The European Group for Blood and Marrow - Grrr-OH

January 31, 2018 | Author: Anonymous | Category: Science, Health Science, Immunology
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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%
View more...

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