Tyrosine Kinase Inhibition to Treat Myeloid Hypereosinophilic Syndrome

NCT00044304 | Active Not Recruiting Phase 2

• 2 other identifiers: 02028602-I-0286
• Study Type: interventional
• Target: 70
• Locations: 1 country
• Sites: 1

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. ...

Conditions

Eosinophilic Myeloid Neoplasm; Hypereosinophilic Syndrome

Keywords

Janus Kinase; Imatinib; Ruxolitinib; Myeloid Neoplasm; Platelet-Derived Growth Factor Receptor Alpha; Hypereosinophilic Syndrome; HES

Outcome Measures

Primary Outcomes (1)

• peripheral blood absolute eosinophil count.

  The percentage of subjects who reach an eosinophil count in the normal range

  one month (for imatinib) and 3 months (for ruxolitinib).

Secondary Outcomes (4)

• peripheral blood eosinophil count

  3,6,9 and 12 months

• peripheral blood eosinophil count

  1, 3, 6, 9, and 12 months

• abnormal tyrosine kinase (i.e., FIP1L1-PDGFRA, JAK2 V617F)

  every 3 months for 5 years

• clinical, hematologic and molecular remission

  every 3 months for 5 years

Study Arms (2)

Imatinib

EXPERIMENTAL

open label imatinib mesylate treatment

Drug: Imatinib

Ruxolitinib

EXPERIMENTAL

open label ruxolitinib treatment

Drug: Ruxolitinib

Interventions

Imatinib DRUG

The dosing regimen to be used initially (400 mg po qd in adults and 260 mg/m2/day in children with food and a glass of water) is identical to that recommended by the FDA for the treatment of the chronic phase of chronic myelogenous leukemia (CML) (Prod Info Gleevec ). In patients with ANC \<1500/mm3, platelet counts \< 75,000mm3 or abnormal liver function tests (ALT or AST \> 2.5 or bilirubin \> 3 times the upper limit of normal), the starting dose will be reduced to 300 mg po qD.

Imatinib

Ruxolitinib DRUG

The dosing regimen to be used initially (15 mg po bid) is identical to that recommended by the FDA for the treatment of myelofibrosis with platelet counts of 100-200,000/mm3 (Prod Info ruxolitinib). In patients with platelet counts \<100,000/mm3, moderate renal impairment (CrCl \<60 mL/min) or abnormal liver function tests (ALT or AST \> 2.5 or bilirubin \> 3 times the upper limit of normal), the starting dose will be reduced to 10 mg bid. The recommended guidelines for dose adjustment during therapy and discontinuation of therapy in myelofibrosis will be followed.

Ruxolitinib

Eligibility Criteria

• Age: 2 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• In order to be eligible to participate in this study, an individual must meet all of the following criteria:
• Male or female, at least 2 years of age for imatinib therapy and \>=18 years of age for ruxolitinib therapy.
• 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).
• All participants must fit one of the following four categories:
• Myeloid neoplasm associated with a PDGFRA or PDGFRB rearrangement.
• Myeloid neoplasm associated with rearrangement or mutation involving the JAK-STAT pathway.
• 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.

You may not qualify if:

• An individual who meets any of the following criteria will be excluded from participation in this study:
• Pregnant or nursing women.\*
• D816V KIT-positive systemic mastocytosis
• Uncontrolled HIV infection (absolute lymphocyte count \<200/mm\^3 and/or HIV RNA level \>500 copies/ml)
• ANC \<1000/mm\^3 or platelet count \<10,000/mm\^3 or \<50,000/m\^3 with clinical evidence of bleeding.
• Elevated transaminases (\>5 times the upper limit of normal) or elevated bilirubin (\>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.
• An individual who meets any of the following criteria will be excluded from participation in the ruxolitinib treatment arm of this study:
• Evidence of B-cell clonality by PCR or flow cytometry.
• Active tuberculosis, or acute or chronic active infection with hepatitis B or C\*.
• Treatment with fluconazole \>200 mg daily.

Sponsors & Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID): lead

Study Sites (1)

National Institutes of Health Clinical Center

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Khoury P, Desmond R, Pabon A, Holland-Thomas N, Ware JM, Arthur DC, Kurlander R, Fay MP, Maric I, Klion AD. Clinical features predict responsiveness to imatinib in platelet-derived growth factor receptor-alpha-negative hypereosinophilic syndrome. Allergy. 2016 Jun;71(6):803-10. doi: 10.1111/all.12843. Epub 2016 Mar 2.

  PMID: 26797802 BACKGROUND

• King B, Lee AI, Choi J. Treatment of Hypereosinophilic Syndrome with Cutaneous Involvement with the JAK Inhibitors Tofacitinib and Ruxolitinib. J Invest Dermatol. 2017 Apr;137(4):951-954. doi: 10.1016/j.jid.2016.10.044. Epub 2016 Nov 22. No abstract available.

  PMID: 27887955 BACKGROUND

• Klion AD. How I treat hypereosinophilic syndromes. Blood. 2015 Aug 27;126(9):1069-77. doi: 10.1182/blood-2014-11-551614. Epub 2015 May 11.

  PMID: 25964669 BACKGROUND

• Klion AD, Robyn J, Maric I, Fu W, Schmid L, Lemery S, Noel P, Law MA, Hartsell M, Talar-Williams C, Fay MP, Dunbar CE, Nutman TB. Relapse following discontinuation of imatinib mesylate therapy for FIP1L1/PDGFRA-positive chronic eosinophilic leukemia: implications for optimal dosing. Blood. 2007 Nov 15;110(10):3552-6. doi: 10.1182/blood-2007-07-100164. Epub 2007 Aug 20.

  PMID: 17709602 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Hypereosinophilic Syndrome

Interventions

Imatinib Mesylate; ruxolitinib

Condition Hierarchy (Ancestors)

Eosinophilia; Leukocyte Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases

Intervention Hierarchy (Ancestors)

Benzamides; Amides; Organic Chemicals; Benzoates; Acids, Carbocyclic; Carboxylic Acids; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Piperazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines

Study Officials

• Amy D Klion, M.D.

  National Institute of Allergy and Infectious Diseases (NIAID)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 24, 2002
• First Posted: August 26, 2002
• Study Start: September 26, 2002
• Primary Completion: November 16, 2023
• Study Completion (Estimated): March 10, 2027
• Last Updated: March 16, 2026

Record last verified: 2026-03-04

Locations

US (1)