Tyrosine Kinase Inhibition to Treat Myeloid Hypereosinophilic Syndrome

Description

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. ...

Conditions

Eosinophilic Myeloid Neoplasm, Hypereosinophilic Syndrome

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Study Overview

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Study Details

Study overview

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. ...

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

Tyrosine Kinase Inhibition to Treat Myeloid Hypereosinophilic Syndrome

Condition
Eosinophilic Myeloid Neoplasm
Intervention / Treatment

-

Contacts and Locations

Bethesda

National Institutes of Health Clinical Center, Bethesda, Maryland, United States, 20892

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

For general information about clinical research, read Learn About Studies.

Eligibility Criteria

  • 1. Male or female, at least 2 years of age for imatinib therapy and \>=18 years of age for ruxolitinib therapy.
  • 2. Documented diagnosis of HES: eosinophilia \>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).
  • 3. All participants must fit one of the following four categories:
  • 1. Myeloid neoplasm associated with a PDGFRA or PDGFRB rearrangement.
  • 2. Myeloid neoplasm associated with rearrangement or mutation involving the JAK-STAT pathway.
  • 3. Presence of \>=4 of the following laboratory criteria suggestive of a myeloid disorder:
  • * Dysplastic eosinophils on peripheral smear
  • * Serum B12 level \>= 1000 pg/mL.
  • * Serum tryptase level \>= 12.
  • * Anemia and/or thrombocytopenia.
  • * Bone marrow cellularity \> 80% with left shift in maturation.
  • * Dysplastic (spindle-shaped) mast cells on bone marrow biopsy.
  • * Evidence of fibrosis on bone marrow biopsy.
  • * Dysplastic megakaryocytes on bone marrow biopsy.
  • 4. Refractory to or intolerant of steroids without evidence of a myeloid disorder.
  • 4. Negative serum beta-human chorionic gonadotropin 24 hours prior to drug administration for women of childbearing potential to exclude early pregnancy.
  • 5. Agrees to practice abstinence or effective contraception during administration of imatinib mesylate or ruxolitinib and for 6 months after discontinuation of the drug. Women of childbearing potential who are using hormonal contraceptives and taking ruxolitinib will also be required to use a barrier method.\*\*
  • 6. Participation in protocol 94-I-0079 (Activation and function of eosinophils in conditions with blood or tissue eosinophilia).
  • 1. Pregnant or nursing women.\*
  • 2. D816V KIT-positive systemic mastocytosis
  • 3. Uncontrolled HIV infection (absolute lymphocyte count \<200/mm\^3 and/or HIV RNA level \>500 copies/ml)
  • 4. ANC \<1000/mm\^3 or platelet count \<10,000/mm\^3 or \<50,000/m\^3 with clinical evidence of bleeding.
  • 5. Elevated transaminases (\>5 times the upper limit of normal) or elevated bilirubin (\>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.
  • 1. Evidence of B-cell clonality by PCR or flow cytometry.
  • 2. Active tuberculosis, or acute or chronic active infection with hepatitis B or C\*.
  • 3. Treatment with fluconazole \>200 mg daily.
  • * Participants with active tuberculosis will be excluded. The most current Infectious Diseases Society of America guidelines will be followed regarding isoniazid therapy for latent tuberculosis. Participants who refuse recommended prophylactic therapy for tuberculosis will be counseled regarding the risks of reactivation of tuberculosis during ruxolitinib therapy but will not be systematically excluded. Molecular and serologic tests for hepatitis B and serology for hepatitis C will be performed regardless of vaccination history. Participants with evidence of active or chronic infection with hepatitis B or positive hepatitis C serology will be excluded from participation in the ruxolitinib arm of the protocol. Specifically, a positive hepatitis B serology indicative of previous immunization (i.e., hepatitis B anti-surface antibody-positive and hepatitis B anti-core antibody-negative) or a fully resolved acute hepatitis B infection is not an exclusion criterion. Patients with an indolent chronic hepatitis B infection (normal alanine aminotransferase \[ALT\], aspartate aminotransferase \[AST\], and albumin, and no radiographic or biopsy evidence of cirrhosis) will be evaluated by an NIH hepatologist and may be eligible. Patients who choose to remain on study with evidence of prior hepatitis B infection will be counseled regarding the risks of reactivation prior to initiation of ruxolitinib therapy.

Ages Eligible for Study

2 Years to

Sexes Eligible for Study

ALL

Accepts Healthy Volunteers

No

Collaborators and Investigators

National Institute of Allergy and Infectious Diseases (NIAID),

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

Study Record Dates

2026-01-01