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Haem/Onc > Myeloproliferative, Myelodysplastic, and Histiocytic Disorders, ASPHO > Flashcards

Myeloproliferative, Myelodysplastic, and Histiocytic Disorders, ASPHO Flashcards

1
Q

Myelodysplastic syndromes: most common cytogenetics? (3)

A

Monosomy 7!!!> trisomy 8= trsiomy 21….may have non-down MDS with germline mosaiscism

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2
Q

what is strongest predictor for poor outcome in MDS?

A

3 or more chromosomal aberrations

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3
Q

secondary MDS can occur with what? 3

A

chemo
radiation
inherited BMF disorders
familial diseases

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4
Q

give 4 inherited bone marrow failure syndromes that can lead to refracotry cytopenia of childhood

A 
fanconi anemia
dyskeratosis congenita
Down syndrome
schwachman diamond
blackfan diamond
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5
Q

3 germline mutations–> risk of MDS?

A

RUNX1
CEBPA
GATA2

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6
Q

which germlime mutations predispose AML

A

RUNX1

CEBPA

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7
Q

GATA germline mutation associated with?

A

immune def (absent/decreased monos or macs)…more likely to get mycobacterial infection, HPV

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8
Q

prevalence of MDS?

A

1-4 per million

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9
Q

MDS median age?

A

6.8 years

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10
Q

MDS seen in boys vs. girls?

A

=

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11
Q

MDS: more advanced disease seen when?

A

older kids

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12
Q

what is refractory cytopenia of childhood?

A

peripheral blood blasts <2% or BM blasts <5%

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13
Q

what is refractory anemia with excess blasts?

A

PB blasts 2-19% adn or BM blasts 5-19%

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14
Q

what is refractory anemia with excess blasts in transformation?

A

peripheral blasts and or BM blasts 20-29%

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15
Q

MDS-related neoplasms?

A

JMML, CML, BCR-ABL neg CML…and in Down sydrnme: TAM, MDS/AML

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16
Q

which non-heme disorders can cause MDS? (4)

A 
infection, eg parvovrius
vitamin b12 def
folate def
vit E def
metabolic disorders like mevalonate kinase def
JIA with MAS
Persons= mito disorder
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17
Q

heme disordrs associated with MDS?

A

inherited BMF syndromes
severe AA
RCC
paroxysmal nocturnal hemoglobinuria with BM failure
-B-cell ALL pre-phase
-hemophagocytic lymphohistiocytosis
-autoimmune lymphoproliferative syndrome(s)

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18
Q

refractory anemia with excess blasts in kids: give one way diff from in adults

A

counts may be stable for months

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19
Q

RAEB: treat how?

A

sometimes AML type chemo not needed before going for BMT

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20
Q

what might you seen on histo in MDS?

A

abrnomal erythroyid maturation, megalbolastic erythroidmaturation, dysplastic megakaryocyte, nuclear bridging in neutrophils

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21
Q

tx MDS how?

A
  • oberve in approp
  • eval for inherited DNA repair defect
  • immune suppression someties: ATG and cyclosproine
  • transfusion as needed
  • sometimes give AML therapy
  • Allo HCT= only curative therapy,..need to make sure sibling not carrier
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22
Q

problem with AML therapy in MDS?

A

high treatment related mortality in MDS (40%!)…3 yr OS only 15% for MDS…vs 16% adn 35% in AML

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23
Q

OS if do Allo BMT in MDS with no prior AML therapy?

A

60-70%

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24
Q

what is associatd iwth better survival with BMT for MDS pts?

A

> 12% bone marrow blasts

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25
Q

long term issues of AML therpay and BMT for MDS?

A

cytopenias
secondary leuekmia
deccreased growth
decreased fertility

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26
Q

give 3 categories of myeloproliferative disorders

A

Down syndrome associated, JMML, CML

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27
Q

what pathway’s mutations= drivers in JMML?

A

MAPK pathway muations

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28
Q

down syndrome patient develops ___ somatic mutation in fetal ___–> abrnomal ___ production

A

GATA1; liver; megakaryocyte

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29
Q

can you distinguish because TAM blast and DS-AMKL blast?

A

no

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30
Q

relevatn GATA 1 mutations occur in which exon? seen in which diseases?

A

2; TAM and DS-AMKL

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31
Q

other than GATA-1 which other mutations do you seen in DS-AMKL?

A 
trisomy 8
JAK2/3
CTCR
EZH
MPL
SH2B3
RAS pathway
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32
Q

TAM: __% of all children with DS

A

10%

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33
Q

TAM: what percent early death?

A

15%

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34
Q

if you screen for TAM in DS waht woudl the prevalence be in this case?/

A

30%

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35
Q

median onset age for TAM in DS?

A

1.6 months

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36
Q

TAM: prog?

A

spontaneous resoultion in >80% by 3 months…however 20%–> AML (90% M7) by 2-4 years….so mortality, 20% with OS 80%…EFS 60%…20-30% develop AML

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37
Q

RFs for death in children with TAM (4)

A
  • Pre-term delivery
  • congestive heart/liver failure
  • hyperviscosity/hyperleukocytosis
  • DIC
  • pleural and cardiac effusions
  • organomegaly
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38
Q

which study make risk categories for TAM?

A

COGA2971

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39
Q

OS in low risk TAM?

A

92%

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40
Q

OS in iintermed risk TAM?

A

77%

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41
Q

OS in high risk TAM?

A

51%

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42
Q

BM in TAM: hypo or hypercellular? what is common to see? blasts %?

A

can be either; fibrosis; 30% (range varies)

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43
Q

immunotype with TAM typically more ___ than in AML

A

mature

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44
Q

immunophenotype in TAM?

A 
CD33= myeloid
CD45= pan leuk
CD52= pan leuk
\+/- CD34, 117 = HSC
\+/- CD41, 42b, 61= plts
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45
Q

how do you treat TAM?

A

most can be observed.

IF: hydrops, organ failure, hyperleuk: exchange transfusion, leukaphersis, cytarabine 1 mg/kg q12h x 7 days

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46
Q

outcome for DS AML?

A

89% disease free survival

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47
Q

what 2 things would make outcome worse in DS AML?

A 
age >4 (EFS 33% vs 81%
normal karyotype (only 42% survival)
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48
Q

ALL: AML rate in DS vs. non-DS?

A

1.7…6.5

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49
Q

long term issues in DS-AML?

A

cytopenias, seconary leukemia

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50
Q

In JMML, MAPK pathway involved: waht are these steps?

A

RAS-> RAF-> MEK-> ERK

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51
Q

2 syndromes associated with JMML?

A

NF (10-15%)…get loss of WT NF1. (200-500x more likely to get JMML with this!)…and Noonan syndrome or leopard syndrome (35%)

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52
Q

what germline muations are associated with Noonan or Leopard JMML?

A

PTPN11/SHP-2

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53
Q

Give 6 muations seen in JMML,and assocated syndrome

A 
NF1 loss: NF
PTPN11/SHP-2: noonan or leopard syndrome
CBL: CBL germline syndrome
NRAS: Ras-Associated LPD
KRAS: CFC syndrome
KRAS: noonan syndrome
54
Q

about ___ of JMML patients with germline mutations have ___ mutations leading to a ___ prog

A

1/3; secondary; worse

55
Q

JMML with Noonan: age? survival? tx? myelopoeisis is ____…cytogenetics?

A

younger (vs somatic mutations); better survival vs somatic; occasional spont resolution!…polyclonal…normal

56
Q

JMML % of all leuks? prev?

A

1%; 1.2 per million

57
Q

JMML median age of dx?

A

2 years

58
Q

JMML boys vs. girls?

A

male predom 2.5: 1

59
Q

JMML: clinical pres?

A

may relate to leukocytosis: pallor, fever, rash (eczema, xanthogranuloma, leukemia cutis, cafe au lait spots), LAD, hepatomegaly, splenomegaly, resp symptoms, diarrhea, FTT…anemia, elevated WBC, decresed plts, MONOCYTOSIS, INCREASED FETAL HGB

60
Q

outcome in JMML?

A

EFS 52% (rare spont resolution)

61
Q

more likely to have spont resoultion in JMML if?

A
  • Germline PTPN11 (noonan syndrome), K-RAS,N-RAS, CBL
  • male
  • <3 yrs
  • plts >33 x 10^9/L
  • low age adjusted fetal hgb (<15%)
62
Q

peripheral blood smear in JMML?

A

incresaed immat myeloid cells, nuc RBCs, dysplastic monocytes

63
Q

BM in JMML?

A

erythroid and myeloid hyperplasia, immat monocytic series, decreased megakaryocytes

64
Q

dx criteria for JMML?

A

clinical (need all): BAMBS

  • absence of bcr-abl fusion
  • monocytosis>1000/ul
  • blast percenage in periphaerl blood and BM <20%
  • splenomegaly
  • age <13

mutation analysis (need 1)

  • somatic or germline muts in PTPN11, K-RAS, N-RAS
  • germline homozygous for CBL or NF1 (with clinical BF)
  • monosomy 7

if no mutation (need 2) GFP10

  • WBC>10
  • GM-CSF hypersensitivty in grwoth colony assay
  • increased Hgb F
  • increased circ’ing myeloid precursors
65
Q

which pts may have spont regression of JMML?

A

noonan

66
Q

pre-trnslant tx for JMML?

A

6MP for mild
low-dose cytarabine for mod
high-dose cytarabine + fludarabine for severe

67
Q

relapse rate with JMML transplant?

A

high! like 30-40%

68
Q

4 diffs between JMML adn CML

A
  • CML= RAS activation, s. BCR-ABL in CML t(9;22)
  • Ph+ CML associated with priapism
  • alpha interferon can be used in CML
  • imatinib can be used for CML
69
Q

histiocyte=?

A

tissue cell

70
Q

langerhans cell histiocytosis due to?

A

dendritic cell proliferation

71
Q

macrophage prolif associated iwth what 4 diseases?

A

juvenile xanthogranuloma, erdheim-chester disease, rosai-dorfman disease, hemophagocytic lymphohistiocytosis

72
Q

macropahges, dendritic cells can arise from where?

A

bone marrow
fetal liver
yolk sac

73
Q

major mut in LCH?

A

BRAF-V600E in 65%

74
Q

LCH more common in M or F?

A

M

75
Q

median age of LCH pres?

A

2 yrs

76
Q

what does risk cateogry correlate to in LCH?

A

risk of death

77
Q

what constitutes high risk in LCH?

A

involvemetn of liver, BM, spleen

78
Q

multisystem LR LCH can involve?

A

any organs other than liver, BM, or spleen…like skin, bones, LNs, pituitary, lungs, etc

79
Q

CNS risk means what?

A

risk of developing neurodegen or pit involvement

80
Q

CNS LCH typically where?

A

in skull, pituitary

81
Q

MOST important stain in LCH?

A

CD207+

82
Q

other stain seen in LCH?

A

CD1a+

83
Q

see what on EM in LCH?

A

Birbeck granules

84
Q

LCH pres?

A 
BM:
cytopenias
hemophagocytosis (not HLH)
Spleen:
splenoemgaly
abdo pain
low plts
LIVER:
hepatomegaly
jaundice 
ascite
SKIN: rash
Bone fidnings
Pulmonary:
interstitial pattern with cysts, nodules, spont pneumonothorax
GI: diarrhea, fever, edema
endo:
DI, GH def, hypoT4, hypoadrenalism, hypogonadism
85
Q

rash in LCH?

A

pruritic, scaly, erytheamtous

86
Q

bone LCH can present how?

A

pain, swelling, mastoiditis

87
Q

jaw invovlement of LCH?

A

early eruption of teeth…“floating” teeth

88
Q

work-up for LCH? (6)

A
  • cbc
  • bma and bx if <2 yrs of age of if cytoepnias other than isolated anemia
  • Liver enzymes, GGT, bili, albumin, total protein, PT/PTT
  • sodium, urine/serum osmols if worried about DI
  • BRAF/V600E qPCR of blood
  • CXR
  • skeletal survey
  • Chest CT if abbnormal CXR or if <2 yrs
  • US if hepatomegaly…but also consider CT/mRI
  • PET/CT!
  • CT of skull if orbit or mastoid invovlement
  • MRI of brain if worried re: pit involvement
  • MRI spine when vertebra plana or neuro sx
89
Q

LCH tx for skin only?

A

oral mtx

sometimes vbl/pred if doesn’t work

90
Q

low risk LCH (bone +/- skin, LN, etc) tx?

A

vbl/pred x 12 mos

91
Q

High risk LCH tx?

A

vbl/pred/6MP

92
Q

role or radiotherpay or intra-lesion steroids in LCH?

A

only for spine/femur/non-CNS risk isoalted bone lesions

93
Q

LR LCH: morality? EFS?

A

Mort= 0% but EFS only 50% (lots of relapse)

94
Q

HR LCH mort?

A

10%, highest in pts who don’t respond to indcution therapy

95
Q

HR LCH EFS?

A

50% (lots of relapse)

96
Q

risk sites for neurodegen? (4)

A

pit, mastoid, orbital sphenoid, temporal bone lesions

97
Q

what helps decrease risk of DI in those with risk of neurodeg?

A

vbl/pred decreases risk from 40–> 20%

98
Q

when does neurodegen present in LCH?

A

may be acute or may be 20 yrs after initial dx

99
Q

other than DI, other symptoms of neurodegen in LCH? cause?

A 
ataxia
dysarthria
dysmetria
behviour changes
...brain infiltration from BRAF or MEK-mutated dendritic cells
100
Q

2nd+ line therapy in LR LCH?

A

cytarabine/clofarabine

BRAF/MEK inhibitors

101
Q

2nd+ line therapy in high risk LCH?

A

cytarabine/clofarabibne
2-CdA/ARA-C
BRAF/MEK inhibitors

102
Q

2nd+ line therapy in LCH with neurodegen?

A

BRAK/MEK inhibitors, cytarabine

103
Q

long term complciations in LCH?

A

hearing loss
othopedic defects
poor dentition
DI

104
Q

Rosai Dorfman caused by abnormalities in __ lineage

A

macrophage

105
Q

Rosai Dorfamn: pres?

A

LNs, skin soft tissue, nasal cavity, eye, bone= msot common spots

106
Q

finding in RD on histo?

A

emperiopolesis= viable lymphocytes trafficking thru histiocytes; CD163+, S100A+

107
Q

ddx for Rosai Dorfman? (5)

A 
reactive hyperplasia
ALPS
hemato-lymphoid malig
mets
storage disorders
LCH
JXG
108
Q

tx for Rosai Dorfman?

A
  • steroids (transient response)
  • clofaraine
  • if classic LAD no tx needed generally unless impingement of airway
109
Q

JXG: juvenile xanthogranuloma stains how?

A

CD 163

110
Q

JXG: usually presents where?

A

skin! can also have hepatosplenomegaly, kdieny invovlement..brain rare

111
Q

HLH: involves which cell lineages?

A

macrophage and lymphocyte

112
Q

surivival in HLH?

A

50% if tx’ed

113
Q

pathophys of HLH?

A

lymphocytes are unable to control dendritic cell stimulation, which should normaly be limited…overactive t-cells–> production of interferon gamma and inflammation

114
Q

genes in HLH?

A 
PRF1
UNC13D
STX11
RAB27A= griscelli syndrome
STXBP2
AP3B1= hermansky pudlak 2
115
Q

8 criteira for HLH (need 5)

A
  • fever
  • splenomegaly
  • cytopenias (2 lines)
  • increased triglycerides and/or low fibrinogen
  • hemophagocytosis
  • ferritin>500
  • elevated IL-2Ra>2400
  • decreased NK cell activity
  • or, gene mutations
116
Q

imp issues not included HLH crtieria?

A 
hepatitis, liver failure
renal failure
pulm failure
low BP, cardiac failure
CNS cahgnes: sz, alerted MS
117
Q

virus asscoaited with HLH?…tx modification?

A

EBV…early introduction of etop–> improved outcomes

118
Q

causes of seconary HLH? (8)

A 
EBV
CMV
Parvo
HHV8
Fungal 
bacterial 
ALCL
NK/T cell maligs
primary immune defs
acquired immune defs (chemo)
JIA
SLE
can get "synthetic" HLH after CAR Ts
119
Q

MAS=?

A

HLH iwth underlying autoimmune disease

120
Q

MAS feature?

A

IL-18 super high&raquo_space;>100k

121
Q

muts seen in MAS?

A

PRF1, MUNC

122
Q

HLH work up? 10

A 
CBC and smear
ferritin (often >10k)
interferon-gamma
IL-18
sIL-2 receptor alpha
TNF alpha
sCD163 (macrophage)
Bone marrow (hemophagocytosis though no sens/spec)
LFTs
renal function studies
AUS
brain MRI and /or LP
DIC panel
NK cell function
CD107 mobilization assay
perforin
XLP protein expression
WES
look for infections, including herpes viruses
eval for malig (PET)
eval for autoimmune disease
123
Q

signs taht the dx is NOT HLH?

A
  • prominent LAD: lymphoma? castlemans? HIV? mycobacterial?
  • sCD25>10-20x above normal and nromal/low ferritin: likelylymphoma
  • early isolated and aggressive CNS relapse…think malig
  • normal or slightly high sCD25 with very high ferritin…maybe infection or primary immune def
124
Q

HLH tx:

A
  • trend CXCL9, sCD25, ferrtin, LFTs, d-dimer
  • supportive care
  • etopsoide/dexamethasone x 8 weeks
  • IT mtx/hydroctor for CNS+ (sx or LP, MRI)
125
Q

HLH-2004 study showed?

A

no different in outcomes when adding cyclosporine upfront

126
Q

LP findings in CNS + HLH?

A

pleocytosis

increased protein

127
Q

if unsure of diagnosis of HLH or think possible autoimmuen issue, give what?

A

IVIG
plasmaphereiis
cytokine neutralization
ritux for EBV

128
Q

tx if HLH pt relapses before SCT?

A

alemtuzumab, IFN-gamma antibody= emapalumab

129
Q

indications for SCT in HLH?

A

genetic defect/familia
CNS+
realpse

130
Q

conditoning for HLH SCT?

A

RIC

131
Q

late effects of HLH?

A

leukemia if etop >3 g/m2
short stature
decreased fert

Haem/Onc (30 decks)

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