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