Transcript Current Strategies for Management of GVHD Dr K M Chang MRCP, FRCPA(Haem) Haematology Department Hospital Ampang.

Current Strategies for
Management of GVHD
Dr K M Chang
MRCP, FRCPA(Haem)
Haematology Department
Hospital Ampang
Solid organ vs stem cell transplants
Immunoablative/suppressive conditioning
High passenger donor Iymphocyte
State of immune tolerance
GVHD
• Graft must contain immunologically competent cells
• Recipient express tissue antigens not found in donor
• Patients too immunosuppressed to reject this
response/cells
GVHD
T cells – the main cause
Can occur in other settings
• Transfusions, DLI, immunocompromised
Recognise genetically different proteins
• Class I HLA (A,B,C) and Class II HLA(DR,DP,DQ)
• mHA
– HY and HA-3 expressed on all tissues
– HA-1 and HA-2 on blood cells
Cytokine polymorphism
• TNFa, IL-10 and INF-g
Increasing incidence
Advanced disease
Patient age
Expanding donor pool
– Non HLA id donors, unrelated
Donor lymphocyte infusions
Use of alternative sources
– PBSC>BM>Cord
Definition
Category
Time to onset aGvHD features cGvHD
features
aGvHD
Classic
<=100d
Yes
No
Persistent,recurr >100d
ent, late onset
cGvHD
Yes
No
Classic
No time limit
No
Yes
Overlap synd
No time limit
Yes
Yes
Frequency of Gd II-IV aGvHD in HLAmatch HSTx
70
60
50
40
Gd II-IV %
30
20
10
0
Sibs
Unrelated
DLI
Marrow harvesting
PBSC harvesting
PBSC collected by
apheresis
2X donor blood
volume processed
4-6 days of G-CSF
1-3 apheresis
procedures
Cord blood
1st case 1988 Fanconi’s anaemia
EBMT 1997 NEJM
78 recipients survival 63% 1year
GVHD 9% HLA matched
50% HLA unmatched
Pathophysiology of aGvHD
Conditioning effect
• Epithelial cell damage
• Injury to GIT
• APC activation
T-cell activation
• Donor T cells CD4+ and CD8+
• IL-2, IFNg, TNF
Effector phase
• Cytokine storm – TNFa, IFNg, IL-1, NO
• CTLs CD8+
• NK cells
AGVHD
Presentation
– Skin, liver, GI tract, nausea
Skin
Upper GIT
• Anorexia, nausea
Lower GIT
• Watery diarrhoea >500ml
• Sever abd pain
• Bloody diarrhoea
Liver
• Cholestatic hyperbilirubinaemia
Grading system
Stage
Skin
Rash
Liver
Bilirubin
Gut
Diarrhoea
+
<25%
2 – 3mg/dl
>500ml/d
++
25 – 50%
3 – 6mg/dl
>1000ml/d
+++
> 50%
6 – 15mg/dl
>1500ml/d
++++
Generalised
erythroderma,
bullae
>15mg/dl
Abd pain, ileus
Grading system (Glucksberg)
Grade
Degree of organ inv
I
Skin + to ++
3y OS 74%
II
Skin + to +++
Gut and/or liver +
Mild decrease in performance
3y OS 64%
III
Skin ++ to +++
Gut and/or liver ++ to +++
Marked decrease in clinical performance
3y OS 37%
IV
Skin ++ to ++++
Gut and /or liver ++ to ++++
Extreme decrease in clinical performance
3y OS 10%
Chronic GVHD
> 100 days or less
35-50%
Onset - de novo
progressive
quiescent
explosive
CGVHD
Pathogenesis unclear
donor alloreactive T-cells vs mHA
aberrant thymic edn
Th2 activation
B cells
Incidence
HLA-id sibs
40%
partial match related
50%
Matched unrelated
70%
>100d, rarely >500d
CGVHD risk factors
HLA disparity
Age of recipient
– <10y 13%, >20y 46%
Prior AGVHD
PBSC 54% vs 32%
Latent CMV
Marrow boosts, DLI
Short course CSA
Target organs
Skin
Mouth
Eyes
Liver
Respiratory tract
GI tract
Musculoskeletal
Neurologic
Haemopoietic
Genitourinary
Infections
autoimmune
Graft Versus Host Disease (GVHD)
GVHD
Biopsy
• Experienced pathologists
• Exclude concommitant infections, drug toxicity
Grading
Extent of organ involvement
Severity
• Life threatening
• Organ threatening
AGVHD - management
Treatment outcome is poor
Prophylaxis is mainstay
– Minimise tissue damage
– T cell reduction
•
•
•
•
T depletion
CD34 selection
Antibodies – ATG, Campath
Pharmacological
AGvHD – prophylaxis
CSA – Mtx prophylaxis
Incidence GVHD 20 - 30%
Other combinations
CSA-Mtx-steroids
CSA-steroids
ATG-CSA-Mtx
FK506- Mtx
CSA-MMF
AGvHD - therapy
First line therapy: steroids + calcineurin inh
• MP 2mg/kg/day
• CR 25-40%
• 53% ptt hv durable response
Failure of response or severe GVHD
•
•
•
•
•
•
Progression after 3 d
No change after 7d
Incomplete response after 14d
Add 2nd line
RR 35%-70%
1y OS 30%
Second line therapy
Methylpred 10-30mg/kg/d
Tacrolimus
ATG
MMF
Sirolimus
Daclizumab or other IL-2R antagonist
anti-TNF e.g Etanercept
Pentostatin
Extracorporeal photopheresis
Non-absorbable steroids - beclomethasone
Others – Campath, ABX/CBL, Mesenchymal SC
Steroid refractory AGvHD
Mycophenolate mofetil
• Prodrug of mycophenolic acid, inhibits IMPDH required for de
novo purine synthesis
• 42-46% RR
• 16% 2y survival
• 21% early discontinuation for meutropenia, nausea
» Nash, Blood 1997
Rapamycin (Sirolimus)
• Complexes with FKBP and binds mTOR which regulates S6
kinase and CDK2
• 21 pt, 4-5mg/m2/d X 14d
• RR 57%, CR 23%, survival 28%
• 23% HUS
» Berito, Transplantation 2001
TNF antibodies
Infliximab (chimeric human/mouse anti-TNF Ab)
Adalimumab (humanised anti-TNF antibody)
Etanercept (rh TNF receptor type II fusion protein )
–
–
–
–
–
TNF infl cytokine
Used in 1st and 2nd line
Early response
Rebound
Infections
Mesenchymal stem cell therapy
Rare stromal popn in BM and adipose tissue
Inhibit naïve and memory T-cells effectively
Inhibit B-cell proliferation and IL-2 induced NK
proliferation
APC tolerogenic
–
–
–
–
40ptt, Grade III-IV aGvHD
Median MSC dose 1.0(0.4-9)106cells/kg
19/40CR, 9/40PR, 4/40 stable, 7/40NR, 1 died
21ptt alive between 6wks to 3.5y
» Le Blanc et al, EBMT 2008
Proteomic patterns predict AGvHD after
alloHSCT
Capillary electrophoresis coupled with mass
spectrophotometry (CE-MS)
13 AGvHD samples vs 50 control non-GvHD samples
170 GvHD specific polypeptides were detected and
aGvHD specific model consisting of 31 polypeptides
599 blinded samples tested
Sensitivity 83.1%, specificity 75.6%
• Weissinger et al, Blood 2007;109:5511-5519
?early screening and preemptive threrapy
A biomarker panel for AGvHD
Paczesny et al,Blood Jan 2009
Chronic GVHD management
Prevention
– Reduce AGVDH 15 – 20% vs 40 – 100%
– T- cell depletion
– HLA matching
Treatment
– Multidisplinary management
– Diagnosis
– Evaluation
Chronic GVHD management
CSA alt Pred (Seattle)
Alternative regimens if no improvement in 3mths
–
–
–
–
–
–
–
–
Pentostatin
FK506
MMF
Extracorporeal photopheresis
PUVA
Etretinate
Plaquenil
Anti-CD20 (Rituximab)
Pred vs CSA/pred as initial therapy of
cGvHD
CSA/pred
Pred
CI discontinued Rx 54%
at 5y
Survival 5y
67%
53%
Median to
1.6y
discontinuation Rx
Avascular necrosis 18/142 (13%)
2.2y
72%
32/145 (22%),
p=0.04
Phase I/II studies in steroid refractory
cGvHD
Hi dose steroids: 48% major RR
Tacrolimus-MMF: 46% RR
Sirolimus: 62% RR, side-effects
Rituximab
–
–
–
–
–
–
Abs vs mHAgs in cGvHD
autoAb production by B cells
IL-6 production by B-cells lead to sclerosis
Cutaneous, rheumatologic
No oral or ocular responses
Allow prednisolone taper, no fatal infections, well-tolerated, QOL
improvement
Different assessments and end-points
Extracorporeal photopheresis
5 X 109 leucocytes are treated with 8-methoxypsoralen
and UVA light
Infusion of apoptosis cells induces tolerance and APC
modulation
Decrease production of proinflammatory cytokines
Increase antiinflammatory cytokines
Decrease T-cell stimulation
Delete cytolytic CD8+ effector cells
Induce regulatory T cells
ECP
AGVHD – what do I do?
Grade 1
– watch
Grade 2-3
– iv methylpred 2mg/kg/d 7-14d wks, then 1mg/kg/d 2 wks then
25% taper every 2wks
– Failure of response D3, progression or relapse with taper,
consider iv methylpred 30mg/kg/d or iv MMF or anti-TNF
Grade 4
– iv methylpred 30mg/kg/d 3d
– + iv MMF
– +/- anti-TNF
AGVHD - management
High index of suspicion
– Biopsy, exclude CMV
Aggressive institution of treatment
– Achieve CR
– AGVHD confers no leukaemia-free benefit
– Mortality or chronic morbidity
Adequate prophylaxis
– CMV,fungal, PCP, bacterial
IVIG 0.4g/kg weekly till D90 (Sullivan et al)
CGVHD – what do I do?
Regular physical exam
Limited or extensive
Organ threatening – lung, liver, keratitis
Pred 2mg/kd/d 2 wks then 1mg/kg/d 2 wks then taper
20% every 2 wks
CSA 6mths then slow taper
MMF – steroid sparer
PUVA/ ECP
Rituximab
CGVHD – what do I do?
Oral/dental hygiene
Eye care
Avoid sun
Diet
Physiotherapy
Infection prophylaxis
IVIgG > 500mg/dL
Hep B reactivation
Ethic difference in TRM
Current approaches
Donor
• Better HLA matches, NK mismatch
• Graft source
Recipient
• Cytokine gene polymorphism
Better prophylaxis
• Reduced conditioning
• Cytokine shields – IL-11, KGF
• Drug combination
T-cell/ B cell manipulation
• Induction of tolerance
• Mesenchymal stem cells
• Costimulatatory blockade
• T regs expansion
Preemptive startegy
• proteomics