HSCT in St. László Hospital Experience and results · Immundeficiency No. of cases % of all cases...

transcript

HSCT in St. László Hospital Experience and results

Kriván Gergely MD, PhD

E. Donnall Thomas (1920-2012)

Schema of hematopoiesis

Patient cured

Rationale for stem cell

transplant

allogeneic

autologous freezing

irradiation engraftment

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

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.)

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

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

Transplants according to disease categories 101.01.1992.- 31.10.2017.

Metabolic disease 27/657

Autoimmun 7/657

Immunodeficiency 58/657

Malignant hematological 298/657

Non malignant hematological 63/657

Solid tumor 204/657

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

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

About autologous transplantations

National working group

Protocol No. of pts. Event free survival

Overall survival

Austria A-NB94 28 43% (3 y)

France LMCE1

F-NB97

Germany NB85

Spain N-I-87

N-II-92

30% (4 y)

United Kingdom ENSG5

-OPEC/OJEC

-COJEC

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%

NBL - OS according to disease status

Cumulative Proportion Surviving (Kaplan-Meier)

Complete Censored

recidiva

PR0 2 4 6 8 10 12

lative

Follow up (years)

About allogeneic transplantations

HLA antigens on cell surface - codominant

expression

Probability of sibling donors

probability of a match

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.

idegen

családi

Distribution of allo transplants

according to donor type

(3 time periods)

n =84 n = 171

01.01.1992. – 31.12.2002.

MUD 16,6% Testvér 65,6%

Haplo 16,6% Családi 1,2%

55% 34%

01.01.2003. – 28.02.2012.

MUD 55% Testvér 34,5% Haplo 10,5%

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%

PBSC 365/657

BMT 233/657

CBU 57/657

PB+BM 2/657

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

CBU transplants overall survival

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

n=43 66,7%

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)

lative

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

iruses

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

Infection-control

• Protective environment

• Isolation technics:

– Single room

– sterile box

– HEPA-filter

– High pressure air flow: 0,5 bar

– laminar air flow

• Surveillance

Neutrophils, monocytes, NK

B and CD8 T cells

Weeks Months Years

Time elapsed since Txp

CD4 T cells

al range

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 %

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

HSCT in St. László Hospital Experience and results · Immundeficiency No. of cases % of all cases...

Documents