Graft-versus-host disease (GVHD): prophylaxis, grading and treatment

Learning objectives and key messages

Learning objectives: after this lesson you should be able to (1) explain the mechanism and risk factors of acute and chronic GVHD; (2) choose an appropriate prophylaxis regimen with exact doses; (3) grade acute GVHD with the MAGIC criteria and chronic GVHD with the NIH 2014 criteria; and (4) choose first-line and steroid-refractory treatment based on evidence.
30 to 50% of allogeneic transplant recipients develop acute GVHD (grade I to IV) and about 14% the severe form (III to IV); HLA mismatch, unrelated donor, female donor for a male recipient, peripheral blood grafts and conditioning intensity are risk factors ^[1].
In the BMT CTN 1703 trial, post-transplant cyclophosphamide (PTCy) + tacrolimus + mycophenolate gave 1-year GVHD-free, relapse-free survival of 52.7% vs 34.9% with tacrolimus + methotrexate ^[2].
The 2024 EBMT guideline: rabbit ATG or PTCy is standard prophylaxis for peripheral blood grafts from unrelated donors, and ruxolitinib is the new standard treatment for steroid-refractory acute and chronic GVHD ^[3].
First-line treatment of grade II to IV acute GVHD is methylprednisolone 2 mg/kg a day, and 1 mg/kg is enough for upper GI GVHD ^[4]; in REACH2, ruxolitinib raised the day-28 response to 62% vs 39% ^[5].
In steroid-refractory or steroid-dependent chronic GVHD, ruxolitinib in REACH3 raised the week-24 response to 49.7% vs 25.6%; ibrutinib, belumosudil and axatilimab are options in later lines ^{[6, 7, 8, 9]}.

Biology and risk factors of GVHD

Acute GVHD

GVHD occurs when immunocompetent T cells in the graft recognise the recipient's tissues as foreign and, acquiring cytolytic capacity, attack them; the main features of acute GVHD are a maculopapular rash, hyperbilirubinaemia from injury to small bile ducts, nausea and anorexia, and watery or bloody diarrhoea ^[1]. Based on animal models, three key events are proposed ^[1]:

Tissue injury: the conditioning regimen or infection releases damage-associated molecular patterns (DAMPs, such as ATP and uric acid) and pathogen-associated patterns (PAMPs, such as lipopolysaccharide from gut bacteria) and activates antigen-presenting cells.
T-cell activation: through three signals: the T-cell receptor, co-stimulation (such as CD28) and cytokines (IL-1β and Th1 cytokines including IFN-γ, IL-2 and TNF).
Effector phase: T cells kill epithelial cells through FAS ligand, perforin and granzyme B and cytokines such as TNF-α; gut dysbiosis and loss of protective microbial metabolites (such as butyrate) make the injury worse.

Chronic GVHD

Chronic GVHD requiring systemic treatment occurs in about 30 to 40% of recipients within 2 years and is more common and longer-lasting after peripheral blood grafts ^[10]. Both B and T cells are involved in its mechanism ^[7]; ROCK2 inhibition with belumosudil reduces type 17 and follicular helper T cells and increases regulatory T cells ^[8], and CSF1R-dependent monocytes and macrophages are key mediators of the disease ^[9]. These mechanisms are the basis of the new targeted drugs.

GVHD prophylaxis

Treatment regimens and doses: index12 regimens

Calcineurin inhibitor + methotrexate: since the Storb trial (1986), ciclosporin or tacrolimus with "mini-dose" methotrexate has been the basis of prophylaxis; in that study, adding methotrexate to ciclosporin reduced grade II to IV acute GVHD from 54% to 33% and gave 1.5-year survival of 80% vs 55% ^[11].

Post-transplant cyclophosphamide (PTCy): high-dose cyclophosphamide after transplant spares haematopoietic stem cells and limits GVHD ^[2]; it was first used in haploidentical transplant with non-myeloablative conditioning, and grade III to IV acute GVHD by day 200 was only 6% ^[12]. In the phase 3 BMT CTN 1703 trial (431 patients; peripheral blood grafts after reduced-intensity conditioning from a matched sibling or an 8/8 or 7/8 unrelated donor), PTCy + tacrolimus + mycophenolate vs tacrolimus + methotrexate gave 1-year GVHD-free, relapse-free survival of 52.7% vs 34.9% (hazard ratio 0.64); grade III to IV acute GVHD (6.3% vs 14.7%) and 1-year chronic GVHD (21.9% vs 35.1%) were lower, and overall survival, relapse and transplant-related mortality did not differ markedly; grade 2 to 3 infections were more common (40.0% vs 30.4%) ^[2].

Antithymocyte globulin (ATG): adding ATG-F in matched unrelated transplant reduced grade II to IV acute GVHD (33.0% vs 51.0%) and extensive chronic GVHD (12.2% vs 42.6%) without increasing relapse or non-relapse mortality ^[13]; in peripheral blood grafts from matched siblings after myeloablative conditioning, it reduced 2-year chronic GVHD from 68.7% to 32.2% with similar survival ^[14]; and rabbit ATG (thymoglobulin) in unrelated transplant raised the proportion of patients off immunosuppression at month 12 to 37% vs 16% but increased EBV reactivation ^[15]. EBMT 2024 considers rabbit ATG or PTCy standard prophylaxis for peripheral blood grafts from unrelated donors ^[3].

Abatacept: in the phase 2 ABA2 trial, adding abatacept to a calcineurin inhibitor + methotrexate in 8/8 unrelated transplant gave grade III to IV acute GVHD of 6.8% vs 14.8% (P=0.13) and day-180 severe GVHD-free survival of 93.2% vs 82%; in the 7/8 group the incidence was 2.3% ^[16]. The FDA has approved it for prophylaxis of acute GVHD with a calcineurin inhibitor and methotrexate in transplant from a matched or one-allele-mismatched unrelated donor ^[17].

GVHD prophylaxis regimens

Tacrolimus + methotrexate

Standard prophylaxis in transplant from a matched sibling or unrelated donor (control arm of BMT CTN 1703)

Drug	Dose	Route	Schedule
Prophylaxis
Tacrolimus	0.05 to 0.06 mg/kg a day orally or 0.02 to 0.03 mg/kg a day IV; adjusted by blood level (suggested 5 to 15 ng/mL)	Oral or IV	From day −3; taper from day 90 in the absence of active GVHD and stop by day 180
Methotrexate	15 mg/m² on day 1, then 10 mg/m²	IV (bolus)	Day 1, then days 3, 6 and 11 after transplant

Cycle length: A continuous post-transplant schedule
Duration: Tacrolimus about 6 months; methotrexate 4 doses

Doses as in the control arm of BMT CTN 1703 ^{[2, 18]}. Give the day 1 methotrexate dose at least 24 hours after the cell infusion; dose reduction for falling creatinine clearance, high drug levels or mucositis, and leucovorin per local protocol, are allowed ^[19]. Ciclosporin is an alternative (in the ATG-F trial, targeting a trough level above 200 ng/mL from day −1 to day 100) ^[20]. When posaconazole is started, reduce tacrolimus to about one third and ciclosporin to about three quarters of the dose and monitor blood levels ^[21].

Post-transplant cyclophosphamide + tacrolimus + mycophenolate (PTCy/Tac/MMF)

Peripheral blood grafts after reduced-intensity conditioning from a matched sibling or an 8/8 or 7/8 unrelated donor (BMT CTN 1703); the basis of prophylaxis in haploidentical transplant

Drug	Dose	Route	Schedule
Prophylaxis
Cyclophosphamide	50 mg/kg a day (ideal body weight; if actual weight is lower, actual weight)	IV, 1 to 2 hours	Day 3 (60 to 72 hours after the start of cell infusion) and day 4 after transplant
Mesna	A daily total equal to 80% of the daily cyclophosphamide dose, in divided doses	IV	30 minutes before and 3, 6 and 8 hours after each cyclophosphamide dose
Tacrolimus	0.05 to 0.06 mg/kg a day orally or 0.02 to 0.03 mg/kg a day IV; suggested level 5 to 15 ng/mL	Oral or IV	From day 5 after transplant; taper from day 90 and stop by day 180 in the absence of active GVHD
Mycophenolate mofetil	15 mg/kg three times a day (actual weight; maximum 1 g three times a day)	Oral or IV	Days 5 to 35 after transplant

Cycle length: A continuous post-transplant schedule
Duration: Cyclophosphamide 2 doses; mycophenolate until day 35; tacrolimus about 6 months

This combination was first used in haploidentical transplant and was then tested in matched-donor transplant ^[2]. Doses as in the experimental arm of BMT CTN 1703 ^{[2, 18]}, and mesna as in the BMT CTN 1301 protocol ^[19]. Measure tacrolimus levels on day 7 and then weekly ^[18]. Neutrophil recovery by day 28 was slightly lower (90.3% vs 93.4%) ^[2].

Rabbit ATG (thymoglobulin) with standard prophylaxis

Unrelated donor transplant with myeloablative or reduced-intensity conditioning

Drug	Dose	Route	Schedule
Prophylaxis
Rabbit ATG (thymoglobulin)	4.5 mg/kg in total: 0.5, then 2.0 and 2.0 mg/kg	IV	2 days before transplant, 1 day before transplant and 1 day after transplant

Cycle length: One course of 3 doses
Duration: Together with local standard prophylaxis

Dose as in the phase 3 trial by Walker and colleagues; EBV reactivation was much more common in the ATG group (20 vs 2 patients), and the authors recommended prospective EBV monitoring and rituximab if needed ^[15].

ATG-F (rabbit anti-lymphocyte globulin) + ciclosporin + methotrexate

Matched unrelated transplant after myeloablative conditioning (the Finke trial)

Drug	Dose	Route	Schedule
Prophylaxis
ATG-F	20 mg/kg a day (60 mg/kg in total)	IV, diluted in 500 mL saline as a slow infusion	Days −3, −2 and −1
Ciclosporin	Adjusted for a trough level above 200 ng/mL	IV or oral	Day −1 to day 100
Methotrexate	15 mg/m² on day 1, then 10 mg/m²	IV	Days 1, 3, 6 and 11 after transplant

Cycle length: A continuous post-transplant schedule
Duration: Ciclosporin until day 100 (then according to GVHD status)

Doses as in the Finke trial protocol registered on ClinicalTrials.gov ^{[13, 20]}. In peripheral blood grafts from matched siblings after myeloablative conditioning (the Kröger trial), ATG-F was used at 10 mg/kg a day on days −3, −2 and −1 ^{[14, 22]}.

Abatacept with a calcineurin inhibitor + methotrexate

Transplant from a matched or one-allele-mismatched unrelated donor; adults and children aged 2 and over (FDA label)Cycle length: 4 doses

Transplant from a matched or one-allele-mismatched unrelated donor; adults and children aged 2 and over (FDA label)

Drug	Dose	Route	Schedule
Prophylaxis
Abatacept	10 mg/kg (maximum 1000 mg) in patients aged 6 and over	IV, 60-minute infusion	Day −1 and days 5, 14 and 28 after transplant

Cycle length: 4 doses
Duration: Until day 28 with background prophylaxis

Dose as in the FDA label; before the first dose, start antiviral prophylaxis for EBV reactivation and continue for 6 months after transplant, and also consider CMV prophylaxis ^[17]. Evidence: the ABA2 trial ^[16].

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Acute GVHD: grading with the MAGIC criteria

Target organ staging in acute GVHD (Mount Sinai Acute GVHD International Consortium, MAGIC) ^[23]

Stage	Skin (active erythema only)	Liver (total bilirubin, mg/dL)	Upper GI	Lower GI (adult; daily stool)
0	No active GVHD rash	Below 2	No nausea, vomiting or anorexia, or intermittent	Below 500 mL or fewer than 3 episodes
1	Maculopapular rash below 25% of body surface area	2 to 3	Persistent nausea, vomiting or anorexia	500 to 999 mL or 3 to 4 episodes
2	Maculopapular rash 25 to 50% of body surface area	3.1 to 6	—	1000 to 1500 mL or 5 to 7 episodes
3	Maculopapular rash above 50% of body surface area	6.1 to 15	—	Above 1500 mL or more than 7 episodes
4	Generalised erythroderma (above 50%) with bullae and desquamation above 5% of body surface area	Above 15	—	Severe abdominal pain with or without ileus, or grossly bloody stool regardless of volume

Overall grade by the most severe involvement: grade I = skin stage 1 to 2 without liver or GI involvement; grade II = skin stage 3 and/or stage 1 liver, upper GI or lower GI; grade III = stage 2 to 3 liver and/or lower GI, with skin 0 to 3 and/or upper GI 0 to 1; grade IV = stage 4 skin, liver or lower GI, with upper GI 0 to 1. Liver stage is set by total bilirubin only, and acute GVHD is a clinical diagnosis that is not excluded by a non-diagnostic biopsy ^[23].

Treatment of acute GVHD

Algorithm for treating acute GVHD

1
Diagnosis and staging
Diagnosis is made by clinical and laboratory assessment and biopsy of target organs ^[1]; record each organ's stage from quantitative measurement of symptoms (percentage of body surface area, total bilirubin, stool volume) ^[23].
2
First-line systemic treatment (grade II to IV)
Methylprednisolone 2 mg/kg a day or prednisone 2 to 2.5 mg/kg a day; higher doses gave no benefit, and in grade II a dose of 1 mg/kg was not worse. Upper GI GVHD responds to 1 mg/kg and topical steroid treatment ^[4].
3
Response assessment and definition of refractoriness
Steroid-refractory: progression in any organ within 3 to 5 days on at least 2 mg/kg prednisone, no improvement within 5 to 7 days, or incomplete response after more than 28 days of treatment. Steroid-dependent: inability to taper prednisone below 2 mg/kg, or flare during tapering ^[24].
4
Second line: ruxolitinib
EBMT 2024 considers ruxolitinib the standard for steroid-refractory acute GVHD ^[3]. In REACH2 (309 patients aged 12 and over), ruxolitinib 10 mg twice a day vs investigator's choice of 9 common treatments raised the day-28 overall response to 62% vs 39% and the durable day-56 response to 40% vs 22%, and median failure-free survival was 5.0 vs 1.0 months; overall survival did not differ significantly (11.1 vs 6.5 months; hazard ratio 0.83) ^[5]. Steroids continue after starting the second-line drug and are tapered with improvement ^[4].
5
Steroid taper
Start tapering once manifestations improve substantially; tapering too fast raises the risk of GVHD flare and tapering too slowly raises the risk of steroid complications, and the optimal rate has not been defined ^[4].

Acute GVHD treatment regimens

Methylprednisolone (first line)

Grade II to IV acute GVHD; upper GI GVHD at a lower doseCycle length: Continuous

Grade II to IV acute GVHD; upper GI GVHD at a lower dose

Drug	Dose	Route	Schedule
Initial treatment
Methylprednisolone	2 mg/kg a day (or prednisone 2 to 2.5 mg/kg a day); upper GI GVHD: 1 mg/kg a day	IV or oral	Daily until response, then gradual taper

Cycle length: Continuous
Duration: According to response; start tapering with substantial improvement

As in the ASBMT recommendations; higher doses (such as 10 mg/kg) gave no benefit ^[4]. In the randomised Ruutu trial, ursodeoxycholic acid 12 mg/kg a day from the day before conditioning to day 90 reduced grade III to IV acute GVHD (5 of 123 vs 17 of 119) ^[25].

Ruxolitinib (steroid-refractory acute GVHD)

Steroid-refractory acute GVHD in adults and children aged 12 and over (FDA label)Cycle length: Continuous

Steroid-refractory acute GVHD in adults and children aged 12 and over (FDA label)

Drug	Dose	Route	Schedule
Treatment
Ruxolitinib	5 mg twice a day; after at least 3 days, if neutrophils and platelets have not fallen by 50% or more, increase to 10 mg twice a day	Oral	Continuous

Cycle length: Continuous
Duration: After 6 months in a responding patient who has stopped therapeutic steroids, reduce by one dose level every 8 weeks

Dose as in the FDA label (Jakafi); REACH2 used 10 mg twice a day ^{[5, 26]}. Monitor blood counts and bilirubin before starting and every 2 to 4 weeks until the dose is stable. Clinically significant thrombocytopenia: reduce by one dose level; drug-related neutrophils below 1 × 10⁹/L: hold for up to 14 days and resume one level lower. With fluconazole up to 200 mg, start at 5 mg once a day; avoid fluconazole above 200 mg ^[26]. The most common adverse events by day 28 in REACH2: thrombocytopenia (33% vs 18%), anaemia and CMV infection (26% vs 21%) ^[5].

Chronic GVHD: diagnosis and severity (NIH 2014)

Diagnostic and distinctive features of chronic GVHD according to the NIH 2014 consensus ^[27]

Organ	Diagnostic feature (sufficient on its own)	Distinctive feature (needs confirmation)
Skin	Poikiloderma; lichen planus-like changes; sclerotic changes; morphoea-like; lichen sclerosus-like	Depigmentation; papulosquamous lesions
Nails	—	Dystrophy; longitudinal ridging, splitting or brittleness; onycholysis; nail pterygium; nail loss (usually symmetrical)
Hair and scalp	—	New scarring or non-scarring alopecia after recovery from chemotherapy; loss of body hair; scaling
Mouth	Lichen planus-like changes	Xerostomia; mucocoele; mucosal atrophy; ulcers; pseudomembranes
Eyes	—	New-onset dry, gritty or painful eyes; cicatricial conjunctivitis; keratoconjunctivitis sicca; confluent punctate keratopathy
Genitalia	Lichen planus-like or lichen sclerosus-like; women: vaginal scarring or clitoral and labial agglutination; men: phimosis or urethral scarring and stenosis	Erosions; fissures; ulcers
Gastrointestinal tract	Oesophageal web; stricture of the upper to middle third of the oesophagus	—
Liver	—	— (a rise in bilirubin, alkaline phosphatase or ALT above 2 × the upper limit is a feature common to acute and chronic GVHD)
Lung	Bronchiolitis obliterans on lung biopsy; bronchiolitis obliterans syndrome (BOS)	Air trapping and bronchiectasis on chest CT
Muscle, fascia and joints	Fasciitis; joint stiffness or contractures from fasciitis or sclerosis	Myositis or polymyositis (needs a biopsy)

Diagnosis requires at least one diagnostic feature, or one distinctive feature plus a confirmatory biopsy, test, specialist assessment or imaging in the same or another organ; infection, drug effects, malignancy and other causes must be excluded. BOS is diagnostic of lung chronic GVHD only if there is a distinctive feature in another organ: FEV1/VC below 0.7, FEV1 below 75% of predicted with a fall of at least 10% in less than 2 years, absence of infection, and evidence of air trapping on expiratory CT or lung function tests ^[27].

Overall severity of chronic GVHD (NIH 2014) ^[27]

Severity	Definition
Mild	Involvement of 1 or 2 organs with a maximum score of 1 and a lung score of zero
Moderate	Involvement of 3 or more organs with a maximum score of 1, or at least one organ (other than lung) with a score of 2, or a lung score of 1
Severe	At least one organ with a score of 3, or a lung score of 2 or 3

Eight organs are scored: skin, mouth, eyes, GI tract, liver, lung, joints and fascia, and genitalia. FEV1 is used for the lung in overall severity. Mild symptomatic GVHD is often controlled with topical treatment; with involvement of 3 or more organs or a score of 2 or more in any organ, systemic treatment should be considered ^[27].

Treatment of chronic GVHD and supportive care

First line: prednisone 1 mg/kg a day with a long taper; in the randomised Koc trial, adding ciclosporin did not reduce transplant-related mortality (17% vs 13% at 5 years) but reduced avascular necrosis (13% vs 22%) ^[28].

Definition of refractoriness: progression on prednisone at least 1 mg/kg a day within 1 to 2 weeks, or stable disease on at least 0.5 mg/kg a day for 1 to 2 months; dependence means inability to taper prednisone below 0.25 mg/kg a day in at least two attempts 8 weeks apart ^[24].

Steroid-refractory or steroid-dependent treatment: in REACH3 (329 patients with moderate or severe chronic GVHD), ruxolitinib 10 mg twice a day vs investigator's choice of 10 common treatments raised the week-24 overall response to 49.7% vs 25.6%, median failure-free survival to more than 18.6 vs 5.7 months, and symptom response to 24.2% vs 11.0% ^[6]; EBMT 2024 considers it the new standard and belumosudil an added option ^[3]. In later lines: ibrutinib in an open-label multicentre study (42 patients after failure of 1 to 3 treatments) gave a best overall response of 67%, and 71% of responders had a sustained response for at least 20 weeks ^[7]; belumosudil (a ROCK2 inhibitor) in ROCKstar after 2 to 5 lines of treatment gave a best overall response of 74% with 200 mg daily and 77% with 200 mg twice a day ^[8]; and axatilimab (an anti-CSF1R antibody) in AGAVE-201 at 0.3 mg/kg every 2 weeks gave an overall response of 74%, with discontinuation for adverse events at this dose of 6% ^[9].

Chronic GVHD treatment regimens

Prednisone ± ciclosporin (first line)

Chronic GVHD needing systemic treatment (involvement of 3 or more organs or a score of 2 or more in one organ)Cycle length: Continuous

Chronic GVHD needing systemic treatment (involvement of 3 or more organs or a score of 2 or more in one organ)

Drug	Dose	Route	Schedule
Initial treatment
Prednisone	1 mg/kg a day	Oral	Daily, then a long gradual taper
Initial treatment (optional)
Ciclosporin	6 mg/kg twice a day, every other day	Oral	Every other day

Cycle length: Continuous
Duration: Months; according to response

Doses as in the randomised Koc trial (patients with platelets above 100,000/µL) ^[28]; the indication for systemic treatment is based on NIH 2014 ^[27].

Ruxolitinib

Chronic GVHD after failure of 1 or 2 lines of systemic treatment; adults and children aged 12 and over (FDA label)Cycle length: Continuous

Chronic GVHD after failure of 1 or 2 lines of systemic treatment; adults and children aged 12 and over (FDA label)

Drug	Dose	Route	Schedule
Treatment
Ruxolitinib	10 mg twice a day	Oral	Continuous

Cycle length: Continuous
Duration: After 6 months in a responder off therapeutic steroids, reduce by one dose level every 8 weeks

Dose as in the FDA label; with fluconazole up to 200 mg: 5 mg twice a day, and avoid fluconazole above 200 mg. Platelets below 20 × 10⁹/L or neutrophils below 0.75 × 10⁹/L: reduce by one level; neutrophils below 0.5 × 10⁹/L: hold for up to 14 days ^[26]. Common grade 3 or higher adverse events in REACH3: thrombocytopenia (15.2% vs 10.1%) and anaemia (12.7% vs 7.6%); CMV infection was similar ^[6].

Ibrutinib

Chronic GVHD after failure of one or more lines of systemic treatment; age 12 and over (FDA label)Cycle length: Continuous

Chronic GVHD after failure of one or more lines of systemic treatment; age 12 and over (FDA label)

Drug	Dose	Route	Schedule
Treatment
Ibrutinib	420 mg once a day	Oral	Continuously until GVHD progression, recurrence of malignancy or unacceptable toxicity

Cycle length: Continuous
Duration: As long as GVHD treatment is needed

Dose as in the FDA label. With voriconazole 200 mg twice a day or posaconazole suspension up to 200 mg twice a day: 280 mg daily; with posaconazole delayed-release tablets 300 mg daily, IV posaconazole 300 mg or suspension 200 mg three times a day: 140 mg daily; avoid other strong CYP3A inhibitors ^[29]. Evidence: the study by Miklos and colleagues ^[7].

Belumosudil

Chronic GVHD after failure of at least two lines of systemic treatment; age 12 and over (FDA label)Cycle length: Continuous

Chronic GVHD after failure of at least two lines of systemic treatment; age 12 and over (FDA label)

Drug	Dose	Route	Schedule
Treatment
Belumosudil	200 mg once a day with food	Oral	Continuous

Cycle length: Continuous
Duration: Until progression of GVHD requiring new systemic treatment

Dose as in the FDA label; with a proton pump inhibitor or a strong CYP3A inducer, increase the dose to 200 mg twice a day; monitor bilirubin and transaminases at least monthly ^[30]. Evidence: ROCKstar ^[8].

Axatilimab

Chronic GVHD after failure of at least two lines of systemic treatment; weight 40 kg or more (FDA label)Cycle length: Every 2 weeks

Chronic GVHD after failure of at least two lines of systemic treatment; weight 40 kg or more (FDA label)

Drug	Dose	Route	Schedule
Treatment
Axatilimab	0.3 mg/kg (maximum 35 mg)	IV, 30-minute infusion	Every 2 weeks

Cycle length: Every 2 weeks
Duration: Until progression or unacceptable toxicity

Dose as in the FDA label; monitor AST, ALT, alkaline phosphatase, CPK, amylase and lipase before starting, every 2 weeks in the first month and then every 1 to 2 months; infusion reactions occurred in 18% ^[31]. Evidence: AGAVE-201 ^[9].

Supportive care in chronic GVHD (NIH 2014)

Infection prevention

Pneumocystis prophylaxis throughout immunosuppressive treatment (co-trimoxazole first choice), prophylaxis against encapsulated bacteria throughout systemic treatment, and in patients at high risk of mould infection (such as prednisone above 0.5 to 1 mg/kg a day), primary prophylaxis with posaconazole or voriconazole in many centres ^[32]; in a randomised trial, posaconazole reduced invasive aspergillosis compared with fluconazole (2.3% vs 7.0%) ^[33].

Immunoglobulin and vaccines

Routine IVIG after transplant gives no benefit; it can be considered with recurrent sinopulmonary infections and IgG below 400 mg/dL. Conjugate vaccines are recommended from 3 to 6 months after transplant ^[32].

Herpes zoster

30 to 60% of patients develop shingles in the first year after post-transplant prophylaxis is stopped; some specialists use long-term antiviral prophylaxis in severe, prolonged immunodeficiency ^[32].

Bone health

Measure calcium and vitamin D at baseline and at least yearly; if steroids continue for more than 3 months, consider bone density testing and antiresorptive treatment (with a dental assessment beforehand) ^[32].

Topical treatment

In the mouth, eyes and genitalia, active topical treatment alone may be enough, because these organs may respond poorly to systemic treatment ^[27].

Practical and exam points

MAGIC: liver stage is set only by total bilirubin and lower GI by stool volume; stage 2 to 3 liver or lower GI involvement means grade III ^[23].
Steroid refractoriness in acute GVHD: progression within 3 to 5 days, or no improvement within 5 to 7 days, on at least 2 mg/kg ^[24].
Ruxolitinib: start at 5 mg twice a day in acute GVHD and 10 mg twice a day in chronic GVHD; with fluconazole up to 200 mg, 5 mg once a day and 5 mg twice a day respectively ^[26].
PTCy: cyclophosphamide 50 mg/kg on days 3 and 4; tacrolimus and mycophenolate from day 5 ^[18].
Posaconazole and calcineurin inhibitors: reduce tacrolimus to about one third and ciclosporin to about three quarters of the dose; combined use with sirolimus is contraindicated ^[21].
ATG: reduces chronic GVHD (32.2% vs 68.7% in matched sibling transplant) but increases EBV reactivation ^{[14, 15]}.
Abatacept: EBV prophylaxis from before the first dose until 6 months after transplant ^[17].
NIH 2014: lichen planus-like changes in the mouth are enough on their own to diagnose chronic GVHD, but dry eyes or dry mouth are only distinctive features ^[27].

Self-assessment: questions and answers

A patient 21 days after transplant has a maculopapular rash over 40% of the body surface, total bilirubin of 2.5 mg/dL and diarrhoea of 800 mL a day. What are the organ stages and the overall grade?

Skin stage 2, liver stage 1 and lower GI stage 1; overall grade II, because grade III needs stage 2 to 3 liver or lower GI involvement ^[23].

After 5 days of methylprednisolone 2 mg/kg, the patient's diarrhoea has worsened. How is this defined and what is the next step?

This is steroid-refractory acute GVHD (progression within 3 to 5 days) ^[24]. Ruxolitinib is the standard second-line treatment ^{[3, 5]}, and steroids continue and are tapered with improvement ^[4].

Based on BMT CTN 1703, which patients are candidates for PTCy instead of tacrolimus + methotrexate?

Adults receiving peripheral blood grafts after reduced-intensity conditioning from a matched sibling or an 8/8 or 7/8 unrelated donor; in this group, 1-year GVHD-free, relapse-free survival was 52.7% with PTCy/Tac/MMF vs 34.9% ^[2]. For peripheral blood grafts from unrelated donors, EBMT considers both rabbit ATG and PTCy standard ^[3].

A patient 8 months after transplant has lichen planus-like changes in the oral mucosa and new-onset dry eyes. Is the diagnosis of chronic GVHD definite?

Yes; lichen planus-like changes in the mouth are a "diagnostic" feature and enough on their own, whereas dry eyes are a "distinctive" feature. After diagnosis, each organ is scored and the overall severity (mild, moderate or severe) is determined ^[27].

A patient with steroid-dependent chronic GVHD is taking fluconazole 400 mg daily. How do you start ruxolitinib?

According to the label, fluconazole above 200 mg daily should be avoided with ruxolitinib; if the fluconazole dose is reduced to at most 200 mg, the starting dose in chronic GVHD is 5 mg twice a day (otherwise 10 mg twice a day) ^[26].

A patient with chronic GVHD on ibrutinib is taking posaconazole delayed-release tablets 300 mg daily for mould prophylaxis. What is the ibrutinib dose?

140 mg once a day (instead of 420 mg) ^[29].

References

33 references

Show all referencesClose the reference list

Numbers in the text, such as ^[1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.

1
Acute Graft-versus-Host Disease — Biologic Process, Prevention, and TherapyZeiser R, Blazar BR · N Engl J Med · 2017;377:2167-2179
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Post-Transplantation Cyclophosphamide-Based Graft-versus-Host Disease ProphylaxisBolaños-Meade J, Hamadani M, Wu J, Al Malki MM, Martens MJ, Runaas L, et al · N Engl J Med · 2023;388:2338-2348
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Prophylaxis and management of graft-versus-host disease after stem-cell transplantation for haematological malignancies: updated consensus recommendations of the European Society for Blood and Marrow TransplantationPenack O, Marchetti M, Aljurf M, Arat M, Bonifazi F, Duarte RF, et al · Lancet Haematol · 2024;11:e147-e159
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First- and Second-Line Systemic Treatment of Acute Graft-versus-Host Disease: Recommendations of the American Society of Blood and Marrow TransplantationMartin PJ, Rizzo JD, Wingard JR, Ballen K, Curtin PT, Cutler C, et al · Biol Blood Marrow Transplant · 2012;18:1150-1163
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Ruxolitinib for Glucocorticoid-Refractory Acute Graft-versus-Host DiseaseZeiser R, von Bubnoff N, Butler J, Mohty M, Niederwieser D, Or R, et al · N Engl J Med · 2020;382:1800-1810
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Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host DiseaseZeiser R, Polverelli N, Ram R, Hashmi SK, Chakraverty R, Middeke JM, et al · N Engl J Med · 2021;385:228-238
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Ibrutinib for chronic graft-versus-host disease after failure of prior therapyMiklos D, Cutler CS, Arora M, Waller EK, Jagasia M, Pusic I, et al · Blood · 2017;130:2243-2250
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Belumosudil for chronic graft-versus-host disease after 2 or more prior lines of therapy: the ROCKstar StudyCutler C, Lee SJ, Arai S, Rotta M, Zoghi B, Lazaryan A, et al · Blood · 2021;138:2278-2289
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Axatilimab in Recurrent or Refractory Chronic Graft-versus-Host DiseaseWolff D, Cutler C, Lee SJ, Pusic I, Bittencourt H, White J, et al · N Engl J Med · 2024;391:1002-1014
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How we treat chronic graft-versus-host diseaseFlowers MED, Martin PJ · Blood · 2015;125:606-615
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Methotrexate and Cyclosporine Compared with Cyclosporine Alone for Prophylaxis of Acute Graft versus Host Disease after Marrow Transplantation for LeukemiaStorb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W, et al · N Engl J Med · 1986;314:729-735
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HLA-Haploidentical Bone Marrow Transplantation for Hematologic Malignancies Using Nonmyeloablative Conditioning and High-Dose, Posttransplantation CyclophosphamideLuznik L, O'Donnell PV, Symons HJ, Chen AR, Leffell MS, Zahurak M, et al · Biol Blood Marrow Transplant · 2008;14:641-650
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Standard graft-versus-host disease prophylaxis with or without anti-T-cell globulin in haematopoietic cell transplantation from matched unrelated donors: a randomised, open-label, multicentre phase 3 trialFinke J, Bethge WA, Schmoor C, Ottinger HD, Stelljes M, Zander AR, et al · Lancet Oncol · 2009;10:855-864
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Antilymphocyte Globulin for Prevention of Chronic Graft-versus-Host DiseaseKröger N, Solano C, Wolschke C, Bandini G, Patriarca F, Pini M, et al · N Engl J Med · 2016;374:43-53
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Pretreatment with anti-thymocyte globulin versus no anti-thymocyte globulin in patients with haematological malignancies undergoing haemopoietic cell transplantation from unrelated donors: a randomised, controlled, open-label, phase 3, multicentre trialWalker I, Panzarella T, Couban S, Couture F, Devins G, Elemary M, et al · Lancet Oncol · 2016;17:164-173
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Phase II Trial of Costimulation Blockade With Abatacept for Prevention of Acute GVHDWatkins B, Qayed M, McCracken C, Bratrude B, Betz K, Suessmuth Y, et al · J Clin Oncol · 2021;39:1865-1877
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ORENCIA (abatacept) — prescribing informationU.S. Food and Drug Administration / DailyMed · DailyMed · 2025
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TAC/MTX vs. TAC/MMF/PTCY for Prevention of Graft-versus-Host Disease (BMT CTN 1703/1801) — NCT03959241ClinicalTrials.gov · ClinicalTrials.gov · 2019
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Calcineurin Inhibitor-Free Interventions for Prevention of Graft-versus-Host Disease (BMT CTN 1301) — NCT02345850ClinicalTrials.gov · ClinicalTrials.gov · 2015
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Acute Graft-Versus-Host Disease (aGvHD) Prophylaxis With ATG-Fresenius in Matched Unrelated Donor Stem Cell Transplantation — NCT00655343ClinicalTrials.gov · ClinicalTrials.gov · 2008
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NOXAFIL (posaconazole) — prescribing informationU.S. Food and Drug Administration / DailyMed · DailyMed · 2026
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Chronic Graft-versus-host Disease (cGvHD) Prophylaxis With or Without ATG Prior to Stem Cell Transplantation From HLA-identical Siblings in Patients With Acute Leukemia — NCT00678275ClinicalTrials.gov · ClinicalTrials.gov · 2008
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International, Multicenter Standardization of Acute Graft-versus-Host Disease Clinical Data Collection: A Report from the Mount Sinai Acute GVHD International ConsortiumHarris AC, Young R, Devine S, Hogan WJ, Ayuk F, Bunworasate U, et al · Biol Blood Marrow Transplant · 2016;22:4-10
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EBMT−NIH−CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessmentSchoemans HM, Lee SJ, Ferrara JL, Wolff D, Levine JE, Schultz KR, et al · Bone Marrow Transplant · 2018;53:1401-1415
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Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantationRuutu T, Eriksson B, Remes K, Juvonen E, Volin L, Remberger M, et al · Blood · 2002;100:1977-1983
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JAKAFI (ruxolitinib) tablets — prescribing informationU.S. Food and Drug Administration / DailyMed · DailyMed · 2026
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National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group ReportJagasia MH, Greinix HT, Arora M, Williams KM, Wolff D, Cowen EW, et al · Biol Blood Marrow Transplant · 2015;21:389-401.e1
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Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone aloneKoc S, Leisenring W, Flowers MED, Anasetti C, Deeg HJ, Nash RA, et al · Blood · 2002;100:48-51
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IMBRUVICA (ibrutinib) — prescribing informationU.S. Food and Drug Administration / DailyMed · DailyMed · 2026
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REZUROCK (belumosudil) tablets — prescribing informationU.S. Food and Drug Administration / DailyMed · DailyMed · 2026
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NIKTIMVO (axatilimab-csfr) injection — prescribing informationU.S. Food and Drug Administration / DailyMed · DailyMed · 2026
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National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: V. The 2014 Ancillary Therapy and Supportive Care Working Group ReportCarpenter PA, Kitko CL, Elad S, Flowers ME, Gea-Banacloche JC, Halter JP, et al · Biol Blood Marrow Transplant · 2015;21:1167-1187
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Posaconazole or Fluconazole for Prophylaxis in Severe Graft-versus-Host DiseaseUllmann AJ, Lipton JH, Vesole DH, Chandrasekar P, Langston A, Tarantolo SR, et al · N Engl J Med · 2007;356:335-347
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