Sickle Cell Disease
Conditions
Brief 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).
Interventions
DRUGImatinib Mesylate
The starting dose for subjects will be 340 mg/m2/day with a maximum dose of 600 mg daily. Patients will receive Imatinib orally once daily for 6 months.
Sponsors
Indiana University
Purdue University
Children's Hospital Medical Center, Cincinnati
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 25 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Biochemical Effects - Band 3 Phosphorylation | Change from baseline Band 3 Phosphorylation at 7 months | Percent change in Band 3 Phosphorylation tested in red blood cells. Band 3 is a protein found on the membrane of red blood cells. |
| Change in Amount of Microparticles Released From Red Blood Cells | change from baseline microparticle release at 7 months | Change in Microparticles released from red blood cells. Microparticles are small vesicles released from red blood cells during aging, stress, or other types of damage that contain various proteins from inside the red blood cell, as well as from its membrane. |
| Change in Percent Irreversibly Sickled Cells | Change from baseline of percent irreversibly sickled cells at 7 months | Functional RBCs is analyzed by two components, one of which is percent irreversibly sickled cells. The percent of irreversibly sickled cells is measure by ektacytometry. Red blood cells that sickle and then cannot revert back to its normal shape are considered irreversibly sickled, increasing the likelihood of adhesion to vessel walls, as well as breakdown or hemolysis. Understanding the point of susceptibility of sickling helps us at what partial pressure of oxygen the red blood cell will sickle. The higher the partial pressure, the more resistant the red blood cell is to sickling/breakdown. |
| Change in Point of Susceptibility to Sickling by OxygenScan | Change from baseline of point of susceptibility of sickling at 7 months | Functional RBCs is analyzed by two components, one of which is Change in Point of Susceptibility to Sickling. This is measured by OxygenScan. The point of susceptibility of sickling shows at what partial pressure of oxygen (mmHg) the red blood cell will sickle. The higher the partial pressure, the more resistant the red blood cell is to sickling/breakdown. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Instances of Vaso-occlusive Crisis (VOC) | Assessed monthly from treatment start up to 7 months | Defined as 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 opiate agents and/or parenteral nonsteroidal anti-inflammatory agents. Degree of pain was measured by the standard numerical pain scale (0 being little to no pain, 10 being the worst pain). |
| Number of Instances of Acute Chest Syndrome (ACS) | Assessed monthly from treatment start up to 7 months | Defined as respiratory distress (hypoxia, shortness of breath, chest pain, tachypnea) with evidence of an infiltrate on chest x-ray Measured with clinical evaluation. |
| Opioid Use | Assessed monthly from treatment start up to 7 months | Defined as oral opioid use. Oral use will be documented in pain diary by patient/guardian and reviewed at each visit. |
| Number of Hospitalizations | Assessed monthly from treatment start up to 7 months | Defined as an emergency room or clinic visit resulting in an inpatient admission or observation for a sickle cell-related event (e.g. vaso-occlusive pain, acute chest syndrome, etc). |
| Assessment of Toxicities of Imatinib in Patients With Sickle Cell Anemia | Assessed monthly from treatment start up to 7 months | Assessment of toxicities based on clinical and laboratory evaluation |
Countries
United States
Participant flow
Pre-assignment details
7 met inclusion criteria. 3 of the participants were on treatment arm and 4 were healthy participants.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Disease Status | 3 Participants |
| Organ Function | 3 Participants |
| Performance Level | 3 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 0 Participants |
| Sex: Female, Male Female | 1 Participants |
| Sex: Female, Male Male | 2 Participants |
| Sickle Cell Genotype: HbSS | 3 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 3 |
| other Total, other adverse events | 3 / 3 |
| serious Total, serious adverse events | 2 / 3 |
Outcome results
None listed