National Heart, Lung, and Blood Institute Release: Studies Assess Hydroxyurea Therapy and Pre-Operative Transfusions for Patients with Sickle Cell Disease

SAN DIEGO, Dec. 11, 2011 /PRNewswire-USNewswire/ -- Research assessing the safety and efficacy of hydroxyurea therapy in pediatric patients with sickle cell disease (SCD) and the use of pre-operative transfusions for patients with SCD who undergo low- and moderate-risk elective surgery will be presented today at the 53rd Annual Meeting of the American Society of Hematology.

An estimated 90,000 to 100,000 Americans are affected each year by SCD, a serious disorder that causes normal red blood cells to become rigid and form in a crescent "sickle" shape.[1] The abnormal shape of these cells causes them to clump together and become embedded in the blood vessels of organs, causing pain, infection, potential organ damage, and stroke. Even with advancements in drug therapies and prevention methods, safe and effective treatment options remain limited, especially for children and patients facing surgery who have an increased risk for complications.

"The studies presented today underscore the need to assess the quality and effectiveness of therapy for sickle cell disease, particularly in the pediatric population, and investigate the strategic use of pre-operative transfusion for sickle cell patients," said Susan B. Shurin, MD, moderator of the press conference and Acting Director of the National Heart, Lung, and Blood Institute (NHLBI) in Bethesda, Md.

Dr. Shurin, who has been instrumental in the U.S. Department of Health and Human Services' (HHS) recent initiative to promote research advances in SCD, stated, "I am hopeful that discoveries like these, combined with continuing efforts to develop new treatments, share public health data, and provide evidence-based guidelines, will soon lead to significant improvement in the lives of patients with SCD."

This press conference will take place on Sunday, December 11, at 10:00 a.m. PST.

Hydroxyurea Treatment of Young Children with Sickle Cell Anemia: Safety and Efficacy of Continued Treatment -- the BABY HUG Follow-up Study [Abstract 7]

Hydroxyurea is the only federally approved therapy to prevent sickle cell complications in adults with sickle cell anemia (SCA). However, based on positive results from previous trials assessing clinical benefits for use in children, specialists are increasingly considering the use of hydroxyurea in their pediatric patients. Results from the BABY HUG Follow-up Study I suggest that continued use of hydroxyurea is both safe and effective in infants with SCA.

The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) was a multicenter, randomized clinical trial that assessed the clinical benefits of hydroxyurea in very young patients with SCA. Results from the study demonstrated that hydroxyurea administered to infants with SCA provided substantial clinical benefit over placebo.

Researchers launched the BABY HUG Follow-Up Study I in 2008 to assess the safety and efficacy of continued treatment with hydroxyurea in infants with SCA. The Follow-Up Study I included 163 children between the ages of 28 and 44 months who had participated in the BABY HUG trial and who had completed at least 18 months of randomized treatment of either hydroxyurea or placebo. Investigators collected clinical and laboratory data every six months from patient medical records, including use and dosage of hydroxyurea, blood counts, clinical imaging, and frequency of sickle cell-related complications.

At Follow-Up Study entry, families enrolling their children did not know their child's randomized study treatment assignment in BABY HUG; 82 percent initially chose clinical prescription of open-label hydroxyurea, demonstrating a high acceptance rate for the drug. Through the 36 months of follow-up, acceptance remained high, with 68 to 75 percent of the participating families reporting that their children continued to take hydroxyurea.

Follow-Up Study I data indicate that children who continue to take hydroxyurea have statistically lower rates of pain crises requiring emergency room visits, episodic transfusions, and hospital admissions for any reason when compared to those taking placebo. These clinical benefits are similar to those demonstrated by the drug in BABY HUG, the results of which were published earlier this year and are consistent with previously published trials that detail the therapy's benefits in older children and adults.

"Our study data reveal not only that the clinical benefits of hydroxyurea continue with ongoing administration, but also the wide acceptance of the treatment by the families of our patients, demonstrated by the high percentage of families that continued their children on hydroxyurea after the randomized trial ended," said lead author Zora R. Rogers, MD, Professor of Pediatrics at UT Southwestern Medical Center Dallas and Clinical Director of the Bone Marrow Failure and General Hematology Program at Children's Medical Center Dallas. "Analysis of growth and development assessments obtained in the Follow-Up Study along with these clinical results will further enhance our understanding of the benefits of the use of starting hydroxyurea in children with sickle cell disease at a very young age."

The BABY HUG Follow-Up Study I is funded by the National Heart, Lung, and Blood Institute (NHLBI) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD).

Dr. Rogers will present this study in an oral presentation on Sunday, December 11, at 4:30 p.m. PST at the Manchester Grand Hyatt in the Elizabeth Ballroom AB.

Genotoxicity Associated with Hydroxyurea Exposure in Infants with Sickle Cell Anemia: Results From the BABY-HUG Phase III Clinical Trial [Abstract 8]

Using data from the largest clinical trial to date to assess the use of hydroxyurea in pediatric patients with sickle cell anemia (SCA), researchers have provided further evidence that the therapy likely does not cause long-term genetic damage (known as genotoxicity) in young patients with SCA.

To assess whether hydroxyurea potentially causes genotoxic effects in infants with SCA, researchers analyzed patient data from the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG). This multicenter, randomized clinical trial assessed the clinical benefits of hydroxyurea in infants with SCA.

In this study, 193 infants between the ages of nine and 18 months were randomized to receive either hydroxyurea or placebo over the course of two years. An important secondary objective of the study was the in vivo measurement of acquired genotoxic effects of hydroxyurea, which was obtained by tracking the frequency of several laboratory-based measures of DNA damage. These markers include breaks in chromosomes or chromatids (DNA double-strands), abnormal recombination of DNA in cells of the immune system, and the formation of micronucleated reticulocytes (abnormal young red blood cells).

At the conclusion of the study, children receiving hydroxyurea did not show any significant differences in the numbers of any of the damage markers when compared with children on placebo. These data suggest that conventional doses of hydroxyurea do not appear to cause DNA damage as suggested by laboratory-based experiments that have used higher concentrations of the drug, providing reassurance that hydroxyurea presents low genotoxic risk to children.

"Although the clinical benefits of hydroxyurea for children with sickle cell disease are well recognized, treatment in young patients is limited due to concerns about potential long-term genotoxic effects," said lead author Patrick T. McGann, MD, Fellow in the Department of Pediatrics in the Hematology-Oncology Section at Baylor College of Medicine in Houston. "Results from this study contribute to a growing body of evidence suggesting that in vivo genotoxicity of hydroxyurea in sickle cell anemia appears to be low. Taken together with the clinical benefits demonstrated in the BABY HUG study, hydroxyurea may be considered as a potential therapeutic option for even very young, asymptomatic children with sickle cell anemia."

Dr. McGann will present this study in an oral presentation on Sunday, December 11, at 4:45 p.m. PST at the Manchester Grand Hyatt in the Elizabeth Ballroom AB.

Pre-Operative Transfusion Reduces Serious Adverse Events in Patients with Sickle Cell Disease (SCD): Results From the Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) Randomised Controlled Multicentre Clinical Trial [Abstract 9]

New research suggests that patients with sickle cell disease (SCD) who are undergoing surgeries, such as abdominal surgery or tonsillectomy, should receive pre-operative transfusions to reduce their risk of post-operative complications.

Pre-operative blood transfusions have been used to reduce complications after surgery for SCD patients, who are at higher risk for these complications than the general population. However, some experts have claimed that the procedure is not necessary and can be safely omitted prior to surgery.

To assess the clinical benefit of pre-operative transfusion to alleviate perioperative complications in patients with SCD undergoing low- or medium-risk surgery, researchers embarked on the multicenter, randomized controlled Transfusion Alternatives Pre-Operatively in Sickle Cell Disease (TAPS) Trial. The trial was carried out between November 2007 and March 2011 at 22 clinical sites in the United Kingdom, the Netherlands, and Canada.

Patients with HbSS and HbSb^o thalassemia, the most severe forms of SCD, were randomized to two treatment arms: patients in Arm A received a pre-operative blood transfusion, while patients in Arm B did not. The primary outcome of the TAPS trial was the proportion of patients experiencing any significant complication between time of randomization into the study and 30 days post-surgery.

Of the 343 patients screened for the trial, 70 were randomized into treatment arms at time of study termination. The trial was closed early because of an excess of serious adverse events (SAEs), which were a subset of complication reports, in the untransfused arm (Arm A). Thirty-three patients in Arm A and 34 patients in Arm B were included in the final analysis. Researchers found that 39 percent of patients who did not receive pre-operative transfusions experienced a perioperative complication, compared to 15 percent of patients in the transfusion arm. There was also a difference in the rate of SAEs between the two arms; 30 percent of patients who did not receive a transfusion experienced an SAE, compared to only 3 percent of patients who received one prior to surgery. The majority of SAEs reported were acute chest syndrome, a life threatening complication of SCD.

"Currently, many patients with SCD are not receiving pre-operative transfusions, which may be putting them at risk of serious complications. The results from our trial demonstrate a striking increase in the total number of complications, both common and life-threatening, in patients who did not receive a blood transfusion before surgery," said lead author Jo Howard, MD, Consultant Hematologist at Guy's and St. Thomas Hospital in London. "Moving forward, we recommend that clinicans take these results into consideration when deciding on pre-operative transfusion and suggest that patients with HbSS and HbSB(degree)thalassaemia receive a blood transfusion before surgery."

The TAPS trial and was sponsored and funded by NHS Blood and Transplant in the United Kingdom.

Dr. Howard will present this study in an oral presentation on Sunday, December 11, at 5:00 p.m. PST at the Manchester Grand Hyatt in the Elizabeth Ballroom AB.

American Society of Hematology 53rd Annual Meeting

The study authors and press program moderator will be available for interviews after the press conference or by telephone. Additional press briefings will take place throughout the meeting on new treatment techniques for patients with bleeding and clotting disorders, targeted therapies for acute and chronic leukemia, improving recovery and outcomes in transplantation, and emerging treatments for lymphoma and myeloma. For the complete annual meeting program and abstracts, visit www.hematology.org/2011abstracts. Get up-to-date information about the annual meeting by following ASH on Twitter @ASH_hematology.

The American Society of Hematology (www.hematology.org) is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems by promoting research, clinical care, education, training, and advocacy in hematology. The official journal of ASH is Blood (www.bloodjournal.org), the most cited peer-reviewed publication in the field, which is available weekly in print and online.

[1] Sickle Cell Disease: Data & Statistics. http://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed October 18, 2011

SOURCE American Society of Hematology