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Chronic Graft versus Host Disease Diagnosis and Treatment – Adult – Inpatient/Ambulatory

Chronic Graft versus Host Disease Diagnosis and Treatment – Adult – Inpatient/Ambulatory - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Oncology


1
Chronic Graft-Versus-Host Disease
Diagnosis and Treatment
Adult – Inpatient/Ambulatory
Clinical Practice Guideline
Note: Active Table of Contents – Click to follow link
EXECUTIVE SUMMARY ........................................................................................................... 3
SCOPE ................................................................................................................................... 4
METHODOLOGY .................................................................................................................... 5
DEFINITIONS.......................................................................................................................... 5
INTRODUCTION ..................................................................................................................... 6
RECOMMENDATIONS ............................................................................................................ 6
SCREENING FOR cGVHD ........................................................................................................... 6
DIAGNOSIS AND STAGING OF cGVHD ..................................................................................... 7
TREATMENT FOR cGVHD ....................................................................................................... 11
SUPPORTIVE CARE THERAPIES FOR cGVHD ........................................................................... 21
PHYSICAL FITNESS REHABILITATION FOR cGVHD .................................................................. 24
RESPONSE ASSESSMENT ........................................................................................................ 24
QUALITY OF LIFE/ PATIENT REPORTED OUTCOMES MEASUREMENT ................................... 25
UW HEALTH IMPLEMENTATION ........................................................................................... 26
APPENDIX A. EVIDENCE GRADING SCHEME(S) ...................................................................... 28
REFERENCES ........................................................................................................................ 29
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Contact for Content:
Name: Mark Juckett, MD ±Medicine- Hematology/Oncology
Phone Number: (608) 265-4363
Email Address: mbj@medicine.wisc.edu
Name: Walter Longo, MD ±Medicine- Hematology/Oncology
Phone Number: (608) 265-8690
Email Address: wll@medicine.wisc.edu
Contact for Changes:
Name: Lindsey Spencer, MS ± Center for Clinical Knowledge Management (CCKM)
Phone Number: (608) 890-6403
Email Address: lspencer2@uwhealth.org
Coordinating Team Members:
Linda Eckstein, NP ± Bone Marrow Transplant
Blythe Gage, NP ± Bone Marrow Transplant
Amanda Swiecichowski- RN, BSN, CHPN ± Bone Marrow Transplant
Bethaney Campbell, MN, RN, AOCNS ± Bone Marrow Transplant
Mary Mably, RPh, BCOP - Pharmacy
Sara Koth, PharmD ± Pharmacy
Sara Shull, PharmD, BCPS ± Drug Policy Program
Chris Nemergut, PharmD ± Center for Clinical Knowledge Management (CCKM)
Kris Hahn, PharmD ± Center for Clinical Knowledge Management (CCKM)
Deb Dunham, RPh ± Center for Clinical Knowledge Management (CCKM)
Review Individuals/Bodies:
Bone Marrow Transplant Disease Oriented Team -Medicine- Hematology/Oncology
Barry Fox, MD ± Medicine- Infectious Disease
Lucas Schulz, PharmD, BCPS ± Pharmacy
Paula Breihan, RT ± Respiratory Therapy
Andrew Peterson, PT, MHS ± Rehab-Medical/Surgical
Inga Werginz, OT ± Rehab-Medical/Surgical
Committee Approvals/Dates:
Questionnaire Workgroup (04/07/16)
Clinical Knowledge Management (CKM) Council (Last Periodic Review: 07/28/16)
Release Date: July 2016 | Next Review Date: July 2018
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Executive Summary
Guideline Overview
UW Health has internally developed a guideline based heavily on the National Institutes of
Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-
Host Disease (cGVHD).1-3

Key Practice Recommendations
SCREENING FOR cGVHD
1. It is recommended to screen all allogeneic BMT patients for cGVHD with a brief set of
simplified questions. Screening should begin prior to transplant to establish baseline.
Screening should be repeated at each clinic visit after BMT. (UW Health Very low quality
evidence, weak/conditional recommendation)
2. It is recommended to screen all allogeneic BMT patients for bronchiolitis obliterans (BOS)
with spirometry at day 100, 6 months after transplant, 1 year after transplant and yearly
thereafter.1,4,5 (UW Health Very low quality evidence, strong recommendation)

DIAGNOSIS AND STAGING OF cGVHD
1. It is recommended to assess patients for diagnosis and staging for those whose screening
responses show a change. Assessment for staging should occur at the time of initial
diagnosis of cGVHD and at selected times thereafter (e.g., development of new symptoms,
for recurrent disease, or major change in therapy). (UW Health Low quality evidence, strong
recommendation)
2. It is recommended to screen for bronchiolitis obliterans (BOS) with spirometry at initial
diagnosis of cGVHD and at 3 to 6-month intervals for the first 2 years after the initial
diagnosis.1,3-7 (UW Health Low quality evidence, strong recommendation)

TREATMENT OF cGVHD
1. It is recommended upon diagnosis of severe cGVHD, patient should be considered for
ongoing clinical trials. (UW Health Low quality evidence, strong recommendation) If the patient
does not qualify or there are not any open clinical trials, concurrent therapy with prednisone
2 mg/kg by mouth daily with taper, sirolimus 2 mg by mouth daily, and any applicable topical
and/or adjunct therapies should be initiated.8-13 (UW Health Low quality of evidence, strong
recommendation)
2. It is recommended upon diagnosis of moderate cGVHD, concurrent therapy with prednisone
1 mg/kg by mouth daily with taper and any applicable topical and/or adjunct therapies
should be initiated.8,13 (UW Health Moderate quality of evidence, strong recommendation)
3. It is recommended upon diagnosis of mild cGVHD, therapy with organ-specific topical and
adjunct therapies should be initiated.8 (UW Health Moderate quality evidence, strong
recommendation)

SUPPORTIVE CARE THERAPIES FOR cGVHD
1. It is recommended that patients receiving long-term prednisone greater than or equal to 20
mg daily receive stress ulcer prophylaxis.3 (UW Health Very low quality evidence,
weak/conditional recommendation)
2. It is recommended that patients on chronic steroids receive anti-resorptive therapy14,15 (UW
Health Moderate quality evidence, strong recommendation) and vitamin D and calcium
supplementation to prevent bone loss. (UW Health Very low quality evidence, strong
recommendation)
3. It is recommended that patients on systemic immunosuppressive therapies receive
prophylaxis to cover viral3,16-18 (UW Health Moderate quality evidence, strong recommendation),
fungal3,16-18 (UW Health Moderate quality evidence, strong recommendation), S. pneumoniae3,16,18
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(UW Health Very low quality evidence, strong recommendation) and Pneumocystis jiroveci
infections.3,17,18 (UW Health High quality evidence, strong recommendation)
4. It is recommended that immunizations are not delayed in cGVHD patients, except for live
vaccines.3,16-19 (UW Health Very low quality evidence, strong recommendation)
5. It is recommended that patients with recurrent sinopulmonary infections and serum IgG
levels less than 400 mg/dL be evaluated for IVIG administration.3,18 (UW Health Moderate
quality evidence, strong recommendation)
RESPONSE ASSESSMENT
1. It is recommended to assess response at approximately 4 weeks after treatment is initiated
and then at 8 weeks after treatment is initiated. Further assessment frequency depends on
response and complexity of medication regimen and should continue every 4 to 12 weeks
until after end of therapy.2 (UW Health Low quality evidence, strong recommendation)
Companion Documents
1. Chronic GVHD Screening Form
2. Chronic GVHD Diagnosis and Staging Form
3. Genital Tract Scoring Form
4. Chronic GVHD Response Assessment Form
5. Lee Symptom Scale
6. Scoring Algorithm for Lee cGVHD Symptom Scale
7. Extracorporeal Photopheresis Therapy
8. Interleukin-2 Therapy
Scope
Disease/Condition(s):
Chronic Graft Versus Host Disease (cGVHD) following allogeneic Bone Marrow Transplant.
Clinical Specialty: Bone Marrow Transplant
Intended Users: Bone Marrow Transplant (BMT) Coordinator, BMT Physicians and BMT
Advanced Practice Providers
Objective(s): To outline evidence-based recommendations for the screening, diagnosis,
staging, treatment and assessment of cGVHD.
Target Population: Adult patients aged 18 years or older who have received allogeneic BMT
and are being seen in the BMT clinic or inpatient settings.
Interventions and Practices Considered:
ξ Screening
ξ Diagnosis and Staging
ξ Treatment and Response Assessment
ξ Patient Reported Quality of Life
Major Outcomes Considered:
ξ Overall Survival and Failure Free Survival
ξ Non-relapse Mortality
ξ Quality of Life
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Methodology
Methods Used to Collect/Select the Evidence:
Electronic database searches (e.g., PUBMED) were conducted by the guideline author(s) and
workgroup members to collect evidence for review. Expert opinion and clinical experience were
also considered during discussions of the evidence.

Methods Used to Formulate the Recommendations:
The workgroup members agreed to adopt recommendations developed by external
organizations and/or arrived at a consensus through discussion of the literature and expert
experience. All recommendations endorsed or developed by the guideline workgroup were
reviewed and approved by other stakeholders or committees (as appropriate).

Methods Used to Assess the Quality of the Evidence/Strength of the Recommendations:
Recommendations developed by external organizations maintained the evidence grade
assigned within the original source document and were adopted for use at UW Health.

Internally developed recommendations, or those adopted from external sources without an
assigned evidence grade, were evaluated by the guideline workgroup using an algorithm
adapted from the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) methodology (see Figure 1 in Appendix A).

Rating Scheme for the Strength of the Evidence/Recommendations:
See Appendix A for the rating scheme(s) used within this document.

Recognition of Potential Health Care Disparities:
Hispanics have been shown to be 53% less likely to report severe/life threatening/disabling
conditions after hematopoietic stem cell transplant (HCT) than non-Hispanic whites. Chronic
GVHD was significantly associated with severe/life threatening conditions.20
Definitions
Acute Graft Versus Host Disease: 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 donor lymphocyte infusion (DLI) in a
patient not meeting criteria for the diagnosis of cGVHD, 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 cGVHD (often seen
during the taper or after withdrawal of immune suppression).1

Chronic Graft Versus Host Disease: Chronic GVHD is a syndrome of variable clinical features
UHVHPEOLQJ�DXWRLPPXQH�DQG�RWKHU�LPPXQRORJLF�GLVRUGHUV��VXFK�DV�VFOHURGHUPD��6M|JUHQ¶V�
syndrome, primary biliary cirrhosis, wasting syndrome, bronchiolitis obliterans, immune
cytopenias, and chronic immunodeficiency.21,22 The pathophysiology of the cGVHD syndrome
may involve inflammation, cell-mediated immunity, humoral immunity, and fibrosis. Clinical
manifestations nearly always present during the first year after transplantation, but some cases
develop many years after hematopoietic cell transplantation (HCT). Manifestations of cGVHD
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 therapy. Chronic GVHD included 2 subcategories: (1) classic cGVHD
without features characteristic of acute GVHD, and (2) an overlap syndrome, in which features
of chronic and acute GVHD appear together.1
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Diagnostic signs of cGVHD: Diagnostic signs and symptoms refer to those manifestations that
establish the presence of cGVHD without need for further testing or evidence of other organ
involvement.1

Distinctive signs of cGVHD: Distinctive signs and symptoms of cGVHD refer to those
manifestations that are not ordinarily found in acute GVHD but are not considered sufficient in
isolation to establish an unequivocal diagnosis of cGVHD.1

Overlap Syndrome: 7KH�WHUP�³RYHUODS´�UHIHUV�WR�WKH�SUHVHQFH�RI���RU�PRUH�DFXWH�*9+'�
manifestation in a patient with a diagnosis of cGVHD. Manifestations of acute GVHD can be
present at initial diagnosis of cGVHD or can develop after the diagnosis of cGVHD and may
recur with or without resolution of prior cGVHD manifestations. Findings indicating the overlap
subcategory can be transient, often depend on the degree of immunosuppression, and are
subject to changes during the disease course. Many patients who present witK�³RYHUODS´�FGVHD
have resolution of the acute features, whereas cGVHD features persist. Similarly, patients with
classic cGVHD may develop acute GVHD features when immunosuppression is tapered.1
Introduction
Chronic GVHD is the primary cause of non-relapse morbidity and mortality in patients surviving
longer than 100 days after allogeneic hematopoietic stem cell transplant (HSCT) and is the
major determinant of long term quality-of-life for HSCT patients.1 The greatest risk factor for the
development of cGVHD is antecedent acute GVHD; therefore effective prophylaxis for acute
GHVD is the best strategy for prevention of cGVHD. Approximately 30 to 70% of recipients of
HSCT allografts will develop cGVHD. The known risk factors predicting poor outcome for
cGVHD are: thrombocytopenia, progressive presentation of GVHD from acute to chronic,
lichenoid skin histology, and elevation of serum bilirubin. The clinical syndrome resembles an
RYHUODS�RI�YDULRXV�DXWRLPPXQH�GLVHDVHV�VXFK�DV�SURJUHVVLYH�V\VWHPLF�VFOHURVLV�6MRJUHQ¶V�
syndrome, systemic lupus erythematosus, lichen planus, and primary biliary cirrhosis. The
pathophysiology of this disease process includes the formation of autoantibodies and the
inability to produce protective antibodies against environmental pathogens. Patients with
extensive, multi-organ cGVHD have a poor prognosis, but if they can be supported for the first
few years post-BMT the usual course is for tolerance to occur, with the disease process
³EXUQLQJ�RXW´� The following guideline outlines the expected care at UW Health which includes
recommendations based on recent evidence and /or expert opinion/consensus.
Recommendations
SCREENING FOR cGVHD
The goal of screening patients is to prompt early diagnosis and staging of cGVHD. It is
recommended to screen all allogeneic BMT patients for cGVHD. (UW Health Very low quality
evidence, weak/conditional recommendation) Screening should begin prior to transplant to establish
a baseline. Screening should be repeated at each clinic visit after BMT. Screening should also
be completed at any time when patients report symptoms or symptoms are suspected by clinical
staff or a provider. (UW Health Very low quality evidence, weak/conditional recommendation)

Many patients with bronchiolitis obliterans (BOS) are asymptomatic early in the disease
process; therefore, screening with spirometry is recommended at day 100 after transplant, 6
months after transplant, 1 year after transplant, and annually thereafter.1,4,5 (UW Health Very low
quality evidence, strong recommendation)

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How to screen for cGVHD (Chronic GVHD Screening Form)
A brief set of simplified questions have been developed to screen patients that may need further
assessment for cGVHD. Common areas of concern are addressed (e.g. skin, lungs, joints, oral
mucosa, eyes and genitalia).23
DIAGNOSIS AND STAGING OF cGVHD
It is recommended to assess patients for diagnosis and staging for those whose screening
responses show a change in reported symptoms. (UW Health Very low quality evidence, strong
recommendation) Assessment for staging should occur at the time of initial diagnosis of cGVHD
and at selected times thereafter (e.g., development of new symptoms, for recurrent disease, or
major change in therapy). (UW Health Very low quality evidence, weak/conditional recommendation)

Patients diagnosed with cGVHD other than bronchiolitis obliterans (BOS) are at increased risk
of developing BOS. Because patients with BOS are asymptomatic early in the disease process,
screening with spirometry is recommended at initial diagnosis of cGVHD and at 3 to 6-month
intervals for the first 2 years after the initial diagnosis.1,3-7 (UW Health Very low quality evidence,
strong recommendation)

How to diagnose cGVHD
Signs and symptoms of chronic GVHD have been reviewed and reported by the NIH Consensus
Working Group to standardize criteria for diagnosis and classification of cGVHD for the purpose
of clinical trials (Table 1).1 Although developed and intended to help standardize clinical trial
eligibility, the tools translate well for use in patients not enrolled on a clinical trial. The diagnosis
of cGVHD has no time limit and requires the presence of at least one diagnostic clinical sign of
cGVHD (e.g. poikiloderma or esophageal web) or the presence of at least one distinctive
manifestation (e.g. keratoconjunctivitis sicca) confirmed by pertinent biopsy or other relevant
tests (e.g. pulmonary function tests (PFT), 6FKLUPHU¶V�WHVW) in the same or another organ.

The criteria for the diagnosis of cGVHD include1:
i. Distinction from acute GVHD.
ii. Presence of at least one diagnostic clinical manifestation OR at least one distinctive
manifestation confirmed by pertinent biopsy or other relevant tests (Table 1.)
iii. Exclusion of other possible diagnosis for the clinical manifestation (e.g., infection,
drug effect, others).

Table 1. Signs and Symptoms of cGVHD1
Organ or Site

Diagnostic (Sufficient to
Establish the Diagnosis
of
cGVHD)
Distinctive* (Seen
in cGVHD, but
Insufficient Alone
Other Features or
Unclassified
Entities†
Common‡ (Seen
with Both Acute
and cGVHD)
Skin

Poikiloderma
Lichen planus-like features
Sclerotic features
Morphea-like features
Lichen sclerosus-like
features
Depigmentation
Papulosquamous
lesions
Sweat impairment
Ichthyosis
Keratosis pilaris
Hypopigmentation
Hyperpigmentation
Erythema
Maculopapular rash
Pruritus
Nails
Dystrophy
Longitudinal ridging,
splitting or brittle
features
Onycholysis
Pterygium unguis

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Organ or Site

Diagnostic (Sufficient to
Establish the Diagnosis
of
cGVHD)
Distinctive* (Seen
in cGVHD, but
Insufficient Alone
Other Features or
Unclassified
Entities†
Common‡ (Seen
with Both Acute
and cGVHD)
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
Scaling
Thinning scalp hair,
typically patchy,
coarse or dull (not
explained by
endocrine or other
causes)
Premature gray hair

Mouth Lichen planus-like
changes
Xerostomia
Mucoceles
Mucosal atrophy
Ulcers
Pseudomembranes

Gingivitis
Mucositis
Erythema
Pain
Eyes
New onset dry, gritty,
or
painful eyes
Cicatricial
conjunctivitis
KCS
Confluent areas of
punctate keratopathy
Photophobia
Periorbital
hyperpigmentation
Blepharitis
(erythema of the
eyelids with edema)

Genitalia
Lichen planus-like features
Lichen sclerosus-like
features
Erosions
Fissures
Females
Vaginal scarring or
clitoral/labial
Agglutination
Ulcers


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
insufficiency
Anorexia
Nausea
Vomiting
Diarrhea
Weight loss
Failure to thrive
(infants
and children
Liver Total bilirubin,
alkaline
phosphatase > 2
times upper
limit of normal
ALT > 2 times upper
limit of
normal
Lung
Bronchiolitis obliterans
diagnosed with lung
biopsy
BOS¥
Air trapping and
bronchiectasis on
chest CT
Cryptogenic
organizing
pneumonia
Restrictive lung
disease£

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Organ or Site

Diagnostic (Sufficient to
Establish the Diagnosis
of
cGVHD)
Distinctive* (Seen
in cGVHD, but
Insufficient Alone
Other Features or
Unclassified
Entities†
Common‡ (Seen
with Both Acute
and cGVHD)
Muscles,
fascia,
Joints
Fasciitis
Joint stiffness or
contractures
secondary to fasciitis or
sclerosis
Myositis or
polymyositis±
Edema
Muscle cramps
Arthralgia or arthritis

Hematopoietic
and Immune
Thrombocytopenia
Eosinophilia
Lymphopenia
Hypo- or hyper-
gammaglobulinemia
Autoantibodies
(AIHA, ITP)
5D\QDXG¶V�
phenomenon

Other
Pericardial or pleural
effusions
Ascites
Peripheral
neuropathy
Nephrotic syndrome
Myasthenia gravis
Cardiac conduction
abnormality or
cardiomyopathy


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 cGVHD manifestations if diagnosis is confirmed.
Á Common refers to shared features by both acute and cGVHD.
¥ BOS can be diagnostic for lung cGVHD only if distinctive sign or symptom present in another organ (see text).
£ Pulmonary entities under investigation or unclassified.
± Diagnosis of cGVHD requires biopsy.


How to score each organ/site severity with cGVHD
The scoring system (0 to 3) is used to describe the severity of cGVHD for each organ or site
taking functional impact into account. The Chronic GVHD Diagnosis and Staging Form contains
a modified cGVHD Scoring and Assessment form to help physicians evaluate their patients with
cGVHD. The Genital Tract Scoring Form contains a supplemental Genital Tract Scoring form. If
a specialist is unavailable, external examination may be performed to determine ³GLVFRPIRUW�RQ�
H[DP´�DV�GHVFULEHG�LQ�WKLV�IRUP�1 Several studies have validated the scoring system as an
indicator of disease severity.24,25

How to assess overall severity of cGVHD - Global Assessment
Manifestations of cGVHD may be restricted to a single organ or tissue or may be widespread.
Historically, c*9+'�ZDV�FODVVLILHG�DV�³OLPLWHG´�RU�³H[WHQVLYH´�EDVHG�RQ�D�VPDOO�FRKRUW�of patients
reported more than two decades ago.26 Because of inadequacies of the original classification
(e.g., difficulty to apply the historical criteria in patients transplanted with newer HSCT
approaches and progress in our understanding of cGVHD), overtime, this widely adopted
cGVHD classification system has proved to have limitation.27,28

The newer global assessment of cGVHD severity (mild, moderate or severe) is based on
numbers of organs/sites involved and the degree of involvement in affected organs/sites (Table
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2).1 Causes beyond GVHD should be investigated and ruled out (e.g., respiratory syncytial virus
(RSV) or drug rash). Organ disfunction/abnormality that is completely attributed to a non-GVHD
source is not scored. If there is uncertainty or multifactorial causes (e.g., GVHD and RSV) are
likely both contributing to the symptoms then the symptoms are fully scored and graded.1
Several studies have validated that NIH global severity scores are a reliable measure of disease
burden and can predict long-term outcomes.24,29

Table 2. NIH Global Severity of cGVHD1
Mild cGVHD
1 or 2 organs involved with no more than score 1
PLUS
Lung score 0
Moderate cGVHD
3 or more organs involved with no more than score 1
OR
At least 1 organ (not lung) with a score of 2
OR
Lung score 1
Severe cGVHD
At least 1 organ with a score of 3
OR
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 severity.

If the entire abnormality in an organ is noted to be unequivocally 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).



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TREATMENT FOR cGVHD
Treatment is based on severity (severe, moderate and mild) and organ specific manifestations
of cGVHD.

Severe cGVHD (see Figure 1 and Table 3)
ξ Upon diagnosis of severe cGVHD, patients should be considered for ongoing clinical trials.
(UW Health Low quality evidence, strong recommendation)
o If the patient does not qualify or there are not any open clinical trials, concurrent
therapy with prednisone 2 mg/kg by mouth daily with taper (see Table 6), sirolimus 2
mg by mouth daily, and any applicable topical and/or adjunct therapies should be
initiated.8-13 (UW Health Low quality evidence, strong recommendation)
ξ Response to therapy should be assessed after four weeks, and patients should be exposed
to therapeutic drug levels for at least four weeks before concluding treatment failure. (UW
Health Moderate quality evidence, weak/conditional recommendation) Most therapies did not
reach therapeutic peak until 8-12 weeks in published literature.13
ξ If patients have progression of cGVHD after four weeks, a new treatment may be
considered in addition to the current regimen.13 (UW Health Low quality evidence,
weak/conditional recommendation)


Figure 1: Pharmacologic Management of Severe cGVHD
or
and
and
Sirolimus 2 mg by
mouth daily
INITIAL THERAPY
Week 4
assessment =
progressive
disease?
Continue current
course of therapy
NoAdd ECP
Week 8
assessment =
Stable and/or
progressive
disease?
Continue current
course of therapy
No
Consider adding
organ-specific
systemic therapy
Week 8
assessment=
progressive
disease?
Continue current
course of therapy
Prednisone
2 mg/kg by mouth
daily or IV
equivalent
Organ-specific
topical and/or
adjunct therapy
Is ECP feasible due to
insurance or practical
considerations?
Add organ-specific
systemic therapy
Consider adding ECP
or organ-specific
systemic therapy
Yes
Re-evaluate ECP
at 3 months
Re-evaluate ECP
at 3 months
Consider clinical trial
No
Yes Yes
No
Yes

*ECP = extracorporeal photopheresis (Extracorporeal Photopheresis Therapy)
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Table 3: Pharmacologic Management of Severe cGVHD *For each location, agents are listed in order of preference
cGVHD (Severe) Medication recommendation Evidence Quality
Recommendation
Strength
Initial
therapy
Systemic therapy
Prednisone 2 mg/kg/day8 by mouth (equivalent to methyl-prednisolone IV 1.6
mg/kg/day) High Strong
Sirolimus 2 mg by mouth daily (1 mg/m2/day if less than 40 kg) (target level 3-
12 ng/mL) 9-13
Sirolimus 1 mg by mouth daily is a reasonable starting dose for patients taking
concurrent medications with significant drug interactions such as voriconazole
and posaconazole.
Moderate Strong
Refractory disease
ECP (extracorporeal photopheresis)8,9,13,16,30-35
See Extracorporeal Photopheresis Therapy Moderate Strong
Tacrolimus 0.01-0.02 mg/kg by mouth twice daily (target 5-10 ng/mL) 8,9,13,36
It is reasonable to substitute tacrolimus for sirolimus if refractory disease after
ECP or if unable to tolerate sirolimus
Moderate Strong
Cyclosporine 1-2 mg/kg by mouth twice daily (target 120-200 ng/mL)8,9,13,36
It is reasonable substitute cyclosporine for tacrolimus if unable to tolerate
tacrolimus
Moderate Strong
Cutaneous
Topical
therapy
Entire
body
Tacrolimus 0.1% ointment to the affected area two times daily3,8,16
For duration greater than two weeks Low Strong
Neck
and
below
Betamethasone dipropionate 0.05% ointment to the affected area two times
daily3,8,16
Use is not recommended for longer than two weeks
Low Strong
Triamcinolone 0.5% cream to the affected area two times daily3,8,16
Use is not recommended for longer than two weeks
Though slightly less potent than betamethasone ointment, this is a reasonable
alternative for patients unable to tolerate ointment
Very low Weak/conditional
Face Hydrocortisone 1% ointment twice daily
3,8,16

Use is not recommended for longer than two weeks Very low Strong
Systemic therapy for
refractory disease
Rituximab 375 mg/m2 IV weekly x 4 doses9,13,37-42 Moderate Weak/conditional
Imatinib 200 mg by mouth daily9,13,37,43-46 Low Weak/conditional
Etanercept 25 mg subcutaneous 2 times weekly x 4 weeks, then 25 mg
weekly x4 weeks9,47,48 Low Weak/conditional
Hydroxychloroquine 6 mg/kg/day by mouth twice daily9,49 Low Weak/conditional
Mycophenolate mofetil 100 mg by mouth twice daily9,13,50 Low Weak/conditional
Ruxolitinib 5-10 mg by mouth twice daily51 Low Weak/conditional
Infliximab 10 mg/kg IV weekly x413 Low Weak/conditional
Interleukin-2 (aldesleukin) 1x106 IU/m2 subcutaneous daily x 8 weeks, followed
by 4 weeks off52,53
See Interleukin-2 Therapy
Very low Weak/conditional
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cGVHD (Severe) Medication recommendation Evidence Quality
Recommendation
Strength
Gastro-
intestinal
Topical therapy
Budesonide 9 mg by mouth one time daily8 Moderate Strong
Beclomethasone 2 mg by mouth four times daily54,55 Low Strong
Systemic therapy for
refractory disease
Etanercept 25 mg subcutaneous 2 times weekly x 4 weeks, then 25 mg
weekly x4 weeks9,13,47,48 Low Weak/conditional
Rituximab 375 mg/m2 IV weekly x 4 doses9,13,37-42 Low Weak/conditional
Ruxolitinib 5-10 mg by mouth twice daily51 Low Weak/conditional
Imatinib 200 mg by mouth daily9,13,37,43,44 Low Weak/conditional
Infliximab 10 mg/kg IV weekly x413 Low Weak/conditional
Interleukin-2 (aldesleukin) 1x106 IU/m2 subcutaneous daily x 8 weeks, followed
by 4 weeks off52,53
See Interleukin-2 Therapy
Very low Weak/conditional
Genital
Topical therapy
Tacrolimus 0.1% ointment twice daily3,8,16 For duration greater than two
weeks Low Strong
Betamethasone dipropionate3,8,16 0.05% to the affected area twice daily
Gel preferred for vaginal involvement; ointment preferred for vulvar
involvement; use not recommended beyond two weeks
Low Strong
Hydrocortisone 25 mg suppository intravaginally twice daily3,8 Very low Strong
Systemic therapy for
refractory disease
Rituximab 375 mg/m2 IV weekly x 4 doses9,13,37-42 Low Weak/conditional
Liver Systemic therapy for
refractory disease
Rituximab 375 mg/m2 IV weekly x 4 doses9,13,37-42 Low Weak/conditional
Mycophenolate mofetil 100 mg by mouth twice daily9,13,50 Low Weak/conditional
Ruxolitinib 5-10 mg by mouth twice daily51 Low Weak/conditional
Interleukin-2 (aldesleukin) 1x106 IU/m2 subcutaneous daily x 8 weeks,
followed by 4 weeks off52,53
See Interleukin-2 Therapy
Very low Weak/conditional
Musculo-
skeletal
Systemic therapy for
refractory disease
Rituximab 375 mg/m2 IV weekly x 49,13,37-42 Moderate Weak/conditional
Ruxolitinib 5-10 mg by mouth twice daily51 Low Weak/conditional
Interleukin-2 (aldesleukin) 1x106 IU/m2 subcutaneous daily x 8 weeks, followed
by 4 weeks off52,53
See Interleukin-2 Therapy
Very low Weak/conditional
Ocular
Topical therapy
Artificial tears PRN3,8,16
Ointment is more effective than solution for dry eyes but can lead to cloudy
vision
Very low Strong
Prednisolone acetate 1% in affected eye(s) four times daily with
ophthalmology consult3,8 Low Strong
Cyclosporine 0.05% in affected eye(s) twice daily3,8 Low Strong
Antibiotic drops or ointment may be considered if infectious concerns3,8,16 Low Strong
Systemic therapy for
refractory disease
Rituximab 375 mg/m2 IV weekly x 4 doses9,13,37-42 Low Weak/conditional
Imatinib 200 mg by mouth daily9,13,37 Low Weak/conditional
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cGVHD (Severe) Medication recommendation Evidence Quality
Recommendation
Strength
Oral
Topical
therapy
Generalized
disease
Budesonide 3 mg/10 mL water mouthwash ± swish 10 mL for 5 minutes and
spit, 2-4 times daily3,8,16,56-62
Do not eat or drink for 15-20 minutes after
Moderate Strong
Add tacrolimus to mouthwash (equal parts tacrolimus : budesonide) if
inadequate response with budesonide after 4 weeks3,8,16,60,61,63 Low Weak/conditional
Dexamethasone 0.1 mg/mL solution ± swish 10 mL for 5 minutes and spit, 2-4
times daily3,8,16,60,61
Use if patient is unable to obtain budesonide
Low Weak/conditional
Focal
disease
Clobetasol 0.05% gel to lesions 2-4 times daily3,8,60,61
Hold gel to area with gauze for 10-15 minutes Low Strong
Lip
involvement Tacrolimus 0.1% ointment 2-4 times daily
3,8,60,61
Low Strong
Salivary
gland
(xerostomia)
Pilocarpine 5 mg by mouth three times daily3,60,61 Low Strong
Cevimeline 30 mg by mouth three times daily3,60,61
If inadequate response to pilocarpine after 8-12 weeks Low Weak/conditional
Systemic therapy for
refractory disease
Rituximab 375 mg/m2 IV weekly x 4 doses9,13,37-42 Low Weak/conditional
Hydroxychloroquine 6 mg/kg/day by mouth twice daily9,49 Low Weak/conditional
Mycophenolate mofetil 100 mg by mouth twice daily9,13,50 Low Weak/conditional
Methotrexate 5-10 mg/m2 by mouth weekly9,13 Low Weak/conditional
Pulmonary
Adjunctive therapy
(FAM)
Fluticasone 440 mcg inhaled twice daily3,8,16,64
Moderate Strong Azithromycin 250 mg by mouth every MWF3,8,16,64
Montelukast 10 mg by mouth daily3,8,16,64
Systemic therapy for
refractory disease
Imatinib 200 mg by mouth daily9,13,16,37,43,44,65 Low Weak/conditional
Rituximab 375 mg/m2 IV weekly x 4 doses9,13,37-42 Low Weak/conditional
Ruxolitinib 5-10 mg by mouth twice daily51 Low Weak/conditional
Interleukin-2 (aldesleukin) 1x106 IU/m2 subcutaneous daily x 8 weeks, followed
by 4 weeks off52,53
See Interleukin-2 Therapy
Very low Weak/conditional
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Moderate cGVHD (see Figure 2 and Table 4)
ξ Upon diagnosis of moderate cGVHD, concurrent therapy with prednisone 1 mg/kg by mouth
daily with taper (see Table 6) and any applicable topical and/or adjunct therapies should be
initiated.8,13 (UW Health Moderate quality evidence, strong recommendation)
ξ It is reasonable to add organ-specific topical therapy as an adjunct to systemic prednisone
initially or if disease is stable at four weeks.8,9,13 (UW Health Moderate quality evidence,
weak/conditional recommendation)
ξ If disease is progressive at four weeks, it is reasonable tR�WUHDW�SHU�WKH�³6HYHUH�F*9+'´�
table. (UW Health Low quality evidence, weak/conditional recommendation)

Figure 2: Pharmacologic Management of Moderate cGVHD

and
Add organ-specific
topical therapy if
not already done
INITIAL THERAPY
Week 4
assessment of
disease
severity
Continue current
course of therapy
Improved
7UHDW�SHU�³6HYHUH�
F*9+'´�
recommendations
Progressive
Prednisone
1 mg/kg by mouth
daily
Start sirolimus
2 mg by mouth
daily
Stable
Organ-specific
topical and/or
adjunct therapy
(optional)



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Table 4: Pharmacologic Management of Moderate cGVHD
*For each location, agents are listed in order of preference
cGVHD (Moderate) Medication recommendation Evidence Quality
Recommendation
Strength
Initial systemic therapy Prednisone 1 mg/kg by mouth daily8 High Strong
Cutaneous Topical
therapy
Entire body
Tacrolimus 0.1% ointment to the affected
area two times daily3,8,16
For duration greater than two weeks
Low Strong
Neck and
below
Betamethasone dipropionate 0.05%
ointment to the affected area two times
daily3,8,16
Use is not recommended for longer than
two weeks
Low Strong
Triamcinolone 0.5% cream to the affected
area two times daily3,8,16
Use is not recommended for longer than
two weeks
Though slightly less potent than
betamethasone ointment, this is a
reasonable alternative for patients unable
to tolerate ointment
Very low Weak/conditional
Face
Hydrocortisone 1% ointment twice
daily3,8,16
Use is not recommended for longer than
two weeks
Very low Strong
Gastrointestinal Topical therapy
Budesonide 9 mg by mouth one time
daily8
Moderate Strong
Beclomethasone 2 mg by mouth four
times daily54,55 Low Strong
Genital Topical therapy
Tacrolimus 0.1% ointment twice daily3,8,16
For duration greater than two weeks Low Strong
Betamethasone dipropionate 0.05% to
the affected area twice daily3,8,16
Gel preferred for vaginal involvement;
ointment preferred for vulvar involvement;
use not recommended beyond two weeks
Low Strong
Hydrocortisone 25 mg suppository
intravaginally twice daily3,8 Very low Strong
Liver Systemic therapy (prednisone) – no topical therapies available8,13 High Strong
Musculoskeletal Systemic therapy (prednisone) – no topical therapies available8 High Strong
Ocular Topical therapy
Artificial tears PRN3,8,16
Ointment is more effective than solution
for dry eyes but can lead to cloudy vision
Very low Strong
Prednisolone acetate 1% in affected
eye(s) four times daily with ophthalmology
consult3,8
Low Strong
Cyclosporine 0.05% in affected eye(s)
twice daily3,8 Low Strong
Antibiotic drops or ointment may be
considered if infectious concerns3,8,16
Low Strong
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cGVHD (Moderate) Medication recommendation Evidence Quality
Recommendation
Strength
Oral Topical
therapy
Generalized
disease
Budesonide 3 mg/10 mL water
mouthwash ± swish 10 mL for 5 minutes
and spit, 2-4 times daily3,8,16,56-62
Do not eat or drink for 15-20 minutes after
Moderate Strong
Add tacrolimus to mouthwash (equal
parts tacrolimus : budesonide) if
inadequate response with budesonide
after 2-4 weeks3,8,16,60,61,63
Low Weak/conditional
Dexamethasone 0.1 mg/mL solution ±
swish 10 mL for 5 minutes and spit, 2-4
times daily8,16,60,61,63
Use of patient is unable to obtain
budesonide
Low Weak/conditional
Oral Topical
therapy
Focal
disease
Clobetasol 0.05% gel to lesions 2-4 times
daily8,60,61
Hold gel to area with gauze for 10-15
minutes
Low Strong
Lip
involvement
Tacrolimus 0.1% ointment 2-4 times
daily8,60,61
Low Strong
Salivary
gland
(xerostomia)
Pilocarpine 5 mg by mouth three times
daily60,61
Low Strong
Cevimeline 30 mg by mouth three times
daily60,61
If inadequate response to pilocarpine
after 8-12 weeks
Low Weak/conditional
Pulmonary
Adjunctive therapy
(FAM)
Fluticasone 440 mcg inhaled twice
daily3,8,16,64
Moderate Strong Azithromycin 250 mg by mouth every
MWF3,8,16,64
Montelukast 10 mg by mouth daily3,8,16,64
Systemic therapy
Imatinib 200 mg by mouth
daily9,13,16,37,43,44,65
Consider adding with initial therapy due to
the high mortality associated with cGVHD
Low Weak/conditional
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Mild cGVHD (See Table 5)
ξ Upon diagnosis of mild cGVHD, therapy with organ-specific topical and adjunct therapies
should be initiated.8 (UW Health Moderate quality evidence, strong recommendation)
ξ If GVHD has not improved at four weeks, systemic therapy with prednisone should be
added. (UW Health Low quality evidence, weak/conditional recommendation)
ξ If GVHD has progressed, it is reasonable to WUHDW�SHU�WKH�³0RGHUDWH�F*9+'´�WDEOH. (UW
Health Low quality evidence, weak/conditional recommendation)
Table 5: Pharmacologic Management of Mild cGVHD
*For each location, agents are listed in order of preference
cGVHD (Mild) Medication recommendation Evidence Quality
Recommendation
Strength
Cutaneous Topical
therapy
Entire body
Tacrolimus 0.1% ointment to the
affected area two times daily3,8,16
For duration greater than two weeks
Low Strong
Neck and
below
Betamethasone dipropionate 0.05%
ointment to the affected area two times
daily3,8,16
Use is not recommended for longer
than two weeks
Low Strong
Triamcinolone 0.5% cream to the
affected area two times daily3,8,16
Use is not recommended for longer
than two weeks
Though slightly less potent than
betamethasone ointment, this is a
reasonable alternative for patients
unable to tolerate ointment
Very low Weak/conditional
Face
Hydrocortisone 1% ointment twice
daily3,8,16
Use is not recommended for longer
than two weeks
Very low Strong
Gastro-
intestinal Topical therapy
Budesonide 9 mg by mouth one time
daily8
Moderate Strong
Beclomethasone 2 mg PO four times
daily54,55
Low Strong
Genital Topical therapy
Tacrolimus 0.1% ointment twice
daily3,8,16
For duration greater than two weeks
Low Strong
Betamethasone dipropionate 0.05% to
the affected area twice daily3,8,16
Gel preferred for vaginal involvement;
ointment preferred for vulvar
involvement; use not recommended
beyond two weeks
Low Strong
Hydrocortisone 25 mg suppository
intravaginally twice daily3,8 Very low Strong
Liver Systemic therapy (prednisone) – no topical therapies available8 High Strong
Musculo-
skeletal
Systemic therapy (prednisone) – no topical therapies available8 High Strong
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cGVHD (Mild) Medication recommendation Evidence Quality
Recommendation
Strength
Ocular Topical therapy
Artificial tears PRN3,8,16
Ointment is more effective than solution
for dry eyes but can lead to cloudy vision
Very low Strong
Prednisolone acetate 1% in affected
eye(s) four times daily with
ophthalmology consult3,8
Low Strong
Cyclosporine 0.05% in affected eye(s)
twice daily3,8 Low Strong
Antibiotic drops or ointment may be
considered if infectious concerns3,8,16
Low Strong
Oral Topical
therapy
Generalized
disease
Budesonide 3 mg/10 mL water
mouthwash ± swish 10 mL for 5 minutes
and spit, 2-4 times daily3,8,16,56-62
Do not eat or drink for 15-20 minutes
after
Moderate Strong
Add tacrolimus to mouthwash (equal
parts tacrolimus : budesonide) if
inadequate response with budesonide
after 2-4 weeks3,8,16,60,61,63
Low Weak/conditional
Dexamethasone 0.1 mg/mL solution ±
swish 10 mL for 5 minutes and spit, 2-4
times daily3,8,16,60,61,63
Use of patient is unable to obtain
budesonide
Low Weak/conditional
Focal
disease
Clobetasol 0.05% gel to lesions 2-4
times daily3,8,60,61
Hold gel to area with gauze for 10-15
minutes
Low Strong
Lip
involvement
Tacrolimus 0.1% ointment 2-4 times
daily3,8,60,61
Low Strong
Salivary
gland
(xerostomia)
Pilocarpine 5 mg by mouth three times
daily3,60,61
Low Strong
Cevimeline 30 mg by mouth three times
daily3,60,61
If inadequate response to pilocarpine
after 8-12 weeks
Low Weak/conditional
Pulmonary
Adjunctive therapy
(FAM)
Fluticasone 440 mcg inhaled twice
daily3,8,16,64
Moderate Strong Azithromycin 250 mg by mouth every
MWF3,8,16,64
Montelukast 10 mg by mouth daily3,8,16,64
Systemic therapy
It is reasonable to add prednisone 1
mg/kg by mouth daily with initial therapy
due to the high mortality associated with
cGVHD8,16
Low Strong
Systemic therapy
Prednisone 0.5 mg/kg by mouth daily8,13
For mild cGVHD, systemic therapy
should only be considered for patients
with hepatic, musculoskeletal or
pulmonary involvement
High Strong


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Tapering of cGVHD Systemic Therapies

ξ mTOR inhibitors66 (UW Health Low quality evidence, weak/conditional recommendation)
o It is reasonable to taper sirolimus over 1-3 months, after prednisone has been
discontinued.
o Monitor and confirm stability of cGVHD response for 1-3 months after tapering
sirolimus.

ξ Calcineurin inhibitors66 (UW Health Low quality evidence, weak/conditional recommendation)
o It is reasonable to taper tacrolimus and cyclosporine over 3-6 months, after
prednisone has been discontinued.
o Monitor and confirm stability of cGVHD response for 1-3 months after tapering
tacrolimus or cyclosporine.

ξ Prednisone23 (UW Health Low quality evidence, weak/conditional recommendation)

Table 6: Recommended Prednisone Taper
From 2 mg/kg/day to 1 mg/kg/day
Day (starting at initiation of prednisone) AM prednisone dose PM prednisone dose
1 1 mg/kg 1 mg/kg
6 1 mg/kg 0.8 mg/kg
8 1 mg/kg 0.6 mg/kg
10 1 mg/kg 0.4 mg/kg
12 1 mg/kg 0.2 mg/kg
14 1 mg/kg STOP PM doses


From 1 mg/kg/day to discontinuation
Day (initial taper) AM prednisone dose
Continue until objective evidence of
improvement in manifestations of cGVHD 1 mg/kg daily
Begin initial taper within 2 weeks of first evidence of improvement
1 0.9 mg/kg daily
8 0.8 mg/kg daily
15 0.7 mg/kg daily
22 0.6 mg/kg daily
29
1 mg/kg every other day
(equivalent to 0.5 mg/kg daily – starting dose for mild
cGVHD)
It is reasonable to continue dose for 10-12 weeks until all reversible manifestations resolve
Day (alternate day taper) AM prednisone dose (mg/kg)
1 0.9 mg/kg every other day
8 0.8 mg/kg every other day
15 0.7 mg/kg every other day
22 0.6 mg/kg every other day
29 0.5 mg/kg every other day
It is reasonable to observe for 2 months prior to tapering completely off prednisone
1 0.4 mg/kg every other day
8 0.3 mg/kg every other day
15 0.2 mg/kg every other day
22 0.1 mg/kg every other day
29 STOP
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If a patient experiences an exacerbation or recurrence of cGVHD during the prednisone taper (UW Health
Very low quality evidence, weak/conditional recommendation):
ξ Prednisone dose should be increased by two dosing levels
ξ If on an every other day dosing schedule, the patient should transition to daily dosing for two
weeks
o Example: for a patient taking 0.5 mg/kg every other day, the dose would be increased to
0.35 mg/kg daily (equivalent to 0.7 mg/kg every other day)
ξ After two weeks of daily dosing, the patient can resume every other day dosing and should continue
at that dosing level for three months before a taper is again attempted
SUPPORTIVE CARE THERAPIES FOR cGVHD

1. Acid Suppression
1.1. Patients receiving long-term prednisone at doses greater than or equal to 20 mg daily
should receive stress ulcer prophylaxis.3 (UW Health Very low quality evidence,
weak/conditional recommendation)
1.2. Initial therapy should begin with ranitidine 150 mg by mouth 2 times daily or equivalent
histamine-2 receptor antagonist (H2RA).67 (UW Health Low quality evidence,
weak/conditional recommendation).
1.3. If H2RA therapy fails, pantoprazole 40 mg by mouth one time daily or equivalent proton
pump inhibitor (PPI) should be used. (UW Health Very low quality evidence, weak/conditional
recommendation).
2. Bone Health
2.1. Screening
2.1.1. In patients with cGVHD, a baseline calcium (total and ionized) and vitamin D
level should be tested in patients on systemic steroid therapy.3,16 (UW Health Low
quality evidence, strong recommendation)
2.1.2. Post-menopausal women and men greater than 50 years old should undergo a
DEXA scan within the first month of treatment.14,15 (UW Health Moderate quality
evidence, strong recommendation)
2.1.3. Pre-menopausal women and men less than 50 years old who are expected to be
on prednisone for more than three months should be evaluated with a DEXA scan.14
(UW Health Low quality evidence, strong recommendation)
2.1.4. Supplementation of calcium and vitamin D. Supplementation is recommended
unless a patient has elevated serum calcium or vitamin D levels. (UW Health Very low
quality evidence, strong recommendation)
2.1.5. For patients with normal serum calcium and vitamin D levels, target doses of
calcium 1200 mg and cholecalciferol (vitamin D3) 1000 IU are recommended.3,14-16
(UW Health High quality evidence, strong recommendation)
2.1.6. For patients with low serum vitamin D levels, ergocalciferol (vitamin D2) 50,000
IU once weekly for at least 8 weeks to achieve a 25-hydroxyvitamin D level greater
than 30 ng/mL is recommended. Once this level has been attained, a maintenance
dose of cholecalciferol (vitamin D3) 1500-2000 IU daily should be started.68 (UW
Health Moderate quality evidence, strong recommendation)
2.1. Anti-resorptive therapy
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2.1.1. Treatment with zoledronic acid (RECLAST) 5 mg IV every 12 months is
recommended for the following groups:
ξ Patients of any age receiving systemic steroids for more than
three months.14 (UW Health Moderate quality evidence, strong
recommendation)
ξ Post-menopausal women receiving systemic steroids regardless
of duration.14,15 (UW Health High quality evidence, strong
recommendation)
ξ Men greater than age 50 receiving systemic steroids regardless of
duration.14 (UW Health Moderate quality evidence, strong
recommendation)
2.1.2. Alternatives to zoledronic acid include alendronate and risendronate, though
these may not be as well absorbed, especially in patients with cGVHD involving the
GI tract.14,15 (UW Health High quality evidence, strong recommendation)
2.1.3. Alendronate is preferred for women of child-bearing potential.14 (UW Health High
quality evidence, strong recommendation)
2.1.4. Risendronate and teriparatide are alternatives to alendronate in women of
childbearing potential.14 (UW Health Low quality evidence, strong recommendation)
2.1.5. Therapy should continue until prednisone doses are less than 7.5 mg daily in the
absence of osteoporosis or fracture history.14 (UW Health High quality evidence, strong
recommendation)
2.1.6. Patients who have been diagnosed with osteoporosis should continue treatment
even when prednisone doses are less than 7.5 mg daily.14 (UW Health High quality
evidence, strong recommendation)
3. Anti-infective Prophylaxis
3.1. Viral prophylaxis
3.1.1 Acyclovir 400 mg by mouth two times daily is recommended for three months
after discontinuation of all systemic immunosuppressive therapy.3,16,17,69 (UW
Health Moderate quality evidence, strong recommendation)
3.2 Fungal prophylaxis
3.2.1 Posaconazole Delayed Release (DR) tabs 300 mg by mouth daily is
recommended for patients receiving prednisone doses greater than or equal to
20 mg per day or dual systemic immunosuppressive therapies.3,16,17,69 (UW Health
Moderate quality evidence, strong recommendation)
3.3 S. pneumoniae prophylaxis
3.3.1 Azithromycin 250 mg by mouth every Monday, Wednesday and Friday may be
considered for patients receiving systemic immunosuppressive therapy.3,16,69 (UW
Health Very low quality evidence, strong recommendation)
3.3.2 Penicillin VK 250 mg by mouth two times daily may be considered as an
alternative to azithromycin for patients receiving systemic immunosuppressive
therapy but are unable to receive azithromycin.3,16,69 (UW Health Very low quality
evidence, weak/conditional recommendation)
3.4 Pneumocystis jiroveci prophylaxis
3.4.1 Sulfamethoxazole/trimethoprim (800mg/160mg) ± 1 tablet by mouth daily on
Mondays, Wednesdays, and Fridays is recommended for patients receiving
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prednisone doses greater than or equal to 20 mg per day or dual systemic
immunosuppressive therapies.3,17,69 (UW Health High quality evidence, strong
recommendation)
3.4.1.1 An alternative dosing regimen is 1 tablet by mouth twice daily on Saturdays
and Sundays. (UW Health Low quality evidence, strong recommendation)
3.4.2 Sulfa desensitization should be considered for patients with a previous allergic
reaction to sulfa.70 (UW Health Very low quality of evidence, strong recommendation)
After 30 days of continuous therapy without a reaction, use a standard dosing
regimen (i.e., Mondays, Wednesdays, and Fridays) as outlined above.70
3.4.3 For patients unable to tolerate sulfamethoxazole/trimethoprim or undergo sulfa
desensitization, the following agents may be considered:
3.4.3.1 Pentamidine 300 mg inhaled every 28 days.17 (UW Health Moderate quality
evidence, strong recommendation)
3.4.3.2 Pentamidine 300 mg IV every 28 days may be considered in patients unable
to tolerate inhaled. (UW Health Low quality evidence, weak/conditional
recommendation)
3.4.3.3 Atovaquone 750 mg by mouth one time daily.17 (UW Health Moderate quality
evidence, strong recommendation)
3.4.3.3.1 Patients with relapsed disease may receive atovaquone 1500 mg by
mouth one time daily. (UW Health Moderate quality evidence, strong
recommendation)
3.4.3.4 Dapsone 100 mg by mouth once daily or in 2 divided doses.17 (UW Health
Moderate quality evidence, strong recommendation)
3.4.3.4.1 Glucose-6-Phosphate Dehydrogenase testing is recommended before
initiation of dapsone. (UW Health Moderate quality evidence, strong
recommendation)
4. Immunizations
4.1 Live vaccines [e.g., measles, mumps, rubella, intranasal influenza, herpes zoster
(shingles), etc.] should be delayed until resolution of cGVHD and discontinuation of all
immunosuppressive therapies.3,17,19 (UW Health Very low quality evidence, strong
recommendation) Other vaccines may be administered without delay.16,17,19,69 (UW Health
Very low quality evidence, strong recommendation)
4.2 Patients should receive the inactivated influenza vaccine annually.3,16,17,19 (UW Health
High quality evidence, strong recommendation)
4.3 It may be beneficial to assess antibody levels before and after vaccination to determine if
there is a need for booster immunizations.17,19 (UW Health Very low quality evidence,
weak/conditional recommendation)
4.3.1 Pre vaccination testing for: measles, mumps, rubella and varicella at the time
patients are due for the vaccines. The recommended time is 2 years after
transplant. If positive, then no vaccine is given.70 (UW Health Very low quality
evidence, weak/conditional recommendation)
4.3.2 Post vaccination testing for: HBV, measles, tetanus, diphtheria, polio and
pneumococcus. The recommended time varies from 2 to 4 years after transplant.
It is also recommended that titers be checked every 4 years or so for those on
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chronic immune suppression.70 (UW Health Very low quality evidence,
weak/conditional recommendation)
4.4 It may be beneficial to administer Pneumococcal Conjugate Vaccine, 13-Valent (PCV-
13) rather than Pneumococcal Polysaccharide Vaccine, 23-Valent (PPSV-23) for the
fourth dose in patients with cGVHD.17,19 (UW Health Very low quality evidence,
weak/conditional recommendation)


5. Hypogammaglobulinemia
5.1 Intravenous Immune Globulin (IVIG) may be considered for patients who have recurrent
sinopulmonary infections and serum IgG levels less than 400 mg/dL more than 90 days
after transplant3,69 (UW Health Moderate quality evidence, strong recommendation) Use of
IVIG should be re-evaluated after 180 days of treatment. (UW Health Very low quality
evidence, weak/conditional recommendation)
PHYSICAL FITNESS REHABILITATION FOR cGVHD
Due to the impact of cGVHD on musculoskeletal and lung organ systems, physical therapy,
occupational therapy and pulmonary rehabilitation are potential ancillary therapy options for
patients. Physical and occupational therapy may be considered for patients who have a
decreased ability to perform activities of daily living, work-related activities or impaired quality of
life because of pain or muscle weakness.3 (UW Health Very low quality evidence, weak/conditional
recommendation) In particular, patients with scleroderma or fasciitis may benefit from range of
motion and muscle strengthening exercises to minimize loss of function.3,18,71 (UW Health Very
low quality evidence, weak/conditional recommendation) Patients with BOS may benefit from
pulmonary rehabilitation.3,72 (UW Health Low quality evidence, weak/conditional recommendation)
Pulmonary rehabilitation has been shown to improve 6-minute walk distance, subjective
symptoms of dyspnea, and exercise tolerance in patients with BOS.72
RESPONSE ASSESSMENT
Signs and symptoms of cGVHD have been reviewed and reported by the NIH consensus
Working Group to standardize criteria for classification of cGVHD for the purpose of clinical
trials. Although developed and intended to help standardize clinical trial eligibility, the tools
translate well for use in patients not enrolled on a clinical trial. Published evidence supports its
use to measure cGVHD disease activity.73

It is recommended to assess response at approximately 4 weeks after treatment is initiated and
then at 8 weeks after treatment is initiated. Further assessment frequency depends on response
and complexity of medication regimen and should continue every 4 to 12 weeks until after end
of therapy.2 (UW Health Very Low quality evidence, weak/conditional recommendation)

How to assess response to cGVHD (Chronic GVHD Response Assessment Form)

The Chronic GVHD Response Assessment Form contains an Activity Assessment form to help
physicians evaluate response assessment for their patients with cGVHD.

How to score response assessment
To assess response, disease manifestations at 2 predefined time points must be compared, and
a judgment must be made as to whether the magnitude of any change qualifies as improvement
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25


or deterioration. This magnitude of change should reflect genuine clinical change, and the
criteria should be clarified and standardized as much as possible to avoid measurement error.
The NIH Working Group proposes the following consensus definitions for assessment of overall
response and for measurable organ response (Table 8).2

Table 8. Response Determination for cGVHD2


QUALITY OF LIFE/ PATIENT REPORTED OUTCOMES MEASUREMENT
Lee and colleagues developed a symptom scale designed for individuals with cGVHD.74 The
questionnaire asks patients to indicate the dHJUHH�RI�³ERWKHU´�WKDW�WKH\�H[SHULHQFHG�GXULQJ�WKH�
past 4 weeks due to symptoms in 7 domains potentially affected by cGVHD (skin, eyes and
mouth, breathing, eating and digestion, muscles and joints, energy, emotional distress).
Published evidence supports its validity, reliability, and sensitivity to cGVHD severity.25,73,75-78

1. It is recommended to assess at a minimum of every 4 weeks until improvement in NIH
response scores and then every 3 months.2 (UW Health Low quality evidence, weak/conditional
recommendation)

How to monitor patient reported cGVHD symptoms
The Lee Symptom Scale can be completed in approximately 5 minutes. The reporting time
frame may be decreased to 1 week to specifically capture more recent symptoms.2

How to score Lee Symptom Scale
See the Scoring Algorithm for Lee cGVHD Symptom Scale.

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26


UW Health Implementation
Potential Benefits:
ξ Systematic evaluation of patient centered outcomes
ξ Increased patient satisfaction and quality of life
ξ Improved value of health services delivered
ξ Increased Overall Survival and Failure Free Survival
ξ Reduced Non-relapse Mortality

Potential Harms: Adverse reactions to pharmacotherapy

Pertinent UW Health Policies & Procedures
UWHC Clinical, Department Specific: Nursing Patient Care 1.05A, Photopheresis (Adult)

Patient Resources
1. Health Facts For You: 415 ± Graft Versus Host Disease Diet Recommendations
2. Healthwise: Graft Versus Host Disease
3. Lexicomp- Graft Versus Host Disease
4. BMT Patient Education Binder

Guideline Metrics
1. % of patients with cGVHD who have a stage determined.
2. % of patients with a given stage who have a response assessment.
3. % of patients with patient reported outcome assessment (Lee symptom scale).
4. % of patients screened for cGVHD
5. % of patients with positive screen that were assessed for cGVHD diagnosis/staging

Implementation Plan/Clinical Tools
1. Guideline will be posted on U-Connect in a dedicated location for Clinical Practice
Guidelines.
2. Release of the guideline will be advertised in the Physician/APP Briefing newsletter.
3. Content and hyperlinks within clinical tools, documents, or Health Link related to the
guideline recommendations (such as the following) will be reviewed for consistency and
modified as appropriate.

Delegation Protocols
Post‐Hematopoietic Stem Cell Transplant (HSCT) Immunosuppressive Therapy ± Adult ±
Ambulatory ‐ Oncology Clinic [125]

Order Sets & Smart Sets
OP ± Day 100 Allogeneic Transplant Follow Up ± Adult ± Clinic Visit [5213]
OP ± Day 180 Allogeneic Transplant Follow Up ± Adult ± Clinic Visit [5214]
OP ± Day 270 Allogeneic Transplant Follow Up ± Adult ± Clinic Visit [5222]
OP ± Year 1 Allogeneic Transplant Follow Up ± Adult ± Clinic Visit [5223]

Beacon Protocols
CSC SC Immunizations Post Hematopoetic Stem Cell Transplant [1961]
CSC SC BMT Aldesleukin (Interleukin-2) [5271]
CSC SC Etanercept for GVHD [5772]


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27


Disclaimer
Clinical practice guidelines assist clinicians by providing a framework for the evaluation and
treatment of patients. This guideline outlines the preferred approach for most patients. It is not
LQWHQGHG�WR�UHSODFH�D�FOLQLFLDQ¶V�MXGJPHQW�RU�WR�HVWDEOLVK�D�SURWRFRO�IRU�DOO�SDWLHQWV��,W�LV�
understood that some patients will not fit the clinical condition contemplated by a guideline and
that a guideline will rarely establish the only appropriate approach to a problem.

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Appendix A. Evidence Grading Scheme(s)

Grading of Recommendations Assessment, Development and Evaluation (GRADE)

Figure 1. GRADE Methodology adapted by UW Health

GRADE Ranking of Evidence
High We are confident that the effect in the study reflects the actual effect.
Moderate We are quite confident that the effect in the study is close to the true effect, but it
is also possible it is substantially different.
Low The true effect may differ significantly from the estimate.
Very Low The true effect is likely to be substantially different from the estimated effect.

GRADE Ratings for Recommendations For or Against Practice
Strong The net benefit of the treatment is clear, patient values and
circumstances are unlikely to affect the decision.
Weak/Conditional
Recommendation may be conditional upon patient values and
preferences, the resources available, or the setting in which the
intervention will be implemented.








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References
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54. Villanueva FN, Perez-Simon JA, Silva FF, et al. Oral beclomethasone dipropionate for the
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Chronic GVHD Screening

Check the symptoms you have had in the last week.
Does your skin:
□ Feel tight or hard?
□ Have increased dryness?
□ Feel very itchy?
□ Have new rashes or changes in the color of your skin?
□ Are you unable to sweat or unable to keep your body warm?
□ Do you have recent loss of hair (scalp or body)?
□ Do you have nail changes?

□ Do you have stiffness or pain in the wrists, fingers or other joints?

Are your eyes:
□ Dry?
□ Sensitive to wind or air conditioning?
□ Painful or gritty?

Is your mouth:
□ Dry?
□ Sensitive to hot/cold or strong flavors?
□ Do you have mouth ulcers or sores?
□ Do you have taste changes?
□ Do foods or pills get stuck upon swallowing?

Are you short of breath:
□ At rest?
□ With activity?
□ Do you have a cough or wheeze?

□ Any unexplained weight loss or inability to gain weight?

Females:
□ Do you have discomfort or pain with sexual intercourse?
□ Do you have vaginal dryness or itching?
Males:
□ Do you have burning or difficulty with urination?
□ Do you have genital pain?

□ I have none of the above symptoms

Overall, since the last visit, are you feeling:
□ Better?
□ Worse?
□ The same?
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 Organ Specific Severity Scoring


Organ Scoring of Chronic GVHD: ECOG indicates Eastern Cooperative Oncology Group; KPS, Karnofsky Performance Status;
LPS, Lansky Performance Status; BSA, body surface area; ADL, activities of daily living; LFTs, liver function tests; AP, alkaline
phosphatase; ALT, alanine aminotransferase; ULN, normal upper limit.*Weight loss within 3 months. †Skin scoring should use both
percentage of BSA involved by disease signs and the cutaneous features scales. When a discrepancy exists between the percentage of
total body surface (BSA) score and the skin feature score, OR if superficial sclerotic features are present (Score 2), but there is impaired
mobility or ulceration (Score 3), the higher level should be used for the final skin scoring. ‡To be completed by specialist or trained
medical providers (see Supplement Figure – Genital Tract Scoring Form). **Lung scoring should be performed using both the symptoms
and FEV1 scores whenever possible. FEV1 should be used in the final lung scoring where there is discrepancy between symptoms and
FEV1 scores.
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised:
 
08/2016CCKM@uwhealth.org

  
Organ Scoring of Chronic GVHD: ECOG indicates Eastern Cooperative Oncology Group; KPS, Karnofsky Performance Status;
LPS, Lansky Performance Status; BSA, body surface area; ADL, activities of daily living; LFTs, liver function tests; AP, alkaline
phosphatase; ALT, alanine aminotransferase; ULN, normal upper limit.*Weight loss within 3 months. †Skin scoring should use both
percentage of BSA involved by disease signs and the cutaneous features scales. When a discrepancy exists between the percentage of
total body surface (BSA) score and the skin feature score, OR if superficial sclerotic features are present (Score 2), but there is impaired
mobility or ulceration (Score 3), the higher level should be used for the final skin scoring. ‡To be completed by specialist or trained
medical providers (see Supplement Figure – Genital Tract Scoring Form). **Lung scoring should be performed using both the symptoms
and FEV1 scores whenever possible. FEV1 should be used in the final lung scoring where there is discrepancy between symptoms and
FEV1 scores.
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised:
 
08/2016CCKM@uwhealth.org


 
 
 
 
 
 
Organ Scoring of Chronic GVHD: ECOG indicates Eastern Cooperative Oncology Group; KPS, Karnofsky Performance Status;
LPS, Lansky Performance Status; BSA, body surface area; ADL, activities of daily living; LFTs, liver function tests; AP, alkaline
phosphatase; ALT, alanine aminotransferase; ULN, normal upper limit.*Weight loss within 3 months. †Skin scoring should use both
percentage of BSA involved by disease signs and the cutaneous features scales. When a discrepancy exists between the percentage of
total body surface (BSA) score and the skin feature score, OR if superficial sclerotic features are present (Score 2), but there is impaired
mobility or ulceration (Score 3), the higher level should be used for the final skin scoring. ‡To be completed by specialist or trained
medical providers (see Supplement Figure – Genital Tract Scoring Form). **Lung scoring should be performed using both the symptoms
and FEV1 scores whenever possible. FEV1 should be used in the final lung scoring where there is discrepancy between symptoms and
FEV1 scores.
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised:
 
08/2016CCKM@uwhealth.org

 
Supplement Figure – Genital Tract Chronic Graft-versus-Host Assessment and
Scoring Form
Name:________________________ Date of birth: _________Assessment date:
___________
SCORE 0 SCORE 1 SCORE 2
SCORE 3
GENITAL
TRACT
Check:

Male Female
No signs


Mild signs and
females may
have
symptoms*
WITH
discomfort on
exam
Moderate signs
and may have
symptoms* with
discomfort on
exam
Severe signs
with
or without
symptoms *

Currently sexually active:
Yes No

Check all signs that apply:

Lichen planus-like features
Lichen sclerosis-like features
Vaginal scarring (female)
Clitoral/labial agglutination (female)
Labial resorption (female)






Erosions
Fissures
Ulcers
Phimosis (male)
Urethral meatus scarring/ stenosis (male)
Abnormality present but NOT thought to represent GVHD (specify
cause):_________ _______________________
Abnormality thought to represent GVHD PLUS other causes(specify
cause):_________ ______________________

*Genital symptoms are not specific to cGVHD and can repres ent premature gonadal
failure or genital tract infection.
 
 
 
 
 
 
 
 
 
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised:
 
08/2016CCKM@uwhealth.org


 
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised:
 
08/2016CCKM@uwhealth.org


Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised:
 
08/2016CCKM@uwhealth.org


 
 
 
 
 
 
 
 
 
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised:
 
08/2016CCKM@uwhealth.org

Lee cGVHD Symptom Scale
Please let us know if you have been bothered by any of the following problems in the past month.
 








 
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised:
 
08/2016CCKM@uwhealth.org

Scoring Algorithm for the Lee Chronic GVHD Symptom Scale
The Lee Chronic GVHD Symptom Scale is a 30 item instrument with 7 subscales (skin, eyes, mouth, lung, nutrition,
energy and psych) containing 2-��LWHPV��5HVSRQVH�RSWLRQV�IRU�³OHW�XV�NQRZ�LI�\RX�KDYH�EHHQ�ERWKHUHG�E\�DQ\�RI�WKH�
IROORZLQJ�LQ�WKH�SDVW�PRQWK´�range from 0-4 (Not at all, Slightly, Moderately, Quite a bit, Extremely). Some investigators
have used the scale in reference to the past 7 days. (Lee SJ, Cook EF, Soiffer R, Antin JH. Development and validation of a scale
to measure symptoms of chronic graft-versus-host disease. Biol Blood Marrow Transplant 2002; 8:444-452)
Subscale
name
Number
of items
Items
Skin 5 a. Abnormal skin color
b. Rashes
c. Thickened skin
d. Sores on skin
e. Itchy skin
Eye 3 f. Dry eyes
g. Need to use eyedrops frequently
h. Difficulty seeing clearly
Mouth 2 i. Need to avoid certain foods due to mouth pain
j. Ulcers in mouth
Lung 5 l. Frequent cough
m. Colored sputum
o. Shortness of breath at rest
p. Need to use oxygen
aa. Fevers
Nutrition 5 k. Receiving nutrition from an intravenous line or feeding tube
q. Difficulty swallowing solid foods
r. Difficulty swallowing liquids
s. Vomiting
t. Weight loss
Energy 7 n. Shortness of breath with exercise
u. Joint and muscle aches
v. Limited joint movement
w. Muscle cramps
x. Weak muscles
y. Loss of energy
z. Need to sleep more/take naps
Psych 3 bb. Depression
cc. Anxiety
dd. Difficulty sleeping
Bold indicates items that are scored under a different subscale than where they are located
Scoring rules:
1. Note that the subscales do not conform exactly to the categories in the patient survey.
2. Subscales may be scored if 50% of more of the items in the subscale are completed.
3. Scores are linearly transformed to a 0-����VFDOH�ZKHUH���PHDQV�DOO�DQVZHUHG�LWHPV�ZHUH�D�³�´�DQG
³���´�PHDQV�WKDW DOO�DQVZHUHG�LWHPV�ZHUH�D�³�´
4. Missing items are not included in the scoring.
5. The summary score is the average of the subscale scores, as long as 4 or more subscales are
available.
6. Higher scores indicate more severe symptoms.
7. A clinically meaningful difference for each subscale or the summary score is considered to be half a
standard deviation of the baseline score for the population, based on the distribution method of
determining clinically meaningful change
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised:
 
08/2016CCKM@uwhealth.org

Extracorporeal photopheresis (ECP)
1. Extracorporeal photopheresis should be initiated in patients with severe cGVHD who
have disease progression after four weeks of therapy with concurrent prednisone and
sirolimus.
1-7
(UW Health Moderate quality evidence, strong recommendation)
2. Treatment schedule
2.1. Treatment should be initiated with one cycle (two treatments on consecutive
days) every week for four weeks (weeks 1 through 4), then every other week for
four weeks (weeks 5, 7, 9, and 11), then every four weeks for four months. (UW
Health Low quality evidence, strong recommendation) Patients should complete their
entire treatment schedule unless they meet stopping points as described below.
2.2. If patient continues to respond to ECP therapy, it may be reasonable to
continue beyond the above schedule. (UW Health Very low qual ity evidence,
weak/conditional recommendation)
3. Response assessments should be conducted at:
3.1. Four weeks after initiation of therapy:
3.1.1. If cGVHD has rapidly progressed, therapy should be discontinued.
(UW Health Moderate quality evidence, strong recommendation)
3.1.2. If cGVHD is stable or has improved, therapy should continue. (UW
Health Moderate quality evidence, strong recommendation)
3.2. Three months after initiation of therapy:
3.2.1. If patient has cGVHD progression or no change from initiation of
ECP, therapy should be discontinued.
1
(UW Health High quality evidence,
strong recommendation)
3.2.2. If patient has any improvement and/or reduction in systemic
immunosuppression, ECP therapy should continue. (UW Health Moderate
quality evidence, strong recommendation)
3.3. Every three months for the duration of therapy and upon completion. (UW
Health Very low quality evidence, strong recommendation)
4. When to discontinue treatment
4.1. If rapid progression at 4 week response assessment. (UW Health Very l ow
quality evidence, weak/conditional recommendation)
4.2. If progression or no change from initiation at 3 month response assessment.
(UW Health Very low quality evidence, weak/conditional recommendation)
4.3. After at least 3 months, if progression of cGVHD at any time unrelated to an
attempt to taper systemic immunosuppression.
1
(UW Health Moderate quality
evidence, strong recommendation)
4.2.1. If flare correlates to a taper attempt, ECP therapy may be
continued.
1
(UW Health Moderate quality evidence, strong recommendation)
4.4. Once patient has reached maximum, stable response if therapy has
continued beyond initial treatment schedule. (UW Health Very low quality evidence,
weak/conditional recommendation)
5. The following patients are at increased risk of complications from ECP
1
:
5.1. On medications that cause photosensitivity
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised:
 
08/2016CCKM@uwhealth.org

5.2. History of heparin-induced thrombocytopenia (HIT)
5.3. Difficulty handling fluid shifts
5.4. Active and uncontrolled infection

1. Scarisbrick JJ, Taylor P, Holtick U, et al. U.K. consensus statement on the use of
extracorporeal photopheresis for treatment of cutaneous T-cell lymphoma and chronic graft-
versus-host disease. Br J Dermatol. 2008;158(4):659-678.
2. Dignan FL, Amrolia P, Clark A, et al. Diagnosis and management of chronic graft-versus-
host disease. Br J Haematol. 2012;158(1):46- 61.
3. Wolff D, Gerbitz A, Ayuk F, et al. Consensus conference on clinical practice in chronic
graft-versus-host disease (GVHD): first-line and topical treatment of chronic GVHD. Biol
Blood Marrow Transplant. 2010;16(12):1611-1628.
4. Bredeson C, Rumble RB, Varela NP, Kuruvilla J, Kouroukis CT. Extracorporeal
photopheresis in the management of graft-versus-host disease. Curr Oncol.
2014;21(2):e310-325.
5. Abu-Dalle I, Reljic T, Nishihori T, et al. Extracorporeal photopheresis in steroid-refractory
acute or chronic graft-versus-host disease: results of a systematic review of prospective
studies. Biol Blood Marrow Transplant. 2014;20(11):1677- 1686.
6. de Waure C, Capri S, Veneziano MA, et al. Extracorporeal Photopheresis for Second-
Line Treatment of Chronic Graft-versus-Host Diseases: Results from a Health Technology
Assessment in Italy. Value Health. 2015;18(4):457-466.
7. Bertani G, Santoleri L, Ferri U, et al. Response of steroid-refractory chronic graft-versus-
host disease to extracorporeal photopheresis correlates with the dose of CD3+ lymphocytes
harvested during early treatment cycles. Transfusion. 2015.
Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised:
 
08/2016CCKM@uwhealth.org

Interleukin-2 (IL-2) Therapy

1. IL-2 therapy with aldesleukin may be considered for patients with active cGVHD despite at least four weeks
of treatment with concurrent prednisone and sirolimus and who are either refractory to or do not qualify for
other preferred treatments.
1,2
(UW Health Very low quality evidence, weak / conditional recommendation)
1.1. Patients receiving both sirolimus and tacrolimus concurrently should not receive IL-2 due to the risk of
renal failure.
1,2
(UW Health Moderate quality evidence, strong recomm endation)
2. Treatment may be initiated at a dose of aldesleukin 1 x 10
6
international units/m
2
subcutanous daily for
eight weeks followed by four weeks off.
1
(UW Health Very low quality evidence, weak/conditional
recommendation)
2.1. If patient begins to experience toxicities, the daily dose may be reduced to aldesleukin 0.3 x 10
6

international units/m
2
subcutaneous.
2.2. Aldesleukin should not be administered by intravenous bolus or infusion.
2.3. Patients who experience clinical benefit after the initial eight weeks of therapy may continue at the
initial dose level.
3. Aldesleukin may be administered in the home or outpatient setting. (UW Health Very low quality evidence,
strong recommendation)
3.1. Patients should receive education about appropriate storage, preparation, and administration of this
product upon initiation of therapy and reinforcement of proper technique throughout therapy. (UW
Health Very low quality evidence, strong recommendation)
4. Patients receiving IL-2 should be monitored according to the supportive care plan. (CSC SC BMT
Aldesleukin (Interleukin-2) [5271]).
1,2
(UW Health Very low quality evidence, strong recommendation)
4.1. If patient develops common terminology criteria for adverse events (CTCAE) grade 3 toxicity, therapy
should be discontinued. (UW Health Very low quality evidence, strong recommendation)


1. Koreth J, Matsuoka K, Kim HT, et al. Interleukin-2 and regulatory T cells in graft-versus-host disease. N
Engl J Med. 2011;365(22):2055-2066.
2. Koreth J, Kim HT, Jones KT, et al. Efficacy, durability, and response predictors of low-dose interleukin-
2 therapy for chronic graft vs. host disease. Blood. 2016.

Copyright © 201� University of Wisconsin Hospital s and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised:
 
08/2016CCKM@uwhealth.org