
==== Front
Curr Hematol Malig Rep
Curr Hematol Malig Rep
Current Hematologic Malignancy Reports
1558-8211
1558-822X
Springer US New York

39037514
738
10.1007/s11899-024-00738-7
Article
Approach to the patient with eosinophilia in the era of tyrosine kinase inhibitors and biologicals
Lübke Johannes
Metzgeroth Georgia
Reiter Andreas
Schwaab Juliana juliana.schwaab@medma.uni-heidelberg.de

grid.411778.c 0000 0001 2162 1728 Department of Hematology and Oncology, University Hospital Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany
22 7 2024
22 7 2024
2024
19 5 208222
2 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Purpose of Review

In this review, we aim to explore the optimal approach to patients presenting with eosinophilia, considering recent advances in diagnostic and therapeutic strategies. Specifically, we focus on the integration of novel therapies into clinical practice to improve patient outcomes.

Recent Findings

Advanced insights into the clinical and genetic features of eosinophilic disorders have prompted revisions in diagnostic criteria by the World Health Organization classification (WHO-HAEM5) and the International Consensus Classification (ICC). These changes reflect a growing understanding of disease pathogenesis and the development of targeted treatment options. The therapeutic landscape now encompasses a range of established and novel therapies. For reactive conditions, drugs targeting the eosinophilopoiesis, such as those aimed at interleukin-5 or its receptor, have demonstrated significant potential in decreasing blood eosinophil levels and minimizing disease flare-ups and relapse. These therapies have the potential to mitigate the side effects commonly associated with prolonged use of oral corticosteroids or immunosuppressants. Myeloid and lymphoid neoplasms with eosinophilia and tyrosine kinase (TK) gene fusions are managed by various TK inhibitors with variable efficacy.

Summary

Diagnosis and treatment rely on a multidisciplinary approach. By incorporating novel treatment options into clinical practice, physicians across different disciplines involved in the management of eosinophilic disorders can offer more personalized and effective care to patients. However, challenges remain in accurately diagnosing and risk-stratifying patients, as well as in navigating the complexities of treatment selection.

Keywords

Eosinophilia
Hypereosinophilia
MLN-TK
CEL
HES
http://dx.doi.org/10.13039/100008672 Wilhelm Sander-Stiftung 2023.120.1 2023.120.1 2023.120.1 Lübke Johannes Reiter Andreas Schwaab Juliana Medizinische Fakultät Mannheim der Universität Heidelberg (8990)Open Access funding enabled and organized by Projekt DEAL.

issue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2024
==== Body
pmcIntroduction

Eosinophilia and hypereosinophilia (HE) are defined as an absolute eosinophil count of ≥ 0.5 × 109/L and ≥ 1.5 × 109/L in peripheral blood (PB), with an arbitrarily distinction into mild (< 1.5 × 109/L), moderate (1.5–5 × 109/L), and severe (≥ 5 × 109/L) eosinophilia. The underlying etiology of eosinophilia ranges from benign reactive conditions to life-threatening neoplasms and its correct attribution is often challenging. After confirmation of HE, the diagnostic workup should progress in a stepwise manner, first by excluding the most frequent secondary/reactive causes (e.g., allergies, infections but also autoimmunopathies such as eosinophilic granulomatosis with polyangiitis [EGPA]), followed by evaluating potential primary/neoplastic causes (e.g., myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions [MLN-TK], chronic eosinophilic leukemia [CEL], eosinophilia associated with other myeloid neoplasms), and ultimately by confirming or excluding the diagnosis of lymphocytic (L-HES) or idiopathic hypereosinophilic syndrome (iHES, Fig. 1).Fig. 1 Diagnostic approach to the patient with eosinophilia. Abbreviations: ALL, acute lymphoid leukemia; AML, acute myeloid leukemia; ANA, antinuclear antibodies; ANCA, antineutrophil cytoplasmic antibodies; BAL, bronchoalveolar lavage; BM, bone marrow; CCP, cyclic citrullinated peptide; CEL, NOS; chronic eosinophilic leukemia, not otherwise specified; CML, chronic myeloid leukemia; CNS, central nervous system; ECG, electrocardiogram; FG, fusion gene(s); FISH, fluorescence in situ hybridization; GI, gastrointestinal; HE, hypereosinophilia; HES, hypereosinophilic syndrome; HEus, hypereosinophilia with undetermined significance; HL, Hodgkin’s lymphoma; IgE immunoglobulin E; iHES, idiopathic hypereosinophilic syndrome; MDS, myelodysplastic neoplasm; MDS/MPN, myelodysplastic/ myeloproliferative neoplasm; MLN-TK; myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions; MPN, myeloproliferative neoplasm; MRI, magnetic resonance imaging; NGS, next-generation-sequencing; NHL, non-Hodgkin’s lymphoma; PB, peripheral blood; PCR, polymerase chain reaction; RNA-seq, RNA sequencing; TCR, T cell receptor; WHO, World Health Organization Modified from Gotlib et al. [1] and Wang et al. [2]

Recent advances in our understanding of HE related clinical and genetic features have led to significant revisions in diagnostic criteria by the World Health Organization classification (WHO-HAEM5) and the International Consensus Classification (ICC), reflecting a growing appreciation of the complex (genetic) pathogenesis underlying different eosinophilic disorders [3, 4].

In this manuscript, we aim to provide a comprehensive overview of the expanding therapeutic landscape, encompassing both established treatment modalities and innovative therapeutic agents of which some are currently undergoing evaluation in clinical trials. Through a comprehensive examination of recent developments and emerging trends in the field, we try to offer insights into the management of eosinophilic disorders that will inform clinical decision-making and improve patient outcomes.

Secondary/reactive eosinophilia

Eosinophilia is predominantly of secondary/reactive origin with a multitude of different causes (Table 1). Globally, parasitic infections and drug reactions to medications are among the most common causes for eosinophilia. Furthermore, mild to moderate PB eosinophilia is associated with several autoimmune conditions. EGPA is classified as a small-vessel, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) [5, 6]. However, only approximately 30–47% of EGPA patients test positive for ANCA, predominantly showing anti-myeloperoxidase (MPO) ANCA positivity [7]. Recent studies have revealed that ANCA-positive and -negative EGPA are linked to distinct genetic polymorphisms, suggesting different underlying pathogenic mechanisms [8]. [9–13]. Patients with ANCA-positive EGPA are more likely to develop a vasculitic phenotype, whereas patients without ANCA are more predisposed to eosinophilic end organ damage. However, ANCA status alone is insufficient to predict the individual clinical presentation or guide treatment decisions. Oral corticosteroids are the standard of care [6]. In cases with end-organ involvement or life-threatening symptoms, corticosteroids are administered along with immunosuppressive drugs (e.g., cyclophosphamide, azathioprine or rituximab) [6]. Most recently, the MIRRA trial (NCT02020889) demonstrated that approximately half of the participants with relapsing or refractory EGPA who were treated with the anti-interleukin (IL)-5 monoclonal antibody mepolizumab had clinically relevant improvements in the rates of protocol-defined remission (28% vs. 3% for placebo) and relapse (annualized relapse rate 1.14 vs. 2.27 for placebo), and were able to reduce the dose of steroids (< 4.0 mg prednisolone per day, 44% vs. 7% for placebo) compared to placebo [14].Table 1 Non-exhaustive list of possible secondary/reactive causes for eosinophilia

• Drugs (e.g., antiepileptics, antibiotics, Drug reaction with eosinophilia and systemic symptoms, most common cause in industrialized countries)	
• Allergic disorders (e.g., asthma, atopic dermatitis/eczema, seasonal allergic disorders)	
• Rheumatological disease (e.g., eosinophilic granulomatosis with polyangiitis, systemic lupus erythematosus, rheumatoid arthritis, and eosinophilic fasciitis)	
• Pulmonary disease (e.g., Loffler syndrome, sarcoidosis)	
• Gastrointestinal disorders (e.g., primary gastrointestinal eosinophilic disorders including eosinophilic esophagitis and chronic pancreatitis)	
• Dermatological disorders (e.g., Wells syndrome, angiolymphoid hyperplasia)	
• Neoplasms (non‐hematologic and hematologic: e.g., T‐cell lymphomas, Hodgkin lymphoma, systemic mastocytosis, solid tumors)	
• Parasitic infections (e.g., helminth infections, most common cause worldwide)	
Modified from Larsen et al. [15]

Neoplastic conditions, both hematologic (e.g., systemic mastocytosis, acute leukemias, myeloproliferative neoplasms, lymphoma) and non-hematologic (e.g., solid tumors), can also trigger eosinophilia.

Administered medications (e.g., corticosteroids) and transient medical conditions (e.g., bacterial infections) may temporarily lower the absolute eosinophil count, masking the real degree of eosinophilia. If secondary causes of eosinophilia have been excluded or are unlikely, and the cause of eosinophlia remains unclear, screening for a primary eosinophilic disorder is necessary, ideally before a potential end-organ damage occurs.

Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK)

According to the 2022 WHO/ICC classification, the term “myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1::JAK2” has been replaced with MLN-TK to specify the underlying molecular genetic changes and to include cases with ETV6::ABL1, FLT3 fusions, or other tyrosine kinase (TK) gene fusions [2, 4, 16]. Nearly 100 different TK fusion genes, involving at least six TK (PDGFRA, PDGFRB, FGFR1, JAK2, ABL1, FLT3), have been identified in distinct MLN with or without eosinophilia [17, 18]. A comprehensive overview of the most common fusion partners is provided in Table 2. Besides eosinophilia, patients often present with monocytosis and an elevated serum tryptase, particularly in cases with PDGFRA or PDGFRB fusion genes [18, 19]. Elevated vitamin B12 levels are a common, yet non-specific marker for myeloproliferative neoplasms in general.Table 2 Genetic abnormalities, clinical manifestation and specific treatment approaches for myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (MLN-TK) as per 2022 World Health Organization classification and International Consensus Classification [3, 4]

TK gene	Most common fusion	Analyses	Other partner genes/ variants	Typical clinical and BM manifestation	Accompanying mutations	Targeted therapy	Prognosis	
PDGFRA	Cryptic deletion 4q12/

FIP1L1:: PDGFRA

	FISH, RT-PCR	CDK5RAP2; STRN; KIF5B; TNKS2; ETV6, BCR	Common: CEL-like BM, extramedullary involvement

Others: B-ALL (in children), AML or mast cell proliferations

	20–50%: ASXL1, BCOR, DNMT3A, RUNX1, SRSF2, TET2	Imatinib, may be terminated	Durable and complete hematologic, cytogenetic and molecular remission	
PDGFRB	t(5;12)(q32;p13.2)/

ETV6::PDGFRB

	Karyotype, FISH, RT-PCR	 > 30 partners, some cryptic	Common: CEL-like or monocytosis with eosinophilia

Others: ALL, AML or mast cell proliferations

	30–50%: ASXL1, BCOR, DNMT3A, NRAS, STAG2, STAT5B, TET2, ZSRS2	Imatinib, may be terminated	Durable and complete hematologic, cytogenetic and molecular remission	
FGFR1	t(8;13)(p11.2;q12.1)/

ZMYM2::FGFR1

	Karyotype, FISH, RT-PCR	15 other partners including BCR	Common: Extramedullary sites, T-ALL with BM MPN-like or blast phase of MPN;

Others: B-ALL, myeloid sarcoma, AML or MPAL

	70–80%: RUNX1, ASXL1, CSFR3, STAG2	Pemigatinib (anti-FGFR1-3), Futibatinib (anti-FGFR1-4)	Pemigatinib: Complete clinical and cytogenetic response, more durable in chronic vs. blast phase, consider alloHCT	
JAK2	t(8;9)(p22;p24.1)/

PCM1::JAK2

	Karyotype, FISH	ETV6 and BCR	Common: MPN or MDS/MPN like BM with eosinophilia

Others: B- and T-ALL with BM MPN

	14–50%: ASXL1, BCOR, BCORL1, CD36, EP300, ETV6, RUNX1, SRSF2, TET2, TP53	Ruxolitinib	Hematologic and cytogenetic response, not durable, consider alloHCT	
FLT3	t(12;13)(p13.2;q12.2)/

ETV6::FLT3

	Karyotype, FISH, RT-PCR	ZMYM2, TRIP11, SPTBN1, GOLGB1, CCDC88C, MYO18A, BCR	T-ALL or myeloid sarcoma with CEL-like or MDS/MPN BM features	 ~ 50%: ASXL1, RUNX1, STAT5B, SRSF2, TET2, TP53, U2AF1	Sorafenib, Sunitinib, Midostaurin, Gilteritinib	Various hematologic and cytogenetic responses	
ETV6::ABL1	t(9;12)(q34.1;p13.2)/

ETV6::ABL1

	FISH, RT-PCR	Unknown	CML-like with frequent eosinophilia in chronic or blast phase	40–50%: ARID2, CDKN1B, TP53, SMC1A	Dasatinib, Nilotinib

(Imatinib)

	Variable durable hematologic and cytogenetic response	
Abbreviations: ALL, acute lymphoid leukemia; alloHCT, allogeneic stem cell transplantation; AML, acute myeloid leukemia; BM, bone marrow; CEL, chronic eosinophilic leukemia; CML, chronic myeloid leukemia; FISH, fluorescence in situ hybridization; MDS/MPN, myelodysplastic/ myeloproliferative neoplasm; MPAL, mixed-phenotype acute leukemia; MPN, myeloproliferative neoplasms; RT-PCR, reverse transcription-polymerase chain reaction; TK, tyrosine kinase

Modified from Tzankov et al. [20] and Wang et al. [2]

The blast phase in the bone marrow (BM) or at extramedullary sites (extramedullary disease, EMD), which is often initially diagnoses as myeloid sarcoma or high-grade (T-/B-cell) lymphoma without knowledge of an underlying TK fusion gene, may be present at diagnosis (primary blast phase) or develops in due course (secondary blast phase) [21]. Patients should undergo imaging (e.g., computed tomography) to check for extramedullary manifestation. In a recently published register based study on 135 MLN-TK patients, primary or secondary blast phase manifested with similar frequency either in the BM or as EMD in 28% of patients, of which 61% were of myeloid and 39% of lymphoid origin [18]. Primary or secondary blast phase in the BM was equally prevalent (each 50%), whereas primary EMD was more common (83%) than secondary EMD (17%). A discordance between myeloid and lymphoid lineage involvement in BM and at extramedullary sites was regularly seen in 50% of patients. Patients with PDGFRA and PDGFRB fusion genes (16%) were less likely to exhibit primary blast phase compared to those with FGFR1, JAK2, and ETV6::ABL1 fusion genes (26%). Secondary blast phase was also only observed in 6% of patients with PDGFRA and PDGFRB fusion genes after a median of 87 months. In addition to eosinophilia, BM morphology in MLN-TK frequently displayed an increase of mast cells and fibrosis [22]. In cases with dense mast cell aggregates and/or an elevated serum tryptase, molecular studies with high sensitivity (e.g., digital PCR) should be conducted to rule out a KIT D816V mutation for systemic mastocytosis [22–27]. The detection of fusion genes may be challenging due to variable clinical presentation, cryptic fusions or unknown fusion partners. Therefore, integrating conventional molecular- and cytogenetic analysis, along with advanced sequencing technologies such as RNA sequencing or next-generation-sequencing (NGS), might be necessary.

Considering the risks of both irreversible end-organ damage associated with persistent HE and possible transformation into blast phase with poor prognosis, it is recommended to initiate treatment immediately irrespective of the clinical symptoms [28]. Potentially effective targeted treatment with tyrosine kinase inhibitors (TKI) exist for all individual TK fusion genes. Imatinib has been proven to be highly effective in MLN with PDGFRA and PDGFRB fusion genes, with achievement of durable complete hematologic, cytogenetic (e.g., PDGFRB fusion genes) and molecular (e.g., FIP1L1::PDGFRA) remissions in more than 90% of patients. Patients are initially treated with a daily dose of 100–400 mg. Maintenance treatment with 100 mg three times per week is sufficient for complete molecular remissions [29–40]. Retrospective studies have examined the possibility of discontinuing imatinib once complete molecular remission of FIP1L1::PDGFRA is achieved [39, 40]. In one study involving 12 patients with the FIP1L1::PDGFRA fusion gene, the median time to relapse after stopping imatinib was 5.6 months, with approximately 30–40% of patients experiencing a treatment-free remission lasting longer than 3 years and a rapid second hematologic and molecular response to imatinib in those with a relapse [18]. While secondary resistance to imatinib is rare, it typically involves one of two specific mutations: PDGFRA T674I, which has shown in vitro response to ponatinib, or PDGFRA D842V, for which avapritinib, approved for gastrointestinal stromal tumors (GIST), holds promise [41–43].

In contrast, TK fusion genes with involvement of FGFR1, JAK2 or FLT3 are associated with a more aggressive phenotype and clinical course with variable sensitivity to TKI. RUNX1 mutations, reflecting clonal stem cell impairment, are identifiable in the majority of patients with FGFR1 fusion genes (70–80%) and typically correlate with a poorer prognosis [44]. The 1-year survival rate in FGFR fusion driven patients is approximately 40% [45]. Therefore, there is a high unmet need for effective treatment options. Pemigatinib, an oral inhibitor selective for FGFR1-3 given at an oral dose of 13.5 mg once daily, has been approved for adults with MLN-TK harboring FGFR1 fusion genes based on data from an ongoing phase 2, open-label, multicenter trial (NCT03011372) [46]. Complete remission rate was 65%; cytogenetic response rate was 77.4%. Among patients achieving complete remission, a significant reduction in FGFR1 fusion transcripts was observed, with 81% experiencing a > 2-log reduction and 48% a > 3-log reduction [47]. Although complete clinical and cytogenetic responses were also observed in blast phase, they were less frequent and less durable compared to chronic phase disease [46, 47]. A retinal pigment epithelial detachment (RPED) occurred in 26% of patients, with no instances of severe (grade 3–4) RPED observed. Before and during treatment, ophthalmological examinations are therefore recommended. Hyperphosphatemia was reported in 74% of patients, with severe (grade 3–4) hyperphosphatemia observed in 2.9% of cases. A low phosphate-diet and phosphate-lowering therapies should be initiated based on the severity. Overall, 80% of patients starting on the recommended dosage required dose reductions of pemigatinib due to adverse events. Depending on the severity of adverse events, initial dose reduction is recommended to 9 mg once daily, followed by subsequent reductions to 4.5 mg once daily, and 4.5 mg once daily for the first 14 days of each 21-day cycle. Pemigatinib may serve as a bridge to allogeneic stem cell transplantation (alloHCT) in these patients. In a retrospective study involving 22 patients with FGFR1 fusions who underwent alloHCT, the estimated 5-year survival rate was 74%, with progression-free survival at 63%. The rates of non-relapse mortality and relapse were 14% and 23%, respectively [48]. The potential of combining pemigatinib with chemotherapy in transplant-ineligible patients, particularly for aggressive phenotypes, warrants further investigation, as does the use of pemigatinib as maintenance therapy following alloHCT.

Futibatinib, an oral selective small molecule inhibitor of FGFR1-4, given at an oral dose of 20 mg once daily, has been assessed in a 55-year-old male, resulting in the first reported case of complete hematologic and cytogenetic remission in an FGFR1-driven myeloid neoplasm [49]. This has led to an ongoing, phase 2, open-label, multicenter trial for transplant-ineligible patients (NCT04189445) [50].

Six distinct fusion genes involving JAK2 are yet identified, with PCM1::JAK2 being the most common. Treatment with ruxolitinib (usually doses of 10 mg per day BID or higher) may lead to transient remission rates, but should primarily be seen as bridge to alloHCT in fit patients [51]. Although we currently lack data, fedratinib, momelotinib, or pacritinib could potentially demonstrate efficacy. ETV6::FLT3 constitutes about half of seven distinct FLT3 fusion genes. Partial and frequently transient effectiveness was observed with sorafenib, sunitinib, midostaurin, and gilteritinib. AlloHCT was documented in three patients, all of whom were in complete response at the time of reporting [52–57]. While ETV6::PDGFRB usually nicely responds to imatinib, fusions like ETV6::ABL1 and others often show lack of remission to imatinib but require nilotinib or ponatinib for achievement of remission [58]. Further treatment options are presented in Tables 2, 3.Table 3 Active clinical trials as per clin-trial.gov in February 2024

Drug (NCT number) a	Adminis-tration	Trial name	Design	Start date – estimated completion date	Estimated enrollment	Primary outcome	Locations	
Benralizumab, anti-IL-5r mAb

(NCT04191304)

	sc	A Multicentre, Randomised, Double-blind, Parallel-group, Placebo-controlled, 24 Week Phase III Study With an Open-label Extension to Evaluate the Efficacy and Safety of Benralizumab in Patients With Hypereosinophilic Syndrome (NATRON)	Phase 3 (double-blind, comparator: placebo)	July 2020 – November 2026	120 participants (≥ 12 years)	Time to first HES worsening/flares	Austria, Belgium, Denmark, France, Germany, Israel, Italy, Japan, Netherlands, Poland, Switzerland, United States	
Depemokimab, anti-IL-5 mAb

(NCT05334368)

	sc	A Randomized, Double-blind, Placebo-controlled Study to Investigate the Efficacy and Safety of Depemokimab in Adults With Hypereosinophilic Syndrome (HES) (DESTINY)	Phase 3 (double-blind, comparator: placebo)	September 2022 – March 2026	120 participants (≥ 18 years)	Frequency of HES flares	China, Japan, Republic of Korea, Spain, United States	
Futibatinib, FGFR1-4 inhibitor

(NCT04189445)

	oral	A Phase 2 Study of Futibatinib in Patients With Specific FGFR Aberrations (TAS-120–202)	Phase 2 (open-label)	August 2020–June 2024	115 participants (≥ 18 years) with 20 participants with MLN-TK	Complete response as per MLN criteria	Belgium, France, Germany, Hong Kong, Italy, Japan, Netherlands, Portugal, Republic of Korea, Singapore, Spain, Sweden, Turkey, United Kingdom, United States	
Imatinib, TKI; Ruxolitinib, JAK-inhibitor (NCT00044304)	oral	Efficacy of Tyrosine Kinase Inhibition in Reducing Eosinophilia in Patients With Myeloid and/or Steroid-Refractory Hypereosinophilic Syndrome	Phase 2 (open-label)	September 2002 – January 2026	60 participants (≥ 2 years for imatinib and ≥ 18 years for ruxolitinib)	Peripheral blood absolute eosinophil count	United States	
Mepolizumab, anti-IL-5 mAb (NCT04965636)	sc	A Phase 3, 52-week, Open-label, Single Arm Study to Investigate the Efficacy and Safety of Mepolizumab SC in Participants Aged 6 to 17 Years With Hypereosinophilic Syndrome (SPHERE)	Phase 3

(open-label)

	July 2022 – September 2024	25 participants (6–17 years)	Frequency of HES flares	Argentina, Spain, United States	
Pemigatinib	oral	A Phase 2, Open-Label, Monotherapy, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib (INCB054828) in Subjects With Myeloid/Lymphoid Neoplasms With FGFR1 Rearrangement (FIGHT-203)	Phase 2 (open-label)	April 2017 – July 2024	47 participants (≥ 18 years)	Complete response as per MLN criteria	Austria, Belgium, Canada, France, Germany, Italy, Japan, Spain, Switzerland, United Kingdom, United States	
Ruxolitinib, JAK inhibitor (NCT03801434)	oral	Phase 2 Study of Ruxolitinib in Idiopathic Hypereosinophilic Syndrome and Primary Eosinophilic Disorders	Phase 2 (open- label)	November 2019 – November 2025	25 participants (≥ 18 years)	Overall hematologic response rate	United States	
Abbreviations: HES, hypereosinophilic syndrome; mAb, monoclonal abbreviations; M/LN-eo-TK, myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions; r, receptor; sc, subcutaneously; TKI, tyrosine kinase inhibitor

a Only active clinical trials as clin-trial.gov are reported

Modified from Tzankov et al. [20] and Wang et al.[2]

Chronic eosinophilic leukemia

CEL is a heterogenous disorder that is characterized by persistent eosinophilia while not meeting criteria for other genetically defined entities (Table 4). Diagnostic criteria further mandate abnormal BM morphology (e.g., dysplastic megakaryocytes with or without dysplastic features in other lineages or increased blasts ≥ 5% in the BM and/or ≥ 2% in the PB) as well as demonstration of a clonal cytogenetic abnormality and/or somatic mutation(s) [2, 4, 59]. Additionally, the BM typically displays significant fibrosis associated with an eosinophilic infiltrate [59]. Most of the reported mutations have been identified in genes associated with DNA methylation and chromatin modification, including ASXL1, TET2, EZH2, and DNMT3A [59–61]. However, mutations have also been observed in other genes such as SRSF2, TP53, and SETBP1 [59, 60]. One recent study detected the STAT5B N642H mutation as a recurrent event (1.6%) in patients referred with a diagnosis of eosinophilia, including those who would have otherwise been diagnosed with iHES [62]. In a separate investigation conducted by the French referral center for hypereosinophilic syndromes (CEREO), 64 individuals with TK fusion-negative HE underwent screening via NGS using a customized panel comprising 149 genes to detect somatic mutations. Among these, 35 patients (54%) exhibited at least one mutation within the JAK-STAT pathway, encompassing mutations in STAT5B (n = 18; N642H, n = 13), JAK1 (indels in exon13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Additionally, previously unreported somatic mutations were identified in JAK2, JAK1, STAT5B, and STAT5A, with three patients sharing the same STAT5A V707fs mutation [63]. Exclusion of systemic mastocytosis by high sensitivity molecular studies (e.g., digital PCR) is recommend. Due to the lack of specific treatment options and rapid transformation into secondary blast phase, prognosis of CEL is generally poor. In a case series of 10 patients reported by Wang et al., the median overall survival was only 22 months with 5 patients developing AML after a median of 20 months from diagnosis [64]. Consensus on the optimal frontline treatment for CEL remains elusive [21]. While corticosteroids, hydroxyurea, PEG-IFN-α, and imatinib have been employed to mitigate leukocytosis and HE, their effectiveness tends to be temporary. PEG-IFN-α has shown partial success in inducing hematologic and molecular/cytogenetic responses, along with ameliorating end-organ damage, also in patients resistant or refractory to corticosteroids and hydroxyurea [65–67]. Hematologic improvements from empiric imatinib usage, in the absence of a specific tyrosine kinase target, may primarily result from nonspecific myelosuppression. Hypomethylating agents and/or alloHCT are further treatment options.Table 4 Diagnostic criteria for idiopathic hypereosinophilic syndrome as per International Consensus Classification [4]

1. Persistent peripheral blood hypereosinophilia (eosinophil count ≥ 1.5 × 109/L and ≥ 10% eosinophils) a	
2. Organ damage and/or dysfunction attributable to tissue eosinophilic infiltrate b	
3. No evidence of a reactive, well-defined autoimmune disease or neoplastic condition/disorder underlying the hypereosinophilia	
4. Exclusion of lymphocyte variant hypereosinophilic syndrome	
5. Bone marrow morphologically within normal limits except for increased eosinophils	
6. No molecular genetic clonal abnormality, with the caveat of clonal hematopoiesis of indeterminate potential (CHIP)	
The diagnosis of iHES requires all 6 criteria

a Preferably a minimal duration of 6 months if documentation is available. In patients with end-organ damage requiring prompt treatment, the diagnosis can be established after 4 weeks or with a repeated complete blood count after a minimum interval of 2 weeks

b Hypereosinophilia of uncertain significance has no tissue damage, but otherwise fulfills the same diagnostic criteria

c An abnormal T-cell population must be detected by flow cytometry with or without T-cell receptor clonality by molecular analysis

Idiopathic hypereosinophilic syndrome

iHES is characterized by (i) persistent HE in PB (≥ 6 months or ≥ 2 weeks if end-organ damage necessitates immediate treatment), (ii) end-organ damage caused by eosinophilic infiltration and (iii) absence of a reactive, familial or neoplastic etiology, as well as exclusion of L-HES (Table 5) [4]. L-HES is a distinct subtype, characterized by aberrant clonal T-cell populations that produce eosinophil-promoting cytokines [17]. In contrast to CEL, the BM of patients with iHES appears normal with age-adjusted cellularity and regular eosinophils with bilobated nuclei [22, 59]. However, a subset of eosinophils may also display slight irregularities such as uneven cytoplasmic granulation and hypersegmentation [59]. As opposed to patients with MLN-TK, increased levels of serum tryptase are usually absent in iHES thus making it suitable as a rapid and cost-effective screening tool. The presence of genetic alterations should be ruled out by molecular studies (including PCR for the most frequent aberrations such as FIP1L1:PDGFRA, FISH analysis for other recurrent fusion genes and PCR for KIT D816V and JAK2 V617F). If negative, NGS with the caveat of CHIP mutations (e.g., DNMT3A, TET2 and ASXL1, usually present as single mutations with a low variant allele frequency) or RNA-sequencing might be applied in patients highly suspicious of clonal disease [2, 4, 59, 68].Table 5 Diagnostic criteria for chronic eosinophilic leukemia (CEL) as per International Consensus Classification [4]

1. Peripheral blood hypereosinophilia (eosinophil count ≥ 1.5 × 109/L and eosinophils ≥ 10% of white blood cells)	
2. Blasts constitute < 20% cells in peripheral blood and bone marrow, not meeting other diagnostic criteria for AMLa	
3. No tyrosine kinase gene fusion including BCR::ABL1, other ABL1, PDGFRA, PDGFRB, FGFR1, JAK2, or FLT3 fusions	
4. Not meeting criteria for other well-defined MPN; chronic myelomonocytic leukemia, or SM b	
5. Bone marrow shows increased cellularity with dysplastic megakaryocytes with or without dysplastic features in other lineages and often significant fibrosis, associated with an eosinophilic infiltrate or increased blasts ≥ 5% in the bone marrow and/or ≥ 2% in the peripheral blood	
6. Demonstration of a clonal cytogenetic abnormality and/or somatic mutation(s) c	
The diagnosis of CEL requires all 6 criteria

a AML with recurrent genetic abnormalities with < 20% blasts is excluded

b Eosinophila can be seen in association with SM. However, “true” CEL may occur as systemic mastocytosis associated with a myeloid neoplasms

c In the absence of a clonal cytogenetic abnormality and/or somatic mutation(s) or increased blasts, bone marrow findings supportive of the diagnosis will suffice in the presence of persistent eosinophilia, provided other causes of eosinophilia having been excluded

The clinical presentation of iHES is heterogeneous and varies in the pattern and extent of single, multi-organ and potentially life-threatening organ damage. In cases with multi-organ involvement (e.g., lung, cardiac, gastrointestinal, cutaneous manifestations), the main differential diagnosis is EGPA. iHES or ANCA-negative EGPA can lead to cardiac involvement in up to 60% of affected patients, thus having a potential impact on morbidity and mortality [69–72]. Cardiac involvement often occurs early in the course of iHES or EGPA (predominantly in ANCA-negative EGPA patients) [9–13]. The onset of restrictive cardiomyopathy is associated with early death [73]. Clinical examination, electrocardiography, and cardiac biomarkers like N-terminal prohormone B-type natriuretic peptide (NT-proBNP) and troponin I provide important information. While conventional transthoracic echocardiography and endomyocardial biopsy have long been recognized as the standard diagnostic procedures, their sensitivity for early detection of myocardial infiltration/fibrosis is limited [71, 74–76]. Cardiac magnetic resonance imaging (MRI) has emerged as a valuable alternative imaging modality, providing non-invasive assessment of both structural and functional changes. In a study involving 62 patients with iHES, abnormal findings of cardiac MRI were correlated with elevated cardiac biomarkers and the pattern of organ involvement, indicating a risk of life-threatening cardiac events. Over a median follow-up of 108 months, 24% of patients experienced cardiac events, with the majority showing abnormal cardiac MRI and elevated biomarkers [77]. Accurate diagnosis of iHES, with confirmed exclusion of clonal eosinophilia, usually indicates a less aggressive disease course, with mortality rates ranging from 10–15% according to historical cohorts [59, 78–80].

Systemic corticosteroids are pivotal in treating patients with iHES [81]. Their usage is also highly informative for the distinction between reactive and clonal eosinophilia as there is usually no sustained effect of steroids on eosinophil counts in clonal disease. However, despite their effectiveness in responsive patients, prolonged use of high doses of systemic corticosteroids is often limited by severe adverse effects and long-term consequences. Therefore, the treatment goal is to gradually taper corticosteroids to a dose < 7 mg (prednisolone equivalent) per day. In cases of aggressive disease progression affecting multiple organs, a high "Five-factor-score" or resistance to systemic corticosteroids, early initiation of additional immunomodulatory agents like cyclophosphamide is highly recommended following re-evaluation for eosinophil clonality.

In a randomized, multicenter, double-blind, placebo-controlled, phase 3 trial, the treatment of iHES patients with mepolizumab (300 mg subcutaneously every month for a total of 32 weeks) significantly reduced the occurrence of flares (defined as worsening of HES-related symptoms necessitating therapy escalation or ≥ 2 courses of blinded rescue oral corticosteroids) and fatigue [82]. The open-label extension study (300 mg subcutaneously every month for a total of 20 weeks) demonstrated a continued control of disease flares (annualized flare rate 0.14 vs. 0.37 for placebo), a mean reduced corticosteroid dose ≥ 50% in 28% of patients and stabilized reduced blood eosinophil counts [83]. The most frequently reported flare symptoms were constitutional (94% of flares), dermatological (82% of flares) and respiratory (72% of flares) [84]. Symptom improvement was seen across all symptom groups except for skin and was highest for breathing symptoms [85]. A post hoc analysis revealed that treatment of mepolizumab was effective (flare outcome, symptom burden) independently of baseline eosinophil counts (minimal eosinophil count 1 × 109/L) and IL-5 levels [86]. Furthermore, poorly controlled symptoms in patients with iHES could be alleviated irrespective of baseline therapy [87].

Benralizumab, a monoclonal antibody against the IL-5 receptor (IL5R) which is expressed by eosinophils, showed promising results in a randomized, double-blind, placebo-controlled, phase 2 trial when administered in a series of three-monthly subcutaneous injections at a dose of 30 mg. Benralizumab met the primary end point with at least 50% absolute eosinophil count reduction at week 12 in 90% of patients (vs. 30% for placebo). Subsequent open-label phase findings showed clinical and hematologic responses in 89% of patients. Notably, 64% of patients were able to reduce background therapies including systemic corticosteroids [88]. Benralizumab is currently undergoing a multicenter, randomized, double-blind, placebo-controlled, 24-week phase 3 study with an open-label extension (NCT04191304). Primary endpoint is the time to first HES worsening/flares. Benralizumab is approved as an add-on maintenance treatment in patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus long-acting β-agonists [89, 90].

Depemokimab is an anti-IL-5 monoclonal antibody that is currently studied in a multicenter, randomized, double-blind, placebo-controlled, 52-week phase 3 study (NCT05334368). It is administered subcutaneously every 26 weeks at a dose of 200 mg as a result from an encouraging phase 1 study in patients with asthma, where it showed an extended half-life, supporting less frequent dosing. [91]. As primary outcome, frequency of HES flares is measured. Consequently, the non-inferiority of switching participants who have benefitted from mepolizumab or benralizumab to depemokimab will explicitly be assessed in another ongoing clinical trial (NCT04718389).

Reslizumab, an anti-IL-5 monoclonal antibody, was investigated in four individuals with iHES [92, 93]. Patients were administered a single intravenous dose of 1 mg/kg. Following drug administration, two patients exhibited a favorable response with a decrease in PB eosinophils to normal levels within 48 h; eosinophil counts remained suppressed for up to 12 weeks post-treatment. The response was independent of IL-5 levels. In another study involving ten patients with EGPA, reslizumab (at a dose of 3 mg/kg) led to a significant reduction in daily oral corticosteroid usage [94]. On basis of two phase 3 trials, reslizumab was approved for add-on therapy in patients with severe eosinophilic asthma inadequately controlled despite high-dose inhaled corticosteroids plus another medicinal product for maintenance treatment (NCT01287039, NCT01285323) [95]. No clinical trial for evaluation in patients with iHES is currently listed for reslizumab. However, considering its intravenous administration based on body weight, as opposed to other anti-IL5(R) monoclonal antibodies, this drug may hold promise for patients with high BMI who have not responded to previous therapies.

Dexpramipexole, a synthetic aminobenzothiazole, was administered to 10 patients with iHES at a dose of 150 mg orally twice daily [96]. Results showed that 40% of patients experienced a reduction of ≥ 50% in their corticosteroid dose, while 30% exhibited a decline in PB eosinophils to < 0.01 × 109/L with a depletion of eosinophils in the BM. Currently, there is no ongoing clinical trial enrolling patients with iHES.

Lirentelimab, a monoclonal antibody targeting sialic acid-binding immunoglobulin-like lectin (Siglec)-8, has been studied in various conditions including allergic conjunctivitis, chronic spontaneous/inducible urticaria, eosinophilic gastritis/duodenitis and indolent systemic mastocytosis [97–100]. These studies have demonstrated significant reductions in eosinophils in both PB and gastrointestinal tissue. Consistent with these findings, patients with ISM treated with lirentelimab showed rapid and specific decreases in eosinophil counts within one day of treatment, which were sustained throughout the 30-day treatment period. Currently, there is no ongoing clinical trial enrolling patients with iHES.

Navigating future challenges and directions

Eosinophilic disorders encompass a spectrum of conditions ranging from reactive causes to clonal neoplasms. One pivotal diagnostic challenge lies in distinguishing between patients with iHES and ANCA-negative EGPA given the overlapping clinical, radiologic, and histologic features, and biomarker profile [101–104]. While the "5-Factor-Score" serves as a validated tool for predicting outcomes and guiding treatment approaches in EGPA, biomarkers predicting disease activity and prognosis remain largely elusive in iHES. The range (single vs. multiple organ involvement) and severity (constitutional versus cardiac symptoms) of possible organ manifestations complicates accurate assessment of overall disease activity as no specialized clinical, radiological and pathological assessment tools are currently defined. To date, primary endpoints in clinical settings frequently involve assessing the frequency of flares defined by worsening of HES-related symptoms necessitating therapy escalation, such as systemic corticosteroid administration. Evaluation based solely on blood eosinophil counts and tissue eosinophil infiltration is constrained, as symptoms and active disease complications may persist despite absence of eosinophilia, and validated thresholds for tissue eosinophilia remain lacking across most organ systems. Moreover, the absence of patient-reported outcome instruments validated for application in iHES limits the comprehensive assessment of health-related quality of life. With an expanding landscape of (approved) novel treatment options, further research regarding the optimal selection of initial therapy, potential factors contributing to treatment failure, and alternative therapeutic options for patients encountering incomplete response or disease progression is warranted.

With the advent and widespread application of NGS studies, individuals previously categorized as iHES may also undergo reclassification based on the mutational profile. However, expensive molecular analyses may be dispensable in clinically clear reactive cases (e.g., rapid remission on oral steroids) and a thorough interpretation of mutational alterations is warranted with the caveat of CHIP mutations as confounding factors [26]. Future priorities for patients with clonal eosinophilia will include the need for standard response criteria, the incorporation and harmonization of standard cytogenetic/FISH and molecular monitoring of fusion genes into clinical decision-making, refining dosing regimens, and exploring novel therapeutic modalities such as hypomethylating agents in CEL [21].

Conclusions

In summary, our manuscript offers a thorough exploration of the evolving therapeutic options for eosinophilic disorders, covering established treatments as well as novel agents under investigation in clinical trials in reactive, clonal and idiopathic eosinophilic disorders. While patients with PDGFRA and PDGFRB fusion genes, who are receiving imatinib treatment, generally have a favorable prognosis, the advent of FGFR1 inhibitors offers hope for individuals with clonal eosinophilia and FGFR1 fusion genes. New IL-5(R) antibodies mitigate morbidity and, consequently also mortality in cases of secondary and idiopathic eosinophilia. It is to emphasize that diagnosis and treatment of eosinophilic disorders rely on a multidisciplinary approach. Fostering collaborative research endeavors and interdisciplinary partnerships will help to gain new insights into the pathogenesis, diagnosis, and management of these complex disorders.

Author contributions

All authors contributed to concept and design. All authors were involved in manuscript writing. All authors contributed to critical revision of the manuscript and for important intellectual content. All authors read and approved the final manuscript. All authors are accountable for all aspects of the work.

Funding

Open Access funding enabled and organized by Projekt DEAL.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Competing interests

JL and GM declare no competing interest. AR received consulting fees, honoraria and research funding from Abbvie, AOP Orphan Pharmaceuticals, Blueprint Medicines Corporation, BMS, GlaxoSmithKline, Incyte and Novartis and was member on an entity's Board of Directors or advisory committees of Abbvie, AOP Orphan Pharmaceuticals, Blueprint Medicines, BMS, GSK, Incyte and Novartis. JS received consulting fees from Blueprint Medicines, Astra Zeneca and GlaxoSmithKline, honoraria from Blueprint Medicines, GlaxoSmithKline and Novartis and research funding from GlaxoSmithKline, Blueprint Medicines and Cogent.

Competing interest

JL and GM declare no competing interest. AR received consulting fees, honoraria and research funding from Abbvie, AOP Orphan Pharmaceuticals, Blueprint Medicines Corporation, BMS, GlaxoSmithKline, Incyte and Novartis and was member on an entity's Board of Directors or advisory committees of Abbvie, AOP Orphan Pharmaceuticals, Blueprint Medicines, BMS, GSK, Incyte and Novartis. JS received consulting fees from Blueprint Medicines, Astra Zeneca and GlaxoSmithKline, honoraria from Blueprint Medicines, GlaxoSmithKline and Novartis and research funding from GlaxoSmithKline, Blueprint Medicines and Cogent.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Gotlib J World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management Am J Hematol 2017 92 11 1243 1259 10.1002/ajh.24880 29044676
Gotlib J. World Health Organization-defined eosinophilic disorders: 2017 update on diagnosis, risk stratification, and management. Am J Hematol. 2017;92(11):1243–59.29044676
2. Wang SA Orazi A Gotlib J Reiter A Tzankov A Hasserjian RP The international consensus classification of eosinophilic disorders and systemic mastocytosis Am J Hematol 2023 98 8 1286 1306 10.1002/ajh.26966 37283522
Wang SA, Orazi A, Gotlib J, Reiter A, Tzankov A, Hasserjian RP, et al. The international consensus classification of eosinophilic disorders and systemic mastocytosis. Am J Hematol. 2023;98(8):1286–306.37283522
3. Khoury JD Solary E Abla O Akkari Y Alaggio R Apperley JF The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic Dendritic Neoplasms Leukemia. 2022 36 1703 19 10.1038/s41375-022-01613-1 35732831
Khoury JD, Solary E, Abla O, Akkari Y, Alaggio R, Apperley JF, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic Dendritic Neoplasms. Leukemia. 2022;36:1703–19.35732831
4. Arber DA Orazi A Hasserjian RP Borowitz MJ Calvo KR Kvasnicka HM International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data Blood 2022 140 11 1200 1228 10.1182/blood.2022015850 35767897
Arber DA, Orazi A, Hasserjian RP, Borowitz MJ, Calvo KR, Kvasnicka HM, et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: integrating morphologic, clinical, and genomic data. Blood. 2022;140(11):1200–28.35767897
5. Grayson PC Ponte C Suppiah R Robson JC Craven A Judge A 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis With Polyangiitis Arthritis Rheumatol 2022 74 3 386 392 10.1002/art.41982 35106968
Grayson PC, Ponte C, Suppiah R, Robson JC, Craven A, Judge A, et al. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis With Polyangiitis. Arthritis Rheumatol. 2022;74(3):386–92.35106968
6. Emmi G Bettiol A Gelain E Bajema IM Berti A Burns S Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis Nat Rev Rheumatol 2023 19 6 378 393 10.1038/s41584-023-00958-w 37161084
Emmi G, Bettiol A, Gelain E, Bajema IM, Berti A, Burns S, et al. Evidence-Based Guideline for the diagnosis and management of eosinophilic granulomatosis with polyangiitis. Nat Rev Rheumatol. 2023;19(6):378–93.37161084
7. Trivioli G Marquez A Martorana D Tesi M Kronbichler A Lyons PA Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management Nat Rev Rheumatol 2022 18 10 559 574 10.1038/s41584-022-00819-y 36109667
Trivioli G, Marquez A, Martorana D, Tesi M, Kronbichler A, Lyons PA, et al. Genetics of ANCA-associated vasculitis: role in pathogenesis, classification and management. Nat Rev Rheumatol. 2022;18(10):559–74.36109667
8. Lyons PA Peters JE Alberici F Liley J Coulson RMR Astle W Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status Nat Commun 2019 10 1 5120 10.1038/s41467-019-12515-9 31719529
Lyons PA, Peters JE, Alberici F, Liley J, Coulson RMR, Astle W, et al. Genome-wide association study of eosinophilic granulomatosis with polyangiitis reveals genomic loci stratified by ANCA status. Nat Commun. 2019;10(1):5120.31719529
9. Sablé-Fourtassou R Cohen P Mahr A Pagnoux C Mouthon L Jayne D Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome Ann Intern Med 2005 143 9 632 638 10.7326/0003-4819-143-9-200511010-00006 16263885
Sablé-Fourtassou R, Cohen P, Mahr A, Pagnoux C, Mouthon L, Jayne D, et al. Antineutrophil cytoplasmic antibodies and the Churg-Strauss syndrome. Ann Intern Med. 2005;143(9):632–8.16263885
10. Sinico RA Di Toma L Maggiore U Bottero P Radice A Tosoni C Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome Arthritis Rheum 2005 52 9 2926 2935 10.1002/art.21250 16142760
Sinico RA, Di Toma L, Maggiore U, Bottero P, Radice A, Tosoni C, et al. Prevalence and clinical significance of antineutrophil cytoplasmic antibodies in Churg-Strauss syndrome. Arthritis Rheum. 2005;52(9):2926–35.16142760
11. Sada KE Amano K Uehara R Yamamura M Arimura Y Nakamura Y A nationwide survey on the epidemiology and clinical features of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) in Japan Mod Rheumatol 2014 24 4 640 644 10.3109/14397595.2013.857582 24289197
Sada KE, Amano K, Uehara R, Yamamura M, Arimura Y, Nakamura Y, et al. A nationwide survey on the epidemiology and clinical features of eosinophilic granulomatosis with polyangiitis (Churg-Strauss) in Japan. Mod Rheumatol. 2014;24(4):640–4.24289197
12. Comarmond C Pagnoux C Khellaf M Cordier JF Hamidou M Viallard JF Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort Arthritis Rheum 2013 65 1 270 281 10.1002/art.37721 23044708
Comarmond C, Pagnoux C, Khellaf M, Cordier JF, Hamidou M, Viallard JF, et al. Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): clinical characteristics and long-term followup of the 383 patients enrolled in the French Vasculitis Study Group cohort. Arthritis Rheum. 2013;65(1):270–81.23044708
13. Healy B Bibby S Steele R Weatherall M Nelson H Beasley R Antineutrophil cytoplasmic autoantibodies and myeloperoxidase autoantibodies in clinical expression of Churg-Strauss syndrome The Journal of allergy and clinical immunology. 2013 131 571-6.e1-6 10.1016/j.jaci.2012.05.058 22920496
Healy B, Bibby S, Steele R, Weatherall M, Nelson H, Beasley R. Antineutrophil cytoplasmic autoantibodies and myeloperoxidase autoantibodies in clinical expression of Churg-Strauss syndrome. The Journal of allergy and clinical immunology. 2013;131:571-6.e1-6.22920496
14. Wechsler ME Akuthota P Jayne D Khoury P Klion A Langford CA Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis N Engl J Med 2017 376 20 1921 1932 10.1056/NEJMoa1702079 28514601
Wechsler ME, Akuthota P, Jayne D, Khoury P, Klion A, Langford CA, et al. Mepolizumab or Placebo for Eosinophilic Granulomatosis with Polyangiitis. N Engl J Med. 2017;376(20):1921–32.28514601
15. Larsen RL Savage NM How I investigate Eosinophilia Int J Lab Hematol 2019 41 2 153 161 10.1111/ijlh.12955 30499630
Larsen RL, Savage NM. How I investigate Eosinophilia. Int J Lab Hematol. 2019;41(2):153–61.30499630
16. Arber DA Orazi A Hasserjian R Thiele J Borowitz MJ Le Beau MM The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia Blood 2016 127 20 2391 2405 10.1182/blood-2016-03-643544 27069254
Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127(20):2391–405.27069254
17. Reiter A Gotlib J Myeloid neoplasms with eosinophilia Blood 2017 129 6 704 714 10.1182/blood-2016-10-695973 28028030
Reiter A, Gotlib J. Myeloid neoplasms with eosinophilia. Blood. 2017;129(6):704–14.28028030
18. Metzgeroth G Steiner L Naumann N Lübke J Kreil S Fabarius A Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: reevaluation of the defining characteristics in a registry-based cohort Leukemia 2023 37 9 1860 1867 10.1038/s41375-023-01958-1 37454239
Metzgeroth G, Steiner L, Naumann N, Lübke J, Kreil S, Fabarius A, et al. Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions: reevaluation of the defining characteristics in a registry-based cohort. Leukemia. 2023;37(9):1860–7.37454239
19. Klion AD Noel P Akin C Law MA Gilliland DG Cools J Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness Blood 2003 101 12 4660 4666 10.1182/blood-2003-01-0006 12676775
Klion AD, Noel P, Akin C, Law MA, Gilliland DG, Cools J, et al. Elevated serum tryptase levels identify a subset of patients with a myeloproliferative variant of idiopathic hypereosinophilic syndrome associated with tissue fibrosis, poor prognosis, and imatinib responsiveness. Blood. 2003;101(12):4660–6.12676775
20. Tzankov A Reichard KK Hasserjian RP Arber DA Orazi A Wang SA Updates on eosinophilic disorders Virchows Arch 2023 482 1 85 97 10.1007/s00428-022-03402-8 36068374
Tzankov A, Reichard KK, Hasserjian RP, Arber DA, Orazi A, Wang SA. Updates on eosinophilic disorders. Virchows Arch. 2023;482(1):85–97.36068374
21. Gotlib J Available and emerging therapies for bona fide advanced systemic mastocytosis and primary eosinophilic neoplasms Hematology Am Soc Hematol Educ Program 2022 2022 1 34 46 10.1182/hematology.2022000368 36485158
Gotlib J. Available and emerging therapies for bona fide advanced systemic mastocytosis and primary eosinophilic neoplasms. Hematology Am Soc Hematol Educ Program. 2022;2022(1):34–46.36485158
22. Schwaab J Jawhar M Naumann N Schmitt-Graeff A Fabarius A Horny HP Diagnostic challenges in the work up of hypereosinophilia: pitfalls in bone marrow core biopsy interpretation Ann Hematol 2016 95 4 557 562 10.1007/s00277-016-2598-x 26797429
Schwaab J, Jawhar M, Naumann N, Schmitt-Graeff A, Fabarius A, Horny HP, et al. Diagnostic challenges in the work up of hypereosinophilia: pitfalls in bone marrow core biopsy interpretation. Ann Hematol. 2016;95(4):557–62.26797429
23. Naumann N Lübke J Baumann S Schwaab J Hoffmann O Kreil S Adverse Prognostic Impact of the KIT D816V Transcriptional Activity in Advanced Systemic Mastocytosis Int J Mol Sci 2021 22 5 2562 10.3390/ijms22052562 33806359
Naumann N, Lübke J, Baumann S, Schwaab J, Hoffmann O, Kreil S, et al. Adverse Prognostic Impact of the KIT D816V Transcriptional Activity in Advanced Systemic Mastocytosis. Int J Mol Sci. 2021;22(5):2562.33806359
24. Schwaab J Cabral do OHN, Naumann N, Jawhar M, Weiß C, Metzgeroth G, Importance of adequate diagnostic work-up for correct diagnosis of advanced systemic mastocytosis J Allergy Clin Immunol Pract. 2020 8 3121-7 10.1016/j.jaip.2020.05.005 32422371
Schwaab J, Cabral do OHN, Naumann N, Jawhar M, Weiß C, Metzgeroth G, et al. Importance of adequate diagnostic work-up for correct diagnosis of advanced systemic mastocytosis. J Allergy Clin Immunol Pract. 2020;8:3121–7.32422371
25. Jawhar M Schwaab J Horny HP Sotlar K Naumann N Fabarius A Impact of centralized evaluation of bone marrow histology in systemic mastocytosis Eur J Clin Invest 2016 46 5 392 397 10.1111/eci.12607 26914980
Jawhar M, Schwaab J, Horny HP, Sotlar K, Naumann N, Fabarius A, et al. Impact of centralized evaluation of bone marrow histology in systemic mastocytosis. Eur J Clin Invest. 2016;46(5):392–7.26914980
26. Schwaab J Umbach R Metzgeroth G Naumann N Jawhar M Sotlar K KIT D816V and JAK2 V617F mutations are seen recurrently in hypereosinophilia of unknown significance Am J Hematol 2015 90 9 774 777 10.1002/ajh.24075 26017288
Schwaab J, Umbach R, Metzgeroth G, Naumann N, Jawhar M, Sotlar K, et al. KIT D816V and JAK2 V617F mutations are seen recurrently in hypereosinophilia of unknown significance. Am J Hematol. 2015;90(9):774–7.26017288
27. Erben P Schwaab J Metzgeroth G Horny HP Jawhar M Sotlar K The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis Ann Hematol 2014 93 1 81 88 10.1007/s00277-013-1964-1 24281161
Erben P, Schwaab J, Metzgeroth G, Horny HP, Jawhar M, Sotlar K, et al. The KIT D816V expressed allele burden for diagnosis and disease monitoring of systemic mastocytosis. Ann Hematol. 2014;93(1):81–8.24281161
28. Gerds AT Gotlib J Bose P Deininger MW Dunbar A Elshoury A Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology J Natl Compr Canc Netw. 2020 18 1248 69 10.6004/jnccn.2020.0042 32886902
Gerds AT, Gotlib J, Bose P, Deininger MW, Dunbar A, Elshoury A, et al. Myeloid/Lymphoid Neoplasms with Eosinophilia and TK Fusion Genes, Version 3.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2020;18:1248–69.32886902
29. Klion AD Robyn J Akin C Noel P Brown M Law M Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome Blood 2004 103 2 473 478 10.1182/blood-2003-08-2798 14504092
Klion AD, Robyn J, Akin C, Noel P, Brown M, Law M, et al. Molecular remission and reversal of myelofibrosis in response to imatinib mesylate treatment in patients with the myeloproliferative variant of hypereosinophilic syndrome. Blood. 2004;103(2):473–8.14504092
30. Pardanani A Ketterling RP Li CY Patnaik MM Wolanskyj AP Elliott MA FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature Leuk Res 2006 30 8 965 970 10.1016/j.leukres.2005.11.011 16406016
Pardanani A, Ketterling RP, Li CY, Patnaik MM, Wolanskyj AP, Elliott MA, et al. FIP1L1-PDGFRA in eosinophilic disorders: prevalence in routine clinical practice, long-term experience with imatinib therapy, and a critical review of the literature. Leuk Res. 2006;30(8):965–70.16406016
31. Jovanovic JV Score J Waghorn K Cilloni D Gottardi E Metzgeroth G 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 Blood 2007 109 11 4635 4640 10.1182/blood-2006-10-050054 17299092
Jovanovic JV, Score J, Waghorn K, Cilloni D, Gottardi E, Metzgeroth G, et al. 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. Blood. 2007;109(11):4635–40.17299092
32. Baccarani M Cilloni D Rondoni M Ottaviani E Messa F Merante S The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study Haematologica. 2007 92 1173 9 10.3324/haematol.11420 17666373
Baccarani M, Cilloni D, Rondoni M, Ottaviani E, Messa F, Merante S, et al. The efficacy of imatinib mesylate in patients with FIP1L1-PDGFRalpha-positive hypereosinophilic syndrome. Results of a multicenter prospective study. Haematologica. 2007;92:1173–9.17666373
33. Klion AD Robyn J Maric I Fu W Schmid L Lemery S Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing Blood 2007 110 10 3552 3556 10.1182/blood-2007-07-100164 17709602
Klion AD, Robyn J, Maric I, Fu W, Schmid L, Lemery S, et al. Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing. Blood. 2007;110(10):3552–6.17709602
34. David M Cross NC Burgstaller S Chase A Curtis C Dang R Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders Blood 2007 109 1 61 64 10.1182/blood-2006-05-024828 16960151
David M, Cross NC, Burgstaller S, Chase A, Curtis C, Dang R, et al. Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders. Blood. 2007;109(1):61–4.16960151
35. Pardanani A D'Souza A Knudson RA Hanson CA Ketterling RP Tefferi A Long-term follow-up of FIP1L1-PDGFRA-mutated patients with eosinophilia: survival and clinical outcome Leukemia 2012 26 11 2439 2441 10.1038/leu.2012.162 22705991
Pardanani A, D’Souza A, Knudson RA, Hanson CA, Ketterling RP, Tefferi A. Long-term follow-up of FIP1L1-PDGFRA-mutated patients with eosinophilia: survival and clinical outcome. Leukemia. 2012;26(11):2439–41.22705991
36. Cheah CY Burbury K Apperley JF Huguet F Pitini V Gardembas M Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib Blood 2014 123 23 3574 3577 10.1182/blood-2014-02-555607 24687085
Cheah CY, Burbury K, Apperley JF, Huguet F, Pitini V, Gardembas M, et al. Patients with myeloid malignancies bearing PDGFRB fusion genes achieve durable long-term remissions with imatinib. Blood. 2014;123(23):3574–7.24687085
37. Naumann N Schwaab J Metzgeroth G Jawhar M Haferlach C Gohring G Fusion of PDGFRB to MPRIP, CPSF6, and GOLGB1 in three patients with eosinophilia-associated myeloproliferative neoplasms Genes Chromosomes Cancer 2015 54 12 762 770 10.1002/gcc.22287 26355392
Naumann N, Schwaab J, Metzgeroth G, Jawhar M, Haferlach C, Gohring G, et al. Fusion of PDGFRB to MPRIP, CPSF6, and GOLGB1 in three patients with eosinophilia-associated myeloproliferative neoplasms. Genes Chromosomes Cancer. 2015;54(12):762–70.26355392
38. Jawhar M Naumann N Schwaab J Baurmann H Casper J Dang TA Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase Ann Hematol 2017 96 9 1463 1470 10.1007/s00277-017-3067-x 28725989
Jawhar M, Naumann N, Schwaab J, Baurmann H, Casper J, Dang TA, et al. Imatinib in myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRB in chronic or blast phase. Ann Hematol. 2017;96(9):1463–70.28725989
39. Rohmer J, Couteau-Chardon A, Trichereau J, Panel K, Gesquiere C, Ben Abdelali R, et al. Epidemiology, clinical picture and long-term outcomes of FIP1L1-PDGFRA-positive myeloid neoplasm with eosinophilia: Data from 151 patients. Am J Hematol. 2020;95(11):1314-23.
40. Metzgeroth G Schwaab J Naumann N Jawhar M Haferlach T Fabarius A Treatment-free remission in FIP1L1-PDGFRA-positive myeloid/lymphoid neoplasms with eosinophilia after imatinib discontinuation Blood Adv 2020 4 3 440 443 10.1182/bloodadvances.2019001111 31995156
Metzgeroth G, Schwaab J, Naumann N, Jawhar M, Haferlach T, Fabarius A, et al. Treatment-free remission in FIP1L1-PDGFRA-positive myeloid/lymphoid neoplasms with eosinophilia after imatinib discontinuation. Blood Adv. 2020;4(3):440–3.31995156
41. Metzgeroth G Erben P Martin H Mousset S Teichmann M Walz C Limited clinical activity of nilotinib and sorafenib in FIP1L1-PDGFRA positive chronic eosinophilic leukemia with imatinib-resistant T674I mutation Leukemia 2012 26 1 162 164 10.1038/leu.2011.181 21818111
Metzgeroth G, Erben P, Martin H, Mousset S, Teichmann M, Walz C, et al. Limited clinical activity of nilotinib and sorafenib in FIP1L1-PDGFRA positive chronic eosinophilic leukemia with imatinib-resistant T674I mutation. Leukemia. 2012;26(1):162–4.21818111
42. Jones RL Serrano C von Mehren M George S Heinrich MC Kang YK Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial Eur J Cancer 2021 145 132 142 10.1016/j.ejca.2020.12.008 33465704
Jones RL, Serrano C, von Mehren M, George S, Heinrich MC, Kang YK, et al. Avapritinib in unresectable or metastatic PDGFRA D842V-mutant gastrointestinal stromal tumours: Long-term efficacy and safety data from the NAVIGATOR phase I trial. Eur J Cancer. 2021;145:132–42.33465704
43. Heinrich MC Jones RL von Mehren M Schöffski P Serrano C Kang YK Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial Lancet Oncol 2020 21 7 935 946 10.1016/S1470-2045(20)30269-2 32615108
Heinrich MC, Jones RL, von Mehren M, Schöffski P, Serrano C, Kang YK, et al. Avapritinib in advanced PDGFRA D842V-mutant gastrointestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Lancet Oncol. 2020;21(7):935–46.32615108
44. Baer C Muehlbacher V Kern W Haferlach C Haferlach T Molecular genetic characterization of myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2 Haematologica 2018 103 8 e348 e350 10.3324/haematol.2017.187302 29567772
Baer C, Muehlbacher V, Kern W, Haferlach C, Haferlach T. Molecular genetic characterization of myeloid/lymphoid neoplasms associated with eosinophilia and rearrangement of PDGFRA, PDGFRB, FGFR1 or PCM1-JAK2. Haematologica. 2018;103(8):e348–50.29567772
45. Umino K Fujiwara SI Ikeda T Toda Y Ito S Mashima K Clinical outcomes of myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangement Hematology (Amsterdam, Netherlands) 2018 23 8 470 477 29486661
Umino K, Fujiwara SI, Ikeda T, Toda Y, Ito S, Mashima K, et al. Clinical outcomes of myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangement. Hematology (Amsterdam, Netherlands). 2018;23(8):470–7.29486661
46. Gotlib J Kiladjian J-J Vannucchi AM Rambaldi A Reiter A Shomali W A Phase 2 Study of Pemigatinib (FIGHT-203; INCB054828) in Patients with Myeloid/Lymphoid Neoplasms (MLNs) with Fibroblast Growth Factor Receptor 1 (FGFR1) Rearrangement (MLN FGFR1) [Abstract] Blood 2021 138 385 10.1182/blood-2021-148103
Gotlib J, Kiladjian J-J, Vannucchi AM, Rambaldi A, Reiter A, Shomali W, et al. A Phase 2 Study of Pemigatinib (FIGHT-203; INCB054828) in Patients with Myeloid/Lymphoid Neoplasms (MLNs) with Fibroblast Growth Factor Receptor 1 (FGFR1) Rearrangement (MLN FGFR1) [Abstract]. Blood. 2021;138:385.
47. Reiter A, Kiladjian J-J, Patel JM, Shomali W, Rambaldi A, Verstovsek S, et al. Deep and Durable Cytogenetic and Molecular Responses with Pemigatinib in Myeloid/Lymphoid Neoplasms with Fibroblast Growth Factor Receptor 1 Rearrangement: The Fight-203 Study [Abstract]. Blood. 2023.
48. Hernández-Boluda JC Pereira A Zinger N Gras L Martino R Nikolousis E Allogeneic hematopoietic cell transplantation in patients with myeloid/lymphoid neoplasm with FGFR1-rearrangement: a study of the Chronic Malignancies Working Party of EBMT Bone Marrow Transplant 2022 57 3 416 422 10.1038/s41409-021-01553-x 35066569
Hernández-Boluda JC, Pereira A, Zinger N, Gras L, Martino R, Nikolousis E, et al. Allogeneic hematopoietic cell transplantation in patients with myeloid/lymphoid neoplasm with FGFR1-rearrangement: a study of the Chronic Malignancies Working Party of EBMT. Bone Marrow Transplant. 2022;57(3):416–22.35066569
49. Kasbekar M Nardi V Dal Cin P Brunner AM Burke M Chen YB Targeted FGFR inhibition results in a durable remission in an FGFR1-driven myeloid neoplasm with eosinophilia Blood Adv 2020 4 13 3136 3140 10.1182/bloodadvances.2020002308 32649766
Kasbekar M, Nardi V, Dal Cin P, Brunner AM, Burke M, Chen YB, et al. Targeted FGFR inhibition results in a durable remission in an FGFR1-driven myeloid neoplasm with eosinophilia. Blood Adv. 2020;4(13):3136–40.32649766
50. Kiladjian J-J Shitara K Rosen LS Rha SY He A Oh D-Y A Phase 2 Study of Futibatinib (TAS-120) in Patients with Myeloid or Lymphoid Neoplasms Harboring Fibroblast Growth Factor Receptor (FGFR) 1 Rearrangements Blood 2021 138 3656 10.1182/blood-2021-150630
Kiladjian J-J, Shitara K, Rosen LS, Rha SY, He A, Oh D-Y, et al. A Phase 2 Study of Futibatinib (TAS-120) in Patients with Myeloid or Lymphoid Neoplasms Harboring Fibroblast Growth Factor Receptor (FGFR) 1 Rearrangements. Blood. 2021;138:3656.
51. Kaplan HG Jin R Bifulco CB Scanlan JM Corwin DR PCM1-JAK2 Fusion Tyrosine Kinase Gene-Related Neoplasia: A Systematic Review of the Clinical Literature Oncologist 2022 27 8 e661 e670 10.1093/oncolo/oyac072 35472244
Kaplan HG, Jin R, Bifulco CB, Scanlan JM, Corwin DR. PCM1-JAK2 Fusion Tyrosine Kinase Gene-Related Neoplasia: A Systematic Review of the Clinical Literature. Oncologist. 2022;27(8):e661–70.35472244
52. Jawhar M Naumann N Knut M Score J Ghazzawi M Schneider B Cytogenetically cryptic ZMYM2-FLT3 and DIAPH1-PDGFRB gene fusions in myeloid neoplasms with eosinophilia Leukemia 2017 31 10 2271 2273 10.1038/leu.2017.240 28751768
Jawhar M, Naumann N, Knut M, Score J, Ghazzawi M, Schneider B, et al. Cytogenetically cryptic ZMYM2-FLT3 and DIAPH1-PDGFRB gene fusions in myeloid neoplasms with eosinophilia. Leukemia. 2017;31(10):2271–3.28751768
53. Tang G, Tam W, Short NJ, Bose P, Wu D, Hurwitz SN, et al. Myeloid/lymphoid neoplasms with FLT3 rearrangement. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2021;34(9):1673–85.
54. Walz C Erben P Ritter M Bloor A Metzgeroth G Telford N Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3 Blood 2011 118 8 2239 2242 10.1182/blood-2011-03-343426 21705501
Walz C, Erben P, Ritter M, Bloor A, Metzgeroth G, Telford N, et al. Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3. Blood. 2011;118(8):2239–42.21705501
55. Chao AK Meyer JA Lee AG Hecht A Tarver T Van Ziffle J Fusion driven JMML: a novel CCDC88C-FLT3 fusion responsive to sorafenib identified by RNA sequencing Leukemia 2020 34 2 662 666 10.1038/s41375-019-0549-y 31511612
Chao AK, Meyer JA, Lee AG, Hecht A, Tarver T, Van Ziffle J, et al. Fusion driven JMML: a novel CCDC88C-FLT3 fusion responsive to sorafenib identified by RNA sequencing. Leukemia. 2020;34(2):662–6.31511612
56. Falchi L Mehrotra M Newberry KJ Lyle LM Lu G Patel KP ETV6-FLT3 fusion gene-positive, eosinophilia-associated myeloproliferative neoplasm successfully treated with sorafenib and allogeneic stem cell transplant Leukemia 2014 28 10 2090 2092 10.1038/leu.2014.168 24854988
Falchi L, Mehrotra M, Newberry KJ, Lyle LM, Lu G, Patel KP, et al. ETV6-FLT3 fusion gene-positive, eosinophilia-associated myeloproliferative neoplasm successfully treated with sorafenib and allogeneic stem cell transplant. Leukemia. 2014;28(10):2090–2.24854988
57. Munthe-Kaas MC Forthun RB Brendehaug A Eek AK Høysæter T Osnes LTN Partial Response to Sorafenib in a Child With a Myeloid/Lymphoid Neoplasm, Eosinophilia, and a ZMYM2-FLT3 Fusion J Pediatr Hematol Oncol 2021 43 4 e508 e511 10.1097/MPH.0000000000001890 32852395
Munthe-Kaas MC, Forthun RB, Brendehaug A, Eek AK, Høysæter T, Osnes LTN, et al. Partial Response to Sorafenib in a Child With a Myeloid/Lymphoid Neoplasm, Eosinophilia, and a ZMYM2-FLT3 Fusion. J Pediatr Hematol Oncol. 2021;43(4):e508–11.32852395
58. Schwaab J Naumann N Luebke J Jawhar M Somervaille TCP Williams MS Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1-JAK2, BCR-JAK2 and ETV6-ABL1 fusion genes Am J Hematol 2020 95 7 824 833 10.1002/ajh.25825 32279331
Schwaab J, Naumann N, Luebke J, Jawhar M, Somervaille TCP, Williams MS, et al. Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1-JAK2, BCR-JAK2 and ETV6-ABL1 fusion genes. Am J Hematol. 2020;95(7):824–33.32279331
59. Wang SA Hasserjian RP Tam W Tsai AG Geyer JT George TI Bone marrow morphology is a strong discriminator between chronic eosinophilic leukemia, not otherwise specified and reactive idiopathic hypereosinophilic syndrome Haematologica 2017 102 8 1352 1360 10.3324/haematol.2017.165340 28495918
Wang SA, Hasserjian RP, Tam W, Tsai AG, Geyer JT, George TI, et al. Bone marrow morphology is a strong discriminator between chronic eosinophilic leukemia, not otherwise specified and reactive idiopathic hypereosinophilic syndrome. Haematologica. 2017;102(8):1352–60.28495918
60. Morsia E Reichard K Pardanani A Tefferi A Gangat N WHO defined chronic eosinophilic leukemia, not otherwise specified (CEL, NOS): A contemporary series from the Mayo Clinic Am J Hematol 2020 95 7 E172 E174 10.1002/ajh.25811 32243620
Morsia E, Reichard K, Pardanani A, Tefferi A, Gangat N. WHO defined chronic eosinophilic leukemia, not otherwise specified (CEL, NOS): A contemporary series from the Mayo Clinic. Am J Hematol. 2020;95(7):E172–4.32243620
61. Wang SA Tam W Tsai AG Arber DA Hasserjian RP Geyer JT Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified Mod Pathol 2016 29 8 854 864 10.1038/modpathol.2016.75 27174585
Wang SA, Tam W, Tsai AG, Arber DA, Hasserjian RP, Geyer JT, et al. Targeted next-generation sequencing identifies a subset of idiopathic hypereosinophilic syndrome with features similar to chronic eosinophilic leukemia, not otherwise specified. Mod Pathol. 2016;29(8):854–64.27174585
62. Cross NCP Hoade Y Tapper WJ Carreno-Tarragona G Fanelli T Jawhar M Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia Leukemia 2019 33 2 415 425 10.1038/s41375-018-0342-3 30573779
Cross NCP, Hoade Y, Tapper WJ, Carreno-Tarragona G, Fanelli T, Jawhar M, et al. Recurrent activating STAT5B N642H mutation in myeloid neoplasms with eosinophilia. Leukemia. 2019;33(2):415–25.30573779
63. Groh M, Fenwarth L, Labro M, Boudry A, Fournier E, Wemeau M, et al. Involvement of the JAK-STAT pathway in the molecular landscape of tyrosine kinase fusion-negative hypereosinophilic syndromes: A nationwide CEREO study. Am J Hematol. 2024.
64. Helbig G Soja A Bartkowska-Chrobok A Kyrcz-Krzemien S Chronic eosinophilic leukemia-not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation Am J Hematol 2012 87 6 643 645 10.1002/ajh.23193 22473587
Helbig G, Soja A, Bartkowska-Chrobok A, Kyrcz-Krzemien S. Chronic eosinophilic leukemia-not otherwise specified has a poor prognosis with unresponsiveness to conventional treatment and high risk of acute transformation. Am J Hematol. 2012;87(6):643–5.22473587
65. Quiquandon I Claisse JF Capiod JC Delobel J Prin L alpha-Interferon and hypereosinophilic syndrome with trisomy 8: karyotypic remission Blood 1995 85 8 2284 2285 10.1182/blood.V85.8.2284.bloodjournal8582284 7718904
Quiquandon I, Claisse JF, Capiod JC, Delobel J, Prin L. alpha-Interferon and hypereosinophilic syndrome with trisomy 8: karyotypic remission. Blood. 1995;85(8):2284–5.7718904
66. Yamada O Kitahara K Imamura K Ozasa H Okada M Mizoguchi H Clinical and cytogenetic remission induced by interferon-alpha in a patient with chronic eosinophilic leukemia associated with a unique t(3;9;5) translocation Am J Hematol 1998 58 2 137 141 10.1002/(SICI)1096-8652(199806)58:2<137::AID-AJH9>3.0.CO;2-T 9625582
Yamada O, Kitahara K, Imamura K, Ozasa H, Okada M, Mizoguchi H. Clinical and cytogenetic remission induced by interferon-alpha in a patient with chronic eosinophilic leukemia associated with a unique t(3;9;5) translocation. Am J Hematol. 1998;58(2):137–41.9625582
67. Helbig G Stella-Holowiecka B Majewski M Lewandowska M Holowiecki J Interferon α induces a good molecular response in a patient with chronic eosinophilic leukemia (CEL) carrying the JAK2V617F point mutation Haematologica 2007 92 11 e118 e119 10.3324/haematol.11841 18024388
Helbig G, Stella-Holowiecka B, Majewski M, Lewandowska M, Holowiecki J. Interferon α induces a good molecular response in a patient with chronic eosinophilic leukemia (CEL) carrying the JAK2V617F point mutation. Haematologica. 2007;92(11):e118–9.18024388
68. Kelemen K Saft L Craig FE Orazi A Nakashima M Wertheim GB Eosinophilia/Hypereosinophilia in the Setting of Reactive and Idiopathic Causes, Well-Defined Myeloid or Lymphoid Leukemias, or Germline Disorders Am J Clin Pathol 2021 155 2 179 210 10.1093/ajcp/aqaa244 33367563
Kelemen K, Saft L, Craig FE, Orazi A, Nakashima M, Wertheim GB, et al. Eosinophilia/Hypereosinophilia in the Setting of Reactive and Idiopathic Causes, Well-Defined Myeloid or Lymphoid Leukemias, or Germline Disorders. Am J Clin Pathol. 2021;155(2):179–210.33367563
69. Anselmino M Novara M Bellone A Minelli M Cardiac involvement in hypereosinophilic syndrome J Cardiovasc Med (Hagerstown) 2011 12 12 919 921 10.2459/JCM.0b013e32833e57e1 20733510
Anselmino M, Novara M, Bellone A, Minelli M. Cardiac involvement in hypereosinophilic syndrome. J Cardiovasc Med (Hagerstown). 2011;12(12):919–21.20733510
70. Ogbogu PU Bochner BS Butterfield JH Gleich GJ Huss-Marp J Kahn JE Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy J Allergy Clin Immunol 2009 124 6 1319 25.e3 10.1016/j.jaci.2009.09.022 19910029
Ogbogu PU, Bochner BS, Butterfield JH, Gleich GJ, Huss-Marp J, Kahn JE, et al. Hypereosinophilic syndrome: a multicenter, retrospective analysis of clinical characteristics and response to therapy. J Allergy Clin Immunol. 2009;124(6):1319-25.e3.19910029
71. Ogbogu PU Rosing DR Horne MK 3rd Cardiovascular manifestations of hypereosinophilic syndromes Immunol Allergy Clin North Am 2007 27 3 457 475 10.1016/j.iac.2007.07.001 17868859
Ogbogu PU, Rosing DR, Horne MK 3rd. Cardiovascular manifestations of hypereosinophilic syndromes. Immunol Allergy Clin North Am. 2007;27(3):457–75.17868859
72. Cereda AF Pedrotti P De Capitani L Giannattasio C Roghi A Comprehensive evaluation of cardiac involvement in eosinophilic granulomatosis with polyangiitis (EGPA) with cardiac magnetic resonance Eur J Intern Med 2017 39 51 56 10.1016/j.ejim.2016.09.014 27727077
Cereda AF, Pedrotti P, De Capitani L, Giannattasio C, Roghi A. Comprehensive evaluation of cardiac involvement in eosinophilic granulomatosis with polyangiitis (EGPA) with cardiac magnetic resonance. Eur J Intern Med. 2017;39:51–6.27727077
73. Kleinfeldt T Nienaber CA Kische S Akin I Turan RG Körber T Cardiac manifestation of the hypereosinophilic syndrome: new insights Clin Res Cardiol 2010 99 7 419 427 10.1007/s00392-010-0144-8 20333409
Kleinfeldt T, Nienaber CA, Kische S, Akin I, Turan RG, Körber T, et al. Cardiac manifestation of the hypereosinophilic syndrome: new insights. Clin Res Cardiol. 2010;99(7):419–27.20333409
74. Mankad R Bonnichsen C Mankad S Hypereosinophilic syndrome: cardiac diagnosis and management Heart 2016 102 2 100 106 10.1136/heartjnl-2015-307959 26567231
Mankad R, Bonnichsen C, Mankad S. Hypereosinophilic syndrome: cardiac diagnosis and management. Heart. 2016;102(2):100–6.26567231
75. Srichai MB Junor C Rodriguez LL Stillman AE Grimm RA Lieber ML Clinical, imaging, and pathological characteristics of left ventricular thrombus: a comparison of contrast-enhanced magnetic resonance imaging, transthoracic echocardiography, and transesophageal echocardiography with surgical or pathological validation Am Heart J 2006 152 1 75 84 10.1016/j.ahj.2005.08.021 16824834
Srichai MB, Junor C, Rodriguez LL, Stillman AE, Grimm RA, Lieber ML, et al. Clinical, imaging, and pathological characteristics of left ventricular thrombus: a comparison of contrast-enhanced magnetic resonance imaging, transthoracic echocardiography, and transesophageal echocardiography with surgical or pathological validation. Am Heart J. 2006;152(1):75–84.16824834
76. Dennert RM van Paassen P Schalla S Kuznetsova T Alzand BS Staessen JA Cardiac involvement in Churg-Strauss syndrome Arthritis Rheum 2010 62 2 627 634 10.1002/art.27263 20112390
Dennert RM, van Paassen P, Schalla S, Kuznetsova T, Alzand BS, Staessen JA, et al. Cardiac involvement in Churg-Strauss syndrome. Arthritis Rheum. 2010;62(2):627–34.20112390
77. Lübke J, Hohneck A, Leipe J, Naumann N, Fabarius A, Hofmann W, et al. Diagnosis and Outcome of Patients with Idiopathic Hypereosinophilic Syndrome and Cardiac Involvement. ASH. 2023.
78. Pardanani A Lasho T Wassie E Finke C Zblewski D Hanson CA Predictors of survival in WHO-defined hypereosinophilic syndrome and idiopathic hypereosinophilia and the role of next-generation sequencing Leukemia 2016 30 9 1924 1926 10.1038/leu.2016.73 27125206
Pardanani A, Lasho T, Wassie E, Finke C, Zblewski D, Hanson CA, et al. Predictors of survival in WHO-defined hypereosinophilic syndrome and idiopathic hypereosinophilia and the role of next-generation sequencing. Leukemia. 2016;30(9):1924–6.27125206
79. Podjasek JC Butterfield JH Mortality in hypereosinophilic syndrome: 19 years of experience at Mayo Clinic with a review of the literature Leuk Res 2013 37 4 392 395 10.1016/j.leukres.2012.12.016 23332454
Podjasek JC, Butterfield JH. Mortality in hypereosinophilic syndrome: 19 years of experience at Mayo Clinic with a review of the literature. Leuk Res. 2013;37(4):392–5.23332454
80. Xue J Jiang J Liu Y The Neutrophil/Lymphocyte Ratio is an Independent Predictor of All-Cause Mortality in Patients with Idiopathic Hypereosinophilic Syndrome J Inflamm Res 2022 15 1899 1906 10.2147/JIR.S357758 35313675
Xue J, Jiang J, Liu Y. The Neutrophil/Lymphocyte Ratio is an Independent Predictor of All-Cause Mortality in Patients with Idiopathic Hypereosinophilic Syndrome. J Inflamm Res. 2022;15:1899–906.35313675
81. Barnes PJ How corticosteroids control inflammation: Quintiles Prize Lecture 2005 Br J Pharmacol 2006 148 3 245 254 10.1038/sj.bjp.0706736 16604091
Barnes PJ. How corticosteroids control inflammation: Quintiles Prize Lecture 2005. Br J Pharmacol. 2006;148(3):245–54.16604091
82. Roufosse F Kahn JE Rothenberg ME Wardlaw AJ Klion AD Kirby SY Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial J Allergy Clin Immunol 2020 146 6 1397 1405 10.1016/j.jaci.2020.08.037 32956756
Roufosse F, Kahn JE, Rothenberg ME, Wardlaw AJ, Klion AD, Kirby SY, et al. Efficacy and safety of mepolizumab in hypereosinophilic syndrome: A phase III, randomized, placebo-controlled trial. J Allergy Clin Immunol. 2020;146(6):1397–405.32956756
83. Gleich GJ Roufosse F Chupp G Faguer S Walz B Reiter A Safety and Efficacy of Mepolizumab in Hypereosinophilic Syndrome: An Open-Label Extension Study J Allergy Clin Immunol Pract 2021 9 12 4431 40.e1 10.1016/j.jaip.2021.07.050 34389506
Gleich GJ, Roufosse F, Chupp G, Faguer S, Walz B, Reiter A, et al. Safety and Efficacy of Mepolizumab in Hypereosinophilic Syndrome: An Open-Label Extension Study. J Allergy Clin Immunol Pract. 2021;9(12):4431-40.e1.34389506
84. Pane F Lefevre G Kwon N Bentley JH Yancey SW Steinfeld J Characterization of disease flares and impact of mepolizumab in patients with hypereosinophilic syndrome Front Immunol 2022 13 935996 10.3389/fimmu.2022.935996 36091012
Pane F, Lefevre G, Kwon N, Bentley JH, Yancey SW, Steinfeld J. Characterization of disease flares and impact of mepolizumab in patients with hypereosinophilic syndrome. Front Immunol. 2022;13: 935996.36091012
85. Roufosse F Butterfield J Steinfeld J Bentley JH von Maltzahn R Kwon N Mepolizumab therapy improves the most bothersome symptoms in patients with hypereosinophilic syndrome Front Med 2023 10 1035250 10.3389/fmed.2023.1035250
Roufosse F, Butterfield J, Steinfeld J, Bentley JH, von Maltzahn R, Kwon N, et al. Mepolizumab therapy improves the most bothersome symptoms in patients with hypereosinophilic syndrome. Front Med. 2023;10:1035250.
86. Rothenberg ME Roufosse F Faguer S Gleich GJ Steinfeld J Yancey SW Mepolizumab Reduces Hypereosinophilic Syndrome Flares Irrespective of Blood Eosinophil Count and Interleukin-5 J Allergy Clin Immunol Pract 2022 10 9 2367 74.e3 10.1016/j.jaip.2022.04.037 35568330
Rothenberg ME, Roufosse F, Faguer S, Gleich GJ, Steinfeld J, Yancey SW, et al. Mepolizumab Reduces Hypereosinophilic Syndrome Flares Irrespective of Blood Eosinophil Count and Interleukin-5. J Allergy Clin Immunol Pract. 2022;10(9):2367-74.e3.35568330
87. Reiter A Lefevre G Cid MC Kwon N Mavropolou E Yancey SW Association Between Baseline Therapy and Flare Reduction in Mepolizumab-Treated Patients With Hypereosinophilic Syndrome Front Immunol 2022 13 840974 10.3389/fimmu.2022.840974 35493455
Reiter A, Lefevre G, Cid MC, Kwon N, Mavropolou E, Yancey SW, et al. Association Between Baseline Therapy and Flare Reduction in Mepolizumab-Treated Patients With Hypereosinophilic Syndrome. Front Immunol. 2022;13: 840974.35493455
88. Kuang FL Legrand F Makiya M Ware J Wetzler L Brown T Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome N Engl J Med 2019 380 14 1336 1346 10.1056/NEJMoa1812185 30943337
Kuang FL, Legrand F, Makiya M, Ware J, Wetzler L, Brown T, et al. Benralizumab for PDGFRA-Negative Hypereosinophilic Syndrome. N Engl J Med. 2019;380(14):1336–46.30943337
89. Laviolette M Gossage DL Gauvreau G Leigh R Olivenstein R Katial R Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia J Allergy Clin Immunol 2013 132 5 1086 96.e5 10.1016/j.jaci.2013.05.020 23866823
Laviolette M, Gossage DL, Gauvreau G, Leigh R, Olivenstein R, Katial R, et al. Effects of benralizumab on airway eosinophils in asthmatic patients with sputum eosinophilia. J Allergy Clin Immunol. 2013;132(5):1086-96.e5.23866823
90. Busse WW Katial R Gossage D Sari S Wang B Kolbeck R Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma J Allergy Clin Immunol 2010 125 6 1237 44.e2 10.1016/j.jaci.2010.04.005 20513521
Busse WW, Katial R, Gossage D, Sari S, Wang B, Kolbeck R, et al. Safety profile, pharmacokinetics, and biologic activity of MEDI-563, an anti-IL-5 receptor alpha antibody, in a phase I study of subjects with mild asthma. J Allergy Clin Immunol. 2010;125(6):1237-44.e2.20513521
91. Singh D Fuhr R Bird NP Mole S Hardes K Man YL A Phase 1 study of the long-acting anti-IL-5 monoclonal antibody GSK3511294 in patients with asthma Br J Clin Pharmacol 2022 88 2 702 712 10.1111/bcp.15002 34292606
Singh D, Fuhr R, Bird NP, Mole S, Hardes K, Man YL, et al. A Phase 1 study of the long-acting anti-IL-5 monoclonal antibody GSK3511294 in patients with asthma. Br J Clin Pharmacol. 2022;88(2):702–12.34292606
92. Klion AD Law MA Noel P Kim YJ Haverty TP Nutman TB Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome Blood 2004 103 8 2939 2941 10.1182/blood-2003-10-3620 15070668
Klion AD, Law MA, Noel P, Kim YJ, Haverty TP, Nutman TB. Safety and efficacy of the monoclonal anti-interleukin-5 antibody SCH55700 in the treatment of patients with hypereosinophilic syndrome. Blood. 2004;103(8):2939–41.15070668
93. Kim YJ Prussin C Martin B Law MA Haverty TP Nutman TB Rebound eosinophilia after treatment of hypereosinophilic syndrome and eosinophilic gastroenteritis with monoclonal anti-IL-5 antibody SCH55700 J Allergy Clin Immunol 2004 114 6 1449 1455 10.1016/j.jaci.2004.08.027 15577851
Kim YJ, Prussin C, Martin B, Law MA, Haverty TP, Nutman TB, et al. Rebound eosinophilia after treatment of hypereosinophilic syndrome and eosinophilic gastroenteritis with monoclonal anti-IL-5 antibody SCH55700. J Allergy Clin Immunol. 2004;114(6):1449–55.15577851
94. Manka LA Guntur VP Denson JL Dunn RM Dollin YT Strand MJ Efficacy and safety of reslizumab in the treatment of eosinophilic granulomatosis with polyangiitis Ann Allergy Asthma Immunol 2021 126 6 696 701.e1 10.1016/j.anai.2021.01.035 33548468
Manka LA, Guntur VP, Denson JL, Dunn RM, Dollin YT, Strand MJ, et al. Efficacy and safety of reslizumab in the treatment of eosinophilic granulomatosis with polyangiitis. Ann Allergy Asthma Immunol. 2021;126(6):696-701.e1.33548468
95. Castro M Zangrilli J Wechsler ME Bateman ED Brusselle GG Bardin P Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials Lancet Respir Med 2015 3 5 355 366 10.1016/S2213-2600(15)00042-9 25736990
Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for inadequately controlled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. Lancet Respir Med. 2015;3(5):355–66.25736990
96. Panch SR Bozik ME Brown T Makiya M Prussin C Archibald DG Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes Blood 2018 132 5 501 509 10.1182/blood-2018-02-835330 29739754
Panch SR, Bozik ME, Brown T, Makiya M, Prussin C, Archibald DG, et al. Dexpramipexole as an oral steroid-sparing agent in hypereosinophilic syndromes. Blood. 2018;132(5):501–9.29739754
97. Altrichter S Staubach P Pasha M Singh B Chang AT Bernstein JA An open-label, proof-of-concept study of lirentelimab for antihistamine-resistant chronic spontaneous and inducible urticaria J Allergy Clin Immunol 2022 149 5 1683 90.e7 10.1016/j.jaci.2021.12.772 34954198
Altrichter S, Staubach P, Pasha M, Singh B, Chang AT, Bernstein JA, et al. An open-label, proof-of-concept study of lirentelimab for antihistamine-resistant chronic spontaneous and inducible urticaria. J Allergy Clin Immunol. 2022;149(5):1683-90.e7.34954198
98. Dellon ES Peterson KA Murray JA Falk GW Gonsalves N Chehade M Anti-Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis N Engl J Med 2020 383 17 1624 1634 10.1056/NEJMoa2012047 33085861
Dellon ES, Peterson KA, Murray JA, Falk GW, Gonsalves N, Chehade M, et al. Anti-Siglec-8 Antibody for Eosinophilic Gastritis and Duodenitis. N Engl J Med. 2020;383(17):1624–34.33085861
99. Anesi SD Tauber J Nguyen QD Chang P Berdy GJ Lin CC Lirentelimab for severe and chronic forms of allergic conjunctivitis J Allergy Clin Immunol 2022 150 3 631 639 10.1016/j.jaci.2022.03.021 35390403
Anesi SD, Tauber J, Nguyen QD, Chang P, Berdy GJ, Lin CC, et al. Lirentelimab for severe and chronic forms of allergic conjunctivitis. J Allergy Clin Immunol. 2022;150(3):631–9.35390403
100. Siebenhaar F Altrichter S Bonnekoh H Hawro T Hawro M Michaelis EG Safety and efficacy of lirentelimab in patients with refractory indolent systemic mastocytosis: a first-in-human clinical trial Br J Dermatol 2023 189 5 511 519 10.1093/bjd/ljad191 37290787
Siebenhaar F, Altrichter S, Bonnekoh H, Hawro T, Hawro M, Michaelis EG, et al. Safety and efficacy of lirentelimab in patients with refractory indolent systemic mastocytosis: a first-in-human clinical trial. Br J Dermatol. 2023;189(5):511–9.37290787
101. Kuang FL Khoury P Weller PF Wechsler ME Klion AD Biologics and Hypereosinophilic Syndromes: Knowledge Gaps and Controversies J Allergy Clin Immunol Pract 2023 11 9 2666 2671 10.1016/j.jaip.2023.07.026 37507068
Kuang FL, Khoury P, Weller PF, Wechsler ME, Klion AD. Biologics and Hypereosinophilic Syndromes: Knowledge Gaps and Controversies. J Allergy Clin Immunol Pract. 2023;11(9):2666–71.37507068
102. Wechsler ME Hellmich B Cid MC Jayne D Tian X Baylis L Unmet needs and evidence gaps in hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis J Allergy Clin Immunol 2023 151 6 1415 1428 10.1016/j.jaci.2023.03.011 37086239
Wechsler ME, Hellmich B, Cid MC, Jayne D, Tian X, Baylis L, et al. Unmet needs and evidence gaps in hypereosinophilic syndrome and eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol. 2023;151(6):1415–28.37086239
103. Leurs A Chenivesse C Lopez B Gibier JB Clément G Groh M C-Reactive protein as a diagnostic tool in differential diagnosis of hypereosinophilic syndrome and antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis J Allergy Clin Immunol Pract 2019 7 4 1347 51.e3 10.1016/j.jaip.2018.10.002 30317003
Leurs A, Chenivesse C, Lopez B, Gibier JB, Clément G, Groh M, et al. C-Reactive protein as a diagnostic tool in differential diagnosis of hypereosinophilic syndrome and antineutrophil cytoplasmic antibody-negative eosinophilic granulomatosis with polyangiitis. J Allergy Clin Immunol Pract. 2019;7(4):1347-51.e3.30317003
104. Khoury P Akuthota P Kwon N Steinfeld J Roufosse F HES and EGPA: Two Sides of the Same Coin Mayo Clin Proc 2023 98 7 1054 1070 10.1016/j.mayocp.2023.02.013 37419574
Khoury P, Akuthota P, Kwon N, Steinfeld J, Roufosse F. HES and EGPA: Two Sides of the Same Coin. Mayo Clin Proc. 2023;98(7):1054–70.37419574
