We and others have found that patients with HbSS who die prematurely have more evidence of renal, hepatic, and cardiopulmonary damage. Our recent work revealed that only 65% of patients with HbSS screened at the NIH Clinical Center were treated with HU despite the vast majority meeting disease criteria severe enough to warrant initiating HU. Because we are a referral center and most patients are managed by their outside hematologists, we have not been able to control what percentage of patients who are followed at outside institutions start HU. While our study suggests that any HU treatment improves survival in patients with HbSS, the effect was most pronounced in those taking the recommended dose of 15-35 mg/kg/day. Further, patients with higher HbF levels appeared more likely to survive and had less evidence of liver damage over time. Due to the complexity involved in their care, often the focus has not been to push the HU to the maximum tolerated dose (MTD). Ideally, a dosing algorithm would make the HU dose titration process easier, more effective, and less intimidating for primary providers who frequently manage adult patients with HbSS. Further, a computer program which is able to calculate a HU dose based on patients' blood counts and the timing of most recent HU dose titration would improve the percentage of patients whose HU is increased to MTD. Hydroxyurea dosing in our protocol is based on a written algorithm which is derived manually, and by a computer program which was developed at the NIH Clinical Center. Clinical, laboratory, and echocardiographic parameters are monitored at baseline and after treatment to further study the effect of maximum HbF response on acute complications associated with HbSS and on organ function. Since the protocol was approved last year, 8 subjects with homozygous sickle cell disease have been enrolled, 7 of whom have initiated the hydroxyurea treatment period with follow-up ranging from almost 1 month to almost 9 months. The protocol also seeks to develop laboratory measures to evaluate clinical response to HU. First, HU is known to exert its beneficial effect by increasing fetal hemoglobin (HbF) levels, thereby decreasing red blood cell sickling. However, HU response not only depends on how much total HbF levels increase, but on the concentration of HbF within each HbF-producing red blood cell (F-cell). We are attempting to measure HbF concentration within each individual F-cell using the ImageStream imaging flow cytometer, and are continuing to work to optimize this technique. We are also working on measuring gamma-globin expression as a means to predict early response to HU. Lastly, because hemoglobin polymerizes and red blood cells sickle upon deoxygenation, red blood cell density increases. Since HbF decreases red blood cell sickling, we are measuring red blood cell density before and during HU treatment. These laboratory studies are ongoing.
| Hsieh, Matthew M; Fitzhugh, Courtney D; Weitzel, R Patrick et al. (2014) Nonmyeloablative HLA-matched sibling allogeneic hematopoietic stem cell transplantation for severe sickle cell phenotype. JAMA 312:48-56 |
| Gharwan, Helen; Neary, Nicola M; Link, Mary et al. (2014) Successful fertility restoration after allogeneic hematopoietic stem cell transplantation. Endocr Pract 20:e157-61 |
| Jung, M; Ranpura, V N; Dunbar, C E et al. (2014) Angioedema in patients treated with sirolimus and ACE inhibitor post hematopoietic SCT. Bone Marrow Transplant 49:1448-9 |
| Fitzhugh, C D; Weitzel, R P; Hsieh, M M et al. (2013) Sirolimus and post transplant Cy synergistically maintain mixed chimerism in a mismatched murine model. Bone Marrow Transplant 48:1335-41 |
