B3.052 Hematopoietic Stem Cell Transplant Flashcards
4 major causes of pancytopenia
hematopoietic stem cell injury clonal hematopoietic cell mutation myelophthisis defective maturation enhanced peripheral destruction
disorders associated with hematopoietic stem cell injury
aplastic anemia (idiopathic, immune mediated, secondary to drugs, toxins, etc) Fanconi anemia
disorders associated with clonal hematopoietic cell mutation
acute leukemia
myelodysplasia
paroxysmal nocturnal hemoglobinuria
disorders associated with melophthisis
metastatic cancer
granulomatous disorders, TB
lymphoma
myelofibrosis
disorders associated with defective maturation
megaloblastic anemias
disorders associated with enhanced peripheral destruction
hypersplenism
autoimmune disorders
hemophagocytic lymphohistiocytosis
affected cell in myelodysplastic syndrome
myeloid stem cell
all cell lines affected, clonal hematopoiesis
kinetics of myelodysplastic syndrome
ineffective hematopoiesis (apoptosis of maturing cells in marrow)
what types of gene mutations are associated with MDS?
more than 90% of patients have mutations
more than 40 genes
commonly DNA methylation proteins
5q and 7q deletions common
what are some prognostic variables of MDS?
cytogenetics bone marrow blast % Hbg conc platelet count neutrophil count
treatment for MDS
only definitive therapy is allogenic stem cell transplantation
what are the overarching goals of HCT?
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
totipotent stem cells
cell can develop into complete organism
unlimited capacity
found in early embryos
pluripotent stem cells
can form any of >200 cell types
located in undifferentiated inner cell mass of the blastocyst
found in early embryos
multipotent stem cells
committed cell that can form other tissues
located in fetal tissue, cord blood and adult somatic tissue
what are 4 factors associated with identification of stem cells
TPO - self renewal
SCF - proliferation/differentiation
TGFB- cell cycle dormancy
Ang-1 - cell cycle dormancy
what are the 5 major steps in stem cell transplant?
- collection
- processing
- cryopreservation
- chemotherapy
- infusion
what is autologous stem cell transplant and when is it used?
patients own stem cells
a technique to give high dose chemo
no immunological barriers
cons to autologous transplant
“tumor contamination”
not useful for bone marrow failure syndromes
what factors plays a dominant role in donor selection?
HLA Typing
what is HLA?
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)
how is HLA typing done?
serology w antigen specific anti sera
DNA code in cell’s nucleus
what is a novel immunologic condition that arises in marrow transplantation?
rejection is bidirectional
-graft rejection
-graft versus host disease (GVHD)
tolerance develops, immunosuppression not lifelong
what are components of small cell graft
facilitating cells NK cells dendritic cells T and B lymphocytes stem cells, progenitors
T lymphocyte functions in the patients
GVL
GVHD
essential factors necessary for GVHD to occur
immunologically competent donor graft
histo-incompatilbility between donor and host
immunologically incompetent host
how is GVHD related to graft versus malignancy effect?
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
which disorders have a high sens to graft vs tumor effects?
CML
CLL
low grade NHL
mantle cell NHL
which disorders have a medium sens to graft vs tumor effects?
AML
intermediate grade NHL
HL
MM
which disorders have a low sens to graft vs tumor effects?
ALL
high grade NHL
3 primary sources of stem cells
BM
peripheral blood (at conc of approx. 1% found in BM)
umbilical cord blood
advantages to BM collection
typically only one collection
usually enough cells collected
low T cell content
disadvantages to BM collection
not readily available surgical procedure risks to donor costly high risk of tumor cell contamination restrictive HLA-matching requirements
agents that mobilize stem cells to peripheral blood
filgrastim
sargramostin
plerixafor
chemo (autologous donations only)
advantages of using PBSC
less complex procedure stem cell count adequate higher progenitor cell content low risk of tumor cell contamination fastest engraftment time
disadvantages of using PBSC
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
advantages of using UCB
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
disadvantages of using UCB
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
components of the preparative regimen
radiation
high doses of chemo
targeted agents
how is graft rejection prevented?
eradicate host immune system (T cells)
immunosuppressive component of conditioning regiment
how is GVHD prevented?
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
what is the tradeoff between prophylaxis and other outcomes?
aggressive prophylaxis: -less GVHD -MORE infection -MORE relapse minimal prophylaxis: -MORE GVHD -less infection -less relapse
things that can cause acute toxicities after HCT
thrombotic microangiopathy
GVHD
infections
symptoms of acute toxicities
mucositis nausea/vomiting diarrhea pulmonary sinusoidal obstructive syndrome iron overload drug toxicity hemorrhagic cystitis drug toxicity
what is SOS
sinusoidal obstructive syndrome
obliteration of small intrahepatic central venules
pathophys of SOS
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
clinical manifestations of SOS
hyperbilirubinemia
ascites
weight gain
hepatomegaly
what is TMA
generalized endothelial dysfunction resulting from chemo and other triggers
causes microangiopathic hemolytic anemia and platelet consumption
thrombosis and fibrin deposition in microcirculation
risk factors for TMA
therapy: TBA, calcineurin inhibitos, sirolimus
GVHD
infections: aspergillus, CMV, adenovirus
clinical features of TMA
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
diagnosis and management of TMA
discontinue calcineurin inhibitor
plasma exchange
phase 1 of HCT infectious disease path
day 0 to 15045 (engraftment)
carrier breakdown and neutropenia
phase 2 of HCT infectious disease path
day 15-45 to 100
impaired cellular and humoral immunity
NK cells followed by start of CD8+ T cell recovery
phase 3 of HCT infectious disease path
day 100 to 365+
impaired cellular and humoral immunity
slowly B cell and CD4+ T cell recovery and diversification of cells
why can CMV infection occur post HCT?
reactivation of latent virus or newly acquired virus from donor graft or blood transfusions
common in allogenic but rare in autologous
how is CMV prevented?
allogenic HCT recipients are monitored with plasma CMV PCR assays at least weekly through day 100 after HCT
treated preemptively if values exceed threshold
pathophys of chronic GVHD
less well understood than acute GVHD
late expression of alloreactivity
dysfunctional immune reconstitution
symptoms of chronic GVHD
dry eyes oral lesions nail dystrophy skin sclerosis deep sclerosis bronchiolitis obliterans loss of bile ducts fasciitis skin ulcers
what are Pseufo-Pelger Huet cells
bilobed neutrophils frequently seen in myelodysplastic syndrome
