Protocol Number: 02-I-0286

Title:

A Pilot Study of the Safety and Efficacy of Imatinib Mesylate in Reducing Eosinophilia in Patients with the Myeloproliferative Variant Hypereosinophilic Syndrome (HES) or Non-Myeloproliferative HES Refractory to Standard Therapy

Number:

02-I-0286

Summary:

The purpose of this study is to evaluate the safety and efficacy of the tyrosine kinase inhibitor, imatinib mesylate (Gleevec ™ (Trademark)) in reducing peripheral blood eosinophilia in patients with the myeloproliferative form of hypereosinophilic syndrome (HES). Patients with the hypereosinophilic syndrome who meet a set of criteria designed to select patients with the myeloproliferative form of the disease, as well as patients without myeloproliferative disease who are refractory to standard therapy for HES, will be admitted on this protocol. A thorough clinical evaluation will be performed with emphasis on potential sequelae of eosinophil-mediated tissue damage. A baseline bone marrow will be obtained to exclude leukemia or lymphoma and to assess the degree and nature of eosinophilopoiesis. Bone marrow, blood cells and/or serum will also be collected to test for the presence of a recently described mutation that is associated with imatinib-responsiveness in HES, and to provide reagents (such as DNA, RNA, and specific antibodies) and for use in the laboratory to address issues related to the mechanism of action of imatinib mesylate in HES. Imatinib mesylate will be initiated at a dose of 400 mg daily, the FDA-approved dose for the treatment of chronic myelogenous leukemia. In patients who demonstrate a complete clinical and hematologic response to imatinib therapy and who do not have life-threatening disease, the dose will be decreased gradually to 100mg daily and then discontinued. In order to minimize bone marrow suppression, other myelosuppressive agents will be tapered and discontinued during the first week of therapy with imatinib mesylate. Complete blood counts will be performed weekly for the first month and biweekly thereafter. Clinical assessments will be performed every three months to assess progression of end organ damage.

In patients who demonstrate a complete clinical and hematologic response to imatinib therapy and who do not have life-threatening disease, the dose will be decreased gradually to 100 mg daily and then discontinued. In the event of clinical, hematologic or molecular relapse during the taper, the imatinib dose will be increased to a maximum of 600 mg daily to achieve a second remission. Laboratory monitoring will be performed as above except for molecular monitoring which will be monitored monthly if drug is discontinued or molecular relapse occurs. Once a stable dosing regimen is achieved for greater than or equal to 6 months in subjects who have undergone dose descalation or greater than or equal to 2 years in subjects receiving 300-400 mg of imatinib daily who did not qualify for dose de-escalation, the frequency of NIH visits and end organ assessments will be decreased to 6 months, with molecular monitoring every 3 months and monthly routine laboratory assessments.

Sponsoring Institute:

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Participants currently recruited/enrolled

Gender: Male & Female

Referral Letter Required: No

Population Exclusion(s): None

Eligibility Criteria:

INCLUSION CRITERIA:

All subjects must meet the established diagnostic criteria for idiopathic hypereosinophilic syndrome: eosinophilia greater than 1,500/mm3 on two occasions at least 6 months apart, no known etiology for the eosinophilia despite careful clinical evaluation, and evidence of end organ damage (histologic evidence of tissue infiltration by eosinophils and/or objective evidence of clinical pathology in any organ system that is temporally associated with eosinophilia and not clearly attributable to another cause).

All subjects must fit one of the following three categories:

(a) refractory to or intolerant of steroids, interferon alpha and hydroxyurea

(b) presence of FIP1L1/PDGFRA or bcr-abl detected by RT-PCR

(c) presence of greater than or equal to 4 of the following laboratory criteria suggestive of a myeloproliferative disorder:

i. dysplastic eosinophils on peripheral smear

ii. serum B12 level greater than or equal to 1000 pg/ml

iii. serum tryptase level greater than or equal to 12

iv. anemia and/or thrombocytopenia

v. bone marrow cellularity greater than 80% with left shift in maturation

vi. dysplastic (spindle-shaped) mast cells on bone marrow biopsy

vii. evidence of fibrosis on bone marrow biopsy

viii. dysplastic megakaryocytes on bone marrow biopsy

All subjects must be at least 2 years of age.

Negative serum beta-hCG within 24 hours prior to drug administration for women of childbearing potential to exclude early pregnancy.

All subjects (men and women) must agree to practice abstinence or effective contraception during administration of imatinib mesylate and for 6 months after discontinuation of drug.

Of note, failure of the standard chemotherapeutic agents (steroids, hydroxyurea, and interferon alpha) will not be a prerequisite for participation in this protocol for the following reasons. 1) There is no approved therapy for HES. 2) Steroid therapy in the myeloproliferative subset of HES patients is generally ineffective. 3) Although hydroxyurea and interferon alpha are initially effective in most cases, a majority of patients become refractory to or intolerant of these agents within a relatively short period of time (less than 1 year). 4) Data from other myeloproliferative disorders, including CML, suggest that interferon and imatinib mesylate, but not hydroxyurea, are associated with cytogenetic remission. 5) The reported incidence and severity of side effects from imatinib mesylate in patients with CML appears comparable to (or less than) those associated with interferon alpha.

Although a private physician is not required for inclusion in the study, it is strongly recommended that all subjects have a physician outside the NIH for routine medical care and emergencies.

EXCLUSION CRITERIA:

Pregnancy or nursing women

HIV positivity or other known immunodeficiency

Systemic mastocytosis

Absolute neutrophil count less than 1000/mm3 or platelet count less than 10, 000/mm3 or less than 50,000/m3 with clinical evidence of bleeding.

Elevated transaminases (greater than 5 times the upper limit of normal) or elevated bilirubin (greater than 3 times the upper limit of normal)

Any condition that, in the investigator's opinion, places the patient at undue risk by participating in the study

Special Instructions:

Currently Not Provided

Keywords:

Treatment

Eosinophil

Tyrosine Kinase Inhibitor

Hypereosinophilia

Biologicals

Chemotherapy

Gleevec

Eosinophils

Recruitment Keyword(s):

Hypereosinophilic Syndrome

HES

Condition(s):

Hypereosinophilic Syndrome

Investigational Drug(s):

None

Investigational Device(s):

None

Intervention(s):

Drug: Imatinib Mesylate

Supporting Site:

National Institute of Allergy and Infectious Diseases

Contact(s):

Patient Recruitment and Public Liaison Office
Building 61
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
Fax: 301-480-9793

Electronic Mail:prpl@mail.cc.nih.gov

Citation(s):

Aractingi S, Janin A, Zini JM, Gauthier MS, Chauvenet L, Tobelem G, Prin L, Chosidow O, Frances C. Specific mucosal erosions in hypereosinophilic syndrome. Evidence for eosinophil proteindeposition. Arch Dermatol. 1996 May;132(5):535-41. Review.

Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood. 1994 May 15;83(10):2759-79. Review. No abstract available.

Nadarajah S, Krafchik B, Roifman C, Horgan-Bell C. Treatment of hypereosinophilic syndrome in a child using cyclosporine: implication for a primary T-cell abnormality. Pediatrics. 1997 Apr;99(4):630-3. No abstract available.

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