ETV6–FLT3 fusion gene-positive, eosinophilia-associated myeloproliferative neoplasm successfully treated with sorafenib and allogeneic stem cell transplant

Falchi, Lorenzo; Mehrotra, Meenakshi; Newberry, Kate J.; Lyle, Lindsey; Lu, Gary; Patel, Keyur P.; Luthra, Raja; Popat, Uday; Verstovšek, Srđan

doi:10.1038/leu.2014.168

Cited by 39 publications

(38 citation statements)

References 11 publications

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“…43,44 Another extremely rare condition, ETV6–FLT3 -positive MN-eos, has been reported in 5 cases. 45–48 Three patients received a FLT3 inhibitor 46,48 and achieved clinical and cytogenetic responses. Because these 2 entities have a clinical-hematological phenotype similar to that of WHO-defined MN-eos and are driven by targetable molecular lesions, their recognition in the WHO framework appears appropriate.…”

Section: Eosinophilic Myeloid Disordersmentioning

confidence: 99%

Eosinophilia in Hematologic Disorders

Falchi¹,

Verstovšek²

2015

Immunology and Allergy Clinics of North America

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Synopsis A finding of eosinophilia in the peripheral blood can be the manifestation of a large number of different medical conditions, including benign or malignant disorders. From a diagnostic standpoint eosinophilia can be divided into reactive (secondary) or clonal (primary). There are three main types of WHO-defined eosinophilia-associated myeloid neoplasms (MN-eos): 1) myeloid and lymphoid neoplasms associated with rearrangements of PDGFRA, PDGFRB or FGFR1; 2) chronic eosinophilic leukemia, not otherwise specified (CEL-NOS); and 3) idiopathic hypereosinophilic syndrome (HES). Imatinib mesylate, a PDGFRA and PDGFRB inhibitor, has revolutionized the treatment of molecularly defined MN-eos. Second generation molecules are available for patients who fail imatinib. Novel agents, such as the anti-IL5 antibody mepolizumab, have been successfully used for the treatment of HES. The discovery of new, recurrent molecular alterations in patients with MN-eos may improve the diagnosis and therapy of this group of patients. This review focuses on the hematologist’s approach to a patient with eosinophilia as well as treatment options for patients with eosinophilic myeloid neoplasms.

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Section: Eosinophilic Myeloid Disordersmentioning

confidence: 99%

Eosinophilia in Hematologic Disorders

Falchi¹,

Verstovšek²

2015

Immunology and Allergy Clinics of North America

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“…More importantly, several recent reports describing the oncogenic behavior and therapeutic response of tumors driven by extremely rare fusions highlight their clinical impact. For example, individual cases of myeloid neoplasms driven by fusions involving JAK2 and FLT3 are sensitive to JAK inhibitor (ruxolitinib) (8) and tyrosine kinase inhibitor (sorafenib) (9), respectively. Likewise, we recently reported an oncogenic fusion involving the RET kinase in a single medullary thyroid carcinoma patient whose activity is highly sensitive to multiple tyrosine kinase inhibitors (10).…”

Section: Introductionmentioning

confidence: 99%

Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer

Villafañe

Dogruluk

et al. 2017

Cancer Research

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Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in TCGA datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2, and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors. Our fusion construction strategy also enabled domain-function studies of BRAF fusion genes. Our results confirmed other reports that the transforming activity of BRAF fusions results from truncation-mediated loss of inhibitory domains within the N-terminus of the BRAF protein. BRAF mutations residing within this inhibitory region may provide a means for BRAF activation in cancer, therefore we leveraged the modular design of our fusion gene construction methodology to screen N-terminal domain mutations discovered in tumors that are wild-type at the BRAF mutation hotspot, V600. We identified an oncogenic mutation, F247L, whose expression robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors. When applied broadly, these tools will facilitate rapid fusion gene construction for subsequent functional characterization and translation into personalized treatment strategies.

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“…85 More promising, Falchi et al described a patient with ETV6-FLT3-positive CEL who achieved a complete hematologic and partial cytogenetic remission after only 1.5 months of treatment with sorafenib. 84 The patient subsequently underwent matched sibling donor allogeneic HSCT and was alive and in remission 11 months after initial diagnosis. These studies suggest a potential role of FLT3 inhibitors, but monotherapy is unlikely to elicit long-term disease control and should instead be used as a bridge to allogeneic HSCT.…”

Section: Etv6-flt3 and Other Flt3 Fusion Genesmentioning

confidence: 99%

“…The majority of cases with a FLT3 rearrangement have involved ETV6-FLT3, with 6 cases reported since 2006. [83][84][85][86][87][88] The ETV6-FLT3 fusion causes IL-3-independent transformation of Ba/F3 murine hematopoietic cells. 83 It is hypothesized that the helix-loop-helix oligomerization domain of ETV6-FLT3 promotes ligand-independent dimerization, resulting in constitutive TK activity.…”

Section: Etv6-flt3 and Other Flt3 Fusion Genesmentioning

confidence: 99%

Myeloid neoplasms with eosinophilia

Reiter

Gotlib

2017

Blood

227

274

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Molecular diagnostics has generated substantial dividends in dissecting the genetic basis of myeloid neoplasms with eosinophilia. The family of diseases generated by dysregulated fusion tyrosine kinase (TK) genes is recognized by the World Health Organization (WHO) category, “Myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2.” In addition to myeloproliferative neoplasms (MPN), these patients can present with myelodysplastic syndrome/MPN, as well as de novo or secondary mixed-phenotype leukemias or lymphomas. Eosinophilia is a common, but not invariable, feature of these diseases. The natural history of PDGFRA- and PDGFRB-rearranged neoplasms has been dramatically altered by imatinib. In contrast, patients with FGFR1 and JAK2 fusion TK genes exhibit a more aggressive course and variable sensitivity to current TK inhibitors, and in most cases, long-term disease-free survival may only be achievable with allogeneic hematopoietic stem cell transplantation. Similar poor prognosis outcomes may be observed with rearrangements of FLT3 or ABL1 (eg, both of which commonly partner with ETV6), and further investigation is needed to validate their inclusion in the current WHO-defined group of eosinophilia-associated TK fusion-driven neoplasms. The diagnosis chronic eosinophilic leukemia, not otherwise specified (CEL, NOS) is assigned to patients with MPN with eosinophilia and nonspecific cytogenetic/molecular abnormalities and/or increased myeloblasts. Myeloid mutation panels have identified somatic variants in patients with a provisional diagnosis of hypereosinophilia of undetermined significance, reclassifying some of these cases as eosinophilia-associated neoplasms. Looking forward, one of the many challenges will be how to use the results of molecular profiling to guide prognosis and selection of actionable therapeutic targets.

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ETV6–FLT3 fusion gene-positive, eosinophilia-associated myeloproliferative neoplasm successfully treated with sorafenib and allogeneic stem cell transplant

Cited by 39 publications

References 11 publications

Eosinophilia in Hematologic Disorders

Eosinophilia in Hematologic Disorders

Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer

Myeloid neoplasms with eosinophilia

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