Myeloid neoplasm post cytotoxic therapy
Haematolymphoid Tumours (5th ed.)
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Primary Author(s)*
Shawn A. Silver, DO, Shashi Shetty, Ph.D.
Cancer Category / Type
Therapy related myeloid neoplasms
Cancer Sub-Classification / Subtype
Therapy related cases of:
- Acute myeloid leukemia (tAML)
- Myelodysplastic syndrome (tMDS)
- Myelodysplastic/myeloproliferative neoplasm (tMDS/MPN)
Definition / Description of Disease
-Therapy related disease that occurs as a complication of cytotoxic chemotherapy and/or radiation therapy administered for a prior neoplastic or non-neoplastic disorder.
-Excluded from this category are progression of MPN and primary MDS or MDS/MPN to AML as progression to AML is part of the natural history of the primary disease and is nearly impossible to distinguish.
Synonyms / Terminology
-Therapy related acute myeloid leukemia
-Alkylating agent related
-Epipodophyllotoxin related
-Therapy related acute myeloid leukemia, NOS
Epidemiology / Prevalence
-Therapy related myeloid neoplasms (tMN) account for 10-20% of all cases of AML, MDS, and MDS/MPN. The incidence of tMN amongst treated patients depends on the underlying disease and the treatment strategy (see table below).
-Data suggest that about 70% of patients have been treated previously for a solid tumor and 30% have been treated for a hematological neoplasm. Breast cancer and non-Hodgkin lymphoma account for the largest number of cases, respectively.
-Between 5-20% of cases occur following therapy for a non-neoplastic disorder.
-All age groups affected, but risk rises with age.
Clinical Features
Put your text here and fill in the table (Instruction: Can include references in the 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.Two subsets of tMNs are generally recognized clinically:
More common, occurs 5-10 years after exposure to alkylating agents and/or ionizing radiation. Often present with an MDS with bone marrow failure and one or more cytopenias. Rare subset may present with tMDS/MPN or tAML.
- Commonly associated with unbalanced loss of gtenetic material, often involving chromosomes 5 and/or 7, as well as complex karyotypes and mutations or loss of TP53.
- Accounts for 20-30% of cases and has a shorter latent period of about 1-5 years. Usually follows treatment with DNA topoisomerase II. Most cases present with overt AML and often associated with a balanced chromosomal translocation.
Sites of Involvement
Bone marrow and blood. Initial presentation as extramedullary myeloid sarcoma has been reported.
Sites of Involvement
Put your text here (Instruction: Indicate physical sites; Example: nodal, extranodal, bone marrow)
Morphologic Features
-Most patients present with MDS or acute leukemia associated with multi-lineage dysplasia.
-Peripheral blood shows one or more cytopenias.
-Anemia is almost always present and RBC morphology is usually macrocytic and poikilocytic.
-neutrophils show abnormal nuclear segmentation and hypogranulation.
-basophilia is often present.
-Bone marrow may be hypo/hyper/or normocellular. Reticulin fibrosis is common.
-Dysgranulopoiesis and dyserythropoiesis is common.
-Dysplastic megakaryocytes with non lobated or hypolobated neuclie or widely separated lobes are common.
Immunophenotype
Put your text here and fill in the table (Instruction: Can include references in the 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.-Immunophenotypic findings reflect the heterogeneity of the underlying morphology.
-Blasts are generally CD34+ and express pan-myeloid antigens: CD13, CD 33, and MPO (MPO may be downregulated).
Additional Description:
-p53 positive cells in bone marrow biopsies have been demonstrated to correlate well with TP53 mutations and with a poor prognosis.
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)
Prognosis is generally poor, common reported 5 year survival rates are <10%.
Cases with abnormalities in chromosome 5 and/or 7, TP53 mutations, and a complex karyotype have a particularly poor outcome with mean survival time of <1 year.
Cases with balanced chromosomal translocations generally have a better prognosis, however, such cases (except those with t(15;17), inv(16), or t(16;16)) have a shorter median survival time than their de novo counterparts.
Patients with therapy related APL with PML-RARA should be managed with the same urgency as de novo APL.
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.)
| 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)
| 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.-Leukemic cells of >90% of patients with tMN show an abnormal karyotype.
A) Approximately 70% of patients harbor unbalanced chromosomal aberrations, most commonly:
Loss of chromosome 7 or del(7q)
Partial loss of 5q or t(5q)
Loss of 5q is associated with:
del(13q)
del(20q)
del(11q)
del(3p)
Loss of 17p or chromosome 17
Loss of chromosome 18 or 21
Gain of chromosome 8
*Up to 80% of patients with del(5q) have mutations or deletion of TP53 as a result of abnormalities of 17p.
These changes are associated with: long latent period, preceding myelodysplastic phase or tAML with dysplastic features, and alkylating agent and/or radiation therapy.
B) 20-30% of patients have balance translocations that involve rearrangements of 11q23.3, including:
t(9;11)(p21.3;q23.3)
t(11;19)(q23.3;p13.1)
21q22.1
t(8;21)(q22;22.1)
t(3;21)(q26.2q22.1)
t(15;17)(q24.1;q21.1)
inv(16)(p13.1q22)
These translocations are associated with: short latent period, present as tAML without a preceding myelodysplastic phase, prior topoisomerase II inhibitor therapy or radiation alone.
A small percentage of tMN patients have a reported normal karyotype.
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 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.)
| 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.NA
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 |
editv4:Genes and Main Pathways InvolvedThe content below was from the old template. Please incorporate above.Thought to be the consequence of mutation events in hematopoietic stem cells induced by cytotoxic therapy or selection of a myeloid clone with a mutator phenotype. Only a small proportion of patients treated with identical protocols develop tMN, suggesting that some individuals may have predisopistion due to mutations in DNA damage sensing or prepair genes, or polymorphisms in genes that affect drug metabolism, transport, or repair.
Genetic Diagnostic Testing Methods
Diagnosis is typically made by in the same fashion as the de novo counterparts with the added history of prior cytotoxic chemotherapy and/or radiation.
Familial Forms
Unknown
Additional Information
Agents implicated in therapy related myeloid neoplasms:
Alkylating Agents: Melphalan, cyclophosphamide, nitrogen mustard, chlorambucil, busulfan, carboplatin, cisplatin, dacarbazine, procarbazine, carmustine, mitomycin C, thiotepa, Iomustine.
Ionizing Radiation Therapy: Large fields containing active bone marrow.
Topoisomerase II Inhibitors: Etoposide, teniposide, doxorubicin, daunorubicin, mitoxantrone, amsacrine, actinomycin.
Others: Thiopurines, mycophenolate mofetil, fludarabine, vincristine, vinblastine, vindesine, paclitaxel, docetaxel.
-Use of adjuvant hematopoietic growth factors will typically increase the risk of developing tMN.
Links
NA
References
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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: “Myeloid neoplasm post cytotoxic therapy”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 12/13/2023, https://ccga.io/index.php/HAEM5:Myeloid_neoplasm_post_cytotoxic_therapy.