B-Lymphoblastic Leukemia/Lymphoma with Recurrent Genetic Abnormalities Flashcards
What is the definition of B-ALL with
t(9;22)(q34.1;q11.2), BCR-ABL1 ?
- specific type of B-ALL where the blasts harbor the BCR-ABL1 translocation
- BCR on chromosome 22
- ABL1 on chromsome 9
What is the epidemiology of t(9;22) B-ALL ?
- relatively more common in adults than in children
- account for ~25% of adult ALL
- only 2-4% of childhood cases
What are the clinical features of B-ALL with BCR-ABL1 ?
- 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
What is the immunophenotype of B-ALL
with BCR-ABL1 ?
- 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
What is the cell of origin for B-ALL
with BCR-ABL1 ?
- some evidence that this cell of origin is more immature than that of other B-ALL cases
What are the key genetic findings/features of
B-ALL with t(9;22) ?
- 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
What are the prognosis and predictive
factors for B-ALL with BCR-ABL1 ?
- 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
What is the definition of B-ALL with
t(v;11q23.3) or KMT2A rearrangement ?
- 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.
What is the epidemiology of B-ALL
with KMT2A rearrangement ?
- most common leukemia in infants aged <1 year old
- less common in older children
- increases in incidence with increasing age into adulthood
What is the etiology of B-ALL with KMT2A rearrangement ?
- etiology is truly unknown
- KMT2A translocations can occur in utero with a short latency between the translocation and development of the malignancy
What are the clinical features of B-ALL
with KMT2A ?
- 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
What are characteristic findings on microscopy
in B-ALL with KMT2A ?
- 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
What is the immunophenotype of B-ALL
with KMT2A ?
- 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
What is the genetic profile seen in B-ALL with
KMT2A ?
- 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
What are the major translocations partners
of KMT2A ?
- 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)
What is the prognosis and predictive
factors for B-ALL with KMT2A ?
- KMT2A-AFF1 - poor prognosis
- Debate about if other KMT2A translocations also have poor prognosis
- infants. < 6 months have a particularly poor prognosis
What is the epidemiology and clinical features of B-ALL with
t(12;21)(p12.2;q22.1)// ETV6-RUNX1 ?
- 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
What is the immunophenotype for
B-ALL with ETV6-RUNX1 ?
- 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
What is another name for ETV6-RUNX1 ?
- TEL/AML1
What are the key genetic considerations in
B-ALL with ETV6-RUNX1 ?
- 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
What are the prognostic and predictive factors
of B-ALL with ETV6-RUNX1 ?
- 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
What is the definition of
B-ALL with hyperdiploidy ?
- 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
What is the epidemiology of B-ALL
with hyperdiploidy ?
- 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
What is the immunophenotype of B-ALL
with hyperdiploidy ?
- CD19 and CD10 positive
- CD34 is positive in most cases and CD45 is usually negative
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
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
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
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
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)
What is the distinct genetic lesion
associated with near-haploid ALL ?
- RAS or receptor tyrosine kinase mutations
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
- some of the TP53 mutations are germline
IMP: these lesions do not occur with high hypodiploid ALL
- it does not have any specific gene alterations
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
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
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
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
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
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
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
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
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
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
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
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
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
- IGH/CRLF2
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
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
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
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
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
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
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
- translocations between PDGFRB and EBF1
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
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
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
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
- many other chromosome abnormalities are seen, most common include:
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
