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Hematopoietic Countermeasures


Growth Factors/Cytokines for White Blood Cells 1 2

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    CytokineAdults†Children†Pregnant Women*Precautions
    G-CSF or filgrastim
    • Subcutaneous administration
    • 5 ug/kg of body weight per day
    • Continued until ANC > 1.0 x 109 cells/L
    • Subcutaneous administration
    • 5 ug/kg of body weight per day
    • Continued until ANC > 1.0 x 109 cells/L
    		Class C (Same as adults) Consider discontinuation if pulmonary infiltrates develop at neutrophil recovery for patients with:
    • Sickle-cell hemoglobinopathies
    • Significant coronary artery disease
    • Acute Respiratory Distress Syndrome
    Pegylated G-CSF or pegfilgrastim
    • 1 subcutaneous dose, 6 mg
    • For adolescents >45 kg: 1 subcutaneous dose, 6 mg
    		Class C (Same as adults) Consider discontinuation if pulmonary infiltrates develop at neutrophil recovery for patients with:
    • Sickle-cell hemoglobinopathies
    • Significant coronary artery disease
    • Acute Respiratory Distress Syndrome
    GM-CSF or sargramostim
    • Subcutaneous administration
    • 250 ug/m2 per day
    • Continued until ANC > 1.0 x 109 cells/L
    • Subcutaneous administration
    • 250 ug/m2 per day
    • Continued until ANC > 1.0 x 109 cells/L
    		Class C (Same as adults) Consider discontinuation if pulmonary infiltrates develop at neutrophil recovery for patients with:
    • Sickle-cell hemoglobinopathies
    • Significant coronary artery disease
    • Acute Respiratory Distress Syndrome
    For healthy people exposed to radiation, consider discontinuation of growth factors if signs of respiratory distress (e.g., cough, dyspnea, or peripheral edema) occur.
    ANC = absolute neutrophil count; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony-stimulating factor.

    † When to initiate treatment:
    • Initiate treatment with granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor in victims who develop an absolute neutrophil count < 0.500 x 109 cells/L and are not already receiving colony-stimulating factor.
    • Consider initiating therapy at lower whole body exposure dose in nonadolescent children and elderly persons because their marrow reserve may be compromised.
    • More details on Diagnose/manage exposure: acute radiation syndrome
    • More details on Manage subsyndromes of ARS
    • More details on Hematopoietic subsyndrome treatment
    * 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.

    References:

Additional issues/warning suggested by REMM consultants:

  • The growth factors listed are currently not approved by FDA for use in acute radiation syndrome.
  • No prospective randomized trials have proven the benefit of hematopoietic growth factors in humans exposed to accidental or intentional radiation. However, clinical value has been observed with their use in incidents involving small numbers of patients tracked by REAC/TS.
  • Safety and effectiveness 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.
  • Daily G-CSF (filgrastim and pegfilgrastim) therapy leads to splenic enlargment in a majority of patients, and splenic rupture has been documented. Therefore, treatment with this particular growth factor should be interrupted and the patient assessed if there is a complaint of upper abdominal or left shoulder pain. Health care providers should avoid all but minimal left upper quadrant trauma (maximum is abdominal palpation) for at least a week after G-CSF has been discontinued.
  • Allergic reactions involving skin, respiratory, and cardiovascular symptoms have been reported in patients administered filgrastim and pegfilgrastim. Although these 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.

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Growth Factors/Cytokines for Platelets 4 5

  • IL-11 (Interleukin 11)
    • IL-11 is a stromal-derived HGF (hematopoietic growth factor) that stimulates thrombopoiesis and differentiation of bone marrow progenitor cells.
    • In the US, IL-11 has been approved by the FDA for the prevention of severe thrombocytopenia after myelosuppressive chemotherapy in patients who are at high risk of severe thrombocytopenia.
    • Treatment with rhIL-11 in humans has been associated with significant adverse events including amblyopia, paresthesia, dehydration, skin discoloration, exfoliative dermatitis, and ocular hemorrhage.
    • The extent of these adverse effects has limited the clinical use of IL-11.
  • Thrombopoietin (Other names: Tpo, c-Mpl ligand, megakaryocyte growth and differentiation factor)
    • Tpo acts primarily to regulate megakaryocytopoiesis and platelet production.
    • Not currently approved for human use, but in an emergency the FDA may be petitioned for an EUA (Emergency Use Authorization).

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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. Kuter DJ. New thrombopoietic growth factors. Blood. 2007 Feb 8 [PubMed Citation]
  6. Rizzo JD, Lichtin AE, Woolf SH, Seidenfeld J, Bennett CL, Cella D, Djulbegovic B, Goode MJ, Jakubowski AA, Lee SJ, Miller CB, Rarick MU, Regan DH, Browman GP, Gordon MS; American Society of Clinical Oncology, American Society of Hematology. Use of epoetin in patients with cancer: evidence-based clinical practice guidelines of the American Society of Clinical Oncology and the American Society of Hematology. J Clin Oncol. 2002 Oct 1;20(19):4083-107. [PubMed Citation]
  7. Powell J, Gurk-Turner C, Darbepoetin Alfa (Aranesp) (PDF - 78 KB). Baylor University Medical Center Proceedings 2002; 15(3):332-335.
  8. 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]
  9. 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]
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