Dennis L. Confer

Medical Management of the Acute Radiation Syndrome: Recommendations of the Strategic National Stockpile Radiation Working Group

The events of September 11, 2001, confirmed the vulnerability of the United States and other nations to acts of terrorism. While our ability to react to and treat victims of biological terrorism has significantly improved, a terrorist event involving radioactive material remains a threat for which improved preparation is requisite. Several international conferences on treatment of acute radiation injury have been held in the past 2 decades (1-8). The conclusions of these conferences, together with mounting preclinical data showing the benefit of early cytokine use in combination with aggressive clinical support in irradiated animals (9-13), provide valuable information to clinicians faced with treating the acute radiation syndrome. Scenarios for terrorist acts involving radioactive material have been developed, some of which indicate that mass casualties can occur. However, little information is currently available in the medical literature concerning guidelines for the medical management of large-scale, complex radiation injuries, such as those that might occur in an urban area (14-17). Therefore, this consensus document was created to help physicians who may be involved in evaluation, triage, or medical management of victims with acute radiation injury. Methods The Strategic National Stockpile (SNS) convened the SNS Radiation Working Group (Appendix) to address issues of medical management and stockpiling of pharmaceutical agents in case of a significant radiologic event. Participants were selected on the basis of their established expertise in the field. The deliberations of the SNS Radiation Working Group during a series of 4 consensus meetings beginning in August 2002 and 4 additional conference calls were used as a basis to create this document. The group reviewed the available information for cases recorded in the radiation accident registries maintained by the Radiation Emergency Assistance Center/Training Site (REAC/TS), Oak Ridge, Tennessee, and the University of Ulm, Germany (6). This information was supplemented by outcomes of clinical management and therapy for cases reported in the scientific literature. Since no prospective, controlled clinical trials have been conducted in patients with acute radiation injury, the SNS Radiation Working Group reviewed management strategies used in accidental exposures of humans and evaluated results of prospective, controlled studies of acutely irradiated animals. In some cases, recommendations for therapy are based on results of animal studies. For radiologic terrorism events, definitive studies are required in animals to demonstrate impact on mortality and other clinical end points, according to requirements for licensure under the U.S. Food and Drug Administrations Animal Rule. In cases where the members of the SNS Radiation Working Group failed to achieve consensus, the alternatives are presented with relevant reference to the published literature. The Centers for Disease Control and Prevention provided funding to some of the participants for attendance at meetings. This support played no role in the composition, deliberations, or report of the SNS Radiation Working Group. Because new approaches to individual biodosimetry and therapy that will apply to treatment of acutely irradiated persons are likely to emerge, the SNS Radiation Working Group will review scientifically based guidance annually. Defining the Threat and Public Health Response The lethality of a nuclear device was demonstrated when a 15-kiloton improvised nuclear device was detonated over Hiroshima, Japan, in 1945, resulting in approximately 150000 casualties and 75000 fatalities (18). Virtually all survivors of Hiroshima had estimated exposure of less than 3 Gy (19). Recent review of data suggests that the mean lethal dose of radiation required to kill 50% of humans at 60 days (LD50/60) of whole-body radiation is between 3.25 Gy and 4 Gy in persons managed without supportive care and 6 to 7 Gy when antibiotics and transfusion support are provided (20). Although most radiation injuries in the past 50 years have been due to accidents, society must be prepared for the intentional detonation of nuclear or radiologic devices. Modern nuclear threats can be divided into 5 general categories: 1) an attack on nuclear power plants, 2) a malevolent act using simple radiologic devices, 3) terrorist use of a radiologic dispersal device or dirty bomb, 4) detonation of an improvised nuclear device, and 5) detonation of a sophisticated nuclear weapon (21). Whereas incidents involving simple devices and radiologic dispersal devices would probably cause a limited number of casualties, those involving improvised nuclear devices and small nuclear weapons would result in mass casualties. The Joint Commission on Accreditation of Healthcare Organizations and government leaders have mandated that the health care system develop plans to prepare for response to a radiologic terrorist event. The Hospital Emergency Incident Command System (22) provides a command and coordination approach that is useful for radiation response planning. Emergency plans should clarify authority, command, and control; define organizational responsibilities; develop procedures that integrate efforts of all response agencies; identify logistic support, supplies, and equipment; and assess incident conditions and consequences (23). Given the devastation that would accompany a nuclear detonation, plans should incorporate contingency planning for significant loss of infrastructure and health care personnel in the radiation field and its environs. Contingency planning should include relocation of victims to nearby operational hospitals and medical centers and activation of regional and state disaster plans that are coordinated with federal agencies. Approaches to radiologic monitoring, triage, and therapy for exposed populations will vary, depending on the number of casualties and resources available on the scene and in emergency treatment centers and hospitals. Although disaster planning is beyond the scope of this document, it is hoped that this clinical guideline defines a need for formalization and coordinated testing of such plans by hospitals and government agencies (see www.ncrp.com). Barriers to the provision of optimal medical care include limitation of resources, loss of infrastructure, a high volume of victims, and presence of combined injury. Allocation of potentially limited resources should be determined by the number of victims and their long-term prognosis. Estimation of individual radiation dose is recommended for determining survivability of patients in a range of doses that indicate predisposition to the acute radiation syndrome. Treatment recommendations are based on this dose range, which becomes increasingly narrower as the number of casualties increases and with the occurrence of combined injuries. Essentials of Radiation Exposure and Injury Radiation injury can occur from external irradiation; external contamination with radioactive materials; and internal contamination by inhalation, ingestion, or transdermal absorption with incorporation of radiologic materials into the bodys cells and tissues. These 3 types of exposure can occur in combination and can be associated with thermal burns and traumatic injuries. Injury from a nuclear detonation varies, depending on the location of the victim relative to the hypocenter and the consequent exposure to different types of energy. Three forms of energy are released from a nuclear detonation: heat, accounting for approximately 35% of total energy; shock or bomb blast, accounting for approximately 50% of total energy; and radiation, accounting for the remaining 15% of total energy. Heat and light cause thermal injury, including flash burns, flame burns, flash blindness (due to temporary depletion of photopigment from retinal receptors), and retinal burns. The blast wave results in fractures, lacerations, rupture of viscera, and pulmonary hemorrhage and edema. Radiation causes the acute radiation syndrome; cutaneous injury and scarring; chorioretinal damage from exposure to infrared energy; and, depending on radiation dose and dose rate, increased long-term risk for cancer, cataract formation (particularly with neutron irradiation), infertility, and fetal abnormalities (that is, growth retardation, fetal malformations, increased teratogenesis, and fetal death). We refer the reader to several excellent in-depth reviews of radiation effects (21, 23-25). The Acute Radiation Syndrome Studies in animals and humans exposed to radiation have allowed researchers to describe the acute radiation syndrome, also known as radiation sickness. The acute radiation syndrome occurs after whole-body or significant partial-body irradiation of greater than 1 Gy delivered at a relatively high-dose rate. The most replicative cells are the most sensitive to the acute effects of radiation, particularly spermatocytes, lymphohematopoietic elements, and intestinal crypt cells. The inherent sensitivity of these cells results in a constellation of clinical syndromes that predominates within a predictable range of doses of whole-body or significant partial-body exposure. Clinical components of the acute radiation syndrome include the hematopoietic, gastrointestinal, and cerebrovascular syndromes. The time course and severity of clinical signs and symptoms for the component syndromes at different dose ranges are reviewed in Figure 1. Each syndrome can be divided into 4 phases: prodromal, latent, manifest illness, and recovery or death. Figure 1. Approximate time course of clinical manifestations. GI CNS Depending on the absorbed dose, symptoms appear within hours to weeks, following a predictable clinical course. The prodromal phase of the acute radiation syndrome usually occurs in the first 48 hours but may develop up to 6 days after exposure. The latent phase is a short period characterized by improvement of sy

Peripheral-Blood Stem Cells versus Bone Marrow from Unrelated Donors

BACKGROUND Randomized trials have shown that the transplantation of filgrastim-mobilized peripheral-blood stem cells from HLA-identical siblings accelerates engraftment but increases the risks of acute and chronic graft-versus-host disease (GVHD), as compared with the transplantation of bone marrow. Some studies have also shown that peripheral-blood stem cells are associated with a decreased rate of relapse and improved survival among recipients with high-risk leukemia. METHODS We conducted a phase 3, multicenter, randomized trial of transplantation of peripheral-blood stem cells versus bone marrow from unrelated donors to compare 2-year survival probabilities with the use of an intention-to-treat analysis. Between March 2004 and September 2009, we enrolled 551 patients at 48 centers. Patients were randomly assigned in a 1:1 ratio to peripheral-blood stem-cell or bone marrow transplantation, stratified according to transplantation center and disease risk. The median follow-up of surviving patients was 36 months (interquartile range, 30 to 37). RESULTS The overall survival rate at 2 years in the peripheral-blood group was 51% (95% confidence interval [CI], 45 to 57), as compared with 46% (95% CI, 40 to 52) in the bone marrow group (P=0.29), with an absolute difference of 5 percentage points (95% CI, -3 to 14). The overall incidence of graft failure in the peripheral-blood group was 3% (95% CI, 1 to 5), versus 9% (95% CI, 6 to 13) in the bone marrow group (P=0.002). The incidence of chronic GVHD at 2 years in the peripheral-blood group was 53% (95% CI, 45 to 61), as compared with 41% (95% CI, 34 to 48) in the bone marrow group (P=0.01). There were no significant between-group differences in the incidence of acute GVHD or relapse. CONCLUSIONS We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD. (Funded by the National Heart, Lung, and Blood Institute-National Cancer Institute and others; ClinicalTrials.gov number, NCT00075816.).

HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry.

BACKGROUND Hematopoietic stem-cell transplantation (HSCT) is a potentially lifesaving therapy for several blood cancers and other diseases. For patients without a suitable related HLA-matched donor, unrelated-donor registries of adult volunteers and banked umbilical cord-blood units, such as the Be the Match Registry operated by the National Marrow Donor Program (NMDP), provide potential sources of donors. Our goal in the present study was to measure the likelihood of finding a suitable donor in the U.S. registry. METHODS Using human HLA data from the NMDP donor and cord-blood-unit registry, we built population-based genetic models for 21 U.S. racial and ethnic groups to predict the likelihood of identifying a suitable donor (either an adult donor or a cord-blood unit) for patients in each group. The models incorporated the degree of HLA matching, adult-donor availability (i.e., ability to donate), and cord-blood-unit cell dose. RESULTS Our models indicated that most candidates for HSCT will have a suitable (HLA-matched or minimally mismatched) adult donor. However, many patients will not have an optimal adult donor--that is, a donor who is matched at high resolution at HLA-A, HLA-B, HLA-C, and HLA-DRB1. The likelihood of finding an optimal donor varies among racial and ethnic groups, with the highest probability among whites of European descent, at 75%, and the lowest probability among blacks of South or Central American descent, at 16%. Likelihoods for other groups are intermediate. Few patients will have an optimal cord-blood unit--that is, one matched at the antigen level at HLA-A and HLA-B and matched at high resolution at HLA-DRB1. However, cord-blood units mismatched at one or two HLA loci are available for almost all patients younger than 20 years of age and for more than 80% of patients 20 years of age or older, regardless of racial and ethnic background. CONCLUSIONS Most patients likely to benefit from HSCT will have a donor. Public investment in donor recruitment and cord-blood banks has expanded access to HSCT. (Funded by the Office of Naval Research, Department of the Navy, and the Health Resources and Services Administration, Department of Health and Human Services.).

Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation

Invasive fungal infection (IFI) is a serious threat after allogeneic hematopoietic cell transplant (HCT). This multicenter, randomized, double-blind trial compared fluconazole (N = 295) versus voriconazole (N = 305) for the prevention of IFI in the context of a structured fungal screening program. Patients undergoing myeloablative allogeneic HCT were randomized before HCT to receive study drugs for 100 days, or for 180 days in higher-risk patients. Serum galactomannan was assayed twice weekly for 60 days, then at least weekly until day 100. Positive galactomannan or suggestive signs triggered mandatory evaluation for IFI. The primary endpoint was freedom from IFI or death (fungal-free survival; FFS) at 180 days. Despite trends to fewer IFIs (7.3% vs 11.2%; P = .12), Aspergillus infections (9 vs 17; P = .09), and less frequent empiric antifungal therapy (24.1% vs 30.2%, P = .11) with voriconazole, FFS rates (75% vs 78%; P = .49) at 180 days were similar with fluconazole and voriconazole, respectively. Relapse-free and overall survival and the incidence of severe adverse events were also similar. This study demonstrates that in the context of intensive monitoring and structured empiric antifungal therapy, 6-month FFS and overall survival did not differ in allogeneic HCT recipients given prophylactic fluconazole or voriconazole. This trial was registered at www.clinicaltrials.gov as NCT00075803.

Adverse events among 2408 unrelated donors of peripheral blood stem cells: results of a prospective trial from the National Marrow Donor Program

Limited data are available describing donor adverse events (AEs) associated with filgrastim mobilized peripheral blood stem cell (PBSC) collections in unrelated volunteers. We report results in 2408 unrelated PBSC donors prospectively evaluated by the National Marrow Donor Program (NMDP) between 1999 and 2004. Female donors had higher rates of AEs, requiring central line placement more often (17% vs 4%, P< .001), experiencing more apheresis-related AEs (20% vs 7%, P< .001), more bone pain (odds ratio [OR]=1.49), and higher rates of grades II-IV and III-IV CALGB AEs (OR=2.22 and 2.32). Obese donors experienced more bone pain (obese vs normal, OR=1.73) and heavy donors had higher rates of CALGB toxicities (>95 kg vs <70 kg, OR=1.49). Six percent of donors experienced grade III-IV CALGB toxicities and 0.6% experienced toxicities that were considered serious and unexpected. Complete recovery is universal, however, and no late AEs attributable to donation have been identified. In conclusion, PBSC collection in unrelated donors is generally safe, but nearly all donors will experience bone pain, 1 in 4 will have significant headache, nausea, or citrate toxicity, and a small percentage will experience serious short-term adverse events. In addition, women and larger donors are at higher risk for donation-related AEs.

A perspective on the selection of unrelated donors and cord blood units for transplantation

Selection of a suitable graft for allogeneic hematopoietic stem cell transplantation involves consideration of both donor and recipient characteristics. Of primary importance is sufficient donor-recipient HLA matching to ensure engraftment and acceptable rates of GVHD. In this Perspective, the National Marrow Donor Program and the Center for International Blood and Marrow Transplant Research provide guidelines, based on large studies correlating graft characteristics with clinical transplantation outcomes, on appropriate typing strategies and matching criteria for unrelated adult donor and cord blood graft selection.

One million haemopoietic stem-cell transplants: a retrospective observational study

BACKGROUND The transplantation of cells, tissues, and organs has been recognised by WHO as an important medical task for its member states; however, information about how to best organise transplantation is scarce. We aimed to document the activity worldwide from the beginning of transplantation and search for region adapted indications and associations between transplant rates and macroeconomics. METHODS Between Jan 1, 2006, and Dec 31, 2014, the Worldwide Network for Blood and Marrow Transplantation collected data for the evolution of haemopoietic stem-cell transplantation (HSCT) activity and volunteer donors in the 194 WHO member states. FINDINGS 953,651 HSCTs (553,350 [58%] autologous and 400,301 [42%] allogeneic) were reported by 1516 transplant centres from 75 countries. No transplants were done in countries with fewer than 300,000 inhabitants, a surface area less than 700 km(2), and a gross national income per person of US

Twenty Years of Unrelated Donor Hematopoietic Cell Transplantation for Adult Recipients Facilitated by the National Marrow Donor Program

1260 or lower. Use of HSCT increased from the first transplant in 1957 to almost 10,000 by 1985. We recorded a cumulative total of about 100,000 transplants by 1995, and an estimated 1 million by December, 2012. Unrelated donor registries contributed 22·3 million typed volunteer donors and 645,646 cord blood products by 2012. Numbers of allogeneic HSCTs increased in the past 35 years with no signs of saturation (R(2)=0·989). Transplant rates were higher in countries with more resources, more transplant teams, and an unrelated donor infrastructure. INTERPRETATION Our findings show achievements and high unmet needs and give guidance for decisions; to grant access for patients, to provide a donor infrastructure, and to limit overuse by defining risk and region adapted indications for HSCT as an efficient and cost-effective approach for life-threatening, potentially curable diseases. FUNDING Funding for this study was indirectly provided by support of the WBMT.

Donor, recipient, and transplant characteristics as risk factors after unrelated donor PBSC transplantation: beneficial effects of higher CD34 + cell dose

For more than 20 years the National Marrow Donor Program has facilitated unrelated donor hematopoietic cell transplants for adult recipients. In this time period, the volunteer donor pool has expanded to nearly 12 million adult donors worldwide, improvements have occurred in the understanding and technology of HLA matching, there have been many changes in clinical practice and supportive care, and the more common graft source has shifted from bone marrow (BM) to peripheral blood stem cells (PBSCs). The percentage of older patients who are receiving unrelated donor transplants is increasing; currently over 1 in 10 adult transplant recipients is over the age of 60 years. Chronic myelogenous leukemia (CML) was previously the most common diagnosis for unrelated donor transplantation, but it now comprises less than 10% of transplants for adult recipients. Transplants for acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), and myelodysplastic syndromes (MDS) all outnumber CML. Treatment-related mortality (TRM) has declined significantly over the years, particularly in association with myeloablative transplant preparative regimens. Correspondingly, survival within each disease category has improved. Particularly gratifying are the results in severe aplastic anemia (AA) where 2-year survival has doubled in just 10 years.

Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation.

We report outcomes of 932 recipients of unrelated donor peripheral blood stem cell hematopoietic cell transplantation (URD-PBSC HCT) for acute myeloid leukemia, acute lymphoblastic leukemia, chronic myelogenous leukemia, and myelodysplastic syndrome enrolled on a prospective National Marrow Donor Program trial from 1999 through 2003. Preparative regimens included myeloablative (MA; N = 611), reduced-intensity (RI; N = 160), and nonmyeloablative (NMA; N = 161). For MA recipients, CD34(+) counts greater than 3.8 x 10(6)/kg improved neutrophil and platelet engraftment, whereas improved overall survival (OS) and reduced transplant-related mortality (TRM) were seen for all preparative regimens when CD34(+) cell doses exceeded 4.5 x 10(6)/kg. Higher infused doses of CD34(+) cell dose did not result in increased rates of either acute or chronic graft-versus-host disease (GVHD). Three-year OS and disease-free survival (DFS) of recipients of MA, RI, and NMA approaches were similar (33%, 35%, and 32% OS; 33%, 30%, and 29% DFS, respectively). In summary, recipients of URD-PBSC HCT receiving preparative regimens differing in intensity experienced similar survival. Higher CD34(+) cell doses resulted in more rapid engraftment, less TRM, and better 3-year OS (39% versus 25%, MA, P = .004; 38% versus 21% RI/NMA, P = .004) but did not increase the risk of GVHD. This trial was registered at www.clinicaltrials.gov as #NCT00785525.