Myeloid/lymphoid neoplasms with eosinophilia/ basophilia and ETV6-ABL1 fusion: cell-of-origin and response to tyrosine kinase inhibition

Yao, Jinjuan; Xu, Lianrong; Aypar, Umut; Meyerson, Howard; Londono, Dory; Gao, Qi; Baik, Jeeyeon; Dietz, James; Benayed, Ryma; Sigler, Allison; Yabe, Mariko; Doğan, Ahmet; Arcila, Maria E.; Roshal, Mikhail; Zhang, Yanming; Mauro, Michael J.; Xiao, Wenbin

doi:10.3324/haematol.2020.249649

Cited by 14 publications

(23 citation statements)

References 16 publications

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“…In conclusion, this infant presented with clinical features suggesting JMML but was ultimately identified to have a tyrosine kinase fusion-driven MLN-Eo. Our clinical experience, as well as others reported in the literature, 2,3,6,20,21 suggests that a strategy incorporating tyrosine kinase inhibitors with hematopoietic stem cell transplantation is an effective treatment paradigm for this rare group of kinase-driven MPN. Ex vivo patient-specific data suggested preferential sensitivity to type I FLT3 inhibitors, which aided our selection of a more sensitive inhibitor and ultimately a cytogenetic complete response for our patient.…”

Section: Discussionsupporting

confidence: 70%

ETV6-FLT3–positive myeloid/lymphoid neoplasm with eosinophilia presenting in an infant: an entity distinct from JMML

et al. 2021

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Myeloid/lymphoid neoplasm with eosinophilia (MLN-Eo) is a World Health Organization (WHO) established category of hematologic malignancies primarily arising in adults. We discuss an 8-month-old infant who presented with clinical features similar to those of juvenile myelomonocytic leukemia (JMML) but who was diagnosed with MLN-Eo driven by an ETV6-FLT3 fusion. Results of patient-derived leukemia ex vivo studies demonstrated increased sensitivity to type I FLT3 inhibitors as compared with type II inhibitors. Treatment with the type I inhibitor gilteritinib resulted in complete immunophenotypic and cytogenetic remission. This patient subsequently underwent a hematopoietic stem cell transplant and remains in complete remission 1 year later. This is the youngest patient reported with an ETV6-FLT3 fusion and adds to the mounting reports of FLT3-rearranged MLN-Eo, supporting its addition to the WHO classification. Furthermore, this case highlights the clinical utility of ex vivo drug testing of targeted therapies.

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Section: Discussionsupporting

confidence: 70%

ETV6-FLT3–positive myeloid/lymphoid neoplasm with eosinophilia presenting in an infant: an entity distinct from JMML

et al. 2021

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“…ETV6::ABL1, the new member of this category, often shows clinicopathological features reminiscent of CML with eosinophilia; however, some cases may resemble atypical CML (aCML) or essential thrombocythemia. 25 Cases with FGFR1 rearrangement typically show BM features of a MPN, with eosinophilia seen in 60%-70% cases. M/LN-eo associated with t(8;13)(p11;q12)/ZMYM2::FGFR1 frequently presents with nodal (or extranodal) T-LBL admixed with scattered or perivascular myeloid blasts, being labeled as "bilineal lymphoma".…”

Section: Histopathologymentioning

confidence: 99%

“…16,58,59 In PCM1::JAK2 M/LN-eo, mutations are reported in 14%-50% of cases, 16,22,58 In M/LN-eo with ETV6::ABL1, although data are also limited, mutations involving ARID2, TP53, SETD2, CDKN1B, PTPN11, and SMC1A genes have been reported in approximately 50% of cases. 25,60,61 In M/LN-eo with FLT3 fusions, mutations of ASXL1, PTPN11, RUNX1, SETBP1, SRSF2, STAT5B, TET2, TP53, and U2AF1…”

Section: Mutationsmentioning

confidence: 99%

“…with an elevated white blood cell count (WBC), eosinophilia (>90% cases), and some with increased (>1%) basophils. 25,60 Prior to the identification of the fusion ETV6::ABL1, cases in adults were often diagnosed as MPN with marked eosinophilia, or CEL, NOS. Of note, these cases only rarely present in blast phase.…”

Section: Clinical Presentationsmentioning

confidence: 99%

“…Patients with ETV6::ABL1 have shown variable responses to TKI targeted therapy. 24,25,60,79,80 Second-or third-generation TKI 24 appear to be superior to imatinib in inducing responses. Durable hematological and molecular remissions have been observed in a significant number of patients presenting in chronic phase, but not patients in blast phase.…”

Section: Treatment and Prognosismentioning

confidence: 99%

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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 and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management

Shomali,

Gotlib

2024

American J Hematol

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Disease OverviewThe eosinophilias encompass a broad range of non‐hematologic (secondary or reactive) and hematologic (primary or clonal) disorders with the potential for end‐organ damage.DiagnosisHypereosinophilia (HE) has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 109/L, and may be associated with tissue damage. After the exclusion of secondary causes of eosinophilia, diagnostic evaluation of primary eosinophilias relies on a combination of various tests. They include morphologic review of the blood and marrow, standard cytogenetics, fluorescence in situ hybridization, molecular testing and flow immunophenotyping to detect histopathologic or clonal evidence for an acute or chronic hematolymphoid neoplasm.Risk StratificationDisease prognosis relies on identifying the subtype of eosinophilia. After evaluation of secondary causes of eosinophilia, the 2022 World Health Organization and International Consensus Classification endorse a semi‐molecular classification scheme of disease subtypes. This includes the major category “myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions” (MLN‐eo‐TK), and the MPN subtype, “chronic eosinophilic leukemia” (CEL). Lymphocyte‐variant HE is an aberrant T‐cell clone‐driven reactive eosinophila, and idiopathic hypereosinophilic syndrome (HES) is a diagnosis of exclusion.Risk‐Adapted TherapyThe goal of therapy is to mitigate eosinophil‐mediated organ damage. For patients with milder forms of eosinophilia (e.g., <1.5 × 109/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. Pemigatinib was recently approved for patients with relapsed or refractory FGFR1‐rearranged neoplasms. 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, is approved by the U.S Food and Drug Administration for patients with idiopathic HES. Cytotoxic chemotherapy agents, and hematopoietic stem cell transplantation have been used for aggressive forms of HES and CEL, with outcomes reported for limited numbers of patients. Targeted therapies such as the IL‐5 receptor antibody benralizumab, IL‐5 monoclonal antibody depemokimab, and various tyrosine kinase inhibitors for MLN‐eo‐TK, are under active investigation.

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Myeloid/lymphoid neoplasms with eosinophilia/ basophilia and ETV6-ABL1 fusion: cell-of-origin and response to tyrosine kinase inhibition

Cited by 14 publications

References 16 publications

ETV6-FLT3–positive myeloid/lymphoid neoplasm with eosinophilia presenting in an infant: an entity distinct from JMML

ETV6-FLT3–positive myeloid/lymphoid neoplasm with eosinophilia presenting in an infant: an entity distinct from JMML

The international consensus classification of eosinophilic disorders and systemic mastocytosis

World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management

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