Myeloid Cytokines (Growth Factors, Colony-stimulating Factors) for Radiation-induced Myelosuppression
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|Pegylated G-CSF: pegfilgrastim
Recently developed granulocyte colony-stimulating factors (G-CSFs)
- Neither is FDA-approved for radiation-induced myelosuppression.
- tbo-filgrastim (Granix®) (Teva)
- Was approved initially for clinical use in the US by the FDA in August 2012.
- Drug labeling was updated to reflect licensing for self-administration by patients and caregivers in December 2014.
- Drug label for tbo-filgrastim (PDF - 1.6 MB)
- 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, but not for radiation-induced myelosuppression (see label).
- The formulation of ZARXIO™ differs from that of US-licensed Neupogen® in one inactive component.
- Drug label for filgrstim-sndz (PDF - 2.9 MB)
- tbo-filgrastim (Granix®) (Teva)
- This class of drugs is referred to by various names.
- Myeloid, white cell, or leukocyte cytokines
- Myeloid, white cell, or leukocyte growth factors
- Myeloid, white cell, or leukocyte 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 for using these drugs to treat radiation-induced myelosuppression in the context of the Acute Radiation Syndrome.
- The goals of using a myeloid colony-stimulating factor for radiation-induced myelosuppression
- Shorten the duration of severe neutropenia
- Minimize the severity of neutropenia-associated complications, including infection
- Improve survival of adults and children exposed to myelosuppressive doses of radiation.
- Initiation of treatment in a radiation incident should be strongly considered for patients 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 500 cells/mm3
- Will likely have prolonged periods of significant neutropenia (See diagram).
- Have significant radiation exposure plus trauma and/or burns, which worsens the clinical outcome compared to radiation exposure alone.
- REMM provides various interactive biodosimetry tools to help estimate the dose of whole body radiation received.
- As of March 2015, of the 5 myeloid cytokines listed on this page, only Neupogen® has been FDA-approved for the indication of radiation-induced myelosuppression.
- Consult REMM's Interactive Scarce Resources Tool to assist with patient triage and allocation of scarce resources including these cytokines in the first 96 hours of a mass casualty incident such as detonation of an Improvised Nuclear Device (IND).
- Administration of myeloid cytokine is recommended as early as possible after expected or confirmed exposure to radiation, and usually within 24 hours after the end of radiation exposure.
- Approval of Neupogen® for radiation-induced myelosuppression was based on FDA's "Animal Rule".
- See the Neupogen® drug label update from March 2015 for details about approval for this indication.
- How and when to consider Neupogen® to treat myelosuppression from radiation exposure
- The recommended dose of Neupogen® is 10 mcg/kg as a single daily subcutaneous injection for adult and pediatric patients exposed to myelosuppressive doses of radiation.
- Administer Neupogen® as soon as possible after suspected or confirmed exposure to radiation doses greater than 2 gray (Gy).
- Estimate a patient's absorbed radiation dose based on
- Information from public health authorities (e.g., dose reconstruction)
- Biodosimetry, if available
- Clinical findings such as time to onset of vomiting or lymphocyte depletion kinetics.
- Obtain a baseline complete blood count (CBC) and then serial CBCs approximately every third day until the absolute neutrophil count (ANC) remains greater than 1,000/mm3 (= 1.0 x 109 cells/L) for 3 consecutive CBCs. (REMM Note: More frequent CBCs, including daily CBCs, are likely to be ordered if laboratory resources permit.)
- Do not delay administration of Neupogen® if a CBC is not readily available.
- Continue administration of Neupogen® until the absolute neutrophil count (ANC) remains
- Greater than 1,000/mm3 (= 1.0 x 109 cells/L) for 3 consecutive CBCs or
- Exceeds 10,000/mm3 (= 10 x 109 cells/L) after a radiation-induced nadir
- REMM Note: CBCs with the target ANC level on 3 consecutive days is also acceptable as a stopping point for drug administration.
- How the daily dose was selected
- Because of the uncertainty associated with extrapolating animal efficacy data to humans, the selection of human dose for Neupogen® is aimed at providing exposures to filgrastim that exceed those observed in animal efficacy studies.
- The 10 mcg/kg daily dose is selected for humans exposed to myelosuppressive doses of radiation because the exposure associated with such a dose is expected to exceed the exposure associated with a 10 mcg/kg dose in non-human primates.
- The safety of Neupogen® at a daily dose of 10 mcg/kg has been assessed on the basis of clinical experience in other approved indications.
- Ethics of using Neupogen®: comments from the drug label
- No prospective randomized human clinical trials have proven either the efficacy or long- term safety of myeloid growth factors for radiation-induced myelosuppression in humans.
- Efficacy studies of Neupogen® could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons.
- Approval of this indication was based on efficacy studies conducted in animals and data supporting the use of Neupogen® for other approved indications.
- Clinicians should advise patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome) that efficacy studies of Neupogen® for this indication could not be conducted in humans for ethical and feasibility reasons and that, therefore, approval of this use was based on efficacy studies conducted in animals.
- (REMM Note: Considerable clinical experience has been gained worldwide using myeloid cytokines to treat patients after accidental radiation exposure.)
- Neupogen®, which has been FDA-approved for the indication of radiation-induced myelosuppression, would not require an EUA, if used as advised on the drug label.
- Obtaining and using most myeloid cytokines for radiation-induced myelosuppression from the Strategic National Stockpile would require a formal FDA Emergency Use Authorization (EUA).
- In a very large mass casualty incident such as a nuclear detonation, off-label use of these cytokines by individual clinicians might occur from sources outside the SNS. Senior medical incident managers will probably provide guidance on this issue.
- If there are significant shortages of resources, including myeloid cytokines, modification of standard dosing schedules may be recommended by senior medical incident managers for drug not stored in the SNS and/or by FDA's Emergency Use Authorization or Emergency Use Instruction for the supply of drug in the SNS.
- If resources are scarce, including cytokines, triage modification including when to use cytokines may be considered in order to provide the greatest good for the greatest number.
- For each drug noted on this page, consult the FDA drug label for information about side effects.
- For radiation-induced myelosuppression in pregnant women
- Experts in biodosimetry should 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.
- Advise females of reproductive potential that Neupogen® should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus
- Pediatric Use
- Use of Neupogen® to increase survival in patients acutely exposed to myelosuppressive doses of radiation is based on studies conducted in animals and clinical data supporting the use of Neupogen® in other approved indications.
- The pharmacokinetics of filgrastim in pediatric patients after chemotherapy are similar to those in adult patients receiving the same weight-normalized doses, suggesting no age-related differences in the pharmacokinetics of filgrastim.
- The pediatric dose is the same as the adult dose: 10 mcg/kg/day.
- Warning and Precautions on the drug label for each of the products in this category should be noted. Below is a list of serious adverse effects note on the Neupogen® drug label. Most are rare.
- Splenic enlargement and rupture
- Acute Respiratory Distress Syndrome
- Serious allergic reactions
- Sickle cell disorders: Sickle cell crisis, in some cases fatal, has been reported with the use of Neupogen® in patients with sickle cell trait or sickle cell disease.
- Alveolar hemorrhage and hemoptysis
- Capillary leak syndrome
- Thrombocytopenia and Leukocytosis
- Dainiak N, Gent RN, et al. First Global Consensus for Evidence-Based Management of the Hematopoietic Syndrome Resulting From Exposure to Ionizing Radiation. Disaster Med Public Health Prep. 2011 Oct;5(3):202-212. [PubMed Citation]
- Myeloid Growth Factors, National Comprehensive Cancer Network (NCCN): Clinical Practice Guidelines in Oncology: Myeloid Growth Factors 2009 (requires registration). See section entitled "NCCN Guidelines for Supportive Care".
- American Society of Clinical Oncology (2006)
- Myeloid Growth Factors, NCCN Guidelines Version 2.2014, 5/2/2014, Registration on the NCCN.org web site required to access this guideline. It is listed under "Guidelines for supportive care". Extensive oncology bibliography is included.
See: REMM Bibliography for Acute Radiation Injury > Cytokine Section