Myeloid neoplasm post cytotoxic therapy

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Haematolymphoid Tumours (WHO Classification, 5th ed.)

editContent Update To WHO 5th Edition Classification Is In Process; Content Below is Based on WHO 4th Edition Classification
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Primary Author(s)*

Shawn A. Silver, DO, Shashi Shetty, Ph.D.

WHO Classification of Disease

Structure Disease
Book Haematolymphoid Tumours (5th ed.)
Category Myeloid proliferations and neoplasms
Family Myeloid neoplasms, secondary
Type Myeloid neoplasms and proliferations associated with antecedent or predisposing conditions
Subtype(s) Myeloid neoplasm post cytotoxic therapy

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. 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 Features
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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.

  1. 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.
  2. 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

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


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-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)

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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).


editv4:Chromosomal Rearrangements (Gene Fusions)
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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

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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).

editv4:Genomic Gain/Loss/LOH
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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).

editv4:Characteristic Chromosomal Aberrations / Patterns
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-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)

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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)
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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 Involved
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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 09/6/2024, https://ccga.io/index.php/HAEM5:Myeloid_neoplasm_post_cytotoxic_therapy.