HAEM5:Acute myeloid leukaemia, myelodysplasia-related

Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Acute Myeloid Leukemia (AML) with Myelodysplasia-Related Changes.

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Primary Author(s)*

Fei Yang, MD, FACMG
Oregon Health & Science University, Portland, OR

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Acute myeloid leukaemia
Type	Acute myeloid leukaemia with defining genetic abnormalities
Subtype(s)	Acute myeloid leukaemia, myelodysplasia-related

Definition / Description of Disease

Acute myeloid leukemia with myelodysplastic-related changes (AML-MRC) is an acute leukemia with 20% peripheral blood or bone marrow blasts with morphological features of myelodysplasia, or occurring in patients with a prior history of a MDS or MDS/MPN, or with MDS-related cytogenetic abnormalities, in the absence of prior history of cytotoxic or radiation therapy for an unrelated disease, and of recurrent cytogenetic aberrations or genetic abnormalities (mutated NPM1 or biallelic mutation of CEBPA) as described in HAEM4:Acute Myeloid Leukemia (AML) with Recurrent Genetic Abnormalities. This category has been retained in the 2016 revision to the World Health Organization (WHO) classification system with more refined criteria.

Synonyms / Terminology

Acute myeloid leukemia with multilineage dysplasia; acute myeloid leukemia with prior myelodysplastic syndrome

Epidemiology / Prevalence

AML-MRC is reported to account for 24-35% of all cases in AML. It occurs mainly in elderly patients and is rare in children.

Clinical Features

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Signs and Symptoms	EXAMPLE: Asymptomatic (incidental finding on complete blood counts) EXAMPLE: B-symptoms (weight loss, fever, night sweats) EXAMPLE: Fatigue EXAMPLE: Lymphadenopathy (uncommon)
Laboratory Findings	EXAMPLE: Cytopenias EXAMPLE: Lymphocytosis (low level)

editv4:Clinical Features

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AML-MRC often presents with severe pancytopenia. Cases with 20-29% blasts may present a stable clinical course and slow progression similar to that of MDS than that of AML.

Sites of Involvement

Bone marrow.

Morphologic Features

• Multilineage dysplasia: present in ≥50% of the cells in at least two haematopoietic cell lines.
• Dysgranulopoiesis: neutrophils is characteristic of hypogranular cytoplasm, hyposegmented or bizarrely segmented nuclei.
• Dyserythropoiesis: ring sideroblasts, cytoplasmic vacuoles, periodic acid-Schiff (PAS) positivity.
• Dysmegakaryopoiesis: micromegakaryocytes, normal- or large-sized megakaryocytes with non-lobated or multiple nuclei.

Immunophenotype

Immunophenotyping results are variable due to the heterogeneity of the underlying genetic changes.

• Myeloblasts have an expression of CD34, CD117, increased expression in CD14, variable expression in panmyeloid markers (CD13, CD33).
• Background granulocytic cells may have higher CD33 expression, and under-expression of CD45, CD11b, and CD15.
• Background monocytes have lower expression of CD14, CD56, and CD45.

Finding	Marker
Positive (universal)	EXAMPLE: CD1
Positive (subset)	EXAMPLE: CD2
Negative (universal)	EXAMPLE: CD3
Negative (subset)	EXAMPLE: CD4

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: 3'ABL1 / 5'BCR	EXAMPLE: der(22)	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add reference)	Yes	No	Yes	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).

editv4:Chromosomal Rearrangements (Gene Fusions)

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Balanced translocations are less common in AML-MRC, and often involve 5q32-33 and 11q23.3.

Chromosomal Rearrangement	Genes in Fusion (5’ or 3’ Segments)	Pathogenic Derivative	Prevalence
t(3;5)(q25.3;q35.1)	5'NPM1/3'MLF1	der(5)	unknown
t(11;16)(q23;p13.3)	5'KMT2A/3'CREBBP or 5'CREBBP/3'KMT2A	der(11) or der(16)	unknown
t(2;11)(p21;q23.3)	KMT2A rearrangement, partner gene unknown	unknown	unknown
t(2;11)(p21;q23.3)	MiR-125b-1 overexpression	der(11)	unknown

editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).

Please incorporate this section into the relevant tables found in:

• Chromosomal Rearrangements (Gene Fusions)
• Individual Region Genomic Gain/Loss/LOH
• Characteristic Chromosomal Patterns
• Gene Mutations (SNV/INDEL)

Diagnosis

• FCI assessment of granulocytes and monocytes, in addition to blasts, may be valuable in aid distinguishing AML-MRC from AML-NOS.
• Characteristic cytogenetic aberrations mentioned above are sufficient for the diagnosis of AML-MRC in the context of other criteria being met.
• Differential diagnosis are MDS with excess blasts, pure erythroid leukemia, acute megakaryoblastic leukemia and AML-NOS.

Prognosis

• AML-MRC generally has a poor prognosis with a lower rate of complete remission than in other AML subtypes.
• TP53 mutations are associated with a complex karyotype and an even worse prognosis in this entity.
• ASXL1 mutations are more frequent in AML-MRC, and are associated with a higher proportion of marrow dysgranulopoiesis and inferior 2-year overall survival.
• Mutations in spliceosome gene U2AF1 are associated with trilineage morphologic dysplasia, absence of clinical remission, poor overall survival and poor disease-free survival.

Individual Region Genomic Gain / Loss / LOH

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Chr #	Gain / Loss / Amp / LOH	Minimal Region Genomic Coordinates [Genome Build]	Minimal Region Cytoband	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7:1- 159,335,973 [hg38]	EXAMPLE: chr7	Yes	Yes	No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8:1-145,138,636 [hg38]	EXAMPLE: chr8	No	No	No	EXAMPLE: Common recurrent secondary finding for t(8;21) (add reference).

editv4:Genomic Gain/Loss/LOH

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Genomic copy number gain or loss have not been described in AML-MRC currently. There is a case report describing isochromosome 17q and LOH in a patient with AML-MRC, whose clinical presentation involved extreme thrombocytosis.

Chromosome Number	Gain/Loss/Amp/LOH	Region
17	LOH	chr17:59,000,001-159,138,663

Characteristic Chromosomal Patterns

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Chromosomal Pattern	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: Co-deletion of 1p and 18q	Yes	No	No	EXAMPLE: See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editv4:Characteristic Chromosomal Aberrations / Patterns

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Cytogenetic abnormalities sufficient for the diagnosis of AML-MRC when ≥20% peripheral blood or bone marrow blasts are present and prior therapy has been excluded:

Complex karyotype (3 or more abnormalities)

Unbalanced abnormalities:
Loss of chromosome 7 or del(7q)
del(5q) or t(5q)
Isochromosome 17q or t(17p)
Loss of chromosome 13 or del(13q)
del(11q)
del(12p) or t(12p)
idic(X)(q13)

Balanced abnormalities:
t(11;16)(q23.3;p13.3)
t(3;21)(q26.2;q22.1)
t(1;3)(p36.3;q21.2)
t(2;11)(p21;q23.3)
t(5;12)(q32;p13.2)
t(5;7)(q32;q11.2)
t(5;17)(q32;p13.2)
t(5;10)(q32;q21.2)
t(3;5)(q25.3;q35.1)

Gene Mutations (SNV / INDEL)

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Gene; Genetic Alteration	Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)	Prevalence (COSMIC / TCGA / Other)	Concomitant Mutations	Mutually Exclusive Mutations	Diagnostic Significance (Yes, No or Unknown)	Prognostic Significance (Yes, No or Unknown)	Therapeutic Significance (Yes, No or Unknown)	Notes
EXAMPLE: TP53; Variable LOF mutations EXAMPLE: EGFR; Exon 20 mutations EXAMPLE: BRAF; Activating mutations	EXAMPLE: TSG	EXAMPLE: 20% (COSMIC) EXAMPLE: 30% (add Reference)	EXAMPLE: IDH1 R123H	EXAMPLE: EGFR amplification				EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

editv4:Gene Mutations (SNV/INDEL)

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Somatic genetic mutations commonly found in AML or MDS have been reported in AML-MRC. There are no characteristic genetic mutations fully specific for this entity. The most frequently mutated genes reported in AML-MRC are listed below.

Gene	Mutation	Oncogene/Tumor Suppressor/Other	Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)	Prevalence (COSMIC/TCGA/Other)
TP53	Missense, nonsense, frameshift	Tumor Suppressor	LOF	22%
ASXL1	Frameshift, nonsense, missense	Tumor Suppressor	LOF	21-35%
U2AF1	Missense	Oncogene	GOF	16%
SF3B1	Missense	Oncogene	GOF	5.8%

Other Mutations

Type	Gene/Region/Other
Concomitant Mutations	EXAMPLE: IDH1 R123H
Secondary Mutations	EXAMPLE: Trisomy 7
Mutually Exclusive	EXAMPLE: EGFR Amplification

Epigenomic Alterations

Epigenetic aberration has not been described in AML-MRC currently.

Genes and Main Pathways Involved

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Gene; Genetic Alteration	Pathway	Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations	EXAMPLE: MAPK signaling	EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations	EXAMPLE: Cell cycle regulation	EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations	EXAMPLE:  Histone modification, chromatin remodeling	EXAMPLE:  Abnormal gene expression program

Genetic Diagnostic Testing Methods

Conventional chromosome analysis; FISH with MDS and AML panel; molecular genetic analysis for mutations such as targeted Next-generation sequencing (NGS) panel.

Familial Forms

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Additional Information

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Links

http://atlasgeneticsoncology.org/Anomalies/TL_t0305q25q35ID3404.html
http://atlasgeneticsoncology.org/Anomalies/t1116q23p13ID1120.html
http://atlasgeneticsoncology.org/Anomalies/t0211p21q23ID1333.html

References

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Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “Acute myeloid leukaemia, myelodysplasia-related”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Acute_myeloid_leukaemia,_myelodysplasia-related.