imatinib for pain in sickle cell anemia

Conditions: Sickle Cell Disease

Summary: in this protocol, the investigators propose to evaluate the biochemical effects of imatinib on sickle red blood cells (rbcs). patients will be administered imatinib mesylate orally following the guidelines previously established for use of imatinib in other disorders. the biochemical effects of imatinib on sickle rbcs will be examined, including changes in their levels of band 3 tyrosine phosphorylation and the abundances of rbc-derived microparticles in their blood. in addition, the patients will be monitored for symptoms of sickle cell disease (scd). the investigators expect band 3 tyrosine phosphorylation to decrease dramatically in patients treated with imatinib. the investigators also anticipate a reduction in the numbers of rbc-derived microparticles in circulation (quantitated by assaying the number of glycophorin a positive microparticles in peripheral blood samples by flow cytometry. most importantly, the investigators expect to see a reduction in the frequency of vaso-occlusive crises, and possibly acute chest syndrome and utilization of opioids. the study duration is planned as 6 months in order to provide adequate time for potential change in the primary endpoints (e.g. percent irreversibly sickled cells).


Eligibility criteria:
inclusion criteria: 1. age: patients must be ≥18 years of age and ≤25 years of age at the time of study entry. 2. diagnosis: patients must have documented diagnosis of sickle cell disease (hemoglobin ss disease or s-beta 0 thalassemia) by either high pressure liquid chromatography (hplc) or hemoglobin electrophoresis 3. disease status: patients must have at least 2 documented episodes of vaso-occlusive pain in the prior year as defined by an acute episode of pain lasting greater than 24 hours, with no medically determined cause other than a vaso-occlusive event that resulted in treatment with oral or parenteral opiates or with a parenteral nonsteroidal anti-inflammatory drug. 4. performance level: karnofsky ≥80 for patients \>10 years of age and lansky ≥80 for patients ≤10 years of age. patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. 5. organ function requirements: a. adequate bone marrow function defined as i. peripheral absolute neutrophil count (anc) ≥1000/µl ii. platelet count ≥100,000/ µl (transfusion independent) b. adequate renal function defined as i. creatinine clearance or radioisotope glomerular filtration rate (gfr) ≥70 ml/min/1.73 m2 or ii. a serum creatinine based on age/gender c. adequate liver function defined as: i. total bilirubin (sum of conjugated + unconjugated) ≤1.5 times upper limit of normal (uln) for age, and ii. serum glutamate pyruvate transaminase (sgpt or alt) \<2.5 upper limit of normal. for the purpose of this study, the uln for sgpt is 45 u/l iii. serum albumin ≥2 g/dl d. adequate cardiac function defined as: i. shortening fraction or ejection fraction greater than the institutional norm, and ii. corrected qt interval ≤450 msec 6. informed consent: all patients and/or their parents or legal guardians must sign a written informed consent. assent, when appropriate, will be obtained according to institutional guidelines. exclusion criteria: 1. chronic transfusion protocol. a. patients currently on a chronic transfusion protocol are not eligible 2. hydroxyurea intolerance a. patients who are ineligible for hydroxyurea due to persistent marrow suppression (e.g. thrombocytopenia, neutropenia) 3. pregnancy or breast-feeding a. pregnancy tests must be obtained in girls who are post-menarchal. males or females of reproductive potential may not participate unless they have agreed to use an effective contraceptive method. 4. concomitant medications 1. investigational drugs: patients who are currently receiving another investigational drug. 2. anti-cancer agents: patients who are currently receiving other anti-cancer agents. 3. the following cyp3a4 inducers are prohibited 14 days before the start of imatinib and during the study with imatinib: rifampin, rifabutin, carbamazepine, phenobarbital, phenytoin, st. john's wort, efavirenz, and tipranavir. 4. the following cyp3a4 inhibitors are prohibited 7 days before the start of imatinib and during the study with imatinib: azole antifungals (itraconazole, ketoconazole); clarithromycin, erythromycin, diltiazem, verapamil, hiv protease inhibitors (indinavir, saquinavir, ritonavir, atazanavir, nelfainavir); delavirdine. 5. patients who have an uncontrolled infection. 6. prior use of imatinib: patients who have previously received imatinib are not eligible for study. 7. patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study. 8. patient is \< 5 years free of a malignancy. existence of any other malignant disease is not allowed. 9. patient with grade iii/iv cardiac problems as defined by the new york heart association criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study). 10. patients with a history of qt prolongation, need for concomitant use of anti-arrhythmics or other agents known to prolong qt interval, or electrolyte derangement that cannot be corrected to within normal limits prior to initiation of study drug. 11. patients with a family history of sudden cardiac death. 12. patient has a severe and/or uncontrolled medical disease other than sickle cell disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection). 13. patient has known chronic liver disease (i.e., chronic active hepatitis, and cirrhosis). 14. patient has a known diagnosis of human immunodeficiency virus (hiv) infection. 15. patient had a major surgery within 2 weeks prior to study entry.