acute graft versus host disease€¦ · • demographics and population at riskdemographics and...
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Acute Graft versus Host Disease
Mukta Arora MD MSMukta Arora MD. MS.
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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
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Factors affecting acute graft versus h t dihost disease
Increased riskUnrelated donor
Peripheral blood stem cell Older age
HLA mismatchTransplant from alloimmune female donor
Higher dose TBIDecreased risk
Cord Blood (severe acute GVHD)Non myeloablative conditioning
T cell depletion
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Increasing number of allogeneic HCT
40 000ts
30,000
35,000
40,000
nsp
lan
t
20,000
25,000 Autologous
of
Tra
n
5 000
10,000
15,000
Allogeneic
Nu
mb
er
0
5,000
1970 1975 1980 1985 1990 1995 2000 2005
N
YearCIBMTR summary slides
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Increasing frequency of URD HCT
3,500
4,000
4,500
5,000
ts
Related Unrelated – BM or PB Unrelated – CB
1,500
2,000
2,500
3,000
3,500
Tra
nsp
lant
In children
0
500
1,000
1989-90
1991-92
1993-94
1995-96
1997-98
1999-00
2001-02
2003-04
2005-0612,000
7,000
8,000
9,000
10,000
11,000
lan
ts In Adults
2 000
3,000
4,000
5,000
6,000
Tra
nsp
l
CIBMTR summary slides
0
1,000
2,000
'89-90 '91-92 '93-94 '95-96 '97-98 '99-00 '01-02 '03-04 '05-06
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Increasing use of PBSCTIncreasing use of PBSCT
100
80
100
%
Bone Marrow (BM) Peripheral Blood (PB) Cord Blood (CB)
60
pla
nts
, %
20
40
Tra
nsp
01997-2001 2002-2006 1997-2001 2002-2006
CIBMTR summary slides
Age ≤20 yrs Age >20 yrs
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More frequent use of reduced qintensity conditioning
8 000
6,000
7,000
8,000
s
Reduced Intensity Conditioning
Standard Myeloablative Conditioning
4,000
5,000
,
nsp
lants
2,000
3,000
Tra
n
0
1,000
1998 1999 2000 2001 2002 2003 2004 2005 2006*
* Data incomplete
CIBMTR summary slides
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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%
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AGVHD is major cause of nonAGVHD is major cause of non relapse mortality
HLA-identical SiblingGVHD (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
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Timing, Diagnosis and g, gOrgan Stage/ Grade of
acute GVHDacute GVHD
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Transplant EventsTransplant Events
-8 -1 0 1mo 3mo 6mo
Conditioning Transplant EngraftmentConditioning Transplant
MucositisOrgan toxicity
Engraftment
(VOD)Acute GVHD Chronic GVHD
snf
ectio
ns
Bacterial CMV VaricellaFungus
I
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Clinical Manifestations of acute GVHDClinical Manifestations of acute GVHDSkin
• Maculopapular rash
Upper GI• Nausea, vomiting or both
Lower GI• Watery diarrhea Watery diarrhea
• Severe • Bloody diarrhea or ileus (after exclusion of
infectious causes)infectious causes)
Liver• Cholestatic hyperbilirubinaemia
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Clinical Manifestations of chronic GVHD
Ski
GVHD
SkinDyspigmentation, new-onset alopecia, poikiloderma, lichen
planus-like eruptions, or sclerotic featuresp p ,Nails
Nail dystrophy or lossMouthMouth
Xerostomia, ulcers, lichen-type features, restrictions of mouth opening from sclerosis
EEyesDry eyes, sicca syndrome, cicatricial conjunctivitis
Muscles, fascia, jointsjFasciitis, myositis, or joint stiffness from contractures
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Clinical Manifestations of chronic GVHD
Female genitalia
GVHD
Vaginal sclerosis, ulcerationsGI
Anorexia, weight loss, oesophageal web orAnorexia, weight loss, oesophageal web or strictures
LiverJaundice transaminitisJaundice, transaminitis
LungsRestrictive or obstructive defects on pulmonary function tests, bronchiolitis obliterans, pleural
effusionsMarrowMarrow
Thrombocytopenia, anemia, neutropenia
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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,
HyperkeratosisGI: wasting, dysphagia,Enteritis GI: wasting, dysphagia, odynophagia, strictures
Eye: keratoconjunctivitis siccaLungs: Bronchiolitis obliterans
Oth f i l it lOthers: myofascial, genital
Acute GVHD Chronic GVHD
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Diagnosis of GVHD
C t Time after AGVHD CGVHD
Diagnosis of GVHD
Category HCT or DLI Features FeaturesAcute GVHDClassic AGVHD ≤100 d Yes NoPersistent,Persistent, recurrent, or late-onset AGVHD
>100 d Yes No
Chronic GVHDClassic CGVHD No time limit No YesClassic CGVHD No time limit No Yes
Overlap syndrome No time limit Yes Yes
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This patient presented at day 110 with skin rashwith skin rash
Acute or chronic ?
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Presented at day 80 with mouth painAcute or chronic ?
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A t h i ?Acute or chronic ?
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A t h i ?Acute or chronic ?
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Acute GVHD: Clinical Stageg
Skin Liver GutSkin Liver Gut
Stage % BSA Bilirubin ( /dl)
Diarrhea ( l/d )(mg/dl) (ml/day)
I <25 2-3 500-1000
II 25-50 3.1-6 1000-15000
III Generalized erythroderma
6.1-15 >1500
IV Bullae >15 Pain+/-ileus
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Acute GVHD: Clinical GradeAcute GVHD: Clinical Grade
Overall Skin Liver GI Upper GIOverall Grade
Skin Liver GI Upper GI
1 1-2 0 0 01 1 2 0 0 0
II 1-3 1 1 1
III 2-3 2-4 2-3
IV 4 - 4
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Clinical Presentation
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Clinical Case I• 62 years old woman with AML
Clinical Case I62 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: ?
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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:?
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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 forearmsUpper GI endoscopy + biopsy: diagnostic of acute GVHD•Upper GI endoscopy + biopsy: diagnostic of acute GVHD
•Stage: skin: stage I, upper GI: stage I; grade?
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Standard therapy for AGVHDpy• Grade I (skin stage I or II): Topical steroids• Moderate to Severe: Methylprednisone• Moderate to Severe: Methylprednisone
N 443G d I 27%Grade I 27%Grade II 60%Grade III/IV 13% Factors associated with CR/PR28 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.
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Clinical Case I contd.
•62 year old female diagnosed with grade III acute
C ca Case co td
y g gGVHD at day 28, started therapy with systemic steroids.•1 week later: Rash is still present (less prominent), no change in diarrhea.•Treatment:?
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Secondary treatment of Acute GVHDy
Polyclonal anti T cell Abs ATGy
Anti cytokine agents InfliximabEtanerceptEtanercept
Antimetabolites MMFPentostatinPentostatin
Macrolides Sirolimus, TacrolimusAnti T cell fusion proteins Denileukin DiftitoxpMonoclonal anti T cell Abs Daclizumab, VisilizumabMonoclonal anti T & B cell Abs AlemtuzumabPhotopheresis ECP
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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
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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
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Clinical Case III contd
•62 years old diagnosed with grade II acute
Clinical Case III contd.
y g gGVHD 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
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Update on BMT CTN Clinical Trials
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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
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Cumulative I id f CR Overall SurvivalIncidence of CR O e a Su a
MMFDenileukin
Pentostatin
Etanercept
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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
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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.
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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 withPlacebo 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
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Form 2100