Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®) 2/9 –Health Professional Version - National Cancer Institute

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Acute Lymphoblastic Leukemia Treatment (PDQ®)–Health Professional Version

World Health Organization (WHO) Classification System for Childhood ALL

In This Section

• 2016 WHO Classification of B-Lymphoblastic Leukemia/Lymphoma
• 2016 WHO Classification of T-Lymphoblastic Leukemia/Lymphoma
• 2016 WHO Classification of Acute Leukemias of Ambiguous Lineage

The 2016 revision to the WHO classification of tumors of the hematopoietic and lymphoid tissues lists the following entities for acute lymphoid leukemias:[1]

2016 WHO Classification of B-Lymphoblastic Leukemia/Lymphoma

• B-lymphoblastic leukemia/lymphoma, not otherwise specified (NOS).
• B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities.
• B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2); BCR-ABL1.
• B-lymphoblastic leukemia/lymphoma with t(v;11q23.3); KMT2A rearranged.
• B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1); ETV6-RUNX1.
• B-lymphoblastic leukemia/lymphoma with hyperdiploidy.
• B-lymphoblastic leukemia/lymphoma with hypodiploidy.
• B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3); IL3-IGH.
• B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3); TCF3-PBX1.
• Provisional entity: B-lymphoblastic leukemia/lymphoma, BCR-ABL1–like.
• Provisional entity: B-lymphoblastic leukemia/lymphoma with iAMP21.

2016 WHO Classification of T-Lymphoblastic Leukemia/Lymphoma

• Provisional entity: Early T-cell precursor lymphoblastic leukemia.

2016 WHO Classification of Acute Leukemias of Ambiguous Lineage

For acute leukemias of ambiguous lineage, the group of acute leukemias that have characteristics of both acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL), the WHO classification system is summarized in Table 1.[2,3] The criteria for lineage assignment for a diagnosis of mixed phenotype acute leukemia (MPAL) are provided in Table 2.[1]

Table 1. Acute Leukemias of Ambiguous Lineage According to the World Health Organization Classification of Tumors of Hematopoietic and Lymphoid Tissuesa

Condition	Definition
NOS = not otherwise specified.
aBéné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009.[2] Obtained from Haematologica/the Hematology Journal website http://www.haematologica.orgExit Disclaimer.
Acute undifferentiated leukemia	Acute leukemia that does not express any marker considered specific for either lymphoid or myeloid lineage
Mixed phenotype acute leukemia with t(9;22)(q34;q11.2); BCR-ABL1	Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have the (9;22) translocation or the BCR-ABL1 rearrangement
Mixed phenotype acute leukemia with t(v;11q23); KMT2A (MLL) rearranged	Acute leukemia meeting the diagnostic criteria for mixed phenotype acute leukemia in which the blasts also have a translocation involving the KMT2A gene
Mixed phenotype acute leukemia, B/myeloid, NOS	Acute leukemia meeting the diagnostic criteria for assignment to both B and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR-ABL1 or KMT2A
Mixed phenotype acute leukemia, T/myeloid, NOS	Acute leukemia meeting the diagnostic criteria for assignment to both T and myeloid lineage, in which the blasts lack genetic abnormalities involving BCR-ABL1 or KMT2A
Mixed phenotype acute leukemia, B/myeloid, NOS—rare types	Acute leukemia meeting the diagnostic criteria for assignment to both B and T lineage
Other ambiguous lineage leukemias	Natural killer–cell lymphoblastic leukemia/lymphoma

Table 2. Lineage Assignment Criteria for Mixed Phenotype Acute Leukemia According to the 2016 Revision to the World Health Organization Classification of Myeloid Neoplasms and Acute Leukemiaa

Lineage	Criteria
aAdapted from Arber et al.[1]
bStrong defined as equal to or brighter than the normal B or T cells in the sample.
Myeloid lineage	Myeloperoxidase (flow cytometry, immunohistochemistry, or cytochemistry); or monocytic differentiation (at least two of the following: nonspecific esterase cytochemistry, CD11c, CD14, CD64, lysozyme)
T lineage	Strongb cytoplasmic CD3 (with antibodies to CD3 epsilon chain); or surface CD3
B lineage	Strongb CD19 with at least one of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10; or weak CD19 with at least two of the following strongly expressed: CD79a, cytoplasmic CD22, or CD10

Leukemias of mixed phenotype may be seen in various presentations, including the following:

1. Bilineal leukemias in which there are two distinct populations of cells, usually one lymphoid and one myeloid.
2. Biphenotypic leukemias in which individual blast cells display features of both lymphoid and myeloid lineage.

Biphenotypic cases represent the majority of mixed phenotype leukemias.[4] Patients with B-myeloid biphenotypic leukemias lacking the TEL-AML1 fusion have lower rates of complete remission (CR) and significantly worse event-free survival (EFS) rates compared with patients with B-ALL.[4] Some studies suggest that patients with biphenotypic leukemia may fare better with a lymphoid, as opposed to a myeloid, treatment regimen.[5-8] A large retrospective study from the international Berlin-Frankfurt-Münster (BFM) group demonstrated that initial therapy with an ALL-type regimen was associated with a superior outcome compared with AML-type or combined ALL/AML regimens, particularly in cases with CD19 positivity or other lymphoid antigen expression. In this study, hematopoietic stem cell transplantation (HSCT) in first CR was not beneficial, with the possible exception of cases with morphologic evidence of persistent marrow disease (≥5% blasts) after the first month of treatment.[8]

Key clinical and biological characteristics, as well as the prognostic significance for these entities, are discussed in the Cytogenetics/Genomics of Childhood ALL section of this summary.

References

1. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PUBMED Abstract]
2. Béné MC: Biphenotypic, bilineal, ambiguous or mixed lineage: strange leukemias! Haematologica 94 (7): 891-3, 2009. [PUBMED Abstract]
3. Borowitz MJ, Béné MC, Harris NL: Acute leukaemias of ambiguous lineage. In: Swerdlow SH, Campo E, Harris NL, et al., eds.: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008, pp 150-5.
4. Gerr H, Zimmermann M, Schrappe M, et al.: Acute leukaemias of ambiguous lineage in children: characterization, prognosis and therapy recommendations. Br J Haematol 149 (1): 84-92, 2010. [PUBMED Abstract]
5. Rubnitz JE, Onciu M, Pounds S, et al.: Acute mixed lineage leukemia in children: the experience of St Jude Children's Research Hospital. Blood 113 (21): 5083-9, 2009. [PUBMED Abstract]
6. Al-Seraihy AS, Owaidah TM, Ayas M, et al.: Clinical characteristics and outcome of children with biphenotypic acute leukemia. Haematologica 94 (12): 1682-90, 2009. [PUBMED Abstract]
7. Matutes E, Pickl WF, Van't Veer M, et al.: Mixed-phenotype acute leukemia: clinical and laboratory features and outcome in 100 patients defined according to the WHO 2008 classification. Blood 117 (11): 3163-71, 2011. [PUBMED Abstract]
8. Hrusak O, de Haas V, Stancikova J, et al.: International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia. Blood 132 (3): 264-276, 2018. [PUBMED Abstract]