INTRODUCTION — The hypereosinophilic syndromes (HES) are a group of rare disorders marked by the sustained overproduction of eosinophils, in which eosinophilic infiltration and mediator release cause damage to multiple organs. The urgency of treatment and choice of therapy is based on the patient's presentation, as well as laboratory findings and the results of mutational analysis.
The treatment and prognosis of HES will be reviewed here. The clinical features, pathophysiology, evaluation, and diagnosis of HES are discussed separately. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis".)
OVERVIEW — Some patients with HES require immediate treatment, while others can be safely monitored.
Goals of therapy — The overall goals of therapy are reduction of the absolute eosinophil count (AEC), amelioration of signs and symptoms, and prevention of disease progression .
Timing — The urgency with which patients are treated depends on the severity of hypereosinophilia (HE) and the presence of signs and symptoms of the disease :
●In rare instances, patients may present with extremely elevated eosinophil levels (eg, AEC above 100 x 109/L [>100,000 cells/microL]) or signs and symptoms of hyperleukocytosis. In these situations, hypercellularity should be rapidly reduced before additional treatments are considered. (See 'Immediate treatment for severe disease' below.)
●The majority of patients are symptomatic and have less severe degrees of eosinophilia. The goals of pharmacologic therapy are to reduce the signs and symptoms of eosinophilic disease and to maintain the AEC below 1.5 x 109/L (1500 cells/microL) to help prevent the development of end-organ damage.
Choice of initial therapy — The choice of the initial therapeutic agent or agents for a given patient depends mainly on whether the patient has clinical features consistent with a myeloid disorder (eg, dysplastic eosinophils) with or without a FIP1L1::PDGFRA fusion. Patients with myeloid variants (eg, PDGFRA-positive HES) are treated initially with imatinib mesylate, while those with other types of HES are treated with an initial trial of glucocorticoids.
Patients who can be observed initially — Two groups of patients who can be safely managed with close observation are:
●Asymptomatic familial eosinophilia – Familial eosinophilia with autosomal dominant transmission is described. Patients without clinical manifestations or evidence of organ involvement can be observed and monitored. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Familial HES'.)
●Hypereosinophilia of unknown significance (HEus) – These patients present with asymptomatic but marked eosinophilia AEC >1.5 x 109/L (>1500 cells/microL) and no evidence of clinical manifestations or organ involvement. HEus is not considered a form of HES, because eosinophil-mediated complications are absent.
Patients in these groups do not require therapy initially but should be monitored regularly for the development of clinical manifestations, since progression to more aggressive forms of HES can occur. (See 'Monitoring' below.)
IMMEDIATE TREATMENT FOR SEVERE DISEASE
Indications for emergency treatment — There are certain uncommon circumstances in which patients with hypereosinophilia (HE) should be treated immediately (algorithm 1):
●Extremely elevated eosinophil levels (eg, absolute eosinophil count [AEC] >100 x 109/L; >100,000 cells/microL).
●Signs and symptoms of leukostasis (ie, pulmonary or neurologic dysfunction in the setting of a white blood cell count >50 x 109/L [>50,000 cells/microL]). (See "Hyperleukocytosis and leukostasis in hematologic malignancies", section on 'Signs and symptoms'.)
●Signs and symptoms or other evidence of potentially life-threatening complications of HE (eg, acute heart failure, thromboembolic events). These can include:
•Evidence of likely developing eosinophil-mediated cardiac damage (based on either clinical findings or elevated serum troponin levels when cardiac impairment is not yet clinically evident).
•Thromboemboli, often of cardiac origin and arterial, can present as diffuse watershed central nervous system (CNS) infarctions or focal CNS thromboemboli (check for retinal hemorrhages and splinter hemorrhages) .
•For those with pulmonary involvement, computed tomography (CT) imaging of the chest demonstrating substantial eosinophil-associated disease (eg, extensive interstitial infiltrates, ground glass opacities, condensation) in concert with clinical symptoms can necessitate immediate treatment.
Studies to obtain urgently — Important tests to exclude other disorders in the differential diagnosis that can be obtained should be performed, particularly if glucocorticoid therapy is imminent, as therapy may alter the results. We suggest obtaining blood for the following studies before initiating therapy, although it is not necessary to wait for the results:
●Complete blood count with differential to determine abnormalities of other cell lines. Absolute numbers of other white blood cells must be determined because relative percentages may be lowered in the setting of increased eosinophils.
●Peripheral blood smear (to evaluate for immature white blood cells, dysplastic features that would suggest primary hematologic disorder) should be reviewed and kept for future reference.
●Tests of hepatic and renal function (for evidence of hepatic involvement or renal insufficiency).
●Troponin (for evidence of subclinical eosinophil-associated myocarditis).
●Vitamin B12 (elevated in myeloid variants of HES [M-HES], other myeloid neoplasms, and autoimmune lymphoproliferative syndrome [ALPS]).
●Serum tryptase (most consistently elevated in M-HES, variable in other subtypes).
●Antineutrophil cytoplasmic antibodies (ANCA) for patients with features suggestive of eosinophilic granulomatosis with polyangiitis (EGPA), such as asthma and chronic rhinosinusitis with nasal polyposis. (See "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)
●Lymphocyte phenotyping by flow cytometry (may show abnormal T cell subsets in lymphocytic variants of HES [L-HES] or lymphoid malignancy).
●Blood for genetic analyses, namely FIP1L1::PDGFRA mutational analysis, BCR::ABL1, and T cell receptor (TCR) gene rearrangement studies (to detect T cell clonality as seen in peripheral T cell lymphoma or L-HES), although these are unaffected by glucocorticoid therapy.
When possible, it is also advisable to draw some extra samples of blood and serum to be frozen in case there are additional tests needed later or new etiologies or mutations are identified in the future for which the patient could be tested.
In addition to the tests listed above, we try to obtain:
●A bone marrow aspirate and biopsy prior to the administration of high-dose glucocorticoids, if possible, since glucocorticoids can alter the interpretation of these studies. Material should be obtained for cytogenetic analysis.
●A high resolution chest CT or if not available, a chest radiograph (for evidence of pulmonary involvement).
Further evaluation is discussed separately. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis'.)
High-dose glucocorticoids — High-dose intravenous glucocorticoid therapy is indicated for any of the situations outlined above. Intravenous dosing is preferred to ensure adequate drug delivery in patients who are acutely ill or have gastrointestinal involvement. (See 'Indications for emergency treatment' above.)
The mechanism of action of glucocorticoids in HES is not entirely clear. Glucocorticoids interfere with eosinophilopoiesis, but this is unlikely to account for the observation that eosinopenia may occur as early as four hours after glucocorticoid administration . Accelerated apoptosis and/or sequestration of eosinophils may also play a role .
It is critical to assess the patient's risk of Strongyloides infection prior to the administration of glucocorticoids, since glucocorticoids can precipitate potentially fatal dissemination in infected patients.
Assess for risk of Strongyloides infection — Prior to the administration of glucocorticoids, the patient's risk of Strongyloides infection must be assessed, since glucocorticoids can precipitate potentially fatal dissemination in infected patients (hyperinfection syndrome). Individuals with any potential exposure to Strongyloides should be treated empirically for strongyloidiasis with ivermectin (200 mcg/kg daily for two days). This may be given concomitantly with glucocorticoids, since the latter should not be delayed. Strongyloides is endemic in tropical and subtropical regions (ie, bordering the tropical regions to the north or south) worldwide and occurs sporadically in temperate areas. In the United States, the highest rates of infection are among residents from rural areas of the southeastern states. All at-risk individuals should be treated, even if the serology is negative, because the reliability of serologic testing is variable, and stool examination for larvae is insensitive. (See "Strongyloidiasis", section on 'Serology'.)
Dosing — High-dose intravenous glucocorticoids are initiated at doses ranging from 1 mg/kg of prednisone to 1 gram of methylprednisolone. For most patients, 1 mg/kg of prednisone is appropriate, but if the clinical presentations and associated complications are acute and life-threatening, pulses of 1 gram of methylprednisolone should be administered for one to two days.
Expected response — In response to high-dose glucocorticoids, the eosinophil count typically either drops dramatically (eg, by more than 50 percent of the original value) within 24 hours or remains the same (no response).
Most patients who respond can be stabilized within one week. If there is minimal initial response, then glucocorticoids alone are unlikely to be effective for that patient, although glucocorticoids are usually continued until a second agent has been added and a decrease in blood eosinophil count is seen.
Acute therapies in steroid-unresponsive patients — For patients with features of EGPA (ie, asthma, sinus disease, pulmonary infiltrates) and severe organ involvement (cardiac, renal, neurologic) who are unresponsive to glucocorticoids, we favor treatment with either cyclophosphamide or rituximab [6,7]. (See "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis", section on 'Severe EGPA'.)
•Imatinib mesylate – At doses of 400 mg daily, this agent may be effective in some steroid-refractory patients, since these patients may have FIP1L1::PDGFRA-positive HES or another mutation involving an imatinib-sensitive tyrosine kinase, and it is relatively less toxic than vincristine. Imatinib must be administered in conjunction with glucocorticoids in patients with evidence of cardiac involvement (eg, elevated serum troponin suggesting myonecrosis). A response typically occurs within one to several days in FIP1L1::PDGFRA-positive patients but may only be apparent after several weeks in FIP1L1::PDGFRA-negative patients. (See 'Imatinib mesylate' below and 'Concomitant glucocorticoids in patients with cardiac disease' below.)
•Vincristine – The cytoreductive agent vincristine has been administered at doses of 1 to 2 mg/m2 intravenously, weekly to monthly, in a subset HES patients requiring urgent therapy, ie, those with extremely elevated blood leucocytes and those with signs/symptoms of leukostasis . Glucocorticoids are continued when vincristine is added. In responsive patients, eosinophil counts begin to fall within hours.
•Hydroxyurea – In patients who fail to respond to high-dose glucocorticoids, hydroxyurea may be administered orally at an initial dose of 500 to 1000 mg/day and quickly increased to 2000 mg/day, as tolerated, if the response is suboptimal. Of note, a response to this agent can take one to two weeks to become evident. High-dose hydroxyurea (50 to 100 mg/kg as a single dose; maximum dose 6 grams) can be used to rapidly lower eosinophil counts in patients with eosinophilia >100 x 109/L who do not respond to glucocorticoid therapy. (See 'Hydroxyurea' below.)
Once the patient has stabilized and eosinophil counts are lowered, a full evaluation can proceed, as discussed separately. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Evaluation and diagnosis'.)
NON-EMERGENCY TREATMENT — For patients who do not require immediate therapy, the first decision is whether to initiate therapy or simply monitor the patient at regular intervals. (See 'Monitoring' below.)
Patients with known or suspected imatinib-sensitive variants (eg, most commonly PDGFRA-positive myeloid variants of HES [M-HES]) are treated initially with imatinib mesylate (with concomitant glucocorticoids if there is evidence of cardiac involvement), while those with other types of HES, such as lymphocytic variants of HES (L-HES) or idiopathic HES, are initially treated with glucocorticoids alone.
Myeloid variants — Patients with M-HES have clinical features consistent with a myeloid disorder or have a specific gene mutation (eg, FIP1L1::PDGFRA fusion). (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Myeloproliferative HES variants'.)
PDGFRA-positive HES — Patients with PDGFRA-positive HES often have an aggressive course with disabling complications and high mortality in the absence of treatment. However, this is not universal, and case reports describe patients presenting with minimal symptoms (eg, cough) in whom the disease did not progress for several years . Conversely, it cannot be assumed that patients with mild disease do not have the FIP1L1::PDGFRA mutation. Thus, a more nuanced understanding of the clinical significance of the FIP1L1::PDGFRA mutation is developing over time.
First-line therapy for all patients with the FIP1L1::PDGFRA mutation is the tyrosine kinase inhibitor, imatinib mesylate. This should be offered to all patients. Treatment should be initiated as soon as the diagnosis is established to prevent progression of cardiac disease and other severe end-organ damage. If mutational analysis is not available and treatment is required, the presence of a markedly elevated serum B12 level (>2000 pg/mL) and/or an elevated serum tryptase level (>11.5 ng/mL) and/or splenomegaly can be a marker for the presence of the FIP1L1::PDGFRA mutation .
Imatinib mesylate — Imatinib mesylate is a potent inhibitor of ABL, KIT, PDGFRA, and platelet-derived growth factor receptor beta (PDGFRB) kinase activities [12,13]. It induces disease remission and prevents progression of disease in sensitive patients. Patients with potential cardiac disease, as assessed by elevated serum troponin levels and/or abnormalities on echocardiography, should receive concomitant glucocorticoids when therapy with imatinib is initiated to prevent acute necrotizing myocarditis. (See 'Concomitant glucocorticoids in patients with cardiac disease' below.)
The FIP1L1::PDGFRA fusion is exquisitely sensitive to imatinib, and doses required to induce molecular remission are lower than those used for treating chronic myeloid leukemia (CML). Studies have demonstrated clinical, hematologic, and molecular remission in the majority of patients with FIP1L1::PDFGRA-associated HES who are treated with imatinib [12,14-22]. Clinical symptoms due to hypereosinophilia (HE) resolve and eosinophil counts normalize generally within one to two weeks. In contrast, cardiac symptoms due to structural abnormalities resulting from endomyocardial fibrosis and fixed neurologic deficits may not improve with imatinib therapy [17,23,24]. (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'Clinical features'.)
●Retrospective review of patients with glucocorticoid-resistant FIP1L1::PDGFRA-positive myeloid neoplasm reported complete hematologic response (CHR) in all 148 patients treated with imatinib; all 84 patients who were monitored by molecular testing achieved complete molecular response . Among 46 patients who discontinued imatinib, 57 percent relapsed. Rates of overall survival (OS) at 1, 5, and 10 years were 99, 95, and 84 percent, respectively.
●In a prospective multicenter study of 72 Italian patients with idiopathic or primary HES, 63 were treated with imatinib, 100 to 400 mg/day . Of the 63 male patients, 27 carried the FIP1L1::PDGFRA rearrangement. These 27 achieved CHR and remained in remission at the time of publication (median follow-up of 25 months). Treatment was continued indefinitely at doses of 100 to 400 mg/day.
Because HES requires lower doses of imatinib than CML, dose-related side effects, such as myalgia, peripheral edema, and diarrhea, are uncommon in patients with HES. However, serious complications requiring immediate interruption of treatment have been reported and include neutropenia, life-threatening myocarditis, and hepatic necrosis [15,20,23,27]. Imatinib therapy can usually be reinitiated once the complication has resolved . (See 'Concomitant glucocorticoids in patients with cardiac disease' below.)
Primary resistance to imatinib in patients with the FIP1L1::PDGFRA mutation has been uncommonly reported . In one patient, two point mutations were detected in the PDGFRA domain, the functional significance of which has not been explored . Secondary resistance is discussed below. (See 'Imatinib-resistant disease' below.)
Dosing — Understanding of the most appropriate dose and duration of imatinib therapy is evolving. We suggest an initial dose of 400 mg per day, given orally. Typically, symptoms improve, and eosinophil counts normalize within one to two weeks after initiation of imatinib. In patients who do not respond within two to four weeks, imatinib should be discontinued and other therapies considered. For those who respond, the maintenance therapy is administered at a reduced dose. (See 'Maintenance therapy' below.)
Initial doses of imatinib as low as 100 mg daily (or even weekly) have proven effective in controlling the eosinophilia and clinical symptoms in most patients with the FIP1L1::PDGFRA mutation [31-33], although molecular evidence of the FIP1L1::PDGFRA mutation may persist on low-dose therapy [20,34]. Experience with imatinib in the treatment of CML suggests that clinical relapse is more common in patients with detectable residual disease, and so initiating therapy at a higher dose (400 mg daily) may be preferred.
Concomitant glucocorticoids in patients with cardiac disease — Imatinib is generally well tolerated. However, patients with HES and cardiac involvement, as assessed by echocardiographic evidence of myocarditis and/or elevated serum troponin levels, may be at risk for left ventricular dysfunction and cardiogenic shock when imatinib treatment is initiated. Presumably, the mechanism involves massive release of eosinophil granule proteins and subsequent damage to the myocardium, although this has not been conclusively demonstrated. Heart failure was reportedly reversible with prompt institution of systemic glucocorticoids, intensive support, and discontinuation of imatinib [15,23]. Therefore, concomitant treatment with systemic glucocorticoids (prednisone 1 to 2 mg/kg daily or equivalent) for one to two weeks when imatinib is initiated is recommended for patients with any evidence of cardiac involvement (even limited to asymptomatic elevations in troponin levels) .
Family planning — Imatinib is a potential teratogen, although data are limited and mostly come from the use of imatinib in the setting of CML. Preclinical studies have reported teratogenicity of imatinib in some animals but not others . Human case reports have described significant congenital abnormalities in the offspring of some women treated with imatinib, and women are advised to take measures to avoid pregnancy while taking this agent . Imatinib is also contraindicated in lactating women.
●We advise male patients who require imatinib that it may cause oligospermia and reduced fertility, although it is unclear how often this occurs [35,37,38]. The available data regarding men receiving imatinib for CML are mostly reassuring, and successful pregnancies have been reported [39,40]. If a male patient's female partner becomes pregnant, the patient should use barrier protection in order to limit exposure of the developing fetus to imatinib.
●For women requiring imatinib, we advise effective contraception to prevent pregnancy . Whether imatinib therapy will affect future fertility in women is unknown. Primary ovarian insufficiency associated with imatinib therapy has been described in a case report . For women who do become pregnant while taking imatinib, advice is more difficult. Some couples have decided on therapeutic termination of the pregnancy, others have continued treatment throughout the pregnancy, and still others have discontinued imatinib and were treated with other agents (eg, interferon) during the remainder of the pregnancy, with reinstitution of imatinib following delivery [36,42]. It may also be possible to discontinue imatinib therapy once the patient has entered remission. (See 'Maintenance therapy' below.)
Maintenance therapy — Once symptoms improve and eosinophil counts normalize, which usually occurs within one to two weeks after initiation of imatinib, the dose should be reduced to the lowest effective dose that maintains suppression of polymerase chain reaction (PCR)-detectable FIP1L1::PDGFRA transcript levels, as well as blood eosinophilia. This dose is then continued for several years.
Although early reports suggested that reducing or stopping imatinib in patients with the FIP1L1::PDGFRA mutation resulted in return of transcripts in at least 50 percent of patients [22,34,43,44], a subsequent study suggested that patients who achieve complete molecular remission and continue imatinib therapy for a prolonged period (ie, ≥7 years) are less likely to relapse after imatinib discontinuation . This is consistent with observations in CML. The optimal duration of therapy has not been determined, but we suggest continuing imatinib therapy for at least seven years.
The strategy used to determine a maintenance therapy dose differs depending on the resources available. Imatinib 100 mg daily is frequently employed for maintenance when cost is not limiting. If cost is an issue, the dose may be gradually reduced (eg, to 100 mg every other day, then 100 mg twice per week, and then 100 mg weekly). If the gene transcript reappears, the dose should be increased to the last dose that suppressed it. Molecular remission should then be confirmed again.
Imatinib-resistant disease — A few cases of acquired resistance to imatinib among FIP1L1::PDGFRA-positive patients have been reported. Testing for resistance mutations in blood or bone marrow is commercially available . These were most commonly associated with a single base (T6741) substitution in the imatinib-binding portion of the kinase, similar to the T3151 mutation in ABL described in imatinib-resistant CML [12,20]. A second mutation, D842V, which is known to cause imatinib resistance in gastrointestinal stromal tumors associated with PDGFRA mutations, has also been reported in FIP1L1::PDGFRA-positive HES . The best approach to managing patients with acquired imatinib resistance has not been extensively studied, although options include increasing the dose of imatinib, use of other tyrosine kinase inhibitors (eg, dasatinib or nilotinib), or allogeneic hematopoietic cell transplantation (HCT). If not already pursued, referral to a center with expertise in HES should be arranged. (See 'Hematopoietic cell transplantation' below.)
Other tyrosine kinase inhibitors — Although imatinib is the only commercially available tyrosine kinase inhibitor with proven activity in HES, several agents with activity against PDGFR, including dasatinib, sorafenib, and nilotinib, are available for other clinical use [12,48-50]. Nilotinib was studied in a phase 2 trial that included 12 patients with HES . Sorafenib showed efficacy in a case report of imatinib-resistant HES, although the duration of response was short-lived . (See "Overview of the treatment of chronic myeloid leukemia", section on 'Treatment of disease resistance or drug intolerance'.)
Other myeloid variants — Some patients with HES and features of myeloid disease have responded to imatinib despite a negative test for the FIP1L1::PDGFRA mutation [12,52-54]. These individuals usually have an aggressive clinical course, dysplastic eosinophils in the peripheral blood, and bone marrow findings consistent with chronic myeloid disease. Some cases have mutations involving PDGFRA or PDGFRB with other fusion partners [53-55]. While testing for these alternative mutations is not widely available, the vast majority of patients with PDGFRB mutations will have translocations involving 5q31-33, including t(5;12) . Imatinib therapy may be considered for patients presenting with HES and features of myeloid disease (ie, after an initial glucocorticoid challenge but before any other therapeutic intervention). In one study, the response rate was 54 percent in patients with four or more features of myeloproliferative disease .
The starting dose of imatinib is 400 mg daily. Responses may be slower than in PDGFRA-positive disease, and dose escalation up to 800 mg daily may be considered in patients with inadequate response . In patients who do not respond within one to three months, imatinib should be discontinued and other therapies considered, such as hydroxyurea or interferon alfa. Otherwise healthy patients with treatment refractory HES may be candidates for allogeneic HCT. (See 'Steroid-sparing and second-line therapies' below and 'Hematopoietic cell transplantation' below.)
Several small reports have described the activity of imatinib in the treatment of patients with myeloid neoplasms with a PDGFRB fusion gene [57-59]. As an example, a retrospective analysis of 26 patients with myeloid neoplasms with PDGFRB rearrangements treated with imatinib (100 to 400 mg daily) and followed for a median of 10.2 years reported an overall response rate of 96 percent [52,54]. Most patients who achieved a hematologic response did so within two months, suggesting that a three-month trial was sufficient. At the time of publication, no relapses had occurred in the 13 patients who achieved a complete cytogenetic response or in the 8 patients who achieved a molecular remission. The estimated progression-free survival at six years was 88 percent. Two patients died: one of invasive fungal infection after transformation to blast crisis, and one of intracranial hemorrhage due to thrombocytopenia.
PDGFRB-associated myeloid neoplasms usually present with features consistent with chronic myelomonocytic leukemia (CMML). Although peripheral eosinophilia can be marked, eosinophilic end-organ manifestations are uncommon. The clinical presentation and management of PDGFRB-associated myelodysplastic/myeloid neoplasms (MDS/MPN) are reviewed separately. (See "Treatment of lower-risk myelodysplastic syndromes (MDS)", section on 'MDS/MPN'.)
HES without myeloid features — HES without myeloid features includes T cell lymphocytic variants (L-HES) and idiopathic HES (table 1). Glucocorticoids are the initial therapy of choice for patients with organ involvement who do not have the FIP1L1::PDGFRA fusion or another imatinib-sensitive tyrosine kinase mutation (eg, PDGFRA with other fusion partners).
Second-line therapies are used for patients whose disease has not responded to glucocorticoids or in combination with glucocorticoids as steroid-sparing agents. (See 'Steroid-sparing and second-line therapies' below.)
When to treat
●Symptomatic patients or those with evidence of end-organ damage should be initiated on therapy.
●Some patients with intermittent symptoms, such as angioedema, urticaria, and gastrointestinal symptoms, can be treated with short courses of glucocorticoids, as needed, if the interval between flares is long . (See 'Monitoring for organ involvement' below.)
●Asymptomatic patients (hypereosinophilia of undetermined significance [HEUS], familial eosinophilia) or those with very mild or recurrent symptoms with long disease-free intervals need not necessarily be treated, but should be monitored every three (at the beginning) to six months for the development of organ involvement and watched for signs and symptoms of cardiovascular and thrombotic complications.
Glucocorticoids — Prednisone is the primary initial therapy for symptomatic FIP1L1::PDGFRA-negative HES without indications for emergency treatment. Appropriate starting doses range from 20 to 60 mg daily, depending on the severity of the disease manifestations and the degree of eosinophilia at presentation. The dose should be adjusted once the patient responds. (See 'Adjusting therapy after initial response' below.)
Prior to administration of glucocorticoids, the clinician must assess the risk of Strongyloides infection and treat any patients with possible exposure with ivermectin. (See 'Assess for risk of Strongyloides infection' above.)
If the eosinophil count does not respond within one week to the initial dose, the dose should be increased. Higher doses (eg, intravenous methylprednisolone, 1 gram daily or 15 mg/kg/day) can be administered for a few days, and some patients may require very high doses initially. However, this dose is too toxic for extended use, and alternative steroid-sparing regimens should be planned. (See 'Steroid-sparing and second-line therapies' below.)
Efficacy — A few studies have provided information about the efficacy of glucocorticoids.
●In a large series of 188 HES patients, 75 percent received glucocorticoids alone as initial therapy, and partial or complete remission was achieved in 85 percent at one month .
●In a second study of 164 patients with FIP1L1::PDGFRA-negative HES, 90 percent of the group responded to glucocorticoids, where response was defined as a reduction of the absolute eosinophil count (AEC) to <1000 cells/microL and control of symptoms . The disease variant was the best and only predictor of response to glucocorticoids. Patients with idiopathic HES or overlap HES (single organ involvement or HES with features of eosinophilic granulomatosis with polyangiitis [EGPA]) were more responsive than those with M-HES or L-HES (table 1).
Adjusting therapy after initial response — Once blood eosinophilia is suppressed and symptoms are controlled, daily glucocorticoid doses are gradually reduced to the lowest dose that maintains control of the eosinophil count and clinical manifestations. In the large series mentioned previously, patients were able to reduce the dose of glucocorticoids to a median dose of prednisone of 10 mg per day . However, 42 percent of 179 patients who were initially treated with glucocorticoids discontinued them, either because of disease resistance or adverse effects.
The tapering schedule is highly variable and should be guided by the severity of the presenting clinical complications and the extent to which eosinophil suppression has been achieved by treatment. Doses can be tapered more rapidly in patients with complications that are not life-threatening and in those whose eosinophil levels plummet dramatically after initiation of glucocorticoids. Eosinophil levels and clinical manifestations should be monitored weekly at the beginning of therapy, changing to progressively longer intervals depending on the response.
Addition of steroid-sparing agents — Once a stable maintenance dose of glucocorticoids has been reached, the dose may be reduced further by introducing a second steroid-sparing agent. We suggest adding a steroid-sparing agent if the patient requires more than 10 mg prednisone daily or demonstrates significant side effects from glucocorticoid therapy. Selection of a steroid-sparing agent is discussed below.
Steroid-sparing and second-line therapies
Choice of therapy — Selection of a second-line or steroid-sparing agent is informed by pathologic/molecular features, toxicity profile, comorbid conditions, availability, and cost. No studies have directly compared various agents regarding outcomes and toxicity, and no agent is optimal for all patients. Our approach to the choice of agent follows:
●Suspected myeloid malignancy – For patients with myeloproliferative features suggestive of a myeloid malignancy, we generally treat with imatinib.
For patients who do not respond adequately to imatinib, we favor treatment with mepolizumab. Where mepolizumab is not available or for patients who do not respond after three to six months of mepolizumab treatment, other options include hydroxyurea, interferon alfa, and kinase inhibitors (eg, tofacitinib, ruxolitinib); these agents are usually administered in conjunction with glucocorticoids.
●Clonal T cells (eg, L-HES) – For patients with abnormal clonal T cells (eg, L-HES), we favor treatment with mepolizumab, although the responses are not as robust as with myeloid malignancies [61,62]. If mepolizumab is not available, addition of interferon alfa to glucocorticoid therapy is an acceptable alternative.
For patients who do not respond adequately to several pharmacologic agents, allogeneic HCT may be considered.
Mepolizumab — Mepolizumab is a monoclonal antibody directed against interleukin-5 (IL-5), a growth factor that is critical for eosinophil maturation, activation, and survival. Mepolizumab can be beneficial in glucocorticoid-sensitive HES, including idiopathic HES, lymphocytic variants of HES (L-HES), and HES/eosinophilic granulomatosis with polyangiitis (EGPA) overlap .
Mepolizumab 300 mg (given as three separate 100 mg injections) is administered subcutaneously once every four weeks; note that this dosing is significantly higher than that approved for asthma. Mepolizumab is generally well-tolerated.
Mepolizumab was shown to be an effective, well-tolerated agent in a multicenter, placebo-controlled, phase 3 trial of 108 patients with FIP1L1::PDGFRA-negative HES . Patients with ≥2 disease flares in the past 12 months and a baseline absolute eosinophil count of at least 1000/microliter were randomly assigned to receive subcutaneous mepolizumab (300 mg) versus placebo every four weeks for 32 weeks, in addition to their existing stable HES therapy. Compared with placebo, mepolizumab was associated with a lower percentage of patients experiencing a subsequent disease flare (28 versus 56 percent of patients); mepolizumab was also associated with a 66 percent reduction in the annualized flare rate and in risk of experiencing a flare. Similar proportions of patients in the mepolizumab and placebo groups experienced on-treatment adverse events (89 versus 87 percent, respectively). Another placebo-controlled phase 3 trial  and other reports [61,65-68] also demonstrated efficacy of mepolizumab as a long-term steroid-sparing agent in HES.
Mepolizumab is approved for treatment of EGPA in adults by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for treatment of HES of ≥6 month duration without an identifiable non-hematologic cause in adults and children ≥12 years .
Hydroxyurea — For patients who have neither L-HES or myeloid features or who are not eligible for mepolizumab, hydroxyurea is a preferred second-line agent. Hydroxyurea has a favorable toxicity profile, low cost, and good efficacy.
Hydroxyurea suppresses eosinophilopoiesis and is usually added to glucocorticoids if steroid toxicity has become dose-limiting or less commonly, used as monotherapy when glucocorticoids have failed . It is administered orally at an initial dose of 500 to 1000 mg/day and increased to 2000 mg/day, as tolerated. Hydroxyurea has relatively few side effects compared with other chemotherapeutic agents, although hematologic toxicity (including thrombocytopenia and anemia) and gastrointestinal side effects may become issues at higher doses [70,71]. Patients should use contraception because hydroxyurea is a teratogen. In HES, this agent is usually given in combination with other agents.
●In one prospective study, combined therapy with hydroxyurea (2000 mg per day) and prednisone (1 mg/kg/day) was administered to 18 patients with FIP1L1::PDGFRA-negative HES, except for three patients who were refractory to glucocorticoid therapy prior to the trial . Among the 15 patients treated with this combination, 9 had a complete response, and 6 had a partial response. After an initial response was observed, doses were tapered progressively, and in most patients, disease was controlled with low-dose hydroxyurea (500 to 1000 mg daily) as a single agent.
●In a series of 188 patients, 36 patients were treated with the combination of hydroxyurea and glucocorticoids, and 25 (69 percent) responded . Of those 18 patients treated with hydroxyurea alone, 13 responded partially or completely.
Interferon alfa — In settings where mepolizumab is not available or in patients not eligible for treatment with mepolizumab, conventional interferon alfa or pegylated interferon alfa are acceptable as second-line therapy for patients with HES who do not respond to glucocorticoids or are GC-dependent and require unacceptable dosing and/or experience toxicity. (See 'Choice of therapy' above.)
In patients who respond only to higher doses of glucocorticoids, interferon alfa is added as a steroid-sparing agent. We usually use it together with low-dose glucocorticoids in patients with L-HES because of a theoretical risk (based on in vitro data) that interferon alfa alone could lead to expansion of the abnormal T cell clones , but this has not been observed in practice. Side effects of interferon alfa include dose-dependent, flu-like symptoms, depression, peripheral neuropathy, fatigue, thyroid dysfunction, induction of autoantibodies, and increased liver transaminases. The interferon dose should be reduced if cytopenias develop or liver enzymes increase and should be discontinued for severe depression.
●Interferon alfa – Doses of interferon alfa for treatment of HES range from 1 to 4 million units per dose subcutaneously, three to seven times weekly. Although the optimal schedule for administration has not been defined, a sample approach is to initiate treatment with 1 million units per injection daily and increase by 0.5 to 1 million units per injection every two weeks until the desired effect is reached or intolerance precludes further escalation. It may take several months to reach the effective dose.
Interferon alfa has been effective in several case series [62,74-79]. In a series of 188 patients, 46 patients received interferon alfa, most with glucocorticoids; response rates to combination therapy and monotherapy were 75 and 50 percent, respectively .
●Pegylated interferon alfa – Pegylated interferon alfa 2a (peginterferon) is associated with efficacy and toxicity that are similar to interferon alfa, but it requires only weekly treatment.
Treatment of seven patients with L-HES with peginterferon (beginning at 45 to 90 micrograms subcutaneous weekly, increasing to a maximum of 180 micrograms weekly) was associated with improved symptoms in all seven; six of the seven patients had a sustained, steroid-free response for a median of 31 months and resolution of eosinophil-related end organ damage . The population of aberrant T cells decreased in all of the patients and four had normalization of their T cell immunophenotype.
The mechanism of action of interferon alfa in HES has not been fully elucidated, although it may involve inhibition of eosinophil differentiation and proliferation and promotion of development of Th1 T-helper lymphocytes .
Imatinib — Some patients with HES and features of myeloid disease have responded to imatinib despite a negative test for the FIP1L1::PDGFRA mutation. A two- to four-week trial of imatinib therapy may be considered in patients presenting with HES and features of myeloid disease (ie, after an initial glucocorticoid challenge but before any other therapeutic intervention). One study found a response rate of 54 percent when four or more features of myeloproliferative disease were present . Glucocorticoids should be continued during this trial in patients with potential cardiac disease, as assessed by elevated serum troponin levels and/or abnormalities on echocardiography. (See 'Other myeloid variants' above.)
In contrast to the subgroups above, imatinib does not appear to be useful in treating L-HES or D816V c-kit mutation-positive systemic mastocytosis with eosinophilia and should not be used in these patients [81-84]. (See "Advanced systemic mastocytosis: Management and prognosis", section on 'Imatinib'.)
Other agents — Other agents that have been used in steroid-unresponsive HES (excluding patients with the FIP1L1::PDGFRA mutation) include methotrexate , cyclophosphamide (useful in patients with eosinophilic vasculitis) [84,85], cyclosporine [26,86], alemtuzumab , Janus kinase (JAK) inhibitors, and azathioprine. Agents that have been tried in small numbers of patients but are rarely used include cladribine, chlorambucil, etoposide , vincristine , and mycophenolate mofetil (MMF) .
In most cases, therapy with chemotherapeutics and immunosuppressive agents should be aimed at controlling organ damage rather than eradicating eosinophilia. Chronic maintenance regimens are more effective and less toxic than courses of aggressive therapy aimed at inducing a hematologic remission of disease .
Alemtuzumab — Some cases of HES will respond to the anti-CD52 antibody alemtuzumab. However, treatment with alemtuzumab is not curative, disease recurs once treatment is interrupted, and severe toxicity (eg, profound immunosuppression) precludes long-term administration. Alemtuzumab has been withdrawn from the United States market but remains accessible through a distribution program for the treatment of several hematologic malignancies .
JAK inhibitors — Tofacitinib and ruxolitinib, inhibitors of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway, have shown efficacy in steroid-refractory HES. (See 'Choice of therapy' above.)
Tofacitinib and ruxolitinib were administered to five patients with either L-HES or idiopathic HES presenting with cutaneous lesions that had not responded adequately to glucocorticoids (and other immunosuppressive agents in three cases). A clinical response and a biologic response (ie, reduction of eosinophilia) was observed in all cases, which allowed for withdrawal of glucocorticoid therapy in all cases but one . This is consistent with another paper reporting a gain-of-function mutation in STAT3 in CD3–CD4+ clonal T cells isolated from one patient with L-HES, leading to overproduction of eosinophil-promoting Th2 cytokines . Minor infections were the only observed adverse events, but follow-up was short (3 to 13 months). (See "Hypereosinophilic syndromes: Clinical manifestations, pathophysiology, and diagnosis", section on 'T cell lymphocytic variants'.)
Other HES variants — Other variants of HES are familial HE, organ-restricted HES, episodic angioedema and eosinophilia (Gleich syndrome), and overlap HES (table 1).
●Patients with familial HE do not require treatment if there is no evidence of end-organ damage .
●Overlap HES – Overlap HES refers to eosinophilic syndromes for which the syndrome definition overlaps with that of HES. These include single organ-restricted disorders, such as eosinophilic gastrointestinal diseases (EGID), chronic eosinophilic pneumonia, eosinophilic fasciitis , eosinophilic cellulitis (Wells syndrome) [97,98], and eosinophilic cystitis [99-101], as well as multisystem disorders, such as EGPA. Although glucocorticoids are the cornerstone of therapy for many of these disorders, therapeutic choices are guided by the specific overlap syndrome (for example, swallowed steroids or dietary therapy are often used for EGID overlap). Chronic eosinophilic pneumonia has been reported to respond well to mepolizumab in several small case series [102-107]. (See "Eosinophilic gastrointestinal diseases" and "Chronic eosinophilic pneumonia" and "Eosinophilic granulomatosis with polyangiitis (Churg-Strauss): Treatment and prognosis".)
●Episodic angioedema with eosinophilia (Gleich syndrome) – This syndrome is characterized by recurrent episodes of multilineage cycling and angioedema that occur approximately every month in the absence of therapy. Accompanying symptoms can include urticaria, fever, significant weight gain, and lymphadenopathy. Elevated serum immunoglobulin M (IgM) and clonal lymphocytes that express CD4 but not CD3 are typical, but these findings also cycle and can be missed . Although most patients respond to intermittent glucocorticoid therapy, some require daily glucocorticoids and/or second-line agents, including mepolizumab [109-111]. Rarely, patients progress to noncyclic HES and more serious end-organ damage .
INVESTIGATIONAL AGENTS — Several  investigational agents have been tried in patients with HES who have failed other therapies. Clinical trials in HES patients have investigated treatment with anti-IL-5 (reslizumab) and anti-IL-5 receptor (benralizumab) antibodies [114,115] and a small molecule of unknown target (dexpramipexole) [116-118].
Clinical trials investigating other targeted therapies may be appropriate for patients with hypereosinophilia (HE) and myeloid features with none of the well-characterized chromosomal rearrangements. In the United States, additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health.
PROBLEM-SPECIFIC INTERVENTIONS — Various interventions may be needed for organ-specific involvement.
Cardiovascular disease — Valve replacement or repair, endomyocardectomy, or thrombectomy can provide benefit to patients with HES who develop valvular compromise or endomyocardial thrombosis or fibrosis . Valve replacement with a bioprosthesis, in contrast to a mechanical valve, is indicated, because thrombosis of mechanical valves has occurred despite therapeutic anticoagulation in patients in whom eosinophilia recurs or cannot be controlled . Of note, imatinib therapy in patients with Fip1-like1-platelet-derived growth factor receptor alpha (FIP1L1::PDGFRA)-associated HES may arrest progression of endomyocardial fibrosis but does not reverse damage unless initiated before the occurrence of structural abnormalities.
Anticoagulation — Anticoagulation with warfarin and/or antiplatelet agents is often instituted once an embolic event has occurred. Warfarin is usually initiated for a mural thrombus in the heart or venous thrombus in an intracranial sinus. However, there is no consensus on the target international normalized ratio (INR). Furthermore, thrombus formation may begin at altered endomyocardial or endothelial sites, so it may not be suppressed by systemic anticoagulation when it is a consequence of local and not systemic proclivity to thrombosis. Anticoagulation is not usually initiated empirically in the absence of an event, as emboli can recur in adequately anticoagulated patients, and efficacy is not certain . Once the eosinophilia is controlled durably with stable therapy, the need for continued anticoagulation should be determined using the same criteria used for patients without eosinophilia. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients" and "Antithrombotic therapy in patients with heart failure".)
Hypersplenism — Splenectomy may be indicated in patients with hypersplenism and/or pain due to splenic distension or infarcts, although it is not indicated in the routine management of HES. (See "Splenomegaly and other splenic disorders in adults", section on 'Abscess and infarction'.)
MONITORING — All patients with HES require monitoring for side effects of therapy, organ involvement, and disease progression. In addition, clinicians must be vigilant for signs or symptoms of thrombotic complications. Monitoring of patients with HES must be individualized. Regular eosinophil counts are recommended with additional testing depending on the therapeutic agent being used and the end organs involved.
Frequency — The frequency of monitoring is also variable. As examples, patients with continued symptoms and eosinophilia despite aggressive therapy may need to be evaluated weekly, while stable patients on chronic low-dose glucocorticoids could be appropriately followed every 6 to 12 months.
Monitoring for organ involvement — End-organ involvement may develop insidiously and is not correlated with the degree of blood eosinophilia. Therefore, all patients, including those who are asymptomatic, should be re-evaluated every three months for the first one to two years after diagnosis with a review of systems to detect new signs or symptoms.
A complete blood count and differential, as well as blood chemistries (including hepatic enzymes and renal function) and troponin should be obtained at each of these visits. If new symptoms or signs are present, the tests listed below should also be performed:
●Electrocardiogram (to evaluate for conduction abnormalities or arrhythmia) and echocardiogram. If serum troponin is elevated and/or if echocardiogram is abnormal, cardiac magnetic resonance imaging (MRI) should be obtained.
●Pulmonary evaluations, including chest computed tomography (CT) and pulmonary function tests as indicated.
Additional testing should be based on signs and symptoms and prior evidence of organ involvement.
Issues relevant to specific subgroups include:
●Patients with FIP1L1::PDGFRA mutation on imatinib should be monitored approximately every three months with a complete blood count with differential and a liver profile once in stable clinical, hematologic, and molecular remission. Troponin should be followed as well, as drug-associated cardiomyopathy has been reported as a rare complication of imatinib in patients being treated for chronic myeloid leukemia (CML) . Optimally, testing for the FIP1L1::PDFGRA transcript by polymerase chain reaction (PCR) or fluorescence in situ hybridization (FISH) should be repeated every three to four months, as this is an early marker of therapeutic failure. In patients with no new symptoms, a yearly echocardiogram is suggested.
●Patients with lymphocytic variants of HES (L-HES) should be evaluated every three to six months with a clinical examination for lymphadenopathy, complete blood count (looking for lymphocytosis and other lineage involvement), serum lactate dehydrogenase, and flow cytometry to quantify the abnormal clone. Patients with an increase in the proportion of aberrant T cells on flow cytometry (eg, CD3–CD4+ cells) are at increased risk for progression to lymphoma and should undergo a repeat bone marrow biopsy, including a karyotype analysis . Enlarged lymph nodes and changing/suspicious skin lesions should also be biopsied. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma".)
Vigilance for thrombotic complications — Thrombotic and thromboembolic events are a major cause of morbidity among patients with HES, and a high degree of suspicion for these complications must be maintained. The available series suggest that about one-quarter of patients with HES develop thromboembolic complications [120,123-125]. These complications are reviewed separately.
Prophylactic use of warfarin and/or antiplatelet agents is not recommended in the absence of documented thrombi, in part because the effectiveness of these interventions is unclear. Recurrent thrombotic events have occurred in adequately anticoagulated HES patients . (See 'Anticoagulation' above.)
PLANNING FOR DISEASE PROGRESSION — Early human leukocyte antigen (HLA) typing for possible allogeneic hematopoietic cell transplantation should be considered for patients with any of the following:
●Potentially life-threatening end-organ involvement (especially cardiac or central nervous system [CNS] involvement)
●Features of myeloid disease (eg, dysplastic eosinophils, anemia, thrombocytopenia, splenomegaly, elevated serum B12 or tryptase)
(See 'Hematopoietic cell transplantation' below.)
HEMATOPOIETIC CELL TRANSPLANTATION — There is limited experience in the use of allogeneic hematopoietic cell transplantation (HCT), including nonmyeloablative HCT, to treat HES [126-132]. This intervention may be useful in patients with treatment refractory HES, particularly those rare patients with imatinib-resistant PDGFRA-associated disease, although the risks of the procedure do not justify its routine use. Transplantation should also be considered for patients with lymphocytic variants of HES (L-HES) who develop T cell lymphoma, which may be resistant to classic chemotherapeutic regimens. (See "Initial treatment of peripheral T cell lymphoma".)
HCT is associated with more morbidity than medical therapy, but for those patients who fail the available pharmacologic therapies, it offers the potential for long-term remission and possible cure .
●One patient with a clonal population of CD3–CD4+ T cells (L-HES) and an intraventricular thrombus was successfully treated with reduced-intensity peripheral blood progenitor cell transplantation (HLA identical brother) and remained in remission 30 months later .
●In another report, two patients were treated with HCT (one with an HLA-matched unrelated donor and the other with a related donor) and remained in remission 10 months after transplantation .
The eligibility for allogeneic transplantation varies by institution. General eligibility criteria are discussed separately. (See "Determining eligibility for allogeneic hematopoietic cell transplantation".)
PROGNOSIS — Features that portend a better prognosis include the absence of cardiac or neurologic involvement, lower eosinophil counts, and steroid-responsiveness [4,5,16,134].
Lymphocytic variants of HES (L-HES) usually represent benign lymphoproliferative disorders, although progression toward full blown T cell lymphoma has been reported in approximately 10 percent of cases [62,135-138]. Malignant progression in such patients may be heralded by the appearance of cytogenetic changes .
Survival — Initial case series of HES showed a poor prognosis, with a mean survival of nine months and a three-year survival of only 12 percent . However, most patients in early series presented with advanced disease and significant cardiovascular compromise. Many deaths that were due to end-stage heart failure or other complications of endomyocardial damage in the past, are amenable to improvements in medical and surgical management . Furthermore, patients with Fip1-like1-platelet-derived growth factor receptor alpha (FIP1L1::PDGFRA)-positive HES, who had an extremely poor prognosis prior to the availability of imatinib therapy, were likely over-represented in these series.
Over time, earlier diagnosis of HES, close clinical and echocardiographic monitoring for heart disease, and improved medical and surgical management of cardiac complications have improved the longevity of HES patients. A 1989 French series of 40 patients (including 17 with an associated myeloproliferative syndrome) reported prior to the availability of testing for mutations in PDGFRA noted an 80 percent survival at 5 years and a 42 percent survival at 15 years . In a subsequent retrospective study of 44 patients with FIP1L1::PDGFRA-positive disease treated with imatinib, all but one were alive at a median follow-up of 52 months . While prospective studies are needed to confirm the good prognosis, these results suggest that the introduction of targeted therapies, including imatinib, has further reduced overall mortality in patients presenting with HES.
SPECIAL CONSIDERATIONS DURING THE COVID-19 PANDEMIC — The coronavirus disease 2019 (COVID-19) pandemic has increased the complexity of cancer care. Important issues include balancing the risk from treatment delay versus harm from COVID-19, ways to minimize negative impacts of social distancing during care delivery, and appropriately and fairly allocating limited health care resources. Additionally, immunocompromised patients are candidates for a modified vaccination schedule (figure 1), other preventive strategies (including pre-exposure prophylaxis), and the early initiation of COVID-directed therapy. These issues and recommendations for cancer care during the COVID-19 pandemic are discussed separately. (See "COVID-19: Considerations in patients with cancer".)
SUMMARY AND RECOMMENDATIONS
●Pharmacologic therapy for the hypereosinophilic syndromes (HES) is determined by a number of factors, including the severity of patient's signs and symptoms, whether the clinical presentation is suggestive of a myeloid neoplasm, and the results of molecular studies (eg, mutational analysis for the presence of FIP1L1::PDGFRA-associated disease). The goals of therapy are reduction of the absolute eosinophil count (AEC), amelioration of signs and symptoms, and prevention of disease progression. (See 'Overview' above.)
●For the rare patient who presents with very high eosinophil levels, symptoms of leukostasis, or potentially life-threatening complications of hypereosinophilia (HE) (eg, acute heart failure, thromboembolic events), immediate therapy should be initiated to rapidly reduce counts. We suggest high-dose intravenous glucocorticoids as an initial intervention (algorithm 1) (Grade 2C). Doses ranging from 1 mg/kg of prednisone to 1 gram of methylprednisolone have been used successfully. Important tests to exclude other disorders in the differential diagnosis and to differentiate disease variants should be performed prior to glucocorticoid administration, although they should not delay treatment. Patients at risk for infection with Strongyloides should be treated with ivermectin, concomitantly with glucocorticoids. (See 'Immediate treatment for severe disease' above.)
●All patients require baseline testing, some of which should be done before initiating therapy, as glucocorticoids, in particular, can alter the results. Once treatment has been initiated, all patients require periodic monitoring for organ involvement, which is not correlated with the degree of blood eosinophilia and may develop insidiously. Patients with aggressive disease should undergo human leukocyte antigen (HLA) typing in preparation for possible allogeneic hematopoietic cell transplantation (HCT). (See 'Studies to obtain urgently' above and 'Monitoring' above.)
●For all patients with the FIP1L1::PDGFRA mutation (even if asymptomatic), we recommend imatinib mesylate for initial therapy, in preference to other available agents (Grade 1B). We also suggest the use of imatinib for patients with HES with myeloproliferative features in the absence of the FIP1L1::PDGFRA mutation who have failed initial treatment with glucocorticoids and/or as glucocorticoid-sparing treatment (Grade 2C). We begin imatinib at a dose of 400 mg/day. Patients with cardiac involvement should receive glucocorticoids (1 to 2 mg/kg daily for one to four weeks) at the same time that imatinib is initiated to prevent acute cardiac injury. Typically, symptoms improve, and eosinophil counts normalize within one to two weeks in patients with the FIP1L1::PDGFRA mutation. In others, this may take longer and/or require a higher dose of imatinib. Thereafter, the dose is reduced to the lowest effective dose that maintains molecular remission and continued for a minimum duration of seven years. It may be possible to withdraw treatment thereafter, provided patients are followed regularly to detect early recurrence of the fusion gene, as prolonged treatment-free remission has been observed. (See 'Imatinib mesylate' above and 'Myeloid variants' above.)
●For patients with the FIP1L1::PDGFRA mutation who develop secondary resistance to imatinib mesylate or are intolerant of it, we suggest a trial of another tyrosine kinase inhibitor, such as dasatinib, nilotinib, or sorafenib (Grade 2C). If not already pursued, referral to a center with expertise in HES should be arranged. (See 'Imatinib-resistant disease' above.)
●For symptomatic patients with HES without myeloid features, including those with lymphocytic variants of HES (L-HES) and idiopathic HES, we recommend systemic glucocorticoids as initial therapy (Grade 1B). We typically administer prednisone at a dose of 20 to 60 mg daily, for one to two weeks. (See 'Glucocorticoids' above.)
•If blood eosinophilia is suppressed, doses are slowly tapered to an alternate-day schedule of the lowest dose that maintains control of the eosinophil count and clinical disease.
•If blood eosinophilia is not suppressed or if the dose of glucocorticoids required to maintain a response is judged excessive (ie, either >10 mg/day and/or poor tolerance), a second agent should be added. The choice of second-line agent depends on the clinical features and suspected underlying cause, as described above. (See 'Steroid-sparing and second-line therapies' above.)
●Patients may require interventions for specific cardiac complications, such as valve replacement or repair, endomyocardectomy or thrombectomy, or anticoagulation if embolic events develop. (See 'Problem-specific interventions' above.)
●For HES patients (with or without the FIP1L1::PDGFRA fusion) who fail pharmacologic management, allogeneic HCT offers a chance of long-term remission. (See 'Hematopoietic cell transplantation' above.)
ACKNOWLEDGMENT — The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.
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