View source for HAEM5:Myeloid neoplasm post cytotoxic therapy

{{DISPLAYTITLE:Myeloid neoplasm post cytotoxic therapy}}
[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (WHO Classification, 5th ed.)]]

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Note: Need to check if content remains same
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<span style="color:#0070C0">(General Instructions – The main focus of these pages is the clinically significant genetic alterations in each disease type. Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ 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 </span><u>[[Author_Instructions]]</u><span style="color:#0070C0"> and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>])</span>

==Primary Author(s)*==

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

__TOC__

==WHO Classification of Disease==

{| class="wikitable"
!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 <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>
{| class="wikitable"
|'''Signs and Symptoms'''
|<span class="blue-text">EXAMPLE:</span> Asymptomatic (incidental finding on complete blood counts)

<span class="blue-text">EXAMPLE:</span> B-symptoms (weight loss, fever, night sweats)

<span class="blue-text">EXAMPLE:</span> Fatigue

<span class="blue-text">EXAMPLE:</span> Lymphadenopathy (uncommon)
|-
|'''Laboratory Findings'''
|<span class="blue-text">EXAMPLE:</span> Cytopenias

<span class="blue-text">EXAMPLE:</span> Lymphocytosis (low level)
|}


<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Features|The 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.

</blockquote>
==Sites of Involvement==

Put your text here <span style="color:#0070C0">(''Instruction: Indicate physical sites; <span class="blue-text">EXAMPLE:</span> nodal, extranodal, bone marrow'') </span>

==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 <span style="color:#0070C0">(''Instruction: Can include references in the table. Do not delete table.'') </span>

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||<span class="blue-text">EXAMPLE:</span> CD1
|-
|Positive (subset)||<span class="blue-text">EXAMPLE:</span> CD2
|-
|Negative (universal)||<span class="blue-text">EXAMPLE:</span> CD3
|-
|Negative (subset)||<span class="blue-text">EXAMPLE:</span> 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.

</blockquote>
==Chromosomal Rearrangements (Gene Fusions)==

Put your text here and fill in the table

{| class="wikitable sortable"
|-
!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
|-
|<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)||<span class="blue-text">EXAMPLE:</span> 3'ABL1 / 5'BCR||<span class="blue-text">EXAMPLE:</span> der(22)||<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)
<span class="blue-text">EXAMPLE:</span> 30% (add reference)
|Yes
|No
|Yes
|<span class="blue-text">EXAMPLE:</span>

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).
|}		
			

<blockquote class='blockedit'>{{Box-round|title=v4:Chromosomal Rearrangements (Gene Fusions)|The content below was from the old template. Please incorporate above.}}

NA
</blockquote>


<blockquote class='blockedit'>{{Box-round|title=v4: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.

</blockquote>
==Individual Region Genomic Gain / Loss / LOH==

Put your text here and fill in the table <span style="color:#0070C0">(''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.'') </span>

{| class="wikitable sortable"
|-
!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
|-
|<span class="blue-text">EXAMPLE:</span>

7
|<span class="blue-text">EXAMPLE:</span> Loss
|<span class="blue-text">EXAMPLE:</span>

chr7:1- 159,335,973 [hg38]
|<span class="blue-text">EXAMPLE:</span>

chr7
|Yes
|Yes
|No
|<span class="blue-text">EXAMPLE:</span>

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).
|-
|<span class="blue-text">EXAMPLE:</span>

8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>

chr8:1-145,138,636 [hg38]
|<span class="blue-text">EXAMPLE:</span>

chr8
|No
|No
|No
|<span class="blue-text">EXAMPLE:</span>

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

<blockquote class='blockedit'>{{Box-round|title=v4:Genomic Gain/Loss/LOH|The content below was from the old template. Please incorporate above.}}

NA
</blockquote>
==Characteristic Chromosomal Patterns==

Put your text here <span style="color:#0070C0">(''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.'')</span>

{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|<span class="blue-text">EXAMPLE:</span>

Co-deletion of 1p and 18q
|Yes
|No
|No
|<span class="blue-text">EXAMPLE:</span>

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

<blockquote class='blockedit'>{{Box-round|title=v4:Characteristic Chromosomal Aberrations / Patterns|The 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

<nowiki>*</nowiki>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.

</blockquote>
==Gene Mutations (SNV / INDEL)==

Put your text here and fill in the table <span style="color:#0070C0">(''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.'') </span>

{| class="wikitable sortable"
|-
!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
|-
|<span class="blue-text">EXAMPLE:</span> TP53; Variable LOF mutations

<span class="blue-text">EXAMPLE:</span>

EGFR; Exon 20 mutations

<span class="blue-text">EXAMPLE:</span> BRAF; Activating mutations
|<span class="blue-text">EXAMPLE:</span> TSG
|<span class="blue-text">EXAMPLE:</span> 20% (COSMIC)

<span class="blue-text">EXAMPLE:</span> 30% (add Reference)
|<span class="blue-text">EXAMPLE:</span> IDH1 R123H
|<span class="blue-text">EXAMPLE:</span> EGFR amplification
|
|
|
|<span class="blue-text">EXAMPLE:</span>  Excludes hairy cell leukemia (HCL) (add reference).
<br />
|}
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.


<blockquote class='blockedit'>{{Box-round|title=v4:Gene Mutations (SNV/INDEL)|The content below was from the old template. Please incorporate above.}}

NA
===Other Mutations===
NA

</blockquote>
==Epigenomic Alterations==

Unknown

==Genes and Main Pathways Involved==

Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Can include references in the table. Do not delete table.'')</span>
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|<span class="blue-text">EXAMPLE:</span> BRAF and MAP2K1; Activating mutations
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|-
|<span class="blue-text">EXAMPLE:</span> CDKN2A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|-
|<span class="blue-text">EXAMPLE:</span>  KMT2C and ARID1A; Inactivating mutations
|<span class="blue-text">EXAMPLE:</span>  Histone modification, chromatin remodeling
|<span class="blue-text">EXAMPLE:</span>  Abnormal gene expression program
|}

<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The 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.

</blockquote>
==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==
<nowiki>*</nowiki>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.
<nowiki>*</nowiki>''Citation of this Page'': “Myeloid neoplasm post cytotoxic therapy”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/HAEM5:Myeloid_neoplasm_post_cytotoxic_therapy</nowiki>.
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