What is the ALL (Acute Lymphoblastic Leukemia) regimen for a patient with Mixed Phenotype Acute Leukemia (MPAL)?

ALL Regimen for Mixed Phenotype Acute Leukemia (MPAL)

For patients with Mixed Phenotype Acute Leukemia (MPAL), initiate acute lymphoblastic leukemia (ALL)-directed chemotherapy regimens rather than acute myeloid leukemia (AML) protocols, as ALL-based treatment demonstrates superior response rates and outcomes. 1

Rationale for ALL-Directed Therapy in MPAL

The evidence consistently supports using ALL regimens for MPAL despite the mixed lineage expression:

• ALL-based chemotherapy achieves better response rates compared to AML regimens (p = 0.001), with superior complete remission rates and overall survival in both pediatric and adult MPAL patients 2

• The NCCN explicitly states that ALL-directed therapy can be initiated for MPAL, acknowledging that myeloid-associated antigens (CD13, CD33) may be expressed without excluding ALL diagnosis or indicating adverse prognosis 1

• In a pediatric cohort treated with the EORTC 58951 ALL protocol, 90% of MPAL patients achieved morphologic complete remission at end of induction, with 3-year event-free survival and overall survival rates of 60% 3

Specific ALL Regimen Components for MPAL

Induction Phase (4-Drug Backbone)

The standard induction includes: 4, 5, 6

• Corticosteroid: Prednisone or dexamethasone (dexamethasone provides better CNS penetration but higher toxicity risk) 5
• Vincristine: 1.4 mg/m² IV weekly (maximum 2 mg) 6
• Anthracycline: Daunorubicin 25-30 mg/m² IV weekly or doxorubicin 5, 6
• L-asparaginase: Pegaspargase 2,500 IU/m² IV (1-3 doses during induction) 6

CNS Prophylaxis (Critical Component)

• Intrathecal chemotherapy with triple therapy (methotrexate, cytarabine, dexamethasone) must begin during induction and continue throughout treatment 6
• High-dose systemic methotrexate during consolidation phases 4, 6

Consolidation/Intensification

Following remission achievement: 4, 6

• High-dose methotrexate
• Cyclophosphamide
• Cytarabine
• Mercaptopurine
• Additional pegaspargase doses
• Continued intrathecal chemotherapy

Maintenance Therapy

Standard maintenance continues for approximately 2-3 years total from diagnosis: 4, 6

• Daily oral mercaptopurine
• Weekly oral methotrexate
• Monthly vincristine pulses
• Pulse dexamethasone

Critical MRD Monitoring

Minimal residual disease (MRD) assessment is the most critical prognostic factor in MPAL treated with ALL regimens: 6, 7

• End-of-induction (EOI) MRD <0.01% predicts superior outcomes, with 5-year event-free survival significantly better than MRD-positive patients (HR = 6.00, p < 0.001) 7
• MRD positivity at EOI requires therapy intensification and consideration for allogeneic hematopoietic stem cell transplantation 4, 6
• 70% of pediatric MPAL patients achieve MRD-negative remission with ALL induction therapy 7

Age-Specific Considerations

Pediatric Patients (Including Infants)

• Standard-risk patients may receive 3-drug induction (without anthracyclines), though most MPAL cases warrant 4-drug induction given disease biology 4, 5
• For infants under 1 year, prednisone is preferred over dexamethasone to minimize osteonecrosis risk 6
• Dose modifications may be necessary for very young patients, particularly those with KMT2A rearrangements 6

Adolescent and Young Adult (AYA) Patients

• AYA patients benefit from pediatric-inspired ALL regimens with modifications including addition of cyclophosphamide to the 4-drug induction 5
• Treatment may be appropriate for patients up to age 30 years in pediatric oncology settings 1

Older Adults (≥65 years)

• Treatment intensity should be reduced for patients ≥65 years or those with substantial comorbidities, using low-intensity options (vincristine and prednisone or POMP) or moderate-intensity regimens (ALLOLD07, EWALL, GMALL, or GRAALL) 4

Common Pitfalls and Caveats

Critical diagnostic consideration: MPAL classification must be based on WHO 2022 criteria, as the presence of myeloid-associated antigens (CD13, CD33) in ALL does not exclude ALL diagnosis and should not prompt switching to AML therapy 1

Dexamethasone versus prednisone trade-off: While dexamethasone significantly reduces CNS relapse risk, it carries higher risks of induction mortality, neuropsychiatric events, and myopathy without conclusive overall survival advantage 5

Transplant consideration: Unlike adult MPAL where allogeneic transplantation is frequently recommended, ALL therapy without transplantation is adequate for most pediatric MPAL patients, particularly those achieving early MRD negativity 7

Treatment setting: Given the complexity of therapy and need for intensive supportive care, treatment should be administered at specialized centers with expertise in ALL management 6

Special Molecular Considerations

• BCR-ABL positive MPAL (detected in 13.7-20% of cases) may benefit from tyrosine kinase inhibitor addition to ALL backbone, though specific data in MPAL is limited 3, 2
• KMT2A rearrangements, while associated with poor prognosis in ALL, were notably absent in some MPAL cohorts, suggesting different biology 3