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Managing the Fallout

April 20, 2022

May 2022

Hematologists are key players in radiologic emergency response, applying lessons learned from hematologic cancer and bone marrow transplants to the treatment of acute radiation syndrome.

The Russian invasion of Ukraine has the world watching, with a keen awareness of the country’s active nuclear power plants and the potential for a significant nuclear-radiologic event.

In early March 2022, Russian forces took control of the Zaporizhzhia plant in the southeastern part of Ukraine, but not before artillery shelling caused fires to break out at the plant. The International Atomic Energy Agency (IAEA), the United Nations’ nuclear watchdog, reported that the reactors were not affected and radiation levels remained safe, but they continued to monitor Zaporizhzhia and other sites throughout Ukraine, including the shuttered Chernobyl facility.1,2

The prospect of a significant nuclear accident in Ukraine conjures images of the 1986 disaster at the Chernobyl nuclear power plant that killed around 28 of the site’s workers within a few months of the event and resulted in acute radiation sickness (ARS) in more than 100 people. Over the long term, the radiation exposure has been linked to thousands of cases of thyroid cancer.3,4 More recently, a 2011 earthquake and resulting tsunami caused a significant radiation accident at the Fukushima Daiichi Nuclear Power Station in Japan, leading to the evacuation of more than 100,000 people from the surrounding area, though no deaths or cases of radiation sickness have been directly attributed to the accident.5

These events have provided critical information about the natural history of ARS, medical response to nuclear-radiologic emergencies, and the development of radiation countermeasures. But additional lessons on the treatment of ARS come from the treatment of hematologic cancers, specifically the supportive measures that hematologists use to help patients recover from radiation therapeutics.

“We’re all familiar with how radiation injures the marrow. Hematologists have experience and skill taking care of people who had marrow injury,” said Daniel J. Weisdorf, MD, a professor of medicine and the deputy director of the Clinical and Translational Science Institute at the University of Minnesota in Minneapolis.

Dr. Weisdorf, who is a transplant specialist, was involved early on with the Radiation Injury Treatment Network (RITN), a national network of medical centers that seeks to harness the skills of hematologists and other specialists to respond to ARS cases following a mass casualty disaster involving radiologic, nuclear, or chemical agents with marrow toxicity.

ASH Clinical News spoke with Dr. Weisdorf and other experts about the RITN and other organizations, what goes into triaging a radiation disaster, the symptoms and presentation of ARS, and how hematologists are involved with preparing for and responding to radiologic disasters.

What Is RITN?

RITN puts hematologists front-and-center in the response to a radiologic mass casualty event on U.S. soil. The network, which is led by the National Marrow Donor Program and the American Society for Transplantation and Cellular Therapy (ASTCT), was officially launched in 2006 with 13 medical centers across the country on standby to treat a surge of patients with ARS resulting from mass casualty radiologic, nuclear, or chemical incidents. RITN focuses on incidents, such as a terrorist attack, that could cause thousands or tens of thousands of casualties and overwhelm local medical facilities.

The history behind RITN goes back to the mid-1980s when the U.S. Office of Naval Research, which provides additional funding for the network, contracted with the National Marrow Donor Program to help improve outcomes from bone marrow transplants. Over the years, officials have worked on ideas to integrate the country’s transplant centers into the national response to a radiologic event. But it was the events of September 11, 2001, that galvanized the effort to prepare for a potential terrorist attack that could have radiologic implications, explained Cullen Case Jr., senior manager of business continuity at the National Marrow Donor Program and RITN program director. These potential dangers include an improvised nuclear device (IND), a radiologic exposure device in which a radiation source is placed in a public space, or a radiologic dispersal device, otherwise known as a “dirty bomb,” which combines a conventional explosive with radiologic material.

RITN’s mission is to take an active role before, during, and after a radiologic disaster. To help medical centers prepare, RITN experts have developed treatment guidelines for managing hematologic toxicity among casualties of radiation exposure. RITN also conducts regular training exercises and holds educational conferences.

During a potential disaster, RITN centers would be activated to provide comprehensive evaluation and treatment in both the inpatient and outpatient settings, as well as coordinate the response with government agencies. After a disaster, RITN centers would collect and share patient data for research through the Center for International Blood and Marrow Transplantation Research.

Over the past 16 years, RITN has grown to include 74 medical centers across 35 states. To participate, a medical center must have a hematology/oncology department with expertise in the management of bone marrow failure and be able to handle the complications that come with total body irradiation as part of a conditioning regimen. As part of participation, these centers keep RITN up to date on their capacity to accept patients with ARS, including bed availability reporting, details on staff, and their available stock of cytokine therapies (filgrastim, pegfilgrastim, sargramostim, and romiplostim). These centers also participate in RITN drills using a federal Government Emergency Telecommunications Service card that allows them to make phone calls when they would otherwise get an “all circuits are busy” message.

Participating RITN centers are required to engage in web-based training or attend education conferences on radiologic emergency response and preparedness. For instance, one of the offerings on the RITN website is a course from the National Alliance for Radiation Readiness that explores radiation-specific issues that should be considered in the first 96 hours after an event and beyond. Clinicians are then expected to bring that information back to their institutions by leading grand rounds lectures to educate their medical staff.

Finally, medical centers in the RITN network are asked to engage in annual tabletop exercises that allow hematologists, other specialists, and federal officials to role-play how they would handle a potential mass casualty event. Consider this scenario: a nuclear bomb is detonated in Chicago and 5,000 patients are transported to a medical center in Phoenix. How does that medical center coordinate with local public health and emergency management officials to ensure that patients with potential ARS are routed to their facility? How do the staff screen patients for radioactive contamination and begin their assessment for treatment?

“Hematologists are not driving the ambulances,” Dr. Weisdorf said. “We are handling the later consequences of radiation exposure or down-wind complications of a bomb’s fallout.”

Working With Partners

There are a number of organizations that are mobilized in the event of a radiologic mass casualty event in the U.S. Within the Department of Health and Human Services, the Office of the Assistant Secretary for Preparedness and Response (ASPR) manages the National Disaster Medical System, which leads the radiologic disaster response by contacting the National Marrow Donor Program to start preparing RITN centers to receive patients. The National Disaster Medical System transports patients away from the event site to medical centers across the country and handles reimbursement for care for patients who do not have health insurance, ensuring that participation in RITN is not a financial loss for medical centers, Mr. Case said.

In the meantime, the National Marrow Donor Program is prepared to scale its donor registry searches, allowing it to conduct tens of thousands of searches daily, if needed. Additionally, the program can activate more donor workup specialists if an increased need for hematopoietic cell donors arises. Currently, each search of the National Marrow Donor Program provides patients with access to more than 39 million potential donors and nearly 806,000 cord blood units within U.S. and global registries.

While RITN medical centers are selected for their expertise in treating bone marrow injury, many patients are likely to also have trauma or burns. For RITN centers that only handle the treatment of patients with cancer, such as Memorial Sloan Kettering in New York, physicians there would work collaboratively with nearby trauma centers. RITN has also developed joint educational materials with the American Burn Association to guide the management of patients with burns, trauma, and ARS.

“There are patients that are going to have that combined injury and we’re going to need to care for them,” Mr. Case said. “The question is how to work together to make sure that first they’re going to get stabilized for that trauma, and then that the trauma physician knows to reach out to the hematology or oncology department to ask for supportive care for the [ARS], which could be part of that patient’s injuries.”

Triage and Preparation

RITN is primarily made up of large medical centers and cancer institutes, strategically located around the U.S. But smaller, community hospitals are an important part of the response too, Mr. Case said, because they are the places within the event area that will likely perform the initial triage of patients. With that in mind, RITN has created both referral guidelines for patients with potential ARS and just-in-time training materials.

The RITN referral guidelines recommend laboratory evaluation that includes a complete blood count with differential, absolute lymphocyte count (ALC), and absolute neutrophil count (ANC), as well as a metabolic panel including electrolytes, renal, and hepatic markers, and prothrombin time/​­activated partial thromboplastin time.6

The referral guidelines call for considering an RITN center consultation or referral if the patient has an ANC of <1,000/µL; an ALC <1,000/µL; severe nausea, vomiting, or anorexia; a localized cutaneous radiation injury that requires extensive management; suspected or known internal contamination that involves an open wound; or breathing or swallowing radioactive materials. Referrals may also be appropriate if the facility is not equipped to provide irradiated, leukoreduced blood products.

For hematologists not involved in RITN, the best way to prepare is to have awareness of the possibility of a radiation attack and their role in it, Dr. Weisdorf said. “It’s about awareness and information,” he noted. “The whole purpose of this is not to use this tool but to be aware of what you might do if the worst happened.”

Dr. Weisdorf advised hematologists to visit the RITN website for tools like the referral guidelines, as well as triage guidelines related to the administration of cytokine therapy to adults and children, and resources for estimating radiation dosimetry.

“The goal is to have cues to be able to look things up quickly, efficiently, and reliably,” he added. “That’s really what people need. Hematologists are not radiation biologists; what we need is to be able to promptly identify reliable information.”

ARS Presentation and Treatment

The type of radiologic event will have a big effect on the injuries created. In an IND event, for instance, nearly 90% of the casualties would likely have combined injuries of trauma, burns, and potential ARS. Patients would be treated first by trauma specialists and then have their radiation-related symptoms assessed. About 10% would have radiation-only injuries and be triaged to RITN medical centers. Of that 10%, most would have low levels of radiation exposure and could be assessed and have their complete blood count monitored on an outpatient basis. Nearly 30% would require intensive inpatient supportive therapy, and just 1% would be candidates for marrow transplant, according to RITN.

“Bone marrow transplant would only be required in a small percentage of clinically significant ARS cases,” Mr. Case said. “However, the level of clinical care and need is ultimately determined by the amount and duration of exposure to radiation.”

Transplant is only a suitable option for patients with pure bone marrow aplasia from radiation, said Nelson J. Chao, MD, chief of the division of hematologic malignancies and cell therapy at Duke University School of Medicine in Durham, North Carolina. Dr. Chao helped establish RITN when he was the president of ASBMT (now ASTCT) and is a member of the RITN executive committee.

“If you’re sick with other things, if you have burns and marrow aplasia, it’s probably not going to be that helpful,” he said. “The number of patients that it would be helpful to would be pretty limited.”

Alla Shapiro, MD, PhD, a pediatric hematologist-oncologist and former medical officer with the U.S. Food and Drug Administration’s Counter-Terrorism and Emergency Coordination Staff, saw the impact of combined injuries firsthand when she responded to the 1986 Chernobyl disaster.

“We had lot of patients with radiation skin burns, really severe burns covering a significant surface of the body, along with bone marrow failure,” she said.

But medical responders didn’t have the proper knowledge about the treatment approach that has been gained over time. They attempted bone marrow transplant on 13 patients who were exposed to high doses of radiation and, despite well-matched bone marrow, 11 of the patients died. The two patients who did not have severe radiation burns survived the transplant.

“At this point, we know much more about combined radiation injuries and how to approach them,” said Dr. Shapiro.

One of the big differences for hematologists in the treatment of ARS from a terrorist incident is that the radiation will be unfractionated, which means that people will be exposed to high-dose radiation over a short period of time. As a result, patients are likely to display the full spectrum of marrow, gastrointestinal, skin, and blood toxicities at once.

Another difference with a terrorist event is that the exposure will be heterogeneous. Rather than the total body irradiation given in medical settings, it’s likely that some part of the patient’s body would be shielded from exposure because they were sitting behind a metal desk or walking behind a car. “That makes it a little more difficult to determine who is going to recover and who is not,” Dr. Chao said.

People in the event area who are exposed to radiation may present with significant vomiting as their chief symptom, Dr. Weisdorf explained. Determining the best management strategy from there depends in part on understanding where they were in the event radius to estimate their radiation exposure, but that information may not be readily available so clinicians have to rely on the patient’s blood counts and symptoms, he added.

For most exposures, there would be full marrow recovery within two to three weeks, assuming that the radiation exposure was external and people were evacuated from the area immediately after the event. Internal exposure, from inhaling radioactive dust, may have a longer recovery time and require more intensive treatment, Dr. Weisdorf said.

The treatment for any event will be dose dependent, Dr. Chao said, but the greatest unknown is the treatment for combined injuries.

“If you get 4 Gray of radiation and you get cut by shrapnel, shattered glass, or you’re in a car accident, that actually increases the toxicity from the radiation dramatically. That adds another layer of complexity,” he said.

A mass casualty event with either a dirty bomb or a nuclear bomb is also likely to produce a large number of “worried well” patients who were close to the event but not in the epicenter. The assessment of those large numbers of patients has the potential to overwhelm the medical system, Dr. Chao said.

Research Transfer

Research is another key component of RITN’s work. The Office of Naval Research provides funding to the National Marrow Donor Program that is used in part to fund research grants.

“Even though it would help a radiologic disaster, certainly it’s helping any patient that needs to have a transplant or some kind of cellular therapy,” Mr. Case said. “It’s definitely mutually beneficial. Conversely, anything that’s being done to improve transplant outcomes or long-term survival rates, all of that is going to help someone who would potentially be a victim of a radiologic disaster. It’s a great merging of the needs.”

RITN also collaborates with the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, on radiologic-nuclear research. NIAID funding has been used to support approaches to treat ARS and the delayed effects of acute radiation exposure through growth factors, cellular therapies, fusion proteins, and small molecules. NIAID has also funded work into the identification and validation of biomarkers and bioassays to assess radiation exposure levels and predict outcomes.

Challenges

Dr. Shapiro sees the lack of awareness of the potential for radiation mass casualty events from the general public and non-specialist medical professionals as a significant challenge. She suggested that more needs to be done within the media to raise public awareness of the risks and that understanding of radiation-related injuries should become a standard part of graduate medical education.

Despite the planning and drills, Dr. Chao said one of the biggest challenges of preparing for a radiologic mass casualty event is that there are so many compounding potential scenarios depending on the type of event. With a blast event, for example, one variable is where the event occurs, starting with the effects of the blast itself and cascading down to car accidents among drivers who are blinded by the flash.

“It’s not like a hurricane where you know something is coming and you can position assets ahead of time and then you have a playbook that you can revise because things have happened in the past,” Dr. Chao said. “We don’t have any of that, so we’re trying to make some of this up as we go and, hopefully, we never have to use any of this.”

By Mary Ellen Schneider

References

  1. United Nations. Russian military control of Ukraine nuclear plants cause for grave concern, nuclear energy agency warns. Published March 6, 2022. Accessed March 11, 2022. https://news.un.org/en/story/2022/03/1113382.
  2. International Atomic Energy Agency. Update 17 – IAEA Director General Statement on Situation in Ukraine. Published March 10, 2022. Accessed March 11, 2022. https://www.iaea.org/newscenter/pressreleases/update-17-iaea-director-general-statement-on-situation-in-ukraine.
  3. U.S. Nuclear Regulatory Commission. Backgrounder on Chernobyl nuclear power plant accident. Updated March 1, 2022. Accessed March 11, 2022. https://www.nrc.gov/reading-rm/doc-collections/fact-sheets/chernobyl-bg.html.
  4. Baverstock K, Williams D. The Chernobyl accident 20 years on: an assessment of the health consequences and the international responseEnviron Health Perspect. 2006;114(9):1312-1317.
  5. World Nuclear Association. Fukushima Daiichi accident. Updated April 2021. Accessed March 11, 2022. https://world-nuclear.org/information-library/safety-and-security/safety-of-plants/fukushima-daiichi-accident.aspx.
  6. Radiation Injury Treatment Network. Guidelines for identifying radiation injury and considering transfer to a specialized facility. Revised August 2021. Accessed March 11, 2022. https://ritn.net/WorkArea/DownloadAsset.aspx?id=17179869248.

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