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. 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 HbSbo 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 HbSbo 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.
1Sickle Cell Disease: Data & Statistics. http://www.cdc.gov/ncbddd/sicklecell/data.html. Accessed October 18, 2011
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 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, the most cited peer-reviewed publication in the field, which is available weekly in print and online.
[7] Hydroxyurea Treatment of Young Children with Sickle Cell Anemia: Safety and Efficacy of Continued Treatment — the BABY HUG Follow-up Study
Zora R. Rogers, MD1, Billie Fish, CCRP2*, Zhaoyu Luo, PhD2*, Rathi V. Iyer, MD3, Courtney D. Thornburg, MD, MS4, Sharada A. Sarnaik, MD5, Sohail R. Rana, MD6*, Lori Luchtman-Jones, MD7, Sherron M. Jackson, MD8*, Thomas H. Howard, MD9, James F. Casella, MD10, R. Clark Brown, MD, PhD11, Ofelia A. Alvarez, MD12, Jonathan C. Goldsmith, MD13, Scott T. Miller, MD14 and Winfred C. Wang, MD15
1Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
2Clinical Trials & Surveys Corporation , Owings Mills, MD
3University if Mississippi, Jackson, MS
4Duke University Medical Center, Durham, NC
5Children’s Hosp. of Michigan, Detroit, MI
6Howard University, Washington, DC
7Children’s National Medical Center, Washington, DC
8Medical University of South Carolina, Charleston, SC
9University of Alabama at Birmingham, Birmingham, AL
10The Johns Hopkins University School of Medicine, Baltimore, MD
11Emory University / Children’s Healthcare of Atlanta, Atlanta, GA
12Univ. of Miami School of Med., Miami, FL
13National Heart Lung and Blood Institute, NIH, Bethesda, MD
14SUNY – Brooklyn, Brooklyn, NY
15St. Jude Children’s Research Hospital, Memphis, TN
BABY HUG [Clinical Trials #NCT00006400], an NIH-NICHD sponsored randomized placebo-controlled trial showed that hydroxyurea (HU) administered to 9-18 month old children with sickle cell anemia (SCA) provides substantial clinical benefit. Benefits include a decrease in pain crises, acute chest syndrome events, need for transfusion and hospital admission; hematologic improvement include higher total and fetal hemoglobin concentration, larger red cell size, and lower WBC counts with toxicity limited to transient reduction in absolute neutrophil count (ANC) [Lancet 2011; 377:1663-72]. The parent or guardian of all 176 children who completed at least 18 months of randomized treatment were offered participation in an initial observational BABY HUG Follow-Up Study and 163 (93%) consented to participate. Clinical and laboratory data were collected every 6 months by structured abstraction of the medical record regarding use of clinically prescribed HU (dose escalation recommended), blood counts, clinical imaging, and sickle cell-related events. At the time of enrollment the family did not know their child’s randomized study treatment assignment; 133 (82%) initially chose clinical prescription of open-label HU. Acceptance of HU has remained high through 36 months of follow-up; during each 6 month data collection period 68-75% of participants reported having taken HU.
Only 2 patients have left the study (due to relocation) and more than 93% of expected data have been collected. Preliminary analyses as of May 2011, including 417 patient years (pt-yrs) of follow up, demonstrate that in comparison to participants not taking HU, children who continue to take HU have statistically lower rates of pain crises requiring emergency department (ED) visits, episodic transfusions, and hospital admissions for any reason, including acute chest syndrome or febrile illness (see table). The substantial decrease in acute chest syndrome episodes is similar to the effect demonstrated with HU use in the randomized BABY HUG trial in younger infants and consistent with published trials detailing the benefit of HU therapy in older children and adults. The decrease in the rate of admission for febrile events in HU-treated patients is also comparable to that in the randomized trial, but the reason for this benefit is uncertain. There was no difference in hospitalization rates for painful events including dactylitis. Two patients in the non-HU group had a stroke. There were no differences between groups in the frequency of a palpable spleen or rate of acute splenic sequestration crises. Through 36 months of follow up children taking HU had persistently higher hemoglobin and MCV, and lower WBC and ANC than those not taking HU.
Results of these analyses including growth and development assessments will enhance our understanding of the impact of HU use in children with SCA starting at a very young age. The accruing data from the BABY HUG Follow-Up Study demonstrate a continuation of the substantial benefits of early HU therapy with no discernable additional toxicities. Ongoing follow up of this cohort is essential to fully define these benefits as children grow, and to observe for late toxicity.
Disclosures: Off Label Use: Hydroxyurea is not indicated for treatment of children with sickle cell disease. Use of this medication was for clinical indications and not mandated by this observational study.
[8] Genotoxicity Associated with Hydroxyurea Exposure in Infants with Sickle Cell Anemia: Results From the BABY-HUG Phase III Clinical Trial
Patrick T. McGann, MD1, Jonathan M Flanagan, PhD2, Thad A Howard, MS2*, Stephen D Dertinger, PhD3*, Jin He, MD4*, Anita S Kulharya, PhD5*, Bruce W Thompson, PhD6* and Russell E. Ware, MD, PhD2
1Texas Children’s Hospital Hematology Center, Baylor College of Medicine, Houston, TX
2Baylor College of Medicine, Houston, TX
3Litron Laboratories, Rochester, NY
4St. Jude Children’s Research Hospital, Memphis, TN
5Pathology, Georgia Health Sciences University, Augusta, GA
6Clinical Trials and Surveys Corp., Owings Mills, MD
The laboratory and clinical benefits of hydroxyurea therapy for children with sickle cell anemia (SCA) are well recognized, but treatment in young patients is limited in part by concerns about long-term genotoxicity, and specifically possible carcinogenicity. To date, few prospective data have been available to assess the mutagenic and carcinogenic potential of hydroxyurea in young patients with SCA. The Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) was a multi-center double-blinded placebo-controlled randomized clinical trial (NCT00006400) testing whether hydroxyurea could prevent chronic organ damage in very young patients with SCA. BABY HUG was conducted across 14 centers and was approved by the local institutional review boards of all participating centers. A total of 193 infants (mean 13.6 months) with SCA (HbSS or HbS/ß0-thalassemia) were randomized to receive hydroxyurea (fixed dose of 20 mg/kg/day) or placebo for two years. An important secondary objective of the study was the in vivo measurement of acquired genotoxicity using three laboratory assays: chromosomal karyotype including quantitation of chromosomal breaks, chromatid breaks, and fusion events; illegitimate VDJ recombination events representing inversion events on chromosome 7 with juxtaposition of T-cell receptor Vg and Jb and gene loci; and micronucleated reticulocyte formation signifying aberrant erythroid production. Subjects in both the hydroxyurea and placebo groups had significantly increased numbers of total chromosome breaks and similar numbers of chromatid breaks at study exit compared to study entry. However, at study exit, subjects with hydroxyurea exposure had similar numbers of chromosome and chromatid breaks as subjects receiving placebo (0.5 ± 1.4 chromosome breaks per 100 metaphases vs. 0.4 ± 2.5, p=NS; 0.6 ± 1.1 chromatid breaks per 100 metaphases vs.0.8 ± 3.4, p=NS). There were no changes in the number of illegitimate VDJ recombination events observed, comparing study entry and exit samples either in the hydroxyurea or the placebo treatment group. At study exit, subjects treated with hydroxyurea had similar numbers of illegitimate VDJ recombination events as subjects receiving placebo (0.7 ± 0.5 events per µg of DNA versus 0.7 ± 0.4 events, p=NS). Subjects treated with hydroxyurea had a similar number of early reticulocytes containing micronuclei at study exit compared to subjects receiving placebo (0.3 ± 0.2% versus 0.3 ± 0.2%, p=NS). Together, these data indicate that hydroxyurea treatment in very young patients with SCA was not associated with any significant increases in genotoxicity compared to placebo treatment. These data provide evidence of cytogenetic stability in this susceptible population of young children and contribute to a growing body of evidence to suggest that in vivo genotoxicity of hydroxyurea in patients with SCA appears to be low.
Disclosures: Dertinger: Litron Laboratories: Employment.
[9] 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
Jo Howard, MB, BChir, MRCP, FRCPath1*, Moira Malfroy, RN2*, Llewelyn Charlotte, PhD2*, Louise Choo, PhD3*, David Rees, FRCPath4*, Isabeau Walker, FRCA5*, Tony Johnson, PhD3*, Louise Tillyer, FRCPath6*, Karin Fijnvandraat, MD, PhD7, Melanie Kirby-Allen, MD8*, Renate Hodge, MSc2*, Shilpi Purohit2*, Sally C. Davies, FRCP, FMedSci9 and Lorna M Williamson, FRCPath2*
1Haematology, Guy’s and St Thomas’ NHS Foundation Trust, LONDON, United Kingdom
2NHSBT/MRC Clinical Studies Unit, NHS Blood and Transplant
3Clinical Trials Unit, Medical Research Council
4Haematology, Kings College Hospital NHS Foundtion Trust
5Great Ormond Street Hospital NHS Trust
6Haematology, Royal Brompton and Harefield NHS Foundation Trust
7Academic Medical Center (AMC), Amsterdam, Netherlands
8Hospital for Sick Children Toronto
9Department of Health, London
Introduction: The rate of complications after surgery is increased in patients with Sickle Cell Disease (SCD) and pre-operative blood transfusion has historically been used to decrease this risk. Observational studies and one limited Randomised Controlled Trial (RCT) have suggested that in some patients, transfusion can safely be omitted. Since transfusion is associated with complications including alloimmunisation and increased post-operative infections, we performed a RCT to address whether overall peri-operative complications in SCD are reduced by pre-operative transfusion.
Methods: TAPS was a Phase III multicentre, pragmatic, randomised controlled trial with a parallel group sequential superiority design, carried out between November 2007 and March 2011 at 22 sites in the UK, Netherlands and Canada. Eligible patients had HbSS or HbSβ0thal, were aged one year or more and were having low risk (eg adenoidectomy, dental surgery) or medium risk (eg joint replacement, cholecystectomy, tonsillectomy) elective surgery. Patients were excluded if they had a haemoglobin (Hb) <6.5g/dl, had received a blood transfusion within the last 3 months or had severe SCD. Patients were randomly assigned to Arm A, which received no pre-operative transfusion, or Arm B, which received a top-up transfusion if Hb<9g/dl or a partial exchange if Hb9g/dl. Sites followed their own standards for all other aspects of peri-operative care, although guidance was provided. The primary outcome was all significant complications between randomisation and 30 days post surgery as defined in the protocol. These were sent blinded to the End-Point Review Panel for final classification. Complications which were life-threatening or resulted in death or persistent or significant incapacity/disability and other important medical events were also recorded as Serious Adverse Events (SAEs) and were reviewed by an Independent Data Monitoring Committee (IDMC). Due to a major imbalance in the number of SAEs between treatment groups, the trial was terminated early following an IDMC recommendation.
Results: 333 patients were screened for the trial and 70 patients were randomised at the time the trial was terminated. Thirty three completed 30 day follow up in Arm A and 34 in Arm B. Both groups were comparable with respect to age, gender, severity of SCD, type of surgery and baseline Hb. Only 13 patients had low risk surgery. The pre-operative (post-transfusion) Hb was higher in Arm B (9.7g/dl vs 7.7g/dl) and 5 patients in Arm B received partial exchange transfusion with a mean pre-operative HbS% of 47.2%. There were no differences in peri-operative management, including fluid support and oxygen therapy, between the two groups.
There were 11 SAEs (33%) in patients who did not receive a pre-operative transfusion, compared to only 1 SAE (3%) in patients who did receive a top-up transfusion or partial exchange. Eleven of the SAEs were Acute Chest Syndrome (ACS). Patients in the no pre-operative transfusion group also had more significant complications (13/33, 39%), which included SAEs, as compared to patients in the top-up/exchange group (5/34, 15%).
Type of surgery: 58% of patients underwent abdominal or ENT surgery. Four out of 13 patients (31%) who had abdominal surgery in Arm A had ACS events compared to none out of 10 patients in Arm B. Out of the 9 patients who had Tonsillectomy in Arm A, 3 patients had ACS events (33%) compared to none in 7 patients in Arm B.
Discussion: This RCT has shown a large increase in SAEs in un-transfused patients with HbSS and HbSβ0thal having low and moderate risk surgery. In particular there was a striking increase in ACS, a potentially life-threatening complication. We therefore recommend that pre-operative transfusion should be strongly considered for patients with HbSS and HbSβ0thal undergoing moderate risk surgery, in particular abdominal surgery and tonsillectomy. There was no evidence of increased benefit of exchange transfusion over top-up, although numbers were small, and exchange transfusions should be reserved for patients with a Hb>9g/dl. There is insufficient evidence to reach a conclusion on the role of pre-operative transfusion in other types of surgery or in patients with other sickle genotypes. Pre-operative transfusion in these patients should be decided on a case by case basis.
Acknowledgement: submitted on behalf of the TAPS Trial Investigators.
Disclosures: No relevant conflicts of interest to declare.
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