HSCT in St. László Hospital Experience and results · Immundeficiency No. of cases % of all cases Severe combined immunodeficiency (SCID) 19 3,21 Wiscott -Aldrich syndrome 7 1,18

HSCT in St. László Hospital Experience and results

Kriván Gergely MD, PhD

E. Donnall Thomas (1920-2012)

Schema of hematopoiesis

drug

donor

Patient cured

Rationale for stem cell

transplant

allogeneic

autologous freezing

irradiation engraftment

No of transplants 01. 01. 1992.– 31. 10. 2017.

0

5

10

15

20

25

30

35

40

45

50

19

92

19

93

19

94

19

95

19

96

19

97

19

98

19

99

20

00

20

01

20

02

20

03

20

04

20

05

20

06

20

07

20

08

20

09

20

10

20

11

20

12

20

13

20

14

20

15

20

16

20

17

Autologous 239/657

Allogeneic 418/657

Total 657

(n=657)

Szent László Kh OS in different treatment periods

p=0,001

I.period: 01.01.1992.-30.12.2000. (77 pts.) II.period: 01.01.2001.-31.12.2008. (189 pts.) III.period: 01.01.2009.- 04.12.2017. (331 pts.)

46,9%

52,9%

75,5%

Transplant indications 1.

Diagnosis No. of cases Diagnosis %

Malignant hematological diseases

ALL 100 16,92

AML 50 8,46

CML 19 3,21

Non-Hodgkin lymphoma 23 3,89

Myelodysplastic syndrome 52 8,81

Hodgkin’s lymphoma 13 2,21

Juvenile myelomonocytic leukemia 6 1,01

Histiocytosis X 2 0,34

Total 265 44,85

n=591

Transplkant indications 2.

Non malignant hematological diseases No. of cases Diagnosis %

Acquired severe aplastic anemia 35 5,92

Fanconi anemia 8 1,35

Blackfan-Diamond anemia 2 0,34

Congenital dyserythropoetic anemia 1 0,17

B-thalassaemia 3 0,51

Essential thrombocytosis 1 0,17

Total: 50 8,46

n=591

Transplants according to disease categories 101.01.1992.- 31.10.2017.

27

7

58

263

204

Metabolic disease 27/657

Autoimmun 7/657

Immunodeficiency 58/657

Malignant hematological 298/657

Non malignant hematological 63/657

Solid tumor 204/657

n=657

Transplant indications

(immunodeficiencies)

Immundeficiency No. of cases % of all cases

Severe combined immunodeficiency (SCID) 19 3,21

Wiscott -Aldrich syndrome 7 1,18

X-linked lymphoproliferative disease 6 1,02

Leukocyte adhesion deficiency 1 0,17

WHIM syndrome 1 0,17

Schwachman-Diamond syndrome 1 0,17

CD 40 ligand deficiency 4 0,68

DOCK8 deficiency 1 0,17

IPEX 1 0,17

Chronic granulomatosis (CGD) 4 0,68

Total: 45 7,62

n=591

OS of pts with or without infections at transplantation

Median follow up time: 2,89 years (0,06–25,31)

P<0,001

n=15, 33,3%

n=27; 88,6%

without infection with active infection

Transplant indications 4.

Inherited metabolic disorders No of cases Diagnosis %

Adrenoleukodystrophy 6 1,02

Hurler-syndrome 9 1,52

Lesch-Nyhan syndrome 1 0,17

Mucolipidosis II 1 0,17

Osteopetrosis 2 0,34

Total: 19 3,22

Solid tumors

Neuroblastoma 77 13,02

Ewing-sarcoma 45 7,61

Medulloblastoma 38 6,43

Germ cell tumors 3 0,51

Atypical teratoid/rhabdoid tumor 4 0,68

Primitive neuroectodermal tumor 14 2,37

Rhabdomyosarcoma 5 0,85

Hepatoblastoma 1 0,17

Pineoblastoma 1 0,17

Wilms tumor 5 0,85

Total: 193 32,66

Autoimmun disease 6 1,02

n=591

About autologous transplantations

National working group

Protocol No. of pts. Event free survival

Overall survival

Austria A-NB94 28 43% (3 y)

France LMCE1

LMCE3

F-NB97

72

99

47

8%

29%

Germany NB85

NB90

135

206

20%

32%

Italy

NB-85

NB-89

NB-92

106

76

170

18%

17%

16%

27%

26%

28%

Spain N-I-87

N-II-92

60

72

24%

30% (4 y)

United Kingdom ENSG5

-OPEC/OJEC

-COJEC

130

125

17,7%

31,3%

18,6%

39,6%

Results- NBL

alive mortality 5 y OS

CR 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

PR0 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

lative

Pro

po

rtio

n S

urv

ivin

g

Follow up (years)

About allogeneic transplantations

HLA antigens on cell surface - codominant

expression

Probability of sibling donors

probability of a match

0.00%

10.00%

20.00%

30.00%

40.00%

50.00%

60.00%

70.00%

80.00%

90.00%

100.00%

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

No of children

probability

Probability = 1-(3/4)n-1 where n=number of children

Submissions for stem cell

transplant

Year Autologous Allogeneic MUD search

2004 33 46 26 (56%)

2006 20 29 19 (66%)

2008 36 41 29 (71%)

2010 35 42 38 (90%)

2015 37 67 45 (67%)

Unrelated transplants in Hungary

1990-2015 (n=661)

Distribution of allo transplants

according to donor type 01.01.1992.-31.10.2017.

53%

11%

36%

idegen

haplo

családi

n=418

Distribution of allo transplants

according to donor type

(3 time periods)

n =84 n = 171

17%

65%

17%

1%

01.01.1992. – 31.12.2002.

MUD 16,6% Testvér 65,6%

Haplo 16,6% Családi 1,2%

55% 34%

11%

01.01.2003. – 28.02.2012.

MUD 55% Testvér 34,5% Haplo 10,5%

68%

18%

10%

3%

1%

01.03.2012. – 31.10.2017.

MUD 68% Testvér 18% Haplo 10%

Családi 3% Szingén 1%

n = 163

Bone marrow Peripheral blood Cord blood

Stem cell sources

Peripheral stem cell Txp advantages

and disadvantages

Advantages:

• 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 transplants according to

graft source 01.01.1992.-31.10.2017.

56%35%

9%

0%

PBSC 365/657

BMT 233/657

CBU 57/657

PB+BM 2/657

N=657

Changes in distribution of graft source

1992.01.01. - 2002.12.31.

PBSC 31,5%

BM 67,6%

CBU 0,9%

n=546 n=111

CBU transplants in St László Hospital

N=57

CBU transplants overall survival

Median follow up: 4,14 (0,05-13,64) y

n=43 66,7%

N=57

Passweg et al. BMT 2017

Txp trends in Europe

For HAPLO:

CD3(alpha/beta)/CD19 cell depletion or

CD34+ selection

CD34 selected graft

– Contains only CD34+ stem cells

TcRαβ/CD19 depleted graft contains

– CD34+ stem cells

– CD34- stem cells

– Immunocompetent cells (eg. NK cells)

– Monocytes

– Committed progenitors (eg. myeloid lineage)

– Engraftment facilitating cells

– Citokin producing cells

→ prevention of GvHD and post-transplant lymphoproliferative disease (PT-LPD), enhancement of engraftment, shortened immunodeficient state

CBU or haplo?

Comparison if CBU and haplo

approach

CBU Haplo

Costs 20-30 thousand USD/unit

Low donor search expenditure

Difficulties in donor search

In ethnic minorities Almost everybody has a family donor

GvHD Less severe Could be severe in case of incomplete T cell depletion

Infection risk Yes, mainly viral Yes

DLI possible No Yes

Stages of transplantation

• Conditioning

• Immediate posttransplant period

aplasia (0-30. days)

• Early posttransplant period

(30-100. days)

• Late posttransplant period

(100-365. days)

Main txp. complications

Chemotherapy (severe mucositis Grade III-IV)

GvHD – graft versus host disease

Infections

Long term severe neutropenia

Full T- and B-cell deficiency, lack of immunoglobulins

Citokines, complement

Vascular complications

Other complications

Prerequisites of acute graft versus

host disease (GvHD)

• Graft must contain immunocompetent cells

• Donor – host alloantigens are different

• Host cells are severely immunodeficient

Underlying disease

Conditioning

Concomittant

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 GvHD

nincs akut GvHD0 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

Cu

mu

lative

Pro

po

rtio

n S

urv

ivin

g

No aGvHD: 93%

Acute GvHD: 37%

p=0,015

N=27 pts.

Akut máj GvH

Possible role of mesenchymal stem cells

Eun-Jung Kim et al. Exp Mol. Med, 2013

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

1. phase: before engraftment 2. phase: after engraftment 3. phase: late

Graft versus host disease: acute chronic

Neutropenia, Barrier damage (mucositis, central catheter)

Decreased humoral and cellular immunity; NK cells appear first, but restricted T cell repertoire

Decreased humoral and cellular immunity; B- and CD4 T cell count increases with a widening repertoire

Bacte

ria V

iruses

Fungi

Day 0. Day 15 - 45. Day 100. Beyond day 365.

Gram negative bacteria

Gram positive bacteria

Gastrointestinal streptococci

Encapsulated bacteria

Herpes simplex CMV

Varicella zoster Respiratory and enteral viruses

Other viruses: pl. HHV EBV PTLD

Aspergillus species Aspergillus species

Candida species

Pneumocystis

Rare

C

omm

on

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 range

0

Plasma- and dendritic cells

Transplantation

Immunologic recovery after Txp

Toxoplasmosis

High risk patients

• Unrelated donors (MUD, MMUD)

• CBU

• T-cell depletion (in vivo or ex vivo)

• Severe GvHD (Grade III-IV)

• Severe lymphopenia

Cumulative incidence of viral infections after pediatric alloHSCT

Styczisky és mtsai: Clin Microbiol Infect 2016; 22: 179.e1–179.e10

Total: 49.1 %

CMV

Deaths attributed to viral infections

• St. László Hospital: – Adults (10 years – 2005-2014) 15 pts

• CMV: 10 pts • EBV: 4 pts • Adeno: 1 pt

– Paediatric (6 years - 2009-2014) 11 pts • CMV: 5 pts • EBV: 2 pts • Adeno: 4 pts

• Pediatric SOT Txp. (5 years - 2010-14) 3 pts – Heart: 1 CMV – Liver: 1 EBV – Lung: 1 CMV

29 pts

Otherwise successful transplants; Dg. in time, treated but…

Adoptive T cell therapy using antigen-specific T cells enriched from CliniMACS Prodigy

Mononuclear Cells

Activation of virus-specific T-cells

IFNg-bi-specific mAB & magnetic nanoparticle AB

Purified, virus-specific T-cells

Donor Patient

Results…

• 9 pediatric pts with cytotoxic T-cell therapy – 5 male, 4 female

– Median age: 11 y (1,5 – 16)

Malignant

hematologicaldisease; 6

Immune defect; 2

Thalassaemia; 1

Unrelated: 7

Haploidentical1

Sibling 1

Indications

Vírus 1. Highest copy

number Disease/ organ Vírus 2.

Highest copy number

Disease/ organ

GvHD/ immun-szuppression

1 CMV 212 000 Pneumonitis - - - No

2 CMV 10 800 - AdV 501 000 Nephritis Gr II GvHD + IS

3 EBV 11 800 PTLD - - - No

4 CMV 5 370 Colitis - - - Gr IV GvHD + IS

5 AdV 2 850 - - - - Gr IV GvHD + IS

6 CMV 2 875 506 Pneumonitis - - - No

7 CMV 6 146 094 Colitis EBV 18 040 - Gr IV GvHD + IS

8 EBV 1 342 PTLD,

Isolated CNS DLBCL

- - - No

9 CMV 20 522 - AdV 1 350 enteritis Gr IV GvHD + IS

Outcome

Cells infused without side effects

First negative PCR after Tx: median +13. day

8/9 pts. became symptomless (7/9 microbiologically negative)

Flare up of aGvHD was not observed

Median follow up time: 301 days (106-552)

1 pt. limited cGvHD

6/9 pts are alive; 3 died: ◦ 2 invasive aspergillosis

◦ 1 CMV pneumonitis