy. [1]

Social: Schoolteacher, currently on reduced duties due to fatigue; lives with his wife (a nurse) in their own home. Walked 5 km daily until six months ago; now limited to 500 metres by breathlessness. Never smoker; alcohol 6 standard drinks per week. Married 27 years; two adult children. [1]

Examination:

• Alert, thin, withdrawn. Temperature 36.8. Pulse 84 regular. Blood pressure 128/78. Respiratory rate 22. SpO2 94 per cent room air at rest, dropping to 89 per cent on walking 50 metres.
• Sclerotic, hidebound skin over forearms and shins with reduced pinchability; lichenoid violaceous plaques at the wrists; poikiloderma over the dorsal hands; patchy scalp alopecia.
• Fingernails show longitudinal ridging and early pterygium.
• Oral cavity: lichenoid white striae on buccal mucosa and lateral tongue; dry furrowed tongue; accelerated dental caries; mouth opening two finger-breadths (microstomia).
• Elbow extension limited to 20 degrees short of full extension bilaterally, due to skin tightness.
• Eyes: dry with conjunctival injection; Schirmer test 4 mm at five minutes (normal over 10).
• Respiratory: chest clear to auscultation; no wheeze; vesicular breath sounds; no consolidation. Slight expiratory prolongation.
• Cardiovascular: jugular venous pressure not elevated; heart sounds dual; no murmurs; no peripheral oedema.
• Abdomen: soft, non-tender; no hepatosplenomegaly.
• Neurological: no focal deficits; cognition intact; mood flat. [1]

Investigations:

• Haemoglobin 118 g/L; MCV 92 fL; white cell count 6.4 (neutrophils 4.2, lymphocytes 1.6); platelets 180.
• Sodium 138; potassium 4.1; creatinine 92; eGFR 82; corrected calcium 2.32; albumin 38.
• ALT 34; ALP 120; bilirubin 12; LDH 220.
• Thyroid stimulating hormone 3.1 milliunits per litre (within range on thyroxine).
• Random blood glucose 9.2; HbA1c 7.1 per cent.
• Morning testosterone 6.5 nanomoles per litre (low; reference 8 to 30).
• CMV PCR undetectable; EBV viral load low positive (under threshold for intervention).
• Spirometry: FEV1 1.85 litres (52 per cent predicted); FVC 3.0 litres (78 per cent predicted); FEV1/FVC ratio 0.62; no bronchodilator response.
• Lung diffusion capacity (DLCO) 55 per cent predicted (corrected for haemoglobin).
• Chest CT (inspiratory and expiratory): mosaic attenuation with air trapping on expiratory images; no consolidation, no nodules, no pleural disease; no mediastinal lymphadenopathy.
• Echocardiogram: ejection fraction 58 per cent; no valvular disease; estimated right ventricular systolic pressure 28 mmHg.
• DEXA: T-score minus 2.3 at the lumbar spine (osteoporosis); minus 1.6 at the femoral neck (osteopenia). [1]

Candidate's opening statement (SASPOP)

"This is Mr D, a 52-year-old schoolteacher presenting two years after a haploidentical stem cell transplant from his daughter for relapsed acute myeloid leukaemia, with active chronic graft-versus-host disease affecting skin, mouth, eyes and oesophagus, now complicated by progressive exertional dyspnoea with an obstructive defect on spirometry and mosaic attenuation on CT — consistent with bronchiolitis obliterans, a pulmonary manifestation of chronic GVHD. His main problems are the chronic GVHD itself (steroid-refractory, on ruxolitinib and low-dose prednisolone), the newly diagnosed bronchiolitis obliterans which is a high-risk manifestation requiring urgent intensification of immunosuppression before the obstruction becomes fixed, the cumulative late effects of his transplant and chronic immunosuppression (hypothyroidism, hypogonadism with erectile dysfunction, osteoporosis, poorly controlled diabetes), the need for continued infection prophylaxis and malignancy surveillance, and the significant psychosocial impact on him and his wife. My priorities are to intensify immunosuppression for the bronchiolitis obliterans in conjunction with his haematology and respiratory team, to address his late effects and metabolic control in a survivorship framework, and to support his psychosocial and sexual health." [1]

Structured problem list (numbered, prioritised)

1. Bronchiolitis obliterans from chronic GVHD — new diagnosis, with FEV1 52 per cent predicted, obstructive defect, mosaic attenuation; high risk of progression to fixed obstruction and respiratory failure if not treated promptly.
2. Active chronic graft-versus-host disease — sclerotic and lichenoid subtype, steroid-refractory, currently on ruxolitinib 10 mg twice daily and prednisolone 10 mg daily; requires optimisation and multidisciplinary supportive care.
3. Hypogonadism and erectile dysfunction — low morning testosterone, unsuccessful sildenafil; affecting quality of life and relationships.
4. Osteoporosis — T-score minus 2.3 at the lumbar spine, on chronic corticosteroid; risk of fragility fracture and avascular necrosis.
5. Type 2 diabetes with suboptimal control — HbA1c 7.1 per cent on no medication; worsened by chronic corticosteroid.
6. Infection prophylaxis and surveillance — continued co-trimoxazole, aciclovir, posaconazole, penicillin V; CMV and EBV surveillance; vaccination status.
7. Secondary malignancy surveillance — skin, thyroid, oral cavity; EBV-driven PTLD surveillance.
8. Psychosocial and sexual health — withdrawal, erectile dysfunction, reduced work capacity, impact on his marriage. [1]

Integrated management plan

Step 1 — Bronchiolitis obliterans (the priority): [1]

The combination of progressive exertional dyspnoea, an obstructive defect on spirometry (FEV1 52 per cent predicted, FEV1/FVC ratio 0.62, no bronchodilator response) and mosaic attenuation with air trapping on CT is diagnostic of bronchiolitis obliterans, a pulmonary manifestation of chronic GVHD. The histological changes are often irreversible by the time of diagnosis, so the priority is to intensify immunosuppression before the obstruction becomes fixed. I would: [1]

• Intensify immunosuppression in conjunction with his haematology team. I would increase ruxolitinib to 15 mg twice daily if cytopenias permit (supported by the REACH3 trial for chronic GVHD, Zeiser, NEJM 2021, PMID 34260836) [1], and maintain or modestly increase prednisolone to 0.5 mg/kg per day (around 30 mg daily) with a weaning plan once respiratory function stabilises.
• Consider extracorporeal photopheresis as a steroid-sparing adjunct with a favourable infection profile.
• Refer to respiratory and physiotherapy for pulmonary rehabilitation, inhaled bronchodilators (limited benefit but may help symptomatically), and oxygen assessment. I would assess for home oxygen if his resting saturation drops below 88 per cent or if he has exertional desaturation limiting function.
• Maintain and intensify infection prophylaxis — co-trimoxazole for PJP, posaconazole for mould (given intensification of immunosuppression) [5], aciclovir for HSV and VZV, penicillin V for encapsulated bacteria. Weekly CMV PCR given his prior reactivations and the intensified immunosuppression.
• Continue surveillance with serial spirometry every four to eight weeks, respiratory symptom review, and chest CT if there is clinical deterioration.
• Set realistic expectations — bronchiolitis obliterans carries a significant mortality, often progresses despite intensification, and some patients progress to respiratory failure. Lung transplantation is a consideration in selected patients with end-stage disease.

Step 2 — Chronic GVHD optimisation: [1]

• Multidisciplinary chronic GVHD clinic: dermatology (topical corticosteroids, phototherapy, skin care and surveillance), ophthalmology (ciclosporin eye drops, punctal plugs, serum eye drops for severe sicca), dentistry (preventive care for xerostomia-related caries), gastroenterology (oesophageal dilation for the web), physiotherapy and occupational therapy (joint range of motion, contracture prevention).
• Pharmacological optimisation: I would discuss with haematology whether ruxolitinib dose escalation (to 15 mg twice daily) is appropriate given his cytopenias; consider adding or alternating extracorporeal photopheresis; keep tacrolimus at a low dose; maintain prednisolone at the minimum effective dose (currently 10 mg daily) with bone and metabolic protection.
• Functional and quality of life measures: assess for contracture progression, microstomia affecting nutrition, and sicca affecting vision and oral intake. [1]

Step 3 — Late effects and survivorship: [1]

• Hypogonadism and erectile dysfunction: I would confirm with a repeat morning testosterone and gonadotropins (his level of 6.5 nmol/L with likely elevated gonadotropins indicates primary gonadal failure from conditioning), discuss testosterone replacement (after counselling on cardiovascular and prostatic implications, given his elevated cardiovascular risk and family history), and involve a sexual health or urology service if first-line measures fail.
• Osteoporosis: I would start a bisphosphonate (alendronate 70 mg weekly or zoledronic acid 5 mg annually) with calcium and vitamin D supplementation, given his T-score of minus 2.3 and chronic corticosteroid exposure. I would arrange a DEXA annually and assess for avascular necrosis (hip and shoulder MRI) if he develops new joint pain.
• Diabetes: I would optimise glycaemic control (HbA1c 7.1 per cent) with metformin given his BMI and preserved eGFR, titrated to target, and consider a GLP-1 receptor agonist or SGLT2 inhibitor for cardiovascular protection and weight management. The corticosteroid will continue to challenge this, and sliding scale or basal insulin may be required during exacerbations.
• Cardiovascular risk: I would assess and modify his risk factors — blood pressure, lipids, glycaemic control, weight, activity — given that transplant survivors are a high-risk group. [1]

Step 4 — Infection prophylaxis and vaccination: [1]

• Continue co-trimoxazole (PJP), posaconazole (mould), aciclovir (HSV, VZV) and penicillin V (encapsulated bacteria) for as long as he is on immunosuppression or has active chronic GVHD.
• Weekly CMV PCR; monthly EBV viral load; prompt investigation of any fever or new symptom.
• Inactivated vaccines annually (influenza, pneumococcal, COVID); ensure hepatitis B, tetanus and Haemophilus influenzae are up to date.
• Live vaccines (MMR, varicella) are contraindicated while on immunosuppression and for at least two years post-transplant off immunosuppression. [1]

Step 5 — Secondary malignancy surveillance: [1]

• Annual dermatology review for skin cancer (squamous cell carcinoma is the most common secondary solid tumour, and UV protection is critical).
• Annual thyroid ultrasound and function.
• Annual oral cavity examination by a dentist or oral medicine specialist.
• Breast and colorectal cancer screening per age-appropriate guidelines (he is male, so breast screening is not relevant; colorectal screening via colonoscopy or faecal immunochemical test per guidelines).
• Maintain EBV surveillance for PTLD, particularly during periods of intensified immunosuppression. [1]

Step 6 — Psychosocial and sexual health: [1]

• I would address his withdrawal directly — depression and anxiety are common in chronic GVHD, and ruxolitinib and chronic corticosteroid both affect mood. I would involve a clinical psychologist and the transplant survivorship nurse, and consider an SSRI if depression is confirmed (mindful of drug interactions with tacrolimus and ruxolitinib).
• I would discuss the erectile dysfunction openly — it is multifactorial (gonadal failure, vascular disease, psychological, medication) and treatable.
• I would support a graduated return to work if he wishes, and offer peer support through a transplant survivorship group.
• I would offer his wife carer support and education. [1]

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

I would frame this as a chronic-disease consultation, not an acute admission. The transplant has cured his leukaemia; the chronic GVHD is now the dominant health problem, with bronchiolitis obliterans as the urgent priority. I would explain the bronchiolitis obliterans diagnosis in plain language, the plan to intensify immunosuppression, the trade-offs (infection risk versus GVHD control), and the prognosis honestly — progression is possible despite treatment, and we will monitor closely. I would document the shared decisions, give written information and a named contact, and arrange review in the chronic GVHD clinic within two weeks and with respiratory within one week. [1]

Probing questions the examiner would ask

Q: How would you confirm the diagnosis of bronchiolitis obliterans, and would you biopsy? [1]

A: "The diagnosis of bronchiolitis obliterans in a chronic GVHD patient is made on clinical and radiological grounds — the combination of progressive exertional dyspnoea, an obstructive defect on spirometry with no bronchodilator response (FEV1 less than 75 per cent predicted, FEV1/FVC ratio under 0.7), absence of infection on CT (which shows mosaic attenuation and air trapping), and the clinical context of chronic GVHD. A biopsy is not routinely required because the histological changes are patchy and transbronchial biopsy has a low yield; surgical lung biopsy carries significant risk in an immunosuppressed patient. The NIH diagnostic criteria for bronchiolitis obliterans as a chronic GVHD manifestation do not require biopsy if the clinical and physiological criteria are met. I would, however, exclude infection aggressively — induced sputum or bronchoalveolar lavage if there is any clinical or radiological suspicion of infection — because respiratory infection in this population can mimic or coexist with bronchiolitis obliterans." [1]

Q: What is the mechanism of post-transplant cyclophosphamide, and why was it used in his haploidentical transplant? [1]

A: "Post-transplant cyclophosphamide, given at 50 mg per kilogram on days 3 and 4 after the stem cell infusion, selectively deletes the rapidly proliferating alloreactive T-cells that drive graft-versus-host disease and graft rejection, while sparing the resting regulatory T-cells and haematopoietic stem cells because the spared cells express the detoxifying enzyme aldehyde dehydrogenase [4]. This Baltimore platform, developed by the Johns Hopkins group, made haploidentical transplantation feasible by dramatically reducing the historic barriers of GVHD and graft failure, and it means that a donor (almost always a family member who is half-HLA-matched) can be found for nearly every patient. Mr D's daughter was his haploidentical donor, and his conditioning was reduced-intensity fludarabine plus melphalan because of his BMI and diabetes. The platform allows curative allogeneic transplantation in patients who would previously have had no donor."

Q: How does the grading of acute GVHD differ from the staging of chronic GVHD? [1]

A: "Acute GVHD is graded using the Glucksberg-Przepiorka system [6], which stages each of three organs — skin by body surface area, liver by bilirubin, gut by diarrhoea volume — and combines the stages into an overall grade I (mild) to IV (life-threatening). The 100-day boundary separates acute from chronic in the classic framework, though late acute and overlap syndromes blur this. Chronic GVHD is staged using the NIH consensus criteria, which score eight organs (skin, mouth, eyes, gastrointestinal, liver, lungs, joints and fascia, genital) from 0 to 3 based on severity and functional impact, and combine into a global severity of mild, moderate or severe. Bronchiolitis obliterans, sclerotic skin limiting joint motion, weight loss from GI disease, and other functional impairments elevate the global severity. Mr D's sclerotic skin with microstomia and joint restriction plus bronchiolitis obliterans place him in the severe category."

Q: What is the role of ruxolitinib in chronic GVHD, and what are its principal adverse effects? [1]

A: "Ruxolitinib is a JAK1/JAK2 inhibitor approved for steroid-refractory chronic GVHD based on the REACH3 phase 3 trial (Zeiser, NEJM 2021), which demonstrated an overall response rate at week 24 of 50 per cent versus 26 per cent with best available therapy, and improved failure-free survival [1]. Its principal adverse effects are cytopenias (thrombocytopenia, anaemia, neutropenia), infections (particularly viral reactivation and bacterial infection), and a small risk of herpes zoster; it also has drug interactions via CYP3A4 inhibition. It is given at 10 mg twice daily, with dose reduction for cytopenias. It should not be stopped abruptly because of the risk of GVHD flare — taper over four to eight weeks if discontinuation is required. In Mr D's case, the cytopenia risk must be weighed against the benefit for his bronchiolitis obliterans; I would monitor his blood count weekly during any dose escalation."

Q: He asks whether he will ever be able to stop his immunosuppression. How do you answer? [1]

A: "I would answer honestly. The chronic GVHD trajectory is variable — approximately 50 per cent of patients are off systemic immunosuppression by five years, but those with severe, sclerotic or bronchiolitis obliterans disease are often on therapy for many years, and some indefinitely. The goal is to find the minimum effective dose that controls the disease while preserving quality of life and minimising infection risk. With the bronchiolitis obliterans now diagnosed, I would expect at least another one to two years of intensified immunosuppression before a taper could be considered, and only if respiratory function is stable. I would frame the trajectory as a partnership — we will taper when it is safe to do so, monitor closely during taper for flare, and always weigh the trade-offs together. I would also emphasise that even when systemic therapy is tapered, topical and supportive measures (skin care, eye drops, dental care, physiotherapy) often continue indefinitely." [1]

Q: What is his prognosis? [1]

A: "His leukaemia is likely cured — he is two years out from a haploidentical transplant in second complete remission with full donor chimerism, and relapse is uncommon beyond this point. His prognosis now is driven by the chronic GVHD and its complications. Bronchiolitis obliterans carries a significant mortality — five-year survival of approximately 50 to 60 per cent in modern series, worse in severe or progressive disease. The principal causes of death are respiratory failure, opportunistic infection (particularly invasive fungal and viral pneumonia), and secondary malignancy. His prognosis is also affected by his comorbidities — diabetes, cardiovascular risk, osteoporosis with fracture risk, and the cumulative effects of chronic immunosuppression. I would set realistic expectations, emphasise the treatable components (infection prophylaxis, metabolic control, malignancy surveillance, psychosocial support), and involve palliative care early if respiratory failure develops — not to withdraw disease-modifying therapy, but to align his care with his goals as the trajectory clarifies." [1]

Q: Why does he need irradiated blood products? [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 (lifelong for allogeneic recipients); patients treated with purine analogues (fludarabine, cladribine); patients with Hodgkin lymphoma; and patients on certain immunosuppressive biologics. Mr D, as an allogeneic transplant recipient, requires irradiated red cells and platelets for life, regardless of how far out from transplant he is. The standard is to flag this requirement on his blood bank record and to provide him with a card or alert to show any clinician who might transfuse him." [1]

Communication and shared decision-making

"I would frame this consultation as a comprehensive survivorship review, not a crisis. The transplant has achieved its goal — his leukaemia is in remission. The chronic GVHD and its complications are now the central health issues, and the new diagnosis of bronchiolitis obliterans is the priority. I would explain the bronchiolitis obliterans finding in plain language — that the immune process affecting his skin and mouth is also affecting the small airways of his lungs, that we will intensify his immunosuppression to try to prevent the obstruction from becoming permanent, and that we will monitor his breathing closely with regular spirometry. I would discuss the trade-offs of intensified immunosuppression — lower GVHD activity but higher infection risk — and document his preferences. I would address his erectile dysfunction and withdrawal directly, offer concrete help (testosterone assessment, psychology referral, SSRI if appropriate), and involve his wife as his carer. I would lay out the survivorship plan — infection prophylaxis, vaccination, endocrine and bone health, malignancy surveillance, psychosocial support — as a partnership over the coming years. I would give him written information, a named contact, and a clear follow-up plan, and I would review his goals of care explicitly, including his preferences around intensive care and respiratory support if the bronchiolitis obliterans progresses." [1]