Stem Cell Transplant Revision 2016

STEM CELL TRANSPLANT
TITILOLA AKINGBOLA
REVISION 2016
Figure 1. Scanning under low power reveals a heterogenous population of cells
Maslak, P. ASH Image Bank 2005;2005:101401
Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.

Background
• First successful transplants—late 1960s
• 30,000-40,000 transplants performed yearly
worldwide
• >20,000 patients have survived >5 years
Lazarus HM. Autologous and allogeneic transplantation procedures for

hematologic malignancies. Manual of Clinical Hematology, 3rd edition
2002:399-409
Background
• Hematopoietic stem cell transplantation
– Intravenous infusion of autologous or allogeneic stem cells
• Collected from bone marrow, peripheral blood or umbilical cord
blood
– Re-establish hematopoietic function in patients with
damaged/defective bone marrow or immune systems
– Potentially curative for a wide variety of disorders

2002:399-409
Graft Sources
• Allogeneic: from another person
• Syngeneic: from an identical twin
• Autologous: from the patient
• Choice of graft is based on disease type,

patient condition, donor compatibility and
health
Father turns tragedy into hope through cord blood bank
• State lawmakers recognize the importance of

the cord blood. A bill passed recently by
Connecticut legislators requires doctors to
give cord blood information regarding banking
and donating to every pregnant woman
Brief history of HSCT
• End of 19th Century: Reports patients given BM orally as
a Rx for haematological dx . Raw or cooked spleen
• Pt received 18mls of bone marrow ivfrom his mother to
treat AA
• 1945 The search for stem cells began after the bombing
in Hiroshima & Nagasaki
• 1950 – 1962 203 allogeneic BMT all failed
• Late 1960s HLA System discovered
• 1968 The first successful allo SCT. Doctors at Mattel
Children's Hospital
Dr Ted Collins
Current Status of Bone Marrow Transplantation in Nigeria I.
• The strongest indication for allogeneic bone marrow

transplantation in Nigeria remains sickle cell disease.
• Over 4Million Nigerians have sickle cell diseases and
other 25Million Nigerians are carriers.
• The Sickle Cell Disease is among the top ten Non-
Communicable Disease [NCD] causing significant
disability, morbidity and mortality
Current Status of Bone Marrow Transplantation in
Nigeria I.
• This was at a ceremony welcoming Dr Allan

Wayne who carried out BMT on two Nigerian
over ten years now.
• A number of Nigerians have benefited from
BMT and have had some form hands on
experience on BMT.
• A few Nigerians have been exposed to
international training in BMT and enjoyed
collaborative research.
AWARENESS AMONGST NIGERIANS
• The issue of bone marrow transplantation is gaining recognition in the

treatment of sickle cell disease; yet there is no established centre for BMT for
so long. UBTH the 1st Transplant centre in Nigeria
• An example is the story of a mother appreciating the Nigerian government for

the support given. “Mrs. Abiodun Adelere, a fashion designer expressed
gratitude to the state government who footed the treatment bill and provided
ticket money for two.”
• Another likely beneficiary from Nigeria was in the Yale Law School. Yale Law
School students gathered a particular Monday for a bone marrow drive in
support of a recent graduate — Nigeria’s first Winter Olympian hopeful — who
has been diagnosed with aggressive cancer.
• Adebiyi’s goal, he said, is to sign up 10,000 people to the registry. Eventually,
he hopes to start the first bone marrow registry in Nigeria, where he was born.
Ethics of Stem Cell Research
• First published Fri Apr 25, 2008
• Human embryonic stem cell (HESC) research offers
much hope for alleviating the human suffering brought
on by the ravages of disease and injury.
• HESCs are characterized by their capacity for self-
renewal and their ability to differentiate into all types of
cells of the body.
• The main goal of HESC research is to identify the
mechanisms that govern cell differentiation and to turn
HESCs into specific cell types that can be used for
treating debilitating and life-threatening diseases and
injuries
Graft Sources
• Autologous Transplant
– No evidence of disease in the blood or bone
marrow
– Transplant related mortality (TRM) lowest with
autos (<5%)
– Relapse rates are higher depending on the disease
– Absence of graft versus tumor effects

2002:399-409
Graft Sources
• Allogeneic Transplants
– High TRM (30-50%)
– Lower relapse rates due to graft versus tumor effects
– Graft versus host effects
• Matched Related Donor (siblings)
– 25% chance a sibling will be a match
– The more siblings a patient has the better chance for a
match

2002:399-409
Graft Sources
• Alternative Donors
– Matched Unrelated Donors (MUD)
– Haploidentical Donors
• From parent, child or sibling
• Must have many stem cells to overcome risk of graft rejection
• Increased risk of GVHD

2002:399-409
HLA Typing
• HLA typing became feasible in 1960s
• Linked on chromosome 6
• Inherited as haplotypes
• 1 in 4 chance a sibling will be identical
Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-

1826.
HLA Matching
• 6/6, 8/8, or 10/10
– HLA loci on chromosome 6
– HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, HLA-DP
• ABO incompatibility is not an exclusion

2002:399-409
Eligibility
• Age < 65
– Autologous, mini-allo
• Age < 55
– Myeloablative allogeneic
• Exclusions
– CHF, uncontrolled diabetes mellitus, active
infections, renal insufficiency
Indications Autologous Transplant
• Autoimmune
Multiple myeloma
disorders
• NHL
Amyloidosis
• Hodgkin’s disease
• AML
• Neuroblastoma
• Ovarian cancer
• Germ-cell tumors
1826.
Indications for Allogeneic Transplant
• Aplastic anemia
AML
• ALL
PNH
• CML
Fanconi’s anemia
• MDS
Blackfan-Diamond
• MPD
Thalessemia major
• NHL cell anemia
Sickle
• Hodgkin’s Disease
SCID
• CLL
Wiskott-Aldrich
• Multipleerrors
Inborn myeloma
of metabolism
• Juvenile CML

1826.
Preparative Regimens
• Myeloablative
– High doses of chemotherapy +/- radiation
– 3 goals
• Eliminate malignancy
• Immunosuppression to allow engraftment
• Decrease graft versus host effects

1826.
2002:399-409
Myeloablative Regimens
• Myeloablative Regimens
– Most common regimens
• Cyclophosphamide/TBI
• Busulfan/Cyclophosphamide
• Stem cells are essential to restore marrow
function

1826.
2002:399-409
Myeloablative Regimens
• Therapy is based on disease
• Other drugs
– Etoposide, BCNU, cytarabine, melphalan
• Graft versus leukemia effects in allogeneic
donors

2002:399-409
1826.
Preparative Regimens
• Nonmyeloablative (Mini-allo)
– Sufficient immunosuppression to allow donor cell
engraftment
– Injury to organs less, fewer infections, fewer
transfusions
– Higher relapse rates
– May have mixed chimerism
– Graft versus tumor effects

2002:399-409
Non-myeloablative Conditioning
• Alternative to conventional myeloablative
regimens
• Older patients or patients with comorbid
conditions
• Therapeutic graft versus tumor effect
– Mediated by allogeneic T-cells
– Donor T-cells eradicate the host’s malignant cells
Georges GE, Storb R. Review of “minitransplantation”: nonmyeloablative

allogeneic hematopoietic stem cell transplantation. Int J Hematol. 2003;77:3-
14.
Non-myeloablative Regimens
• Nonmyeloablative Regimens
– Usually fludarabine based
– ATG is added
– May be combined with other drugs
• Busulfan, cyclophosphamide, melphalan

2002:399-409
Non-myeloablative Regimens
• Better for slow growing cancers
– CLL, NHL
• Graft eradicates the cancer not the chemo
• High relapse rates

1826.
Reduced Intensity Conditioning Regimens
• Advantages
– Reduction in mortality
– Reduction in non-relapse mortality
– Reduced PRBC and platelet transfusions
– Duration of neutropenia reduced
– Reduced numbers of bacteremias
– Able to give to heavily pretreated patients
Sandmaier BM, Mackinnon S, Childs RW. Reduced intensity conditioning

for allogeneic hematopoietic stem cell transplanation: Current
perspectives. Biol Blood Marrow Transplant. 2007;13:87-97.
Reduced Intensity Conditioning Regimens
• Reduced GVHD compared to myeloablative

• Late onset acute GVHD occurring beyond day
100
Sandmaier BM, Mackinnon S, Childs RW. Reduced intensity conditioning

for allogeneic hematopoietic stem cell transplanation: Current
perspectives. Biol Blood Marrow Transplant. 2007;13:87-97.
Principals of Conditioning
• Donor Lymphocyte Infusions (DLI)
– T cells and NK cells
– Additional anticancer effects
– Preventing relapse or eliminating active disease
• CML and multiple myeloma

2002:399-409
Introduction
• In recipients of allogeneic hematopoietic-cell
transplants, peripheral-blood cells mobilized
with the use of filgrastim (recombinant granulocyte
colony-stimulating factor) engraft more rapidly than
bone marrow. However, the relative effects of these
techniques on the rates of acute and chronic graft-
versus-host disease, overall survival, and disease-
free survival have not been determined in
randomized studies.
• EMATOPOIETIC cells reside predominantly in the bone marrow but can be
mobilized in large numbers in the blood
by the administration of filgrastim (recombinant granulocyte colony-stimulating factor
[G-CSF]). Apheresis products containing G-CSF–
mobilized peripheral-blood cells are now widely used
instead of bone marrow for autologous transplantation.1 Peripheral-blood cells engender
hematopoietic
recovery after transplantation more rapidly than does
marrow. These favorable results with autologous cells
prompted phase 1 and 2 evaluations of the use of allogeneic peripheral-blood cells for hematopoietic
rescue.2-4 The results of these studies, which used historical controls, suggested that the recovery of
neutrophils,
red cells, and platelets was faster with the use of peripheral-blood cells than with the use of marrow,
with no
apparent increase in the incidence of acute graft-versushost disease (GVHD).5-7 In these retrospective
analyses, however, the outcomes with respect to chronic
GVHD, relapse, and survival were conflicting.8-14
Bone Marrow Transplants to Cure
Lymphomas/Thymomas
• Whole Body Irradiation to remove endogenous immune system
and tumor
– Also total lymphoid irradiation with antithymocyte serum
• Injection of bone marrow from a well matched donor to re-
establish immune system
• Regulation of immune response to prevent graft versus host
reaction.
• Autologous donation possible if one can purify and remove
tumor cells, enriching for stem cells..
• Allogeneic donors have advantage of graft versus tumor reaction
to kill any remaining tumor cells.
• Allogeneic donors have the disadvantage of graft versus host
reaction if they are not well matched.
Judith Shizuru
Figure 2. The posterior iliac crests (arrows) are common sites for bone marrow aspiration
and biopsy
Maslak, P. ASH Image Bank 2005;2005:101279
Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.

Collection of Stem Cells
• Stem Cell Collection (mobilization)
– Stem cells circulate in the blood
– Identified by CD34+ by flow cytometry
– Filgrastim, sargramostim, AMD 3100
– Stem cells are collected through an apheresis catheter
– More cells are collected
– Higher chronic GVHD than bone marrow harvest
– More rapid marrow recovery

2002:399-409
Infusion of Stem Cells
• Stem cells may be infused fresh within a few
hours of collection
• May be frozen using DMSO
– Creamed corn or garlic smell
• Umbilical cord blood is obtained from one of
the umbilical cord veins and frozen with an
anticoagulant and nutrient media

2002:399-409
Stem Cell Manipulation
• ABO incompatible
– Removal of isoagglutinins or RBCs
• T-cell depletion
– Reduce incidence of GVHD
– Increased graft failure
– Increased relapse rates
• In vitro purging
– Removal of tumor cells
– Positive selection of CD34+ cells

2002:399-409
Complications
• Early
– Mucositis
– Sinusoidal obstructive syndrome (VOD)
• Fluid retention, jaundice, hepatomegaly
– Transplant related infections
• Damage to mouth, gut and skin
• Prolonged neutropenia

1826.
Complications
• Early
– Pancytopenia
• PRBC and platelet transfusions
• Broad spectrum antimicrobials
• Antifungals if prolonged fevers 3-5 days

2002:399-409
Complications
• Early
– Graft Versus Host Disease
• Acute GVHD to day 100
– Skin, GI tract, liver

1826.
2002:399-409
Complications
• Early
– Graft Rejection
• Host versus graft
• Drug injury to marrow
• Viral infections: CMV, HHV-6 & 8
– Interstitial Pneumonitis
• Diffuse alveolar hemorrhage
• Too few donor stem cells
• ARDS often caused by CMV

2002:399-409

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STEM CELL TRANSPLANT

Maslak, P. ASH Image Bank 2005;2005:101401

Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.

Lazarus HM. Autologous and allogeneic transplantation procedures for

Lazarus HM. Autologous and allogeneic transplantation procedures for

• Choice of graft is based on disease type,

• State lawmakers recognize the importance of

• The strongest indication for allogeneic bone marrow

• This was at a ceremony welcoming Dr Allan

• The issue of bone marrow transplantation is gaining recognition in the

• An example is the story of a mother appreciating the Nigerian government for

Lazarus HM. Autologous and allogeneic transplantation procedures for

Lazarus HM. Autologous and allogeneic transplantation procedures for

Lazarus HM. Autologous and allogeneic transplantation procedures for

Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-

Lazarus HM. Autologous and allogeneic transplantation procedures for

Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-

Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-

Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-

Lazarus HM. Autologous and allogeneic transplantation procedures for

Lazarus HM. Autologous and allogeneic transplantation procedures for

Georges GE, Storb R. Review of “minitransplantation”: nonmyeloablative

Lazarus HM. Autologous and allogeneic transplantation procedures for

Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-

Sandmaier BM, Mackinnon S, Childs RW. Reduced intensity conditioning

• Reduced GVHD compared to myeloablative

Sandmaier BM, Mackinnon S, Childs RW. Reduced intensity conditioning

Lazarus HM. Autologous and allogeneic transplantation procedures for

Maslak, P. ASH Image Bank 2005;2005:101279

Copyright ©2005 American Society of Hematology. Copyright restrictions may apply.

Lazarus HM. Autologous and allogeneic transplantation procedures for

Lazarus HM. Autologous and allogeneic transplantation procedures for

Lazarus HM. Autologous and allogeneic transplantation procedures for

Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-

Lazarus HM. Autologous and allogeneic transplantation procedures for

Copelan EA. Hematopoietic stem-cell transplantation. NEJM 2006;354:1813-

Lazarus HM. Autologous and allogeneic transplantation procedures for

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