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You are here: Home > Exposure: Diagnose/Manage Acute Radiation Syndrome > Myeloid Cytokines (Growth Factors, Colony-stimulating Factors)


Myeloid Cytokines (Growth Factors, Colony-stimulating Factors)

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CytokineAdult DosePregnant Women
G-CSF: filgrastim
(Neupogen®)
  • Subcutaneous administration
  • 5 ug/kg/day via single daily injection
  • Continued until absolute neutrophil count > 1.0 x 109 cells/L
Class C (Same as adults)
Pegylated G-CSF: pegfilgrastim
(Neulasta®)
  • 1 subcutaneous dose, 6 mg
  • Consider second 6 mg dose 7 or more days after initial dose, if significant neutropenia persists
Class C (Same as adults)
GM-CSF: sargramostim
(Leukine®)
  • Subcutaneous administration
  • 250 ug/m2/day
  • Continued until absolute neutrophil count > 1.0 x 109 cells/L
Class C (Same as adults)
G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor.

General comments:
  • This class of drugs is referred to by various names
    • Myeloid cytokines
    • Myeloid growth factors
    • Myeloid colony-stimulating factors (CSFs)
  • Specific individual drugs in this class target specific kinds of myeloid cell(s)
    • Neutrophil only (granulocyte-G) only (e.g., filgrastim, a G-CSF)
    • Neutrophil and monocytes/macrophages and myeloid-derived dendritic cells (e.g. sargramostim, a GM-CSF)
  • Listing on this page does NOT mean that each product is in the U.S. Strategic National Stockpile (SNS).
  • Consult hyperlinks in the first column of the table for important drug information.
  • See REMM Exposure Algorithm for the clinical context of G-CSF use
Recently developed granulocyte colony-stimulating factors (G-CSFs)
  • Two newer G-CSFs not listed in the table above
    • tbo-filgrastim (Neutroval®) (Granix, Teva)
    • filgrastim-sndz (Zarxio®) (Sandoz/Novartis)
      • FDA approved filgrastim-sndz (ZARXIO™ Injection, Sandoz Inc.), as biosimilar to US-licensed Neupogen® on March 6, 2015. The date for drug availability in the US has not yet been announced.
      • It was approved for the five indications for which US-licensed Neupogen® is approved.
      • The formulation of ZARXIO™ differs from that of US-licensed Neupogen® in one inactive component.
      • Drug label for filgrstim-sndz (PDF - 2.9 MB)
Clinical utility
  • The potential need for G-CSFs can be estimated using biodosimetry tools
  • Initiation of treatment in a radiation incident should be strongly considered for victims who
    • Are likely to have received ≥2 Gy whole body exposure or ≥ 2 Gy significant partial body exposure
    • Are likely to develop an absolute neutrophil count of <0.500 x 109 cells/L
    • Will likely have prolonged periods of significant neutropenia (See diagram.)
    • Have significant radiation exposure plus trauma and/or burns
  • The goal of using granulocyte colony-stimulating factors is to
    • Shorten the duration of severe neutropenia
    • Minimize the severity of neutropenia-associated complications, including infection
  • Most experts recommend using white cell cytokines as early as possible and usually within 24 hours after the end of radiation exposure.
    • These timing data are based mostly on evidence from animal studies. (See references.)
  • In a large mass casualty radiation incident such as a nuclear detonation, there may be significant shortages of resources including myeloid cytokines.
  • Consult REMM's Interactive Scarce Resources Tool to assist with triage and allocation of scarce resources including these cytokines in the first 96 hours of an IND detonation.
FDA issues
  • Although the 4 drugs listed on this page are FDA approved for the treatment of chemotherapy-induced neutropenia, none is currently approved by the FDA for radiation-induced neutropenia.
    • No prospective randomized human clinical trials have proven either the efficacy or long term safety of myeloid growth factors .
    • However, experience using white cell cytokines after accidental radiation exposure has been gained during incidents involving small numbers of patients, as tracked by REAC/TS, and in smaller clinical studies.
  • Procurement and use of these drugs from the Strategic National Stockpile would require a formal Emergency Use Authorization (EUA).
  • In a large mass casualty event, off label use by individual clinicians might occur from sources outside the SNS, but FDA still recommends an EUA. Incident managers will probably provide direction on this issue during a mass casualty event.
Other safety issues
  • For each drug noted on this page, consult the FDA drug label for information about side effects.
  • For radiation exposure in pregnant women and cytokines use
    • Experts in biodosimetry must be consulted.
    • Any pregnant patient with exposure to radiation should be evaluated by a health physicist and maternal-fetal specialist for an assessment of risk to the fetus.
    • Class C refers to U.S. Food and Drug Administration Pregnancy Category C, which indicates that studies have shown animal, teratogenic, or embryocidal effects, but there are no adequate controlled studies in women; or no studies are available in animals or pregnant women.
    • See recent FDA update for use of cytokines in pregnancy
  • Safety and efficacy of growth factors in pediatric patients have not been established; however, available safety data for some of the growth factors (e.g., GM-CSF) indicate that this particular growth factor does not produce any greater toxicity in pediatric patients than in adults. Emergency use authorization would be required in a mass casualty event.
  • Daily G-CSF (filgrastim and pegfilgrastim) therapy leads to splenic enlargement in a very small fraction of patients, and very rare cases of splenic rupture have been documented.
  • Allergic reactions involving skin, respiratory, and cardiovascular symptoms have been reported in patients administered filgrastim and pegfilgrastim. Although these side effects have occurred at a relatively low rate (<1 in 4000 patients for filgrastim), in a large scale radiological incident there may be patients who experience this side effect.
  • Severe or fatal sickle cell crises can develop in patients with sickle cell disease who received G-CSFs. Special care should be taken in prescribing this drug in patients with sickle cell disease and they should be carefully monitored.
  • Capillary leak syndrome is also a rare, but potentially very serious complication.
Practice guidelines for G-CSFs

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References

See: REMM Bibliography for Acute Radiation Injury > Cytokine Section




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