haematopoietic stem cell transplantation

Hematopoietic stem cell transplant (HSCT)

STEM CELL BIOLOGY AND REGENERATIVE MEDICINESABER ALZAHRANISALEM ALANAZI04 OCTOBER 2016

Outlines

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

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

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

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

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

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

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

Sources of Hematopoietic stem cells

Bone marrow (BM). Peripheral blood (PBSC) 1986 Umbilical cord blood (UCB) 1988

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.

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

Indication for Indication for Allogenic transplant Allogenic 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

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

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.

BMDWBMDW

France Greffe de Moelle 183,454183,454 Austrian Bone

Marrow Donors

60,860 60,860

National Marrow Donor Program

(USA) 19808,000,0008,000,000

Anthony Nolan Research

Center(UK) 411,912 411,912

AustralianBone Marrow Donor

Registry

182,367 182,367

German Registry of

Bone Marrow Donors 3,939,5383,939,538

Bone Marrow Donors registry Bone Marrow Donors registry WorldwideWorldwide44 countries44 countries

September 2015 September 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.

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

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.

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.

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

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.

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.

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).

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

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

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

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.

References Aschan, Johan. 2006. "Allogeneic Haematopoietic Stem Cell Transplantation: Current Status and Future Outlook." British medical bulletin 77

(1): 23-36. Ballen, Karen K, and Hillard Lazarus. 2016. "Cord Blood Transplant for Acute Myeloid Leukaemia." British journal of haematology. Bennett-Rees, N., & Hopkins, S. 2008. Part 2 - Haematopoietic Stem Cell Transplantation - Chapter 07: Background to the Haematopoietic

Stem Cell Transplant (Hsct) Procedure. Hoboken, Cancer in Children and Young People . . Byrne, Michael, Bipin N. Savani, Mohamad Mohty, and Arnon Nagler. 2016. "Peripheral Blood Stem Cell Versus Bone Marrow Transplantation:

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References

Holtick, Udo, Melanie Albrecht, Jens M. Chemnitz, Sebastian Theurich, Alexander Shimabukuro-Vornhagen, Nicole Skoetz, Christof Scheid, and Michael von Bergwelt-Baildon. 2015. "Comparison of Bone Marrow Versus Peripheral Blood Allogeneic Hematopoietic Stem Cell Transplantation for Hematological Malignancies in Adults—a Systematic Review and Meta-Analysis." Critical Reviews in Oncology/Hematology 94 (2): 179-188. doi: http://dx.doi.org/10.1016/j.critrevonc.2014.12.007.

Hübel, Kai, Javier Rubia, Nabih Azar, and Paolo Corradini. 2015. "Current Status of Haematopoietic Autologous Stem Cell Transplantation in Lymphoid Malignancies: A European Perspective." European journal of haematology 94 (1): 12-22.

Kondo, Motonari. 2010. Hematopoietic Stem Cell Biology: Springer. Körbling, Martin, and Emil J Freireich. 2011. "Twenty-Five Years of Peripheral Blood Stem Cell Transplantation." Blood 117

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Matching and Donor Selection for Haematopoietic Progenitor Cell Transplantation." International Journal of Immunogenetics.