A Report from the Radiation Injury Treatment Network State-of-the-Science Workshop on Radiation, Medical Countermeasures, and Treatment
Nelson Chao, MD, MBA
Donald D. and Elizabeth G. Cooke Professor, Professor of Medicine and Immunology, Duke University Medical Center
Editor’s Note: Dr. Chao was president of the American Society of Blood and Marrow Transplantation when he worked with the National Marrow Donor Program to found the Radiation Injury Treatment Network (RITN). Currently, he serves as co-chair of RITN.
It seems that these days the only thing that is certain is uncertainty. The threat of a nuclear catastrophe is real given both the increase in activity of global terrorist organizations and the lax security of nuclear material in some countries that has led to a rise in illicit trafficking of radioactive materials. Additionally, failure of safeguards in one of our nuclear reactors could result in a national tragedy of the same or greater magnitude as that which followed the earthquake and tsunami in Japan in March 2011. The Radiation Injury Treatment Network (RITN) was established in 2006 as a joint effort of the American Society of Blood and Marrow Transplantation and the National Marrow Donor Program with support from the Office of Naval Research. RITN serves to assist with the medical and logistic concerns of the hematology community in response to a mass casualty event involving radiation exposure. If a nuclear disaster occurred today, hematologists would be key figures in the response effort. Such a central role is logical in that the bone marrow is highly sensitive to radiation, and hematologists are experienced in dealing with the complications of bone marrow failure. Additionally, transplant physicians have expertise in managing patients who have received ablative doses of radiation. Accordingly, their experience would be invaluable in determining the need for hematopoietic stem cell support and in caring for patients with multi-organ damage associated with high-dose radiation exposure. Physician members provide the RITN with the expert advice needed both to marshal and to allocate resources properly. In the event of a nuclear emergency, the response effort would be coordinated by RITN, which has a memorandum of understanding with the Office of the Assistant Secretary for Preparedness and Response under the Department of Health and Human Services (HHS). Following activation by HHS, RITN would be responsible for coordinating the care of affected individuals, utilizing the resources of medical centers across the country or abroad if necessary.
This past October, RITN hosted a State-of-the-Science Workshop titled “Radiation, Medical Countermeasures and Treatment.” The program included such topics as radiation biology, biodosimetry, supportive care, hematopoietic and immune reconstitution, and specific organ toxicity. With funding support from the National Institutes of Allergy and Infectious Diseases through its Centers for Medical Countermeasures Against Radiation, investigators reported the results of studies aimed at identifying methods for assessing and ameliorating radiation toxicity. Among the highlights of the workshop were reports of the progress made in the area of biodosimetry, especially the development of automated techniques and the use of genetic signatures. Automation now allows for two established manual assays that measure absorbed doses of radiation to be done in a mechanical fashion so that several thousand analyses can be performed in parallel. Further, by taking advantage of state-of-the-art molecular techniques, gene array chip signatures that are useful in quantifying the dose of radiation exposure have been developed. Data from rodents and from non-human primates demonstrate conclusively the utility of providing rapid, supportive-care measures in the form of intravenous fluids, antibiotics, blood products, and hematopoietic growth factors. Two available drugs (human growth hormone and insulin-like growth factor 1) that stimulate hematopoiesis were shown to improve outcomes after irradiation. Novel agents that showed promise in pre-clinical studies or in phase I trials include flagellin, pleotrophin, meloxicam, thrombopoietin receptor agonists, Notch ligand stimulators, and GS-Nitroxide. Moreover, a number of strategies for enhancing immune reconstitution following radiation are under investigation. For example, both animal and limited human data suggest that IL-7, keratinocyte growth factor, and sex steroid inhibition with leuprolide have efficacy in this setting. Others have been investigating cell-based approaches to radiation injury including the use of mesenchymal stromal/stem cells and myeloid progenitors. An issue that generated considerable debate because of the Fukushima experience was the role of banking hematopoietic stem cells of radiation first-responders. In the end, a global consensus statement sponsored by the World Health Organization concluded that evidenced-based medicine supported a strong recommendation for the use of myeloid colony-stimulating factors and a weak recommendation for both erythropoiesisstimulating agents and hematopoietic stem cell transplantation in the management of patients with radiation injury.
While it appears that we are still far away from a magical drug, or drugs, for the management of exposed individuals, the consensus from the attendees was that we have come a long way in re-invigorating research in this important public health area that had fallen into neglect with the end of the Cold War. Still, much needs to be done and important questions need to be answered. Foremost, we need to develop agents that can unequivocally mitigate radiation toxicity. The list of potentially effective agents is extensive, and while the basic science is interesting, there is a sense of urgency that these agents be tested in vivo according to the “two animal rule” and Good Laboratory Practices so as to generate data sufficient for FDA approval for use in humans. Nonetheless, the RITN workshop can be counted a success as it established a foundation for future research, articulated clear questions to be addressed by the field, and set uniform standards for comparing research going forward.
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