Imatinib for Pain in Sickle Cell Anemia
Imatinib for Pain in Sickle Cell Anemia
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).
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. Anti-thrombotic and anti-platelet agents: warfarin (Coumadin), heparin, low
 molecular weight heparin.

 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.