ICC/WHO‐Defined and NGS‐Annotated Idiopathic Hypereosinophilia (iHES/iHE): Mutations, Clinical and Treatment Details, and Predictors of Survival

To the Editors,

1.

Idiopathic hypereosinophilic syndrome (iHES) is defined by persistent peripheral blood (PB) hypereosinophilia (HE) (absolute eosinophil count [AEC] ≥ 1.5 × 10⁹/L and ≥ 10% circulating eosinophils) with eosinophil‐mediated overt organ damage. Idiopathic hypereosinophilia (iHE), on the other hand, is characterized by persistent HE in the absence of overt tissue involvement. An iHES/iHE diagnosis requires the careful exclusion of underlying reactive causes as well as myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions (M/LN‐eo‐TK), eosinophilia associated with other myeloid neoplasms, chronic eosinophilic leukemia‐not otherwise specified (CEL‐NOS) and lymphocyte‐variant HES (LV‐HES) [1, 2, 3, 4, 5, 6].

iHES/iHE represents a heterogeneous clinical spectrum ranging from asymptomatic HE to life‐threatening end‐organ damage involving the heart, skin, lungs, and nervous system [7]. The prognosis of iHES/iHE is variable, ranging from a largely indolent course to significant morbidity due to eosinophil‐mediated end‐organ damage or transformation into an overt myeloid malignancy. The therapeutic landscape for iHES/iHE has historically relied on corticosteroids [8] and cytotoxic agents with considerable long‐term toxicity. Mepolizumab, a humanized anti‐IL‐5 monoclonal antibody, demonstrated in a pivotal phase III randomized placebo‐controlled trial [9] with a 50% reduction in iHES flares and a 92% reduction in blood eosinophil count, leading to approval for patients aged ≥ 12 years with iHES, at a dose of 300 mg subcutaneously every 4 weeks. Despite the expanding use of NGS and increasingly refined molecular criteria, published literature on NGS‐validated iHES/iHE remains limited. The objective of the current study was to outline the clinical spectrum, mutational profile, treatment outcomes, and prognosis, including the real‐world efficacy of mepolizumab in patients with NGS‐validated and ICC/WHO‐defined iHES/iHE.

Institutional review board approval was obtained from the Mayo Clinic in accordance with the Declaration of Helsinki; informed consent was waived due to the retrospective nature of the study. Pathology diagnoses were rendered by board‐certified hematopathologists following the 2022 WHO/2023 ICC criteria [1, 10]. Patients were identified through a Mayo Clinic enterprise‐wide database search conducted between September 2013 and January 2026. Cytogenetic results were reported according to the International System for Human Cytogenetic Nomenclature (ISCN). A CLIA‐approved next‐generation sequencing (NGS) with multigene myeloid panel was used to obtain mutational data. All patients were followed until death or their last follow‐up, as assessed by medical records or through direct contact with the patients or their physicians. All patients underwent a bone marrow (BM) biopsy, flow cytometry (FC), and T‐cell receptor (TCR) gene rearrangement studies. Organ involvement was determined by clinical presentation, imaging, or biopsy. The treatment received, often at the discretion of the treating physician, at any time during the disease course, was reviewed and documented. Chi‐square and correlation analyses were used to compare clinical and laboratory parameters. The Kaplan–Meier method was used to construct time‐to‐event curves, which were compared using the log‐rank test. Receiver operating characteristic (ROC) curve analysis was performed to determine optimal threshold values for continuous variables. Multivariable logistic regression analysis was used to adjust for confounding variables. A p‐value of ≤ 0.05 was considered statistically significant. Statistical analyses were conducted using JMP Pro 18.0.1 software (SAS Institute, Cary, NC, USA).

A total of 48 NGS‐annotated patients with ICC/WHO‐defined iHES/iHE (median age 56 years; 52% males) were studied (Tables 1 and 2). Initial clinical presentation included pulmonary (n = 12; 25%), gastrointestinal (n = 12; 25%), cutaneous (n = 9; 18%), and cardiac (n = 6; 13%) involvement; constitutional symptoms and neurologic involvement were reported in 6 (13%) and 3 (6%) patients, respectively. Cumulative organ involvement over the full disease course included pulmonary (46%), cutaneous (33%) [11], gastrointestinal (31%), and cardiac (21%) manifestations. Thrombotic events were documented in 7 patients (15%) at or prior to diagnosis and in 5 (10%) thereafter. The median absolute eosinophil count (AEC) at diagnosis and the median peak AEC documented were 4.7 × 10⁹/L and 5.9 × 10⁹/L, respectively. Among serum biomarkers, elevated IgE was documented in 16 of 36 patients tested (44%), elevated Interleukin‐5 (IL‐5) in 2 of 11 (18%), elevated B12 in 3 of 39 (8%), and elevated tryptase in 6 of 38 (16%); none of these latter 6 patients harbored NGS‐detected KIT mutation and BM CD117 stain showed no evidence of abnormal mast cells; furthermore 3 of these 6 patients with the highest serum tryptase levels (19.6–29.5 ng/mL) had undergone a more sensitive (analytic sensitivity o.1%) KITD816V PCR mutation screen which was negative. Karyotype data were available for 46 of 48 patients; two patients demonstrated an isolated loss of the Y chromosome (‐Y) and the remainder had normal karyotypes. Fluorescence in situ hybridization (FISH) for chronic eosinophilia‐associated rearrangements was negative in all tested patients.

TABLE 1.

Demographic and clinical parameters among 48 patients with iHES/iHE, stratified by mutation status.

	All cases N = 48	NGS with pathogenic mutations a N = 6	NGS without pathogenic mutations N = 42	p
Age in years, median (range)	56 (21–83)	70 (46–83)	53 (21–83)	0.08
Age ≥ 65 years, n (%)	15 (31)	5 (83)	11 (24)	< 0.01
Male sex, n (%)	25 (52)	3 (50)	22 (52)	0.91
Hemoglobin g/dL, median (range)	13 (8.5–16.2)	14 (12.3–16.2)	13 (8.5–16.1)	0.37
Leukocytes ×109/L, (range)	12.2 (4.1–103)	17.6 (4.1–23)	12 (6.1–103)	0.38
Platelets ×109/L, median (range)	243 (65–511)	302 (192–475)	243 (65–511)	NA
Absolute Neutrophil count ×109/L, median (range)	5.4 (1.6–41.3)	5.1 (1.6–7.9)	5.3 (1.6–41.3)	NA
Peak Absolute Eosinophil count ×109/L, median (range)	5.9 (1.6–79)	10.4 (2.2–28.4)	5.4 (1.6–79)	0.38
Absolute Lymphocyte count ×109/L, median (range)	2.2 (0.5–29)	1.9 (0.6–2.7)	2.2 (0.5–29)	NA
Absolute Lymphocyte count ≤ 0.96 × 109/L at diagnosis, n (%)	4 (8)	2 (33)	2 (5)	0.05
H/o Allergic conditions, n (%)	34 (71)	4 (67)	30 (71)	0.81
Thrombosis at or prior to diagnosis	7 (15)	2 (33)	5 (12)	0.21
Thrombosis after diagnosis	5 (10)	1 (17)	4 (10)	0.61
Eosinophilic Organ involvement present, n (%)	47 (98)	5 (83)	42 (100)	0.04
Pulmonary involvement, n (%)	22 (46)	4 (67)	18 (43)	0.27
Skin involvement, n (%)	16 (33)	1 (17)	15 (36)	0.33
GI involvement, n (%)	15 (31)	2 (33)	13 (31)	0.91
Cardiac involvement, n (%)	10 (21)	2 (33)	8 (19)	0.44

^a Pathogenic mutations found on NGS (VAF%): DNMT3A (11% and 4%), ASXL1 (36%), TET2 (41%), SF3B1 (47%), CBL (2%), CHEK2 (48%).

TABLE 2.

Clinical and molecular characteristics among 6 patients with idiopathic hypereosinphilic syndrome with (iHES) or without (iHE) overt organ involvement and pathogenic mutations on next‐generation sequencing (NGS).

Patient	Gender	Age at diagnosis (years)	Absolute eosinophil count at diagnosis (x 109/L)	Presenting symptoms	Mutations on NGS	Mutation variant allele frequency (%)	Karyotype
#1	M	65	17	Neurologic	ASXL1 DNMT3A	36 11	46,XY[20]
#2	F	46	11	Pulmonary Gastrointestinal	CBL	2	46,XX[20]
#3	F	70	12	Cardiac Pulmonary, Neurologic	CHEK2	48	46,XX[20]
#4	M	76	2	Cardiac Gastrointestinal	DNMT3A	4	46,XY[20]
#5	M	83	5	Skin	SF3B1	47	46,XY[20]
#6	F	70	2	Pulmonary	TET2	41	46,XX[20]

Pathogenic mutations were documented in 6 (12%) patients, predominantly involving clonal hematopoiesis of indeterminate potential (CHIP)‐associated genes (Table 2), including DNMT3A (VAF 4%), ASXL1 + DNMT3A (36% and 11%), TET2 (41%), SF3B1 (47%), CBL (2%), and CHEK2 (48%). Mutations were significantly associated with older age (≥ 65 years) (83% vs. 24%; p < 0.01) and a lower likelihood of organ involvement (83% vs. 100%; p = 0.04). Notably, an absolute lymphocyte count (ALC) ≤ 0.96 × 10⁹/L at diagnosis was more frequently observed in patients with pathogenic mutations compared to those without (33% vs. 5%; p = 0.05), though median AEC did not differ significantly between the two groups. Additionally, a clonal TCR gene rearrangement, in the absence of an aberrant T‐cell immunophenotype, was noted in 3 patients (6%) who were retained under the iHES diagnosis per the ICC criteria¹; clonal TCR status was significantly associated with cutaneous involvement, including eosinophilic fasciitis and a generalized skin rash (100% vs. 29%; p < 0.01). Additional apparent associations included increased tryptase with an AEC > 5 × 10 (9)/L, anemia, and male sex (p < 0.05) and elevated IgE with skin involvement and allergic conditions (p < 0.05 for all).

Mepolizumab was administered to 35 (73%) patients and enabled corticosteroid discontinuation in 20 (59%); the median AEC at treatment initiation and 6 and 12 months post‐treatment were 2.6, 0.1, and 0.07 (×10⁹/L), respectively. At a post‐treatment median follow‐up of 14 months, mepolizumab was discontinued in 13 (37%) patients, with continued treatment more likely in the presence of an allergy history (63% vs. 16%; p < 0.01). Other medications on record included corticosteroids (n = 46), hydroxyurea (n = 8), dupilumab (n = 7), benralizumab (n = 6), imatinib (n = 6), ruxolitinib (n = 3) and alemtuzumab (n = 2). One patient required a hematopoietic stem cell transplant (HSCT), and another required a cardiac transplant due to refractory disease. The first patient was a 24‐year‐old male with aggressive iHES complicated by eosinophilic cardiac involvement and an aortic thrombus, which was refractory to medical therapy with corticosteroids, benralizumab, alemtuzumab, and hydroxyurea; he ultimately underwent a hematopoietic stem cell transplant. The second patient was a 52‐year‐old female with iHES complicated by eosinophilic cardiac involvement and a biventricular thrombus, which was refractory to medical management with mepolizumab and corticosteroids; she required cardiac transplantation.

At a median follow‐up of 29 months, two deaths were documented. The first patient was a 71‐year‐old female with iHES and cardiac, pulmonary, and cutaneous involvement who, despite good eosinophil control on mepolizumab, died at 14 months from progressive hypoxic respiratory failure secondary to multifactorial interstitial lung disease (ILD). The second patient was a 61‐year‐old cardiac transplant recipient who developed recurrent eosinophilic endomyocarditis with new‐onset PB HE and BM eosinophilia, consistent with iHES with cardiac involvement. Although he responded to mepolizumab and high‐dose corticosteroids, he died at 12 months from progressive cardiac dysfunction. Overall survival (OS) was comparable between patients with or without pathogenic mutations (Figure 1a; p = 0.56) or clonal TCR (p = 0.69). On univariate analysis, cardiac involvement (2‐year OS: 55% vs. 87%; p = 0.01; Figure 1b) and ALC ≤ 0.96 × 10⁹/L (59% vs. 100%; p < 0.01; Figure 1c) predicted inferior survival which is consistent with previous studies [12]. In age‐adjusted multivariable analysis, only ALC ≤ 0.96 × 10⁹/L remained significant.

FIGURE 1.

Overall survival data in 48 patients with idiopathic hypereosinophilic syndrome (iHES) or without (iHE) overt organ involvement, stratified by mutation status (Figure 1a), cardiac involvement (Figure 1b), or absolute lymphocyte count (ALC; Figure 1c).

Taken together, our observations suggest that somatic mutations in iHES/iHE are infrequent but not rare (12%), are often associated with older age and are qualitatively aligned with age‐related CHIP mutations. Accordingly, their attribution to the underlying clonal eosinophilia might notnecessarily be accurate and, therefore, such information should not be used for classification as “CEL, NOS,” especially in the absence of abnormal BM morphology. The clonal TCR findings merit separate consideration. The ICC criteria require an aberrant immunophenotype (e.g., CD3⁻CD4⁺/CD3⁺CD4⁺CD7⁻/CD8⁺CD5⁻CD56⁺) with or without a clonal T‐cell population for an LV‐HES designation; the absence of the latter in our three cases mandated iHES classification. However, the strong association of a clonal TCR rearrangement with cutaneous involvement aligns with the cutaneous tropism well recognized in LV‐HES and raises the possibility of a biologically distinct iHES subset warranting prospective characterization, though its survival impact was negligible in this series. The mepolizumab data confirm and extend pivotal trial observations. A reduction in median AEC from 2.6 to 0.07 × 10⁹/L at 12 months, with corticosteroid discontinuation achieved in more than half of the treated patients, represents a compelling real‐world effect size [13]. Cardiac involvement and lymphopenia identify the highest‐risk patients, warranting intensified monitoring and earlier escalation of eosinophil‐directed therapy. The adverse survival impact of cardiac involvement is among the most consistently replicated observations in iHES/iHE [12], and cardiac transplantation in one of our patients attests to the potential severity of this complication. Lymphocytopenia as an independent survival predictor is less well‐characterized and may reflect systemic inflammatory burden or immune dysregulation; prospective validation in a larger cohort is warranted.

Author Contributions

A.T. and S.P.P. designed the study and wrote the paper. M.Y., R.A., P.F., S.P.U., A.K.B., and A.B.B. participated in data collection and analysis; N.G. and A.P. participated in patient care; C.J.Z.M., K.K.R., D.S.V., and R.H. provided hemato‐pathology expertise; all authors reviewed and approved the manuscript.

Funding

The authors have nothing to report.

Ethics Statement

Institutional review board approval was obtained from Mayo Clinic in accordance with the Declaration of Helsinki; informed consent was waived due to the retrospective nature of the study.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

By e‐mail request to the corresponding author.