1. RITN Radiation Grand RoundsRev. 2 2008 Delete this slide prior to presenting. Use the speaker notes provided for additional details about each slide, not all slides have notes prepared. Presenters; for questions or comments about this presentation please contact: Cullen Case | ccase@nmdp.org | 612.884.8402 David Weinstock, M.D. | DavidM_Weinstock@DFCI.HARVARD.EDU | 617.632.4245ccase@nmdp.orgDavidM_Weinstock@DFCI.HARVARD.EDU

2. Medical Response to Radiation Exposure: the Role of Hematologists Presenter Affiliation Date

3. RITN Radiation Grand RoundsRev. 2 2008 Agenda Describe the Radiation Injury Treatment Network Radiological Event Scenarios Radiation Basics Radiation Biology/Acute Radiation Syndrome Biodosimetry Incident Response Treatment Available resources

4. RITN Radiation Grand RoundsRev. 2 2008 4 Radiation Injury Treatment Network (RITN) Network of 36 stem cell transplant centers, 9 donor centers, and 7 umbilical cord blood banks Partnership between: –National Marrow Donor Program –American Society for Blood and Marrow Transplantation

5. RITN Radiation Grand RoundsRev. 2 2008 5 Radiation Injury Treatment Network (RITN) The goals of RITN are to: –educate hematologists, oncologists, and stem cell transplant practitioners about their potential involvement in the response to a radiation event –provide treatment expertise in the aftermath of a radiation event RITN centers are NOT…. –First responders –Victim triage experts –Decontamination specialists

6. RITN Radiation Grand RoundsRev. 2 2008 6 Not RITN Source: http://www.wdhr.com/news/uploaded_images/100_3114-737293.JPG

7. RITN Radiation Grand RoundsRev. 2 2008 7 Location of RITN Centers

8. RITN Radiation Grand RoundsRev. 2 2008 8 Radiation Injury Treatment Network (RITN) In the aftermath of a radiological event, RITN centers may be asked to: –Accept patient transfers to their institutions –Provide treatment expertise to practitioners caring for victims at other centers –Travel to other centers to provide medical expertise –Provide data on victims treated at their centers

9. RITN Radiation Grand RoundsRev. 2 2008 9 RITN Efforts Standard Operating Procedures Standardized admission and treatment orders Standardized data collection protocol Training Coordination with international organizations Conduct readiness exercises Emergency communications equipment

10. RITN Radiation Grand RoundsRev. 2 2008 Radiological Event Scenarios 10

11. RITN Radiation Grand RoundsRev. 2 2008 11 Radiological Events Weinstock et al. Blood 2008. EventsDescriptionAnticipated deaths Radioactive source accident Loss or theft of a radiological source (e.g. Goiania) 0-100s Nuclear reactor accident Release of radioactive gas or material (e.g. Chernobyl) 0-1,000s Radiological dispersal device Device or scheme for dispersing radioactive isotope (e.g., dirty bomb or radioactive material in the food supply) 0-100s Radiological exposure device (open source) Radioactive material intended to expose people in the vicinity (e.g. Cesium source on a train) 100s-1,000s Improvised nuclear device Incorporates radioactive material intended to produce a low yield nuclear explosion 1,000s-1,000,000s Military-grade nuclear device Incorporates radioactive material intended to produce a fusion detonation 1,000,000s

12. RITN Radiation Grand RoundsRev. 2 2008 12 Threat Planning by the U.S. Government 1)10-Kiloton Improvised Nuclear Device 2)Aerosol Anthrax 3)Pandemic Influenza 4)Plague 5)Blister Agent 6)Toxic Industrial Chemicals 7)Neurotoxin 8)Chlorine Tank Explosion 9)Major Earthquake 10) Major Hurricane 11) Radiological Dispersal Devices 12) Improvised Explosive Devices 13) Food Contamination 14) Foreign Animal Disease (Foot and Mouth Disease) 15) Cyber Attack http://media.washingtonpost.com/wpsrv/nation/nationalsecurity/earlywarning/NationalPlanningScenariosApril2005.pdf

13. RITN Radiation Grand RoundsRev. 2 2008 13 Alexander Litvinenko –Fell ill November 1, 2006 –Died November 23, 2006 –Ingestion of 1 mg of Polonium-210 Isotope Ingestion

14. RITN Radiation Grand RoundsRev. 2 2008 14 Open Source Exposure Taiwanese graduate student –October 1994 - February 1996 –Survived attempts by fellow student to poison with 32 P and other chemicals Taiwan scientist rivalry –In 2003, a nuclear scientist planted Iridium-192 pellets in the office of a business rival –Sickened the rival and 74 other people

15. RITN Radiation Grand RoundsRev. 2 2008 15 Open Radiation Sources Goiania, Brazil – 1987 –Cesium-137 source taken from vacant clinic –Source opened to separate metals to sell to recycler –Glowing blue Cesium handled by adults and children –28 cases of radiation sickness –112,000 people screened Russia -2002 & 2003 –Nuclear generators used to power remote lighthouses –Generators are unguarded and frequently stolen/vandalized by scrap metal hunters –Russia has 1000 of these generators –Many incidents have occurred resulting in exposed cores and injuries

16. RITN Radiation Grand RoundsRev. 2 2008 16 Contaminated soil for extended storage in Goiania, Brazil Temporary concrete storage of contaminated materials in Goiania, Brazil Decontamination

17. RITN Radiation Grand RoundsRev. 2 2008 17 Open Radiation Sources North America – 1984 –Cobalt-60 pellets from junked radiotherapy device –Recycled into steel and used for construction –>200 people exposed from Mexico to Illinois –1 fatality, 4 injuries –109 homes demolished as part of decontamination

18. RITN Radiation Grand RoundsRev. 2 2008 18 Houston, TX – 1980 (7 fatalities) Columbus, OH – 1974-76 (10 fatalities, 78 injuries) Epinal, France – 2004-05 (1 fatality, 13 injuries) Panama City, Panama – 2000-01 (17 deaths, 11 injuries) Miscalibrated Radiotherapy Devices

19. RITN Radiation Grand RoundsRev. 2 2008 19 Radiological Dispersal Device (RDD) Chechen Rebels, 1995 –Planted cesium and explosives device in a playground –Notified local TV station –Never detonated Chechen Rebels 1998 –Chechen Security Service renders safe a dirty bomb planted next to a railway line

20. RITN Radiation Grand RoundsRev. 2 2008 20 Theft or Loss of Radiological Materials Reported to the IAEA Source of graph: IAEA 2006 Illicit Trafficking Database Report 10 million radiation sources worldwide

21. RITN Radiation Grand RoundsRev. 2 2008 21 Interpreted from the U.S. National Planning Scenarios found on www.washingtonpost.com 10 kiloton Improvised Nuclear Device detonation - Scenario planning

22. RITN Radiation Grand RoundsRev. 2 2008 22 Interpreted from the U.S. National Planning Scenarios found on www.washingtonpost.com Limited survival due to: 1)Overpressure (blast) 2)Thermal damage 3)Prompt radiation 10 kiloton Improvised Nuclear Device detonation - Scenario planning 0.5 mi

23. RITN Radiation Grand RoundsRev. 2 2008 23 Interpreted from the U.S. National Planning Scenarios found on www.washingtonpost.com Limited survival due to: 1)Overpressure (blast) 2)Thermal damage 3)Prompt radiation Fallout over 24 hours 1)> 400 REM exposure 2)202,000 non-fatal casualties (40,000 hospital beds in US) 3)180,000 fatalities 10 kiloton Improvised Nuclear Device detonation - Scenario planning 0.5 mi 9 miles

24. Comparison of Intensities of Detonations Yield Height (x 1000 feet) Height (x 1000 meters) 0 = Approximate altitude band commercial aircraft use 1 = Fat Man 22.5 kilotons (Nagasaki). Little Boy (Hiroshima) was ~10-15 kilotons. 2 = Castle Bravo 15 megatons (1st US nuclear bomb test on Bikini Atoll)

25. RITN Radiation Grand RoundsRev. 2 2008 Radiation Basics 25

26. RITN Radiation Grand RoundsRev. 2 2008 26 Types of Ionizing Radiation

27. RITN Radiation Grand RoundsRev. 2 2008 27 Radioactive Contamination Internal contamination requires medical decorporation 90% of external contamination can be cleansed by removing clothing and washing exposed body parts

28. RITN Radiation Grand RoundsRev. 2 2008 28 Reducing Radiation Exposure 3 steps for protection: 1) Keep your DISTANCE 2) Limit your TIME exposed 3) SHIELD yourself from exposure

29. RITN Radiation Grand RoundsRev. 2 2008 29 Protection from Radiation Protective Not protective

30. RITN Radiation Grand RoundsRev. 2 2008 Acute Radiation Syndrome 30

31. RITN Radiation Grand RoundsRev. 2 2008 31 Acute Radiation Syndrome Weeks After Exposure 123456780 0 2 4 6 8 10 0% 50% 100% Prodromal nausea/vomiting GI symptoms Onset of signs of hematopoietic injury Approximate time of death 100% mortality (may be higher dose with HSCT) >100 CNS injury (100% mortality within days) Mortality Radiation dose (Gy)

32. RITN Radiation Grand RoundsRev. 2 2008 32 Toxicity is Proportional to Dose LD 50 for humans: LD 50 is the level of exposure that is lethal to 50% of people exposed to that dose –3.5 to 4 Gy Without supportive care However the use of antibiotics and transfusions may decrease the chance of morbidity –4.5 to 7 Gy With antibiotics, transfusions and other supportive care –Greater than 10 Gy With HSCT In a radiation incident, shielding will result in heterogenous body dosing

33. RITN Radiation Grand RoundsRev. 2 2008 33 Acute Radiation Syndrome - Combined Injury Most victims with significant injury will have multi-organ dysfunction –Trauma/wounds/burns –Gastrointestinal –Hematologic –Neurologic –Psychiatric

34. RITN Radiation Grand RoundsRev. 2 2008 34 Acute Radiation Syndrome - Neurovascular SymptomsDegree of severity 1 to 4 NauseaMild to excruciating Vomiting1 per day to >10 times per day AnorexiaAble to drink to requiring parenteral nutrition FatigueNormal activity to prevents activity HeadacheMinimal to intense Neurological deficitsNo deficits to unarousable

35. RITN Radiation Grand RoundsRev. 2 2008 35 SymptomsDegree of severity 1 to 4 Diarrhea - frequencyTwice/day >10 times/day Stool - consistencyBulky to watery Blood in stoolsOccult to gross hemorrhage Abdominal pain/crampsMinimal to excruciating NauseaMild to excruciating Vomiting1 per day to >10 times per day Acute Radiation Syndrome - Gastrointestinal

36. RITN Radiation Grand RoundsRev. 2 2008 36 Acute Radiation Syndrome - Cutaneous SymptomsDegree of severity 1 to 4 ErythemaMinimal to severe Altered sensation/ItchingPruritis to severe EdemaAsymptomatic to total dysfunction BlisteringRare to bullae with hemorrhage DesquamationAbsent to confluent Ulcer/necrosisEpidermal only to muscle/bone Hair lossThinning to complete OnycholysisAbsent to complete

37. RITN Radiation Grand RoundsRev. 2 2008 37 Cutaneous Injuries from Open Sources

38. RITN Radiation Grand RoundsRev. 2 2008 38 Acute Radiation Syndrome - Hematopoietic

39. RITN Radiation Grand RoundsRev. 2 2008 Biodosimetry 39

40. RITN Radiation Grand RoundsRev. 2 2008 40 Biodosimetry Tools Definition –Biodosimetry is the use of biological markers to estimate dose –Dosing after radiological and nuclear events is complicated by a variety of factors, including shielding Standard approaches –Lymphocyte Depletion Kinetics –Dicentric Chromosomes in Peripheral Blood Lymphocytes Research approaches –Proteomics –Markers of DNA damage

41. RITN Radiation Grand RoundsRev. 2 2008 41 From: CDC Radiological Terrorism Emergency Management Pocket Guide for Clinicians Pocket Guide: www.bt.cdc.gov/radiation/pocket.asp ARS – Time to vomiting as a marker of dose

42. RITN Radiation Grand RoundsRev. 2 2008 42 Acute Radiation Syndrome - Lymphocyte Kinetics

43. RITN Radiation Grand RoundsRev. 2 2008 43 Biodosimetry Tools AFRRI Biodosimetry Assessment Tool (BAT) –Downloadable software Radiation Event Medical Management (REMM) www.remm.nlm.gov www.remm.nlm.gov –Web-based software –Provides suggested treatments based on estimated dose –Standardized admission and treatment order templates

44. RITN Radiation Grand RoundsRev. 2 2008 44

45. RITN Radiation Grand RoundsRev. 2 2008 Incident Response 45

46. RITN in Federal Response Planning: Improvised Nuclear Device MC AC MC Evacuation centers RTR3 (collection) AC RTR1 (collection) AC RITN center Modified from Weinstock et al. Blood 2008 RTR1 (blast) RTR2 (plume) MC RTR2 (plume) Ambulatory Critical

47. RITN Radiation Grand RoundsRev. 2 2008 Hematopoietic Stem Cell Transplantation After a Radiological Event 47

48. RITN Radiation Grand RoundsRev. 2 2008 HSCT After a Radiological Event Affected population Marrow injury Potentially irreversible marrow injury Salvageable Minimal combined injury Expedited HLA typing Myeloablation Available donor Acceptable pre-transplant condition HSCT Supportive care 48 RITN Treatment Support

49. RITN Radiation Grand RoundsRev. 2 2008 Management of Urgent Donor Searches NMDP-contracted HLA laboratories: –Currently perform 5-6,000 HLA typings weekly but could be increased to more than 10,000 assuming HLA is prioritized over other work –Data is transmitted directly from the labs to NMDP via Internet –Use automated matching of adult donors/CBUs to potential transplant recipients 49

50. RITN Radiation Grand RoundsRev. 2 2008 Management of Urgent Donor Searches NMDP-computer systems: –Facilitate contact, communication and coordination with the adult donors/CBU banks –Are available 24x7 to meet the demands of the increased search load HapLogic uses advanced logic to predict high- resolution matches –Easier identification of donors and/or CBUs most likely to match patients –Reduction in the number of donors called for testing that would be unlikely to match the patient –Faster matches for some patients, which may mean getting to transplant sooner resulting in improved survival 50

51. RITN Radiation Grand RoundsRev. 2 2008 51 Hematopoietic Stem Cell Transplantation for Acute Radiation Syndrome 31 patients have undergone allogeneic HSCT after accidental radiation exposure Median survival after transplant ~ 1 month All four patients who survived one year reconstituted autologous hematopoiesis Graft-versus-host-disease contributed to mortality in >20% Weinstock et al. Blood 2008.

52. RITN Radiation Grand RoundsRev. 2 2008 52 Standardized RITN regimen: –Reduced intensity conditioning, based on the Blood and Marrow Transplant Clinical Trials Network (BMT CTN Protocol 0301) Weinstock et al. Blood 2008. G-CSF Mycophenolate, d -3 to +30 Cyclosporine or tacrolimus, days -3 to +100 -3-2-4-7-6-5301000 Cyclophosphamide 50 mg/kg Fludarabine 30 mg/m 2 Anti-thymocyte globulin (Thymoglobulin ® ) 3 mg/kg -3-2-4Day -7-6-5+30+1000 Allograft infusion Hematopoietic Stem Cell Transplantation for Acute Radiation Syndrome

53. RITN Radiation Grand RoundsRev. 2 2008 53 Data Collection Protocol Incorporated into standard NMDP data collection protocol Will feed consistent information for review after an event Will track progress of victims –Online data entry –Real-time feedback of data

54. RITN Radiation Grand RoundsRev. 2 2008 54 What RITN is Doing to Prepare Standard Operating Procedures Standardized admission and treatment orders Training –Basic radiation training (over 700 completed in 2007) –Training resources on the RITN Web site (www.RITN.net)www.RITN.net Organize coordination with international organizations Conduct readiness exercises –Annual tabletop exercise –Participate in national exercises (TOPOFF 4, Pinnacle 07) Emergency communications equipment –GETS cards and satellite telephones

55. RITN Radiation Grand RoundsRev. 2 2008 55 Summary There are a variety of event scenarios Hematologists, oncologists, and stem cell transplant experts may be called upon to care for victims Have a plan and get involved!

56. RITN Radiation Grand RoundsRev. 2 2008 56 Resources for further investigation Incidents: –IAEA nuclear events list: http://www-news.iaea.org/news/http://www-news.iaea.org/news/ –www.johnstonsarchive.net/nuclear/radevents/index.htmlwww.johnstonsarchive.net/nuclear/radevents/index.html Treatment: –Radiation Injury Treatment Network (RITN): www.RITN.netwww.RITN.net –Radiation Event Medical Management (REMM): www.remm.nlm.govwww.remm.nlm.gov –Radiation Emergency Assistance Center/Training Site (REAC/TS): www.orau.gov/reacts www.orau.gov/reacts –Radiation Countermeasures Center of Research Excellence (RadCCORE): www.radccore.orgwww.radccore.org Bio-dosimetry & Treatment: –Armed Forces Radiobiology Research Institute (AFRRI): www.afrri.usuhs.mil www.afrri.usuhs.mil Other: –IAEA Library: http://www.iaea.org/DataCenter/Library/catresources.html http://www.iaea.org/DataCenter/Library/catresources.html

57. 57 For treatment guidelines, references: www.REMM.NLM.gov www.RITN.net