“Acute Graft-vs.-Host Disease after
Allogeneic stem cell transplantation:
an Update”
Mohamad MOHTY, MD, PhD
Hématologie Clinique et Thérapie Cellulaire
Université Pierre & Marie Curie
Hôpital Saint-Antoine
Paris
HSCT Activity in Europe 1990-2011:
Transplant type 1st HSCT
The European Group for Blood and Marrow Transplantation
HSCT Activity in Europe 1990-2011:
donor origin 1st HSCT
The European Group for Blood and Marrow Transplantation
Reduced Mortality after allo-HSCT
over the past decade
Gooley, TA. et al. N Engl J Med 2010;363:2091-101
Reduced NRM after allo-HSCT over the past 3
decades (Nantes Program)
NRM
1983-1990
1991-2000
2001-2010
Years after transplantation
Malard et al. Biol Blood Marrow Transplant 2014
HSCT Activity in Europe 2000-2011:
MAC vs RIC
38%
The European Group for Blood and Marrow Transplantation
How to improve allo-SCT outcome?
1
Patient
(age, gender,
CMV,
comorbidities…)
3
5
Conditioning
Graft
6
Disease
features
-6 -5 -4
2
-3 -2 -1
4
0
Supportive Care and
prevention of relapse
+14
+21
+100
>180
GVHD prophylaxis and therapy
The European Group for Blood and Marrow Transplantation
The “GVL Effect” in Humans

20 yr ♂ with AML: 2 × 400 rad TBI plus
marrow from 6 relatives

A brother’s marrow engrafted

Severe “secondary disease”

† 20 months without leukemia !
Mathé et al., Br Med J, 1963
The European Group for Blood and Marrow Transplantation
Acute GvHD
• Inflammatory condition affecting one or more of the skin,
gastrointestinal tract and liver, and occurring within 100
days of allogeneic transplantation
• Later acknowledgement of similar syndrome occurring
beyond day 100, known as late onset acute GvHD
(particularly after RIC and DLI)
• Affects 35-45% of recipients of HLA matched, and up to
60-80% of mismatched transplants
• Affects approximately 40% of recipients of DLI but
incidence rises with increasing cell dose
The European Group for Blood and Marrow Transplantation
Acute GvHD: Skin
•
>80% of cases of aGvHD
• Macular papular rash affecting any part of the body,
typically palmar & plantar erythema and sparing the
scalp
• Apoptosis at base of epidermal rete pegs
• Dyskeratosis with adjacent satellite lymphocytes
• perivascular lymphocytic infiltration in the dermis.
The European Group for Blood and Marrow Transplantation
Acute GvHD: GUT
• Approximately 50% of cases
• Nausea, vomiting and anorexia
• Watery diarrhoea (typically green) and abdo cramps
progressing to ileus and bloody diarrhoea
• Endoscopy: patchy ulceration
• CT scan: luminal dilatation with thickening of small
bowel wall (ribbon sign), may have fluid levels
• Pathology: apoptotic bodies in base of crypts, crypt
abscesses, loss and flattening of surface epithelium
The European Group for Blood and Marrow Transplantation
Acute GvHD: Liver
• Approximately 50% of cases
• Cholestatic hyperbilirubinaemia
• Difficult to distinguish from other causes of hepatic toxicity i.e.
veno-occlusive disease, drugs, viral infections, sepsis, iron
overload
• Pathology: endothelialitis, lymphocytic infiltrate of portal areas,
pericholangitis, bile duct destruction
• Biopsy often not performed because of concurrent
thrombocytopenia
The European Group for Blood and Marrow Transplantation
Acute GvHD: Staging
stage
skin
Liver
1
<25%
34-50
Gut
diarrhoea
>500 ml
2
25-50%
51-102
>1000
3
>50%
103-255
>1500
4
Bullous
disease
>255
pain++
(bil:µmol/l)
The European Group for Blood and Marrow Transplantation
Acute GvHD: Grading
grade
skin
liver
gut
I
1-2
0
0
5 year survival
II
3, or
1, or
1
Grade III: 25%
III
0-3
2-3, or
2-4
Grade IV: 5%
IV
4, or
4
0-4
The European Group for Blood and Marrow Transplantation
Acute GvHD: Pathophysiology

First recognised in 1950s as ‘runt disease’ in mice

Graft must contain immunologically competent cells

Recipient must express tissue antigens not present in
the donor

Recipient incapable of monitoring an effective
response to reject transplanted cells
Billingham
The European Group for Blood and Marrow Transplantation
Acute GvHD:
Pathophysiology
Acute GvHD:
Pathophysiology
The European Group for Blood and Marrow Transplantation
Acute GvHD: Risk Factors
•
•
•
•
•
•
•
Degree of HLA disparity
Recipient age
Conditioning regimen
R/D gender combination
Stem cell source
Disease phase
Viral infections
The European Group for Blood and Marrow Transplantation
Acute GvHD: Prevention and treatment
Pharmacological
 Immunosuppression
 Corticosteroids
 Methotrexate

Inhibition of cytoplasmic calcineurine
 Cyclosporine or Tacrolimus (FK506)

Mycophenylate mofetil (MMF)
 Active compound, mycophenolic acid, Inhibits inosine
monophosphate dehydrogenase (enzyme essential to de novo
synthesis of guanosine nucleotides) and terminates DNA
synthesis

Sirolimus (binds to FKBP12) can be used in combination with
FK506
The European Group for Blood and Marrow Transplantation
Acute GvHD: Prevention and treatment
Immunological and Cellular
 Antithymocyte globulin (ATG, ALG)

Monoclonal antibodies
 CD20: rituximab
 CD52: alemtuzamab (Campath)
 CD2: alefacept (Blocks CD3-LFA3 interaction)
 CD3: OKT3, visilizumab
 TNF: infliximab, etanercept, adalimumab, certolizumab
 IL2/IL2R (CD25): dacluzamab, inolimomab, basiliximab, denileukin diftitox

Extracorporeal photophoresis

Cellular
 T-cell depletion
 Mesenchymal stem cells
 T-regulatory cells
 Suicide gene therapy of donor T-cells
The European Group for Blood and Marrow Transplantation
Acute GvHD: Prevention

Gold standard is cyclosporine and methotrexate
 CsA/MTX and FK506/MTX better than CsA
alone
 No benefit in adding corticosteroid
 FK506/MTX may be better than CsA/MTX
The European Group for Blood and Marrow Transplantation
Acute GvHD: Prevention
Hoyt et al, BMT 2008
The European Group for Blood and Marrow Transplantation
Evidence for immune control
• Allogeneic BMT
– GVHD / Relapse
– T Cell depletion
N
100
100
T Dep
Non T Dep
57
35
Agvhd
5%
35 %
Cgvhd
13 %
40 %
DC de GVHD
7%
26 %
Rejet
26 %
0%
Rechute
47 %
17 %
DFS
50
50
Non
NonTdep
Tdep
TTDep
Dep
00
00
11
22
33
44
55
66
77
88
Maraninchi et al., Lancet 1987
Acute GvHD: Prevention
70
60
% of patients
60
50
47
43
44
40
40
30
48
31
26
no ATG
ATG
20
10
0
aGvHD II+
cGvHD
survival 2 yy long term 6
yy
109 unrelated donor transplants
BBMT 2006 12: 560
The European Group for Blood and Marrow Transplantation
Acute GvHD: Unrelated transplants
Parameter
CsA-MTX-ATG %
N=103
CsA-MTX %
N-98
P value
aGvHD > I
33
51
0.01
aGvHD > II
12
24.5
0.054
Any cGvHD
31
59
<0.0001
Ext CGvHD
12
43
<0.0001
100d TRM
11
13
NS
2yr TRM
20
29
NS
2yr relapse
29
24
NS
2yr DFS
52
48
NS
Finke et al, Lancet Oncol 2009
The European Group for Blood and Marrow Transplantation
Acute GvHD: Treatment

Grade I skin disease may be controlled with topical steroids
alone

For GvHD > grade I, gold standard is corticosteroid
 2mg/kg methylprednisolone
 Several studies show no benefit in increasing dose
 One study of steroid plus etanercept showed 70% resolution
in one month

Steroid refractory aGvHD
 ATG
 MoAbs
 MSC
 ECP

Supportive care is critical !
The European Group for Blood and Marrow Transplantation
Acute GvHD: Treatment
Van Lint et al (GITMO) Blood 1998: 95 pts with > grade I aGvHD
The European Group for Blood and Marrow Transplantation
Acute GvHD: 2nd line treatment
Treatment
ATG
Anti-IL2R
Anti-TNF
CsA to tacro
Tacro + ATG
MMF
Pentostatin
OKT3
Response
51%
40-70%
67%
10%
40%
50%
50%
Survival
35%
<30%
38%
35%
16% - 37%
26%
45%
The European Group for Blood and Marrow Transplantation
Acute GvHD: 3nd line treatment - MSC
Le Blanc et al, Lancet 2008
The European Group for Blood and Marrow Transplantation
Acute GvHD: what does the future hold?
• Invariant NKT cells
• Mesenchymal stromal cells
• T-regulatory cells
• Dendritic cells
• Engineering specific anti-leukemic T-cells
The European Group for Blood and Marrow Transplantation
Immunosuppressive drugs and
sites of action in the three-signal model
Treg
Methotrexate
Adapted from Halloran P, N Engl J Med 2004
Immunosuppression:
“the Promise of Specificity”
T Cell
TNF:TNF-R Super family
CD28:B7 Super family
APC
CD83
LAT (linker for
activation of T cells
MERCI
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