You Make the Call: How would you treat a patient with erythroderma and progressive eosinophilia?

William Shomali, MD
Clinical Assistant Professor, Hematology
Stanford Cancer Institute/Stanford University School of Medicine

CLINICAL DILEMMA

A 62-year-old male presented with erythroderma, first located at the head and upper limbs but later turned into generalized erythroderma. He was being followed by dermatology, and multiple skin biopsies were taken with the following results: psoriasiform pattern with eosinophilic isolates with immunohistochemistry positive for CD3, CD5, and CD7 and negative for CD20 and CD30 with a Ki67 of 2%. Rheumatologic workup was negative. A tuberculin test was not feasible because there was not enough uncompromised skin to be able to perform the test. He was prescribed treatment for psoriasis with steroids, methotrexate, and cyclosporine but had no response.

He also had progressive eosinophilia in peripheral blood plus a severe increase in immunoglobulin E, and the erythroderma was accompanied by angioedema, mainly in the hands. At the same time, additional testing ruled out Sezary syndrome, but the presence of a small clonal T-cell population in peripheral blood was found on flow cytometry: CD3(+) weak, CD4(-), CD7(+), DC8(+), CD5(+), and CD2(+). A bone marrow biopsy and aspirate were performed. Flow cytometry of the bone marrow aspirate was consistent with that of the peripheral blood. The bone marrow biopsy revealed hypercellularity, eosinophilia, dysmegakaryopoiesis, and isolated CD4 and CD8 lymphocytes. Imaging studies, including a PET scan, were performed without any areas of metabolic uptake.

The patient continued with treatment for his skin condition with secukinumab without response. A new bone marrow aspirate indicated the presence of abundant eosinophils. Repeat flow cytometry showed the same small clonal T-cell population. Fluorescence in situ hybridization was performed for PDGFRA fusions, which were negative. Now, the patient presents with severe skin compromise with erythroderma and conjunctival compromise. Do you think the patient may have a lymphocytic variant of hypereosinophilic syndrome? Would treatment with interferon be a possible strategy?

EXPERT OPINION

The patient’s clinical presentation fits lymphocyte-variant hypereosinophilic syndrome (L-HES). L-HES is driven by the clonal expansion of aberrant T cells that secrete eosinophilopoietic cytokines such as IL-5 and IL-4, resulting in a reactive hypereosinophilia.¹ The size of the abnormal T-cell clone is generally small, and most patients do not have significant lymphocytosis.

The immunophenotypic abnormalities of T-cell lymphocytes on flow cytometry can include absence (dim) of surface CD3, increased CD5 expression on CD3(-) and CD4(+) cells, double negative immature T cells (CD3[+], CD4[-], and CD8[-]), and loss of surface CD7.^1,2 Discrepancy can be seen between flow cytometry and immunohistochemistry (IHC), due to staining of cytoplasmic cluster domains by IHC. Next-generation sequencing is helpful in identifying somatic driver mutations, such as STAT3 mutations (e.g., Y640F, G618R, and S614R), which have been reported in a subset of patients with L-HES.³

Dermatologic manifestations are most common, but other organ systems can be involved, including lymph nodes, gastrointestinal tract, pulmonary, neurologic, and cardiovascular. Ruling out T-cell lymphoma (including Sezary syndrome) with biopsies of the skin (and other involved organs) and imaging is important, as it can present concomitantly or follow the diagnosis of L-HES.^1,4

Corticosteroids are the first-line treatment. However, many patients become corticosteroid-dependent or have inadequate response, necessitating alternative forms of therapy. The therapeutic armamentarium in L-HES has expanded. Interferon (IFN) alpha, cyclosporine, hydroxyurea, anti-IL-5 (mepolizumab), and anti-IL-5 receptor (benralizumab) antibody therapy have been used successfully. IFN alpha has been associated with a decrease in abnormal T-cell clones and, in some cases, reversion of the abnormal immunophenotype.⁵ Responses to mepolizumab and benralizumab have been less durable when compared to patients who had a normal T-cell immunophenotype.⁶ Most recently, JAK inhibition with tofacitinib and ruxolitinib has been promising in this variant⁷ and is under study in two prospective clinical trials (NCT03801434, NCT00044304).⁸ In addition, romidepsin has been used in refractory cases.⁹ It is important to note that resolution of eosinophilia in the blood does not always correlate with symptomatic improvement due to persistent tissue infiltration by eosinophils, organ damage, or a combination of both, and a change in therapy may be required in such cases.

References

1. Simon HU, Plötz SG, Dummer R, et al. Abnormal clones of T cells producing interleukin-5 in idiopathic eosinophilia. N Engl J Med. 1999;341(15):1112-1120.
2. Lefèvre G, Copin M-C, Staumont-Sallé D, et al. The lymphoid variant of hypereosinophilic syndrome: study of 21 patients with CD3-CD4+ aberrant T-cell phenotype. Medicine (Baltimore). 2014;93(17):255-266.
3. Walker S, Wang C, Walradt T, et al. Identification of a gain-of-function STAT3 mutation (p.Y640F) in lymphocytic variant hypereosinophilic syndrome. Blood. 2016;127(7):948-951.
4. Shomali W, Gotlib J. World Health Organization and International Consensus Classification of eosinophilic disorders: 2024 update on diagnosis, risk stratification, and management. Am J Hematol. 2024;99(5):946-968.
5. Choi C, Moller D, Tan J, et al. Pegylated interferon alpha 2a is an effective and well-tolerated treatment option for lymphocyte-variant hypereosinophilic syndrome. Br J Haematol. 2020;188(5):e68-e72.
6. Roufosse F, De Lavareille A, Schandené L, et al. Mepolizumab as a corticosteroid-sparing agent in lymphocytic variant hypereosinophilic syndrome. J Allergy Clin Immunol. 2010;126:828-835.e3.
7. Faguer S, Groh M, Vergez F, et al. JAK inhibition for CD3- CD4+ lymphocytic-variant hypereosinophilic syndrome. Clin Immunol. 2023;251:109275.
8. Anderson C, Khoury P, Makiya M, et al. A pilot phase 2 study of ruxolitinib for the treatment of steroid-refractory hypereosinophilic syndrome. J Allergy Clin Immunol. 2024:153(2):AB64.
9. Baulier G, Asli B, Galicier L, et al. Romidepsin is an effective and well-tolerated therapy in CD3-CD4+ lymphocyte-variant hypereosinophilic syndrome: a case report. J Allergy Clin Immunol Pract. 2019;7(8):2885-2887.e1.

NEXT MONTH'S CLINICAL DILEMMA

A 39-year-old female has a history of bilateral pulmonary embolism after taking oral contraceptive pills, as well as a subsequent deep vein thrombosis (DVT) in the left calf after a long car ride. Given the recurrent event and her history of venous thromboembolism, would you treat with indefinite anticoagulation? For both provoked and unprovoked below-the-knee DVT, I typically treat for three months, but for recurrent, provoked below-the-knee DVT, what would you recommend? Could you treat either situation for three months, and use 5 mg of oral apixaban as prophylaxis prior to flying or long car rides?

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