HAEM4Backup:Mixed-Phenotype Acute Leukemia, Not Otherwise Specified (NOS), Rare Types

Primary Author(s)*

Elicia Goodale, MD, Medical University of South Carolina

Daynna Wolff, PhD, Medical University of South Carolina

Cancer Category/Type

Acute Leukaemias of ambiguous lineage

Cancer Sub-Classification / Subtype

Mixed-phenotype acute leukaemia (MPAL), not otherwise specified, 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

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)

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.

Characteristic Chromosomal Aberrations / Patterns

Not reported.

Genomic Gain/Loss/LOH

See Genes and Main Pathways Involved.

Gene Mutations (SNV/INDEL)

See Genes and Main Pathways Involved.

Epigenomics (Methylation)

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

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.

Diagnostic Testing Methods

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

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

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.

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

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