Myeloproliferative, Myelodysplastic, and Histiocytic Disorders, ASPHO Flashcards
(131 cards)
1
Q
Myelodysplastic syndromes: most common cytogenetics? (3)
A
Monosomy 7!!!> trisomy 8= trsiomy 21….may have non-down MDS with germline mosaiscism
2
Q
what is strongest predictor for poor outcome in MDS?
A
3 or more chromosomal aberrations
3
Q
secondary MDS can occur with what? 3
A
chemo
radiation
inherited BMF disorders
familial diseases
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
5
Q
3 germline mutations–> risk of MDS?
A
RUNX1
CEBPA
GATA2
6
Q
which germlime mutations predispose AML
A
RUNX1
CEBPA
7
Q
GATA germline mutation associated with?
A
immune def (absent/decreased monos or macs)…more likely to get mycobacterial infection, HPV
8
Q
prevalence of MDS?
A
1-4 per million
9
Q
MDS median age?
A
6.8 years
10
Q
MDS seen in boys vs. girls?
A
=
11
Q
MDS: more advanced disease seen when?
A
older kids
12
Q
what is refractory cytopenia of childhood?
A
peripheral blood blasts <2% or BM blasts <5%
13
Q
what is refractory anemia with excess blasts?
A
PB blasts 2-19% adn or BM blasts 5-19%
14
Q
what is refractory anemia with excess blasts in transformation?
A
peripheral blasts and or BM blasts 20-29%
15
Q
MDS-related neoplasms?
A
JMML, CML, BCR-ABL neg CML…and in Down sydrnme: TAM, MDS/AML
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
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)
18
Q
refractory anemia with excess blasts in kids: give one way diff from in adults
A
counts may be stable for months
19
Q
RAEB: treat how?
A
sometimes AML type chemo not needed before going for BMT
20
Q
what might you seen on histo in MDS?
A
abrnomal erythroyid maturation, megalbolastic erythroidmaturation, dysplastic megakaryocyte, nuclear bridging in neutrophils
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
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
23
Q
OS if do Allo BMT in MDS with no prior AML therapy?
A
60-70%
24
Q
what is associatd iwth better survival with BMT for MDS pts?
A
> 12% bone marrow blasts
25
long term issues of AML therpay and BMT for MDS?
cytopenias
secondary leuekmia
deccreased growth
decreased fertility
26
give 3 categories of myeloproliferative disorders
Down syndrome associated, JMML, CML
27
what pathway's mutations= drivers in JMML?
MAPK pathway muations
28
down syndrome patient develops ___ somatic mutation in fetal ___--> abrnomal ___ production
GATA1; liver; megakaryocyte
29
can you distinguish because TAM blast and DS-AMKL blast?
no
30
relevatn GATA 1 mutations occur in which exon? seen in which diseases?
2; TAM and DS-AMKL
31
other than GATA-1 which other mutations do you seen in DS-AMKL?
```
trisomy 8
JAK2/3
CTCR
EZH
MPL
SH2B3
RAS pathway
```
32
TAM: __% of all children with DS
10%
33
TAM: what percent early death?
15%
34
if you screen for TAM in DS waht woudl the prevalence be in this case?/
30%
35
median onset age for TAM in DS?
1.6 months
36
TAM: prog?
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
37
RFs for death in children with TAM (4)
- Pre-term delivery
- congestive heart/liver failure
- hyperviscosity/hyperleukocytosis
- DIC
- pleural and cardiac effusions
- organomegaly
38
which study make risk categories for TAM?
COGA2971
39
OS in low risk TAM?
92%
40
OS in iintermed risk TAM?
77%
41
OS in high risk TAM?
51%
42
BM in TAM: hypo or hypercellular? what is common to see? blasts %?
can be either; fibrosis; 30% (range varies)
43
immunotype with TAM typically more ___ than in AML
mature
44
immunophenotype in TAM?
```
CD33= myeloid
CD45= pan leuk
CD52= pan leuk
+/- CD34, 117 = HSC
+/- CD41, 42b, 61= plts
```
45
how do you treat TAM?
most can be observed.
| IF: hydrops, organ failure, hyperleuk: exchange transfusion, leukaphersis, cytarabine 1 mg/kg q12h x 7 days
46
outcome for DS AML?
89% disease free survival
47
what 2 things would make outcome worse in DS AML?
```
age >4 (EFS 33% vs 81%
normal karyotype (only 42% survival)
```
48
ALL: AML rate in DS vs. non-DS?
1.7...6.5
49
long term issues in DS-AML?
cytopenias, seconary leukemia
50
In JMML, MAPK pathway involved: waht are these steps?
RAS-> RAF-> MEK-> ERK
51
2 syndromes associated with JMML?
NF (10-15%)...get loss of WT NF1. (200-500x more likely to get JMML with this!)...and Noonan syndrome or leopard syndrome (35%)
52
what germline muations are associated with Noonan or Leopard JMML?
PTPN11/SHP-2
53
Give 6 muations seen in JMML,and assocated syndrome
```
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
about ___ of JMML patients with germline mutations have ___ mutations leading to a ___ prog
1/3; secondary; worse
55
JMML with Noonan: age? survival? tx? myelopoeisis is ____...cytogenetics?
younger (vs somatic mutations); better survival vs somatic; occasional spont resolution!...polyclonal...normal
56
JMML % of all leuks? prev?
1%; 1.2 per million
57
JMML median age of dx?
2 years
58
JMML boys vs. girls?
male predom 2.5: 1
59
JMML: clinical pres?
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
outcome in JMML?
EFS 52% (rare spont resolution)
61
more likely to have spont resoultion in JMML if?
- 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
peripheral blood smear in JMML?
incresaed immat myeloid cells, nuc RBCs, dysplastic monocytes
63
BM in JMML?
erythroid and myeloid hyperplasia, immat monocytic series, decreased megakaryocytes
64
dx criteria for JMML?
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
which pts may have spont regression of JMML?
noonan
66
pre-trnslant tx for JMML?
6MP for mild
low-dose cytarabine for mod
high-dose cytarabine + fludarabine for severe
67
relapse rate with JMML transplant?
high! like 30-40%
68
4 diffs between JMML adn CML
- 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
histiocyte=?
tissue cell
70
langerhans cell histiocytosis due to?
dendritic cell proliferation
71
macrophage prolif associated iwth what 4 diseases?
juvenile xanthogranuloma, erdheim-chester disease, rosai-dorfman disease, hemophagocytic lymphohistiocytosis
72
macropahges, dendritic cells can arise from where?
bone marrow
fetal liver
yolk sac
73
major mut in LCH?
BRAF-V600E in 65%
74
LCH more common in M or F?
M
75
median age of LCH pres?
2 yrs
76
what does risk cateogry correlate to in LCH?
risk of death
77
what constitutes high risk in LCH?
involvemetn of liver, BM, spleen
78
multisystem LR LCH can involve?
any organs other than liver, BM, or spleen...like skin, bones, LNs, pituitary, lungs, etc
79
CNS risk means what?
risk of developing neurodegen or pit involvement
80
CNS LCH typically where?
in skull, pituitary
81
MOST important stain in LCH?
CD207+
82
other stain seen in LCH?
CD1a+
83
see what on EM in LCH?
Birbeck granules
84
LCH pres?
```
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
rash in LCH?
pruritic, scaly, erytheamtous
86
bone LCH can present how?
pain, swelling, mastoiditis
87
jaw invovlement of LCH?
early eruption of teeth..."floating" teeth
88
work-up for LCH? (6)
- 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
LCH tx for skin only?
oral mtx
| sometimes vbl/pred if doesn't work
90
low risk LCH (bone +/- skin, LN, etc) tx?
vbl/pred x 12 mos
91
High risk LCH tx?
vbl/pred/6MP
92
role or radiotherpay or intra-lesion steroids in LCH?
only for spine/femur/non-CNS risk isoalted bone lesions
93
LR LCH: morality? EFS?
Mort= 0% but EFS only 50% (lots of relapse)
94
HR LCH mort?
10%, highest in pts who don't respond to indcution therapy
95
HR LCH EFS?
50% (lots of relapse)
96
risk sites for neurodegen? (4)
pit, mastoid, orbital sphenoid, temporal bone lesions
97
what helps decrease risk of DI in those with risk of neurodeg?
vbl/pred decreases risk from 40--> 20%
98
when does neurodegen present in LCH?
may be acute or may be 20 yrs after initial dx
99
other than DI, other symptoms of neurodegen in LCH? cause?
```
ataxia
dysarthria
dysmetria
behviour changes
...brain infiltration from BRAF or MEK-mutated dendritic cells
```
100
2nd+ line therapy in LR LCH?
cytarabine/clofarabine
| BRAF/MEK inhibitors
101
2nd+ line therapy in high risk LCH?
cytarabine/clofarabibne
2-CdA/ARA-C
BRAF/MEK inhibitors
102
2nd+ line therapy in LCH with neurodegen?
BRAK/MEK inhibitors, cytarabine
103
long term complciations in LCH?
hearing loss
othopedic defects
poor dentition
DI
104
Rosai Dorfman caused by abnormalities in __ lineage
macrophage
105
Rosai Dorfamn: pres?
LNs, skin soft tissue, nasal cavity, eye, bone= msot common spots
106
finding in RD on histo?
emperiopolesis= viable lymphocytes trafficking thru histiocytes; CD163+, S100A+
107
ddx for Rosai Dorfman? (5)
```
reactive hyperplasia
ALPS
hemato-lymphoid malig
mets
storage disorders
LCH
JXG
```
108
tx for Rosai Dorfman?
- steroids (transient response)
- clofaraine
- if classic LAD no tx needed generally unless impingement of airway
109
JXG: juvenile xanthogranuloma stains how?
CD 163
110
JXG: usually presents where?
skin! can also have hepatosplenomegaly, kdieny invovlement..brain rare
111
HLH: involves which cell lineages?
macrophage and lymphocyte
112
surivival in HLH?
50% if tx'ed
113
pathophys of HLH?
lymphocytes are unable to control dendritic cell stimulation, which should normaly be limited...overactive t-cells--> production of interferon gamma and inflammation
114
genes in HLH?
```
PRF1
UNC13D
STX11
RAB27A= griscelli syndrome
STXBP2
AP3B1= hermansky pudlak 2
```
115
8 criteira for HLH (need 5)
- 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
imp issues not included HLH crtieria?
```
hepatitis, liver failure
renal failure
pulm failure
low BP, cardiac failure
CNS cahgnes: sz, alerted MS
```
117
virus asscoaited with HLH?...tx modification?
EBV...early introduction of etop--> improved outcomes
118
causes of seconary HLH? (8)
```
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
MAS=?
HLH iwth underlying autoimmune disease
120
MAS feature?
IL-18 super high >>>100k
121
muts seen in MAS?
PRF1, MUNC
122
HLH work up? 10
```
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
signs taht the dx is NOT HLH?
- 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
HLH tx:
- trend CXCL9, sCD25, ferrtin, LFTs, d-dimer
- supportive care
- etopsoide/dexamethasone x 8 weeks
- IT mtx/hydroctor for CNS+ (sx or LP, MRI)
125
HLH-2004 study showed?
no different in outcomes when adding cyclosporine upfront
126
LP findings in CNS + HLH?
pleocytosis
| increased protein
127
if unsure of diagnosis of HLH or think possible autoimmuen issue, give what?
IVIG
plasmaphereiis
cytokine neutralization
ritux for EBV
128
tx if HLH pt relapses before SCT?
alemtuzumab, IFN-gamma antibody= emapalumab
129
indications for SCT in HLH?
genetic defect/familia
CNS+
realpse
130
conditoning for HLH SCT?
RIC
131
late effects of HLH?
leukemia if etop >3 g/m2
short stature
decreased fert
