Transcript Hematopoietic Stem Cell Transplant

Hematopoietic Stem Cell
Transplant
Angela Smith, MD
Assistant Professor
University of Minnesota
Outline
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Basic Principles
Donor Sources
Stem Cell Sources
Conditioning Therapy
Risks and Benefits
HSCT in DBA
Basic Principles of HSCT
• Delivery of chemotherapy +/- radiation
therapy to create space in the bone
marrow and immunosuppress the
recipient.
• Replacement of the abnormally functioning
bone marrow derived cells with healthy
hematopoietic cells.
Hematopoietic Stem Cells
Pre-T cell
T Lymphocyte
Pre-B cell
Pluripotent
Stem Cell
Lymphoid
Stem Cell
Myeloid
Stem Cell
BFU-E
B Lymphocyte
CFU-E
Erythrocyte
CFU-Mk
Megakaryocyte /
Platelets
CFU-Mast
Basophil /
Mast cell
CFU-Eos
Self-renewal
CFU-GM
Eosinophil
CFU-G
CFU-M
CFU-Ost
(?)
Neutrophil
Monocyte /
Macrophage
Osteoclast
Treatment Principles
Bone
marrow
Hematopoietic
stem cells
Conditioning Therapy
Mobilized
blood
Umbilical
cord blood
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-1
0
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Immune suppression
Myeloablation
Destroy BM cells
and the Host’s
Immune System
Principles
Immunosuppression
Prevention of Graft
Failure and GVHD
Engraftment
8
6
4
2
WBC Counts (x10e9)
White Cell Recovery
0
0
2
4
6
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10
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26
28
Days
Pace of recovery
after marrow
infusion
What do we use HSCT for?
• Cancer – leukemia, lymphoma, solid tumors.
• Bone marrow failure/Blood disorders – Diamond Blackfan
Anemia, severe aplastic anemia, Dyskeratosis Congenita,
Fanconi anemia, PNH, SDS, Thalassemia, Sickle cell disease.
• Immune deficiency – Severe combined immune deficiency,
Wiskott-Aldrich syndrome, HLH.
• Metabolic disorders – Hurler syndrome, leukodystrophies.
Types of HSCT
• Autologous
• Allogeneic
– Related/Unrelated
– Match/Mismatch
– Source of stem cells
Related Donors
• Sibling
– Factors to consider include HLA match, age,
disease status (if genetic), health, ease of
getting stem cells etc.
• Haploidentical
– “Half matched” transplant – generally a parent
or sibling.
– Special considerations for prevention of graft
vs. host disease (GVHD).
Likelihood of a Having a
Related Donor
• Sibling
– Assuming shared mother and father, each
child has a 20-25% chance of being HLA
matched.
• Haploidentical
– Parents ~100% chance, full siblings 50%
chance
Unrelated Donors
• Adult volunteer donors
• Umbilical cord blood
Growth of Adult Donors on the Be The
Match Registry®
Growth of Cord Blood Units on the Be
The Match Registry®
HLA Matching
• The transplantation antigens
(HLA) are located on
chromosome 6.
• They are important in
immune recognition of tissue
compatibility.
• Risk of graft failure, GVHD
and mortality increase in
parallel with the number of
HLA disparities.
HLA Genes
• HLA genes are extremely diverse.
• HLA genes tend to run within racial groups.
HLA-A
697
HLA-B
1010
HLA-C
382
> 1.4 X 1023 unique
combinations
HLADR
603
HLA Matching Requirements
for Unrelated Adult Donors
• At least 8 HLA genes are reviewed (A, B, C, DRB1), but some
centers review 10 (including DQ).
• Must match at a minimum of 7/8 or 9/10 HLA genes.
Likelihood of Finding a
Matching Unrelated Adult
Donor
X
X
X
X
X
75%
30-50%
34%
30-40%
19%
SOURCE: National Marrow Donor Program / Be The Match 2013 fiscal year reports.
HLA Matching Requirements
for UCB donors
• Because cord blood cells are less
mature than adult donor cells they have
less strict matching criteria.
• Must match at least 4 of 6 HLA genes
– Look at HLA-A, -B and –DRB1.
Likelihood of Finding a
Matching UCB Unit
• Depends more on size/age of patient rather than
ethnic group.
– However, double cord transplant and expanded cord
blood units are becoming increasingly available making
age/size less of an issue.
• Very few have 6/6 HLA matches available
regardless of age/size.
• 4/6 or 5/6 HLA matched units are available for
95+% of those <20 years of age and >80% of
those >20 years.
Stem Cell Sources
• Bone Marrow (BM)
– Traditional source of stem cells.
– Obtained from the iliac crests in the OR.
• Peripheral Blood (PBSC)
– Growth factor used to increase number of
stem cells in the blood.
– Collected by apheresis.
Stem Cell Sources (cont’d)
• Umbilical Cord Blood (UCB)
– Blood from umbilical cord and placenta are
rich in stem cells.
– Harvested from umbilical cord/placenta
after delivery.
Advantages of Stem Cell
Sources
• BM
– Most experience with this
source
– Faster engraftment than
cord blood
– Able to re-approach donor if
needed
• PBSC
– Quick time to engraftment
– Able to re-approach donor if
needed
• UCB
– No risk to the donor
– Rapid availability
– Large and ethnically diverse
inventories
– Can be cryopreserved and
stored
– Limited GVH activity (acute
+/- chronic)
– Lower infectious risk (EBV,
CMV)
– HLA mismatch more
acceptable
Limitations of Stem Cell
Sources
• BM
– Risk of
anesthesia/discomfort for
the donor
– Lack of HLA-matched
donors
– Long wait time
– Risk of GVHD is 30-60%
• PBSC
– High risk of GVHD
– Lack of HLA-matched
donors
– Long wait time
• UCB
– Limited by size of the units
(i.e. cell dose is fixed in
each unit)
– Longer time to engraftment
– Unable to use the donor
again in the case of disease
progression/relapse
– Less experience
– Theoretical risk of
transmission of genetic
diseases
How Do We Choose a Donor and
Stem Cell Source for DBA Patients??
• Individualized
– Sibling > Unrelated donor
– Adult donor > UCB
– BM > PBSC
– Haploidentical?
Conditioning Therapy
• Overall Goals:
– Ablate the bone marrow and create space
for donor cells.
– Suppress the recipients immune system to
prevent rejection.
• Historically includes both Total Body
Irradiation (TBI) and Chemotherapy.
Conditioning Therapy
• Chemotherapy only regimens – to prevent
complications associated with TBI in certain
populations.
– Very young children
– History of radiation
– Nonmalignant diseases
• Regimen used depend on the underlying disease
being treated, desired conditioning intensity and
the stem cell source used.
Conditioning Intensity
Conditioning Intensity
Conditioning Intensity
• MA regimens limited by toxicity.
– Infections, organ toxicity, etc.
• RIC and NMA regimens allow HSCT to be an
option for patients with nonmalignant
diseases and those who would otherwise be
ineligible due to underlying medical problems.
– Decreased toxicity
– Increased risk of graft rejection, especially in those
with nonmalignant disorders.
How Do We Choose The Conditioning
Regimen/Intensity for DBA Patients?
• Individualized
– Donor
– Health status
• Age, iron status, comorbid conditions
– Patient/family preference
Risks and Benefits of HSCT
High Risk : Benefit
Ratio
Restoration of Normal Blood
Making Capacity
Risk of Early and Late
Toxicities
• No transfusion need
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• Avoidance of steroids and
subsequent side effects
• Improved iron status
RRT (e.g. mucositis, VOD)
Acute GVHD
Chronic GVHD
Endocrinopathies
Sterility
Second malignancies
Early Complications
• Expected
– Nausea, vomiting, loss of appetite, diarrhea,
fatigue, hair loss, mucositis (mouth sores).
• Potential
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Infection
Organ toxicity
Graft vs. Host disease (GVHD)
Graft Failure
Infection Risk
Infection Prophylaxis
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Antiviral
Antifungal
Antibacterial
Isolation, HEPA filtered air
systems/laminar airflow rooms, masks,
hand washing, oral hygiene
Organ Toxicity
• Kidney damage (generally from
medications)
• Lung damage (infection, fluid, bleeding)
• Liver damage (VOD/SOS)
• High blood pressure
Organ Toxicity
Prevention/Treatment
• Optimizing function before HSCT
• Targeted medication dosing (e.g.
busulfan, CSA)
• Chelation pre-HSCT, ursodiol for VOD
prevention.
– Early defibrotide if SSx’s of VOD
• Antihypertensives
Graft-Versus-Host Disease
(GVHD)
• Cause = activated donor T cells
directed against the patient.
• Range in severity from mild to severe.
GVHD
Acute GVHD
Chronic GVHD
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• Usually 3-6 months after HSCT
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Usually within first 3 months after
HSCT
Fever, rash, nausea, diarrhea, liver
issues
• Insidious onset
• Dry eyes, dry mouth, loss of appetite,
weight loss, rash, poor lung function, liver
abnormalities, weakness, contractures,
decreasing blood counts
Risk of GVHD
• Depends on HLA disparity, donor source, age,
etc.
– PBSC > BM > UCB
– Unrelated > Related
– Adults > Children
• Acute
– 20-30% in children
• Chronic
– 10-20% in children
GVHD Prophylaxis
• All patients get prophylaxis.
• Generally multimodal immune
suppression.
– Cyclosporine, tacrolimus, MMF, steroids,
methotrexate.
• T cell depletion.
– Haploidentical transplants
Graft Failure/Rejection
• Contributing factors
– HLA disparity, allosensitization from transfusions,
too few stem cells, low conditioning intensity, etc.
• Prevention
– HLA matching, intensify conditioning therapy, etc.
• Treatment
– Nothing, stem cell boost, 2nd transplant.
Late Complications
• Number and severity depend on age, lifestyle factors,
conditioning intensity, type/severity of early
complications.
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Endocrine (thyroid, growth)
Fertility
Cardiac/Lung issues
Bone health
Metabolic syndrome
Secondary cancers
Infections
Late Complications Follow-up
• All patients should be followed life long
for the development of complications.
– Close monitoring and routine screening.
• Most large centers have Long Term
Follow-up clinics run by oncologists and
transplant physicians.
HSCT for DBA
• First HSCT for DBA was reported in
1976, confirming DBA was a
“transplantable” disease.
• HSCT is the only definitive treatment for
the hematologic manifestations of DBA.
HSCT Outcomes in DBA
• Matched sibling donor
– Excellent outcomes (75-100%), best if younger.
• Unrelated donor
– Early reports discouraging (30-40%).
– Significantly improved in recent era (70-90%).
• Haploidentical donor
– Very little data.
Conditioning Choice for HSCT
in DBA
• Most experience with myeloablative
conditioning.
– Better outcomes without the use of radiation.
• Reduced intensity conditioning has been
used with success, but less experience.
– Indicated in adults with high iron burden or anyone
with serious underlying medical conditions.
HSCT Outcomes in DBA
• Overall significantly better since the
year 2000 and in patients younger than
10 years of age.
• Iron burden prior to HSCT could have
negative effect on outcomes.
– Best outcomes observed when aggressive
chelation is administered prior to HSCT to
achieve good iron balance.
Indications for HSCT in DBA
• Highly individualized.
• Must take into account clinical status,
response to therapies, quality of life,
donor options, patient/family
preferences.
When to Consider HSCT in
DBA
• Patients with unaffected matched sibling donors.
– Ideally early in childhood (<10 years of age).
• Transfusion dependent patients that are
refractory to steroids and other therapies
regardless of donor options.
• Secondary aplastic anemia, MDS/leukemia,
steroid intolerance, transfusion intolerance,
development of red cell antibodies or chelator
intolerance.
HSCT for DBA
• Transplant consults for all transfusion
dependent patients for HLA typing,
education, discussion of the
risks/benefits.
• Strongly recommend cord blood storage
from subsequent pregnancies.
– Sibling must be proven to be unaffected
before use.
Questions??