Mixed-phenotype acute leukaemia, rare types

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

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Primary Author(s)*

Elicia Goodale, MD, Medical University of South Carolina

Daynna Wolff, PhD, Medical University of South Carolina

WHO Classification of Disease

Structure	Disease
Book	Haematolymphoid Tumours (5th ed.)
Category	Myeloid proliferations and neoplasms
Family	Acute leukaemias of mixed or ambiguous lineage
Type	Acute leukaemia of ambiguous lineage, immunophenotypically defined
Subtype(s)	Mixed-phenotype acute leukaemia, rare types

Definition / Description of Disease

In rare documented cases of leukemia, blasts may show clear features of biphenotypic leukemia (both T-cel and B-cell lineage) or even trilineage (also includes myeloid lineage). The European Group for the Immunological Characterization of Leukemias (EGIL) provides these criteria, which may provide for overestimation of dual lineage based on CD79a expression. CD79a and CD10 "should not be considered evidence of B-cell differentiation...because CD79a can be detected in T-lymphoblastic leukaemia with some antibodies. Ultimately, very little is known regarding clinical features and prognosis due to the rarity of the disease.

If erythroid and megakaryocytic lineages are the earliest branch points from pluripotency, as has been speculated, then T-cell, B-cell, and myeloid lineages have the greatest neoplastic potential. It would be possible for undetected erythroid or megakaryocytic lineages to occur, as they would not express MPO.

Synonyms / Terminology

Mixed-phenotype acute leukaemia (MPAL), not otherwise specified, rare types should be distinguished from Mixed-phenotype acute leukaemia (MPAL), B/myeloid, not otherwise specified and from Mixed-phenotype acute leukaemia (MPAL), T/myeloid, not otherwise specified.

Epidemiology / Prevalence

See Definition.

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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Median age: 45 years old

Peripheral blood: 34% blasts

Bone marrow: 84% blasts

Complex karyotype is expected.

Sites of Involvement

Bone Marrow

Morphologic Features

Immunophenotype is most important for this diagnosis.

Immunophenotype

MPAL, not otherwise specified, should reveal clear elements of both B-cell lineage and T-cell lineage.

Finding	Marker
Positive (T-cell component)	CD3, cCD3
Positive (B-cell component)	Strong CD19 + at least 1 of: CD10, cCD79a, CD22
Positive (B-cell component)	Weak CD19 + at least 2 of: CD10, cCD79a, CD22
Positive (myeloid component)	cMPO

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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It should be noted that the classification of MPAL excludes cases that can be otherwise categorized, such as recurrent t(8;21), inv(16), or PML-RARA.

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

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

Unclear due to rarity of disease.

Venetoclax and Decitabine have been used to treat MPAL, T/myeloid, NOS, with some success.

Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate and cytarabine) followed by SCT has been used to treat one B/T MPAL patient in a study.

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).

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See Genes and Main Pathways Involved.

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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Not reported.

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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See Genes and Main Pathways Involved.

Epigenomic Alterations

Chromatin regulation via the ASXL1 gen is seen in over 20% of MPAL, B/myeloid, not otherwise specified and in over 10% of MPAL, T/myeloid, not otherwise specified.

Methylation via the DNMT3A gene and IDH2 gene is affected in over 30% of MPAL, T/myeloid, not otherwise specified.

Methylation via the IDH1 and TET2 genes is affected in over 15% of MPAL, B/myeloid, not otherwise specified, but in 0% of MPAL, T/myeloid, not otherwise specified.

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

editv4:Genes and Main Pathways Involved

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The NOTCH1 pathway is mutated in 50% of MPAL, T/myeloid, not otherwise specified.

RNA splicing (SRSF2) is mutated in over 20% of MPAL, B/myeloid, not otherwise specified.

The RTK-RAS pathway, via FLT3 and NRAS genes, is mutated in a over 20% of MPAL, B/myeloid, not otherwise specified.

Transcription factor pathways, via RUNX1, is mutated in a over 45% of MPAL, B/myeloid, not otherwise specified.

Transcription factor pathways, via PHF6, is mutated in a over 20% of MPAL, T/myeloid, not otherwise specified.

Genetic Diagnostic Testing Methods

Immunophenotype is essential. Based on newer information, genetic mutation profile may also help.

Familial Forms

Not currently reported.

Links

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References

1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
2. Quesada AE, Hu Z, Routbort MJ, et al. Mixed phenotype acute leukemia contains heterogeneous genetic mutations by next-generation sequencing. Oncotarget. 2018;9(9):8441-8449. Published 2018 Jan 3. doi:10.18632/oncotarget.23878.
3. Takahashi, K., Wang, F., Morita, K. et al. Integrative genomic analysis of adult mixed phenotype acute leukemia delineates lineage associated molecular subtypes. Nat Commun 9, 2670 (2018). https://doi.org/10.1038/s41467-018-04924-z
4. Heather Klocke, Zhao Ming Dong, Craig O’Brien, Nicholas Burwick, Robert E. Richard, Daniel Y. Wu, Thomas R. Chauncey, Solomon A. Graf, "Venetoclax and Decitabine for T/Myeloid Mixed-Phenotype Acute Leukemia Not Otherwise Specified (MPAL NOS)", Case Reports in Hematology, vol. 2020, Article ID 8811673, 4 pages, 2020. https://doi.org/10.1155/2020/8811673

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: “Mixed-phenotype acute leukaemia, rare types”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/6/2024, https://ccga.io/index.php/HAEM5:Mixed-phenotype_acute_leukaemia,_rare_types.