B-Lymphoblastic Leukemia/Lymphoma with Recurrent Genetic Abnormalities Flashcards
(57 cards)
1
Q
What is the definition of B-ALL with
t(9;22)(q34.1;q11.2), BCR-ABL1 ?
A
- specific type of B-ALL where the blasts harbor the BCR-ABL1 translocation
- BCR on chromosome 22
- ABL1 on chromsome 9
2
Q
What is the epidemiology of t(9;22) B-ALL ?
A
- relatively more common in adults than in children
- account for ~25% of adult ALL
- only 2-4% of childhood cases
3
Q
What are the clinical features of B-ALL with BCR-ABL1 ?
A
- similar to those seen in B-ALL NOS
- in children they are high risk based on age and white blood cell count
- there may be organ involvement with this subtype but lymphomatous presentations are rare
4
Q
What is the immunophenotype of B-ALL
with BCR-ABL1 ?
A
- the histology is not unique and looks like other B-ALL
- Immunophenotype
- positive for: CD10, CD19, and TdT
- frequently positive for CD13, CD33 but should be negative for CD117
- IMP
- CD25 positivity is associated with BCR-ABL in adults
Note: rare cases of ALL with BCR-ABL1 have a T-cell precursor phenotype
5
Q
What is the cell of origin for B-ALL
with BCR-ABL1 ?
A
- some evidence that this cell of origin is more immature than that of other B-ALL cases
6
Q
What are the key genetic findings/features of
B-ALL with t(9;22) ?
A
- t(9;22)
- occurs from fusion of BCR at 22q11.2 and the cytoplasmic tyrosine kinas ABL1 at 9q34.1
- childhood cases
- p190 fusion is produced
- adult cases
- about half the cases produce p210 fusion protein similar to CML
- while the remainder produce p190
- No clinical differences are attributed to the different gene products
7
Q
What are the prognosis and predictive
factors for B-ALL with BCR-ABL1 ?
A
- both in children and adults, B-ALL with BCR-ABL1 is thought to have the worst prognosis of the major cytogenetic subtypes
- this is partially due to the fact that it is more common in adults
- Favorable clinical featues in kids include:
- younger age
- lower WBC count
- response to therapy
- IMP
- treatment with TKIs has had a signifiant favorable outcome
8
Q
What is the definition of B-ALL with
t(v;11q23.3) or KMT2A rearrangement ?
A
- blasts harbor translocation between KMT2A (MLL) at band 11q23.3
- there can be many different fusion partners
- break apart probe by FISH
IMP: leukemias that have deletions of 11q23.2 without KMT2A rearrangement are not included in this group.
9
Q
What is the epidemiology of B-ALL
with KMT2A rearrangement ?
A
- most common leukemia in infants aged <1 year old
- less common in older children
- increases in incidence with increasing age into adulthood
10
Q
What is the etiology of B-ALL with KMT2A rearrangement ?
A
- etiology is truly unknown
- KMT2A translocations can occur in utero with a short latency between the translocation and development of the malignancy
11
Q
What are the clinical features of B-ALL
with KMT2A ?
A
- usually patients present with a very high WBC
- > 100 x10^9/L
- also very high frequency of CNS involvement
- organ involvement may be seen
- but pure lymphomatous presentations are not typical
12
Q
What are characteristic findings on microscopy
in B-ALL with KMT2A ?
A
- no unique morphological or cytochemical findings
- IMP
- in some cases it is possible to distinguish a lymphoblastic and monoblastic population
- but in these cases, it should be called a B/Myeloid leukemia
13
Q
What is the immunophenotype of B-ALL
with KMT2A ?
A
- for cases with the t(4;11)
- CD19+, CD10-, CD24-
- CD15+
- pro-B immunophenotype
- also the NG2 homologue encoded by CSPG4 is also characteristically expressed and is relatively specific
14
Q
What is the genetic profile seen in B-ALL with
KMT2A ?
A
- KMT2A gene is on chromosome 11q.23.3 and it is a very promiscuous oncogene
- > 100 fusion partners
- translocations can be identified by:
- standard karyotype
- FISH with break apart probe
- PCR for major translocation partners but a negative result would not exclude any translocations
- Leukemias with KMT2A are often associated with overexpression of FLT3.
- B-ALL with KMT2A has very few associated additional mutations
15
Q
What are the major translocations partners
of KMT2A ?
A
- AFF1 (AF4)- most common partner, chromosome 4q21
- Other partner genes
- MLLT1 ( chromosome 19p13.3)
- fusion with this gene is also seen inT-ALL
- MLLT3 (chromosome 9p21.3)
- fusion with this gene are also commonly seen in AML
- MLLT1 ( chromosome 19p13.3)
16
Q
What is the prognosis and predictive
factors for B-ALL with KMT2A ?
A
- KMT2A-AFF1 - poor prognosis
- Debate about if other KMT2A translocations also have poor prognosis
- infants. < 6 months have a particularly poor prognosis
17
Q
What is the epidemiology and clinical features of B-ALL with
t(12;21)(p12.2;q22.1)// ETV6-RUNX1 ?
A
- this B-ALL is NOT seen in infants
- most frequent in children
- 25% of all cases
- decreases in frequency with age
- rare in adulthood
- Clinical features are the same as other B-ALL
- Also no unique morphological or cytochemical features
18
Q
What is the immunophenotype for
B-ALL with ETV6-RUNX1 ?
A
- positive for CD19, CD10 and CD34 (usually)
- complete absence of CD9, CD20 and CD66c are relatively specific
- CD13 (myeloid associated antigen)
- frequently expressed
- it is thought this derives from a B-cell progenitor rather than a stem cell
19
Q
What is another name for ETV6-RUNX1 ?
A
- TEL/AML1
20
Q
What are the key genetic considerations in
B-ALL with ETV6-RUNX1 ?
A
- the fusion protein is thought to interfere with normal function of the transciption factor RUNX1
- considered to be an early lesion in leukemogenesis but alone is not sufficient to cause leukemia
- demonstrated by fusion FISH probes
21
Q
What are the prognostic and predictive factors
of B-ALL with ETV6-RUNX1 ?
A
- favorable prognosis
- cure rate of. >90%
- relapses occur much later than other types of ALL
- children with adverse prognostic factors such as:
- age >10 years
- high WBC count
- do not have as good of a prognosis
22
Q
What is the definition of
B-ALL with hyperdiploidy ?
A
- leukemia whose blasts contain > 50 chromsomes but < 66
- typically without translocations or other alterations
- debate about whether specific extra chromsomes should be part of the definition or just extra chromosomes in general
23
Q
What is the epidemiology of B-ALL
with hyperdiploidy ?
A
- common in children and accounts for ~25% of cases
- NOT seen in infants
- decreases in frequency among older children
- uncommon in adults
- 8% of cases
- Clinical features are generally similar to those of other ALL
- No unique features on microscopy
24
Q
What is the immunophenotype of B-ALL
with hyperdiploidy ?
A
- CD19 and CD10 positive
- CD34 is positive in most cases and CD45 is usually negative
25
What are the specific genetic considerations in
B-ALL with hyperdiploidy ?
* B-ALL with extra chromosomes
* The chromosomes are NOT random
* 21, X, 14 and 4 are the most commonly seen
* 1, 2, and 3 are the least common seen
* These can be detected by conventional karyotyping, FISH or flow cytometric DNA index
* CAUTION: some cases by karyotype of hyperdiploid ALL may actually be hypodiploid that has undergone endoreduplication (doubling of chromsomes)
* Chromsomes 4 and 10
* carry the best prognosis
26
What are the prognosis and predictive
factors of hyperdiploid B-ALL ?
* very favorable prognosis with cure rates seen in \>90% of cases
* even in children with adverse prognostic features
* advanced patient age
* high WBC count
* too few adults have been studied with this to determine prognosis
27
What is the definition of hypodiploid B-ALL ?
* blasts contain \<46 chromosomes
* Three (sometimes 4 categories)
* near haploid ALL (23-29 chromosomes)
* low hypodiploid (33-39 chromosomes)
* high hypodiploid (40-43 chromsomes)
* Fourth category sometimes seen
* near diploid ALL (44-45 chromsomes)
* not included at least for treatment purposes because they do not share the poor prognostic features of the other 3 categories
28
What is the epidemiology of hypodiploid
B-ALL ?
* about 5% of all ALL cases
* but if you restrict the definition to \<45 chromosomes it accounts for only 1% of all cases
* occurs in both children and adults
* but near-haploid ALL (23-29 chromosomes) is mostly seen in children
* No unique clinical or morphologic features
* No unique immunophenotype
29
What are key considerations in the genetic
profile of hypodiploid B-ALL ?
* structural abnormalities can be present in the remaining chromosomes (though none are specific)
* but nearly never seen in near-haploid ALL
* Near-haploid ALL can be missed by karyotyping
* due to endoreduplication
* generally flow and FISH will show chromosomes that are hypodiploid or DNA \<1 (flow)
30
What is the distinct genetic lesion
associated with near-haploid ALL ?
* RAS or receptor tyrosine kinase mutations
31
What are the distinctive genetic lesions
associated with low hypodiploid ALL ?
* most distinctive class
* loss of function mutations in TP53 and RB1
* some of the TP53 mutations are germline
* suggests a form of Li Fraumeni syndrome
IMP: these lesions do not occur with high hypodiploid ALL
* it does not have any specific gene alterations
32
What are the prognosis and predictive
factors for hypodiploid ALL ?
* poor prognosis
* near haploid ALL having the worst prognosis
IMP: in this category there is some evidence that even if there is no MRD after treatment these patients still fair poorly
33
What is the definition of B-ALL with
t(5;14)(q31.1;q32.1), IGH-IL3 ?
* blasts harbor a translocation between IL3 and IGH gene
* results in variable eosinophilia
* this diagnosis can be made based on the genetics even if the bone marrow blast percentage is low
34
What is the epidemiology and clinical features of B-ALL with
IL-3-IGH t(5;14) ?
* very rare ALL, \<1% of all cases
* occurs in both kids and adults
* clinical features are similar with the exception of asymptomatic eosinophilia
* blasts may be absent from the PB
35
What are the microscopic and immunophenotypic
findings of B-ALL with IL-3-IGH ?
* blasts have the typical morphology
* marked eosinophilia is associated with this neoplasm
* eos are reactive and not part of the clone \*\*
* blasts have the usual CD19+ and CD10+ immunophenotype
36
What are the genetic considerations for
B-ALL with IL-3/IGH ?
* IL3 gene is on chromosome 5
* IHG gene is on chromosome 14
* other than eosinophilia the functional consequences of this rearrangement are not completely understood
* Can be detected by:
* conventional karyotype
* FISH
* but the probes are not widely available
37
What are the prognostic and predictive
factors for B-ALL with IL-3/IGH ?
* prognosis is not thought to be different than other types of ALL
* but there are really too few cases to be certain
* blast percentage at diagnosis is not known to be a predictive factor
38
What is the definition of B-ALL with t(1;19)(q23;p13.3)
TCF3-PBX1 ?
* this is a translocation between TCF3 (also known as E2A on chromosome 19 and PBX1 on chromosome 1
39
What is the etiology, clinical and microscopic
features of B-ALL with t(1;19) ?
* this translocation is relatively common in children
* accounts for about 6% of cases of B-ALL
* it is less common in adults
* clinical features are the same
* microscopic features are the same
40
What is the immunophenotype of the
blasts in B-ALL with
t(1;19) ?
* blasts typically have a pre-B phenotype
* positive for CD19, CD10 and cytoplasmic mu chain
* IMP
* not all cases of pre-B-ALL have the t(1;19)
* diagnosis can be suspected even if cytoplasmic mu is not detected
* leukemias show
* strong expression of CD9
* lack CD34 or very little CD34 on a minor portion of leukemic cells
41
What is the genetic profile for B-ALL with
t(1;19) ?
* this oncogenic fusion protein interferes with normal function of the transcription factors coded by TCF3 and PBX1
* this is a unique lesion identified by gene expression profiling
* Alternative translocation:
* t(17;19) TCF3 with HLF
* associated with dismal prognosis
* IMP:
* a subset of B-ALL cases, hyperdiploid type, have a karyotype identical to t(1;19) that does not involve either TCF3 or PBX1
* these entities should not be considered the same
42
What are the prognosis and predictive factors
for B-ALL with t(1;19), TCF3-PBX1 ?
* in early studies it was associated with a poor prognosis, but with modern intensive therapy they do ok
* BUT
* increased relative risk of CNS relapse
43
What is the definition of B-ALL,
BCR-ABL1- like ?
* lack BCR-ABL1 translocation but by gene expression profiling show a similar pattern to those with the BCR-ABL1 translocation
* Often have translocations affecting other tyrosine kinases:
* alternative translocations involving CRLF2
* less commonly, rearrangements leading to truncation and activation of the EPO receptor
44
What is the epidemiology of B-ALL with
BCR-ABL1-like ?
* this leukemia is relatively common, 10-25% of ALL patients
* progressively higher incidence in kids with high risk ALL, adolescents and adults
* Down Syndrome kids
* very high frequency of ALL with CRLF2 translocation
* Frequency of some genomic alterations vary with ethnicity
* IGH/CRLF2
* more comon in hispanics and Native Americans
45
What is the etiology of
BCR-ABL1-like B-ALL ?
* no definitive details on etiology
* certain inherited GATA3 variants confer an increased risk of this entity
46
What are the clinical and microscopic findings
of BCR-ABL1-like B-ALL ?
* generally similar clinical presentation
* tend to havce higher WBC counts
* No unique morphologic or cytochemical features
47
What is the immunophenotype of
BCR-ABL1-like B-ALL ?
* Blasts usually have a CD19+ CD10+ phenotype
* CRLF2 translocation cases
* can show very high levels of expression of the protein by flow cytometry
* can be used to screen for cases with this translocation
* No specific immunophenotypic features for cases with translocations involving EPOR or tyrosine kinases
48
What are the key considerations for the
genetic profile for BCR-ABL1 like B-ALL ?
* show various types of chromosomal rearrangements
* involve many genes and gene partners
* CRLF2 rearrangments
* account for 1/2 the cases
* often show an interstitial deletion of PAR1 family gene on Xp22.3 and Yp11.3
* this juxtaposes CRLF2 to the promoter of the P2RY8 gene
* also an alternative translocation involving IGH
49
What is true regarding the alternative tyrosine kinase type
translocations in BCR-ABL1-like B-ALL ?
* reported to involve ABL1 with partners other than BCR
* more than 30 partner genes have been described
* Kinase translocations only rarely exist with CRLF2 rearrangements
50
What modalities can be used to detect genetic alterations
in BCR-ABL1-like B-ALL ?
* some can be detected by standard karyotype but many are cryptic
* particularly those involving the interstitial deletion of CRLF2
* Also many cases show deletions or mutations in other genes known to be important in leukemogenesis
* IKZF1
* CDKN2A/B
* IMP
* about 1/2 the cases with CRLF2 rearranged ALL show mutations in JAK2 or JAK1
51
What are the prognosis and predictive factors for
BCR-ABL1-like B-ALL ?
* overall poor prognosis
* higher risk of positive MRD
* CRLF2 translocations have specifically been associated with poor outcomes
* Resistance to induction chemotherapy has been most frequently seen with:
* translocations between PDGFRB and EBF1
* these patients respond to TKIs like Imatinib
52
What is the definition of B-ALL with
iAMP21 ?
* amplification of a portion of chromosome 21
* typically detected by FISH
* probe is for RUNX1
* shows \>5 copies of the gene or
* \>3 extra copies on a single abnormal chromosome 21
53
What is the epidemiology of
B-ALL with iAMP21 ?
* low incidence, 2% of cases in children
* uncertain about incidence in adults
* more common in older children who present with lower WBC counts
54
What is the etiology, clinical features and microscopic
findings of B-ALl with iAMP21 ?
* not sure but people with rare constitutional Robertsonian translocation rob(15;21)
* 3000 fold risk of developing leukemia
* no unique clinical or morphologic features
55
What are the important genetic considerations
in B-ALL with iAMP21 ?
* disease is detected with FISH probes against ETV6-RUNX1 but the disease does not involve pathogenesis of RUNX1
* in 20% of cases this is the only abnormality
* many other chromosome abnormalities are seen, most common include:
* gains of chromsome X and abnormalities of chromosome 7
* also associated with deletions of RB1 and ETV6, also have rearrangments of CRLF2 (greater frequency than other ALLs)
* IMP: role of all these alterations is uncertain
56
What are the prognostic and predictive
factors of B-ALL with iAMP21 ?
* relatively poor prognosis among kids
* but it is militated with more intensive chemotherapy
57
