Recently, clinical case reports [5-7] suggested that interferon- may be an effective treatment for patients with the hypereosinophilic syndrome who are resistant to glucocorticoids and hydroxyurea. We examined the effects of interferon- in six patients with the hypereosinophilic syndrome, five of whom were unresponsive to or intolerant of conventional therapy.

Methods

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Men or nonpregnant women 18 years of age or older meeting criteria for the hypereosinophilic syndrome [1-3] were candidates for inclusion in this phase I study. This study was approved by the Institutional Review Board of the Mayo Clinic. After giving informed consent, patients were carefully screened to exclude secondary causes of eosinophilia. Screening entailed taking a general medical history and examination; obtaining bone marrow biopsy specimens (if not previously done); and thoroughly reviewing previous laboratory reports, radiographs, clinical studies, and records of previous or current therapy.

Interferon- 2B (Intron A, Schering-Plough Research Institute, Kenilworth, New Jersey) was administered daily as a single subcutaneous injection. The initial dose of interferon- ranged from 1.0 to 6.25 x 10⁶ U/d and was individualized for each patient depending on clinical status and tolerance. As the eosinophil count decreased, concurrent medications were tapered and, if possible, discontinued. Peripheral blood counts (including hemoglobin, platelet count, and leukocyte count and differential) were measured daily during initial dose escalation and every 3 to 4 weeks thereafter. The goal was to decrease the total eosinophil count by 90% or to fewer than 1000 cells/mm³. Each patient received interferon- for a minimum of 9 months, and a bone marrow biopsy specimen was obtained again after each patient completed at least 9 months of therapy. Serum levels of eosinophil major basic protein were determined in each patient using a specific double-antibody radioimmunoassay [8].

Patient Histories

Figure 1 shows levels of blood eosinophils and interferon- dosages for patients 1 to 6.

View larger version (73K): [in this window] [in a new window]   Figure 1. Summary of blood eosinophil levels and interferon- dosages for all six patients. Time 0 is normalized to the beginning of interferon- treatment for each patient. The solid line shows eosinophils/mm3, the hatched area shows interferon- (MU/d) dosages, and the vertical line at right of hatched area shows end of treatment (death in patient 2).

Patient 1

A 42-year-old white man presented in August 1991 with fatigue, cough, and eosinophilia (leukocyte count, 18.2 x 10⁹/L [18 200/mm³]; 54% eosinophils). He had had no previous response to or had been intolerant of prednisone, hydroxyurea, etoposide, and a combination of cyclosporine and prednisone; he developed cognitive dysfunction, visual loss, and probable central nervous system demyelination (identified by magnetic resonance imaging scan). When he was seen at our clinic in August 1992, he complained of weakness and visual blurring associated temporally with high eosinophil counts. His medications were prednisone (20 mg/d) plus one aspirin per day. His physical examination showed a 1 to 2 out of 6 systolic murmur at the lower left sternal border, which radiated to the cardiac apex, and hypertension of 160 to 170/100 to 110 mm Hg.

The bone marrow specimen showed approximately 30% eosinophils. His serum vitamin B₁₂ and IgE levels were normal. An echocardiogram showed metallic brightness of the anterior mitral leaflet and mitral regurgitation and suggested the presence of an additional tissue layer laterally and inferiorly from the tip of the posterior mitral leaflet to the apex. An electrocardiogram showed evidence of left ventricular hypertrophy with QRS widening. Test results from methacholine inhalation challenge indicated the presence of reactive airway disease. The leukocyte count was 17.5 x 10⁹/L (17 500/mm³) with 52% eosinophils, 25.5% segmented neutrophils, 1.5% bands, 2% basophils, and 16.5% lymphocytes. The hemoglobin level was 135 g/L, and the platelet count was 133 x 10⁹/L.

The patient was started on subcutaneous interferon- (1 MU/d) in August 1992, and his dosage was increased as tolerated to 3.5 MU/d at 14 weeks. The total leukocyte count and percentage of eosinophils decreased to 5.8 x 10⁹/L (5800/mm³) and 10%, respectively; however, because of thrombocytopenia (63 x 10⁹/L), the dosage of interferon- was subsequently decreased. He has continued receiving a maintenance interferon- dosage of 1.5 to 2.0 MU/d for 23 months; his total leukocyte count stabilized at 3.7 x 10⁹/L (3700/mm³) with 9% eosinophils. During therapy with interferon-, the serum level of eosinophil major basic protein decreased from 9020 to 3174 ng/mL (normal level, 538 ±144 ng/mL). He discontinued prednisone therapy. Since then, his clinical symptoms have included paroxysmal cough and dyspnea unresponsive to glucocorticoids; pansinusitis shown by computed tomographic scanning; and recurrent abdominal discomfort, vomiting, and diarrhea. He has fixed visual and neurologic deficits, particularly of fine motor movements, neither of which have progressed since he started interferon- therapy.

Patient 2

A 23-year-old white man presented to our clinic in July 1990 with chest and abdominal pain and gastric erosions necessitating treatment with a histamine-2 (H₂)-receptor antagonist and transfusion of 4 units of packed red blood cells. Physical examination showed splenomegaly. An echocardiogram in October 1990 showed trivial mitral regurgitation and a decreased cardiac ejection fraction (45%). The serum vitamin B₁₂ level was more than 1480 pmol/L (normal level, 150 to 750 pmol/L). Peripheral blood counts (leukocyte count, 31.3 x 10⁹/L [31 300/mm³]; 68% eosinophils) and bone marrow eosinophils were increased. Cytogenetic studies showed no apparent abnormal clones on this or numerous subsequent bone marrow aspirates.

Initial therapy with various dosages of prednisone and hydroxyurea was ineffective. Splenectomy was done to relieve thrombocytopenia. He was hospitalized in August 1991 for progressive leukocytosis and eosinophilia (leukocyte count, 216 x 10⁹/L [216 000/mm³]; 41% eosinophils). At this time, he was given intravenous methylprednisolone (2 g daily for 4 days), interferon- (5 MU/d subcutaneously), vincristine (2 mg/wk intravenously), therapeutic leukapheresis, and transfusions with platelets and packed red blood cells. He remained platelet- and transfusion-dependent for 3 months. Subsequently, he required interferon- (5 to 6 MU/d five days per week) and aspirin (one tablet daily); prednisone (10 to 20 mg every other day) was tapered and discontinued. Another echocardiogram in December 1991 showed left ventricular enlargement, an ejection fraction of 53%, and an immobile posterior leaflet of the mitral valve with moderate-to-severe mitral regurgitation. In August 1992, there was a decrease in the degree of mitral regurgitation and improvement in the ejection fraction (62%) but no change in appearance of the posterior leaflet of the mitral valve. His wife became pregnant while he was taking interferon-, and she gave birth to a healthy baby boy.

After 15 months of treatment with interferon-, the patient suddenly had midthoracic myelopathic symptoms. A magnetic resonance imaging scan showed spinal cord compression by extradural masses at T7, T10, and L3. Open biopsy showed that the masses were granulocytic sarcomas (chloromas), and radiation therapy was administered. After radiation therapy, the dosage of interferon- was increased to 6.5 MU/d for 5 of 7 days. His total leukocyte count decreased to 6.6 x 10⁹/L (6600/mm³) with 12% eosinophils. During treatment with interferon-, his serum level of eosinophil major basic protein decreased from 25 687 to 10 320 ng/mL. He continued to have joint and muscle pain in the lower extremities. An area of hypesthesia developed in the right cheek. Six months later, he had documented recurrence of chloromas at several spinal cord levels and intracranial areas. A second course of radiation therapy was begun; however, the patient became septic and died in June 1993.

Patient 3

A 32-year-old white man had eosinophilia (leukocyte count, 20 x 10⁹/L [20 000/mm³]; 25% eosinophils) in June 1989 several months after a flu-like illness. He felt well until December 1989 when he developed recurrent episcleritis, dizziness, dysphonia, and progressive fatigue. In June 1990, he developed waxing and waning mouth ulcers, a penile ulcer, and a fine erythematous rash on the thighs. He also developed furuncles on his legs and arms that grew Staphylococcus aureus. His skin lesions were partially responsive to prednisone and colchicine. A physical examination at our clinic in December 1990 showed splenomegaly; no cardiac abnormalities were evident. The glans penis was occupied by a yellow dried exudate from a chronic ulceration. Furunculoid lesions were present on the elbows and left calf. A tiny aphthous-type oral ulcer was present. Bone marrow aspiration showed 60% eosinophils; levels of peripheral blood eosinophils were 6000 to 12 000/mm³. An echocardiogram and the level of serum IgE were normal.

Treatment with interferon- (6.25 MU/d) was started in January 1991, and after 8 weeks of therapy, his penile and mucosal ulcers healed. These ulcers have not recurred; he is less fatigued, and he has been able to return to work. Since beginning interferon- therapy, he has had three episodes of cellulitis involving the left groin with associated high fever and adenopathy; these symptoms improved after intravenous cefazolin. His eosinophil count has averaged less than 1000/mm³. Another bone marrow biopsy specimen showed 10% eosinophils after 9 months of treatment with interferon-. During interferon- therapy, serum levels of eosinophil major basic protein decreased from 5173 to 4780 ng/mL. The patient has continued interferon- therapy, 6.0 MU/d, for more than 42 months.

Patient 4

A 35-year-old black man presented in January 1990 with multiple aphthous-type oral ulcers and fever. Biopsy specimens showed a nonspecific inflammatory reaction. His leukocyte count was 8.8 x 10⁹/L (8800/mm³) with 30% eosinophils. The serum vitamin B₁₂ level was more than 1480 pmol/L, and the serum IgE level was normal. Initially, he was treated with acyclovir and subsequently with high-dose prednisone. He had erosive duodenitis and esophagitis with ulcerations and had an erythrocyte sedimentation rate of 38 mm/h (normal levels, 0 to 22 mm/h).

He was hospitalized from May 1990 until July 1990, at which time treatment with hydroxyurea was added, the oral ulcers partially responded, and his prednisone dosage was tapered. However, his oral ulcers returned in September 1990. He was hospitalized from October 1990 until January 1991 for fever, mucositis, and a penile ulcer; because of these symptoms, hydroxyurea and prednisone were again given. His mucosal ulcers never completely resolved, but for several months the ulcers were only slightly symptomatic. He was rehospitalized in February 1992 for weight loss, a worsening penile ulcer, fever, chills, night sweats, right medial thigh and axillary abscesses, and oral mucositis despite therapy with prednisone and hydroxyurea. His echocardiogram was normal, and serologic results for human immunodeficiency virus were negative.

In March 1992, he started to receive interferon-, 3 MU/d, as therapy for his ulcers. However, this dosage worsened ulcer pain and mucositis, and it interfered with oral intake and ability to handle secretions. He was transferred to a Mayo Clinic-affiliated hospital after 2 weeks, hydroxyurea was discontinued, prednisone was increased to 50 mg twice daily, and interferon- therapy was temporarily discontinued. Esophagogastroduodenoscopy showed a granular and erythematous esophagus with no frank ulcers. Nasal mucosal biopsy specimens showed no evidence of vasculitis. After 3 days, interferon- was restarted at 0.5 MU/d. This dosage was increased by 0.25 MU/d every 2 weeks as tolerated, and prednisone was tapered and eventually discontinued. On this therapeutic protocol, his penile lesions healed, and his oral lesions slowly resolved after 20 weeks. His most recent dose of interferon- was 2.5 MU/d, and he has remained free of mucosal and penile ulcers as of November 1993 when he was lost to follow-up. His eosinophil count has fluctuated since discontinuing prednisone and hydroxyurea, but it has generally remained less than 2500/mm³. During therapy with interferon-, the level of serum eosinophil major basic protein increased from 3466 to 3958 ng/mL (14%). Figure 2 shows the appearance of his tongue lesions before (top) and during (bottom) treatment with interferon-.

View larger version (101K): [in this window] [in a new window]   Figure 2. Response of mucosal ulcers to interferon-. Top. Tongue lesion of patient 4 before interferon- therapy. Sharply marginated, painful ulcers are present that were unresponsive to therapy with prednisone and hydroxyurea. Bottom. During therapy with interferon-, 2.5 MU/d, complete healing of the tongue is evident.

Patient 5

A 41-year-old white man presented in March 1992 with memory loss, dizziness, and chest pains. His leukocyte count was 33 x 10⁹/L (33 000/mm³) with 50% eosinophils. His echocardiogram was normal. His initial treatment (elsewhere) with prednisone was of no benefit, and he started hydroxyurea, 500 mg twice daily. He required blood transfusions on two occasions for anemia. Physical examination at our clinic in September 1992 showed a 1 out of 6 systolic murmur at the lower left sternal border and splenomegaly. The leukocyte count was 12.8 x 10⁹/L (12 800/mm³) with 44% eosinophils, 31.5% segmented neutrophils, 10% bands, 9.5% lymphocytes, 4.5% monocytes, and 0.5% basophils. The serum level of vitamin B₁₂ was more than 1480 pmol/L, but other routine tests, including measurements of serum IgE, were normal. The echocardiogram showed mitral leaflets that were thickened at the base of the leaflet, but there was no limit in mobility.

He was treated with interferon-, 1 MU/d, and the dose was increased as tolerated to 8 MU/d; the total eosinophil count then decreased to 792/mm³. During therapy, his serum level of eosinophil major basic protein decreased from 20 971 to 4392 ng/mL. After 9 months, this patient discontinued interferon-. During the subsequent 4 months, his total leukocyte count and percentage of eosinophils rebounded and exceeded pretreatment levels. He continued to have episodic chest pains of undetermined cause and lost approximately 4.5 kg (10 lb), but he was lost to follow-up in April 1994.

Patient 6

A 36-year-old white man had had eosinophilia since age 30 (1986) when he first went to an emergency room for abdominal pain. Subsequently, he had an 18-kg (40-lb) weight loss, night sweats, and malaise. His bone marrow evaluation in August 1987 showed 100% cellularity with 60% eosinophils. His echocardiogram was reportedly normal in 1987; however, his blood pressure was increased and his serum creatinine value was 130 µmol/L. Treatment with high-dose prednisone caused fluid retention, weight gain, and hypertension.

His medical care was irregular until June 1990, at which time he presented elsewhere with hypertension, hepatosplenomegaly, and renal failure. He had balloon angioplasty for congenital right renal artery stenosis. In November 1990, he started treatment with hydroxyurea for eosinophilia. Because of blurred vision and right arm weakness, he started to receive warfarin in March 1991. In April 1991, he was treated with ciprofloxacin for salmonellosis. In August 1991, an echocardiogram was consistent with atypical Ebstein malformation causing pulmonary hypertension. In March 1992, he developed diplopia and gait ataxia. Physical examination showed splenomegaly 4 cm below the right costal margin. His serum vitamin B₁₂ level was less than 1480 pmol/L, and the serum IgE level was normal.

In July 1992, he started to receive interferon-, 1 MU/d. At this time, he was also taking prednisone (20 mg/d), hydroxyurea (1000 mg/d), aspirin, and erythropoietin (Epogen, 4000 units, three times weekly). While taking interferon-, he has been able to discontinue prednisone, hydroxyurea, and erythropoietin. His only side effect to date has been an episode of watery stools and of minor nausea and vomiting. As the dose of interferon- was increased to 6.0 MU/d and then tapered to 4 MU/d, the percentage of eosinophils decreased from as high as 88% down to 14% to 23% despite cessation of cytotoxic and glucocorticoid medications. The serum level of eosinophil major basic protein decreased from 13 088 to 2548 ng/mL. He has now taken interferon- (4.0 MU/d) for 23 months.

Results

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The duration of documented eosinophilia before institution of interferon- therapy ranged from 6 months (patient 5) to 59 months (patient 6). Four patients (patients 1, 2, 5, and 6) had abnormal patterns in their echocardiograms and evidence of neurologic involvement. Four patients (patients 2, 3, 5, and 6) had splenomegaly, and two patients (patients 3 and 4) had mucosal ulcers. While taking interferon-, five of six patients had eosinophil counts decrease to <1000/mm³; in these same five patients, serum levels of eosinophil major basic protein decreased by 8% to 81%. For the group as a whole, a statistically significant decrease was noted in the mean serum level of eosinophil major basic protein, from 12 900 ±8857 ng/mL (mean ±1 SD) to 4862 ±2794 ng/mL P < 0.05 by paired t-test (normal from Blood Bank control, 538 ±144 ng/mL. Table 1 shows that in four of five patients in whom bone marrow differential counts were done, the percentage of eosinophils decreased during treatment.

View this table: [in this window] [in a new window]   Table 1. Bone Marrow and Blood Responses to Interferon-

Discussion

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Interferon- has been used successfully to treat chronic myelogenous leukemia [9] and hairy cell leukemia [10]. In vitro studies [11] suggest that interferon-alfa inhibits colony formation by human bone marrow multipotential, erythroid, granulocyte-macrophage, and eosinophil colony-forming cells. Recent studies [12] suggest that the hypereosinophilic syndrome may be due to clonal proliferation of abnormal cells. These eosinophils may have a prolonged half-life in peripheral blood [13]. Successful interferon- therapy for malignant hypereosinophilic syndrome with or without associated T-cell lymphoma has been associated with a dramatic decrease in elevated serum levels of soluble interleukin-2 receptor [14].

We found interferon- to be effective in patients with the hypereosinophilic syndrome resistant to conventional therapy and for mucosal ulcers associated with this syndrome. Interferon- was generally well tolerated and safe at dosages of 1.5 to 8.0 MU/d. Use of interferon- allowed discontinuation of glucocorticoid or cytotoxic medications and transfusions. Our results support previous case reports [5-7, 14-16], suggesting that interferon- improves outcome in patients with treatment-resistant hypereosinophilic syndrome. Our study increases the number of patients who have been treated with interferon-. Our results show that the eosinopenic response to continued treatment with interferon- may be long-lasting and that the response is caused by decreases in the total leukocyte count and in the percentage of eosinophils (Table 1). Moreover, as shown by the response of patient 5, cessation of interferon- is followed by a rapid rebound of eosinophilia.

The effective dose of interferon- varied widely among our patients. Two patients (patients 2 and 3) tolerated high initial doses of interferon-, 5.0 MU/d and 6.25 MU/d, respectively. After the adverse response of patient 4 to interferon-, the starting dose for the remaining three patients (patients 1, 5, 6) was decreased to 1.0 MU/d and was increased by 0.5 MU to 1.0 MU every 1 to 2 weeks depending on the level of the patient's eosinophils and on clinical tolerance.

Interferon- was useful as a component of the induction protocol in patient 2, who had a rapidly deteriorating clinical condition and uncontrolled eosinophilia with a total leukocyte count of 273 x 10⁹/L (273 000/mm³). We believe that interferon- was life-prolonging in this patient. The poor prognosis of patients with the hypereosinophilic syndrome who have leukocyte counts of more than 100 x 10 (⁹)/L (100 000/mm³) has previously been recognized [1]. An echocardiogram in patient 2 showed an improvement in cardiac function and a decrease in mitral regurgitation after interferon- therapy improved his eosinophilia. However, in the same patient, interferon- did not prevent development of recurrent granulocytic sarcomas.

Two patients with recurrent mucosal ulcers had healing of these previously intractable lesions after institution of interferon- therapy. In our experience, these ulcers have been refractory to therapy, interfere with adequate hygiene and nutrition, and indicate a subset of patients with the hypereosinophilic syndrome who have a poor prognosis, with death from vascular events or infection [17].

Therapy for the hypereosinophilic syndrome has not been uniform, reflecting the heterogeneous nature of this disorder. Glucocorticoids have remained a major therapeutic modality, especially in patients with the hypereosinophilic syndrome who have increased IgE levels [1, 18] or angioedema [2]. Patients who are responsive to glucocorticoids appear to comprise a subset of those with the hypereosinophilic syndrome who have a benign overall prognosis. Unresponsiveness to glucocorticoids in patients with the hypereosinophilic syndrome may be caused by loss of glucocorticoid-binding sites on eosinophils [19]. The addition of hydroxyurea, a DNA inhibitor [20, 21], has been valuable in some patients with the hypereosinophilic syndrome who are resistant to glucocorticoids [12, 13]. Numerous other potentially effective medical programs for the hypereosinophilic syndrome have been described in case reports [22-31], in addition to surgical approaches for cardiovascular complications associated with this syndrome.

A clinical grading system for the hypereosinophilic syndrome, devised by Schooley and colleagues [32], has been used to predict which patients with this syndrome require no specific antieosinophilic therapy and which patients require progressively more intensive therapy with glucocorticoid or cytotoxic medications (or both). Based on Schooley and colleagues' clinical groups, our patients are included in those cohorts with incomplete responses to conventional therapy, the most severely affected patients. Nonetheless, five of six patients had their eosinophilia improve with interferon- therapy. Whether interferon- could forestall or prevent disease progression in patients with the hypereosinophilic syndrome who are less severely ill and whether interferon- has potential use as a first-line medication for this syndrome are important questions that need to be answered.