Sargramostim in acute radiation syndrome

ABSTRACT

Introduction

Since 1944, nearly 400 radiologic accidents/incidents have exposed about 3,000 people to substantial doses of ionizing radiation, with more than 125 deaths. Known are the Chernobyl and Fukushima nuclear power facility accidents, but the recent war in Ukraine has refocused attention on this issue. Therapy of acute, high-dose, whole-body exposures to ionizing radiation includes transfusions, antimicrobial drugs, molecularly cloned hematopoietic growth factors, and hematopoietic cell transplants (HCT).

Areas covered

We focus on approved therapies including recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF, sargramostim). Animal data indicate sargramostim accelerates marrow recovery and increases survival. In 2018, the United States Food and Drug Administration approved sargramostim for persons acutely exposed to myelosuppressive radiation doses based on two large nonhuman primate studies. In seven radiation accidents since 1986, 28 victims exposed to acute high-dose ionizing radiation received rhu GM-CSF alone or with other hematopoietic growth factors. Therapy appeared effective with few, if any, adverse events; 18 survived.

Expert opinion

This favorable benefit-to-risk ratio suggests giving sargramostim soon after exposure and is favored over HCT based on greater safety and fewer resource requirements, especially in the context of large-scale exposures which might occur after use of a tactical nuclear weapon or nuclear terrorism.

KEYWORDS:

• Acute radiation syndrome
• colony-stimulating factor
• filgrastim
• G-CSF
• myeloid growth factors
• radiation and nuclear countermeasures
• recombinant human granulocyte-macrophage colony-stimulating factor (rhu GM-CSF)
• sargramostim

Acknowledgments

RP Gale acknowledges support from the United Kingdom National Institute of Health Research (NIHR) Biomedical Research Centre funding scheme, Newcastle University.

Article highlights

• Threats of radiation and nuclear accidents/incidents and nuclear terrorism are increasing. The best treatment for victims experiencing severe myelosuppression from exposure to acute, high-dose, and high-dose-rate ionizing radiation is not established.

• Conducting prospective, randomized clinical trials in victims of radiation exposure clearly is not possible for many reasons including a low incidence rate, unpredictability of incidents from year-to-year and inability to predict where incidents may occur. Further, the fact is that incidents will occur where infrastructure will be challenged or lacking, and subjects and investigators will be exposed to extraordinary threats. Because of the rarity and the overwhelming pragmatic and logistic issues complicating these incidents, we must rely on surrogate data from in vitro, non-clinical and limited, historical data from victims of nuclear accidents and incidents.

• Herein we note and briefly comment upon unapproved products but focus on those agents that have been approved, compare them, and comment on treatment gaps. We adhere to the theme of products approved by the United States Food and Drug Administration (US FDA) under the ‘Animal Rule’ (US Congressional Record; 21 CFR 601.90-95).

• We discuss in detail the recombinant myeloid growth factor sargramostim (rhu GM-CSF) that has been used clinically and displays a favorable benefit-to-risk ratio suggesting it be given soon after exposure.

• Unmet needs include dosimetry for accuracy of individual dose exposure, and better agents for use soon after acute radiation exposure to prevent, lessen the severity, or reverse radiation-induced skin, GI tract, lung, and other organ damage.

This box summarizes key points contained in the article.

Declaration of interest

HM Lazarus is a paid consultant to Partner Therapeutics and has stock options and is a paid consultant to Pluristem Therapeutics. RP Gale is a consultant to NexImmune Inc. and Ananexa Pharma Ascentage Pharm Group, Antengene Biotech LLC, Medical Director, FFF Enterprises Inc.; partner, AZAC Inc.; Board of Directors, Russian Foundation for Cancer Research Support; and Scientific Advisory Board: StemRad Ltd. RP Gale received funds from Partner Therapeutics for consulting within the past 3 years but none in relation to this publication. J McManus is an employee of and has stock options for Partner Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

The authors contributed equally to design and preparation of the typescript, take responsibility for the content and agree to submit for publication.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

Partner Therapeutics, Inc. funded the open access fees.