B3.052 Hematopoietic Stem Cell Transplant

Question 1

4 major causes of pancytopenia

Answer 1

hematopoietic stem cell injury
clonal hematopoietic cell mutation
myelophthisis
defective maturation
enhanced peripheral destruction

Question 2

disorders associated with hematopoietic stem cell injury

Answer 2

aplastic anemia (idiopathic, immune mediated, secondary to drugs, toxins, etc)
Fanconi anemia

Question 3

disorders associated with clonal hematopoietic cell mutation

Answer 3

acute leukemia
myelodysplasia
paroxysmal nocturnal hemoglobinuria

Question 4

disorders associated with melophthisis

Answer 4

metastatic cancer
granulomatous disorders, TB
lymphoma
myelofibrosis

Question 5

disorders associated with defective maturation

Answer 5

megaloblastic anemias

Question 6

disorders associated with enhanced peripheral destruction

Answer 6

hypersplenism
autoimmune disorders
hemophagocytic lymphohistiocytosis

Question 7

affected cell in myelodysplastic syndrome

Answer 7

myeloid stem cell

all cell lines affected, clonal hematopoiesis

Question 8

kinetics of myelodysplastic syndrome

Answer 8

ineffective hematopoiesis (apoptosis of maturing cells in marrow)

Question 9

what types of gene mutations are associated with MDS?

Answer 9

more than 90% of patients have mutations
more than 40 genes
commonly DNA methylation proteins
5q and 7q deletions common

Question 10

what are some prognostic variables of MDS?

Answer 10

cytogenetics
bone marrow blast %
Hbg conc
platelet count
neutrophil count

Question 11

treatment for MDS

Answer 11

only definitive therapy is allogenic stem cell transplantation

Question 12

what are the overarching goals of HCT?

Answer 12

restore normal hematopoiesis in bone marrow failure syndromes
replace diseased marrow with healthy marrow
rescue after marrow ablative treatments
correcting genetic diseases
establishes a graft-versus-leukemia (tumor) effect

Question 13

totipotent stem cells

Answer 13

cell can develop into complete organism
unlimited capacity
found in early embryos

Question 14

pluripotent stem cells

Answer 14

can form any of >200 cell types
located in undifferentiated inner cell mass of the blastocyst
found in early embryos

Question 15

multipotent stem cells

Answer 15

committed cell that can form other tissues

located in fetal tissue, cord blood and adult somatic tissue

Question 16

what are 4 factors associated with identification of stem cells

Answer 16

TPO - self renewal
SCF - proliferation/differentiation
TGFB- cell cycle dormancy
Ang-1 - cell cycle dormancy

Question 17

what are the 5 major steps in stem cell transplant?

Answer 17

1. collection
2. processing
3. cryopreservation
4. chemotherapy
5. infusion

Question 18

what is autologous stem cell transplant and when is it used?

Answer 18

patients own stem cells
a technique to give high dose chemo
no immunological barriers

Question 19

cons to autologous transplant

Answer 19

“tumor contamination”

not useful for bone marrow failure syndromes

Question 20

what factors plays a dominant role in donor selection?

Answer 20

HLA Typing

Question 21

what is HLA?

Answer 21

distinguishes self from non self
human leukocyte antigen
cell surface glycoproteins encoded on chromosome 6
inherited as haplotypes (1 in 4 chance a sibling will be identical)

Question 22

how is HLA typing done?

Answer 22

serology w antigen specific anti sera

DNA code in cell’s nucleus

Question 23

what is a novel immunologic condition that arises in marrow transplantation?

Answer 23

rejection is bidirectional
-graft rejection
-graft versus host disease (GVHD)
tolerance develops, immunosuppression not lifelong

Question 24

what are components of small cell graft

Answer 24

facilitating cells
NK cells
dendritic cells
T and B lymphocytes
stem cells, progenitors

Question 25

T lymphocyte functions in the patients

Answer 25

GVL | GVHD

Question 26

essential factors necessary for GVHD to occur

Answer 26

immunologically competent donor graft histo-incompatilbility between donor and host immunologically incompetent host

Question 27

how is GVHD related to graft versus malignancy effect?

Answer 27

lower incidence of leukemic relapse of patients who get GVHD higher relapse in syngeneic vs allogenic BMT high relapse rates in T cell depleted BMT cytogenetic remission induced after post BMT relapse of CML by infusion of donor leukocytes

Question 28

which disorders have a high sens to graft vs tumor effects?

Answer 28

CML CLL low grade NHL mantle cell NHL

Question 29

which disorders have a medium sens to graft vs tumor effects?

Answer 29

AML intermediate grade NHL HL MM

Question 30

which disorders have a low sens to graft vs tumor effects?

Answer 30

ALL | high grade NHL

Question 31

3 primary sources of stem cells

Answer 31

BM peripheral blood (at conc of approx. 1% found in BM) umbilical cord blood

Question 32

advantages to BM collection

Answer 32

typically only one collection usually enough cells collected low T cell content

Question 33

disadvantages to BM collection

Answer 33

``` not readily available surgical procedure risks to donor costly high risk of tumor cell contamination restrictive HLA-matching requirements ```

Question 34

agents that mobilize stem cells to peripheral blood

Answer 34

filgrastim sargramostin plerixafor chemo (autologous donations only)

Question 35

advantages of using PBSC

Answer 35

``` less complex procedure stem cell count adequate higher progenitor cell content low risk of tumor cell contamination fastest engraftment time ```

Question 36

disadvantages of using PBSC

Answer 36

``` requires catheter placement and medical therapy to stimulate cell production limited availability can require multiple collections high T cell content HLA matching restrictive high risk for chronic GVHD ```

Question 37

advantages of using UCB

Answer 37

``` non invasive/ no risk readily available and no donor attrition high number of minority donors less stringent HLA matching decreased viral transmission decreased rate of GVHD robust graft versus leukemia effects ```

Question 38

disadvantages of using UCB

Answer 38

``` specialized training for collection size limitations of unit no donor lymphocyte infusion theoretical genetic disease transmission theoretical concern for maternal contamination (GVHD) slowest engraftment time increased risk of graft failure ```

Question 39

components of the preparative regimen

Answer 39

radiation high doses of chemo targeted agents

Question 40

how is graft rejection prevented?

Answer 40

eradicate host immune system (T cells) | immunosuppressive component of conditioning regiment

Question 41

how is GVHD prevented?

Answer 41

suppress donor immune system and minimize recognition of host cells as foreign immunosuppressive medications starting before stem cell infusion and typically continues at least 6 months past HCT

Question 42

what is the tradeoff between prophylaxis and other outcomes?

Answer 42

``` aggressive prophylaxis: -less GVHD -MORE infection -MORE relapse minimal prophylaxis: -MORE GVHD -less infection -less relapse ```

Question 43

things that can cause acute toxicities after HCT

Answer 43

thrombotic microangiopathy GVHD infections

Question 44

symptoms of acute toxicities

Answer 44

``` mucositis nausea/vomiting diarrhea pulmonary sinusoidal obstructive syndrome iron overload drug toxicity hemorrhagic cystitis drug toxicity ```

Question 45

what is SOS

Answer 45

sinusoidal obstructive syndrome | obliteration of small intrahepatic central venules

Question 46

pathophys of SOS

Answer 46

``` injury to: -sinusoidal endothelial cells -hepatocytes -stellate cells in the venules causes: -microthrombosis -fibrin deposition -ischemia -fibrinogenesis systemically causes: -portal hypertension -hepatorenal syndrome -multi organ failure ```

Question 47

clinical manifestations of SOS

Answer 47

hyperbilirubinemia ascites weight gain hepatomegaly

Question 48

what is TMA

Answer 48

generalized endothelial dysfunction resulting from chemo and other triggers causes microangiopathic hemolytic anemia and platelet consumption thrombosis and fibrin deposition in microcirculation

Question 49

risk factors for TMA

Answer 49

therapy: TBA, calcineurin inhibitos, sirolimus GVHD infections: aspergillus, CMV, adenovirus

Question 50

clinical features of TMA

Answer 50

microangiopathic hemolytic anemia + increased LDH or other markers of hemolysis thrombocytopenia or increase platelet transfusion requirements renal dysfunction or neurological abnormalities PRES= posterior reversible encephalopathy syndrome

Question 51

diagnosis and management of TMA

Answer 51

discontinue calcineurin inhibitor | plasma exchange

Question 52

phase 1 of HCT infectious disease path

Answer 52

day 0 to 15045 (engraftment) | carrier breakdown and neutropenia

Question 53

phase 2 of HCT infectious disease path

Answer 53

day 15-45 to 100 impaired cellular and humoral immunity NK cells followed by start of CD8+ T cell recovery

Question 54

phase 3 of HCT infectious disease path

Answer 54

day 100 to 365+ impaired cellular and humoral immunity slowly B cell and CD4+ T cell recovery and diversification of cells

Question 55

why can CMV infection occur post HCT?

Answer 55

reactivation of latent virus or newly acquired virus from donor graft or blood transfusions common in allogenic but rare in autologous

Question 56

how is CMV prevented?

Answer 56

allogenic HCT recipients are monitored with plasma CMV PCR assays at least weekly through day 100 after HCT treated preemptively if values exceed threshold

Question 57

pathophys of chronic GVHD

Answer 57

less well understood than acute GVHD late expression of alloreactivity dysfunctional immune reconstitution

Question 58

symptoms of chronic GVHD

Answer 58

``` dry eyes oral lesions nail dystrophy skin sclerosis deep sclerosis bronchiolitis obliterans loss of bile ducts fasciitis skin ulcers ```

Question 59

what are Pseufo-Pelger Huet cells

Answer 59

bilobed neutrophils frequently seen in myelodysplastic syndrome