Chronic Myeloid Leukemia BCR-ABL1 Positive Flashcards
What is the definition of CML ?
- 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
What is the epidemiology of CML ?
- 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
What is the etiology of CML ?
- 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
What is the localization of CML ?
- 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
What are the clinical features of CML ?
- 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
What is an atypical presentation for CML ?
- marked thrombocytosis without leukocytosis
- this mimics ET or other MPNs
Note:
- ~5% cases are diagnosed in accelerated or blast phase
What are the clinical findings of patient’s
the present in accelerated or blast phase ?
- declining performance status
- fever, weight loss
- symptoms related to anemia, thrombocytopenia, increased WBC
- splenic enlargement (blast phase)
With TKI therapy what is the
projected 10 year overall outcome ?
- 80-90%
What are the microscopic features
of chronic phase ?
- 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
What is necessary for diagnosis of CML ?
- 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
What are the typical microscopic
findings in the bone marrow in chronic phase ?
- 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
What is the characteristic morphology
of the megakaryocytes ?
- 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
What is the normal reticulin
fibrosis present in CML ?
- 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
What is the cause of splenic enlargement
in CML ?
- caused by infiltration of the red pulp by mature and immature granulocytes
- similar infiltrate can be seen in the hepatic sinuses and portal areas
How has diagnosis of CML phases changed ?
- 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
What are the characteristics of
accelerated phase of CML ?
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
What are the usual additional clonal
chromosomal abnormalities present
in accelerated phase CML ?
- 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
What are the provisional response to TKI
critiera that can define accelerated phase ?
- 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
What can be seen during AP in CML
that is not seen in CP ?
- 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
What do lymphoblasts likely signifiy in CML ?
- 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
What features are diagnostic of blast phase
of CML ?
- >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.
What is the definition of a complete hematological
response in CML ?
- 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
Where do extramedullary blast
proliferations tend to occur in CML ?
- 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
What key immunophenotypic expressions are
present in CML ?
- 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
What antigens do the myeloid blasts in BP usually express ?
- 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
What can be seen in lymphoblasts of BP CML ?
- 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)
What is the cell of origin
in CML ?
- abnormal, pluripotent bone marrow stem cells
- disease progression may occur in more commited cells
What is the genetic profile of CML ?
- 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
What are the breakpoints in CML ?
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
What was the first drug created to
treat CML ?
- 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
What is the molecular basis of transformation ?
- 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
What genes have been reported to be altered
in the transformed stages of CML ?
*exact role of these is uncertain
- TP53
- RB1
- MYC
- CDKN2A (p16INK4a)
- NRAS
- KRAS
- RUNX1 (AML1)
- MECOM (EVI1)
- TET2
- CBL
- ASXL1
- IDH1 and IDH2
What are the prognostic and predictive factors
in CML ?
- 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
What mutation in the kinase domain
can confer resistance to most TKI s?
Which TKI still works?
- T3I5I mutation in kinase domain confers resistance
- Ponatinib
- only TKI found to be effective in light of mutation
