What is the definition and treatment approach for a patient with Mixed Phenotype Acute Leukemia (MPAL)?

Mixed Phenotype Acute Leukemia (MPAL) Definition

MPAL is a rare acute leukemia (2-5% of all acute leukemias) characterized by blast cells expressing lineage-defining markers of more than one hematopoietic lineage—either as a single blast population with multilineage markers (biphenotypic) or as distinct blast populations of different lineages (bilineage). 1

Diagnostic Criteria

Lineage Assignment Requirements

The 2016 WHO classification establishes specific immunophenotypic criteria for lineage assignment 1:

Myeloid lineage requires:

• Myeloperoxidase (MPO) expression by flow cytometry, immunohistochemistry, or cytochemistry, OR
• Monocytic differentiation demonstrated by at least 2 of: nonspecific esterase cytochemistry, CD11c, CD14, CD64, or lysozyme 1, 2

B-lineage requires:

• Strong CD19 expression (equal to or brighter than normal B cells) PLUS at least one of: cytoplasmic CD79a, cytoplasmic CD22, or CD10 strongly expressed, OR
• Weak CD19 with at least 2 of the following strongly expressed: CD79a, cCD22, or CD10 1

T-lineage requires:

• Strong cytoplasmic CD3 (with antibodies to CD3ε chain) or surface CD3 1

WHO Classification Subtypes

MPAL is subgrouped into 1:

• MPAL with BCR-ABL1 rearrangement (t(9;22))
• MPAL with rearranged KMT2A (11q23)
• MPAL with B-cell/myeloid features, not otherwise specified
• MPAL with T-cell/myeloid features, not otherwise specified
• Acute undifferentiated leukemia (separate category)

Critical Diagnostic Distinctions

Biphenotypic vs. Bilineage: Biphenotypic refers to expression of both cytochemical and/or immunophenotypic characteristics of both lineages on the same cells, whereas bilineage refers to expression of lineage-specific characteristics on different populations of leukemia cells 1

Important caveat: The presence of myeloid-associated antigens such as CD13 and CD33 in ALL does NOT constitute MPAL—these markers may be aberrantly expressed in up to 40% of ALL cases without changing the diagnosis or adversely affecting prognosis 1

Mandatory Diagnostic Workup

Essential Testing

• Bone marrow examination: ≥20% blasts required (same threshold as AML/ALL) with examination of ≥500 nucleated cells on marrow smears containing spicules 3, 4, 5
• Multiparameter flow cytometry: Mandatory to establish lineage involvement using the specific markers outlined above 1, 3, 4
• Cytogenetic analysis: Conventional karyotyping with minimum 20 metaphase cells analyzed to identify BCR-ABL1 or KMT2A rearrangements 1, 3, 5
• Molecular testing: FISH for BCR-ABL1 and KMT2A rearrangements; consider broader molecular profiling as targetable mutations are found in 56% of cases 6

Consultation Requirement

Due to the rarity of MPAL, consultation with an experienced hematopathologist is mandatory 1

Genetic Landscape

Recent genomic studies reveal frequent abnormalities 6:

• Complex karyotype (29% of cases)
• BCR-ABL1 translocation (21%)
• Most frequently mutated genes: TP53, RUNX1, WT1, FLT3, MLL2
• AML-MRC-defining cytogenetic abnormalities present in 26%
• Targetable or potentially targetable biomarkers in 56% of cases

Treatment Approach

Recommended Strategy

ALL-directed induction therapy followed by allogeneic hematopoietic stem cell transplantation (HSCT) is the preferred approach, as this strategy demonstrates superior outcomes compared to AML-directed therapy or consolidation chemotherapy alone. 1, 2, 7

Specific Recommendations

• For BCR-ABL1-positive MPAL: Treat with tyrosine kinase inhibitor-based ALL regimens 1, 6
• For transplant-eligible patients: Early HLA typing of patient and family members at diagnosis; initiate donor search during induction therapy 1, 3
• Consolidation: Allogeneic HSCT in first remission significantly improves overall survival (p=0.0013) 6

Treatment Pitfalls

• No prospective trial data exists due to disease rarity 2, 8, 7
• Treatment decisions must incorporate unique immunophenotypic and cytogenetic features 8
• MPAL generally carries worse prognosis than either AML or ALL alone, with median overall survival of 19.5 months without transplant 2, 6, 7

Prognostic Factors

Adverse features include:

• Complex karyotype
• TP53 mutations
• Absence of BCR-ABL1 (paradoxically, BCR-ABL1-positive cases may respond better to targeted therapy)
• Failure to proceed to allogeneic HSCT 6, 7, 9