Tyrosine Kinase Inhibition to Treat Myeloid Hypereosinophilic Syndrome

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Brief Title

Tyrosine Kinase Inhibition to Treat Myeloid Hypereosinophilic Syndrome

Official Title

Efficacy of Tyrosine Kinase Inhibition in Reducing Eosinophilia in Patients With Myeloid and/or Steroid-Refractory Hypereosinophilic Syndrome

Brief Summary

      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.

      ...
    

Detailed Description

      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.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

peripheral blood absolute eosinophil count.

Secondary Outcome

 peripheral blood eosinophil count

Condition

Eosinophilic Myeloid Neoplasm

Intervention

Imatinib

Study Arms / Comparison Groups

 Imatinib
Description:  open label imatinib mesylate treatment

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

60

Start Date

September 26, 2002

Completion Date

January 1, 2026

Primary Completion Date

January 1, 2025

Eligibility Criteria

        -  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)
      

Gender

All

Ages

2 Years - 100 Years

Accepts Healthy Volunteers

No

Contacts

Amy D Klion, M.D., (301) 402-7823, [email protected]

Location Countries

United States

Location Countries

United States

Administrative Informations


NCT ID

NCT00044304

Organization ID

020286

Secondary IDs

02-I-0286

Responsible Party

Sponsor

Study Sponsor

National Institute of Allergy and Infectious Diseases (NIAID)


Study Sponsor

Amy D Klion, M.D., Principal Investigator, National Institute of Allergy and Infectious Diseases (NIAID)


Verification Date

March 6, 2020