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

Clinical presentation ranges from asymptomatic to fulminant, life threatening multi-system organ failure. Presenting signs and symptoms are typically related to eosinophilic infiltration, and consistent with hypereosinophilic syndromes of any cause. The largest clinical analysis of patients with hypereosinophilic syndromes (HES) demonstrated the following manifestations at presentation:<ref>{{Cite journal|last=Ogbogu|first=Princess U.|last2=Bochner|first2=Bruce S.|last3=Butterfield|first3=Joseph H.|last4=Gleich|first4=Gerald J.|last5=Huss-Marp|first5=Johannes|last6=Kahn|first6=Jean Emmanuel|last7=Leiferman|first7=Kristin M.|last8=Nutman|first8=Thomas B.|last9=Pfab|first9=Florian|date=2009|title=Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy|url=https://www.ncbi.nlm.nih.gov/pubmed/19910029|journal=The Journal of Allergy and Clinical Immunology|volume=124|issue=6|pages=1319–1325.e3|doi=10.1016/j.jaci.2009.09.022|issn=1097-6825|pmc=2829669|pmid=19910029}}</ref>

Neoplastic PDGFRA-associated hypereosinophilic syndromes are more likely to present with eosinophilic cardiopulmonary disease than HES of any cause. A survey of 44 cases demonstrated skin, spleen, lung, and heart involvement in 57, 52, 45, and 34 percent of cases respectively with a similar rate of asymptomatic cases. <ref name=":8">{{Cite journal|last=Legrand|first=Fanny|last2=Renneville|first2=Aline|last3=MacIntyre|first3=Elizabeth|last4=Mastrilli|first4=Samuel|last5=Ackermann|first5=Felix|last6=Cayuela|first6=Jean Michel|last7=Rousselot|first7=Philippe|last8=Schmidt-Tanguy|first8=Aline|last9=Fain|first9=Olivier|date=2013|title=The Spectrum of FIP1L1-PDGFRA-Associated Chronic Eosinophilic Leukemia: New Insights Based on a Survey of 44 Cases|url=https://www.ncbi.nlm.nih.gov/pubmed/23982058|journal=Medicine|volume=92|issue=5|pages=e1–e9|doi=10.1097/MD.0b013e3182a71eba|issn=1536-5964|pmc=4553979|pmid=23982058}}</ref>  

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==Sites of Involvement==

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* Individual Region Genomic Gain/Loss/LOH

* Characteristic Chromosomal Patterns

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>.

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==Individual Region Genomic Gain / Loss / LOH==

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

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==Gene Mutations (SNV / INDEL)==

An activating point mutation in PDGFRA has also been described <ref>{{Cite journal|last=Elling|first=Christian|last2=Erben|first2=Philipp|last3=Walz|first3=Christoph|last4=Frickenhaus|first4=Marie|last5=Schemionek|first5=Mirle|last6=Stehling|first6=Martin|last7=Serve|first7=Hubert|last8=Cross|first8=Nicholas C. P.|last9=Hochhaus|first9=Andreas|date=2011|title=Novel imatinib-sensitive PDGFRA-activating point mutations in hypereosinophilic syndrome induce growth factor independence and leukemia-like disease|url=https://www.ncbi.nlm.nih.gov/pubmed/21224473|journal=Blood|volume=117|issue=10|pages=2935–2943|doi=10.1182/blood-2010-05-286757|issn=1528-0020|pmid=21224473}}</ref>.

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==Epigenomic Alterations==

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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>

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==Genetic Diagnostic Testing Methods==