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Hemat/Onc EXAM 4
Hemat/Onc EXAM 4 - Heigham BMT
48
Pharmacology
Graduate
02/14/2012

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Term
bone marrow
Definition
blood making organ

bone marrow produces stem cells
Term
hematopoietic stem cells
Definition
immature cell

parent cells to other blood cell lines: WBC, RBC, platelets
Term
2 main reasons for transplant
Definition
1

to CURE the patient by REPLACING defective bone marrow with a healthy marrow

"marrow is bad"

2

to RESCUE the patient by RESTORING their bone marrow after high dose chemotherapy

"treatment is bad"
Term
host
Definition
person receiving the stem cells

undergoing transplant
Term
donor
Definition
person providing hematopoietic stem cells

provides the "graft"
Term
engraftment
Definition
newly transplanted cells begin to function and produce new blood cells within the host

defined as ANC > 500 for 3 consecutive days

can usually take 10-16 days
Term
relapse
Definition
recurrence of disease
Term
rejection
Definition
(<1%)

host immune system does not tolerate foreign cells

transplant fails

very small chance of rejection
Term
graft versus host disease
Definition
graft mounts an immune response against the host (donor rejecting recipient)

liver, skin, gut
Term
graft versus disease
Definition
graft mounts an immune response against the disease

helpful in preventing relapse

"graft vs. leukemia" or "graft vs. tumor"

having graft vs. disease lessens the chance that the patient will have a relapse
Term
where do you get stem cells?
Definition
BONE MARROW

harvested

multiple needle aspirations

requires general anesthesia

PERIPHERAL STEM CELLS

pheresis

colony stimulating factor (mobilization)

stem cells that have been released from the bone marrow

taking just the pluripotent stem cells

UMBILICAL CORD BLOOD

issue is small volume of stem cells (not enough to support an adult sized person)
Term
source of stem cells: time to engraftment, risk of relapse, and risk of GVHD (graft vs. host disease)
Definition
BONE MARROW:
time to engraftment: moderate
risk of relapse: lower
risk of GVHD: higher

PERIPHERAL BLOOD:
time to engraftment: fastest
risk of relapse: lower
risk of GVHD: higher

CORD BLOOD:
time to engraftment: slowest
risk of relapse: highest
risk of GVHD: lowest
Term
types of transplants
Definition
allogeneic: family/unrelated donor

autologous: self-donation

syngeneic: identical twin
Term
goals of treatment
Definition
cure by replacing
"marrow is bad"

rescue by restoring
"treatment is bad"
Term
allogeneic transplant
Definition
allogeneic = CURE

to replace missing or abnormal component

to rescue from myeloablative treatment regimens

to establish graft vs. disease effect
destruction or inhibition of unwanted host cell

donors:
matched sibling donor
mismatched sibling or related donor
matched unrelated donor
mismatched unrelated donor

disease states:
"marrow is bad"
leukemia (ALL, AML, CML, CLL)
aplastic anemia
myelodysplastic syndrome (MDS)
severe combined immunodeficiency disease (SCID)
severe autoimmune diseases

risk/benefit:
increased risk of graft vs. host disease
decreased risk for disease relapse (graft vs. tumor advantage)
usually more complications
Term
syngeneic transplant
Definition
stem cells from an identical twin

higher risk for disease relapse

decreased risk of GVHD
Term
autologous transplant
Definition
autologous = RESCUE

to restore a patients' bone marrow after high dose chemotherapy

patient's OWN stem cells

"self" transplant

disease states:
"treatment is bad"
disease states not involving bone marrow: hodgkin's lymphoma, non-hodgkin's lymphoma, solid tumors (usually relapsed), sarcomas (usually relapsed)
allows use of higher doses of chemotherapy (in order to treat disease or tumor)
stem cells collected before high dose chemo

risk/benefit:
decreased risk of graft versus host disease
decreased risk of rejection
less immunosuppression
increased risk of disease relapse
Term
donor types: relative risk of relapse, GVHD, and other complications
Definition
ALLOGENEIC:
relapse +
GVHD +++
other complications +++

SYNGENEIC
relapse ++
GVHD -
other complications +

AUTOLOGOUS
relapse +++
GVHD -
other complications +
Term
conditioning regimens
Definition
chemotherapy +/- irradiation

given prior to transplant

kill remaining cancerous cells

suppress immune reactions
to facilitate engraftment

create sufficient space needed in the marrow for new cells

provide some mild GVHD/GVD

given over 3-10 days prior to transplant

one or two days of "rest"

DAY 0 = DAY OF TRANSPLANT
Term
goals for hematologic malignancies
Definition
ablation of stem cells with chemotherapy

replace the disease free cells to repopulate the marrow
Term
goals for solid tumors
Definition
stem cells are not completely ablated

more potent conditioning/chemotherapy regimens can be given

able to "rescue" patient after treatment

some graft versus tumor effects
Term
goals for non-malignant disease states
Definition
powerful immunosuppression
facilitate engraftment

host versus graft tolerance develops

"mixed chimerism"
the host's old cells and the new cells battle with each other for which one will develop
hopefully the donor cells will win and normal cell line will be produced
Term
risks for poor outcome
Definition
more advanced disease or later in course

unrelated donor

increased mismatch between host and donor

increased age

decreased performance status

co-morbid illness or significant organ dysfunction pre-transplant
Term
myelosuppression
Definition
suppression of bone marrow activity

pancytopenia = decreased # of cells

produces anti tumor effect

neutropenia, infection, mucositis
Term
immunosuppression
Definition
eradication or suppression of immune system

T cells are suppressed in order to prevent rejection

decreased ability to fight infection

viral and fungal infections, EBV associated, lymphoproliferation
Term
ideal transplant regimen
Definition
suppress host immune system
to facilitate engraftment

provide long term stable engraftment

minimize regimen related toxicity

utilize best stem cell source available

provide lower, milder rates of GVHD
some graft versus leukemia/disease

eliminate risk of graft rejection

facilitate early immune reconstitution

ALLOGENEIC MALIGNANT DISEASE
immunosuppressive (anti graft rejection): yes
make space (ablate): yes
eradicate malignancy (anti tumor): yes
avoid overlapping toxicities: yes

ALLOGENEIC NON-MALIGNANT DISEASE
immunosuppressive (anti graft rejection): yes
make space (ablate): yes
eradicate malignancy (anti tumor): no
avoid overlapping toxicities: yes

AUTOLOGOUS MALIGNANT DISEASE
immunosuppressive (anti graft rejection): no
make space (ablate): yes
eradicate malignancy (anti tumor): yes
avoid overlapping toxicities: yes
Term
conditioning regimens: myeloablative, reduced intensity (if a person couldn't tolerate a very aggressive preparative regimen), non-myeloablative
Definition
MYELOABLATIVE relative risk of:
rejection +
immunosuppression +++
myelosuppression +++
toxicity +++
GVHD +++

REDUCED INTENSITY relative risk of:
rejection ++
immunosuppression +++
myelosuppression ++
toxicity +
GVHD ++

NON MYELOABLATIVE relative risk of:
rejection +++
immunosuppression ++
myelosuppression +
toxicity +
GVHD +
Term
drugs used in transplant
Definition
alemtuzumab

busulfan

carboplatin

carmustine

cyclophosphamide

cytarabine

etoposide

fludarabine

melphalan

thiotepa
Term
alemtuzumab toxicities
Definition
immunosuppressive

infusion reaction

GI effects
Term
busulfan toxicities
Definition
seizures - have to provide seizure prophylaxis

pulmonary fibrosis

VOD (veno-occlusive disease)

BMS (bone marrow suppression)
Term
carboplatin toxicities
Definition
N/V

nephrotoxicity

ototoxicity

BMS
Term
carmustine toxicities
Definition
BMS

VOD

pulmonary toxicity

N/V
Term
cyclophosphamide toxicities
Definition
hemorrhagic cystitis

SIADH

VOD

nephrotoxicity

leukopenia

cardiac toxicity
Term
cytarabine toxicity
Definition
ara-C syndrome

conjunctivitis

BMS
Term
etoposide toxicities
Definition
N/V

mucositis

secondary malignancy

BMS
Term
fludarabine toxicity
Definition
neurotoxicity

BMS

pulmonary toxicity
Term
melphalan toxicity
Definition
GI effects

mucositis

BMS
Term
thiotepa toxicity
Definition
adverse skin effects
partially eliminated through the sweat glands

BMS

mucositis

neurotoxicity
Term
complications
Definition
infection (40-60%)

fluid overload

graft vs. host disease (GVHD)
acute GVHD
chronic GVHD

veno occlusive disease of the liver (VOD)

GI complications (mucositis)
Term
infection time line
Definition
Phase I: pre engraftment <30 days
respiratory and enteric viruses
herpes simplex virus
gram negative bacilli
staphylococci epidermidis
GI tract (Streptococci species)
all Candida species
Aspergillus species

Phase II: post engraftment 30-100 days
respiratory and enteric viruses
cytomegalovirus
protozoal infection
Staphylococci epidermidis
GI tract (Streptococci species0
all Candida species
Aspergillus species

Phase III: late phase > 100 days
respiratory and enteric viruses
cytomegalovirus
varicella-zoster virus
protozoal infections
encapsulated bacteria
Aspergillus species

[image]
Term
early infections
Definition
viral:
human herpes virus (HSV)
other community acquired viruses

bacterial:
Staphylococcus sp.
Streptococcus sp.
gram negative bacilli

Candida species

community respiratory viruses:
respriatory syncytial virus (RSV)
influenza A and B
parainfluenza type 1,2,+3
adenovirus
rhinovirus
Term
late infections
Definition
fungal infections:
Candida species
Aspergillus species

encapsulated bacteria

varicella zoster virus (VZV)

cytomegalovirus (CMV)

epstein barr virus (EBV)

pneumocystis jiroveci pneumonia (PCP)
Term
preventing infections
Definition
acyclovir, valacyclovir

fluconazole
prophylaxis for Candida species

sulfamethoxazole/trimethoprim
pentamidine
dapsone
atovaquone

ampicillin
gram positives

IVIG
viral infections

immunizations
Term
GVHD
Definition
complication of allogeneic transplant

host appears foreign to the graft

graft with immunocompetent cells

host incapable of mounting an effective immunological reaction to the graft

ACUTE GVHD: day 30 through day 100

CHRONIC GVHD: beyond day 100
developed after day 100 or lasts past day 100
Term
acute GVHD
Definition
skin: maculopapular, erythematous rash

gut: secretory, watery diarrhea; cramping

liver: hyperbilirubinemia; hepatotoxicity

prevention: methotrexate, cyclosporine, tacrolimus, cyclophosphamide, steroids, sirolimus

treatment: maximize cyclosporine treatment then first line is STEROIDS, monoclonal antibodies, MMF (mycophenalate)
Term
chronic GVHD
Definition
not necessarily related to presence of acute GVHD

40% with identical sib

> 50% with mismatched related sib

70% unrelated mismatched

skin (dark pigmentation)

nails/scalp/hair

mouth

eyes

genitalia

GI tract

liver

lung (difficulty breathing)

muscle/joint (stiffening)

hamatopoietic/immune

supportive care and steroids
remain on cyclosporine for a prolonged period of time
Term
veno occlusive disease (VOD)
Definition
obliteration of small intrahepatic central venules

liver's ability to remove waste is impaired

veins and liver become blocked

increased bilirubin

weight gain

ascites

hepatomegaly

supportive care
fluid restriction
Term
GI effects
Definition
mucositis: increased risk with myeloablative regimens; irradiation; etoposide; melphalan

inadequate nutrition, pain, or infection

oral hygiene and oral care products

skin breakdown associated with thiotepa
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