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Chronic Graft-versus-Host Disease
Stephanie J. Lee, MD MPHFred Hutchinson Cancer Research Center
February 2010
Materials
• Follow up form: Q276-347• Filipovich et al, BBMT 2005; 11: 945
Chronic GVHD
• Most common long-term complication of allogeneic hematopoietic cell infusion– Affects 30-70% of allogeneic recipients
M di t 4 6 th– Median onset 4-6 months– 5-10% of cases diagnosed beyond 1 year – Leading cause of transplant related mortality in
people who survive 2 years without relapse
• Both inflammatory and fibrotic components– Symptoms vary – 50% have 3 or more involved organs
• Treatment is prolonged and may contribute to bidit d t litmorbidity and mortality
– Median duration of treatment is 2-3 years– 15% still require treatment after 7 years– Infections cause 60-85% of deaths
NIH Consensus Development Project on Criteria for Clinical Trials
in Chronic GVHD (2004-2006)Chairs: Steve Pavletic & Georgia Vogelsang
• Diagnosis and scoring (Filipovich et al)
• Pathology (Shulman et al)gy ( )
• Biomarkers (Schultz et al)
• Response criteria (Pavletic et al)
• Supportive Care (Couriel et al)
• Clinical trials (Martin et al)
Biol BMT 2005; 11: 9452006; 12: 31
12: 12612: 25212: 37512: 491
Acute and Chronic GVHD
ACUTE CHRONIC
Day 0 Day 100Graft infused
ACUTE CHRONIC
2
2006 NIH Revision
CLASSIC ACUTE OVERLAP (20 48%) CLASSIC CHRONIC (9 60%)
LATE ACUTE(15-48%)
Day 0 Day 100Graft infused
CLASSIC ACUTE OVERLAP (20-48%) CLASSIC CHRONIC (9-60%)
Jagasia 2007; Arora 2008; Cho 2008; Vigorito 2009
Criteria for Chronic GVHD Diagnosis
• Distinction from acute GVHD• Presence of at least one diagnostic clinical
manifestation OR at least one distinct manifestation confirmed by pertinentmanifestation confirmed by pertinent biopsy or other relevant tests
• Exclusion of other possible etiologies for the clinical manifestation (e.g., infection, drug toxicity)
Diagnostic vs. DistinctiveOrgan Diagnostic Distinctive
Skin sclerosis, morphea, lichen-planus depigmentation
Nails - dystrophy, onycholysis
Mouth lichen planus, decreased range of motion
xerostomia, ulcers
Eyes keratoconjunctivitis siccaEyes - keratoconjunctivitis sicca
Genitalia lichen planus erosions, fissures, ulcers
GI tract esophageal web or strictures -
Liver - -
Lung bronchiolitis obliterans bronchiolitis obliterans syndrome (BOS)
Musculo-skeletal
fasciitis, contractures myositis
Q.276-283
• Prognostic factors: – type of onset, KPS, platelet count, maximum
grade of chronic GVHD, overall severityDefinitions are in fl and ill be pdated• Definitions are in flux and will be updated
0 40.50.60.70.80.9
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Skin Mouth Liver GI Eye Lung
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FHCRC, 1994-2000 FHCRC 2003-2005N= 159 N=1,148
74%-75% 51%-87% 29%-51% 23%-
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Score 3
4
Treister et al, BBMT 2008, 14: 110-5
5
Treatment (Q.314-347)
• Initial therapy is steroids at 1 mg/kg/day– Data do not support the need for a calcineurin
inhibitor (Koc Blood 2002; 100:49)
About 30% of people respond and never need– About 30% of people respond and never need additional treatment (Flowers Blood 2002; 100: 415)
Secondary therapy• Mycophenolate mofetil• Extracorporeal
photopheresis (ECP)• Sirolimus
• Acitretin/etretinate• Alefacept• Alemtuzumab
ATG• Sirolimus• Rituximab• Pulse steroids• Thalidomide• Pentostatin
• ATG• Azathioprine• Bortezomib• Clofazimine• Daclizumab
Secondary therapy cont.
• Etanercept• Halofuginone• Infliximab
• Montelukast• Pravastatin• Psoralen/UVA
Thoraco abdominal• Imatinib• Lidocaine• Mesenchymal stem cells• Methotrexate
• Thoraco-abdominal radiation
• T reg infusions• Ursodeoxycholic acid• UVB
N=29 (3 not approved for any uses)Salvage response: 20-82%
Case #1
• 38 y/o man with AML in first complete remission undergoing HLA-identical sibling transplantation using cytoxan/TBIA t GVHD f th ki d GI t t d• Acute GVHD of the skin and GI tract on day +30
• Despite treatment with steroids, mycophenolate mofetil, ATG and infliximab, he has lingering red skin and diarrhea on day +110
• Does he have chronic GVHD?• If so, what is the day of diagnosis?• What type of onset?
– Progressive, interrupted, de novo• What is the maximum grade?
– Limited, extensive• What is the overall severity?
– Mild, moderate, severe
Case #1
• His skin erythema and diarrhea resolve• At day +150, he develops dry eyes, dry
mouth, lichen planus in his mouth, and obstructive changes on pulmonary functionobstructive changes on pulmonary function tests
• Clinic notes state: “He has chronic GVHD and was started on prednisone. Tacrolimus was increased to full dose.”
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• Does he have chronic GVHD?• If so, what is the day of diagnosis?• What type of onset?• What is the maximum grade?• What is the overall severity?• What organs are involved?• What treatment was given?
Case #2
• A 60 y/o man with CLL has a matched unrelated donor non-myeloablative transplant. He does not have any skin rash, liver function abnormalities or diarrhealiver function abnormalities, or diarrhea
• On day +90 he develops mouth sensitivity with erythema and his absolute eosinophil count is 720
• Does he have chronic GVHD?• If so, what is the day of diagnosis?• What type of onset?• What is the maximum grade?• What is the overall severity?
Case #2
• On day +120 he has increased liver function tests, a pleural effusion, a lichen planus-like rash of the skin and mouth, and oral ulcers. Skin biopsy on day +122 shows p y yGVHD
• He is started on prednisone with some improvement but when the prednisone is tapered his pleural effusion returns and mouth pain increases.
• He then starts sirolimus
• Does he have chronic GVHD?• If so, what is the day of diagnosis?• What type of onset?• What is the maximum grade?• What is the overall severity?• What organs are involved?• What treatment was given?
Case #3
• A 48 y/o woman with MDS has a double cord blood graft using fludarabine/cytoxan and TBI
• On day +50 she has grade III acute GVHD with a skin rash and diarrheaskin rash and diarrhea
• She receives steroids + MMF/placebo on a clinical trial, continues tacrolimus, and her symptoms improve
• At day +110 she is seen with a red rash and diarrhea x 3 days. Her prednisone dose is increased and her symptoms improve
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• Does she have chronic GVHD?• If so, what is the day of diagnosis?• What type of onset?• What is the maximum grade?• What is the overall severity?• What organs are involved?• What treatment was given?
Case #3
• On day +276 she notes dry eyes and dry mouth. The physician note says that this is likely chronic GVHD and prescribes topical cyclosporine for her eyes and pilocarpinecyclosporine for her eyes and pilocarpine for her mouth
• Does she have chronic GVHD?• If so, what is the day of diagnosis?• What type of onset?• What is the maximum grade?• What is the overall severity?
Case #3• On day +365 she is seen in clinic. Sclerosis
around her waistline is noted. Fasciitis of her upper extremities prevents full range of motion at the shoulders and wrists. In retrospect, she first noticed problems 2 months before Her eyes andnoticed problems 2 months before. Her eyes and mouth remain dry. Prednisone is started.
• On day +400 she reports difficulty swallowing. Tests show an esophageal stricture which is dilated. She begins extracorporeal photopheresis (ECP)
• By day +500 she has lost 8 kg
• Does she have chronic GVHD?• If so, what is the day of diagnosis?• What type of onset?• What is the maximum grade?• What is the overall severity?• What organs are involved?• What treatment was given?
Measuring therapeutic response in chronic GVHD Trials: An instructional manualhttp://www.asbmt.org/GVHDForms.htm
Recommended post-transplant carehttp://www.marrow.org/md-guidelines
NPGW
Biology of Blood and Marrow Transplantation 11:945-955 (2005)� 2005 American Society for Blood and Marrow Transplantation1083-8791/05/1112-0002$30.00/0doi:10.1016/j.bbmt.2005.09.004
B
ational Institutes of Health Consensus Developmentroject on Criteria for Clinical Trials in Chronicraft-versus-Host Disease: I. Diagnosis and Stagingorking Group Report
Alexandra H. Filipovich,1 Daniel Weisdorf,2 Steven Pavletic,3 Gerard Socie,4 John R. Wingard,5
Stephanie J. Lee,6 Paul Martin,7 Jason Chien,7 Donna Przepiorka,8 Daniel Couriel,9
Edward W. Cowen,3 Patricia Dinndorf,10 Ann Farrell,10 Robert Hartzman,11 Jean Henslee-Downey,12
David Jacobsohn,13 George McDonald,7 Barbara Mittleman,14 J. Douglas Rizzo,15 Michael Robinson,16
Mark Schubert,7 Kirk Schultz,17 Howard Shulman,7 Maria Turner,3 Georgia Vogelsang,18
Mary E.D. Flowers7
1Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio; 2University ofMinnesota, Minneapolis, Minnesota; 3National Cancer Institute, National Institutes of Health, Bethesda, Maryland;4Hopital Saint Louis, Paris, France; 5University of Florida Shands Cancer Center, Gainsville, Florida; 6Dana-Farber Cancer Institute, Boston, Massachusetts; 7Fred Hutchinson Cancer Research Center, University ofWashington School of Medicine, Seattle, Washington; 8University of Tennessee, Memphis, Tennessee; 9Universityof Texas M.D. Anderson Cancer Center, Houston, Texas; 10US Food and Drug Administration, Rockville,Maryland; 11C.W. Bill Young/Department of Defense Marrow Donor Recruitment and Research Program, NavalMedical Research Center, Silver Spring, Maryland; 12National Heart, Lung and Blood Institute, National Institutesof Health, Bethesda, Maryland; 13Children’s Memorial Hospital, Northwestern University School of Medicine,Chicago, Illinois; 14National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes ofHealth, Bethesda, Maryland; 15Center for International Blood and Marrow Transplant Research, Medical Collegeof Wisconsin, Milwaukee, Wisconsin; 16National Eye Institute, National Institutes of Health, Bethesda, Maryland;17University of British Columbia, British Columbia Children’s Hospital, Vancouver, British Columbia, Canada;18Johns Hopkins University School of Medicine, Baltimore, Maryland
Correspondence and reprint requests: Alexandra H. Filipovich, MD, Division of Hematology/Oncology, CincinnatiChildren’s Hospital, 333 Burnet Ave., MLC 7015, Cincinnati, OH 45229 (e-mail: [email protected]).
Received September 9, 2005; accepted September 9, 2005
ABSTRACTThis consensus document is intended to serve 3 functions. First, it standardizes the criteria for diagnosis ofchronic graft-versus-host disease (GVHD). Second, it proposes a new clinical scoring system (0-3) thatdescribes the extent and severity of chronic GVHD for each organ or site at any given time, taking functionalimpact into account. Third, it proposes new guidelines for global assessment of chronic GVHD severity thatare based on the number of organs or sites involved and the degree of involvement in affected organs (mild,moderate, or severe). Diagnosis of chronic GVHD requires the presence of at least 1 diagnostic clinical signof chronic GVHD (e.g., poikiloderma or esophageal web) or the presence of at least 1 distinctive manifestation(e.g., keratoconjunctivitis sicca) confirmed by pertinent biopsy or other relevant tests (e.g., Schirmer test) inthe same or another organ. Furthermore, other possible diagnoses for clinical symptoms must be excluded. Notime limit is set for the diagnosis of chronic GVHD. The Working Group recognized 2 main categories ofGVHD, each with 2 subcategories. The acute GVHD category is defined in the absence of diagnostic ordistinctive features of chronic GVHD and includes (1) classic acute GVHD occurring within 100 days aftertransplantation and (2) persistent, recurrent, or late acute GVHD (features of acute GVHD occurring beyond100 days, often during withdrawal of immune suppression). The broad category of chronic GVHD includes (1)classic chronic GVHD (without features or characteristics of acute GVHD) and (2) an overlap syndrome inwhich diagnostic or distinctive features of chronic GVHD and acute GVHD appear together. It is currentlyrecommended that systemic therapy be considered for patients who meet criteria for chronic GVHD ofmoderate to severe global severity.
© 2005 American Society for Blood and Marrow Transplantation945B & M T
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KEY WORDSChronic graft-versus-host disease ● Allogeneic hematopoietic cell transplantation ● Consensus
● Diagnosis ● Staging
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ACKGROUND
Chronic graft-versus-host disease (GVHD) is aajor complication of allogeneic hematopoietic cell
ransplantation (HCT). The syndrome has featuresesembling autoimmune and other immunologic dis-rders such as scleroderma, Sjögren syndrome, pri-ary biliary cirrhosis, wasting syndrome, bronchiolitis
bliterans (BO), immune cytopenias, and chronic im-unodeficiency. The pathogenesis of chronic GVHD
s poorly understood [1].Symptoms usually present within 3 years after
llogeneic HCT and are often preceded by a history ofcute GVHD. Manifestations of chronic GVHD maye restricted to a single organ or tissue or may beidespread. Chronic GVHD can lead to debilitating
onsequences, e.g., joint contractures, loss of sight,nd-stage lung disease, or mortality resulting fromrofound chronic immune suppression leading to re-urrent or life-threatening infections. Historically,hronic GVHD was classified as limited or extensiven the basis of the results of a small retrospective study2], although this classification has not been shown toe reproducible or predictive of late treatment-relatedortality (TRM).
Reported incidence rates of chronic GVHD afterllogeneic transplantation range from 6% to 80% ac-ording to recipient age, donor type, HCT sourceperipheral blood, bone marrow, or umbilical cordlood stem cells), graft manipulation (T-cell deple-ion), and use of posttransplantation donor lympho-yte infusions (DLIs) [3-5]. Reliable incidence esti-ates in different cohorts of HCT recipients are
ompromised by (1) lack of standardized, widely usediagnostic guidelines; (2) variability in observer expe-ience; (3) limited expert follow-up at a distance fromransplant centers; (4) differences in the statisticalethods applied (e.g., use of the Kaplan-Meier versus
umulative incidence estimates and variable require-ent for some minimal survival [60-100 days] for
atients to be considered at risk of chronic GVHD);nd (5) the sometimes protean nature of early chronicVHD symptoms, which mimic alternative diag-
oses. Previous articles have identified risk factors forhronic GVHD after HCT, including prior acuteVHD, older patient age, the use of female donors
or male recipients, use of DLI, use of unrelated orLA-mismatched donors, and, more recently, the use
f growth factor–mobilized peripheral blood leuko-
he opinions expressed here are those of the authors and do not representhe official position of the National Institutes of Health or the US Gov-
prnment.
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ytes as opposed to marrow as a source of stem cells6-18].
URPOSE OF THIS DOCUMENT
The goals of this consensus document are to es-ablish standardized criteria for the diagnosis ofhronic GVHD and to propose tools for scoringhronic GVHD organ involvement and assessingverall severity. Specifically, the Working Groupought to (1) develop minimal criteria for the clinicaliagnosis of chronic GVHD; (2) propose a new scor-ng system that describes the extent and severity ofhronic GVHD for each organ or site at any givenime, taking functional impact into account; (3) pro-ose new guidelines for global assessment of chronicVHD severity; and (4) propose indications for top-
cal or systemic therapies.The recommendations of the Working Group
epresent a consensus opinion supplemented by eval-ation of available peer-reviewed literature. The pro-osed methods and tools for diagnosis and scoring ofhronic GVHD are provisional and will be updatedccording to the results of prospective validation stud-es.
UMMARY OF RECOMMENDATIONS
The diagnosis of chronic GVHD requires the fol-owing:
1. Distinction from acute GVHD.2. Presence of at least 1 diagnostic clinical sign of
chronic GVHD or presence of at least 1 distinc-tive manifestation confirmed by pertinent bi-opsy or other relevant tests.
3. Exclusion of other possible diagnoses.Scoring of organ manifestations requires careful
ssessment of signs, symptoms, laboratory values, andther study results.
A clinical scoring system (0-3) is provided forvaluation of the involvement of individual organs andites.
The proposed global assessment of severity (mild,oderate, or severe) is derived by combining organ-
nd site-specific scores.Systemic therapy should be considered for pa-
ients who meet criteria for moderate to severe globaleverity.
IAGNOSIS OF CHRONIC GVHD
In the past, any manifestation of GVHD that was
resent (or continued) at 100 days after HCT or
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Diagnosis and Staging of Chronic Graft-versus-Host Disease
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hereafter was arbitrarily defined as chronic GVHDven if the clinical manifestation was indistinguishablerom that of acute GVHD. Advances in HCT practicen the past 2 decades have profoundly altered theresentation and natural history of both acute andhronic GVHD and bring previous definitions intouestion. For instance, acute GVHD may presenteyond 3 months in patients who have received re-uced-intensity conditioning [19,20], whereas mani-estations of acute and chronic GVHD can be presentimultaneously, for example, in patients treated withLI. Therefore, the current consensus is that clinicalanifestations, and not the time to symptomatic onset
fter transplantation, determine whether the clinicalyndrome of GVHD is considered acute or chronic.
Throughout this article, diagnostic signs and symp-oms refer to those manifestations that establish theresence of chronic GVHD without the need forurther testing or evidence of other organ involve-
ent. Distinctive signs and symptoms of chronicVHD refer to those manifestations that are not
rdinarily found in acute GVHD but are not consid-red sufficient to establish an unequivocal diagnosis ofhronic GVHD without further testing or additionalrgan involvement. Other features of chronic GVHDefine the rare, controversial, or nonspecific featuresf chronic GVHD that cannot be used to establish theiagnosis of chronic GVHD. Common signs and symp-oms of chronic GVHD refer to manifestations foundn both chronic and acute GVHD (Table 1).
The Working Group recommends that the diag-osis of chronic GVHD require at least 1 diagnosticanifestation of chronic GVHD or at least 1 distinc-
ive manifestation, with the diagnosis confirmed byertinent biopsy, laboratory tests, or radiology in theame or another organ. As in acute GVHD, infectionnd other causes may confound or complicate theifferential diagnosis of chronic GVHD (e.g., nailystrophies associated with onychomycosis, herpesimplex, or Candida albicans infections of the oral cav-ty; drug toxicity) and must be excluded. Diagnosticnd distinctive manifestations of chronic GVHD cane found in the skin and appendages, mouth, eyes,emale genitalia, esophagus, lungs, and connective tis-ues. Biopsy or other testing is always encouraged andften valuable to confirm the presence of chronicVHD, but it is not always feasible and is not man-
atory if the patient has at least 1 of the diagnosticndings of chronic GVHD (Table 1). Please note thatn in-depth discussion of recommended terminologyor histopathologic interpretation may be found in aorthcoming histopathology working group report. Aiopsy read as “consistent with” or “unequivocal”hronic GVHD will be considered sufficient to estab-ish the diagnosis of chronic GVHD if accompaniedy at least 1 distinctive clinical manifestation.
Characteristics that establish the diagnosis of n
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hronic GVHD might not serve as the most appro-riate parameters for assessing the severity of chronicVHD. Valid and reliable diagnostic criteria might
ot be sufficiently sensitive to change to be useful asreatment-response criteria. Conversely, a sensitiveeasure of chronic GVHD response might not nec-
ssarily serve as an appropriate diagnostic and scoringool.
RGAN-SPECIFIC MANIFESTATIONS OF CHRONICVHD
In all cases, drug reaction, infection, recurrent orew malignancy, and other causes must be excluded.iagnostic clinical or laboratory features sufficient for
he diagnosis of chronic GVHD are italicized in theections below.
kin
Diagnostic manifestations include poikilodermae.g., atrophic and pigmentary changes), lichen planus-ike eruption (e.g., erythematous/violaceous flat-toppedapules or plaques with or without surface reticula-ions or a silvery or shiny appearance on direct light),eep sclerotic features (e.g., smooth, waxy, induratedkin—“thickened or tight skin,” caused by deep andiffuse sclerosis over a wide area), morphea-like super-cial sclerotic features (e.g., localized patchy areas ofoveable smooth or shiny skin with a leathery-like
onsistency, often with dyspigmentation), or lichenclerosus-like lesions (e.g., discrete to coalescent gray tohite moveable papules or plaques, often with follic-lar plugs, with a shiny appearance and leathery con-istency). Severe sclerotic features characterized byhickened, tight, and fragile skin are often associatedith poor wound healing, inadequate lymphatic drain-
ge, and skin ulcers from minor trauma.A distinctive feature for chronic GVHD (not seen
n acute GVHD, but not sufficiently unique to beonsidered diagnostic of chronic GVHD) is depig-entation. However, depigmentation would contrib-
te to the diagnosis of chronic GVHD in combinationith biopsy or laboratory confirmation of GVHD in
kin or another organ. Sweat impairment and intoler-nce to temperature change from loss of sweat glandsre seen in chronic GVHD. Other common, nondis-inctive skin manifestations found with both acute andhronic GVHD include erythema, maculopapularash, and pruritus.
ails
Dystrophy consisting of longitudinal ridging, nailplitting or brittleness, onycholysis, pterygium unguis,nd nail loss (usually symmetric and affecting mostails) are distinctive signs of chronic GVHD but are
ot sufficient for diagnosis.947
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able 1. Signs and Symptoms of Chronic GVHD
Organ or Site
Diagnostic (Sufficient toEstablish the Diagnosis of
Chronic GVHD)
Distinctive (Seen in Chronic GVHD, butInsufficient Alone to Establish a
Diagnosis of Chronic GVHD) Other Features*
Common (Seen withBoth Acute andChronic GVHD)
kin Poikiloderma Depigmentation Sweat impairment ErythemaLichen planus-like features Ichthyosis Maculopapular rashSclerotic features Keratosis pilaris PruritusMorphea-like features HypopigmentationLichen sclerosus-like features Hyperpigmentation
ails DystrophyLongitudinal ridging, splitting, or brittle
featuresOnycholysisPterygium unguisNail loss (usually symmetric; affects
most nails)†calp andbody hair
New onset of scarring or nonscarringscalp alopecia (after recovery fromchemoradiotherapy)
Scaling, papulosquamous lesions
Thinning scalphair, typicallypatchy, coarse,or dull (notexplained byendocrine orother causes)
Premature grayhair
outh Lichen-type features Xerostomia GingivitisHyperkeratotic plaques Mucocele MucositisRestriction of mouth
opening from sclerosisMucosal atrophyPseudomembranes†Ulcers†
ErythemaPain
yes New onset dry, gritty, or painful eyes‡ PhotophobiaCicatricial conjunctivitisKeratoconjunctivitis sicca‡Confluent areas of punctate keratopathy
Periorbitalhyperpigmentation
Blepharitis(erythema ofthe eyelids withedema)
enitalia Lichen planus-like features Erosions†Vaginal scarring or stenosis Fissures†
Ulcers†I tract Esophageal web
Strictures or stenosis in theupper to mid third of theesophagus†
Exocrinepancreaticinsufficiency
AnorexiaNauseaVomitingDiarrheaWeight lossFailure to thrive
(infants and children)iver Total bilirubin, alkaline
phosphatase >2 �
upper limit ofnormal†
ALT or AST >2 �
upper limit ofnormal†
ung Bronchiolitis obliteransdiagnosed with lung biopsy
Bronchiolitis obliterans diagnosed withPFTs and radiology‡
BOOP
uscles,fascia,joints
FasciitisJoint stiffness or
contractures secondary to
Myositis or polymyositis‡ EdemaMuscle crampsArthralgia or
sclerosis arthritis
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Diagnosis and Staging of Chronic Graft-versus-Host Disease
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air
Distinctive features of chronic GVHD includeew scarring and nonscarring scalp alopecia (afterecovery from chemotherapy or radiotherapy) and lossf body hair. Other characteristics seen with chronicVHD include premature graying, thinning, or brit-
leness, but these findings are not diagnostic.
outh
Diagnostic features of oral chronic GVHD in-lude lichen planus-like changes (white lines and lacy-ppearing lesions of the buccal mucosa, tongue, pal-te, or lips), hyperkeratotic plaques (leukoplakia), orecreased oral range of motion in patients with scleroticeatures of skin GVHD. Distinctive features of chronic
VHD include xerostomia (dryness), mucoceles, mu-osal atrophy, pseudomembranes, and ulcers (infec-ious pathogens such as yeast or herpesvirus; second-ry malignancy must be excluded). Manifestationsommon to both acute and chronic GVHD includeingivitis, mucositis, erythema, and pain.
yes
Distinctive manifestations of chronic GVHD in-lude new onset of dry, gritty, or painful eyes; cicatri-ial conjunctivitis; keratoconjunctivitis sicca; and con-uent areas of punctate keratopathy. Other features
able 1. Continued
Organ orSite
Diagnostic(Sufficient to Establish the
Diagnosis of Chronic GVHD)
D(Seen in Chronic
AloneDiagnosis o
ematopoieticandimmune
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VHD indicates graft-versus-host disease; ALT, alanine aminotranorganizing pneumonia; PFTs, pulmonary function tests; AIHpurpura.
Can be acknowledged as part of the chronic GVHD symptomatoIn all cases, infection, drug effects, malignancy, or other causes mDiagnosis of chronic GVHD requires biopsy or radiology confirm
nclude photophobia, periorbital hyperpigmentation, t
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ifficulty in opening the eyes in the morning becausef mucoid secretions, and blepharitis (erythema of theye lids with edema). New ocular sicca documented byow Schirmer test values with a mean value of bothyes �5 mm at 5 minutes or a new onset of kerato-onjunctivitis sicca by slit-lamp examination withean values of 6 to 10 mm on the Schirmer test is
ufficient for the diagnosis of chronic GVHD if ac-ompanied by distinctive manifestations in at least 1ther organ.
enitalia
Diagnostic features for the genitalia include lichenlanus-like features and vaginal scarring or stenosis (oftenssociated with oral GVHD).
astrointestinal Tract
Diagnostic features for the gastrointestinal (GI)ract include esophageal web, stricture, or concentric ringsocumented by endoscopy or barium contrast radio-raph. Chronic GVHD may be associated with pan-reatic exocrine insufficiency, which often improvesith enzyme supplementation. Manifestations com-on to both acute and chronic GVHD (as well as
ther causes, such as drug side effects, motility disor-ers, infections, or malabsorption) include anorexia,ausea, vomiting, diarrhea, weight loss, and failure to
ve, but Insufficientblish anic GVHD) Other Features*
Common(Seen with Both Acute
and Chronic GVHD)
ThrombocytopeniaEosinophiliaLymphopeniaHypo- or
hypergammaglobulinemiaAutoantibodies
(AIHA and ITP)Pericardial or
pleural effusionsAscitesPeripheral
neuropathyNephrotic
syndromeMyasthenia gravisCardiac
conductionabnormality orcardiomyopathy
AST, aspartate aminotransferase; BOOP, bronchiolitis obliterans-oimmune hemolytic anemia; ITP, idiopathic thrombocytopenic
the diagnosis is confirmed.excluded.(or Schirmer test for eyes).
istinctiGVHD
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hrive. Wasting syndrome may be a manifestation of
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hronic GVHD but is often multifactorial (e.g., de-reased caloric intake, poor absorption, increased rest-ng energy expenditures, and hypercatabolism). Endo-copic findings of mucosal edema and erythema orocal erosions with histologic changes of apoptoticpithelial cells and crypt cell dropout may be seen butre not considered diagnostic of chronic GVHD un-ess the patient also has distinctive features in aon-GI system. Patients with unresolved acuteVHD may have more severe intestinal mucosal le-
ions, including ulcers and mucosal sloughing.
iver
Hepatic acute and chronic GVHD typically pre-ents as cholestasis, with increased bilirubin or alkalinehosphatase, but it may also present as acute hepatitis21,22]. Because of many possible alternative diag-oses, liver biopsy is required to confirm GVHD
nvolvement of the liver. Note that because of theistologic similarity between acute and chronic liverVHD, the diagnosis of chronic GVHD cannot beade on the basis of liver biopsy alone but requires a
istinctive manifestation in at least 1 other organ sys-em.
ungs
The only diagnostic manifestation of chronicVHD is biopsy-proven BO. BO diagnosed via pul-onary function and radiologic testing requires at
east 1 other distinctive manifestation in a separatergan system to establish the diagnosis of chronicVHD. BO is characterized by the new onset of an
bstructive lung defect. Clinical manifestations maynclude dyspnea on exertion, cough, or wheezing.ome patients may be asymptomatic early in the dis-ase process. Pneumothorax, pneumomediastinum,nd subcutaneous emphysema are rare and often rep-esent advanced disease. Restrictive pulmonary func-ion abnormalities secondary to advanced sclerosis ofhe chest wall are attributable to skin GVHD. BO islinically diagnosed when all of the following criteriare met:. Forced expiratory volume in 1 second/forced vital
capacity ratio �0.7 and forced expiratory volume in1 second �75% of predicted.
. Evidence of air trapping or small airway thickeningor bronchiectasis on high-resolution chest com-puted tomography (with inspiratory and expiratorycuts), residual volume �120%, or pathologic con-firmation of constrictive bronchiolitis.
. Absence of infection in the respiratory tract, doc-umented with investigations directed by clinicalsymptoms, such as radiologic studies (radiographsor computed tomographic scans) or microbiologic
cultures (sinus aspiration, upper respiratory tract r50
viral screen, sputum culture, or bronchoalveolarlavage).
. BO-organizing pneumonia not due to infectionsmay represent a manifestation of either acute orchronic GVHD and is considered a commonfeature.
usculoskeletal System
Diagnostic features include fascial involvement oftenffecting the forearms or legs and often associated withclerosis of the overlying skin and subcutaneous tissue.ascial involvement may develop without overlying scle-otic changes of the skin and can result in joint stiffness orontractures when present near joints. Fasciitis is detectedn examination by stiffness, a restricted range of motione.g., often decreased dorsal wrist flexion or inability tossume a Buddha prayer posture), edema of the extrem-ties with or without erythema (early sign), peau d’orangeedematous skin with prominent pores resembling theurface of an orange), or joint contractures (late complica-ions). Clinical myositis with tender muscles and in-reased muscle enzymes is a distinctive but nondiagnos-ic manifestation of chronic GVHD. Myositis mayresent as proximal myopathy, but this complication isare and does not explain the frequent complaints ofevere cramps. Evaluation of myositis involves electro-yography and measurement of creatine phosphokinase
r aldolase. Arthralgia and arthritis are uncommon andre occasionally associated with the presence of autoan-ibodies.
ematopoietic and Immune Systems
Abnormalities are common in chronic GVHD butannot be used to establish the diagnosis of chronicVHD. Cytopenias may result from stromal damage
r autoimmune processes. Lymphopenia (�500/�L),osinophilia (�500/�L), hypogammaglobulinemia, orypergammaglobulinemia may be present. Autoanti-odies may develop with autoimmune hemolytic ane-ia and idiopathic thrombocytopenic purpura.hrombocytopenia (�100 000/�L) at the time of
hronic GVHD diagnosis has been associated with aoor prognosis.
ther Findings
Serositis (pericardial or pleural effusions or as-ites), peripheral neuropathy, myasthenia gravis, ne-hrotic syndrome, and cardiac involvement have beenttributed to chronic GVHD, but these manifesta-ions are rare. For these manifestations, chronicVHD is often a diagnosis of exclusion.
IFFERENTIAL DIAGNOSIS BETWEEN ACUTE ANDHRONIC GVHD
The Working Group recognized 2 main catego-
ies of GVHD, each with 2 subcategories (Table 2).
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Diagnosis and Staging of Chronic Graft-versus-Host Disease
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he broad category of acute GVHD includes (1) clas-ic acute GVHD (maculopapular rash, nausea, vomit-ng, anorexia, profuse diarrhea, ileus, or cholestaticepatitis) occurring within 100 days after transplanta-ion or DLI (without diagnostic or distinctive signs ofhronic GVHD) and (2) persistent, recurrent, or latecute GVHD: features of classic acute GVHD with-ut diagnostic or distinctive manifestations of chronicVHD occurring beyond 100 days of transplantation
r DLI (often seen after withdrawal of immune sup-ression). The broad category of chronic GVHD in-ludes (1) classic chronic GVHD without featuresharacteristic of acute GVHD and (2) an overlap syn-rome in which features of chronic and acute GVHDppear together. In the absence of histologic or clin-cal signs or symptoms of chronic GVHD, the persis-ence, recurrence, or new onset of characteristic skin,I tract, or liver abnormalities should be classified as
cute GVHD regardless of the time after transplanta-ion. With appropriate stratification, patients withersistent, recurrent, or late acute GVHD or overlapyndrome can be included in clinical trials with pa-ients who have chronic GVHD.
LINICAL SCORING OF ORGAN SYSTEMS
Figure 1 shows the consensus scoring system forndividual organs. Several considerations explain theelection of the features for the proposed scoring sys-em versus the response criteria discussed in a separaterticle. (1) Scoring criteria are intended for baseline orross-sectional use, whereas response criteria are in-ended for serial use in therapeutic trials over a rela-ively short period of time. (2) Scoring measures muste designed so that they can be easily performed in theffice by general practitioners. By design, the onlyequired laboratory testing needed to complete thecoring table is measurement of liver function. (3) Theroad scoring categories help classify patients androvide immediate, clinically meaningful data abouthe disease extent and severity. (4) The scoring systemoes not attempt to distinguish between disease activ-
ty and fixed deficits.
able 2. Categories of Acute and Chronic GVHD
CategoryTime ofafter H
cute GVHDClassic acute GVHD <
Persistent, recurrent, or late-onset acute GVHD >hronic GVHDClassic chronic GVHD No tiOverlap syndrome No ti
VHD indicates graft-versus-host disease; HCT, hematopoietic ceSee Table 1 for features.
Organ sites considered for scoring include skin, o
B & M T
outh, eyes, GI tract, liver, lungs, joints and fascia,nd the female genital tract. Each organ or site iscored according to a 4-point scale (0-3), with 0 rep-esenting no involvement and 3 reflecting severe im-airment. In addition, performance status is capturedn a 0 to 3 scale, and check boxes note the presence orbsence of other specific manifestations.
Note that Figure 1 should be completed on theasis of an assessment of current status without con-ideration of past manifestations or a requirement forttribution of abnormalities to chronic GVHD versusnother preexisting condition.
LOBAL SCORING OF CHRONIC GVHD
The time-honored description of limited versusxtensive chronic GVHD was proposed from only 20ases published in 1980 [2]. The Working Grouproposes a new global assessment of chronic GVHDeverity that is clinically suitable and is appropriate forse as an inclusion criterion in therapeutic clinicalrials or as an indication for systemic immunosuppres-ive treatment. The global scoring system reflects thelinical effect of chronic GVHD on the patient’s func-ional status.
Elements included in the proposed global scoringystem include both the number of organs or sitesnvolved and the severity within each affected organnote that performance status scoring is not incorpo-ated into the global scoring system). The global de-criptions of mild, moderate, and severe were choseno reflect the degree of organ impact and functionalmpairment due to chronic GVHD. Although scorings often used at the time of initial diagnosis, evaluatinghe clinical score periodically during the course ofhronic GVHD may revise prognostic expectationsnd better describe the current severity of chronicVHD. Note that the global scoring system can be
pplied only after the diagnosis of chronic GVHD isonfirmed by either (1) the presence of a diagnosticeature or, if a diagnostic feature is not present, (2) ateast 1 distinctive manifestation of chronic GVHDith the diagnosis supported by histologic, radiologic,
omsDLI
Presence of AcuteGVHD Features*
Presence of ChronicGVHD Features*
Yes NoYes No
it No Yesit Yes Yes
splantation; DLI, donor lymphocyte infusion.
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A. H. Filipovich et al.
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SCORE 0 SCORE 1 SCORE 2 SCORE 3
PERFORMANCE
SCORE:
KPS ECOG LPS
Asymptomatic and fully active (ECOG 0; KPS or LPS 100%)
Symptomatic, fully ambulatory, restricted only in physically strenuous activity (ECOG 1, KPS or LPS 80-90%)
Symptomatic, ambulatory, capable of self-care, >50% of waking hours out of bed (ECOG 2, KPS or LPS 60-70%)
Symptomatic, limited self-care, >50% of waking hours in bed (ECOG 3-4, KPS or LPS <60%)
SKINClinical features:
Maculopapular rash
Lichen planus-like features
Papulosquamous lesions or ichthyosis
Hyperpigmentation Hypopigmentation Keratosis pilaris Erythema Erythroderma Poikiloderma Sclerotic features Pruritus Hair involvement Nail involvement
% BSA involved
No Symptoms <18% BSA with disease signs but NO sclerotic features
19-50% BSA OR involvement with superficial sclerotic features “not hidebound” (able to pinch)
>50% BSA ORdeep sclerotic features “hidebound” (unable to pinch) ORimpaired mobility, ulceration or severe pruritus
MOUTH No symptoms Mild symptoms with disease signs but not limiting oral intake significantly
Moderate symptoms with disease signs withpartial limitation of oral intake
Severe symptoms with disease signs on examination withmajor limitation of oral intake
EYES
Mean tear test (mm): >106-10 <5Not done
No symptoms Mild dry eye symptoms not affecting ADL (requiring eyedrops < 3 x per day) ORasymptomatic signs of keratoconjunctivitis sicca
Moderate dry eye symptoms partially affecting ADL (requiring drops > 3 x per day or punctal plugs), WITHOUT vision impairment
Severe dry eye symptoms significantly affecting ADL (special eyeware to relieve pain) ORunable to work because of ocular symptoms OR loss of vision caused by keratoconjunctivitis sicca
GI TRACT No symptoms Symptoms such as dysphagia, anorexia, nausea, vomiting, abdominal pain or diarrhea without significant weight loss (<5%)
Symptoms associated with mild to moderate weight loss (5-15%)
Symptoms associated with significant weight loss >15%, requires nutritional supplement for most calorie needs OResophageal dilation
LIVER Normal LFT Elevated Bilirubin, AP*, AST or ALT <2 x ULN
Bilirubin >3 mg/dl or Bilirubin, enzymes 2-5 x ULN
Bilirubin or enzymes > 5 x ULN
igure 1. Organ scoring of chronic GVHD. *AP may be elevated in growing children, and not reflective of liver dysfunction. †Pulmonarycoring should be performed using both the symptom and pulmonary function testing (PFT) scale whenever possible. When discrepancy exists
etween pulmonary symptom or PFT scores the higher value should be used for final scoring. Scoring using the Lung Function Score (LFS)52
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Diagnosis and Staging of Chronic Graft-versus-Host Disease
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SCORE 0 SCORE 1 SCORE 2 SCORE 3
LUNGS†
FEV1
DLCO
No symptoms
FEV1 > 80% ORLFS=2
Mild symptoms (shortness of breath after climbing one flight of steps)
FEV1 60-79% OR LFS 3-5
Moderate symptoms (shortness of breath after walking on flat ground)
FEV1 40-59% OR LFS 6-9
Severe symptoms (shortness of breath at rest; requiring 02)
FEV1 <39% ORLFS 10-12
JOINTS AND
FASCIANo symptoms Mild tightness of
arms or legs, normal or mild decreased range of motion (ROM) AND not affecting ADL
Tightness of arms or legs ORjoint contractures, erythema thought due to fasciitis, moderate decrease ROM AND mild to moderate limitation of ADL
Contractures WITH significant decrease of ROMAND significant limitation of ADL (unable to tie shoes, button shirts, dress self etc.)
GENITAL TRACT No symptoms Symptomatic with mild signs on exam AND no effect on coitus and minimal discomfort with gynecologic exam
Symptomatic with moderate signs on exam AND with mild dyspareunia or discomfort with gynecologic exam
Symptomatic WITH advanced signs (stricture, labial agglutination or severe ulceration) AND severe pain with coitus or inability to insert vaginal speculum
Other indicators, clinical manifestations or complications related to chronic GVHD (check all that apply and assign a score to its severity (0-3) based on its functional impact where applicable (none – 0,mild -1, moderate -2, severe – 3)
Esophageal stricture or web___ Pericardial Effusion___ Pleural Effusion(s)___
Ascites (serositis)___ Nephrotic syndrome___ Peripheral Neuropathy___
M yasthenia Gravis___ Cardiomyopathy___ Eosinophilia > 500µl___
Polymyositis___ Cardiac conduction defects___ Coronary artery involvement___
Platelets <100,000/µl ___ Progressive onset___
OTHERS: Specify:_______________________________________________________________________________
igure 1 (continued). is preferred, but if DLCO is not available, grading using FEV1 should be used. The LFS is a global assessment of lungunction after the diagnosis of bronchiolitis obliterans has already been established [29]. The percent predicted FEV1 and DLCO (adjustedor hematocrit but not alveolar volume) should be converted to a numeric score as follows: �80% � 1; 70-79% � 2; 60-69% � 3; 50-59%
4; 40-49% � 5; �40% � 6. The LFS � FEV1 score � DLCO score, with a possible range of 2-12. GVHD indicates graft versus hostisease; ECOG, Eastern Cooperative Oncology Group; KPS, Karnofsky Performance Status; LPS, Lansky Performance Status; BSA, bodyurface area; ADL, activities of daily living; LFTs, liver function tests; AP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate
minotransferase; ULN, upper limit of normal.953B & M T
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Mild chronic GVHD involves only 1 or 2 organs orites (except the lung: see below), with no clinically sig-ificant functional impairment (maximum of score 1 inll affected organs or sites). Moderate chronic GVHDnvolves (1) at least 1 organ or site with clinically signif-cant but no major disability (maximum score of 2 in anyffected organ or site) or (2) 3 or more organs or sitesith no clinically significant functional impairment
maximum score of 1 in all affected organs or sites). Aung score of 1 will also be considered moderate chronic
VHD. Severe chronic GVHD indicates major disabil-ty caused by chronic GVHD (score of 3 in any organ orite). A lung score of 2 or greater will also be consideredevere chronic GVHD.
NDICATIONS FOR SYSTEMIC THERAPY
Symptomatic mild chronic GVHD may often bereated with local therapies alone (e.g., topical steroidso the skin). However, in patients with chronicVHD that involves 3 or more organs or with a score
f 2 or greater in any single organ, systemic immuno-uppressive therapy may be considered. Good medicalractice and judgment dictate flexibility in this recom-endation. Some experts incorporate the presence or
bsence of published high-risk features (e.g., throm-ocytopenia) and the underlying reason for transplan-ation (e.g., malignant versus nonmalignant underly-ng disease) into the decision of whether or not toreat with systemic immunosuppression. Early inter-ention with effective systemic therapy may preventrogression to severe chronic GVHD, whereas co-orbid infections may also modify decisions regard-
ng the timing and intensity of therapy. Effective im-une modulating therapy given to patients with
linically significant chronic GVHD involvement hashe potential to ameliorate the clinical manifestations,educe TRM, or both. In patients who are alreadyeceiving immune-suppressive medications, the dos-ge may be increased, or other agents can be added.atients with chronic GVHD, especially those receiv-
ng systemic immunosuppressive therapy, are immu-ocompromised and should receive infection-preven-ion measures as outlined in the forthcoming Ancillaryherapy and Supportive Care Working Group docu-ent.
SSESSMENT OF RISK OF TRM
Chronic GVHD is the major cause of late TRMfter allogeneic HCT. Previous studies have identifiedeveral factors associated with an increased risk ofRM among patients with chronic GVHD, including
he involvement of multiple organs or sites, a de-reased clinical performance score, thrombocytopenia
platelet count �100 000/�L) at the time of diagnosis, e54
rogressive onset of chronic GVHD from prior acuteVHD, hyperbilirubinemia, a higher percentage of
kin involvement at the time of diagnosis, and others18,23-28]. Across studies, the characteristics consis-ently associated with an increased risk of late TRMmong patients with chronic GVHD are thrombocy-openia and progressive onset of chronic GVHD fromcute GVHD.
Validation of risk factors for late TRM in patientsith chronic GVHD should be a major goal of future
esearch, so that patients with the poorest prognosesill be included in clinical trials of systemic therapies
imed at changing the natural history of chronicVHD. Conversely, patients judged at low risk forRM might be preferentially enrolled in studies ofew topical or organ-specific therapies. The standard-
zed approach for scoring chronic GVHD proposedere is suitable for use in future clinical studies tovaluate the extent to which the severity of specificnd combined organ/site involvement correlates withate TRM in patients with chronic GVHD.
CKNOWLEDGMENTSThis project was supported by the National Insti-
utes of Health’s (NIH’s) National Cancer Institute,ffice of the Director, Cancer Therapy Evaluationrogram, Intramural Research Program, and Center
or Cancer Research; National Heart Lung and Bloodnstitute, Division of Blood Diseases and Resources;ffice of Rare Diseases, NIH, Office of the Director;ational Institute of Allergy and Infectious Disease,ransplantation Immunology Branch; the Health Re-
ources and Services Administration, Division ofransplantation; and the Naval Medical Researchenter, C.W. Bill Young/Department of Defensearrow Donor Recruitment and Research Program.he authors would also like to acknowledge the fol-
owing individuals and organizations that, by theirarticipation, made this project possible: Americanociety for Blood and Marrow Transplantation, Cen-er for International Bone and Marrow Transplantesearch, Blood and Marrow Transplant Clinical Tri-
ls Network, Canadian Blood and Marrow Transplantroup, European Group for Blood and Marrowransplantation, Pediatric Blood and Marrow Trans-lant Consortium, and the representatives of theouth American transplant centers (Drs. Luis F. Bou-as and Vaneuza Funke). This project was conductedn coordination with the American Society for Clinical
ncology and the American Society of Hematologyliaisons were Dr. Michael Bishop and Jeff Coughlin).he organizers are also in debt to patients and patient
nd research advocacy groups, who made this processuch more meaningful by their engagement. Special
hanks also go to Paula Kim, who coordinated these
fforts. The project group also recognizes the contri-
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Diagnosis and Staging of Chronic Graft-versus-Host Disease
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utions of numerous colleagues in the field of bloodnd marrow transplantation, medical specialists andonsultants, the pharmaceutical industry, and theIH and US Food and Drug Administration profes-
ional staff for their intellectual input, dedication, andnthusiasm on the road to completion of these docu-ents.
PPENDIX: NATIONAL INSTITUTES OF HEALTHONSENSUS-DEVELOPMENT PROJECT ON CRITERIAOR CLINICAL TRIALS IN CHRONIC GVHD STEERINGOMMITTEE
Members of this committee included Steven Pav-etic and Georgia Vogelsang (project chairs), LeeAnnensen (planning committee chair), Lisa FilipovichDiagnosis and Staging), Howard Shulman (Histopa-hology), Kirk Schultz (Biomarkers), Dan CourielAncillary and Supportive Care), Stephanie Lee (De-ign of Clinical Trials), James Ferrara, Mary Flowers,ean Henslee-Downey, Paul Martin, Barbara Mittle-an, Shiv Prasad, Donna Przepiorka, Douglas Rizzo,aniel Weisdorf, and Roy Wu (members).
EFERENCES
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2. Shulman HM, Sullivan KM, Weiden PL, et al. Chronic graftvs. host syndrome in man. A long-term clinicopathologic studyof 20 Seattle patients. Am J Med. 1980;69:204-217.
3. Rocha V, Wagner JE, Sobocinski KA, et al. Graft vs. hostdisease in children who received a cord blood or bone marrowtransplant from an HL-A identical sibling. N Engl J Med.2000;342:1846-1854.
4. Sullivan KM, Agura E, Anasetti C, et al. Chronic graft-versus-host disease and other late complications of bone marrow trans-plantation. Semin Hematol. 1991;28:250-259.
5. Remberger M, Aschan J, Lonnqvist B, et al. An ethnic rolefor chronic, but not acute graft-vs. host disease after HLA-identical bone marrow transplantation. Eur J Haematol.2001;66:50-56.
6. Storb R, Prentice RL, Sullivan KM, et al. Predictive factors inchronic graft-versus-host disease in patients with aplastic ane-mia treated by marrow transplantation from HLA-identicalsiblings. Ann Intern Med. 1983;98:461-466.
7. Ringden O, Paulin T, Lonnqvist B, et al. An analysis of factorspredisposing to chronic graft-versus-host disease. Exp Hematol.1985;13:1062-1067.
8. Atkinson K, Horowitz MM, Gale RP, et al. Risk factors forchronic graft-versus-host disease after HLA-identical siblingbone marrow transplantation. Blood. 1990;75:2459-2464.
9. Boström L, Ringdén O, Jacobsen N, Zwaan F, Nilsson B. AEuropean multicenter study of chronic graft-versus-host dis-ease. The role of cytomegalovirus serology in recipients anddonors—acute graft-versus-host disease, and splenectomy.
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0. Ochs LA, Miller WJ, Filipovich AH, et al. Predictive factors forchronic graft-versus-host disease after histocompatible siblingdonor bone marrow transplantation. Bone Marrow Transplant.1994;13:455-460.
1. Carlens S, Ringden O, Remberger M, et al. Risk factors forchronic graft-versus-host disease after bone marrow transplan-tation: a retrospective single centre analysis. Bone MarrowTransplant. 1998;22:755-761.
2. Kondo M, Kojima S, Horibe K, Kato K, Matsuyama T. Riskfactors for chronic graft-versus-host disease after allogeneicstem cell transplantation in children. Bone Marrow Transplant.2001;27:727-730.
3. Kollman C, Howe CWS, Anasetti C, et al. Donor characteris-tics as risk factors in recipients after transplantation of bonemarrow from unrelated donors: the effect of donor age. Blood.2001;98:2043-2051.
4. Cutler C, Giri S, Jeyapalan S, Paniagua D, Viswanathan A,Antin JH. Acute and chronic graft-versus-host disease afterallogeneic peripheral-blood stem-cell and bone marrow trans-plantation: a meta-analysis. J Clin Oncol. 2001;19:3685-3691.
5. Przepiorka D, Anderlini P, Saliba R, et al. Chronic graft-versus-host disease after allogeneic blood stem cell transplan-tation. Blood. 2001;98:1695-1700.
6. Remberger M, Kumlien G, Aschan J, et al. Risk factors formoderate-to-severe chronic graft-versus-host disease after allo-geneic hematopoietic stem cell transplantation. Biol Blood Mar-row Transplant. 2002;8:674-682.
7. Randolph SSB, Gooley TA, Warren EH, Appelbaum FR, Rid-dell SR. Female donors contribute to a selective graft versusleukemia effect in male recipients of HLA matched relatedhematopoietic cell transplants. Blood. 2004;103:347-352.
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3. Wingard JR, Piantadose S, Vogelsang GB, et al. Predictors ofdeath from chronic graft versus host disease after bone marrowtransplantation. Blood. 1989;74:1428-1435.
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384-390.
Tandem 2010 Chronic GVHD DM conference Stephanie J. Lee, MD MPH February 23, 2010 Case #1 38 y/o man with AML in first complete remission undergoing HLA identical sibling transplantation using Cytoxan/TBI. Acute GVHD of the skin and GI tract on day +30. Despite treatment with steroids, mycophenolate mofetil, ATG and infliximab, he has lingering red skin and diarrhea on day +110. • Does he have chronic GVHD? • If so, what is the day of diagnosis? • What type of onset? • What is the maximum grade? • What is the overall severity? His skin erythema and diarrhea resolve. At day +150, he develops dry eyes, dry mouth, lichen planus in his mouth, and obstructive changes on pulmonary function tests. The notes state: “He was started on prednisone. Tacrolimus was increased to full dose.” • Does he have chronic GVHD? • If so, what is the day of diagnosis? • What type of onset? • What is the maximum grade? • What is the overall severity? • What organs are involved? • What treatment was given? Case #2 A 60 y/o man with CLL has a matched unrelated donor non-myeloablative transplant. He does not have any skin rash, liver function abnormalities or diarrhea. On day +90 he develops mouth sensitivity with erythema and his absolute eosinophil count is 720. • Does he have chronic GVHD? • If so, what is the day of diagnosis? • What type of onset? • What is the maximum grade? • What is the overall severity? On day +120 he has increased liver function tests, a pleural effusion, a lichenoid rash of the skin and mouth, and oral ulcers. He is started on prednisone with some improvement but when the prednisone is tapered his pleural effusion returns and the mouth pain increases. He is started on sirolimus. • Does he have chronic GVHD? • If so, what is the day of diagnosis? • What type of onset? • What is the maximum grade? • What is the overall severity? • What organs are involved? • What treatment was given?
Case #3 A 48 y/o woman with MDS has a double cord blood graft using fludarabine/cytoxan and TBI. On day +50 she has grade III acute GVHD with a skin rash and diarrhea. She received steroids + MMF/placebo on a clinical trials, continues tacrolimus, and her symptoms improve. At day +110 she is seen with a red rash and diarrhea x 3 days. Her prednisone dose is increased and her symptoms resolve. • Does she have chronic GVHD? • If so, what is the day of diagnosis? • What type of onset? • What is the maximum grade? • What is the overall severity? • What organs are involved? • What treatment was given? On day +276 she notes dry eyes and dry mouth. The physician prescribes topical cyclosporine for her eyes and pilocarpine for her mouth. • Does she have chronic GVHD? • If so, what is the day of diagnosis? Day • What type of onset? • What is the maximum grade? • What is the overall severity? On day +365 she is seen. Sclerosis around her waistline is noted. Fasciitis of her upper extremities prevents full range of motion. Prednisone is started. In retrospect, she first noticed problems 2 months before. On day +400 she reports difficulty swallowing. EGD shows a stricture which is dilated. She is scheduled to start ECP. On day +500 she has lost 8 kg. • Does she have chronic GVHD? • If so, what is the day of diagnosis? • What type of onset? • What is the maximum grade? • What is the overall severity? • What organs are involved? • What treatment was given?