Compendium of Cancer Genome Aberrations

HAEM5:Acute myeloid leukaemia with BCR::ABL1 fusion: Difference between revisions

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==WHO Essential and Desirable Genetic Diagnostic Criteria==
{| class="wikitable"
|+
|WHO Essential Criteria (Genetics)*
|a myeloid neoplasm with >20% blasts expressing a myeloid immunophenotype in the bone marrow and/or peripheral blood; detection of ''BCR::ABL1'' at initial diagnosis; lack of features of chronic myeloid leukaemia (CML) before or at diagnosis or after therapy.
|-
|WHO Desirable Criteria (Genetics)*
|presence of t(9;22)(q34;q11.2) on conventional karyotyping; determination of the ''BCR::ABL1'' transcript subtype and establishment of a baseline level of ''BCR::ABL1'' transcript subtype and establishment of a baseline level of ''BCR::ABL1'' transcript for monitoring treatment response.
|-
|Other Classification
|
|}
<nowiki>*</nowiki>Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the [https://tumourclassification.iarc.who.int/home <u>WHO Classification of Tumours</u>].
==Related Terminology==
==Related Terminology==
{| class="wikitable"
{| class="wikitable"
|+
|+
|Acceptable
|Acceptable
|acute myeloid leukaemia with t(9;22)(q34;q11.2)
|Acute myeloid leukaemia with t(9;22)(q34;q11.2)
|-
|-
|Not Recommended
|Not Recommended
|
|N/A
|}
|}


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|t(9;22)(q34;q11.2)
|t(9;22)(q34;q11.2)
|Common (CML); Rare (AML).<!-- The new version WHO indicates BCR::ABL1 is rare in AML, only accounts less than 0.5%, but the literature I found typically is 0.5-3%, the previous version also indicates the prevalence is <3%. Pls advice which number I should use. -->
|Common (CML); Rare (AML).<!-- The new version WHO indicates BCR::ABL1 is rare in AML, only accounts less than 0.5%, but the literature I found typically is 0.5-3%, the previous version also indicates the prevalence is <3%. Pls advice which number I should use. -->
|'''Diagnosis:''' BCR-ABL1 positive AML is an emerging entity. The proliferation of ''BCR-ABL1'' positive blasts present a diagnostic dilemma. While it may be difficult, it is essential to distinguish between BCR-ABL1 positive AML and Chronic Myeloid Leukemia in Myeloid Blast Crisis (CML-MBC), in order to choose the most appropriate therapy (e.g., intensive induction chemotherapy versus tyrosine kinase inhibitor (TKI) followed by an early allogeneic stem cell transplant). After the exclusion of acute leukemia of ambiguous lineage (a separate entity according to WHO) by flow cytometry, it is helpful to note any past history of antecedent hematological disease. Compared to CML-MBC, a higher percentage of blasts (median: 47% vs 13%), a lower percentage of basophils (median: 0% vs 2.5%) and absolute basophil count, a lower frequency of splenomegaly (25% vs 65%), lower cellularity, fewer dwarf megakaryocytes, and normal M:E ratio favor the diagnosis of BCR-ABL1 positive AML<ref name=":4" /><ref name=":3" />. The detection of p190 transcript and the occurrence of any BCR-ABL1 transcript in less than 100% of metaphases supports the diagnosis of AML rather than CML. Persistent CCyR (Complete Cytogenetic Response) after conventional chemotherapy is unusual for CML-MBC and supports the diagnosis of BCR-ABL1 positive AML<ref name=":2" />. Karyotype analysis that identifies the t(9;22)(q34;q11.2) translocation, either alone or in conjunction with additional chromosomal abnormalities, characterizes BCR-ABL1 positive AML<ref name=":3" /><ref name=":4" />. In addition, molecular methods including dual-colour dual-fusion FISH, RT-PCR, qPCR, and RNA or DNA sequencing are used to identify all common breakpoint variants when applicable.   
|Diagnosis: BCR-ABL1 positive AML is an emerging entity. The proliferation of ''BCR-ABL1'' positive blasts present a diagnostic dilemma. While it may be difficult, it is essential to distinguish between BCR-ABL1 positive AML and Chronic Myeloid Leukemia in Myeloid Blast Crisis (CML-MBC), in order to choose the most appropriate therapy (e.g., intensive induction chemotherapy versus tyrosine kinase inhibitor (TKI) followed by an early allogeneic stem cell transplant). After the exclusion of acute leukemia of ambiguous lineage (a separate entity according to WHO) by flow cytometry, it is helpful to note any past history of antecedent hematological disease. Compared to CML-MBC, a higher percentage of blasts (median: 47% vs 13%), a lower percentage of basophils (median: 0% vs 2.5%) and absolute basophil count, a lower frequency of splenomegaly (25% vs 65%), lower cellularity, fewer dwarf megakaryocytes, and normal M:E ratio favor the diagnosis of BCR-ABL1 positive AML<ref name=":4" /><ref name=":3" />. The detection of p190 transcript and the occurrence of any BCR-ABL1 transcript in less than 100% of metaphases supports the diagnosis of AML rather than CML. Persistent CCyR (Complete Cytogenetic Response) after conventional chemotherapy is unusual for CML-MBC and supports the diagnosis of BCR-ABL1 positive AML<ref name=":2" />. Karyotype analysis that identifies the t(9;22)(q34;q11.2) translocation, either alone or in conjunction with additional chromosomal abnormalities, characterizes BCR-ABL1 positive AML<ref name=":3" /><ref name=":4" />. In addition, molecular methods including dual-colour dual-fusion FISH, RT-PCR, qPCR, and RNA or DNA sequencing are used to identify all common breakpoint variants when applicable.   




'''Prognosis:''' The overall prognosis of BCR-ABL1 positive AML is poor, with a median survival time of <9 months<ref>{{Cite journal|last=Cuneo|first=A.|last2=Ferrant|first2=A.|last3=Michaux|first3=J. L.|last4=Demuynck|first4=H.|last5=Boogaerts|first5=M.|last6=Louwagie|first6=A.|last7=Doyen|first7=C.|last8=Stul|first8=M.|last9=Cassiman|first9=J. J.|date=1996|title=Philadelphia chromosome-positive acute myeloid leukemia: cytoimmunologic and cytogenetic features|url=https://pubmed.ncbi.nlm.nih.gov/8952155|journal=Haematologica|volume=81|issue=5|pages=423–427|issn=0390-6078|pmid=8952155}}</ref><ref name=":3" />. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for AML categorize this entity into the poor-risk group, comparable with complex aberrant karyotype AML<ref name=":6">Pollyea DA, Altman JK, (2025). NCCN Clinical Practice Guidelines in Oncology: AML. Version 2. Available at: NCCN.org.</ref>. It appears that the prognosis of BCR-ABL1 positive AML depends more on the genetic background (concurrent aberrations) than on BCR-ABL1 itself. Unlike in CML, BCR-ABL1 does not appear to be the key driver in AML though may provide a proliferative advantage to a particular BCR-ABL1 positive subclone.
Prognosis: The overall prognosis of BCR-ABL1 positive AML is poor, with a median survival time of <9 months<ref>{{Cite journal|last=Cuneo|first=A.|last2=Ferrant|first2=A.|last3=Michaux|first3=J. L.|last4=Demuynck|first4=H.|last5=Boogaerts|first5=M.|last6=Louwagie|first6=A.|last7=Doyen|first7=C.|last8=Stul|first8=M.|last9=Cassiman|first9=J. J.|date=1996|title=Philadelphia chromosome-positive acute myeloid leukemia: cytoimmunologic and cytogenetic features|url=https://pubmed.ncbi.nlm.nih.gov/8952155|journal=Haematologica|volume=81|issue=5|pages=423–427|issn=0390-6078|pmid=8952155}}</ref><ref name=":3" />. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for AML categorize this entity into the poor-risk group, comparable with complex aberrant karyotype AML<ref name=":6">Pollyea DA, Altman JK, (2025). NCCN Clinical Practice Guidelines in Oncology: AML. Version 2. Available at: NCCN.org.</ref>. It appears that the prognosis of BCR-ABL1 positive AML depends more on the genetic background (concurrent aberrations) than on BCR-ABL1 itself. Unlike in CML, BCR-ABL1 does not appear to be the key driver in AML though may provide a proliferative advantage to a particular BCR-ABL1 positive subclone.




'''Therapeutics:''' There is currently no standardized treatment approach for BCR-ABL1 positive AML. Therapy with TKI alone does not produce sustained responses in BCR-ABL1 positive AML<ref name=":3" />. This may be due to a very rapid clonal evolution, resulting in resistance in a much higher proportion of patients and in a significantly shorter time than in CML<ref name=":2" />.Venetoclax and TKI combination regimens have shown good response in some studies<ref>{{Cite journal|last=Maiti|first=Abhishek|last2=Franquiz|first2=Miguel J.|last3=Ravandi|first3=Farhad|last4=Cortes|first4=Jorge E.|last5=Jabbour|first5=Elias J.|last6=Sasaki|first6=Koji|last7=Marx|first7=Kayleigh|last8=Daver|first8=Naval G.|last9=Kadia|first9=Tapan M.|date=2020|title=Venetoclax and BCR-ABL Tyrosine Kinase Inhibitor Combinations: Outcome in Patients with Philadelphia Chromosome-Positive Advanced Myeloid Leukemias|url=https://pubmed.ncbi.nlm.nih.gov/32289808|journal=Acta Haematologica|volume=143|issue=6|pages=567–573|doi=10.1159/000506346|issn=1421-9662|pmc=7839068|pmid=32289808}}</ref>.
Therapeutics: There is currently no standardized treatment approach for BCR-ABL1 positive AML. Therapy with TKI alone does not produce sustained responses in BCR-ABL1 positive AML<ref name=":3" />. This may be due to a very rapid clonal evolution, resulting in resistance in a much higher proportion of patients and in a significantly shorter time than in CML<ref name=":2" />.Venetoclax and TKI combination regimens have shown good response in some studies<ref>{{Cite journal|last=Maiti|first=Abhishek|last2=Franquiz|first2=Miguel J.|last3=Ravandi|first3=Farhad|last4=Cortes|first4=Jorge E.|last5=Jabbour|first5=Elias J.|last6=Sasaki|first6=Koji|last7=Marx|first7=Kayleigh|last8=Daver|first8=Naval G.|last9=Kadia|first9=Tapan M.|date=2020|title=Venetoclax and BCR-ABL Tyrosine Kinase Inhibitor Combinations: Outcome in Patients with Philadelphia Chromosome-Positive Advanced Myeloid Leukemias|url=https://pubmed.ncbi.nlm.nih.gov/32289808|journal=Acta Haematologica|volume=143|issue=6|pages=567–573|doi=10.1159/000506346|issn=1421-9662|pmc=7839068|pmid=32289808}}</ref>.
|Yes (WHO, NCCN)
|Yes (WHO, NCCN)
|The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context<ref>{{Cite journal|last=Cross|first=Nicholas C. P.|last2=Ernst|first2=Thomas|last3=Branford|first3=Susan|last4=Cayuela|first4=Jean-Michel|last5=Deininger|first5=Michael|last6=Fabarius|first6=Alice|last7=Kim|first7=Dennis Dong Hwan|last8=Machova Polakova|first8=Katerina|last9=Radich|first9=Jerald P.|date=2023-11|title=European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/37794101|journal=Leukemia|volume=37|issue=11|pages=2150–2167|doi=10.1038/s41375-023-02048-y|issn=1476-5551|pmc=10624636|pmid=37794101}}</ref><ref>{{Cite journal|last=Sawyers|first=C. L.|date=1999-04-29|title=Chronic myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/10219069|journal=The New England Journal of Medicine|volume=340|issue=17|pages=1330–1340|doi=10.1056/NEJM199904293401706|issn=0028-4793|pmid=10219069}}</ref>. The prevalence of BCR"" ABL1 in CML is common ~90-95%<ref>{{Cite journal|last=Sharma|first=Diwakar|last2=Wilson|first2=Christine|last3=Kumar|first3=Sachin|last4=Ghose|first4=Sampa|last5=Sahoo|first5=Ranjit|last6=Sharawat|first6=Surender K.|date=2024-08-01|title=Does presence of complex translocations involving BCR::ABL1 in chronic myeloid leukemia affect the response rate to tyrosine kinase inhibitors? A systematic review of the literature|url=https://linkinghub.elsevier.com/retrieve/pii/S1092913424000406|journal=Annals of Diagnostic Pathology|volume=71|pages=152303|doi=10.1016/j.anndiagpath.2024.152303|issn=1092-9134}}</ref>. This fusion is responsive to targeted therapy such as Imatinib (Gleevec)<ref>{{Cite journal|last=Cortes|first=Jorge E.|last2=Talpaz|first2=Moshe|last3=Giles|first3=Francis|last4=O'Brien|first4=Susan|last5=Rios|first5=Mary Beth|last6=Shan|first6=Jianqin|last7=Garcia-Manero|first7=Guillermo|last8=Faderl|first8=Stefan|last9=Thomas|first9=Deborah A.|date=2003-05-15|title=Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy|url=https://pubmed.ncbi.nlm.nih.gov/12560227|journal=Blood|volume=101|issue=10|pages=3794–3800|doi=10.1182/blood-2002-09-2790|issn=0006-4971|pmid=12560227}}</ref>.  
|The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context<ref>{{Cite journal|last=Cross|first=Nicholas C. P.|last2=Ernst|first2=Thomas|last3=Branford|first3=Susan|last4=Cayuela|first4=Jean-Michel|last5=Deininger|first5=Michael|last6=Fabarius|first6=Alice|last7=Kim|first7=Dennis Dong Hwan|last8=Machova Polakova|first8=Katerina|last9=Radich|first9=Jerald P.|date=2023-11|title=European LeukemiaNet laboratory recommendations for the diagnosis and management of chronic myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/37794101|journal=Leukemia|volume=37|issue=11|pages=2150–2167|doi=10.1038/s41375-023-02048-y|issn=1476-5551|pmc=10624636|pmid=37794101}}</ref><ref>{{Cite journal|last=Sawyers|first=C. L.|date=1999-04-29|title=Chronic myeloid leukemia|url=https://pubmed.ncbi.nlm.nih.gov/10219069|journal=The New England Journal of Medicine|volume=340|issue=17|pages=1330–1340|doi=10.1056/NEJM199904293401706|issn=0028-4793|pmid=10219069}}</ref>. The prevalence of BCR"" ABL1 in CML is common ~90-95%<ref>{{Cite journal|last=Sharma|first=Diwakar|last2=Wilson|first2=Christine|last3=Kumar|first3=Sachin|last4=Ghose|first4=Sampa|last5=Sahoo|first5=Ranjit|last6=Sharawat|first6=Surender K.|date=2024-08-01|title=Does presence of complex translocations involving BCR::ABL1 in chronic myeloid leukemia affect the response rate to tyrosine kinase inhibitors? A systematic review of the literature|url=https://linkinghub.elsevier.com/retrieve/pii/S1092913424000406|journal=Annals of Diagnostic Pathology|volume=71|pages=152303|doi=10.1016/j.anndiagpath.2024.152303|issn=1092-9134}}</ref>. This fusion is responsive to targeted therapy such as Imatinib (Gleevec)<ref>{{Cite journal|last=Cortes|first=Jorge E.|last2=Talpaz|first2=Moshe|last3=Giles|first3=Francis|last4=O'Brien|first4=Susan|last5=Rios|first5=Mary Beth|last6=Shan|first6=Jianqin|last7=Garcia-Manero|first7=Guillermo|last8=Faderl|first8=Stefan|last9=Thomas|first9=Deborah A.|date=2003-05-15|title=Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy|url=https://pubmed.ncbi.nlm.nih.gov/12560227|journal=Blood|volume=101|issue=10|pages=3794–3800|doi=10.1182/blood-2002-09-2790|issn=0006-4971|pmid=12560227}}</ref>.  
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{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|7
|7
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!Chromosomal Pattern
!Chromosomal Pattern
!Molecular Pathogenesis
!Molecular Pathogenesis
!'''Prevalence -'''
!Prevalence -  
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|inv(16)(p13.1q22) or t(16;16)(p13.1;q22)
|inv(16)(p13.1q22) or t(16;16)(p13.1;q22)
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{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|''RUNX1''
|''RUNX1''
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<br />
<br />


[[File:BCR-ABL1 translocation image.jpg|Figure 1. Philadelphia chromosome. A piece of chromosome 9 and a piece of chrosomome 22 break off and trade places. The BCR-ABL1 gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called Philadelphia chromosome. Image from National Cancer Institute website https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bcr-abl-fusion-gene|frame|center]][[File:Screenshot 2025-05-11 181714.png|thumb|Figure 2. Signal transduction pathway of the BCR-ABL fusion gene]]<!-- why my figure is not in the middle? LOL --><br />
[[File:BCR-ABL1 translocation image.jpg|Figure 1. Philadelphia chromosome. A piece of chromosome 9 and a piece of chrosomome 22 break off and trade places. The BCR-ABL1 gene is formed on chromosome 22 where the piece of chromosome 9 attaches. The changed chromosome 22 is called Philadelphia chromosome. Image from National Cancer Institute website https://www.cancer.gov/publications/dictionaries/cancer-terms/def/bcr-abl-fusion-gene|frame|alt=|none]][[File:Screenshot 2025-05-11 181714.png|thumb|Figure 2. Signal transduction pathway of the BCR-ABL fusion gene|alt=|none]]
 
 
 
 
 
 
 
 
==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


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