Therapeutic Class Overview Colony Stimulating Factors Therapeutic Class Overview/Summary: This review will focus on the granulocyte colony stimulating factors (G-CSFs) and granulocyte- macrophage colony stimulating factors (GM-CSFs).1-5 Colony-stimulating factors (CSFs) fall under the naturally occurring glycoprotein cytokines, one of the main groups of immunomodulators.6 In general, these proteins are vital to the proliferation and differentiation of hematopoietic progenitor cells.6-8 The G- CSFs commercially available in the United States include pegfilgrastim (Neulasta®), filgrastim (Neupogen®), filgrastim-sndz (Zarxio®), and tbo-filgrastim (Granix®). While filgrastim-sndz and tbo- filgrastim are the same recombinant human G-CSF as filgrastim, only filgrastim-sndz is considered a biosimilar drug as it was approved through the biosimilar pathway. At the time tbo-filgrastim was approved, a regulatory pathway for biosimilar drugs had not yet been established in the United States and tbo-filgrastim was filed under its own Biologic License Application.9 Only one GM-CSF is currently available, sargramostim (Leukine). These agents are Food and Drug Administration (FDA)-approved for a variety of conditions relating to neutropenia or for the collection of hematopoietic progenitor cells for collection by leukapheresis.1-5 Due to the pathway taken, tbo-filgrastim does not share all of the same indications as filgrastim and these two products are not interchangeable. It is important to note that although filgrastim-sndz is a biosimilar product, and it was approved with all the same indications as filgrastim at the time, filgrastim has since received FDA-approval for an additional indication that filgrastim-sndz does not have, to increase survival in patients with acute exposure to myelosuppressive doses of radiation.1-3A complete list of indications for each agent can be found in Table 1. Differences among dosing schedules also exist between the agents. Pegfilgrastim is administered at a fixed dose (6 mg subcutaneously once per chemotherapy cycle), while both filgrastim, filgrastim-sndz, tbo-filgrastim, and sargramostim are dosed based on patient’s body weight and are administered daily.1-5 The G-CSFs are generally used in patients with cancer to reduce the incidence of adverse events associated with chemotherapy, such as febrile neutropenia, infections and delayed neutrophil recovery time. Neutrophils are the body’s defense system against infection and play a key role in the process of acute inflammation.10 Chemotherapy and radiation can affect neutrophil function as well as decrease the production of neutrophils in the bone marrow. When the absolute neutrophil count (ANC) falls below 1,500 cells/μL, this is defined as neutropenia. Patients who have severe neutropenia (ANC <500 cells/μL) are at high risk for infection.10 Endogenous G-CSF is a growth factor produced by monocytes, fibroblasts and endothelial cells that acts upon the bone marrow to increase the production of neutrophils. In addition to increasing neutrophil production, G-CSF also enhances phagocytic and cytotoxic actions of mature neutrophils.1,2 Filgrastim, tbo-filgrastim, filgrastim-sndz and pegfilgrastim are produced by recombinant deoxyribonucleic acid (DNA) technology via the insertion of the human G-CSF gene into Escherichia coli (E coli) bacteria.1-3,5 Pegfilgrastim, a long-acting formulation of filgrastim, is produced by conjugating filgrastim with polyethylene glycol, thereby increasing the molecular weight and delaying kidney excretion.3 GM-CSF is primarily used to accelerate myeloid recovery in oncology patients following myelosuppressive treatment regimens. Endogenous GM-CSF is predominantly found in T lymphocytes, monocytes, macrophages, fibroblasts and endothelial cells.6 In addition to increasing the production of neutrophils, GM-CSF also increases other white blood cells including monocytes, macrophages and eosinophils in the bone marrow as well as promoting their function. Like the G-CSFs, sargramostim is also produced utilizing recombinant DNA technology; however it is derived in yeast (Saccharomyces cerevisiae) expression system rather than from E coli bacteria.4 Based on current guidelines regarding the general use of CSFs such as the National Comprehensive Cancer Network (NCCN) Myeloid Growth Factors Clinical Practice Guideline in Oncology and the American Society of Clinical Oncology (ASCO) 2006 Update of Recommendations for the Use of White Blood Cell Growth Factors, both recognize the importance of preventing and limiting the duration of febrile Page 1 of 6 Copyright 2015 • Review Completed on 8/5/2015 Therapeutic Class Overview: colony stimulating factors neutropenia. Similarly, both guidelines recommend primary prophylaxis with a CSF when the risk of febrile neutropenia is >20%. In addition, they recommend that the therapeutic use of a CSF be considered only when a patient with febrile neutropenia is at high risk of infection-related complications based on prognostic factors.11,12 There is currently no general consensus among the guidelines regarding the specific CSFs within the class. The NCCN states that when choosing an agent for the treatment of prophylaxis of febrile neutropenia, filgrastim and pegfilgrastim are considered to have stronger data to support their use compared to sargramostim.11,13 The European Organization for Research and Treatment of Cancer recommends the use of filgrastim and pegfilgrastim while stating that there is some evidence showing G-CSF and GM-CSF are comparable in efficacy.14 The ASCO state that due to the lack of information, no recommendation can be made with regards to the equivalency of the two G-CSFs.12 1-5,15-17 Table 1. Current Medications Available in the Therapeutic Class Generic Food and Drug Administration-Approved Dosage Generic (Trade Name) Indications Form/Strength Availability Filgrastim To decrease the incidence of infection Vial: (Neupogen®) associated with severe neutropenia in 300 μg/1 mL patients receiving myelosuppressive 480 μg/1.6 mL therapy for nonmyeloid malignancies; To reduce the time to neutrophil recovery and Prefilled Syringe: the duration of fever following induction or 300 μg/0.5 mL consolidation chemotherapy for acute 480 μg/0.8 mL myeloid leukemia; To reduce the duration of neutropenia and neutropenia-related clinical sequelae in patients with nonmyeloid malignancies undergoing myeloablative a* chemotherapy followed by bone marrow transplantation; To mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; To reduce the incidence and duration of sequelae of neutropenia in symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia†; To increase survival in patients acutely exposed to myelosuppressive doses of radiation. Filgrastim-sndz To decrease the incidence of infection Vial: (Zarxio®*) associated with severe neutropenia in 300 μg/1 mL patients receiving myelosuppressive 480 μg/1.6 mL therapy for nonmyeloid malignancies; To reduce the time to neutrophil recovery and Prefilled Syringe: the duration of fever following induction or 300 μg/0.5 mL consolidation chemotherapy for acute 480 μg/0.8 mL myeloid leukemia; To reduce the duration of neutropenia and neutropenia-related clinical a* sequelae in patients with nonmyeloid malignancies undergoing myeloablative chemotherapy followed by bone marrow transplantation; To mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis; To reduce the incidence and duration of sequelae of neutropenia in symptomatic patients with congenital Page 2 of 6 Copyright 2015 • Review Completed on 8/5/2015 Therapeutic Class Overview: colony stimulating factors Generic Food and Drug Administration-Approved Dosage Generic (Trade Name) Indications Form/Strength Availability neutropenia‚ cyclic neutropenia‚ or idiopathic neutropenia†. Pegfilgrastim To decrease the incidence of infection Prefilled Syringe: (Neulasta®) associated with severe neutropenia in 6 mg/0.6 mL - patients receiving myelosuppressive therapy for nonmyeloid malignancies. Sargramostim Allogeneic or autologous bone marrow Vial (powder for (Leukine®) transplantation in which engraftment is reconstitution): delayed or has failed; To reduce the time to 250 μg neutrophil recovery and the duration of fever following induction chemotherapy for Vial (solution) acute myeloid leukemia‡; To accelerate 500 μg/1 mL myeloid recover in patients with non- - Hodgkin’s lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin’s disease undergoing autologous bone marrow transplantation; To mobilize autologous hematopoietic progenitor cells into the peripheral blood for collection by leukapheresis. Tbo-Filgrastim To decrease the incidence of infection (Granix®) associated with severe neutropenia in - patients receiving myelosuppressive therapy for nonmyeloid malignancies. *Zarxio® is a bio-similar medication and interchangeable with the reference drug Neupogen®. †Indicated for chronic use. ‡Safety and efficacy has not been established in patients <55 years of age. Evidence-based Medicine • The safety and efficacy of the granulocyte and granulocyte-macrophage colony stimulating factors have been evaluated in several clinical trials, however, there are few trials that compare G-CSFs to GM-CSFs.18-53 • Two retrospective trials evaluated the differences in efficacy between filgrastim and pegfilgrastim in patients with nonmyeloid malignancies who underwent chemotherapy. Pegfilgrastim was associated with fewer episodes of febrile neutropenia as well as fewer hospitalizations for febrile neutropenia compared to filgrastim18,19 • There were no significant differences between treatment groups in the duration of severe neutropenia and the depth of ANC nadir in all cycles when single-dose pegfilgrastim is compared to daily filgrastim.21 • When comparing filgrastim to sargramostim, there was no significant difference among the treatment groups in the mean number of days to reach an ANC 500 cells/μL (P=0.32); however, the mean number of days to reach an ANC 1,000 and 1,500 cells/μL was significantly lower in the filgrastim group compared to the sargramostim group (P=0.009 and P=0.0001, respectively).22 • A Cochrane review of 13 randomized, placebo-controlled trials was performed to evaluate the efficacy and safety of filgrastim, lenograstim (not available in the United States) or sargramostim compared to placebo in patients who were receiving nonmyeloablative chemotherapy for malignant lymphomas. Sensitivity analyses that were performed in this review concluded that there were no differences between G-CSF and GM-CSF in their effects on overall survival, freedom from treatment failure and risk reduction in incidence of neutropenia or febrile neutropenia.24 • Additional studies generally suggest that filgrastim provides statistically significant efficacy compared to sargramostim, however there is data in several trails saying there is no difference or that sargramostim is more effective.37,44,50 Page 3 of 6 Copyright 2015 • Review Completed on 8/5/2015 Therapeutic Class Overview: colony stimulating factors • The FDA-approval of tbo-filgrastim was evaluated in a single multi-center, placebo- and active- controlled, randomized control trial that evaluated patients with breast cancer. Patients received tbo- filgrastim, filgrastim, or placebo for cycle one. For cycle two to four, the patients that received placebo were switched to tbo-filgrastim. Doses were 5μg/kg daily for both active treatment groups for all cycles. The primary efficacy endpoint was duration of severe neutropenia in cycle one. When compared to placebo, tbo-filgrastim was provided a statistically significant improvement in duration of severe neutropenia (no P value reported). When compared to filgrastim, tbo-filgrastim was considered equivalent with a least square mean difference of 0.028 (95% CI, -0.262 to 0.325). Secondary endpoints showed no differences between tbo-filgrastim and filgrastim during any cycle or overall.38 Two additional studies published showed similar results but in patients with aggressive non- o Hodgkin’s lymphoma and small cell or non-small cell lung cancer.39,40 Key Points within the Medication Class • According to Current Clinical Guidelines: Primary prophylaxis with a CSF is recommended when the risk of febrile neutropenia is o greater than 20%11,12 Therapeutic use of a CSF be considered only when a patient with febrile neutropenia is at o high risk of infection-related complications based on prognostic factors.11,12 There is currently no general consensus among the guidelines regarding the specific CSFs o within the class. § The National Comprehensive Cancer Network filgrastim and pegfilgrastim are considered to have stronger data to support their use compared to sargramostim.11,13 § The European Organization for Research and Treatment of Cancer recommends the use of filgrastim and pegfilgrastim while stating that there is some evidence showing G-CSF and GM-CSF are comparable in efficacy.14 § The American Society of Clinical Oncology states that due to the lack of information, no recommendation can be made with regards to the equivalency of the two G- CSFs.12 • Other Key Facts: Filgrastim and filgrastim-sndz are approved for use in pediatric patients (no age restriction)1,2 o Dosing for pegfilgrastim is less frequent (once per chemotherapy cycle) than other CSFs o (daily for five to 12 days) due to its long half-life.1-5 All agents except sargramostim are available as prefilled syringes. Pegfilgrastim and tbo- o filgrastim are not available in as a single-use vial.1-5 Although filgrastim-sndz is a biosimilar agent, it does not share the indication of increasing o survival in patients acutely exposed to myelosuppressive doses of radiation with its reference product, filgrastim.1,2 References 1. Neupogen® [package insert]. Thousand Oaks (CA): Amgen Inc.; 2015 Mar. 2. Zarxio® [package insert]. Princeton (NJ): Sandoz Inc.; 2015 Mar. 3. Neulasta® [package insert]. Thousand Oaks (CA): Amgen Inc.; 2014 Dec. 4. Leukine® [package insert]. Bridgewater (NJ): Sanofi-Aventis U.S. LLC; 2013 Apr. 5. Granix® [package insert]. North Wales (PA): Teva Pharmaceuticals USA, Inc.; 2014 Dec. 6. Liles WC. Immunomodulators. In: Mandell GL, Bennett JE, Dolin R, editors. Manell, Bennett, & Dolin: Principles and Practice of Infectious Diseases [monograph on the internet]. 7th ed. Philadelphia: Churchill Livingston: 2009 [cited 2011 Apr 19]. Available from: http://www.mdconsult.com/das/book/body/110770361-5/773675061/1259/315.html#4-u1.0-B0-443-06643-4.50042-8-- cesec1_1721. 7. Blood Formation, Coagulation, and Thrombosis agents 20.00, Hematopoietic Agents 20.16. In: McEvoy GK, editor: American Hospital Formulary Service. AHFS drug information 2011 [monograph on the internet]. Bethesda (MD): American Society of Health-System Pharmacists; 2011 [cited 2011 Apr 19]. Available from: http://online.statref.com. 8. Medina PJ, Fausel C. Cancer treatment and chemotherapy. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: a pathophysiologic approach. 7th edition. New York (NY): McGraw-Hill; 2008. p. 2085-119. 9. Pappas AL, Hanna, S. TBO-filgrastim (granix). Pharmacy Times (2014) Retrieved Aug, 2015, from http://www.pharmacytimes.com/publications/health-system-edition/2014/march2014/tbo-filgrastim-granix. Page 4 of 6 Copyright 2015 • Review Completed on 8/5/2015 Therapeutic Class Overview: colony stimulating factors 10. Baehner R. Neutrophil functions other than movement. In: Basow DS (Ed). UpToDate [database on internet]. Waltham (MA): UpToDate; 2011 [cited 2011 Apr 19]. Available from: http://www.utdol.com/utd/index.do. 11. The NCCN Myeloid Growth Factors Clinical Practice Guidelines in Oncology (Version 1.2010). Fort Washington (PA): National Comprehensive Cancer Network, Inc. 2011 [accessed 2011 Apr 17]. Available from: http://www.nccn.org/index.asp. 12. Smith TJ, Khatcheressian J, Lyman GH, et al. 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. 13. The NCCN Acute Myeloid Leukemia Clinical Practice Guidelines in Oncology (Version 2.2011). Fort Washington (PA): National Comprehensive Cancer Network, Inc. 2011 [accessed 2011 Apr 17]. Available from: http://www.nccn.org/index.asp. 14. Aapro MS, Bohlius J, Cameron DA, Dal Lago L, Donnelly JP, Kearney N, et al. 2010 update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours. Eur J Cancer. 2011 Jan;47(1):8-32. 15. Micromedex® Healthcare Series [intranet database]. Version 5.1. Greenwood Village, Colo: Thomson Healthcare. [Cited 2014 Sep]. Available from: http://www.thomsonhc.com/. 16. Drug Facts and Comparisons [database on the Internet]. St. Louis: Wolters Kluwer Health, Inc.; 2013 [cited 2014 Sep]. Available from: http://online.factsandcomparisons.com. 17. Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2015 [cited: Aug 4 2015]. Available from: http://www.clinicalpharmacology.com. 18. Almenar D, Mayans J, Juan O, Bueno JM, Lopez JI, Frau A, et al. Pegfilgrastim and daily granulocyte colony-stimulating factor: patterns of use and neutropenia-related outcomes in cancer patients in Spain-results of the LEARN Study. Eur J Cancer Care (Engl). 2009 May;18(3):280-6. 19. Weycker D, Malin J, Kim J, Barron R, Edelsberg J, Kartashov A, et al. Risk of hospitalization for neutropenic complications of chemotherapy in patients with primary solid tumors receiving pegfilgrastim or filgrastim prophylaxis: a retrospective cohort study. Clin Ther. 2009 May;31(5):1069-81. 20. Weycker D, Malin J, Barron R, Edelsberg J, Kartashov A, Oster G. Comparative effectiveness of filgrastim, pegfilgrastim, and sargramostim as prophylaxis against hospitalization for neutropenic complications in patients with cancer receiving chemotherapy. Am J Clin Oncol. 2011 Mar 2 [Epub ahead of print]. doi: 10.1097/COC.0b013e31820dc075. 21. Holmes FA, O'Shaughnessy JA, Vukelja S, et al. Blinded, randomized, multicenter study to evaluate single administration pegfilgrastim once per cycle versus daily filgrastim as an adjunct to chemotherapy in patients with high-risk stage II or stage III/IV breast cancer. J Clin Oncol. 2002 Feb 1;20(3):727-31. 22. Beveridge RA, Miller JA, Kales AN, et al. A comparison of efficacy of sargramostim (yeast-derived RhuGM-CSF) and filgrastim (bacteria-derived RhuG-CSF) in the therapeutic setting of chemotherapy-induced myelosuppression. Cancer Invest. 1998;16(6):366-73. 23. Beveridge RA, Miller JA, Kales AN, et al. Randomized trial comparing the tolerability of sargramostim (yeast-derived RhuGM- CSF) and filgrastim (bacteria-derived RhuG-CSF) in cancer patients receiving myelosuppressive chemotherapy. Support Care Cancer. 1997 Jul;5(4):289-98. 24. Bohlius J, Herbst C, Reiser M, Schwarzer G, Engert A. Granulopoiesis-stimulating factors to prevent adverse effects in the treatment of malignant lymphoma. Cochrane Database Syst Rev. 2008 Oct 8;(4):CD003189. 25. Heaney ML, Toy EL, Vekeman F, Laliberté F, Dority BL, Perlman D, et al. Comparison of hospitalization risk and associated costs among patients receiving sargramostim, filgrastim, and pegfilgrastim for chemotherapy-induced neutropenia. Cancer. 2009 Oct 15;115(20):4839-48. 26. Nemunaitis J, Rabinowe SN, Singer JW, et al. Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid cancer. N Engl J Med. 1991 Jun 20;324(25):1773-8. 27. Lazarus HM, Andersen J, Chen MG, et al. Recombinant granulocyte-macrophage colony-stimulating factor after autologous bone marrow transplantation for relapsed non-Hodgkin's lymphoma: blood and bone marrow progenitor growth studies. A phase II Eastern Cooperative Oncology Group Trial. Blood. 1991 Aug 1;78(3):830-7. 28. Rabinowe SN, Neuberg D, Bierman PJ, et al. Long-term follow-up of a phase III study of recombinant human granulocyte- macrophage colony-stimulating factor after autologous bone marrow transplantation for lymphoid malignancies. Blood. 1993 Apr 1;81(7):1903-8. 29. Nemunaitis J, Rosenfeld CS, Ash R, et al. Phase III randomized, double-blind placebo-controlled trial of rhGM-CSF following allogeneic bone marrow transplantation. Bone Marrow Transplant. 1995 Jun;15(6):949-54. 30. Bernini JC, Wooley R, Buchanan GR. Low-dose recombinant human granulocyte colony-stimulating factor therapy in children with symptomatic chronic idiopathic neutropenia. J Pediatr. 1996 Oct;129(4):551-8. 31. Welte K, Zeidler C, Reiter A, et al. Differential effects of granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in children with severe congenital neutropenia. Blood. 1990 Mar 1;75(5):1056-63. 32. Grigg A, Solal-Celigny P, Hoskin P, et al. Open-label, randomized study of pegfilgrastim vs daily filgrastim as an adjunct to chemotherapy in elderly patients with non-Hodgkin's lymphoma. Leuk Lymphoma. 2003 Sep;44(9):1503-8. 33. Holmes FA, Jones SE, O'Shaughnessy J, et al. Comparable efficacy and safety profiles of once-per-cycle pegfilgrastim and daily injection filgrastim in chemotherapy-induced neutropenia: a multicenter dose-finding study in women with breast cancer. Ann Oncol. 2002 Jun;13(6):903-9. 34. Green MD, Koelbl H, Baselga J, et al. VA randomized double-blind multicenter phase III study of fixed-dose single- administration pegfilgrastim versus daily filgrastim in patients receiving myelosuppressive chemotherapy. Ann Oncol. 2003 Jan;14(1):29-35. 35. Vose JM, Crump M, Lazarus H, et al. Randomized, multicenter, open-label study of pegfilgrastim compared to daily filgrastim after chemotherapy for lymphoma. J Clin Oncol. 2003 Feb 1;21(3):514-9. 36. Staber PB, Holub R, Linkesch W, Schmidt H, Neumeister P. Fixed-dose single administration of Pegfilgrastim vs daily Filgrastim in patients with hematological malignancies undergoing autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 2005 May;35(9):889-93. Page 5 of 6 Copyright 2015 • Review Completed on 8/5/2015 Therapeutic Class Overview: colony stimulating factors 37. Milkovich G, Moleski RJ, Reitan JF, et al. Comparative safety of filgrastim versus sargramostim in patients receiving myelosuppressive chemotherapy. Pharmacotherapy. 2000 Dec;20(12):1432-40. 38. del Giglio A, Eniu A, Ganea-Motan D, Topuzov E, Lubenau H. XM02 is superior to placebo and equivalent to Neupogen in reducing the duration of severe neutropenia and the incidence of febrile neutropenia in cycle 1 in breast cancer patients receiving docetaxel/doxorubicin chemotherapy. BMC Cancer. 2008 Nov 12;8:332. doi: 10.1186/1471-2407-8-332. 39. Engert A, Griskevicius L, Zyuzgin Y, Lubenau H, del Giglio A. XM02, the first granulocyte colony-stimulating factor biosimilar, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with non- Hodgkin lymphoma receiving chemotherapy. Leuk Lymphoma. 2009 Mar;50(3):374-9. doi: 10.1080/10428190902756081. 40. Gatzemeier U, Ciuleanu T, Dediu M, Ganea-Motan E, Lubenau H, Del Giglio A. XM02, the first biosimilar G-CSF, is safe and effective in reducing the duration of severe neutropenia and incidence of febrile neutropenia in patients with small cell or non- small cell lung cancer receiving platinum-based chemotherapy. J Thorac Oncol. 2009 Jun;4(6):736-40. doi: 10.1097/JTO.0b013e3181a52964. 41. Weisdorf DJ, Verfaillie CM, Davies SM, et al. Hematopoietic growth factors for graft failure after bone marrow transplantation: a randomized trial of granulocyte-macrophage colony-stimulating factor (GM-CSF) vs sequential GM-CSF plus granulocyte-CSF. Blood. 1995 Jun 15;85(12):3452-6. 42. Nemunaitis J, Singer JW, Buckner CD, et al. Use of recombinant human granulocyte-macrophage colony-stimulating factor in graft failure after bone marrow transplantation. Blood. 1990 Jul 1;76(1):245-53. 43. Putkonen M, Rauhala A, Pelliniemi TT, Remes K. Single-dose pegfilgrastim is comparable to daily filgrastim in mobilizing peripheral blood stem cells: a case-matched study in patients with lymphoproliferative malignancies. Ann Hematol. 2009 Jul;88(7):673-80. 44. Martino M, Pratico` G, Messina G, et al. Pegfilgrastim compared to filgrastim after high-dose melphalan and autologous hematopoietic peripheral blood stem cell transplantation in multiple myeloma patients. Eur J Haematol. 2006 Nov;77(5):410-5. 45. Martino M, Pratico` G, Messina G, et al. Pegfilgrastim compared to filgrastim after high-dose melphalan and autologous hematopoietic peripheral blood stem cell transplantation in multiple myeloma patients. Eur J Haematol. 2006 Nov;77(5):410-5. 46. Castagna L, Bramanti S, Levis A, Michieli MG, Anastasia A, Mazza R, et al. Pegfilgrastim vs filgrastim after high-dose chemotherapy and autologous peripheral blood stem cell support. Ann Oncol. 2010 Jul;21(7):1482-5. 47. Mathew S, Adel N, Rice RD, Panageas K, Duck ET, Comenzo RL, et al. Retrospective comparison of the effects of filgrastim and pegfilgrastim on the pace of engraftment in auto-SCT patients. Bone Marrow Transplant. 2010 Oct;45(10):1522-7. 48. Samaras P, Buset EM, Siciliano RD, Haile SR, Petrausch U, Mischo A, et al. Equivalence of pegfilgrastim and filgrastim in lymphoma patients treated with BEAM followed by autologous stem cell transplantation. Oncology. 2010;79(1-2):93-7. 49. Samaras P, Blickenstorfer M, Siciliano RD, Haile SR, Buset EM, Petrausch U, et al. Pegfilgrastim reduces the length of hospitalization and the time to engraftment in multiple myeloma patients treated with melphalan 200 and auto-SCT compared to filgrastim. Ann Hematol. 2011 Jan;90(1):89-94. 50. Jansen J, Thompson EM, Hanks S, et al. Hematopoietic growth factor after autologous peripheral blood transplantation: comparison of G-CSF and GM-CSF. Bone Marrow Transplant. 1999 Jun;23(12):1251-6. 51. Stone RM, Berg DT, George SL, et al. Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. Cancer and Leukemia Group B. N Engl J Med. 1995 Jun 22;332(25):1671- 7. 52. Rowe JM, Andersen JW, Mazza JJ, et al. A randomized placebo-controlled phase III study of granulocyte-macrophage colony- stimulating factor in adult patients (> 55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood. 1995 Jul 15;86(2):457-62. 53. Büchner T, Hiddemann W, Koenigsmann M, et al. Recombinant human granulocyte-macrophage colony-stimulating factor after chemotherapy in patients with acute myeloid leukemia at higher age or after relapse. Blood. 1991 Sep 1;78(5):1190-7. Page 6 of 6 Copyright 2015 • Review Completed on 8/5/2015 Therapeutic Class Review Colony Stimulating Factors Overview/Summary This review will focus on the granulocyte colony stimulating factors (G-CSFs) and granulocyte- macrophage colony stimulating factors (GM-CSFs).1-5 Colony-stimulating factors (CSFs) fall under the naturally occurring glycoprotein cytokines, one of the main groups of immunomodulators.6 In general, these proteins are vital to the proliferation and differentiation of hematopoietic progenitor cells.6-8 The G- CSFs commercially available in the United States include pegfilgrastim (Neulasta®), filgrastim (Neupogen®), filgrastim-sndz (Zarxio®), and tbo-filgrastim (Granix®). While filgrastim-sndz and tbo- filgrastim are the same recombinant human G-CSF as filgrastim, only filgrastim-sndz is considered a biosimilar drug as it was approved through the biosimilar pathway. At this time, filgrastim-sndz has not applied for the interchangeable designation from the FDA. When tbo-filgrastim was approved, a regulatory pathway for biosimilar drugs had not yet been established in the United States and tbo- filgrastim was filed under its own Biologic License Application.9 Only one GM-CSF is currently available, sargramostim (Leukine). These agents are Food and Drug Administration (FDA)-approved for a variety of conditions relating to neutropenia or for the collection of hematopoietic progenitor cells for collection by leukapheresis.1-5 Due to the pathway taken, tbo-filgrastim does not share all of the same indications as filgrastim and these two products are not interchangeable. It is important to note that although filgrastim- sndz is a biosimilar product, and it was approved with all the same indications as filgrastim at the time, filgrastim has since received FDA-approval for an additional indication that filgrastim-sndz does not have, to increase survival in patients with acute exposure to myelosuppressive doses of radiation.1-3A complete list of indications for each agent can be found in Table 2. Differences among dosing schedules also exist between the agents. Pegfilgrastim is administered at a fixed dose (6 mg subcutaneously once per chemotherapy cycle), while both filgrastim, filgrastim-sndz, tbo-filgrastim, and sargramostim are dosed based on patient’s body weight and are administered daily.1-5 The G-CSFs are generally used in patients with cancer to reduce the incidence of adverse events associated with chemotherapy, such as febrile neutropenia, infections and delayed neutrophil recovery time. Neutrophils are the body’s defense system against infection and play a key role in the process of acute inflammation.10 Chemotherapy and radiation can affect neutrophil function as well as decrease the production of neutrophils in the bone marrow. When the absolute neutrophil count (ANC) falls below 1,500 cells/μL, this is defined as neutropenia. Patients who have severe neutropenia (ANC <500 cells/μL) are at high risk for infection.10 Endogenous G-CSF is a growth factor produced by monocytes, fibroblasts and endothelial cells that acts upon the bone marrow to increase the production of neutrophils. In addition to increasing neutrophil production, G-CSF also enhances phagocytic and cytotoxic actions of mature neutrophils.1,2 Filgrastim, tbo-filgrastim, filgrastim-sndz and pegfilgrastim are produced by recombinant deoxyribonucleic acid (DNA) technology via the insertion of the human G-CSF gene into Escherichia coli (E coli) bacteria.1-3,5 Pegfilgrastim, a long-acting formulation of filgrastim, is produced by conjugating filgrastim with polyethylene glycol, thereby increasing the molecular weight and delaying kidney excretion.3 GM-CSF is primarily used to accelerate myeloid recovery in oncology patients following myelosuppressive treatment regimens. Endogenous GM-CSF is predominantly found in T lymphocytes, monocytes, macrophages, fibroblasts and endothelial cells.6 In addition to increasing the production of neutrophils, GM-CSF also increases other white blood cells including monocytes, macrophages and eosinophils in the bone marrow as well as promoting their function. Like the G-CSFs, sargramostim is also produced utilizing recombinant DNA technology; however it is derived in yeast (Saccharomyces cerevisiae) expression system rather than from E coli bacteria.4 Based on current guidelines regarding the general use of CSFs such as the National Comprehensive Cancer Network (NCCN) Myeloid Growth Factors Clinical Practice Guideline in Oncology and the American Society of Clinical Oncology (ASCO) 2006 Update of Recommendations for the Use of White Page 1 of 59 Copyright 2015 • Review Completed on 8/5/2015 Therapeutic Class Review: colony stimulating factors Blood Cell Growth Factors, both recognize the importance of preventing and limiting the duration of febrile neutropenia. Similarly, both guidelines recommend primary prophylaxis with a CSF when the risk of febrile neutropenia is >20%. In addition, they recommend that the therapeutic use of a CSF be considered only when a patient with febrile neutropenia is at high risk of infection-related complications based on prognostic factors.11,12 There is currently no general consensus among the guidelines regarding the specific CSFs within the class. The NCCN states that when choosing an agent for the treatment of prophylaxis of febrile neutropenia, filgrastim and pegfilgrastim are considered to have stronger data to support their use compared to sargramostim.11,13 The European Organization for Research and Treatment of Cancer recommends the use of filgrastim and pegfilgrastim while stating that there is some evidence showing G-CSF and GM-CSF are comparable in efficacy.14 The ASCO state that due to the lack of information, no recommendation can be made with regards to the equivalency of the two G-CSFs.12 Medications Table 1. Medications Included Within Class Review Generic Name (Trade name) Medication Class Generic Availability Filgrastim (Neupogen®) Granulocyte colony stimulating factor a* Filgrastim-sndz (Zarxio®*) Granulocyte colony stimulating factor - Pegfilgrastim (Neulasta®) Granulocyte colony stimulating factor - Sargramostim (Leukine®) Granulocyte-macrophage colony stimulating factor - Tbo-Filgrastim (Granix®) Granulocyte colony stimulating factor - *Zarxio® is a biosimilar to the reference drug Neupogen®. Indications 1-5 Table 2. Food and Drug Administration-Approved Indications dz m m m Indication Filgrastim Filgrastim-sn pegfilgrasti Sargramosti Tbo-Filgrasti Allogeneic or autologous bone marrow transplantation in which engraftment is a delayed or has failed. To decrease the incidence of infection associated with severe neutropenia in a a a a patients receiving myelosuppressive therapy for nonmyeloid malignancies. To reduce the time to neutrophil recovery and the duration of fever following a a a† induction chemotherapy for acute myeloid leukemia. To reduce the time to neutrophil recovery and the duration of fever following a a consolidation chemotherapy for acute myeloid leukemia. To reduce the duration of neutropenia and neutropenia-related clinical sequelae in patients with nonmyeloid malignancies undergoing myeloablative a a chemotherapy followed by bone marrow transplantation. To accelerate myeloid recover in patients with non-Hodgkin’s lymphoma (NHL), acute lymphoblastic leukemia (ALL) and Hodgkin’s disease a undergoing autologous bone marrow transplantation. To mobilize autologous hematopoietic progenitor cells into the peripheral a a a blood for collection by leukapheresis. To reduce the incidence and duration of sequelae of neutropenia in a* a* symptomatic patients with congenital neutropenia‚ cyclic neutropenia‚ or Page 2 of 59 Copyright 2015 • Review Completed on 8/5/2015 Therapeutic Class Review: colony stimulating factors dz m m m Indication Filgrastim Filgrastim-sn pegfilgrasti Sargramosti Tbo-Filgrasti idiopathic neutropenia. To increase survival in patients acutely exposed to myelosuppressive doses a of radiation (Hematopoietic Syndrome of Acute Radiation Syndrome). *Indicated for chronic use †Safety and efficacy has not been established in patients <55 years of age. Although not Food and Drug Administration (FDA) approved, filgrastim has been used for the treatment of graft failure after bone marrow transplantation, neutropenia associated with myelodysplastic syndrome, hairy cell leukemia, aplastic anemia, acquired immune deficiency syndrome and zidovudine- and other drug-induced neutropenias. Pegfilgrastim has been used for peripheral blood stem cell leukapheresis prior to autologous stem cell transplantation. Sargramostim has also been used for non-FDA approved indications. It has been most commonly used to treat Crohn’s disease. Other uses of sargramostim include the treatment of melanoma, neutropenia associated with myelodysplastic syndrome or aplastic anemia, oral mucositis, pulmonary alveolar proteinosis, sepsis and neutropenia in the newborn, stomatitis, zidovudine- and other drug-induced neutropenia and wound healing. Sargramostim has also been used as a vaccine adjuvant and an adjunct to high-dose chemotherapy.15,16 Pharmacokinetics Table 3. Pharmacokinetics1-5,17 Active Serum Half- Generic Name(s)* Bioavailability (%) Renal Excretion (%) Metabolites Life (hours) Filgrastim 60 to 70 (SC) Not reported Not reported 3.5 Filgrastim-sndz 60 to 70 (SC) Not reported Not reported 3.5 Pegfilgrastim Not reported Not reported Not reported 15 to 18 1 (IV) Sargramostim Not reported Not reported Not reported 2 to 3 (SC) Tbo-Filgrastim 33* Not reported Not reported 3.2 to 3.8 SC=subcutaneous, IV=intravenous *Absolute bioavailability based on a dose of 5 μg/kg injected subcutaneously. Clinical Trials The safety and efficacy of the granulocyte and granulocyte-macrophage colony stimulating factors have been evaluated in several clinical trials, however, there are few trials that compare G-CSFs to GM- CSFs.18-53 Two retrospective trials evaluated the differences in efficacy between filgrastim and pegfilgrastim in patients with nonmyeloid malignancies who underwent chemotherapy. In Almenar et al, a multicenter, retrospective, observational trial, pegfilgrastim was associated with fewer episodes of febrile neutropenia compared to filgrastim (10.7 vs 24.3%, respectively; P value not reported) as well as fewer hospitalizations for febrile neutropenia (9.3 vs 19.8%, respectively; P value not reported).18 Results from Weycker et al also showed that the risk of hospitalization for febrile neutropenia or infection was lower with pegfilgrastim compared to filgrastim (odds ratio, 0.64; 95% CI, 0.48 to 0.85; P=0.002).19 Page 3 of 59 Copyright 2015 • Review Completed on 8/5/2015 Therapeutic Class Review: colony stimulating factors A multicenter, randomized, double-blind, active-control trial compared single-dose pegfilgrastim to daily filgrastim in reducing neutropenia in 310 patients who received four cycles of myelosuppressive chemotherapy for high-risk breast cancer. There were no significant differences between treatment groups in the duration of severe neutropenia and the depth of ANC nadir in all cycles. Overall, the incidence of febrile neutropenia was less in the pegfilgrastim group than in the filgrastim group (9 vs 18%; P=0.029). The difference in the mean duration of severe neutropenia between the pegfilgrastim and filgrastim treatment groups was less than one day. Adverse event profiles in the pegfilgrastim and filgrastim groups were similar. A single injection of pegfilgrastim per cycle was as safe and effective as daily injections of filgrastim in reducing neutropenia and its complications in patients who received four cycles of chemotherapy.121 One randomized, double-blind, multicenter trial compared filgrastim and sargramostim in 181 patients with chemotherapy-induced febrile neutropenia (absolute neutrophil count [ANC] ≤500 cells/μL). Patients were given daily subcutaneous injections of either agent until ANC levels reached ≥1,500 cells/μL. Overall, the mean number of days patients received filgrastim (4.60±0.14 days) was significantly shorter than sargramostim (5.70±0.23 days; P=0.0001). There was no significant difference among the treatment groups in the mean number of days to reach an ANC 500 cells/μL (filgrastim, 3.60±0.16 vs sargramostim, 3.30±0.16; P=0.32); however, the mean number of days to reach an ANC 1,000 and 1,500 cells/μL was significantly lower in the filgrastim group (4.50±0.13 and 4.60±0.14, respectively) compared to the sargramostim group (5.10±0.22 and 5.70±0.23, respectively; P=0.009 and P=0.0001, respectively). In regards to the other endpoints reported, patients in the sargramostim group had fewer hospitalizations with febrile neutropenia or intravenous (IV) antibiotics (P=0.46), shorter mean length of hospitalization (P=0.58) and shorter mean duration of fever (P=0.14) compared to patients in the filgrastim group; however, these endpoints did not reach statistical significance. Overall the agents were well tolerated and had comparable efficacy and tolerability in the treatment of standard-dose chemotherapy-induced myelosuppression in community practice.22 A second prospective, randomized, double-blind, multicenter trial comparing sargramostim and filgrastim published by the same author found that with the exception of a slightly higher incidence of grade 1 fever (37.1 to 38.0°C) with sargramostim compared to filgrastim (48 vs 26%, respectively; P=0.01), there were no statistically significant differences in the incidence or severity of local or systemic adverse events potentially related to CSFs. Although the study was not designed to evaluate efficacy directly, there were also no statistically significant differences between treatment groups in total days of growth factor therapy, days of hospitalization or days of IV antibiotic therapy during the treatment period. Both agents were well tolerated and there were no clinically significant differences between them.23 A Cochrane review of 13 randomized, placebo-controlled trials was performed to evaluate the efficacy and safety of G-CSF (filgrastim and lenograstim [not available in the United States]) or GM-CSF (sargramostim) compared to placebo in patients who were receiving nonmyeloablative chemotherapy for malignant lymphomas. Sensitivity analyses that were performed in this review concluded that there were no differences between G-CSF and GM-CSF in their effects on overall survival, freedom from treatment failure and risk reduction in incidence of neutropenia or febrile neutropenia.24 Two retrospective, case-controlled cohort trials were conducted to compare filgrastim, pegfilgrastim and sargramostim in reducing the risks of neutropenia-related hospitalizations in cancer patients receiving chemotherapies. Weycker et al found that the use of pegfilgrastim was associated with fewer hospitalizations for neutropenic complications compared to filgrastim and sargramostim (1.1, 2.1 and 2.5%, respectively; P<0.001 for both filgrastim and sargramostim compared to pegfilgrastim).20 Heaney et al found that sargramostim was associated with fewer infection-related hospitalizations compared to filgrastim (12 vs 26%, respectively; P=0.0422) and pegfilgrastim (24%; P=0.0628). The incidence of hospitalizations for febrile neutropenia was also lower in the sargramostim group compared to the filgrastim and pegfilgrastim groups; however, these differences were not statistically significant.25 Page 4 of 59 Copyright 2015 • Review Completed on 8/5/2015