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Engraftment
25 May 2018
Annette TrickettPrincipal Scientist | BMT Laboratory | NSW Health Pathology, Randwick Hospitals
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Scope
Aim:
• Provide a better understanding of the engraftment
timeline and impacting factors
Objectives:
• Define haematological reconstitution
• What can affect engraftment?
• Recovery of immune function
• Failure of engraftment and rescue strategies
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Haematological reconstitution
• Recovery of neutrophil and platelet counts after the nadir induced by
conditioning therapy
• Sustained absolute neutrophil count (ANC) ≥ 0.5 x 109/L
– 1st of 3 consecutive days
• Unsupported platelet count ≥ 20 x 109/L
– 7 days after last platelet infusion
• Recovery of neutrophil and platelet counts after the nadir induced by
conditioning therapy
• Time of engraftment = Number of days between HPC infusion and
neutrophil or platelet recovery
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Stem cell journey
• HPC transplant (intravenous infusion)
• Stem cells circulate via the blood stream
• “Home” to bone marrow niches within 24 hrs
• Proliferate & differentiate to generate mature
blood cells
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Stem cell homing (1)
Migrate from circulation to marrow cavity
• Roll along vessel wall
• Attach to endothelium via adhesion molecules and
chemo attractants (like “grip ball”)
• Migrate through endothelial cells
• Lodge into BM niche which provides the
environment for proliferation
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Stem cell homing (2)
Annals of NY Acad Sci 2014: 301; 119-128
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HPC proliferation & differentiation
https://commons.wikimedia.org/w/index.php?curid=9420824
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Engraftment
Mature blood cells migrate from the marrow niche into the
blood vessels https://basicmedicalkey.com/hemopoiesis/
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A B C D E F G H I J K L0
5
10
15
20
25
30
35
40
Days t
o A
NC
0.5
x10
9/L
BMT Program
0
1
2
3
4
5
6
7
8
vC
D34 D
os
e (x
10
6/k
g) (th
aw
ed
co
un
t)
NSW UK
Inter-site comparison - ANC
Neutrophil recovery after autologous HPC-A transplant
BMT 2017: 52; 992BMT Network 2018
Median = 11 days Median = 12 days
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Inter-site comparison - Plt
Platelet recovery after autologous HPC-A transplant
BMT Network 2018 BMT 2017: 52; 992
A B C D E F G H I J K L0
10
20
30
40
50
60
70
80
90
100
110
120
130
Days
to
PL
T
20x10
9/L
BMT Program
0
1
2
3
4
5
6
7
8
vC
D34 D
ose
(x10
6/k
g) (th
aw
ed
co
un
t)
Median = 16 days Median = 24 days
NSW UK
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Effect of donor & HPC source
Bone Marrow Transplantation 2013: 48; 691-697
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Differential WBC recovery
Bone Marrow Transplantation 2009: 44; 457-462
% R
eco
very
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Recovery of immune function
Donor type affects rate of immune function recovery
- Autologous > Related allogeneic > Unrelated allogeneic
Innate (non-specific) immunity recovers within months
– Monocytes > Granulocytes > NK cells
Adaptive (cellular & humoral) immunity takes at least 1-2 years
– Expansion of infused donor T cells
– Thymic T cell generation from donor HPC (needs functional thymus)
– B cells recover by 6-9 months; function dependent on T cell help
– Hence prolonged risk of infection
10.1182/asheducation-2015.1.215 ASH Education Book December 5, 2015 vol. 2015 no. 1 215-219
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Graft failure
Primary
– Failure to attain sustained ANC ≥ 0.5 x 109/L, Plt ≥ 20 x 109/L,
RBC transfusion independence
– Failure to achieve donor chimerism
Secondary
– Loss of graft / donor chimerism
– Usually within 6 months but can occur later
• Higher risk in non-malignant disorders
• Often precedes relapse in malignant disorders
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Incidence of graft failure
• Autologous < 1%
• Allogeneic HLA matched sibling donor 1 – 2%
• Risk factors:
– HLA or ABO group mismatch
– Donor: female, older age
– Non-malignant disorder, # blood transfusions
– Conditioning regimen
– HPC cell source, dose, quality & manipulation
– Post transplant myelosuppresive drugs
– Infection
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Rescue strategies
• Growth factors, e.g. G-CSF
• Increase immunosuppression
• Donor lymphocyte infusions (DLI)
• Stem cell boost
• HPC transplant (same or different donor)
• Autologous HPC rescue (cryopreserved cells)
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Summary
• Engraftment:
– 1st of 3 consecutive days with blood ANC ≥ 0.5 x 109/L
– Platelet count ≥ 20 x 109/L, 7 days after last platelet infusion
• Many factors influence engraftment rate
• Graft failure rate is low in autologous & MSD transplant
• Recovery of immune function takes months – years