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Protocol Details

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

This study is currently recruiting participants.

Summary | Eligibility | Citations | Contacts

Summary

Number

02-I-0286

Sponsoring Institute

National Institute of Allergy and Infectious Diseases (NIAID)

Recruitment Detail

Type: Participants currently recruited/enrolled
Gender: Male & Female
Min Age: 2 Years
Max Age: N/A

Referral Letter Required

No

Population Exclusion(s)

None

Keywords

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

Recruitment Keyword(s)

Hypereosinophilic Syndrome;
HES

Condition(s)

Eosinophilic Myeloid Neoplasm;
Hypereosinophilic Syndrome

Investigational Drug(s)

None

Investigational Device(s)

None

Intervention(s)

Drug: Imatinib
Drug: Ruxolitinib

Supporting Site

National Institute of Allergy and Infectious Diseases

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.

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Eligibility

INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following 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 hypereosinophilic syndrome: 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 subjects must fit one of the following four categories:

a) myeloid neoplasm associated with a PDGFRA or PDGFRB rearrangement

b) myeloid neoplasm associated with rearrangement or mutation involving the JAK-STAT pathway

c) 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

d) refractory to or intolerant of steroids without evidence of a myeloid disorder

4. Negative serum beta-hCG 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)

NOTE: 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. Subjects who meet inclusion criteria, but are already receiving ruxolitinib, may be enrolled at the investigator s discretion if baseline data is available and they have received ruxolitinib at the dose specified in the protocol for less than 2 months (primary endpoint).

Effective contraception includes the use of hormonal (birth control pills, for example) and/or barrier (condoms and diaphragms, for example) methods by subjects and/or their partners to prevent pregnancy in women of childbearing potential. For women of childbearing potential who use hormonal methods as their primary means of contraception and will be receiving treatment

with ruxolitinib, barrier methods will also be required due to possible interference of ruxolitinib with hormonal contraceptives.

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:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Pregnant or nursing women

2. HIV positivity or other known immunodeficiency

3. D816V KIT-positive systemic mastocytosis

4. Absolute neutrophil count < 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

An individual who meets any of the following criteria will be excluded from participation in the ruxolitinib treatment arm of this study:

1. Evidence of B cell clonality by PCR or flow cytometry

2. Active tuberculosis, acute or chronic active infection with hepatitis B or C

3. Treatment with fluconazole >200 mg daily

Subjects with active tuberculosis will be excluded. The most current IDSA guidelines will be followed regarding isoniazid therapy for latent tuberculosis. Subjects 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. Subjects 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., HBsAb positive and HBc Ab negative) or a fully resolved acute hepatitis B infection is not an exclusion criterion. Patients with an indolent chronic hepatitis B infection (normal ALT, AST, albumin and no radiographic or biopsy evidence of cirrhosis) will be evaluated by NIDDK 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.


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Citations:

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.

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.

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.

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Contacts:

Principal Investigator

Referral Contact

For more information:

Amy D. Klion, M.D.
National Institute of Allergy and Infectious Diseases (NIAID)
NIHBC 04 BG RM B1-28
4 MEMORIAL DR
BETHESDA MD 20892
(301) 435-8903
aklion@niaid.nih.gov

Thomas W. Brown Jr, R.N.
National Institute of Allergy and Infectious Diseases (NIAID)
National Institutes of Health
Building 10
Room 12C103-20
10 Center Drive
Bethesda, Maryland 20892
(301) 402-7823
browntw@mail.nih.gov

Office of Patient Recruitment
National Institutes of Health Clinical Center (CC)
Building 61, 10 Cloister Court
Bethesda, Maryland 20892
Toll Free: 1-800-411-1222
Local Phone: 301-451-4383
TTY: TTY Users Dial 7-1-1
ccopr@nih.gov

Clinical Trials Number:

NCT00044304

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