HAEM5:Acute myeloid leukaemia with BCR::ABL1 fusion: Difference between revisions
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|''ABL1''||''BCR::ABL1''||The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. | |''ABL1''||''BCR::ABL1''||The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1. | ||
|t(9;22)(q34;q11.2) | |t(9;22)(q34;q11.2) | ||
|Common | |Common (CML); Rare (AML)<ref name=":5">{{Cite journal|last=Al Hamad|first=Mohammad|date=2021|title=Contribution of BCR-ABL molecular variants and leukemic stem cells in response and resistance to tyrosine kinase inhibitors: a review|url=https://pubmed.ncbi.nlm.nih.gov/35284066|journal=F1000Research|volume=10|pages=1288|doi=10.12688/f1000research.74570.2|issn=2046-1402|pmc=8886173|pmid=35284066}}</ref>.<!-- 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. | ||
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'''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>. 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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There is a single case report of | The prevalence of BCR::ABL1 in AML is rare (~0.5 - 3%)<ref name=":5" />, per 5th WHO guideline the prevalence is <0.5%<ref>Tumours, 5th edition, IARC Press:Lyon, 2024. Online at: WHO Classification of Tumours.</ref>. | ||
There is a single case report of an AML patient with BCR::ABL1 achieving molecular remission with dasatinib and chemotherapy<ref>{{Cite journal|last=Shao|first=Xiaoyan|last2=Chen|first2=Dangui|last3=Xu|first3=Peipei|last4=Peng|first4=Miaoxin|last5=Guan|first5=Chaoyang|last6=Xie|first6=Pinhao|last7=Yuan|first7=Cuiying|last8=Chen|first8=Bing|date=2018-11|title=Primary Philadelphia chromosome positive acute myeloid leukemia: A case report|url=https://pubmed.ncbi.nlm.nih.gov/30383645|journal=Medicine|volume=97|issue=44|pages=e12949|doi=10.1097/MD.0000000000012949|issn=1536-5964|pmc=6221582|pmid=30383645}}</ref>. | |||
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|- | |- | ||
|AML-myelodysplasia-related (AML-MR) cytogenetic aberrations: | |AML-myelodysplasia-related (AML-MR) cytogenetic aberrations: | ||
• del(5q), t(5q) | • del(5q), t(5q) | ||
• inv(3)(q21q26) | • inv(3)(q21q26) | ||
• ‐7, del(7q) | • ‐7, del(7q) | ||
|Unknown | |Unknown | ||
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|The rarity of Philadelphia-positive subclones in AML patients with specific genetic lesions requires more cases for conclusive prognosis and therapeutic insights<ref name=":12" />. | |The rarity of Philadelphia-positive subclones in AML patients with specific genetic lesions requires more cases for conclusive prognosis and therapeutic insights<ref name=":12" />. | ||
In AML, BCR-ABL appears to interact with specific aberrations like inv(16) and myelodysplasia-related cytogenetic changes, but the mechanisms of disease initiation and cooperation remain unclear<ref name=":2" />. | In AML, BCR-ABL appears to interact with specific aberrations like inv(16) and myelodysplasia-related cytogenetic changes, like del(5q), t(5q)<ref name=":12" />, inv(3)(q21q26)<ref name=":12" />, ‐7, del(7q)<ref>{{Cite journal|last=Tirado|first=Carlos A.|last2=Valdez|first2=Federico|last3=Klesse|first3=Laura|last4=Karandikar|first4=Nitin J.|last5=Uddin|first5=Naseem|last6=Arbini|first6=Arnaldo|last7=Fustino|first7=Nicholas|last8=Collins|first8=Robert|last9=Patel|first9=Sangeeta|date=2010-07|title=Acute myeloid leukemia with inv(16) with CBFB–MYH11, 3′CBFB deletion, variant t(9;22) with BCR–ABL1, and del(7)(q22q32) in a pediatric patient: case report and literature review|url=https://doi.org/10.1016/j.cancergencyto.2010.03.001|journal=Cancer Genetics and Cytogenetics|volume=200|issue=1|pages=54–59|doi=10.1016/j.cancergencyto.2010.03.001|issn=0165-4608}}</ref>, but the mechanisms of disease initiation and cooperation remain unclear<ref name=":2" />. | ||
|}<br /> | |}<br /> | ||
==Gene Mutations (SNV/INDEL)== | ==Gene Mutations (SNV/INDEL)== | ||
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|Common (BCR-ABL1 AML) | |Common (BCR-ABL1 AML) | ||
|D,P | |D,P | ||
| | |No | ||
|AML with ''RUNX1'' mutation is associated with a poorer prognosis<ref name=":6" />. ''RUNX1'' was the most commonly mutated gene, altered in eight of 21 BCR-ABL1 AML cases (38%)<ref name=":13" />. | |AML with ''RUNX1'' mutation is associated with a poorer prognosis<ref name=":6" />. ''RUNX1'' was the most commonly mutated gene, altered in eight of 21 BCR-ABL1 AML cases (38%)<ref name=":13" />. | ||
Mutations in five genes (''BCOR, BCORL1, SF3B1, SRSF2,'' and ''STAG2''), along with ''ASXL1'' and ''RUNX1'' mutations, are linked to the proposed high-risk AML chromatin-spliceosome group<ref name=":13" />. | Mutations in five genes (''BCOR, BCORL1, SF3B1, SRSF2,'' and ''STAG2''), along with ''ASXL1'' and ''RUNX1'' mutations, are linked to the proposed high-risk AML chromatin-spliceosome group<ref name=":13" />. | ||