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

|Acute myeloid leukaemia with t(9;22)(q34;q11.2)

|N/A

|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.   

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>.

|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>.  

Three BCR-ABL chimeric proteins result from varying mRNA fusions of the ABL and BCR genes. The most common breakpoint occurs in BCR intron 13 or 14, fusing to ABL1 exon a2 (e13a2, e14a2), yielding a 210 kilodalton protein (p210 BCR-ABL1) found in 95% of CML cases. A rare alternative (<1%) is the e19a2 fusion, producing a 230 kilodalton protein (p230 BCR-ABL1), a marker for neutrophilic-chronic myeloid leukemia. The e1a2 fusion results in the p190 BCR-ABL1 protein, prevalent in B cell ALL, less common in AML, and rare in CML<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>.

 

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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!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

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

!Prevalence -  

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

• del(5q), t(5q)  

• inv(3)(q21q26)   

• ‐7, del(7q)

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" />.

!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

|No

[[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]]

Bone marrow with myeloid blasts >20% combined with detection of t(9,22) by karyotype analysis or BCR-ABL1 using FISH or reverse transcriptase-quantitative PCR (RT-qPCR) and RNA or DNA seq<ref name=":2" />.  A graphic of the clinical path for the differential diagnosis of BCR-ABL1 positive acute myeloid leukemia and chronic myeloid leukemia-myeloid blast crisis (CML-MBC) is presented<ref name=":2" />.