Tyrosine Kinase Inhibition to Treat Myeloid Hypereosinophilic Syndrome
Fjalë kyçe
Abstrakt
Përshkrim
This study will evaluate the safety and effectiveness of imatinib mesylate in reducing the number of eosinophils (a type of white blood cell) in patients with hypereosinophilic syndrome (HES). Patients with HES have elevated counts of eosinophils in the blood and body tissues, which can cause damage to these tissues. Although HES can involve any tissues, the heart, nerves, and skin are most often affected. Several drugs, including steroids, interferon, and hydroxyurea can lower eosinophil counts; however, these drugs have drawbacks in that they do not work in all patients with HES, or they may work only temporarily, or patients may develop side effects that require stopping the drugs. Imatinib mesylate is a new drug approved to treat gastrointestinal tumors and chronic myelogenous leukemia. Some data suggest that imatinib mesylate may be useful in treating a subgroup of patients with HES.
Patients with HES who are 18 years of age and older may be eligible for this study. Candidates will be screened with a medical history, physical examination, blood tests, electrocardiogram (EKG), echocardiogram (ultrasound examination of the heart), pulmonary (lung) function tests, eye exam and a bone marrow examination to determine if they fall into the subgroup of patients likely to respond to this therapy. For the bone marrow procedure, an area of skin and bone is numbed and a very sharp needle is inserted into the bone to draw out a sample of bone marrow for evaluation under the microscope.
Patients enrolled in the study will take imatinib mesylate daily. Any other drugs they may be taking for HES, as well as other drugs they are taking that may interact with imatinib mesylate, will be tapered and stopped. If it is not possible to stop taking certain drugs for other conditions, their dosages may be adjusted. Patients will be monitored weekly with laboratory testing during the first month of treatment and whenever neutrophil counts drop below 1500/mm3 or platelets fall below 100,000/mm3. If blood counts remain high enough, monitoring will be reduced to every 2 weeks for 3 months and once a month after that. Patients will have a clinic visit at NIH 1 month after beginning the drug for a clinical and laboratory evaluation, including a repeat bone marrow examination. Patients whose eosinophil counts are not lowered after 4 weeks of treatment will leave the study. Those who respond to therapy will return to NIH every 3 months for a history and physical examination, laboratory tests, EKG, echocardiogram, and pulmonary function testing to determine how treatment is affecting disease progression. In some participants with stable disease where an optimal dose of imatinib mesylate has been identified, visits may be extended to every six months. In addition, the following procedures will be done solely for research purposes:
- Blood tests to determine the effects of imatinib mesylate on immune cells, including eosinophils.
- Leukapheresis to study the effects of imatinib mesylate on eosinophils: For this procedure, whole blood is collected through a needle in an arm vein, similar to donating blood. The blood circulates through a machine that separates it into its components, and the white cells are removed. The rest of the blood is returned to the body, either through the same needle or through another needle in the other arm.
- Bone marrow examinations will be done during the screening tests and again 1 month after starting treatment to look at newly developing cells in the bone marrow.
- Genetic testing to determine how imatinib mesylate is able to lower eosinophil counts in patients with HES.
Datat
| Verifikuar së fundmi: | 03/05/2020 |
| Paraqitur së pari: | 08/23/2002 |
| Regjistrimi i vlerësuar u dorëzua: | 08/23/2002 |
| Postuar së pari: | 08/25/2002 |
| Përditësimi i fundit i paraqitur: | 11/03/2020 |
| Përditësimi i fundit i postuar: | 11/04/2020 |
| Data e fillimit të studimit aktual: | 09/25/2002 |
| Data e vlerësuar e përfundimit primar: | 12/31/2024 |
| Data e vlerësimit të përfundimit të studimit: | 12/31/2025 |
Gjendja ose sëmundja
Ndërhyrja / trajtimi
Drug: Imatinib
Drug: Ruxolitinib
Faza
Grupet e krahëve
| Krah | Ndërhyrja / trajtimi |
|---|---|
| Experimental: Imatinib open label imatinib mesylate treatment | Drug: Imatinib 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 poqD. |
| Experimental: Ruxolitinib open label ruxolitinib treatment | Drug: Ruxolitinib 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. |
Kriteret e pranimit
| Moshat e pranueshme për studim | 2 Years Për të 2 Years |
| Gjinitë e pranueshme për studim | All |
| Pranon Vullnetarë të Shëndetshëm | po |
| Kriteret | - INCLUSION CRITERIA: All subjects must meet the established diagnostic criteria for hypereosinophilic syndrome: eosinophilia greater than 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 subjects must fit one of the following three categories: 1. refractory to or intolerant of steroids 2. presence of FIP1L1/PDGFRA by RT-PCR 3. presence of greater than or equal to 4 of the following laboratory criteria suggestive of a myeloid disorder: i. dysplastic eosinophils on peripheral smear ii. serum B12 level greater than or equal to 1000 pg/ml iii. serum tryptase level greater than or equal to 12 iv. anemia and/or thrombocytopenia v. bone marrow cellularity greater than 80% with left shift in maturation vi. dysplastic (spindle-shaped) mast cells on bone marrow biopsy vii. evidence of fibrosis on bone marrow biopsy viii. dysplastic megakaryocytes on bone marrow biopsy 3. All subjects must be at least 2 years of age. 4. Negative serum beta-hCG within 24 hours prior to drug administration for women of childbearing potential to exclude early pregnancy. 5. All subjects (men and women) must agree to practice abstinence or effective contraception during administration of imatinib mesylate or ruxolitinib and for 6 months after discontinuation of drug. Of note, failure of the standard chemotherapeutic agents (steroids, hydroxyurea, and interferon alpha) will not be a prerequisite for participation in this protocol for the following reasons. 1) There is no approved therapy for HES. 2) steroid therapy in the myeloid subset of HES patients is generally ineffective. 3) Although hydroxyurea and interferon alpha are initially effective in most cases, a majority of patients become refractory to or intolerant of these agents within a relatively short period of time (less than 1 year). 4) Data from other myeloid neoplasms and disorders, including CML, suggest that interferon, imatinib mesylate, and ruxolitinib, but not hydroxyurea, are associated with cytogenetic remission. 5) The reported incidence and severity of side effects from imatinib mesylate in patients with CML and ruxolitinib in myelofibrosis and polycythemia vera appear comparable to (or less than) those associated with interferon alpha. 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. 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: 1. Pregnancy or nursing women 2. HIV positivity or other known immunodeficiency 3. D816V KIT-positive systemic mastocytosis 4. Absolute neutrophil count less than 1000/mm(3) or platelet count less than 10,000/mm(3) or less than 50,000/m(3) with clinical evidence of bleeding. 5. Elevated transaminases (greater than 5 times the upper limit of normal) or elevated bilirubin (greater than 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 7. Evidence of B cell clonality by PCR or flow cytometry (exclusion criteria for ruxolitinib only) |
Rezultati
Masat Kryesore të Rezultateve
1. peripheral blood absolute eosinophil count. [one month (for imatinib) and 3 months (for ruxolitinib).]
Masat dytësore të rezultateve
1. peripheral blood eosinophil count [3,6,9 and 12 months]
2. peripheral blood eosinophil count [1, 3, 6, 9, and 12 months]
3. abnormal tyrosine kinase (i.e., FIP1L1-PDGFRA, JAK2 V617F) [every 3 months for 5 years]
4. clinical, hematologic and molecular remission [every 3 months for 5 years]
