As detailed above, aGVHD typically occurs within the first 100 days after HSCT, though “late acute” forms may present beyond this window due to delayed immune reconstitution or prolonged immunosuppression. The canonical pathophysiological framework consists of three interconnected phases involving tissue injury, donor T-cell activation, and effector-mediated target organ damage. This model has been substantially refined by recent advances emphasizing the critical contribution of innate immunity, host tissue-resident immune cells, and cytokine networks [4, 15, 17–19].

CGVHD is a multisystem alloimmune and autoimmune syndrome involving inflammation, immune dysregulation, and fibrotic tissue remodeling that may emerge following aGVHD or develop independently. Impaired immune tolerance, aberrant B-cell and T-cell interactions, innate immune activation, and progressive tissue fibrosis characterize its pathophysiology [16].

Clinical manifestations of aGVHD include specific derangements in the skin, liver, and gastrointestinal tract, and occasionally the eyes and oral mucosa. The disease is often characterized by a maculopapular skin eruption, diarrhea, and cholestatic liver disease (diagnosed by elevated bilirubin levels), and may be associated with recurrent infections. aGVHD onset typically occurs within a timeframe ranging from two to 42 weeks following stem-cell transplantation [6]. The clinical grading and staging of aGVHD is determined by the extent of skin, liver, upper, and lower GI tract involvement. Initially, individual organ involvement is assessed, followed by determination of the overall GVHD grade by the combination of organ stages, with the severity of the condition ranging from stages 1–4. Multiple systems for GVHD severity assessment exist in the literature. Tables 1, 2 present the most common staging and grading systems, respectively, with the overall grade determined according to modified Glucksberg criteria, which overlap significantly with the Mount Sinai International Consortium (MAGIC) criteria [6, 15].

AGVHD skin disease is often preceded by pruritus and dysesthesia, followed by the sudden onset of erythematous, maculopapular, morbilliform eruptions (Figs 2, 3). Early skin manifestations typically appear two to eight weeks after HSCT and present as folliculocentric blanching, erythematous macules, or papules with a predilection for ears and cheeks, sides of the neck, palms, soles, and upper back. Late onset aGVHD (> 100 days after HSCT) presents with clinical features of classic acute GVHD and may be discerned from chronic GVHD by sparing of flexural sites, lack of lichenoid features, and type of concomitant organ involvement (Fig. 4).

Mild to moderate forms of acute cutaneous GVHD (Fig. 2) may either resolve spontaneously or in response to first-line therapy (see chapter below), potentially leaving post-inflammatory dyspigmentation. In more severe reactions (Fig. 3), lesions may extend to the trunk and progress to erythroderma with bulla formation, desquamation, and necrosis. The latter can remain localized to pressure sites or can disseminate. In the most severe cases, epidermolysis can be observed, clinically resembling toxic epidermal necrolysis [27–31].

Acute cutaneous GVHD is staged from 0 to 4 according to the presence of symptoms (maculopapular eruption, erythroderma with blisters or epidermolysis) and the percentage of the body’s surface area (BSA) affected, as detailed in Table 1 [29].

GVHD accounts for at least 25% of transplant-related deaths following allogeneic HSCT [32]. The mortality risk associated with aGVHD varies depending on the severity of the condition. Grade I acute GVHD carries limited direct mortality risk and does not typically require systemic treatment. Grade II disease confers a moderate mortality risk, while grades III and IV are associated with reported mortality risks up to 80%. In Europe, an EBMT study of 102,557 patients demonstrated improving outcomes over time, attributable to improved conditioning and prophylaxis regimens: 3-year survival after grades II–IV acute GVHD increased from 38% (1990–1995) to 45% (2011–2015), while 3-year survival after the more severe grades III–IV subset increased from 22% to 29% over the same period. Correspondingly, 3-year non-relapse mortality after grades II–IV declined from 47% to 36% [33].

A critical prognostic determinant across all grades is the response to first-line corticosteroid therapy, which declines markedly with increasing disease severity—from 86% in grade II to 55% in grade III and 30% in grade IV—underscoring the clinical urgency of early and accurate grading [34, 35]. Steroid-refractory aGVHD represents the highest risk subset, with 70.2% mortality at a median of 117.5 days from diagnosis, and patients with maximum grade III/IV disease or lower gastrointestinal involvement had mortality rates of 80.2% and 85.7%, respectively [34].

Compared to chronic GVHD, in aGVHD, involvement of the oral or genital mucosa is an uncommon occurrence. Its diagnosis is complicated due to other factors resulting in mucositis and development of oral lesions during the first 28 days following transplant, including conditioning chemotherapy, concurrent radiation, neutropenia, herpes simplex infection (HSV), and treatment with cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF). Notably, oral mucositis was an exceedingly common adverse event after allo-HSCT, but did not correlate with the occurrence of cutaneous or gastrointestinal aGVHD in a cohort from Vienna, Austria [36].

Nevertheless, oral lesions described in aGVHD include erythematous, erosive, ulcerated, and lichenoid lesions associated with clinical signs of salivary gland dysfunction, xerostomia, and pain. Lesions that persist or exacerbate for more than three weeks after HSCT, particularly when involving the hard palate, as chemotherapy-induced mucositis rarely affects this area of the mouth, are considered indicative of aGVHD [2, 29, 37, 38].

In the absence of concomitant extracutaneous manifestations, the diagnosis of aGVHD may be challenging. The clinical findings are non-specific and can be difficult to distinguish from other skin eruptions that commonly occur in post-HSCT patients, most notably morbilliform drug eruptions and viral exanthema. Furthermore, the lack of pathognomonic histopathologic features underscores the importance to establish a correlation between clinical and pathological findings [39].

Overlap syndrome is defined by the concurrent presence of features of both acute and chronic GVHD and is associated with significantly higher morbidity and mortality. Clinically, an erythematous or maculopapular eruption resembling acute GVHD may develop in patients with an established diagnosis of cutaneous or extra-cutaneous chronic GVHD. Gastrointestinal involvement may manifest as nausea, vomiting, or diarrhea, while hepatic involvement can present with cholestatic hepatitis and abnormal liver function tests. Histological features may overlap with those of both acute and chronic GVHD [8, 40, 41].

Besides detailed anamnesis and close clinical inspection, skin biopsies should be considered as a standard procedure in line with European consensus recommendations. The National Institutes of Health (NIH) advises that a skin biopsy is indicated in suspected cutaneous GVHD lacking diagnostic features and is regularly performed to exclude differential diagnoses. However, these procedures should never result in delays to management, since early treatment is associated with improved prognosis. It is important to note that no direct relation exists between clinical and histopathological grading, except for advanced stages, with epidermal detachment. Therefore, a clinical-histopathological correlation is essential [2, 40, 42].

CGVHD can directly evolve from aGVHD (progressive chronic form), follow a disease-free period, or develop independently of prior GVHD signs de novo, and is a major cause of morbidity in long-term survivors of allo-HSCT [27, 30]. The classic presentation, characterized by the distinctive signs and symptoms of cGVHD with no time restrictions, is distinguished from an overlap syndrome, in which both acute and chronic GVHD symptoms are present. CGVHD is a multisystem disease that can affect one or several organs at a time: Skin and oral mucosa involvement are the most common presentations, followed by liver, eye, intestinal, and lung involvement in decreasing order of frequency [8, 27, 30, 40].

The NIH has published guidelines for classifying clinical manifestations and skin involvement in the context of cGVHD (Tables 4, 5). These guidelines aim to facilitate the diagnostic process, recommending that each manifestation be categorized into one of four distinct groups. The first category, diagnostic features, encompasses the presence of poikiloderma, lichen planus-like, lichen sclerosus-like, morphea-like, and deep sclerotic eruptions, and is sufficient for the diagnosis of cGVHD in the absence of skin biopsies or additional tests. The second category, distinctive manifestations, comprises depigmentation, vitiligo-like and papulosquamous lesions, which, although indicative of cGVHD, are not sufficient for a definitive diagnosis. The third category encompasses other features, which include more unspecific eruptions, such as keratosis pilaris, sweat gland impairment, hypopigmentation, and hyperpigmentation. The final category comprises common manifestations, including erythema, maculopapular eruption, and pruritus, which are present in both acute and cGVHD. The presence of at least one diagnostic manifestation or one distinctive feature confirmed by biopsy, laboratory tests, or radiology in the same or another organ is necessary for cGVHD diagnosis [3].

In the absence of diagnostic clinical findings, the NIH consensus recommendation is for a skin biopsy to confirm the diagnosis of cGVHD. While tissue biopsies are generally advised to confirm a diagnosis, they are not necessarily required if a patient exhibits diagnostic signs or symptoms. While biopsies may be indicative of either chronic or acute GVHD, they are not specific for either condition [38, 40].

Standard prophylaxis for GVHD, including cutaneous manifestations, consists of a calcineurin inhibitor (either tacrolimus or cyclosporine A) combined with methotrexate or mycophenolate mofetil [69]. T-cell depletion strategies, such as anti-thymocyte globulin (ATG) and post-transplant cyclophosphamide (PTCy), are increasingly used to reduce both aGVHD and cGVHD incidence. ATG is recommended for matched unrelated donor transplants, and recent randomized trials demonstrate that PTCy-based regimens (e.g., PTCy plus tacrolimus and mycophenolate mofetil) significantly lower the rates and severity of GVHD, including cutaneous involvement, compared to standard prophylaxis [70, 71].

Abatacept, a selective T-cell co-stimulation blocker, is FDA-approved for aGVHD prophylaxis in combination with a calcineurin inhibitor and methotrexate for matched or single-allele mismatched unrelated donor transplants. Large registry analyses show improved survival and relapse-free outcomes with abatacept plus calcineurin inhibitor/methotrexate compared to calcineurin inhibitor/methotrexate alone or calcineurin inhibitor/methotrexate plus ATG, and outcomes similar to PTCy-based regimens [72].

Currently, no reliable predictive tool exists to forecast GVHD occurrence safely; risk stratification is based on clinical and transplant-related factors. Graft manipulation techniques, such as ex vivo T-cell depletion, are also under investigation for prevention [15, 73].

Topical corticosteroids are the standard treatment for limited cutaneous aGVHD, with potent agents such as clobetasol propionate commonly used. Their efficacy is supported by clinical experience, although high-quality evidence is limited [74, 75]. Potency should be tailored to the site and severity, with low-potency steroids preferred for sensitive or facial areas and higher-potency agents for thicker skin or more pronounced lesions. Topical calcineurin inhibitors (tacrolimus ointment, pimecrolimus cream) may be considered, especially for sensitive areas or as steroid-sparing agents, albeit these are more established in cGVHD and have less robust data in aGVHD [74].

For more extensive skin involvement or internal organ disease in aGVHD, the most up-to-date consensus is initiation of systemic corticosteroids (oral prednisone or intravenous methylprednisolone at 1–2 mg/kg/day) as first-line therapy [69, 15]. Approximately half of patients respond to corticosteroids, but steroid-refractory disease is common [76, 77].

For steroid-refractory aGVHD, the preferred second-line agent is ruxolitinib, a Janus kinase (JAK1/2) inhibitor, which is FDA- and EMA-approved and has demonstrated superior response rates and durable control compared to best available therapy [69, 78]. The consensus regimen for patients aged ≥12 years is 10 mg orally twice daily. Initial dosing may begin at 5 mg twice daily and increase to 10 mg twice daily after 3 days if tolerated. Lower or shorter dosing regimens (e.g., 5 mg twice daily) are sometimes used in clinical practice for patients with cytopenias or other dose-limiting toxicities [69].

Other second-line and adjunctive options include extracorporeal photopheresis, used for steroid-refractory or steroid-dependent aGVHD, especially with skin involvement. The procedure involves leukapheresis followed by ex vivo exposure of peripheral blood mononuclear cells to 8-methoxypsoralen and ultraviolet A (UVA) irradiation, after which the treated cells are reinfused into the patient. The treatment is typically administered on two consecutive days every week during the initial phase, with intervals subsequently extended according to clinical response. Therapy is generally continued for at least 3–6 months [79].

Additional second-line treatment options involve mycophenolate mofetil (may be added for additional immunosuppression), mTOR inhibitors (e.g., sirolimus) used in select cases, often as adjuncts, TNF-alpha antagonists (e.g., etanercept, infliximab, in gastrointestinal GVHD) considered for refractory cases, but associated with increased infectious risk, as well as alemtuzumab, anti-thymocyte globulin, and other cellular therapies used in highly refractory cases, with variable efficacy and increased risk of infection [69].

In summary, systemic corticosteroids are the cornerstone of initial therapy for aGVHD, with ongoing calcineurin inhibitor-based prophylaxis. Ruxolitinib is the preferred second-line agent for steroid-refractory disease, and other immunosuppressive and cellular therapies are considered in refractory cases, but these are associated with increased infectious risk and lack robust comparative data.

Compared to classic aGVHD, overlap GVHD is associated with greater disease severity and reduced overall survival [80]. Due to exclusion of this complicated constellation from many clinical studies, there is no distinct algorithm for overlap GVHD management. Generally, treatment follows cGVHD principles, with therapy selection guided by the predominant clinical manifestations, organ involvement, disease severity, and patient comorbidities [81].

Systemic corticosteroids (prednisone 1 mg/kg/day) remain the standard first-line therapy for cGVHD. Prolonged corticosteroid use is associated with significant morbidity, including increased risk of opportunistic infections [69, 82]. Skin-directed therapies, such as topical corticosteroids and topical calcineurin inhibitors, are adjuncts for cutaneous involvement; caution is warranted with topical tacrolimus in patients on systemic tacrolimus due to potential toxicity [69, 82].

For steroid-refractory cGVHD, four agents are FDA-approved: ibrutinib (Bruton’s tyrosine kinase inhibitor), ruxolitinib (Janus kinase 1/2 inhibitor), belumosudil (ROCK2 inhibitor), and axatilimab (CSF1R inhibitor, not available in Europe outside of studies). Ibrutinib is approved after failure of one or more lines of systemic therapy, ruxolitinib after failure of one or two lines, belumosudil after at least two prior lines, and axatilimab for patients failing at least two prior lines [83]. These agents have distinct mechanisms and efficacy profiles, and selection is individualized based on organ involvement, prior therapies, and comorbidities [84, 85].

In cGVHD, extracorporeal photopheresis is widely used as a steroid-sparing option, especially in patients with cytopenias or active infections [69, 86]. ECP is typically administered in cycles consisting of two consecutive treatment days. During the initial phase, cycles are generally performed weekly for approximately three months, or until GVHD stabilizes. Thereafter, treatment is usually continued every two weeks and gradually tapered according to clinical response and disease severity. The overall duration of therapy is individualized and guided by the patient’s therapeutic response [79].

Other agents used in selected cases include rituximab, imatinib, mTOR inhibitors, mycophenolate, and proteasome inhibitors [69, 87]. The management beyond second-line therapy is heterogeneous and often guided by institutional protocols and clinical trial availability [60, 66]. Post-transplant cyclophosphamide has reduced cGVHD incidence without increasing relapse or infection rates but is not a treatment for established cGVHD [69, 84].

Overall, therapy is tailored to disease severity, organ involvement, and patient-specific factors, with ongoing research into combination and biomarker-driven strategies. Ruxolitinib, ibrutinib, belumosudil, and axatilimab are the principal novel agents with proven efficacy for skin involvement in acute and chronic GVHD, with additional investigational molecules in late-phase trials showing promise for future management. Ivarmacitinib, TDI-01, rovadicitinib, and pimicotinib are other emerging agents in advanced clinical trials which target inflammatory and fibrotic pathways and have demonstrated organ-specific responses, including cutaneous disease, though these are not yet approved [88].

Notably, patients with long-standing cGVHD carry a substantially elevated risk of developing secondary malignancies, particularly cutaneous squamous cell carcinoma. The overall skin cancer risk is increased 10-fold compared to the general population, with cGVHD conferring a hazard ratio of 2.86 for any skin cancer and 3.68 specifically for SCC. Mucocutaneous GVHD involvement further increases risk, as does prolonged immunosuppression and voriconazole exposure [89]. The latter has been independently associated with cutaneous SCC through a mechanism of chronic phototoxicity and accelerated photocarcinogenesis. International guidelines recommend routine skin cancer screening for all allogeneic transplant recipients, with heightened surveillance in those with cGVHD [90]. Given this cumulative risk profile, routine dermatologic and mucosal surveillance should be considered an integral component of long-term cGVHD management [91, 92].