Hematopoietic stem cell transplant (HSCT) involves transplanting hematopoietic stem cells to re-establish normal bone marrow function in patients with blood disorders or cancer. HSCT has become an established treatment for many malignant and non-malignant blood diseases. HSCT sources include bone marrow, peripheral blood, and umbilical cord blood. The transplant process involves stem cell collection, processing, conditioning chemotherapy, stem cell infusion, and recovery. Complications can include graft-versus-host disease. Matching HLA antigens between donor and recipient is important for transplant success, especially in allogeneic HSCT. Advances have improved outcomes, but further progress is still needed.

1. Hematopoietic stem cell
transplant (HSCT)
STEM CELL BIOLOGY AND REGENERATIVE MEDICINE
SABER ALZAHRANI
SALEM ALANAZI
04 OCTOBER 2016

2. Outlines

3. Hematopoietic stem cells (HSCs)
 HSCs formation start during embryonic development.
 Found in bone marrow and umbilical cord blood.
 Hemati= Greek prefix “blood’
 Poiesis/Poietic= Greek suffix ‘formation”
 express CD34

4. Hematopoietic stem cells (HSCs)
 Multipotent ,self-renewing
progenitor cells give rise to all
blood cells (Haematopoiesis).
 Maintain the production of all
blood cells throughout life

5. Bone marrow transplantation (BMT)
 BMT Refers to infusion of autologous or allogeneic BM to re-
establish normal bone marrow function.
1. Autologous BMT :Patients receive their own stem cells.
2. Allogeneic BMT : related or unrelated donor

6. History of BM transplantation
 Early attempt was in 1891
 Oral administration of healthy BM to patient with defective blood
formation.
 not successful, but physicians had the right idea: donor marrow cells----
may find their way into the BM cavity.
 Some unsuccessful BMT in 1930s and 1940s

7. History of BM transplantation
Hope within Tragedy:
 After World War II
 Nuclear bomb Inspire the research into the effects of the
radiation on the bone marrow of survivors in Hiroshima and
Nagasaki.
 BM is very sensitive organ to radiation.
 This led to major breakthroughs for bone marrow transplants
in the 1950s

8. History of BM transplantation
 1956 – The First successful Transplantation Between Identical Twins with total body
irradiation.
E. Donnall Thomas
 Performed total body irradiation followed by infusion of bone marrow from an identical
twin could result in complete remission of leukemia.
 The Nobel Prize, 1990

9. History of BM transplantation
 1958 – an Important Discovery
 Allogeneic BMT was not performed on large scale until Jean Dausset, a French medical
researcher, made a critical discovery about the human immune system : Human
histocompatibility antigens “HLA”
 Dausset describe HLA as “proteins on the surface of most cells in the body. The immune system
uses these proteins to identify which cells belong in the body”
 The better the antigen match = less likely T cells of the donor will react against the patient’s body.
 The Nobel Prize, 1980
 1968 – First Bone Marrow Transplant Between HLA matched Siblings

10. Sources of Hematopoietic stem cells
 Bone marrow (BM).
 Peripheral blood (PBSC) 1986
 Umbilical cord blood (UCB) 1988

11. Hematopoietic stem cell transplant
(HSCT)
 The term BMT has been change to Hematopoietic stem cell
transplant (HSCT) since the introduction of peripheral blood
and umbilical cord stem cells
 HSCTs become an established standard treatment for malignant
and non-malignant blood disorders.
 >60,000 transplants performed yearly worldwide.

12. Indication for autologous transplantIndication for autologous transplant
Malignant disorders
 Non-Hodgkin lymphoma
 Hodgkin’s disease
 Acute myeloid leukemia (AML)
 Multiple myeloma
 Neuroblastoma
 Ovarian cancer
 Germ-cell tumors
Non-Malignant disorders
 Autoimmune disorders
SLE, Systemic sclerosis
 Amyloidosis

13. Indication forIndication for Allogenic transplantAllogenic transplant
Malignant disorders
 Acute myeloid leukemia (AML)
 Non-Hodgkin lymphoma
 Hodgkin’s Disease
 Acute lymphoblastic leukemia (ALL)
 Chronic myeloid leukemia (CML)
 Chronic lymphoblastic leukemia (CLL)
 Myeloproliferative disorders MPD
 Myelodysplastic syndromes
 Multiple Myloma*
Non-Malignant disorders
 Aplastic anemia
 Thalassemia
 Sickle Cell Disease
 SCID
 Fanconi’s anemia
 Blackfan-Diamond
 Wiskott-Aldrich
 Inborn errors of metabolism
 Auto immune disordre

14. HLA system ?
 HLA= Human leukocyte Antigen.
 The genes for the HLA proteins are clustered in the major histocompatibility
complex (MHC), located on the short arm of chromosome 6.
 Essential for Allogeneic transplant.
 Class I (HLA-A,HLA-B,HLA-C) Class II (HLA-DR,HLA-DQ) (10/10 match ).
 The most polymorphic gene >15,000 alleles

15. Donor selection for
allogenic transplant
 Class I (HLA-A,HLA-B,HLA-C) Class II (HLA-DR,HLA-DQ) (10/10 match ).
 ABO system :4 possible combinations (A,B,O,AB)
 HLA system : >1 million combinations
 Matched Related Donor (siblings)
 25% chance a sibling will be full match
 The more siblings a patient has the better chance for a match
 If no matched is available.
 Search for Matched Unrelated Donors (MUD).
 through bone marrow registry databases.

16. BMDWBMDW
France Greffe
de Moelle
183,454183,454 Austrian Bone
Marrow Donors
60,86060,860
National Marrow
Donor Program
(USA) 1980
8,000,0008,000,000
Anthony Nolan
Research
Center(UK)
411,912411,912
Australian
Bone Marrow Donor
Registry
182,367182,367
German
Registry of
Bone Marrow
Donors
3,939,5383,939,538
Bone Marrow Donors registryBone Marrow Donors registry
WorldwideWorldwide
44 countries44 countries
September 2015September 2015
25,000,000 Donors25,000,000 Donors
64 Registries64 Registries
Marrow Donor
Registry (India)6,500
Stem cell Donor
Registry (Saudi Arabia)
10,000
One is most likely to find a match within donors of similar ethnic
background.

18. Transplant process:
1-Stem cells collection
 Bone marrow harvesting.
 General anaesthetic
 Marrow aspirated from pelvis.
 Peripheral blood harvesting.
 Stem cells mobilised – G-CSF
 On day 5 : stem cells is collection (apheresis ) machine
3 hours session

19. Transplant process:
2-Processing & Cryopreservation
 Processing
 BM /PBSC processed and stem cells concentrated and
purify and prepared for freezing process.
 Cryopreservation.
 Stem cells are preserved by freezing to keep stem cells
alive until day of infusion into the patient.

20. Transplant process:
3-Conditioning (Chemotherapy Regimen)
 The conditioning period 7-10 days.
 By delivery of chemotherapy and/or radiation
 To eliminate malignancy.
 To suppress the patient’s immune system from rejecting the new
stem cells
 To create space for the new cells.

21. Transplant process:
3-Conditioning (Chemotherapy Regimen)
 The conditioning period 7-10 days.
 By delivery of chemotherapy and/or radiation
 To eliminate malignancy.
 To suppress the patient’s immune system from rejecting the new
stem cells
 To create space for the new cells.
 Bone marrow transplantation regimens vary from one patient to
another, and depend upon the type of cancer

22. Transplant process:
4-Stem cells infusion
 Infusion - 20 minutes to an hour, varies depending on the
volume infused.
 Infused through a central venous line CVL, much like a
blood transfusion.
 Premedication with acetaminophen and diphenhydramine
to prevent reaction.

23. Transplant process:
5-Recovery

 Neutropenic phase
 (2-4 wk), during this period the patient essentially
has no effective immune system
 Supportive care and antibiotic therapy are the
mainstays of successful passage through this
phase.

24. Transplant process:
5-Recovery

 Engraftment phase
 Recovery of normal levels cells is called engraftment
 Bone Marrow (2-6 weeks)
 PBSC ( 8-10 days for neutrophil & 10-12 days for platelets )
 Cord blood (Neutrophil is 4 weeks)
 Neutrophil engraftment is important (may give G-CSF)
 Platelets are the next to return with red cells last (Commonly patients
require transfusion of red cells and platelets).

25. Complications
• Graft Verses Host Disease (GVHD)
• Lymphocytes from the donor graft attack the cells of the host
• GVHD can usually be treated with steroids or other immunosuppressive agents.
• Acute GVHD occurs before day 100 post-transplant
• Chronic GVHD occurs beyond day 100
• Recent advances have reduced the incidence and severity of this post-transplant
complication, but GVHD, directly or indirectly, still accounts for approximately 15% of
deaths in stem cell transplant patients
• Chronic GVHD can develop months or even years post-transplant

26. Post -monitoring of the engraftment
 Chimerism test / Engraftment Analysis
 The test performed by the analysis of genomic
polymorphisms short tandem repeat (STR)
sequences in multiple chromosome
 STR test is done 1,2,3,6 months and 1 year

27. Challenges
 Haploidentical Transplant.
 Most patients will have haploidentical donor: parents, siblings, children
 High risk of rejection and GVHD
 Progress T cell depletion to decrease GVHD.
 Approach in establishing HLA Compatible Stem Cell Banks iPSC banking
 Homozygous HLA haplotype lines

28. Summary
 HSCT is a unique effective treatment modality providing normal stem
cells production for many malignancies and genetic disorders
 HLA matching is critical in allogeneic transplant.
 HLA Allele level matching is associated with lower risks of graft failure,
GVHD and transplant related mortality.

29. References
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30. References
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