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Haem/Onc > Bone Marrow Failure, ASPHO > Flashcards

Bone Marrow Failure, ASPHO Flashcards

1
Q

give 5 causes of inherited bone marrow failure

A 
Fanconi Anemia
Schwachmond Diamond
Dyskeratosis Congenita
Diamond-Blackfan anemia
Severe congenital neutropenia
Thrombocytopenia Absent Radii
Congenital Amegakaryocytic thrombocytopenia
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2
Q

Give 5 causes of acquired bone marrow failure = acquire AA

A 
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.

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3
Q

why is imp to distinguish type of IBMFS?

A
  • conventional tx have lots of toxicityrequire diff txs
  • donor selection for HSCT
  • implciations for family planning
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4
Q

how does AA present? 4

A
  • 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
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5
Q

def’in of severe AA?

A

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
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6
Q

def’in of VERY severe AA?

A

ANC <200/ml

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7
Q

specific causes/questions to ask on hx when suspect acquired AA?

A
  • 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
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8
Q

in hepatitis-associated AA< the hepatitis is _____ . cytoepnias occur when?

A

sero-negative; after hepatitis resolves

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9
Q

tx for hep-associated AA?

A

HSCT, immunosuppressive tx ( ATG, cyclosporine) just like for regular AA

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10
Q

work up for AA?

A
  • 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
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11
Q

pathophys of idiopathic AA?

A

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

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12
Q

IST tx?

A
  • 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
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13
Q

is there a clear role for GCSF/GMCSF in AA?

A

no…can –> MDS/AML

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14
Q

how does cyclosporine work?

A

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

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15
Q

how does tacrolimus work?

A

blocks t-cell activation by calcineurin inhibition..2nd line agent in IST

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16
Q

ATG side effects?

A
  • 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
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17
Q

Eltrombopag mech?

A

Thrombopoeitin receptor agonist…first line adn rescue therapy of SAA

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18
Q

goal plts in eltrombopag use?

A

50-200k

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19
Q

need to dose reduce eltrombopag in whom?

A

southeast asian population

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20
Q

AEs in eltromobpag?

A

hepatic decompensation (ALT, bili monitoring needed), skin rash, hyperpigmenation, cataracts, myelofibrosis

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21
Q

cocnern of eltrombopag?

A

more rapid progression from MDS to AML

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22
Q

what fraction of AAA respond to IST?

A

> 80%, with 10-30% needing ongoing CsA or relapsing

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23
Q

time frame to response in IST?

A

3-6 months

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24
Q

complete vs partial response in IST?

A

complete: noramlization of counts
partial: transfusion-indepentn

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25
Q

response in HSCT for AA?

A

80-90% (same for IST) but IST has higher rates of relapse and clonal evolution

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26
Q

diffs in disease free survival in IST and HSCT for AA?

A

IST: better 6 month short term surivival, but continues to decline as far out as 6-10 yrs….HSCT curve palteaus after 2 yrs

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27
Q

type of conditioning used in AA?

A

reduced intesnity regimen

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28
Q

for AAA, patients with SAA younger than ___ yrs of age do better with ____ ___ ___ ___. reasonable alternative if not available?

A

40; allogenic sibling match HSCT…IST with ATG/cyclopsorine

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29
Q

TRANSIT study showed what?

A

first line URD HSCT vs IST promising in SAA

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30
Q

Salvage tx for response failure in 3-6 months for IST?

A
  • URD donor HSCT
  • IST retreatment, alternate source ATG? eltrombopag?
  • high dose cyclophos
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31
Q

paroxysmal nocturnal hemobloginuria: what is this?

A

acquired clonal stem cell disorder due to acquired somatic mutations in the PIG-A gene (Xp22.1)

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32
Q

Function of PIG-A?

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

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33
Q

dx PNH how?

A

flow cytometry of CD55,59 to determine % of GPI deficient anchored protein on granulocytes and other cell lineages

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34
Q

findings in PNH?

A

hemolysis
hemoglobinuria
fatal thrombosis (venous, mesenteric)

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35
Q

Describe classical presentation of PNH

A
  • overt hemolysis with high retics
  • may have secondary IDA
  • marrow is HYPER or NORMOcellular!
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36
Q

Describe aplstic anemia with PNH clone

A
  • 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
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37
Q

PNh tx?

A
  • only curative tx= HSCT

- eculizumab can reduce RBC hemolysis and thrombosis risk

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38
Q

what is eculizumab?

A

humanized anti-C5 monoclonal antibody taht inhibits terminal complement activation

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39
Q

side effects fo eculizimab?

A

headache, nasopharyngitis, back pain, URI, risk of n. meingitides- vaccine needed!

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40
Q

for IBMFS, are heme findings usually present at birth?

A

no

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41
Q

cancers seen more often in IBFMS?

A

MDs/AML, squamous epidermal ca

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42
Q

give 3 tumours seen in FA

A

MDS/AML
SCC
wilms
brain tumours

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43
Q

do FA patients always have congen anoms?

A

no

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44
Q

give 4 anoms seen in FA

A

cafe au lait
short stature
lack of thumb/hypoplastic thumb
hypopigmentation

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45
Q

dx FA how?

A
  • 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
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46
Q

FA protein function?

A

nuclear protein complex that repairs DNA

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47
Q

muts in FA?

A

FANC-A>

FANC-C

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48
Q

diff between FANC-A and FANC-C?

A

FANC-C= more severe

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49
Q

FANC genes are inherited how?

A

aut recessive for all except Fanc B, which is x-linked recessive

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50
Q

FA tx?

A
  • 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
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51
Q

AEs of oxymetholone= androgen

A
  • virlization
  • growth spurt followed by premat epiphyseal closure adn adult short stature
  • hyperactivity
  • transaminitis/cholestatic jaundice
  • hepatic adenoma
  • HCC
  • peliosis hepatis
  • htn
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52
Q

risk of malig in FA?

A

1000x higher than normal! 30% have cancer by adulthood

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53
Q

tumours seen in FA? 3

A 
10% AML>ALL
10% SCC head and neck
liver adenoma
liver hepatoma
female GU tract cancers
54
Q

risks of HSCT in FA pts?

A

risks of SCC becomes 4x higher

age of solid tumours shifted 16 yrs earlier

55
Q

major problem with FA and malig?

A

excessive toxicity from standard chemo

56
Q

dyskeratosis congenita: pathology? triad?

A
  • DNA repair defect
  • reticulated skin hyperpigmentation, dystrophic nails, mucous membrane leukoplakia develops with age…but don’t need these features for dx!
57
Q

aplastic anemia seen in what proportion of DC pts?

A

1/2

58
Q

when woudl AA develop in DC pts?

A

2-3rd decade or later

59
Q

cancers seen in DC?

A

head, neck, GI, leuekmia in 3-4th decades, MDS/AML, carcinomas of lung, tongue, larynx, esoph,panncreas, skin

60
Q

key features of DC?

A

-pulmonary disease!
-early greying
-microcephaly
-esophagel stricture
-ataxia
-deafness
etc

61
Q

DC inherited how?

A

AD, AR, x-linked

62
Q

does neg genetic testing rule out DC?

A

no

63
Q

hallmark of DC?

A

very short telomeres! <1%ile for age in >3 lymphocyte subsets

64
Q

most common gene mut in DC? Inheritance?

A

DKC1, x-linked

65
Q

tx for DC?

A

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

66
Q

Schwachman-DIamond: heme findings?

A

fluctuating neutropenia, imapired chemotaxis; anemia in 1/3, low plts in 1/5…aplasia in 10-25%–> MDS/AML

67
Q

non-heme findings in SDS? 3

A
  • 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
68
Q

SDS inheritance?

A

AR!

69
Q

SDS: male or female more often?

A

male 1.7x more often

70
Q

SDS gene?

A

SBDS gene or SBDSP

71
Q

SBDS gene function?

A

ribosome biogenesis

72
Q

SDS ddx?

A

CF
SCN, like kostmann and cyclic neutorpenia
pearson syndrome

73
Q

SDS tx?

A
  • 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
74
Q

give 3 congential neutorpenia syndromes

A

Kostmann’s syndrome
cyclic neutropenia
WHIM syndrome

75
Q

often see what else on CBC in SCN?

A

monocytosis

eosinophilia

76
Q

in SDS, do del20q adn iso7q indicate progression to MDS?

A

not necessarily

77
Q

ANC in Kostmann’s?

A

<500, usually <200 from birth

78
Q

major infetions seen in Kostmann’s?

A

S. aureus, Pseudomonas

79
Q

mech of Kostmann’s?

A

accelerated apoptosis of myeloid precursors, maturational arrest at myelocyte/ promyelocyte stage

80
Q

GCSF dose in Kostmann’s?

A

3-100 mcg/kg/day

81
Q

goal ANC in Kostmanns’?

A

1000/uL

82
Q

risk of MDS/AML in Kostmann’s?

A

2% per year

83
Q

how does MDS/AML present in Kostmann’s?

A

monosomy 7, trisomy 21

84
Q

inheritance of SCN mutations?

A

AR, AD, X-linked

85
Q

60% of europeans/middle eastern pts with SCN have which muts?

A

ELA-2–> now called ELANE

86
Q

Most common inheritance of ELA-2?

A

AD

87
Q

most pts with SCN and AML have what germline mut?

A

homozygous SCN7= CSF3R

88
Q

ELA-2 mutated in what 2 diseases?

A

SCN adn cyclic neutropenia! just diff exons!

89
Q

Cyclic neutropenia: inheritance?

A

AD and sporadic

90
Q

cyles of how long or cyclic neutropenia?

A

21 +/- 7 days

91
Q

cyclic neutropenia: ANC goes down to what, for how long?

A

<200 for 3-5 days

92
Q

mech of cyclic neutropenia?

A

marrow arrest at myelocyte level

93
Q

signs and symptoms of cyclic nuetorpenia?

A 
fever
pharyngitis
apthous ulcers
periodontitis
symptoms often improve with age!
94
Q

other heme features in cyclic neutorpenia?

A

may have cyclic plts and retics too

95
Q

manage cyclic neutropenia how?

A
  • aggressive care for infections

- GCSF q2 days

96
Q

Myelokathexis/WHIM syndrome=?

A

nuetropenia with Warts, Hypogammaglobulinemia, Infections, Myelokathexis

97
Q

pts with WHIM syndrome susceptible to what virus?

A

HPV

98
Q

mech of whim syndrome?

A

noncyclic neutropenia with myeloid hyperplaisa of marrow…retention of myeloid cells in marrow

99
Q

mut in WHIM syndrome?

A

CXCR4, AD

100
Q

tx for WHIM?

A

GCSF–> makes neutropenia, apopotosis, hypogammaglobulinemia better

101
Q

Diamond Blackfan Anemia: dx criteria?

A

“PALM”

  • age <1 yr
  • macrocytic anemia
  • low retics
  • paucity of erythroid precursors in marrow
102
Q

DBA: classic has ___ dx crtieria

A

ALL

103
Q

supporting criteria for DBA: Major?

A

pathogenic mutations, pos fam hx

104
Q

supporting critiera for DBA: minor?

A

elevated red cell ADA, cong anoms, elevated hgb F, no other BMFS

105
Q

congen anoms in DBA?

A 
tow colored hair
blue sclerae
glaucoma
short stature
upper extremity/thumbs abN
GU anomalies
cardiac anomalies
bony abNs
can have low ANC, low plts
106
Q

DBA genetics?

A

AD, RPS19 is most common mut…many mutations unknown…RPS19= a ribosomal protein

107
Q

DBA tx?

A
  • 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)
108
Q

for infants with DBA, what change to tx?

A

1x monthly pRBCs to avoid high steroids/PJP risk

109
Q

outcome in DBA?

A
  • 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!
110
Q

maligs in DBA?

A

AML/MDS, Osteosarcoma, hodgkins

111
Q

WHat’s TEC?

A

spont cessation of eythropoeisis in an otherwise healthy kid…may also have low ANC and plts

112
Q

manage TEC how?

A

serial blood counts, increase in retics as first sign of marrow recovery…transfuson if necessary for Hgb<50 with low retics…follow to resolution

113
Q

diffs between TEC adn DBA?

A
  • DBA: phys anoms in 50% vs. none in TEC

- TEC usually responds after ~6 weeks

114
Q

amegakaryocytic thrombocytopenia: inheritance? mut?

A

AR; c-MPL gene mutation

115
Q

see what in CAMT?

A

low plts AT BIRTH! (unlike other inherited marrow disorders)

116
Q

heme changes seen in CAMT?

A
  • rbcs large
  • increased fetal hgb
  • normal plt size and morph
117
Q

risk of what in amegakayrocytic thrombocytoepnia?

A

high risk of MDS–> AML

118
Q

CAMT: can present __ or ___

A

early or late

119
Q

CAMT: tx?

A

stem cell transplant

120
Q

TAR=?

A

thrombocytoepnia absent radius…low plts also at birth!!!

121
Q

gene in TAR?

A

RBM8A

122
Q

in TAR, do you have thumb?

A

yes

123
Q

other features in TAR?

A

high eos
webbed neck
micrognathia

124
Q

pearosn syndrome: what is this?

A

refractory siderobalstic anemia by 6 months of age…marrow shows vaculated precursors and ringed sideroblasts

125
Q

features of pearson syndrome?

A

Red cell issue but can also have low AC, plts

  • exocrine panc dysfunction
  • renal failure
126
Q

genetis of pearson?

A

mitochondrial DNA deletion

127
Q

<5% marrow balsts with dysplastic changes..think?

A

Refractory cytoepnia of childhood

128
Q

MDS due to germline predispositon: monosomy 7, del7q…think?

A

IBFMS

129
Q

low monocytes, myobaceria infections, warts…think?

A

GATA2 disorders

130
Q

adrenal insuff, immunodef…thnk?

A

SAMD9

131
Q

red flags for IBMFS?

A
  • 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

Haem/Onc (30 decks)

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