Acute undifferentiated leukaemia
Haematolymphoid Tumours (WHO Classification, 5th ed.)
 | This page is under construction |
editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition ClassificationThis page was converted to the new template on 2023-12-07. The original page can be found at HAEM4:Acute Undifferentiated Leukemia.
(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column to a table, click within the table and select the > symbol that appears to be given options. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support)
Primary Author(s)*
Amelia Nakanishi, MD and Shashi Shetty, PhD
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Haematolymphoid Tumours (5th ed.) |
| Category | Myeloid proliferations and neoplasms |
| Family | Acute leukaemias of mixed or ambiguous lineage |
| Type | Acute leukaemia of ambiguous lineage, immunophenotypically defined |
| Subtype(s) | Acute undifferentiated leukaemia |
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
Put your text here and fill in the table (Instruction: Can include references in the table. Do not delete table.)
| 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) |
editv4:Clinical FeaturesThe content below was from the old template. Please incorporate above.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
Put your text here and fill in the table (Instruction: Can include references in the table. Do not delete table.)
| Finding | Marker |
|---|---|
| Positive (universal) | EXAMPLE: CD1 |
| Positive (subset) | EXAMPLE: CD2 |
| Negative (universal) | EXAMPLE: CD3 |
| Negative (subset) | EXAMPLE: CD4 |
editv4:ImmunophenotypeThe content below was from the old template. Please incorporate above.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)
Put your text here and fill in the table
| 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). |
editv4:Chromosomal Rearrangements (Gene Fusions)The content below was from the old template. Please incorporate above.NA
editv4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).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
Put your text here and fill in the table (Instructions: Includes aberrations not involving gene fusions. Can include references in the table. Can refer to CGC workgroup tables as linked on the homepage if applicable. Do not delete table.)
| 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). |
editv4:Genomic Gain/Loss/LOHThe content below was from the old template. Please incorporate above.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). |
editv4:Characteristic Chromosomal Aberrations / PatternsThe content below was from the old template. Please incorporate above.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.
editv4:Gene Mutations (SNV/INDEL)The content below was from the old template. Please incorporate above.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
Put your text here and fill in the table (Instructions: Can include references in the table. Do not delete table.)
| 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 |
editv4:Genes and Main Pathways InvolvedThe content below was from the old template. Please incorporate above.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
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.)
- ↑ 1.0 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.
- ↑ 2.0 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.
- ↑ 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.
- ↑ 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.
- ↑ 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 09/6/2024, https://ccga.io/index.php/HAEM5:Acute_undifferentiated_leukaemia.