Researchers Discover Test to Predict Which Patients With Rare Blood Disease Will Respond To Only FDA Approved Treatment And Identify Alternative Therapy

David Fajgenbaum, MD, MBA, MSc, is the lead author of the study and an iMCD patient.

PHILADELPHIA— New research has uncovered a precision medicine test using blood proteins to identify a new subset of patients with idiopathic multicentric Castleman’s disease (iMCD), a rare blood disorder, who are more likely to respond to siltuximab, the only FDA approved treatment for the disease. The international study was led by researchers from Penn Medicine and the Castleman Disease Collaborative Network (CDCN).

Previous research suggests that half of patients do not respond to treatment with the monoclonal antibody, siltuximab. For these patients, prompt administration of other treatments is necessary to prevent deterioration, so it is essential to understand who is likely to benefit. This study also found that an existing drug approach, Janus kinase inhibitors (JAKs), which are already approved for the treatment of certain cancers and rheumatoid arthritis, are a promising alternative treatment option for unresponsive patients. with siltuximab. The study, which is the largest to date for iMCD, is published in The blood is advancing.

“This discovery has the potential to improve precision medicine for iMCD, the concept that the right patient receives the right drug at the right time. Knowing which patients are likely to benefit from which drugs is a key piece of this puzzle, ”said David Fajgenbaum, MD, MBA, M.Sc., assistant professor of translational medicine and human genetics, director of Cytokine Storm Processing Center and Laboratory To the Perelman School of Medicine at the University of Pennsylvania, co-founder of CDCN, and associate director of patient impact at Penn Orphan Disease Center, and the lead author of the study. Fajgenbaum is also a Patient iMCD.

Castleman’s disease is not really a unique disease. The term describes a group of inflammatory disorders and is diagnosed in approximately 5,000 people of all ages each year in the United States, making it about as common as amyotrophic lateral sclerosis (ALS). Patients present with a range of symptoms – from a single enlarged lymph node with mild flu-like symptoms (unicentric) to enlarged lymph nodes located throughout their body, abnormal blood cell counts and life-threatening failure of several systems. organic (multicentric). The most serious subtype is iMCD, which has similarities to autoimmune diseases and cancer, and involves a cytokine storm. A cytokine storm describes what happens when the immune system gets carried away, as seen in severe cases of COVID-19 and a number of other conditions. About 35 percent of patients with iMCD will die within five years of diagnosis.

Studies have shown that siltuximab can send between one third and one half of patients into remission which usually lasts for years. However, patients who are in intensive care and do not respond to siltuximab have few options and limited time. They usually receive chemotherapy, but often relapse, which means that many iMCD patients go through months without proper treatment. It took over 11 weeks for Fajgenbaum to be properly diagnosed, during which time he experienced two life-threatening episodes of the disease, did not respond to siltuximab, and had to be treated with rapid chemotherapy.

For this study, the researchers examined blood samples from 88 iMCD patients and measured 1,178 blood proteins in each of those samples, identifying seven blood proteins that could effectively predict the subset of patients most likely to respond to siltuximab. The results were then validated in an independent cohort of 23 iMCD patients.

“If this test had been available to me, I probably would have gotten second-line treatment sooner, lowering my risk of death while waiting to see if first-line treatment would work. But just as important, this study also identifies another potential treatment for inclusion in our arsenal, ”said Fajgenbaum.

Previous research has shown that in many cases the cytokine storm in iMCD is linked to a cytokine, or inflammatory mediator, called interleukin-6 (IL-6), which in turn is connected to another pathway called mTOR, opening up a new possibility of treatment with mTOR inhibitors. Fajgenbaum discovered mTOR inhibitors as the first new treatment for iMCD in 25 years and started taking an mTOR inhibitor himself called sirolimus. This study advanced these findings and found that another pathway called JAK appears to be an essential mediator of the cytokine storm, with JAK inhibitors like ruxolitinib and baricitinib potentially providing relief.

“These are not discoveries that require decades of study before they can benefit patients. These drugs can potentially be used immediately to help iMCD patients without further options, as they are already approved by the FDA for other illnesses. We essentially seek and find solutions that are hidden in plain sight, ”said Sheila Pierson, MS, Director of Registry Entries for the CDCN as well as Associate Director of Clinical Research for the Center for Cytokine Storm Treatment at the University of Pennsylvania, and first author of the study.

In fact, in a article published in The Lancet in May 2021, Fajgenbaum and his co-authors described a patient diagnosed with iMCD, who received and responded to a combination of therapies, including baricitinib, based on the results provided by this study. As the patient deteriorated until baricitinib was added and there was a noticeable improvement thereafter, more work is needed to investigate the role of this treatment for iMCD and to improve the clinical applicability of the precision medicine test.

This study involved an international collaboration between researchers at Penn Medicine, CDCN, Medidata Solutions, who provided machine learning and other bioinformatics support, Janssen Pharmaceuticals and seven academic institutions in Japan, Norway, UK and in the USA.

This study was funded by a research grant from the Center for Orphan Diseases at the University of Pennsylvania in partnership with the Castleman Disease Collaborative Network, Janssen Pharmaceuticals, and the National Heart Lung & Blood Institute (R01HL141408).

Editor’s Note: The Fajgenbaum research team received research funding from EUSA Pharma for the ACCELERATE registry for Castleman’s disease. EUSA Pharma manufactures siltuximab.

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 Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the country’s first medical school) and the University of Pennsylvania Health System, which together form an $ 8.9 billion company.

The Perelman School of Medicine has been ranked among the top medical schools in the United States for more than 20 years, according to the US News & World Report’s survey of research-driven medical schools. The school is consistently among the top recipients of funding from the National Institutes of Health, with $ 496 million awarded in fiscal year 2020.

Patient care facilities in the University of Pennsylvania Health System include: University of Pennsylvania Hospital and Penn Presbyterian Medical Center, recognized as one of the nation’s top hospitals by US News & World Report: Chester County Hospital; Lancaster General Health; Penn Medicine Princeton Health; and Pennsylvania Hospital, the country’s first hospital, founded in 1751. Other facilities and businesses include Good Shepherd Penn Partners, Penn Medicine at Home, Lancaster Behavioral Health Hospital, and Princeton House Behavioral Health, among others.

Penn Medicine is fueled by a talented and dedicated workforce of over 44,000 people. The organization has also forged alliances with top community health systems in southeastern Pennsylvania and southern New Jersey, creating more options for patients no matter where they live.

Penn Medicine is committed to improving lives and health through a variety of community programs and activities. In fiscal 2020, Penn Medicine provided over $ 563 million to benefit our community.

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