Approximately 35% to 50% of patients otherwise cured of hematologic malignancies after allogeneic hematopoietic stem cell transplantation will develop the pleomorphic autoimmune-like syndrome known as chronic graft-versus-host disease (cGVHD). Since in 2005, National Institutes of Health (NIH) consensus panels have proposed definitions and classifications of disease to standardize treatment trials. Recently, the first agent was approved by the US Food and Drug Administration for steroid-refractory cGVHD. Despite these advances, most individuals do not achieve durable resolution of disease activity with initial treatment. Moreover, standardized recommendations on how to best implement existing and novel immunomodulatory agents and taper salvage agents are often lacking. Given the potential life-threatening nature of cGVHD, we employ in our practice patient assessment templates at each clinic visit to elucidate known prognostic indicators and red flags. We find NIH scoring templates practical for ongoing assessments of these complex patient cases and determination of when changes in immunosuppressive therapy are warranted. Patients not eligible or suitable for clinical trials have systemic and organ-directed adjunctive treatments crafted in a multidisciplinary clinic. Herein, we review these treatment options and offer a management and monitoring scaffold for representative patients with cGVHD not responding to initial therapy.

Although first described nearly 40 years ago,1-3  chronic graft-versus-host disease (cGVHD) is still a common and often devastating consequence of allogeneic hematopoietic stem cell transplantation (HSCT) after cure of an otherwise fatal malignancy. Despite completion of randomized phase 3 prophylaxis trials,4,5  preventing cGVHD without compromising its antitumor effects remains a largely unmet goal.6  With >30 000 allogeneic transplantations performed worldwide each year7  and 35% to 50% of recipients developing cGVHD, this complication remains a frequent and formidable foe.8 

First-line corticosteroid treatment, alone or with additional agents, has been widely adopted since publication of the initial randomized trial in cGVHD.9  A comprehensive discussion of initial treatments for National Institutes of Health (NIH) consensus-defined cGVHD was provided by Flowers and Martin10  in their 2015 article “How we treat chronic GVHD.” Since that publication, 2 major advances have occurred: first, outcome studies have shown that <20% of patients with cGVHD achieve a durable partial (PR) or complete response (CR) and survive 1 year after initial therapy without additional systemic therapy,11  indicating that treatment-refractory cGVHD is relatively common12  and patients likely will require ongoing therapy; and second, in 2017, ibrutinib was approved for steroid-refractory cGVHD,13  and other novel agents14  and existing treatments are being tested in controlled trials as ongoing research continues to elucidate new pathways and targets for drug development.15-18  Choices of salvage therapy for cGVHD represent collective clinical experience and an aggregate consideration of risk of disease mortality, relative treatment toxicity, and availability of regimens and clinical trials.19 

If no clinical trial is available or suitable, treatment choice becomes a shared decision, integrating published literature on biology and treatment results with physician experience and patient values.20,21  This process takes time to ensure that patients understand the biology of disease, expectations regarding treatment outcomes, adverse effects, convenience, and cost.22,23  The Seattle Long-Term Follow-Up team, the Chronic GVHD Consortium, and NIH consensus groups have advanced the field by providing guidelines for cGVHD definition, end point reporting, and trial design.11,12,24,25  Ultimately, shared treatment decisions with patients reflect informed intuition, an amalgam of evidence-based facts, consensus opinion, and subjective feelings.20,21  In practice, simplified Web-based versions of NIH consensus guidelines26,27  can be used to objectively monitor treatment-refractory cGVHD.24  Herein, we present our practice of evidence/consensus-based approaches to patients with ongoing cGVHD (cases presented are composites of actual patients).

A 40-year-old woman with T-cell non-Hodgkin lymphoma underwent 10/10 HLA-matched unrelated-donor peripheral blood HSCT after total-body irradiation with 13 Gy and VP-16 conditioning. Despite methotrexate and IV tacrolimus (10-15 ng/mL), grade 4 acute GVHD of the skin developed and was successfully treated with high-dose corticosteroids followed by extracorporeal photopheresis (ECP). After 12 weeks of steroids and ECP, GVHD resolved, and serum tacrolimus levels were maintained at low therapeutic levels before gradually weaning off by 11 months after transplantation. With physical therapy and steroid taper, strength improved. At the 12-month post-HSCT visit, T-cell non-Hodgkin lymphoma restaging was negative for malignancy, but the patient had had clear clinical decline. She was unable to eat because of severe oral pain, had lost 10 pounds in <2 weeks, and reported sensations of sand in the eyes. On examination, mouth sores and weight loss were apparent; she also had an erythematous macular rash over the flanks, chest, back, and upper thighs, but no sclerosis or restricted range of motion and no pulmonary abnormalities. Laboratory studies showed no hepatic or blood count abnormalities. Infection prophylaxis with posaconazole, acyclovir, and dapsone was provided. Ophthalmology consultants confirmed ocular GVHD. Although opthalmic steroids and cyclosporine (0.05%) afforded improvement, subsequent hyperemia and eye pain developed. Pain was evaluated the same day by the ophthalmologist, and Staphylococcus superinfection was diagnosed and successfully treated.

Oral prednisone (1 mg/kg) was started for cGVHD of moderate global severity, and the patient was enrolled in a clinical trial for new-onset cGVHD, testing addition of a novel agent vs placebo. Three weeks later, the rash had diminished, oral pain had improved, and she had gained weight; steroids were slowly tapered. Three months later, she presented with severe sclerosis over the limbs and asymmetric erythema and sclerosis over the scapula and shoulder consistent with refractory cGVHD, warranting removal from the clinical trial and reinitiation of tacrolimus and high-dose steroids. Ruxolitinib was also added after insurance approval 2 weeks later. The patient continued to improve, and by 25 months post-HSCT, she was working full time while receiving tacrolimus (5-10 ng/mL), ruxolitinib, and low-dose prednisone.

How do we choose immunosuppressive/immunomodulating agents for refractory cGVHD?

Published definitions of global cGVHD severity and steroid response (refractory, intolerant, or dependent [flares during taper with response at higher doses])24,25  effectively guide practitioners regarding when to modify treatment (Figure 1).28  However, outside of clinical trials, the choice of specific agents remains patient and provider specific. Ibrutinib demonstrated clinical improvement in ∼65% of patients when administered in the landmark trial29  to patients with steroid-refractory GVHD with oral or skin disease. These encouraging results in steroid-refractory disease led to a pivotal phase 3 trial examining ibrutinib as upfront cGVHD treatment. A recent study of current practice revealed use of a variety of therapies in refractory cGVHD, including tacrolimus, sirolimus, rituximab, ruxolitinib, hydroxychloroquine, imatinib, bortezomib, ibrutinib, ECP, nilotinib, pomalidomide, and methotrexate, with a wide range of cost effectiveness.23  Therefore, despite US Food and Drug Administration approval of ibrutinib,13  testing of other agents continues, as evidenced by >20 trials currently being conducted.30 

Figure 1.

NIH global severity assessments to determine need for intervention in patients with ongoing cGVHD.24,25  Our approach to patients seen in our multidisciplinary clinic for ongoing refractory cGVHD entails assessment of global severity score as well as assessment of treatment response measures per consensus publications (yellow box, top left). Patients without treatment response and/or worsening disease require addition of immunosuppressive therapy (IST) and may also require modification of IST. The group of patients with stable or fixed disease (gray box, bottom left) may have unacceptable toxicity from steroids or may have what has been deemed steroid intolerance. For patients with unresponsive cGVHD or fixed organ damage, tapering steroids is typically recommended (to avoid further steroid toxicity) while maintaining other agents that may be keeping disease in a stable state. *After ≤2 weeks if lung or liver or moderate to severe disease; otherwise, after 4 weeks if no life-sustaining organs are involved. †NIH cGVHD consensus definitions: steroid refractory, steroid dependent, steroid intolerant.24,25  LFT, liver function tests; PFT, pulmonary function tests.

Figure 1.

NIH global severity assessments to determine need for intervention in patients with ongoing cGVHD.24,25  Our approach to patients seen in our multidisciplinary clinic for ongoing refractory cGVHD entails assessment of global severity score as well as assessment of treatment response measures per consensus publications (yellow box, top left). Patients without treatment response and/or worsening disease require addition of immunosuppressive therapy (IST) and may also require modification of IST. The group of patients with stable or fixed disease (gray box, bottom left) may have unacceptable toxicity from steroids or may have what has been deemed steroid intolerance. For patients with unresponsive cGVHD or fixed organ damage, tapering steroids is typically recommended (to avoid further steroid toxicity) while maintaining other agents that may be keeping disease in a stable state. *After ≤2 weeks if lung or liver or moderate to severe disease; otherwise, after 4 weeks if no life-sustaining organs are involved. †NIH cGVHD consensus definitions: steroid refractory, steroid dependent, steroid intolerant.24,25  LFT, liver function tests; PFT, pulmonary function tests.

Given these many treatment options, management decisions in refractory ongoing cGVHD are often aided by real-time discussions within a multidisciplinary team. In case 1, we continued 2 agents that were empirically started, noted a response, and pursued a prednisone wean. Although evidence is lacking, use of rapamycin for joint involvement, tacrolimus for myositis, and ruxolitinib for scleroderma can be effective. In our patient, as is commonly done, tacrolimus was reinitiated as a possible steroid-sparing agent. Depending on individual circumstances, tacrolimus may not always be the best choice.31,32  On the basis of randomized phase 2 data33,34  and institutional experience, we often offer ECP for steroid-refractory skin disease, especially sclerodermatous cGVHD. Efficacy data can be found for other agents, including ruxolitinib,35  low-dose interleukin-2,36  nilotinib,37  and rituximab.38,39  Currently, the choice of therapy after failure to achieve PR or CR25  with initial treatment remains patient specific, with comorbidities and history of infectious complications heavily influencing agent choice. These factors, coupled with organ function, toxicities of agents (Table 1), patient preferences, and provider experience, collectively determine the preferred next agent.

Table 1.

Adverse reactions of commonly used therapies in refractory chronic GVHD14 

AgentPotential major adverse effects (with major study citations)Common (>10%) generally less severe adverse effects
Bortezomib Peripheral neuropathy, thrombocytopenia, malignancy relapse106  Herpes virus reactivation 
ECP Vascular access complications107  Thrombocytopenia 
FAM New FDA MedWatch warning; warning only applies to azithromycin use in prophylactic (not treatment) setting108,109   
Ibrutinib (Imbruvica R) Pneumonia,29  impaired platelet function Fatigue, muscle pain, peripheral edema 
Imatinib  Peripheral edema 
Interleukin-2 Injection site induration, infections36  Constitutional flu-like symptoms 
MMF (Cellcept) Viral reactivation, hypertension, pneumonia, posttransplantation lymphoproliferative disease110  GI toxicity, neutropenia, leukopenia 
Pamolidomide Tremor, muscle cramps, peripheral neuropathy111  Skin rash 
Rituximab (Rituxan R) Infection, late neutropenia38,39,112  B lymphopenia 
Ruxolitinib (Jakafi R) Viral reactivation/infection, bacterial infections35  Cytopenias 
Sirolimus (Rapamune) TAM when used in combination with calcineurin inhibitors, renal insufficiency,113  proteinuria Peripheral edema, hyperlipidemia, cytopenias 
AgentPotential major adverse effects (with major study citations)Common (>10%) generally less severe adverse effects
Bortezomib Peripheral neuropathy, thrombocytopenia, malignancy relapse106  Herpes virus reactivation 
ECP Vascular access complications107  Thrombocytopenia 
FAM New FDA MedWatch warning; warning only applies to azithromycin use in prophylactic (not treatment) setting108,109   
Ibrutinib (Imbruvica R) Pneumonia,29  impaired platelet function Fatigue, muscle pain, peripheral edema 
Imatinib  Peripheral edema 
Interleukin-2 Injection site induration, infections36  Constitutional flu-like symptoms 
MMF (Cellcept) Viral reactivation, hypertension, pneumonia, posttransplantation lymphoproliferative disease110  GI toxicity, neutropenia, leukopenia 
Pamolidomide Tremor, muscle cramps, peripheral neuropathy111  Skin rash 
Rituximab (Rituxan R) Infection, late neutropenia38,39,112  B lymphopenia 
Ruxolitinib (Jakafi R) Viral reactivation/infection, bacterial infections35  Cytopenias 
Sirolimus (Rapamune) TAM when used in combination with calcineurin inhibitors, renal insufficiency,113  proteinuria Peripheral edema, hyperlipidemia, cytopenias 

This list of agents represents a fraction of agents being actively evaluated. Preferred use of any agent still requires validation via larger clinical trials.

ECP, extracorporeal photopheresis; FAM, fluticasone, azithromycin, and montelukast; FDA, US Food and Drug Administration; GI, gastrointestinal; MMF, mycophenolate mofetil; TAM, transplantation-associated microangiopathy.

Case 1 also illustrates the unfortunate gap between recommendations and practice. Rather than being seen monthly as recommended, the patient did not return until 3 months after initial diagnosis of cGVHD. This was because the patient lived a considerable distance from the transplantation center, a factor that has been associated with poorer outcome.40 

What do we use as adjunctive nonsystemic therapies?

Experience and evidence-based consensus opinion support organ-directed topical treatments in cGVHD.41  Although few generalizable standards currently exist, aggressive local therapies may be crucial in managing morbidities.

Adjunctive measures in oral cGVHD

Dexamethasone rinse given twice daily is our preferred topical steroid because it has known benefit in cGVHD,42  although another trial suggested clobetasol oral rinse may be more effective in reducing ulcers and symptoms.43  Some practitioners prefer budesonide rinses over dexamethasone, with studies showing equal efficacy.44  In severe cases, we often use high-potency topical steroids, such as clobetasol 0.05% gel or ointment, 2 to 3 times a day, applied to the buccal mucosal or palate in a manner similar to treatment of autoimmune blistering diseases and oral lichen planus.45,46  Dental trays are useful in applying gels or ointments to the gingiva, but because high-potency topical steroids increase the risk of mucosal candidiasis, we add nystatin rinses.

In patients with ongoing mouth sores, it is important to exclude other contributing causes, including infection and alcohol-based rinses. Even when prescribed as alcohol free, pharmacies may dispense steroid or calcineurin compounded in alcohol-based products, with resulting worsening of symptoms. Oral infections with herpes simplex virus, Epstein-Barr virus, cytomegalovirus, and Candida may also contribute to symptoms. Delay in identifying acyclovir-resistant herpes simplex virus has been associated with increased hospitalization and kidney injury from acyclovir.47  Oral colonization with Candida occurs in half of immunosuppressed patients and fosters chronic oral ulcers.48,49 

To identify dysplasia, referral to an oral surgeon for biopsy should be considered. Oral lichen planus has been associated with development of squamous cell carcinoma (SCC), and individuals with oral cGVHD are at higher risk of developing SCC.50  Some authors suggest that chronic mucosal inflammation is the predisposing factor for SCC in oral lichen planus and that treatment with topical steroids may help ameliorate risk.51,52  An international case-control study noted that those undergoing allogeneic HSCT who received systemic immunosuppressive therapy for ≥24 months had a 5.6-fold higher relative risk of developing buccal mucosal SCC, and the risk for those with cGVHD was even higher.53  Azathioprine rinse has been evaluated in treatment of oral mucosal inflammatory diseases such as cGVHD,54,55  but we do not include this in our therapy algorithm because of the association of systemic azathioprine with SCC.53 

Adjunctive treatments for skin involvement and sclerodermatous cGVHD

Although sclerodermatous dermal manifestations can reverse, they may also be refractory to therapy, with waxing and waning findings. Unfortunately, it is not possible to determine which lesions are fixed and which will improve over time. New agents and concepts of the pathobiology of cGVHD and inflammation-driven fibrosis suggest scleroderma reversibility.15,56,57  In individuals with skin flares, it is crucial to exclude sun exposure or other immune/tissue-inciting events. Trauma from clothing, repetitive movements, or the sun can incite sclerodermatous changes.58  The isomorphic response or Koebner phenomenon (development of disease in otherwise uninvolved skin in response to injury) and the isotopic response (development of disease in areas of prior inflammation or old damage) are described in several cutaneous inflammatory disorders. Injury leading to GVHD can be induced by UV damage, mechanical trauma, irradiation, and infections (viral exanthems).59  Chronic cutaneous GVHD has been observed at injection sites, pressure areas from waistbands, and prior varicella infection. Our first patient’s clinical presentation was striking for the asymmetric sclerosis of the skin over the scapula, which was part of a radiation field before transplantation.60  Measures to minimize additional injury include use of sun protective clothing, UVA- and UVB-blocking sunscreen, and avoidance of constrictive clothing.

Topical agents can be useful adjuncts in the management of cutaneous cGVHD. Tacrolimus 0.1% ointment can improve erythema and pruritus in patients with steroid-refractory skin disease.61  Although dermal application of tacrolimus does not lead to dermal atrophy, the risk of developing skin cancers with prolonged use remains an unsettled issue.62,63  Topical corticosteroids, however, remain a mainstay of therapy, even if controlled trials are lacking.64  Techniques for maximizing benefit include choosing a high-potency topical medication, adequately hydrating the skin before application of topical steroids, and occluding the treated area after application of topical medications. Treatment with high-potency steroids over large body-surface areas can be as effective as and safer than systemic corticosteroids in the treatment of severe cutaneous autoimmune disease.65  Hydrating the skin before application of topical steroids and occlusion with wet wraps or a sauna suit increase penetration of the medication into the skin but also increase the risk of systemic absorption and contribute to cutaneous atrophy and depigmentation. Many practitioners recommend limiting the use of wet-wrap therapy with topical steroids to once a day for no more than 14 days with 10% dilution of either 0.1% triamcinolone or mometasone to minimize the risk of hypothalamic pituitary axis suppression.

Peripheral edema also has been associated with subsequent onset of sclerotic cGVHD and deep cutaneous/fascial involvement.66  Maximizing edema control can provide additional relief and prevent sclerosis in individuals who have significant bipedal edema. Patients who have normal or only minimally impaired arterial flow (indicated by ankle brachial index of ≥0.8) will likely tolerate compression. For more complex edema or if leg ulcers are present, wound clinic evaluation is sought for compression bandage wraps or home compression pumps as appropriate. Finally, we and others find intensive physical therapy provides significant functional improvement.67,68  Comprehensive local therapy offers patients with sclerodermatous lesions potential symptomatic relief.

Adjunctive measures in ocular cGVHD

Eye complaints are common in cGVHD, and ophthalmologists can diagnose involvement based on hallmark findings of new onset of keratoconjunctivitis sicca (ie, dry eye) with conjunctival hyperemia, confluent areas of punctate keratopathy on fluorescein staining, corneal epithelial defects, or overt fibrosis of the tarsal conjunctiva. In contrast to acute GVHD, chronic ocular disease is scored with a combined score using conjunctival hyperemia and corneal staining, which are parameters of sicca.69  Increased exudates reflecting additional pathologic processes require skilled attention. The best early marker for ocular cGVHD, however, is the patient’s history, and revised NIH criteria now score eye disease according to number of times per day that patients use moisturizing eye drops.25  Use of topical steroids and cyclosporine can lessen ocular involvement of the conjunctiva and cornea, and these are used to treat conjunctivitis and keratitis.70-72  Necrotizing keratolysis with corneal thinning (ie, melt) is uncommon in the absence of infection. Although evidence-based standardized treatment of ocular cGVHD is lacking,73  improved understanding of the immunology of ocular surface inflammation and communication with ophthalmologists can ensure implementation of effective therapies beyond steroids. In patients with mild ocular cGVHD, first-line therapy includes both lubrication and ophthalmic prednisolone with cyclosporine (0.05% to 0.5%). High-dose steroids should be used for only short periods.70  If after 4 to 6 weeks there is no improvement, additional therapies are indicated. Systemic agents (eg, FK506, SYK or JAK inhibitors) have been formulated for ophthalmic use.70,74  Although use of autologous serum tears remains controversial, some patients achieve life-improving benefit with a 4- to 8-week course.75,76  The lymphocyte function-associated antigen 1 antagonist lifitegrast ophthalmic 5% (Xiidra R) is US Food and Drug Administration approved for dry eye disease77  and was used in our patient. Finally, scleral lenses can be key to improving chronic sicca symptoms or fibrosis of the tarsal conjunctiva.

Ongoing ocular cGVHD is more than a lacrimal gland problem and can occur irrespective of total-body irradiation exposure.78  The pathobiology of ocular cGVHD is thought to be due to atrophy and fibrosis of lacrimal glands. In addition to tear production defects, there is also a lack of oil production by meibomian glands and gland dropout, which is a hallmark finding. Conjunctival complications occur in 4 stages.69  In the first 2 stages, patients have clinical conjunctivitis (hyperemia with or without serosanguinous exudates), as was found in our patient. In stage 3, conjunctival pseudomembranes form. When sloughing of the corneal epithelium occurs, patients have stage 4 conjunctival disease. Both keratinization and development of symblepharon (adhesion of the palpebral conjunctiva to the bulbar conjunctiva) and entropion (rolling inward of the eyelid against the ocular surface) lead to mechanical issues with eye closing and moisture maintenance. Conjunctival and subconjunctival fibrosis and conjunctival/subepithelial scarring occur in cGVHD. In addition to de novo corneal involvement (keratopathy), involvement of the eyelid (including skin) is an important factor in development of eye dryness and downstream pathologic findings on the corneal surface. Corneal surface damage occurs as a result of ongoing trauma from eyelid/eyelash movement over nonlubricated surface.

Corneal abrasion and ulcerations require urgent attention because they can lead to blindness. As with our patient, eye pain or altered vision should prompt same-day ophthalmologic evaluation. In patients not improving, confirmation that artificial tears and other agents are preservative free is imperative, because preservatives can exacerbate irritation. Additionally, a high suspicion for superimposed infection is important. Patients often downplay eye findings when the systemic issues worsen, and re-referral to ophthalmology can be inadvertently delayed. Use of any of several types of scleral lenses (in large part determined by insurance availability) requires proper lens care and hygiene. As with our patient, bacterial or other treatable infections require urgent intervention to avert permanent corneal scarring and blindness.

How do we track patients with ongoing cGVHD and modify immunosuppression?

Individuals with complex and multisystem disease are best served in a multidisciplinary care setting. Transdisciplinary care of recipients of HSCT for autoimmune diseases confirms that dedicated and experienced multidisciplinary teams improve outcomes. Because such clinics are not always available, Syrjala et al79  report a means to integrate long-distance care. Even so, in patients with refractory cGVHD, the level of response or lack of response is often difficult to objectively measure. Another caveat is that providers and patients are reticent to add systemic to topical therapy in certain instances of moderate cGVHD. For example, 3 organs may include limited involvement of mouth, skin, and eye, manageable without systemic immunosuppression, despite being deemed moderate cGVHD by NIH consensus criteria. Accordingly, the NIH consensus working group on clinical trial development has proposed hard primary end points that can be employed in the clinic.80  Although the NIH treatment criteria were designed to assist drug trial reporting, organ-based NIH scoring is also useful in monitoring and treatment.24  Routine blood count checks in our patient did not reveal thrombocytopenia or lymphopenia with eosinophilia,81  2 features associated with poor prognosis. We also routinely check pulmonary function tests (PFTs) at the time of diagnosis and every 3 to 6 months depending on trends, because drop in forced expiratory volume (FEV1) levels precedes radiographic or overt clinical findings, and preemptive treatment is effective. As soon as PFT abnormalities raise concern for lung involvement, we obtain chest computed tomography (CT) scans as part of a workup to rule out infectious etiology. This includes a potential bronchoscopy for diagnostic alveolar lavage fluid. If there is no active infection, we start the FAM regimen and monitor as outlined in “How I treat bronchiolitis obliterans.”82 

Individuals with moderate or severe disease require initial weekly reassessments. For consistent assessment, we have the 2014 NIH cGVHD score and global severity score templates in our electronic chart in clinic (supplemental Table 1, available on the Blood Web site). The NIH cGVHD severity score and a determination as to whether the patient is responding to steroids are useful benchmarks for adjustments in treatment (Figure 1). Clinical responses were recently found to be significantly associated with NIH-defined PR and CR measures. Patients require modification of immunosuppression if they have not at least achieved a PR per NIH criteria or are deemed steroid dependent or intolerant. Individuals who are clinically stable with unresponsive disease despite increasing immunosuppression may have fixed organ damage.25  Although ill defined, expert opinion suggests some nonresponding patients without active cGVHD manifestations do not warrant an increase in therapy, but rather, watchful waiting may be appropriate in some nonresponding patients who do not have active cGVHD manifestations.

As novel agents become available, there may be a tendency for practitioners to start with lower doses of steroids to avoid toxicity when treating newly diagnosed cGVHD or flares after immunosuppressive taper. This leads to ping-ponging dosages. Unless a patient has clearly defined steroid intolerance or clear evidence of cGVHD worsening, we use 0.5 to 1 mg/kg daily doses of prednisone for 3 to 4 weeks, guided by the global severity score as to when immunosuppression should be changed. On the basis of experience at many centers, changing agents too frequently has not been beneficial. Recent natural history data from the cGVHD consortium affirm that patients who have a flare of cGVHD on first wean of immunosuppression are highly likely to remain on therapy, and subsequent tapers of agents are associated with reflares.10,12,24,83  When cGVHD flares during immunosuppression wean, readministration of steroids commonly occurs, especially with manifestations involving life-sustaining organs. Data are lacking regarding when and whether to reinstitute steroids or whether other agents would benefit patients. Consistent with consensus group recommendations, it seems reasonable to make treatment changes after 2 unsuccessful attempts to wean steroids within 4 months.28,84,85 

A 54-year-old man developed moderate cGVHD 7 months after myeloablative matched-sibling HSCT for acute leukemia. Two weeks before the clinic visit, the patient had started 0.5 mg/kg of prednisone for new-onset skin, eye, and mouth findings consistent with cGVHD. Because he did not show up for clinic follow-up, the nurse called and learned he felt too ill to drive to the transplantation center. The next day, the local oncologist evaluated the patient and found that he felt better, with no concerning findings on examination, but had developed new-onset thrombocytopenia. The patient reported substantial symptom relief from local mouth, eye, and skin treatments. Improvements and hyperglycermia led to the local decision to start an early steroid taper. Two weeks later, the patient drove the 3 hours to his transplantation center for evaluation. His complaint was worsening fatigue.

How we routinely screen for associated comorbidity

Most individuals with cGVHD experience severe fatigue, but approximately one-third of these patients have reversible causes. Constitutional complaints such as fatigue are especially difficult to address in cGVHD, because patients have become so accustomed to feeling poorly, they are unable to articulate a change. At each clinic visit, systematic review of specific objective prognosticators86,87  can be helpful (Figure 2). Reversible causes of chronic fatigue, such as adrenal insufficiency, hypothyroidism, vitamin-deficiency anemia, or infection, may go undiagnosed. Tertiary adrenal insufficiency can occur on slow steroid tapers and in patients receiving high-dose progestin treatment of anorexia. Overuse of benzodiazepines or opiates may also lead to profound fatigue and decreased cortisol production after steroid weaning. In addition, sirolimus may contribute to fatigue.88  Anemia causing fatigue is not uncommon and is often dismissed as being related to graft function or chronic disease. Patients with cGVHD may have poor nutrition, warranting B12 and folate studies and, for those with known gastrointestinal absorption issues, copper and zinc testing. Reciprocally, concomitant psychological issues warrant frequent readdressing, especially given that cGVHD patients with self-reported depression or anxiety and financial burdens are at risk for poor outcome.89-91  Accordingly, we find same-day telephone calls to no-show clinic patients are useful to assess clinical status and encourage in-person evaluation. Acute or subacute onset of fatigue should always raise suspicion for infection, which may be deadly. Likewise, treatable deep venous thrombosis should be considered, because deep venous thrombosis is relatively common in cGVHD.92  Additionally, cardiopulmonary symptoms should raise suspicion of pleural effusion or pericarditis as serosal manifestations of disease. Therefore, systematic evaluation for poor prognostic factors in cGVHD is imperative (Figure 2).

Figure 2.

Assessment of worsening cGVHD reflective of cGVHD pathophysiology that requires urgent attention. (A) Decrease in FEV1 may reflect pathology of bronchiolitis obliterans found in cGVHD. High lung symptom score carries a high risk of death.102  Pulmonary function test abnormalities, specifically evidence of obstruction (FEV1/FVC <0.7) and decreases in FEV1, should raise strong suspicion for development of lung cGVHD, because FEV1 decrease without evidence of restrictive disease may reflect underlying small airway occlusion related to extracellular matrix deposited within or around the airways in cGVHD. Because a drop of FEV1 alone is an indicator of impaired lung function and could be also due to restrictive lung disease, FEV1 is a useful indicator of obstruction only when FEV1/FVC is <0.7 (consistent with obstructive lung disease). (B) Abnormal liver tests may reflect liver pathology in cGVHD that is associated with increased mortality.103  cGVHD of the liver can be diagnosed and tracked in patients using total bilirubin and alkaline phosphatase per NIH consensus criteria.25  An increase in total bilirubin occurs when conjugated bilirubin is not excreted, either because of inflammation or loss of the ducts. When the ducts are not functioning properly, alkaline phosphatase rises. Dysfunctional bile ducts can be due to bile duct dropout, presumably a result of cellular damage and preceding inflammation or (more rarely) fibrosis. Infectious or drug-induced causes, in some cases, should be ruled out via biopsy. (C) Significant weight loss with or without diarrhea warrants further investigation because of its association with increased mortality.94,104  The etiology of weight loss may be multifactorial and, importantly, may be reversible (eg, decreased calorie intake related to oral cGVHD, esophageal stricture, or intestinal malabsorption). (D) Abnormalities found on the complete blood count are known prognostic factors,9,79,101,105  including in newly diagnosed cGVHD.81,105  CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; PCR, polymerase chain reaction.

Figure 2.

Assessment of worsening cGVHD reflective of cGVHD pathophysiology that requires urgent attention. (A) Decrease in FEV1 may reflect pathology of bronchiolitis obliterans found in cGVHD. High lung symptom score carries a high risk of death.102  Pulmonary function test abnormalities, specifically evidence of obstruction (FEV1/FVC <0.7) and decreases in FEV1, should raise strong suspicion for development of lung cGVHD, because FEV1 decrease without evidence of restrictive disease may reflect underlying small airway occlusion related to extracellular matrix deposited within or around the airways in cGVHD. Because a drop of FEV1 alone is an indicator of impaired lung function and could be also due to restrictive lung disease, FEV1 is a useful indicator of obstruction only when FEV1/FVC is <0.7 (consistent with obstructive lung disease). (B) Abnormal liver tests may reflect liver pathology in cGVHD that is associated with increased mortality.103  cGVHD of the liver can be diagnosed and tracked in patients using total bilirubin and alkaline phosphatase per NIH consensus criteria.25  An increase in total bilirubin occurs when conjugated bilirubin is not excreted, either because of inflammation or loss of the ducts. When the ducts are not functioning properly, alkaline phosphatase rises. Dysfunctional bile ducts can be due to bile duct dropout, presumably a result of cellular damage and preceding inflammation or (more rarely) fibrosis. Infectious or drug-induced causes, in some cases, should be ruled out via biopsy. (C) Significant weight loss with or without diarrhea warrants further investigation because of its association with increased mortality.94,104  The etiology of weight loss may be multifactorial and, importantly, may be reversible (eg, decreased calorie intake related to oral cGVHD, esophageal stricture, or intestinal malabsorption). (D) Abnormalities found on the complete blood count are known prognostic factors,9,79,101,105  including in newly diagnosed cGVHD.81,105  CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; PCR, polymerase chain reaction.

Our patient had no dyspnea at rest, and his lung examination was unrevealing. With prompting, he admitted diminished ability to conduct normal activities, and he had stopped climbing stairs because of dyspnea. After walking <1 minute in clinic, oxygen saturation fell from 100% to 82%. With evidence of lung involvement concerning for cGVHD progression, he was admitted for further workup and management. Empiric antibiotics for atypical and typical organisms were initiated that day. High-resolution CT imaging revealed classic lucencies or air trapping in lung parenchyma during expiration. Methylprednisolone and the FAM regimen were initiated, PFTs were ordered, and tacrolimus was administered, and FEV1 subsequently stabilized. However, during outpatient steroid taper, total bilirubin increased to 4.8 mg/dL. Accordingly, ursodiol and IV tacrolimus were added. A liver biopsy showed cholestasis and bile duct damage with bile duct dropout; trichrome stains showed minimal fibrosis. Bronchoscopy with alveolar lavage had been unrevealing for infectious causes. Over the next 10 days, serum bilirubin improved to 2.5 mg/dL, but the patient had progressive respiratory failure.

How we routinely screen for poor prognostic factors and red flags in patients with ongoing cGVHD

Patients with increased total bilirubin, thrombocytopenia at cGVHD onset, progressive-type cGVHD, increased transplant recipient age, and/or donor HLA mismatch have associated increased mortality.93,94  We find that frequent follow-up visits to the transplantation clinic are critical in assessing GVHD response and detecting potentially life-threatening but reversible complications. We have summarized these red flags and prognostic indicators in Figure 2. As with our patient in case 2, the 2-minute walk test is an objective measure of exertional hypoxia, and studies from the Chronic GVHD Consortium support its prognostic value.95  Bronchiolitis obliterans is a notoriously insidious and deadly manifestation of cGVHD.82  The revised NIH consensus criteria and European consensus statement96  deem FEV1 to be the most useful PFT in this patient population. In individuals without restrictive findings and FEV1/FVC <0.7, FEV1 decline reflects airways that are either obliterated or compressed by the extracellular matrix. Expiratory chest CT scan can then be pathognomonic, highlighting air trapping consistent with bronchiolitis obliterans.

Evaluation for potential liver cGVHD includes determination of whether transaminases are increased to >3 times the normal levels; however, these are not prognostic indicators. Total bilirubin and alkaline phosphatase elevations may reflect life-threatening hepatic cGVHD that can be halted with corticosteroid retreatment. Total bilirubin and alkaline phosphatase reflect underlying cholestasis and bile duct dysfunction, which lead to abrogation or dropout (Figure 2). Ursodiol may also be of benefit.97  Significant weight loss may result from multiple etiologies, including esophageal stricture.98  Although less well studied than other target organs, gastrointestinal cGVHD has been associated with increased morbidity and mortality. Persisting diarrhea, nausea, or weight loss should prompt evaluations for Clostridioides difficile or enteric viruses. Similarly, polymerase chain reaction of stool samples for enteroviruses and endoscopy are employed to rule out viral infection. Evidence suggests that endoscopic sampling of both upper and lower gastrointestinal sites increases the likelihood of diagnosing cGVHD and viral etiologies.99  cGVHD mortality, however, remains high in these patients despite endoscopy as part of a diagnostic workup, suggesting that ongoing vigilance is warranted.100 

Improved understanding of GVHD biology15  and identification of new therapeutic targets have enhanced our ability to treat refractory cGVHD, a preeminent complication of allogeneic HSCT. Although guided by clinical trial evidence and expert consensus, therapeutic choices in cGVHD remain patient and provider specific. This approach, which is now being termed interpersonal medicine, affords effective care while taking into account the patient’s circumstances and preferences.101  Along with systemic immunosuppressive/immunomodulatory therapy, aggressive organ-based adjunctive management of cGVHD is warranted. Because this complex disease may present multiple manifestations over time, the continuing care of patients with cGVHD requires frequent monitoring to detect warning signs of disease change or intercurrent, potentially reversible, illnesses.

The online version of this article contains a data supplement.

The authors thank the Duke multidisciplinary clinic providers, especially Matthew Williams and Krista Rowe. Victor L. Perez, Nelson Chao, and Joel Ross assisted with the manuscript.

The work was supported in part by funding from the National Institutes of Health, National Heart, Lung, and Blood Institute (R01HL129061; S.S.).

Contribution: S.S., A.R.C., and K.M.S. wrote the manuscript.

Conflict-of-interest disclosure: S.S. received a research grant from Gilead and served on advisory boards for Pharmacyclics. The remaining authors declare no competing financial interests.

Correspondence: Stefanie Sarantopoulos, Department of Medicine, Box 3961, Duke University Medical Center, Durham, NC 27710; e-mail: stefanie.sarantopoulos@duke.edu.

1.
Graze
PR
,
Gale
RP
.
Chronic graft versus host disease: a syndrome of disordered immunity
.
Am J Med
.
1979
;
66
(
4
):
611
-
620
.
2.
Shulman
HM
,
Sullivan
KM
,
Weiden
PL
, et al
.
Chronic graft-versus-host syndrome in man. A long-term clinicopathologic study of 20 Seattle patients
.
Am J Med
.
1980
;
69
(
2
):
204
-
217
.
3.
Sullivan
KM
,
Shulman
HM
,
Storb
R
, et al
.
Chronic graft-versus-host disease in 52 patients: adverse natural course and successful treatment with combination immunosuppression
.
Blood
.
1981
;
57
(
2
):
267
-
276
.
4.
Soiffer
RJ
,
Kim
HT
,
McGuirk
J
, et al
.
Prospective, randomized, double-blind, phase III clinical trial of anti-T-lymphocyte globulin to assess impact on chronic graft-versus-host disease-free survival in patients undergoing HLA-matched unrelated myeloablative hematopoietic cell transplantation
.
J Clin Oncol
.
2017
;
35
(
36
):
4003
-
4011
.
5.
Kröger
N
,
Solano
C
,
Wolschke
C
, et al
.
Antilymphocyte globulin for prevention of chronic graft-versus-host disease
.
N Engl J Med
.
2016
;
374
(
1
):
43
-
53
.
6.
Socié
G
,
Ritz
J
.
Current issues in chronic graft-versus-host disease
.
Blood
.
2014
;
124
(
3
):
374
-
384
.
7.
Niederwieser
D
,
Baldomero
H
,
Szer
J
, et al
.
Hematopoietic stem cell transplantation activity worldwide in 2012 and a SWOT analysis of the Worldwide Network for Blood and Marrow Transplantation Group including the global survey
.
Bone Marrow Transplant
.
2016
;
51
(
6
):
778
-
785
.
8.
Arai
S
,
Arora
M
,
Wang
T
, et al
;
Graft-vs-Host Disease Working Committee of the CIBMTR
.
Increasing incidence of chronic graft-versus-host disease in allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research
.
Biol Blood Marrow Transplant
.
2015
;
21
(
2
):
266
-
274
.
9.
Sullivan
KM
,
Witherspoon
RP
,
Storb
R
, et al
.
Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-v-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation
.
Blood
.
1988
;
72
(
2
):
546
-
554
.
10.
Flowers
ME
,
Martin
PJ
.
How we treat chronic graft-versus-host disease
.
Blood
.
2015
;
125
(
4
):
606
-
615
.
11.
Martin
PJ
,
Storer
BE
,
Inamoto
Y
, et al
.
An endpoint associated with clinical benefit after initial treatment of chronic graft-versus-host disease
.
Blood
.
2017
;
130
(
3
):
360
-
367
.
12.
Martin
PJ
,
Lee
SJ
,
Przepiorka
D
, et al
.
National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: VI. The 2014 Clinical Trial Design Working Group report
.
Biol Blood Marrow Transplant
.
2015
;
21
(
8
):
1343
-
1359
.
13.
Jaglowski
SM
,
Blazar
BR
.
How ibrutinib, a B-cell malignancy drug, became an FDA-approved second-line therapy for steroid-resistant chronic GVHD
.
Blood Adv
.
2018
;
2
(
15
):
2012
-
2019
.
14.
Im
A
,
Hakim
FT
,
Pavletic
SZ
.
Novel targets in the treatment of chronic graft-versus-host disease
.
Leukemia
.
2017
;
31
(
3
):
543
-
554
.
15.
Zeiser
R
,
Blazar
BR
.
Pathophysiology of chronic graft-versus-host disease and therapeutic targets
.
N Engl J Med
.
2017
;
377
(
26
):
2565
-
2579
.
16.
MacDonald
KP
,
Hill
GR
,
Blazar
BR
.
Chronic graft-versus-host disease: biological insights from preclinical and clinical studies
.
Blood
.
2017
;
129
(
1
):
13
-
21
.
17.
MacDonald
KPA
,
Betts
BC
,
Couriel
D
.
Emerging therapeutics for the control of chronic graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2018
;
24
(
1
):
19
-
26
.
18.
Cooke
KR
,
Luznik
L
,
Sarantopoulos
S
, et al
.
The biology of chronic graft-versus-host disease: a task force report from the National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2017
;
23
(
2
):
211
-
234
.
19.
Cutler
CS
,
Koreth
J
,
Ritz
J
.
Mechanistic approaches for the prevention and treatment of chronic GVHD
.
Blood
.
2017
;
129
(
1
):
22
-
29
.
20.
Gorry
GA
.
A piece of my mind. Decisions, decisions
.
JAMA
.
2010
;
304
(
21
):
2339
-
2340
.
21.
Sullivan
KM
,
Horwitz
M
,
Osunkwo
I
,
Shah
N
,
Strouse
JJ
.
Shared decision-making in hematopoietic stem cell transplantation for sickle cell disease
.
Biol Blood Marrow Transplant
.
2018
;
24
(
5
):
883
-
884
.
22.
Fried
TR
.
Shared decision making--finding the sweet spot
.
N Engl J Med
.
2016
;
374
(
2
):
104
-
106
.
23.
Yalniz
FF
,
Murad
MH
,
Lee
SJ
, et al
.
Steroid refractory chronic graft-versus-host disease: cost-effectiveness analysis
.
Biol Blood Marrow Transplant
.
2018
;
24
(
9
):
1920
-
1927
.
24.
Lee
SJ
,
Wolff
D
,
Kitko
C
, et al
.
Measuring therapeutic response in chronic graft-versus-host disease. National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. The 2014 Response Criteria Working Group report
.
Biol Blood Marrow Transplant
.
2015
;
21
(
6
):
984
-
999
.
25.
Jagasia
MH
,
Greinix
HT
,
Arora
M
, et al
.
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 report
.
Biol Blood Marrow Transplant
.
2015
;
21
(
3
):
389
-
401.e1
.
26.
American Society for Blood and Marrow Transplantation
.
Practice resources
.
Available at: www.asbmt.org/practice-resources. Accessed 1 February 2019
.
27.
UZ Leuven
.
eGVHD
.
Available at: www.uzleuven.be/egvhd. Accessed 1 February 2019
.
28.
Schoemans
HM
,
Lee
SJ
,
Ferrara
JL
, et al
;
EBMT (European Society for Blood and Marrow Transplantation) Transplant Complications Working Party and the “EBMT−NIH (National Institutes of Health)−CIBMTR (Center for International Blood and Marrow Transplant Research) GvHD Task Force”
.
EBMT-NIH-CIBMTR Task Force position statement on standardized terminology & guidance for graft-versus-host disease assessment
.
Bone Marrow Transplant
.
2018
;
53
(
11
):
1401
-
1415
.
29.
Miklos
D
,
Cutler
CS
,
Arora
M
, et al
.
Ibrutinib for chronic graft-versus-host disease after failure of prior therapy
.
Blood
.
2017
;
130
(
21
):
2243
-
2250
.
30.
US National Library of Medicine
.
ClinicalTrials.gov
.
Available at: www.clinicaltrials.gov. Accessed 1 February 2019
.
31.
Orlandi
V
,
Campieri
C
,
Mosconi
G
, et al
.
Tacrolimus-associated myositis: a case report in a renal transplant patient
.
Transplant Proc
.
2004
;
36
(
3
):
708
-
710
.
32.
Vattemi
G
,
Marini
M
,
Di Chio
M
,
Colpani
M
,
Guglielmi
V
,
Tomelleri
G
.
Polymyositis in solid organ transplant recipients receiving tacrolimus
.
J Neurol Sci
.
2014
;
345
(
1-2
):
239
-
243
.
33.
Gandelman
JS
,
Song
DJ
,
Chen
H
, et al
.
A prospective trial of extracorporeal photopheresis for chronic graft-versus-host disease reveals significant disease response and no association with frequency of regulatory T cells
.
Biol Blood Marrow Transplant
.
2018
;
24
(
12
):
2373
-
2380
.
34.
Flowers
ME
,
Apperley
JF
,
van Besien
K
, et al
.
A multicenter prospective phase 2 randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease
.
Blood
.
2008
;
112
(
7
):
2667
-
2674
.
35.
Zeiser
R
,
Burchert
A
,
Lengerke
C
, et al
.
Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey
.
Leukemia
.
2015
;
29
(
10
):
2062
-
2068
.
36.
Koreth
J
,
Matsuoka
K
,
Kim
HT
, et al
.
Interleukin-2 and regulatory T cells in graft-versus-host disease
.
N Engl J Med
.
2011
;
365
(
22
):
2055
-
2066
.
37.
van der Wagen
L
,
Te Boome
L
,
Schiffler
M
, et al
.
Prospective evaluation of sequential treatment of sclerotic chronic graft versus host disease with rituximab and nilotinib
.
Bone Marrow Transplant
.
2018
;
53
(
10
):
1255
-
1262
.
38.
Zaja
F
,
Bacigalupo
A
,
Patriarca
F
, et al
;
GITMO (Gruppo Italiano Trapianto Midollo Osseo)
.
Treatment of refractory chronic GVHD with rituximab: a GITMO study
.
Bone Marrow Transplant
.
2007
;
40
(
3
):
273
-
277
.
39.
Cutler
C
,
Miklos
D
,
Kim
HT
, et al
.
Rituximab for steroid-refractory chronic graft-versus-host disease
.
Blood
.
2006
;
108
(
2
):
756
-
762
.
40.
Abou-Nassar
KE
,
Kim
HT
,
Blossom
J
, et al
.
The impact of geographic proximity to transplant center on outcomes after allogeneic hematopoietic stem cell transplantation
.
Biol Blood Marrow Transplant
.
2012
;
18
(
5
):
708
-
715
.
41.
Wolff
D
,
Gerbitz
A
,
Ayuk
F
, et al
.
Consensus conference on clinical practice in chronic graft-versus-host disease (GVHD): first-line and topical treatment of chronic GVHD
.
Biol Blood Marrow Transplant
.
2010
;
16
(
12
):
1611
-
1628
.
42.
Treister
N
,
Li
S
,
Kim
H
, et al
.
An open-label phase II randomized trial of topical dexamethasone and tacrolimus solutions for the treatment of oral chronic graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2016
;
22
(
11
):
2084
-
2091
.
43.
Noce
CW
,
Gomes
A
,
Shcaira
V
, et al
.
Randomized double-blind clinical trial comparing clobetasol and dexamethasone for the topical treatment of symptomatic oral chronic graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2014
;
20
(
8
):
1163
-
1168
.
44.
Park
AR
,
La
HO
,
Cho
BS
, et al
.
Comparison of budesonide and dexamethasone for local treatment of oral chronic graft-versus-host disease
.
Am J Health Syst Pharm
.
2013
;
70
(
16
):
1383
-
1391
.
45.
Carbone
M
,
Conrotto
D
,
Carrozzo
M
,
Broccoletti
R
,
Gandolfo
S
,
Scully
C
.
Topical corticosteroids in association with miconazole and chlorhexidine in the long-term management of atrophic-erosive oral lichen planus: a placebo-controlled and comparative study between clobetasol and fluocinonide
.
Oral Dis
.
1999
;
5
(
1
):
44
-
49
.
46.
Lozada-Nur
F
,
Miranda
C
,
Maliksi
R
.
Double-blind clinical trial of 0.05% clobetasol propionate (corrected from proprionate) ointment in orabase and 0.05% fluocinonide ointment in orabase in the treatment of patients with oral vesiculoerosive diseases
.
Oral Surg Oral Med Oral Pathol
.
1994
;
77
(
6
):
598
-
604
.
47.
Ariza-Heredia
EJ
,
Chemaly
RF
,
Shahani
LR
,
Jang
Y
,
Champlin
RE
,
Mulanovich
VE
.
Delay of alternative antiviral therapy and poor outcomes of acyclovir-resistant herpes simplex virus infections in recipients of allogeneic stem cell transplant - a retrospective study
.
Transpl Int
.
2018
;
31
(
6
):
639
-
648
.
48.
Dongari-Bagtzoglou
A
,
Dwivedi
P
,
Ioannidou
E
,
Shaqman
M
,
Hull
D
,
Burleson
J
.
Oral Candida infection and colonization in solid organ transplant recipients
.
Oral Microbiol Immunol
.
2009
;
24
(
3
):
249
-
254
.
49.
Epstein
JB
,
Truelove
EL
,
Hanson-Huggins
K
, et al
.
Topical polyene antifungals in hematopoietic cell transplant patients: tolerability and efficacy
.
Support Care Cancer
.
2004
;
12
(
7
):
517
-
525
.
50.
Demarosi
F
,
Lodi
G
,
Carrassi
A
,
Soligo
D
,
Sardella
A
.
Oral malignancies following HSCT: graft versus host disease and other risk factors
.
Oral Oncol
.
2005
;
41
(
9
):
865
-
877
.
51.
Mignogna
MD
,
Fedele
S
,
Lo Russo
L
,
Lo Muzio
L
,
Bucci
E
.
Immune activation and chronic inflammation as the cause of malignancy in oral lichen planus: is there any evidence?
Oral Oncol
.
2004
;
40
(
2
):
120
-
130
.
52.
Otero-Rey
EM
,
Suarez-Alen
F
,
Peñamaria-Mallon
M
,
Lopez-Lopez
J
,
Blanco-Carrion
A
.
Malignant transformation of oral lichen planus by a chronic inflammatory process. Use of topical corticosteroids to prevent this progression?
Acta Odontol Scand
.
2014
;
72
(
8
):
570
-
577
.
53.
Curtis
RE
,
Metayer
C
,
Rizzo
JD
, et al
.
Impact of chronic GVHD therapy on the development of squamous-cell cancers after hematopoietic stem-cell transplantation: an international case-control study
.
Blood
.
2005
;
105
(
10
):
3802
-
3811
.
54.
Epstein
JB
,
Gorsky
M
,
Epstein
MS
,
Nantel
S
.
Topical azathioprine in the treatment of immune-mediated chronic oral inflammatory conditions: a series of cases
.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod
.
2001
;
91
(
1
):
56
-
61
.
55.
Epstein
JB
,
Nantel
S
,
Sheoltch
SM
.
Topical azathioprine in the combined treatment of chronic oral graft-versus-host disease
.
Bone Marrow Transplant
.
2000
;
25
(
6
):
683
-
687
.
56.
MacDonald
KP
,
Blazar
BR
,
Hill
GR
.
Cytokine mediators of chronic graft-versus-host disease
.
J Clin Invest
.
2017
;
127
(
7
):
2452
-
2463
.
57.
Socié
G
.
Treating chronic GVHD-induced fibrosis?
Blood
.
2018
;
131
(
13
):
1396
-
1397
.
58.
Atkinson
K
.
Chronic graft-versus-host disease
.
Bone Marrow Transplant
.
1990
;
5
(
2
):
69
-
82
.
59.
Cohen
PR
.
Isomorphic sclerotic-type cutaneous chronic graft-versus-host disease: report and review of chronic graft-versus-host disease in a cutaneous immunocompromised district
.
Dermatol Ther (Heidelb)
.
2013
;
3
(
2
):
215
-
222
.
60.
Socie
G
,
Gluckman
E
,
Cosset
JM
, et al
.
Unusual localization of cutaneous chronic graft-versus-host disease in the radiation fields in four cases
.
Bone Marrow Transplant
.
1989
;
4
(
1
):
133
-
135
.
61.
Choi
CJ
,
Nghiem
P
.
Tacrolimus ointment in the treatment of chronic cutaneous graft-vs-host disease: a case series of 18 patients
.
Arch Dermatol
.
2001
;
137
(
9
):
1202
-
1206
.
62.
Margolis
DJ
,
Hoffstad
O
,
Bilker
W
.
Lack of association between exposure to topical calcineurin inhibitors and skin cancer in adults
.
Dermatology
.
2007
;
214
(
4
):
289
-
295
.
63.
Ring
J
,
Möhrenschlager
M
,
Henkel
V
.
The US FDA ‘black box’ warning for topical calcineurin inhibitors: an ongoing controversy
.
Drug Saf
.
2008
;
31
(
3
):
185
-
198
.
64.
Carpenter
PA
,
Kitko
CL
,
Elad
S
, et al
.
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 report
.
Biol Blood Marrow Transplant
.
2015
;
21
(
7
):
1167
-
1187
.
65.
Joly
P
,
Roujeau
JC
,
Benichou
J
, et al
;
Bullous Diseases French Study Group
.
A comparison of oral and topical corticosteroids in patients with bullous pemphigoid
.
N Engl J Med
.
2002
;
346
(
5
):
321
-
327
.
66.
Huang
JT
,
Duncan
CN
,
Boyer
D
,
Khosravi
H
,
Lehmann
LE
,
Saavedra
A
.
Nail dystrophy, edema, and eosinophilia: harbingers of severe chronic GVHD of the skin in children
.
Bone Marrow Transplant
.
2014
;
49
(
12
):
1521
-
1527
.
67.
Mohammed
J
,
Savani
BN
,
El-Jawahri
A
,
Vanderklish
J
,
Cheville
AL
,
Hashmi
SK
.
Is there any role for physical therapy in chronic GvHD?
Bone Marrow Transplant
.
2018
;
53
(
1
):
22
-
28
.
68.
Couriel
D
,
Carpenter
PA
,
Cutler
C
, et al
.
Ancillary therapy and supportive care of chronic graft-versus-host disease: national institutes of health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: V. Ancillary Therapy and Supportive Care Working Group report
.
Biol Blood Marrow Transplant
.
2006
;
12
(
4
):
375
-
396
.
69.
Ogawa
Y
,
Kim
SK
,
Dana
R
, et al
.
International Chronic Ocular Graft-vs-Host-Disease (GVHD) Consensus Group proposed diagnostic criteria for chronic GVHD (part I)
.
Sci Rep
.
2013
;
3
:
3419
.
70.
Abud
TB
,
Amparo
F
,
Saboo
US
, et al
.
A clinical trial comparing the safety and efficacy of topical tacrolimus versus methylprednisolone in ocular graft-versus-host disease
.
Ophthalmology
.
2016
;
123
(
7
):
1449
-
1457
.
71.
Kiang
E
,
Tesavibul
N
,
Yee
R
,
Kellaway
J
,
Przepiorka
D
.
The use of topical cyclosporin A in ocular graft-versus-host-disease
.
Bone Marrow Transplant
.
1998
;
22
(
2
):
147
-
151
.
72.
Robinson
MR
,
Lee
SS
,
Rubin
BI
, et al
.
Topical corticosteroid therapy for cicatricial conjunctivitis associated with chronic graft-versus-host disease
.
Bone Marrow Transplant
.
2004
;
33
(
10
):
1031
-
1035
.
73.
Dietrich-Ntoukas
T
,
Cursiefen
C
,
Westekemper
H
, et al
.
Diagnosis and treatment of ocular chronic graft-versus-host disease: report from the German-Austrian-Swiss consensus conference on clinical practice in chronic GVHD
.
Cornea
.
2012
;
31
(
3
):
299
-
310
.
74.
Kheirkhah
A
,
Di Zazzo
A
,
Satitpitakul
V
,
Fernandez
M
,
Magilavy
D
,
Dana
R
.
A pilot randomized trial on safety and efficacy of a novel topical combined inhibitor of Janus kinase 1/3 and spleen tyrosine kinase for GVHD-associated ocular surface disease
.
Cornea
.
2017
;
36
(
7
):
799
-
804
.
75.
Anitua
E
,
Muruzabal
F
,
Tayebba
A
, et al
.
Autologous serum and plasma rich in growth factors in ophthalmology: preclinical and clinical studies
.
Acta Ophthalmol
.
2015
;
93
(
8
):
e605
-
e614
.
76.
Ali
TK
,
Gibbons
A
,
Cartes
C
, et al
.
Use of autologous serum tears for the treatment of ocular surface disease from patients with systemic autoimmune diseases
.
Am J Ophthalmol
.
2018
;
189
:
65
-
70
.
77.
Holland
EJ
,
Luchs
J
,
Karpecki
PM
, et al
.
Lifitegrast for the treatment of dry eye disease: results of a phase III, randomized, double-masked, placebo-controlled trial (OPUS-3)
.
Ophthalmology
.
2017
;
124
(
1
):
53
-
60
.
78.
Pathak
M
,
Diep
PP
,
Lai
X
,
Brinch
L
,
Ruud
E
,
Drolsum
L
.
Ocular findings and ocular graft-versus-host disease after allogeneic stem cell transplantation without total body irradiation
.
Bone Marrow Transplant
.
2018
;
53
(
7
):
863
-
872
.
79.
Syrjala
KL
,
Martin
PJ
,
Lee
SJ
.
Delivering care to long-term adult survivors of hematopoietic cell transplantation
.
J Clin Oncol
.
2012
;
30
(
30
):
3746
-
3751
.
80.
Pavletic
SZ
,
Martin
P
,
Lee
SJ
, et al
;
Response Criteria Working Group
.
Measuring therapeutic response in chronic graft-versus-host disease: National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: IV. Response Criteria Working Group report
.
Biol Blood Marrow Transplant
.
2006
;
12
(
3
):
252
-
266
.
81.
Moon
JH
,
Hamad
N
,
Sohn
SK
, et al
.
Improved prognostic stratification power of CIBMTR risk score with the addition of absolute lymphocyte and eosinophil counts at the onset of chronic GVHD
.
Ann Hematol
.
2017
;
96
(
5
):
805
-
815
.
82.
Williams
KM
.
How I treat bronchiolitis obliterans syndrome after hematopoietic stem cell transplantation
.
Blood
.
2017
;
129
(
4
):
448
-
455
.
83.
Lee
SJ
,
Nguyen
TD
,
Onstad
L
, et al
.
Success of immunosuppressive treatments in patients with chronic graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2018
;
24
(
3
):
555
-
562
.
84.
Wolff
D
,
Bertz
H
,
Greinix
H
,
Lawitschka
A
,
Halter
J
,
Holler
E
.
The treatment of chronic graft-versus-host disease: consensus recommendations of experts from Germany, Austria, and Switzerland
.
Dtsch Arztebl Int
.
2011
;
108
(
43
):
732
-
740
.
85.
Martin
PJ
,
Weisdorf
D
,
Przepiorka
D
, et al
;
Design of Clinical Trials Working Group
.
National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: VI. Design of Clinical Trials Working Group report
.
Biol Blood Marrow Transplant
.
2006
;
12
(
5
):
491
-
505
.
86.
Lazaryan
A
,
Arora
M
.
Evolving concepts in prognostic scoring of chronic GvHD
.
Bone Marrow Transplant
.
2017
;
52
(
10
):
1361
-
1366
.
87.
Baird
K
,
Steinberg
SM
,
Grkovic
L
, et al
.
National Institutes of Health chronic graft-versus-host disease staging in severely affected patients: organ and global scoring correlate with established indicators of disease severity and prognosis
.
Biol Blood Marrow Transplant
.
2013
;
19
(
4
):
632
-
639
.
88.
Jim
HS
,
Barata
A
,
Small
BJ
,
Jacobsen
PB
,
Pidala
J
.
Quality of life associated with sirolimus for prevention of graft-versus-host disease: results from a randomized trial
.
Haematologica
.
2014
;
99
(
3
):
548
-
553
.
89.
El-Jawahri
A
,
Pidala
J
,
Khera
N
, et al
.
Impact of psychological distress on quality of life, functional status, and survival in patients with chronic graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2018
;
24
(
11
):
2285
-
2292
.
90.
Khera
N
,
Hamilton
BK
,
Pidala
JA
, et al
.
Employment, insurance, and financial experiences of patients with chronic graft-versus-host disease in North America [published online ahead of print 5 October 2018]
.
Biol Blood Marrow Transplant
.
91.
Lee
SJ
,
Onstad
L
,
Chow
EJ
, et al
.
Patient-reported outcomes and health status associated with chronic graft-versus-host disease
.
Haematologica
.
2018
;
103
(
9
):
1535
-
1541
.
92.
Kekre
N
,
Kim
HT
,
Ho
VT
, et al
.
Venous thromboembolism is associated with graft-versus-host disease and increased non-relapse mortality after allogeneic hematopoietic stem cell transplantation
.
Haematologica
.
2017
;
102
(
7
):
1185
-
1191
.
93.
Arora
M
,
Klein
JP
,
Weisdorf
DJ
, et al
.
Chronic GVHD risk score: a Center for International Blood and Marrow Transplant Research analysis
.
Blood
.
2011
;
117
(
24
):
6714
-
6720
.
94.
Arora
M
,
Hemmer
MT
,
Ahn
KW
, et al
.
Center for International Blood and Marrow Transplant Research chronic graft-versus-host disease risk score predicts mortality in an independent validation cohort
.
Biol Blood Marrow Transplant
.
2015
;
21
(
4
):
640
-
645
.
95.
Pidala
J
,
Chai
X
,
Martin
P
, et al
.
Hand grip strength and 2-minute walk test in chronic graft-versus-host disease assessment: analysis from the Chronic GVHD Consortium
.
Biol Blood Marrow Transplant
.
2013
;
19
(
6
):
967
-
972
.
96.
Hildebrandt
GC
,
Fazekas
T
,
Lawitschka
A
, et al
.
Diagnosis and treatment of pulmonary chronic GVHD: report from the consensus conference on clinical practice in chronic GVHD
.
Bone Marrow Transplant
.
2011
;
46
(
10
):
1283
-
1295
.
97.
Fried
RH
,
Murakami
CS
,
Fisher
LD
,
Willson
RA
,
Sullivan
KM
,
McDonald
GB
.
Ursodeoxycholic acid treatment of refractory chronic graft-versus-host disease of the liver
.
Ann Intern Med
.
1992
;
116
(
8
):
624
-
629
.
98.
McDonald
GB
,
Sullivan
KM
,
Plumley
TF
.
Radiographic features of esophageal involvement in chronic graft-vs.-host disease
.
AJR Am J Roentgenol
.
1984
;
142
(
3
):
501
-
506
.
99.
Wild
D
,
Sung
AD
,
Cardona
D
, et al
.
The diagnostic yield of site and symptom-based biopsies for acute gastrointestinal graft-versus-host disease: A 5-year retrospective review
.
Dig Dis Sci
.
2016
;
61
(
3
):
806
-
813
.
100.
Sung
AD
,
Hassan
S
,
Cardona
DM
, et al
.
Late gastrointestinal complications of allogeneic hematopoietic stem cell transplantation in adults
.
Biol Blood Marrow Transplant
.
2018
;
24
(
4
):
734
-
740
.
101.
Chang
S
,
Lee
TH
.
Beyond evidence-based medicine
.
N Engl J Med
.
2018
;
379
(
21
):
1983
-
1985
.
102.
Palmer
J
,
Williams
K
,
Inamoto
Y
, et al
.
Pulmonary symptoms measured by the National Institutes of Health lung score predict overall survival, nonrelapse mortality, and patient-reported outcomes in chronic graft-versus-host disease
.
Biol Blood Marrow Transplant
.
2014
;
20
(
3
):
337
-
344
.
103.
Gooley
TA
,
Rajvanshi
P
,
Schoch
HG
,
McDonald
GB
.
Serum bilirubin levels and mortality after myeloablative allogeneic hematopoietic cell transplantation
.
Hepatology
.
2005
;
41
(
2
):
345
-
352
.
104.
Vigorito
AC
,
Campregher
PV
,
Storer
BE
, et al
;
National Institutes of Health
.
Evaluation of NIH consensus criteria for classification of late acute and chronic GVHD
.
Blood
.
2009
;
114
(
3
):
702
-
708
.
105.
Kuzmina
Z
,
Eder
S
,
Böhm
A
, et al
.
Significantly worse survival of patients with NIH-defined chronic graft-versus-host disease and thrombocytopenia or progressive onset type: results of a prospective study
.
Leukemia
.
2012
;
26
(
4
):
746
-
756
.
106.
Pai
CC
,
Chen
M
,
Mirsoian
A
, et al
.
Treatment of chronic graft-versus-host disease with bortezomib
.
Blood
.
2014
;
124
(
10
):
1677
-
1688
.
107.
Adamski
J
.
Vascular access considerations for extracorporeal photopheresis
.
Transfusion
.
2018
;
58
(
suppl 1
):
590
-
597
.
108.
US Food and Drug Administration
.
Zithromax. Zmax (azithromycin): FDA warning – increased risk of cancer relapse with long-term use after donor stem cell transplant
.
.
109.
Bergeron
A
,
Chevret
S
,
Granata
A
, et al
;
ALLOZITHRO Study Investigators
.
Effect of azithromycin on airflow decline-free survival after allogeneic hematopoietic stem cell transplant: the ALLOZITHRO randomized clinical trial
.
JAMA
.
2017
;
318
(
6
):
557
-
566
.
110.
Furlong
T
,
Martin
P
,
Flowers
ME
, et al
.
Therapy with mycophenolate mofetil for refractory acute and chronic GVHD
.
Bone Marrow Transplant
.
2009
;
44
(
11
):
739
-
748
.
111.
Pusic
I
,
Rettig
MP
,
DiPersio
JF
, et al
.
Phase-1/-2 study of pomalidomide in chronic GvHD
.
Bone Marrow Transplant
.
2016
;
51
(
4
):
612
-
614
.
112.
Clavert
A
,
Chevallier
P
,
Guillaume
T
, et al
.
Safety and efficacy of rituximab in steroid-refractory chronic GVHD
.
Bone Marrow Transplant
.
2013
;
48
(
5
):
734
-
736
.
113.
Couriel
DR
,
Saliba
R
,
Escalón
MP
, et al
.
Sirolimus in combination with tacrolimus and corticosteroids for the treatment of resistant chronic graft-versus-host disease
.
Br J Haematol
.
2005
;
130
(
3
):
409
-
417
.

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