Myeloproliferative, Myelodysplastic, and Histiocytic Disorders, ASPHO Flashcards
Myelodysplastic syndromes: most common cytogenetics? (3)
Monosomy 7!!!> trisomy 8= trsiomy 21….may have non-down MDS with germline mosaiscism
what is strongest predictor for poor outcome in MDS?
3 or more chromosomal aberrations
secondary MDS can occur with what? 3
chemo
radiation
inherited BMF disorders
familial diseases
give 4 inherited bone marrow failure syndromes that can lead to refracotry cytopenia of childhood
fanconi anemia dyskeratosis congenita Down syndrome schwachman diamond blackfan diamond
3 germline mutations–> risk of MDS?
RUNX1
CEBPA
GATA2
which germlime mutations predispose AML
RUNX1
CEBPA
GATA germline mutation associated with?
immune def (absent/decreased monos or macs)…more likely to get mycobacterial infection, HPV
prevalence of MDS?
1-4 per million
MDS median age?
6.8 years
MDS seen in boys vs. girls?
=
MDS: more advanced disease seen when?
older kids
what is refractory cytopenia of childhood?
peripheral blood blasts <2% or BM blasts <5%
what is refractory anemia with excess blasts?
PB blasts 2-19% adn or BM blasts 5-19%
what is refractory anemia with excess blasts in transformation?
peripheral blasts and or BM blasts 20-29%
MDS-related neoplasms?
JMML, CML, BCR-ABL neg CML…and in Down sydrnme: TAM, MDS/AML
which non-heme disorders can cause MDS? (4)
infection, eg parvovrius vitamin b12 def folate def vit E def metabolic disorders like mevalonate kinase def JIA with MAS Persons= mito disorder
heme disordrs associated with MDS?
inherited BMF syndromes
severe AA
RCC
paroxysmal nocturnal hemoglobinuria with BM failure
-B-cell ALL pre-phase
-hemophagocytic lymphohistiocytosis
-autoimmune lymphoproliferative syndrome(s)
refractory anemia with excess blasts in kids: give one way diff from in adults
counts may be stable for months
RAEB: treat how?
sometimes AML type chemo not needed before going for BMT
what might you seen on histo in MDS?
abrnomal erythroyid maturation, megalbolastic erythroidmaturation, dysplastic megakaryocyte, nuclear bridging in neutrophils
tx MDS how?
- 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
problem with AML therapy in MDS?
high treatment related mortality in MDS (40%!)…3 yr OS only 15% for MDS…vs 16% adn 35% in AML
OS if do Allo BMT in MDS with no prior AML therapy?
60-70%
what is associatd iwth better survival with BMT for MDS pts?
> 12% bone marrow blasts
long term issues of AML therpay and BMT for MDS?
cytopenias
secondary leuekmia
deccreased growth
decreased fertility
give 3 categories of myeloproliferative disorders
Down syndrome associated, JMML, CML
what pathway’s mutations= drivers in JMML?
MAPK pathway muations
down syndrome patient develops ___ somatic mutation in fetal ___–> abrnomal ___ production
GATA1; liver; megakaryocyte
can you distinguish because TAM blast and DS-AMKL blast?
no
relevatn GATA 1 mutations occur in which exon? seen in which diseases?
2; TAM and DS-AMKL
other than GATA-1 which other mutations do you seen in DS-AMKL?
trisomy 8 JAK2/3 CTCR EZH MPL SH2B3 RAS pathway
TAM: __% of all children with DS
10%
TAM: what percent early death?
15%
if you screen for TAM in DS waht woudl the prevalence be in this case?/
30%
median onset age for TAM in DS?
1.6 months
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
RFs for death in children with TAM (4)
- Pre-term delivery
- congestive heart/liver failure
- hyperviscosity/hyperleukocytosis
- DIC
- pleural and cardiac effusions
- organomegaly
which study make risk categories for TAM?
COGA2971
OS in low risk TAM?
92%
OS in iintermed risk TAM?
77%
OS in high risk TAM?
51%
BM in TAM: hypo or hypercellular? what is common to see? blasts %?
can be either; fibrosis; 30% (range varies)
immunotype with TAM typically more ___ than in AML
mature
immunophenotype in TAM?
CD33= myeloid CD45= pan leuk CD52= pan leuk \+/- CD34, 117 = HSC \+/- CD41, 42b, 61= plts
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
outcome for DS AML?
89% disease free survival
what 2 things would make outcome worse in DS AML?
age >4 (EFS 33% vs 81% normal karyotype (only 42% survival)
ALL: AML rate in DS vs. non-DS?
1.7…6.5
long term issues in DS-AML?
cytopenias, seconary leukemia
In JMML, MAPK pathway involved: waht are these steps?
RAS-> RAF-> MEK-> ERK
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%)
what germline muations are associated with Noonan or Leopard JMML?
PTPN11/SHP-2
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
about ___ of JMML patients with germline mutations have ___ mutations leading to a ___ prog
1/3; secondary; worse
JMML with Noonan: age? survival? tx? myelopoeisis is ____…cytogenetics?
younger (vs somatic mutations); better survival vs somatic; occasional spont resolution!…polyclonal…normal
JMML % of all leuks? prev?
1%; 1.2 per million
JMML median age of dx?
2 years
JMML boys vs. girls?
male predom 2.5: 1
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
outcome in JMML?
EFS 52% (rare spont resolution)
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%)
peripheral blood smear in JMML?
incresaed immat myeloid cells, nuc RBCs, dysplastic monocytes
BM in JMML?
erythroid and myeloid hyperplasia, immat monocytic series, decreased megakaryocytes
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
which pts may have spont regression of JMML?
noonan
pre-trnslant tx for JMML?
6MP for mild
low-dose cytarabine for mod
high-dose cytarabine + fludarabine for severe
relapse rate with JMML transplant?
high! like 30-40%
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
histiocyte=?
tissue cell
langerhans cell histiocytosis due to?
dendritic cell proliferation
macrophage prolif associated iwth what 4 diseases?
juvenile xanthogranuloma, erdheim-chester disease, rosai-dorfman disease, hemophagocytic lymphohistiocytosis
macropahges, dendritic cells can arise from where?
bone marrow
fetal liver
yolk sac
major mut in LCH?
BRAF-V600E in 65%
LCH more common in M or F?
M
median age of LCH pres?
2 yrs
what does risk cateogry correlate to in LCH?
risk of death
what constitutes high risk in LCH?
involvemetn of liver, BM, spleen
multisystem LR LCH can involve?
any organs other than liver, BM, or spleen…like skin, bones, LNs, pituitary, lungs, etc
CNS risk means what?
risk of developing neurodegen or pit involvement
CNS LCH typically where?
in skull, pituitary
MOST important stain in LCH?
CD207+
other stain seen in LCH?
CD1a+
see what on EM in LCH?
Birbeck granules
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
rash in LCH?
pruritic, scaly, erytheamtous
bone LCH can present how?
pain, swelling, mastoiditis
jaw invovlement of LCH?
early eruption of teeth…“floating” teeth
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
LCH tx for skin only?
oral mtx
sometimes vbl/pred if doesn’t work
low risk LCH (bone +/- skin, LN, etc) tx?
vbl/pred x 12 mos
High risk LCH tx?
vbl/pred/6MP
role or radiotherpay or intra-lesion steroids in LCH?
only for spine/femur/non-CNS risk isoalted bone lesions
LR LCH: morality? EFS?
Mort= 0% but EFS only 50% (lots of relapse)
HR LCH mort?
10%, highest in pts who don’t respond to indcution therapy
HR LCH EFS?
50% (lots of relapse)
risk sites for neurodegen? (4)
pit, mastoid, orbital sphenoid, temporal bone lesions
what helps decrease risk of DI in those with risk of neurodeg?
vbl/pred decreases risk from 40–> 20%
when does neurodegen present in LCH?
may be acute or may be 20 yrs after initial dx
other than DI, other symptoms of neurodegen in LCH? cause?
ataxia dysarthria dysmetria behviour changes ...brain infiltration from BRAF or MEK-mutated dendritic cells
2nd+ line therapy in LR LCH?
cytarabine/clofarabine
BRAF/MEK inhibitors
2nd+ line therapy in high risk LCH?
cytarabine/clofarabibne
2-CdA/ARA-C
BRAF/MEK inhibitors
2nd+ line therapy in LCH with neurodegen?
BRAK/MEK inhibitors, cytarabine
long term complciations in LCH?
hearing loss
othopedic defects
poor dentition
DI
Rosai Dorfman caused by abnormalities in __ lineage
macrophage
Rosai Dorfamn: pres?
LNs, skin soft tissue, nasal cavity, eye, bone= msot common spots
finding in RD on histo?
emperiopolesis= viable lymphocytes trafficking thru histiocytes; CD163+, S100A+
ddx for Rosai Dorfman? (5)
reactive hyperplasia ALPS hemato-lymphoid malig mets storage disorders LCH JXG
tx for Rosai Dorfman?
- steroids (transient response)
- clofaraine
- if classic LAD no tx needed generally unless impingement of airway
JXG: juvenile xanthogranuloma stains how?
CD 163
JXG: usually presents where?
skin! can also have hepatosplenomegaly, kdieny invovlement..brain rare
HLH: involves which cell lineages?
macrophage and lymphocyte
surivival in HLH?
50% if tx’ed
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
genes in HLH?
PRF1 UNC13D STX11 RAB27A= griscelli syndrome STXBP2 AP3B1= hermansky pudlak 2
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
imp issues not included HLH crtieria?
hepatitis, liver failure renal failure pulm failure low BP, cardiac failure CNS cahgnes: sz, alerted MS
virus asscoaited with HLH?…tx modification?
EBV…early introduction of etop–> improved outcomes
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
MAS=?
HLH iwth underlying autoimmune disease
MAS feature?
IL-18 super high»_space;>100k
muts seen in MAS?
PRF1, MUNC
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
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
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)
HLH-2004 study showed?
no different in outcomes when adding cyclosporine upfront
LP findings in CNS + HLH?
pleocytosis
increased protein
if unsure of diagnosis of HLH or think possible autoimmuen issue, give what?
IVIG
plasmaphereiis
cytokine neutralization
ritux for EBV
tx if HLH pt relapses before SCT?
alemtuzumab, IFN-gamma antibody= emapalumab
indications for SCT in HLH?
genetic defect/familia
CNS+
realpse
conditoning for HLH SCT?
RIC
late effects of HLH?
leukemia if etop >3 g/m2
short stature
decreased fert