Mixed Phenotype Acute Leukemia (MPAL), T/Myeloid, Not Otherwise Specified

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Primary Author(s)*

Narsis Attar, MD, PhD, Fabiola Quintero-Rivera, MD University of California, Irvine

Cancer Category/Type

Acute leukemia

Acute leukemias of ambiguous lineage

Cancer Sub-Classification / Subtype

Mixed-phenotype acute leukemia (MPAL), T/myeloid, not otherwise specified (NOS)

Definition / Description of Disease

This malignancy is defined as a distinct entity in the WHO classification as a subtype of mixed-phenotype acute leukemia (MPAL). It fulfills the criteria for both T-cell and myeloid lineage and requires the absence of genetic mutations associated with other MPAL subtypes (e.g. KMT2A or BCR-ABL1 rearrangement)[1].

Epidemiology / Prevalence

A rare entity accounting for <1% of all leukemias. It is seen both in adult and pediatric populations.

Clinical Features

Patient with mixed-phenotype acute leukemia, T/myeloid, NOS present with signs and symptoms similar to other acute leukemias including an elevated white blood cell count.

Sites of Involvement

Bone marrow

Morphologic Features

Blasts with no distinguishing features resembling lymphoblastic leukemia OR a dimorphic blast population with some resembling lymphoblasts and others myeloblasts[1].

Immunophenotype

The blasts must meet criteria for both T-cell and myeloid lineage assignment.

According to the WHO, T-cell assignment is defined as having cytoplasmic CD3 (using antibody to CD3 epsilon chain). The European Group for the Immunological Characterization of Leukemias (EGIL) criteria also includes CD7, CD5 and CD2. The WHO myeloid lineage assignment requires MPO expression (by flow cytometry, immunohistochemistry or cytochemistry) or monocytic differentiation with 2 of the following CD11c, CD14, CD64, lysozyme, non-specific esterase. The EGIL criteria also considers CD13, CD33 and CD117 (c-kit), among a number of other markers that are variably weighted, in defining the myeloid lineage[1][2][3].   

Chromosomal Rearrangements (Gene Fusions)

Must lack t(v;11q23.3); KMT2A rearrangement and t(9;22)(q34.1;q11.2); BCR-ABL1 rearrangement   

Characteristic Chromosomal Aberrations / Patterns

Clonal chromosomal abnormalities including complex karyotypes are observed in the majority of cases but no specific aberration or pattern has been assigned to this leukemia[4][5].

Gene Mutations (SNV/INDEL)

MPALs with T-lineage differentiation are more often found to have either PHF6 or DNMT3A mutations[6]. Genetic lesions in NOTCH1 have also been reported in a subset of cases and are thought to be exclusively associated with T/myeloid MPAL. The overall mutational burden may be higher in MPALs with T-lineage differentiation[5][6][7].

Epigenomics (Methylation)

Methylation status is not determined for this subtype of MPAL. Mutations in epigenetic regulatory genes (DNMT3A, IDH2, EZH2, WT1, RUNX1, ETV6, and ASXL1) have been reported in MPAL with T/myeloid phenotype[6][7]. Of note, DNMT3A mutations were observed in 33% of adult MPAL patients[7].

Diagnostic Testing Methods

Diagnosis rests on immunophenotypic features. Flow cytometry and immunohistochemistry are the methods of choice.

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Prognosis: Although data is limited, MPAL T-myeloid, NOS is considered to have a poor prognosis.

Treatment: Retrospective studies suggest higher rates of complete remission and at least equivalent overall survival with ALL-therapy regimen compared with AML therapy. Allogeneic hematopoietic stem cell transplantation is utilized and may be effective in MPAL[8][9][10]. High quality prospective studies are needed to determine the optimal therapy for MPAL.

References

  1. 1.0 1.1 1.2 Borowitz MJ, et al., (2017) Acute leukaemias of ambiguous lineage, in WHO 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, p185-186.
  2. Arber, Daniel A.; et al. (2016). "The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia". Blood. 127 (20): 2391–2405. doi:10.1182/blood-2016-03-643544. ISSN 1528-0020. PMID 27069254.
  3. Charles, Nathan J.; et al. (2017). "Mixed-Phenotype Acute Leukemia: Diagnostic Criteria and Pitfalls". Archives of Pathology & Laboratory Medicine. 141 (11): 1462–1468. doi:10.5858/arpa.2017-0218-RA. ISSN 1543-2165. PMID 29072953.
  4. Yan, Lingzhi; et al. (2012). "Clinical, immunophenotypic, cytogenetic, and molecular genetic features in 117 adult patients with mixed-phenotype acute leukemia defined by WHO-2008 classification". Haematologica. 97 (11): 1708–1712. doi:10.3324/haematol.2012.064485. ISSN 1592-8721. PMC 3487445. PMID 22581002.
  5. 5.0 5.1 Matutes, Estella; et al. (2011). "Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification". Blood. 117 (11): 3163–3171. doi:10.1182/blood-2010-10-314682. ISSN 1528-0020. PMID 21228332.
  6. 6.0 6.1 6.2 Xiao, Wenbin; et al. (2018). "PHF6 and DNMT3A mutations are enriched in distinct subgroups of mixed phenotype acute leukemia with T-lineage differentiation". Blood Advances. 2 (23): 3526–3539. doi:10.1182/bloodadvances.2018023531. ISSN 2473-9537. PMC 6290101. PMID 30530780.
  7. 7.0 7.1 7.2 Eckstein, Olive S.; et al. (2016). "Mixed-phenotype acute leukemia (MPAL) exhibits frequent mutations in DNMT3A and activated signaling genes". Experimental Hematology. 44 (8): 740–744. doi:10.1016/j.exphem.2016.05.003. ISSN 1873-2399. PMC 4956537. PMID 27208809.
  8. Maruffi, Maria; et al. (2018). "Therapy for children and adults with mixed phenotype acute leukemia: a systematic review and meta-analysis". Leukemia. 32 (7): 1515–1528. doi:10.1038/s41375-018-0058-4. ISSN 1476-5551. PMID 29550836.
  9. Liu, Qi-Fa; et al. (2013). "Allo-HSCT for acute leukemia of ambiguous lineage in adults: the comparison between standard conditioning and intensified conditioning regimens". Annals of Hematology. 92 (5): 679–687. doi:10.1007/s00277-012-1662-4. ISSN 1432-0584. PMID 23274355.
  10. Shimizu, Hiroaki; et al. (2015). "Allogeneic hematopoietic stem cell transplantation for adult patients with mixed phenotype acute leukemia: results of a matched-pair analysis". European Journal of Haematology. 95 (5): 455–460. doi:10.1111/ejh.12516. ISSN 1600-0609. PMID 25605541.

Notes

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