Introduction:

• They are leukaemias composed of >/= 20% abnormal progenitors that do not show differentiation along a single lineage
• 2 types of acute leukemias are included into this category:
  • Acute undifferentiated leukemias:  Leukemias in which morphologic, cytochemical and immunophenotyping features of proliferating blasts lack sufficient evidence to classify as lymphoid or myeloid origin
  • Mixed phenotype acute leukemias: Leukemias which have morphologic / immunophenotyping characteristics of both myeloid and lymphoid cells or both B & T cell lineages. This has 2 subtypes:
    • Bilineal: Dual population of blasts with each population expressing markers of a distinct lineage i.e. myeloid and lymphoid or B and T (For diagnosis, >5% blasts must show a different lineage expression. If <5% such blasts are present, then it should reported as ”Predominantly AML/ALL with a small leukemic population of lymphoid/myeloid lineage detected of uncertain significance” )
    • Biphenotypic: Blasts which co express myeloid and T or B lineage specific antigens, or concurrent B & T lineage antigens

Epidemiology

• Account for <4% of all acute leukemias

Morphology:

• Morphologically they resemble AML-M0 or ALL
• >20% blasts are necessary in PS/BM for diagnosis of ALAL

Immunophenotyping

• Requirements for assigning  lineage to a  blast population
  • Myeloid lineage (Any one of below)
    • Myeloperoxidase 
    • Monocytic differentiation (Atleast 2 of the following NSE, CD11c, CD14, CD64, Lysozyme)
  • T Lineage
    • Cytoplasmic/ surface CD3
  • B Lineage- Multiple antigens are required (Any one of the following)
    • Strong CD19 with at least one of the following strongly expressed: CD79a, CytoCD22, CD10
    • Weak CD 19 with at least two of the following strongly expressed: CD79a, CytoCD22, CD10
• Note: Co expression of 1-2 cross lineage antigens is not a sufficient criteria for diagnosis. Myeloid antigen presenting ALL and lymphoid antigen presenting AML are often found and they should not be called biphenotypic.

Cytogenetics:  

• Abnormal karyotype is seen in 64% to 87% cases
• 1/3^rd have Ph. Chromosomes
• t (4;11), 11q23 abnormalities

Criteria for diagnosis of subtypes of ALAL:

MPAL with BCR:ABL translocation

• Essential:
  • ≥20% blasts in bone marrow and/or blood with an immunophenotype that meets the diagnostic criteria for MPAL
  • BCR::ABL1 and/or t(9;22)(q34;q11.2) detected at initial diagnosis.
  • No prior or subsequent evidence of chronic myeloid leukaemia.
  • No history of exposure to cytotoxic therapy.
• Desirable
  • Determination of the BCR::ABL1 transcript subtype and establishment of a quantitative baseline for monitoring treatment response.

MPAL with KMT2A gene rearrangements

• Essential
  • ≥20% blasts in bone marrow and/or blood with an immunophenotype that meets the diagnostic criteria for MPAL
  • Presence of a KMT2A rearrangement.
  • No history of exposure to cytotoxic therapy.
• Desirable
  • Identification of the KMT2A fusion partner.

ALAL with other defined genetic alterations: 

• It includes:
  • MPAL with ZNF384 rearrangements
  • MPAL with BCL11B activation

Mixed-phenotype acute leukaemia, B/myeloid

• Essential
  • ≥20% blasts in bone marrow and/or blood expressing B lineage and myeloid lineage antigens.
  • Not fulfilling diagnostic criteria of MPAL with defined genetic alterations.
  • No history of exposure to cytotoxic therapy

Mixed-phenotype acute leukaemia, T/myeloid

• Essential
  • ≥20% blasts in bone marrow and/or blood expressing T lineage and myeloid lineage antigens.
  • Not fulfilling diagnostic criteria of MPAL with defined genetic alterations.
  • No history of exposure to cytotoxic therapy.

Mixed-phenotype acute leukaemia, rare types

• Essential
  • ≥20% blasts in bone marrow and/or blood expressing combinations of B, T, myeloid and megakaryocytic lineage markers.
  • Not fulfilling diagnostic criteria of MPAL with defined genetic alterations, MPAL B/Myeloid, or MPAL T/Myeloid.
  • No history of exposure to cytotoxic therapy.
  • No history of myeloid neoplasms.

Acute leukaemia of ambiguous lineage, NOS

• Essential
  • ≥20% blasts in bone marrow and/or blood expressing combinations of immunophenotypic lineage markers that do not permit definitive lineage assignments.
  • Not fulfilling diagnostic criteria of MPAL with defined genetic alterations.

Acute undifferentiated leukaemia

• Essential
  • ≥20% blasts in bone marrow and/or blood lacking expression of immunophenotypic lineage markers.
  • Not fulfilling diagnostic criteria of MPAL with defined genetic alterations or rare MPAL subtypes.
• AUL must be distinguished from AML with minimal differentiation in which ≥ 2 myeloid associated markers (e.g. CD13, CD33, and CD117) are expressed.

Prognosis: 

• Poor, particularly in adults

Pretreatment Workup: 

• History
• Examination
• WHO P. S.
• BSA
• Flow cytometry
• BMA and Bx
• Hemoglobin
• TLC, DLC
• Platelet count
• Peripheral smear
• Coagulation tests; PT:         APPT:           Fibrinogen:
• LFT: Bili- T/D                         SGPT:                                 SGOT:
• Creatinine
• Electrolytes: Na:                K:               Ca:Mg:              PO4:
• Uric acid
• LDH
• HIV
• HBsAg
• HCV
• UPT
• Cytogenetics
• NGS panel for myeloid neoplasms
• Prognostic category
• ECHO/ MUGA Scan:  LVEF-               %
• HLA typing for HSCT fit patient
• MRI Brain with contrast (In patient suspected with leukemic meningitis)
• LP- CSF with TIT (If symptomatic)
• Chemotherapy consent after informing about disease, prognosis, cost of therapy, side effects, hygiene, food and contraception
• Fertility preservation
• PICC line insertion and Chest X ray after line insertion
• Tumor board meeting and decision
• Attach supportive care drug sheet
• Inform primary care physician

Treatment:

• MPAL: ALL type induction chemotherapy, followed by Allo HSCT in CR1
• Others: AML or ALL type induction chemotherapy, followed by Allo HSCT in CR1
• Add TKI if BCR:ABL Positive
• Note: Lineage switch is commonly seen during treatment