Emerging therapies and promising new insights in the treatment of sickle cell disease represent a significant step toward improving outcomes and reducing the treatment burden for affected children and adults. Studies reporting these advances will be presented today at the 57th American Society of Hematology (ASH) Annual Meeting and Exposition.
Sickle cell disease (SCD) is an inherited, chronic disorder affecting nearly 100,000 Americans. Individuals with the disease produce abnormal hemoglobin, a protein in red blood cells that attaches to oxygen in the lungs and carries it to all parts of the body. This abnormal hemoglobin causes the red blood cells to become rigid and sickle-shaped, which causes them to stick together and block the flow of blood and oxygen to the body, leading to intense pain and other serious issues such as stroke, infection, and pulmonary complications. While stem cell transplantation is an available cure for SCD, it is associated with potentially fatal side effects. In the absence of a widely accessible cure, the few treatment options for SCD are aimed at decreasing pain, preventing serious associated health problems, and improving quality of life. The only established long-term therapy for SCD is hydroxyurea, a pill approved more than a decade ago to treat complications stemming from the disease.
New research presented today demonstrates potentially practice-changing advances in improving outcomes for patients with SCD. Two studies present promising new insights for managing the disease in children. One of these explores a less burdensome strategy for preventing stroke, a serious SCD complication more common in children than in adults, by using hydroxyurea in a new way. The other pediatric study reports on positive outcomes from a large, long-term analysis of children with SCD who received a stem cell transplant from a sibling with identical, matching tissues. Finally, promising new data demonstrate that a new oral agent may be a safe, effective way to manage SCD by reducing the sickling of red blood cells.
"Patients with sickle cell disease face a lifetime of challenges, and more research is desperately needed to address evidence gaps and improve our understanding of the best possible care for these patients," said Alexis Thompson, MD, MPH, moderator of the press conference and professor of pediatrics at the Ann & Robert H. Lurie Children's Hospital of Chicago. "Studies presented today address existing and new treatment methods that may have significant and practice-changing implications for patients with sickle cell disease."
This press conference will take place on Sunday, December 6, at 9:00 a.m. in Room W208AB of the Orange County Convention Center.
Oral Medication May Be Safe, Effective Alternative to Transfusion in Primary Stroke Prevention for Children with Sickle Cell Anemia
TCD with Transfusions Changing to Hydroxyurea (TWiTCH): Hydroxyurea Therapy as an Alternative to Transfusions for Primary Stroke Prevention in Children with Sickle Cell Anemia 
- Stroke is a devastating complication of sickle cell anemia (SCA) that occurs in young children. Transcranial Doppler (TCD) screening, which measures the velocity of blood flow through the brain's vessels, can identify children at risk for stroke, with abnormally elevated TCD velocities conferring the highest risk.
- Transfusions offer effective protection against primary stroke in these high-risk children but must be continued indefinitely, leading to iron overload and causing serious health problems.
- This study examined whether hydroxyurea, an alternative treatment strategy, was non-inferior to transfusions and could offer similar, effective protection against primary stroke in children with SCA and abnormal TCD velocities.
- This NHLBI-funded multi-center, Phase III randomized clinical trial in 26 pediatric programs across the United States and Canada compared 24 months of standard treatment (transfusions) to alternative treatment (hydroxyurea) in 121 children with SCA (61 were given transfusions; 60 were given hydroxyurea) who were currently receiving monthly transfusions for abnormal TCD but without severe vasculopathy.
- TCD examinations were performed every 12 weeks during treatment. After full enrollment, the first scheduled interim data analysis demonstrated an average TCD velocity of 143 cm/sec on the transfusion arm and 138 cm/sec on the hydroxyurea arm. After confirmation of the results, NHLBI terminated the study early.
- In the transfusion arm, 42 patients completed all treatment, 11 had truncated treatment, and eight withdrew from the study. In the hydroxyurea arm, 41 patients completed all treatment, 13 completed truncated treatment, and six withdrew from the study.
- No child suffered a stroke and normal TCD velocities were maintained in both treatment arms. No child reverted from normal to abnormal TCD velocities, and exit brain imaging examinations documented no new cerebral infarcts in either treatment arm.
- The results indicate that for children with SCA and abnormal TCD velocities who have received several years of blood transfusions and have not developed severe vasculopathy, hydroxyurea at maximum tolerated dose was not inferior to transfusions for maintaining normal TCD velocities. In this setting, hydroxyurea can serve as an alternative to indefinite transfusions for the prevention of primary stroke in this high-risk population.
Russell E. Ware, MD, PhD, Cincinnati Children's Hospital Medical Center, Cincinnati, will present this study during the Plenary Scientific Session on Sunday, December 6, at 2:00 p.m. in Hall D, level 2 of the Orange County Convention Center.
Large Analysis Shows Stem Cell Transplant is Successful in Most Children with Sibling Donors
Hematopoietic Stem Cell Transplantation from HLA Identical Sibling for Sickle Cell Disease: An International Survey on Behalf of Eurocord-Monacord, EBMT Pediatric Disease Working Party and CIBMTR 
- While stem cell transplant is the only curative therapy for sickle cell disease (SCD) patients, it is offered to relatively few patients for a variety of reasons, including the risk of graft-versus-host disease for patients without matched donors and lack of consensus on which patients are candidates for transplant.
- To date, most stem cell transplants for SCD are performed in children and adolescents who have sibling donors with identical tissues. In this study, investigators sought to understand the outcomes of this procedure on a large scale.
- The study reported on the outcomes of 1,000 patients with SCD, with a median age of nine years, who received stem cell transplantation from a sibling with identical tissues during the period from 1991 to 2001.
- The three year overall survival was 99 percent for patients who received donor cord blood, 94 percent for those who received donor bone marrow, and 80 percent for those who received transplanted peripheral blood.
- Seventy-three patients rejected donated tissues and cells, and 67 died mainly due to graft-versus-host disease or infection.
- This large registry study demonstrated that transplant from a matched sibling donor is successful in more than 90 percent of patients with severe SCD.
- These findings may increase awareness of the importance of early referrals for patients with severe SCD to receive transplant.
Barbara Cappelli, MD, Eurocord International Registry, Paris, France, will present this study during an oral presentation on Monday, December 7, at 10:30 a.m. in room W340, level 3 of the Orange County Convention Center.
Novel Therapy Decreases Red Blood Cell Sickling in Patients with Sickle Cell Disease
GBT440, a Potent Anti-Sickling Hemoglobin Modifier Reduces Hemolysis, Improves Anemia and Nearly Eliminates Sickle Cells in Peripheral Blood of Patients with Sickle Cell Disease 
- GBT440 is an exploratory oral therapy that works by increasing hemoglobin's affinity for oxygen and targets the underlying mechanism of red blood cell sickling.
- The first in-human randomized, double-blind Phase I/II study examined if this therapy could interrupt red blood cell destruction, prevent sickling, and potentially become a safe and effective disease-modifying therapy for patients with sickle cell disease (SCD). The study enrolled patients with SCD between 18-60 years old along with healthy volunteers to evaluate safety, pharmacokinetics, and pharmacodynamics.
- During part A of the study, cohorts of healthy volunteers and SCD patients received single doses of GBT440 or placebo. During part B, cohorts of healthy volunteers and patients received multiple doses of GBT440 or placebo.
- As of October 2015, eight SCD patients had completed part A of the study, 16 had completed part B at 700 mg per day, and 14 patients had completed or were ongoing in Part B at 500 mg per day. No SCD patients discontinued GBT440. There have been no drug-related severe or serious adverse events.
- After 28 days of treatment in SCD patients, a marked reduction of sickled cells was observed compared with no changes in the placebo group. Increased hemoglobin and reductions in multiple markers of red cell destruction were also observed, beginning as early as eight days after therapy. Decreases in reticulocyte count and erythropoietin were seen, which are consistent with decreased sickling, improved red blood cell survival, and improved tissue oxygen delivery.
- These results demonstrate that GBT440 rapidly reduced the rate of red blood cell destruction, improved oxygen delivery to tissues, and reduced the number of circulating sickled cells. These results support further clinical investigation of this agent as a potentially disease-modifying therapy for sickle cell disease.
Claire Hemmaway, MD, Queens Hospital, Essex, United Kingdom, will present this study during an oral presentation on Monday, December 7, at 10:45 a.m. in room W340, level 3 of the Orange County Convention Center.
American Society of Hematology