Biology of Blood and Marrow Transplantation 11 :945-955 (2005)
`© 2005 American Society for Blood and Marrow Transplantation
`I 083-8791 /05/ I I 12-0002$30.00/0
`doi: I 0.10 I 6/j.bbmt.2005.09 .004
`
`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
`
`Alexandra H. Filipovich, 1 Daniel Weisdoif, 2 Steven Pavletic,3 Gerard Socie,4 John R. Wingard/
`Stephanie J. Lee,6 Paul Martin, 7 Jason Chien,7 Donna Przepiorka, 8 Daniel Couriel,9
`Edward W Cowen,3 Patricia Dinndoif, 10 Ann Fai7"ell, 10 Robert Hartznzan, 11 Jean Henslee-Downey,1 2
`David Jacobsohn, 13 George McDonald, 7 Barbara Mittleman, 14 J. Douglas Rizzo,1 5 Michael Robinson, 16
`Mark Schubert,7 Kirk Schultz, 17 Howard Shuhnan, 7 Maria Tumer, 3 Geoixia Vogelsang, 18
`Maiy E.D. Flowen7
`
`1Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio; 2University of
`Minnesota, 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(cid:173)
`Farber Cancer Institute, Boston, Massachusetts; 7Fred Hutchinson Cancer Research Center, University of
`Washington School of Medicine, Seattle, Washington; 8University of Tennessee, Memphis, Tennessee; 9University
`of Texas M.D. Anderson Cancer Center, Houston, Texas; 10US Food and Drug Administration, Rockville,
`Maryland; 11 C.W. Bill Young/Department of Defense Marrow Donor Recruitment and Research Program, Naval
`Medical Research Center, Silver Spring, Maryland; 12National Heart, Lung and Blood Institute, National Institutes
`of 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 of
`Health, Bethesda, Maryland; 15Center for International Blood and Marrow Transplant Research, Medical College
`of 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, Cincinnati
`Children's Hospital, 333 Burnet Ave., MLC 7015, Cincinnati, OH 45229 (e-mail: lisa.filipovich@cchmc.org).
`
`Received September 9, 2005; accepted September 9, 2005
`
`ABSTRACT
`This consensus document is intended to serve 3 functions. First, it standardizes the criteria for diagnosis of
`chronic graft-versus-host disease (GVHD). Second, it proposes a new clinical scoring system (0-3) that
`describes the extent and severity of chronic GVHD for each organ or site at any given time, tiling functional
`impact into account. Third, it proposes new gnidelines for global assessment of chronic GVHD severity that
`are 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 sign
`of 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) in
`the same or another organ. Furthermore, other possible diagnoses for clinical symptoms must be excluded. No
`time limit is set for the diagnosis of chronic GVHD. The Working Group recognized 2 main categories of
`GVHD, each with 2 subcategories. The acute GVHD category is defined in the absence of diagnostic or
`distinctive features of chronic GVHD and includes (1) classic acute GVHD occurring within 100 days after
`transplantation and (2) persistent, recurrent, or late acute GVHD (features of acute GVHD occurring beyond
`100 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 in
`which diagnostic or distinctive features of chronic GVHD and acute GVHD appear together. It is currently
`recommended that systemic therapy be considered for patients who meet criteria for chronic GVHD of
`moderate to severe global severity.
`© 2005 Ame1-ican Society for Blood and Mai7ow Transplantation
`
`Pharmacyclics Exhibit 2047
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`A. H. Filipovich et al.
`
`KEY WORDS
`Chronic graft-versus-host disease
`• Staging
`• Diagnosis
`
`• Allogeneic hematopoietic cell transplantation
`
`• Consensus
`
`BACKGROUND
`
`Chronic graft-versus-host disease (GVHD) is a
`major complication of allogeneic hematopoietic cell
`transplantation (HCT). The syndrome has features
`resembling autoimmune and other immunologic dis(cid:173)
`orders such as scleroderma, Sjogren syndrome, pri(cid:173)
`mary biliary cirrhosis, wasting syndrome, bronchiolitis
`obliterans (BO), immune cytopenias, and chronic im(cid:173)
`munodeficiency. The pathogenesis of chronic GVHD
`is poorly understood [l].
`Symptoms usually present within 3 years after
`allogeneic HCT and are often preceded by a history of
`acute GVHD. Manifestations of chronic GVHD may
`b~ restricted to a ~ingle organ or tissue or may be
`widespread. Chrome GVHD can lead to debilitating
`consequences, e.g., joint contractures, loss of sight,
`end-stage lung disease, or mortality resulting from
`profound chronic immune suppression leading to re(cid:173)
`curre1:t or life-threatening infections. Historically,
`chrome GVHD was classified as limited or extensive
`on the basis of the results of a small retrospective study
`[2], although this classification has not been shown to
`be reproducible or predictive of late treatment-related
`mortality (TRM).
`Reported incidence rates of chronic GVHD after
`allogeneic transplantation range from 6% to 80% ac(cid:173)
`cording to recipient age, donor type, HCT source
`(peripheral blood, bone marrow, or umbilical cord
`~lood stem cells), graft manipulation (T-cell deple(cid:173)
`tion),_ and_ use of posttransplantation donor lympho(cid:173)
`cyte mfus10ns (DLis) [3-5]. Reliable incidence esti(cid:173)
`mates in different cohorts of HCT recipients are
`compromised by (1) lack of standardized, widely used
`diagnostic guidelines; (2) variability in observer expe(cid:173)
`rience; (3) limited expert follow-up at a distance from
`transplant centers; ( 4) differences in the statistical
`methods applied (e.g., use of the Kaplan-Meier versus
`cumulative incidence estimates and variable require(cid:173)
`me~t for some minimal survival [ 60-100 days] for
`patients to be considered at risk of chronic GVHD);
`and (5) the sometimes protean nature of early chronic
`GVHD symptoms, which mimic alternative diag(cid:173)
`noses. Previous articles have identified risk factors for
`chronic GVHD after HCT, including prior acute
`GVHD, older patient age, the use of female donors
`for male recipients, use of DLI, use of unrelated or
`HLA-mismatched donors, and, more recently, the use
`of growth factor-mobilized peripheral blood leuko-
`
`cytes as opposed to marrow as a source of stem cells
`[6-18].
`
`PURPOSE OF THIS DOCUMENT
`
`The goals of this consensus document are to es(cid:173)
`tablis~ standardized criteria for the diagnosis of
`chron~c GVHD and to propose tools for scoring
`chrome GVHD organ involvement and assessing
`overall severity. Specifically, the Working Group
`sought to (1) develop minimal criteria for the clinical
`diagnosis of chronic GVHD; (2) propose a new scor(cid:173)
`ing s~stem that describes the extent and severity of
`c?-romc GVHD for each organ or site at any given
`time, taking functional impact into account; (3) pro(cid:173)
`pose new guidelines for global assessment of chronic
`?VHD severi_ty; and (4) propose indications for top(cid:173)
`ical or systemic therapies.
`The recommendations of the Working Group
`represent a consensus opinion supplemented by eval(cid:173)
`uation of available peer-reviewed literature. The pro(cid:173)
`posed _methods and tools for diagnosis and scoring of
`chrom~ GVHD are provisional and will be updated
`~ccordmg to the results of prospective validation stud(cid:173)
`ies.
`
`SUMMARY OF RECOMMENDATIONS
`
`The diagnosis of chronic GVHD requires the fol(cid:173)
`lowing:
`1. Distinction from acute GVHD.
`2. Prese~ce of at least 1 diagnostic clinical sign of
`chrome GVHD or presence of at least 1 distinc(cid:173)
`tive manifestation confirmed by pertinent bi(cid:173)
`opsy or other relevant tests.
`3. Exclusion of other possible diagnoses.
`Scoring of organ manifestations requires careful
`assessment of signs, symptoms, laboratory values, and
`other study results.
`A clinical scoring system (0-3) is provided for
`e:valuation of the involvement of individual organs and
`sites.
`The proposed global assessment of severity (mild,
`moderate, or severe) is derived by combining organ(cid:173)
`and site-specific scores.
`. Systemic therapy should be considered for pa(cid:173)
`tients_ who meet criteria for moderate to severe global
`seventy.
`
`The opinions expressed he1·e are those of the authors and do not represent
`the official position of the National Institutes of Health or the US Gov(cid:173)
`emnzent.
`
`DIAGNOSIS OF CHRONIC GVHD
`
`In the past, any manifestation of GVHD that was
`present (or continued) at 100 days after HCT or
`
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`thereafter was arbitrarily defined as chronic GVHD
`even if the clinical manifestation was indistinguishable
`from that of acute GVHD. Advances in HCT practice
`in the past 2 decades have profoundly altered the
`presentation and natural history of both acute and
`chronic GVHD and bring previous definitions into
`question. For instance, acute GVHD may present
`beyond 3 months in patients who have received re(cid:173)
`duced-intensity conditioning [19,20], whereas mani(cid:173)
`festations of acute and chronic GVHD can be present
`simultaneously, for example, in patients treated with
`DLI. Therefore, the current consensus is that clinical
`manifestations, and not the time to symptomatic onset
`after transplantation, determine whether the clinical
`syndrome of GVHD is considered acute or chronic.
`Throughout this article, diagnostic signs and symp(cid:173)
`toms refer to those manifestations that establish the
`presence of chronic GVHD without the need for
`further testing or evidence of other organ involve(cid:173)
`ment. Distinctive signs and symptoms of chronic
`GVHD refer to those manifestations that are not
`ordinarily found in acute GVHD but are not consid(cid:173)
`ered sufficient to establish an unequivocal diagnosis of
`chronic GVHD without further testing or additional
`organ involvement. Other features of chronic GVHD
`define the rare, controversial, or nonspecific features
`of chronic GVHD that cannot be used to establish the
`diagnosis of chronic GVHD. Common signs and symp(cid:173)
`toms of chronic GVHD refer to manifestations found
`in both chronic and acute GVHD (Table 1).
`The Working Group recommends that the diag(cid:173)
`nosis of chronic GVHD require at least 1 diagnostic
`manifestation of chronic GVHD or at least 1 distinc(cid:173)
`tive manifestation, with the diagnosis confirmed by
`pertinent biopsy, laboratory tests, or radiology in the
`same or another organ. As in acute GVHD, infection
`and other causes may confound or complicate the
`differential diagnosis of chronic GVHD (e.g., nail
`dystrophies associated with onychomycosis, herpes
`simplex, or Candida albicans infections of the oral cav(cid:173)
`ity; drug toxicity) and must be excluded. Diagnostic
`and distinctive manifestations of chronic GVHD can
`be found in the skin and appendages, mouth, eyes,
`female genitalia, esophagus, lungs, and connective tis(cid:173)
`sues. Biopsy or other testing is always encouraged and
`often valuable to confirm the presence of chronic
`GVHD, but it is not always feasible and is not man(cid:173)
`datory if the patient has at least 1 of the diagnostic
`findings of chronic GVHD (Table 1). Please note that
`an in-depth discussion of recommended terminology
`for histopathologic interpretation may be found in a
`forthcoming histopathology working group report. A
`biopsy read as "consistent with" or "unequivocal"
`chronic GVHD will be considered sufficient to estab(cid:173)
`lish the diagnosis of chronic GVHD if accompanied
`by at least 1 distinctive clinical manifestation.
`Characteristics that establish the diagnosis of
`
`Diagnosis and Staging of Chronic Graft-versus-Host Disease
`
`chronic GVHD might not serve as the most appro(cid:173)
`priate parameters for assessing the severity of chronic
`GVHD. Valid and reliable diagnostic criteria might
`not be sufficiently sensitive to change to be useful as
`treatment-response criteria. Conversely, a sensitive
`measure of chronic GVHD response might not nec(cid:173)
`essarily serve as an appropriate diagnostic and scoring
`tool.
`
`ORGAN-SPECIFIC MANIFESTATIONS OF CHRONIC
`GVHD
`
`In all cases, drug reaction, infection, recurrent or
`new malignancy, and other causes must be excluded.
`Diagnostic clinical or laboratory features sufficient for
`the diagnosis of chronic GVHD are italicized in the
`sections below.
`
`Skin
`
`Diagnostic manifestations include poikiloderma
`(e.g., atrophic and pigmentary changes), lichen planus(cid:173)
`like eruption (e.g., erythematous/violaceous flat-topped
`papules or plaques with or without surface reticula(cid:173)
`tions or a silvery or shiny appearance on direct light),
`deep sclerotic features (e.g., smooth, waxy, indurated
`skin-"thickened or tight skin," caused by deep and
`diffuse sclerosis over a wide area), morphea-like super(cid:173)
`ficial sclerotic features (e.g., localized patchy areas of
`moveable smooth or shiny skin with a leathery-like
`consistency, often with dyspigmentation), or lichen
`sclei-osus-like lesions (e.g., discrete to coalescent gray to
`white moveable papules or plaques, often with follic(cid:173)
`ular plugs, with a shiny appearance and leathery con(cid:173)
`sistency). Severe sclerotic features characterized by
`thickened, tight, and fragile skin are often associated
`with poor wound healing, inadequate lymphatic drain(cid:173)
`age, and skin ulcers from minor trauma.
`A distinctive feature for chronic GVHD (not seen
`in acute GVHD, but not sufficiently unique to be
`considered diagnostic of chronic GVHD) is depig(cid:173)
`mentation. However, depigmentation would contrib(cid:173)
`ute to the diagnosis of chronic GVHD in combination
`with biopsy or laboratory confirmation of GVHD in
`skin or another organ. Sweat impairment and intoler(cid:173)
`ance to temperature change from loss of sweat glands
`are seen in chronic GVHD. Other common, nondis(cid:173)
`tinctive skin manifestations found with both acute and
`chronic GVHD include erythema, maculopapular
`rash, and pruritus.
`
`Nails
`
`Dystrophy consisting of longitudinal ridging, nail
`splitting or brittleness, onycholysis, pterygium unguis,
`and nail loss (usually symmetric and affecting most
`nails) are distinctive signs of chronic GVHD but are
`not sufficient for diagnosis.
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`Diagnostic (Sufficient to
`Establish the Diagnosis of
`Chronic GVHD)
`
`Distinctive (Seen in Chronic GVHD, but
`Insufficient Alone to Establish a
`Diagnosis of Chronic GVHD)
`
`Other Features*
`
`Common (Seen with
`Both Acute and
`Chronic GVHD)
`
`Depigmentation
`
`Poikiloderma
`Lichen planus-like features
`Sclerotic features
`Morphea-like features
`Lichen sclerosus-like features
`
`Sweat impairment Erythema
`Maculopapular rash
`lchthyosis
`Pruritus
`Keratosis pilaris
`Hypopigmentation
`Hyperpigmentation
`
`Dystrophy
`Longitudinal ridging, splitting, or brittle
`features
`Onycholysis
`Pterygium unguis
`Nail loss (usually symmetric; affects
`most nails)t
`New onset of scarring or nonscarring
`scalp alopecia (after recovery from
`chemoradiotherapy)
`Scaling, papulosquamous lesions
`
`Lichen-type features
`Hyperkeratotic plaques
`Restriction of mouth
`opening from sclerosis
`
`Xerostomia
`Mucocele
`Mucosal atrophy
`Pseudomembranest
`Ulcerst
`New onset dry, gritty, or painful eyes:j:
`Cicatricial conjunctivitis
`Keratoconjunctivitis sicca:j:
`Confluent areas of punctate keratopathy
`
`Thinning scalp
`hair, typically
`patchy, coarse,
`or dull (not
`explained by
`endocrine or
`other causes)
`Premature gray
`hair
`
`Gingivitis
`Mucositis
`Erythema
`Pain
`
`Photophobia
`Periorbital
`hyperpigmentation
`
`Blepharitis
`(erythema of
`the eyelids with
`edema)
`
`Erosionst
`Fissurest
`Ulcerst
`
`Lichen planus-like features
`Vaginal scarring or stenosis
`
`Esophageal web
`Strictures or stenosis in the
`upper to mid third of the
`esophagust
`
`Exocrine
`pancreatic
`insufficiency
`
`Anorexia
`Nausea
`Vomiting
`Diarrhea
`Weight loss
`Failure to thrive
`(infants and children)
`Total bilirubin, alkaline
`phosphatase > 2 x
`upper limit of
`normalt
`ALT or AST > 2 x
`upper limit of
`normalt
`BOOP
`
`A. H. Filipovich et al.
`
`Table I. Signs and Symptoms of Chronic GVHD
`
`Organ or Site
`
`Skin
`
`Nails
`
`Scalp and
`body hair
`
`Mouth
`
`Eyes
`
`Genitalia
`
`GI tract
`
`Liver
`
`Lung
`
`Muscles,
`fascia,
`joints
`
`Bronchiolitis obliterans
`diagnosed with lung biopsy
`Fasciitis
`Joint stiffness or
`contractures secondary to
`sclerosis
`
`Bronchiolitis obliterans diagnosed with
`PFTs and radiology:j:
`Myositis or polymyositis:j:
`
`Edema
`Muscle cramps
`Arthralgia or
`arthritis
`
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`

`Table I. Continued
`
`Diagnosis and Staging of Chronic Graft-versus-Host Disease
`
`Organ or
`Site
`
`Hematopoietic
`and
`immune
`
`Other
`
`Diagnostic
`(Sufficient to Establish the
`Diagnosis of Chronic GVHD)
`
`Distinctive
`(Seen in Chronic GVHD, but Insufficient
`Alone to Establish a
`Diagnosis of Chronic GVHD)
`
`Other Features*
`
`Common
`(Seen with Both Acute
`and Chronic GVHD)
`
`Thrombocytopenia
`Eosinophilia
`Lymphopenia
`Hypo- or
`hypergammaglobulinemia
`Autoantibodies
`(AIHA and ITP)
`Pericardia! or
`pleural effusions
`Ascites
`Peripheral
`neuropathy
`Nephrotic
`syndrome
`Myasthenia gravis
`Cardiac
`conduction
`abnormality or
`cardiomyopathy
`
`GVHD indicates graft-versus-host disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BOOP, bronchiolitis obliterans(cid:173)
`organizing pneumonia; PFrs, pulmonary function tests; AIHA, autoimmune hemolytic anemia; ITP, idiopathic thrombocytopenic
`purpura.
`*Can be acknowledged as part of the chronic GVHD symptomatology if the diagnosis is confirmed.
`t In all cases, infection, drug effects, malignancy, or other causes must be excluded.
`+Diagnosis of chronic GVHD requires biopsy or radiology confirmation (or Schirmer test for eyes).
`
`Hair
`
`Distinctive features of chronic GVHD include
`new scarring and nonscarring scalp alopecia (after
`recovery from chemotherapy or radiotherapy) and loss
`of body hair. Other characteristics seen with chronic
`GVHD include premature graying, thinning, or brit(cid:173)
`tleness, but these findings are not diagnostic.
`
`Mouth
`
`Diagnostic features of oral chronic GVHD in(cid:173)
`clude lichen planus-like changes (white lines and lacy(cid:173)
`appearing lesions of the buccal mucosa, tongue, pal(cid:173)
`ate, or lips), hyperkeratotic plaques (leukoplakia), or
`decreased oral range of motion in patients with sclerotic
`features of skin GVHD. Distinctive features of chronic
`GVHD include xerostomia (dryness), mucoceles, mu(cid:173)
`cosal atrophy, pseudomembranes, and ulcers (infec(cid:173)
`tious pathogens such as yeast or herpesvirus; second(cid:173)
`ary malignancy must be excluded). Manifestations
`common to both acute and chronic GVHD include
`gingivitis, mucositis, erythema, and pain.
`
`Eyes
`
`Distinctive manifestations of chronic GVHD in(cid:173)
`clude new onset of dry, gritty, or painful eyes; cicatri(cid:173)
`cial conjunctivitis; keratoconjunctivitis sicca; and con(cid:173)
`fluent areas of punctate keratopathy. Other features
`include photophobia, periorbital hyperpigmentation,
`
`difficulty in opening the eyes in the morning because
`of mucoid secretions, and blepharitis (erythema of the
`eye lids with edema). New ocular sicca documented by
`low Schirmer test values with a mean value of both
`eyes ::=;5 mm at 5 minutes or a new onset of kerato(cid:173)
`conjunctivitis sicca by slit-lamp examination with
`mean values of 6 to 10 mm on the Schirmer test is
`sufficient for the diagnosis of chronic GVHD if ac(cid:173)
`companied by distinctive manifestations in at least 1
`other organ.
`
`Genitalia
`
`Diagnostic features for the genitalia include lichen
`planus-like features and vaginal scarring or stenosis (often
`associated with oral GVHD).
`
`Gastrointestinal Tract
`
`Diagnostic features for the gastrointestinal (GI)
`tract include esophageal web, stricture, or concentric rings
`documented by endoscopy or barium contrast radio(cid:173)
`graph. Chronic GVHD may be associated with pan(cid:173)
`creatic exocrine insufficiency, which often improves
`with enzyme supplementation. Manifestations com(cid:173)
`mon to both acute and chronic GVHD (as well as
`other causes, such as drug side effects, motility disor(cid:173)
`ders, infections, or malabsorption) include anorexia,
`nausea, vomiting, diarrhea, weight loss, and failure to
`thrive. Wasting syndrome may be a manifestation of
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`A. H. Filipovich et nl.
`
`chronic GVHD but is often multifactorial (e.g., de(cid:173)
`creased caloric intake, poor absorption, increased rest(cid:173)
`ing energy expenditures, and hypercatabolism). Endo(cid:173)
`scopic findings of mucosa! edema and erythema or
`focal erosions with histologic changes of apoptotic
`epithelial cells and crypt cell dropout may be seen but
`are not considered diagnostic of chronic GVHD un(cid:173)
`less the patient also has distinctive features in a
`non-GI system. Patients with unresolved acute
`GVHD may have more severe intestinal mucosa! le(cid:173)
`sions, including ulcers and mucosa! sloughing.
`
`Liver
`Hepatic acute and chronic GVHD typically pre(cid:173)
`sents as cholestasis, with increased bilirubin or alkaline
`phosphatase, but it may also present as acute hepatitis
`[21,22]. Because of many possible alternative diag(cid:173)
`noses, liver biopsy is required to confirm GVHD
`involvement of the liver. Note that because of the
`histologic similarity between acute and chronic liver
`GVHD, the diagnosis of chronic GVHD cannot be
`made on the basis of liver biopsy alone but requires a
`distinctive manifestation in at least 1 other organ sys(cid:173)
`tem.
`
`Lungs
`The only diagnostic manifestation of chronic
`GVHD is biopsy-proven BO. BO diagnosed via pul(cid:173)
`monary function and radiologic testing requires at
`least 1 other distinctive manifestation in a separate
`organ system to establish the diagnosis of chronic
`GVHD. BO is characterized by the new onset of an
`obstructive lung defect. Clinical manifestations may
`include dyspnea on exertion, cough, or wheezing.
`Some patients may be asymptomatic early in the dis(cid:173)
`ease process. Pneumothorax, pneumomediastinum,
`and subcutaneous emphysema are rare and often rep(cid:173)
`resent advanced disease. Restrictive pulmonary func(cid:173)
`tion abnormalities secondary to advanced sclerosis of
`the chest wall are attributable to skin GVHD. BO is
`clinically diagnosed when all of the following criteria
`are met:
`1. Forced expiratory volume in 1 second/forced vital
`capacity ratio <0. 7 and forced expiratory volume in
`1 second <75% of predicted.
`2. Evidence of air trapping or small airway thickening
`or bronchiectasis on high-resolution chest com(cid:173)
`puted tomography (with inspiratory and expiratory
`cuts), residual volume >120%, or pathologic con(cid:173)
`firmation of constrictive bronchiolitis.
`3. Absence of infection in the respiratory tract, doc(cid:173)
`umented with investigations directed by clinical
`symptoms, such as radiologic studies (radiographs
`or computed tomographic scans) or microbiologic
`cultures (sinus aspiration, upper respiratory tract
`
`950
`
`viral screen, sputum culture, or bronchoalveolar
`lavage).
`4. BO-organizing pneumonia not due to infections
`may represent a manifestation of either acute or
`chronic GVHD and is considered a common
`feature.
`
`Musculoskeletal System
`Diagnostic features include fasci.al involvement often
`affecting the forearms or legs and often associated with
`sclerosis of the overlying skin and subcutaneous tissue.
`Fascia! involvement may develop without overlying scle(cid:173)
`rotic changes of the skin and can result in joint stiffness or
`contractures when present near joints. Fasci.itis is detected
`on examination by stiffness, a restricted range of motion
`(e.g., often decreased dorsal wrist flexion or inability to
`assume a Buddha prayer posture), edema of the extrem(cid:173)
`ities with or without erythema ( early sign), peau d' orange
`(edematous skin with prominent pores resembling the
`surface of an orange), or joint contractures (late complica(cid:173)
`tions). Clinical myositis with tender muscles and in(cid:173)
`creased muscle enzymes is a distinctive but nondiagnos(cid:173)
`tic manifestation of chronic GVHD. Myositis may
`present as proximal myopathy, but this complication is
`rare and does not explain the frequent complaints of
`severe cramps. Evaluation of myositis involves electro(cid:173)
`myography and measurement of creatine phosphokinase
`or aldolase. Arthralgia and arthritis are uncommon and
`are occasionally associated with the presence of autoan(cid:173)
`tibodies.
`
`Hematopoietic and Immune Systems
`Abnormalities are common in chronic GVHD but
`cannot be used to establish the diagnosis of chronic
`GVHD. Cytopenias may result from stromal damage
`or autoimmune processes. Lymphopenia (::5500/µL),
`eosinophilia (2::500/µL), hypogammaglobulinemia, or
`hypergammaglobulinemia may be present. Autoanti(cid:173)
`bodies may develop with autoimmune hemolytic ane(cid:173)
`thrombocytopenic purpura.
`idiopathic
`mia and
`Thrombocytopenia (<100 000/µL) at the time of
`chronic GVHD diagnosis has been associated with a
`poor prognosis.
`
`Other Findings
`Serositis (pericardia! or pleural effusions or as(cid:173)
`cites ), peripheral neuropathy, myasthenia gravis, ne(cid:173)
`phrotic syndrome, and cardiac involvement have been
`attributed to chronic GVHD, but these manifesta(cid:173)
`tions are rare. For these manifestations, chronic
`GVHD is often a diagnosis of exclusion.
`
`DIFFERENTIAL DIAGNOSIS BETWEEN ACUTE AND
`CHRONIC GVHD
`The Working Group recognized 2 main catego(cid:173)
`ries of GVHD, each with 2 subcategories (Table 2).
`
`

`

`I?
`
`Diagnosis and Staging of Chronic Graft-versus-Host Disease
`
`Table 2. Categories of Acute and Chronic GVHD
`
`Category
`
`Time of Symptoms
`after HCT or DLI
`
`Presence of Acute
`GVHD Features*
`
`Presence of Chronic
`GVHD Features*
`
`Acute GVHD
`Classic acute GVHD
`Persistent, recurrent, or late-onset acute GVHD
`Chronic GVHD
`Classic chronic GVHD
`Overlap syndrome
`
`SIOO d
`>100 d
`
`No time limit
`No time limit
`
`Yes
`Yes
`
`No
`Yes
`
`No
`No
`
`Yes
`Yes
`
`GVHD indicates graft-versus-host disease; HCT, hematopoietic cell transplantation; DLI, donor lymphocyte infusion.
`*See Table 1 for features.
`
`The broad category of acute GVHD includes (1) clas(cid:173)
`sic acute GVHD (maculopapular rash, nausea, vomit(cid:173)
`ing, anorexia, profuse diarrhea, ileus, or cholestatic
`hepatitis) occurring within 100 days after transplanta(cid:173)
`tion or DLI (without diagnostic or distinctive signs of
`chronic GVHD) and (2) persistent, recurrent, or late
`acute GVHD: features of classic acute GVHD with(cid:173)
`out diagnostic or distinctive manifestations of chronic
`GVHD occurring beyond 100 days of transplantation
`or DLI (often seen after withdrawal of immune sup(cid:173)
`pression). The broad category of chronic GVHD in(cid:173)
`cludes (1) classic chronic GVHD without features
`characteristic of acute GVHD and (2) an overlap syn(cid:173)
`drome in which features of chronic and acute GVHD
`appear together. In the absence of histologic or clin(cid:173)
`ical signs or symptoms of chronic GVHD, the persis(cid:173)
`tence, recurrence, or new onset of characteristic skin,
`GI tract, or liver abnormalities should be classified as
`acute GVHD regardless of the time after transplanta(cid:173)
`tion. With appropriate stratification, patients with
`persistent, recurrent, or late acute GVHD or overlap
`syndrome can be included in clinical trials with pa(cid:173)
`tients who have chronic GVHD.
`
`CLINICAL SCORING OF ORGAN SYSTEMS
`
`Figure 1 shows the consensus scoring system for
`individual organs. Several considerations explain the
`selection of the features for the proposed scoring sys(cid:173)
`tem versus the response criteria discussed in a separate
`article. (1) Scoring criteria are intended for baseline or
`cross-sectional use, whereas response criteria are in(cid:173)
`tended for serial use in therapeutic trials over a rela(cid:173)
`tively short period of time. (2) Scoring measures must
`be designed so that they can be easily performed in the
`office by general practitioners. By design, the only
`required laboratory testing needed to complete the
`scoring table is measurement of liver function. (3) The
`broad scoring categories help classify patients and
`provide immediate, clinically meaningful data about
`the disease extent and severity. (4) The scoring system
`does not attempt to distinguish between disease activ(cid:173)
`ity and fixed deficits.
`Organ sites considered for scoring include skin,
`
`mouth, eyes, GI tract, liver, lungs, joints and fascia,
`and the female genital tract. Each organ or site is
`scored according to a 4-point scale (0-3), with O rep(cid:173)
`resenting no involvement and 3 reflecting severe im(cid:173)
`pairment. In addition, performance status is captured
`on a O to 3 scale, and check boxes note the presence or
`absence of other specific manifestations.
`Note that Figure 1 should be completed on the
`basis of an assessment of current status without con(cid:173)
`sideration of past manifestations or a requirement for
`attribution of abnormalities to chronic GVHD versus
`another preexisting condition.
`
`GLOBAL SCORING OF CHRONIC GVHD
`
`The time-honored description of limited versus
`extensive chronic GVHD was proposed from only 20
`cases published in 1980 [2]. The Working Group
`proposes a new global assessment of chronic GVHD
`severity that is clinically suitable and is appropriate for
`use as an inclusion criterion in therapeutic clinical
`trials or as an indication for systemic immunosuppres(cid:173)
`sive treatment. The global scoring system reflects the
`clinical effect of chronic GVHD on the patient's func(cid:173)
`tional status.
`Elements included in the proposed global scoring
`system include both the number of organs or sites
`involved and the severity within each affected organ
`(note that performance status scoring is not incorpo(cid:173)
`rated into the global scoring system). The global de(cid:173)
`scriptions of mild, moderate, and severe were chosen
`to reflect the degree of organ impact and functional
`impairment due to chronic GVHD. Although scoring
`is often used at the time of initial diagnosis, evaluating
`the clinical score periodically during the course of
`chronic GVHD may revise prognostic expectations
`and better describe the current severity of chronic
`GVHD. Note that the global scoring system can be
`applied only after the diagnosis of chronic GVHD is
`confirmed by either (1) the presence of a diagnostic
`feature or, if a diagnostic feature is not present, (2) at
`least 1 distinctive manifestation of chronic GVHD
`with the diagnosis supported by histologic, radiologic,
`or laboratory evidence of GVHD from any site.
`
`BB&MT
`
`951
`
`

`

`A. H. Filipovich et al.
`
`PERFORMANCE
`SCORE:
`
`I
`
`KPS ECOG LPS
`
`□ Asymptomatic
`and fully active
`(ECOG O; 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(cid:173)
`care, >50% of
`waking hours out
`of bed (ECOG 2,
`KPS or LPS 60-
`
`□ Symptomatic,
`limited self-care,
`>50% of waking
`hours in bed (ECOG
`3-4, KPS or LPS
`<60%)
`
`□ <18% BSA with
`disease signs but
`NO sclerotic
`features
`
`□ 19-50%BSA
`OR involvement
`with superficial
`sclerotic features
`"not hidebound"
`(able to pinch)
`
`□ >50%BSAOR
`deep sclerotic
`features "hidebound"
`(unable to pinch) OR
`impaired mobility,
`ulceration or severe
`pruritus
`
`□ No Symptoms
`
`SKIN
`Clinical features:
`□ Maculopapular
`rash
`□ Lichen pla