Tyrosine Kinase Inhibition to Treat Myeloid Hypereosinophilic Syndrome
Tyrosine Kinase Inhibition to Treat Myeloid Hypereosinophilic Syndrome
The purpose of this study is to evaluate the safety and efficacy of the tyrosine kinase
 inhibitor, imatinib mesylate (Gleevec ) in reducing peripheral blood eosinophilia in patients
 with the myeloid form of hypereosinophilic syndrome (HES). Patients with the
 hypereosinophilic syndrome who meet a set of criteria designed to select patients with the
 myeloid form of the disease, as well as patients without myeloid 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.
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, eye exam 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 repeat 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 some participants with stable disease where an optimal dose
 of imatinib mesylate has been identified, visits may be extended to every six months. 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.
-  INCLUSION CRITERIA:

 All subjects must meet the established diagnostic criteria for hypereosinophilic syndrome:
 eosinophilia greater than 1,500/mm(3) on two occasions, no secondary 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:

 1. refractory to or intolerant of steroids

 2. presence of FIP1L1/PDGFRA by RT-PCR

 3. presence of greater than or equal to 4 of the following laboratory criteria suggestive
 of a myeloid 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

 3. All subjects must be at least 2 years of age.

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

 5. All subjects (men and women) must agree to practice abstinence or effective
 contraception during administration of imatinib mesylate or ruxolitinib 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
 myeloid 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 myeloid neoplasms and disorders, including CML, suggest
 that interferon, imatinib mesylate, and ruxolitinib, but not hydroxyurea, are associated
 with cytogenetic remission. 5) The reported incidence and severity of side effects from
 imatinib mesylate in patients with CML and ruxolitinib in myelofibrosis and polycythemia
 vera appear comparable to (or less than) those associated with interferon alpha.

 Subjects who meet inclusion criteria, but are already receiving imatinib, may be enrolled
 in the dose de-escalation portion of the study at the investigator s discretion.

 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:

 1. Pregnancy or nursing women

 2. HIV positivity or other known immunodeficiency

 3. D816V KIT-positive systemic mastocytosis

 4. Absolute neutrophil count less than 1000/mm(3) or platelet count less than
 10,000/mm(3) or less than 50,000/m(3) with clinical evidence of bleeding.

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

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

 7. Evidence of B cell clonality by PCR or flow cytometry (exclusion criteria for
 ruxolitinib only)