2. Acute Graft-versus-Host DiseaseAcute Graft versus Host Disease
• Demographics and population at riskDemographics and population at risk
• Diagnosis and staging
• Clinical presentation response to treatmentClinical presentation, response to treatment
• BMT CTN trials
• Form 2100• Form 2100
3. Factors affecting acute graft versus
h t dihost disease
Increased risk
Unrelated donor
Peripheral blood stem cell
Older age
HLA mismatch
Transplant from alloimmune female donor
Higher dose TBI
Decreased risk
Cord Blood (severe acute GVHD)
Non myeloablative conditioning
T cell depletion
4. Increasing number of allogeneic
HCT
40 000
ts
30,000
35,000
40,000
nsplant
20,000
25,000
Autologous
ofTran
5 000
10,000
15,000
Allogeneic
Number
0
5,000
1970 1975 1980 1985 1990 1995 2000 2005
N
Year
CIBMTR summary slides
6. Increasing use of PBSCTIncreasing use of PBSCT
100
80
100
%
Bone Marrow (BM)
Peripheral Blood (PB)
Cord Blood (CB)
60
plants,%
20
40
Transp
0
1997-2001 2002-2006 1997-2001 2002-2006
CIBMTR summary slides
Age ≤20 yrs Age >20 yrs
7. More frequent use of reducedq
intensity conditioning
8 000
6,000
7,000
8,000
s
Reduced Intensity Conditioning
Standard Myeloablative Conditioning
4,000
5,000
,
nsplants
2,000
3,000
Tran
0
1,000
1998 1999 2000 2001 2002 2003 2004 2005 2006*
* Data incomplete
CIBMTR summary slides
8. Incidence of acute GVHD
Incidence of grade II-IV acute GVHD has been
reported to vary between 20-85%reported to vary between 20-85%
9. AGVHD is major cause of nonAGVHD is major cause of non
relapse mortality
HLA-identical Sibling
GVHD (13%)
Unrelated Donor
Other
(16%)
Relapse (41%)
GVHD (13%) Relapse (34%)
GVHD (14%)
(16%)
Other (16%)
Organ
toxicity
(10%)
Infection
(17%)
Organ toxicity
(10%)
IPn (3%)
Infection (20%)
IPn (6%)
( )
CIBMTR Summary slides
12. Clinical Manifestations of acute GVHDClinical Manifestations of acute GVHD
Skin
• Maculopapular rash
Upper GI
• Nausea, vomiting or both
Lower GI
• Watery diarrheaWatery diarrhea
• Severe
• Bloody diarrhea or ileus (after exclusion of
infectious causes)infectious causes)
Liver
• Cholestatic hyperbilirubinaemia
13. Clinical Manifestations of chronic
GVHD
Ski
GVHD
Skin
Dyspigmentation, new-onset alopecia, poikiloderma, lichen
planus-like eruptions, or sclerotic featuresp p ,
Nails
Nail dystrophy or loss
MouthMouth
Xerostomia, ulcers, lichen-type features, restrictions of mouth
opening from sclerosis
EEyes
Dry eyes, sicca syndrome, cicatricial conjunctivitis
Muscles, fascia, jointsj
Fasciitis, myositis, or joint stiffness from contractures
14. Clinical Manifestations of chronic
GVHD
Female genitalia
GVHD
Vaginal sclerosis, ulcerations
GI
Anorexia, weight loss, oesophageal web orAnorexia, weight loss, oesophageal web or
strictures
Liver
Jaundice transaminitisJaundice, transaminitis
Lungs
Restrictive or obstructive defects on pulmonary
function tests, bronchiolitis obliterans, pleural
effusions
MarrowMarrow
Thrombocytopenia, anemia, neutropenia
15. Diagnosis of acute GVHD
Skin: Lichen planus
Diagnosis of acute GVHD
Dermatitis
+
Skin: Lichen planus,
Hyper/ hypo pigmentation,
ichthyosis,
onychodystrophy, morphea,
Hepatitis
+
Enteritis
scleroderma, hair changes.
Oral: sicca, atrophy, lichenoid,
Hyperkeratosis
GI: wasting, dysphagia,Enteritis GI: wasting, dysphagia,
odynophagia, strictures
Eye: keratoconjunctivitis sicca
Lungs: Bronchiolitis obliterans
Oth f i l it lOthers: myofascial, genital
Acute GVHD Chronic GVHD
16. Diagnosis of GVHD
C t
Time after AGVHD CGVHD
Diagnosis of GVHD
Category
HCT or DLI Features Features
Acute GVHD
Classic AGVHD ≤100 d Yes No
Persistent,Persistent,
recurrent, or late-
onset AGVHD
>100 d Yes No
Chronic GVHD
Classic CGVHD No time limit No YesClassic CGVHD No time limit No Yes
Overlap syndrome No time limit Yes Yes
25. Clinical Case I
• 62 years old woman with AML
Clinical Case I
62 years old woman with AML
• Reduced intensity conditioning followed by an
HLA matched URD transplantp
• GVHD prophylaxis: CSA + MMF
• Day 28: Diffuse maculopapular rash + diarrheaDay 28: Diffuse maculopapular rash diarrhea
1100 ml/ day. A skin biopsy is performed.
• Dx : AGVDH skin + + +, GI + +G s , G
• Grade: ?
26. Cli i l C II
• 45 years old male with ALL
Clinical Case II
45 years old male with ALL
• Myeloablative conditioning: Cy/ TBI, matched sibling
donor transplantp
• GVHD prophylaxis: CSA + MTx
• Neutropenic fever mucositisNeutropenic fever, mucositis
• Day 35: diffuse maculopapular skin rash + diarrhea:
700 ml/day +hyperbilirubinemia: 2.5 mg/dl00 /day ype b ub e a 5 g/d
• Dx: AGVHD: skin +++, GI:+ liver: +
• Grade:?Grade:?
27. Cli i l C III
•62 years old with NHL
Clinical Case III
62 years old with NHL
•Reduced intensity conditioning followed a matched URD
transplant
•GVHD prophylaxis: CSA and MMF
•Day 45 post HCT: has persistent nausea, intermittent
vomiting and weight loss, has skin rash involving face and
both forearms
Upper GI endoscopy + biopsy: diagnostic of acute GVHD•Upper GI endoscopy + biopsy: diagnostic of acute GVHD
•Stage: skin: stage I, upper GI: stage I; grade?
28. Standard therapy for AGVHDpy
• Grade I (skin stage I or II): Topical steroids
• Moderate to Severe: Methylprednisone• Moderate to Severe: Methylprednisone
N 443
G d I 27%Grade I 27%
Grade II 60%
Grade III/IV 13% Factors associated with CR/PR
28 d % CR 35% Related donor, GVHD prophylaxis
th th MT lother than MTx alone%PR 20%
Survival@ 1 year 53% Factors associated with mortality
Age, higher grade, unrelated donor.
BBMT 2002,MacMillan et al.
29. Clinical Case I contd.
•62 year old female diagnosed with grade III acute
C ca Case co td
y g g
GVHD at day 28, started therapy with systemic
steroids.
•1 week later: Rash is still present (less prominent),
no change in diarrhea.
•Treatment:?
30. Secondary treatment of Acute GVHDy
Polyclonal anti T cell Abs ATGy
Anti cytokine agents Infliximab
EtanerceptEtanercept
Antimetabolites MMF
PentostatinPentostatin
Macrolides Sirolimus, Tacrolimus
Anti T cell fusion proteins Denileukin Diftitoxp
Monoclonal anti T cell Abs Daclizumab, Visilizumab
Monoclonal anti T & B cell Abs Alemtuzumab
Photopheresis ECP
31. Clinical Case I contd
•62 year old female diagnosed with grade III acute
Clinical Case I contd.
•62 year old female diagnosed with grade III acute
GVHD at day 28, started therapy with systemic
steroids.
•1 week later: Rash is less prominent, no change in
diarrhea.
•Treated with ATG: rash and diarrhea respond.
•Develops CMV reactivation along new pneumonia.p g p
•BAL: + CMV
32. Cli i l C II tdClinical Case II contd.
•45 years old diagnosed with grade II acute GVHD
at day 35
•Treated with systemic steroids
•Responds well, and is gradually tapered off
steroids, during taper
•Develops a dry mouth with ulcerations and dry
eyes.
•Lip biopsy + chronic GVHD
33. Clinical Case III contd
•62 years old diagnosed with grade II acute
Clinical Case III contd.
y g g
GVHD at day 45
•Treated with systemic steroids and gradually
tapered off steroids.
•Able to completely discontinue all
immunosuppression by 6 months and has no
active GVHD
35. Phase II randomized clinical trial of
Etanercept, mycophenolate,
Denileukin or pentostatin along withDenileukin or pentostatin along with
corticosteroids for acute GVHD
N =180 patients, median follow up: 9 months
36. Cumulative
I id f CR
Overall Survival
Incidence of CR
O e a Su a
MMF
Denileukin
Pentostati
n
Etanercept
37. Cumulative Incidence of toxicities, infections
and relapse
Cumulative
Incidence
Etanercept
%
Mycophenolate
%
Denileukin
%
Pentostatin
%
D 56 d 3 5 76 80 76 67D 56 grade 3-5
toxicity
76 80 76 67
Severe 47 44 62 57Severe
infections at day
270
47 44 62 57
Relapse at day
180
15 11 15 20
38. C l iConclusion
Efficacy and toxicity data suggest the
use of MMF plus corticosteroids is the mostuse of MMF plus corticosteroids is the most
promising regimen to compare
against corticosteroids alone in a definitive
phase 3 trial.
39. BMT CTN: 0802 A Multi-center
Randomized Double Blind Phase IIIRandomized, Double Blind, Phase III
Trial Evaluating Corticosteroids
with Mycophenolate Mofetil versuswith Mycophenolate Mofetil versus
Corticosteroids with
Placebo as Initial Systemic Treatment ofPlacebo as Initial Systemic Treatment of
Acute GVHD
Primary Objective: To estimate the GVHD free survival at
day 56 after randomization without additional therapy
