Acute Graft versus Host Disease

Mukta Arora MD MSMukta Arora MD. MS.

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

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

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

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

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

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

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%

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

Timing, Diagnosis and g, gOrgan Stage/ Grade of

acute GVHDacute GVHD

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

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

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

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

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

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

This patient presented at day 110 with skin rashwith skin rash

Acute or chronic ?

Presented at day 80 with mouth painAcute or chronic ?

A t h i ?Acute or chronic ?

A t h i ?Acute or chronic ?

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

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

Clinical Presentation

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: ?

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:?

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?

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.

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:?

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

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

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

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

Update on BMT CTN Clinical Trials

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

Cumulative I id f CR Overall SurvivalIncidence of CR O e a Su a

MMFDenileukin

Pentostatin

Etanercept

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

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.

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

Form 2100