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 Form of Hypereosinophilic Syndrome (HES) or Non-Myeloproliferative HES Refractory to Standard Therapy

Number:

02-I-0286

Summary:

This study will evaluate the safety and effectiveness of imatinib mesylate in reducing the number of eosinophils (a type of white blood cell) in patients with hypereosinophilic syndrome (HES). Patients with HES have elevated counts of eosinophils in the blood and body tissues, which can cause damage to these tissues. Although HES can involve any tissues, the heart, nerves, and skin are most often affected. Several drugs, including steroids, interferon, and hydroxyurea can lower eosinophil counts; however, these drugs have drawbacks in that they do not work in all patients with HES, or they may work only temporarily, or patients may develop side effects that require stopping the drugs. Imatinib mesylate is a new drug approved to treat gastrointestinal tumors and chronic myelogenous leukemia. Some data suggest that imatinib mesylate may be useful in treating a subgroup of patients with HES.

Patients with HES who are 18 years of age and older may be eligible for this study. Candidates will be screened with a medical history, physical examination, blood tests, electrocardiogram (EKG), echocardiogram (ultrasound examination of the heart), pulmonary (lung) function tests, and a bone marrow examination to determine if they fall into the subgroup of patients likely to respond to this therapy. For the bone marrow procedure, an area of skin and bone is numbed and a very sharp needle is inserted into the bone to draw out a sample of bone marrow for evaluation under the microscope.

Patients enrolled in the study will take imatinib mesylate daily. Any other drugs they may be taking for HES, as well as other drugs they are taking that may interact with imatinib mesylate, will be tapered and stopped. If it is not possible to stop taking certain drugs for other conditions, their dosages may be adjusted. Patients will be monitored weekly with laboratory testing during the first month of treatment and whenever neutrophil counts drop below 1500/mm3 or platelets fall below 100,000/mm3. If blood counts remain high enough, monitoring will be reduced to every 2 weeks for 3 months and once a month after that. Patients will have a clinic visit at NIH 1 month after beginning the drug for a clinical and laboratory evaluation, including a bone marrow examination. Patients whose eosinophil counts are not lowered after 4 weeks of treatment will leave the study. Those who respond to therapy will return to NIH every 3 months for a history and physical examination, laboratory tests, EKG, echocardiogram, and pulmonary function testing to determine how treatment is affecting disease progression. In addition, the following procedures will be done solely for research purposes:

- Blood tests to determine the effects of imatinib mesylate on immune cells, including eosinophils.

- Leukapheresis to study the effects of imatinib mesylate on eosinophils: For this procedure, whole blood is collected through a needle in an arm vein, similar to donating blood. The blood circulates through a machine that separates it into its components, and the white cells are removed. The rest of the blood is returned to the body, either through the same needle or through another needle in the other arm.

- Bone marrow examinations will be done during the screening tests and again 1 month after starting treatment to look at newly developing cells in the bone marrow.

- Genetic testing to determine how imatinib mesylate is able to lower eosinophil counts in patients with HES.

Sponsoring Institute:

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Active Accrual Of New Subjects

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 18 years of age.

Negative serum beta-hCG within 24 hours of 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.

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 Keywords:

Hypereosinophilic Syndrome

HES

Conditions:

Hypereosinophilic Syndrome

Investigational Drug(s):

None

Investigational Device(s):

None

Contacts:

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

Citations:

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 protein deposition. Arch Dermatol. 1996 May;132(5):535-41. Review. PMID: 8624150

Weller PF, Bubley GJ. The idiopathic hypereosinophilic syndrome. Blood. 1994 May 15;83(10):2759-79. Review. No abstract available. PMID: 8180373

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. PMID: 9093318

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