The role of hematopoietic stem cell transplantation in treatment of radiation exposure

by Alexey Bersenev on May 25, 2011 · 0 comments

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Intro:
Because of recent Japanese Fukushima nuclear disaster, I was trying to investigate the significance of stem cell transplantation in treatment of severe radiation exposure. I’ve proposed to select rescue workers based on data about available HLA-matched sample in Japanese bone marrow registry. But, probably, the best solution could be the harvest of autologous hematopoietic stem cells (HSC), mobilized in peripheral blood, before the rescue operation and use it in case of dangerous radiation exposure. Japanese hematologists proposed this in the recent Lancet article:

On March 25, we proposed the collection and storage of autologous peripheral-blood stem cells (PBSCs) for the nuclear workers in Fukushima in case of accidental major radiation exposure. This scheme has several advantages. First, autologous PBSC transplantation does not cause GVHD, which further exacerbates gut injury mediated by radiation exposure. Second, it does not require immunosuppressants, which make radiation victims more susceptible to severe infections. Third, PBSCs can induce more rapid haemopoietic recovery than can haemopoietic growth-factor support alone or bone-marrow cells. Fourth, they are easy to store by cryopreservation. Fifth, the short-term and long-term safety of this PBSC-collecting procedure has been confirmed in a large number of healthy donors for patients with haematological cancers. Finally, long-term autologous PBSC banking might also have a therapeutic role for possible leukaemia in future, because radiation is a well known carcinogen in the long term.

This approach was highly discussed in the mass media. Despite discussion, it still unclear (correct me if I’m wrong) whether or not this approach will be applied. You can follow updates from this blog – Blood Stem Cell Collection for Workers in Fukushima Nuclear Plant. Obviously, proposal has raised some questions, such as: Will collected HSC actually be used? Will these HSC helpful in case of multi-organ failure and burns? Will it be cost-effective? Finally:

The Nuclear Safety Commission of Japan, an advisory panel made up of non-government experts, reportedly stated that there is no need to collect and store autologous PBSCs. The reasons given are the physical and psychological burden for nuclear workers, no consensus among international authoritative bodies, and no sufficient agreement among the Japanese public.

Historical data:
I’ve searched for any available historical information about previous accidents and HSC transplants. What do we know about it so far? I’d like to share some statistical data that I’ve discovered from EBMT education resource – Nuclear Accident Educational Presentations. Now, I’m going to cite some historical data that I grab from presentations of Leif Stenke, Tony Pagliuca and Ray Powles.

  • According IAEA in 1947-2004 were documented 180 severe accidents (out of 3000 total number of radiation events) Acute Radiation Syndrome (ARS).
  • Since 1945 – at least 800 victims with ARS (in 70 instances).
  • In 1958-1999 totally 48 patients got HSC transplantation from 14 incidents; 22 transplants only from Chernobyl disaster alone.
  • Out of 48 patients transplanted wit HSC, 48% died post transplant within 50 days, 9 had evidence of engraftment! So, we picked wrong winners! 16 patients had evidence of autologous recovery (overtreated!) We didn’t get it right!
  • There were no correlation between dose exposure and autologous marrow recovery in Chernobyl accident (Baranov et al, NEMJ 1989; 321: 205) – one patient got 10.2 Gy of total body irradiation and showed own marrow recovery, other patient got 6.6 Gy and showed no recovery!
  • First patients was treated by cord blood HSC in 1999 Tokaimura accident. In this accident only 2 patients were transplanted – one mobilized peripheral blood stem cells, another – cord blood on day 10th after exposure. Both patients engrafted with mixed chimerism and both died (83 and 211 days) from multi-organ failure (MOF).
  • Who will gain from the transplant? Grade H4 of damage according METREPOL scale considered as essentially irreversible damage of stem cell pool. Donor’s search should be initiated if total body exposure exceeded 4 Gy (also depends on lymphocyte and neutrophil count), coexistence of trauma and burns reduces the threshold of donor searching.
  • Marrow recovery impossible unless BMT: lymphocytes < 0.5×10^9/L- 24h, <0.1×10^9/L – 48h; granulocytes: <0.5×10^9/L or initial granulocytosis; thrombocytes: <20×10^9/L.
  • Only 5 transplants were performed after 1986 – all in H4 grade patients, done at median of 7 days after radiation accident, all of them died of MOF and burns.
  • HSC transplantation – never an emergency, never done before day 14-21 (manage neuthropenia first, burns and MOF), but start immediate HLA-typing.

The bottom line: We have very limited experience with HSC transplantation in few radiation accidents. In the last 60 years only 48 patients underwent HSC transplantation. Radiation exposure and patient cohorts were too heterogeneous for solid conclusions. Most of patients died despite transplant. Most of patients died from multi-organ failure.

Unresolved questions and difficulties:

  1. We still don’t know how to select patients which can benefit from HSC transplant.
  2. We still don’t know how to predict spontaneous marrow recovery. If we don’ t get it right, overtreated patients can die from transplant-related complications.
  3. There is no good experimental model to test HSC transplant in radiation exposure (We can’t irradiate people experimentally).
  4. Retrospective historical analysis is complicated by small number of victims and heterogeneity of exposure and associate organ damage.
  5. We don’t know what kind of HSC transplant would be better – autologous or allogeneic. In autologous settings HSC or progenitors can acquire and accumulate radiation-induced mutations with unknown consequences.

Future directions and perspectives:

  1. International efforts and collaboration was initiated by EBMT NAC (the European Group for Blood and Marrow Transplantation Nuclear Accident Committee) in order to set up the algorithm of actions in case of radiation accidents. The Commettee proposed to use 500 BMT centers as useful networking resource in case of radiation events.
  2. Number of specialists are working on biological dosimetry assays and identification of clinical parameters (identification of markers) for prediction of spontaneous marrow recovery after radiation exposure.
  3. In my opinion, international community should appreciate a number of experimental cellular therapies for radioprotection. Some “off-the-shelf” cell products potentially could be used as radioprotectors. For example, “non-HLA-matched” cryopreserved expanded hematopoietic progenitors could be used for treatment of severe neutrophenia and thrombocytopenia in ARS. Repositories of such cell products together with cord blood banks can play an important role in biodefense.
  4. Taking in account remarkable “survival qualities” of HSC, we probably should pay more attention to pharmacological radioprotectors, which could protect survived stem cells and stimulate spontaneous marrow recovery. For example, reversible pharmacological manipulation of stem/ progenitor cell quiescence and apoptosis by puma, p53 and cell cycle inhibitors.

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