French guidelines for the etiological workup of eosinophilia and the management of hypereosinophilic syndromes

AimsGeneral goals

The goal of the management of HES is to achieve remission of the clinical symptoms associated with HES. In case of severe organ involvement (cardiac or central neurological involvement, thrombosis, etc.), a further goal is to achieve hematologic remission (eosinophil count < 0.5 × 109/L) to minimize the risk of relapse and, above all, of irreversible sequelae [3, 20]. Otherwise (non-serious dermatological, gastrointestinal, or other manifestations), normalization of the eosinophil count is not mandatory in all cases (the main objective rather being in the latter case to control symptoms and monitor the possible occurrence of other clinical manifestations related to eosinophil toxicity).

Other specific objectives based on the type of HESClonal HES

The goal of treatment for clonal HES is to achieve sustained clinical and hematologic (i.e., normalization of the CBC) as well as cytogenetic and/or molecular remission (depending on the underlying disorder identified) in order both to prevent eosinophil-induced organ involvement and transformation into acute leukemia [8, 91].

Lymphocytic HES

Although systemic corticosteroids, immunomodulatory or immunosuppressive agents may all decrease the number of abnormal lymphocytes, there is currently no established strategy to eliminate the relevant lymphocyte population.

Professionals involved

Therapeutic management is generally multidisciplinary, coordinated by a physician with specific expertise in eosinophilic disorders and undertaken in partnership with a reference center for eosinophil-associated disorders (the list of French referral centers is detailed in Additional file 2: Appendix 2 and is available at www.cereo.fr).

It is provided by the same professionals as those involved in the baseline assessment as well as (if needed) other allied health professionals (nutritionists, physiotherapists, psychologists, child psychologists, child psychiatrists) and welfare professionals (social workers, care assistants).

Pharmacological treatmentsAntiparasitic treatment

In the absence of available studies, the usefulness of empirical antiparasitic treatment in unexplained chronic HE is disputed. However, we believe that it may be appropriate in specific situations, for the following reasons:

Variable sensitivity of parasite serology and parasitological examination of the stool.

Risk of severe strongyloidiasis during treatment with systemic corticosteroids.

Excellent tolerability of antiparasitic drugs (adverse reactions are exceptional).

Clinical experience with situations in which empirical antiparasitic treatment allowed complete and sustained normalization of otherwise unexplained HE (despite negative well-conducted parasite tests).

Low cost.

When effective, avoids the need for additional, potentially invasive and/or costly second-line investigations.

The initiation of antiparasitic treatment may be contra-indicated or carry a risk of complications in certain situations, including the following: acute schistosomiasis (exposure < 3 months), filariasis, neurocysticercosis or toxocariasis with ophthalmological and/or cardiac involvement. When in doubt, we recommend postponing the initiation of antiparasitic treatment and seeking specialist advice.

Empirical antiparasitic treatment in the absence of a history of travel to a specific endemic area

In patients with moderate eosinophilia (0.5–1.5 × 109/L), history-taking must include questions about the shedding of parasites (including in the form of segments: Taenia) or itching around the anus mainly at night (pinworm). Empirical antiparasitic treatment with flubendazole (100 mg for 3 days, supplemented by a single dose of 100 mg 15 days later) or albendazole (400 mg/day with meals for 1–3 days, then 400 mg/day at D15) is indicated for any eosinophilia < 1.5 × 109/L in the absence of an obvious cause and contraindications. Main targets: Oxyuris, Ascaris.

A single dose of praziquantel (15 mg/kg taken during a meal) is recommended in the presence of eosinophilia with spontaneous passing of segments through the anus or in the stool (to be sent for parasitological examination if possible), even if the parasitological examination of the stool is negative. Main targets: Taenia, Bothriocephalus, Hymenolepis.

Albendazole (10–15 mg/kg/day, up to a maximum of 800 mg/day, taken twice daily with meals, for 10–15 days) is recommended for unexplained HE > 1.5 × 109/L. Main targets: Toxocariasis, trichinosis, ascariasis, pinworm infection (do not prescribe flubendazole in this case).

Empirical antiparasitic treatment in case of history of travel to an endemic area (African continent, including the Maghreb and Middle East, Southeast Asia, Central and South America, Caribbean and Indian and Pacific Oceans)

This recommendation applies even to stays that date back more than 20 years, and only after investigation and consultation with a parasitologist. Depending on the patient's condition and risk factors and the endemic areas visited, an antiparasitic treatment consisting of all or some of the following compounds may be offered:

Main targets: Strongyloides (also present in Spain, Portugal, Italy, Eastern Europe, and USA), causative agents of filariasis.

Additional targets: Schistosomiasis, certain trematode infections.

D3–D18 albendazole: 10–15 mg/kg/day, up to a maximum of 800 mg/day, taken twice daily with meals for 5–15 days.

Main targets: Toxocariasis, hookworm infection, pinworm infection, ascariasis, trichuriasis.

Note: modalities for the treatment of toxocariasis are not standardized (whether in terms of dose or duration), but treatment with albendazole (10–15 mg/kg/day, up to a maximum of 800 mg/day) for 10 days seems to be appropriate. In case of strong suspicion of toxocariasis and failure of first-line treatment with albendazole, second-line treatment with diethylcarbamazine may be considered on a case-by-case basis after consultation with an infectious disease specialist or parasitologist.

Indications, modalities, and measures associated with systemic corticosteroid therapyIndications and modalities

Systemic corticosteroid therapy is indicated in the following situations:

Life-threatening emergency situations.

First-line treatment for lymphocytic or idiopathic HES.

As a one-time therapeutic test to assess HE response to corticosteroids.

In an emergency situation (myocarditis, acute respiratory distress, central or peripheral neurological involvement, venous or arterial thrombosis, etc.), regardless of the cause of HES (including parasitic causes, with the exception of severe strongyloidiasis), the initial management of severe visceral involvement secondary to eosinophil toxicity relies primarily on corticosteroid therapy: 1 mg/kg/day prednisone, possibly preceded by intravenous pulses of methylprednisolone (5–15 mg/kg/day, up to a maximum of 1000 mg for 3 days), while awaiting the initial diagnostic workup, which then allows targeted management to be offered if necessary.

Therapeutic test with corticosteroids. For the diagnostic workup of unexplained HE, in the absence of clear characterization of the etiology of HE despite a well-conducted first-line workup (as detailed in Box 4), and in case of persistent HE despite antiparasitic treatment, assessment of the corticosteroid sensitivity of HE (CBC at D3 and D7) following short-term empirical corticosteroid therapy (e.g., 0.5–1 mg/kg/day for 7 days) may be useful (even in the absence of an otherwise indication for long-term treatment with corticosteroids).

The purpose of this therapeutic test is twofold:

To guide the indication of molecular blood tests: if the eosinophilia is fully steroid-sensitive, tests for clonal HE/HES (which is usually steroid-resistant), may reasonably be waived.

Confirm that corticosteroids will be effective in the event of a subsequent acute exacerbation of HES requiring systemic therapy.

Measures related to corticosteroid therapy

Preemptive treatment with ivermectin (200 µg/kg on an empty stomach) is recommended (in the absence of contraindications) for prophylaxis of severe strongyloidiasis.

If corticosteroid therapy is prolonged, standard practices associated with the prescription of corticosteroid therapy should be applied, including:

Compliance with health and dietary rules (adequate calcium and vitamin D intake, limitation of overall calorie intake to prevent weight gain, low-carbohydrate diet with high glycemic index to prevent steroid-induced diabetes, low-sodium diet only in case of poorly controlled arterial hypertension and/or heart or kidney failure and/or portal hypertension, physical activity to mitigate steroid myopathy and prevent potential metabolic adverse reactions of steroids).

Prevention of steroid-induced osteoporosis according to current recommendations (including the prescription of bisphosphonates when indicated) and in the absence of contraindications.

Prevention of infectious complications on a case-by-case basis (presence or absence of underlying lung disease, underlying immunodeficiency, dose, and duration of corticosteroid therapy, etc.). This can involve ensuring that all vaccinations are up to date, annual influenza vaccination, prime-boost pneumococcal vaccination (13-valent conjugate vaccine followed at least 8 weeks later by a 23-valent polysaccharide vaccine), vaccination against SARS-CoV-2 (whereas live attenuated vaccines are contraindicated in patients receiving corticosteroid therapy at doses ≥ 10 mg/day prednisone-equivalent for ≥ 15 days), prevention of HBV reactivation, prevention of TB reactivation, and possible initiation of pneumocystis pneumonia prophylaxis.

Screening and management of cardiovascular risk factors.

Management of FIP1L1::PDGFRA–positive chronic eosinophilic leukemiaIndications

Given the risk of both irreversible tissue damage (particularly cardiac) in persistent HE and of transformation into acute leukemia, it is recommended that treatment be initiated in any patient with F/P + chronic eosinophilic leukemia, symptomatic or not [91]. In addition, as the time to initiation of treatment appears to be correlated with the risk of relapse following attempts to discontinue treatment, it is recommended that treatment be initiated promptly once a diagnosis of F/P + chronic eosinophilic leukemia has been made [19].

First-line treatment

First-line treatment consists of imatinib, a tyrosine kinase inhibitor, which achieves laboratory and molecular remission in 100% of cases in our experience. A dose of 100 mg daily is sufficient to achieve a complete response, while improving tolerability [19, 92]. The introduction of imatinib may be recommended even before the result of the FIP1L1::PDGFRA test when the patient's condition is severe, and the clinical and laboratory findings are suggestive of such diagnosis.

It is important to note that treatment with imatinib requires the use of both male and female contraception. The practicalities of prescribing imatinib are detailed in Box 8.

Box 8 Prescribing guidelines for imatinib

In case of HES-specific cardiac involvement, there is a theoretical risk of initial worsening upon initiation of imatinib (toxicity induced by eosinophil lysis during treatment). This warrants laboratory monitoring of troponin 48 h after initiation of treatment (which should be done in hospital in case of severe eosinophilic heart disease), and the prescription of a short course of corticosteroids if troponin increases during imatinib treatment (e.g., 1 mg/kg/day corticosteroids for 5–7 days).

When F/P + leukemia is diagnosed in the acute phase (acute leukemia) or in the form of other aggressive hematological presentations (lymphoblastic lymphoma), treatment should be discussed in a multidisciplinary team meeting of experts in hematology. Indeed, while molecular remission has been reported in some patients treated with imatinib monotherapy, the addition of a combination of cytarabine and daunorubicin in the initial phase of treatment should be considered depending on the patient's condition [91, 93]. Once molecular remission has been achieved, maintenance therapy with imatinib monotherapy usually makes it possible to defer first-line allogeneic bone marrow transplantation.

What to do in case of non-response or secondary loss of response after first-line treatment with imatinib

In case of lack of effectiveness of imatinib, the two most common scenario to consider are:

Non-compliance to treatment (or a pharmacokinetic issue related to imatinib malabsorption). Although no target residual plasma levels are defined in the context of F/P + chronic eosinophilic leukemia, undetectable drug plasma levels can avoid unnecessary sequencing of PDGFRA.

Another cause of HE (other than F/P + chronic eosinophilic leukemia) that should warrant minimal reinvestigation (as detailed in “Pharmacological treatments” Section).

In addition, there have been exceptional reports in the literature of mutations of the PDGFRA gene (particularly the T674I—which is analogous to the T315I mutation in BCR::ABL1, and D842V mutations) that confer resistance to imatinib. Second-generation tyrosine kinase inhibitors (TKIs), such as dasatinib and nilotinib, have been shown to be effective in vitro on both wild-type and mutated tyrosine kinases, and treatment success has been described with both compounds in this situation [94]. To date, given the rarity of the situation, there is no robust data favoring one or the other compound, and the choice should be based primarily on the tolerability profile and the physician's prescribing habits.

Duration of treatment

There have been reports of sustained remission after cessation of imatinib (possibly permanent cure). Our experience (which is consistent with other data in the literature) suggests that ≈ 40% of patients can maintain sustained molecular remission after initial discontinuation of imatinib [19, 95].

In the largest reported case series of 151 patients with F/P + chronic eosinophilic leukemia (46 of whom discontinued treatment with imatinib), the factors that correlated with the risk of relapse following cessation of imatinib were a long delay between the onset of HE and initiation of imatinib, and a short duration of treatment [19]. Treatment with imatinib 100 mg/day can be administered on a long-term basis, but cessation can also be attempted on a case-by-case basis after a minimum of 5 years of treatment in patients in prolonged molecular remission. Regular molecular follow-up (even in the absence of recurrence of eosinophilia) is mandatory (e.g., every 3 months in the first year and every 6 months thereafter). Unlike chronic myeloid leukemia, a consensus definition of molecular remission in F/P + chronic eosinophilic leukemia is lacking. Currently, it relies either on a negative RT-PCR or Q-PCR assay.

In the event of clinical/hematological/molecular relapse after a first attempt to discontinue treatment with imatinib, resumption of treatment usually leads to renewed molecular remission (although rare cases of secondary resistance have been reported). At present, data regarding second attempts to discontinue treatment are scarce.

Management of non-F/P-associated clonal HES

The management of non-F/P-associated clonal HES is not standardized, and literature data are even sparser than those available for F/P + chronic eosinophilic leukemia [8, 91]. The therapeutic approach generally depends on the molecular/cytogenetic abnormality reported, and discussion in a multidisciplinary team meeting is recommended. Nonetheless, a few trends emerge.

Rearrangements involving PDGFRA (other than FIP1L1::PDGFRA)

Clonal forms of HES involving PDGFRA and a partner gene (such as BCR, ETV6, KIF5B, etc.) other than FIP1L1 are possible. Although exceedingly rare, and by analogy with F/P + chronic eosinophilic leukemia, they are also particularly sensitive to low dose imatinib (i.e., 100 mg daily), and their long-term prognosis seems to be excellent [8, 91].

Rearrangements involving PDGFRB

Rearrangements involving PDGFRB and other partners (about 30 to date) have been reported, including ETV6::PDGFRB, which may also be responsible for a chronic myelomonocytic leukemia phenotype with HE due to t(5;12)(q32;p13). These cases are generally responsive to imatinib (MA), but initially at higher doses (400 mg daily) than those used to treat F/P + chronic eosinophilic leukemia [33, 91]. These dosages generally result in prolonged molecular remission with continued treatment. Once molecular remission is achieved, careful reduction of the doses to 100 mg imatinib may be suggested, subject to regular molecular monitoring.

JAK2 rearrangements

JAK2 rearrangements (including PCM1::JAK2 due to t(8;9)(p22;p24) and BCR::JAK2 due to t(9;22)(p24;q11)) are sensitive to JAK2 inhibitors, including ruxolitinib (off label). However, response to treatment may be transient and this therapeutic approach is usually a bridge to allogeneic bone marrow transplantation, which should be considered (depending on the patients’ age and comorbidities) [91, 96].

FGFR1 rearrangements

FGFR1 rearrangements, including FGFR1::ZMYM2 due to t(8;13)(p11;q12), are associated with aggressive clinical phenotypes with, in the absence of treatment, constant and rapid progression (in one to two years) towards a high-grade hematological malignancy (acute myeloid leukemia, lymphoblastic lymphoma) resistant to standard TKIs (including ponatinib). In the FIGHT-203 study, a phase 2 multicenter trial assessing the safety and efficacy of pemigatinib (13.5 mg QD on a 21-day cycle with 2 weeks on and 1 week off)), complete hematological and cytological response rates reached 76% and 71%, respectively in 35 previously treated patients in both chronic and blast phase. Additionally, both treatment-naive patients on chronic phase achieved hematological and cytological responses, while one in three treatment-naive patients with blast phase disease achieved hematological and cytological responses. Overall, despite high rates of treatment-emergent adverse events (with hyperphosphatemia, alopecia, diarrhea and stomatitis being at the forefront), pemigatinib may offer a long-term treatment option for patients ineligible for hematopoietic stem cell transplantation, or may otherwise facilitate bridging to transplantation [97]. Of note, pemigatinib was approved by the FDA on August 2022 in this setting.

FLT3 rearrangements

Recently, FLT3 rearrangements have been included within the subgroup of “Myeloid/lymphoid neoplasms with eosinophilia and tyrosine kinase gene fusions” in the 2022 International Consensus Classification of myeloid neoplasms and acute leukemias [6]. Patients with FLT3 rearrangements generally have an aggressive phenotype resistant to the main TKI. Thus, as for rearrangements involving FGFR1, it seems appropriate to encourage enrollment in clinical trials assessing tyrosine kinase inhibitors showing in vitro activity against FLT3 (sorafenib, sunitinib, gilteritinib) either alone (in case of diagnosis at a chronic phase) or in combination with intensive multiagent chemotherapy, followed by early allogeneic bone marrow transplantation (when feasible) [91].

Chronic eosinophilic leukemia–not otherwise specified (CEL-NOS)

Although this is likely a heterogeneous condition (especially when the presumed clonality of eosinophils is based "only" on the presence of cytogenetic (karyotype / FISH) and/or molecular (NGS-based gene panel test) abnormalities, it appears to have a poor prognosis, with high rates of progression to acute myeloid leukemia in the main series reported to date. Thus, a case-by-case assessment considering the patient's cytogenetic and molecular findings is recommended. Case reports (and CEREO experience) have shown that probabilistic treatment with tyrosine kinase inhibitors (imatinib as well as second-generation TKIs or JAK inhibitors) can sometimes elicit a complete hematologic response in this setting, including in patients with no overt molecular abnormality. Empirical (or even sequential, if first-line treatment with imatinib fails) use of these treatments may be considered. In young people, if this strategy fails (and/or if there is cytogenetic evidence of a poor prognosis), allogeneic bone marrow transplantation should also be considered. Cytoreductive therapy with hydroxycarbamide (off-label) is often administered to reduce blood HE (and possibly limit eosinophil toxicity) even though its effectiveness on the natural course of the blood disorder (including the risk of transformation to acute myeloid leukemia) has not been demonstrated. Finally, in the case of multiple documented molecular abnormalities with a significant allele frequency (≥ 5%) and/or a borderline form with a myelodysplastic syndrome, treatment with a hypomethylating agent (azacytidine, off-label) or allogeneic bone marrow transplantation may also be considered on a case-by-case basis [8, 98].

Management of idiopathic HES (whether single-organ or systemic)Indications

In case of recurrent transient paroxysmal non-severe manifestations (such as most cutaneous or gastrointestinal symptoms), short courses of corticosteroids (topical or systemic) are usually preferred to long-term exposure to treatment.

Conversely, long-term treatment is required in case of severe and/or disabling clinical manifestations, or in case of recurrent paroxysmal events.

First-line treatment: topical and/or systemic corticosteroid therapy

Corticosteroid therapy is generally the first-line treatment for idiopathic HES, and rapid response (complete or partial) is the norm.

Depending on the clinical manifestations, the use of locally active steroids (topical corticosteroids, orodispersible budesonide for esophagitis, gastro-resistant budesonide for lower GI manifestations and inhaled corticosteroid therapy or nasal spray) is encouraged to reduce the use of systemic corticosteroids.

When organs not accessible (or resistant) to topical corticosteroids are involved, systemic corticosteroids are the first-line treatment for idiopathic HES. The loading dose (0.5–1 mg/kg/day prednisone (off-label)), possibly preceded by pulses of methylprednisolone (15 mg/kg/day for 1–3 days) in case of organ- or life-threatening manifestations, should be tailored to the severity of symptoms before gradual tapering. Overall, the minimum effective dose should be used, and weaning should always be discussed: in acute forms, cessation of corticosteroid therapy may be attempted after a few weeks of treatment; in the case of chronic disease, a treatment period of approximately 12 months seems advisable before considering cessation.

Second-line treatments

To minimize the potential adverse reactions of systemic corticosteroid therapy, steroid-sparing treatment may be considered in patients with high dose corticosteroid dependence, considering the patient's specific comorbidities).

To date, being the only drug having been assessed in prospective randomized controlled trials, we currently recommend mepolizumab (300 mg subcutaneous monthly) as the first-line steroid-sparing agent. Contrariwise, all other compounds are prescribed off-label based essentially on the available retrospective data.

Following two clinical trials that demonstrated the superiority of mepolizumab, an IgG1 kappa monoclonal antibody targeting IL-5, vs. placebo in terms of reduction of the number of clinical relapses and steroid-sparing effect, mepolizumab was approved by the FDA in September 2020, by the EMA in November 2021 [99, 100]. Conversely, although preliminary data suggest that mepolizumab could remain efficacious even at lower “asthma” doses (i.e. 100 mg subcutaneous monthly) in other eosinophil-associated diseases (e.g. EGPA or idiopathic chronic eosinophilic pneumonia), it should be emphasized that, to date, standard treatment of HES relies on a full dose regimen i.e. 300 mg mepolizumab subcutaneous monthly [101].

Specifically, we suggest using mepolizumab in the following settings:

Chronic AND idiopathic AND oral-corticosteroid-dependent HES (meaning that the efficacy of oral corticosteroids has previously been established, and that an attempt to withdraw oral corticosteroids has been followed by both a clinical AND a hematological relapse)

Relapsing (either single-organ OR systemic) HES with at least 3 yearly flares requiring short courses of oral costicosteroids.

Under treatment with mepolizumab, once that sustained clinical and hematological remission have been achieved, the tapering (or even withdrawal) of both oral corticosteroids and other cytotoxic-immunosuppressive drugs is strongly encouraged.

Contrariwise, it should also be emphasized that there is to date no rationale for the prescription of mepolizumab either as first-line therapy (even in the setting of organ or life-threatening HES—where systemic corticosteroids, along with antiparasitic treatments and anticoagulants are usually effective, as detailed in “Follow-up of F/P + HE/HES” Section). Likewise, in patients under low dose oral corticosteroids and with no treatment-related side effect, maintenance treatment with low dose oral corticosteroids monotherapy is acceptable.

In case of failure of mepolizumab, further-line steroid-sparing treatments include:

Interferon alfa-2a, an immunomodulatory agent acting on both eosinophilia and Th2-polarized T cells [102]. Currently, only the pegylated form is available (Pegasys®). Although the reported efficacy is relatively high, its safety profile can be a barrier to its use and long-term maintenance [103]. It is therefore standard practice to start with the lowest possible dosage (e.g., 45 µg pegylated interferon alfa-2a weekly by subcutaneous injection) and to increase it gradually monthly if necessary, depending on tolerability. The practicalities of prescribing pegylated interferon alfa-2a are detailed in Box 9.

Hydroxycarbamide, a non-specific myelotoxic agent with anti-eosinophilic activity. In practice, it is usually started at a low dosage (1 g/day in a single dose) and then increased if necessary (up to 2 g/day in a single dose) depending on effectiveness and tolerability [8]. The practicalities of prescribing hydroxycarbamide are detailed in Box 10.

Although its primary indication is clonal HES (specifically F/P + chronic eosinophilic leukemia), imatinib (400 mg/day) may also be used empirically (and off label) in patients with laboratory and clinical findings suggestive of underlying myeloid malignancies (although by definition, idiopathic HES does not show the cytogenetic or molecular abnormalities characteristic of clonal HES) e.g. splenomegaly, elevated vitamin B12 or tryptase, presence of other CBC abnormalities, nonresponse to corticosteroid therapy (or corticosteroid dependence on more than 10 mg/day prednisone) [104]. In the absence of response at 1 month after initiation of imatinib, the latter should be discontinued and replaced by another steroid-sparing drug.

Conventional immunosuppressive agents (cyclosporine, methotrexate, and mycophenolate mofetil): limited data are available regarding their benefit in HES. For the time being, their use in this indication is limited.

Recent preliminary data suggest that benralizumab (a monoclonal antibody targeting the alpha subunit of IL-5 receptor, IL-5Rα) could be a promising treatment for HES [105], and a prospective randomized placebo-controlled trial is underway.

Box 9 Prescribing guidelines for pegylated interferon alfa-2aBox 10 Prescribing guidelines for hydroxycarbamide

In daily practice, pegylated interferon alfa-2a is often favored in young patients because of the theoretical long-term leukemogenic risk of hydroxycarbamide, and the need for male and female contraception during treatment and up to 3–6 months after cessation. However, the indications for treatment with pegylated interferon alfa-2a must be assessed on a case-by-case basis, particularly in patients with a significant psychiatric history, liver disease and/or a history of concurrent underlying autoimmune disease (particularly lupus).

Therapeutic management of lymphocytic HESIndications

If a close clinical and laboratory monitoring is performed, non-treatment is perfectly acceptable in asymptomatic patients with lymphocytic HE.

In the event of clinical manifestations attributable to eosinophil toxicity and/or to the abnormal T-cell population (lymphocytic HES), treatment strategies (with a preference for topical corticosteroids and short-term rather than long-term treatment) share similarities with those previously described for the management of idiopathic HES, with the noteworthy exception that there is solid data supporting the use of Interferon alfa-2a in this setting.

First-line treatments

In general, lymphocytic HES is highly responsive to corticosteroids.

Topical corticosteroids can be effective on localized inflammatory lesions, keeping in mind the cumulative dose.

Inhaled corticosteroids are recommended for recurrent and/or persistent moderate respiratory manifestations.

Oral corticosteroid therapy is the usual first-line treatment of lymphocytic HES. The loading dose (0.5–1 mg/kg/day prednisone) should be tailored to the severity of the symptoms related to eosinophilia, before gradual tapering. Overall, the lowest effective dose should be used and weaning attempted as early as possible.

Second-line treatments

Mirroring the fact that lymphocytic HES is usually highly sensitive to systemic corticosteroids, high-dose steroid dependence is also common (possibly due to high levels of serum IL-5 and/or persistent underlying T-cell lymphoproliferative disease). To minimize the potential adverse reactions of systemic corticosteroids, steroid-sparing treatment may be considered in steroid-dependent patients.

Currently mepolizumab and interferon alfa-2a are the preferred first-line steroid-sparing treatments for lymphocytic-HES patients with high-dose corticosteroid dependency.

Interferon alfa-2a, an immunomodulatory agent acting on both eosinophils and Th2-polarized T cells. Retrospective of both series Both Belgian, Canadian, and French retrospective showed marked clinical and hematological efficacy [10, 11, 106]. Nevertheless, the drug tolerability can be a barrier to its use and long-term maintenance. In daily practice, to minimize potential side effects and to promote adherence to treatment, we suggest starting at the lowest possible dose of the pegylated form (e.g., weekly subcutaneous injections 45 µg pegylated interferon alfa-2a) and to increase it gradually based on tolerability.

Mepolizumab has also showed efficacy and steroid-sparing effect in lymphocytic HES, with a presumed better safety profile than interferon [107]. Yet persistent symptoms (despite normal absolute eosinophil counts) have also been reported [11].

In case of failure of both mepolizumab and interferon, further-line steroid-sparing drugs may be discussed in expert centers. These include:

A few cases of successful treatment of refractory lymphocytic HES with romidepsin have been reported [108]. However, the small number of cases (n < 5) and short follow-up do not currently make it possible to clearly define the place of this compound in the therapeutic arsenal against lymphoid variant of HES, the indication of which may be discussed in a multidisciplinary team meeting.

The membrane expression of CCR4 by clonal T cells suggests that mogamulizumab may be of interest, but its relevance remains to be determined.

Following the identification of acquired abnormalities in factors affecting the JAK-STAT signaling pathway (including gain-of-function mutations of STAT3) in lymphocytic HES [108, 109], the potential effectiveness of JAK inhibitors (ruxolitinib and tofacitinib) has been suggested in small case series, surprisingly even in the absence of gene mutations of the JAK/STAT pathway [110, 111].

Despite an attractive rationale for their use, limited data are available on immunosuppressive agents that can target T cells, such as cyclosporine, methotrexate, and mycophenolate mofetil.

Therapeutic management of reactive HES (other than lymphocytic)

As a general rule, when an underlying factor is identified as the cause of HE/HES, its management is based on the etiological treatment of the underlying disorder (discontinuation of the causal drug/antiparasitic treatment/chemotherapy).

In addition, in the event of organ involvement related to eosinophil toxicity, oral corticosteroid therapy may be recommended at the acute phase, pending the effects of the etiological treatment, and with the aim of weaning the patient from systemic steroids within than three months, if possible.

Management of HE of undetermined significance

The management of HEUS is not standardized. Some teams have reported prolonged follow-up (several years) in patients with significant HE (sometimes > 5.0 × 109/L in the absence of any treatment [12]. However, the time between the onset of HE and the first related clinical manifestation can also be prolonged. The therapeutic approach should therefore be discussed with patients on a case-by-case basis, depending on their possible comorbidities, their understanding of the situation and their compliance with follow-up. Although there is no strict correlation between the levels of blood HE and tissue HE, it is conceivable not to initiate treatment in patients with asymptomatic HE < 5.0 × 109/L b

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