R/R KMT2Ar acute leukemia: an urgent clinical need for targeted therapy
Acute leukemias with a KMT2A rearrangement (KMT2Ar), including translocations, are aggressive diseases associated with a poor prognosis and high relapse rates. KMT2Ar acute leukemia is also known as “mixed-lineage leukemia rearranged” or MLLr.1,2
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Rearrangements (including translocations) of the KMT2A gene can occur in AML, ALL, and mixed-phenotype acute leukemia (MPAL) across multiple age groups1
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The median age at diagnosis for KMT2Ar AML is 52 years—much lower than for AML in general (68 years)3,4
Detection of KMT2Ar at acute leukemia diagnosis:
Patient
population
AML cases1,5
ALL cases1,6
Infant
~35%-60%
~80%
Pediatric
~10%-15%
~5%-6%
Adult
~5%-10%
~5%-15%
KMT2Ar AML rapidly progresses and has high
rates of resistance and relapse3:
82%
RELAPSE
Up to 82% of adult patients
relapse within the first year
following second-line therapy
9%
CR + CRi
Only 9% of adult patients
achieve CR or CRi following
third-line or later therapy
ALL=acute lymphoblastic leukemia; AML=acute myeloid leukemia; CR=complete remission; CRi=complete remission with incomplete hematologic recovery; KMT2Ar=lysine methyltransferase 2A rearranged; R/R=relapsed/refractory.
KMT2A translocations: an actionable biomarker in R/R disease
Early identification of KMT2A translocations is critical given the rapid onset and quick progression of KMT2A-translocated acute leukemias3,7
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Request and confirm with your pathologist that KMT2A translocations are included when testing at diagnosis and relapse
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Detecting KMT2A translocations can help determine a specific course of action and identify R/R patients who may benefit from a targeted treatment
~95% of patients with KMT2Ar acute leukemia have a KMT2A translocation, a type of rearrangement that occurs when part of one chromosome breaks and fuses to a different chromosome8
A combination of cytogenetics, FISH, and RNA-based fusion testing can capture nearly all KMT2A translocations8-10
A KMT2A rearrangement may appear on a pathology report as:
KMT2Ar (KMT2A rearranged)
MLLr (mixed-lineage leukemia rearranged)
11q23 chromosomal translocations affecting the KMT2A (MLL) gene
If a KMT2A rearrangement is detected, take a closer look at the pathology report to identify whether it is a translocation
A reliance on menin-KMT2A complexes1
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KMT2A-translocated acute leukemias are dependent on menin interactions with KMT2A (MLL1) fusion proteins
Common translocations and oncogenic fusion partners involved in driving KMT2A-translocated acute leukemias (AML, ALL, and MPAL)1,3,8:
Cytogenetic
abnormality
t(9;11)(p21;q23)
t(6;11)(q27;q23)
t(11;19)(q23;p13.1)
t(11;19)(q23;p13.3)
t(11;19)(q23;p13)
t(10;11)(p12;q23)
t(4;11)(q21;q23)
Common
fusion genes
KMT2A-MLLT3
KMT2A-MLLT4
KMT2A-ELL
KMT2A–MLLT1
KMT2A-EEN
KMT2A-MLLT10
KMT2A-MLLT2
The following are NOT a KMT2A translocation:
KMT2A partial tandem duplication (KMT2A-PTD), KMT2A deletion, KMT2A amplification, and KMT2A point mutations
Revuforj is the first and only FDA-approved menin inhibitor for the treatment of adult and pediatric patients 1 year and older with any lineage of relapsed/refractory acute leukemia with a KMT2A translocation
ALL=acute lymphoblastic leukemia; AML=acute myeloid leukemia; FISH=fluorescence in situ hybridization; KMT2A=lysine methyltransferase 2A; KMT2Ar=lysine methyltransferase 2A rearranged; MLL1=mixed-lineage leukemia protein-1; MPAL=mixed-phenotype acute leukemia; RNA=ribonucleic acid; R/R=relapsed/
refractory.
References: 1. Issa GC, et al. Leukemia. 2021;35:2482-2495. 2. Issa GC, et al. J Clin Oncol. 2025;43(1):75-84. doi:10.1200/JCO.24.00826 3. Issa GC, et al. Blood Cancer J. 2021;11:162. 4. Appelbaum FR, et al. Blood. 2006;107:3481-3485. 5. Conneely SE, Rau RE. Cancer Metastasis Rev. 2020;39(1):189-209. 6. Górecki M, et al. Biomedicines. 2023;11:821. 7. Nguyen D, et al. Cancer. 2023;129(12):1856-1865. 8. Meyer C, et al. Leukemia. 2023;37:988-1005. 9. Quessada J, et al. Genes. 2021;12(6):924. 10. Hoffmeister LM, et al. Leukemia. 2024;38(3):538-544.