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