AML, ASPHO Flashcards
what are the BIG FOUR cytogen anomalies in AML?
t(8;21)= AML1-ETO;
inv (16)/t16;16) CBFB MYH11;
t(15;17) PML-RARA, variants
abnormal 11q23 MLL-partner
characteristics of AML with t(8;21)?:
Auer rods, chloromas, good prognosis
characteristics of AML with inv(16)/t(16;16)?
Eos with baso granules, chloromas, good prog
characteristics of AML with (15;17)?
granules/auer rods, DIC, bleeding, good prog with ATRA/arsenic
characteristics of AML with 11q23?
infant WBC/skin/CNS/gums t-AML after top II inh
in APML, cells blocked where during dev?
promeylocyte
what does ATRA do in AML?
overcomes the “differentiation block” at the promyelocyte stage
Give 5 major myeloid luekemia predispositions
Germline mutations in CEBPA, DDX41, RUNX1, ANKRD26, ETV6, GATA2…also bone marrow failure syndromes (fanconi anemia, Dyskeratosis congenita), T21, NF1 (JMML), Noonan (JMML)
2 marrow failure syndromes–> pancytopenia taht are associated with MDS/AML
Fanconi anemia, Dyskeratosis congenita
marrow failure syndrome–> anemia associated with MDS?
Diamond Blackfan Anemia
marrow failure syndrome–> neutropenia associated with MDS?
Schwachman-Diamond, Kostmann Syndrome
marrow failure syndrome–> thrombocytoepnia associated with MDS/AML?
congenital amegakaryocytic thrombocytopenia (MPL mutation)
environemntal causes of AML?
alkylating agents, radiation, toposiomerase II inhibitors (etoposide> anthracyclines)
What is the difference in latency between AML caused by different environemntal agents?
alkylating agents and radiation: 5-7 years from exposure, common preceding MDS
topoisomerase II inhibitors: short latency (1-2 years) from exposure, rare preceding MDS
give the diff in cytogenetics between AML caused by different envrionemntal agents?
alkylating agents and radiation: monosomy 7, 7q deletions, monosomy 5, 5q deletions
topoisomerase II inhibitors: 11q23 rearrangement most common, but t(8;21), t(15;17), t(9;22), and inv(16) can also occur
what tends to be more refractory to treatment? treatment-related AML/MDS or de novo AML/MDS?
treatment-related
AML and CML are most common in what age group?
> 50 years
concordance rate of AML/ALL in identical twins= monozygotic?
depends on age of first twin when diagnosed…<1 year: close to 100% concordance (suggests prenatal preleuekmic event= KMT2A and intrauterine transfer)….age 1-5: 10-20% concordance, most = clonal, longer-latency between twins A and B…likely a prenatal preleuk event (ETV6-RUNX1, RUNX1T1, eg, intrauterine transfer); relatively lower risk of cooperating hits (unlike KMT2A)….case 6+: minimal increased risk
concordance for ALL/AML in fraternal twins?
minimal increased risk
In AML, is age used to risk stratify? gender? race? BMI? pharmacogenomics? high WBC?
No for all…except WBC>10k is high risk in APL–> use anthracycline or gemtuzumab immediately….but note that non-whites have inferior survival, under-BMI and over-BMI have inferior survival as well
Give 4 favourable risk stratifiers in AML
T21 (esp if <4); APL with t(15;17); inv (16) or t(8;21); NPM1 or CEBPA mutations
Give 4 unfavourable risk stratifiers in AML
treatment-related AML, MDS-related AML, monosomy 7, 5 q deletion, abnormal 3q, FT3/ITD especially if high allelic ratio (0.4+), mutation, primary induction failure =>5% blasts after course 2
Intermediate risk AML can be subclassified into favourable or unfavourable how?
MRD by flow cytometry after first block of therapy…using threshold of 0.1%
describe M0 AML
“aml without differentiation”…not differentiated, no MPO expressed
describe M2 AML
AML with differenitation…8;21 translocation, lots of auer rods, chloromas, good prog
describe M3 AML
“APL= acute promyelocytic leukemia, hyergranular variant”, t(15;17), bleeding/DIC
describe M3v AML
APL, microgranular variant of M3
Describe M1 AML
“AML with minimal differentiation”…minimal diff, MPO detectable
describe M4 AML
“acute myelomonocytic AML”…myeloblasts + monoyctic blasts…peripheral monos too
Describe M4Eo
“AMML with eosinophilia”..abnormal eos precursors in marrow, inv(16)
M5 AML?
“acute monocytic leukemia”…MLL11q23! CNS involvement, chloromas, gingival hyperplasia
M6 AML?
“acute erythroblastic leuk”..rare in kids
M7 AML?
“acute megakaryoblastic leuk”…T21, gata 1 mutations, myelofibrosis common
WHO classification requires how many blasts?
20% blasts in marrow (unlike 30% in FAB)
which AML Dx’s can be made by yes/no qs on the WHO criteria?
Therapy-related AML= t-AML; DS-related AML, AML with abnormality (if recurreing molecular abnormality present, regardless of blast count), AML with MDS-related changes (if dysplasia, prior MDS and/or MDS-related mutation= monosomy 7, del 5q, etc)…if no to all, AML NOS and use FAB to subclassify
what is myeloid sarcoma
chloroma…can be manifestation of AML for any AML dx
give 6 mutations seen in AML
t(8;21) inv(16) t(9;11) MLLT3-KMT21 t(6;9) DEK-NUP214 inv(3) q3 mutations; t(3;3) gata2, MECOM megakaryblasts with t(1;22) RBM15-MKL1 mutated NPM1 biallelic mutations of CEBPA
give 3 pan-myeloid markers…which FAB type is an exception?
MPO, CD13, CD33…but not in M7 (no MPO, rare CD13)
what marker is specific to M7?
CD41a!!!!! 42, 61, no MPO!
which markers are specific to monocytic AML M4, 5
CD14! CD11b
which markers are specific to erythrocytic AML M6
glycophorin A= cd235a
APL markers? (M3)
- these cells AUTO-FLUORESCE…high on the diff axes even without diff Abs
- CD33 (think gemtuzumab), HLA-DR negative, CD34 neg
t(8;21) AML marker?
can often co-express CD19+
what is the RAM immunophenoytpe?
flow pattern characterized by bright CD56, min CD45, min CD38, neg HLA-DR–> poor prognosis
acute luekemia of ambigous lineage: 2 types?
- acute undifferenatied leukemia
- mixed phenotype acute leukemia
what do you see in acute undifferenatied leukemia?
no lineage-specific markers
what do you see in mixed phenotype acute leukemia?
-distinct populations of blasts from diff lineages and/or sngle opulation of blasts co-expressing antigens of multiple lineages
mixed phenotype acute leuekmia are often what?
MLL-rearranged (“mixed lineage leukemia); t/myeloid, b/myeloid most common mixtures
current standard of care for AML, first part?
-Remission induction = two 4-week courses of intense chemo: Doxo and Ara-C and Etop, 10 days for first course, 8 days for second course; gemtuzumab= anti-CD 33 immunotoxin for first course
what’s concernign about first part of AML tx?
- high risk of invasive infection
- only 75-80% go into complete remission
post-remission consolidation invovles what?
two ways: transplant or go to more chemo
- transplant all high risk patients with best available donor…don’t transplant the LR…typically occurs after 1 chemo consoliation course with high dose Ara-C (3 courses total)
- additional chemo intesnifiation courses 2-3, for any HR pts without any donor, and all LR pts…2 courses sufficient for LR with low MRD but 3 courses best for everyone else…usually give high dose Ara-C combine with drugs not used in induction like mitoxantrone, L-asp
role of CNS ppx in AML?
- much less intense than in ALL due to low rates of CNS realpse in AML
- if CNS + at dx, give weekly IT triples= MTx, Ara-C, HC) until CSF clears, then once per course
do you give cranial radiation in AML?
no
is there a role of maintenance chemo in AML?
no (excpet APML)
what’s the new guideline re: LP for AML?
wait until day 8 for LP to avoid contamination wtih peripheral blasts
AML patients should be admitted during periods of ?
neutropenia
bacterial infections that we worry about in AML?
strep viridans, gram neg enterics: E. coli, pseudomonas, klebsiella
what type of ppx is used in AML?
- bacterial ppx controversial
- septra for PCP
- fungal ppx used (fluco?)
- dexrazoxane for heart protection
use GCSF in AML?
no, due to concern re: promoting leukemia cell growth/survival
m3 AML= APML..high risk of what? do waht?
life-threatening bleeds due to DIC, fibrinolyisis + low plts…close monitoring of INR, PTT, fibirngeon, d-dimer, plts with liberal use of plts, cryo, FFP…give ATRA ASAP!
what are the features of differention syndrome? 5
Fever edema pulm infiltrates hypoxia resp distress hypotension renal dysufnction hepatic dysufnction effusions rash
higher risk of differentiation if what is present?
high WBC
tx differnetion syndrome how?
dexmathesone; hold ATRA until resolved
tx for APML other than ATRA?…benefit?
arsenic trioxide, helps reduce anthra exposure
diff between AML in kids and audlts?
in adults, usually starts iwth MDS
tx for MDS?
SCT
hyperluekocytosis=?
WBC>100k
hyperleuk more common in AML or ALL?
AML
organs affected in hyperleuk?
brain, lungs, kidney
manage hyperleuk how?
- treat leuk asap
- exhcnage trasnfusion vs. leukopheresis if symptoms
3 major late effects in AML?
- cardiomyopathy due to anthracyclins…doxo 450 mg/m2
- translplant-related MDS/AML from etoposide
- neurotox from high dose Ara-C
2 ways to reduce cardiotox
dexrazoxane, ACE inhibitors
indications for radiation in AML?
- emergent treatment for life-threatneing tx of chloromas, like spinal cord compression
- TBI is NOT a typical component of conditioning for SCT in AML
mutation in CML?
t(9;22) BCR-ABL1
3 phases of CML?
chronic phase (<10% blasts in marrow and blood)
- accelerated phase (10-19% in marrow or blood of at least 20% basophilis in blood)
- blast crisis= acute leukemia, either lymphoid or myeloid, at least 20% blasts in marrow
most CML patients diagnosed in which pahse?
chronic
CBC findings in CML at dx?
- high WBC, left shift
- may have anemia
- may have high plts
- basophilia
- may have eosinophilia
symptoms in CML?
- abdo pain
- dysphagia
- increased abdo girth, splenomegaly
- fatigue
- wt loss
- night sweats
- bleeding (rarely) because high plts–> acquired VWD
- leukostasis/priapsim
CML: blast crisis more likely to be AML or ALL?
AML in 2/3, ALL in 1/3
p190 bcr-abl fusion in?
pH+ ALL
p210 in?
CML
do what for recurrent or refractory chornic phase CML?
-try higher dose TKI and/or new TKI, then SCT if tx failure
for accelerated phase or blast crisis, do what?
TKI to get them back into chronic phase, then take them to transplant
1st gen TKI?
imatinib
2nd gen TKI?
Dasatinib, Nilotinib
newer TKI?
Ponatinib…active against T315I mutation
proven cure for CML?
SCT
major prog factor for SCT?
disease phase! CP>AP>BC
CML is VERY sensitive to waht? do what if relapse after HSCT?
graft vs. leukemia effect! …give DLI! especially if no GVH with first HST
when HSCT is used, typically do what after?
TKI maintenance to prevent relapse
3 ways to assess CML repsonse to tx?
- HEME response: normal counts, no HSM
- CYTOGENETIC response: bcr-abl fish on BMA…complete = no Ph+ vs. partial
- MOLECULAR: BCR-ABL qPCR on peripoheral blood…complete= PCR neg…major= bcr-abl: abl ratio <0.1% or 3 log reduction in copy #…this is different from complete molec response = 4.5 log or 0.0032%
do you need to do FISH BMA for CML if you can do pcr on peripheral blood?
no
check CML response how often?
q3 mos til major molec response then q3-6 mos
by what point should CML patient have major molec response = qPCR<0.1%
12 months
what if pt has suboptimal response or tx failure?
-do mutation testing to guide alternative TKI to use
