Myeloid/lymphoid neoplasms with FLT3 rearrangement

Tang, Guilin; Short, Nicholas J.; Bose, Prithviraj; Wu, David; Hurwitz, Stephanie N.; Bagg, Adam; Rogers, Heesun J.; Hsi, Eric D.; Quesada, Andres; Wang, Wei; Miranda, Roberto N.; Bueso‐Ramos, Carlos E.; Medeiros, L. Jeffrey; Nardi, Valentina; Arber, Daniel A.; Orazi, Attilio; Foucar, Kathryn; Wang, Sa A.

doi:10.1038/s41379-021-00817-7

Cited by 24 publications

(29 citation statements)

References 33 publications

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“…MLN-TK with FLT3 fusions remain rare, yet increased recognition of this entity fostered by its recent inclusion in the WHO and ICC classifications of hematologic neoplasms ( Arber et al 2022 ; Khoury et al 2022 ) will allow us to better delineate disease characteristics of this entity. At the time of writing, 34 cases have been reported ( Table 3 ; Vu et al 2006 ; Grand et al 2007 ; Tzankov et al 2008 ; Walz et al 2011 ; Chonabayashi et al 2014 ; Falchi et al 2014 ; Hosseini et al 2014 ; Sato et al 2015 ; Chung et al 2017 ; Jawhar et al 2017 ; Roberts et al 2017 ; Troadec et al 2017 ; Zhang et al 2018 ; Chao et al 2020 ; Shao et al 2020 ; Zhou et al 2020 ; Munthe-Kaas et al 2021 ; Spitzer et al 2021 ; Tang et al 2021 ; Belhassan et al 2022 ; Kurihara et al 2022 ). Although the spectrum of neoplasms with documented FLT3 rearrangements is wide, myeloid malignancies appear overrepresented with a predilection for myeloproliferative neoplasms with eosinophilia (51.6%).…”

Section: Discussionmentioning

confidence: 99%

“…From a treatment perspective, 58.8% of patients received an allogeneic stem cell transplantation and 73.5% required multiagent systemic therapy. A TKI with anti-FLT3 activity (including sunitinib, sorafenib, quizartinib, and gilteritinib) was attempted in 11 patients and at least a partial or transient response to this therapy was achieved in all patients ( Walz et al 2011 ; Falchi et al 2014 ; Jawhar et al 2017 ; Chao et al 2020 ; Shao et al 2020 ; Munthe-Kaas et al 2021 ; Tang et al 2021 ). Patient outcome was variable across reports with 50% of patients succumbing to their disease and 41.2% achieving or maintaining a complete remission at the time of their respective publication.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to these two types of variants, rare occurrences of gene fusions involving FLT3 have been reported in the literature. These have been documented in a wide variety of hematologic malignancies often with concurrent eosinophilia ( Vu et al 2006 ; Grand et al 2007 ; Tzankov et al 2008 ; Walz et al 2011 ; Chonabayashi et al 2014 ; Falchi et al 2014 ; Hosseini et al 2014 ; Chung et al 2017 ; Jawhar et al 2017 ; Troadec et al 2017 ; Zhang et al 2018 ; Chao et al 2020 ; Zhou et al 2020 ; Tang et al 2021 ) and have recently been included among myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) in the World Health Organization (WHO) classification ( Khoury et al 2022 ) and International Consensus Classification (ICC) ( Arber et al 2022 ) of hematologic malignancies.…”

Section: Introductionmentioning

confidence: 99%

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ATRIP11:: FLT3gene fusion in a patient with myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions: a case report and review of the literature

Venable

Gagnon

Pitel

et al. 2023

Cold Spring Harb Mol Case Stud

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Myeloid/lymphoid neoplasms with FLT3 gene fusions have recently been included among myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) in the World Health Organization classification and International Consensus Classification. As this entity remains remarkably rare, its scope and phenotypic features are evolving. In this report, we describe a 33-year-old male with MLN-TK. Conventional chromosome analysis revealed a t(13;14)(q12;q32). Further analysis with mate-pair sequencing (MPseq) confirmed a TRIP11::FLT3 gene fusion. A diagnosis of MLN-TK was rendered. To the best of our knowledge, we report the third case of MLN-TK with a TRIP11::FLT3 gene fusion. In contrast to previously described cases, our case exhibited distinctly mild clinical features and disease behavior, emphasizing the diverse spectrum of MLN-TK at primary presentation and variability in disease course. MLN-TK with FLT3 gene fusions are a genetically defined entity which may be targetable with tyrosine kinase inhibitors with anti-FLT3 activity. Accordingly, from diagnostic and therapeutic viewpoints, genetic testing for FLT3 rearrangements using FISH or sequencing-based assays should be pursued for patients with chronic eosinophilia.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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ATRIP11:: FLT3gene fusion in a patient with myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions: a case report and review of the literature

Venable

Gagnon

Pitel

et al. 2023

Cold Spring Harb Mol Case Stud

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“…In some cases, the MC proliferation may form dense clusters, showing histopathological features reminiscent of SM. 16,[18][19][20][21] Such cases often have accompanying eosinophilia and are often diagnosed as SM-AMN before the detection of the TK fusion. Some characteristic histopathological features have been observed in association with certain specific fusion genes.…”

Section: Histopathologymentioning

confidence: 99%

“…44 Therefore, for the time being, only FLT3 rearrangement in hematolymphoid neoplasms is uncommon, with around 30 cases reported. 20,32,[45][46][47][48][49][50][51][52][53][54][55][56][57] The most common is t(12;13) (p13;q12)/ETV6::FLT3, which is typically not cryptic. Other partner genes reported are ZMYM2/13q12, 32,50 appears to be rearranged with yet uncharacterized partner genes at 3q27, 5q15, 5q35, 7q36, and 13q22.…”

Section: Histopathologymentioning

confidence: 99%

The international consensus classification of eosinophilic disorders and systemic mastocytosis

et al. 2023

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Based on new data and increased understanding of disease molecular genetics, the international consensus classification (ICC) has made several changes in the diagnosis and classification of eosinophilic disorders and systemic mastocytosis. Myeloid/lymphoid neoplasms with eosinophilia (M/LN‐eo) and gene rearrangements have been renamed as M/LN‐eo with tyrosine kinase gene fusions (M/LN‐eo‐TK). The category has been expanded to include ETV6::ABL1 and FLT3 fusions, and to accept PCM1::JAK2 and its genetic variants as formal members. The overlaps and differences between M/LN‐eo‐TK and BCR::ABL1‐like B‐lymphoblastic leukemia (ALL)/de novo T‐ALL sharing the same genetic lesions are addressed. Besides genetics, ICC for the first time has introduced bone marrow morphologic criteria in distinguishing idiopathic hypereosinophilia/hypereosinophilic syndrome from chronic eosinophilic leukemia, not otherwise specified. The major diagnostic criteria for systemic mastocytosis (SM) in the ICC remain largely based on morphology, but several minor modifications/refinements have been made in criteria related to diagnosis, subclassification, and assessment of disease burden (B‐ and C‐findings). This review is to focus on the ICC updates related to these disease entities, illustrated through changes related to morphology, molecular genetics, clinical features, prognosis, and treatment. Two practical algorithms are provided in navigating through the diagnosis and classification systems of hypereosinophilia and SM.

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World Health Organization‐defined eosinophilic disorders: 2022 update on diagnosis, risk stratification, and management

2021

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Disease Overview: The eosinophilias encompass a broad range of nonhematologic (secondary or reactive) and hematologic (primary or clonal) disorders with potential for end-organ damage.Diagnosis: Hypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1.5 Â 10 9 /L. After exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ hybridization, next generation sequencing gene assays, and flow immunophenotyping to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm.Risk Stratification: Disease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2016 World Health Organization endorses a semi-molecular classification scheme of disease subtypes. This includes the major category "myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1 or with PCM1-JAK2", and the myeloproliferative neoplasm subtype, "chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS). Lymphocyte-variant HE is an aberrant T-cell clone-driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion. Risk-adapted Therapy:The goal of therapy is to mitigate eosinophil-mediated organ damage. For patients with milder forms of eosinophilia (eg, < 1.5 Â 10 9 /L) without symptoms or signs of organ involvement, a watch and wait approach with close follow-up may be undertaken. Identification of rearranged PDGFRA or PDGFRB is critical because of the exquisite responsiveness of these diseases to imatinib. Corticosteroids are first-line therapy for patients with lymphocyte-variant HE and HES.Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES. Mepolizumab, an interleukin-5 (IL-5) antagonist monoclonal antibody, was recently approved by the US Food and Drug Administration for patients with idiopathic HES. The use of the IL-5 receptor antibody benralizumab, as well as other targeted therapies such as JAK2 and FGFR1 inhibitors, is under active investigation.

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Myeloid/lymphoid neoplasms with FLT3 rearrangement

Cited by 24 publications

References 33 publications

ATRIP11:: FLT3gene fusion in a patient with myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions: a case report and review of the literature

ATRIP11:: FLT3gene fusion in a patient with myeloid/lymphoid neoplasm with eosinophilia and tyrosine kinase gene fusions: a case report and review of the literature

The international consensus classification of eosinophilic disorders and systemic mastocytosis

World Health Organization‐defined eosinophilic disorders: 2022 update on diagnosis, risk stratification, and management

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