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Medical Management of Radiological & Nuclear Events: The Place of Bone Marrow Transplantation

This course discusses the role of bone marrow transplantation in large radiation incidents, covering scenarios, secondary triage, treatment options, and what the EBMT can offer in such events.

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Medical Management of Radiological & Nuclear Events: The Place of Bone Marrow Transplantation

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  1. 4th International Expert Course on the Medical Management of Radiological and Nuclear Events Stockholm 15-17th May 2013 The Place Of Bone Marrow Transplantation in Large Radiation incidents Prof Ray Powles Chairman European Blood Marrow Transplant EBMT Nuclear Accident Committee Head Haemato-oncology Cancer Centre London

  2. Background

  3. European Blood and Marrow Transplant EBMT Nuclear Accident Committee • `Formed after 9/11 because it was proposed to the EBMT Board.... ............that our 500 BMT Centres may be a useful resource in the event of a massive terrorist radiation incident

  4. EBMT Network • All 500 BMT centres in 27 EU countries • World Health Organisation (Collaborating Centre • IAEA • United States Radiation Injury Treatment Network (RITN) Memorandum of Understanding (MUO) • Since Fukushima......extending network • India Pakistan • Saudi Iran Israel • China Taiwan Japan Korea • Russia USA

  5. Plan of the Talk • Scenarios • Secondary Triage • Treatment • Allografting • Autografting • RDD • What can the EBMT offer

  6. Possible Large Scenarios100-3000+ victims • Nuclear Power station Failure Fukushima Cherobyl • Terrorist incidents

  7. Radiation Exposure Devise • RED – Radiological Exposure / Emplaced Device • Taking a physically small but intense radioactive source and putting somewhere to expose people

  8. Attack on a Nuclear Site • Taking something ‘large and energetic’ and impacting it on a nuclear site • Nuclear reactors are incredibly strong • A nuclear explosion is technically impossible

  9. Improvised Nuclear Device • Needs resources of a nation state to produce a feasible nuclear weapon (Iran) • But with enough correct material and knowledge an improvised device could be made with a much lower yield

  10. The U.S. government is planning to respond to a 1 and 10 kiloton (IND) improvised nuclear device (terrorist nuclear bomb) Affected Population

  11. So lets go into more detail how EBMT can help in a major radiation incident

  12. the key to primary triage Covert (obvious)......1/ move from source 2/ then decontaminate 3/ assess acute co-morbidities Overt (hidden)............ more complex? 1/ Disseminated from Metro incident 2/ Atom Bomb Flee in chaos from fall-out zone

  13. Structural, radiation and medicalresponse zones RTR – Radiation TRiage, TReatment, TRansportation, TRansplantation

  14. Plan of the Talk • Scenarios • Secondary Triage • Treatment • Allografting • Autografting • RDD • What can the EBMT offer

  15. Secondary triage • How do we identify a group of irradiated patients that will develop bone marrow failure • In whom treatment can savethem? i.e. NOT those who will die anyway, or have had minimal irradiation

  16. Biological Dosimetry Assays Not logistically feasible for large radiation incidents But a few marker patients might map out picture of dose distribution • Cytogenetic Assays currently available and calibrated: • Dicentrics • Micronuclei • FISH translocations • Premature chromosomal condensation • Others ‘on the near horizon’: • Serum biomarkers • γH2AX foci • genomic markers David Lloyd - HPA

  17. Tokaimura Accident • September 30th 1999 • 3 victims exposed to substantial amount mixed neutron/photon ionizing irradiation • 2 received stem cell transplantation (matched sister and cord blood) within 10 days • Both engrafted with mixed chimerism • Both died (83 and 211 days) of multi-organ failure

  18. Wall B A C Ｗ Floor

  19. Prodromal Symptoms of Three Workersat the Tokai-mura accident Worker A 8Gy+ Nausea, Vomiting Diarrhea Loss of consciousness High fever (38.5 ℃) < 10 min < 60 min last for 10-20 sec Worker B 6Gy+ Nausea, Vomiting ≒1 hr a few hr Worker C 2-3GY Nausea

  20. Clinical PictureTokaï-Mura Accident ( Japan 1999) 8Gy+ Aplasia Hemophagocytosis PBSCT Haematopoietic syndrome GI bleeding Diarrhoea Gastrointestinal disease Erythema, Blister Massive exudate Cutaneous syndrome Lung disease Lung oedema Renal Failure Liver dysfunction 1 2 3 4 5 6 7 8 9 10 11 Time after irradiation (weeks) Death

  21. General Principles for ‘Accidental’ exposure to irradiation Small numbers of victims ? Contamination Inhalation Other injuries HETEROGENEOUS EXPOSURE. Great difficulty working out dose Since 1945……at least 800 victims with Acute Radiation Sickness in …….. 70 instances

  22. Biological effects of accidental irradiation • Prof Ted Fleidner WHO REMPAN Centre Ulm • SEARCH programme • Since 1945 found 800 radiation victims in 70 incidents worldwide • He devised a scoring system to determine clinically whether the victim would • a/ die regardless of any treatment • b/ survive if appropriate treatment given • c/ not need any treatment

  23. Initial (1st 48 hrs) Biological effects of irradiation • Haematological • Cutaneous • Gastrointestinal • Central nervous system

  24. But a new approach was needed if a very large incident occurred

  25. EBMT Consensus Pocket Guide • On EBMT Website.......... ...........Google EBMT and go to NAC

  26. Organ specific checklists Blood count anytime L: Reference value: (1.5-4) x 109/l G: Reference value: (4-9) x 109/l T: Reference value: (140-400) x 109/l T.M. Fliedner et al., Br J Radiol. 2001

  27. Granulocyte/Platelet changes in 17 patients characteristic for Grade H4 (essentially irreversible damage of stem cell pool) Courtesy: Prof T Fliedner

  28. the key to secondary triage • ........firstly do leukocyte counts. • Secondarily........clinical manifextations

  29. Summary of Pocket Guide • Score 1.... no treatment needed (less than 1Gy?).... • Score 2.....support only (2Gy-5Gy?) • Score 3... stem cell transplant....... (6Gy-9Gy?)......... • BUT it is the clinical score that counts, not the dose estimation

  30. Plan of the Talk • Scenarios • Secondary Triage • Treatment • Allografting • Autografting • RDD • What can the EBMT offer

  31. Treatment • In a pragmatic world the key to treatment is not bone marrow transplantation • Give marrow failure support......antibiotics etc

  32. Haemopoetic support • Almost exactly the same as for treating AML, or Aplastic Anaemia.. • Clean single room with clean air • Washing hands etc • Antibiotics • Antifungals • Antivirals • Blood Products • And........immunoglogulins etc

  33. Plan of the Talk • Scenarios • Secondary Triage • Treatment • Allografting • Autografting • RDD • What can the EBMT offer

  34. Indications for transplant(allotransplantation) • Background.........previous attempts

  35. Biological effects of accidental irradiation • Prof Ted Fleidner (SEARCH) • Since 1945 found 800 radiation victims in 70 incidents worldwide • Of these found 48 patients from 14 radiation incidents receiving haemopoetic stem cell transplants

  36. Radiation Accidents from 1958-1999(48 transplants, 14 incidents): ~20 yrs old Location Date # ARS Victims # HSC HSC source Vinca, YU 10/15/58 6 5 marrow Obnisnsk, RU 11/2/62 1 1 marrow Arzamas,RU 3/11/63 2 1 marrow Pittsburgh, US 10/2/67 3 1 marrow Sungul, RU 4/5/68 2 2 marrow Chelyabinsk,RU 12/10/68 2 2 marrow Sormovo, RU 1/18/70 5 2 marrow Moscow, RU 5/26/71 4 3 marrow Shanghai, CN 9/1/80 1 fetal liver cells Chernobyl, UA 4/26/86 234 22 marrow, fetal Kaifun, CN 5/26/86 2 1 fetal Sor-Van, IS 6/21/90 1 1 marrow Shanghai, CN 6/25/90 4 4 marrow, liver Tokai-Mura, JP 9/30/99 3 2 peripheral blood, liver Courtesy: Prof Fliedner

  37. 48 Stem Cell Transplants 23/48 (48%) died post transplant within within 50 days 9 had evidence of ‘engraftment’ 16 patients had evidence of autologous recovery Death due to multi-organ failure. Transplant related or acute radiation?

  38. Possible Mechanisms for MOF in Radiation Paralysis of Cell-Mediated Immune Responses (Excessive) Systemic Inflammatory Response Syndrome (SIRS) Systemic Inflammation Sepsis Multiple Organ Failure From Dr Makoto Akashi High-dose Radiation Bleeding Bone Marrow Failure Infection Tissue Damage Disturbance in Microcirculation Endothelial Cell Damage MODS Parenchymal Cell Damage ( Loss of electrolytes )

  39. HSCT for Acute Radiation Syndrome Non-myeloablativeregimen, EBMT NAC HSCT Fludarabine 30mg/m2 ATG 2 mg/m2 -3 -8 -7 -6 -5 -4 -2 -1 0 +14 +21 +100 +180 CSA ( level>150µg/L) - 3 to > +100 MMF (30mg/kg/day)- 3 to + 30 • Eligibility: • Sibling • Unrelated • Cord G-CSF In some protocols

  40. Ann Intern Med 2009; 150:132-138 Choosing an allocation model is a huge challenge

  41. Stem Cell Transplantation ? Never an emergency! Not if MODS Always consider heterogeneity of irradiation and possibility of autologous hematopoietic recovery. Immediate typing Transplant - never before day 14-21 Low immunosuppression: fludarabine ± ATG CSA+MMF. No MTX High cell dose

  42. Pocket Guide Indications for transplant(allotransplantation) • Wait 14-21 days of G-CSF treatment • No co-morbidity • potential donor • Score 3 pocket guide (no circulating neutrophils)

  43. Plan of the Talk • Scenarios • Secondary Triage • Treatment • Allografting • Autografting • RDD • What can the EBMT offer

  44. Indications for autologous transplant • Questions....... • Is multi-organ failure an inevitable consequence of accidental irradiation? • Does autografting makes a difference? i.e. Workers that have stem cells taken before exposure

  45. Background to Fukushima • March 2010 • EBMT mobilized 120 centres in 48 hrs (a further 72 centres agreed to store autologous SC) Current situation at Fukushima..... • Sources still uncontrolled

  46. Members UK Steering Committee • Penny Bevan • Ray Powles • Anthony Bleetman • Bhawna Sirohi • Celia Kendrick • Darren Walter • David Marks • David Temperton • Hilary.Walker • Lesley Prosser • Margaret Spittle • Monika Temple • Richard Rackham nhsbt. • Tony Pagliuca • Verity Kemp • David Brown • Corinne Perry • Chris Hayes

  47. The Place of collecting autologous stem cells after a large radiation incident • Huge controversy after Fukushima Should we collect and store Stem Cells from workers? who may subsequently need to go near a radioactive source to neutralize it? • EBMT NAC meeting March 2011 • EBMT NAC meeting June 2011 • COSTEM July 2011

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