Molecular genetic characterization of myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of <i>PDGFRA, PDGFRB, FGFR1</i> or <i>PCM1-JAK2</i>

Baer, Constance; Muehlbacher, Verena; Kern, Wolfgang; Haferlach, Claudia; Haferlach, Torsten

doi:10.3324/haematol.2017.187302

Cited by 52 publications

(53 citation statements)

References 14 publications

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“…PDGFRB rearrangements in myeloid and lymphoid neoplasms are rare, and disease characteristics have been determined from individual case reports or very small case series 7,10,11,25,26 . To date, only a few studies with >10 cases of PDGFRB ‐rearranged myeloid neoplasms have been published, and the studies were mainly focused on evaluating the response to imatinib or their molecular profiles 3–5,27,28 . PDGFRB rearrangements in B‐ALL are even more rare, and have only appeared in case reports 7–11,26 …”

Section: Discussionmentioning

confidence: 99%

Systematic use of fluorescence in‐situ hybridisation and clinicopathological features in the screening of PDGFRB rearrangements of patients with myeloid/lymphoid neoplasms

et al. 2020

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Section: Discussionmentioning

confidence: 99%

Systematic use of fluorescence in‐situ hybridisation and clinicopathological features in the screening of PDGFRB rearrangements of patients with myeloid/lymphoid neoplasms

et al. 2020

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“…The most frequent mutation seen in these T-cell disorders is STAT5B N642H, but other mutations are also seen, specifically STAT5B Y665F and STAT3 Y640F, N647I and D661V/Y [31]. Isolated reports have identified single cases of myeloid neoplasms, specifically chronic neutrophilic leukemia [32] and MLN-eo [33], that tested positive for STAT5B N642H as well as 2 cases that developed clonal hematopoiesis following aplastic anaemia [34]. Our findings are the first to identify STAT5B N642H as a recurrent mutation in myeloid neoplasms with eosinophilia.…”

Section: Discussionmentioning

confidence: 99%

Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia

et al. 2018

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Determining the underlying cause of persistent eosinophilia is important for effective clinical management but remains a diagnostic challenge in many cases. We identified STAT5B N642H, an established oncogenic mutation, in 27/1715 (1.6%) cases referred for investigation of eosinophilia. Of the 27 mutated cases, a working diagnosis of hypereosinophilic syndrome (HES; n = 7) or a myeloid neoplasm with eosinophilia (n = 20) had been made prior to the detection of STAT5B N642H. Myeloid panel analysis identified a median of 2 additional mutated genes (range 0–4) with 4 cases having STAT5B N642H as a sole abnormality. STAT5B N642H was absent in cultured T cells of 4/4 positive cases. Individuals with SF3B1 mutations (9/27; 33%) or STAT5B N642H as a sole abnormality had a markedly better overall survival compared to cases with other additional mutations (median 65 months vs. 14 months; hazard ratio = 8.1; P < 0.001). The overall survival of STAT5B-mutated HES cases was only 30 months, suggesting that these cases should be reclassified as chronic eosinophilic leukemia, not otherwise specified (CEL-NOS). The finding of STAT5B N642H as a recurrent mutation in myeloid neoplasia with eosinophilia provides a new diagnostic and prognostic marker as well as a potential target for therapy.

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“…Next generation sequencing [NGS] panels can help identify additional somatic mutations in patients with eosinophilia and recurrent gene fusions. The prognostic role of those additional somatic mutations is unclear in the presence of active small molecule inhibitors …”

Section: Diagnosismentioning

confidence: 99%

World Health Organization‐defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management

2019

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Disease overview: The eosinophilias encompass a broad range of non-hematologic (secondary or reactive) and hematologic (primary or clonal) disorders with potential for end-organ damage.Diagnosis: Hypereosinophilia has generally been defined as a peripheral blood eosinophil count greater than 1.5 × 10 9 /L, and may be associated with tissue damage. After 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, flow immunophenotyping, and T-cell clonality assessment 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 MPN subtype, "chronic eosinophilic leukemia, not otherwise specified" (CEL, NOS). Lymphocyte-variant hypereosinophilia 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 × 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 hypereosinophilia and HES. Hydroxyurea and interferon-α have demonstrated efficacy as initial treatment and in steroid-refractory cases of HES. In addition to hydroxyurea, second line 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. The use of antibodies against interleukin-5 (IL-5) (mepolizumab), the IL-5 receptor (benralizumab), as well as other targets on eosinophils remains an active area of investigation.

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Molecular genetic characterization of myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2

Cited by 52 publications

References 14 publications

Systematic use of fluorescence in‐situ hybridisation and clinicopathological features in the screening of PDGFRB rearrangements of patients with myeloid/lymphoid neoplasms

Systematic use of fluorescence in‐situ hybridisation and clinicopathological features in the screening of PDGFRB rearrangements of patients with myeloid/lymphoid neoplasms

Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia

World Health Organization‐defined eosinophilic disorders: 2019 update on diagnosis, risk stratification, and management

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