When Hypereosinophilia Isn't Reactive: A Case of Chronic Eosinophilic Leukemia

Case Presentation

A 44‑year‑old male farmer from rural Alabama presented to the emergency department in January with a six‑month history of progressive dyspnea, pleuritic chest pain, intermittent fevers, unintentional weight loss, abdominal discomfort, and a scattered rash. He had been treated empirically multiple times for bronchitis and adult‑onset asthma with antibiotics and inhalers, but symptoms persisted. Multiple noninvasive diagnostic tests, including CT imaging and laboratory workup, were unremarkable except for eosinophilia and nonspecific splenomegaly, prompting referral to our academic institution.

At admission he was tachycardic and hypoxemic. Physical exam revealed splenomegaly and numerous scattered red-orange papules on the chest, abdomen, arms, back, and feet. Laboratory studies revealed leukocytosis (24 × 10⁹/L) with 9% eosinophils. Imaging demonstrated splenomegaly up to 16.8 cm without lymphadenopathy and small bilateral pleural effusions. Initial differential was broad, and the patient underwent testing for various fungal, parasitic, zoonotic, bacterial, and viral etiologies. Aspergillus, bartonella, blastomycosis, brucella, Q fever, tuberculosis, cryptococcus, histoplasmosis, Epstein-Barr virus, and cytomegalovirus tests were all negative. Autoimmune labs (ANA, anti-dsDNA, anti-SCL70, anti-RNA Poly3, C3/C4, ACE, and anti-CCP) and cortisol levels were within normal limits. Dermatology punch biopsied an abdominal skin lesion given concern for xanthogranuloma vs. histiocytosis vs. Rosai-Dorfman disease; histopathology revealed nonspecific lipidized histiocytes of undetermined significance.

Hematology was consulted for eosinophilia, and peripheral smear showed several bands, activated neutrophils and monocytes, numerous burr cells, and atypical cells closely resembling hypergranular basophils. Bone marrow biopsy (hospital day 4) was normocellular with no dysplasia or increased blasts. Cytogenetics showed a normal karyotype, and flow cytometry was notable for abnormal CD34+ and CD117+ myleoblasts (.15%) of unclear clinical significance. PET scan did not show suspicious metabolic activity. The patient was discharged and workup was continued with splenic biopsy; however, this returned unremarkable.

Further studies on initial bone marrow biopsy with the Oncomine Myeloid Comprehensive Panel by next-generation sequencing revealed pathogenic mutation in NF1 (VAF 70%), which was later confirmed on next-generation sequencing of peripheral blood. The patient was ultimately diagnosed with idiopathic hypereosinophilic syndrome given his extensive negative workup with persistent eosinophilia and associated constitutional symptoms. Over the next four months, he was trialed on mepolizumab (anti-IL-5 antibody) with the addition of hydroxyurea due to persistent eosinophilia and constitutional symptoms. Worsening leukocytosis in August prompted repeat bone marrow biopsy, which redemonstrated NF1 mutation with new hypercellular marrow (90%), without dysplasia or blasts. Imatinib was trialed but not tolerated due to abdominal pain and peripheral edema. A second opinion was sought at an outside institution, where a third bone marrow biopsy in October showed pan hyperplasia with findings consistent with chronic eosinophilic leukemia (CEL). Therapy was changed to ruxolitinib and the patient had improvement in constitutional symptoms. Plans were made for the patient to have eventual stem cell transplantation.

Discussion

Hypereosinophilia is typically caused by reactive etiologies, such as autoimmune, infectious, parasitic, fungal, or allergic. In a small subset of patients, however, neoplasm should be considered. This is particularly true in cases of multiorgan involvement with otherwise negative testing for reactive causes such as infection or autoimmune and allergic pathologies. CEL is a neoplasm characterized by the clonal proliferation of eosinophils. Damage is mediated by eosinophil infiltration into tissues, as well as release of inflammatory mediators such as major basic protein, eosinophil peroxidase, and eosinophil-derived neurotoxin.¹ Presentation of CEL is often varied given the ability for multiple organs to be involved, ranging from vague constitutional symptoms such as fatigue and weight loss to system-specific manifestations. Diagnosis of CEL includes four main criteria: persistent eosinophilia, the presence of clonality or increased blasts along with abnormal bone marrow morphology, exclusion of secondary causes, and exclusion of other malignancies.^2,3 During the initial evaluation of eosinophilia, extensive testing to rule out reactive causes is required. However, even after ruling out other potential causes, diagnosis of CEL is not always immediately apparent due to its indolent nature, with patients often requiring longitudinal monitoring. The condition is often associated with mutations in growth factor receptors such as PDGFRA, PDGFRB, and FGFR1.² Our patient presented with an NF1 mutation, which to the best of our knowledge has not been reported in the literature before. While neurofibromatosis type 1 is associated with an increased risk of juvenile myelomonocytic leukemia in children, its link to myeloproliferative disorders in adults remains unclear and warrants further investigation.

1. Akuthota P, Weller PF. Spectrum of eosinophilic end-organ manifestations. Immunol Allergy Clin North Am. 2015;35(3):403-411.
2. Gerds AT, Gotlib J, Bose P, 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(9):1248-1269.
3. Morales-Camacho RM, Caballero-Velázquez T, Borrero JJ, et al. Hematological neoplasms with eosinophilia. Cancers (Basel). 2024;16(2):337.

Disclosure Statement: The authors indicated no relevant conflicts of interest.

Acknowledgment: This article was reviewed by Ryan Mack, PhD, and Urshila Durani, MD.