HAEM5:Myeloid/lymphoid neoplasm with PDGFRA rearrangement: Difference between revisions

[[HAEM5:Table_of_Contents|Haematolymphoid Tumours (5th ed.)]]

<blockquote class='blockedit'>{{Box-round|title=HAEM5 Conversion Notes|This page was converted to the new template on 2023-11-03. The original page can be found at [[HAEM4:Myeloid/Lymphoid Neoplasms with PDGFRA Rearrangement]].

 

==Cancer Category/Type==

 

Acute Myeloid Leukemia/Myeloid/lymphoid neoplasms  

 

==Cancer Sub-Classification / Subtype==

 

Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement

 

 

Myeloproliferative neoplasms associated with PDGFRA rearrangements are primary/neoplastic hypereosinophilic syndromes associated with recurrent rearrangements of the PDGFRA gene <ref name=":0">Bain BJ, et al., (2017). Myeloid/lymphoid neoplasms with PDGFRA rearrangement 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, p73-75.</ref>. It is most commonly associated with FIP1L1-PDGFRA (F/P) fusion resulting from a cryptic deletion at 4q12, <ref name=":5">{{Cite journal|last=Cools|first=Jan|last2=DeAngelo|first2=Daniel J.|last3=Gotlib|first3=Jason|last4=Stover|first4=Elizabeth H.|last5=Legare|first5=Robert D.|last6=Cortes|first6=Jorges|last7=Kutok|first7=Jeffrey|last8=Clark|first8=Jennifer|last9=Galinsky|first9=Ilene|date=2003|title=A Tyrosine Kinase Created by Fusion of the PDGFRA and FIP1L1 Genes as a Therapeutic Target of Imatinib in Idiopathic Hypereosinophilic Syndrome|url=http://www.nejm.org/doi/abs/10.1056/NEJMoa025217|journal=New England Journal of Medicine|language=en|volume=348|issue=13|pages=1201–1214|doi=10.1056/NEJMoa025217|issn=0028-4793}}</ref> and often presents as chronic eosinophilic leukemia (CEL), or less commonly, acute myeloid leukemia or T-lymphoblastic leukemia/lymphoma. <ref name=":1">{{Cite journal|last=Metzgeroth|first=G.|last2=Walz|first2=C.|last3=Score|first3=J.|last4=Siebert|first4=R.|last5=Schnittger|first5=S.|last6=Haferlach|first6=C.|last7=Popp|first7=H.|last8=Haferlach|first8=T.|last9=Erben|first9=P.|date=2007|title=Recurrent finding of the FIP1L1-PDGFRA fusion gene in eosinophilia-associated acute myeloid leukemia and lymphoblastic T-cell lymphoma|url=https://www.ncbi.nlm.nih.gov/pubmed/17377585|journal=Leukemia|volume=21|issue=6|pages=1183–1188|doi=10.1038/sj.leu.2404662|issn=0887-6924|pmid=17377585}}</ref>

==Synonyms / Terminology==

|'''Signs and Symptoms'''

|EXAMPLE Asymptomatic (incidental finding on complete blood counts)

 

 

 

|'''Laboratory Findings'''

|EXAMPLE Cytopenias

 

!Finding!!Marker

|Positive (subset)||CD25 <ref name=":2" />

|Positive (subset)

|CD23 <ref name=":2" />

|Positive (subset)||CD69 <ref name=":2" />

|Negative (Mast cells)||CD2 <ref name=":3" /><ref name=":1" />

|-

|CD25 <ref name=":3" /><ref name=":1" />

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)

|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)

|Yes

|No

|Yes

|EXAMPLE

 

|}

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

<blockquote class='blockedit'>{{Box-round|title=v4:Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications).|Please incorporate this section into the relevant tables found in:

* Gene Mutations (SNV/INDEL)}}

The responsiveness of F/P associated myeloid/lymphoid neoplasms to imatinib mesylate is well documented <ref name=":6" />.  Adverse outcomes are typically related to late presentation, where irreversible organ damage precedes diagnosis, or when the disease is diagnosed in an accelerated phase when complications are more likely. Induction dosing of imatinib ranges from 100-400 mg daily, with much lower maintenence dosing recommended to prevent relapse <ref>{{Cite journal|last=Baccarani|first=Michele|last2=Cilloni|first2=Daniela|last3=Rondoni|first3=Michela|last4=Ottaviani|first4=Emanuela|last5=Messa|first5=Francesca|last6=Merante|first6=Serena|last7=Tiribelli|first7=Mario|last8=Buccisano|first8=Francesco|last9=Testoni|first9=Nicoletta|date=2007|title=The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study|url=https://www.ncbi.nlm.nih.gov/pubmed/17666373|journal=Haematologica|volume=92|issue=9|pages=1173–1179|doi=10.3324/haematol.11420|issn=1592-8721|pmid=17666373}}</ref> <ref>{{Cite journal|last=Jovanovic|first=Jelena V.|last2=Score|first2=Joannah|last3=Waghorn|first3=Katherine|last4=Cilloni|first4=Daniela|last5=Gottardi|first5=Enrico|last6=Metzgeroth|first6=Georgia|last7=Erben|first7=Philipp|last8=Popp|first8=Helena|last9=Walz|first9=Christoph|date=2007|title=Low-dose imatinib mesylate leads to rapid induction of major molecular responses and achievement of complete molecular remission in FIP1L1-PDGFRA-positive chronic eosinophilic leukemia|url=https://www.ncbi.nlm.nih.gov/pubmed/17299092|journal=Blood|volume=109|issue=11|pages=4635–4640|doi=10.1182/blood-2006-10-050054|issn=0006-4971|pmid=17299092}}</ref>. Complete hematologic and molecular remission is observed in nearly all patients taking imatinib, usually within 3 months. <ref>{{Cite journal|last=Baccarani|first=Michele|last2=Cilloni|first2=Daniela|last3=Rondoni|first3=Michela|last4=Ottaviani|first4=Emanuela|last5=Messa|first5=Francesca|last6=Merante|first6=Serena|last7=Tiribelli|first7=Mario|last8=Buccisano|first8=Francesco|last9=Testoni|first9=Nicoletta|date=2007|title=The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study|url=https://www.ncbi.nlm.nih.gov/pubmed/17666373|journal=Haematologica|volume=92|issue=9|pages=1173–1179|doi=10.3324/haematol.11420|issn=1592-8721|pmid=17666373}}</ref> <ref>{{Cite journal|last=Quéméneur|first=Thomas|last2=Mouthon|first2=Luc|last3=Cacoub|first3=Patrice|last4=Meyer|first4=Olivier|last5=Michon-Pasturel|first5=Ulrique|last6=Vanhille|first6=Philippe|last7=Hatron|first7=Pierre-Yves|last8=Guillevin|first8=Loïc|last9=Hachulla|first9=Eric|date=2013|title=Systemic vasculitis during the course of systemic sclerosis: report of 12 cases and review of the literature|url=https://www.ncbi.nlm.nih.gov/pubmed/23263715|journal=Medicine|volume=92|issue=1|pages=1–9|doi=10.1097/MD.0b013e31827781fd|issn=1536-5964|pmc=5370746|pmid=23263715}}</ref> <ref>{{Cite journal|last=Helbig|first=Grzegorz|last2=Stella-Hołowiecka|first2=Beata|last3=Majewski|first3=Mirosław|last4=Całbecka|first4=Małgorzata|last5=Gajkowska|first5=Jolanta|last6=Klimkiewicz|first6=Ryszard|last7=Moskwa|first7=Andrzej|last8=Grzegorczyk|first8=Janina|last9=Lewandowska|first9=Monika|date=2008|title=A single weekly dose of imatinib is sufficient to induce and maintain remission of chronic eosinophilic leukaemia in FIP1L1-PDGFRA-expressing patients|url=https://www.ncbi.nlm.nih.gov/pubmed/18307562|journal=British Journal of Haematology|volume=141|issue=2|pages=200–204|doi=10.1111/j.1365-2141.2008.07033.x|issn=1365-2141|pmid=18307562}}</ref> Imatinib maintains efficacy in accelerated or blast phase disease, and resistance is rare <ref name=":8" /> <ref>{{Cite journal|last=Lierman|first=E.|last2=Michaux|first2=L.|last3=Beullens|first3=E.|last4=Pierre|first4=P.|last5=Marynen|first5=P.|last6=Cools|first6=J.|last7=Vandenberghe|first7=P.|date=2009|title=FIP1L1-PDGFRalpha D842V, a novel panresistant mutant, emerging after treatment of FIP1L1-PDGFRalpha T674I eosinophilic leukemia with single agent sorafenib|url=https://www.ncbi.nlm.nih.gov/pubmed/19212337|journal=Leukemia|volume=23|issue=5|pages=845–851|doi=10.1038/leu.2009.2|issn=1476-5551|pmid=19212337}}</ref>.

!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

 

|EXAMPLE Loss

|EXAMPLE

 

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

 

|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

 

|EXAMPLE Gain

|EXAMPLE

 

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

 

|No

|No

|No

|EXAMPLE

 

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

==Characteristic Chromosomal Patterns==

!Diagnostic Significance (Yes, No or Unknown)

!Prognostic Significance (Yes, No or Unknown)

!Therapeutic Significance (Yes, No or Unknown)

!Notes

|EXAMPLE

 

|Yes

|EXAMPLE:

 

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.}}

Cytogenetic studies are usually normal though trisomy of chromosome 8 has been described, and may represent disease evolution <ref name=":0" />.

!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

|}

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.}}

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

|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

<blockquote class='blockedit'>{{Box-round|title=v4:Genes and Main Pathways Involved|The content below was from the old template. Please incorporate above.}}

the F/P tyrosine kinase is thought to become constitutively active in the setting of PDGRA juxtamembrane interruption as breakpoints in the PDGRA gene are tightly clustered, resulting in the removal of a portion of the juxtamembrane domain and activation of the kinase domain upon rearrangement. The role of the FIP1L1 in the neoplastic process is thought to be less significant. <ref>{{Cite journal|last=J. Cools|last2=Gotlib|first2=J.|date=2008|title=Five years since the discovery of FIP1L1–PDGFRA : what we have learned about the fusion and other molecularly defined eosinophilias|url=https://www.nature.com/articles/leu2008287|journal=Leukemia|language=en|volume=22|issue=11|pages=1999–2010|doi=10.1038/leu.2008.287|issn=1476-5551}}</ref>  The eosinophilic proliferation observed in these patients is thought to result from multiple signalling pathways including phosphoinositol 3-kinase, ERK 1/2 and STAT5, though the precise mechanism remains elusive. <ref name=":5" /><ref>{{Cite journal|last=Buitenhuis|first=Miranda|last2=Verhagen|first2=Liesbeth P.|last3=Cools|first3=Jan|last4=Coffer|first4=Paul J.|date=2007|title=Molecular mechanisms underlying FIP1L1-PDGFRA-mediated myeloproliferation|url=https://www.ncbi.nlm.nih.gov/pubmed/17440089|journal=Cancer Research|volume=67|issue=8|pages=3759–3766|doi=10.1158/0008-5472.CAN-06-4183|issn=0008-5472|pmid=17440089}}</ref>

(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''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.''</span> <span style="color:#0070C0">''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''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">) </span> <references />

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