ALL, ASPHO Flashcards
Name 2 ALL abnormalities that can arise in utero
- KMT2A=ALL
- Hyperdiploid ALL
What percent of baby with ETV/RUNX1 detectable on cord blood will develop ALL?
1%
For kids under 15, what % of leukemias are ALL? AML?
ALL=80%
AML=15%
For kids 15-19, what % of leukemias are ALL? AML?
ALL= 56% AML= 31%
what’s the peak age for ALL dx? AML?
ALL= 2-4; AML= no peak incidence
Childhood leuk represents what % of all new childhood cancer cases?
26.1%
Give 3 factors that have led to improved ALL survival
- CNS ppx started in 1970s
- Intensified therapies for identified risk groups with higher rates of relapse
- Improved supportive care
Give 6 ALL predispo syndromes
DNA CBNNRKL DNA NotBadLuck Down Syndrome NF1 Ataxia Telangiectasia (T-ALL) Noonan Syndrome Bloom Syndrome Li Fraumeni Syndrome
Also:
Constitutinal Robertsonia Translocation, Nijmegen Breakage syndrome, Constitutional Mismatch repair deficiencies, Klinefelter sydnrome
Risk increase for leukemia if T21?
20x
Higher risk of leukemia in T21 pertains to what age?
First 3 decades of life
Although the relative risk of AML is ___ than ____, ____ is more common than ___ except in the ___ yr of life
- higher
- ALL
- DS-ALL
- DS-AML
- first
what percent of children with B-precursor ALL have DS?
3%
Which common sentinel genetic alterations in ALL are less common if DS-ALL?
KMT2A translocations
ETV-RUNX1
BCR/ABL rearrangement
Trisomy 4+10
which sentinel genetic alteration in ALL is more common if DS-ALL?
CRLF2 overexpression+ accompanying JAK and IL7R mutations
which genetic mutation has better outcome in DS-ALL than non DS ALL?
CRLFr
in general who does better non-DS or DS ALL?
non-DS…unless you discount common genetic mutations, then they are the same
there’s more mortality due to what in DS-ALL?
toxic related death
give 5 germline mutations predisposing towards ALL
PAX5 G183S mutations TP53 (hypodiploid) ETV6 (hyper) FANCA (hypo) MLL3 (hypo)
what percent of childhood leukemia is associated with deleterious germline mutations?
~5%
Discuss concordance rates for ALL in identical twins by age…why? usually due to what genetic alteration in infants?
<12 mos: close to 100%
after 12 mos: 10-15%….concordance in infant twins due to early chrom translocations and transplacental trasnfer or leuk/preleuk cells to other twin…KMT2A
Give symptoms/signs of ALL
- Bone pain/refusal to walk
- Decreased energy, pallor, loss of appetite
- Adenoapthy/HSM
- mediastinal mass, SOB, unable to lie flat
- headache, neck pain, sz, CN Palsy if CNS invovled
- painless enlarged testes
TLS associated with what type of ALL
t-cell
risks of hyperleuk more in ALL or AML?
AML
What can genotype of ALL help determine? (3)
prognosis, tx stratification, and soemtimes use of targeted therapies (eg TKI for Ph+ ALL)
WHat defines NCI risk group?
age and WBC (doesn’t apply to T_ALL)…wbc and age at dx NOT prognostic in T-ALL!
what’s the strongest prognostic factor
response to therapy
About what % are SR and what % are high risk in B-ALL?
about 2/3 SR and about 1/3 HR
What indicates SR in B-ALL?
age 1.00-9.99 years; WBC<50,000/microliter
EFS in SR B-ALL?
90%
WHat indicates HR in B-ALL?
age>10 years OR WBC>50,000/microliter
5-yr EFS in HR B-ALL in non-infants?
75-80%
what % of B-ALL patients are infants? outcomes are ___
1%; poor
Describe principle re: giving diff treatment to HR groups:
Improviing outcomes by giving more intense tx to HR groups that LR groups would otherwise not need
what is the relevance of t(1;19) in B-ALL?
used to be associated with poor outcome, but now irrelevant if give more intense therapy
How does BFM redefine initial risk?
Gives 7 days prophase of steroids with one IT mtx to determine initial risk, then refines based on MRD and some genetics
what percent of ALL cases are B precursor?
80-85%
What marker distinguishes lymphoid from myeloid?
CD45 positive in lymphoid
other than CD45 + for lymphoid, what else do you see in B-precurosr ALL? (3) +3
CD19+, CD22+, CD79a+…MOST are also CD10+= cALLA+; TdT+, HLA-DR+
About half of KMT2A-R ALL lack what expression?
CD10
early B lineage ALLs are negative in what?
cytoplasmic immunoglobulin=cIg
Pre-B ALL is cIg ____ and sIg ____
pos, neg
co-expression of what myeloid antigens is common in B-precurosr ALL?
CD13,CD33…this does NOT make if acute leukemia of ambiguous linegage or mixed phenotype acute leuk!
what % of ALL are T?
15%
T-cell ALL associated with ___ WBC and ___ ___ and increased risk of ____
high; mediastinal masses; TLS
What markers does T-ALL express? (3) and often what? 4
CD3= cCD3+, sCD3+, TdT+
…also: CD2, 4, 7, 8
In T-Cell ALL what expression is variable?
CD10
most T-Cell ALL are HLA-DR ___
neg
Early Thymic precursor T-cell ALL= ETP has what markers?
CD3+, CD7+, weak CD5….also CD177+, CD34+, HLA-DR+, CD13+, CD33+, CD11b+…Cd1a neg, CD8 neg
T-cell ALL ____ to clear MRD by end of induciton
slower….end of consoliation MRD more important than EOI mRD
MPAL= mixed phenotype acute leuk= both myeloid and lymphoid features…reqiuires what?
expression of MPO= myeloperoxidase and B or T cell features
T-cell MPAL tends to overalp with what?
ETP ALL
B-cell MPAL has a hihg incidence of ___ driven leuk
ZNf384
high occurence of what in MPAL?
BCR/ABL1
Bilineal leukemia= ___population of __ and __ blasts…___ prog
distinct, myeloid, lymhoid…poor
should initial therpay with ___ for MPAL
ALL
What are the criteria for myeloid lineage assignment in MPAL?
MPO+ or monocytic differentiation= at least 2 of the following: nonspecific esterase, CD11c, Cd14, CD64, lysozyme
what are the criteria for T-lineage in MPAL?
Strong cytoplasmic CD3 or surface CD3
what are the criteria for B lineage assignment in MPAL?
strong CD19 with at least one of : CD79a, cytoplasmic CD22, CD10…OR weak CD19 with at least 2 of CD79a, cytoplasmic CD22, or CD10
study for using ALL therapy in MPAL?
retrospective study Orgel et al 2020…better OS
what are the 4 cytogenetic aneuplodies?
hyperdiploidy, low hypodiploidy, haploidy, ,masked hypodiploidy
hyperdiploidy: 1-associated iwth what gains/losses? 2- incidence? outcome? age relevance?
gain of 4 and 10= double trisomy; ~25%= most common, excellent, less common in pts >15
low hypodiploidy: asscoaited with waht spceific gains/losses?
modal number 32-39 chromsomes, <3%, poor with modern chemo, no benefit to transplant
haploidy asscociatd with what specific gains/losses? incidence? outcome? comment?
<32 chroms, <3%, poor iwth modern chemo, no benefit to transplant
masked hypodiploidy…what does this mean? incidence? outcome? benefit of hsct?
can masquerade as hyperdiploidy..e.xperienced cytogeneticist can ID using SNP assays…<3%..poor with modern chemo…no benfit to HSCT
give 5 molecular sentinel translocations in B-ALL
ET6-RUNX1, TCF3-PBX1, KMT2A rearranged, BCR-ABL1, Myc fused to IgH, IgI or Igk
ETV6-RUNX1: give translocation, incidence, outocme, comments
t(12;21)(p13, q2) (cryptic); 28%= most common, excellent, less common in pts>15yrs
TCF3=PBX1: give translocation, incidence, outcome, comments
t(1;19)(q23;p13); 5% but 25% in pre B ALL, nuetral, poor outocme in older studies iwth higher incidence of CNS disease and CNS relapse
KMT2A rearranged: give translocation, incidence, outocme, comments
t9v;11) (v;q23); t(11;v)(q23;v)…3%, poor but less signficant than in past, 75% of infants <1 yr have KMT2a-R
BCR-ABL1: give transloc, incidence, outcome, comments
t(9;22) (q32;q11); 4%, poor with chemo alone, rate increases iwth age/treat with TKI+ chemo
Myc fused to IgH, IgI or Igk: give translocation, icndience, outcome, comments
t(8;14)(q24;q32); t2(2;8)(p11;q24); t(8;22)(q24;q11)….rare…treat like burkitt NHL…burkitt leukemia
NCI SR in B-lineage ALL: more than half have what cytogen?
Triple trisomy, ETV-RUNX1
NCI HR in B-lineage ALL: more than half have what cytogen
neutral…but more of BCR-ABL and other less favourable cytogen
what is Ph-like ALL?
defined by activated kinase gene expression similar to that of BCR-ABL1 rearranged Ph+ ALL…often associated with deletions of IKZF1
Ph-like ALL comprimses what % of HR B-ALL in kids/adolescents?
15-20%
pts with Ph-like ALL often present with WBC of what? what about EOI MRD? fare how with reg chemo?
WBC> 50,000/uL, high rate of MRD at EOI, relapse with reg chemo
in ph-like all, what can help iwth EFS and OS?
TKIs
in ph-like all, have >— different fusions involving 19 genes fo what types?
> 70; kinase, cytokine, cytokine receptor genes
in ph-like all, sequence mutation or structural alterations seen in what 5 genes?
SCIRF
SH2B3, CRLF2, IL7R, RAS, FLT3
Dasatinib, imatinib work best for what kinase mutations in Ph-like ALL?
ABL1, ABL2, CSF1R, PDGFRB
Ruxolitinib works best for which kinase muations in ph-like all?
CRLF2, JAK2, EPOR
about 50% of pts with ph-like all will have what rearranged?
CRL2…also often have JAK2 or JAK1 pt mutations
15-20% of ph-like all pts have what rearrangmeents?
jak2, epor
10-15% of ph-like have what alterations?
aBL class= ABL1, ABL2, PDGFRB, CSF1R
ph-like all: lower 3 yr EFS shown in what sutdy?
COG AALL0232
COGAALL0232 showed what with regards to CRLF2-rearragment?
do equally poorly whether or not prseent
3 yr EFS in Ph-like ALL? source of study?
65%; AALL0232
if MRD+ with pH-All, have ___ ___ outcomes
even worse
in infant all, what’s the relevance of having KTM2A-R?
EFS is only 37-49% if present vs 69-95% otherwise
how does infant ALL tend to present?
high WBC, extramedullary sites like chloromas, CNS disease, skull based disease– should image if suspicious!
infant ALL is neg in __
CD10
2 ways to risk classify infant ALL?
age, KMT2A-R status
in infant ALL< KMT2A-R tends to always be present in infants < how many days old?
<100 days
3 path features of infant all?
high expression. ofFLT3, global hypermethylation, abnormal histone modficiation
in infant all, intensive multi agent therapy requires max ___ ___
supportive care…eg foley placement during chemo
is EOI MRD prognostic in T-cell ALL?
no
is age prognostic in t-cell all? WBC?
no, no
what is most prognostic in t-all?
EOC MRD
T-ALL presents with higher rates of what 3 things?
mediastinal mass, coagulopathy, TLS
in T-ALL, which genetic lesions associated iwth prog?
none
study that looked at nelarabine in t-all?
AALL0434
AALL0434 showed __- outcomes in T-ALL, and ___ didn’t really matter
excellent, ETP= early thymic precursor
what’s associated with higher risk of TLS?
higher WBC
what’s the gen approach to SR ALL in terms of chemo?
- 4 week 3-drug (Dex) induction
- 4 week oral consolidation with intensive weekly IT
- 8 week IM with escalating IV Mtx without rescue
- 8-week DI phase with standard re-consolidation
- IM 2 with escalating IV MTX (sometimes)
- Maint with q4 week steroids/vcr pulses…as of 2020, q12 week pulses
what’s the gen appraoch to HR ALL (and T-ALL)?
- 4-week 4-drug induction (Pred 28 or Dex 14)
- 8 week intensive IV consolidation with intensive weekly IT
- 8 week IM wiht HD Mtx or capizzi IV Mtx + ASNase (T-ALL)
- 8 week DI phase with intesnive re-consoidation
- IM 2 Capizzi MTX (soemtimes)
- Main with q4week steroids/VCR pulses…as of 2020, q12week pulses
why do older HR kids get pred instead of dex?
to lower the osteonecrosis risk
in DI for SR, you have modified BFM…in DI for HR you have modified augmented BFM, what’s the diff?
modified: Asp only on Day 4…modified augmented BFM: also includes additional Vcr, Asp on D43 and Vcr on D50
in HR ALL, capizzi mtx includes Asp on what days?
2, 22
how does BFM detrmine early tx response?
peripheral blast count after 7 days of steroids + dose of IT Mtx…wiht good repsosne being <1000 blasts/uL in peripehral blood
how did CCG measure early tx response?
check day 8 for HR and day 15 for SR: BM resposne…M1<5% blasts, M2 5-25% blasts, M3 >25% blasts
how does COG determine early tx response?
day 8 pripheral blood MRD adn d29 BM MRD
what is the best predictor of outcome in terms of early tx response?
BM MRD at D29
MRD should reach sensitivity of what?
at least 1 in 10k
most common way to measure MRD?
flow
name 3 MRD technologies
flow cytometry, PCR amplfication of Ig or TCR, PCR of translocation-derivied fusion transcripts
what’s more sensitive? PCR or flow for MRD?
PCR
how do you define CNS disease in leuk?
CNS1= 0-5 WBCS/chamber, 0 blasts, no clinical signs of CNS leuk….CNS2: <5 WBCs/chamber, presence of lbasts or negative by Steinherz-Bleyer alogorithm if traumatic tap…CNS 3: >5 WBCs/chamger, presence of blasts, signs of clinical leuk, positive by Steinherz-Bleyer if traumatic tap
what is the radiation tx dose for CNS3?
1800cGy, includes posterior halves of globes of the eyes…spinal rad rarely used anymore
often treat CNS2 how?
extra IT during induction
give 4 AEs of IT chemo
arachnoiditis, seizures, transient stroke-like sx, rare subacute encephatlopathy, meylopathy, weakness/paraplegia linked to IT MTx
AE of CNS irrad?
somnolence syndromes 5-7 weeks later
Admin of __ ___ ___ ___ after cXRT is associated with ___ ____
high dose iV mtx; CNS toxicity…give hd mtx BEFORE rad!
5 late complicatins of CNS directed therapy?
- changes on neuroimaging studies, like cortical atrophy
- impaired intellectual function adn school performance…linked to dose and age at time of rad (younger worse)
- secondary brain tumours…meningioma highly curable (10-20 yrs later), others not
- neuroendo changes like impaired GH responses, much lower risk if <2400 Gy
- increased risk of obesity
name 3 new ALL therapies
inotuzumab, blinatumomab, CAR t-cells
inotuzumab: give mech of action, population studied, outcome
CD22-directed humanized monoclonal ab conjugated to calicheamicin…studies in adults with CD22+ with relapsed/refractory B-ALL, 80.7% complete remission /complete remission induction
blina: give mech of action, population studied, outcome
blinatumomab: bispecific t cell receptor engage= BiTE taht redirects CD3+ T cells to CD19+ blasts; studies in adults with r/r ph+ b-ALL and kids with r/r B-ALL…CR in 39%
car t cells: give mech of action, population studied, outcome
t cell transduced ex-vivo with chimeric anti CD19 receptor; kids with cd19+ r/r b-all, 83% CR/CRi
immunotherapies share what 2 AEs?
cytokine release syndrome (associated iwth higher disease burden)…also neuro side effects
inotuzumab associated with what AE?
-sinusoidal obstruction syndrome…higher risk in post-inotuzumab HSCT setting…high rates in kids
management of CRS?
fluids, pressors, tociluzumab= anti-IL6
features of CRS?
fever, myalgias, n/v, hypotension, resp insuff, renal insuff, coagulopathy
neurotox after CAR-T: another name?
CAR-T cell realted encephalopahty syndrome= CRES
similar neurotox to CRES also seen with?
blina
sign/sx of neurotox from CAR-T?
h/a, dysgraphia, tremor, delirum, anxiety, sz, coma, cerebral edema, death
manage neurotox from CAR-T how?
supportive care, steroids
4 prog factors relating to relapse?
site of relapse (BM worse than extramedullary), time to relapse (ealrier worse), age at initial dx (very poor outcome for teens who realpse), immunophenoytpic and genetic featuers (BM relapse of T-ALL has very poor outcome)
early relapse=?
<18 mos; do poorly
late realpse?
> 36 mos
For CNS, give a strong perdictor of outcome
time to realpse…must get effective systemic therapy!! at high risk of subsequent BM relapse!
what % of boys have isolated teseticular relapse?
2%
tx testicular realpse how?
intensive systemic tx + 2400 cGy bilateral testicular irradiation–> otherwise high risk of contralateral testicular realpse…leads to steriliyt, so need hormone repalcement…in europe undergo orchiectomy
how does outcome for unrelated SCT fare vs. matched sib for ALL?
equal
SCT is indicated for ALL with 1st marrow relapse at what time frame?
<3 yrs
there’s an increasing role for transplant for what?
late marrow relapse with high MRD at ned of first course of reinduction therapy
some believe that SCT indicated for what site of release and when?
early CNS relapse (<18 mos)
other than first ALL BM relapse <3 yrs, when else is SCT indicated?
- 2nd relapse
- T-ALL BM relapse
describe relative half lives for different co-stumulatory domains in car t-cells
4-1BB lasts longer than CD28
for CTL-019 CARs (novartis; including 4-1BB), what was CR rate for r/r ALL? 6 month EFS? OS? durable remissions seen how far out?
90%; 78%; 78%…24 mos
list 7 long term risks for survivors of ALL
osteonerosis, cardiac tox, obestiy, neurocog impariment, GH def, insulin resistance, muscule weakness, peripheral neuropathy, liver tox
