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Stem cell transplantation: indications, preparation, follow up, results. Dr Kriván Gergely Szent László Kórház. E. Donnall Thomas (1920-2012). Transplant activity worldwide 1980-2009. 35,000. Autologous Allogeneic. 30,000. 25,000. 20,000. Transplants. 15,000. 10,000. 5,000. 0. - PowerPoint PPT Presentation
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Stem cell transplantation: indications, preparation,
follow up, resultsDr Kriván Gergely
Szent László Kórház
E. Donnall Thomas (1920-2012)
Tra
nsp
lants
Transplant activity worldwide 1980-2009
'80 '81 '82 '83 '84 '85 '86 '87 '88 '89 '90 '91 '92 '93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 '06 '07 '08 '09
Autologous
Allogeneic
20,000
25,000
35,000
30,000
15,000
10,000
5,000
0
drug
donor
Patient cured
Rationale for stem cell transplant
allogeneic
autologousfreezing
irradiation engraftment
No. of transplants 01.01.1992.-06.03.2014.
(n=481)
Distribution of transplants according todisease categories01.01.1992.- 06.03.2014.
20 544
20558
149
Anyagcsere betegség20/481
Autoimmun 5/481
Immundefektus 44/481
Malignus hematológiai205/481
Nem malignushematológiai 58/481
Szolid tumor 149/481
N=481
Sex ratioMedian age at time of transplant: 8,4 years
01. 01. 1992.-28. 02. 2012.
59%41%
Boy 59% (216/ 365)
Girl 41%( 149/ 365)
N=365
About autologous transplantations
Nemzetimunkacsopor
t
Protokol Betegek száma
Eseménymentes túlélés
Összesített túlélés
Ausztria A-NB94 28 43% (3 év)
Franciaország LMCE1LMCE3F-NB97
729947
8%29%
Németország NB85NB90
135206
20%32%
Olaszország NB-85NB-89NB-92
10676
170
18%17%16%
27%26%28%
Spanyolország
N-I-87N-II-92
6072
24%30% (4 év)
Egyesült Királyság
ENSG5-OPEC/OJEC-COJEC
130125
17,7%31,3%
18,6%39,6%
Results- NBL
alive mortality 5 y OSCR 11/24 54% 49%
PR 4/18 78% 30%
Relapse
1/12 92% 17%
CD34 2/7 72%
n=54
NBL - OS according to disease status
Cumulative Proportion Surviving (Kaplan-Meier)
Complete Censored
recidiva CR PR
0 2 4 6 8 10 12
Time
0,0
0,1
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Cu
mu
lativ
e P
rop
ort
ion
Su
rviv
ing
Follow up (years)
About allogeneic transplantations
HLA antigens on cell surface - codominant expression
Donor type
• HLA identical family donor
• HLA identical unrelated donor
• HLA non identical (eg.
haploidentical family member)
• HLA non identical unrelated donor
Submissions for HSCT in Hungary in children
Year Autologus Allogeneic
MUD search needed
2004 33 46 26 (56%)
2006 20 29 19 (66%)
2008 36 41 29 (71%)
2010 35 42 38 (90%)
Unrelated donors for hungarian patients, according to the donor nationality (1990-2009) N: 242
0
20
40
60
80
100
120
140
160
180
német USA olasz belga magyar izraeli ciprusi kanadai portugál
Allogeneic transplants according to donor origin
01. 01. 1992.-31. 12. 2002.
Sibling65,6%
MUD16,6%
Haplo16,6%
Family1,2%
01. 01. 2003.-28. 12. 2012.
Sibling34,5%
MUD55%
Haplo10,5%
n =84 n = 171
Survival of allogeneic transplants according to sibling or unrelated donors
01. 01. 1992. – 30.11.2011. n=198unrelated n=92, sibling n=106
n=
n=
p=
p=n=96
n=66
p=0,082
n=96
n=66
Testvér 61,3%
Idegen %
p=0,082MUD 51,1%
Sibling 61,3% Overall:56,6%
p=0,21
Survival according to donor type
01. 01. 1992. -31. 12. 2002. 01. 01. 2003. - 30. 11. 2011.
p=0,002 P=0,003
Donor types No. of cases %auto 26 42,3haplo 10 50unrelated 14 14,3sibling 53 54,7overall 103 45,6
Donor types No. of cases %Auto 114 75,4Haplo 7 14,3Unrelated 77 57,1Sibling 56 67,9Overall 251 66,5
Stem cell source
•Bone marrow
•Peripheral blood
•Cord blood
Peripheral stem cell Txp advantages and disadvantages
Advanteges:• Rapid engraftment shorter aplasia• Less toxicity• Earlier discharge from hospital• Less costs• More cells could be harvested with repeated apheresis
graft manipulation (CD34+ selection, T cell removal)• More convenient for donors; ambulatory harvesting;
only possibility in case of high donor/recipient bw ratio
Disadvantages: • Higher chronic graft versus host ratio
Advantages and disadvantages of CBUs
Advantages:
• Easy and safe collection; quick delivery
• Contains more premature progenitor cells, superior proliferative capacity
• Less alloreactive lymphocytes (↓ aGvH and cGvH))
• Less probability to transfer infections (eg. CMV)
• Less toxicity
• No need for full HLA match (results with 1 antigen difference and full HLA
matching are identical), greater probability for suitable donor
Disadvantages :
• Limited stem cell content
• Delayed engraftment and immunreconstitution, more infections
• DLI (donor lymphocyta infusion) not available
• Possible transmission of genetic diseases
Distribution of Txp. according to stem cell
source01. 01. 1992. - 28 .02. 2012.
237
129
132
PBSC 59,25%
BM 32,25%
PBSC+BM 0,25%
CBU 8%
n=400
Changes in graft sources
01. 01. 1992. - 31. 12. 2002.
PBSC31,5%
BM 67,6%
CBU 0,9%
01. 01. 2003.-28. 02. 2012.
PBSC69,9%
BM 18,7%
CBU10,7%
BM+PBSC0,7%
n=289
n=111
Survival of cord blood transplants
(02. 10. 2001. -30. 11. 2011.)
n=14
Diagnosis:X-adrenoleukodystrophy 2/26, ALL 3/26; AML 3/26; CML 2/26; Lesch-Nyhan sy. 1/26 MDS 2/26 NHL 1/26; SAA 1/26 , SCID 3/26 Wiscott-Aldrich sy. 1/26 WHIM sy. 1/26. Blackfan-Diamond sy. 1/26, Thalassaemia-beta 1/26, Congenital dyserythropoietic anaemia 1/26, Hurler-syndrome 1/26, Juvenile myelomonocytic leukaemia 1/26, Juvenile rheumatoid arthritis 1/26,
OS:69,2%
n=26
Stages of transplantation
• Conditioning
• Immediate posttransplant period
aplasia (0-30. days)
• Early posttransplant period
(30-100. days)
• Late posttransplant period
(100-365. days)
Conditioning regimen
• Mega chemo-radiotherapy
• Goal:
– Eradication of malignant clones
– Immunosuppression (rejection )
– „Space” for the donor hematopoesis
in the bone marrow stroma
1. phase: before engraftment 2. phase: after engraftment 3. phase: late
Graft versus host disease: acute chronic
Neutropenia, Barrier damage (mucositis, centralcatheter)
Decreased humoral and cellular immunity; NK cells appear first, but restricted T cell repertoire
Decreased humoral and cellular immunity; B- and CD4T cell count increases with awidening repertoire
Bacte
riaV
iruse
sFu
ngi
Day 0. Day 15 - 45. Day 100. Beyond day 365.
Gram negative bacteria
Gram positive bacteria
Gastrointestinal streptococci
Encapsulated bacteria
Herpes simplex CMVVaricella zoster
Respiratory and enteral viruses
Other viruses: pl. HHVEBV PTLD
Aspergillus species Aspergillus species
Candida species
Pneumocystis
Rare
Com
mon
Infection-control
• Protective environment • Isolation technics:
– Single room– sterile box– HEPA-filter– High pressure air flow: 0,5 bar– laminar air flow
• Surveillance
20
40
60
80
100
120
140
Neutrophils, monocytes, NK
B and CD8 T cells
Weeks Months Years
Time elapsed since Txp
CD4 T cells
Norm
al
rang
e
0
Plasma- and dendritic cells
Transplantation
Immunologic recovery after Txp
Immunological reconstitution
• NK (CD16+, CD 56+) cells: < 1 month
• At beginning: ↑CD8+, ↓CD4/CD8
• B cell mitogen responsiveness: 2-3 months
• Antigen specific B cell responsiveness : > 3 months
• Normal IgM production: 4-6 months
• Normal IgG production: 9 months
– T cell depleted graft: > 12 months
• Normal B cell (CD19+) count: 12 months
• IgA, IgG2 and IgG4: > 1 y → sinopulmonary infections,
encapsulated bacteria
• Principal marker: CD4+ (helper) T cell count
Prerequisites of acute graft versus host disease (GvHD)
• Graft must contain immunocompetent
cells
• Donor – host alloantigens are different
• Host cells are severely immunodeficient
Underlying diseaseConditioningConcomittant infection Epithel- and
endothel damage Citokin release (TNF, IL-1, IFN,
GM-CSF, IL-6)
Acute graft versus host disease
MHC II, Adhesion molecule
expression:
Donor T cell activation
Target cell apoptosis
Acute GvHd and survival (SAA)Akut GvHD utáni túlélés (Kaplan-Meier)
Meghalt Túlélő
akut GvHDnincs akut GvHD
0 1000 2000 3000 4000 5000 6000 7000
Transzplantáció óta eltelt idő (napokban)
0,2
0,3
0,4
0,5
0,6
0,7
0,8
0,9
1,0
Cum
ulat
ive
Pro
port
ion
Sur
vivi
ng
No aGvHD: 93%
Acute GvHD: 37%
p=0,015
N=27 pts.
Acute liver GvH
Chronic GvHD
• In early phase: changes resemble to lichen planus poikiloderma
• Localized form: epidermal atrophy, focal fibrosis, morphea-like changes, without significant inflammation
• Generalized form: inflammed changes extended fibrosis, scleroderma
Changes in survival within decades
I. decade: 01.01.1992.- 31.12.2002. (n=104) OS:45,2%II. decade: 01.01.2003.-28.02.2012. (n=253) OS:66,8%
46,7%
65,5%
OS: 45,2%
OS: 66,8%
p=0,025
Survival according to disease groups
01.01.1992. - 28.02.2012.n=354
Diagnosis groupsNo. of cases
survival %
Metabolic disease 13 61,5Immunodeficiency 27 59,3Malignant hematological 163 52,8Non malignant hematological 37 70,3Autoimmune 3 100Solid tumor 114 67,5