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AP/CP Board Review Hemepath > MDS/MPN Syndromes > Flashcards

MDS/MPN Syndromes Flashcards

1
Q

What are the basic diagnostic criteria

of CMML ?

A
  • persistent absolute monocytosis
    • > 1 x 10^9/L or >1,000/uL
  • marrow dysplasia
    • usually dysgranulopoiesis
    • must be in > 10% of cells
  • < 20% blasts including promonocytes
  • absence of Philadelphia chromosome
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2
Q

What is the morphology of the

monocytes in CMML ?

A
  • can be normal to atypical
  • may have a concomitant reactive Blastic Plasmacytoid Dendritic Cell Infiltrate
    • Positive: CD2, CD4, CD5, CD14, CD56, CD68, CD123
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3
Q

What genetic alterations must be excluded if

there is significant eosinophilia seen in a

case of CMML ?

A
  • eosinophilia: > 1.5 x 10^9/L
  • Must exclude rearrangements of:
    • PDGRFB
    • FGFR1
    • PCM-JAK2 (mutations)
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4
Q

What are common genes that are mutated

in CMML ?

A
  • TET2
  • SRSF2
  • SETBP1
  • ASXL1
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5
Q

What is the definition of atypical CMML ?

A
  • Leukocytosis > 13 x 10^9/L
    • composed of a spectrum of mature neutrophils, metamyelocytes, myelocytes and promyelocytes
    • marrow dysplasia
    • <20% of blasts
    • no Philadelphia chromosome
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6
Q

What genes are often mutated in

atypical CMML ?

A
  • SETBP1
  • ETNK1
  • note: some may have JAK2 mutations
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7
Q

What is the definition of Juvenile Myelomonocytic Leukemia ?

A
  • affects children
  • presents with a monocytosis ( >1 x 10^9/L) and/or granulocytosis
  • hepatosplenomegaly
  • constitutional symptoms
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8
Q

What are other findings often seen in JMML ?

A
  • anemia, thrombocytopenia
  • increased HbF
  • clonal chromosomal abnormalities:
    • monosomy 7 in 25%
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9
Q

What is the test used to diagnose JMML ?

A
  • In vitro spontaneous formation of granulocyte-macrophage colonies
    • hypersensitive to GM-CSF
    • confirmatory
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10
Q

What genetic alterations can be seen

in JMML ?

A
  • 10% of patients have NF-1
    • can have elevated HgF
  • Recurrent mutations in:
    • PTPN11
    • KRAS
    • NRAS
    • CBL
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11
Q

What is the definition of Chronic myeloid leukemia (CML)?

A
  • defined by presence of Philadelphia chromosome
    • t(9;22) , produces a BCR-ABL fusion gene
    • translocation occurs: in major breakpoint cluster (M-BCR)
      • produces p210 fusion protein
    • rare cases translocation occurs in different region
      • produces p230 fusion protein
      • associated with marked thrombocytosis, neutrophil maturation
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12
Q

What is the third known breakpoint of CML

and when would you expect to have it ?

A
  • M-BCR breakpoint
    • p190 fusion protein
  • associated with monocytosis
  • also the breakpoint of Ph+ ALL
    • B-ALL in kids with this translocation is poor prognosis
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13
Q

What can be seen at presentation of CML?

A
  • splenomegaly can be seen
  • platelet aggregation defects
    • impaired aggregation in response to epinephrine
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14
Q

How is the chronic phase of CML defined ?

A
  • leukocytosis due to increased neutrophils in all stages of maturation
  • proportion of myelocytes exceeds that of the other mature forms
    • Myelocyte bulge
  • Basophilia, eosinophilia, thrombocytosis
  • Absolute monocytosis in most cases
  • Blasts usually <1%
  • low LAP score
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15
Q

What are the bone marrow findings in

Chronic Myeloid Leukemia ?

A
  • Hypercellular
  • Increased M:E ratio and myelocyte bulge
    • similar to that seen in the blood
  • Increased megakaryocytes
    • often small, hypolobated (Dwarf megas)
  • Immature myeloids are away from the trabeculae
    • thickening of trabecular cuff of immature cells
  • Increased histiocytes
    • gray-green crystal containing, Gaucher like, sea-blue histiocytes
    • indicative of increased cell turnover
  • Dyspoiesis is UNUSUAL in CML
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16
Q

What characterizes the accelerated phase

of CML?

A

Marked by the emergence of 1 or more of the following:

  • progressive basophilia ( >20%)
  • thrombocytopenia ( <100 x10^9/L)
  • thrombocytosis (>1000 x10^9) or leukocytosis
  • clonal cytogenetic progression
    • Philadelphia chromosome with +8, i(17q), +19 or another Ph chromosome
  • increasing blasts >10%
    • but less than 20%
  • clusters of abnormal megakaryocytes
  • LAP score tends to rise
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17
Q

What characterizes the blast phase of

CML ?

A
  • >20% blasts in the marrow or blood or infiltrate into the tissue (chloroma) OR
    • prominent focal accumulation of blasts in the marrow biopsy (fills an intertrabecular space)
  • in blast phase:
    • 70% are AML type
    • 30% are ALL type (often coexpression of myeloid antigens)
  • additional cytogenetic abnormalities
    • most common: duplication of Ph chromosome
    • +8, i(17q)
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18
Q

What is the treatment for CML ?

A
  • Imatinib
    • tyrosine kinase inhibitor
    • second line: nilotinib, desatinib
  • result in prolonged survival
19
Q

What is the most key prognostic factor in CML?

A
  • response to the tyrosine kinase inhibitor
  • measured by quantitative reverse transcriptase real time PCR (RT-PCR)
  • 3 log reduction in first 8-12 months is good response

Note: Imatinib functions through competitive inhibition of the ATP binding site of BCR-ABL

20
Q

What are the modes of development of resistance

to Imatinib ?

A
  • Imatinib also functions against: PDGFR and c-KIT
  • Resistance is present initially in 5% of cases
    • result of distinct mutations in the BCR-ABL gene
    • esp. TK domain: P loop (T315I) - KNOW
  • early treatment with Imatinib lessens the chances of development of resistance

IMP: accelerated or blast phase are more likely to develop resistance to Imatinib

21
Q

What are secondary/other mechanisms of

resistance development in CML ?

A
  • P-glycoprotein (MDR) overexpression
  • Amplification of BCR-ABL leading to bcr-abl kinase
  • acquisition of additional non-Bcr-Abl genetic anomolies (clonal evolution)
22
Q

What is the definition of

minimal residual disease in CML?

A
  • Clinical remission: ~10^9-10^10 leukemic cells (about 2-3 log reduction)
  • MRD generally refers to leukemic cells < 10^9-10^10
  • Complete cytogenetic response:
    • undetectable Philadelphia chromosome in 20 metaphased by conventional cytogenetics
    • generally achieved when the number of leukemic cells is <10^9
      • or a log of 3 reduction
23
Q

In CML, what predicts 0% chance of disease progression

over the course of 2 years?

A
  • a true log of 3 reduction at 12 months
  • confirmed by quantitative PCR for the BCR-ABL transcript
  • BCR-ABL quantitative PCR is used to establish baseline for future MRD monitoring at diagnosis
  • Quantitative PCR (RT-PCR) considered the method of chose for MRD detection
    • esp in patients who have achieved complete cytogenetic remission
24
Q

What is the presentation of patient’s with

polycythemia vera?

A
  • hypertension, thrombosis, pruritis, plethora, erythromelalgia, and or headache
  • spleen is typically enlarged at presentation
  • Budd-Chiari in 10% of cases
  • Most common cause of death:
    • thrombosis (31%)
    • acute leukemia (19%)
25
Q

What are the diagnostic criteria for

Polycythemia Vera?

A

IMP: must differentiate PV from relative polycythemia, secondary polycythemia and CML

Must have 2 major and 1 minor criteria as the minimum:

  • Major:
    • Hgb > 16.5 (men) >16 (women), or Hct: >25%
    • JAK2 V617F or JAK2 exon12 mutation
  • Minor:
    • subnormal serum erythropoitin (EPO)
26
Q

What are causes of relative and secondary

polycythemia ?

A
  • Relative:
    • stress or dehydration
    • called Gaisboch syndrome
  • Secondary:
    • Low PaO2 states (smoking, living at high altitudes)
    • high oxygen affinity hemoglobin variants
    • Neoplasms
      • RCC, Cerebellar hemangioblastoma
      • produce excess EPO
27
Q

What is characteristic of the

Proliferative Phase of Polycythemia Vera?

A
  • erythrocytosis, neutrophilia
    • sometimes basophilia and or thrombocytosis
  • marrow is hypercellular with a low M:E ratio
  • megakaryocyte hyperplasia is often prominent
  • stainable iron is usually decreased or absent
28
Q

What is characteristic of the spent

phase of PV ?

A
  • post polycythemic myelofibrosis with myeloid metaplasia
  • peripheral myelopthisic pattern (marrow replacement)
    • marrow reticulin fibrosis
    • extramedullary hematopoiesis
29
Q

What is endogenous colony formation

used to assess?

A
  • used to evaluate Polycythemia vera
  • use a culture of the patient’s marrow
  • PV
    • spontaneous formation of erythroid colonies
      • without addition of EPO
    • in other conditions, colony formation requires the addition of EPO
30
Q

What is the characteristic JAK2 mutation

identified in many MPNs ?

A
  • JAK2 V617F
    • present in >90% of PV
      • 50% of ET and 50% of PMF
  • the second most common activating mutation is within JAK2 exon 12, which is seen in a small proportion of PV cases
31
Q

In what MPNs would you see mutations

in MPL ?

A
  • small subset of PMF and ET
    • MPL W515L or W515K
    • IMP: these are not seen in PV
32
Q

When would you expect to see a

CALR mutation in an MPN?

A
  • Calreticulin exon 9 mutations
    • seen in JAK2 negative PMF (25-35%)
    • ET (15-24%)
  • CALR type 1 mutation results from a 52 bp deletion
    • type 2 mutations result from a 5 bp insertion
33
Q

What are the diagnostic criteria of

Essential Thrombocythemia ?

A

Need all major or first 3 major and minor criteria

  • Major:
    • sustained thrombocytosis >450 x10^9/L
    • bone marrow megakaryocytic hyperplasia, no panmyelosis
      • no significant increase in granulocytic/erythroid precursors
    • fails to meet criteria for PV, PMF, CML and MDS
    • JAK2 V617F, MPL or CALR mutation
  • Minor:
    • presence of clonal marker or absence of reactive thrombocytosis
34
Q

What is the clinical presentation

of ET?

A
  • bimodal age distribution: peaks at age 30 and 60
    • female predominance, esp for JAK2 mutations
    • men tend to have more of the CALR
  • presents as isolated thrombocytosis
    • some patients can present with thrombosis or mucosal hemorrhages
35
Q

What are the histological findings of

Essential Thrombocythemia?

A
  • increase in mature appearing, large, hyperlobated megakaryocytes (stag-horn like)
    • paratrabecular in distribution
    • may have emperipolesis
  • unlike PV and PMF megakaryocyte topography is not altered
    • no significant megakaryocyte clumping
  • stainable iron is present
    • helps rule out iron deficiency
  • significant reticulin fibrosis is not present
36
Q

What conditions must be ruled out

before making a diagnosis of ET?

A
  • Reactive thrombocytopenia
    • seen in iron deficiency
    • chronic inflammation
    • asplenia
    • other hematolymphoid malignancies
      • CML
37
Q

What is the morphology of the cellular

or prefibrotic phase of PMF ?

A

Presentation: anemia, mild leukocytosis, and thrombocytosis

  • marrow is hypercellular with increased granulocytic precursors and increased megakaryocytes
  • erythroid precursors
    • relatively diminished with maturation arrest
    • helps differentiate it from Panmyelosis
  • granulocytes have normal distribution and lack a myelocyte bulge (different than CML)
38
Q

What is the morphology of

PMF megakaryocytes ?

A
  • morphologically abnormal
    • aberrantly lobulated with clumped, hyperchromatic chromatin/ink like
    • clusters are prominent
      • found adjacent to sinuses and trabeculae
39
Q

What is characteristic of the fibrotic

phase of PMF ?

A
  • Leukoerythroblastic pattern in the peripheral blood
    • dacrocytosis and anisocytosis
  • bone marrow cant be aspirated
  • Key findings:
    • reticulin/collagen fibrosis
    • intrasinusoidal hematopoiesis
    • morphologically abnormal clusters of megakaryocytes
40
Q

What is the clinical presentation of

Chronic Eosinophilic Leukemia (CEL) ?

A
  • predominantly a disease of men 9:1 ratio
  • peripheral blood eosinophilia
    • >1.5 x 10^9/L
    • often with evidence of tissue infiltration and damage
  • Common sites involved:
    • heart, GI tract, lung and CNS
    • endomyocardial fibrosis can be seen in the heart
  • Eosinophil Morphology
    • hypogranular with cytoplasmic vacuolization
    • if no clonality seen blasts must be >2% in PB and >5% in BM but <20% overall
41
Q

What must be excluded in order

to diagnose Chronic Eosinophilic Leukemia ?

A
  • No identifiable cause of secondary eosinophilia
  • No evidence of a defined syndrome associated with eosinophilia: PDGFRA, PDGFRB and FGFR1
  • If there is evidence of clonality by cytogenetics or increased blasts (must be <20%)
    • can make the diagnosis of CEL
  • IF these are lacking you call it hypereosinophilic syndrome
42
Q

What are common causes of

Hypereosinophilia ?

A
  • allergic reactions
  • parasitic infections
  • collagen vascular diseases
  • mastocytosis
  • other hematolymphoid neoplasms
43
Q

What are the 3 myeloid neoplasms with

associated eosinophilia ?

A
  • PDGFRa rearrangment
  • PDGFRb rearrangment
  • FGFR1 rearrangment

Note: endomyocardial fibrosis can occur with any of these conditions.

PDGFRa and PDGFRb rearrangements are responsive to Imatinib and other Tyrosine Kinase inhibitors

44
Q

What is known about the PDGFRa

neoplasm?

A
  • presents like Chronic eosinophilic leukemia
    • also can be AML with eos and T-ALL with eos
  • epidemiology:
    • M:F 17:1 (median 40 years)
  • No abnormal karyotype
  • Usual gene rearrangements:
    • NFIP1L1/PDGFRa
      • cryptic del(4q12)

AP/CP Board Review Hemepath (12 decks)

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