1. MANAGEMENT OF
ACUTE GRAFT VERSUS HOST
DISEASE (GVHD)
Mahmoud A. Hashim Ahmed Khalaf
Visiting Students
UAB School of Medicine
Hem-Onc Department
Bone Marrow Transplantation Unit

2. DEFINITION
 Multisystem Disorders due to immune
reaction caused by transplanted cells from a
non-identical donor (the graft) that
recognize recipient cells
(the host) as foreign, thus disease is caused
in the recipient organs.
 It can be fatal in up to 15% of HSCT
recipients.

3. PATHOGENESIS

4. CLASSIFICATION
 Patients with GVHD are sub classified based upon the timing of presentation and the features
present:
 Classic acute GVHD
 Cases present within 100 days of hematopoietic cell transplant (HCT).
 Shows features of acute GVHD.
 Diagnostic features of chronic GVHD are absent.
 Persistent, recurrent, late onset acute GVHD
 Cases present greater than 100 days post-HCT.
 Shows features of acute GVHD.
 Diagnostic features of chronic GVHD are absent.
 Classic chronic GVHD
 Cases may present at any time post-HCT.
 Diagnostic features of chronic GVHD are present.
 There are no features of acute GVHD.
 Overlap syndrome “Acute on Chronic GVHD”
 Cases may present at any time post-HCT .
 Shows features of both chronic GVHD and acute GVHD.

5. CLINICAL MANIFESTATIONS AND GRADING
I. Maculopapular rash. “ 1st and most common symptom”
II. GI Symptoms “ 2nd commonest symptoms”
 Diarrhea with or without Abd. Pain.
 Persistent nausea and/or emesis.
III. Jaundice
“Glucksberg Criteria”

6. Overall Grading of
Acute GVHD
If Karnofsky Performance <30%, then Grade 4

7. DIAGNOSES
I. Clinical Evaluation
The diagnosis of aGvHD is
predominantly based on clinical
findings.
II. Histological Tests
A. Skin Biopsy is important in absence
of the classic symptoms.
 Skin biopsy was not found to be
useful in predicting severity of
disease.
B. Rectosigmoid Biopsy was found to
be the most informative.
C. Transjugular liver biopsy can show
Endothelialitis, Lymphocytic
infiltration of the portal area,
pericholangitis and Bile duct
obstruction.
III. Imaging
 upper GI endoscopy as well as lower
endoscopic biopsy may show
Luminal Dilatation and Thckening of
small bowel wall.
IV. Biomarkers
 There are many candidate biomarkers
but none are ready for clinical
application.

8. MANAGEMENT
 The choice of initial therapy for patients with acute graft-verus-host
disease (GVHD) depends upon :
Overall grading of Acute GVHD.
Grade 1 GVHD Management
A. Topical steroids are the most commonly used skin-directed
therapy for acute GVHD.
B. Antihistamines may be used as supportive therapy for
patients with pruritus.
C. In Resistant grade 1 aGVHD,
Topical Tacrolimus may be useful.
D. Optimizing prophylactic agents
When acute GVHD of any grade develops, to ensure a
therapeutic level.
For those no longer receiving prophylaxis, the prior
prophylactic agent should be restarted again.

9. GRADE 2-4 GVHD
 Patients with grade 2-4 disease are likely
to require addition of Systemic agents to
achieve a response and Optimizing
prophylactic calcineurin inhibitors
agents.
A. First Line of Treatment:
Corticosteroids
 Most centres used 2 mg/kg /day of
methylprednisolone to be the standard
primary dose.
 Oral beclomethasone, a non-
absorbable glucocorticoid, is added
for most patients with GI involvement.
 Topical steroids can be added for
further control of Skin lesions.
 Steroids are continued for several weeks in
responders and then gradually tapered over
a period of several months.
 Patients who shows progression of disease
by day 5 or non-response by day 7 are
considered to have corticosteroid resistance.
 Use of Steroids results in complete response
rates ranging from 25 to 40 %.

10. HOW TO TAPER THE STEROIDS AFTER INITIAL RESPONSE?
Conclusion
I. Tapering of steroid doses should begin as soon as GVHD
manifestations show major improvement.
II. Inappropriately rapid taper rates carry a risk of GVHD
exacerbation or recurrence, while inappropriately slow taper rates
increase the risk of steroid-related complications.
III. Doses should be gradual reduced 0.2 mg/kg/day every 3–5 days,
after prednisone doses are decreased to less than 20–30 mg/day,
slower tapering rate is required.

11. B. Second Line of Treatment:
 Given in Patients who fail to respond
to
2 mg/kg/day Methylprednisolone for
5 d or progressive symptoms after 72
h.
 There is nostrong comparative data
showing superior efficacy for any
particular agent over others, so the
choice of a second-line regimen
should be guided by
1. Considerations of potential toxicity,
interactions with other agents
2. Expense
3. The familiarity of the physician with
the agent
4. The prior experience of the
physician
 Includes:
1. Mycophenolate mofetil (MMF)
2. Etanercept “ Anti TNF Antibodies”
3. Pentostatin
4. Sirolimus
5. Basiliximab
6. Extracorporeal Photopheresis

12. I. MYCOPHENOLATE MOFETIL (MMF)
Mechanism of Action:
I. MMF is a prodrug of mycophenolic acid (MPA), an inhibitor of inosine monophosphate
dehydrogenase (IMPDH).
 This is the rate-limiting enzyme in de novo synthesis of guanosine nucleotides.
 T- and B-lymphocytes are more dependent on this pathway than other cell types are.
II. MPA can induce apoptosis of activated T-lymphocytes.
III. MMF dose in Adults is 2 gm/kg/day.
 Side Effects
 Dose related Cytopenia and gastrointestinal toxicity.
 Moderate High possibility of Viral reactivation.

13. II. ETANERCEPT
 A recombinant human TNF-alpha
receptor fusion protein.
 Given SC at a dose of 0.4 mg/kg
per dose, Twice/ week.
(maximum dose, 25 mg/week).
 Mechanism
 A purine analog, a potent inhibitor
of adenosine deaminase.
 T and NK Cells Death occurs due to
accumulation of 2-deoxyadenosine
5-triphosphate.
 Dose: 1.5 mg/m2 IV /day for three
days.
 Pentostatin should be used with
caution in patients with
renal insufficiency.
 A 50 % dose reduction has been
suggested for patients with an
estimated creatinine clearance of
30 to 50 mL/min/1.73 m2
III. Pentostatin

14. IV. SIROLIMUS
(RAPAMYCIN)
 Mechanism
 Exerts its immunosuppressive effect through
inhibition of mTOR.
 Loading dose of 6 mg/m2 followed by a daily
dose of 3 mg/m2 daily for 13 days .
 At a dose of 4 -5 mg/m2 without a loading
dose for 14 days.
 Reversible cytopenia, hypertriglyceridemia,
and nephrotoxicity (HUS) and neurotoxicity
when combined with calcineurin inhibitors.
 The use of Sirolimus has also been associated
with sinusoidal obstruction syndrome (SOS)
following conditioning regimens especially,
Busulfan.
 Mechanism
 Humanized monoclonal antibodies
directed against the interleukin-2
receptor leading to prevention of T-
cell proliferation.
V. BASILIXIMAB
VI. DENILEUKIN
DIFTITOX
 Mechanism
Recombinant fusion molecule of
human IL-2 and diphtheria toxin
that binds to the IL-2R-α and
triggers apoptosis in activated T
cells.

15. VII.EXTRACORPOREAL PHOTOPHERESIS
 Infusion of ultraviolet-A irradiated
autologous peripheral lymphocytes
which have been collected by
apheresis and incubated with 8-
methoxypsoralen.
 ECP induces apoptosis of all
leucocytes (including activatedn T-
cells) within 24 h of return.
 Several studies have suggested that
ECP may have a role in the treatment
of acute GVHD.
 Better results are expected in patients
with disease limited to the skin.
 Side effects is mild including
hypotension, fevers and reduced
hemoglobin level.

16. GvHD
Diagnosing
and Grading
Grade 1
Topical
steroid
Grade 2-4
First Line
Systemic
steroids
2mg/kg/day
Second Line
CONCLUSION
MMF
Etanercept
Pentostatin
Sirolimus
Extracorporeal
Photopheresis
BASILIXIMAB

17. REFERENCES
I. Advances in graft-versus-host disease biology and therapy,2013,
Bruce R. Blazar, William J. Murphy, and Mehrdad Abedi
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3552454/
II. Diagnosis and management of acute graft-versus-host disease,
2012, Fiona L. Dignan et al.
http://www.bcshguidelines.com/documents/bjh_9129_Rev_EV.pdf
III. First and Second-Line Systemic Treatment of Acute Graft-versus-
host Disease: Recommendations of the American Society of Blood
and Marrow Transplantation, Paul J. Martin et al.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3404151/
IV. Management of Acute GVHD, Uptodate.com
V. Extracorporeal photopheresis in the management of graft-versus-
host disease, Bredeson C et al.
http://www.ncbi.nlm.nih.gov/pubmed/24764713