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Hematopathology > MPNs > Flashcards

MPNs Flashcards

1
Q

CML Chronic Phase

A

<10% blasts (usually less than 2%)

Often anemia and thrombocytosis

Paratrabecular cuff immature grans 5-10

Megas tend to cluster, unlike AML t(3;3), inv(3)

40% have mildly increased reticulin fibrosis

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2
Q

CML Accelerated Phase

A

One or more of the following:

Persistent or increasing WBC (>10 x 109/L) or splenomegaly

Persistant thrombocytosis (>1000 x 109/L)

Persistant thrombocytopenia (<100 x 109/L)

Cytogenetic evidence of clonal evolution

PB basophils ≥ 20%

10-19% blasts in PB or BM

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3
Q

CML Blast Phase

A

One or more of the following:

PB or BM blasts ≥ 20% (70% AML, 25% B-ALL, rare T-ALL)

Extramedullary blast proliferation (i.e. myeloid sarcoma)
Large foci or clusters of blasts in the BM bx (entire intertrabecular region)

*Still continue to treat with TKIs, not chemo*

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4
Q

CML vs Leukemoid Rxn

A

CML:
decreased alkaline phosphatase (decreased LAP score)

myelocyte bulge

Leukemoid Rxn:

increased alkaline phosphatase (increased LAP score)

no myelocyte bulge

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5
Q

BCR-ABL1

A
  • 90-95% have the Ph (del22) chromosome
  • Most of the remaining cases have variant genetic abnormalities that resutl in the BCR-ABL1 fusion gene but involve other chromosomes in addition to 9 and 22
  • Very few have cryptic BCR-ABL1 translocations that cannot be identified by routine karyotyping and requite molecular or FISH
  • Remember BCR is on chr.22 and ABL1 is on chr.9
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6
Q

Sensitivities of Techniques for BCR-ABL1

A

karyotype= 90-95%

RT-PCR= 99%

FISH= >99%

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7
Q

p210

A

BCR exons 12-16

Transcripts:

b2a2

b3a2 (most common translocation)

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8
Q

p230

A

BCR exons 17-20

Transcript: e19a2

Marked thrombocytosis or neutrophilia (resembling CNL)

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9
Q

p190

A

BCR exons 1-2

Transcript: e1a2 (less commonly e1a3)

B-ALL
CML with increased monocytes (resembling CMML)

***A small amount of the p190 transcript can be detectedin >90% of pts with p210 CML due to alternative splicing of the BCR gene***

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10
Q

Cytogenetic changes seen in transformation

A

extra Ph

+8

+19

i(17q)

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11
Q

Which pts should have kinase domain mutation testing?

A

1) all high risk pts
2) standard risk pts who fail to achieve complete cytogenetic response by 6mos
3) pts showing loss of response to imatinib, relapse to Ph+, or increased BCR-ABL1 transcript by ≥1 log
4) at time of progression to accelerated or blast phase

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12
Q

Complete Hematologic Response

A

PB counts completely return to normal, including plt count

No blasts or immature cells circulating

No signs/sx of disease including no enlarged spleen

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13
Q

Complete Cytogenetic Response

A

No Ph chromosome detected with BM cytogenetics

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14
Q

Partial Cytogenetic Response

A

1-35% of cells have the Ph chromosome on BM cytogenetics

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15
Q

Major Cytogenetic Response

A

0-15% of cells have the Ph chromosome on BM cytogenetics

(complete + partial response)

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16
Q

Complete Molecular Response

A

No BCR-ABL1 copies detectable by QPCR using the IS

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17
Q

Major Molecular Response

A

≥3 log reduction in BCR-ABL1 levels

OR

BCR-ABL1 0.1% by QPCR using IS

18
Q

Relapse

A
  • Any sign of loss of response: defined as hematologic or cytogenetic relapse
  • A 1-log increase in BCR-ABL1 levels with loss of major molecular response should prompt BM evaluation (but is not alone defined as relapse)
19
Q

Most important prognostic indicator

A

Response to TKI at the hematologic, cytogenetic, and molecular level

20
Q

Minor Cytogenetic Response

A

>35% of cells have the Ph chromosome on BM cytogenetics

21
Q

Cytogenetic Response Rate to Imatinib

A

70-90%, with 5 year progression free survival/overall survival 80-95%

22
Q

BCR gene

A

25 exons, including two putative alternative first (e1’) and second (e2’) exons

23
Q

ABL1 breakpoints

A

Almost invariably occur:

1) upstream of exon Ib
2) b/w exon Ib and Ia
3) b/w Ia and a2

24
Q

Mechanisms of Drug Resistance

A
  • kinase domain mutations
  • BCR-ABL1 gene amplification or protein overexpression
  • alterations in drug efflux kinetics
  • upregulation of other kinase pathways
  • rare BCR-ABL1 mutations outside of the kinase domain
25
Q

Drugs for pts with Imatinib resistance

A

dasatinib

nilotinib

bosutinib

26
Q

Relapsed Ph+ ALL

A

80-90% will have a BCR-ABL kinase domain mutation

27
Q

Kinase Domain Mutation Testing

A
  • Direct sequencing of BCR-ABL1 gene by Sanger method (because detection of low level mutant clones may not be clinically significant)- detects a mutation in 1 in 5 BCR/ABL1 transcripts
  • low level imatinib resistance in M351T, with probable response to dose escalation
  • high level resistance T315I, Y253H, E255K, with need for change in therapy
  • T315I mutation is relatively common and the worst (resistant to almost all TKIs)
28
Q

Diagnostic Criteria for CNL

A
  • WBC ≥25 x 109/L (>80% PMNs & bands, <10% pros/myelos/metas, <1% blasts)
  • hypercellular BM
  • hepatosplenomegaly (most have splenomegaly)
  • no BCR-ABL1 fusion gene
  • no rearrangement of PDGFRA, PDGFRB, FGFR1
  • no evidence of PV, ET, or PMF
  • no evidence of MDS or MDS/MPN (no dysplasia, monos<1 x 109/L)
  • no physiologic cause for neutrophilia or if so, demonstration of myeloid clonality
29
Q

Morphology of CNL

A
  • Marked increase in PMNs and bands, almost never myeloblasts
  • PMNs appear toxic
  • Up to 20% of cases are associated with another neoplasm, usually myeloma (where CNL is thought to be 2º to abnormal cytokine release from neoplastic plasma cells)
  • If plasma cell dyscrasia is present, clonality of PMN lineage shoudl be proven by cytogenetics or molecular studies before diagnosing CNL
30
Q

Mutation Associated with CNL

A
  • many cases show a mutation of the CSF3R gene
  • cytogenetics normal in 90% cases
  • JAK2 mutations have also been described
  • ?SETBP1?
31
Q

3 Phases of Polycythemia Vera

A

1) Prodromal (prepolycythemic) phase: symptoms suggestive of PV, borderline-mild erythrocytosis
2) Overt polycythemic phase: significant ↑ RBC mass
3) “Spent”/post-polycythemic phase: cytopenias (including anemia), PB leukoerythroblastosis, BM fibrosis, splenomegaly, and extramedullary hematopoiesis

32
Q

Signs and Symptoms of PV

A

HTN

vascular abnormalities (venous/arterial thrombosis, MI/stroke, Budd-Chiari)

plethora/pruritis

HA/dizziness

visual changes

gout (hyperuricemia from high cell turnover)
hepatosplenomegaly (usually mild)

33
Q

PV Diagnostic Criteria

A

Requires both major + 1 minor OR first major + 2 minor
Major:

  1. Hgb >18.5 g/dL in men, >16.5 g/dL in women (or other evidence of ↑ red cell volume)
  2. JAK2 V617F or JAK2 exon 12 mutation

Minor:
1. Hypercellular marrow showing panmyelosis

  1. Low serum EPO
  2. Endogenous erythroid colony formation in vivo
34
Q

Pre-polycythemic and Polycythemic Stages

A

PB shows increase in all 3 lineages (thrombocytosis in about 50%)

BM shows:

  • left shifted granulocytes
  • pleomorphic megas (less than PMF, more than ET) dispersed or loosely clustered
  • enlarged erythroid islands that tend to form sheets
  • absent stainable iron***
35
Q

“Spent”/Post-polycythemic Phase

A

PB shows leukoerythroblastosis, poikilocytosis with frequent dacrocytes

BM shows reticulin & collagen fibrosis

↑ splenomegaly 2º/2 EMH

***Lymphoid aggregates are seen in 20%***

36
Q

JAK2

A
  • cytoplasmic tyrosine kinase acts through JAK-STAT family of nuclear receptors
  • V617F is most common mutation, due to G→T point mutation in exon 12 (valine to phenylalanine)
  • mutation happens in pseudokinase domain (usually turns of TK activity), leads to constitutive activation of JAK2
  • mutually exclusive with CALR mutations
37
Q

Cytogenetic Abnormalities PV

A

10-20% of patients

+8

+9

del(20q)

del(13p)

del(1p)

38
Q

PV Treatment & Prognosis

A

Phlebotomy

Pegylated interferon effective in reducing risk of thrombosis and progression to fibrosis

Most pts die from thrombosis/hemorrhage (median survival 10yrs)

Up to 20% pts develop MDS or AML

39
Q

Primary Myelofibrosis Clinical

A

90% of patients have splenomegaly

40
Q

BCR/ABL1 Drug Resistance Mutations- General

A
  • among pts with chronic phase CML, who develop secondary resistance to imatinib, 30-50% will have one or more BCR/ABL1 kinase domain mutations detectable by DNA sequencing
  • mutation frequency higher in those with accelerated/blast phase (especially lymphoid blast phase)
  • 80-90% pts w/relapsed Ph+ ALL will have BCR/ABL1 KD mutation
  • absence of mutation does not exclude resistance by other mechanisms
41
Q

BCR/ABL1 Drug Resistance Mutations- Indications for Testing

A
  • chronic phase for those with inadequate initial response to TKIs or those with evidece of loss of response (10-fold or greater increase in transcript levels)
  • at time of progression to accelerated or blast phase

Hematopathology (15 decks)

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