Haematopoietic Stem Cell Transplantation — Viva Defence

Long Case Viva Defence

The scenario

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 was conditioned with fludarabine plus melphalan (reduced-intensity, given a body mass index of 31 and diet-controlled type 2 diabetes), with post-transplant cyclophosphamide on days 3 and 4 plus tacrolimus and mycophenolate for graft-versus-host disease prophylaxis. He engrafted on day 18. He developed grade II acute skin GVHD at day 35, treated with topical corticosteroid and a short course of oral prednisolone with resolution. [1]

At eight months post-transplant he developed chronic GVHD with sclerotic skin changes over the forearms and shins, a lichenoid oral eruption, dry eyes and mouth, and an oesophageal web. He has been on prednisolone (currently 10 mg daily) and ruxolitinib 10 mg twice daily (added after steroid-refractory progression at 12 months), with topical tacrolimus and artificial tears. He also takes aciclovir 400 mg twice daily, co-trimoxazole 480 mg daily, posaconazole 300 mg daily, penicillin V 500 mg twice daily, and thyroxine 100 micrograms daily (hypothyroidism diagnosed at one year). He is EBV and CMV seropositive and has had two episodes of CMV reactivation treated with valganciclovir. [1]

He now presents to the outpatient clinic with three months of progressive exertional dyspnoea, fatigue, and a dry cough. He also reports dry eyes and mouth, oral discomfort, tightness of the skin over his forearms limiting elbow extension, and erectile dysfunction. His wife reports he has become withdrawn. [1]

Opening statement (SASPOP)

"This is Mr D, a 52-year-old schoolteacher presenting two years after a haploidentical stem cell transplant for relapsed AML, with active chronic graft-versus-host disease affecting skin, mouth, eyes and oesophagus, now complicated by progressive exertional dyspnoea that I am most concerned represents bronchiolitis obliterans — a pulmonary manifestation of chronic GVHD. His main problems are the chronic GVHD itself (which is steroid-refractory and currently managed with ruxolitinib and low-dose prednisolone), the new pulmonary symptom requiring urgent assessment for bronchiolitis obliterans versus opportunistic infection, the cumulative late effects of his transplant and chronic immunosuppression (hypothyroidism, gonadal failure and erectile dysfunction, osteoporosis risk, secondary malignancy surveillance, psychosocial withdrawal), and the need for a coordinated survivorship plan addressing infection prophylaxis, vaccination, endocrine replacement, bone health, and psychological support. My priorities are to assess the dyspnoea urgently with spirometry and CT to distinguish bronchiolitis obliterans from infection or anaemia, to intensify immunosuppression if bronchiolitis obliterans is confirmed before the obstruction becomes fixed, and to address his late effects and quality of life in a survivorship framework." [1]

Problem list (numbered, prioritised)

1. Chronic graft-versus-host disease — active, sclerotic and lichenoid subtype affecting skin, oral mucosa, eyes and oesophagus, currently steroid-refractory and on ruxolitinib and low-dose prednisolone.
2. Progressive exertional dyspnoea — the priority is to distinguish bronchiolitis obliterans (a chronic GVHD pulmonary manifestation) from opportunistic infection, anaemia, cardiac dysfunction or pulmonary embolism.
3. Cumulative late effects of transplant and chronic immunosuppression — hypothyroidism (on thyroxine), gonadal failure with erectile dysfunction, osteoporosis and avascular necrosis risk, metabolic syndrome, cardiovascular risk.
4. Secondary malignancy surveillance — skin, thyroid, oral cavity; EBV-driven PTLD surveillance.
5. Infection prophylaxis — continued co-trimoxazole (PJP), aciclovir (HSV, VZV), posaconazole (mould), penicillin V (encapsulated bacteria with chronic GVHD); CMV surveillance.
6. Psychosocial and sexual health — withdrawal, erectile dysfunction, return to work, impact on his marriage.
7. Long-term survivorship plan — vaccination status, endocrine follow-up, bone density, dermatology and ophthalmology review, psychological support. [1]

Integrated management plan

Pillar 1 — Urgent assessment of the dyspnoea: "The priority is to distinguish bronchiolitis obliterans from the alternatives. I would arrange spirometry today — looking for an obstructive defect with no bronchodilator response, low FEV1 and a reduced FEV1/FVC ratio — plus a chest CT with inspiratory and expiratory phases looking for mosaic attenuation and air trapping, the radiological hallmark of bronchiolitis obliterans. I would send a full blood count to exclude anaemia, an ECG and echocardiogram to exclude a cardiac cause, a D-dimer and CT pulmonary angiogram if the clinical picture raised suspicion of pulmonary embolism, and a CMV PCR to exclude reactivation. I would examine for respiratory rate, oxygen saturation, auscultatory findings (wheeze is often absent early in bronchiolitis obliterans), and signs of cor pulmonale. If bronchiolitis obliterans is confirmed, the priority is to intensify immunosuppression before the obstruction becomes fixed, because the histological changes are often irreversible by the time of diagnosis. I would add or increase ruxolitinib, consider extracorporeal photopheresis, and maintain infection prophylaxis (co-trimoxazole for PJP, posaconazole for mould) given the intensification." [1]

Pillar 2 — Chronic GVHD optimisation: "He is already on ruxolitinib 10 mg twice daily, supported by 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 [1]. I would consider escalating ruxolitinib to 15 mg twice daily if tolerated, adding extracorporeal photopheresis for the skin and oral disease, and topical measures (clobetasol oral rinse for lichenoid lesions, topical tacrolitus to skin, punctal plugs and cyclosporine eye drops for the dry eyes, oesophageal dilation for the web). I would involve a multidisciplinary chronic GVHD clinic — dermatology, ophthalmology, dentistry, gastroenterology, physiotherapy for joint range of motion. I would not taper prednisolone below 10 mg per day until the pulmonary status is clear, given the risk that steroid taper may worsen bronchiolitis obliterans."

Pillar 3 — Late effects and survivorship: "For his hypothyroidism, I would continue thyroxine 100 micrograms and check thyroid function every six to twelve months. For gonadal failure and erectile dysfunction, I would check a morning testosterone and offer testosterone replacement if low, with discussion of the cardiovascular implications. I would arrange a DEXA for bone density (he is at risk of osteoporosis and avascular necrosis from chronic corticosteroid) and start a bisphosphonate if osteoporotic. I would review his metabolic parameters — weight, blood pressure, fasting glucose and lipids — and address aggressively given his elevated cardiovascular risk. I would ensure skin cancer surveillance with annual dermatology review, thyroid ultrasound, and breast and oral cavity screening per the late-effects schedule." [1]

Pillar 4 — Infection prophylaxis: "He must continue co-trimoxazole for PJP, posaconazole for mould cover, aciclovir for HSV and VZV, and penicillin V for encapsulated bacteria — all for as long as he remains on immunosuppression or has active chronic GVHD [5]. I would continue weekly to fortnightly CMV PCR surveillance given his prior reactivations. I would ensure he is up to date with inactivated vaccines (annual influenza, pneumococcal, Haemophilus influenzae, hepatitis B, tetanus, polio, COVID) and defer live vaccines (MMR, varicella) until he is at least two years post-transplant and fully off immunosuppression."

Pillar 5 — Psychosocial and sexual health: "I would address his withdrawal directly — depression and anxiety are common in chronic GVHD patients, and ruxolitinib and chronic corticosteroid both affect mood. I would involve a clinical psychologist and the transplant survivorship nurse. I would discuss the erectile dysfunction openly — it is often multifactorial (gonadal failure, vascular disease, psychological, medication) and treatable. I would support his return to work in a graduated way if he wishes, and offer peer support through a transplant survivorship group." [1]

Probing questions the examiner would ask

Q: What is the mechanism by which post-transplant cyclophosphamide allows a haploidentical transplant to succeed? [1]

A: "Post-transplant cyclophosphamide, given at 50 mg per kilogram on days 3 and 4 after the stem cell infusion, exploits a metabolic difference between cell populations. The rapidly proliferating alloreactive T-cells that drive graft-versus-host disease and graft rejection have low levels of the detoxifying enzyme aldehyde dehydrogenase and are killed by cyclophosphamide. In contrast, haematopoietic stem cells and regulatory T-cells express high levels of aldehyde dehydrogenase and are spared. The result is selective deletion of alloreactive cells with preservation of tolerance and graft function — the Baltimore platform described by McCurdy and Luznik (Blood 2019) [4]. This made haploidentical transplantation feasible for nearly every patient by reducing the historic barriers of GVHD and graft failure."

Q: How does bronchiolitis obliterans present, and why is early diagnosis so important? [1]

A: "Bronchiolitis obliterans is a late pulmonary manifestation of chronic GVHD affecting the small airways. It presents with progressive exertional dyspnoea and dry cough, typically six months to several years after transplant. Spirometry shows an irreversible obstructive defect — low FEV1 with a reduced FEV1/FVC ratio and no bronchodilator response — and chest CT shows mosaic attenuation and air trapping on expiratory images. The histological changes, fibrotic narrowing of the bronchiolar lumen, are often irreversible by the time of diagnosis. This is why early recognition is critical: intensification of immunosuppression at the stage of physiological obstruction may prevent progression to fixed obstruction, whereas waiting until the obstruction is anatomically established leaves no room for recovery. A registrar who attributes progressive dyspnoea in a chronic GVHD patient to deconditioning or anaemia and omits spirometry misses this diagnosis until it is too late. Mortality is high once respiratory failure develops." [1]

Q: He has had two CMV reactivations. How is CMV managed in the allogeneic transplant patient, and why is preemptive therapy preferred over universal prophylaxis? [1]

A: "CMV is managed by weekly whole-blood quantitative PCR surveillance from engraftment to day 100, and longer in high-risk patients such as those with steroid-treated GVHD, T-cell depletion or haploidentical transplant. A rising PCR or a threshold viral load triggers preemptive therapy — valganciclovir 900 mg twice daily for 14 to 21 days then maintenance, or intravenous ganciclovir or foscarnet. The goal is to prevent progression to symptomatic CMV disease — colitis, pneumonitis, retinitis, marrow suppression — which carries significant morbidity and mortality. Preemptive therapy is preferred over universal prophylaxis because it exposes only patients with active reactivation to the myelosuppressive and renal toxicities of the antivirals, while still preventing end-organ disease. Letermovir, a CMV terminase inhibitor with a better toxicity profile, is increasingly used as universal prophylaxis in CMV-seropositive recipients from engraftment to day 100, and has reduced CMV reactivation rates in this group. Both strategies are valid; preemptive therapy remains the ANZ default in many units, with letermovir prophylaxis growing." [1]

Q: How would your management differ if his ruxolitinib were contraindicated or ineffective? [1]

A: "If ruxolitinib were contraindicated or ineffective, I would consider extracorporeal photopheresis as a steroid-sparing immunomodulator with a favourable infection profile, particularly effective for skin and oral chronic GVHD. Ibrutinib, a Bruton tyrosine kinase inhibitor, is approved for refractory chronic GVHD after failure of corticosteroid and ruxolitinib, with response rates around 40 to 60 per cent but with bleeding and infective adverse effects. Belumosudil, a ROCK2 inhibitor, is a newer option with response rates around 75 per cent in phase 2. Abatacept is approved for prophylaxis rather than treatment. I would also consider reintroducing or optimising a calcineurin inhibitor, adding mycophenolate, and in selected cases considering low-dose methotrexate or sirolimus. The principle is that chronic GVHD management is sequential and individualised, with multidisciplinary supportive care as the backbone." [1]

Q: What vaccinations should he receive, and when? [1]

A: "He should receive annual influenza vaccine (inactivated) and the pneumococcal vaccines (PCV13 then PPSV23, or the modern PCV20) plus Haemophilus influenzae type B, hepatitis B, tetanus, polio and COVID, starting from six months post-transplant when immune reconstitution is adequate. Live vaccines — measles-mumps-rubella and varicella — are contraindicated while he remains on immunosuppression or has active chronic GVHD, and are deferred until at least two years post-transplant and off all immunosuppression, with immunological assessment before administration. His household contacts should be fully vaccinated including annual influenza, to provide herd protection. The timing matters because immune response to vaccination is attenuated in the first six months and during active GVHD." [1]

Q: How would you counsel him about his risk of secondary malignancy, and what surveillance would you arrange? [1]

A: "I would explain that long-term survivors of allogeneic transplantation have an elevated risk of secondary malignancies, with the cumulative incidence rising steadily over decades. The principal categories are post-transplant lymphoproliferative disorder (EBV-driven, usually within the first year, more common with T-cell depletion or heavy immunosuppression), solid tumours (skin, thyroid, breast, oral cavity — rising over years and decades, higher with total body irradiation conditioning), and myelodysplasia or secondary leukaemia (more common after autologous transplant). For surveillance, I would arrange annual dermatology review for skin cancer (with patient education on sun protection and self-examination), annual thyroid ultrasound and function, breast cancer screening from eight years post-transplant or age 40 (whichever first) for patients who received chest radiation, and annual oral cavity examination. I would maintain EBV and CMV surveillance while on immunosuppression. I would advise him to report new or changing lesions promptly and to maintain regular primary care follow-up for age-appropriate cancer screening." [1]

Communication and shared decision-making

"I would frame Mr D's situation as a chronic-disease consultation, not an acute admission. The transplant has cured his leukaemia, and the chronic GVHD is now the dominant health problem, with the new dyspnoea as the priority. I would explain the bronchiolitis obliterans concern in plain language — that the same immune process that caused his skin and mouth problems can affect the small airways of the lung, that the test today (spirometry and CT) will clarify this, and that if confirmed we will intensify his immunosuppression to try to prevent the obstruction from becoming permanent. I would discuss openly the trade-offs of continued immunosuppression — lower GVHD activity but higher infection risk — and document his preferences. I would address his withdrawal and erectile dysfunction directly and offer concrete help. I would emphasise the survivorship plan — infection prophylaxis, vaccination, endocrine and bone health, malignancy surveillance, psychological support — as an ongoing partnership, not a one-off visit. And I would reassure him and his wife that the chronic GVHD trajectory is variable and that many patients achieve a tolerable equilibrium with the right combination of systemic and topical therapy, rehabilitation and support." [1]

Short Case Discussion — Skin Examination in Chronic GVHD

Instruction: "Examine this patient's skin and oral cavity." [1]

Systematic examination routine

1. End of bed — observe for general appearance, sclerotic tightness of the face, joint contractures, mobility aids, weight loss. Note alopecia, vitiligo or dyspigmentation.
2. Hands and forearms — look for sclerotic changes (hidebound skin, reduced pinchability), lichenoid lesions (violaceous flat-topped papules), poikiloderma (atrophy, telangiectasia, pigmentation), nail dystrophy (pterigyium, onycholysis, longitudinal ridging). Test for joint range of motion — elbow, wrist, finger extension limited by sclerotic skin or fasciitis.
3. Arms and trunk — examine for the distribution of sclerotic plaques, morphea-like lesions, depigmentation (resembling vitiligo), and erythematous maculopapular remnants of acute GVHD that may persist.
4. Face — look for perioral sclerosis with reduced mouth opening (microstomia), xerostomia, teleangiectasia, a saddle-nose deformity (rare), eyelid involvement.
5. Oral cavity — inspect for lichenoid lesions (white striae, reticular pattern on buccal mucosa and tongue), mucositis, ulcers, xerostomia (dry, furrowed tongue), atrophy of the filiform papillae, dental caries (accelerated by xerostomia), oral candidiasis. Assess mouth opening in finger-breadths.
6. Eyes — assess for dry eyes (xerophthalmia), conjunctival injection, teleangiectasia; ask about grittiness and photophobia. (Ophthalmology assessment with Schirmer test confirms sicca.)
7. Nails and scalp — nail dystrophy (longitudinal ridging, pterygium, onycholysis), scalp alopecia (patchy or diffuse).
8. Joints — range of motion at shoulders, elbows, wrists, fingers, knees, ankles; fasciitis limits motion and causes pain.
9. General — examine for hepatosplenomegaly, lymphadenopathy, and signs of opportunistic infection (line sites, chest). [1]

Key physical signs the patient demonstrates (for this case)

• Sclerotic, hidebound skin over the forearms and shins with reduced pinchability
• Lichenoid white striae on the buccal mucosa and lateral tongue
• Reduced mouth opening (microstomia), two finger-breadths
• Xerostomia with a dry, furrowed tongue and accelerated dental caries
• Nail dystrophy with longitudinal ridging of the fingernails
• Limited elbow extension to 20 degrees short of full extension bilaterally, due to skin tightness and fasciitis
• Patchy scalp alopecia
• No hepatosplenomegaly, no lymphadenopathy [1]

Presentation template

"I examined Mr D, a 52-year-old man, who appears thin and withdrawn at the end of the bed, with limited facial expression and reduced mouth opening. The skin over the forearms and shins is sclerotic and hidebound, with reduced pinchability and lichenoid violaceous plaques at the wrists. There is poikiloderma over the dorsal hands. The fingernails show longitudinal ridging and early pterygium. The oral cavity shows lichenoid white striae on the buccal mucosa and lateral tongue, a dry furrowed tongue consistent with xerostomia, accelerated dental caries, and a mouth opening of two finger-breadths consistent with microstomia. Elbow extension is limited to 20 degrees short of full extension bilaterally, due to skin tightness. The scalp shows patchy alopecia. There is no hepatosplenomegaly or lymphadenopathy. These findings are consistent with active chronic graft-versus-host disease of the sclerotic and lichenoid subtypes affecting skin, oral mucosa, nails and scalp, with functional limitation from microstomia and joint restriction. In a patient two years post haploidentical stem cell transplantation, this is a classic chronic GVHD presentation. I would specifically like to assess his respiratory system for bronchiolitis obliterans and his eyes for sicca syndrome." [1]

Discussion questions

Q: What is the significance of sclerotic skin changes in chronic GVHD? [1]

A: "Sclerotic skin changes are a diagnostic manifestation of chronic GVHD under the NIH criteria, meaning they alone are sufficient to establish the diagnosis. They reflect fibrosis of the dermis and subcutaneous tissue driven by the alloimmune reaction, similar pathogenetically to localised scleroderma (morphea) or systemic sclerosis. The clinical importance is threefold: they are a marker of more severe and chronic disease, they cause significant functional impairment (microstomia, joint contractures, impaired wound healing), and they signal a higher risk of other chronic GVHD manifestations including bronchiolitis obliterans. Sclerotic changes may improve with intensified immunosuppression and with physiotherapy, but the fibrotic component is often slow to reverse. I would involve dermatology, physiotherapy and occupational therapy in a coordinated approach." [1]

Q: How is chronic GVHD staged? [1]

A: "Chronic GVHD is staged using the NIH consensus criteria, which score each of eight organs (skin, mouth, eyes, gastrointestinal tract, liver, lungs, joints and fascia, and genital tract) from 0 to 3 based on severity and functional impact. The global severity is then categorised as mild, moderate or severe. Mild disease involves only one or two sites with no functional impairment; moderate involves three or more sites or one site with functional impairment; severe involves major functional impairment (such as bronchiolitis obliterans, sclerotic skin limiting joint motion, weight loss from GI disease). The global severity drives treatment decisions — mild disease may be managed topically, while moderate to severe requires systemic therapy. Mr D, with sclerotic skin, microstomia, joint restriction and possible bronchiolitis obliterans, is at least moderate to severe by these criteria." [1]

Q: How does the skin of chronic GVHD differ from that of systemic sclerosis? [1]

A: "The sclerotic changes of chronic GVHD and systemic sclerosis are clinically and histologically similar — both show dermal fibrosis, hidebound skin, microstomia and joint contractures. The key differences are in the distribution and the associated features. Chronic GVHD sclerotic changes are more often patchy and may show coexisting lichenoid lesions (white striae, violaceous papules) and depigmentation; systemic sclerosis tends to be more acral and symmetric with proximal progression, and is associated with Raynaud phenomenon, nailfold capillary changes, pulmonary arterial hypertension and renal crisis, anti-Scl-70 or anti-centromere antibodies, and the characteristic facial features (beaked nose, radial perioral furrows). Chronic GVHD occurs only after allogeneic transplantation and often coexists with other GVHD manifestations (oral lichenoid lesions, sicca, oesophageal web). The distinction is clinical and contextual, and both conditions may require similar systemic immunosuppression." [1]

Q: What infection prophylaxis should this patient continue? [1]

A: "Mr D, with active chronic GVHD on ruxolitinib and prednisolone, should continue co-trimoxazole 480 mg daily for Pneumocystis prophylaxis, posaconazole for mould cover given the immunosuppression and steroid exposure [5], aciclovir 400 mg twice daily for HSV and VZV prophylaxis, and penicillin V 500 mg twice daily for encapsulated bacteria (functional hyposplenism and chronic GVHD both increase the risk of pneumococcal sepsis). He should receive inactivated vaccines annually (influenza, pneumococcal) and be up to date with hepatitis B, tetanus and COVID. Live vaccines (MMR, varicella) are contraindicated while he remains on immunosuppression and for at least two years post-transplant off immunosuppression. His household contacts should be fully vaccinated. The principle is that prophylaxis continues for as long as the patient is immunosuppressed or has active chronic GVHD — stopping at the standard six-month mark in a chronic GVHD patient is a common and dangerous error."