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Acute Graft versus Host Disease - Adult/Pediatric - Inpatient/Ambulatory

Acute Graft versus Host Disease - Adult/Pediatric - Inpatient/Ambulatory - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Oncology


1



Acute Graft Versus Host Disease –
Adult/Pediatric – Inpatient/Ambulatory
Clinical Practice Guideline


Note: Active Table of Contents – Click to follow link
EXECUTIVE SUMMARY ........................................................................................................................................... 3
SCOPE .................................................................................................................................................................... 3
METHODOLOGY ..................................................................................................................................................... 4
DEFINITIONS .......................................................................................................................................................... 5
INTRODUCTION ..................................................................................................................................................... 5
RECOMMENDATIONS ............................................................................................................................................ 6
CLINICAL PRESENTATION AND DIFFERENTIAL DIAGNOSIS.......................................................................................................... 6
When to consider a biopsy .................................................................................................................................... 6
STAGING AND GRADING DISEASE........................................................................................................................................ 7
RISK ASSESSMENT .......................................................................................................................................................... 8
Refined Risk Score ................................................................................................................................................. 9
ACUTE GVHD TREATMENT .............................................................................................................................................. 9
Therapy Recommendations for Adults ................................................................................................................ 12
Therapy Recommendations for Pediatrics .......................................................................................................... 14
SUPPORTIVE CARE RECOMMENDATIONS ........................................................................................................................... 15
Nutrition .............................................................................................................................................................. 15
Distress/Psychosocial concerns ........................................................................................................................... 19
Sun exposure ....................................................................................................................................................... 19
Exercise and Referring to Physical/Occupational Therapy .................................................................................. 20
UW HEALTH IMPLEMENTATION ........................................................................................................................... 21
APPENDIX A. EVIDENCE GRADING SCHEME(S) ..................................................................................................... 23
APPENDIX B. CLINICAL STAGING, GRADING AND REFINED RISK SCORE FOR ACUTE GVHD PATIENTS ................... 24
APPENDIX C. EXAMPLE STEROID TAPER SCHEDULE ............................................................................................. 25
REFERENCES ......................................................................................................................................................... 26



2


Contact for Content:
Name: Mark Juckett, MD – Hematology/Oncology
Phone Number: (608) 265-4363
Email Address: mbj@medicine.wisc.edu

Name: Inga Hoffman, MD – Pediatric Hematology/Oncology
Phone Number: (608) 263-8558
Email Address: ihofmann@wisc.edu

Contact for Changes:
Name: Katherine Le, PharmD – Center for Clinical Knowledge Management
Phone Number: (608) 890-5898
Email Address: kle@uwhealth.org

Coordinating Team Members:
Jessica Becher, NP – Hematology/Oncology
Natalie Callander, MD – Hematology/Oncology
Bethaney Campbell, RN – Bone Marrow Transplant
Emily Dworkin, PharmD – Oncology Pharmacy
Aric Hall, MD – Hematology/Oncology
Christine Killips, RDN – Pediatric Clinical Nutrition
Sara Koth, PharmD – Oncology Pharmacy
Walt Longo, MD – Hematology/Oncology
Lauren McGinty, PharmD – Oncology Pharmacy
Kelly Nuckolls, RDN – Clinical Nutrition
Corbin Pozar – Quality, Safety and Innovation
Dawn Reininger, RN – Oncology
Katherine Saunders, PharmD – Oncology Pharmacy
Lindsey Spencer – Center for Clinical Knowledge Management
Amanda Swiecichowski, RN – Bone Marrow Transplant

Review Individuals/Bodies:
Erin Costanzo, PhD – Cancer Psychology
Robin Crist, RDN – Clinical Nutrition
Lisa Keller, NP – Pediatric Medicine
Andrea Magee, RDN – Clinical Nutrition
Bethany Severson, RN – Pediatric Specialties Ambulatory Clinic
Sara Shull, PharmD, MBA – Drug Policy Program
Darcy Stagman, RDN – Clinical Nutrition
Emily Wallace, RDN – Clinical Nutrition
David Yang, MD – Pathology and Laboratory Medicine

Committee Approvals/Dates:
Clinical Knowledge Management (CKM) Council (Last Periodic Review: 07/27/17)


Release Date: July 2017 | Next Review Date: April 2019


3


Executive Summary
Guideline Overview
This guideline has been developed to assist in the assessment and management of patients
with acute Graft versus Host Disease. The recommendations include staging and grading
criteria to use, medication treatment recommendations, and supportive care recommendations
such as nutritional guidance.

Key Practice Recommendations
1. A skin biopsy should be considered in all patients where the skin is the only organ involved
and lacking features of chronic GVHD, since it is minimally invasive and low-risk to the
patient.
1
A biopsy is especially recommended if the patient will receive systemic therapy for
treatment.
2. Endoscopy is recommended for patients with persistent anorexia, persistent
nausea/vomiting and/or unexplained gastrointestinal symptoms (e.g., adult patient with ≥ 3
watery stools per day or diarrhea ≥ 500 mL/day.)
3. If the liver is the only organ involved, a biopsy is recommended.
4. It is recommended to consider a patient’s risk using the University of Minnesota refined risk
score criteria when initiating treatment therapy in an adult patient.
5. For pediatric patients that do not have mild cutaneous skin aGVHD, it is recommended to
initiate methylprednisolone IV 2 mg/kg/day
2,3
in divided doses or prednisone/prednisolone by
mouth 2.5 mg/kg/day in divided doses as initial aGVHD treatment.
6. For adult patients assessed as “standard risk” and who will require systemic therapy,
suggested initial dosing of prednisone 1mg/kg/day orally. For patients assessed as “high
risk,” suggested initial dosing is methylprednisolone 2mg/kg/day IV or prednisone orally
2.5mg/kg/day in divided doses.
7. Patients whose disease worsens after 3 days or who have no response after 7 days of
appropriately dosed systemic steroid treatment are considered to have “steroid refractory
disease” and therapy should be escalated accordingly (e.g., from standard risk steroid
therapy dosing to high risk steroid therapy dosing.)
8. It is recommended to order a nutrition consult or schedule an outpatient nutrition
appointment for patients with GVHD who are at nutrition risk.
9. Patients with a new acute GVHD diagnosis that will require systemic therapy or who are
deemed “high risk” for not achieving a complete or partial response to therapy at 28 days
should be assessed for distress using the National Comprehensive Cancer Network (NCCN)
Distress Thermometer (DT).
10. Given immune suppression in aGVHD patients, multi-disciplinary care is crucial and
supportive services (e.g., nutrition, Health Psych) should be considered early and involved.

Companion Documents
1. NCCN Distress Thermometer
2. Patient Health Questionnaire (PHQ-9)
Scope
Disease/Condition(s): Acute Graft versus Host Disease (aGVHD)

Clinical Specialty: Hematology/Oncology/Blood and Marrow Transplant (BMT), Pharmacy,
Nutrition, Social Work, Health Psychology

Intended Users: Physicians, Advanced Practice Providers, Registered Nurses, Pharmacists,
Registered Dieticians, Social Workers, Health Psychologists

4



Objective(s): To outline evidence-based recommendations for the screening, diagnosis,
staging, treatment and monitoring of aGVHD.

Target Population: Adult and pediatric patients who have received allogeneic Bone Marrow
Transplants (BMT) and are being seen in the BMT clinic or inpatient settings.

Interventions and Practices Considered:
• Staging and Grading
• Risk Assessment for initial therapy response and transplant-related mortality
• Treatment
• Nutrition
• Patient Reported Quality of Life

Major Outcomes Considered:
• Overall survival
• Non-relapse mortality
• Quality of Life

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: None identified


5


Definitions

Acute Graft versus Host Disease (aGVHD): Acute GVHD is defined as the following:
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 chronic
GVHD and
2. persistent, recurrent, or late onset acute GVHD: features of classic acute GVHD occurring
beyond 100 days after transplantation or DLI in a patient not meeting criteria for the
diagnosis of chronic GVHD (often seen during the taper or after withdrawal of immune
suppression.)
4


Chronic Graft versus Host Disease (cGVHD): Chronic GVHD is a syndrome of variable
clinical features resembling autoimmune and other immunologic disorders, such as
scleroderma, Sjögren’s syndrome, primary biliary cirrhosis, wasting syndrome, bronchiolitis
obliterans, immune cytopenias, and chronic immunodeficiency.
5,6
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 includes 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.
7


Overlap Syndrome: The term “overlap” refers to the presence of 1 or more acute GVHD
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 with “overlap” cGVHD
have resolution of the acute features, whereas cGVHD features persist. Similarly, patients with
classic cGVHD may develop acute GVHD features when immunosuppression is tapered.
7

Introduction
Acute graft versus host disease is an immunologic process that involves 3 phases: 1) afferent
phase where damage to the host tissue occurs by the preparative regimen; 2) induction and
expansion phase where there is triggering and activation of donor-derived T-cells by recipient
and donor antigen-presenting cells (APC) as well as inflammatory cytokines; 3) effector phase
with target tissue damage induced directly by cytotoxic T cells and indirectly by inflammatory
cytokines.
2,8


Acute GVHD is a major post-transplant complication and is the leading cause of non-relapse
mortality post hematopoietic stem cell transplantation (HSCT).
7
The incidence is between 10-
80% for adults and pediatric patients have a lower incidence than adults.
9,10
Historically, acute
GVHD was differentiated from chronic GVHD based on time of presentation with acute GVHD
occurring before day 100 post-HSCT and chronic GVHD occurring after day 100.
8
Classic acute
GVHD usually occurs within the first 3 or 4 months after HSCT while both late-onset and overlap
acute GVHD tend to occur after reduced-intensity conditioning, after initial taper of
immunosuppression, or after donor lymphocyte infusion.
9


6


Recommendations
Clinical presentation and differential diagnosis

Acute GVHD is usually suspected when a patient develops any or all symptoms in the skin,
gastrointestinal tract, and/or liver. It is recommended that an acute GVHD diagnosis be based
on clinical criteria versus post-transplant time only.
11
(UW Health strong quality evidence, strong
recommendation)

The most commonly involved organ in acute GVHD is the skin, followed by the gastrointestinal
tract and lastly the liver. A characteristic maculopapular rash that is pruritic and can spread on
the body, sparing the scalp, is the most common skin presentation. Gastrointestinal (GI)
involvement typically manifests as diarrhea but can also include anorexia, vomiting, abdominal
pain or a combination of these symptoms if severe. Liver involvement usually presents with
cholestatic jaundice and elevated liver enzymes
12,13


Table 1 lists the most common symptoms and other possible diagnoses for the clinical
manifestation.

Table 1. Acute GVHD symptoms and Differential Diagnosis
9,10,12-14

Symptoms Differential diagnosis
Skin
• Maculopapular skin rash
• Drug hypersensitivity
• Allergic reaction
• Infection (e.g. viral exanthem)
• Regimen-related toxicity
• Engraftment syndrome
Upper gastrointestinal tract
• Nausea, vomiting
• Anorexia
• Infection (viral, fungal, bacterial)
• Regimen-related toxicity
• Medication side-effect
• Increased intracranial pressure
• Phlegmonous gastritis

Lower gastrointestinal tract
• Watery diarrhea (≥500 mL)
• Severe abdominal pain
• Bloody diarrhea or ileus
• Infection (viral, fungal, bacterial, parasitic)
• Opiate withdrawal
• Regimen-related toxicity

Liver
• Jaundice
• Elevated liver enzymes
• Hyperbilirubinemia
• Sinusoidal obstruction syndrome
• Medication toxicities (e.g. azoles)
• Sepsis
• Viral infections (e.g. cytomegalovirus, Epstein-Barr virus,
Hepatitis B)
• Hemolysis
When to consider a biopsy
Given acute GVHD symptoms are quite non-specific, biopsies may be helpful in determining
appropriate etiology if the diagnosis is unclear. However, histologic confirmation should not
delay treatment or management.
11
The following are general recommendations on when to
obtain a biopsy:
• A skin biopsy should be considered in all patients where the skin is the only organ
involved and lacking features of chronic GVHD, since it is minimally invasive and low-
risk to the patient.
1
A biopsy is especially recommended if the patient will receive
systemic therapy for treatment. (UW Health Low quality of evidence, weak/conditional
recommendation.)

7


• Endoscope is recommended for patients with persistent anorexia, persistent
nausea/vomiting, and/or unexplained gastrointestinal symptoms (e.g., an adult patient
with ≥ 3 watery stools per day or diarrhea ≥ 500 mL/day.) (UW Health Low quality of
evidence, weak/conditional recommendation.)
• If the liver is the only organ involved, a biopsy is recommended. (UW Health Low quality of
evidence, weak/conditional recommendation.)
Staging and grading disease
Once a patient is diagnosed with acute GVHD, the severity of the disease is determined by
assessing the degree of skin, gastrointestinal tract, and liver involvement. An overall grade is
assigned based off of the combination of specific organ stages. It is recommended to use the
Consensus grading system (Table 2) to promote standardization across clinic workflows and
support required registry reporting. (UW Health Low quality of evidence, strong recommendation.)

Considerations when staging acute GVHD
There can be significant variance between transplant centers and between independent
reviewers within an organization. Moreover, it may be difficult on occasion for a clinician to
translate patient reported symptoms into staging criteria. For example, it can be difficult to
extrapolate volume of diarrhea from patient reported episodes of diarrhea that are unmeasured.
It is recommended to consider the following when staging patients to decrease practice variation
and increase uniformity. Table 2 and Appendix B summarize these considerations with clinical
staging and grading criteria for adult and pediatric patients.

Skin
• It is recommended to document if desquamation or fluid-filled bullae are present
because these are findings are key characteristics of stage 4 GVHD.
15
(UW Health Low
quality of evidence, weak/conditional recommendation.)
Lower GI
• Consider staging lower GI GVHD as Stage 4 if severe abdominal, ileus, and/or stool with
frank blood or melena, is present, regardless of stool volume.
15,16

• When only number of diarrhea episodes is available, consider calculating average
volume as 200 mL/episode or 3 mL/kg for children < 50 kg.
17

• When grading lower GI GVHD based on volume of diarrhea, use these indicators in the
following order: (1) average of 3 consecutive days, (2) average of 2 consecutive days, or
(3) the volume on day of assessment.
16
(UW Health Low quality of evidence,
weak/conditional recommendation.)
Upper GI
• An upper GI biopsy is required for staging
18
when utilizing Consensus criteria, however
a biopsy may not always be done. This can result in under-reporting of the incidence of
upper GI GVHD, thus it is recommended to stage upper GI if there is persistent nausea
or vomiting with or without anorexia.
16
(UW Health Low quality of evidence, strong
recommendation.)
• Consider alternate etiologies for symptoms besides acute GVHD if:
o nausea persists fewer than 3 days
o if there are fewer than 2 vomiting episodes per day for at least 2 days, or
o if anorexia without weight loss is present.
16




8


Table 2. Staging and Grading Criteria for Acute GVHD
Stage Skin

Liver (bilirubin) Lower Gastrointestinal tract
£
Upper
Gastrointestinal
tract


0 No rash, no rash
attributable to acute
GVHD
No liver acute
GVHD/bilirubin
< 2.0 mg/dL (<34
µmol/L)
No diarrhea, no diarrhea attributable
to aGVHD;
Adult: Diarrhea < 500mL/day, or < 3
episodes/day
Pediatric: Diarrhea <10 mL/kg/day,
or < 4 episodes/day
No persistent nausea or
vomiting
1

Maculopapular rash,
< 25% of body
surface
2.0-3.0 mg/dL
(34-52 µmol/L)
Adult: Diarrhea 500-1000 mL/day, or
3-4 episodes/day
Pediatric: Diarrhea 10-19.9
mL/kg/day or 4-6 episodes/day
Persistent nausea or
vomiting, with or without
anorexia
2

Maculopapular rash,
25-50%of body
surface
3.1-6.0 mg/dL
(53-103 µmol/L)
Adult: Diarrhea 1001-1500 mL/day
(adult) or 5-7 episodes/day
Pediatric: 20-30 mL/kg/day or 7-10
episodes/day

3

Generalized
erythroderma,
> 50% of body
surface
6.1-15.0 mg/dL
(104-256 µmol/L)
Adult: Diarrhea > 1500 mL/day
(adult) or >7 episodes/day
Pediatric: Diarrhea >30 mL/kg/day
or > 10 episodes/day

4 Generalized
erythema with bullae
formation and/or
desquamation
>15.0 mg/dL
(>256 µmol/L)
Adult/Pediatric: Severe abdominal
pain with or without ileus, and/or
grossly bloody stool (regardless of
stool volume)

£ Diarrhea volumes of liquid stool should be based in the following order: (1) average of 3 consecutive days, (2)
average of 2 consecutive days, or (3) the volume on day of assessment. If diarrhea reported only as episodes,
consider average volume per diarrhea as 200 mL/episode or 3 mL/kg for children <50 kg.
For Stage 4 Lower GI: Bloody diarrhea is staged as 4, independent of volume of diarrhea.
Ω Nausea < 3 days or < 2 vomiting episodes/day for 2 days or anorexia without weight loss should not be staged.
Grade
Skin Liver Lower GI Upper GI
I
Stage 1-2

No liver involvement No gut involvement
II
Stage 3 Stage 1 Stage 1, or Persistent nausea
III
Stage 2-3 Stage 2-4
IV
Stage 4 Stage 4
Risk Assessment
Given the therapeutic challenges faced in treating acute GVHD patients, various algorithms
have been developed and identified to aid clinicians in determining a patient’s likelihood of
achieving a complete or partial response to steroid therapy and risk of non-relapse mortality.
19


Risk Assessment using Biomarkers
One approach to help clinicians determine a patient’s likelihood of non-relapse mortality is
examining biomarkers. A number of biomarkers have been studied and three of interest are
TNF receptor-1 (TNFR1), regenerating islet-derived 3-alpha (REG3α), and suppression of
tumorigenicity 2 (ST2). Using the equation below, the serum or plasma levels of these three
biomarkers have been formulated into a validated algorithm to identify probability of 6-month
and 12-month non-relapse mortality.
9,19,20


log[−log(1−p)] = −9.169 + 0.598(log
2
TNFR1) −0.028(log
2
REG3α) + 0.189(log
2
ST2)

9


It is recommended that clinicians consider obtaining the plasma or serum levels of TNFR1,
REG3α and ST2 in patients diagnosed with acute GVHD to further assess non-relapse mortality
risk, however, the biomarker calculated risk score should not be used to guide treatment
therapy. (UW Health Moderate quality of evidence, weak/conditional recommendation.)
Refined Risk Score
A second approach to consider is using a validated risk assessment model, originally developed
by the University of Minnesota and has since been refined. This tool stratifies a patient into a
standard risk or high risk group at the onset of aGVHD based on the severity of organ
involvement. A patient deemed “high risk” is less likely to achieve a complete or partial
response at day 28 and also has a higher risk of non-relapse mortality.
21,22


The criteria to stratify patients based on organ staging is summarized in Table 3 and also listed
in Appendix B. A web-based program is also available to determine a patient’s risk group and
can be accessed at: http://z.umn.edu/MNAcuteGVHDRiskScore. It is recommended to calculate
a risk score for a patient with aGVHD grade ≥ 2 and/or involvement of more than one organ for
adult patients only; the refined risk score is not used in pediatric practice at UW Health at this
time. (UW Health Low quality of evidence, strong recommendation)

Table 3. Refined Risk Score for Acute GVHD
21

aGVHD
Risk
Score
Organ Involvement
One Organ Two Organ Three Organ
Standard
Risk
• Stage 1-3 Skin
• Stage 1-2 GI

• Stage 1-3 skin + stage 1 GI
• Stage 1-3 skin + stage 1-4 liver
--
High
Risk
• Stage 4 Skin
• Stage 3-4 GI
• Stage 1-4 Liver
• Stage 1-3 skin + stage 2 GI
• Stage 1-2 lower GI + stage 1-3 liver
• Stage 3-4 GI + stage 1-3 skin
• Stage 3-4 GI + stage 1-4 liver
• Stage 1-3 skin + stage 1-2 GI +
stage 1-3 liver
• Stage 1-3 skin + stage 3-4 GI +
stage 1-4 liver
Note: Upper GI plus lower GI considered as single-organ disease

Acute GVHD Treatment
Grade 1 Skin aGVHD only
For patients with Grade 1 skin only acute GVHD, topical therapies should be initiated according
to recommendations listed in Table 4 for adult and Table 7 for pediatric patients.

Initial Therapy For Adults
For adult patients, it it recommended to initiate treatment according to their refined risk score
stratification. (UW Health Low quality of evidence, strong recommendation.) Specific therapy
recommendations according to a patient’s risk score can be found in Table 5. For example, an
adult aGVHD patient with Stage 1 skin and Stage 1 liver is considered “standard risk” and
should be treated with prednisone and topical therapy recommendations. It For patients who
are already taking a calcineurin inhibitor who subsequently develop aGVHD, it is recommended
to optimize calcineurin inhibitor therapy as part of aGVHD treatment. (UW Health Low quality of
evidence, strong recommendation.)

For adult patients with high risk GVHD where there is concern of treating with systemic
corticosteroids dosed by weight, it is reasonable to conduct a short trial of the systemic

10


corticosteroid therapy (e.g., 4 days of therapy.) (UW Health Low quality of evidence,
weak/conditional recommendation)

Initial Therapy For Pediatrics:
For pediatric patients that do not have mild cutaneous skin aGVHD, it is recommended to
initiate methylprednisolone IV 2 mg/kg/day
2,3
in divided doses or prednisone/prednisolone by
mouth 2.5 mg/kg/day in divided doses (Table 7.) (UW Health Low quality of evidence, strong
recommendation.)

Steroid-refractory acute GVHD
If a patient’s disease progresses after 3 days or has no response after 7 days of appropriately
dosed systemic steroids, the patient is considered to have “steroid refractory disease.” Patients
should be tapered off steroids after 5-7 days, irrespective of disease response. (UW Health
Moderate quality of evidence, strong recommendation.) Recommendations for steroid-refractory
acute GVHD are listed in Table 6 and Table 8 for adults and pediatrics respectively. Figure 1
outlines the acute GVHD treatment pathway for adults.

Tapering Glucocorticoids
If aGVHD symptoms begin to resolve after 5-7 days of steroid therapy, it is reasonable to
attempt a taper.
2
(UW Health Strong quality of evidence, strong recommendation.) Inappropriate
rapid tapering poses a risk of GVHD exacerbation or recurrence while inappropriately slow
tapering can increase the risk of steroid-related complications.
23,24
Prednisone may be tapered
by approximately 10% every 5 – 7 days over approximately 8 to 10 weeks depending on rapidity
of response, GVHD risk, and other patient factors.
24
An example of a steroid taper schedule can
be found in Appendix C.

Patient with aGVHD
Stage and grade disease;
assess patient’s risk
Consider biopsy if only skin or only liver; consider
endoscope if persistent anorexia, persistent nausea/
vomitting, and/or unexplained gastrointestinal
symptoms (e.g., diarrhea ≥500 mL/day)
Grade 1
aGVHD Skin only?
Rash <50% B.S.A
Standard risk aGVHD?
NO
Treat with initial
therapy
recommendations for
standard risk aGVHD
Treat according to initial
therapy recommendations
for high risk aGVHD
YES
NO
Treat according to
steroid refractory
recommendations
Severe GI GVHD w/no
improvement after 14 days
or
stable w/no improvement
after 28 days?
Consider switching or add
treatment option for
steroid-refractory disease
YES
Treat according to mild
cutaneous aGVHD
recommendations
Rash rapidly
progressing?
Continue to
treat as
clinically
indicated
Figure 1. Acute Graft versus Host Disease Treatment Pathway for Adults
YES
Monitor for 4 days
Disease progressed
after 3 days?
NO
Condition unchanged
or worse?
Taper
steroid
YES
NO
Disease progressed
after 3 days?
YES
NO
Monitor for 4
days
Condition unchanged
or worse?
GVHD Flare?
Chronic GVHD
present?
YES
Treat for overlap syndrome
(refer to Chronic GVHD guideline)
YES
NO
YES
Taper
steroid
NO
Treat as
clinically
indicated
Monitor iteratively
Measure and document response
every 28 days
NO
YES
YES
Treat as clinically
indicated
NO
NO

12


Therapy Recommendations for Adults
Table 4: Therapy for Grade 1 (mild) cutaneous aGVHD for Adults
It is reasonable in mild GVHD that is confined to the skin and involves less than 50% of the total body surface area to treat with topical treatment alone.
If rash progresses rapidly, patients should be initiated on systemic steroids per Table 2.

aGVHD Medication Recommendation
Evidence
Quality
Recommendation
Strength
Topical
Therapy
Entire
body
Tacrolimus 0.1% ointment to the affected area two times daily
11

It is reasonable to use pimecrolimus cream instead of tacrolimus ointment if insurance dictates topical CNI therapy.
Moderate Strong
Neck and
below
Betamethasone dipropionate 0.05% ointment
11
OR clobetasol 0.05% to the affected area two times daily High Strong
Triamcinolone 0.5% cream to the affected area two times daily
Through slightly less potent, this is a reasonable alternative for patients unable to tolerate or obtain betamethasone
ointment
Very low Weak/conditional
Face
Hydrocortisone 1% ointment to the affected area two times daily
11

High Strong
Calcineurin inhibitor
therapy
Recommend optimizing existing calcineurin inhibitor for GVHD prophylaxis
(Tacrolimus goal serum level is 5-15 ng/mL)
Low Strong

Table 5: Recommendations for Initial Therapy in Standard and High Risk aGVHD for Adults
Risk aGVHD Medication Recommendation
Evidence
Quality
Recommendation
Strength
S
t
a
n
d
a
r
d

R
i
s
k

Gastrointestinal
Topical
Budesonide EC 9 mg by mouth one time daily
25

High Strong
Beclomethasone compounded liquid 2 mg by mouth four times daily (Grade I to II only)
26
Low Weak/conditional
Initial systemic
therapy
Prednisone PO 1 mg/kg/day (Grade I to IIa)
3,27

High Strong
Combination
therapy
It is reasonable in patients with mild GVHD of GI tract with or without a mild rash to consider
combining enteric coated budesonide with immediate release beclomethasone AND low-dose
systemic steroids for initial management
28

Low Weak/conditional
Liver
(with stage I-II skin
involvement)
Initial systemic
therapy
Prednisone PO 2.5 mg/kg/day in divided doses plus topical therapy
3,27

For lower grade liver involvement (i.e., Grade I-II), may consider starting at lower steroid dose and
clinically assessing response.
High Strong
H
i
g
h

R
i
s
k
*

Cutaneous
Initial systemic
therapy
Methylprednisolone IV 2 mg/kg/day
3,27
in divided doses or
Prednisone PO 2.5 mg/kg/day in divided doses plus topical therapy
3,27

High Strong
Gastrointestinal
Initial systemic
therapy
Methylprednisolone IV 2 mg/kg/day
3,27
in divided doses or
Prednisone PO 2.5 mg/kg/day
3,27
in divided doses plus topical therapy
High Strong
Liver
Initial systemic
therapy
Methylprednisolone IV 2 mg/kg/day
3,27
in divided doses or
Prednisone 2.5 mg/kg/day
3,27
in divided doses
High Strong
Calcineurin
inhibitor therapy
It is recommended to initiate a calcineurin inhibitor in patients not already on a calcineurin inhibitor (e.g., received
high-dose Cytoxan only post-transplant) in addition to steroid therapy for high risk aGVHD.
Low Weak/conditional
* For patients with high risk GVHD, it is reasonable to treat aGVHD with systemic corticosteroid dosed by weight for a short trial (e.g., 4 days.)

13


Table 6: Treatment for Steroid-Refractory aGVHD for Adults
£

Steroid-refractory defined as progression of aGVHD with 3 days of appropriately dosed systemic steroids OR no response with 7 days of appropriately dosed systemic steroids.
Steroid therapy should be tapered after 5-7 days, irrespective of disease response.
aGVHD
Medication Recommendation
(Note: Treatments are listed in preferential order of usage)
Evidence
Quality
Recommendation
Strength
Cutaneous
Clinical trial
Non-pharmacologic treatment with psoralen and ultraviolet A irradiation (PUVA) starting three times weekly and tapering to
twice weekly based on response, in conjunction with dermatology consult
29

High Strong
*Sirolimus 2 mg PO daily
30-32
(target trough 3-12 ng/mL)
Low Strong
Etanercept 25 mg subQ twice weekly x 4 weeks initially (may be continued as clinically indicated)
33-35

Low Strong
Ruxolitinib 5-10 mg PO two times daily
36

Low Strong
Tocilizumab 8 mg/kg IV every 3-4 weeks
37,38
≠ Low Strong
Gastrointestinal
α

Clinical trial
Tocilizumab 8 mg/kg IV every 3-4 weeks
37,38

Low Strong
Etanercept 25 mg subQ twice weekly x 4 weeks (may be continued as clinically indicated)
33-35
OR
Infliximab 10 mg/kg IV once weekly
39-42

Low Strong
*Sirolimus 2 mg PO daily (target trough 3-12 ng/mL)
30-32

Low Strong
Ruxolitinib 5-10 mg PO two times daily
36

Low Strong
Liver
Clinical trial
*Sirolimus 2 mg PO daily (target trough 3-12 ng/mL)
30-32

Low Strong
Ruxolitinib 5-10 mg PO two times daily
36

Low Strong

£ For patients already on a calcineurin inhibitor, it is recommended to optimize calcineurin inhibitor and add therapy to treat acute GVHD. (UW Health Low quality
of evidence, strong recommendation.)

α For Grade IV GI GVHD, consider moving to another agent/re-assessing therapy after 14 day response. (UW Health Low quality of evidence, weak/conditional
recommendation.)

≠ For clinically stable patients, consider a 28 day response rate before moving to another agent and/or addition of a third agent. (UW Health Low quality of
evidence, weak/conditional recommendation.)

* For patients with steroid-refractory disease already taking tacrolimus, it is recommended to transition patients off tacrolimus if starting sirolimus therapy.



14


Therapy Recommendations for Pediatrics

Table 7: Recommendations for Initial Therapy for aGVHD in Pediatric Patients
It is reasonable in mild GVHD that is confined to the skin and involves less than 50% of the total body surface area to treat with topical treatment alone.
If rash progresses rapidly, patients should be initiated on systemic steroids per Table 2.
aGVHD Medication Recommendation
Evidence
Quality
Recommendation
Strength
Topical
therapy
(Grade 1
cuteaneous
aGVHD)
Entire body
Tacrolimus 0.1% ointment to the affected area 2 to 3 times daily
2
OR
Triamcinolone 0.1% ointment or cream to the affected area 2 to 3 times daily
2

Very low Strong
Face
Hydrocortisone 1% cream to the affected area 2 to 3 times daily
2

Very low Strong
Cutaneous
Methylprednisolone IV 2 mg/kg/day
2,3
in divided doses or
Prednisone/prednisolone PO 2.5 mg/kg/day in divided doses
High Strong Gastrointestinal
Liver




Table 8: Treatment for Steroid Refractory aGVHD for Pediatrics
Steroid-refractory defined as progression of aGVHD with 3 days of appropriately dosed systemic steroids OR no response with 7 days of appropriately dosed systemic steroids
aGVHD
Medication Recommendation
(Note: Treatments are listed in preferential order of usage)
Evidence
Quality
Recommended
Strength
Cutaneous
Clinical trial

Non-pharmacologic treatment with psoralen and ultraviolet A irradiation (PUVA) starting
three times weekly and tapering to twice weekly based on response, in conjunction with
dermatology consult
29,43

High Strong
Etanercept 0.4 mg/kg (max 25 mg) subQ twice weekly x 4 weeks
35,44-46
Moderate Strong
Tocilizumab 8 mg/kg IV every 3-4 weeks
47-49
Moderate Strong
Gastrointestinal
Clinical trial

Infliximab 10 mg/kg IV once weekly for 4 doses
50-52
OR
etanercept 0.4 mg/kg (max 25 mg) subQ twice weekly x 4 weeks
35,44-46

Low Strong
Tocilizumab 8 mg/kg IV every 3-4 weeks
47-49
Low
Weak/
Conditional
Liver
Clinical trial



15


Supportive Care Recommendations
Nutrition
Patients with aGVHD are at risk for significant weight loss and malnutrition.
53,54
Nutrition-related
side effects of aGVHD that may contribute to poor nutrition include: protein-losing enteropathy,
malabsorption, pancreatic atrophy, and exocrine pancreatic insufficiency.
53
The common
treatment for aGVHD, glucocorticoids, may lead to poor nutrition outcomes including
hyperglycemia, steroid-induced diabetes, loss of lean body mass, and poor bone health.
55
To
prevent or resolve malnutrition, patients with aGVHD often require modified diets, oral nutrition
supplements and/or nutrition support.
56


Stepwise oral diet progression based on the severity of aGVHD has been shown to improve
symptoms.
53,54,57
Nutrition by oral route should be maintained as appropriate to help preserve
intestinal integrity.
58


The exact role of enteral nutrition (EN) and parenteral nutrition (PN) in aGVHD patients has not
been well studied. In general, EN is associated with the preservation of the GI tract and
maintenance of the gut-associated lymphoid tissue (GALT), which protects against infection.
59-61

EN has been shown to be safe and feasible and is linked with decreased mortality from
infection, less time to platelet recovery, and shorter length of stay.
59,62-69

70
EN has shown distinct
advantages for management and treatment of other inflammatory gastrointestinal conditions,
such as Crohn’s disease and ulcerative colitis. Therefore there is likely a role for EN in the
GVHD population, even at a minimum as trophic feeds.
54,71-73


PN is associated with less weight loss and loss of body fat.
56,69,73
Disadvantages of PN include
increased incidence of hyperglycemia, hypertriglyceridemia, volume overload, catheter-related
complications (e.g., infections), and mucosal alterations.
60,61,74,75
To decrease these incidences,
clinicians should consider utilizing both PN and EN, as appropriate, in order to optimize nutrition
status and prevent malnutrition and severe weight loss. Small amounts of EN may also help
reduce infection rates and hepatic complications associated with PN.
58
(UW Health Low quality of
evidence, weak/conditional recommendation.)

Nutrition Assessment
It is recommended to order a nutrition consult (inpatient) or schedule a nutrition appointment for
patients (outpatient) with aGVHD who are at nutrition risk. (UW Health Low quality of evidence,
strong recommendation.) A registered dietitian nutritionist (RDN) will complete a nutrition
assessment.

Characteristics that may place a patient with GVHD at nutrition risk include the following:
• History of malnutrition
• Significant or unintentional weight loss
• Inability to meet at least 50% of estimated calorie needs through oral diet alone
• Symptoms impacting oral intake: mucositis, nausea, vomiting, diarrhea, abdominal pain,
early satiety, dry mouth, altered taste, altered smell
• Previous reliance on nutrition support
• For Pediatrics: Patient’s weight-for-age, BMI, or weight-for-length declining across > 2
growth channels
• For Pediatrics: Patient with BMI or weight-for-length below the 5
th
percentile for age

16


To schedule an outpatient nutrition appointment:
For Pediatrics: Nutrition appointments can be made at the American Family Children’s Hospital
Nutrition Clinic by calling (608) 890-5500. Rather than calling to schedule a future appointment,
you may send an In Basket message to the Pediatric Nutrition Schedulers Pool (37027101) to
request a nutrition appointment. Please call the scheduler for same day appointments.

For Adults: Nutrition appointments can be made at the UW Carbone Cancer Center by calling
(608) 265-1700. Future appointments may be made by sending an In Basket message to the
UWH CC Schedulers Pool (2212601) to request a nutrition appointment. Please call the
scheduler for same day appointments.


Oral Diet
An oral diet is appropriate for patients who can tolerate foods by mouth. (UW Health Moderate
quality evidence, strong recommendation) The oral diet can be advanced depending on symptoms
and tolerance. If the patient is in the hospital, the GVHD diet can be ordered. This diet is low in
lactose, fiber, and fat. The RDN will provide education regarding nutrition supplements. (UW
Health Low quality of evidence, weak/conditional recommendation.)

Appetite Stimulants
For Adults:
For patients with persistent anorexia, consider addition of an appetite stimulant such as
megestrol acetate (Megace
®
) or mirtazapine. (UW Health Low quality of evidence, weak/conditional
recommendation.) Dexamethasone may be used short term for appetite stimulation as well.
76-78

(UW Health Low quality evidence, weak/conditional recommendation) Suggested dosing for megestrol
and mirtazapine is:
• Megestrol acetate 400 mg by mouth twice daily.
73,79-84

• Mirtazapine 15 mg by mouth daily at bedtime.
73,85,86


For Pediatrics:
Appetite stimulants may be used to enhance oral intake in pediatric patients if other barriers to
intake, such as nausea, abdominal pain, and mucositis, are not present. (UW Health Low quality
evidence, weak/conditional recommendation) Cyprohepatadine is the most appropriate appetite
stimulant to use in this population. Medications, such as dronabinol and mirtazapine can be
considered, but these are typically reserved for instances where other conditions, such as
nausea, insomnia, or depression, are present. Suggested dosing for cyproheptadine is as
follows:
• For patients ≥ 2 years: cyproheptadine 0.25 mg/kg/day divided twice daily
87


These appetite stimulants are associated with adverse reactions such as drowsiness,
depression, edema, insomnia, stomach cramps, cholestatic jaundice, and hepatotoxicity. It is
recommended that their usage should be considered with reference to the complete clinical
picture and only if all other methods of improving oral intake have been exhausted.
54
(UW Health
Low quality of evidence, weak/conditional recommendation.)

Enteral Nutrition (EN)
For patients with a functional GI tract but inability to ingest adequate nutrition orally to maintain
weight/lean body mass, consider EN.
56
(UW Health Low quality evidence, weak/conditional
recommendation) If a patient needs enteral nutrition, a nutrition consult is recommended for an
individualized nutrition plan, including selection of the EN formula. (UW Health Low quality of

17


evidence, weak/conditional recommendation.) Additional guidance can be found in the UW Health
Pediatric Enteral Nutrition Handbook, Nutrition Standard of Practice for Pediatric Hematopoietic Stem Cell
Transplant Policy Number E2.600 and the UW Health Adult Enteral Nutrition Support Handbook-
Guidelines for Tube Feeding.

Parenteral Nutrition (PN)
For Adults:
It is recommended to consider parenteral nutrition for patients with poor oral intake and
significant malabsorption.
56,58,70,74
(UW Health Moderate quality of evidence, weak/conditional
recommendation) Examples of when to consider initiating PN include:
• Patients unable to take in and absorb adequate nutrition for 7-14 days.
56

• Patients with diarrhea ≥ 500 mL/day
70,74
(i.e., ≥ Stage 1 Lower GI GVHD)
• Patients who exhibit signs of nutritional depletion without indication of improvement
within 7 days.
70

• Severe malnutrition on admission
58

• Patients unable to tolerate oral diet or fail to meet 60-70% of nutrition requirements over
3 days
58


When beginning PN for a GVHD patient, the UW Health Surgical Nutrition Support Team
(SNST) evaluates the patient’s gastrointestinal losses, acid-base status, and dose of
corticosteroids. Given some patients with acute GI GVHD may have very large amounts of
diarrhea (e.g., diarrhea >5 liters per day) these patients will often require sodium in the PN
equivalent to sodium chloride 0.9%. However, instead of chloride, it is added as the acetate
salt. It is important to remember that the PN will not meet the needed fluid requirements to
replace losses, thus it is recommended that the SNST communicate with the primary team
regarding rate and volume of the PN. (UW Health Very low quality of evidence, weak/conditional
recommendation.)

Most GVHD patients will receive high dose corticosteroids and will require insulin in the PN. If a
patient is hyperglycemic before PN is initiated, a dose of 0.15-0.2 units insulin/gram of dextrose
should be added to the PN. (UW Health Very low quality of evidence, weak/conditional
recommendation.)

Calorie requirements for aGVHD patients are generally higher, ranging from 30-40 kcal/kg.
Protein requirements are usually higher as well, since patients with GI GVHD often have large
protein losses in their stool. Patients will require 1.8 to 2 g protein/kg in the PN. Along with
protein and electrolytes, patients also lose zinc in their stool, so it is customary to supplement
zinc 5-15 mg/day in the PN. For additional guidance refer to the UWHC Clinical Nutrition
Services Policy 3.6- Parenteral Nutrition Assessment, Ordering and Monitoring. For population
specific guidance refer to the UW Health Parenteral Nutrition- Pediatric/Neonatal -
Inpatient/Ambulatory Clinical Practice Guideline or the UW Health Parenteral Nutrition - Adult -
Inpatient/Ambulatory Clinical Practice Guideline .

Parenteral nutrition may be discontinued when the patient’s GI symptoms resolve (i.e., no
intractable vomiting, stool output <500 mL/day for at least 2 consecutive days) and the patient
can tolerate an oral diet or EN is meeting at least 50% of daily estimated caloric needs.
70
(UW
Health Low quality of evidence, weak/conditional recommendation)




18


For Pediatrics:
If a patient has severe GI dysfunction or is unable to meet nutrition requirements with EN alone,
consider PN.
56
(UW Health Low quality evidence, weak/conditional recommendation) If a patient
needs parenteral nutrition, it is recommended to order a nutrition consult and a Pediatric
Nutrition Support Team or Adult Surgical Nutrition Support Team consult. (UW Health Very low
quality of evidence, strong recommendation.)

Vitamin/Mineral Supplements
For Adults:
Common deficiencies among GVHD patients may include vitamin D, vitamin B12, zinc and
magnesium.
53
If a patient is not on nutrition support and does not have impaired kidney function,
consider starting a multivitamin mineral tab daily. (UW Health Very low quality of evidence,
weak/conditional recommendation.) Also consider monitoring electrolytes and supplement if low
(i.e., magnesium, potassium, and phosphate) and check calcium (total and ionized) and vitamin
D levels yearly. (UW Health Very low quality of evidence, weak/conditional recommendation.) For
patients with normal serum calcium and vitamin D levels, consider daily supplementation of
1200 mg calcium and 1000 IU cholecalciferol (vitamin D3). For best absorption of calcium, take
as single doses of less than or equal to 500 mg.
88
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.
89
(UW Health Very low quality of evidence, weak/conditional recommendation.)

For Pediatrics:
Pediatric patients with aGVHD are at risk for vitamin and mineral deficiencies. If the patient is
not on nutrition support, consider starting a daily multivitamin. (UW Health Low quality of evidence,
weak/conditional recommendation.) Patients with GVHD may require additional vitamin D
supplementation
90
thus it is recommended to check the vitamin D level. (UW Health Low quality of
evidence, weak/conditional recommendation.) For most children, dietary reference intakes (DRI)
listed below are reasonable starting points for supplementation: (UW Health Low quality of
evidence, weak/conditional recommendation.)
• Infants (0-1 year): 400 IU
• Children (>1 year): 600 IU

Supplementation can be increased based on baseline level and response to supplementation. If
a patient will be on corticosteroids for an extended period, consider having the patient
supplement with at least 800 IU of vitamin D
91,92
and ensure there is adequate calcium intake.
(UW Health Low quality of evidence, weak/conditional recommendation.) Calcium requirements while
on steroids are listed below. Supplementation may be needed based on adequacy of intake.
93

• 0-6 months: 400 mg
• 6-12 months: 600 mg
• 1-3 years: 800 mg
• 4-8 years: 1200 mg
• 9-18 years: 1500 mg

If a patient is suspected to have vitamin or mineral deficiencies, it is recommended that patient
have a nutrition consult/appointment for an assessment by a RDN including supplementation
recommendations. (UW Health Very low quality of evidence, weak/conditional recommendation.)



19


Nutrition Monitoring:
It is recommended that patients at nutrition risk with GVHD have ongoing nutrition monitoring by
a RDN. (UW Health Low quality of evidence, weak/conditional recommendation.)
Distress/Psychosocial concerns
It is especially important for providers of HSCT patients to be aware of their patients’
psychosocial needs and distress level in the first six months following transplant. For pediatric
patients, one review study noted the first six-month period post-transplant to be a risk factor for
poor quality of life.
94
In adults, patients with aGVHD six months after transplant had a
measurable decline in quality of life compared to those without.
95
An increased risk of aGVHD
has also been associated with pre-transplant depression and post-transplant depression has
been linked to increased mortality.
96

The National Comprehensive Cancer Network (NCCN) estimates that less than 10% of cancer
patients receive adequate psycho-oncological support.
97
Thus it is recommended providers be
cognizant of their HSCT patients’ distress levels and to consider the following:
1. Patients with a new aGVHD diagnosis that will require systemic therapy or who are
deemed “high risk” for not achieving a complete or partial response to therapy at 28
days should be assessed for distress using the NCCN Distress Thermometer (DT).
(UW Health Moderate quality of evidence, strong recommendation.)
2. If the patient has a level of ≥ 4 on the Distress Thermometer, consider further evaluating
the patient.
98,99
For example, if there is concern for depression or suicidal ideation,
perform screening using a validated tool (e.g., PHQ-9.) (UW Health Moderate quality of
evidence, weak/conditional recommendation.)
3. A patient may be referred to Health Psychology if he/she has significant distress after
assessment with distress thermometer (e.g., DT score >4 with any emotional concerns,
treatment decisions, family problems, fatigue, pain and/or sleep disturbance.)
4. If there is clinician concern at any point while a patient is undergoing treatment for
aGVHD, the patient should be assessed for distress.
In some cases, a direct referral to Health Psych may be warranted. Some considerations on
when to refer aGVHD patients to Health Psych include (UW Health Moderate quality evidence,
weak/conditional recommendation):
• Provider has concerns about patient’s emotional or psychological function or feels
patient would benefit from behavioral strategies to manage disease symptoms (e.g.,
fatigue, pain, sleep disturbance.)
• Patient seeks additional assistance in coping with disease, emotions or physical
symptoms.
Sun exposure
It is strongly recommended that HSCT patients, regardless of ethnicity and skin color, protect
themselves from sun exposure because of the potential to cause or trigger GVHD.
100,101
(UW
Health Moderate quality evidence, strong recommendation) Precautions must be taken indefinitely
given the risk for acute or chronic GVHD post-transplant. Patients and parents should be
advised to follow general sun safety recommendations such as limiting outdoor activities during
the day when ultraviolet (UV) radiation peaks (i.e. from 10 a.m. - 2 p.m. and during daylight
saving time 11 a.m. – 3 p.m.) and limiting exposure to 30-60 minutes blocks. (UW Health
Moderate quality of evidence, weak/conditional recommendation.) Patients are also advised to wear
sun-protective clothing such as long sleeve shirts, sunglasses, wide brim hats when outdoors.
102

(UW Health Strong quality of evidence, weak/conditional recommendation.)

20



Patients should be advised as well to follow sunscreen recommendations. For children and
adults, a broad-spectrum sunscreen that is para-aminobenzoic acid free with SPF ≥ 30 should
be applied to sun exposed skin 15 minutes before going outdoors and re-applying every 2
hours, especially after heavy perspiration or swimming.
100,102,103
Patient should be careful in the
setting of water and sand, which can reflect UV rays
102
and sun exposure cautions should also
be followed during the cold weather season as well since snow can also reflect sunlight
100
and
during long car rides and while sitting under an umbrella.
100

Exercise and Referring to Physical/Occupational Therapy
The benefit of exercise for aGVHD patients is not limited to maintaining bone health and
building endurance, but can also help improve mood, health-related quality of life including
cancer-related fatigue, and alleviate stress.
100,101,104
One meta-analysis saw the best results for
exercise at discharge, implying that starting intervention before or just after transplantation
seems effective.
105
Clinicians should encourage patients to exercise and to follow general
physical activity guidelines if possible. For children and adolescents, 60 minutes or more of daily
physical activity is recommended with bone-strengthening activity on at least 3 days of the
week. For adults, the recommended exercise duration is 150 minutes a week of moderate-
intensity.
106
(UW Health Low quality of evidence, weak/conditional recommendation.)

For Pediatrics:
It is recommended that pediatric patients be referred to physical therapy or occupational therapy
upon hospital admission for acute GVHD. (UW Health Low quality of evidence, weak/conditional
recommendation.)

For Adults:
Patients may also be advised of special interest fitness classes such as “Living Falls Free,” an
exercise class with a focus on balance enhancement and teaches falls reduction strategies. (UW
Very Low quality evidence, weak/conditional recommendation)

For aGVHD patients whose disease limits their exercise capacity and/or declining physical
function, a referral to Physical Therapy or Occupational Therapy may be warranted. Some
criteria for referral are (UW Health Low quality of evidence, weak/conditional recommendation):
• Steroid induced myopathy and weakness
• Immobility/poor range of motion due to GVHD
• Neuropathy management
• Edema management due to graft versus host disease
• Balance rehabilitation- chemo induced neuropathy causing poor balance.

In patients with acute GVHD that require treatment for greater than 3 months, supportive care
concerns are likely to closely mirror those for chronic GVHD. Additional guidance on
supportive care recommendations for adults with chronic GVHD (i.e., acid suppression, bone
health, anti-infective prophylaxis and immunizations) can be found in the UW Health Chronic
Graft versus Host Disease Diagnosis and Treatment Guideline.





21


UW Health Implementation
Potential Benefits:
• Decrease in practice variation amongst providers
• Reduced non-relapse mortality

Potential Harms:
• Adverse reactions to pharmacotherapy

Pertinent UW Health Policies & Procedures
1. UWHC 15.2 Medication Use in Outpatient Care Areas
2. UWHC 6.1.9 Restricted Primarily Ambulatory Administered Medications in Hospitalized
Patients

Patient Resources
1. Health Facts For You #415 – Graft Versus Host Disease Diet Recommendations

Guideline Metrics
1. Number of patients with acute GVHD with standard assessment at diagnosis
2. Number of aGVHD patients with risk adjusted treatment
3. Number of aGVHD patients enrolled in a clinical trial for aGVHD treatment

Implementation Plan/Clinical Tools
1. Guideline will be posted on uConnect 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.

Clinical Practice Guidelines
Parenteral Nutrition – Adult – Inpatient/Ambulatory
Parenteral Nutrition – Pediatric/Neonatal – Inpatient/Ambulatory
Guideline for Pediatric Total Parenteral Nutrition
Perioperative Medication Management – Adult/Pediatric – Inpatient/Ambulatory
Renal Function-Based Dose Adjustment – Adult – Inpatient/Ambulatory

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

Beacon Protocols
CSC SC Immunizations Post Hematopoetic Stem Cell Transplant [1961]
CSC SC Etanercept for GVHD [5772]

Order Sets & Smart Sets
OP – Day 100 Allogeneic Transplant Follow Up – Adult – Clinic Visit [5213]
Smart Set- IP- Hematopoietic Stem Cell Transplant – Pediatric – Admission [1710]
Photopheresis- Adult Supplemental Order Set [301440-DT]


22



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
intended to replace a clinician’s judgment or to establish a protocol for all patients. It is
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.

23


Appendix A. Evidence Grading Scheme(s)

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.



24


Appendix B. Clinical Staging, Grading and Refined Risk Score for Acute GVHD Patients
Clinical Staging for Acute GVHD in Adults and Children
16-18

Stage Skin

Liver (bilirubin) Lower Gastrointestinal tract
£
Upper
Gastrointestinal
tract


0 No rash, no rash
attributable to acute GVHD
No liver acute
GVHD/bilirubin
< 2.0 mg/dL (<34 µmol/L)
No diarrhea, no diarrhea attributable to aGVHD;
Adult: Diarrhea < 500mL/day, or < 3 episodes/day
Pediatric: Diarrhea <10 mL/kg/day, or < 4 episodes/day
No persistent nausea
or vomiting
1

Maculopapular rash, < 25%
of body surface
2.0-3.0 mg/dL
(34-52 µmol/L)
Adult: Diarrhea 500-1000 mL/day, or 3-4 episodes/day
Pediatric: Diarrhea 10-19.9 mL/kg/day or 4-6 episodes/day
Persistent nausea or
vomiting, with or
without anorexia
2

Maculopapular rash,
25-50%of body surface
3.1-6.0 mg/dL
(53-103 µmol/L)
Adult: Diarrhea 1001-1500 mL/day (adult) or 5-7 episodes/day
Pediatric: 20-30 mL/kg/day or 7-10 episodes/day

3

Generalized erythroderma,
> 50% of body surface
6.1-15.0 mg/dL
(104-256 µmol/L)
Adult: Diarrhea > 1500 mL/day (adult) or >7 episodes/day
Pediatric: Diarrhea >30 mL/kg/day or > 10 episodes/day

4 Generalized erythema with
bullae formation and/or
desquamation
>15.0 mg/dL
(>256 µmol/L)
Adult/Pediatric: Severe abdominal pain with or without ileus, and/or grossly
bloody stool (regardless of stool volume)

£ Diarrhea volumes of liquid stool should be based in the following order: (1) average of 3 consecutive days, (2) average of 2 consecutive days, or (3) the volume on day of
assessment. If diarrhea reported only as episodes, consider average volume per diarrhea as 200 mL/episode or 3 mL/kg for children <50 kg.
For Stage 4 Lower GI: Bloody diarrhea is staged as 4, independent of volume of diarrhea.
Ω Nausea < 3 days or < 2 vomiting episodes/day for 2 days or anorexia without weight loss should not be staged.
Grade
Skin Liver Lower GI Upper GI
I
Stage 1-2

No liver involvement No gut involvement
II
Stage 3 Stage 1 Stage 1, or Persistent nausea
III
Stage 2-3 Stage 2-4
IV
Stage 4 Stage 4
Refined Risk Score for Acute GVHD
2

Risk Score One Organ Two Organs Three Organs
Standard
Risk

• Stage 1-3 Skin
• Stage 1-2 GI

• Stage 1-3 skin + stage 1 GI
• Stage 1-3 skin + stage 1-4 liver
--
--
High Risk • Stage 4 Skin
• Stage 3-4 GI
• Stage 1-4 Liver
• Stage 1-3 skin + stage 2 GI
• Stage 1-2 lower GI + stage 1-3 liver
• Stage 3-4 GI + stage 1-3 skin
• Stage 3-4 GI + stage 1-4 liver
• Stage 1-3 skin + stage 1-2 GI plus stage 1-3 liver
• Stage 1-3 skin + stage 3-4 GI plus stage 1-4 liver
Note: Upper GI plus lower GI considered single organ

25


Appendix C. Example Steroid Taper Schedule


Prednisone may be tapered by approximately 10% every 5 – 7 days over approximately 8 to 10
weeks depending on rapidity of response, GVHD risk, and other patient factors

More than mild GHVD from 2 mg/kg/day
Day
AM dose
PM dose
Before taper 1 mg/kg 1 mg/kg
1 1 mg/kg 0.8 mg/kg
6 1 mg/kg 0.6 mg/kg
11 1 mg/kg 0.4 mg/kg
16 1 mg/kg 0.2 mg/kg
21 1 mg/kg 0
26 0.8 mg/kg 0
31 0.6 mg/kg 0
36 0.4 mg/kg 0
41 0.2 mg/kg 0
Day X**


Day of taper AM dose daily
1 0.2 mg/kg (not to exceed 20 mg)
2 0.1 mg/kg (not to exceed 10 mg)
3 0.25 mg/kg (not to exceed 25 mg)
4 0.05 mg/kg (not to exceed 5 mg)
5 0.3 (not to exceed 30 mg)
6 0
7 0.2 mg/kg (not to exceed 15 mg)
8 0
9 0.15 mg/kg (not to exceed 10 mg)
10 0
11 0.1 mg/kg (not to exceed 5 mg)
12 STOP



26


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