The European Group for Blood and Marrow - Grrr-OH
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“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
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
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%
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