Abstract

Chronic graft-versus-host disease (GVHD) remains a common and potentially life-threatening complication of allogeneic hematopoietic stem cell transplantation (HCT). The 2-year cumulative incidence of chronic GVHD requiring systemic treatment is ∼30% to 40% by National Institutes of Health criteria. The risk of chronic GVHD is higher and the duration of treatment is longer after HCT with mobilized blood cells than with marrow cells. Clinical manifestations can impair activities of daily living and often linger for years. Hematology and oncology specialists who refer patients to centers for HCT are often subsequently involved in the management of chronic GVHD when patients return to their care after HCT. Treatment of these patients can be optimized under shared care arrangements that enable referring physicians to manage long-term administration of immunosuppressive medications and supportive care with guidance from transplant center experts. Keys to successful collaborative management include early recognition in making the diagnosis of chronic GVHD, comprehensive evaluation at the onset and periodically during the course of the disease, prompt institution of systemic and topical treatment, appropriate monitoring of the response, calibration of treatment intensity over time in order to avoid overtreatment or undertreatment, and the use of supportive care to prevent complications and disability.

Introduction

The prevalence and severity of chronic graft-versus-host disease (GVHD) have increased during the past 2 decades in association with the increasing use of hematopoietic stem cell transplantation (HCT) for treatment of older age patients, the widespread use of mobilized blood cells instead of marrow for grafting, and improvements in survival during the first several months after allogeneic HCT.1-6 

Pathophysiological understanding of chronic GVHD is emerging,7,8  but the long-standing reliance on prednisone described as the mainstay of treatment in Vogelsang’s “How I Treat” review in 2001 has persisted to the present.9  The 2005 National Institutes of Health (NIH) Consensus Conference developed a framework for characterizing the pleomorphic manifestations of chronic GVHD. The consensus project defined minimal criteria for the clinical diagnosis, emphasized differences in the clinical manifestations of chronic and acute GVHD, established criteria for scoring the severity of clinical manifestations in affected organs, and proposed new categories for describing overall disease severity and indications for treatment.10  The consensus project also proposed measures for monitoring disease progression and response to therapy and provided other information for purposes of clinical trials.11-13  In 2014, the NIH Conference was reconvened, and revisions are under consideration to update the recommendations based on available evidence and insights from clinical application of the original recommendations.14-33 

Chronic GVHD has a wide range of pleomorphic manifestations, and many complications can emerge from both the disease and its treatment. A dedicated multidisciplinary team approach with relevant expertise is necessary in order to provide the best care for patients with a chronic illness that can have devastating effects on quality of life. Our approach to treatment emphasizes the importance of early recognition in the management of chronic GVHD, with respect to making the initial diagnosis, monitoring the response to initial treatment, and preventing complications and disability. Nuances applicable only to children are not addressed in this review.

Case summary

A 45-year-old man received growth factor–mobilized blood cells from an HLA-matched unrelated male donor after conditioning with 12 Gy total body irradiation and cyclophosphamide for treatment of acute myeloid leukemia with persistent disease. He received methotrexate and tacrolimus for immunosuppression after HCT. He developed acute GVHD of the skin and gut, which resolved after treatment with steroid cream and oral beclomethasone and budesonide. Because malignant cells persisted after HCT, treatment was administered with azacytidine, and immunosuppression with tacrolimus was withdrawn by day 100, 3 months earlier than originally planned.

Malignant cells disappeared, but 7 months after HCT and 2 months after the third cycle of azacytidine, he was diagnosed with severe chronic GVHD (NIH global score). Affected sites included the skin (erythematous rash involving >50% body surface area [BSA]), mouth (ulcers and lichenoid features), fasciae (wrist tightness and leg edema), liver (alanine aminotransferase twice the normal upper limit with normal total serum bilirubin concentration), and eosinophilia (1800 per μL). Forced expiratory volume in the first second (FEV1) was 79% of predicted, and the ratio of FEV1 to forced vital capacity (FVC) was 78% of predicted, representing an absolute 8% decline from the baseline before HCT.

Treatment was started with prednisone at 1 mg/kg per day, and antibiotic prophylaxis was administered to prevent Pneumocystis pneumonia and infection with encapsulated bacteria. Antiviral prophylaxis was continued with acyclovir. Daily intake of vitamin D 1000 IU and calcium 1500 mg was recommended. After 2 weeks, improvement was noted in wrist discomfort, leg edema, and the extent of rash, with resolution of eosinophilia and liver function abnormalities. The dose of prednisone was tapered to reach 80 mg every other day, with continued clinical monitoring and pulmonary function tests (PFTs) at monthly intervals.

During the next 3 months, PFTs improved, but other manifestations showed progressive worsening, with cutaneous sclerosis involving ∼28% of the BSA with a Rodnan modified total score34  of 8, oral ulceration, and decreased wrist mobility. The patient enrolled in a randomized clinical trial comparing imatinib vs rituximab for steroid-refractory sclerotic GVHD. He was randomized to treatment with imatinib (200 mg daily) while continuing treatment with prednisone 80 mg every other day. Dexamethasone oral rinses and clobetasol ointment were used to control oral ulceration.13 

The extent and severity of sclerosis remained stable for 3 months. Sclerosis then began to progress, involving ∼50% of BSA with a Rodnan score of 28 after 6 months of treatment with imatinib. The patient met the criteria for crossover according to the study design, and he was treated with 2 cycles of rituximab, 375 mg/m2 per week for 4 weeks per cycle. Due to hypertension and hyperglycemia, the dose of prednisone was gradually tapered to 40 mg every other day within 6 months. The patient subsequently reported improved flexibility, and after 7 months, sclerosis remained stable with a Rodnan score of 26.

Eleven months after the last dose of rituximab, fasciitis progressed with further decrease in range of motion while continuing treatment with prednisone at 40 mg every other day. Extracorporeal photopheresis (ECP)35  (reviewed in Inamoto and Flowers36 ), low-dose interleukin-2 (IL-2),37  and sirolimus were considered as possible further treatment. The patient opted for daily low-dose IL-2, but he had significant local reactions, low-grade fever, and no appreciable improvement in GVHD. Three months after treatment with IL-2 was discontinued, he developed a new erythematous maculopapular rash affecting 50% of BSA. The dose of prednisone was increased to 40 mg per day, and sirolimus was added. The rash subsequently improved, but sclerosis and fasciitis continued to worsen, prompting treatment with ECP for the past 3 months. Efficacy cannot yet be assessed because improvement is often not observed until treatment with ECP has been continued for at least 6 months.35,38 

Pathophysiology

Recent laboratory studies have yielded some insights into the pathophysiology of chronic GVHD, and candidate biomarkers that could be used for diagnosis or monitoring have been identified.7,8  The disease likely represents a syndrome in which the respective contributions of inflammation, innate and adaptive cell-mediated immunity, humoral immunity, abnormal immune regulation, and fibrosis vary considerably from 1 patient to the next. The risk of chronic GVHD can be substantially decreased by administration of rabbit anti-thymocyte globulin or alemtuzumab in the conditioning regimen before HCT,39-43  or by administration of high-dose cyclophosphamide on days 3 and 4 after HCT.44,45  These results demonstrate that the pathophysiological mechanisms leading to development of chronic GVHD are set in motion at the time of HCT, even though the manifestations of the disease typically do not become apparent until several months later.

Animal models that replicate many features of the disease have been established, but mechanisms linking inflammation with abnormal immune regulation and mechanisms linking immune-mediated injury with fibrosis have not been well defined. In the absence of a definitive understanding of the pathophysiological mechanisms or clear explanation accounting for the considerable variability of disease manifestations among patients, efforts to develop new treatment have relied on empirical testing of agents approved for other indications where inflammation, abnormal immune regulation, or fibrosis have been implicated as pathogenic mechanisms.

Diagnosis and evaluation

Manifestations of chronic GVHD can resemble autoimmune or other immune-mediated disorders such as scleroderma, Sjögren syndrome, primary biliary cirrhosis, bronchiolitis obliterans, immune cytopenias, and chronic immunodeficiency. Manifestations typically appear within the first year after HCT, most often when doses of immunosuppressive medications are weaned. The disease can begin as early as 2 months and as late as 7 years after HCT, although onset at >1 year from HCT occurs in <10% of cases.46  Chronic GVHD should be suspected at the onset of any perturbation in laboratory tests, symptoms, or signs, especially during the first year after HCT. Conversely, not every problem after allogeneic HCT represents chronic GVHD. Other conditions such as eczema, iron overload, hypothyroidism, adrenal insufficiency, infections, or drug effect can be misdiagnosed as chronic GVHD.47 

Chronic GVHD generally involves several organs or sites, although manifestations are sometimes restricted to a single organ or site. The disease is characterized by features that differ from the typical dermatitis, enteritis, and cholestatic liver manifestations of acute GVHD (Table 1).10  Patients frequently have erythematous rash, enteritis, or hepatic involvement characterized by transaminase elevation or hyperbilirubinemia at initial presentation and intermittently afterward during the course of the disease. The term “overlap syndrome” has been used to indicate that manifestations typical of acute GVHD are present in a patient with chronic GVHD. These inflammatory manifestations are often transient, disappearing when the intensity of immunosuppression is increased and reappearing when the intensity of immunosuppression is tapered. According to NIH criteria, the diagnosis of chronic GVHD requires at least 1 diagnostic sign or at least 1 distinctive sign confirmed by biopsy, other tests, or by radiography in the same or another organ, and exclusion of other diagnoses (Table 1).10  Manifestations of chronic GVHD have a wide range of severity and impact on quality of life after HCT. Certain manifestations are particularly difficult to manage and require prolonged treatment. These include fasciitis or cutaneous sclerosis, severe ocular sicca, and BOS, occurring in ∼20%,48  12%,3  and about 10%3  of patients, respectively. The most common organs and sites affected by chronic GVHD include the skin, mouth, eyes, gastrointestinal tract, and liver (Figure 1).

Table 1

Clinical manifestations of chronic GVHD

Organ or siteDiagnostic (sufficient for diagnosis)Distinctive (insufficient alone for diagnosis)OtherFeatures seen in both acute and chronic GVHD
Skin Poikiloderma Depigmentation  Erythema 
Lichen planus-like Papulosquamous Maculopapular 
Sclerosis Pruritus 
Morphea-like 
Lichen sclerosis-like 
Nails  Dystrophy   
Onycholysis 
Nail loss 
Pterygium unguis 
Scalp and body hair  Alopecia (scarring or nonscarring)   
Scaling 
Mouth Lichen planus-like Xerostomia  Gingivitis 
Mucoceles Mucositis 
Mucosal atrophy Erythema 
Pseudomembranes or ulcers* Pain 
Eyes  New dry, gritty, or painful eyes (sicca)   
Keratoconjunctivitis sicca 
Punctate keratopathy 
Genitalia Lichen planus-like Erosions*   
Lichen sclerosis-like Fissures* 
Female: Ulcers* 
Vagina scarring or stenosis 
Clitoral or labial agglutination 
Male: 
Phimosis 
Urethral scarring or stenosis 
GI tract Esophageal web   Diarrhea 
Esophageal stricture Anorexia 
Nausea or emesis 
Failure to thrive 
Weight loss 
Liver    Total bilirubin, alkaline phosphatase or ALT >2× ULN 
Lung Bronchiolitis obliterans diagnosed by biopsy BOS§  Cryptogenic organizing pneumonia  
Restrictive lung disease 
Muscles, fascia, joints Fasciitis Myositis   
Joint stiffness or contractures due to sclerosis Polymyositis 
Hematopoietic and Immune   Thrombocytopenia  
Eosinophilia 
Hypo- or hypergammaglobulinemia 
Autoantibodies 
Raynaud phenomenon 
Others   Effusions  
Nephrotic syndrome 
Myasthenia gravis 
Peripheral neuropathy 
Organ or siteDiagnostic (sufficient for diagnosis)Distinctive (insufficient alone for diagnosis)OtherFeatures seen in both acute and chronic GVHD
Skin Poikiloderma Depigmentation  Erythema 
Lichen planus-like Papulosquamous Maculopapular 
Sclerosis Pruritus 
Morphea-like 
Lichen sclerosis-like 
Nails  Dystrophy   
Onycholysis 
Nail loss 
Pterygium unguis 
Scalp and body hair  Alopecia (scarring or nonscarring)   
Scaling 
Mouth Lichen planus-like Xerostomia  Gingivitis 
Mucoceles Mucositis 
Mucosal atrophy Erythema 
Pseudomembranes or ulcers* Pain 
Eyes  New dry, gritty, or painful eyes (sicca)   
Keratoconjunctivitis sicca 
Punctate keratopathy 
Genitalia Lichen planus-like Erosions*   
Lichen sclerosis-like Fissures* 
Female: Ulcers* 
Vagina scarring or stenosis 
Clitoral or labial agglutination 
Male: 
Phimosis 
Urethral scarring or stenosis 
GI tract Esophageal web   Diarrhea 
Esophageal stricture Anorexia 
Nausea or emesis 
Failure to thrive 
Weight loss 
Liver    Total bilirubin, alkaline phosphatase or ALT >2× ULN 
Lung Bronchiolitis obliterans diagnosed by biopsy BOS§  Cryptogenic organizing pneumonia  
Restrictive lung disease 
Muscles, fascia, joints Fasciitis Myositis   
Joint stiffness or contractures due to sclerosis Polymyositis 
Hematopoietic and Immune   Thrombocytopenia  
Eosinophilia 
Hypo- or hypergammaglobulinemia 
Autoantibodies 
Raynaud phenomenon 
Others   Effusions  
Nephrotic syndrome 
Myasthenia gravis 
Peripheral neuropathy 

Modified from Stem Cell Trialists’ Collaborative Group.6 

ALT, alanine aminotransferase; BOS, bronchiolitis obliterans syndrome; GI, gastrointestinal; ULN, upper limit of normal.

*

In all cases infection, drug effect, malignancy, endocrine causes must be excluded as applicable.

These pulmonary manifestations are under investigation or unclassified.

Pericardium, pleural, or ascites.

§

BOS can be diagnostic for lung chronic GVHD only, if distinctive feature present in another site.

Figure 1

The frequency of involvement by chronic GVHD varies across organs and sites and is higher after HCT with mobilized blood cells as compared with marrow. (A) The most frequently involved organs and sites are the skin, mouth, eyes, gastrointestinal tract, and liver.3  (B) Chronic GVHD can affect all layers of the skin. Photographs of each manifestation in italic may be found in the supplemental Data, available on the Blood Web site. Artwork by Delilah Cohn, MFA, CMI, used with permission.

Figure 1

The frequency of involvement by chronic GVHD varies across organs and sites and is higher after HCT with mobilized blood cells as compared with marrow. (A) The most frequently involved organs and sites are the skin, mouth, eyes, gastrointestinal tract, and liver.3  (B) Chronic GVHD can affect all layers of the skin. Photographs of each manifestation in italic may be found in the supplemental Data, available on the Blood Web site. Artwork by Delilah Cohn, MFA, CMI, used with permission.

Systematic and comprehensive assessment of organs and sites possibly affected by chronic GVHD is essential for early diagnosis, early recognition of manifestations associated with high morbidity and disability, and assessment of disease progression and response during treatment (Tables 2-3). Once the clinical diagnosis of chronic GVHD is made, the extent and severity of each affected organ must be ascertained using the NIH chronic GVHD diagnosis and scoring consensus criteria.10  Recommended methods for conducting a chronic GVHD-focused evaluation have been published49  (they can be viewed at http://www.fhcrc.org/en/labs/clinical/projects/gvhd.html).50  Comprehensive evaluations should be done at the time of initial diagnosis, at 3- to 6-month intervals thereafter, and at any time when a major change in therapy is made. Evaluations should continue until at least 12 months after systemic treatment has ended.

Table 2

Evaluation and frequency of monitoring according symptoms or affected organs

EvaluationFrequency of evaluation/monitoring
Manifestations presentManifestations absent
Review of systems (see Table 3 for chronic GVHD-specific questions) Every clinic visit Every clinic visit 
Physical examination   
 Complete skin examination (look, touch, pinch) Every clinic visit Every clinic visit 
 Oral examination Every clinic visit Every clinic visit 
 Range of motion assessment Every clinic visit Every clinic visit 
 Performance score Every clinic visit Every clinic visit 
Nurse assessment   
 Weight Every clinic visit Every clinic visit 
 Height/adults Yearly Yearly 
 Height/children Every 3-12 mo Every 3-12 mo 
 Medical photographs ∼100 d after HCT (baseline), at initial diagnosis of chronic GVHD, every 6 mo if skin or joints are involved and during treatment until at least 1 y after discontinuation of treatment ∼100 d after HCT (baseline) 
Other evaluations   
 PFTs ∼100 d after HCT (baseline); see also Table 4  ∼100 d after HCT and every 3 mo for the first year, then yearly if previous PFTs were abnormal or if continuing systemic treatment; reassess at onset of new symptoms 
 Nutritional assessment As clinically indicated and yearly if receiving corticosteroids As clinically indicated 
 Physiotherapy with assessment of range of motion Every 3 mo if sclerotic features affecting range of motion until resolution As clinically indicated 
 Dental or oral medicine consultation with comprehensive soft and hard tissue examination, culture, biopsy, or photographs of lesions, as clinically indicated Every 3-6 mo or more often as indicated Yearly 
 Ophthalmology consultation with Schirmer test, slit-lamp examination, and intraocular pressure At initial diagnosis and every 3-6 mo or more often as indicated ∼100 d after HCT (baseline) and yearly 
 Gynecology examination for vulvar or vaginal involvement Every 6 mo or more often as indicated Yearly 
 Dermatology consultation with assessment of extent and type of skin involvement, biopsy, or photographs As clinically indicated  
 Neuropsychological testing As clinically indicated  
 Bone mineral assessment (DEXA) scan Yearly during corticosteroid treatment or if prior test was abnormal ∼100 d after HCT if continuing corticosteroid treatment (baseline) 
EvaluationFrequency of evaluation/monitoring
Manifestations presentManifestations absent
Review of systems (see Table 3 for chronic GVHD-specific questions) Every clinic visit Every clinic visit 
Physical examination   
 Complete skin examination (look, touch, pinch) Every clinic visit Every clinic visit 
 Oral examination Every clinic visit Every clinic visit 
 Range of motion assessment Every clinic visit Every clinic visit 
 Performance score Every clinic visit Every clinic visit 
Nurse assessment   
 Weight Every clinic visit Every clinic visit 
 Height/adults Yearly Yearly 
 Height/children Every 3-12 mo Every 3-12 mo 
 Medical photographs ∼100 d after HCT (baseline), at initial diagnosis of chronic GVHD, every 6 mo if skin or joints are involved and during treatment until at least 1 y after discontinuation of treatment ∼100 d after HCT (baseline) 
Other evaluations   
 PFTs ∼100 d after HCT (baseline); see also Table 4  ∼100 d after HCT and every 3 mo for the first year, then yearly if previous PFTs were abnormal or if continuing systemic treatment; reassess at onset of new symptoms 
 Nutritional assessment As clinically indicated and yearly if receiving corticosteroids As clinically indicated 
 Physiotherapy with assessment of range of motion Every 3 mo if sclerotic features affecting range of motion until resolution As clinically indicated 
 Dental or oral medicine consultation with comprehensive soft and hard tissue examination, culture, biopsy, or photographs of lesions, as clinically indicated Every 3-6 mo or more often as indicated Yearly 
 Ophthalmology consultation with Schirmer test, slit-lamp examination, and intraocular pressure At initial diagnosis and every 3-6 mo or more often as indicated ∼100 d after HCT (baseline) and yearly 
 Gynecology examination for vulvar or vaginal involvement Every 6 mo or more often as indicated Yearly 
 Dermatology consultation with assessment of extent and type of skin involvement, biopsy, or photographs As clinically indicated  
 Neuropsychological testing As clinically indicated  
 Bone mineral assessment (DEXA) scan Yearly during corticosteroid treatment or if prior test was abnormal ∼100 d after HCT if continuing corticosteroid treatment (baseline) 

Modified from Flowers and Vogelsang.69 

Table 3

Chronic GVHD review of systems

No.System/othersInquire/description
Skin Skin feels tight or hard, increased dryness, pruritus, or looks different (ie, new rash, papules, discoloration, shining scar-like, scaly)? 
Sweat glands Inability to sweat or to keep body warm? 
Skin appendages Loss of hair (scalp or body including bows or lashes), or nail changes (ridges or brittle, loss)? 
Fasciae/joints Stiffness or pain in the wrists, fingers, or other joints? 
Eyes Eye dryness, sensitivity to wind or dry environments (air conditioning), pain? 
Mouth Oral dryness, taste alterations, sensitivities (spicy/carbonate drinks, toothpaste), ulcers/sores, pain? 
Esophagus Foods or pills gets stuck upon swallowing? 
Lungs Cough, dyspnea (on exertion or rest) or wheezes? 
Genital tract Vaginal dryness, pain, dyspareunia (female); pain or dysuria due to stenosis of urethra (male)? 
10 Weight loss Unexplained weight loss or inability to gain weight (pancreatic insufficiency or hypercatabolism)? 
No.System/othersInquire/description
Skin Skin feels tight or hard, increased dryness, pruritus, or looks different (ie, new rash, papules, discoloration, shining scar-like, scaly)? 
Sweat glands Inability to sweat or to keep body warm? 
Skin appendages Loss of hair (scalp or body including bows or lashes), or nail changes (ridges or brittle, loss)? 
Fasciae/joints Stiffness or pain in the wrists, fingers, or other joints? 
Eyes Eye dryness, sensitivity to wind or dry environments (air conditioning), pain? 
Mouth Oral dryness, taste alterations, sensitivities (spicy/carbonate drinks, toothpaste), ulcers/sores, pain? 
Esophagus Foods or pills gets stuck upon swallowing? 
Lungs Cough, dyspnea (on exertion or rest) or wheezes? 
Genital tract Vaginal dryness, pain, dyspareunia (female); pain or dysuria due to stenosis of urethra (male)? 
10 Weight loss Unexplained weight loss or inability to gain weight (pancreatic insufficiency or hypercatabolism)? 

Close serial monitoring of all organ systems is essential in order to ensure early detection, recognition, and intervention directed toward reversing or preventing progression of chronic GVHD manifestations and treatment-associated toxicities. In particular, periodic pulmonary function tests are essential for early detection of lung involvement manifested as BOS because this complication has an insidious onset, and patients may remain asymptomatic until considerable lung function has been lost. We recommend complete pulmonary function testing in all patients before HCT and at ∼3 months after HCT as a baseline for future comparisons (Table 4).10  Follow-up testing should be done at the onset of chronic GVHD and at 3- to 6-month intervals for the first year or more often if testing shows any significant new airflow obstruction or decline in the percent of predicted FEV1. Patient and physician-directed tools to support chronic GVHD monitoring can be found online (http://www.fhcrc.org/en/treatment/long-term-follow-up/information-for-physicians.html).

Table 4

General guidelines for monitoring and management of new airflow obstruction

Guidelines
A. Significant new airflow obstruction with a % predicted FEV1 ≥70% 
 1. Initiate inhaled corticosteroid therapy 
  • Fluticasone (Flovent) 440 mcg BID, or 
  • Advair 500/50 mcg BID (if symptoms of airway obstruction are present) 
  • Treatment should continue until either % FEV1 becomes <70% (see below), or until GVHD resolves (ie, resolution of all reversible manifestations of GVHD without exacerbation after at least 6 mo after discontinuation of all systemic immunosuppressive treatment) 
 2. Other immunosuppressive treatment as indicated to control GVHD in other organs 
  • Treatment should continue until either % FEV1 becomes <70% (see below), or until GVHD resolves (ie, resolution of all reversible manifestation of GVHD without exacerbation after at least 12 mo after discontinuation of all systemic treatments) 
 3. Monitor PFTs or spirometry monthly for at least 3 mo 
  • If % FEV1 stabilizes, PFTs or spirometry every 3 mo for 1 y, then if stable continue at 6-mo intervals for 1 y and at 6-12 mo intervals thereafter 
  • If % FEV1 continues to decrease, go to B below 
B. Significant airflow obstruction with a % FEV1 <70% with/without significant air-trapping by high resolution chest CT 
 1. Consider bronchoscopy to rule out an undetected infectious etiology for airflow obstruction, even if no infiltrate is apparent 
 2. After infection has been ruled out, evaluate the patient eligibility for clinical trial for treatment of BOS and initiate (or increase) prednisone dose to 1 mg/kg/d 
  • Start standard chronic GVHD taper at 2 wk (Table 5
  • Consider continuing inhaled corticosteroids throughout prednisone therapy 
 3. If % FEV1 decreases further to <70% during treatment, discuss changes of immunosuppressive treatment with transplant physician 
 4. CMV monitoring in blood per standard practice 
 5. Monitor PFTs or spirometry monthly for at least 3 mo 
  • If % FEV1 stabilizes, continue PFTs or spirometry every 3 mo for 1 y 
  • If % FEV1 continues to decrease, go to C below 
C. Corticosteroid-resistant airflow obstruction defined as progressive decline of FEV1 by ≥10% despite treatment with 1 mg/kg/d of prednisone (or similar corticosteroids) 
 1. May consider increasing the dose of prednisone to 2 mg/kg/d for a maximum of 2 wk, followed by a taper to reach a dose of 1 mg/kg/d by 2-4 wk 
 2. Another treatment must be considered and discussed with the transplant team 
 3. Monitor CMV in blood per standard practice 
 4. Monitor PFTs monthly for at least 3 mo 
  • If % FEV1 stabilizes, monitor PFTs every 3 mo for 1 y 
D. Additional considerations 
 1. Consider changing prophylaxis for encapsulated bacterial infection to azithromycin 250 mg on Mondays-Wednesdays-Fridays 
  • Assure patient is receiving adequate prophylaxis for Pneumocystis, varicella virus, and herpes simplex virus infections 
  • Fungal prophylaxis per standard practice 
 2. Monitor CMV in blood per standard practice 
 3. May continue inhaled corticosteroids throughout prednisone therapy 
 4. Discontinuation of inhaled corticosteroid treatment can be considered 12 mo after treatment with prednisone has been discontinued 
Guidelines
A. Significant new airflow obstruction with a % predicted FEV1 ≥70% 
 1. Initiate inhaled corticosteroid therapy 
  • Fluticasone (Flovent) 440 mcg BID, or 
  • Advair 500/50 mcg BID (if symptoms of airway obstruction are present) 
  • Treatment should continue until either % FEV1 becomes <70% (see below), or until GVHD resolves (ie, resolution of all reversible manifestations of GVHD without exacerbation after at least 6 mo after discontinuation of all systemic immunosuppressive treatment) 
 2. Other immunosuppressive treatment as indicated to control GVHD in other organs 
  • Treatment should continue until either % FEV1 becomes <70% (see below), or until GVHD resolves (ie, resolution of all reversible manifestation of GVHD without exacerbation after at least 12 mo after discontinuation of all systemic treatments) 
 3. Monitor PFTs or spirometry monthly for at least 3 mo 
  • If % FEV1 stabilizes, PFTs or spirometry every 3 mo for 1 y, then if stable continue at 6-mo intervals for 1 y and at 6-12 mo intervals thereafter 
  • If % FEV1 continues to decrease, go to B below 
B. Significant airflow obstruction with a % FEV1 <70% with/without significant air-trapping by high resolution chest CT 
 1. Consider bronchoscopy to rule out an undetected infectious etiology for airflow obstruction, even if no infiltrate is apparent 
 2. After infection has been ruled out, evaluate the patient eligibility for clinical trial for treatment of BOS and initiate (or increase) prednisone dose to 1 mg/kg/d 
  • Start standard chronic GVHD taper at 2 wk (Table 5
  • Consider continuing inhaled corticosteroids throughout prednisone therapy 
 3. If % FEV1 decreases further to <70% during treatment, discuss changes of immunosuppressive treatment with transplant physician 
 4. CMV monitoring in blood per standard practice 
 5. Monitor PFTs or spirometry monthly for at least 3 mo 
  • If % FEV1 stabilizes, continue PFTs or spirometry every 3 mo for 1 y 
  • If % FEV1 continues to decrease, go to C below 
C. Corticosteroid-resistant airflow obstruction defined as progressive decline of FEV1 by ≥10% despite treatment with 1 mg/kg/d of prednisone (or similar corticosteroids) 
 1. May consider increasing the dose of prednisone to 2 mg/kg/d for a maximum of 2 wk, followed by a taper to reach a dose of 1 mg/kg/d by 2-4 wk 
 2. Another treatment must be considered and discussed with the transplant team 
 3. Monitor CMV in blood per standard practice 
 4. Monitor PFTs monthly for at least 3 mo 
  • If % FEV1 stabilizes, monitor PFTs every 3 mo for 1 y 
D. Additional considerations 
 1. Consider changing prophylaxis for encapsulated bacterial infection to azithromycin 250 mg on Mondays-Wednesdays-Fridays 
  • Assure patient is receiving adequate prophylaxis for Pneumocystis, varicella virus, and herpes simplex virus infections 
  • Fungal prophylaxis per standard practice 
 2. Monitor CMV in blood per standard practice 
 3. May continue inhaled corticosteroids throughout prednisone therapy 
 4. Discontinuation of inhaled corticosteroid treatment can be considered 12 mo after treatment with prednisone has been discontinued 

Before considering treatment, all potential infectious etiologies of airflow obstruction must be investigated and treated if present. Investigations that should be considered (directed by clinical symptoms), include sinus CT scan, nasal washes, sinus aspiration, high-resolution chest CT scan, sputum culture, bronchoalveolar lavage, and lung biopsy.

BID, twice daily; CT, computed tomography scan.

Treatment

Treatment of chronic GVHD is intended to produce a sustained benefit by reducing symptom burden, controlling objective manifestations of disease activity, and preventing damage and disability, without causing disproportionate toxicity or harms related to the treatments themselves. The long-term goal of GVHD treatment is the development of immunologic tolerance, indicated by successful withdrawal of all immunosuppressive treatment without recurrence or clinically significant exacerbation of disease manifestations. The current therapeutic approach functions primarily to prevent immune-mediated damage, while awaiting the development of tolerance. Evidence to suggest that current treatments accelerate the development of immunologic tolerance is lacking. Optimal treatment of chronic GVHD requires a multidisciplinary team approach that includes transplantation specialists, a primary health care provider, organ-specific consultants, nurses, and ancillary services such as social services, vocational specialists, patient and family support groups, and systems.

Systemic therapy for at least 1 year is generally indicated for patients who meet criteria for moderate-to-severe disease according to the NIH consensus criteria: involvement of 3 or more organs, moderate or severe organ involvement in any organ, or any lung involvement.10,51  Systemic treatment is also generally indicated for patients with less severe disease if high-risk features such as thrombocytopenia, hyperbilirubinemia, or onset during corticosteroid treatment are present.2,10,52-54  Symptomatic mild chronic GVHD is often treated with topical therapies alone.13,52  Topical agents may also be used as adjuncts to systemic therapy to improve and accelerate local response. Comprehensive reviews of topical therapies have been published previously.2,13,52  Considerations affecting the choice of treatment include the affected organs or sites, the severity of disease manifestations, the presence of health problems that might be exacerbated by the treatment, possible drug interactions, the intensity of the monitoring needed, and factors that affect access to the treatment such as travel, distance, and cost.

Primary systemic treatment

Management of chronic GVHD has relied on corticosteroids as the mainstay of treatment of >3 decades. Systemic treatment typically begins with prednisone at 0.5 to 1 mg/kg per day, followed by a taper to reach an alternate-day regimen, with or without cyclosporine or tacrolimus. The efficacy of alternate-day vs daily administration of corticosteroids has been reported in pediatric renal transplantation but has not been tested in HCT.55  Prolonged systemic corticosteroid treatment causes significant toxicity, including weight gain, bone loss, myopathy, diabetes, hypertension, mood swings, cataract formation, and increased risk of infection. Many of these toxicities can be mitigated by alternate-day administration of corticosteroids. Alternate-day administration also has an important role in facilitating adrenal recovery long before the end of treatment. In a recent prospective study, the average dose of prednisone was tapered to 0.20 to 0.25 mg/kg per day or 0.4 to 0.5 mg/kg every other day within 3 months after starting treatment.56  Medications used for treatment of chronic GVHD should be withdrawn gradually one at a time after the disease has resolved. As a general principle, withdrawal of systemic treatment should begin with the medication that is most likely to cause long-term toxicity. Withdrawal of prednisone should generally precede withdrawal of a calcineurin inhibitor, unless continued treatment with the calcineurin inhibitor threatens to cause intolerable or irreversible toxicity.

Strategies for tapering the dose of prednisone vary considerably, but as a general principle, efforts should be made to use the minimum dose that is sufficient to control GVHD manifestations (Figure 2). In practice, this means that prednisone doses should be decreased progressively in patients who have had a complete response or a very-good-partial response, and tapering should continue until manifestations begin to recur or show evidence of exacerbation. A prototypic taper schedule (Table 5) is designed to approximate a 20% to 30% dose reduction every 2 weeks, with smaller absolute decrements toward the end of the taper schedule. Toxicity associated with the administration of prednisone may require dose adjustments.

Figure 2

Appropriate management of chronic GVHD requires continuous recalibration of immunosuppressive treatment in order to avoid overtreatment or undertreatment. The intensity of treatment required to control the disease decreases across time. Manifestations of chronic GVHD improve or are absent when the intensity of treatment is above the threshold shown as the orange curve, and they worsen or recur when the intensity of treatment is below the threshold. The slope of the threshold varies among patients and can be determined only by serial attempts to decrease the intensity of treatment. Clinical tolerance is defined by the ability to withdraw all systemic treatment without recurrence of chronic GVHD.

Figure 2

Appropriate management of chronic GVHD requires continuous recalibration of immunosuppressive treatment in order to avoid overtreatment or undertreatment. The intensity of treatment required to control the disease decreases across time. Manifestations of chronic GVHD improve or are absent when the intensity of treatment is above the threshold shown as the orange curve, and they worsen or recur when the intensity of treatment is below the threshold. The slope of the threshold varies among patients and can be determined only by serial attempts to decrease the intensity of treatment. Clinical tolerance is defined by the ability to withdraw all systemic treatment without recurrence of chronic GVHD.

Table 5

Prednisone taper schedule

WeekDose, mg/kg body weight
1.0 
1.0/0.5* (to begin within 2 wk after objective improvement) 
1.0/0.25* 
1.0 qod (continued until resolution of all clinical manifestations) 
0.70 qod (to begin after resolution of all clinical manifestations) 
10 0.55 qod 
12 0.45 qod 
14 0.35 qod 
16 0.25 qod 
18 0.20 qod 
20 0.15 qod 
22 0.10 qod 
WeekDose, mg/kg body weight
1.0 
1.0/0.5* (to begin within 2 wk after objective improvement) 
1.0/0.25* 
1.0 qod (continued until resolution of all clinical manifestations) 
0.70 qod (to begin after resolution of all clinical manifestations) 
10 0.55 qod 
12 0.45 qod 
14 0.35 qod 
16 0.25 qod 
18 0.20 qod 
20 0.15 qod 
22 0.10 qod 

qod, every other day.

*

Alternate-day administration.

A physician or advanced practitioner should examine the patient before each reduction of the prednisone dose. If exacerbation or recurrence of chronic GVHD is evident at any step of the taper, the dose of prednisone should be increased promptly by 2 levels, with daily administration for 2 to 4 weeks, followed by resumption of alternate-day administration. Treatment should then be continued for at least 3 months before attempting to resume the taper. Cycles of attempted tapering and dose escalation should be repeated as needed until the dose reaches 0.10 mg/kg per day, which equates to adrenal replacement therapy. Administration of prednisone may be discontinued after a minimum of at least 4 weeks of treatment at a dose of 0.10 mg/kg every other day. Some patients have recurrent symptoms with doses at or below 0.10 mg/kg every other day, and in this situation, treatment with very low prednisone doses may be required for a year or more.

Combination therapy with other immunosuppressive agents is often considered in hopes of minimizing toxicity caused by prolonged corticosteroid treatment.54  Randomized trials, however, showed no benefit from adding azathioprine,57  thalidomide,58  mycophenolate mofetil,56  or hydroxychloroquine59  to initial treatment of chronic GVHD. A trial comparing cyclosporine plus prednisone vs prednisone alone showed no statistically significant differences in survival or the duration of treatment.60  The incidence of avascular necrosis was lower in the cyclosporine plus prednisone arm, suggesting that cyclosporine could have had a steroid-sparing effect, but steroid doses across time were not measured in this study. Results are pending from a recent randomized, multicenter phase 2 to 3 clinical trial comparing prednisone and sirolimus with or without a calcineurin inhibitor for initial treatment of chronic GVHD. Premature closure of this trial at the end of phase 2 suggests that the expected benefit of omitting the calcineurin inhibitor was not observed. Wherever possible, clinical trials should be considered as the first option for initial systemic treatment of chronic GVHD.

Secondary systemic treatment

Approximately 50% to 60% of patients with chronic GVHD require secondary treatment within 2 years after initial systemic treatment.61,62  Indications for secondary treatment include worsening manifestations of chronic GVHD in a previously affected organ, development of signs and symptoms of chronic GVHD in a previously unaffected organ, absence of improvement after 1 month of standard primary treatment, inability to decrease prednisone below 1 mg/kg per day within 2 months, or significant treatment-related toxicity. Numerous clinical trials have been carried out to evaluate approaches for secondary treatment of chronic GVHD. Reports from retrospective and prospective studies often indicate high response rates, but results are difficult to interpret because of deficiencies in study design.54 

No consensus has been reached regarding the optimal choice of agents for secondary treatment of chronic GVHD, and the published literature provides little useful guidance. Therefore, clinical management requires an empirical approach, as illustrated in “Case summary.” Treatment choices are based on physician experience, ease of use, need for monitoring, risk of toxicity, and potential exacerbation of preexisting comorbidity.63,64  Options for secondary treatment have been recently reviewed and are summarized in Table 6.36 

Table 6

Agents used for secondary treatment of chronic GVHD*

Treatment% Overall response*Survival
ECP 65-70 70%-78% at 1 y 
Rituximab 66-86 72% at 1 y 
Imatinib 22-79 75%-84% at 1.5 y 
Pentostatin 53-56 34%-60% at 1-3 y 
Mesenchymal stem cells 50-74 78% at 2 y 
Mycophenolate mofetil 26-64 67%-96% at 1 y 
mTOR inhibitor 76 72% at 3 y 
Interleukin-2 52 Not reported 
Other therapies summarized in other reviews** 
 Calcineurin inhibitor  
 High-dose methylprednisolone  
 Methotrexate  
 Thalidomide 
 Hydroxychloroquine 
 Clofazimine 
 Thoracoabdominal irradiation 
 Alefacept 
 Infliximab 
 Etanercept70  
Treatment% Overall response*Survival
ECP 65-70 70%-78% at 1 y 
Rituximab 66-86 72% at 1 y 
Imatinib 22-79 75%-84% at 1.5 y 
Pentostatin 53-56 34%-60% at 1-3 y 
Mesenchymal stem cells 50-74 78% at 2 y 
Mycophenolate mofetil 26-64 67%-96% at 1 y 
mTOR inhibitor 76 72% at 3 y 
Interleukin-2 52 Not reported 
Other therapies summarized in other reviews** 
 Calcineurin inhibitor  
 High-dose methylprednisolone  
 Methotrexate  
 Thalidomide 
 Hydroxychloroquine 
 Clofazimine 
 Thoracoabdominal irradiation 
 Alefacept 
 Infliximab 
 Etanercept70  

mTOR, mammalian target of rapamycin.

*

Simplified from Inamoto and Flowers36 ; see Flowers et al,35  Wolff et al,63  and Flowers and Deeg64  for other reviews.

**

20%-82% overall response rates reported.

Ancillary and supportive care

Ancillary and supportive care therapies are commonly used in addition to systemic treatment of GVHD, although in some cases, their use may circumvent the need for systemic treatment or allow doses of systemic agents to be reduced. A detailed list of site-specific therapies has been reported elsewhere.2,13  Specific dispensary information for topical therapies is available online (http://asbmt.affiniscape.com/associations/11741/files/DispensaryGuidelines.pdf).

Symptoms caused by ocular sicca can be relieved by the frequent application of artificial lubricant tears or by plugging or ligation of the tear ducts. Symptoms can be relieved by using specialized moisture-chamber eyewear available from several vendors. Permanent punctal ligation is usually necessary in more severe cases of ocular sicca. Many patients with severe sicca keratitis have reported significant relief of symptoms with prosthetic replacement of the ocular surface ecosystem (PROSE), which refers to a gas-permeable scleral lens.65  Involvement of an ophthalmologist with expertise in the management of dry eye and corneal and conjunctival disease is strongly recommended for patients with ocular manifestations of chronic GVHD.

Oral cavity erythema, ulceration, and gingivitis are often treated with topical steroid rinses or ointments. Vaginal GVHD may respond to topical steroids and dilator therapy, but management should also address any coexisting estrogen deficiency or coexisting yeast or bacterial infection. Sialogogue therapy (to increase the flow rate of saliva) with agents such as cevimeline or pilocarpine may improve symptoms of oral,66  ocular, and vaginal dryness.

Consistent weight-bearing exercise for 30 minutes daily at least 5 days per week and daily stretching are particularly important for preserving bone health, muscle strength, and mobility. Physical therapy to maintain strength and joint mobility can prevent the development of disability during immunosuppressive treatment of chronic GVHD. Deep tissue massage is a helpful adjunct to preserve or improve range of motion in patients with fasciitis or scleroderma.

Close attention must be paid to complications of glucocorticoid treatment through management of hyperglycemia, hypertension, and bone loss. A balanced, healthy diet low in sodium and free sugars and high in calcium with adequate fluid intake is essential. Calcium (1500 mg per day) and vitamin D (1000 IU per day) intake between food and supplements is recommended to retard the development of osteoporosis during glucocorticoid treatment. Clinical trials have not yet been carried out to determine whether bisphosphonates are effective for prevention of glucocorticoid-induced osteoporosis, but some experts recommend the use of these agents for patients with osteopenia.

Both the disease and its treatment with immunosuppressive agents increase the risk of infection in patients with chronic GVHD.2,51  Antibiotic prophylaxis for Pneumocystis pneumonia and encapsulated bacterial infections should be given until 6 months after discontinuation of all systemic treatment. IV administration of γ globulin may help prevent infection in patients who have serum immunoglobulin G (IgG) concentrations <400 mg/dL or IgG2 or IgG4 subclass deficiencies. Cytomegalovirus (CMV) infection poses risks of CMV disease in patients with a history of viral reactivation and in those with low CD4 counts or cord blood donors. All patients with chronic GVHD who are at risk of CMV infection should have regular blood tests for surveillance of viral reactivation. Preemptive antiviral therapy should be instituted whenever surveillance tests show viral reactivation, before the onset of overt CMV disease. CMV-seronegative recipients with CMV-seronegative donors should receive screened or filtered leukocyte-depleted blood products. In addition, long-term administration of valacyclovir or acyclovir is recommended to prevent reactivation of varicella-zoster virus in patients previously infected with this virus.

Prognosis and outcomes

Duration of treatment

Approximately 50% of patients are cured within 7 years after starting systemic treatment, as indicated by resolution of disease manifestations and permanent withdrawal of systemic treatment. Approximately 10% require continued systemic treatment of an indefinite period beyond 7 years, and the remaining 40% have recurrent malignancy or die within 7 years during treatment of chronic GVHD.30 

Growth factor–mobilized apheresis products have replaced marrow as the most frequent source of cells for allogeneic HCT with both related and unrelated donors. The use of mobilized blood cells has been associated with 3 detrimental outcomes with respect to chronic GVHD: a higher incidence, a higher risk of fasciitis and development of fibrotic manifestations affecting the skin and joints, and a longer time to resolution of the disease, development of immunologic tolerance, and withdrawal of systemic treatment.48  The median duration of systemic treatment of chronic GVHD is ∼2 years in patients who had HCT with marrow cells and ∼3.5 years in those who had HCT with mobilized blood cells.

Graft-versus-leukemia associated with chronic GVHD

Chronic GVHD is associated with a reduced risk of recurrent malignancy after hematopoietic cell transplantation, raising the question of whether the intensity of immunosuppression should be attenuated when patients at high risk of recurrent malignancy develop chronic GVHD. This question has not been addressed directly in clinical trials, but several observations are pertinent. First, chronic GVHD increases the risk of nonrelapse mortality, thereby offsetting any benefit gained through the effects on malignant cells in the recipient. The tradeoff between risks of nonrelapse mortality and recurrent malignancy is balanced, such that mortality rates are not affected by the presence or absence of chronic GVHD.67,68  Second, a single-institution study showed that withdrawal of immunosuppression decreased the subsequent risk of recurrent malignancy in patients without prior GVHD but not in those with prior GVHD.67 

These results suggest that attenuation of immunosuppression in patients with active manifestations of chronic GVHD might likewise not decrease the risk of recurrent malignancy. Nonetheless, unnecessary immunosuppressive treatment could increase the risk of recurrent malignancy, as suggested by trends in a prospective study evaluating the use of mycophenolate mofetil added to first-line treatment of chronic GVHD.56  Therefore, the intensity of treatment should be calibrated periodically by lowering the dose of immunosuppressive medications to levels that allow disease manifestations to begin emerging before increasing the dose, as described in Figure 2.

Future perspectives

Participation in a clinical trial represents the first option to consider for eligible patients with chronic GVHD. Novel strategies directed toward depleting or modulating B cells, expanding T or B regulatory cells, and targeting the processes implicated in fibrosis are under active investigation and could lead to future advances in treatment of chronic GVHD. Progress toward decreasing the impact of chronic GVHD after HCT will be made not only through improved treatment but also through development of prevention strategies that do not impair the immunological activity of donor cells against malignant cells in the recipient. In the absence of specific interventions to decrease the risk of chronic GVHD, marrow should be preferred over mobilized blood as a source of stem cells for HCT with myeloablative conditioning regimens.

The online version of this article contains a data supplement.

Acknowledgments

The authors thank Anne Thompson for assistance with preparing the manuscript and Kevin Bray for assistance with hyperlinks.

This work was supported in part by grant CA18029 from the National Cancer Institute at the National Institutes of Health.

Authorship

Contribution: M.E.D.F. and P.J.M. wrote the manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Mary E. D. Flowers, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D5-290, PO Box 19024, Seattle, WA 98109-1024; e-mail: mflowers@fredhutch.org.

References

References
1
Center for International Blood and Marrow Transplant Research
 
CIBMTR 2014. http://www.cibmtr.org. Accessed August 5, 2014
2
Lee
 
SJ
Vogelsang
 
G
Flowers
 
ME
Chronic graft-versus-host disease.
Biol Blood Marrow Transplant
2003
, vol. 
9
 
4
(pg. 
215
-
233
)
3
Flowers
 
ME
Parker
 
PM
Johnston
 
LJ
, et al. 
Comparison of chronic graft-versus-host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long-term follow-up of a randomized trial.
Blood
2002
, vol. 
100
 
2
(pg. 
415
-
419
)
4
Anasetti
 
C
Logan
 
BR
Lee
 
SJ
, et al. 
Peripheral-blood stem cells versus bone marrow from unrelated donors.
N Engl J Med
2012
, vol. 
367
 
16
(pg. 
1487
-
1496
)
5
Gooley
 
TA
Chien
 
JW
Pergam
 
SA
, et al. 
Reduced mortality after allogeneic hematopoietic-cell transplantation.
N Engl J Med
2010
, vol. 
363
 
22
(pg. 
2091
-
2101
)
6
Stem Cell Trialists’ Collaborative Group
Allogeneic peripheral blood stem-cell compared with bone marrow transplantation in the management of hematologic malignancies: an individual patient data meta-analysis of nine randomized trials.
J Clin Oncol
2005
, vol. 
23
 
22
(pg. 
5074
-
5087
)
7
Schroeder
 
MA
DiPersio
 
JF
Mouse models of graft-versus-host disease: advances and limitations.
Dis Model Mech
2011
, vol. 
4
 
3
(pg. 
318
-
333
)
8
Socié
 
G
Ritz
 
J
Current issues in chronic graft-versus-host disease.
Blood
2014
, vol. 
124
 
3
(pg. 
374
-
384
)
9
Vogelsang
 
GB
How I treat chronic graft-versus-host disease.
Blood
2001
, vol. 
97
 
5
(pg. 
1196
-
1201
)
10
Filipovich
 
AH
Weisdorf
 
D
Pavletic
 
S
, et al. 
National Institutes of Health consensus development project on criteria for clinical trials in chronic graft-versus-host disease: I. Diagnosis and Staging Working Group report.
Biol Blood Marrow Transplant
2005
, vol. 
11
 
12
(pg. 
945
-
956
)
11
Pavletic
 
S
Martin
 
P
Lee
 
SJ
, 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. Response Criteria Working Group report.
Biol Blood Marrow Transplant
2006
, vol. 
12
 
3
(pg. 
252
-
266
)
12
Martin
 
PJ
Weisdorf
 
D
Przepiorka
 
D
, et al. 
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
, vol. 
12
 
5
(pg. 
491
-
505
)
13
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
, vol. 
12
 
4
(pg. 
375
-
396
)
14
Palmer
 
JM
Lee
 
SJ
Chai
 
X
, et al. 
Poor agreement between clinician response ratings and calculated response measures in patients with chronic graft-versus-host disease.
Biol Blood Marrow Transplant
2012
, vol. 
18
 
11
(pg. 
1649
-
1655
)
15
Inamoto
 
Y
Martin
 
PJ
Storer
 
BE
, et al. 
Association of severity of organ involvement with mortality and recurrent malignancy in patients with chronic graft-versus-host disease.
Haematologica
2014
, vol. 
99
 
10
(pg. 
1618
-
1623
)
16
Inamoto
 
Y
Jagasia
 
M
Wood
 
WA
, et al. 
Investigator feedback about the 2005 NIH diagnostic and scoring criteria for chronic GVHD.
Bone Marrow Transplant
2014
, vol. 
49
 
4
(pg. 
532
-
538
)
17
Arora
 
M
Pidala
 
J
Cutler
 
CS
, et al. 
Impact of prior acute GVHD on chronic GVHD outcomes: a chronic graft versus host disease consortium study.
Leukemia
2013
, vol. 
27
 
5
(pg. 
1196
-
1201
)
18
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
, vol. 
19
 
4
(pg. 
632
-
639
)
19
Pidala
 
J
Chai
 
X
Kurland
 
BF
, et al. 
Analysis of gastrointestinal and hepatic chronic graft-versus-host disease manifestations on major outcomes: a Chronic Graft-Versus-Host Disease Consortium study.
Biol Blood Marrow Transplant
2013
, vol. 
19
 
5
(pg. 
784
-
791
)
20
Kuzmina
 
Z
Eder
 
S
Bohm
 
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
, vol. 
26
 
4
(pg. 
746
-
756
)
21
Jacobsohn
 
DA
Kurland
 
BF
Pidala
 
J
, et al. 
Correlation between NIH composite skin score, patient reported skin score, and outcome: results from the Chronic GVHD Consortium.
Blood
2012
, vol. 
120
 
13
(pg. 
2545
-
2552
)
22
Pidala
 
J
Vogelsang
 
G
Martin
 
P
, et al. 
Overlap subtype of chronic graft-versus-host disease is associated with an adverse prognosis, functional impairment, and inferior patient-reported outcomes: a Chronic Graft-versus-Host Disease Consortium study.
Haematologica
2012
, vol. 
97
 
3
(pg. 
451
-
458
)
23
Pidala
 
J
Kurland
 
B
Chai
 
X
, et al. 
Patient-reported quality of life is associated with severity of chronic graft-versus-host disease as measured by NIH criteria: report on baseline data from the Chronic GVHD Consortium.
Blood
2011
, vol. 
117
 
17
(pg. 
4651
-
4657
)
24
Arai
 
S
Jagasia
 
M
Storer
 
B
, et al. 
Global and organ-specific chronic graft-versus-host disease severity according to the 2005 NIH Consensus Criteria.
Blood
2011
, vol. 
118
 
15
(pg. 
4242
-
4249
)
25
Pidala
 
J
Kurland
 
BF
Chai
 
X
, et al. 
Sensitivity of changes in chronic graft-versus-host disease activity to changes in patient-reported quality of life: results from the Chronic Graft-versus-Host Disease Consortium.
Haematologica
2011
, vol. 
96
 
10
(pg. 
1528
-
1535
)
26
Grkovic
 
L
Baird
 
K
Steinberg
 
SM
, et al. 
Clinical laboratory markers of inflammation as determinants of chronic graft-versus-host disease activity and NIH global severity.
Leukemia
2012
, vol. 
26
 
4
(pg. 
633
-
643
)
27
Greinix
 
HT
Loddenkemper
 
C
Pavletic
 
SZ
, et al. 
Diagnosis and staging of chronic graft-versus-host disease in the clinical practice.
Biol Blood Marrow Transplant
2011
, vol. 
17
 
2
(pg. 
167
-
175
)
28
Herzberg
 
PY
Heussner
 
P
Mumm
 
FH
, et al. 
Validation of the human activity profile questionnaire in patients after allogeneic hematopoietic stem cell transplantation.
Biol Blood Marrow Transplant
2010
, vol. 
16
 
12
(pg. 
1707
-
1717
)
29
Cho
 
B-S
Min
 
C-K
Eom
 
K-S
, et al. 
Feasibility of NIH consensus criteria for chronic graft-versus-host disease.
Leukemia
2009
, vol. 
23
 
1
(pg. 
78
-
84
)
30
Vigorito
 
AC
Campregher
 
PV
Storer
 
BE
, et al. 
Evaluation of NIH consensus criteria for classification of late acute and chronic GVHD.
Blood
2009
, vol. 
114
 
3
(pg. 
702
-
708
)
31
Jagasia
 
M
Giglia
 
J
Chinratanalab
 
W
, et al. 
Incidence and outcome of chronic graft-versus-host disease using National Institutes of Health consensus criteria.
Biol Blood Marrow Transplant
2007
, vol. 
13
 
10
(pg. 
1207
-
1215
)
32
Arora
 
M
Nagaraj
 
S
Witte
 
J
, et al. 
New classification of chronic GVHD: added clarity from the consensus diagnoses.
Bone Marrow Transplant
2009
, vol. 
43
 
2
(pg. 
149
-
153
)
33
Pérez-Simón
 
JA
Encinas
 
C
Silva
 
F
, et al. 
Prognostic factors of chronic graft-versus-host disease following allogeneic peripheral blood stem cell transplantation: the National Institutes Health Scale plus the type of onset can predict survival rates and the duration of immunosuppressive therapy.
Biol Blood Marrow Transplant
2008
, vol. 
14
 
10
(pg. 
1163
-
1171
)
34
Clements
 
PJ
Lachenbruch
 
PA
Seibold
 
JR
, et al. 
Skin thickness score in systemic sclerosis: an assessment of interobserver variability in 3 independent studies.
J Rheumatol
1993
, vol. 
20
 
11
(pg. 
1892
-
1896
)
35
Flowers
 
ME
Apperley
 
JF
van Besien
 
K
, et al. 
A multicenter prospective phase II randomized study of extracorporeal photopheresis for treatment of chronic graft-versus-host disease.
Blood
2008
, vol. 
112
 
7
(pg. 
2667
-
2674
)
36
Inamoto
 
Y
Flowers
 
ME
Treatment of chronic graft-versus-host disease in 2011.
Curr Opin Hematol
2011
, vol. 
18
 
6
(pg. 
414
-
420
)
37
Koreth
 
J
Matsuoka
 
K
Kim
 
HT
, et al. 
Interleukin-2 and regulatory T cells in graft-versus-host disease.
N Engl J Med
2011
, vol. 
365
 
22
(pg. 
2055
-
2066
)
38
Greinix
 
HT
van Besien
 
K
Elmaagacli
 
AH
, et al. 
Progressive improvement in cutaneous and extracutaneous chronic graft-versus-host disease after a 24-week course of extracorporeal photopheresis-results of a crossover randomized study.
Biol Blood Marrow Transplant
2011
, vol. 
17
 
12
(pg. 
1775
-
1782
)
39
Bacigalupo
 
A
Lamparelli
 
T
Bruzzi
 
P
, et al. 
Antithymocyte globulin for graft-versus-host disease prophylaxis in transplants from unrelated donors: 2 randomized studies from Gruppo Italiano Trapianti Midollo Osseo (GITMO).
Blood
2001
, vol. 
98
 
10
(pg. 
2942
-
2947
)
40
Finke
 
J
Bethge
 
WA
Schmoor
 
C
, et al. 
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 trial.
Lancet Oncol
2009
, vol. 
10
 
9
(pg. 
855
-
864
)
41
Socie
 
G
Schmoor
 
C
Bethge
 
WA
, et al. 
Chronic graft-versus-host disease: long-term results from a randomized trial on graft-versus-host disease prophylaxis with or without anti-T-cell globulin ATG-Fresenius.
Blood
2011
, vol. 
117
 
23
(pg. 
6375
-
6382
)
42
Soiffer
 
RJ
Lerademacher
 
J
Ho
 
V
, et al. 
Impact of immune modulation with anti-T-cell antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell transplantation for hematologic malignancies.
Blood
2011
, vol. 
117
 
25
(pg. 
6963
-
6970
)
43
Devine
 
SM
Carter
 
S
Soiffer
 
RJ
, et al. 
Low risk of chronic graft-versus-host disease and relapse associated with T cell-depleted peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission: results of the Blood and Marrow Transplant Clinical Trials Network protocol 0303.
Biol Blood Marrow Transplant
2011
, vol. 
17
 
9
(pg. 
1343
-
1351
)
44
Luznik
 
L
Bolanos-Meade
 
J
Zahurak
 
M
, et al. 
High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease.
Blood
2010
, vol. 
115
 
16
(pg. 
3224
-
3230
)
45
Raj
 
K
Pagliuca
 
A
Bradstock
 
K
, et al. 
Peripheral blood hematopoietic stem cells for transplantation of hematological diseases from related, haploidentical donors after reduced-intensity conditioning.
Biol Blood Marrow Transplant
2014
, vol. 
20
 
6
(pg. 
890
-
895
)
46
Flowers
 
ME
Inamoto
 
Y
Carpenter
 
PA
, et al. 
Comparative analysis of risk factors for acute graft-versus-host disease and for chronic graft-versus-host disease according to National Institutes of Health consensus criteria.
Blood
2011
, vol. 
117
 
11
(pg. 
3214
-
3219
)
47
Lee
 
SJ
Flowers
 
MED
Gewirtz
 
AM
Muchmore
 
EA
Burns
 
LJ
Recognizing and managing chronic graft-versus-host disease.
Hematology 2008: American Society of Hematology Education Program Book
2008
Washington, DC
American Society of Hematology
(pg. 
134
-
141
)
48
Inamoto
 
Y
Storer
 
BE
Petersdorf
 
EW
, et al. 
Incidence, risk factors and outcomes of sclerosis in patients with chronic graft-versus-host disease.
Blood
2013
, vol. 
121
 
25
(pg. 
5098
-
5103
)
49
Carpenter
 
PA
How I conduct a comprehensive chronic graft-versus-host disease assessment.
Blood
2011
, vol. 
118
 
10
(pg. 
2679
-
2687
)
50
Carpenter
 
PA
 
GVHD Assessment Video: How to Conduct a Comprehensive Chronic GVHD Assessment. http://www.fhcrc.org/en/labs/clinical/projects/gvhd.html. Accessed July 31, 2014
51
Flowers
 
MED
Emerging strategies in the treatment of chronic graft-versus-host disease: traditional treatment of chronic graft-versus-host disease (symposium report).
Blood Marrow Transplant Rev
2002
, vol. 
12
 
1
(pg. 
5
-
8
)
52
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
, vol. 
16
 
12
(pg. 
1611
-
1628
)
53
Martin
 
PJ
Gilman
 
AL
Vogelsang
 
GB
Pavletic
 
SZ
Front line treatment of chronic graft versus host disease.
Chronic Graft Versus Host Disease: Interdisciplianry Management
2009
New York, NY
Cambridge University Press
(pg. 
124
-
133
)
54
Martin
 
PJ
Inamoto
 
Y
Carpenter
 
PA
Lee
 
SJ
Flowers
 
ME
Treatment of chronic graft-versus-host disease: past, present and future.
Korean J Hematol
2011
, vol. 
46
 
3
(pg. 
153
-
163
)
55
Jabs
 
K
Sullivan
 
EK
Avner
 
ED
Harmon
 
WE
Alternate-day steroid dosing improves growth without adversely affecting graft survival or long-term graft function. A report of the North American Pediatric Renal Transplant Cooperative Study.
Transplantation
1996
, vol. 
61
 
1
(pg. 
31
-
36
)
56
Martin
 
PJ
Storer
 
BE
Rowley
 
SD
, et al. 
Evaluation of mycophenolate mofetil for initial treatment of chronic graft-versus-host disease.
Blood
2009
, vol. 
113
 
21
(pg. 
5074
-
5082
)
57
Sullivan
 
KM
Witherspoon
 
RP
Storb
 
R
, et al. 
Prednisone and azathioprine compared with prednisone and placebo for treatment of chronic graft-versus-host disease: prognostic influence of prolonged thrombocytopenia after allogeneic marrow transplantation.
Blood
1988
, vol. 
72
 
2
(pg. 
546
-
554
)
58
Flowers
 
ME
Martin
 
PJ
Evaluation of thalidomide for treatment or prevention of chronic graft-versus-host disease.
Leuk Lymphoma
2003
, vol. 
44
 
7
(pg. 
1141
-
1146
)
59
Gilman
 
AL
Schultz
 
KR
Goldman
 
FD
, et al. 
Randomized trial of hydroxychloroquine for newly diagnosed chronic graft-versus-host disease in children: a Children’s Oncology Group study.
Biol Blood Marrow Transplant
2012
, vol. 
18
 
1
(pg. 
84
-
91
)
60
Koc
 
S
Leisenring
 
W
Flowers
 
ME
, et al. 
Therapy for chronic graft-versus-host disease: a randomized trial comparing cyclosporine plus prednisone versus prednisone alone.
Blood
2002
, vol. 
100
 
1
(pg. 
48
-
51
)
61
Flowers
 
ME
Storer
 
B
Carpenter
 
P
, et al. 
Treatment change as a predictor of outcome among patients with classic chronic graft-versus-host disease.
Biol Blood Marrow Transplant
2008
, vol. 
14
 
12
(pg. 
1380
-
1384
)
62
Inamoto
 
Y
Flowers
 
ME
Sandmaier
 
BM
, et al. 
Failure-free survival after initial systemic treatment of chronic graft-versus host disease.
Blood
2014
, vol. 
124
 
8
(pg. 
1363
-
1371
)
63
Wolff
 
D
Schleuning
 
M
von Harsdorf
 
S
, et al. 
Consensus Conference on Clinical Practice in Chronic GVHD: second-line treatment of chronic graft-versus-host disease.
Biol Blood Marrow Transplant
2011
, vol. 
17
 
1
(pg. 
1
-
17
)
64
Flowers
 
MED
Deeg
 
HJ
Treleaven
 
J
Barrett
 
AJ
Chronic graft-versus-host disease.
Hematopoietic Stem Cell Transplantation in Clinical Practice
2009
Edinburgh, UK
Elsevier Ltd
(pg. 
401
-
407
)
65
Takahide
 
K
Parker
 
PM
Wu
 
M
, et al. 
Use of fluid-ventilated, gas-permeable scleral lens for management of severe keratoconjunctivitis sicca secondary to chronic graft-versus-host disease.
Biol Blood Marrow Transplant
2007
, vol. 
13
 
9
(pg. 
1016
-
1021
)
66
Carpenter
 
PA
Schubert
 
MM
Flowers
 
ME
Cevimeline reduced mouth dryness and increased salivary flow in patients with xerotomia complicating chronic graft-versus-host disease.
Biol Blood Marrow Transplant
2006
, vol. 
12
 
7
(pg. 
792
-
794
)
67
Inamoto
 
Y
Flowers
 
ME
Lee
 
SJ
, et al. 
Influence of immunosuppressive treatment on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation.
Blood
2011
, vol. 
118
 
2
(pg. 
456
-
463
)
68
Gyurkocza
 
B
Storb
 
R
Storer
 
BE
, et al. 
Nonmyeloablative allogeneic hematopoietic cell transplantation in patients with acute myeloid leukemia.
J Clin Oncol
2010
, vol. 
28
 
17
(pg. 
2859
-
2867
)
69
Flowers
 
MED
Vogelsang
 
GB
Vogelsang
 
GB
Pavletic
 
SZ
Clinical manifestations and natural history.
Chronic Graft Versus Host Disease: Interdisciplinary Management
2009
New York, NY
Cambridge University Press
(pg. 
56
-
69
)
70
Yanik
 
GA
Mineishi
 
S
Levine
 
JE
, et al. 
Soluble tumor necrosis factor receptor: enbrel (etanercept) for subacute pulmonary dysfunction following allogeneic stem cell transplantation.
Biol Blood Marrow Transplant
2012
, vol. 
18
 
7
(pg. 
1044
-
1054
)