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Hematopoietic Countermeasures


Growth Factors/Cytokines for White Blood Cells 1 - 6

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CytokineAdult DosePregnant Women
G-CSF
or 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
or pegfilgrastim
(Neulasta)
  • 1 subcutaneous dose, 6 mg


Class C (Same as adults)
GM-CSF
or 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:
  • Prescribers are strongly urged to consult detailed information for each drug in the hyperlinks.
  • Although the 3 drugs listed in the table above are FDA approved for the treatment of chemotherapy induced neutropenia, none is approved for radiation induced neutropenia.
    • No prospective randomized trials have proven either the efficacy or long term safety of hematopoietic growth factors in humans exposed to radiation.
    • 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.
    • Evidence from animal studies indicates that outcomes may be improved if growth factors are administered as soon as possible after radiation exposure, and possibly within 24 hours.
  • In a mass casualty radiation event, procurement and use of these drugs from the Strategic National Stockpile would require a formal Emergency Use Authorization (EUA). Off label use by individual clinicians might occur, but FDA still recommends an EUA. Incident managers will probably provide direction on this issue during a mass casualty event.
  • General guidance on when to initiate treatment with white cell growth factors
    • Initiation of treatment should be strongly considered for victims who develop an absolute neutrophil count of < 0.500 x 109 cells/L and are not already receiving growth factor.
    • In large mass casualty events, some clinicians may suggest early use for victims likely to have been exposed to a whole body dose of ≥2 Gy, rather than waiting for the onset of neutropenia. (See REMM Exposure algorithm, and Emergency Use Authorization)
  • For pregnant women
    • 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.
Additional issues/warning suggested by REMM consultants:
  • 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 enlargment in a very small fraction of patients, and very rare cases of splenic rupture has 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.
  • See practice guidelines for myeloid growth factors from
References:

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Growth Factors/Cytokines for Platelets 7 8 9 10

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Growth Factors/Cytokines for Red Blood Cells

  • There are currently no FDA-approved cytokines recommended for treatment of anemia associated with the Acute Radiation Syndrome (ARS).
  • Given the long life span of red cells (~120 days), clinically significant, early onset, ARS-related anemia is not likely to be a major problem except in patients with
  • Two erythropoeitin stimulating agents (ESAs) have been approved by the FDA for other indications.
    • Epoetin alfa (marketed as Epogen® and Procrit®)
    • Darbepoetin alfa (marketed as Aranesp®)
  • Major indications for ESAs include anemia associated with
    • Certain chronic diseases, including kidney disease
    • Cancer-chemotherapy
    • HIV infection
    • Other indications
  • Epogen® and Procrit® are identical at the molecular level.
    • EPOGEN® is marketed specifically for anemia in dialysis patients.
    • Procrit® is marketed specifically for all indications other than kidney dialysis, including HIV and cancer chemotherapy-induced anemia.
    • Some hospital pharmacies carry only one of these two products, so PROCRIT® is also used in dialysis patients and Epogen® in patients with diagnoses other than anemia with dialysis.
  • Recently, the FDA has significantly revised the indications and contraindications for these medications.
  • Prescribers should review the most current labeling information, reasons for the recent updates, and patient information for these drugs on the FDA web site: http://www.fda.gov/cder/drug/infopage/RHE/default.htm
  • REMM's mention of this drug is for information purposes only.
    • It is NOT an endorsement of its use in ARS.
    • Use of ESAs during a radiation mass casualty emergency would require an FDA Emergency Use Authorization if government supply of this drug were used
  • These agents are currently NOT included in the Strategic National Stockpile.
  • Use of Epoetin alfa and Darbepoetin alfa in Patients With Cancer: 2007 American Society of Clinical Oncology-American Society of Hematology Clinical Practice Guideline and 2008 update

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References

  1. Waselenko JK, MacVittie TJ, Blakely WF, Pesik N, Wiley AL, Dickerson WE, Tsu H, Confer DL, Coleman CN, Seed T, Lowry P, Armitage JO, Dainiak N; Strategic National Stockpile Radiation Working Group. Medical management of the acute radiation syndrome: recommendations of the Strategic National Stockpile Radiation Working Group. Annals of Internal Medicine 2004; Vol. 140:1037-51. [PubMed Citation]
  2. Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L, Bennett CL, Cantor SB, Crawford J, Cross SJ, Demetri G, Desch CE, Pizzo PA, Schiffer CA, Schwartzberg L, Somerfield MR, Somlo G, Wade JC, Wade JL, Winn RJ, Wozniak AJ, Wolff AC. 2006 update of recommendations for the use of white blood cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol. 2006 Jul 1;24(19):3187-205. Epub 2006 May 8. [PubMed Citation]
  3. Kaushansky KN. Lineage-specific hematopoietic growth factors. N Engl J Med. 2006 May 11;354(19):2034-45. [PubMed Citation]
  4. Weisdorf D, Chao N, Waselenko JK, Dainiak N, Armitage JO, McNiece I, Confer D. Acute radiation injury: contingency planning for triage, supportive care, and transplantation. Biol Blood Marrow Transplant. 2006 Jun;12(6):672-82. [PubMed Citation]
  5. Kuderer NM, Dale DC, Crawford J, Lyman GH. Impact of primary prophylaxis with granulocyte colony-stimulating factor on febrile neutropenia and mortality in adult cancer patients receiving chemotherapy: a systematic review. J Clin Oncol. 2007 Jul 20;25(21):3158-67. [PubMed Citation]
  6. Sung L, Nathan PC, Alibhai SM, Tomlinson GA, Beyene J. Meta-analysis: effect of prophylactic hematopoietic colony-stimulating factors on mortality and outcomes of infection. Ann Intern Med. 2007 Sep 18;147(6):400-11. [PubMed Citation]
  7. Kuter DJ, Bussel JB, Lyons RM, Pullarkat V, Gernsheimer TB, Senecal FM, Aledort LM, George JN, Kessler CM, Sanz MA, Liebman HA, Slovick FT, de Wolf JT, Bourgeois E, Guthrie TH Jr, Newland A, Wasser JS, Hamburg SI, Grande C, Lefrere F, Lichtin AE, Tarantino MD, Terebelo HR, Viallard JF, Cuevas FJ, Go RS, Henry DH, Redner RL, Rice L, Schipperus MR, Guo DM, Nichol JL. Efficacy of romiplostim in patients with chronic immune thrombocytopenic purpura: a double-blind randomised controlled trial. Lancet. 2008 Feb 2;371(9610):395-403. [PubMed Citation]
  8. Nurden AT, Nurden P. Increasing the platelet count in chronic ITP. Lancet. 2008 Feb 2;371(9610):362-4. [PubMed Citation]
  9. Bussel JB, Kuter DJ, George JN, McMillan R, Aledort LM, Conklin GT, Lichtin AE, Lyons RM, Nieva J, Wasser JS, Wiznitzer I, Kelly R, Chen CF, Nichol. AMG 531, a thrombopoiesis-stimulating protein, for chronic ITP. N Engl J Med. 2006 Oct 19;355(16):1672-81. Erratum in: N Engl J Med. 2006 Nov 9;355(19):2054.
  10. Kuter DJ, New drugs for familiar therapeutic targets: thrombopoietin receptor agonists and immune thrombocytopenic purpura, Eur J Haematol Suppl, 2008;(69):9-18. [PubMed Citation]
  11. Myeloid Growth Factors, Journal of the National Comprehensive Cancer Network, 2009 Jan; 7(1).
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