Tyrosine Kinase Inhibitors for Hypereosinophilic Syndrome

Recruiting at 1 trial location

Overseen By Amy D Klion, M.D.

Age: Any Age

Sex: Any

Trial Phase: Phase 2

Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

Must be taking: Imatinib, Ruxolitinib

Must not be taking: Fluconazole

Disqualifiers: Pregnancy, Systemic mastocytosis, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 5 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 7

Duration: 12 months

60 Participants Needed

Trial Summary

What is the purpose of this trial?

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. ...

Will I have to stop taking my current medications?

The trial protocol does not specify if you must stop taking your current medications, but it mentions that other myelosuppressive agents (drugs that suppress bone marrow activity) will be tapered and discontinued during the first week of therapy with imatinib mesylate. It's best to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Imatinib for treating hypereosinophilic syndrome?

Research shows that Imatinib is effective in treating hypereosinophilic syndrome in a significant number of patients, particularly those with a specific genetic marker (FIP1L1-PDGFRA fusion gene). However, the response can vary, with some patients experiencing complete remission and others developing resistance or not responding at all. ^{1 2 3 4 5}

Is imatinib safe for treating hypereosinophilic syndrome?

Imatinib has been used to treat hypereosinophilic syndrome and other conditions, showing effectiveness in some patients. However, responses can vary, and some patients may experience resistance or poor tolerability, indicating that while it can be safe for many, it may not be well-tolerated by everyone. ^{1 2 3 5 6}

How does the drug imatinib differ from other treatments for hypereosinophilic syndrome?

Imatinib is unique because it targets a specific protein (tyrosine kinase) involved in the disease, and it is particularly effective in patients with a certain genetic marker (FIP1L1-PDGFRA fusion gene). This makes it different from other treatments that do not target this specific mechanism. ^{1 2 5 6 7}

Research Team

Amy D Klion, M.D.

Principal Investigator

National Institute of Allergy and Infectious Diseases (NIAID)

Eligibility Criteria

This trial is for individuals with myeloid hypereosinophilic syndrome, characterized by high eosinophil counts and organ damage. Participants must be at least 2 years old for imatinib or 18+ for ruxolitinib therapy, agree to use effective contraception, and have no secondary causes of their condition. Those already on imatinib may join the dose reduction part of the study.

Inclusion Criteria

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

I am willing and able to follow all study rules and attend all appointments.

I have been diagnosed with hypereosinophilic syndrome, showing high eosinophil levels and organ damage.

Exclusion Criteria

Pregnant or nursing women

I am HIV positive or have another known immunodeficiency.

My condition is D816V KIT-positive systemic mastocytosis.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

1 visit (in-person)

Treatment

Participants receive imatinib mesylate daily, with weekly monitoring for the first month, then biweekly for 3 months, and monthly thereafter

12 months

Weekly visits for the first month, biweekly for 3 months, then monthly

Follow-up

Participants are monitored for safety and effectiveness after treatment, with clinical assessments every 3 months

5 years

Every 3 months

Open-label extension

Participants may continue treatment with imatinib mesylate if stable dosing is achieved

Long-term

Treatment Details

Interventions

• Imatinib

Trial Overview The trial tests tyrosine kinase inhibitors: imatinib mesylate (Gleevec) starting at 400 mg daily, potentially reduced to 100 mg; and ruxolitinib in eligible patients. It aims to reduce blood eosinophilia in myeloid HES patients, assessing safety and efficacy through regular clinical evaluations.

Participant Groups

Group I: Ruxolitinib Experimental Treatment 1 Intervention

open label ruxolitinib treatment

Group II: Imatinib Experimental Treatment 1 Intervention

open label imatinib mesylate treatment

Imatinib is already approved in European Union, United States, Canada, Japan, Switzerland for the following indications:

Approved in European Union as Gleevec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Approved in United States as Gleevec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Approved in Canada as Glivec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Approved in Japan as Glivec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Approved in Switzerland as Gleevec for:

• Chronic myeloid leukemia
• Gastrointestinal stromal tumors
• Dermatofibrosarcoma protuberans
• Systemic mastocytosis
• Hypereosinophilic syndrome

Who Is Running the Clinical Trial?

National Institute of Allergy and Infectious Diseases (NIAID)

Lead Sponsor

Trials

3,361

Recruited

5,516,000+

Findings from Research

Imatinib mesylate was found to induce a durable and complete clinical and biological remission in a 32-year-old man with idiopathic hypereosinophilic syndrome within just 3 weeks, after previous treatments failed.

This treatment appears to be very safe and effective, although the exact mechanism of how it works in this specific syndrome remains unclear, suggesting that other oncogenes may be involved.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Complete remission with imatinib mesylate (Glivec) of an idiopathic hypereosinophilic syndrome associated with a cutaneous mastocytosis after failure of interferon-alpha]. Pottier, P., Planchon, B., Grossi, O.[2019]

Imatinib-mesylate was effective in treating hypereosinophilic syndrome (HES) in three out of four patients, demonstrating its potential as a treatment option.

However, the response to imatinib varied significantly among patients, with only one achieving prolonged remission, suggesting that individual disease mechanisms may influence treatment outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Heterogeneity of response to imatinib-mesylate (glivec) in patients with hypereosinophilic syndrome: implications for dosing and pathogenesis. Musto, P., Falcone, A., Sanpaolo, G., et al.[2019]

Hypereosinophilic syndromes (HES) are linked to immunological issues and can involve various cell types, including T lymphocytes that produce cytokines like IL-5, which play a role in the disease's pathology.

Imatinib mesylate, originally used for chronic myelogenous leukemia, has been effective in treating certain subgroups of HES, particularly those with increased bone marrow mast cells, indicating a potential targeted therapy approach for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The hypereosinophilic syndromes: still more heterogeneity. Gleich, GJ., Leiferman, KM.[2022]

Imatinib mesylate has shown efficacy in treating hypereosinophilic syndromes (HES), benefiting about 65% of patients, particularly those with the FIP1L1-PDGFRA fusion gene, which is linked to the overproduction of eosinophils.

The study reviewed clinical features and treatment outcomes in 94 patients, highlighting the importance of identifying specific genetic markers like PDGFRA rearrangements to tailor effective therapies for HES.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Imatinib mesylate as a novel treatment option for hypereosinophilic syndrome: two case reports and a comprehensive review of the literature. Müller, AM., Martens, UM., Hofmann, SC., et al.[2016]

The discovery of the FIP1L1-PDGFRA fusion gene in idiopathic hypereosinophilic syndrome highlights its classification as a chronic eosinophilic leukemia, which affects treatment approaches and understanding of the disease's molecular basis.

Imatinib mesylate (Gleevec) has been shown to effectively target the FIP1L1-PDGFRA fusion kinase, providing a rational treatment option, although resistance may develop, necessitating alternative therapies like PKC412.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The FIP1L1-PDGFRalpha kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia. Cools, J., Stover, EH., Wlodarska, I., et al.[2019]

A 25-year-old man with a rare FIP1L1-PDGFRA-negative hypereosinophilic syndrome experienced severe symptoms, including pericardial effusion and pleuritis, which improved significantly after starting treatment with imatinib mesylate.

Imatinib mesylate, typically used for myeloid variants, showed efficacy in this case, allowing the patient to discontinue corticosteroids after 7 months and remain asymptomatic for 23 months, suggesting its potential as a treatment option for similar cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Efficiency of imatinib in polyserositis revealing a FIP1L1-PDGFRA-negative hypereosinophilic syndrome]. Green, L., Kahn, JE., Dufour, JF., et al.[2016]

Idiopathic hypereosinophilic syndrome (HES) can be effectively treated with the tyrosine kinase inhibitor imatinib, especially in patients with the FIP1L1-PDGFRA fusion gene, which predicts a positive response to the treatment.

Imatinib is generally safe with minimal side effects, although there have been rare reports of acute left ventricular dysfunction in some patients during the first week of treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[The idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia]. Chrobák, L., Voglová, J.[2006]

References

1. France pubmed.ncbi.nlm.nih.gov

[Complete remission with imatinib mesylate (Glivec) of an idiopathic hypereosinophilic syndrome associated with a cutaneous mastocytosis after failure of interferon-alpha]. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Heterogeneity of response to imatinib-mesylate (glivec) in patients with hypereosinophilic syndrome: implications for dosing and pathogenesis. [2019]

3. England pubmed.ncbi.nlm.nih.gov

The hypereosinophilic syndromes: still more heterogeneity. [2022]

4. Germany pubmed.ncbi.nlm.nih.gov

Imatinib mesylate as a novel treatment option for hypereosinophilic syndrome: two case reports and a comprehensive review of the literature. [2016]

5. United States pubmed.ncbi.nlm.nih.gov

The FIP1L1-PDGFRalpha kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia. [2019]

6. France pubmed.ncbi.nlm.nih.gov

[Efficiency of imatinib in polyserositis revealing a FIP1L1-PDGFRA-negative hypereosinophilic syndrome]. [2016]

7. Czech Republic pubmed.ncbi.nlm.nih.gov

[The idiopathic hypereosinophilic syndrome and chronic eosinophilic leukemia]. [2006]