Bone marrow neoplastic
Bone marrow - neoplastic myeloid
AML with recurrent genetic abnormalities
AML with other KMT2A rearrangements
Editorial Board Member: Alexa J. Siddon, M.D.
Deputy Editor-in-Chief: Genevieve M. Crane, M.D., Ph.D.
Last author update: 4 March 2024
Last staff update: 27 August 2024
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PubMed Search: AML with other KMT2A rearrangements
Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Diagrams / tables | Diagnosis | Laboratory | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Virtual slides | Peripheral smear description | Peripheral smear images | Positive stains | Negative stains | Flow cytometry description | Flow cytometry images | Molecular / cytogenetics description | Molecular / cytogenetics images | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2Cite this page: Morrow WP, Insuasti-Beltran G. AML with other KMT2A rearrangements. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/bonemarrowneoplasticAMLKMT2A.html. Accessed April 2nd, 2025.
Definition / general
- Acute myeloid leukemia (AML) with other KMT2A rearrangements: subclassification of AML defined by the International Consensus Classification (ICC) as AML with rearrangement of the KMT2A gene other than t(9;11) / MLLT3::KMT2A
- Recurrent translocations recognized in this category include AMLs with t(4;11) AFF1::KMT2A; t(6;11) / AFDN::KMT2A; t(10;11) / MLLT10::KMT2A; t(10;11) / TET1::KMT2A; t(11;19) / KMT2A::ELL; t(11;19) / KMT2A::MLLT1
- In the 5th edition of WHO, the category of AML with KMT2A rearrangement includes any KMT2A gene rearrangement, regardless of the partner gene
Essential features
- KMT2A rearrangement is a recurrent genetic finding identified in both acute lymphoblastic leukemias / lymphomas (ALL) and AML
- KMT2A rearrangement has an inverse association with patient age, with a large subset of infantile cases of AML presenting with KMT2A rearrangement
- AML with KMT2A rearrangement most commonly presents with a monocytic phenotype, with myelomonocytic and myeloid phenotypes less frequent
- KMT2A has numerous partner genes; by International Consensus Classification (ICC) 2022 definition, AML with other KMT2A rearrangements include t(4;11) AFF1::KMT2A; t(6;11) / AFDN::KMT2A; t(10;11) / MLLT10::KMT2A; t(10;11) / TET1::KMT2A; t(11;19) / KMT2A::ELL; t(11;19) / KMT2A::MLLT1
- Overall prognosis is poor but prognosis varies somewhat with fusion gene
- KMT2A rearrangement can be identified by various testing methods including conventional karyotype, FISH, PCR and NGS
Terminology
- KMT2A gene was previously named mixed lineage leukemia (MLL)
- WHO 5th edition classification: acute myeloid leukemia with KMT2A rearrangement
- ICC 2022 classification: acute myeloid leukemia with other KMT2A rearrangements
ICD coding
- ICD-O: 9897/3 - acute myeloid leukemia with KMT2A rearrangement
- ICD-10
- ICD-11: 2A60.0 & XH1E41 - acute myeloid leukemia with recurrent genetic abnormalities & acute myeloid leukemia, 11q23 abnormalities
Epidemiology
- KMT2A rearrangement
- Incidence has an inverse relationship with age (Blood 2003;102:2395)
- Most frequently encountered genetic abnormality in pediatric population, accounting for 20% of pediatric AML cases
- Less common among adult population, accounting for 2 - 3% of adult AML cases
- Has increased prevalence among patients with AML post-cytotoxic therapy (AML pCT) (Cytometry B Clin Cytom 2022;102:123)
Sites
- By definition, AML with other KMT2A rearrangement involves bone marrow and peripheral blood
- Prevalence of extramedullary disease is higher than that of non-KMT2A rearranged leukemia in both adults and pediatric populations with a high frequency of fusion partners (Proc Natl Acad Sci U S A 2020;117:26340)
- Extramedullary disease most frequently manifests in the liver, spleen or CNS; less commonly as myeloid sarcoma in other locations
- Data is limited for low frequency fusion partners
Pathophysiology
- Myeloid precursor cell undergoes genetic event resulting in rearrangement of KMT2A gene on chromosome 11
- KMT2A rearrangement in AML usually manifests as a translocation
- Rearrangement of KMT2A disrupts its usual role in regulating gene expression during early development and hematopoiesis; this disruption will lead to clonal expansion of the myeloid cell lineage harboring the KMT2A (Cancer Lett 2019;458:56)
- Clonal expansion will result in increased myeloid lineage blasts, further developing into bone marrow replacement and subsequent pancytopenias
Etiology
- Definitive etiology is not well understood
- Risk factors in adult patients include cytotoxic chemotherapy and other nonspecific DNA damaging events
Diagrams / tables
Images hosted on other servers:
Frequent KMT2A partner genes
Diagnosis
- WHO criteria for AML with KMT2A rearrangement
- Essential
- Myeloid neoplasm with increased peripheral blood or bone marrow blasts (may be < 20%)
- Blasts express a myeloid immunophenotype, not fulfilling immunophenotypic criteria for mixed phenotype AML
- Presence of KMT2A rearrangement
- Not fulfilling diagnostic criteria for myeloid neoplasm post-cytotoxic therapy
- Desirable
- Identification of the KMT2A fusion partner
- ICC 2022 criteria for AML with other KMT2A rearrangement (Blood 2022;140:1200)
- Overall criteria similar to the WHO, except importantly t(9;11) / MLLT3::KMT2A is categorized as a separate entity
- Recognized recurrent fusion partners are described in other sections
- Identification of KMT2A rearrangement is critical for this diagnosis (see Molecular / cytogenetics description for further description)
- At least 10% myeloblasts in the peripheral blood or bone marrow sampling are required for diagnosis by ICC classification
- Essential
Laboratory
- Anemia and thrombocytopenia likely present at diagnosis
- WBC will vary case to case; ranges from leukopenia to leukocytosis and correlates with number of circulating blasts
Prognostic factors
- In general, prognosis of KMT2A rearranged AML is poor with high risk of relapse; however, prognosis varies upon fusion partner to KMT2A gene (Blood Cancer J 2021;11:162)
- Few partner genes may give intermediate to good prognosis
- Overall median survival in patients with KMT2A rearrangement is 0.9 years
- Additional cytogenetic abnormalities and mutations, especially in myelodysplasia associated genes, worsens prognosis
Case reports
- 31 weeks gestational age female neonate with AFF1::KMT2A fusion AML (Oncol Lett 2022;24:283)
- 6 year old girl with KMT2A::MLLT10 fusion AML (Cancer Genet 2023;276:36)
- 7 year old boy with KMT2A::MLLT1 fusion AML (Cytogenet Genome Res 2019;157:213)
- 43 year old woman with KMT2A::SEPT5 fusion AML (SAGE Open Med Case Rep 2018;6:2050313X17750334)
- 63 year old woman with hepatic gastrointestinal stromal tumor (GIST) and concomitant KMT2A::ELL fusion AML (World J Clin Cases 2020;8:1251)
Treatment
- Intensive chemotherapy as induction followed by additional consolidation therapy
- Trials utilizing novel agents such as MEK inhibitors, demethylating agents and other targeted therapies are ongoing (Front Pharmacol 2022;13:749472)
- Hematopoietic stem cell transplant
Microscopic (histologic) description
- Increased myeloid lineage blasts (percentage will vary case to case)
- WHO 5th edition does not have a blast requirement and the ICC requires at least 10% blasts in peripheral blood or bone marrow
- On the aspirate smears, crush prep or touch prep, blast morphology will vary by phenotype
- Myeloblasts will have open chromatin, high N:C ratio, prominent nucleoli and possible Auer rods in the cytoplasm
- Monoblasts will have open chromatin, lower N:C ratio, possible cytoplasmic vacuoles and larger cell size
- AML with monocytic differentiation tends to have a spectrum of monocyte differentiation, with mature monocytes, promonocytes and monoblasts (Haematologica 2009;94:994)
- Unless there are coinciding myelodysplasia related gene mutations, significant dysplasia is not expected
- On core biopsies, varying degrees of bone marrow involvement by blasts will be seen
- Blasts will appear as immature cells with intermediate to large cell size, open chromatin and usually with prominent nucleoli
- Pattern of involvement may be interstitial, aggregate or sheets
- Degree of bone marrow effacement by leukemia will impact background trilineage hematopoiesis
- Trilineage hematopoiesis will be affected by treatment in follow up bone marrow biopsies
Microscopic (histologic) images
Contributed by William Morrow, M.D.
Aspirate with increased blasts
Aspirate with increased monoblasts
Increased monoblasts
Clot section blast aggregate
Core biopsy blast sheets
Muramidase (lysozyme) IHC
CD4 IHC
Virtual slides
Images hosted on other servers:
Acute myeloid leukemia
Peripheral smear description
- Increased circulating blasts, frequently with monocytic features, such as increased cytoplasm, vacuoles, cleaved or grooved nuclei
- Variable degree of cytopenias depending on level of bone marrow involvement
- Typically a normocytic, normochromic anemia with otherwise unremarkable red blood cell morphology
- Typically a thrombocytopenia with unremarkable platelet morphology
- No features of dysplasia in granulocytes unless there is a coinciding myelodysplasia related gene mutation(s)
- Reference: Haematologica 2009;94:994
Peripheral smear images
Contributed by William Morrow, M.D.
Circulating blasts
Circulating monoblasts
Positive stains
Negative stains
Flow cytometry description
- Immunophenotype by flow cytometry varies but most commonly represents monocytic differentiation, with a smaller subset of cases having myelomonocytic or myeloid immunophenotype
- Cases with monocytic differentiation will be positive for CD33, CD13, CD64, CD4, HLA-DR, CD14 (variable) and negative for CD34, CD117 and MPO
- Cases with myeloid differentiation will be positive for CD34, MPO, CD33, HLA-DR and negative for CD64, CD4 and CD14
- CD123 is positive in 90% of cases with KMT2A rearrangement (Cytometry B Clin Cytom 2022;102:123)
- Markers of lymphoblastic differentiation, such as TdT, CD3, CD19, CD10 are almost universally negative
Flow cytometry images
Contributed by William Morrow, M.D.
Flow CD33 versus CD64
Flow CD11b versus CD64
Flow CD33 versus CD34
Molecular / cytogenetics description
- KMT2A gene (lysine methyltransferase 2A) is located on chromosome 11q23.3
- More than 130 different partners have been recognized in association with KMT2A; AFF1, MLLT1, MLLT3, MLLT10, MLLT4 and ELL are the most frequently recognized partners in order of decreasing frequency (BMC Med Genomics 2020;13:106)
- These genes represent over 90% of KMT2A rearrangement cases and are specifically recognized by the ICC 2022 classification for KMT2A with other rearrangement
- Due to the various different breakpoints in the KMT2A gene, comprehensive testing for KMT2A rearrangement can be challenging
- Different types of structural rearrangements can be the underlying cause of KMT2A fusions, including insertions, deletions, inversions and translocations
- Several different molecular and cytogenetic testing modalities can identify KMT2A rearrangement
- FISH is routinely performed using the aspirate material collected during the bone marrow biopsy procedure; KMT2A break apart probes (with a probe labeling 3’KMT2A and a probe labeling 5’KMT2A) are routinely ordered as part of a FISH panel for a diagnostic leukemia marrow
- Some rearrangements may be cryptic by FISH, such as KMT2A::USP2
- Routine karyotype can detect many translocations involved in KMT2A rearrangement (such as t(9;11)); however, some translocations may be cryptic (such as t(10;11) MLLT10::KMT2A)
- Additional cytogenetic alterations can coincide with KMT2A rearrangement
- PCR can be used to detect specific fusion transcripts
- Some available panels include up to 20 fusion genes, including all the recurrent fusions identified
- Myeloid next generation sequencing (NGS) panels may have KMT2A gene incorporated into a fusion panel and can detect KMT2A
- FISH is routinely performed using the aspirate material collected during the bone marrow biopsy procedure; KMT2A break apart probes (with a probe labeling 3’KMT2A and a probe labeling 5’KMT2A) are routinely ordered as part of a FISH panel for a diagnostic leukemia marrow
- Of note, partial tandem duplication (PTD) of KMT2A may be detected by NGS; PTD of the KMT2A gene does not qualify as KMT2A rearrangement for either classification scheme
Molecular / cytogenetics images
Contributed by William Morrow, M.D.
KMT2A break apart FISH
Images hosted on other servers:
Cryptic KMT2A::MLLT4 fusion
FISH of KMT2A::SEPT5 fusion
Sample pathology report
- Bone marrow, biopsy:
- Acute myeloid leukemia with other KMT2A rearrangement (see comment)
- Comment: Increased blasts (50%) in a hypercellular marrow (90%). The blasts are morphologically and immunophenotypically consistent with myeloblasts. Concurrent FISH studies identified KMT2A rearrangement (see FISH report for full details). Concurrent karyotype studies identified t(10;11) (see karyotype report for full details). A myeloid NGS panel recognized a KMT2A::MLLT10. Overall, these findings are consistent with acute myeloid leukemia with KMT2A rearrangement (WHO 5th edition) or acute myeloid leukemia with other KMT2A rearrangement (ICC 2022).
Differential diagnosis
- Acute myeloid leukemia with t(9;11) / MLLT3::KMT2A:
- Differentiated by defining KMT2A rearrangement
- Classified separately by the ICC
- Shares classification by the WHO 5th edition
- Acute myeloid leukemia with other defining genetic abnormalities:
- Lacks KMT2A rearrangement
- Presence of other defining genetic feature
- Acute lymphoblastic leukemia with KMT2A rearrangement:
- Differentiated by immunophenotype and cell lineage
- Acute monocytic leukemia:
- Myeloid leukemia with monocytic features lacking KMT2A rearrangement
- Chronic myelomonocytic leukemia with KMT2A rearrangement:
- No increase in blasts
- Dysplastic features
- Rare and difficult to diagnose
- Increased blasts and KMT2A rearrangement better classified as AML
Additional references
Board review style question #1
A patient with newly diagnosed acute myeloid leukemia had cytogenetics, FISH and myeloid NGS testing performed. FISH identified findings seen in the above image and myeloid NGS identified a KMT2A::AFDN fusion. Per the ICC 2022 guidelines, which of the following is the best classification of this patient's disease?
- Acute myeloid leukemia, NOS
- Acute myeloid leukemia with myelodysplasia related cytogenetics
- Acute myeloid leukemia with other KMT2A translocation
- Acute myeloid leukemia with t(9;11) / MLLT3::KMT2A
- B lymphoblastic leukemia with t(v;11q23.3) / KMT2A rearrangement
Board review style answer #1
C. Acute myeloid leukemia with other KMT2A translocation. The t(6;11) translocation (KMT2A::AFDN) is recognized by the ICC 2022 classification as one of the recurring KMT2A rearrangements other than MLLT3::KMT2A. Answer A is incorrect because this acute myeloid leukemia has a defining genetic alteration. Answer B is incorrect because the t(6;11) translocation (KMT2A::AFDN) is not recognized as a myelodysplasia related cytogenetic change or gene mutation. Answer D is incorrect because that is not the identified molecular alteration in this case. Answer E is incorrect because the question stem described this case as a myeloid leukemia, as well as a different molecular alteration.
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Reference: AML with other KMT2A rearrangements
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Reference: AML with other KMT2A rearrangements
Board review style question #2
Acute myeloid leukemia with KMT2A rearrangement most commonly presents with what differentiation?
- Eosinophilic
- Lymphoblastic
- Monocytic
- Myeloid
- Myelomonocytic
Board review style answer #2
C. Monocytic. Acute myeloid leukemias with KMT2A rearrangement most commonly present with a monocytic immunophenotype. Answer A is incorrect because acute myeloid leukemia with KMT2A rearrangement does not present with eosinophilic differentiation. Answer B is incorrect because while lymphoblastic leukemias can present with KMT2A rearrangements, the question was asking for differentiation of myeloid leukemias. Answers D and E are incorrect because although acute myeloid leukemia with KMT2A rearrangement can present with myeloid or myelomonocytic differentiation, it is far more common to have pure monocytic differentiation.
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Reference: AML with other KMT2A rearrangements
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Reference: AML with other KMT2A rearrangements
