Hematology

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2017: A banner year for innovation at Children’s National

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In 2017, clinicians and research faculty working at Children’s National Health System published more than 850 research articles about a wide array of topics. A multidisciplinary Children’s Research Institute review group selected the top 10 articles for the calendar year considering, among other factors, work published in high-impact academic journals.

“This year’s honorees showcase how our multidisciplinary institutes serve as vehicles to bring together Children’s specialists in cross-cutting research and clinical collaborations,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “We’re honored that the National Institutes of Health and other funders have provided millions in awards that help to ensure that these important research projects continue.”

The published papers explain research that includes using imaging to describe the topography of the developing brains of infants with congenital heart disease, how high levels of iron may contribute to neural tube defects and using an incisionless surgery method to successfully treat osteoid osteoma. The top 10 Children’s papers:

Read the complete list.

Dr. Batshaw’s announcement comes on the eve of Research and Education Week 2018 at Children’s National, a weeklong event that begins April 16, 2018. This year’s theme, “Diversity powers innovation,” underscores the cross-cutting nature of Children’s research that aims to transform pediatric care.

Kirsten-M.-Williams

Helpful, hopeful news for bone marrow transplant patients

Kirsten-M.-Williams

Research published online Dec. 13, 2017, by The Lancet Haematology and co-led by Kirsten M. Williams, M.D., suggests that a new imaging agent can safely show engraftment as early as days after transplant – giving a helpful and hopeful preview to patients and their doctors.

Leukemia can be a terrifying diagnosis for the more than 60,000 U.S. patients who are told they have this blood cancer every year. But the treatment for this disease can be just as frightening. For patients with certain forms of leukemia, the only chance they have for a cure is to receive a massive dose of radiation and chemotherapy that kills their hematopoietic stem cells (HSCs), the cells responsible for making new blood, and then receive new HSCs from a healthy donor.

While patients are waiting for these new cells to go to the bone marrow factory and begin churning out new blood cells, patients are left without an immune system. Devoid of working HSCs for two to four weeks – or longer, if a first transplant doesn’t take – patients are vulnerable to infections that can be just as deadly as their original cancer diagnosis.

As they wait in the protected confines of a hospital, patients who undergo HSC transplants receive blood tests every day to gauge successful engraftment, searching for the presence of immune cells called neutrophils, explains Kirsten M. Williams, M.D., blood and bone marrow transplant specialist at Children’s National Health System.

“As you head into week three post-transplant and a patient’s cell counts remain at zero, everyone starts to get nervous,” Dr. Williams says. The longer a patient goes without an immune system, the higher the chance that they’ll develop a life-threatening infection. Until recently, Dr. Williams says, there has been no way beyond those daily blood tests to assess whether the newly infused cells have survived and started to grow early healthy cells in the bone marrow, a process called engraftment.

A new study could change that paradigm. Research published online Dec. 13, 2017, by The Lancet Haematology and co-led by Dr. Williams suggests that a new imaging agent can safely show engraftment as early as days after transplant – giving a helpful and hopeful preview to patients and their doctors.

The study evaluated an investigational imaging test called 18F-fluorothymidine (18F-FLT). It’s a radio-labeled analogue of thymidine, a natural component of DNA. Studies have shown that this compound is incorporated into just three white blood cell types, including HSCs. Because it’s radioactive, it can be seen on various types of common clinical imaging exams, such as positron emission tomography (PET) and computed tomography (CT) scans. Thus, after infusion, the newly infused developing immune system and marrow is readily visible.

To see whether this compound can readily and safely visualize transplanted HSCs, Dr. Williams and colleagues tested it on 23 patients with various forms of high-risk leukemia.

After these patients received total-body irradiation to destroy their own HSCs, they received donor HSCs from relatives or strangers. One day before they were infused with these donor cells, and then at five or nine days, 28 days, and one year after transplantation, the patients underwent imaging with the novel PET/and CT scan imaging platform.

Each of these patients had successful engraftment, reflected in blood tests two to four weeks after their HSC transplants. However, the results of the imaging exams revealed a far more complicated and robust story.

With 18F-FLT clearly visible in the scans, the researchers saw that the cells took a complex journey as they engrafted. First, they migrated to the patients’ livers and spleens. Next, they went to the thoracic spine, the axial spine, the sternum, and the arms and legs. By one year, most of the new HSCs were concentrated in the bones that make up the trunk of the body, including the hip, where most biopsies to assess marrow function take place.

Interestingly, notes Dr. Williams, this pathway is the same one that HSCs take in the fetus when they first form. Although experimental model research had previously suggested that transplanted HSCs travel the same route, little was known about whether HSCs in human patients followed suit.

The study also demonstrated that the radiation in 18F-FLT did not adversely affect engraftment. Additionally, images could identify success of their engraftments potentially weeks faster than they would have through traditional blood tests – a definite advantage to this technique.

“Through the images we took, these patients could see the new cells growing in their bodies,” Dr. Williams says. “They loved that.”

Besides providing an early heads up about engraftment status, she adds, this technique also could help patients avoid painful bone marrow biopsies to make sure donor cells have taken residence in the bones or at the very least help target those biopsies. It also could be helpful for taking stock of HSCs in other conditions, such as aplastic anemia, in which the body’s own HSCs fade away. And importantly, if the new healthy cells don’t grow, this test could signal this failure to doctors, enabling rapid mobilization of new cells to avert life-threatening infections and help us save lives after transplants at high risk of graft failure.

“What happens with HSCs always has been a mystery,” Dr. Williams says. “Now we can start to open that black box.”

Dr. Williams’ co-authors include co-lead author Jennifer Holter-Chakrabarty, M.D., Quyen Duong, M.S., Sara K. Vesely, Ph.D., Chuong T. Nguyen, Ph.D., Joseph P. Havlicek, Ph.D., George Selby, M.D., Shibo Li, M.D., and Teresa Scordino, M.D., University of Oklahoma; Liza Lindenberg, M.D., Karen Kurdziel, M.D., Frank I. Lin, M.D., Daniele N. Avila, N.P., Christopher G. Kanakry, M.D., Stephen Adler, Ph.D., Peter Choyke, M.D., and senior author Ronald E. Gress, M.D., National Cancer Institute; Juan Gea-Banacloche, M.D., Mayo Clinic Arizona; and Catherine “Cath” M. Bollard, M.D., MB.Ch.B., Children’s National.

Research reported in this story was supported by the National Institutes of Health, Ben’s Run/Ben’s Gift, Albert and Elizabeth Tucker Foundation, Mex Frates Leukemia Fund, Jones Family fund and Oklahoma Center for Adult Stem Cell Research.

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NIH funding to improve devices and safeguard cardiovascular health

Nearly 15 million blood transfusions are performed each year in the U.S., and pediatric patients alone receive roughly 425,000 transfused units. Endocrine-disrupting chemicals, such as bisphenol A and di-2-ethylhexyl-phthalate (DEHP), can leach from some plastic devices used in such transfusions. However, it remains unclear how many complications following a transfusion can be attributed to the interplay between local and systemic reactions to these chemical contaminants.

NPosnack-Heart-image

Top: Live, excised heart that is being perfused with a crystalloid buffer via the aorta. The heart is stained with a voltage-sensitive fluorescent dye, which is excited by an LED light source. Bottom, right: Cardiac action potentials are optically mapped across the epicardial surface in real-time by monitoring changes in the fluorescence signal that are proportional to changes in transmembrane voltage. Bottom, left: An activation map (middle) depicts the speed of electrical conduction across the heart surface. Credit: Rafael Jaimes, Ph.D.; Luther Swift, Ph.D.; Manelle Ramadan, B.S.; Bryan Siegel, M.D.; James Hiebert, B.S., all of Children’s National Health System; and Daniel McInerney, student at The George Washington University.

The National Heart, Lung and Blood Institute within the National Institutes of Health has awarded a $3.4 million, five-year grant to Nikki Gillum Posnack, Ph.D., assistant professor at the Children’s National Heart Institute within the Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI) at Children’s National Health System, to answer that question and to provide insights that could accelerate development of safer biomaterials.

According to the Food and Drug Administration, patients who are undergoing IV therapy, blood transfusion, cardiopulmonary bypass or extracorporeal membrane oxygenation or who receive nutrition through feeding support tubes have the potential to be exposed to DEHP.

Posnack led a recent study that found that an experimental model exposed to DEHP experienced altered autonomic regulation, heart rate variability and cardiovascular reactivity and reported the findings Nov. 6, 2017, in the American Journal of Physiology. The pre-clinical model study is the first to show such an association between phthalate chemicals used in everyday medical devices like IV tubing and cardiovascular health.

In the follow-on research, Posnack and colleagues will:

  • Use in vivo and whole heart models to define the extent to which biomaterial leaching and chemical exposure alters cardiovascular and autonomic function in experimental models
  • Determine whether biocompatibility and incidental chemical exposure are linked to cardiovascular and autonomic abnormalities experienced by pediatric patients post transfusion
  • Compare and contrast alternative biomaterials, chemicals and manufacturing techniques to identify safer transfusion device options.

“Ultimately, we hope to strengthen the evidence base used to inform decisions by the scientific, medical and regulatory communities about whether chemical additives that have endocrine-disrupting properties should be used to manufacture medical devices,” Posnack says. “Our findings also will highlight incentives that could accelerate development of alternative biomaterials, additives and fabrication techniques to improve safety for patients undergoing transfusion.”

Nikki Gillum Posnack

Experimental model study links phthalates and cardiovascular health

Nikki Gillum Posnack

“Because phthalate chemicals are known to migrate out of plastic products, our study highlights the importance of adopting safer materials, chemical additives and/or surface coatings for use in medical devices to reduce the risk of inadvertent exposure,” explains study senior author Nikki Gillum Posnack, Ph.D.

An experimental model exposed to di-2-ethylhexyl-phthalate (DEHP), a chemical that can leach from plastic-based medical devices, experienced altered autonomic regulation, heart rate variability and cardiovascular reactivity, according to a study published online Nov. 6, 2017 by the American Journal of Physiology. The pre-clinical model study is the first to show such an association between phthalate chemicals used in everyday medical devices like IV tubing and cardiovascular health.

“Plastics have revolutionized medical devices, transformed how we treat blood-based diseases and helped to make innovative cardiology procedures possible,” says Nikki Gillum Posnack, Ph.D., study senior author and assistant professor at the Children’s National Heart Institute within the Sheikh Zayed Institute for Pediatric Surgical Innovation (SZI) at Children’s National Health System. “Because phthalate chemicals are known to migrate out of plastic products, our study highlights the importance of adopting safer materials, chemical additives and/or surface coatings for use in medical devices to reduce the risk of inadvertent exposure.”

According to the Food and Drug Administration, patients who are undergoing IV therapy, blood transfusion, cardiopulmonary bypass or extracorporeal membrane oxygenation or who receive nutrition through feeding support tubes have the potential to be exposed to DEHP.

Patients undergoing extensive interventions to save their lives may be exposed to multiple plastic-based devices that supply oxygen and nutrition or that pump newly oxygenated blood to oxygen-starved organs.

“These interventions keep very fragile kids alive. What’s most important is getting patients the care they need when they need it,” Posnack says. “In the biomaterials field, our ultimate goal is to reduce inadvertent risks to patients that can result from contact with plastic products by identifying replacement materials or safer coatings to lower overall risk.”

In order to assess the safety of phthalate chemicals used in such medical devices, the Children’s-led research team implanted adult experimental models with radiofrequency transmitters that monitored their heart rate variability, blood pressure and autonomic regulation. Then, they exposed the experimental models to DEHP, a softener used in making the plastic polymer, polyvinyl chloride, flexible.

DEHP-treated pre-clinical models had decreased heart rate variability with lower-than-normal variation in the intervals between heart beats. The experimental models also showed an exaggerated mean arterial pressure response to ganglionic blockade. And in response to a stressor, the experimental models in the treatment group displayed enhanced cardiovascular reactivity as well as prolonged blood pressure recovery, according to the study team.

“The autonomic nervous system is a part of the nervous system that automatically regulates such essential functions as blood pressure and breathing rate without any conscious effort by the individual,” Posnack adds. “Because alterations in the autonomic balance provide an early warning sign of trouble – before symptoms of hypertension or atherosclerosis manifest – our findings underscore the importance of additional studies to explore the potential impact of phthalate chemicals on organ function.”

Billie Lou Short, M.D., chief of Children’s Division of Neonatology, called the paper an “important study” that builds on a foundation laid in the late 199os by Children’s researchers who were the first to show that plasticizers migrated from tubing in the extracorporeal membrane oxygenation (ECMO) circuit. Children’s researchers also led a study published in 2004 that evaluated the effect of plasticizers on the human reproductive system. A small number of adolescents who had undergone ECMO as newborns did not experience the complications that had been seen in in experimental models, Dr. Short says.

Posnack’s study co-authors include Rafael Jaimes III, Ph.D., SZI staff scientist; Meredith Sherman, SZI research technician; and Adam Swiercz, Narine Muselimyan and Paul J. Marvar, all of The George Washington University.

Allistair Abraham

Q&A with leading blood and marrow transplantation specialist

Allistair Abraham

Children’s National Health System is proud to be the home of some of the world’s leading hematology experts, including Allistair Abraham, M.D., blood and marrow transplantation specialist within the Center for Cancer and Blood Disorders, who was recently selected to participate in the American Society of Hematology-Harold Amos Medical Faculty Development Program (ASH-AMFDP). Designed to increase the number of underrepresented minority scholars in the field of hematology, the ASH-AMFDP has awarded Dr. Abraham $420,000 that includes an annual stipend and research grant over the next four years. Here, Dr. Abraham tells us more about his research and what it means for the future of patients with sickle cell disease.

Q: What does this award mean to you?
A: This award comes at a critical time in my early career as I learn how to become an independent grant-funded researcher. It gives me an opportunity to dedicate 70 percent of my time to research for the next four years, during which I will hone my research skills and have access to highly accomplished mentors at Children’s National and from the ASH-AMFDP faculty.

Q: Your research for this grant focuses on improving curative hematopoietic stem cell transplantation for sickle cell disease. Why do they need to be improved?

A: Sickle cell disease causes significant health problems for children, which can worsen as they become adults, and even shorten their lifespan. Curative therapies to date are limited for many patients since most do not have a suitably matched donor for a curative bone marrow transplant. Many of us in the field hope we can provide a safe option for as many patients as possible so they can be cured in childhood and not have to face the negative impacts of the disease as they grow older.

Q: You will also be evaluating virus-specific T-cell (VST) recovery after transplantation. What will this mean for patients?

A: As we explore more transplant donor options such as unrelated donors and mismatched family donors, we have observed delayed immune system recovery. Viral infections are particularly problematic, as they can be life-threatening and respond poorly to available medications. Ultimately, a recovered immune system would address the infection problem. We hope to generate immune cells that are protective against viruses from the transplant donor and give them to patients as part of their transplant procedure.

Q: How do you envision your research improving the future of treatment for sickle cell patients?

A: My hope is that we get closer to having a safer transplant option for most patients who, despite optimal therapy, continue to suffer from complications of sickle cell disease. Ideally, these transplants would not only be widely available, but the treatment would also be simplified to the point where most of the therapy could take place in an outpatient setting.

Q:  Why did you decide to work in this field?

A:  Sickle cell disease has lagged behind other disorders in terms of new treatment strategies for quite some time. I experienced this as a medical trainee and struggled when parents would ask me to “do something” for their child when most of the time all I could offer was pain medication. In the last five years or so, there has been more focus on sickle cell disease from the field and the community, so now is the time to work toward developing a widely available cure.

American Society of Hematology logo

Leading blood disorder experts from Children’s National convene in Atlanta for 59th American Society of Hematology annual meeting

In early December 2017, more than 25,000 attendees from around the world, including several experts from Children’s National Health System, convened in Atlanta for the American Society of Hematology’s annual meeting and exposition, the world’s premiere hematology event. For four days, physicians, nurses and other healthcare professionals attended sessions, listened to speakers and collaborated with each other, focusing on enhancing care and treatment options for patients with blood disorders and complications, including leukemia, sickle cell disease and transplants.

As nationally recognized leaders in the field, the Children’s National team led educational sessions and gave keynote speeches highlighting groundbreaking work underway at the hospital, which sparked engaging and productive conversations among attendees. Highlights from the team include:

  • Catherine Bollard, M.D., M.B.Ch.B., Director of the Center for Cancer and Immunology Research, educating global experts on cellular immunotherapy for non-Hodgkin lymphoma.
  • Kirsten Williams, M.D., bone and marrow transplant specialist, presenting novel work utilizing TAA-specific T cells for hematologic malignancies with Dr. Bollard, the sponsor of this first-in-man immunotherapy; moderating sessions on immunotherapy and late complications and survivorship after hematopoietic stem cell transplantation (HSCT).
  • Allistair Abraham, M.D., blood and marrow transplantation specialist, moderating a session on hemoglobinopathies.
  • David Jacobsohn, M.D., ScM, Division Chief of Blood and Marrow Transplantation, moderating a session on allogeneic transplantation results.
  • Naomi Luban, M.D., hematologist and laboratory medicine specialist, introducing a plenary speaker on the application of CRISPR/Cas 9 technology for development of diagnostic reagents for diagnosis of alloimmunization from stem cells.

Additional presentations from the Children’s National team included an oral abstract on the hospital’s work to improve hydroxyurea treatment for sickle cell disease by pediatric resident Sarah Kappa, M.D., who also received an ASH Abstract Achievement Award; another key session on hemoglobinopathies moderated by Andrew Campbell, M.D., director of the Comprehensive Sickle Cell Disease Program; an abstract on the clinical use of CMV- specific T-cells derived from CMV-native donors, presented by Patrick Hanley, Ph.D.; a leukemia study presented by Anne Angiolillo, M.D., oncologist; and a presentation about pain measurement tools in sickle cell disease by Deepika Darbari, M.D., hematologist.

Visit the ASH website to learn more about the conference attendees and their research.

Catherine Bollard and Hemant Sharma

Nationally recognized immunotherapy and pathology experts take on new leading roles at Children’s National

Catherine Bollard and Hemant Sharma

Catherine Bollard, M.D., M.B.Ch.B., has been chosen to serve as director of the Children’s Research Institute’s Center for Cancer and Immunology Research and Hemant Sharma, M.D., M.H.S., will assume the role of chief of the Division of Allergy and Immunology.

Children’s National Health System recently made several exciting leadership announcements in the allergy, immunology and laboratory medicine fields, furthering the hospital’s ongoing commitment to providing the most comprehensive, innovative care for children.

Award-winning hematologist and immunotherapist Catherine Bollard, M.D., M.B.Ch.B., currently chief of the Division of Allergy and Immunology, has been chosen to serve as director of the Children’s Research Institute’s (CRI) Center for Cancer and Immunology Research (CCIR). CCIR includes more than 50 clinicians and scientists performing groundbreaking clinical and translational research in understanding the origins of, and developing and testing novel therapies for childhood cancers and immunologic disorders. The center receives more than $10 million annually from the National Institutes of Health and other external entities. In her new role on the leadership team of CCIR, Dr. Bollard will lead the advancement and oversight of cancer and immunology research performed at Children’s National.

“All of the progress made in cellular immunotherapy here at Children’s National can be attributed to Catherine and her leadership,” says Mark L. Batshaw, M.D., chief academic officer and director of CRI. “We are confident her impact will extend even further in her new role.”

Meghan Delaney

Nationally recognized laboratory medicine expert Meghan Delaney, D.O., M.P.H., has joined Children’s National as chief of pathology and lab medicine.

Hemant Sharma, M.D., M.H.S., will assume the role of chief of the Division of Allergy and Immunology. In 2008, he joined the faculty at Children’s National and started the Food Allergy Program, which he directs today. His areas of interest include health disparities and community-based management of food allergy. He is also site principal investigator of novel clinical trials of immunotherapy for peanut allergy. He serves on the Medical Advisory Board of Food Allergy Research and Education (FARE), and was the recipient of the 2016 FARE Vision Award for his contributions to the national food allergy community. Dr. Sharma also serves as the site director of the allergy immunology fellowship program with the National Institutes of Health and has won various teaching awards.

In addition, nationally recognized laboratory medicine expert Meghan Delaney, D.O., M.P.H., has joined Children’s National as chief of pathology and lab medicine. An expert in the field of transfusion medicine, Dr. Delaney will lead efforts to unify Anatomic Pathology and Laboratory Medicine into a single division, while advancing cutting-edge practices in the lab to ensure the highest standard of quality and safety for patients. Dr. Delaney joins Children’s National from Seattle, where she held many leadership positions including serving as medical director at the Pediatric Apheresis Program at Seattle Children’s Hospital & Seattle Cancer Care Alliance, the blood bank at Seattle Children’s Hospital and the Immunohematology & Red Blood Cell Genomics Reference Laboratory at Bloodworks Northwest.

“Dr. Delaney brings extensive experience in laboratory medicine innovation and program-building, and we are confident she will make a lasting impact on our patients,” said Jeffrey Dome, M.D., Ph.D., vice president for the Center for Cancer and Blood Disorders at Children’s National. “Her leadership will bolster our commitment to providing top quality care for our patients through advancement of lab medicine research and treatments.”

Children’s National Health System advances sickle cell disease cure through Doris Duke Charitable Foundation grant

Sickle-Cell-Blood-Cells

An innovative Children’s National Health System project aimed at improving the only proven cure for sickle cell disease – hematopoietic cell transplantation – will receive more than $550,000 in funding from the Doris Duke Charitable Foundation’s inaugural Sickle Cell Disease/Advancing Cures Awards, which provides grants to advance curative approaches for sickle cell disease. The study, a three-year, multi-center trial that will study a low intensity, chemotherapy-free transplantation approach to cure children with sickle cell disease using a matched related donor, is led by Allistair Abraham, M.D., blood and marrow transplantation specialist, and Robert Nickel, M.D., hematologist, and is one of seven projects receiving approximately $6 million total through the awards.

While transplantation using a matched sibling donor today has a high cure rate (>90 percent) for sickle cell disease, traditional transplant approaches have many risks and side effects in both the short and long term. The study will examine if a chemotherapy-free approach can lead to a successful transplant without resulting in graft-versus-host disease (GVHD). GVHD is one of the most challenging complications of a transplant, in which the transplant immune cells attack the patient’s body. The researchers anticipate that this new transplant approach will be so well tolerated that patients’ quality of life will be maintained and improved throughout the process, with most of the care administered in a clinic setting.

“This approach has proven to be effective for adults with sickle cell disease, so we are grateful for the opportunity to begin this important trial for children thanks to the Doris Duke Charitable Foundation,” says Dr. Abraham. “Children with sickle cell disease are in need of innovative treatments, and we look forward to finding more solutions that improve the quality of life for these patients.”

“Advancing treatment for sickle cell patients to the point where they can live free of the disease is our top priority,” says Dr. Nickel, who is also an assistant professor of pediatrics at the George Washington University School of Medicine and Health Sciences. “This funding is critical to our study and it will accelerate the timeline to achieve the goal of a well-tolerated and safe cure for children with sickle cell disease.”

Matthew Hsieh, M.D., who helped pioneer this work at the National Institute of Health in adults, and Greg Guilcher, M.D., who has used this transplant approach in children, are key collaborators on the project.

The study is projected to begin in December 2018 and continue for three years. The Comprehensive Sickle Cell Disease Program at Children’s National is among the largest in the country, treating more than 1,400 children and young adults with all types of sickle cell disease. Children’s National also offers the largest, most comprehensive blood disorders team in the Washington, D.C., area.

Advances in T-cell immunotherapy at ISCT

Healthy Human T Cell

T-cell immunotherapy, which has the potential to deliver safer, more effective treatments for cancer and life-threatening infections, is considered one of the most promising cell therapies today. Each year, medical experts from around the world – including leaders in the field at Children’s National Health System – gather at the International Society for Cellular Therapy (ISCT) Conference to move the needle on cell therapy through several days of innovation, collaboration and presentations.

Dr. Catherine Bollard, Children’s National chief of allergy and immunology and current president of ISCT, kicked off the week with a presentation on how specific approaches and strategies have contributed to the success of T-cell immunotherapy, a ground-breaking therapy in this fast-moving field.

Later in the week, Dr. Kirsten Williams, a blood and marrow transplant specialist, presented encouraging new findings, demonstrating that T-cell therapy could be an effective treatment for leukemia and lymphoma patients who relapse after undergoing a bone marrow transplant. Results from her phase 1 study showed that four out of nine patients achieved complete remission. Other medical options for the patients involved – those who relapsed between 2 and 12 months post-transplant – are very limited. Looking to the future, this developing therapy, while still in early stages, could be a promising solution.

Other highlights include:

  • Both Allistair Abraham, blood and marrow transplantation specialist, and Dr. Michael Keller, immunologist, presented oral abstracts, the former titled “Successful Engraftment but High Viral Reactivation After Reduced Intensity Unrelated Umbilical Cord Blood Transplantation for Sickle Cell Disease” and the latter “Adoptive T Cell Immunotherapy Restores Targeted Antiviral Immunity in Immunodeficient Patients.
  • Patrick Hanley engaged attendees with his talk, “Challenges of Incorporating T-Cell Potency Assays in Early Phase Clinical Trials,” and his poster presentation “Cost Effectiveness of Manufacturing Antigen-Specific T-Cells in an Academic GMP Facility.” He also co-chaired a session titled “Early Stage Professionals Session 1 – Advanced Strategic Innovations for Cell and Gene Therapies.”
  • To round out this impressive group, Shabnum Piyush Patel gave a talk on genetically modifying HIV-specific T-cells to enhance their anti-viral capacity; the team plans to use these HIV-specific T-cells post-transplant in HIV-positive patients with hematologic malignancies to control their viral rebound.

This exciting team is leading the way in immunology and immunotherapy, as evidenced by the work they shared at the ISCT conference and their ongoing commitment to improving treatments and outcomes for patients at Children’s National and across the country. To learn more about the team, visit the Center for Cancer and Blood Disorders site.

Steven Hardy presents sickle cell findings at ASPHO annual meeting

Steven Hardy

Steven Hardy, Ph.D.

Steven Hardy, Ph.D. recently joined medical leaders in Montréal for the American Society of Pediatric Hematology/Oncology’s 30th Annual Meeting, where he and his team presented key findings from their cognitive and psychosocial research program involving youth with Sickle Cell Disease (SCD).
The first presentation, “Processing Speed and Academic Fluency in Youth With Sickle Cell Disease,” showed that, on average, children with SCD are less able to quickly and efficiently process information than their healthy counterparts. This weakness negatively impacted their academic performance, particularly in math fluency, and increased the children’s odds of having to repeat a grade in school.

A second presentation, “Quality of Life and School Absences in Children With Sickle Cell Disease With and Without Asthma,” explored the differences in quality of life between children with SCD only and children with both SCD and asthma (a common comorbidity). Dr. Hardy and his team found that children with both diseases tend to experience a greater impact on quality of life. Other factors – such as the child’s IQ and the family’s financial, material and social resources – moderated this risk.

The presentations were met with enthusiasm from renowned medical professionals from around the world, all of whom came together for collaborative and constructive sessions to move the needle on pediatric care.

test tubes

2016: A banner year for innovation

test tubes

In 2016, clinicians and research scientists working at Children’s National Health System published more than 1,100 articles in high-impact journals about a wide array of topics. A Children’s Research Institute review group selected the top articles for the calendar year considering, among other factors, work published in top-tier journals with impact factors of 9.5 and higher.

“Conducting world-class research and publishing the results in prestigious journals represents the pinnacle of many research scientists’ careers. I am pleased to see Children’s National staff continue this essential tradition,” says Mark L. Batshaw, M.D., Physician-in-Chief and Chief Academic Officer at Children’s National. “While it was difficult for us to winnow the field of worthy contenders to this select group, these papers not only inform the field broadly, they epitomize the multidisciplinary nature of our research,” Dr. Batshaw adds.

The published papers explain research that includes discoveries made at the genetic and cellular levels, clinical insights and a robotic innovation that promises to revolutionize surgery:

  • Outcomes from supervised autonomous procedures are superior to surgery performed by expert surgeons
  • The Zika virus can cause substantial fetal brain abnormalities in utero, without microcephaly or intracranial calcifications
  • Mortality among injured adolescents was lower among patients treated at pediatric trauma centers, compared with adolescents treated at other trauma center types
  • Hydroxycarbamide can substitute for chronic transfusions to maintain transcranial Doppler flow velocities for high-risk children with sickle cell anemia
  • There is convincing evidence of the efficacy of in vivo genome editing in an authentic animal model of a lethal human metabolic disease
  • Sirt1 is an essential regulator of oligodendrocyte progenitor cell proliferation and oligodendrocyte regeneration after neonatal brain injury

Read the complete list.

Dr. Batshaw’s announcement comes on the eve of Research and Education Week 2017 at Children’s National, a weeklong event that begins April 24. This year’s theme, “Collaboration Leads to Innovation,” underscores the cross-cutting nature of Children’s research that aims to transform pediatric care.

Blood Transfusion

Hydroxycarbamide effective in sickle cell stroke prevention

Blood Transfusion

Hydroxycarbamide treatment is on par with blood transfusions for preventing stroke in patients with sickle cell anemia.

What’s known

Strokes are common and devastating complications for patients with sickle cell anemia, often leading to severe and lifelong motor and neurocognitive problems for people with this congenital blood disorder. Results of a clinical trial published in 1998 showed that having regular blood transfusions could reduce the risk of having a first stroke by 90 percent in children with sickle cell anemia. Since then, doctors have employed this prophylactic treatment widely. However, blood transfusions can be painful, inconvenient and carry substantial risks themselves — including the potential of blood-borne infections, iron overload and immune-related reactions to blood products. Finding a way to reduce stroke risk without over-relying on blood transfusions could substantially benefit patients with sickle cell anemia.

What’s new

A team of researchers, including Naomi L.C. Luban, M.D., a Children’s National Health System hematologist and laboratory medicine specialist, tested transfusions against a drug treatment called hydroxycarbamide in a clinical trial to see if the pharmaceutical intervention could reduce strokes at least as well as transfusions. The clinical trial, known as “TCD With Transfusions Changing to Hydroxyurea (TWiTCH),” assigned 60 patients with sickle cell anemia who had abnormally high transcranial Doppler (TCD) flow velocities—a measure of blood flow in the brain that suggests elevated risk of stroke—to receive hydroxycarbamide instead of transfusions. The research team compared the outcomes for these patients with 61 other patients who received standard prophylactic transfusions. Over the 24-month study period, neither group experienced any strokes, although three transient ischemic attacks (a temporary blockage of blood flow in the brain) occurred in each group. These comparable findings suggest that hydroxycarbamide treatment, also known as hydroxyurea, is on par with transfusions for preventing strokes in patients with sickle cell anemia.

Questions for future research

Q: Does hydroxycarbamide offer a long-term way for patients with sickle cell anemia to avoid transfusions?
Q: Could hydroxycarbamide help patients with sickle cell anemia who already have suffered a stroke or who have had severe problems with blood vessels in their brains that impair blood flow?
Q: Which other treatments can help patients avoid the myriad complications that accompany sickle cell anemia?

Source: Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anemia—TCD With Transfusions Changing to Hydroxyurea (TWiTCH): A multicentre, open-label, phase 3, non-inferiority trial.” Ware, R.E. B. R. Davis, W. H. Schultz, R.C. Brown, B. Aygun, S. Sarnaik, I. Odame, B. Fuh, A. George, W. Owen, L. Luchtman-Jones, Z.R. Rogers, L. Hilliard, C. Gauger, C. Piccone, M.T. Lee, J.L. Kwiatkowski, S. Jackson, S.T. Miller, C. Roberts, M.M. Heeney, T.A. Kalfa, S. Nelson, H. Imran, K. Nottage, O. Alvarez, M. Rhodes, A.A. Thompson, J.A. Rothman, K.J. Helton, D. Roberts, J. Coleman, M.J. Bonner, A. Kutlar, N. Patel, J. Wood, L. Piller, P. Wei, J. Luden, N.A. Mortier, S.E. Stuber, N. L. C. Luban, A.R. Cohen, S. Pressel and R.J. Adams. Published by The Lancet on Feb. 13, 2016.

cord blood

T-cell therapy success for relapsing blood cancer

cord blood

A unique immunotherapeutic approach that expands the pool of donor-derived lymphocytes (T-cells) that react and target three key tumor-associated antigens (TAA) is demonstrating success at reducing or eliminating acute leukemias and lymphomas when these cancers have relapsed following hematopoietic stem cell transplant (HSCT).

“There’s currently a less than 10 percent chance of survival for a child who relapses leukemia or lymphoma after a bone marrow transplant—in part because these patients are in a fragile medical condition and can’t tolerate additional intense therapy,” says Kirsten Williams, M.D., a blood and marrow transplant specialist in the Division of Hematology at Children’s National Health System, and principal investigator of the Research of Expanded multi-antigen Specifically Oriented Lymphocytes for the treatment of VEry High Risk Hematopoietic Malignancies (RESOLVE) clinical trial.

The unique manufactured donor-derived lymphocytes used in this multi-institutional Phase 1 dose-ranging study are receptive to multiple tumor-associated antigens within the cell, including WT1, PRAME, and Survivin, which have been found to be over-expressed in myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), B-cell AML/MDS, B-cell acute lymphoblastic leukemia (ALL), and Hodgkins lymphoma. Modifying the lymphocytes for several antigens, rather than a single target, broadens the ability of the T-cells to accurately target and eradicate cancerous cells.

Preliminary results demonstrate a 78 percent response rate to treatment, and a 44 percent rate of total remission for participating patients. To date, nine evaluable patients with refractory and relapsed AML/MDS, B-cell ALL, or Hodgkins lymphoma have received 1-3 infusions of the expanded T-cells, and of those, seven have responded to the treatment, showing reduction in cancer cells after infusion with little or no toxicity. All of these patients had relapse of their cancer after hematopoietic cell transplantation. The study continues to recruit eligible patients, with the goal of publishing the full study results within the next 12 months.

“Our preliminary data also shows that this new approach has few if any side effects for the patient, in part because the infused T-cells target antigens that are found only in cancer cells and not found in healthy tissues,” Dr. Williams notes.

The approach used to expand existing donor-derived TAA-lymphocytes, rather than using unselected T cells or genetically modified T-cells as in other trials, also seems to reduce the incidence of post infusion graft versus host disease and other severe inflammatory side effects. Those side effects typically occur when the infused lymphocytes recognize healthy tissues as foreign and reject them or when the immune system reacts to the modified elements of the lymphocytes, she adds.

“These results are exciting because they may present a truly viable option for the 30 to 40 percent of children who will relapse post-transplant,” Dr. Williams concludes. “Many of the patients who participated were given two options: palliative care or this trial. To see significant success and fewer side effects gives us, and families with children facing relapsing leukemia, some hope for this new treatment.”

Dr. Williams discussed the early outcomes of the RESOLVE trial during an oral presentation at the American Society for Blood and Marrow Transplantation meeting on February 22, 2017.

“The early indicators are very promising for this patient population,” says Catherine Bollard, M.D., M.B.Ch.B., Chief of the Division of Allergy and Immunology, Director of the Program for Cell Enhancement and Technologies for Immunotherapy (CETI) at Children’s National, and senior author of the study. “If we can achieve this, and continue to see good responses with few side effects, it’s possible these methods could become a viable alternative to HSCT for patients with no donor match or who aren’t likely to tolerate transplant.”

This is one of the first immunotherapeutic approaches to successfully capitalize on the natural ability of human T-cells to kill cancer, though previous research has shown significant success for this approach in reducing the deadly impact of several viruses, including Epstein-Barr virus, adenovirus, and cytomegalovirus, post HSCT. These new findings have led to the development of additional clinical trials to investigate applications of this method of TAA-lymphocyte manufacture and infusion for pre-HSCT MDS/AML, B-cell ALL, Hodgkins Lymphoma, and even some solid tumors.

In Brief- Fetal Medicine

Cognitive training exercises at home help kids with sickle cell boost visuospatial working memory

A team led by Children’s National Health System clinicians and research scientists attempted to identify novel approaches to boost working memory in children who suffer from sickle cell disease.

A team led by Children’s National Health System clinicians and research scientists attempted to identify novel approaches to boost working memory in children who suffer from sickle cell disease.

Youths with sickle cell disease who used hand-held computers to play game-like exercises that get harder as a user’s skill level rises improved their visuospatial working memory (WM). Children with sickle cell disease, however, completed fewer training sessions during an initial study compared with children with other disease-related WM deficits.

A team led by Children’s National Health System clinicians and research scientists attempted to identify novel approaches to boost WM in children who suffer from sickle cell disease. Kids who have this red blood cell disorder inherit abnormal hemoglobin genes from each parent. Rather than slipping through large and small vessels to ferry oxygen throughout the body, their stiff, sickle-shaped red blood cells stick to vessel walls, impeding blood supply and triggering sudden pain. Children with sickle cell disease have more difficulty completing tasks that place demands on one’s WM, the brain function responsible for temporarily remembering information and manipulating that information to facilitate learning and reasoning. As a result, they’re more likely to repeat a grade, require special academic services, and to have difficulty maintaining employment as adults.

Because computerized cognitive training programs have been used with success to boost WM for children with other health conditions, such as childhood cancer, the research team sought to examine the feasibility of using the technique for kids with sickle cell disease. “This small study highlights the challenges and opportunities of implementing a home-based cognitive training intervention with youths who have sickle cell disease,” says Steven J. Hardy, PhD, a pediatric psychologist in the Divisions of Hematology, Oncology, and Blood and Marrow Transplantation at Children’s National. “While a larger, randomized controlled clinical trial is needed to better characterize efficacy, our initial work indicates that Cogmed is acceptable and moderately feasible in this population.”

Children’s National is home to the Sickle Cell Disease (SCD) Program, one of the nation’s largest, most comprehensive pediatric programs that cares for 1,350 patients younger than 21 annually. Over 15 months, the team recruited youths aged 7 to 16 participating in the program who had an intelligence quotient of at least 70 and an absolute or relative memory deficit. Those who lacked access to a tablet computer were loaned an iPad Mini 2 loaded with Cogmed RM, an interactive audiovisual cognitive training program that consists of exercises that get progressively more challenging. A clinical psychologist provided coaching and moral support through weekly telephone calls to review progress and challenges, and to offer tips on how to optimize the youths’ progress.

Six of 12 eligible participants – all girls – completed by finishing at least 20 sessions of the program. The mean number of sessions completed was 15.83, and the kids spent a median of 725 minutes working actively on Cogmed exercises. “Participants who completed Cogmed indicated that they perceived greater levels of social support from teachers,” Hardy and colleagues write in the study, published by Pediatric Blood & Cancer. “[T]here was not a statistical difference in perceived parent support.”

Among those children who completed Cogmed, standard scores increased an average of 5.05 on a measure of visuospatial short-term memory, 19.72 on a measure of verbal WM, 27.53 on a measure of visuospatial short-term memory, and 23.82 on a measure of visuospatial WM. The researchers also observed a normalizing of memory functioning for those who finished Cogmed, as a significant portion of participants scored below the average range before using Cogmed and most scored in the average range or higher on memory tests after finishing the program.

“In this initial feasibility trial, adherence to Cogmed was lower than expected (50 percent completion) compared to adherence rates of other samples of children with medical histories, including patients with symptomatic epilepsy and youth treated for cancer,” Hardy and co-authors write. “Thus, additional modifications may be needed to achieve consistent delivery of the intervention to youth with SCD.”

Related Resources: Research at a Glance

Feasibility of home-based computerized WM training for sickle cell disease

What’s Known
Cognitive deficits are a common complication affecting about one-third of kids who have the higher risk sickle cell disease genotypes, HbSS and HbSβ0 thalassemia. While such deficits have been well-documented, no treatment has been proven to recover cognitive function for kids with sickle cell disease. Sickle cell disease is a group of red blood cell disorders in which abnormal genes that children inherit from parents cause their bodies to make sickle-shaped hemoglobin S. Kids with sickle cell disease are at heightened risk for neurocognitive deficits, which can have practical implications for their ability to learn and to succeed academically.

What’s New
Because home-based computerized cognitive training programs have helped to improve working memory (WM) for children with epilepsy and for childhood cancer survivors, a team led by Children’s National Health System researchers and clinicians sought to gauge the feasibility of using such an approach for a small number of children with sickle cell disease. The pilot study found that girls were more likely to complete the cognitive training exercises than boys. Additionally, children whose teachers showed a high level of support spent more time working on the exercises, completed more sessions, and were more likely to finish the program. The mean number of completed sessions was 15.83. Participants who reported experiencing fewer functional limitations as a result of sickle cell disease-related pain completed more sessions. Overall, children who completed Cogmed exercises showed improvements in verbal WM, and visuospatial short-term memory and WM.

Questions for Future Research
Q: Because sickle cell disease is often accompanied by sudden attacks of severe pain, would concurrent delivery of pain-management interventions impact children’s ability to complete cognitive training exercises?
Q: Would adding functional magnetic resonance imaging help to clarify the association between adaptive cognitive skills training and changes to physiological processes, such as alterations in prefrontal and parietal cortical activity, and functional connectivity?

Source: S.J. Hardy, K.K. Hardy, J.C. Schatz, A.L. Thompson, and E.R. Meier. Feasibility of Home-Based Computerized Working Memory Training With Children and Adolescents With Sickle Cell Disease.” Published online by Pediatric Blood & Cancer May 26, 2016.

Feasibility of home-based computerized working memory training with sickle cell disease patients

Children with sickle cell disease are at heightened risk for neurocognitive deficits. The research team sought to fill a gap in the research by evaluating the feasibility of using a home-based computerized working memory (WM) training intervention for children aged 7 to 16 years with sickle cell disease. Study participants used loaner iPads and were asked to work on Cogmed five days a week for five weeks – or a maximum of 25 sessions. According to research published by Pediatric Blood and Cancer, girls were more likely to complete the assignments, compared with boys. The mean number of sessions completed was 15.83.