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How We Treat Chronic Graft-Versus-Host Disease

How We Treat Chronic Graft-Versus-Host Disease - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Questionnaires, Related

How I Treat
How we treat chronic graft-versus-host disease
Mary E. D. Flowers and Paul J. Martin
Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, WA
Chronic graft-versus-host disease (GVHD)
remains a common and potentially life-
threatening complication of allogeneic
hematopoietic stem cell transplantation
(HCT). The 2-year cumulative incidence of
chronic GVHD requiring systemic treat-
ment is∼30%to40%byNational Institutes
of Health criteria. The risk of chronic
GVHD is higher and the duration of treat-
ment is longer after HCT with mobilized
blood cells than with marrow cells. Clini-
cal manifestations can impair activities of
daily living and often linger for years.
Hematology and oncology specialists who
refer patients to centers for HCT are often
subsequently involved in the management
of chronic GVHD when patients return to
their care after HCT. Treatment of these
patients can be optimized under shared
care arrangements that enable referring
physicians to manage long-term admin-
istration of immunosuppressive medica-
tions and supportive care with guidance
from transplant center experts. Keys to
successful collaborative management
include early recognition in making the
diagnosis of chronic GVHD, comprehen-
sive evaluation at the onset and periodi-
cally during the course of the disease,
prompt institution of systemic and topical
treatment, appropriate monitoring of the
response, calibration of treatment in-
tensity over time in order to avoid over-
treatment or undertreatment, and the use
of supportive care to prevent complications
and disability. (Blood. 2015;125(4):606-615)
The prevalence and severity of chronic graft-versus-host disease
(GVHD) have increased during the past 2 decades in associationwith
the increasing use of hematopoietic stem cell transplantation (HCT)
for treatment of older age patients, the widespread use of mobilized
blood cells instead of marrow for grafting, and improvements in
survival during the �rst several months after allogeneic HCT.
Pathophysiological understanding of chronic GVHD is emerging,
but the long-standing reliance on prednisone described as the main-
stay of treatment in Vogelsang’s “How I Treat” review in 2001 has
The 2005 National Institutes of Health (NIH)
Consensus Conference developed a framework for characterizing
the pleomorphic manifestations of chronic GVHD. The consen-
sus project de�ned minimal criteria for the clinical diagnosis, em-
phasized differences in the clinical manifestations of chronic and
acute GVHD, established criteria for scoring the severity of clinical
manifestations in affected organs, and proposed new categories for
describing overall disease severity and indications for treatment.
The consensus project also proposed measures for monitoring dis-
ease progression and response to therapy and provided other infor-
mation for purposes of clinical trials.
In 2014, the NIH Conference
was reconvened, and revisions are under consideration to update the
recommendations based on available evidence and insights from
clinical application of the original recommendations.
Chronic GVHD has a wide range of pleomorphic manifestations,
and many complications can emerge from both the disease and its
treatment. A dedicated multidisciplinary team approach with rel-
evant expertise is necessary in order to provide the best care for
patients with a chronic illness that can have devastating effects on
quality of life. Our approach to treatment emphasizes the importance
of early recognition in the management of chronic GVHD, with
respect to making the initial diagnosis, monitoring the response to
initial treatment, and preventing complications and disability.
Nuances applicable only to children are not addressed in this review.
Case summary
A 45-year-old man received growth factor–mobilized blood cells
from an HLA-matched unrelated male donor after conditioning with
12 Gy total body irradiation and cyclophosphamide for treatment of
acute myeloid leukemia with persistent disease. He received meth-
otrexate and tacrolimus for immunosuppression after HCT. He
developed acute GVHD of the skin and gut, which resolved after
treatment with steroid cream and oral beclomethasone and budesonide.
Because malignant cells persisted after HCT, treatment was admin-
isteredwith azacytidine, and immunosuppressionwith tacrolimus
was withdrawn by day 100, 3 months earlier than originally planned.
Malignant cells disappeared, but 7 months after HCT and 2
months after the third cycle of azacytidine, he was diagnosed with
severe chronic GVHD (NIH global score). Affected sites included
the skin (erythematous rash involving.50% body surface area [BSA]),
mouth (ulcers and lichenoid features), fasciae (wrist tightness and leg
edema), liver (alanine aminotransferase twice the normal upper limit
with normal total serum bilirubin concentration), and eosinophilia
(1800 per mL). Forced expiratory volume in the �rst second (FEV1)
was 79% of predicted, and the ratio of FEV1 to forced vital capacity
(FVC) was 78% of predicted, representing an absolute 8% decline
from the baseline before HCT.
Treatment was started with prednisone at 1 mg/kg per day, and
antibiotic prophylaxis was administered to prevent Pneumocystis
pneumonia and infection with encapsulated bacteria. Antiviral pro-
phylaxis was continued with acyclovir. Daily intake of vitamin D
1000 IU and calcium 1500 mg was recommended. After 2 weeks,
improvement was noted in wrist discomfort, leg edema, and the
extent of rash, with resolution of eosinophilia and liver function
abnormalities. The dose of prednisone was tapered to reach 80 mg
every other day, with continued clinical monitoring and pulmonary
function tests (PFTs) at monthly intervals.
Submitted August 5, 2014; accepted November 6, 2014. Prepublished online
as Blood First Edition paper, November 14, 2014; DOI 10.1182/blood-2014-
The online version of this article contains a data supplement.
? 2015 by The American Society of Hematology
606 BLOOD, 22 JANUARY 2015 x VOLUME 125, NUMBER 4
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Table 1. Clinical manifestations of chronic GVHD
Organ or site
Diagnostic (sufficient
for diagnosis)
Distinctive (insufficient alone
for diagnosis) Other
Features seen in both acute
and chronic GVHD
Skin Poikiloderma Depigmentation Erythema
Lichen planus-like Papulosquamous Maculopapular
Sclerosis Pruritus
Lichen sclerosis-like
Nails Dystrophy
Nail loss
Pterygium unguis
Scalp and body hair Alopecia (scarring or
Mouth Lichen planus-like Xerostomia Gingivitis
Mucoceles Mucositis
Mucosal atrophy Erythema
or ulcers*
Eyes New dry, gritty, or painful
eyes (sicca)
Keratoconjunctivitis sicca
Punctate keratopathy
Genitalia Lichen planus-like Erosions*
Lichen sclerosis-like Fissures*
Female: Ulcers*
Vagina scarring
or stenosis
Clitoral or labial
Urethral scarring
or stenosis
GI tract Esophageal web Diarrhea
Esophageal stricture Anorexia
Nausea or emesis
Failure to thrive
Weight loss
Liver Total bilirubin, alkaline phospha-
tase or ALT .23 ULN
Lung Bronchiolitis obliterans
diagnosed by biopsy BOS§
Cryptogenic organizing
Restrictive lung disease†
Muscles, fascia,
Fasciitis Myositis
Joint stiffness or
contractures due
to sclerosis
and Immune
Hypo- or hypergamma-
Raynaud phenomenon
Others Effusions‡
Nephrotic syndrome
Myasthenia gravis
Peripheral neuropathy
Modified from Stem Cell Trialists’ Collaborative Group.
ALT, alanine aminotransferase; BOS, bronchiolitis obliterans syndrome; GI, gastrointestinal; ULN, upper limit of normal.
*In all cases infection, drug effect, malignancy, endocrine causes must be excluded as applicable.
†These pulmonary manifestations are under investigation or unclassified.
‡Pericardium, pleural, or ascites.
§BOS can be diagnostic for lung chronic GVHD only, if distinctive feature present in another site.
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During the next 3 months, PFTs improved, but other manifes-
tations showed progressive worsening, with cutaneous sclerosis
involving;28% of the BSAwith a Rodnanmodi�ed total score
8, oral ulceration, and decreased wrist mobility. The patient enrolled
in a randomized clinical trial comparing imatinib vs rituximab for
steroid-refractory sclerotic GVHD. He was randomized to treatment
with imatinib (200 mg daily) while continuing treatment with pred-
nisone 80 mg every other day. Dexamethasone oral rinses and
clobetasol ointment were used to control oral ulceration.
The extent and severity of sclerosis remained stable for 3 months.
Sclerosis then began to progress, involving ;50% of BSA with a
Rodnan score of 28 after 6 months of treatment with imatinib. The
patient met the criteria for crossover according to the study design,
and he was treated with 2 cycles of rituximab, 375 mg/m
per week for
4 weeks per cycle. Due to hypertension and hyperglycemia, the dose
of prednisone was gradually tapered to 40 mg every other day within
6 months. The patient subsequently reported improved �exibility, and
after 7 months, sclerosis remained stable with a Rodnan score of 26.
Elevenmonths after the last dose of rituximab, fasciitis progressed
with further decrease in range of motion while continuing treatment
with prednisone at 40 mg every other day. Extracorporeal photo-
pheresis (ECP)
(reviewed in Inamoto and Flowers
), low-dose
interleukin-2 (IL-2),
and sirolimus were considered as possible
further treatment. The patient opted for daily low-dose IL-2, but he
had signi�cant local reactions, low-grade fever, and no appreciable
improvement in GVHD. Three months after treatment with IL-2
was discontinued, he developed a new erythematous maculopapular
rash affecting 50% of BSA. The dose of prednisone was increased
to 40 mg per day, and sirolimus was added. The rash subsequently
improved, but sclerosis and fasciitis continued to worsen, prompting
treatment with ECP for the past 3 months. Ef�cacy cannot yet be
assessed because improvement is often not observed until treatment
with ECP has been continued for at least 6 months.
Recent laboratory studies have yielded some insights into the
pathophysiology of chronic GVHD, and candidate biomarkers that
could be used for diagnosis or monitoring have been identi�ed.
The disease likely represents a syndrome in which the respective
contributions of in�ammation, innate and adaptive cell-mediated
immunity, humoral immunity, abnormal immune regulation, and
�brosis vary considerably from 1 patient to the next. The risk of
chronic GVHD can be substantially decreased by administration of
rabbit anti-thymocyte globulin or alemtuzumab in the condition-
ing regimen before HCT,
or by administration of high-dose
cyclophosphamide on days 3 and 4 after HCT.
These results
demonstrate that the pathophysiological mechanisms leading
to development of chronic GVHD are set in motion at the time of
HCT, even though the manifestations of the disease typically do
not become apparent until several months later.
Animal models that replicate many features of the disease have
been established, but mechanisms linking in�ammation with abnormal
immune regulation andmechanisms linking immune-mediated injury
Figure 1. The frequency of involvement by chronic
GVHD varies across organs and sites and is higher
after HCT with mobilized blood cells as compared
with marrow. (A) The most frequently involved organs
and sites are the skin, mouth, eyes, gastrointestinal
tract, and liver.
(B) Chronic GVHD can affect all layers
of the skin. Photographs of each manifestation in italic
may be found in the supplemental Data, available on
the Blood Website.ArtworkbyDelilahCohn,MFA,
CMI, used with permission.
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with�brosis have not beenwell de�ned. In the absence of a de�nitive
understanding of the pathophysiological mechanisms or clear expla-
nation accounting for the considerable variability of disease man-
ifestations among patients, efforts to develop new treatment have
relied on empirical testing of agents approved for other indications
where in�ammation, abnormal immune regulation, or �brosis have
been implicated as pathogenic mechanisms.
Diagnosis and evaluation
Manifestations of chronic GVHDcan resemble autoimmune or other
immune-mediated disorders such as scleroderma, Sjo¨gren syn-
drome, primary biliary cirrhosis, bronchiolitis obliterans, immune
cytopenias, and chronic immunode�ciency.Manifestations typically
appear within the �rst year after HCT, most often when doses of
immunosuppressive medications are weaned. The disease can begin
as early as 2 months and as late as 7 years after HCT, although onset
at .1 year from HCT occurs in ,10% of cases.
Chronic GVHD
should be suspected at the onset of any perturbation in laboratory
tests, symptoms, or signs, especially during the �rst year after HCT.
Conversely, not every problem after allogeneic HCT represents
chronic GVHD. Other conditions such as eczema, iron overload,
hypothyroidism, adrenal insuf�ciency, infections, or drug effect can
be misdiagnosed as chronic GVHD.
Chronic GVHD generally involves several organs or sites, al-
though manifestations are sometimes restricted to a single organ or
site. The disease is characterized by features that differ from the typical
dermatitis, enteritis, and cholestatic liver manifestations of acute
GVHD (Table 1).
Patients frequently have erythematous rash,
enteritis, or hepatic involvement characterized by transaminase
elevation or hyperbilirubinemia at initial presentation and inter-
mittently afterward during the course of the disease. The term “overlap
syndrome” has been used to indicate that manifestations typical
of acute GVHD are present in a patient with chronic GVHD.
These in�ammatory manifestations are often transient, disappearing
when the intensity of immunosuppression is increased and reappearing
when the intensity of immunosuppression is tapered. According to
NIH criteria, the diagnosis of chronic GVHD requires at least 1
Table 2. Evaluation and frequency of monitoring according symptoms or affected organs
Frequency of evaluation/monitoring
Manifestations present Manifestations absent
Review of systems (see Table 3 for chronic
GVHD-specific questions)
Every clinic visit Every clinic visit
Physical examination
Complete skin examination (look, touch, pinch) Every clinic visit Every clinic visit
Oral examination Every clinic visit Every clinic visit
Range of motion assessment Every clinic visit Every clinic visit
Performance score Every clinic visit Every clinic visit
Nurse assessment
Weight Every clinic visit Every clinic visit
Height/adults Yearly Yearly
Height/children Every 3-12 mo Every 3-12 mo
Medical photographs ;100 d after HCT (baseline), at initial diagnosis of
chronic GVHD, every 6 mo if skin or joints are
involved and during treatment until at least 1 y
after discontinuation of treatment
;100 d after HCT (baseline)
Other evaluations
PFTs ;100 d after HCT (baseline); see also Table 4 ;100 d after HCT and every 3 mo for the first year,
then yearly if previous PFTs were abnormal or if
continuing systemic treatment; reassess at
onset of new symptoms
Nutritional assessment As clinically indicated and yearly if receiving
As clinically indicated
Physiotherapy with assessment of range of
Every 3 mo if sclerotic features affecting range of
motion until resolution
As clinically indicated
Dental or oral medicine consultation with
comprehensive soft and hard tissue
examination, culture, biopsy, or photographs
of lesions, as clinically indicated
Every 3-6 mo or more often as indicated Yearly
Ophthalmology consultation with Schirmer test,
slit-lamp examination, and intraocular
At initial diagnosis and every 3-6 mo or more often
as indicated
;100 d after HCT (baseline) and yearly
Gynecology examination for vulvar or vaginal
Every 6 mo or more often as indicated Yearly
Dermatology consultation with assessment of
extent and type of skin involvement, biopsy, or
As clinically indicated
Neuropsychological testing As clinically indicated
Bone mineral assessment (DEXA) scan Yearly during corticosteroid treatment or if prior
test was abnormal
;100 d after HCT if continuing corticosteroid
treatment (baseline)
Modified from Flowers and Vogelsang.
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diagnostic sign or at least 1 distinctive sign con�rmed by biopsy,
other tests, or by radiography in the same or another organ, and
exclusion of other diagnoses (Table 1).
Manifestations of chronic
GVHD have a wide range of severity and impact on quality of life
after HCT. Certain manifestations are particularly dif�cult to
manage and require prolonged treatment. These include fasciitis or
cutaneous sclerosis, severe ocular sicca, and BOS, occurring in
and about 10%
of patients, respectively. The
most commonorgans and sites affectedby chronicGVHDinclude
the skin, mouth, eyes, gastrointestinal tract, and liver (Figure 1).
Systematic and comprehensive assessment of organs and sites
possibly affected by chronic GVHD is essential for early diagnosis,
early recognition of manifestations associated with high morbidity
and disability, and assessment of disease progression and response
during treatment (Tables 2-3). Once the clinical diagnosis of chronic
GVHD is made, the extent and severity of each affected organ must
be ascertained using the NIH chronic GVHD diagnosis and scoring
consensus criteria.
Recommended methods for conducting a chronic
GVHD-focused evaluation have beenpublished
(they can be viewed
at http://www.fhcrc.org/en/labs/clinical/projects/gvhd.html).
prehensive evaluations should be done at the time of initial diagnosis,
at 3- to 6-month intervals thereafter, and at any timewhen amajor
change in therapy is made. Evaluations should continue until at least
12 months after systemic treatment has ended.
Close serialmonitoring of all organ systems is essential in order to
ensure early detection, recognition, and intervention directed toward
reversing or preventing progression of chronic GVHD manifes-
tations and treatment-associated toxicities. In particular, periodic
pulmonary function tests are essential for early detection of lung
involvement manifested as BOS because this complication has
an insidious onset, and patients may remain asymptomatic until
considerable lung function has been lost. We recommend complete
pulmonary function testing in all patients before HCT and at ;3
months after HCT as a baseline for future comparisons (Table 4).
Follow-up testing should be done at the onset of chronic GVHD and
at 3- to 6-month intervals for the �rst year or more often if testing
shows any signi�cant new air�ow obstruction or decline in the per-
cent of predicted FEV1. Patient and physician-directed tools to sup-
port chronicGVHDmonitoringcanbe foundonline (http://www.fhcrc.
Treatment of chronic GVHD is intended to produce a sustained
bene�t by reducing symptom burden, controlling objective mani-
festations of disease activity, and preventing damage and disability,
without causing disproportionate toxicity or harms related to the
treatments themselves. The long-term goal of GVHD treatment is
the development of immunologic tolerance, indicated by successful
withdrawal of all immunosuppressive treatment without recurrence
or clinically signi�cant exacerbation of disease manifestations. The
current therapeutic approach functions primarily to prevent immune-
mediated damage, while awaiting the development of tolerance.
Evidence to suggest that current treatments accelerate the devel-
opment of immunologic tolerance is lacking. Optimal treatment
of chronic GVHD requires a multidisciplinary team approach that
includes transplantation specialists, a primary health care provider,
organ-speci�c consultants, nurses, and ancillary services such as
social services, vocational specialists, patient and family support
groups, and systems.
Systemic therapy for at least 1 year is generally indicated for
patients who meet criteria for moderate-to-severe disease according
to the NIH consensus criteria: involvement of 3 or more organs,
moderate or severe organ involvement in any organ, or any lung
Systemic treatment is also generally indicated
for patients with less severe disease if high-risk features such as
thrombocytopenia, hyperbilirubinemia, or onset during corticoste-
roid treatment are present.
Symptomatic mild chronic GVHD
is often treated with topical therapies alone.
Topical agents may
also be used as adjuncts to systemic therapy to improve and accel-
erate local response. Comprehensive reviews of topical therapies
have been published previously.
Considerations affecting the
choice of treatment include the affected organs or sites, the severity
of diseasemanifestations, the presence of health problems that might
be exacerbated by the treatment, possible drug interactions, the
intensity of themonitoring needed, and factors that affect access to
the treatment such as travel, distance, and cost.
Primary systemic treatment
Management of chronic GVHD has relied on corticosteroids as the
mainstay of treatment of .3 decades. Systemic treatment typically
begins with prednisone at 0.5 to 1mg/kg per day, followed by a taper
to reach an alternate-day regimen, with or without cyclosporine or
tacrolimus. The ef�cacy of alternate-day vs daily administration of
corticosteroids has been reported in pediatric renal transplantation
but has not been tested in HCT.
Prolonged systemic corticosteroid
treatment causes signi�cant toxicity, including weight gain, bone
loss, myopathy, diabetes, hypertension, mood swings, cataract for-
mation, and increased risk of infection.Many of these toxicities can be
mitigated by alternate-day administrationof corticosteroids.Alternate-
day administration also has an important role in facilitating adrenal
recovery long before the end of treatment. In a recent prospective
study, the average dose of prednisonewas tapered to 0.20 to 0.25mg/kg
Table 3. Chronic GVHD review of systems
No. System/others Inquire/description
1 Skin Skin feels tight or hard, increased dryness, pruritus, or looks different (ie, new rash, papules, discoloration, shining scar-like, scaly)?
2 Sweat glands Inability to sweat or to keep body warm?
3 Skin appendages Loss of hair (scalp or body including bows or lashes), or nail changes (ridges or brittle, loss)?
4 Fasciae/joints Stiffness or pain in the wrists, fingers, or other joints?
5 Eyes Eye dryness, sensitivity to wind or dry environments (air conditioning), pain?
6 Mouth Oral dryness, taste alterations, sensitivities (spicy/carbonate drinks, toothpaste), ulcers/sores, pain?
7 Esophagus Foods or pills gets stuck upon swallowing?
8 Lungs Cough, dyspnea (on exertion or rest) or wheezes?
9 Genital tract Vaginal dryness, pain, dyspareunia (female); pain or dysuria due to stenosis of urethra (male)?
10 Weight loss Unexplained weight loss or inability to gain weight (pancreatic insufficiency or hypercatabolism)?
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per day or 0.4 to 0.5 mg/kg every other day within 3 months after
starting treatment.
Medications used for treatment of chronicGVHD
should be withdrawn gradually one at a time after the disease has
resolved. As a general principle, withdrawal of systemic treatment
should beginwith themedication that ismost likely to cause long-term
toxicity.Withdrawal of prednisone should generally precedewithdrawal
of a calcineurin inhibitor, unless continued treatmentwith the calcineurin
inhibitor threatens to cause intolerable or irreversible toxicity.
Strategies for tapering the dose of prednisone vary considerably,
but as a general principle, efforts should bemade to use theminimum
dose that is suf�cient to control GVHD manifestations (Figure 2).
In practice, this means that prednisone doses should be decreased
progressively in patients who have had a complete response or a
very-good-partial response, and tapering should continue until man-
ifestations begin to recur or show evidence of exacerbation. A pro-
totypic taper schedule (Table 5) is designed to approximate a 20% to
30%dose reduction every 2weeks,with smaller absolute decrements
toward the end of the taper schedule. Toxicity associated with the
administration of prednisone may require dose adjustments.
A physician or advanced practitioner should examine the patient
before each reduction of the prednisone dose. If exacerbation or
recurrence of chronic GVHD is evident at any step of the taper, the dose
of prednisone should be increased promptly by 2 levels, with daily
administration for 2 to 4weeks, followed by resumption of alternate-day
administration. Treatment should then be continued for at least 3months
before attempting to resume the taper. Cycles of attempted tapering and
dose escalation should be repeated as needed until the dose reaches
0.10 mg/kg per day, which equates to adrenal replacement therapy.
Administration of prednisone may be discontinued after a minimum
of at least 4 weeks of treatment at a dose of 0.10 mg/kg every other
day. Some patients have recurrent symptoms with doses at or below
0.10 mg/kg every other day, and in this situation, treatment with
very low prednisone doses may be required for a year or more.
Combination therapy with other immunosuppressive agents is
often considered in hopes of minimizing toxicity caused by pro-
longed corticosteroid treatment.
Randomized trials, however, showed
no bene�t from adding azathioprine,
late mofetil,
or hydroxychloroquine
to initial treatment of chronic
GVHD. A trial comparing cyclosporine plus prednisone vs pred-
nisone alone showed no statistically signi�cant differences in sur-
vival or the duration of treatment.
The incidence of avascular necrosis
was lower in the cyclosporine plus prednisone arm, suggesting that
cyclosporine could have had a steroid-sparing effect, but steroid
doses across time were not measured in this study. Results are
pending from a recent randomized, multicenter phase 2 to 3 clinical
trial comparing prednisone and sirolimus with or without a calci-
neurin inhibitor for initial treatment of chronic GVHD. Premature
closure of this trial at the end of phase 2 suggests that the expected
bene�t of omitting the calcineurin inhibitor was not observed.
Wherever possible, clinical trials should be considered as the �rst
option for initial systemic treatment of chronic GVHD.
Secondary systemic treatment
Approximately 50% to 60% of patients with chronic GVHD require
secondary treatment within 2 years after initial systemic treatment.
Indications for secondary treatment include worsening manifes-
tations of chronic GVHD in a previously affected organ, devel-
opment of signs and symptoms of chronic GVHD in a previously
unaffected organ, absence of improvement after 1 month of standard
primary treatment, inability to decrease prednisone below 1 mg/kg
per day within 2 months, or signi�cant treatment-related toxicity. Nu-
merous clinical trials have been carried out to evaluate approaches for
secondary treatment of chronic GVHD. Reports from retrospective
and prospective studies often indicate high response rates, but results
are dif�cult to interpret because of de�ciencies in study design.
No consensus has been reached regarding the optimal choice of
agents for secondary treatment of chronic GVHD, and the published
Table 4. General guidelines for monitoring and management of new
airflow obstruction
A. Significant new airflow obstruction with a % predicted FEV1 $70%
1. Initiate inhaled corticosteroid therapy
? Fluticasone (Flovent) 440 mcg BID, or
? Advair 500/50 mcg BID (if symptoms of airway obstruction are present)
? Treatment should continue until either % FEV1 becomes ,70% (see below),
or until GVHD resolves (ie, resolution of all reversible manifestations of GVHD
without exacerbation after at least 6 mo after discontinuation of all systemic
immunosuppressive treatment)
2. Other immunosuppressive treatment as indicated to control GVHD in other
? Treatment should continue until either % FEV1 becomes ,70% (see below),
or until GVHD resolves (ie, resolution of all reversible manifestation of GVHD
without exacerbation after at least 12 mo after discontinuation of all systemic
3. Monitor PFTs or spirometry monthly for at least 3 mo
? If % FEV1 stabilizes, PFTs or spirometry every 3 mo for 1 y, then if stable
continue at 6-mo intervals for 1 y and at 6-12 mo intervals thereafter
? If % FEV1 continues to decrease, go to B below
B. Significant airflow obstruction with a % FEV1 ,70% with/without significant air-
trapping by high resolution chest CT
1. Consider bronchoscopy to rule out an undetected infectious etiology for airflow
obstruction, even if no infiltrate is apparent
2. After infection has been ruled out, evaluate the patient eligibility for clinical trial
for treatment of BOS and initiate (or increase) prednisone dose to 1 mg/kg/d
? Start standard chronic GVHD taper at 2 wk (Table 5)
? Consider continuing inhaled corticosteroids throughout prednisone therapy
3. If % FEV1 decreases further to ,70% during treatment, discuss changes of
immunosuppressive treatment with transplant physician
4. CMV monitoring in blood per standard practice
5. Monitor PFTs or spirometry monthly for at least 3 mo
? If % FEV1 stabilizes, continue PFTs or spirometry every 3 mo for 1 y
? If % FEV1 continues to decrease, go to C below
C. Corticosteroid-resistant airflow obstruction defined as progressive decline of
FEV1 by $10% despite treatment with 1 mg/kg/d of prednisone (or similar
1. May consider increasing the dose of prednisone to 2 mg/kg/d for a maximum of
2 wk, followed by a taper to reach a dose of 1 mg/kg/d by 2-4 wk
2. Another treatment must be considered and discussed with the transplant team
3. Monitor CMV in blood per standard practice
4. Monitor PFTs monthly for at least 3 mo
? If % FEV1 stabilizes, monitor PFTs every 3 mo for 1 y
D. Additional considerations
1. Consider changing prophylaxis for encapsulated bacterial infection to
azithromycin 250 mg on Mondays-Wednesdays-Fridays
? Assure patient is receiving adequate prophylaxis for Pneumocystis, varicella
virus, and herpes simplex virus infections
? Fungal prophylaxis per standard practice
2. Monitor CMV in blood per standard practice
3. May continue inhaled corticosteroids throughout prednisone therapy
4. Discontinuation of inhaled corticosteroid treatment can be considered 12 mo
after treatment with prednisone has been discontinued
Before considering treatment, all potential infectious etiologies of airflow obstruction
must be investigated and treated if present. Investigations that should be considered
(directed by clinical symptoms), include sinus CT scan, nasal washes, sinus aspiration,
high-resolution chest CT scan, sputum culture, bronchoalveolar lavage, and lung biopsy.
BID, twice daily; CT, computed tomography scan.
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literature provides little useful guidance. Therefore, clinical man-
agement requires an empirical approach, as illustrated in “Case
summary.”Treatment choices are based on physician experience, ease
of use, need for monitoring, risk of toxicity, and potential exacerba-
tion of preexisting comorbidity.
Options for secondary treatment
have been recently reviewed and are summarized in Table 6.
Ancillary and supportive care
Ancillary and supportive care therapies are commonly used in
addition to systemic treatment of GVHD, although in some cases,
their use may circumvent the need for systemic treatment or allow
doses of systemic agents to be reduced. A detailed list of site-speci�c
therapies has been reported elsewhere.
Speci�c dispensary in-
formation for topical therapies is available online (http://asbmt.
Symptoms caused by ocular sicca can be relieved by the frequent
application of arti�cial lubricant tears or by plugging or ligation of
the tear ducts. Symptoms can be relieved by using specializedmoisture-
chamber eyewear available from several vendors. Permanent punctal
ligation is usually necessary in more severe cases of ocular sicca. Many
patients with severe sicca keratitis have reported signi�cant relief of
symptoms with prosthetic replacement of the ocular surface ecosystem
(PROSE), which refers to a gas-permeable scleral lens.
of an ophthalmologist with expertise in the management of dry eye and
corneal and conjunctival disease is strongly recommended for patients
with ocular manifestations of chronic GVHD.
Oral cavity erythema, ulceration, and gingivitis are often treated
with topical steroid rinses or ointments.Vaginal GVHDmay respond
to topical steroids and dilator therapy, but management should also
address any coexisting estrogen de�ciency or coexisting yeast or
bacterial infection. Sialogogue therapy (to increase the �ow rate of
saliva) with agents such as cevimeline or pilocarpine may improve
symptoms of oral,
ocular, and vaginal dryness.
Consistent weight-bearing exercise for 30 minutes daily at least
5 days per week and daily stretching are particularly important for
preserving bone health, muscle strength, and mobility. Physical
therapy to maintain strength and joint mobility can prevent the
development of disability during immunosuppressive treatment of
chronic GVHD. Deep tissue massage is a helpful adjunct to preserve
or improve range of motion in patients with fasciitis or scleroderma.
Close attention must be paid to complications of glucocorticoid
treatment through management of hyperglycemia, hypertension,
and bone loss. A balanced, healthy diet low in sodium and free sugars
and high in calcium with adequate �uid intake is essential. Calcium
(1500 mg per day) and vitamin D (1000 IU per day) intake between
food and supplements is recommended to retard the development of
osteoporosis during glucocorticoid treatment. Clinical trials have
not yet been carried out to determinewhether bisphosphonates are
effective for prevention of glucocorticoid-induced osteoporosis, but
some experts recommend the use of these agents for patients with
Both the disease and its treatment with immunosuppressive
agents increase the riskof infection inpatientswith chronicGVHD.
Antibiotic prophylaxis for Pneumocystis pneumonia and encapsulated
bacterial infections should be given until 6 months after discontinua-
tion of all systemic treatment. IV administration of g globulin may help
prevent infection in patients who have serum immunoglobulin G (IgG)
concentrations ,400 mg/dL or IgG2 or IgG4 subclass de�ciencies.
Cytomegalovirus (CMV) infection poses risks of CMV disease in
patients with a history of viral reactivation and in those with low CD4
counts or cord blood donors. All patients with chronic GVHD
who are at risk of CMV infection should have regular blood tests
for surveillance of viral reactivation. Preemptive antiviral therapy
should be instituted whenever surveillance tests show viral re-
activation, before the onset of overt CMVdisease. CMV-seronegative
recipients with CMV-seronegative donors should receive screened or
�ltered leukocyte-depletedbloodproducts. In addition, long-term
administration of valacyclovir or acyclovir is recommended to
prevent reactivation of varicella-zoster virus in patients previously
infected with this virus.
Prognosis and outcomes
Duration of treatment
Approximately 50%of patients are curedwithin 7 years after starting
systemic treatment, as indicated by resolution of disease manifes-
tations and permanent withdrawal of systemic treatment. Approx-
imately 10% require continued systemic treatment of an inde�nite
Figure 2. Appropriate management of chronic GVHD requires continuous re-
calibration of immunosuppressive treatment in order to avoid overtreatment
or undertreatment. The intensity of treatment required to control the disease de-
creases across time. Manifestations of chronic GVHD improve or are absent when
the intensity of treatment is above the threshold shown as the orange curve, and they
worsen or recur when the intensity of treatment is below the threshold. The slope of
the threshold varies among patients and can be determined only by serial attempts
to decrease the intensity of treatment. Clinical tolerance is defined by the ability to
withdraw all systemic treatment without recurrence of chronic GVHD.
Table 5. Prednisone taper schedule
Week Dose, mg/kg body weight
2 1.0/0.5* (to begin within 2 wk after objective improvement)
4 1.0/0.25*
6 1.0 qod (continued until resolution of all clinical manifestations)
8 0.70 qod (to begin after resolution of all clinical manifestations)
10 0.55 qod
12 0.45 qod
14 0.35 qod
16 0.25 qod
18 0.20 qod
20 0.15 qod
22 0.10 qod
qod, every other day.
*Alternate-day administration.
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period beyond 7 years, and the remaining 40% have recurrent ma-
lignancy or die within 7 years during treatment of chronic GVHD.
Growth factor–mobilized apheresis products have replaced
marrow as the most frequent source of cells for allogeneic HCT with
both related and unrelated donors. The use of mobilized blood cells
has been associated with 3 detrimental outcomes with respect to
chronic GVHD: a higher incidence, a higher risk of fasciitis and
development of �brotic manifestations affecting the skin and joints,
and a longer time to resolution of the disease, development of im-
munologic tolerance, and withdrawal of systemic treatment.
median duration of systemic treatment of chronic GVHD is;2 years
in patients who had HCT with marrow cells and;3.5 years in those
who had HCT with mobilized blood cells.
Graft-versus-leukemia associated with chronic GVHD
Chronic GVHD is associated with a reduced risk of recurrent
malignancy after hematopoietic cell transplantation, raising the
question of whether the intensity of immunosuppression should be
attenuated when patients at high risk of recurrent malignancy
develop chronic GVHD. This question has not been addressed
directly in clinical trials, but several observations are pertinent.
First, chronic GVHD increases the risk of nonrelapse mortality,
thereby offsetting any bene�t gained through the effects on
malignant cells in the recipient. The tradeoff between risks of
nonrelapse mortality and recurrent malignancy is balanced, such
that mortality rates are not affected by the presence or absence of
chronic GVHD.
Second, a single-institution study showed that
withdrawal of immunosuppression decreased the subsequent risk of
recurrent malignancy in patients without prior GVHD but not in
those with prior GVHD.
These results suggest that attenuation of immunosuppression in
patients with active manifestations of chronic GVHD might like-
wise not decrease the risk of recurrent malignancy. Nonetheless,
unnecessary immunosuppressive treatment could increase the risk
of recurrent malignancy, as suggested by trends in a prospective
study evaluating the use of mycophenolate mofetil added to �rst-
line treatment of chronic GVHD.
Therefore, the intensity of
treatment should be calibrated periodically by lowering the dose
of immunosuppressive medications to levels that allow disease
manifestations to begin emerging before increasing the dose, as
Future perspectives
Participation in a clinical trial represents the �rst option to consider
for eligible patients with chronic GVHD. Novel strategies directed
toward depleting or modulating B cells, expanding T or B regulatory
cells, and targeting the processes implicated in �brosis are under
active investigation and could lead to future advances in treatment of
chronic GVHD. Progress toward decreasing the impact of chronic
GVHD after HCTwill bemade not only through improved treatment
but also through development of prevention strategies that do not
impair the immunological activity of donor cells against malignant
cells in the recipient. In the absence of speci�c interventions to
decrease the risk of chronic GVHD, marrow should be preferred over
mobilized blood as a source of stem cells for HCTwithmyeloablative
conditioning regimens.
The authors thank Anne Thompson for assistance with preparing the
manuscript and Kevin Bray for assistance with hyperlinks.
This work was supported in part by grant CA18029 from the
National Cancer Institute at the National Institutes of Health.
Contribution: M.E.D.F. and P.J.M. wrote the manuscript.
Con�ict-of-interest disclosure: The authors declare no competing
�nancial interests.
Correspondence: Mary E. D. Flowers, Fred Hutchinson Cancer
Research Center, 1100 Fairview Ave N, D5-290, PO Box 19024,
Seattle, WA 98109-1024; e-mail: m�owers@fredhutch.org.
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Table 6. Agents used for secondary treatment of chronic GVHD*
Treatment % Overall response* Survival
ECP 65-70 70%-78% at 1 y
Rituximab 66-86 72% at 1 y
Imatinib 22-79 75%-84% at 1.5 y
Pentostatin 53-56 34%-60% at 1-3 y
Mesenchymal stem cells 50-74 78% at 2 y
Mycophenolate mofetil 26-64 67%-96% at 1 y
mTOR inhibitor 76 72% at 3 y
Interleukin-2 52 Not reported
Other therapies summarized in other reviews**
Calcineurin inhibitor
High-dose methylprednisolone
Thoracoabdominal irradiation
mTOR, mammalian target of rapamycin.
*Simplified from Inamoto and Flowers
; see Flowers et al,
Wolff et al,
Flowers and Deeg
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**20%-82% overall response rates reported.
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online November 14, 2014
originally publisheddoi:10.1182/blood-2014-08-551994
2015 125: 606-615

Mary E. D. Flowers and Paul J. Martin

How we treat chronic graft-versus-host disease

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