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Hematopathology WHO MPN, Mastocytosis, MPN/MDS, & MDS > Chronic Myeloid Leukemia BCR-ABL1 Positive > Flashcards

Chronic Myeloid Leukemia BCR-ABL1 Positive Flashcards

1
Q

What is the definition of CML ?

A
  • MPN where the granulocytes are the major proliferative component
  • arises from stem cells with characteristic BCR-ABL translocation
    • t(9;22)
    • the fusion gene is found in all myeloid lineage, some lymphoid and endothelial cells
  • usually a biphasic or triphasic disease process
    • chronic phase
    • accelearated phase
    • blast phase
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2
Q

What is the epidemiology of CML ?

A
  • slight male predominance
  • 1-2 cases per 100,000 in the population
    • incidence increases with age
    • generally earlier age onset in areas with lower socioeconomic status
  • TKI treatement
    • reduces mortality by 2-3% per year
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3
Q

What is the etiology of CML ?

A
  • predisposing factors are largely unknown
  • acute radiation exposure has been implicated
    • mostly because it is described in bomb survivors
  • IMP
    • different from other MPNs, there is slight if any inherited predisposition
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4
Q

What is the localization of CML ?

A
  • leukemia cells are minimally invasive and most confined to:
    • bone marrow
    • peripheral blood
    • spleen
    • liver
  • in blast phase
    • blasts can infiltrate other sites
    • predilection for spleen, liver, LN, skin and soft tissue
      • IMP: if the spleen is rapidly enlarging, may indicate progression
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5
Q

What are the clinical features of CML ?

A
  • most patients are diagnosed in chronic phase
    • generally has an insidious onset
  • nearly 50% of cases are asymptomatic when discovered
  • common findings:
    • fatigue, malaise
    • weight loss, night sweats, anemia
    • 50% have palpable splenomegaly
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6
Q

What is an atypical presentation for CML ?

A
  • marked thrombocytosis without leukocytosis
    • this mimics ET or other MPNs

Note:

  • ~5% cases are diagnosed in accelerated or blast phase
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7
Q

What are the clinical findings of patient’s

the present in accelerated or blast phase ?

A
  • declining performance status
  • fever, weight loss
  • symptoms related to anemia, thrombocytopenia, increased WBC
  • splenic enlargement (blast phase)
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8
Q

With TKI therapy what is the

projected 10 year overall outcome ?

A
  • 80-90%
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9
Q

What are the microscopic features

of chronic phase ?

A
  • peripheral blood leukocytosis due to neutrophils in various maturation stages
    • increased myelocytes and segmented neutrophils
    • kids usually have higher counts than adults
  • significant granulocytic dysplasia is absent
  • blasts are <2% of the WBCS
  • absolute basophilia and eosinophilia are common
    • note: absolute monocytosis may be present
    • monocytes are usually <3% except in patietns with p190 BCR-ABL1 isoform
      • can mimic CMML
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10
Q

What is necessary for diagnosis of CML ?

A
  • peripheral blood morphologic findings along with PCR for BCR-ABL1
  • bone marrow aspiration is necessary for complete karyotype and evaluation of disease burden
    • bone marrow is not needed for diagnosis
    • but should be done if the findings in the peripheral blood are atypical
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11
Q

What are the typical microscopic

findings in the bone marrow in chronic phase ?

A
  • hypercellular marrow with marked granulocytic proliferation and maturation pattern similar to that in the blood
    • immature grans 5-10 layers thick at bony trabeculae
    • expansion of the myelocytes
  • No significant dysplasia
  • Blasts are < 5%
    • >10% suggests advanced disease stage
  • erythroids are decreased significantly
  • megakaryocytes usually decreased
    • 40-50% of cases have increased megas
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12
Q

What is the characteristic morphology

of the megakaryocytes ?

A
  • smaller than normal
  • hyposegmented nuclei
  • called “dwarf” megas
    • these are not true micromegs as seen in MDS
  • eosinophils and basophils are increased in number

Note:

  • pseudogaucher cells are seen
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13
Q

What is the normal reticulin

fibrosis present in CML ?

A
  • moderate to marked reticulin fibrosis is seen
    • correlates with the number of megakaryocytes present
  • may be associated with an enlarged spleen
  • previously, fibrosis at diagnosis showed a worse prognosis but no longer the case with TKI therapy
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14
Q

What is the cause of splenic enlargement

in CML ?

A
  • caused by infiltration of the red pulp by mature and immature granulocytes
  • similar infiltrate can be seen in the hepatic sinuses and portal areas
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15
Q

How has diagnosis of CML phases changed ?

A
  • more difficult to differentiate between phases due to use of TKI
  • data shows that even patients in AP can have similar outcomes to CP with TKI therapy
    • but if they develop AP on TKI then poor outcome
  • BP
    • continues to have a poor outcome regardless even with TKI therapy
    • death occurs due to bleeding or infectious complications
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16
Q

What are the characteristics of

accelerated phase of CML ?

A

Must have any one of the following parameters:

  • a persistent or increasing high WBC count (>10 x10^9/L) and or persistent or increasing splenomegaly not responsive to TKI
  • persistent thrombocytosis (>1000 x10^9/L) unresponsive to therapy
  • persistent thrombocytopenia (<100 x10^9/L) unrelated to therapy
  • evidence of clonal cytogenetic evolution defined by cells harbouring the Ph chromosome and additional cytogenetic changes
  • >20% basophils in the peripheral blood
  • 10-19% blasts in the peripheral blood or bone marrow
  • sheets or large clusters of abnormal megas with associated reticulin fibrosis
17
Q

What are the usual additional clonal

chromosomal abnormalities present

in accelerated phase CML ?

A
  • changes occur in cells that harbor the philadelphia chromosome
  • major route abnormalities
    • a second philadelphia chromosome
    • trisomy 8
    • isochromosome 17q
    • trisomy 19
    • complex karyotype
    • abnormalities in 3q26.2
  • any new chromosomal abnormality that occurs during therapy
18
Q

What are the provisional response to TKI

critiera that can define accelerated phase ?

A
  • hematological resistance (or failure to achieve a complete response) to the first TKI
  • any hematological, cytogenetic, or molecular indications of resistance to two sequential TKIs
  • occurance of two or more BCR-ABL fusion gene during TKI therapy
19
Q

What can be seen during AP in CML

that is not seen in CP ?

A
  • dysplasia of the myeloid lineage
  • clusters of megakarocytes, including true micromegs can be seen in AP
    • these can be associated with significant reticulin fibrosis
  • increased blasts can be highlighted by CD34
    • most have a myeloid phenotype
20
Q

What do lymphoblasts likely signifiy in CML ?

A
  • the presence of any lymphoblasts should prompt the concern that a lymphoblastic crisis may be imminent
    • key:
    • this is because lymphoblastic blast phase has an abrupt onset, sometimes without even an accelerated phase
21
Q

What features are diagnostic of blast phase

of CML ?

A
  • >20% blasts in the peripheral blood or bone marrow
  • infiltrative proliferation of blasts in an extramedullary site
  • usually they are myeloid (neutrophilic, monocytic, megakaryocytic, basophilic, eosinophilic, erythroid)
    • occasionally have lymphoblasts (B > T but also NK cell have been reported)
    • sequential lymphoblast and myeloblast crisis have also been reported
  • IMP:
    • expression of more than one lineage in blasts has been reported

Note: some have suggested using a cutoff of 30% for blasts, but patients in blast phase in general have a poor prognosis regardless of the cutoff used.

22
Q

What is the definition of a complete hematological

response in CML ?

A
  • WBC count <10 x!0^9?L
  • platelet count of <450 x10^9/L
  • no immature granulocytes in the differential count
  • spleen is not palpable
23
Q

Where do extramedullary blast

proliferations tend to occur in CML ?

A
  • skin
  • lymph nodes
  • bone
  • CNS
  • but can technically occur anywhere

IMP

  • in the bone marrow if sheets of blasts occupy an entire intertrabecular space or more a presumptive diagnosis of BP can be rendered even if the rest of the marrow looks like CP
24
Q

What key immunophenotypic expressions are

present in CML ?

A
  • expression of CD7 and CD34+ cells has adverse prognostic significance
    • if CD34+ cells show no aberrancies then it predicts a better response to TKI
  • main role of immunophenotyping is for the blast evaluation
    • in many myeloid BP cases the blasts also express one or more lymphoid-related antigens
25
Q

What antigens do the myeloid blasts in BP usually express ?

A
  • strong, weak or no MPO
  • but express one or more antigens associated with granulocytic, monocytic, megakaryocytic, or erythroid lineage
    • CD33, CD13,
    • CD14, CD11b, CD11c
    • CD117, CD15
    • CD41, CD61
    • Glycophorin A and C
26
Q

What can be seen in lymphoblasts of BP CML ?

A
  • usually precursor B cell in origin but T cell also occur
  • expression of one or more myeloid-related antigens by the blasts is common in both B and T cell

Note: bilineage blast phase (two distinct populations) also have been described

  • unusual blast immunophenotypes have been described following TKI therapy (ex: basophilic or megakaryocytes)
27
Q

What is the cell of origin

in CML ?

A
  • abnormal, pluripotent bone marrow stem cells
  • disease progression may occur in more commited cells
28
Q

What is the genetic profile of CML ?

A
  • at diagnosis 90-95% of cases of CML have t(9;22) recipricol translocation
    • results in Ph chromosome
    • BCR gene on chrom 22 with regions of ABL1 on chrom 9
  • other cases have variant translocations or cryptic translocations
29
Q

What are the breakpoints in CML ?

A

the breakpoint on chromosome 22 can influence the phenotype of the disease

  • most cases occur at exons 12-16 on BCR
    • leads to p210
    • which has increased tyrosine kinase activity
    • this is the major BCR breakpoint
  • mu-BCR breakpoint rarely occurs
    • spans exons 17-20
    • causes a larger p230 protein
    • IMP: patients with this show prominent neutrophilic maturation and/or thrombocytosis
  • minor BCR breakpoints
    • exons 1-2
    • lead to p190 fusion protein
    • usually seen in ALL
    • but in CML associated with increased monocytes, looks like CMML
30
Q

What was the first drug created to

treat CML ?

A
  • Imatinib (TKI)
  • competes with ATP for binding to the BCR-ABL1 kinase domain
  • prevents phosphorylation of tyrosine residues on its substrates
  • drug resistance occurs often due to point mutations in BCR-ABL1 that prevent binding of the inhibitor
    • second and third generation TKI s are designed to bypass these point mutations
    • Nilotinib, Dasatinnib, Bosutinib, Ponatinib
31
Q

What is the molecular basis of transformation ?

A
  • it is unknown
  • progression is usually associated with clonal evolution
    • transition from AP to BP, 80% of cases have additional cytogenetic changes
    • major route cytogenetic abnormalities
      • extra Ph chromosome
      • isochromocome 17q
      • gain of chromosome 8 or 19
    • presence of any of the above abnormalities at the initial diagnosis is an indicator of poor prognosis and places the case in AP
32
Q

What genes have been reported to be altered

in the transformed stages of CML ?

A

*exact role of these is uncertain

  • TP53
  • RB1
  • MYC
  • CDKN2A (p16INK4a)
  • NRAS
  • KRAS
  • RUNX1 (AML1)
  • MECOM (EVI1)
  • TET2
  • CBL
  • ASXL1
  • IDH1 and IDH2
33
Q

What are the prognostic and predictive factors

in CML ?

A
  • the most important prognostic indicator is response to treatment at the hematological, cytogenetic and molecular level
    • overall the completel cytogenetic response rate to first line TKI is 75-90% with 5-year progression free survival
    • overall survival rates 80-90%

Note: today few patients die from leukemia and overall survival is that of non-leukemic population

34
Q

What mutation in the kinase domain

can confer resistance to most TKI s?

Which TKI still works?

A
  • T3I5I mutation in kinase domain confers resistance
  • Ponatinib
    • only TKI found to be effective in light of mutation

Hematopathology WHO MPN, Mastocytosis, MPN/MDS, & MDS (17 decks)

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