Newman S.K.,NYU Langone Medical Center |
Jayanthan R.K.,Castleman Disease Collaborative Network |
Jayanthan R.K.,Meharry Medical College |
Mitchell G.W.,Castleman Disease Collaborative Network |
And 15 more authors.
Yale Journal of Biology and Medicine | Year: 2015
Castleman disease (CD†) is a rare and heterogeneous disorder characterized by lymphadenopathy that may occur in a single lymph node (unicentric) or multiple lymph nodes (multicentric), the latter typically occurring secondary to excessive proinflammatory hypercytokinemia. While a cohort of multicentric Castleman disease (MCD) cases are caused by Human Herpes Virus-8 (HHV-8), the etiology of HHV-8 negative, idiopathic MCD (iMCD), remains unknown. Breakthroughs in “omics” technologies that have facilitated the development of precision medicine hold promise for elucidating disease pathogenesis and identifying novel therapies for iMCD. However, in order to leverage precision medicine approaches in rare diseases like CD, stakeholders need to overcome several challenges. To address these challenges, the Castleman Disease Collaborative Network (CDCN) was founded in 2012. In the past 3 years, the CDCN has worked to transform the understanding of the pathogenesis of CD, funded and initiated genomics and proteomics research, and united international experts in a collaborative effort to accelerate progress for CD patients. The CDCN’s collaborative structure leverages the tools of precision medicine and serves as a model for both scientific discovery and advancing patient care. © 2015.
News Article | February 15, 2017
PHILADELPHIA - More than six decades after Castleman disease (CD) was first described, a group of experts from Penn Medicine and other institutions around the world has established the first set of diagnostic criteria for a life-threatening subtype of the condition, idiopathic multicentric CD (iMCD), which is often misdiagnosed as other illnesses. The report was published online ahead of print in the journal Blood. Accurate diagnosis of iMCD has been challenging, with no standard diagnostic criteria to guide physicians and significant overlap with cancer and autoimmune, or infectious disorders. About 1,200 patients are diagnosed with iMCD each year in the United States. It can occur in patients of any age, and about 35 percent of iMCD patients die within five years of diagnosis; 60 percent die within 10 years. "The new criteria will accelerate time to diagnosis and, more importantly, administration of life-saving treatments for iMCD patients," said first author David Fajgenbaum, MD, MBA, MSc, an assistant professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania and associate director of patient impact at the Penn Orphan Disease Center. Many iMCD patients endure months without appropriate treatment, including Fajgenbaum, who is also an iMCD patient. It took over 11 weeks for Fajgenbaum to be correctly diagnosed, during which time he experienced two life-threatening episodes of the disease. "Previously, patients had to hope their doctors were familiar with the Castleman disease medical literature in order for them to even consider an iMCD diagnosis," Fajgenbaum said. "Then, for the doctors considering the diagnosis, actually diagnosing it was very difficult. Now, with these criteria, doctors will know exactly what to look for and what to check off to feel confident about a diagnosis." To establish the criteria, the international working group - led by Fajgenbaum and consisting of 34 pediatric and adult hematopathology, hematology/oncology, rheumatology, immunology, and infectious diseases experts in iMCD and related disorders representing eight countries on five continents, including two physicians that are also iMCD patients - reviewed 244 iMCD cases and 88 lymph node tissue biopsies over 15 months. Other working group members from Penn include senior authors Kojo Elenitoba-Johnson, MD, a professor of Pathology and Laboratory Medicine and director of the Center for Personalized Diagnostics, and Megan Lim, MD, PhD, a professor of Pathology and Laboratory Medicine. The criteria require that for a diagnosis of iMCD to be made, two major criteria and at least two of 11 minor criteria be met, including at least one laboratory abnormality, such as anemia or elevated C-reactive protein in the blood. Additionally, several diseases with similar clinical presentation to iMCD must be excluded, such as another sub-type of CD called HHV-8-associated multicentric CD. Several therapies have been used off-label to treat iMCD patients with varying success, including corticosteroids, cytotoxic chemotherapy, and immunosuppressants. In 2014, siltuximab, an anti-IL6 monoclonal antibody used to treat cancer, became the first U.S. Food and Drug Administration-approved iMCD therapy based on results from an international, randomized controlled trial in which 34 percent of patients had a complete or partial response to the drug compared to zero percent on placebo. "However, the lack of a defined diagnostic criteria has likely impeded the timely administration of treatment for many patients," Fajgenbaum said. "Such delays could lead to organ dysfunction and even death." The working group retrospectively applied the diagnostic criteria to patients from the siltuximab clinical trial. They found that individuals presumed to have iMCD, but who did not meet the diagnostic criteria, had a significantly lower (0 percent) response rate to siltuximab compared to patients who met the diagnostic criteria (43 percent). The working group will continue to improve upon the new diagnostic criteria, in part by relying on the ACCELERATE patient registry. ACCELERATE is a CD natural history registry based at Penn. The data collected from the registry will help researchers validate and potentially tweak the criteria. "I feel so pleased and optimistic that we're finally turning the tide against this disease," Fajgenbaum said. "I've heard of too many patients diagnosed with the disease only after they died and underwent an autopsy, and hopefully this will help doctors to diagnose it before it is too late." Co-authors also include Elaine Jaffe, MD and Thomas S. Uldrick, MD, MS, from the National Cancer Institute's Center for Cancer Research. The study was supported in part by the Castleman Disease Collaborative Network, the Penn Orphan Disease Center, and the Intramural Research Program of the National Institutes of Health. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.
News Article | October 27, 2016
PHILADELPHIA--An innovative, new, patient-driven natural history registry for the rare and poorly understood immune system disorder Castleman disease (CD) will propel care and research for CD through a collaborative research agreement between Janssen Research & Development, LLC; the Castleman Disease Collaborative Network (CDCN); and the University of Pennsylvania. David Fajgenbaum, MD, MBA, MSc, an assistant professor of Medicine at the Perelman School of Medicine at the University of Pennsylvania and associate director of patient impact at the Penn Orphan Disease Center, will lead ACCELERATE (Accelerating Castleman Care with an Electronic Longitudinal registry, E-Repository, And Treatment Effectiveness research), an international, observational, web-based registry that combines clinical data and patient-reported data to aid in the understanding of the disease and facilitate further research projects. Rather than needing physicians to enroll patients and enter patient data, ACCELERATE allows CD patients to enroll themselves into the registry and make their electronic and paper-based medical records available for research. Then, Fajgenbaum and his team will extract key data from patients' medical records--including diagnoses, treatments, and clinical outcomes--into the registry. This first-of-its-kind model gives patients the power to contribute their personal data and the opportunity to be a part of improving understanding and treatment of their disease. Fajgenbaum, who has battled the idiopathic multicentric (iMCD) subtype of CD as a patient since 2010, when he was a student in Penn's Perelman School of Medicine, will serve as the principal investigator for the project. Fajgenbaum spent over six months hospitalized in critical condition and even received Last Rites in November 2010, but after undergoing several rounds of chemotherapy, he rebounded. Since then, he has dedicated his life to advancing research and treatment of the disease. In 2012, Fajgenbaum co-founded the CDCN, a global network dedicated to accelerating research for CD. The CDCN will provide scientific expertise to ACCELERATE through its 28-member Scientific Advisory Board and will engage patients in the research process. "As a patient and researcher, I am very hopeful that this study will provide clues about iMCD and optimal patient care," Fajgenbaum said. "It has the potential to be transformative for the field and for patients." iMCD is one of three subtypes of CD, which involves multiple organ system dysfunction due to uncontrolled immune cell activation for an unknown cause. CD is diagnosed in approximately 6,500 to 7,700 Americans of all ages each year -- about the same incidence as amyotrophic lateral sclerosis (ALS). About 35 percent of iMCD patients die within five years of diagnosis, which is approximately the same as the average across all forms of cancer. CD has a wide spectrum of symptoms, from mild flu-like symptoms to sepsis-like multiple organ failure. There is one U.S. Food and Drug Administration-approved treatment for iMCD, siltuximab, which is an anti-Interleukin-6 monoclonal antibody developed by Janssen. The therapy demonstrated reduction in lymph node size and disease symptoms in a large portion of patients in its registrational trial. Still, many questions exist related to iMCD, particularly for those patients who do not respond to siltuximab. Research is urgently needed, Fajgenbaum said. ACCELERATE's aims are to elucidate the key clinical and laboratory outcomes related to iMCD, track real-world treatment use and safety profiles, and build an infrastructure for future translational research. The team aims to enroll over 1,000 patients within the first five years. Patients from all over the world are able to register. In Europe and other countries where medical records will be provided by healthcare professionals, ACCELERATE will work with clinical sites and medical institutions to collect patient data. The CDCN is also in the process of developing a biobank to streamline the collection, storage, and processing of blood and tissue samples from the CD community. Though this is an unprecedented project, it does reflect several important recent trends, Fajgenbaum said. "More and more patients with rare diseases are taking matters into their own hands to connect patient and physician-researcher communities, generate awareness, and drive scientific efforts. With ACCELERATE, patients power the research," Fajgenbaum said. "It's also reflective of the value that comes from collaborations between industry, research foundations, and academia to answer tough questions that could ultimately lead to better clinical care." Fajgenbaum and his colleagues have authored several key papers in the literature, including a case report on himself in JAMA Dermatology. His publication in the journal Blood initiated a paradigm shift in the iMCD disease model and classification system. He has also co-authored two recent papers, including a systematic literature review in The Lancet Haematology on iMCD and a commentary on CDCN's "Collaborative Network" approach, as well as the largest-ever series on the newly-described TAFRO Syndrome subtype of iMCD in the American Journal of Hematology. Reporting in the March 2016 issue of Lancet Haematology, Fajgenbaum and his co-authors, including Penn's Vera P. Krymskaya, PhD, present several key findings that have advanced the field's understanding of the disease. They found that the prevalence of cancer among iMCD patients was three times higher than people without the disease. Also, 88 percent of patients studied had a two-year survival rate, 22 percent died by the time of follow-up (median time of follow-up was 29 months), and 41 percent of patients did not respond to first-line treatment, the team found. "While studies like this provide much-needed data on this population, I believe ACCELERATE will be the seminal project that helps fill the knowledge gaps and propel research even further," Fajgenbaum said. "As a physician-scientist and patient with a deadly disease, I believe a more collaborative, strategic, and focused approach is necessary to accelerating research. We must work together to make every dollar and second count, because patients--like me--are waiting." Editor's note: Fajgenbaum participated in an unpaid capacity at two ad hoc advisory board meetings designed by Janssen Pharmaceuticals to gather stakeholder feedback. Dr. Fajgenbaum contributed both as a patient and researcher.
News Article | February 5, 2017
David Fajgenbaum was only 25 when he was hit by a rare and devastating illness. A former quarterback at Georgetown, Fajgenbaum was known as the "Beast" for his incredible physique and stature. In July 2010, he had been studying at the University of Pennsylvania when he woke up one night with stabs of abdominal pain, and he was drenched in sweat. During a visit to the emergency room, Fajgenbaum's doctor told him that his kidneys, liver, and bone marrow were not functioning properly. Moreover, his lymph nodes were swollen, red bumps appeared across his chest, and he felt exhausted all the time. Doctors had no idea why his body was failing. Since then, finding out what medical condition ailed him had become Fajgenbaum's life mission. Needless to say, he took the matter into his own hands. As Fajgenbaum's immune system went haywire, his body began to decline rapidly. His left eye became temporarily blind because of a retinal hemorrhage. He gained more than 70 pounds of extra fluid as his liver continued to fail. He got sicker and sicker. Grant Mitchell, Fajgenbaum's former roommate, recalled that his friend's brain also began to slow down. "I would ask him a simple question, and he would answer in a couple words, like 30 seconds to a minute later," Mitchell told the New York Times. Doctors and students at Penn suspected that Fajgenbaum had cancer of the lymphatic system or lymphoma, while others thought it was a severe case of lupus or mononucleosis. However, all tests were inconclusive. By September 2010, doctors gave Fajgenbaum steroids and his body began to fight back the disease. His liver and kidneys functioned properly again, and the extra fluid in his body receded. Fajgenbaum was released from the hospital. But it took only a month for his symptoms to relapse, when he was staying at his childhood home in Raleigh, North Carolina. Doctors there sent a piece of Fajgenbaum's lymph node to pathologists at the Mayo Clinic, where it was finally identified as Castleman Disease. It was such a rare condition that doctors at Raleigh had no experience with it. Castleman disease, which is also called angiofollicular lymph node hyperplasia or giant lymph node hyperplasia, involves the overgrowth of cells in the lymphatic system, the body's disease-fighting network. As of writing, doctors have identified two types of this condition: localized Castleman disease and multicentric Castleman disease, which struck Fajgenbaum. Localized CD is the more common type of the illness and affects a single group of lymph nodes. This usually affects the abdomen and the chest. According to Mayo Clinic, localized CD is usually cured by removing affected lymph nodes through surgery. On the other hand, multicentric CD affects more than one lymph node and can affect other organs that contain lymphoid tissue. It can sometimes affect people with human immunodeficiency virus (HIV). It is also linked to other cell-proliferation diseases, including lymphoma, POEMS syndrome, and Kaposi's sarcoma. Because of this, it's often difficult to distinguish multicentric CD and cancer. MCD causes infections, fevers, fatigue, weight loss, nerve damage, and night sweats. It also weakens the body's immune system, making it difficult for the body to fight infections. In the United States, only about 1,200 to 1,500 people have been diagnosed with multicentric CD. Studies have shown that only about 65 percent of people with the disease live for five years after diagnosis. Over the next few years, Fajgenbaum alternated between periods of frightening relapses and relative health. His condition had been so severe that it stumped even those who were leading experts on the disease, including Dr. Frits van Rhee who has treated about 100 patients with Castleman. Fajgenbaum used his own body as a test subject in the hopes of searching for a cure for this disease. In 2011, Dr. van Rhee acquired permission to treat Fajgenbaum with siltuximab, a drug being developed by Johnson & Johnson to treat patients with multicentric CD. At that time, siltuximab had not been approved by the Food and Drug Administration (FDA) yet, but it would be in 2014. However, like other treatments, the drug did not work on Fajgenbaum. With the zeal he once devoted to bench-pressing 375 pounds, Fajgenbaum decided to dive into scientific research on Castleman disease and familiarized himself with the world's experts. The more he learned, the more he realized that research on the disease was in disarray, he said. Fajgenbaum called Dr. Thomas Uldrick from the National Cancer Institute to help him out with the research. He also began collaborating with Dr. van Rhee. In 2013, Fajgenbaum earned his medical degree. He later entered the Wharton School, but by December 2013, he got sick again that his blood platelets dropped dangerously low. This time, he used his relapse to progress his search for the cure. He collected weekly blood samples as "snapshots" of his immune system, organizing the results into a spreadsheet. When his disease returned, Fajgenbaum persuaded doctors to remove a piece of his lymph node and save it for research. He received another round of chemotherapy and improved enough to work on his research. He found out that five months before he noticed symptoms coming back, the T cells in his body began to activate, preparing for a fight in his body's immune system arsenal. Three months before the relapse, Fajgenbaum noticed his body producing more of a protein that commands the body to create more blood vessels. All these gave Fajgenbaum an idea: perhaps there was a problem with the communication lines in his body, particularly in the area that triggered the production of blood vessels and that activated the T cells. If he could shut down this communication line — known as mTOR pathway — he might be able to prevent a relapse. He prevailed. In January 2014, Fajgenbaum started taking sirolimus or Rapamune, which is often given to kidney transplant patients. After a year, tests revealed that his immune system was returning to normal. Fajgenbaum has started a nonprofit called Castleman Disease Collaborative Network to coordinate research on the disease. Now 31 years old, he is an assistant professor of medicine at Perelman School of Medicine. "I didn't think that I would ever get to leave the hospital, and now here I am, fighting back," said Fajgenabaum. "It's the ultimate motivator." © 2017 Tech Times, All rights reserved. Do not reproduce without permission.