Hematopoietic cells are very sensitive to damage from ionizing radiations [1,2,3,4,5,6]. The estimated 50 percent lethal dose (LD50) to humans is 3–4 Gy without supportive care. Doses > 8–10 Gy are thought to cause irreversible bone marrow damage which can only be reversed by a haematopoietic cell transplant.
In the context of transplants high-dose radiation is typically given as a 10–12 Gy single- dose or in a few fractions at dose-rate <10–20 cGy/min. Often radiation is combined with anti-cancer drugs such as cyclophosphamide [7]. These regimens are widely-termed myelo-ablative. We briefly discussed the jargon use of myelo-ablative previously [8]. In this Commentary we again suggest the term myelo-ablative is wrong and the potential to compromise care of victims of radiation and nuclear accidents. We explain why.
The 1st argument against the term myelo-ablative is the stochastic nature of radiation damage. There cannot be a radiation dose which could kill every hematopoietic stem cell without immediately killing the recipient. The 2nd argument comes from clinical data. In October, 1991 a 34-year-old male operator at an industrial sterilization facility using a 60Co γ source in Nesvizh, Belarus was exposed in 1.5 min to an estimated whole-body radiation dose of 11 ± 1.3 Gy (12–15 Gy), with some sites receiving up to 20 Gy [9, 10]. Estimated whole-body dose from computer simulations was 8–16 Gy, from physical dosimetry (electron spin resonance [ESR]), 11–18 Gy ± 20%, and from biological dosimetry, blood cell concentration declines, 9–11 Gy, cytogenetics, 11 ± 1.3 Gy [9, 10], The estimated dose-rate was 5.33–12 Gy/min or 100 times greater than the dose-rate typically used for pretransplant conditioning. He received supportive care, sargramostim and interleukin-3 but no transplant because of anticipated irreversible lung damage. He died 113 days after exposure from pulmonary failure.
His blood cell concentrations fell immediately after exposure (Fig. 1). At one week a bone marrow biopsy showed severe hypoplasia (Fig. 2a). The blood granulocyte concentrations began to increase on day 23, reaching 0.5 X 10E + 9/L on day 37 and 1.0 X 10E + 9/L on day 60. Bone marrow cellularity began to increase and a bone marrow examination on day 44 after exposure showed improving cellularity (Fig. 2b). A bone marrow examination done on day 113 at autopsy shows near normal cellularity consistent with recovery of blood granulocyte concentrations (Fig. 2c). These data indicate recovery of bone marrow function even after extremely high whole-body dose and dose-rate exposure without a transplant. Clearly this dose and dose-rate, much higher than used for pretransplant conditioning, were not myelo-ablative.
Several people exposed to high-dose and dose-rate ionizing radiations after the Chernobyl nuclear power facility accident in 1986 receiving an allogeneic hematopoietic cell transplant recovered autologous bone marrow function after transient engraftment [11]. There are other examples where people with leukemia receiving high-dose radiation (usually 10 Gy in 1 dose or 12 Gy in 6 fractions) followed by an allotransplant are found to have recovery of endogenous hematopoiesis several years later. These data indicate using the term myelo-ablative for even very high-dose and dose-rate ionizing radiations is wrong. (We note several of the data we cite are from previously healthy persons receiving no prio or concurrent bone marrow damaging drugs ot a whole-body ionizing radiations).
Humans exposed to acute, high-dose and high-dose-rate whole-body ionizing radiations such as after a radiation or nuclear accident develop hematopoietic acute radiation syndrome (H-ARS) characterized by acute severe myelosuppression with resultant infection, bleeding, and anemia. Exposure to >8 Gy whole-body radiation under these circumstances does not necessarily imply a hematopoietic cells transplant is needed to restore normal bone marrow function [12]. However, such exposures require intensive supportive care. Elsewhere we discuss data in experimental animals including monkeys and data from humans suggesting safety and efficacy of molecularly-cloned hematopoietic growth factors such as sargramostim and filgrastim and possibly eltrombopag [13].
The bottom line is use of the term myelo-ablative for radiation-based high-dose pretransplant conditioning regimens is wrong and should be abandoned. A better term would be intensive pretransplant conditioning. We accept we are fighting a losing battle but feel obliged to try.
References
Till JE, McCulloch EA. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res. 1961;14:213–22.
McCulloch EA, Till JE. The radiation sensitivity of normal mouse bone marrow cells, determined by quantitative marrow transplantation into irradiated mice. Radiat Res. 1960;13:115–25.
United Nations Scientific Committee on the Effects of Atomic Radiation. Ionizing radiation: sources and biologic effects: Report to the General Assembly. New York, NY, United Nations, 1982.
Lethality from acute and protracted radiation exposure in man. An account of a forum organized by the Medical Research Council’s Committee on Effects of Ionising Radiation, 17 November 1983. Abstracts. Int J Radiat Biol Relat Stud Phys Chem Med. 1984;46:209–17.
Mettler FA Jr, Moseley RD Jr. Medical effects of ionizing radiation. Orlando, FL: Grune & Stratton; 1985.
Shao L, Luo Y, Zhou D. Hematopoietic stem cell injury induced by ionizing radiation. Antioxid Redox Signal. 2014;20:1447–62. https://doi.org/10.1089/ars.2013.5635.
Sabloff M, Chhabra S, Wang T, Fretham C, Kekre N, Abraham A, et al. Comparison of high doses of total body irradiation in myeloablative conditioning before hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2019;25:2398–407. https://doi.org/10.1016/j.bbmt.2019.08.012.
Gale RP, Lazarus HM. “A rose by any other name would smell as sweet”, or would it? Bone Marrow Transplant. 2013;48:881–3. https://doi.org/10.1038/bmt.2012.275.
Baranov AE, Selidovkin GD, Butturini A, Gale RP. Hematopoietic recovery after 10-Gy acute total body radiation. Blood. 1994;83:596–9.
The radiological accident at the irradiation facility in Nesvizh. Vienna: International Atomic Energy Agency; 1996.
Baranov A, Gale RP, Guskova A, Piatkin E, Selidovkin G, Muravyova L, et al. Bone marrow transplantation after the Chernobyl nuclear accident. N Engl J Med. 1989;321:205–12. https://doi.org/10.1056/NEJM198907273210401. Erratum in: N Engl J Med. 1990;322:280.
Gale RP. Is there a role for haematopoietic cell transplants after radiation and nuclear accidents? J Radiol Prot. 2021;41. https://doi.org/10.1088/1361-6498/abeb24.
Lazarus HM, McManus J, Gale RP. Sargramostim in acute radiation syndrome. Expert Opin Biol Ther. 2022;22:1345–52. https://doi.org/10.1080/14712598.2022.2143261.
Acknowledgements
RPG acknowledges support from the National Institute of Health Research (NIHR) Biomedical Research Centre and the Ministry of Science and Technology of China (84000-51200002).
Author information
Authors and Affiliations
Contributions
The authors contributed equally to the concept and execution of this typescript.
Corresponding author
Ethics declarations
Competing interests
RPG is a consultant to Antengene Biotech LLC, Ascentage Pharma Group and NexImmune Inc.; Medical Director, FFF Enterprises Inc.; A speaker for Janssen Pharma and Hengrui Pharma; Board of Directors: Russian Foundation for Cancer Research Support; and Scientific Advisory Boards, Nanexa AB and StemRad Ltd. HML is a consultant to Partner Therapeutics, Lexington, MA.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
About this article
Cite this article
Gale, R.P., Lazarus, H.M. Is myelo-ablative pretransplant conditioning really myelo-ablative: Implications for radiation and nuclear accidents?. Bone Marrow Transplant 59, 159–161 (2024). https://doi.org/10.1038/s41409-023-02130-0
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41409-023-02130-0