Bone Marrow Failure, ASPHO Flashcards
give 5 causes of inherited bone marrow failure
Fanconi Anemia Schwachmond Diamond Dyskeratosis Congenita Diamond-Blackfan anemia Severe congenital neutropenia Thrombocytopenia Absent Radii Congenital Amegakaryocytic thrombocytopenia
Give 5 causes of acquired bone marrow failure = acquire AA
medications chemicals toxins viral infection PNH idiopathic/immune
Toxins, such as pesticides, arsenic and benzene
Radiation and chemotherapy used to treat cancer
Treatments for other autoimmune diseases, such as rheumatoid arthritis and lupus
Pregnancy - sometimes, this type of aplastic anemia improves on its own after the woman gives birth
Infectious diseases, such as hepatitis, Epstein-Barr virus, cytomegalovirus (si-to-MEG-ah-lo-VI-rus), parvovirus B19 and HIV.
Sometimes, cancer from another part of the body can spread to the bone marrow and cause aplastic anemia.
why is imp to distinguish type of IBMFS?
- conventional tx have lots of toxicityrequire diff txs
- donor selection for HSCT
- implciations for family planning
how does AA present? 4
- insidious; inciting event usually 6-8 weeks earlier
- often present with low plts and bleeding
- MCV HIGH
- fetal hgb often increased and “i” antigen often increased on RBCs
def’in of severe AA?
2/3 peripheral blood critiera:
ANC <500/ml
plts<20k/ml
retics< 1% corrected
1/2 BM criteria:
- <25% cellularity on bx
- cellularity 25-50% with <30% hematopoeitc cells
def’in of VERY severe AA?
ANC <200/ml
specific causes/questions to ask on hx when suspect acquired AA?
- radiation hx?
- cytotoxic agents, benzene, alcohol?
- idiosyncratic: chloramphenicol, anti-epileptic, anti-inflamm, and psychotropic meds
- viruses? EBV, CMV, sero-neg hep!!!, HHV6, HIV
- Autoimmuen diseae
- Immune disease like eosinophilic fasciits, hypogammaglobulinemia
- thymoma
- large granular lymphocytic leukemia
- PNH
- myelodysplasia
in hepatitis-associated AA< the hepatitis is _____ . cytoepnias occur when?
sero-negative; after hepatitis resolves
tx for hep-associated AA?
HSCT, immunosuppressive tx ( ATG, cyclosporine) just like for regular AA
work up for AA?
- BMA and bx
- cytogenetics on marrow; fish for MDS
- rule out IBMFS: chromosomal breakage assessment on peripheral blood with diepoxybutane or mitomycin C for FA; telomere length for DC
- PNH eval on flow of peripheral blood
- viral infection: serology of PCR for EBV, CMV, hep a/b/c, HIV, parvo
- eval of renal, hepatic, thyroid function
pathophys of idiopathic AA?
aberrant immune response to multiple stimuli: oligoclonal t-cell expansion with cytotoxic t-cells mediating stem cell destruction, suppression of normal marrow; also get overproduction of TNF-alpha and interferon-gamma
IST tx?
- Anti-human T cell serum: ATG (horse) or ALG (rabbit)…dosing >150 mg/kg or 40 mg/kg/day x 4 days
- steroids for 10-28 days to prevent serum sickness
- cyclosporine for 12 months; want stable counts for 3 months before tapering cyclosporine
is there a clear role for GCSF/GMCSF in AA?
no…can –> MDS/AML
how does cyclosporine work?
inhbiits prolif of t cells by binding cytosolic immunophili receptor– inhibit gene trx within t cell and also inhibitrs production of IL2 and interferon gamma
how does tacrolimus work?
blocks t-cell activation by calcineurin inhibition..2nd line agent in IST
ATG side effects?
- allergic: fever, rigors, urticaria, anaphylaxis – pre-tx with steroids, antihistamines, meperidine, slower rate of infusion
- serum sickness: fever, MP rash, myalgia, arthralgia, myocarditis, GI/CNS/renal sx…usual time frame: 5-10 days after ATG…tx with steroids
- immune-mediated cytopenias…lymphopenia: consider PCP ppx
Eltrombopag mech?
Thrombopoeitin receptor agonist…first line adn rescue therapy of SAA
goal plts in eltrombopag use?
50-200k
need to dose reduce eltrombopag in whom?
southeast asian population
AEs in eltromobpag?
hepatic decompensation (ALT, bili monitoring needed), skin rash, hyperpigmenation, cataracts, myelofibrosis
cocnern of eltrombopag?
more rapid progression from MDS to AML
what fraction of AAA respond to IST?
> 80%, with 10-30% needing ongoing CsA or relapsing
time frame to response in IST?
3-6 months
complete vs partial response in IST?
complete: noramlization of counts
partial: transfusion-indepentn
response in HSCT for AA?
80-90% (same for IST) but IST has higher rates of relapse and clonal evolution
diffs in disease free survival in IST and HSCT for AA?
IST: better 6 month short term surivival, but continues to decline as far out as 6-10 yrs….HSCT curve palteaus after 2 yrs
type of conditioning used in AA?
reduced intesnity regimen
for AAA, patients with SAA younger than ___ yrs of age do better with ____ ___ ___ ___. reasonable alternative if not available?
40; allogenic sibling match HSCT…IST with ATG/cyclopsorine
TRANSIT study showed what?
first line URD HSCT vs IST promising in SAA
Salvage tx for response failure in 3-6 months for IST?
- URD donor HSCT
- IST retreatment, alternate source ATG? eltrombopag?
- high dose cyclophos
paroxysmal nocturnal hemobloginuria: what is this?
acquired clonal stem cell disorder due to acquired somatic mutations in the PIG-A gene (Xp22.1)
Function of PIG-A?
PIG-A has a role in biosynthesis of glycophosphatidylinositol anchor, which is needed to anchor glycoprotiens to the cell membrane…if deficient in GPI anchored proteins (CD55/59): at risk for complement-lysis fo the RBCs
dx PNH how?
flow cytometry of CD55,59 to determine % of GPI deficient anchored protein on granulocytes and other cell lineages
findings in PNH?
hemolysis
hemoglobinuria
fatal thrombosis (venous, mesenteric)
Describe classical presentation of PNH
- overt hemolysis with high retics
- may have secondary IDA
- marrow is HYPER or NORMOcellular!
Describe aplstic anemia with PNH clone
- can happen before or after therapy
- typically small % PNH clone with scant overt hemolyssi
- HYPOcellular marrow
- severe cytopenias in PNH positive patients may respond to IST…after IST, clone size may increase or a measurable clone develops whihc may progress or be stable
PNh tx?
- only curative tx= HSCT
- eculizumab can reduce RBC hemolysis and thrombosis risk
what is eculizumab?
humanized anti-C5 monoclonal antibody taht inhibits terminal complement activation
side effects fo eculizimab?
headache, nasopharyngitis, back pain, URI, risk of n. meingitides- vaccine needed!
for IBMFS, are heme findings usually present at birth?
no
cancers seen more often in IBFMS?
MDs/AML, squamous epidermal ca
give 3 tumours seen in FA
MDS/AML
SCC
wilms
brain tumours
do FA patients always have congen anoms?
no
give 4 anoms seen in FA
cafe au lait
short stature
lack of thumb/hypoplastic thumb
hypopigmentation
dx FA how?
- chromosal brekaage test: peipheral blood karyotype with and wihtout exposure to patient cells breakage inducing agent: DEB= diepoxybutane or MMC= mitomycin C
- if high clinical suspcion and peripheral blood test equivocal: repeat chrom breakage testing using cultured skin fibroblasts
- specific mut analysis to CONFIRM
FA protein function?
nuclear protein complex that repairs DNA
muts in FA?
FANC-A>
FANC-C
diff between FANC-A and FANC-C?
FANC-C= more severe
FANC genes are inherited how?
aut recessive for all except Fanc B, which is x-linked recessive
FA tx?
- supportive care as long as possible: manage congen anoms, transfusion (fewest units, all irradiated, growth factors?)
- monitor for MDS, AML iwth annual BM bx with FISH
- oxymethalone (androgen) may slow decline…danazol less virilizing for females?
- HSCT with RIC…increased tox due to DNA repair defect; survival of URD approaching sibling donor
AEs of oxymetholone= androgen
- virlization
- growth spurt followed by premat epiphyseal closure adn adult short stature
- hyperactivity
- transaminitis/cholestatic jaundice
- hepatic adenoma
- HCC
- peliosis hepatis
- htn
risk of malig in FA?
1000x higher than normal! 30% have cancer by adulthood
tumours seen in FA? 3
10% AML>ALL 10% SCC head and neck liver adenoma liver hepatoma female GU tract cancers
risks of HSCT in FA pts?
risks of SCC becomes 4x higher
age of solid tumours shifted 16 yrs earlier
major problem with FA and malig?
excessive toxicity from standard chemo
dyskeratosis congenita: pathology? triad?
- DNA repair defect
- reticulated skin hyperpigmentation, dystrophic nails, mucous membrane leukoplakia develops with age…but don’t need these features for dx!
aplastic anemia seen in what proportion of DC pts?
1/2
when woudl AA develop in DC pts?
2-3rd decade or later
cancers seen in DC?
head, neck, GI, leuekmia in 3-4th decades, MDS/AML, carcinomas of lung, tongue, larynx, esoph,panncreas, skin
key features of DC?
-pulmonary disease!
-early greying
-microcephaly
-esophagel stricture
-ataxia
-deafness
etc
DC inherited how?
AD, AR, x-linked
does neg genetic testing rule out DC?
no
hallmark of DC?
very short telomeres! <1%ile for age in >3 lymphocyte subsets
most common gene mut in DC? Inheritance?
DKC1, x-linked
tx for DC?
like FA, supportive care as long as possible…use caution with androgens: viscus rupture risk with androgen…HSCT with RIC and watch for pulmonary toxcity and VOD
Schwachman-DIamond: heme findings?
fluctuating neutropenia, imapired chemotaxis; anemia in 1/3, low plts in 1/5…aplasia in 10-25%–> MDS/AML
non-heme findings in SDS? 3
- exocrine pancreatic insuff
- short stature
- metaphyseal chondrodysplasia= bell-shaped chest
- eczema, icthyosis
- low trypsinogen (<3 yo), pancreatic isoamylase>3 yo…can also check fecal elastase and would see fatty pancreas on imaging
SDS inheritance?
AR!
SDS: male or female more often?
male 1.7x more often
SDS gene?
SBDS gene or SBDSP
SBDS gene function?
ribosome biogenesis
SDS ddx?
CF
SCN, like kostmann and cyclic neutorpenia
pearson syndrome
SDS tx?
- panc enzyme replacment, ADEK suppelements
- managemetn of congen anoms
- GCSF: least amount, shortest time
- transfusions
- monitoring for MDS/AML (annual marrow)
- stem cel transplant (few)…variable results due to conditioning tox
give 3 congential neutorpenia syndromes
Kostmann’s syndrome
cyclic neutropenia
WHIM syndrome
often see what else on CBC in SCN?
monocytosis
eosinophilia
in SDS, do del20q adn iso7q indicate progression to MDS?
not necessarily
ANC in Kostmann’s?
<500, usually <200 from birth
major infetions seen in Kostmann’s?
S. aureus, Pseudomonas
mech of Kostmann’s?
accelerated apoptosis of myeloid precursors, maturational arrest at myelocyte/ promyelocyte stage
GCSF dose in Kostmann’s?
3-100 mcg/kg/day
goal ANC in Kostmanns’?
1000/uL
risk of MDS/AML in Kostmann’s?
2% per year
how does MDS/AML present in Kostmann’s?
monosomy 7, trisomy 21
inheritance of SCN mutations?
AR, AD, X-linked
60% of europeans/middle eastern pts with SCN have which muts?
ELA-2–> now called ELANE
Most common inheritance of ELA-2?
AD
most pts with SCN and AML have what germline mut?
homozygous SCN7= CSF3R
ELA-2 mutated in what 2 diseases?
SCN adn cyclic neutropenia! just diff exons!
Cyclic neutropenia: inheritance?
AD and sporadic
cyles of how long or cyclic neutropenia?
21 +/- 7 days
cyclic neutropenia: ANC goes down to what, for how long?
<200 for 3-5 days
mech of cyclic neutropenia?
marrow arrest at myelocyte level
signs and symptoms of cyclic nuetorpenia?
fever pharyngitis apthous ulcers periodontitis symptoms often improve with age!
other heme features in cyclic neutorpenia?
may have cyclic plts and retics too
manage cyclic neutropenia how?
- aggressive care for infections
- GCSF q2 days
Myelokathexis/WHIM syndrome=?
nuetropenia with Warts, Hypogammaglobulinemia, Infections, Myelokathexis
pts with WHIM syndrome susceptible to what virus?
HPV
mech of whim syndrome?
noncyclic neutropenia with myeloid hyperplaisa of marrow…retention of myeloid cells in marrow
mut in WHIM syndrome?
CXCR4, AD
tx for WHIM?
GCSF–> makes neutropenia, apopotosis, hypogammaglobulinemia better
Diamond Blackfan Anemia: dx criteria?
“PALM”
- age <1 yr
- macrocytic anemia
- low retics
- paucity of erythroid precursors in marrow
DBA: classic has ___ dx crtieria
ALL
supporting criteria for DBA: Major?
pathogenic mutations, pos fam hx
supporting critiera for DBA: minor?
elevated red cell ADA, cong anoms, elevated hgb F, no other BMFS
congen anoms in DBA?
tow colored hair blue sclerae glaucoma short stature upper extremity/thumbs abN GU anomalies cardiac anomalies bony abNs can have low ANC, low plts
DBA genetics?
AD, RPS19 is most common mut…many mutations unknown…RPS19= a ribosomal protein
DBA tx?
- Pred 2 mg/kg/day for 8-12 weeks before declaring failure…then taper to min dose to maintain hgb>90…80% respond!
- if steroid refractory or really high dose of steroids needed, try chronic transfusions (do extended antigen typing of pRBCs, min volumes and tx Fe overload with chelation)
for infants with DBA, what change to tx?
1x monthly pRBCs to avoid high steroids/PJP risk
outcome in DBA?
- 20% remission by age 25
- do HSCT if transfusion-dependent, esp if allo-immunized and/or other cytopenias…but still have solid tumour risk and sibling needs to be checked for DBA!
maligs in DBA?
AML/MDS, Osteosarcoma, hodgkins
WHat’s TEC?
spont cessation of eythropoeisis in an otherwise healthy kid…may also have low ANC and plts
manage TEC how?
serial blood counts, increase in retics as first sign of marrow recovery…transfuson if necessary for Hgb<50 with low retics…follow to resolution
diffs between TEC adn DBA?
- DBA: phys anoms in 50% vs. none in TEC
- TEC usually responds after ~6 weeks
amegakaryocytic thrombocytopenia: inheritance? mut?
AR; c-MPL gene mutation
see what in CAMT?
low plts AT BIRTH! (unlike other inherited marrow disorders)
heme changes seen in CAMT?
- rbcs large
- increased fetal hgb
- normal plt size and morph
risk of what in amegakayrocytic thrombocytoepnia?
high risk of MDS–> AML
CAMT: can present __ or ___
early or late
CAMT: tx?
stem cell transplant
TAR=?
thrombocytoepnia absent radius…low plts also at birth!!!
gene in TAR?
RBM8A
in TAR, do you have thumb?
yes
other features in TAR?
high eos
webbed neck
micrognathia
pearosn syndrome: what is this?
refractory siderobalstic anemia by 6 months of age…marrow shows vaculated precursors and ringed sideroblasts
features of pearson syndrome?
Red cell issue but can also have low AC, plts
- exocrine panc dysfunction
- renal failure
genetis of pearson?
mitochondrial DNA deletion
<5% marrow balsts with dysplastic changes..think?
Refractory cytoepnia of childhood
MDS due to germline predispositon: monosomy 7, del7q…think?
IBFMS
low monocytes, myobaceria infections, warts…think?
GATA2 disorders
adrenal insuff, immunodef…thnk?
SAMD9
red flags for IBMFS?
- physical anoms with heme anoms
- unexpained high MCV
- pts who are very sensitive to chemo/rad
- cancer in an early age, esp head and neck ca before 40 or vulvar before 30 yrs
