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ASPHO Lectures 2021 > Acute Lymphoblastic Leukemia > Flashcards

Acute Lymphoblastic Leukemia Flashcards

1
Q

Sentinel somatic mutations that can arise in utero include?

A
  • KMT2A
  • ETV6/RUNX1
  • ?hyperdiploid ALL
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2
Q

What percentage of infants are born with ETV6/RUNX1 detectable on cord blood?

A

1%

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3
Q

How many of ETV6/RUNX1 positive infants will develop ALL?

A

1/100

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4
Q

What is the first step in leukemogenesis?

A

Developmental arrest

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5
Q

What is the peak incidence of ALL in industrialized countries?

A

2-4 years old

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6
Q

Peak incidence of AML?

A

No peak incidence

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7
Q

Known ALL predisposition syndromes? (9)

A
  • Down Syndrome
  • Constitutional Robertsonian translocation
  • Ataxia telangiectasia (ATM) (T-ALL and NHL)
  • Nijmegen breakage syndrome (NBS 1)
  • Bloom Syndrome
  • Constitutional mismatch repair deficiencies
  • Rasopathies (Neurofibromatosis type 1, Noonan Syndrome)
  • Klinefelter Syndrome
  • Li Fraumeni Syndrome (hypodiploid ALL)
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8
Q

How much more likely are children with Down Syndrome to develop leukemia?

A

20X

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9
Q

How many children with DS have T-ALL or infant ALL (<1 year old)?

A

Almost none

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10
Q

In which leukemia predisposition syndrome is there a decreased rate of common sentinel genetic lesions? Which ones are very rare?

A
  • Down syndrome

- KMT2A and BCR-ABL1

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11
Q

Which genetic lesion occurs more frequently in Down Syndrome ALL compared to non-Down Syndrome ALL? What accompanying mutations?

A
  • Over-expression of CRLF2

- JAK and IL7R accompanying

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12
Q

Outcomes for DS with CRLF2r vs non DS with CRLF2r? Overall outcome of DS ALL? What if limit analysis to cases lacking common sentinel genetic lesions?

A
  • Better
  • Inferior
  • Equivalent
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13
Q

There is an increased risk of ____ in DS-ALL.

A

Toxic death

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14
Q

Germline predisposition mutations for ALL? Other additional in hypodiploid and B-ALL?

A
  • PAX5 G183S
  • TP53 - hypodiploid
  • ETV6 - hyperdiploid
  • Other for hypodiploid: XRCC1, TP53INP1, FANCA, MLL3, ROS1, SH2B3 (LNK)
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15
Q

Concordance rates between identical twins for leukemia in infants <12 mos?

A

Close to 100%

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16
Q

Concordance rates for twins for typical childhood B ALL after infancy?

A

10-15%

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17
Q

Baseline characteristics that influence prognosis outside of NCI risk?

A
  • Presence/absence of extramedullary disease
  • Sex
  • Race
  • Ethnicity
  • ALL genotype **(strong influcence)
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18
Q

What is the strongest prognostic factor?

A

Response to therapy

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19
Q

For what group is NCI risk criteria NOT PROGNOSTIC?

A

T cell ALL

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20
Q

What percentage of B ALL have standard risk based on NCI criteria? High risk? Infant leukemia? EFS for each?

A
  • ~65% are standard; EFS 90%
  • ~34% are high; 5y EFS 75-80% for age >10 (non-infants) or WBC >50
  • ~1% are infant; Outcome poor
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21
Q

What percentage of ALL is B?

A

80-85%

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22
Q

Flow cytometry features of B ALL?

A
  • CD45 positive: distinguishes lymphoid vs. myeloid
  • Almost all cases are CD19+, surface CD22+, CD79a+
  • Most: CD10+(cALLA+), TdT+ and HLA-DR+
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23
Q

About half of KMT2A-R ALL lack ___ expression.

A

CD10

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24
Q

Co-expression of _____ is common (_____).

A
  • Myeloid antigens
  • CD13/33
  • Does not mean it is acute leuk of ambiguous lineage (ALAL) or MPAL!
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25
Q

Early B-lineage ALL are ___ negative. Pre-B ALL is ____.

A
  • cIG-negative

- cIG+, sIG-negative

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26
Q

What percentage of ALL is T ALL?

A

~15%

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27
Q

Flow cytometry features of T ALL?

A
  • cytoplasmic CD3+
  • most sCD3+ and TdT+
  • Often express CD2, 4, 7, 8
  • CD10 variable
  • Most HLA-DR negative
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28
Q

____ is notoriously slower to clear MRD by end of induction. Which value is more important?

A
  • T-cell ALL

- End of consolidation MRD

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29
Q

Flow phenotype for early T precursor (ETP)?

A

-cCD3+, CD7+, weak CD5,
CD1a-, CD8-
-One or more of on at least 25% of lymphoblasts: CD117+, CD34, HLA-DR, CD13. CD33. CD11b

30
Q

What is MPAL?

A
  • A subtype of acute leukemia of ambiguous lineage (ALAL)
  • Biphenotypic leukemia (most common): Myeloid and lymphoid features on the same cell
  • Bilineal leukemia: distinct populations of lymphoid and myeloid blasts (very poor prognosis)
31
Q

B-Myeloid MPAL has a high incidence of ___-driven leukemia.

A

ZNf384

32
Q

Collective data supports initiating therapy for ___ for MPAL.

A

ALL - this is based on a retrospective review that was not powered to determine a difference, however given burden of acute and late effects of ALL vs. AML therapy, feel reasonable to start with ALL.

33
Q

HIgh occurence of ____ fusion in MPAL.

A

BCR/ABL1

34
Q

Cytogenetic aneuploidies with prognostic significance? incidence and outcome?

A
  • Hyperdiploid - Gain of 4 and 10 (“double trisomy”) +/- 17 (“triple trisomy); incidence ~25%; outcome excellent; less common in patients >15 y o
  • Low hypodiploid, haploid, masked hypodiploid (chromosomes doubled): Incidence <3%; poor outcome with modern chemo; ?no benefit to HSCT (2019 papers)
35
Q

Sentinal translocations in BALL? Molecular, Incidence, Outcome, Comments

A

Table in your folder

36
Q

What is Ph-like ALL?

A
  • Defined by an activated kinase gene expression signature similar to that of BCR-ABL1-r (Ph+) ALL
  • Driven by cytogenetically-cryptic genetic alterations that activate constitutive kinase signaling
37
Q

Ph-like ALL is frequently associated with delitions of _____ and other lymphoid transcription factors.

A

IKZF1

38
Q

Patients with Ph-like ALL often present with ____ have have high _____ with conventional chemo.

A
  • WBC>/= 50

- EOI MRD

39
Q

Addition of ____ to chemo may improve event-free and overall survival in Ph-like ALL.

A

-TKIs

40
Q

Most common alterations in Ph-like ALL? Drugs for each?

A
  • 50% CRLF2 rearrangements +/- JAK2 or JAK1 point mutations - Ruxolitinib
  • 15-20% JAK2 or EPOR rearrangements - Ruxolitinib
  • 10-15% ABL class alterations (ABL1, ABL2, CSF1R, PDGFRB rearrangements) - Dasatinib/imatinib
41
Q

What is the most important prognostic factor for ALL in infants less than 12 months of age? EFS vs in non?

A
  • KMT2A-R

- 37-49% vs. 69-95% in non-KMT2A-R

42
Q

Which factors are NOT prognostic in T cell?

A

-Age, WBC, EOI MRD

43
Q

COG approach to ALL treatment?

A

See your folder

44
Q

Techniques to assess MRD should achieve a sensitivity of at least _____.

A

1/10 000 (0.01%)

45
Q

CNS disease definitions?

A
  • CNS 1: (0-5 white cells/chamber, 0 blasts, n clinical signs of CNS leukemia)
  • CNS 2: (<5 white blood cells/chamber, presence of blasts) or negative by Steinherz-Bleyer algorithm if traumatic tap
  • CNS 3: >/=5 white blood cells/chamber, presence of blasts), signs of clinical leukemia, positive by Steinherz/Bleyer algorithm if traumatic tap
46
Q

Current treatment dose of rads for CNS 3? Includes the ________.

A

1800cGy

Posterior halves of globes of eyes

47
Q

Management of CNS 2 disease?

A

Most groups give extra IT during induction to abrogate poor prognosis

48
Q

Acute complications of IT chemo?

A
  • Arachnoiditis (headache, N/V, meningismus)
  • Seizures (1-2%, particularly with repeat ITs)
  • Transient stroke-like symptoms (typically 7-11 days post IT)
  • Rare: subacute encephalopathy, myelopathy, weakness/paraplegia linked to IT MTX
49
Q

Acute complications of cranial irradiation?

A

5-7 weeks post cXRT: somnolence syndrome

50
Q

Administration of high dose IV MTX should be given _____ cXRT due to _____ when given after.

A
  • Before

- Increase CNS toxicity

51
Q

Late complications of CNS-directed therapy?

A
  • Neuroimaging changes: cortical atrophy, necrotizing leukoencephalopathy, subacute leukoencephalopathy, mineralizing leukoencephalopathy (HD MTX may increase risk, uncertain), calcifications (may be most significant finding)
  • Impaired intellectual function and school performance (linked to dose and age at time of cXRT, younger is worse)
  • Development of secondary brain tumours (10+ years post XRT) - meningioma (15-20 years post XRT) highly curable; but can have HGGs
  • Neuroendocrine changes: impaired growth and GH responses; much lower risk if >2400cGy
  • Increased risk of obesity
52
Q

Mechanism of action for inotuzumab, blinatumomab and CAR T cells?

A
  • Inotuzumab: CD22-directed humanized monoclonal antibody conjugated to calicheamicin
  • Blinatumomab: Bispecific T-cell receptor engage (BiTE) that redirects CD3+ T cells to CD19+ blasts
  • CAR T cells: T cells transduced ex-vivo with chimeric anti-CD19 receptor
53
Q

Immunotherapy toxicity?

A
  • CRS (associated with higher disease burden)

- Neurotoxicity

54
Q

Toxicity associated with inotuzumab?

A

-Sinusoidal obstruction syndrome - elevated risk in post-ino HSCT setting, HIGHER rates in children compared to adults

55
Q

Prognostic factors following ALL relapse?

A
  • Site of relapse: Bone marrow worse than extramedullary
  • Time to relapse: earlier much worse than later
  • Age at initial diagnosis: Very poor outcome for teenagers that relapse
  • Immunophenotypic and genetic features: BM relapse of T-ALL has very poor outcome
56
Q

Why is systemic therapy critical for CNS relapse? What is the biggest risk?

A

Subsequent bone marrow relapse is the biggest risk, so systemic therapy is critical

57
Q

What percentage of boys will have an isolated testicular relapse?

A

2%

58
Q

Standard treatment for testicular relapse? Adverse effects?

A
  • Intensive systemic therapy plus 2400cGy bilateral testicular irradiation - risk of contralateral testicular relapse high without irradiation
  • Leads to sterility and need for hormone replacement
59
Q

Indications for HSCT for relapse?

A
  • ALL with early (<3 years) 1st marrow relapse (may be evolving)
  • Increasing use for late marrow relapse with high MRD at end of 1st course of reinduction therapy
  • T-ALL BM relapse
  • Any 2nd relapse
  • Disagreement for early (<18 mos) CNS relapse
60
Q

What are CAR-T cells?

A

Genetically engineered receptors that pair an anti-CD19 single chain Fv domain to intracellular T cell signalling domains that result in redirection of T lymphocytes to recognize B ALL cells that express CD19

61
Q

What determines half life of CAR Ts? Which ones last longer? Role of transplant after infusion?

A
  • Co-stimulatory domains
  • 4-1BB last longer than CD28
  • Role of transplant after infusion is uncertain
62
Q

When using CTL-019 (with 4-1BB): CR for relapsed/refractory ALL? 6 month EFS? OS? Durable remissions were seen as far as _______ out.

A
  • CR: 90%
  • 6 month EFS: 78% (51-88%)
  • OS: 78% (65-95%)
  • 24 months
63
Q

Survivorship issues for leukemia survivors?

A
  • Osteonecrosis
  • Cardiac toxicity
  • Obesity
  • Neurocognitive impairment
  • Growth hormone deficiency (if treated with higher dose cranial radiation)
  • Insulin resistance
  • Muscle weakness
  • Peripheral neuropathy
  • Liver toxicity (previously seen with 6-TF used instead of 6-MP)
64
Q

Which chromosome translocation is most likely to be seen in pediatric T-ALL? How common? Prognostic significance?

A

t(11;14)(p13;q11.2)

in about 7%. Does not appear to have prognostic significance.

65
Q

The t(9;22)(q34;q11) or Philadelphia chromosome occurs in about ___% of B-cell precursor ALL? T-ALL?

A
  • 4% in B

- <1% in T

66
Q

What is the t(8;22)(q24;q11) translocation?

A

fuses c-MYC to the immunoglobulin lambda gene; rare recurrent translocation in Burkitt leukemia and lymphoma

67
Q

What is the t(1;19)(q23;p13) translocation? What percentage of B?

A
  • TCF3-PBX1 (E2A-PBX1) fusion

- 5% of B-ALL

68
Q

What is the t(9;11)(q34.q23) translocation?

A
  • MLL-AF9 fusion

- seen commonly in AML, less commonly in B ALL

69
Q

What is the morphologi finding for Burkitt leukemia?

A

-Deeply basophilic cytoplasm and cytplasmic vacuoles

70
Q

What is t(2;8)(p12;q24)?

A

Translocation that joins c-MYC locus t 8q24 to immunoglobulin heavy or light chain gene. Immunoglobulin kappa gene is located at 2pp12.
Seen in Burkitt Leukemia

71
Q

What is tocilizumab?

A

An IL-6 receptor antibody

ASPHO Lectures 2021 (10 decks)

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