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NIH Consensus Development Project on criteria for clinical trials in cGVHD I

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National Institute
Criteria for Clinic
been made to focus
normalities to chronic
curately measures the
on studies.
rrow Transplantation.
Financial disclosure: See Acknowledgments on page 400.
* Correspondence and reprint requests: Mary E.D. Flowers, MD, Fred
Hutchinson Cancer Research Center, D5-290, P.O. Box 19024, Seattle, WA
E-mail address: m�owers@fredhutch.org (M.E.D. Flowers).
1083-8791/� 2015 American Society for Blood and Marrow Transplantation.
Biol Blood Marrow Transplant 21 (2015) 389e401
Biology of Blood and
Marrow Transplantation
journal homepage: www.bbmt.org
National Institutes of Health
prognosis, guide treatment, and de�ne eligibility for clinical trials. Revisions have
attention on the causes of organ-speci�c abnormalities. Attribution of organ-speci�c ab
GVHD has been addressed. This paradigm shift provides greater speci�city and more ac
global burden of disease attributed to GVHD, and it will facilitate biomarker associati
� 2015 American Society for Blood and Ma
Corey S. Cutler
, Georgia B. Vogelsang
, Stephanie J. Lee
Department of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, Tennessee
Department of Internal Medicine, Medical University of Vienna, Vienna, Austria
Department of Medicine, University of Minnesota, Minneapolis, Minnesota
Center for Cancer Research National Cancer Institute, National Institutes of Health, Bethesda, Maryland
Department of Blood and Marrow Transplantation, Children’s National Health System, Washington, District of Columbia
Department of Internal Medicine, University of Regensburg, Regensburg, Germany
Department of Hematology Oncology/Blood and Marrow Transplant, Mayo Clinic Arizona, Phoenix, Arizona
Department of Surgery, Division of Oral Medicine and Dentistry, Brigham and Women’s Hospital, Boston, Massachusetts
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
Hematology Department, BC Cancer Agency, Vancouver, British Columbia, Canada
Pediatric and Reproductive Endocrinology Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development,
National Institutes of Health, Bethesda, MD
Department of Hematology, Institut Catala d’Oncologia, Barcelona, Spain
Division of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
Hematology and Hemotherapy Center, Hemocentro Unicamp, Campinas, Sao Paulo, Brazil
Department of Blood and Marrow Transplantation, Stanford University Medical Center, Stanford, California
The Eye Clinic, National Eye Institute, National Institutes of Health, Bethesda, Maryland
Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland
Blood and Marrow Transplant Program, University of Michigan Comprehensive Cancer Center, Ann Arbor, Michigan
Department of Applied Research Cancer Control and Population Sciences, National Institutes of Health, Bethesda, Maryland
Cancer Therapy Evaluation Program, National Institutes of Health, Bethesda, Maryland
Division of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
Oncology Department, Johns Hopkins University School of Medicine, Baltimore, Maryland
Article history:
Received 22 November 2014
Accepted 1 December 2014
Key Words:
Chronic graft-versus-host
The 2005 National Institutes of Health (NIH) Consensus Conference proposed new criteria for diagnosing and
scoring the severity of chronic graft-versus-host disease (GVHD). The 2014 NIH consensus maintains the
framework of the prior consensus with further re�nement based on new evidence. Revisions have been made
to address areas of controversy or confusion, such as the overlap chronic GVHD subcategory and the
distinction between active disease and past tissue damage. Diagnostic criteria for involvement of mouth, eyes,
genitalia, and lungs have been revised. Categories of chronic GVHD should be de�ned in ways that indicate
Afonso Vigorito ,Sa
Carrie L. Kitko
, San
I. The 2014 Diag
Madan H. Jagasia
, H
Holly Kerr
, Pamela
s ofHealth ConsensusDevelopment Project on
al Trials in Chronic Graft-versus-Host Disease:
osis and Staging Working Group Report
ldegard T. Greinix
, Mukta Arora
, Kirsten M. Williams
, Daniel Wolff
anne Palmer
, Nathaniel S. Treister
, Guang-Shing Cheng
, George B. McDonald
, Yoshihiro Inamoto
, Manuel B. Datiles
, David Jacobsohn
ra A. Mitchell

M.H. Jagasia et al. / Biol Blood Marrow Transplant 21 (2015) 389e401390
minimal criteria needed to establish the diagnosis for clinical
trials, and (2) re�ne the de�nition of GVHD subcategories
Chronic graft-versus-host disease (GVHD) remains a
serious and common complication of allogeneic hemato-
poietic cell transplantation (HCT), occurring in 30% to 70% of
patients [1]. Chronic GVHD is a syndrome of variable clinical
features resembling autoimmune and other immunologic
disorders, such as scleroderma, Sjögren’s syndrome, pri-
mary biliary cirrhosis, wasting syndrome, bronchiolitis
obliterans, immune cytopenias, and chronic immunode�-
ciency [2,3]. The pathophysiology of the chronic GVHD
syndrome may involve in�ammation, cell-mediated im-
munity, humoral immunity, and �brosis. Clinical manifes-
tations nearly always present during the �rst year after
transplantation, but some cases develop many years after
HCT. Manifestations of chronic GVHD may be restricted to a
single organ or site or may be widespread, with profound
impact on quality of life. Other cases are self-limited and
either smolder or resolve without immunosuppressive
Diagnosing and scoring the severity of chronic GVHD is
challenging for several reasons: limited understanding of the
pathophysiology, coexistence of acute GVHD manifestations,
previously poorly validated measurement tools and scoring
systems, and lack of biomarkers for the diagnosis and
assessment of disease activity.
Overall risk pro�les for acute GVHD and for chronic GVHD
diagnosed according to 2005 National Institutes of Health
(NIH) consensus criteria [4] were similar in a large compar-
ative study [5]. Of interest, risk factors associated with
chronic GVHD were not changed after adjustment for prior
acute GVHD, suggesting that chronic GVHD is not simply an
evolution of preceding acute GVHD [5].
Several retrospective and large prospective studies have
validated many aspects of the 2005 NIH Chronic GVHD
Diagnosis and Staging Consensus criteria [4] including organ
scoring, global severity, and GVHD categories [6-21].
Although these criteria represent advancement in the �eld,
many questions remain, including their role in clinical
practice, biomarker discovery, and regulatory review of new
drugs or devices seeking Food and Drug Administration
approval. For certain organs and sites, the minimal criteria to
diagnose chronic GVHD have not been clearly de�ned. Other
unresolved issues of the 2005 consensus criteria include
confusion about the chronic GVHD subcategories (especially
overlap GVHD), the rules for scoring abnormalities (symp-
toms, signs, diagnostic testing) not due to GVHD, and lack of
distinction between active disease and a �xed de�cit
resulting from prior tissue damage [6,22].
Members of the 2014 International NIH Chronic GVHD
Diagnosis and Staging Consensus Working Group who
contributed to this document were subdivided into organ-
speci�c subgroups. Each subgroup reviewed all evidence
new since 2005 and was asked to address controversies and
unanswered questions about their assigned organ [22]. Their
�ndings were reviewed by all members of the working group
and the steering committee and then were agreed upon to
establish the 2014 Consensus Criteria.
The goals of this consensus document are to revise the
2005 NIH Chronic GVHD Consensus Criteria [4] based on
available evidence, to (1) clarify controversies related to the
and organ severity scoring. The changes proposed in this
added to the GI tract severity score.
E. Liver: Aspartate aminotransferase is no longer
included in liver severity scoring. The cut-off values
for bilirubin, alanine aminotransferase, (ALT) and
alkaline phosphatase have been revised.
F. Lungs: The lung function score, which included
both forced expiratory volume in 1 second (FEV1)
and diffusing capacity of the lung for carbon mon-
oxide (DLCO), has been simpli�ed to include only
the FEV1 (hereafter, FEV1 refers to percent pre-
dicted), thus increasing speci�city for obstructive
lung defects. Rules for �nal lung scoring have been
modi�ed to enhance speci�city and for calculation
of global severity.
G. Joints: Photographic image-based range of motion
[23] has been added to the joint assessment as an
exploratory measure.
cument will help to identify manifestations of the various
ical phenotypes of chronic GVHD at initial diagnosis and
ring the subsequent evolution of the disease for the pur-
se of clinical trials and biomarkers studies needed to
vance the �eld. A summary of the 2014 NIH Chronic GVHD
gnosis and Staging Consensus Recommendations is
wn below.
Summary of recommendations that are new since the
05 Consensus [4]
1. De�nition of overlap chronic GVHD subcategory has
been clari�ed, and speci�c manifestations of both
acute and chronic GVHD have been added to the organ
severity scoring form.
2. Diagnostic criteria for organ system involvement have
been modi�ed as follows:
A. Mouth: Hyperkeratotic plaques have been removed
as a diagnostic feature.
B. Eyes: Evaluation by an ophthalmologist is recom-
mended for eye-speci�c clinical trials. The Schirm-
er’s test has been removed from the severity
scoring form.
C. Lungs: Bronchiolitis obliterans syndrome (BOS)
diagnostic criteria have been modi�ed to enhance
diagnostic sensitivity in the presence of established
chronic GVHD. BOS that meets the new clinical
criteria, plus 1 other distinctive manifestation, is
now suf�cient for chronic GVHD diagnosis.
D. Genitalia: Signs and symptoms for males have been
added, and diagnostic criteria for females have been
3. Organ-speci�c severity scoring has been modi�ed as
follows (Figure 1):
A. Skin: The composite score has been split into 2
scores to separate the extent of skin involvement
(body surface area [BSA]) from the speci�c skin
features. Clinical features to be considered in the
skin scores have been clari�ed, and rules for the
�nal skin scoring have been added for calculation of
global severity.
B. Mouth: Asymptomatic lichen planuselike features
(score 0) has been incorporated.
C. Eye: Keratoconjunctivitis sicca (KCS) con�rmed by
an ophthalmologist in an asymptomatic patient
(score 0) has been incorporated. Scoring for the eye
drop usage criterion has been clari�ed to include
only lubricant drops.
D. Gastrointestinal (GI): Severity of diarrhea has been

BSA, bo
M.H. Jagasia et al. / Biol Blood Marrow Transplant 21 (2015) 389e401 391
H. Genitalia: New criteria are proposed for scoring
severity based on signs as an exploratory measure.
I. Other indicators have been removed, including the
category of progressive onset, and cardiac mani-
festations, such as conduction defects and coronary
artery involvement (Figure 1). Weight loss (not due
to gastrointestinal involvement by GVHD) has been
added to this section.
J. Attributions of abnormalities not due to GVHD have
been incorporated into the organ-speci�c scoring.
1. Organ scoring of chronic GVHD. ECOG indicates Eastern Cooperative Oncology G
dy surface area; ADL, activities of daily living; LFTs, liver function tests; AP, alkali
t loss within 3 months.
Skin scoring should use both percentage of BSA involved by
n the percentage of total body surface (BSA) score and the skin feature score, OR
y or ulceration (Score 3), the higher level should be used for the �nal skin sc
ental Figure). **Lung scoring should be performed using both the symptoms an
where there is discrepancy between symptoms and FEV1 scores.
4. The evaluator’s opinion regarding overall severity of
chronic GVHD has been added to the scoring form
(Figure 1).
Clinical features determine whether the clinical syn-
me of GVHD is considered acute or chronic, not the
poral relationship to transplantation [4]. In the 2005
sensus criteria, the simultaneous presence of acute GVHD
roup; KPS, Karnofsky Performance Status; LPS, Lansky Performance Status;
ne phosphatase; ALT, alanine aminotransferase; ULN, normal upper limit.
disease signs and the cutaneous features scales. When a discrepancy exists
if super�cial sclerotic features are present (Score 2), but there is impaired
To be completed by specialist or trained medical providers (see
d FEV1 scores whenever possible. FEV1 should be used in the �nal lung

M.H. Jagasia et al. / Biol Blood Marrow Transplant 21 (2015) 389e401392
features in patients with chronic GVHD was classi�ed as the
“overlap” subset of chronic GVHD [4]. This subclassi�cation
of chronic GVHD has been a subject of controversy and
confusion (see Differential Diagnosis between Acute and
Chronic GVHD in the next section). The overlap subcategory
of chronic GVHD has been associated with worse survival
compared to the “classic” subcategory (absence of acute
GVHD features) of chronic GVHD [9,13,20,24], but not in all
studies [18]. Hyperbilirubinemia and small intestinal/colonic
involvement are known risk factors for increased mortality
in chronic GVHD patients (reviewed in [2]) [7,25,26]. Based
on current knowledge and in light of the controversy related
to the overlap subcategory, including problems identi�ed in
clinical practice [22], the 2014 consensus criteria have clar-
i�ed the overlap subcategory of chronic GVHD and
Figure 1. (con
recommend documentation of all clinical features in patients
with chronic GVHD that are relevant for prognostication,
treatment guidance, response assessment, biomarker
studies, and clinical trials (see “Differential Diagnosis be-
tween Acute and Chronic GVHD” and “Clinical Scoring of
Organ Systems” sections below).
Throughout this document, diagnostic signs and symp-
toms refer to those manifestations that establish the pres-
ence of chronic GVHD without need for further testing or
evidence of other organ involvement. Distinctive signs and
symptoms of chronic GVHD refer to those manifestations
that are not ordinarily found in acute GVHD but are not
considered suf�cient in isolation to establish an unequivocal
diagnosis of chronic GVHD. Additional testing, such as a bi-
opsy documenting histological features of chronic GVHD (or

M.H. Jagasia et al. / Biol Blood Marrow Transplant 21 (2015) 389e401 393
at least “likely” chronic GVHD, see Histopathology docu-
ment), is needed to establish the diagnosis of chronic GVHD.
Other features or unclassi�ed manifestations of chronic GVHD
de�ne the rare, controversial, or nonspeci�c features of
chronic GVHD that cannot be used to establish the diagnosis
of chronic GVHD. Signs and symptoms found in both
chronic and acute GVHD are referred as common features
(Table 1).
Characteristics of the clinical features that establish the
diagnosis of chronic GVHD might not serve as the most
appropriate parameters for assessing severity of chronic
GVHD. Valid and reliable diagnostic criteria might not be
suf�ciently sensitive to change to be useful as criteria for
response after treatment. Conversely, a sensitive measure of
chronic GVHD response might not necessarily serve as an
appropriate diagnostic and scoring measure.
The Working Group recommends that the diagnosis of
chronic GVHD requires at least 1 diagnostic manifestation of
chronic GVHD or at least 1 distinctive manifestation plus a
pertinent biopsy, laboratory, or other tests (eg, pulmonary
Figure 1. (con
function tests [PFT], Schirmer’s test), evaluation by a
specialist (ophthalmologist, gynecologist), or radiographic
imaging showing chronic GVHD in the same or another or-
gan, unless stated otherwise. As in acute GVHD, infection and
other causes may confound or complicate the differential
diagnosis of chronic GVHD and must be excluded (eg, nail
dystrophy due to onychomycosis, herpes simplex, or Candida
albicans infections of the oral cavity, drug toxicity). Diag-
nostic and distinctive features of chronic GVHD can be found
in the skin and appendages, mouth, eyes, genitalia, esoph-
agus, lungs, and connective tissues. Biopsy or other testing is
always encouraged and often valuable to con�rm the pres-
ence of chronic GVHD, but it is not always feasible and is not
mandatory if the patient has at least 1 of the diagnostic
�ndings of chronic GVHD (Table 1).
In all cases, drug reaction, infection, recurrent or new
malignancy and other causes must be excluded. Diagnostic

rophy, pigmentary changes, and telangiectasia), lichen pla-
or brittleness, onycholysis, pterygium unguis, and nail loss
M.H. Jagasia et al. / Biol Blood Marrow Transplant 21 (2015) 389e401394
(usually symmetric and affecting most nails) are distinctive
signs of chronic GVHD.
nuselike eruption (ie, erythematous/violaceous �at-topped
papules or plaques with or without surface reticulations or a
silvery or shiny appearance), deep sclerotic features (ie,
smooth, waxy, indurated “thickened or tight” skin, caused by
deep and diffuse sclerosis over a wide area generally causing
limitation of joint mobility), morphea-like super�cial scle-
rotic features (ie, localized patchy areas of moveable smooth
or shiny skin, leather-like consistency, often with dyspig-
mentation), or lichen sclerosuselike lesions (ie, discrete to
coalescent, gray to white, moveable papules or plaques, often
with follicular plugs, shiny appearance, and cigarette paper-
likewrinkled texture). Severe sclerotic features characterized
by thickened, tight, and fragile skin are often associated with
poor wound healing, inadequate lymphatic drainage, and
skin ulcers from minor trauma.
Depigmentation (vitiligo) and papulosquamous lesions
are “distinctive” features of chronic GVHD (ie, not seen in
acute GVHD, but are not suf�ciently speci�c to be considered
diagnostic of chronic GVHD). These features contribute to the
diagnosis of chronic GVHD in combination with biopsy or
laboratory con�rmation of GVHD in skin or another organ.
Sweat impairment and intolerance to temperature change
from loss of sweat glands are seen in chronic GVHD and are
considered to be in the “other feature” category, along with
manifestations such as ichthyosis, keratosis pilaris, hypo-
pigmentation, and hyperpigmentation (Table 1). These fea-
tures cannot be used to establish the initial diagnosis of
chronic GVHD. Skin manifestations found in both acute and
chronic GVHD include erythema, maculopapular rash, and
pruritus and are categorized as “common” features. The
presence of 1 ormore of the “common” features alone cannot
be used to establish the initial diagnosis of chronic GVHD
(Table 1).
Assessment of extent and severity of skin chronic GVHD is
complex because some clinical features may re�ect past
“damage” (hypo- and hyperpigmentary changes) or sequelae
of long-standing �brosis (ie, �xed joint contractures after
several years of deep sclerosis). Assessment of disease ac-
tivity is dif�cult in patients with poikiloderma when smol-
dering, ill-de�ned erythema is admixed with pigmentary
changes. Pigmentary change alone (seen in poikiloderma or
more commonly as simple postin�ammatory pigmentary
change not representing active GVHD) is not included in the
percentage of BSA skin score calculation (Table 1, Figure 1).
Erythema, a “common” feature (Table 1), is included in the
BSA skin score calculation as it generally represents in�am-
mation associated with active GVHD. Only the erythema
component of poikiloderma is considered in the BSA skin
score calculation, but it may be dif�cult to quantify because it
is admixed with pigmentary changes.
Dystrophy consisting of longitudinal ridging, nail splitting
clinical or laboratory features suf�cient for the diagnosis of
chronic GVHD are italicized in the sections below.
Diagnostic clinical features include poikiloderma (ie, at-
Distinctive features of chronic GVHD include new scarring
or nonscarring scalp alopecia (not due to chemotherapy or
radiotherapy) and loss of body hair. Other characteristics
seen with chronic GVHD include premature graying, thin-
ning, or brittleness.
Diagnostic features of oral chronic GVHD include lichen
planuselike changes, characterized by hyperkeratotic white
lines and lacy-appearing lesions on the oral mucosa. Changes
are typically observed on the buccal mucosa and tongue,
although all intraoral surfaces and the vermilion lip may be
involved. These diagnostic white changes may be observed
with or without associated erythema or ulcerations, which
are not considered diagnostic features. The presence of iso-
lated hyperkeratotic plaques without lichen planuselike
changes, so-called leukoplakia, is no longer considered a
diagnostic criterion as these lesions should be considered a
separate clinical entity that may imply malignant potential.
Decreased range of motion of the jaw secondary to skin
sclerosis should be assessed according to skin criteria and is
no longer considered a diagnostic criterion in the oral sec-
tion. Distinctive features of chronic GVHD include xero-
stomia (dryness), mucoceles, mucosal atrophy, ulcers, and
pseudomembranes, but infectious pathogens, such as yeast
or herpes virus, and secondary malignancy must be
excluded. Manifestations common to both acute and chronic
GVHD include gingivitis, mucositis, erythema, and pain.
Figure 1 details the scoring and incorporates asymptomatic
oral chronic GVHD as a diagnostic feature.
Distinctive manifestations of chronic GVHD include new
onset of dry, “gritty,” or painful eyes, cicatricial conjunctivitis,
KCS, and con�uent areas of punctate keratopathy. Other
features include photophobia, periorbital hyperpigmenta-
tion, and blepharitis (erythema and edema of the eye lids and
telangiectasia of lid margin). New ocular sicca documented
by low Schirmer’s test with a mean value of �5mmat5
minutes (preferably with con�rmation of normal values at an
established baseline) or a new onset of KCS by slit lamp exam
with mean Schirmer’s test values of 6 to 10 mm (preferably
with con�rmation of normal values at an established base-
line) not due to other causes is suf�cient for the diagnosis of
ocular chronic GVHD for the purpose of treatment and for
clinical trials designed speci�cally for ocular GVHD, but an
additional distinctive feature is necessary to establish eligi-
bility for general chronic GVHD trials. Patients with ocular
symptoms before transplantation should be evaluated by an
ophthalmologist for assessment of ocular surface abnor-
malities, including presence of KCS, conjunctival scarring,
and in�ammation. Some experts strongly encourage baseline
evaluation after transplantation (approximately day 100)
[27,28]. Figure 1 details the scoring and incorporates
asymptomatic ocular chronic GVHD. The scoring of ocular
involvement includes the number of times a patient has to
use lubricant eye drops each day. The international
consensus guidelines on ocular GVHD have proposed a more
detailed scoring schema, which involves comprehensive
ophthalmological evaluation, including pretransplantation
evaluation [28]. These remain to be validated and should be
considered in clinical trials addressing ocular involvement.
Schirmer’s test may be useful for diagnosis of ocular GVHD,

Table 1
Signs and Symptoms of chronic GVHD
Organ or Site Diagnostic (Suf�cient to
Establish the Diagnosis of
chronic GVHD)
Distinctive* (Seen in chronic
GVHD, but Insuf�cient Alone
to Establish a Diagnosis)
Other Features or
Unclassi�ed Entities
(Seen with
Both Acute and
chronic GVHD)
Skin Poikiloderma
Lichen planuselike
Sclerotic features Morphea-
like features
Lichen sclerosuselike
Papulosquamous lesions
Sweat impairment
Keratosis pilaris
Maculopapular rash
Nails Dystrophy
Longitudinal ridging,
splitting or brittle features
Pterygium unguis
Nail loss (usually symmetric,
affects most nails)
Scalp and
body hair
New onset of scarring or
nonscarring scalp
alopecia (after recovery
from chemoradiotherapy)
Loss of body hair
Thinning scalp hair, typically
patchy, coarse or dull
(not explained by endocrine
or other causes)
Premature gray hair
Mouth Lichen planuselike changes Xerostomia
Mucosal atrophy
Eyes New onset dry, gritty, or
painful eyes
Cicatricial conjunctivitis
Con�uent areas of
punctate keratopathy
Periorbital hyperpigmentation
Blepharitis (erythema of the
eyelids with edema)
Genitalia Lichen planuselike features
Lichen sclerosuselike features
UlcersFemales Vaginal scarring or clitoral/labial
Males Phimosis or urethral/meatus
scarring or stenosis
GI Tract Esophageal web
Strictures or stenosis in the upper
to mid third of the esophagus
Exocrine pancreatic insuf�ciency Anorexia
Weight loss
Failure to thrive (infants
and children
Liver Total bilirubin, alkaline
phosphatase > 2 � upper
limit of normal
ALT > 2 � upper limit of
Lung Bronchiolitis obliterans
diagnosed with lung biopsy
Air trapping and
bronchiectasis on chest CT
Cryptogenic organizing
Restrictive lung disease
Muscles, fascia,
Joint stiffness or contractures
secondary to fasciitis or sclerosis
Myositis or polymyositis
Muscle cramps
Arthralgia or arthritis
and Immune
Hypo- or hyper-gammaglobulinemia
Autoantibodies (AIHA, ITP)
Raynaud’s phenomenon
Other Pericardial or pleural effusions
Peripheral neuropathy
Nephrotic syndrome
Myasthenia gravis
Cardiac conduction abnormality or
ALT indicates alanine aminotransferase; AIHA, autoimmune hemolytic anemia; ITP, idiopathic thrombocytopenic purpura.
* In all cases, infection, drug effect, malignancy, or other causes must be excluded.
Can be acknowledged as part of the chronic GVHD manifestations if diagnosis is con�rmed.
Common refers to shared features by both acute and chronic GVHD.
BOS can be diagnostic for lung chronic GVHD only if distinctive sign or symptom present in another organ (see text).
Pulmonary entities under investigation or unclassi�ed.
Diagnosis of chronic GVHD requires biopsy.
M.H. Jagasia et al. / Biol Blood Marrow Transplant 21 (2015) 389e401 395

unavailable, external examination may be performed, but, in
loss occurring over a 3-month period should be documented
with h
cell d
M.H. Jagasia et al. / Biol Blood Marrow Transplant 21 (2015) 389e401396
in clinical trials, regardless of causality, unless a de�nitive
causality other than GVHD is identi�ed. Chronic GVHD may
be associated with pancreatic atrophy and exocrine insuf�-
ciency leading [37] to malabsorption that often improves
with oral pancreatic enzyme supplementation. Endoscopic
�ndings of GI mucosal edema and erythema or focal erosions
this instance, vaginal scarring may be missed (Supplemental
Figure 1).
Female genitalia
The vulva and vagina may be affected by chronic GVHD.
Symptoms may include dryness, burning, pruritus, pain to
touch, dysuria, and dyspareunia either with penile insertion
or deep penetration leading to sexual dysfunction. Signs of
genital chronic GVHD may include patchy or generalized
erythema, tenderness on palpation of vestibular gland
openings or vulvar mucosa with a cotton-tipped applicator,
mucosal erosions or �ssures, lace-like leukokeratosis, labial
resorption, labial fusion or clitoral hood agglutination, �bri-
nous vaginal adhesions, circumferential �brous vaginal
banding, vaginal shortening, synechiae, dense sclerotic
changes, and complete vaginal stenosis [29,31-34].
Male genitalia
Manifestations of chronic GVHD may be under-
recognized and under-reported in men. The glans penis
and the urethra or meatus may be affected. Patients may
report painful sexual intercourse and a burning sensation.
Genital signs of GVHD include noninfectious balanoposthitis,
lichen sclerosuselike or lichen planuselike features, phi-
mosis, or urethra or meatus scarring or stenosis [35,36].
GI Tract
Diagnostic features include esophageal web, stricture, or
concentric rings documented by endoscopy or barium
contrast radiograph. Manifestations common to both acute
and chronic GVHD include anorexia, nausea, vomiting, diar-
rhea, weight loss, and failure to thrive (Table 1). These
symptoms can be due to non-GVHD causes, such as drug side
effects, motility disorders, or infections. Wasting syndrome
may be a manifestation of chronic GVHD but is often multi-
factorial (ie, decreased caloric intake, poor intestinal ab-
sorption of macronutrients, increased resting energy
expenditures, and hypercatabolism). Unintentional weight
but the numerical values are not useful for follow-up of
ocular GVHD due to poor correlation with symptom change
[15]. For this reason, Schirmer’s test values have been
removed from the scoring form in the current recommen-
dation (Figure 1).
Chronic GVHD of the genital tract (female and male) is
often associated with oral chronic GVHD [29,30]. Diagnostic
features of genital chronic GVHD include lichen planuselike
features, lichen sclerosuselike features, vaginal scarring,
clitoral/labial agglutination (females), phimosis and scarring
or stenosis of the urethral or meatus (males). Distinctive
features of genital chronic GVHD include erosion, �ssure, and
ulcer (Table 1).
Genital examination is recommended, even in asymp-
tomatic patients (female and male), especially if signs of
chronic GVHD are present in the mouth. If a gynecologist is
There are no hepatic manifestations that are either
distinctive or diagnostic of chronic GVHD. Liver GVHD can also
beaccompaniedbyclinicalmanifestationsof acuteGVHD,with
or without manifestations of chronic GVHD. Other causes of
liver disease occurring beyond day 100 after HCT include viral
infections, biliary obstruction, drug toxicity, and other less
common disorders (eg, nonalcoholic steatohepatitis). Liver
GVHDcanpresent in2ways afterday100.One resembles acute
hepatitis (steeply rising serum alanine aminotransferase, with
or without jaundice), almost always after tapering of immu-
nosuppressive drugs or after donor lymphocyte infusion (DLI).
This presentation requires a prompt diagnosis and treatment
intervention, and liver biopsymay be needed in the absence of
GVHD in another organ. The other presentation resembles a
slowly progressive cholestatic disorder with elevated serum
alkaline phosphatase and gamma-glutamyl transpeptidase
concentrations, followed by jaundice. Acute hepatitis and
progressive cholestatic features are included in the “common”
category (Table 1). The liver has no clinical features in the
“other” category.
Historically, the only diagnostic pulmonary manifestation
of chronic GVHD was biopsy-proven bronchiolitis obliterans.
However, because biopsy is invasive and associated with risk
of bleeding and other complications, experts now endorse
the diagnosis of BOS using PFT [38,39]. BOS is characterized
by the new onset of an obstructive lung defect. Clinical
manifestations may include dyspnea on exertion, cough, or
wheezing; however, many patients are asymptomatic early
in the disease process. For this reason, screening PFTs are
recommended at day 100 after transplantation, at initial
diagnosis of chronic GVHD, at 1 year after transplantation,
and at 6-month intervals for the �rst 2 years after the initial
diagnosis of chronic GVHD. More frequent PFT monitoring is
recommended in patients diagnosed with BOS and in those
with signi�cant decline in lung volumes but not yet meeting
the criteria for BOS (see upcoming supportive care and
ancillary care NIH consensus document). Pneumothorax,
pneumomediastinum, and subcutaneous emphysema are
rare and often associated with advanced disease. Restrictive
pulmonary function abnormalities are not characteristic of
BOS but may re�ect extra-pulmonary restriction (leading to
nonobstructive reduction of FEV1) secondary to advanced
sclerotic GVHD of the chest wall or intrapulmonary processes
not related to GVHD, such as cryptogenic organizing pneu-
monia or pulmonary �brosis. Further investigation beyond
simple pulmonary testing is needed to evaluate these com-
plex problems.
In the presence of a distinctive manifestation of chronic
GVHD, the clinical diagnosis of BOS is suf�cient to establish
the diagnosis of chronic GVHD for the purposes of enroll-
ment on clinical trials when all of the following criteria are
1. FEV1/vital capacity < .7 or the �fth percentile of
A. Vital capacity includes forced vital capacity or slow
vital capacity, whichever is greater.
B. The �fth percentile of predicted is the lower limit of
the 90% con�dence interval.
istologic changes of apoptotic epithelial cells and crypt
ropout are manifestations of acute GVHD.

M.H. Jagasia et al. / Biol Blood Marrow Transplant 21 (2015) 389e401 397
C. For pediatric or elderly patients, use the lower
limits of normal, de�ned according to National
Health and Nutrition Examination Survey III calcu-
lations [40].
2. FEV1 < 75% of predicted with �10% decline over less
than 2 years. FEV1 should not correct to >75% of pre-
dicted with albuterol, and the absolute decline for the
corrected values should still remain at �10% over 2
3. Absence of infection in the respiratory tract, docu-
mented with investigations directed by clinical
symptoms, such as chest radiographs, computed
tomographic (CT) scans, or microbiologic cultures (si-
nus aspiration, upper respiratory tract viral screen,
sputum culture, bronchoalveolar lavage).
4. One of the 2 supporting features of BOS:
A. Evidence of air trapping by expiratory CT or small
airway thickening or bronchiectasis by high-
resolution chest CT, or
B. Evidence of air trapping by PFTs: residual volume >
120% of predicted or residual volume/total lung
capacity elevated outside the 90% con�dence
If a patient already carries the diagnosis of chronic GVHD
by virtue of organ involvement elsewhere, then only the �rst
3 criteria above are necessary to document chronic GVHD
lung involvement. If BOS is the only clinical manifestation in
a patient without a prior established diagnosis of chronic
GVHD, a lung biopsy is required to establish the diagnosis of
chronic GVHD for the purposes of enrollment on general
chronic GVHD trials.
The current recommended work-up for BOS includes PFTs
and expiratory CT. Because a new diagnostic technique for
BOS termed parametric response mapping is currently under
investigation, a high-resolution (helical) CT of inspiration
and expiration is encouraged if available. This technique will
permit visual representation of lung affected by obstructive
disease (BOS) versus lung tissue with normal aeration or
restrictive disease and may become a valuable measure in
the future [41].
Other entities that currently are not diagnostic or
distinctive of lung chronic GVHD but remain areas of active
investigation include: (1) cryptogenic organizing pneumonia
(formerly known as bronchiolitis obliterans organizing
pneumonia), and (2) progressive restrictive lung disease (in
the absence of extra-pulmonary causes). These unclassi�ed
entities have been placed in the “other” category in Table 1.
There are no “common” pulmonary features of GVHD.
Musculoskeletal System
Diagnostic features include fascial involvement often
affecting the forearms or legs and often associated with
sclerosis of the overlying skin and subcutaneous tissue.
Fascial involvement may develop without overlying sclerotic
changes of the skin and can result in joint stiffness or con-
tractures when present near joints. Early fasciitis may pre-
sent with pain and swelling and with or without erythema.
Fasciitis is detected on examination by stiffness, restricted
range of motion (eg, often decreased dorsal wrist �exion or
inability to assume a Buddha prayer posture), edema of ex-
tremities with or without erythema (early sign), peau d’or-
ange (edematous skin with prominent pores resembling the
surface of an orange) or joint contractures (late complica-
tions). Clinical myositis with muscle tenderness and elevated
muscle enzymes in the blood is a distinctive but non-
diagnostic 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 includes electromyography
and measurement of creatinine phosphokinase or aldolase.
Muscle/sural nerve biopsies should be considered in the
absence of other manifestations of GVHD to rule out other
causes of myositis. Arthralgia and “true” arthritis are un-
common and are occasionally associated with the presence
of autoantibodies.
Hematopoietic and Immune Systems
Hematopoietic and immunological abnormalities are
frequently associated with chronic GVHD but cannot be used
to establish the diagnosis of chronic GVHD. Cytopenias may
result from stromal damage or autoimmune processes.
Lymphopenia (�500/mL), eosinophilia (>500/mL), hypogam-
maglobulinemia, or hypergammaglobulinemia may be pre-
sent. Autoantibodies may develop with autoimmune
hemolytic anemia and idiopathic thrombocytopenic pur-
pura. Thrombocytopenia (<100,000/mL) at the time of
chronic GVHD diagnosis has been associated with a poor
Other Findings
Serositis (pericardial or pleural effusions or ascites), pe-
ripheral neuropathy, myasthenia gravis, nephrotic syndrome,
membranous glomerulonephritis, Raynaud’s phenomenon,
and cardiac involvement have been attributed to chronic
GVHD, but these manifestations are rare. For these entities,
attribution to chronic GVHD is often a diagnosis of exclusion.
As in the 2005 consensus criteria, the 2014 consensus
recognizes 2 main categories of GVHD (acute and chronic).
The broad category of acute GVHD includes (1) classic acute
GVHD (erythema, maculopapular rash, nausea, vomiting,
anorexia, profuse diarrhea, ileus, or cholestatic liver disease)
occurring within 100 days after transplantation or DLI in a
patient not meeting criteria for the diagnosis of chronic
GVHD, and (2) persistent, recurrent, or late-onset acute
GVHD: features of classic acute GVHD occurring beyond 100
days after transplantation or DLI in a patient not meeting
criteria for the diagnosis of chronic GVHD (often seen during
the taper or after withdrawal of immune suppression).
In the 2005 criteria, the broad category of chronic GVHD
included 2 subcategories: (1) classic chronic GVHD without
features characteristic of acute GVHD, and (2) an overlap
syndrome, in which features of chronic and acute GVHD
appear together. Clari�cation of the de�nition of the “over-
lap” subcategory of chronic GVHD is now provided to address
problems identi�ed when applying this terminology in
clinical practice [22]. The term “overlap” refers to the pres-
ence of 1 ormore acute GVHDmanifestation in a patient with
a diagnosis of chronic GVHD. Manifestations of acute GVHD
can be present at initial diagnosis of chronic GVHD or can
develop after the diagnosis of chronic GVHD and may recur
with or without resolution of prior chronic GVHD manifes-
tations. Findings indicating the overlap subcategory can be
transient, often depend on the degree of immunosuppres-
sion, and are subject to changes during the disease course.
Many patients who present with “overlap” chronic GVHD
resolve the acute features, whereas chronic GVHD features

M.H. Jagasia et al. / Biol Blood Marrow Transplant 21 (2015) 389e401398
persist. Similarly, patients with classic chronic GVHD may
develop acute GVHD features when immunosuppression is
The 2014 chronic GVHD consensus recommends docu-
mentation of all speci�c manifestations (acute and chronic)
when scoring organ severity at onset and at any time after
the diagnosis of chronic GVHD (Figure 1). Complete docu-
mentation of all involved organs provides a better descrip-
tion of the chronic GVHD syndrome and more detailed
information for prognostic and biologic studies, while
allowing retrospective con�rmation of the “overlap” desig-
nation rather than relying on clinicians to apply the appro-
priate de�nition. Speci�c manifestations are shown in
Figure 1 and are discussed below with reference to scoring.
For example, skin sclerosis and fasciitis manifestations have
been separated from BSA calculations that are more appli-
cable to other manifestations, such as erythema. Severity of
diarrhea has been added to the GI tract scoring. Liver scoring
was modi�ed to re�ect the biochemical liver abnormalities
that appear in early versus later (or more severe) phases of
In the absence of features ful�lling criteria for the diag-
nosis of chronic GVHD, the persistence, recurrence, or new
onset of characteristic skin, gastrointestinal tract, or liver
abnormalities should be classi�ed as acute GVHD regardless
of the time after transplantation. With appropriate strati�-
cation, however, patients with persistent, recurrent, or late
acute GVHD may be included in clinical trials together with
patients who have NIH chronic GVHD [5].
Modi�cations have been made to the 2005 consensus
organ scoring system based on available evidence, or lack
thereof, and to address concerns raised by investigators and
in clinical practice [22]. Figure 1 shows the consensus scoring
system for individual organs. Several considerations explain
the selection of features for the proposed scoring system
versus the response criteria discussed in a separate article.
First, scoring criteria are intended for baseline or cross-
sectional use, whereas response criteria are intended for
longitudinal evaluation in therapeutic trials. Second, in
general, scoring measures have been designed so that they
can be easily performed by general practitioners (non-
transplantation physicians and nurses). Two organ systems,
eyes and female genitalia (Supplemental Figure 1), are best
assessed by a specialist. By design, the only required labo-
ratory testing needed to complete the scoring table is mea-
surement of liver values. Lung scoring is preferentially
determined by PFTs, when available, but symptoms may be
substituted if PFT results are not available. Third, the broad
scoring categories help to classify patients and provide im-
mediate, clinically meaningful information summarizing
disease extent and severity. Fourth, the scoring system does
not attempt to distinguish between disease activity
(in�ammation and apoptosis of target cells) and �xed
anatomic de�cits from past tissue injury but now in-
corporates the attribution of abnormalities not due to
chronic GVHD. Fifth, the overall skin score is determined by
the higher subscore of the BSA and type of involvement.
Sixth, sites or organs with unequivocal documentation of
attribution other than GVHD cannot be evaluated and are not
included in computing the overall severity, but the data are
collected in the scoring form (Figure 1). For example, 12.5%
BSA skin rash entirely due to varicella zoster is scored as 1 for
skin, shortness of breath after walking on �at ground due to
lobar pneumonia is scored 2 for lung, FEV1 of 60% is scored 1
if it is unchanged from the pretransplantation FEV1 value,
but the box “Abnormality present but explained entirely by
non-GVHD documented cause” should be checked so the
organ can be excluded from global score calculation. We
anticipate that patients will often have multifactorial etiol-
ogies to explain abnormalities (eg, shortness of breath in a
patient with established BOS and now with worsening FEV1
due to superimposed viral bronchiolitis). In these instances,
the abnormality is scored as if the entire de�cit is due to
GVHD. This inherent limitation of the scoring system is un-
avoidable, until better quantitative tests are available to
ascertain abnormalities solely due to chronic GVHD.
Organs and sites to be scored include skin, mouth, eyes,
gastrointestinal tract, liver, lungs, joints and fascia, and the
genital tract. Each organ or site is scored according to a 4-
point scale (0 to 3), with 0 representing no involvement
and 3 re�ecting severe impairment. In addition, performance
status is captured on a 0 to 3 scale, and check boxes note the
presence or absence of other speci�c manifestations.
The current consensus document proposes changes to the
2005 consensus scoring system for some organs, as follows
(Figure 1):
Skin: The composite score is now split into 2 scores to
document the extent of skin involvement (BSA) and the
speci�c skin features, separately. Clinical features to be
considered in the skin scores have been clari�ed. The
higher of the 2 scores is to be used for computation of
global severity.
Mouth: Lichen planuselike features in asymptomatic
patients (score 0) are now incorporated.
Eye: KCS con�rmed by an ophthalmologist in an asymp-
tomatic patient (score 0) is now incorporated. Scoring
regarding the requirement of eye drops is clari�ed to
include only lubricant drops. Schirmer’s test values have
been removed from the scoring form.
GI: The severity of diarrhea is now incorporated as an
additional feature in the GI tract severity scoring system.
Weight loss due to gastrointestinal GVHD is captured
under the GI tract.
Genitalia: Scoring is now based on severity of the signs
instead of symptoms, based on limited available data
[29,31,35,36] and the opinions of experts (Supplemental
Figure 1 represents an exploratory measure to be
completed by specialists or trained practitioners). Female
or male genital GVHD is not scored if a practitioner is
unable to examine the patient.
Liver: Scoring is based on increments in values for total
serum bilirubin, alanine aminotransferase, and alkaline
phosphatase. Aspartate aminotransferase is no longer
considered for the scoring.
Lungs: Lung function score, which used both FEV1 and
diffusing capacity of the lung for carbon monoxide, was
simpli�ed to FEV1 values alone, thus improving speci-
�city. The rule for the �nal lung scoring has been changed
such that the FEV1 score should be used in cases with
discrepancy between symptoms and FEV1 scores.
Joint: Photographic-range of motion [23] has been added
to joint assessment as an exploratory measure but should
not be included in the calculation of global severity
(Figure 1).
Other indicators, clinical manifestations or complications
related to chronic GVHD have been simpli�ed. This in-
cludes the removal of progressive onset-type of chronic

approximately 40% of abnormalities in at least 1 organ were
unequivocally attributed to causes other than chronic GVHD,
resulting in a modest downgrade of global severity after the
confounder was taken into account [44]. As outlined previ-
ously, if the abnormality in an organ is multifactorial, the
organ is scored as if the entire de�cit is due to GVHD.
Symptomatic mild chronic GVHD may often be managed
with local therapies alone (eg, topical corticosteroids for the
skin involvement). In patients with chronic GVHD that in-
volves 3 or more organs or with a score of 2 or greater in any
single organ, however, systemic immunosuppressive therapy
should be considered. In some organ sites (mouth, eyes,
genital tract), aggressive local therapy alone may be
reasonable, as response to systemic therapy may be subop-
timal or may not warrant the risk of treatment. Comorbid-
ities and infections may also modify decisions regarding the
onset and intensity of therapy. Good medical practice and
judgment dictate �exibility in this recommendation.
Comprehensive monitoring for early detection of insidious
disease progression in other sites is essential
when management relies entirely on local therapy. Early
intervention with effective systemic therapy can prevent
If the entire abnormality in an organ is noted to be unequivocally
M.H. Jagasia et al. / Biol Blood Marrow Transplant 21 (2015) 389e401 399
GVHD, cardiomyopathy, cardiac conduction defects, and
coronary artery involvement. Weight loss (measured over
previous 3 months) due to causes other than GI tract
GVHD has been added (Figure 1).
The form shown in Figure 1 should be completed based on
an assessment of current statuswithout consideration of past
manifestations or the causes for the abnormality in each or-
gan. Abnormalitieswith unequivocal causes other thanGVHD
are annotated in scoring each organ or site. This change will
help to address some of the controversies and confusion
raised by investigators [22]. Furthermore, identi�cation of
abnormalities not due to GVHD will help in the selection of
patients for clinical trials and biomarker studies of chronic
GVHD. We realize that abnormalities may have multiple
causes. If GVHD represents a contributing cause, the organ
should be scored as if the entire abnormality is due to GVHD.
Fundamentals of the global scoring of chronic GVHD
remain unchanged from the 2005 NIH consensus criteria [4].
Several studies have shown that the 2005 NIH global severity
score at baseline predicts overall survival and nonrelapse
mortality [11,18,42] and some elements of the score have
been validated with patient-reported quality of life measures
Eight organs or sites (skin, mouth, eyes, gastrointestinal
tract, liver, lungs, joint and fascia, and genital tract) are
considered for calculating global score. Elements included in
the proposed global scoring include both the number of or-
gans or sites involved and the severity score within each
affected organ. Performance status scoring is not incorpo-
rated into the global scoring system. The global descriptions
of mild, moderate, and severe were chosen to re�ect 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. It is important to note that change in global
score over time is not synonymous with response. The global
scoring system can be applied only after the diagnosis of
chronic GVHD is con�rmed by either (1) 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. Table 2 outlines the
computation of the chronic GVHD global severity scoring,
which is categorized as mild, moderate, or severe.
The current consensus incorporates asymptomatic organ
manifestations (eg, asymptomatic oral chronic GVHD). These
do not affect the global scoring of chronic GVHD, because the
recorded score is still 0. Attribution of abnormalities to
causes other than chronic GVHD could have an impact on the
global scoring. For instance, if a patient has a score of � 1in
an organ and if the abnormality is explained entirely and
unequivocally by a non-GVHD cause, the organ is excluded
from calculation of the global severity. Documentation of
potential confounders in organ scoring (attribution due to
other causes than chronic GVHD) will correct any over-
estimation of organ involvement [11,42] and improve the
speci�city of the scoring system. These changes are sup-
ported by the results of a recent prospective study evaluating
the impact of confounders in the organ scoring and in the
global severity of chronic GVHD, and the study showed that
explained by a non-GVHD documented cause, that organ is not included
for calculation of the global severity.
If the abnormality in an organ is attributed to multifactorial causes
(GVHD plus other causes) the scored organ will be used for
calculation of the global severity regardless of the contributing
causes (no downgrading of organ severity score).
other agents can be added. Chronic GVHD itself and systemic
immunosuppressive therapy both impair immune defenses.
Therefore, patients should receive infection prevention
measures as outlined in the forthcoming Ancillary Therapy
and Supportive Care working group document.
Chronic GVHD is 1 of the major causes of late
transplantation-related mortality (TRM) after allogeneic
Table 2
NIH Global Severity of chronic GVHD
Mild chronic GVHD
1 or 2 Organs involved with no more than score 1 plus
Lung score 0
Moderate chronic GVHD
3 or More organs involved with no more than score 1
At least 1 organ (not lung) with a score of 2
Lung score 1
Severe chronic GVHD
At least 1 organ with a score of 3
Lung score of 2 or 3
Key points:
In skin: higher of the 2 scores to be used for calculating global severity.
In lung: FEV1 is used instead of clinical score for calculating global
progression to severe chronic GVHD. Effective immune-
modulating therapy can ameliorate clinical manifestations
and possibly prolong survival. In patients with newly diag-
nosed chronic GVHD who are already taking immune-
suppressive medications, the dosage may be increased or

Janine Clayton, National Eye Institute, NIH, Bethesda, MD,
Financial disclosure: The authors have nothing to disclose.
M.H. Jagasia et al. / Biol Blood Marrow Transplant 21 (2015) 389e401400
HCT. Prospective studies using the 2005 criteria have shown
that the skin score, lung score, and GI score each predict the
risk of TRM [8,10,16,42]. Previous studies have identi�ed
several factors associated with an increased risk of TRM
among patients with chronic GVHD, including involvement
of multiple organs or sites, decreased clinical performance
score, thrombocytopenia (platelet count <100,000/mL) at the
time of diagnosis, progressive onset of chronic GVHD from
prior acute GVHD (or onset of chronic GVHD during steroid
treatment), hyperbilirubinemia, a higher percentage of skin
involvement at the time of diagnosis, and others [5,14,25,45-
51]. Characteristics consistently associated with an increased
risk of late TRM among patients with chronic GVHD are
thrombocytopenia and progressive onset of chronic GVHD
from acute GVHD.
The consensus guidelines for assessment of chronic GVHD
severity summarized in this document can be used inmaking
decisions about treatment and enrollment in clinical trials.
The goals of treatment for chronic GVHD are to relieve
symptoms, control disease activity, and prevent damage and
disability. As a general rule, the intensity of treatment should
be calibrated to the extent and severity of disease manifes-
tations. Patients with mild or asymptomatic manifestations
limited to a single organ or site can often be managed with
close observation or topical treatment or by slowing the ta-
per of prophylactic immunosuppressive treatment. Those
with more severe manifestations or involvement of multiple
organs or sites typically require systemic treatment.
Although it is commonly assumed that systemic treatment
might improve survival, previous randomized trials have not
demonstrated such a bene�t, and some studies have shown
statistically signi�cant differences or trends indicating worse
survival with intensive immunosuppressive treatment.
Therefore, chronic GVHD should bemanagedwith the lowest
amount of treatment needed to control the disease until
immunological tolerance eventually emerges. Therapeutic
interventions that facilitate tolerance induction remain an
unmet clinical need.
This project was supported by the NIH’s National Cancer
Institute, Center for Cancer Research, Intramural Research
Program and Division of Cancer Treatment and Diagnosis,
Cancer Therapy Evaluation Program; Of�ce of Rare Disease
Research, National Center for Advancing Translational Sci-
ences; Eunice Kennedy Shriver National Institute of Child
Health and Human Development; Division of Allergy,
Immunology and Transplantation, National Institute of Al-
lergy and Infectious Diseases; National Heart, Lung, and
Blood Institute, Division of Blood Diseases and Resources.
This work was also supported in part by grants CA18029 and
CA118953 from the National Cancer Institute and the Na-
tional Institutes of Health. The authors want to acknowledge
the following individuals and organizations that, by their
participation, made this project possible: American Society
for Blood and Marrow Transplantation, Center for Interna-
tional Bone and Marrow Transplant Research, US Chronic
GVHD Consortium (supported by ORDR/NCATS and NCI),
German-Austrian-Swiss chronic GVHD Consortium, National
Marrow Donor Program, the Health Resources and Services
Administration, Division of Transplantation, US Department
of Human Health and Services, Canadian Blood and Marrow
Transplant Group, European Group for Blood and Marrow
Transplantation, Pediatric Blood and Marrow Transplant
Consortium, and the representatives of the Brazilian Chronic
Con�ict of interest statement: There are no con�icts of in-
terest to report.
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Members of this committee included Steven Pavletic,
Georgia Vogelsang, and Stephanie Lee (project chairs), Mary
Flowers and Madan Jagasia (diagnosis and staging), David
Kleiner and Howard Shulman (histopathology), Kirk Schultz
and Sophie Paczesny (biomarkers), Stephanie Lee and Steven
Pavletic (response criteria), Dan Couriel and Paul Carpenter
(ancillary and supportive care), Paul Martin and Corey Cutler
(design of clinical trials), Kenneth Cooke and David Miklos
(chronic GVHD biology), Roy Wu, William Merritt, Linda
Grif�th, Nancy DiFronzo, Myra Jacobs, Susan Stewart, and
Meredith Cowden (members).
M.H. Jagasia et al. / Biol Blood Marrow Transplant 21 (2015) 389e401401.e1