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Hematopoietic Cell
Transplantation
Definition
 Hematopoietic cell transplantation
(HCT)
 is a potentially curative treatment for
malignant and nonmalignant
diseases, including leukemia,
lymphoma, multiple myeloma,
aplastic anemia,
hemoglobinopathies, and congenital
immune deficiencies.
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History of Bone Marrow
Transplantation
 First successful human bone
marrow transplantation
procedure (1968).
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Stem cells
 Stem cells are ‘generic’ cells that
develop into particular types of cells.
So they may become
nerve cells, muscle cells,
blood cells…
in fact, any cell in the body!
Stem cells divide over and
over to produce new cells.
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Stem cells, bone marrow
and blood cells
One of the main places you find
stem cells is in bone marrow.
Stem cells in bone marrow produce
new blood cells to replace those that
have died.
When the cells are mature they are
released into the bloodstream.
A ‘bone marrow’ donation is really a
donation of stem cells.
Bone marrow is found in the cavities
inside the long and flat bones of the
body.
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 Types of stem cells:
 Pluripotent
 Multipotent
 Committed
progenitor cells
 Multipotent blood cells:
 Common
lymphoid
 Common myeloid
 Committed stem cell makes
specific blood cells (CFU) –
stimulated by erythropoietin,
thrombopoietin,
granulocyte-mononcyte
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CSF
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Leukocytes
 White blood cells
 Defend body through:
the inflammatory process
 phagocytosis
 removal of cell debris
 immune reactions
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White Blood Cell Types:
Granulocytes and
Agranulocytes
 Granulocytes –visible granules in the
cytoplasm.
 Granules contain:
 Enzymes
 Other biochemicals that serve as
signals and mediators of the
inflammatory response
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Granulocyte cell types:
 Neutrophils – phagocytes
 Eosinophils – red granules, associated
with allergic response and parasitic
worms
 Basophils – deep blue granules Release heparin, histamine and
serotonin
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Agranulocytes
 Granules too small to be visible
 Monocytes – become macrophages
 Lymphocytes – B cells and T cells =
immune functions
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 WBC’s originate in red bone
marrow from stem cells.
 Granulocytes mature in the
marrow and have a lifespan of
hours to days
 Agranulocytes finish maturing in
blood, or in other locations.
Monocytes live about 2 - 3 months,
lymphocytes for years.
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 Production of WBC’s increases in
response to :
 Infection
 Presence of steroids
 Decreased reserve of leukocyte
pool in bone marrow
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Diseases Treated with Bone
Marrow Transplantation
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Acute leukemia (ALL, AML)
Chronic myelogenous leukemia
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Aplastic Anemia
Myeloproliferative Disorders
Multiple Myeloma
Non-Hodgkin’s lymphoma
Hodgkin’s Disease
Chronic lymphocytic leukemia
Genetic Disorders (Thalassemia, others)
Solid tumors (RCC, neuroblastoma, germ cell tumors)
Congenital immunodeficiency diseases
Lymphomas
Metabolic disease of childhood
Myelodisplasia
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Stem cell (“bone marrow”) donation
There are three ways to collect stem cells from a donor:
 Bone marrow
A donor has a small operation under general anesthetic. Marrow is harvested
from the iliac crest under general anesthesia
 Circulating blood
A donor’s circulating stem cells are boosted with a special drug. Then they
are connected to a cell separator machine, which collects the stem cells
and returns the rest of the blood to the donor. Growth factors are frequently
used alone (e.g., granulocyte colony-stimulating factor, or G-CSF) or in
combination with chemotherapy (in autologous HCT) for mobilization•
of
hematopoietic stem cells, which are collected by blood leukapheresis.
Mobilized―
blood cells engraft faster than marrow-derived cells.
 Cord blood
Selected hospitals offer new mothers the chance to donate the blood that
remains in the placenta and umbilical cord after their baby’s birth. Collected
from the umbilical cord after delivery of a baby. Engraftment takes longer
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Advantages / disadvantages for
patients
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Advantages:
Cord blood:
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Bone marrow and circulating blood:
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tend to have a greater number of stem cells in the donation, so tend to be
accepted into the patient’s body more quickly.
Disadvantages
Cord blood:
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hasn’t been exposed to environment so less likely to contain viral infection;
requires less stringent matching;
once collected is banked and can be readily available at short notice.
tends to have less stem cells in the donation.
Bone marrow and circulating blood:
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finding a match and arranging a donation can take weeks, or months
(this is time the patient may not have).
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SOURCE OF STEM CELLS
 Bone Marrow
 Cryopreserved
 “Mobilized”
 Fresh
peripheral blood
stem cells
 Umbilical cord
blood
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Potential Donors
 Self
 HLA-matched sibling
 HLA-mismatched sibling
 Matched unrelated
 Cord blood
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Donor Limitations
 25 – 30% of patients have an HLA-identical
sibling.
 Marrow procured from unrelated living
donor
 Marrow procured from related HLAidentical or HLA non –identical living
donor
 Autologous transolantation(marroe
procured during remession)
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Stages of Allogeneic
Transplantation
Preparation
Immune
suppression
Disease
treatment
Transplantation
IV Infusion
Recovery
GVHD
Prevention
Infection control
Nutrition
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Hematopoietic
recovery
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RATIONALE FOR BMT
 High dose chemotherapy (dose -
response curve)
 Allogeneic effect (graft-versus- tumour
effect)
 Replacement of abnormal stem cells
(aplastic anaemia, thalassaemia, sickle
cell disease, gene therapy etc)
 Immunological effect (autoimmune
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RISKS OF BONE MARROW
TRANSPLANT
 Short term (TRM)
 Sepsis,AGVHD, multi-organ failure or toxic
death
 Longer term
 Chronic graft-versus-host disease (lung,liver,
skin)
 Relapse
 Infection
 Endocrine
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Factors influencing survival
 Disease factors
 Remission, relapse, refractory
 Transplant related mortality
 Donor factors
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Age, sex, conditioning
Recipient factors
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Age, CMV status, performance status
 Risk of graft-versus-host disease
 Donor factors
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Recipient factors
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PBSC, matching, age, parity
Age
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GENERAL PRINCIPLES
 Epidemiology. Current estimates of
annual numbers of HCT are 45,000 to
50,000 worldwide. Approximately two
thirds of patients have autologous
HCT and one third have allogeneic
HCT
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Risk factors
 The likelihood of developing transplant-related
complications depends on:
1/patient age
2/intensity of the preparative regimen
3/type and stage of the underlying disease
4/presence of comorbidities.
5/allogeneic HCT recipients have a greater risk of
transplant-related morbidity and mortality than
autologous HCT recipients
6/HLA disparity between donor and recipient further
increases
the risk owing to the greater likelihood of developing
GVHD
and graft rejection
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Prognosis
Prognosis after HCT is highly variable and is
influenced by numerous factors that predict for
mortality related to the transplant procedure itself
and to recurrent malignancy after surviving the
transplant:
- Patients with chronic myelogenous leukemia
(CML) in chronic phase who have HCT from an
HLA-identical sibling, for example, have a greater
than 80% to 90% chance of long-term survival
-In contrast, less than 50% of patients with more
advanced leukemia at the time of HCT will be
cured
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Transplantation Procedure
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Anesthesic Management
 Intravenouse anesthesia sould be
procured.
 Intravenouse, Thiopental, Fentanyl
,Vecuronium can be used in common
doses
 Maintanance can be provide with Propofol
and Isoflurane.
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Step 1: Bone marrow transplant with less toxic
recipient treatment that includes antibodies.Donor
marrow is T cell depleted
Blood cells are a mixture of donor and host:
Mixed chimerism is achieved without GVHR
Wait 1-2 months. Inflammation from preparative
treatment subsides.
Step 2: Infuse donor T cells.
Donor T cells interact with “presenting
cells” of mixed chimera to maximize
GVHR
Tumor is
killed
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Donor T cells are armed to kill tumor
cells that express recipient antigens.
They stay inside the blood and lymph,
where tumor is.
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T cells don’tofgo
to skin/gut/liver.
There
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is no GVHD.
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TRANSPLANT
RELATED
COMPLICATIONS
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 The problems after HCT that typically
cause procedure-related morbidity
and mortality can broadly be
categorized into five groups:
*hemolysis,
 ** toxicity of the preparative regimen,
***infection,
 **** bleeding,
 ***** GVHD
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Hemolysis
 General principles.
 The inheritance of blood group
antigens (e.g., ABO, Rh) is
independent of that of the HLA
antigens.
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Hemolysis
 Etiology/pathophysiology:
1/ Acute (at the time of infusion) or
delayed (5 to 15 days after HCT)
immunohemolytic complications due to
ABO incompatibility occur in patients with
minor ABO-incompatibility.
2/ Immediate hemolysis occurs if the graft
contains preexisting isohemagglutinins
that lyse recipient RBCs.
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Hemolysis
 Etiology/pathophysiology:
3/ Delayed hemolysis
is due to generation of new•
isohemagglutinins by passenger
lymphocytes•in the graft.
4/Delayed hemolysis due to minor ABO
incompatibility is a rare complication but
can be dramatic and life-threatening.
5/ Major ABO incompatibility (recipientderived isohemagglutinins directed
against donor RBCs) may lead to chronic
hemolysis and
pure red cell anemia
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(PRCA).
Hemolysis
 Diagnosis
1/Clinical presentation:
a/ Mild hemolysis due to major ABO incompatibility
may be associated with prolonged RBC transfusion
requirements .
b/Delayed hemolysis due to minor ABO incompatibility may
cause rapid lysis of all recipient RBCs over a few days.
This may lead to acute renal failure or pulmonary edema
and
may be fatal.
Plasma exchange in the recipient and plasma
removal or RBC removal from the graft are standard
procedures that minimize the risk of preventable hemolytic
complication after ABO-mismatched HCT.
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Hemolysis
 Diagnosis
2/Laboratory and radiologic studies:
a/Emergence of donor-derived RBC and
isohemagglutinin titers should be
monitored after allogeneic HCT
b/Serum levels of (indirect) bilirubin and
lactate dehydrogenase (LDH),
reticulocyte counts, and the direct
agglutinin test (DAT) are useful markers of
hemolysis
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Hemolysis
Diagnosis
3/Differential diagnosis:
a/Parvovirus 19 infection may cause PRCA after HCT.
b/NonABO-related Coombs-positive autoimmune hemolytic
anemia (AIHA) may develop late after HCT
c/Drugs such as fluarabine or infections with mycoplasm may
also produce hemolysis. Thrombotic microangiopathy (TM) is
frequently related to cyclosporine or tacrolimus and associated
with
RBC fragmentation (schistocytes)
d/Hyperbilirubinemia after HCT may have many other causes
(e.g.,
sinusoidal obstruction syndrome [SOS] of the liver; drug
effects)
e/Dimethylsulfoxide (DMSO), a cryoprotectant used to store
autologous stem cells, may cause anaphylactic and nonallergic
reactions (e.g., hypotension, dyspnea, flushing, diarrhea)
during
infusion of thawed
stem cell products.
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Hemolysis
Treatment:
1/ Chronic hemolysis due to major ABO
incompatibility is usually self-limited.
2/ Patients with refractory or more acute immune
hemolysis may require interventions aimed at
suppressing ongoing donor-directed
isohemagglutinin production (corticosteroids,
donor lymphocyte infusion, rituximab) or removal
of the offending antibody (plasma exchange).
3/Supportive care measures to maintain renal
function are critical
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Toxicity of the preparative
regimen
 Cytotoxic chemotherapy with or without
total body irradiation (TBI) may
compromise the function of the lungs,
heart, kidneys, nervous system, and
gastrointestinal tract including the liver.
This type of toxicity occurs predominantly
within the first 3 to 4 weeks after HCT.
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Infection
General principles
Infections are frequent complications after
autologous and allogeneic HCT. Their pattern of
occurrence is determined by a number of factors,
including the recipient's pretransplant history
and underlying disease,
the intensity of the preparative regimen,
the regimen used for infection prevention, the
microbiological flora of the patient and of the
individual transplant unit,
and the degree of immunosuppression after
transplant .
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Bleeding
Etiology/pathophysiology: Bleeding can
occur as a result of thrombocytopenia or
coagulopathy. Breakdown of mucosal
barriers as a result of regimen-related
toxicity and/or GVHD increases the
likelihood of hemorrhage. CNS
hemorrhage can be rapidly fatal. Highdose cyclophosphamide and BK virus
infection are causes of hemorrhagic
cystitis
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Bleeding
Diagnosis: Oropharyngeal bleeding
and epistaxis are obvious.
Endoscopic evaluation
(colonoscopy,
esophagogastroduodenoscopy,
bronchoscopy) or CNS imaging may
be indicated according to the clinical
picture
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Bleeding
Treatment:
A platelet count below 10,000/mm3 increases the
risk of spontaneous bleeding and should be
treated prophylactically with platelet transfusion.
The decision to transfuse platelets above the
prophylactic•threshold of 10,000/mm3 should be
guided by the clinical situation.
Patients who have received multiple transfusions
can become alloimmunized and demonstrate
poor response to platelet transfusion.
Transfusion of unpooled (single-donor) or HLAmatched platelets may be helpful.
Bleeding can be seen on bronchoscopy. The
treatment consists of high doses of
corticosteroidsDr.yekehfallah.-phd
(e.g., 1 g per
day- for 3 days).
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Graft-versus-host disease
General principles
GVHD is a major cause of morbidity and
mortality after allogeneic HCT. Patients
who develop GVHD, however, have lower
relapse rates than patients without GVHD,
which can be explained by an
immunologic graft-versus-tumor effect
that helps eradicate the underlying
malignancy
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Graft-versus-host disease
Etiology/pathophysiology
The GVHD syndrome is caused by donor
T cells that are activated by
immunologically disparate HLA or nonHLA antigens in the recipient, resulting in
an inflammatory immune response. Older
patient age, HCT from a mismatched
and/or unrelated donor, and a female
donor increase the risk of developing
GVHD
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Graft-versus-host disease
Diagnosis
Clinical presentation:
Acute GVHD (defined as occurring
before posttransplant day 100) tends to have a
more sudden onset and may involve the skin,
gastrointestinal tract, and liver.
Signs and symptoms include an erythematous rash, nausea,
vomiting, diarrhea, and liver function abnormalities.
Clinical features of chronic GVHD (defined as
occurring after posttransplant day 100), which
typically has a more insidious onset, may involve
the skin, eyes, joints, and liver and are
reminiscent of autoimmune
diseases such as
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Graft-versus-host disease
 Laboratory and radiologic studies:
Skin punch biopsy,
gastrointestinal endoscopy with biopsy,
and liver biopsy confirm the diagnosis in the
appropriate clinical setting.
Cholestatic jaundice is the hallmark of liver
involvement.
Pulmonary function test and lung biopsy in
patients with presumed BOOP to rule out
infectious etiologies
.
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Graft-versus-host disease
Treatment: Despite prophylaxis
against GVHD (e.g., cyclosporine
plus methotrexate), 40% to 80% of
allogeneic HCT recipients develop
this complication.
Corticosteroids are standard first-line
therapy of GVHD (e.g., prednisone 2
mg/kg per day; slow taper after 2
weeks).
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Graft-versus-host disease
Treatment:
Immunosuppressive treatment of GVHD with
corticosteroids contributes to the
increased susceptibility of patients with
GVHD to a variety of bacterial,
viral, and fungal infections.
Steroid-refractory patients require secondline immunosuppressive therapy and
usually have a poor prognosis.
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Complications
 Rejection by hte host of the marow graft
 Acute graft-vs,-host disease (GVHD)
 Infections
 Chronic GVHD
 Prolonged immunodeficiency
 Disease recurrence
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?
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