Efficacy of Tyrosine Kinase Inhibition in Reducing Eosinophilia in Patients With Myeloid and/or Steroid-Refractory Hypereosinophilic Syndrome
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.
⁃ 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.
⁃ Refractory to or intolerant of steroids without evidence of a myeloid disorder.
• Negative serum beta-human chorionic gonadotropin 24 hours prior to drug administration for women of childbearing potential to exclude early pregnancy.
• 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.\*\*
• Participation in protocol 94-I-0079 (Activation and function of eosinophils in conditions with blood or tissue eosinophilia).
⁃ NOTE: Participants 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. Patients who meet inclusion criteria but are already receiving ruxolitinib may be enrolled at the investigator s discretion if baseline data are 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 participants 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 participants have a physician outside the NIH for routine medical care and emergencies.