Immunophenotype

B-ALL (WHO B-lymphoblastic leukemia). Before 2008, the WHO classified B-lymphoblastic leukemia as precursor B-lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL. Mature B-cell ALL is now termed Burkitt leukemia and requires different treatment than has been given for B-ALL (precursor B-cell ALL). B-ALL, defined by the expression of CD19, HLA-DR, cytoplasmic CD79a, and other B-cell–associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of B-ALL cases express the CD10 surface antigen (formerly known as common ALL antigen). Absence of CD10 is often associated with KMT2A rearrangements, particularly t(4;11)(q21;q23), and a poor outcome.[10,111] It is not clear whether CD10 negativity has any independent prognostic significance in the absence of a KMT2A gene rearrangement.[112] The major immunophenotypic subtypes of B-ALL are as follows:

B-ALL (WHO B-lymphoblastic leukemia). Before 2008, the WHO classified B-lymphoblastic leukemia as precursor B-lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL. Mature B-cell ALL is now termed Burkitt leukemia and requires different treatment than has been given for B-ALL (precursor B-cell ALL). B-ALL, defined by the expression of CD19, HLA-DR, cytoplasmic CD79a, and other B-cell–associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of B-ALL cases express the CD10 surface antigen (formerly known as common ALL antigen). Absence of CD10 is often associated with KMT2A rearrangements, particularly t(4;11)(q21;q23), and a poor outcome.[10,111] It is not clear whether CD10 negativity has any independent prognostic significance in the absence of a KMT2A gene rearrangement.[112] The major immunophenotypic subtypes of B-ALL are as follows:

Common B-ALL (CD10 positive and no surface or cytoplasmic immunoglobulin [Ig]).Approximately three-quarters of patients with B-ALL have the common precursor B-cell immunophenotype and have the best prognosis. Patients with favorable cytogenetics almost always show a common precursor B-cell immunophenotype.

B-ALL (WHO B-lymphoblastic leukemia). Before 2008, the WHO classified B-lymphoblastic leukemia as precursor B-lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL. Mature B-cell ALL is now termed Burkitt leukemia and requires different treatment than has been given for B-ALL (precursor B-cell ALL). B-ALL, defined by the expression of CD19, HLA-DR, cytoplasmic CD79a, and other B-cell–associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of B-ALL cases express the CD10 surface antigen (formerly known as common ALL antigen). Absence of CD10 is often associated with KMT2A rearrangements, particularly t(4;11)(q21;q23), and a poor outcome.[10,111] It is not clear whether CD10 negativity has any independent prognostic significance in the absence of a KMT2A gene rearrangement.[112] The major immunophenotypic subtypes of B-ALL are as follows:

Pro-B ALL (CD10 negative and no surface or cytoplasmic Ig).Approximately 5% of patients have the pro-B immunophenotype. Pro-B is the most common immunophenotype seen in infants and is often associated with KMT2A gene rearrangements.

B-ALL (WHO B-lymphoblastic leukemia). Before 2008, the WHO classified B-lymphoblastic leukemia as precursor B-lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL. Mature B-cell ALL is now termed Burkitt leukemia and requires different treatment than has been given for B-ALL (precursor B-cell ALL). B-ALL, defined by the expression of CD19, HLA-DR, cytoplasmic CD79a, and other B-cell–associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of B-ALL cases express the CD10 surface antigen (formerly known as common ALL antigen). Absence of CD10 is often associated with KMT2A rearrangements, particularly t(4;11)(q21;q23), and a poor outcome.[10,111] It is not clear whether CD10 negativity has any independent prognostic significance in the absence of a KMT2A gene rearrangement.[112] The major immunophenotypic subtypes of B-ALL are as follows:

Pre-B ALL (presence of cytoplasmic Ig).The leukemic cells of patients with pre-B ALL contain cytoplasmic Ig, and 25% of patients with pre-B ALL have the t(1;19)(q21;p13) translocation with the TCF3::PBX1 fusion.[113,114]Approximately 3% of patients have transitional pre-B ALL with expression of surface Ig heavy chain in the absence of Ig light chain expression, MYC gene involvement, and L3 morphology. Patients with this phenotype respond well to therapy used for B-ALL.[115]

B-ALL (WHO B-lymphoblastic leukemia). Before 2008, the WHO classified B-lymphoblastic leukemia as precursor B-lymphoblastic leukemia, and this terminology is still frequently used in the literature of childhood ALL to distinguish it from mature B-cell ALL. Mature B-cell ALL is now termed Burkitt leukemia and requires different treatment than has been given for B-ALL (precursor B-cell ALL). B-ALL, defined by the expression of CD19, HLA-DR, cytoplasmic CD79a, and other B-cell–associated antigens, accounts for 80% to 85% of childhood ALL. Approximately 90% of B-ALL cases express the CD10 surface antigen (formerly known as common ALL antigen). Absence of CD10 is often associated with KMT2A rearrangements, particularly t(4;11)(q21;q23), and a poor outcome.[10,111] It is not clear whether CD10 negativity has any independent prognostic significance in the absence of a KMT2A gene rearrangement.[112] The major immunophenotypic subtypes of B-ALL are as follows:

Mature B-ALL (Burkitt lymphoma/leukemia).Approximately 2% of patients present with mature B-cell leukemia (surface Ig expression, generally with French-American-British criteria L3 morphology and an 8q24 translocation involving MYC), also called Burkitt leukemia. The treatment for mature B-cell ALL is based on therapy for non-Hodgkin lymphoma and is completely different from the treatment for B-ALL. Rare cases of mature B-cell leukemia that lack surface Ig but have L3 morphology with MYC gene translocations should also be treated as mature B-cell leukemia.[115] For more information about the treatment of children with mature B-cell lymphoma/leukemia and Burkitt lymphoma/leukemia, see Childhood Non-Hodgkin Lymphoma Treatment.A small number of cases of IG::MYC-translocated leukemias with precursor B-cell immunophenotype (e.g., absence of CD20 expression and surface Ig expression) have been reported.[116] These cases presented in both children and adults. Like Burkitt lymphoma/leukemia, they had a male predominance and most patients showed L3 morphology. The cases lacked variants in genes recurrently altered in Burkitt lymphoma (e.g., ID3, CCND3, or MYC), whereas variants in RAS genes (frequently altered in B-ALL) were common. The clinical significance and optimal therapy of IG::MYC–translocated leukemias with precursor B-cell phenotype and molecular characteristics requires further study.

T-ALL. T-ALL is defined by expression of the T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-ALL is frequently associated with a constellation of clinical features, including the following:[21,39,82] While not true historically, with appropriately intensive therapy, children with T-ALL now have an outcome approaching that of children with B-ALL.[21,39,42,43,82,117] There are few commonly accepted prognostic factors for patients with T-ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-ALL.[38-45,118] The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.[119] Early T-cell precursor (ETP) ALL. ETP ALL, a distinct subset of childhood T-ALL, was initially defined by identifying T-ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors.[120] The subset of T-ALL cases identified by these analyses represented 13% of all cases, and are characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid markers). Another subgroup of T-ALL, called near-ETP ALL, has a similar immunophenotype as ETP ALL, except with strong CD5 expression. This subtype represents approximately 15% of cases.[46] Initial reports describing ETP ALL suggested that this subset of patients has a poorer prognosis than other patients with T-ALL.[120-122] In addition, studies have reported that patients with ETP and near-ETP ALL have a slower early response and higher frequency of induction failure.[45,46] However, despite higher rates of end-induction MRD and induction failure in these patients, the ETP and near-ETP subtypes do not appear to be independent predictors of inferior EFS or OS.[46,123] For instance, in a study from the U.K. Medical Research Council, the ETP ALL subgroup of patients had nonsignificantly inferior 5-year EFS rates compared with non-ETP patients (76% vs. 84%).[123] Similarly, in the COG AALL0434 [NCT00408005] trial, neither ETP nor near-ETP status had a statistically significant impact on EFS on multivariable analysis.[46] Based on these results, most ALL treatment groups do not change patient treatment based on ETP status.

T-ALL. T-ALL is defined by expression of the T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-ALL is frequently associated with a constellation of clinical features, including the following:[21,39,82] While not true historically, with appropriately intensive therapy, children with T-ALL now have an outcome approaching that of children with B-ALL.[21,39,42,43,82,117] There are few commonly accepted prognostic factors for patients with T-ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-ALL.[38-45,118] The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.[119] Early T-cell precursor (ETP) ALL. ETP ALL, a distinct subset of childhood T-ALL, was initially defined by identifying T-ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors.[120] The subset of T-ALL cases identified by these analyses represented 13% of all cases, and are characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid markers). Another subgroup of T-ALL, called near-ETP ALL, has a similar immunophenotype as ETP ALL, except with strong CD5 expression. This subtype represents approximately 15% of cases.[46] Initial reports describing ETP ALL suggested that this subset of patients has a poorer prognosis than other patients with T-ALL.[120-122] In addition, studies have reported that patients with ETP and near-ETP ALL have a slower early response and higher frequency of induction failure.[45,46] However, despite higher rates of end-induction MRD and induction failure in these patients, the ETP and near-ETP subtypes do not appear to be independent predictors of inferior EFS or OS.[46,123] For instance, in a study from the U.K. Medical Research Council, the ETP ALL subgroup of patients had nonsignificantly inferior 5-year EFS rates compared with non-ETP patients (76% vs. 84%).[123] Similarly, in the COG AALL0434 [NCT00408005] trial, neither ETP nor near-ETP status had a statistically significant impact on EFS on multivariable analysis.[46] Based on these results, most ALL treatment groups do not change patient treatment based on ETP status.

Male sex.

T-ALL. T-ALL is defined by expression of the T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-ALL is frequently associated with a constellation of clinical features, including the following:[21,39,82] While not true historically, with appropriately intensive therapy, children with T-ALL now have an outcome approaching that of children with B-ALL.[21,39,42,43,82,117] There are few commonly accepted prognostic factors for patients with T-ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-ALL.[38-45,118] The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.[119] Early T-cell precursor (ETP) ALL. ETP ALL, a distinct subset of childhood T-ALL, was initially defined by identifying T-ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors.[120] The subset of T-ALL cases identified by these analyses represented 13% of all cases, and are characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid markers). Another subgroup of T-ALL, called near-ETP ALL, has a similar immunophenotype as ETP ALL, except with strong CD5 expression. This subtype represents approximately 15% of cases.[46] Initial reports describing ETP ALL suggested that this subset of patients has a poorer prognosis than other patients with T-ALL.[120-122] In addition, studies have reported that patients with ETP and near-ETP ALL have a slower early response and higher frequency of induction failure.[45,46] However, despite higher rates of end-induction MRD and induction failure in these patients, the ETP and near-ETP subtypes do not appear to be independent predictors of inferior EFS or OS.[46,123] For instance, in a study from the U.K. Medical Research Council, the ETP ALL subgroup of patients had nonsignificantly inferior 5-year EFS rates compared with non-ETP patients (76% vs. 84%).[123] Similarly, in the COG AALL0434 [NCT00408005] trial, neither ETP nor near-ETP status had a statistically significant impact on EFS on multivariable analysis.[46] Based on these results, most ALL treatment groups do not change patient treatment based on ETP status.

Older age.

T-ALL. T-ALL is defined by expression of the T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-ALL is frequently associated with a constellation of clinical features, including the following:[21,39,82] While not true historically, with appropriately intensive therapy, children with T-ALL now have an outcome approaching that of children with B-ALL.[21,39,42,43,82,117] There are few commonly accepted prognostic factors for patients with T-ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-ALL.[38-45,118] The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.[119] Early T-cell precursor (ETP) ALL. ETP ALL, a distinct subset of childhood T-ALL, was initially defined by identifying T-ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors.[120] The subset of T-ALL cases identified by these analyses represented 13% of all cases, and are characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid markers). Another subgroup of T-ALL, called near-ETP ALL, has a similar immunophenotype as ETP ALL, except with strong CD5 expression. This subtype represents approximately 15% of cases.[46] Initial reports describing ETP ALL suggested that this subset of patients has a poorer prognosis than other patients with T-ALL.[120-122] In addition, studies have reported that patients with ETP and near-ETP ALL have a slower early response and higher frequency of induction failure.[45,46] However, despite higher rates of end-induction MRD and induction failure in these patients, the ETP and near-ETP subtypes do not appear to be independent predictors of inferior EFS or OS.[46,123] For instance, in a study from the U.K. Medical Research Council, the ETP ALL subgroup of patients had nonsignificantly inferior 5-year EFS rates compared with non-ETP patients (76% vs. 84%).[123] Similarly, in the COG AALL0434 [NCT00408005] trial, neither ETP nor near-ETP status had a statistically significant impact on EFS on multivariable analysis.[46] Based on these results, most ALL treatment groups do not change patient treatment based on ETP status.

Leukocytosis.

T-ALL. T-ALL is defined by expression of the T-cell–associated antigens (cytoplasmic CD3, with CD7 plus CD2 or CD5) on leukemic blasts. T-ALL is frequently associated with a constellation of clinical features, including the following:[21,39,82] While not true historically, with appropriately intensive therapy, children with T-ALL now have an outcome approaching that of children with B-ALL.[21,39,42,43,82,117] There are few commonly accepted prognostic factors for patients with T-ALL. Conflicting data exist regarding the prognostic significance of presenting leukocyte counts in T-ALL.[38-45,118] The presence or absence of a mediastinal mass at diagnosis has no prognostic significance. In patients with a mediastinal mass, the rate of regression of the mass lacks prognostic significance.[119] Early T-cell precursor (ETP) ALL. ETP ALL, a distinct subset of childhood T-ALL, was initially defined by identifying T-ALL cases with gene expression profiles highly related to expression profiles for normal early T-cell precursors.[120] The subset of T-ALL cases identified by these analyses represented 13% of all cases, and are characterized by a distinctive immunophenotype (CD1a and CD8 negativity, with weak expression of CD5 and coexpression of stem cell or myeloid markers). Another subgroup of T-ALL, called near-ETP ALL, has a similar immunophenotype as ETP ALL, except with strong CD5 expression. This subtype represents approximately 15% of cases.[46] Initial reports describing ETP ALL suggested that this subset of patients has a poorer prognosis than other patients with T-ALL.[120-122] In addition, studies have reported that patients with ETP and near-ETP ALL have a slower early response and higher frequency of induction failure.[45,46] However, despite higher rates of end-induction MRD and induction failure in these patients, the ETP and near-ETP subtypes do not appear to be independent predictors of inferior EFS or OS.[46,123] For instance, in a study from the U.K. Medical Research Council, the ETP ALL subgroup of patients had nonsignificantly inferior 5-year EFS rates compared with non-ETP patients (76% vs. 84%).[123] Similarly, in the COG AALL0434 [NCT00408005] trial, neither ETP nor near-ETP status had a statistically significant impact on EFS on multivariable analysis.[46] Based on these results, most ALL treatment groups do not change patient treatment based on ETP status.

Mediastinal mass.

Myeloid antigen expression. Up to one-third of childhood ALL patients have leukemia cells that express myeloid-associated surface antigens. Myeloid-associated antigen expression appears to be associated with specific ALL subgroups, notably those with KMT2A rearrangements, ETV6::RUNX1, and BCR::ABL1.[124-126] Patients with B-ALL who have gene rearrangements involving ZNF384 also commonly show myeloid antigen expression.[127,128] No independent adverse prognostic significance exists for myeloid-surface antigen expression.[124,125] For information about leukemia of ambiguous lineage, see the 2016 WHO Classification of Acute Leukemias of Ambiguous Lineage section.