Studies Investigate Emerging Trends and Treatment Options for Patients With Sickle Cell Disease

/PRNewswire/ -- Sickle cell disease, a condition characterized by deformed and dysfunctional red blood cells, is one of the most common genetic blood disorders affecting millions of people around the world, including more than 70,000 Americans.(1) Research presented today at the 51st Annual Meeting of the American Society of Hematology highlights intriguing studies on the acute danger that the H1N1 pandemic presents for children with this blood disorder, evaluations of both new and standard treatments for common complications of sickle cell disease, and an expansion of the current understanding of hemoglobin expression in red blood cells that may lead to new treatments.

"Treatment for sickle cell disease consists primarily of life-long supportive care, with the only cure being bone marrow transplantation -- a risky procedure that is not readily available for most patients," said Alexis Thompson, MD, PhD, moderator of the press conference and Hematology Section Head at the Children's Memorial Hospital and Associate Professor of Pediatrics, at Northwestern University Feinberg School of Medicine, Chicago. "Therefore, research in this area is particularly important to help ensure that improved therapies continue to be developed and that patients with sickle cell disease have access to the best possible care."

NOTES:

(1) National Heart, Lung, and Blood Institute. Facts About Sickle Cell Anemia. Available at: http://www.nhlbi.nih.gov/health/public/blood/sickle/sca_fact.pdf.

Control of Hemoglobin Switching by BCL11A [Abstract #5]

As infants develop in the womb, the gamma-globin gene produces a fetal form of hemoglobin, the protein inside red blood cells that carries oxygen. Shortly after birth, a switch to beta-globin gene expression normally occurs, which leads to the production of adult hemoglobin. Both fetal and adult hemoglobin function similarly, though fetal hemoglobin has a greater affinity for binding with oxygen.

Patients with sickle cell disease have a defective form of adult hemoglobin that causes their red blood cells to become deformed and sickle shaped. As a result, the cells are unable to efficiently carry oxygen to the body's tissues and often stick together and jam vessels, causing blood flow obstruction and episodes of severe pain. If a patient with sickle cell could continue production of the fetal hemoglobin and produce less of their defective adult sickle hemoglobin, many of their complications could possibly be reduced or eliminated. A team of researchers from Harvard Medical School in Boston studied the therapeutic possibility of turning the genetic "switch" back on for the production of fetal hemoglobin to replace the defective adult hemoglobin and alleviate these devastating symptoms.

In previous studies, a gene called BCL11A was found to be involved in blocking the expression of fetal hemoglobin in adults. To test these findings in vivo and investigate the role of BCL11A in hemoglobin regulation at different developmental stages, the researchers performed genetic tests in both embryonic and adult mice that were genetically engineered to carry a complete human beta-globin gene cluster capable of producing adult hemoglobin.

In the embryonic mice, inactivation of the BCL11A gene led to a robust expression of gamma-globin (the fetal form of hemoglobin) during late gestation: more than 90 percent of the globin produced was of this type. Tissue-specific deletion of the BCL11A gene in the adult mice (8-10 weeks old) resulted in an increase of more than 1,000-fold in gamma-globin gene expression in the bone marrow erythroblasts (the precursors to red blood cells) of the experimental mice in comparison to control mice. This increase in the gamma-globin expression after inactivation of BCL11A was rapid and persisted during the course of the experiments (up until the mice were 25 weeks old).

"Currently, there are only a limited number of therapies available for patients with sickle cell disease and thalassemia, another disorder involving abnormal hemoglobin," said senior study author Stuart H. Orkin, MD, David G. Nathan Professor of Pediatrics at Dana-Farber Cancer Institute, Children's Hospital Boston, and Harvard Medical School in Boston. "This research opens up a new avenue for treatment, a way to genetically activate healthy fetal hemoglobin in the red blood cells of patients with these lifelong blood disorders."


Hydroxyurea in Children With Sickle Cell Disease: Practice Patterns and Barriers to Utilization

[Abstract #242]

Sickle cell disease is often marked by episodes of severe and incapacitating pain called vaso-occlusive painful events, which can sometimes require hospitalization. Hydroxyurea, an oral drug that is most commonly taken once daily, was approved by the U.S. Food and Drug Administration for use in sickle cell disease patients in 1998. While hydroxyurea remains the standard of care for reducing these painful events in adults, little is known about its practice patterns in children. Researchers from the Medical College of Wisconsin and Children's Research Institute of the Children's Hospital of Wisconsin in Milwaukee investigated the patterns and barriers to hydroxyurea use in children with sickle cell disease.

In this study, researchers surveyed members of the American Society of Pediatric Hematology/Oncology about their practices and patients. Of the 1,128 surveys disseminated, 31 percent (350 surveys) were returned.

To standardize and increase the quality of care for both adults and children with sickle cell disease, the National Heart, Lung, and Blood Institute (NHLBI) provides clinical practice guidelines for the management of this blood disorder. Most of the survey respondents had heard of (87 percent) and read (78 percent) these guidelines, and provider utilization of hydroxyurea correlated with awareness of the NHLBI recommendations.

The survey found that only 8 percent of providers had half or most (50 to 90 percent) of their pediatric patients with sickle cell disease on hydroxyurea. Another 54 percent of providers had 10 to 30 percent of pediatric patients on the therapy, and 10 percent of providers had fewer than 10 percent of pediatric patients on hydroxyurea. Although a majority of providers (90 percent) felt that hydroxyurea was effective or very effective for the prevention of pain, some still did not prescribe the drug to eligible children because of apprehension about future reproductive issues (birth defects and infertility in males), despite insufficient evidence to support this concern. Low patient compliance was cited by 86 percent of providers as another reason they did not prescribe hydroxyurea. Providers reported that children and their families refused hydroxyurea because of a fear of cancer or other possible side effects, concerns that the drug would not work, compliance with required laboratory monitoring, or because they simply did not want to take medication.

The study also found that many providers prescribed hydroxyurea for reasons other than that for which it was intended, despite insufficient evidence of its efficacy for other complications of the disease.

"Our survey suggests a substantial variation in hydroxyurea utilization in children with sickle cell disease with barriers to its use found on the part of both providers and patients," said lead study author Amanda M. Brandow, DO, MS, Assistant Professor of Pediatrics at the Medical College of Wisconsin and the Children's Research Institute of the Children's Hospital of Wisconsin in Milwaukee. "To alleviate this problem, future research in the following areas may help: continued funding of studies to determine the efficacy of hydroxyurea for complications other than pain, evaluating unconfirmed toxicities of the drug that influence practice, exploring how access to care contributes to noncompliance, and research on methods to promote patient adherence to recommended medical care."

Dr. Brandow will present this study during an oral session on Monday, December 7, at 7:15 a.m. in Room 388-390.

Increased Severity of Pandemic H1N1 Influenza in Children and Young Adults With Sickle Cell Disease [Abstract #264]

Patients with sickle cell disease are more susceptible to infection than the general population. In particular, influenza, a viral disease that affects the respiratory system, is more than 50 times more frequent in children with sickle cell disease than in the general population, according to research conducted by John J. Strouse, MD, PhD, the lead author on this study, and colleagues. As H1N1 influenza, which began circulating in the United States in April 2009, has been reported to cause more severe illness in children and young adults than seasonal flu, researchers from The Johns Hopkins University School of Medicine in Baltimore sought to compare the clinical characteristics and complications associated with these infections in sickle cell disease patients under the age of 21 through a prospective analysis of patient discharge and billing records from September 1993 through July 2009.

During the study period, 99 patients who were seen at The Johns Hopkins Hospital in Baltimore were identified as having both sickle cell disease and influenza (89 with seasonal influenza and 10 with H1N1 influenza). Clinical symptoms, such as fever, cough, and runny nose, were similar between the two groups, although those with H1N1 influenza were at an estimated three-fold increased risk for life-threatening complications, such as acute chest syndrome (a severe lung illness), and nine times more likely to require intensive care, such as ventilator support.

"Our findings underscore that receiving a vaccination against H1N1 influenza, in addition to seasonal influenza, is extremely important for the health and safety of children and young adults with sickle cell disease," said lead author John J. Strouse, MD, PhD, Assistant Professor of Pediatrics and Medicine at The Johns Hopkins University School of Medicine in Baltimore.

Dr. Strouse will present this study in an oral session on Monday, December 7, at 8:15 a.m. in Room 220-222.

Safety and Efficacy of Sildenafil Therapy for Doppler-Defined Pulmonary Hypertension in Patients With Sickle Cell Disease: Preliminary Results of the Walk-PHaSST Clinical Trial [Abstract #571]

As patients with sickle cell disease have a high rate of hemolysis (red blood cell destruction), excessive amounts of hemoglobin are released into the blood stream that react with and destroy nitric oxide, a critical regulator that dilates blood vessels and inhibits clotting. This can lead to pulmonary hypertension, or abnormally high blood pressure in the arteries of lungs that also affects the heart. Approximately 10 to 30 percent of patients with sickle cell disease are suspected to have this life-threatening condition.

While the oral drug sildenafil (known as Revatio®) is approved to treat pulmonary arterial hypertension, it is unknown whether it is a safe and effective treatment for pulmonary hypertension in those with sickle cell disease. Therefore, a 16-week, double-blind clinical trial, known as the Walk-PHaSST study (treatment of Pulmonary Hypertension and Sickle cell disease with Sildenafil Therapy) was conducted in 10 medical centers in the United States and United Kingdom to test this application in adults and children over 12 years of age with sickle cell disease.

Before starting treatment, potential study participants were given baseline tests, including a Doppler echocardiogram and a six-minute walk test to measure heart and lung function. Seventy-four patients who had a tricuspid regurgitant jet velocity (TRV) of greater than or equal to 2.7 m/s (a sign of suspected high pulmonary blood pressure) and a six-minute walking distance of only 150-500 meters (reflecting decreased exercise capacity) were included in the study. The researchers then randomly assigned the study participants into two groups of 37 patients each. Half of the patients were treated with sildenafil at escalating doses from 20, 40, and 80 mg three times per day, and the other half received a placebo three times per day. In previous studies of patients with primary pulmonary hypertension, the highest dose of sildenafil (80 mg) had the greatest effect on blood circulation; however, to monitor for possible adverse effects associated with escalating doses, the sildenafil doses in this study were increased slowly, with dose increases made every four weeks.

The study was prematurely stopped when a significant number of the patients in the sildenafil treatment arm (46 percent) began experiencing serious side effects (primarily sickle cell pain crises requiring hospitalization), compared with only 22 percent of those in the placebo arm. Headache and blurred vision, which were expected side effects of sildenafil, were also experienced. The patients in the sildenafil group had more headaches (27 percent versus 14 percent) and more blurred vision (11 percent versus 3 percent) than the placebo group.

Prior to stopping the study, 33 patients had completed the 16-week assessment and were found to have no change in TRV value or in the walking distance test. On pain questionnaires, patients on the sildenafil treatment also reported worsening pain during walking and less enjoyment of life when compared to the patients on placebo.

"Although sildenafil is approved by the U.S. Food and Drug Administration and by the European Medicines Agency for patients with pulmonary arterial hypertension, the Walk-PHaSST study was prematurely stopped for safety concerns. However, these preliminary data should not be interpreted as implying that sildenafil may not be efficacious and safe in select sickle cell patients with documented pulmonary hypertension who are at low risk for vaso-occlusive events," said lead study author Mark Gladwin, MD, Chief of the Division of Pulmonary, Allergy, and Critical Care Medicine and Director of the Vascular Medicine Institute at the University of Pittsburgh Medical Center. "Further investigations are critically needed to find a safe and effective treatment for this patient population at high risk for death from this debilitating condition."

Dr. Gladwin will present this study in an oral session on Monday, December 7, at 2:45 p.m. in Room 220-222.

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VELCADE® (Bortezomib) for Injection Based Regimens Result in Lower Costs and Less Patient Burden Than Other Commonly Used Multiple Myeloma Treatment

(BUSINESS WIRE)--Millennium: The Takeda Oncology Company today announced that two studies presented at the 51st American Society of Hematology (ASH) Annual Meeting found that VELCADE based regimens are more cost-effective for payers and reduced out-of-pocket costs for patients than other commonly used multiple myeloma treatments. The study found that VELCADE-melphalan-prednisone (VMP), a commonly used treatment in multiple myeloma, was more cost-effective compared to MP and delivered more cost-savings compared to melphalan-prednisone-thalidomide (MPT), another commonly used treatment regimen, based on a health economic model.

A second study based on claims data found patients with multiple myeloma treated with VELCADE:

* Incurred fewer out-of-pocket costs than patients treated with the oral drugs thalidomide and lenalidomide
* Did not require significantly more healthcare visits than patients prescribed thalidomide and lenalidomide.

“These studies support VELCADE’s overall cost-effectiveness and reduced out-of-pocket costs. As measured by the number of healthcare visits, VELCADE appears to be as convenient as oral multiple myeloma treatments,” said Dixie-Lee Esseltine, M.D., Vice President, Global Medical Affairs, Millennium. “This is valuable information for healthcare providers, patients and payers.”

The Cost-Effectiveness of Bortezomib for the Initial Treatment of Multiple Myeloma in the United States (Abstract #1379)

Based on a direct comparison of patient-level data, researchers projected that VMP would be cost-effective over a patient’s lifetime compared with MP in the United States. A second indirect comparison across different trials projected the combination of VMP would cost payers 17.7 percent less over a patient’s lifetime and generate better quality-adjusted life expectancy than MPT. Quality-adjusted life years are a measure of disease burden that take into account both the length and quality of life.

The incremental cost-effectiveness of VMP versus MP was found to be within the generally accepted cost-effectiveness range of $50,000-$100,000 per quality-adjusted life year. The projected overall survival years were greatest for patients treated with VMP versus those treated with MPT or MP (4.19, 4.14, and 2.86 years, respectively).

“Cancer can be a costly disease for both payers and patients, and this is certainly true in multiple myeloma,” said Professor Lou Garrison, a study co-author and Associate Director in the Pharmaceutical Outcomes Research and Policy Program, Department of Pharmacy, University of Washington, Seattle. “It is therefore important to identify cost-effective therapies. This trial-based modeling study demonstrates that the first-line regimen using VELCADE is cost-effective compared to other commonly used regimens.”

To assess the relative costs and outcomes of different treatment combinations, study methodology generated modeling projections based on a direct comparison from the Phase III VISTA1 trial, which demonstrated superiority in overall survival of VMP versus MP (San Miguel et al, New England Journal of Medicine 2008) for treatment of multiple myeloma, as well as an indirect comparison of this trial with data published from the IFM 99-06 clinical trial for MPT (Facon et al, Lancet 2007). Costs included per-protocol drug and medical costs, treatment-related adverse events, second-line treatment, and resource utilization during treatment-free interval and progressive disease. Unit costs of medications were obtained from published literature.

Multiple Myeloma: Patient Out-Of-Pocket Costs and Health Care Utilization (Abstract #1366)

In the second study, researchers used data from one of the largest U.S. commercial healthcare plans to evaluate the number of healthcare visits and out-of-pocket costs for multiple myeloma patients being treated with various therapies. After adjusting for patient characteristics, line of treatment, and co-morbidities by multivariate analysis, data showed that patients receiving VELCADE did not have a significantly different number of healthcare visits than those receiving lenalidomide or thalidomide, two oral therapies. Additionally, direct out-of-pocket costs were found to be significantly lower for patients treated with VELCADE than patients treated with thalidomide or lenalidomide.

“There is a common perception that oral drugs are more convenient for patients, but these data show that, in terms of healthcare visits, that perception of convenience is false,” said study author Brett W. Pinsky, i3 Innovus researcher. “These data are consistent with the fact that patients with multiple myeloma typically require a great deal of care and resource utilization; therefore, most patients will not see a major difference in the number of healthcare visits regardless of whether their treatment is oral or infusion – but they may face a significantly higher out-of-pocket cost with oral medications.”

The total patient out-of-pocket costs for the year after treatment initiation were significantly less for patients treated with VELCADE ($3,504) than for those treated with either of the oral drugs thalidomide ($4,443, p<0.05) or lenalidomide ($4,766, p<0.05), after adjusting for patient characteristics, line of treatment, and co-morbidities by multivariate analysis. These differences were greatest for Medicare patients, with the adjusted patient costs nearly two and three times greater for thalidomide ($8,824) and lenalidomide ($12,568), respectively, compared with VELCADE ($4,395).

The study is a retrospective cohort study, which used claims data from a large national U.S. commercial health plan representing approximately 14 million members, and included a total of 2,642 treatment episodes for the 1,900 multiple myeloma patients.

Both studies were supported by Millennium Pharmaceuticals, Inc. The Wang study was also supported by Johnson & Johnson Pharmaceutical Research and Development, L.L.C.

About Multiple Myeloma

Multiple myeloma is the second most common hematologic malignancy and although the disease is predominantly a cancer of the elderly (the median age of onset is 70 years), recent statistics indicate both increasing incidence and younger age of onset. In the U.S., more than 50,000 individuals have MM and 20,000 new cases are diagnosed each year. Worldwide there are approximately 74,000 new cases and over 45,000 deaths annually.

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Study Finds Blood Cells Can Be Reprogrammed to Act as Embryonic Stem Cells

/PRNewswire / -- In a recent study, U.S. researchers have reprogrammed cells found in circulating blood into cells that are molecularly and functionally indistinguishable from embryonic stem cells, a revolutionary achievement that provides a readily accessible source of stem cells and an alternative to harvesting embryonic stem cells. The findings were prepublished online in Blood, the official journal of the American Society of Hematology.

Embryonic stem cells have long been coveted for their potential to treat a multitude of diseases as a result of their unique properties of nearly indefinite self-renewal and pluripotency (the ability to develop into any type of cell in the body), but their use has been the subject of political controversy.

"Our findings provide the first proof that cells from human blood can morph into stem cells," said senior study author George Q. Daley, M.D., Ph.D., an investigator for the Howard Hughes Medical Institute at Children's Hospital, Boston. "Making pluripotent stem cells from blood, which is one of the easiest tissues to obtain, provides an easy strategy for generating patient-specific stem cells that are valuable research tools and may one day be used to treat a number of diseases."

To generate induced pluripotent stem cells (dubbed iPS cells), blood was collected from a 26-year-old male donor. From the blood sample, the researchers isolated CD34+ cells, a type of stem cell that produces only blood cells, and cultured them in growth factors for six days to increase their number.

During the culture, the scientists infected the CD34+ cells with viruses carrying reprogramming factors, genes normally expressed in embryonic stem cells that can reset the blood cells to an embryonic state. Colonies of cells exhibiting physical characteristics similar to embryonic stem (ES) cells appeared about two weeks after the procedure. To determine whether these cells were also functionally similar to ES cells, the scientists analyzed the CD34+ iPS cell lines to see if they had acquired stem cell "markers," the unique combination of proteins that coat the cells' surface and distinguish them from other types of cells. Indeed, the iPS cell lines expressed the same markers as ES cells and further shared the capacity to differentiate into a variety of specialized cell types.

In vitro, the iPS cells readily developed into clusters of cells called embryoid bodies from which cells of virtually any type can develop. These differentiated cells expressed genes for all three embryonic germ layers (the tissues from which all other tissue types in the body develop) and also produced myeloid and granulocyte colonies (types of white blood cells).

The group confirmed that the reprogrammed cells had acquired ES cell characteristics by injecting the newly reprogrammed cells into immunodeficient mice. The cells successfully generated well-differentiated teratomas, benign masses containing all three embryonic germ layers, including respiratory, bone, and neural tissue.

"Not only has this work identified a new programmable cell type, but the cells are easy to obtain and analyze in many research laboratories and bone marrow transplantation centers around the world," said Grover C. Bagby, M.D., Professor of Medicine and Molecular and Medical Genetics at Oregon Health and Science University, who is not affiliated with the study. "These findings will immediately enhance the pace of laboratory research in this field and will ultimately help to determine whether iPS cells have a therapeutic potential equivalent to that of embryonic stem cells."

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. In September 2008, ASH launched Blood: The Vital Connection (www.bloodthevitalconnection.org), a credible online resource addressing bleeding and clotting disorders, anemia, and cancer. It provides hematologist-approved information about these common blood conditions including risk factors, preventive measures, and treatment options.

Blood, the official journal of ASH, is the most cited peer-reviewed publication in the field. Blood is issued to Society members and other subscribers weekly and is available in print and online at www.bloodjournal.org.

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