Definitions applied toward categorization of patient cases
| . | Definition . | Key considerations . | Examples . |
|---|---|---|---|
| LS | Refers to the immunophenotypic transformation of an acute leukemia from 1 immunophenotype (ie, lineage categorization) to another, based on loss of lineage-specific markers and acquisition of new lineage-specific markers, with retention of baseline cytogenetic and/or molecular signatures.3 Confirmed LS: clonality of LS confirmed by retention of baseline cytogenetics, molecular aberrations, and/or NGS (ie, by clonoSEQ, PCR, or other methodologies). Probable LS: clonality of LS unable to be confirmed, but time course and clinical history supportive of LS and not a treatment-related malignancy. | Cytogenetics at LS should demonstrate retention of diagnostic findings w/wo newly acquired cytogenetic changes If cytogenetics are not available (or demonstrate evolution from baseline), retention of diagnostic leukemia-specific immunoreceptor gene rearrangement is sufficient to establish clonal relationship Distinct from treatment related acute leukemias (eg, t-AML) and from cases of ALAL at diagnosis that were miscategorized as B-ALL Includes cases in which previously unappreciated cell subpopulations may be unmasked with lineage-specific–directed therapy Morphology aligned with LS presentation | B-ALL to AML B-ALL to T-ALL T-ALL to AML B-ALL to ALAL AML to ALL |
| Lineage drift | Cases of acute leukemia in which lineage-specific markers are in evolution, such that leukemic blasts may express additional markers of another lineage class but not sufficient to define LS, or loss of lineage-specific antigens without full acquisition of other antigens. | Acquisition of immunophenotypic markers of a new lineage (ie, new myeloid markers) does not in and of itself constitute LS if the underlying disease is still diagnosed by its original immunophenotype Morphology may remain consistent with original leukemia | B-ALL with loss of CD19, retention of CD22, and acquisition of CD33 is still considered as B-ALL if the pathologist has identified it as B-ALL B-ALL with loss of both CD19 and CD22, and acquisition of myeloid antigens may still be considered as B-ALL if other ALL markers have been retained and the pathologist has identified it as B-ALL (not meeting WHO, ICC and/or EGIL criteria for myeloid lineage) |
| ALAL | Acute leukemias that fail to show commitment to a single lineage (myeloid or lymphoid) or that show commitment to >1 lineage24,25,∗ Encompasses: AUL: failure to commit to a single lineage or lack of lineage-specific markers MPAL: Commitment >1 lineage can be ≥2 separate populations (each classified by AML and ALL criteria; bilineal) can be a single population with markers defining >1 lineage (biphenotypic) MPAL with defining genetic alterations: BCR::ABL1, t(v;11q23.3); KMT2A rearranged, ZNF384, BCL11B activation MPAL with defining immunophenotypic changes: B/myeloid, T/myeloid, B/T/myeloid, B/T | May involve ≥2 single lineage populations (bilineal) or a single population with >1 lineage-defining marker (biphenotypic). Small populations of normal myeloid or lymphoid precursors must be differentiated from aberrant clones. In cases with small aberrant clones: >5% consider diagnosis of MPAL73 <5% diagnosis should be based on the major leukemic population with a descriptive modifier (eg, “predominantly ALL with a small leukemic population of myeloid lineage detected of uncertain significance”). | An acute leukemia expressing CD10, TdT, and CD15 but negative for CD19 would be considered AUL An acute leukemia expressing CD19, CD79a, MPO, and CD33 would be considered MPAL B/myeloid |
| Therapy-related acute leukemias (eg, t-AML, t-MDS) | Cases of MDS and/or AML secondary to cytotoxic chemotherapy or radiation that occur after initial treatment of a prior malignancy27 These cases of MDS/AML demonstrate the absence of retained cytogenetics or molecular signatures from baseline as evidence of lack of clonality consistent with the original diagnosis | Frequently characterized by the following cytogenetic changes: Monosomy 7, monosomy 5 KMT2A rearrangements TP53 mutations | AML that presents 5 y after myeloablative HSCT with a novel t(9;11) not present at diagnosis MDS with monosomy 7 presenting 3 y after CR2 in a heavily treated patient |
| . | Definition . | Key considerations . | Examples . |
|---|---|---|---|
| LS | Refers to the immunophenotypic transformation of an acute leukemia from 1 immunophenotype (ie, lineage categorization) to another, based on loss of lineage-specific markers and acquisition of new lineage-specific markers, with retention of baseline cytogenetic and/or molecular signatures.3 Confirmed LS: clonality of LS confirmed by retention of baseline cytogenetics, molecular aberrations, and/or NGS (ie, by clonoSEQ, PCR, or other methodologies). Probable LS: clonality of LS unable to be confirmed, but time course and clinical history supportive of LS and not a treatment-related malignancy. | Cytogenetics at LS should demonstrate retention of diagnostic findings w/wo newly acquired cytogenetic changes If cytogenetics are not available (or demonstrate evolution from baseline), retention of diagnostic leukemia-specific immunoreceptor gene rearrangement is sufficient to establish clonal relationship Distinct from treatment related acute leukemias (eg, t-AML) and from cases of ALAL at diagnosis that were miscategorized as B-ALL Includes cases in which previously unappreciated cell subpopulations may be unmasked with lineage-specific–directed therapy Morphology aligned with LS presentation | B-ALL to AML B-ALL to T-ALL T-ALL to AML B-ALL to ALAL AML to ALL |
| Lineage drift | Cases of acute leukemia in which lineage-specific markers are in evolution, such that leukemic blasts may express additional markers of another lineage class but not sufficient to define LS, or loss of lineage-specific antigens without full acquisition of other antigens. | Acquisition of immunophenotypic markers of a new lineage (ie, new myeloid markers) does not in and of itself constitute LS if the underlying disease is still diagnosed by its original immunophenotype Morphology may remain consistent with original leukemia | B-ALL with loss of CD19, retention of CD22, and acquisition of CD33 is still considered as B-ALL if the pathologist has identified it as B-ALL B-ALL with loss of both CD19 and CD22, and acquisition of myeloid antigens may still be considered as B-ALL if other ALL markers have been retained and the pathologist has identified it as B-ALL (not meeting WHO, ICC and/or EGIL criteria for myeloid lineage) |
| ALAL | Acute leukemias that fail to show commitment to a single lineage (myeloid or lymphoid) or that show commitment to >1 lineage24,25,∗ Encompasses: AUL: failure to commit to a single lineage or lack of lineage-specific markers MPAL: Commitment >1 lineage can be ≥2 separate populations (each classified by AML and ALL criteria; bilineal) can be a single population with markers defining >1 lineage (biphenotypic) MPAL with defining genetic alterations: BCR::ABL1, t(v;11q23.3); KMT2A rearranged, ZNF384, BCL11B activation MPAL with defining immunophenotypic changes: B/myeloid, T/myeloid, B/T/myeloid, B/T | May involve ≥2 single lineage populations (bilineal) or a single population with >1 lineage-defining marker (biphenotypic). Small populations of normal myeloid or lymphoid precursors must be differentiated from aberrant clones. In cases with small aberrant clones: >5% consider diagnosis of MPAL73 <5% diagnosis should be based on the major leukemic population with a descriptive modifier (eg, “predominantly ALL with a small leukemic population of myeloid lineage detected of uncertain significance”). | An acute leukemia expressing CD10, TdT, and CD15 but negative for CD19 would be considered AUL An acute leukemia expressing CD19, CD79a, MPO, and CD33 would be considered MPAL B/myeloid |
| Therapy-related acute leukemias (eg, t-AML, t-MDS) | Cases of MDS and/or AML secondary to cytotoxic chemotherapy or radiation that occur after initial treatment of a prior malignancy27 These cases of MDS/AML demonstrate the absence of retained cytogenetics or molecular signatures from baseline as evidence of lack of clonality consistent with the original diagnosis | Frequently characterized by the following cytogenetic changes: Monosomy 7, monosomy 5 KMT2A rearrangements TP53 mutations | AML that presents 5 y after myeloablative HSCT with a novel t(9;11) not present at diagnosis MDS with monosomy 7 presenting 3 y after CR2 in a heavily treated patient |
AUL, acute undifferentiated leukemia; CR2, second CR; EGIL, European Group for the Immunological Classification of Leukemias; ICC, International Consensus Classification; MDS, myelodysplastic syndrome; MPO, myeloperoxidase; PCR, polymerase chain reaction; TdT, terminal deoxynucleotidyl transferase; WHO, World Health Organization.
Lineage-defining markers per WHO, ICC, or EGIL criteria.28,73