Hematopoietic stem cell transplantation- HSCT

Principle of HSCT

• Myeloablation and eradication of residual disease with hogh dose conditioning regimen

• Repopulation of bone marrow by donnor´s hematopoietic stem cells:1. alogenneic 2.syngenneic, 3.autologous

Hematopoietic stem cell transplantation

• Alogenneic Tx

1. subling

2. Alternatve donnors:

HLA identical related donnor (MUD)

(Haploidentical donnor)

• Autologous Tx:

in vitro purging

in vivo purging

• Syngenneic Tx

Human Leukocyte AntigensHLA

 HLA genes 6. chromosome (6p21) over 100 coding sequences most polymorphic area in human genom

  Genes for class HLA I and II

coding transmembrane glykoproteins. Biologic function: allogenneic restriction 

DP

B2

DP

A2

DP

B1

DP

A1

DQ

B2

DQ

A2

DQ

B3

DQ

B1

DQ

A1

DR

B1

DR

B2-

8

DR

B9

DR

A

HL

A-B

HL

A-C

HL

A-A

q p

HLA class II HLA class I

HLALocalisation: short arm of 6. chromosome

(6p21)

HLA I. class-A -B expressed on all -C nucleated cells

HLA II. class-DRB1-DRB3,4,5-DQB1-other (např. -DPB1)Expression: B-lymphocytes, activated T-lymphocyte, monocytes, macrophages dendritic cells

HLA a HSCT

GvHD – graft versus host disease: donnor´s immune system eliminates incompatible cells of the recipient

+ GvL – graft versus leukemia reaction: Transplanted immune cells eradicate residual

malignant cells.

Sources of hematopoietic stem cells

• Bone marrow: 10-20ml/kg

Repeated punctions at spina & iliac posterior crest

• Peripheral blood after SC mobilization to the blood:

(PBSC – peripheral blood stem cells)

Počet HSCT v r. 1990

HSCT in Europe 1990 vs. 2006

Počet HSCT v r. 2006

Principles and phases (autologous) of autologous hematopoietic

transplantation

Harvest of HSC Myelo(imuno)-ablative therapy

HSCT transplantation

BM (PBSC) (mobilization)

FreezingDefrostIn vitro

purging??

Conditioning regimen

HSC mobilization to peripheral blood

Autologous donnor (= patient): e.g.- Cyklophosphamide 2,5g/m2 + G-CSF (filgrastim) 10µg/kg. Harvest: cca D8-D10

Alogenneic donnor: G-CSF (filgrastim) 5 µg/kg s.c. D1-5, Harvest: in most cases D5

„stem“ cells: CD34+, Graft quality: CD34+ cells >2,0x106/kg recepient CFU-GM: >1,0 x105/kg recepient

Target ammount of SC

Conditioning regimens

Myeloablative : TBI (10-15 Gy), TBI + cyklofosfamid, Busulfan + Cyklofosfamid, BEAM (BCNU, Etoposid, ARA-C, Melfalan)

Non myeloablative: např. Fludarabine + Busulfan + ATG

Transplantation with nonmyeloablative regimen: RIC (reduced intensity conditioning)

Complications after allo HSCT• acute form of GVHD (Graft versus Host Disease): I-IV

• SOS – sinusoidál obstructive syndrome)

•Acute alveolitis (TBI)

• infektions : HSV, CMV, VZV, Adenovirus Candida sp, Aspergillus sp,

•chronic GVHD

Prevention and treatment of GVHD

Prevention1. HLA fully matched donnor 2. Prevention: např. methotrexate + cyclosporine A

acute GVHD

High dose myethylprednisolone, antilymphocytic globulin (ALG), atd

Allogenneic vs. Autologous transplantation in NHL

• Alogenneic(HLA identical)

• Mortality up to 30%• morbidity: chron.

GVHD• Relaps: 18-24%• GVL efekt +• only 30% patients

• Autologous• mortality < 5%• morbidity minimal• Relaps: 38-69%• (graft contamination?)• GVL efect: none

Alogenneic HSCT

HLA identical sibling: genotypic identity: 30%

alternative donnors

Phenotypicly identical unrelated donnor (MUD)

Haploidentical related donnor : parents, children

Indications for allogenneic stem cell transplantation

In general:

• Good performance status and age < 60 years

• Chemosensitive disease

• Hematologic malignancies• Aplastic anaemia• Congenital munodeficiency and metabolic diseases

Hematologic malignancies – indication for alloSCT

• AML v 2. remmission or AML in 1. remmission with high risk of relaps (complex karyotype changes)

• ALL Ph + v 1. remmission, ALL ve 2. remmission

• CML: resistent to TKI (T315I mutation)

• CLL – rezistant to fludarabine

• Hodgkin´s lymphoma: reapeated relaps

• Nonhodgkin lymphoma: chemosensitive repeated relaps

Indication to autologous HSCT

• Multiple myeloma in 1. i 2. line• Agressive NHL (DLBCL) in 2. remmission• Follicular lymphoma or MZL 2. (3.) remmission• Hodgkin´s lymphoma in ve 2. remmission• MCL in 1. remisssion• PTCL in 1. a 2. remmission

Clinical studies:DLBCL in 1. remmission

Autoimune diseases (Multiple sclerosis)

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