Acute undifferentiated leukaemia

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

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This page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Acute Undifferentiated Leukemia.

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Primary Author(s)*

Amelia Nakanishi, MD and Shashi Shetty, PhD

Cancer Category / Type

Hematologic malignancy/ Acute leukemia

Cancer Sub-Classification / Subtype

Acute Leukemias of Ambiguous Lineage (WHO 2017)/ Acute Undifferentiated Leukemia (AUL)

Definition / Description of Disease

An acute leukemia with blasts that are immunophenotypically ambiguous for any one hematopoietic lineage. AUL is a diagnosis of exclusion that is incompatible with the presence of features that meet the criteria for inclusion in any of the other AML groups (i.e. AML with Recurrent Genetic Abnormalities, AML with Myelodysplasia-Related Changes, or Therapy-Related Myeloid Neoplasms).

To support an undifferentiated phenotype, AUL requires an immunophenotypic work up that “excludes unusual lineages such as plasmacytoid dendritic cell precursors, natural killer precursors, basophils, and non-hematologic cells”[1].

Synonyms / Terminology

Blast cell leukemia, stem cell leukemia, stem cell acute leukemia, undifferentiated leukemia.

Epidemiology / Prevalence

Very rare; precise frequency unknown.

Clinical Features

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Signs and Symptoms EXAMPLE: Asymptomatic (incidental finding on complete blood counts)

EXAMPLE: B-symptoms (weight loss, fever, night sweats)

EXAMPLE: Fatigue

EXAMPLE: Lymphadenopathy (uncommon)

Laboratory Findings EXAMPLE: Cytopenias

EXAMPLE: Lymphocytosis (low level)


editHAEM5 Conversion Notes
Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

In one study of 16 cases of adults with AUL, the median age was 63 years (range: 24-84 years) and patients could achieve clinical remission after allogeneic stem cell transplantation[2]. In previous studies that weakly suggest ALL induction regimens over AML induction regimens, there may be selection bias in the patients who were well enough to be transplant candidates[3].

In children, based on limited clinical information in the literature, AUL has been associated with a poor prognosis[4].

Sites of Involvement

Bone marrow and peripheral blood. AUL is so rare, it is unknown if there is a pattern of other sites of involvement.

Morphologic Features

AUL blast morphology is bland and non-specific. Cytoplasmic granulation and disease defining morphology are absent.

Immunophenotype

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Finding Marker
Positive (universal) EXAMPLE: CD1
Positive (subset) EXAMPLE: CD2
Negative (universal) EXAMPLE: CD3
Negative (subset) EXAMPLE: CD4


editHAEM5 Conversion Notes
Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

Per WHO 2017, AUL blasts should express no more than one membrane marker for any lineage.

Positive (universal) Precursor stage: HLA-DR, CD34, and/or CD38, CD117, CD133 [5]
Positive (subset) TdT

CD7 (weak positivity) see below.

Negative (universal) Myeloid: MPO

Monocytic: NSE, CD11c, Cd14, CD64, lysozyme, Cd4, CD11b, CD36, NG2 homologue

T cell: cCD3

B cell: cCD22, cCD79a, strong CD19

Megakaryocytic: CD41, CD61, CD42, CD235a

Negative (subset) NA

Additional Description: Blasts are generally positive for  HLA-DR, CD34, and/or CD38.

-CD7 positivity is associated with T cells, but can also be seen in some CD34+ hematopoietic stem cells and is not unexpected in a stem cell leukemia[1].

-See HAEM4:Acute Leukemias of Ambiguous Lineage for assigning lineage assignment.

Chromosomal Rearrangements (Gene Fusions)

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Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE: t(9;22)(q34;q11.2) EXAMPLE: 3'ABL1 / 5'BCR EXAMPLE: der(22) EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add reference)

Yes No Yes EXAMPLE:

The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).


editHAEM5 Conversion Notes
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NA


editHAEM5 Conversion Notes
Please incorporate this section into the relevant tables found in:
  • Chromosomal Rearrangements (Gene Fusions)
  • Individual Region Genomic Gain/Loss/LOH
  • Characteristic Chromosomal Patterns
  • Gene Mutations (SNV/INDEL)

There is evidence that the genes associated with poor prognosis in acute leukemias, BAALC, ERG, and MN1, are also overexpressed in AUL[1].

Individual Region Genomic Gain / Loss / LOH

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Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE:

7

EXAMPLE: Loss EXAMPLE:

chr7:1- 159,335,973 [hg38]

EXAMPLE:

chr7

Yes Yes No EXAMPLE:

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

EXAMPLE:

8

EXAMPLE: Gain EXAMPLE:

chr8:1-145,138,636 [hg38]

EXAMPLE:

chr8

No No No EXAMPLE:

Common recurrent secondary finding for t(8;21) (add reference).

editHAEM5 Conversion Notes
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NA

Characteristic Chromosomal Patterns

Put your text here (EXAMPLE PATTERNS: hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis. Do not delete table.)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE:

Co-deletion of 1p and 18q

Yes No No EXAMPLE:

See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).

editHAEM5 Conversion Notes
Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

AUL is associated with a high rate of chromosomal abnormalities, but have no characteristic abnormalities[2].

Gene Mutations (SNV / INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent and common as well as either disease defining and/or clinically significant. Can include references in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable. Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Do not delete table.)

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
EXAMPLE: TP53; Variable LOF mutations

EXAMPLE:

EGFR; Exon 20 mutations

EXAMPLE: BRAF; Activating mutations

EXAMPLE: TSG EXAMPLE: 20% (COSMIC)

EXAMPLE: 30% (add Reference)

EXAMPLE: IDH1 R123H EXAMPLE: EGFR amplification EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).


Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


editHAEM5 Conversion Notes
Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

PHF6 a tumor suppressor gene may have implications in AUL though the evidence is limited.

Other Mutations

NA

Epigenomic Alterations

Unknown

Genes and Main Pathways Involved

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Gene; Genetic Alteration Pathway Pathophysiologic Outcome
EXAMPLE: BRAF and MAP2K1; Activating mutations EXAMPLE: MAPK signaling EXAMPLE: Increased cell growth and proliferation
EXAMPLE: CDKN2A; Inactivating mutations EXAMPLE: Cell cycle regulation EXAMPLE: Unregulated cell division
EXAMPLE:  KMT2C and ARID1A; Inactivating mutations EXAMPLE:  Histone modification, chromatin remodeling EXAMPLE:  Abnormal gene expression program
editHAEM5 Conversion Notes
Content Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification

Overexpression of BAALC, ERG, and MN1[1].

Genetic Diagnostic Testing Methods

Morphology, immunohistochemistry, cytochemistry, flow cytometry, cytogenetics, and next generation sequencing.

Familial Forms

Unknown

Additional Information

Although AUL and AML with minimal differentiation are both rare diagnoses, they have similar patient demographics and clinical courses. AUL and AML with minimal differentiation have different molecular abnormalities[2].

Links

HAEM4:Acute Leukemias of Ambiguous Lineage

HAEM5:Mixed-phenotype acute leukaemia, B/myeloid

References

(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking on where you want to insert the reference, selecting the “Cite” icon at the top of the page, and using the “Automatic” tab option to search such as by PMID to select the reference to insert. The reference list in this section will be automatically generated and sorted. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference.)

  1. 1.0 1.1 1.2 1.3 Borowitz MJ, et al., (2017). Acute leukaemias of ambiguous lineage, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p182.
  2. 2.0 2.1 2.2 Heesch, Sandra; et al. (2013). "Acute leukemias of ambiguous lineage in adults: molecular and clinical characterization". Annals of Hematology. 92 (6): 747–758. doi:10.1007/s00277-013-1694-4. ISSN 1432-0584. PMID 23412561.
  3. Weinberg, Olga K.; et al. (2019). "Clinical, immunophenotypic, and genomic findings of acute undifferentiated leukemia and comparison to acute myeloid leukemia with minimal differentiation: a study from the bone marrow pathology group". Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc. 32 (9): 1373–1385. doi:10.1038/s41379-019-0263-3. ISSN 1530-0285. PMID 31000771.
  4. Lee, Hyun Gyung; et al. (2019). "Biphenotypic acute leukemia or acute leukemia of ambiguous lineage in childhood: clinical characteristics and outcome". Blood Research. 54 (1): 63–73. doi:10.5045/br.2019.54.1.63. ISSN 2287-979X. PMC 6439300. PMID 30956966.
  5. Hoffman R, et al., (2018) Hematology, basic principles and practice, 7th edition. Elsevier: Philadelphia. (clinical key excerpt)

Notes

*Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome. *Citation of this Page: “Acute undifferentiated leukaemia”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 09/1/2024, https://ccga.io/index.php/HAEM5:Acute_undifferentiated_leukaemia.