Abstract

Background: One of the most common side effects of chemotherapy in cancer patients is neutropenia that can result in hospitalization. The purpose of this study was to evaluate the efficacy and tolerability of polyethylene glycol (PEG)-filgrastim compared with filgrastim in the recovery of neutropenia. Methods: This study was a Phase I clinical trial conducted among patients with acute lymphoblastic leukemia aged <16 class="b" xss=removed>Results: The mean age of the patients was 8.82 ± 4.36 years (3–15 years). Six boys (54.5%) and five girls (45.5%) participated in the study. ANC increase among patients treated with PEG-filgrastim or filgrastim was analyzed separately, and the results showed statistically significant differences between the study groups (P = 0.038). Conclusions: According to the findings, it can be concluded that the PEG-filgrastim is better than filgrastim alone to improve neutropenia induced by chemotherapy in patients with acute lymphoblastic leukemia.

Introduction

Neutropenia is one of the most common side effects after chemotherapy in patients with malignancy. This is caused by chemotherapeutic drugs and cytotoxic agents due to the lack of the detection of tumor cells from myeloid normal cells.[1],[2] Severe or prolonged neutropenia may lead to treatment discontinuation in addition to patients' admission to the hospital for the treatment of neutropenia and fever with it. Neutropenia following chemotherapy may occur in patients receiving a standard dose that is prescribed for the treatment of various malignancies.[3],[4],[5] Severe decrease in neutrophil cell counts (<500 href="https://www.thieme-connect.com/products/ejournals/html/10.4103/ijmpo.ijmpo_134_18#JR_3" xss=removed>3],[4]

Recombinant human granulocyte colonystimulating factor (G-CSF) and recombinant human granulocyte- macrophage CSF are two drugs that are commonly used to reduce the risk of infection in patients with neutropenia. These drugs could decrease the severity and duration of neutropenia in patients with malignancy after chemotherapy.[1],[2]

G-CSF can be used as a secondary prophylaxis of neutropenia at the end of, chemotherapy which reduces the cases of hospitalization to receive antibiotics, infection, and fever associated with neutropenia.[5],[6],[7] However, fewer studies have been performed in children compared to adults.[8],[9]

Polyethylene glycol (PEG)-filgrastim is a pegylated G-CSF and new drug. The half-life of PEG-filgrastim is 46–62 h and is used as a single dose instead of the daily dose of G-CSF. One molecule of PEG binds to N-terminal of filgrastim and gets converted to PEG-filgrastim that provides low antigenicity, minimal toxicity, and appropriate excretion.[10],[11] The recommended dose of PEG-filgrastim is 6 mg in adults and 100 μg/kg in children (maximum 6 mg) that is given to patients 24 h after chemotherapy.[12],[13]

PEG-filgrastim in adults has better efficiency and can be easily administered compared to G-CSF,[14],[15] but research on the effectiveness these drugs in children is limited.[16],[17]

This study is the 1st clinical trial in Iran that was done for evaluating the side effects and the efficacy of PEG-filgrastim.

Materials and Methods

This clinical study (Phase I clinical trial) was conducted among patients that referred to the Oncology Department at Ali Asghar Hospital, Tehran, Iran, in 2013–2014. Inclusion criteria were as follows: age <16>

Convenience sampling was performed, and the patients who met the inclusion criteria were selected for the study. This study was done as self-control study, and the same patients were considered as a control group in the specified time interval.

All the patients were treated with filgrastim in the 1st period. The same patients were been placed in the opposite group if the patient was readmitted after the 1st treatment period at least one course later. All the patients had similar chemotherapy regimens in both groups. In the 1st period, the patients were treated by filgrastim (PDgrastim® 300 μ, Pooyesh Darou Pharma, Tehran, Iran). Filgrastim was administered at a dose of 5–10 μg/kg/day subcutaneously for 7 consecutive days (standard dose). The patients received PEG-filgrastim after the 2nd course. Each prefilled syringe contains 6 mg of PEG-filgrastim (Pega Gen®, 6 mg/syringe, Cinna Gen, Co, Iran) in 0.6 ml (0.6 mg/ml). The patients received a single subcutaneous injection of 100 μg/kg of PEG-filgrastim. Absolute neutrophil count (ANC) was checked 7 days after the last injection in the two groups. Chemotherapy regimens were similar in the two groups.

Paired t-test and Chi-square test were utilized to determine the difference between categorical variables of the two groups. This study was approved by the Ethics Committee of Tehran University of Medical Sciences and also was recorded in the Iranian Registry of Clinical Trials with IRCT201205279875N1.

Results

A total of 11 patients, 6 boys (54.5%) and 5 girls (45.5%), participated in the study. None of the patients were excluded from the study. The mean age of the patients was 8.82 ± 4.36 years (3–15 years). The patient characteristics are described in [Table 1].

| Figure 1  Differences between pre- and post-treatment absolute neutrophil count|

1. Hoekman K, van der Vijgh WJ, Vermorken JB. Clinical and preclinical modulation of chemotherapy-induced toxicity in patients with cancer. Drugs 1999; 57: 133-55
2. Lowenthal RKM, Eaton K. Toxicity of chemotherapy. Hematol Oncol Clin North Am 1996; 10: 967-90
3. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966; 64: 328-40
4. Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L. 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; 24: 3187
5. Pizzo PA, Poplack DG. Principles and practice of pediatric oncology. 6th ed., Vol. 2. Lippincott Williams & Wilkins (LWW): Philadelphia 2011; 2: p.1177
6. Beveridge RA, Miller JA, Kales AN, Binder RA, Robert NJ, Harvey JH. 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: 366-73
7. Morstyn G, Campbell L, Souza LM, Alton NK, Keech J, Green M. et al. Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet 1988; 1: 667-72
8. Pui CH, Boyett JM, Hughes WT, Rivera GK, Hancock ML, Sandlund JT. et al. Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. N Engl J Med 1997; 336: 1781-7
9. Bunn PAJr, Crowley J, Kelly K, Hazuka MB, Beasley K, Upchurch C. et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: A prospective phase III randomized study of the Southwest oncology group. J Clin Oncol 1995; 13: 1632-41
10. Staar S, Rudat V, Stuetzer H, Dietz A, Volling P, Schroeder M. et al. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001; 50: 1161-71
11. Molineux G. The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta). Curr Pharm Des 2004; 10: 1235-44
12. Zamboni WC. Pharmacokinetics of pegfilgrastim. Pharmacotherapy 2003; 23: 9S-14S
13. Spunt SL, Irving H, Frost J, Sender L, Guo M, Yang BB. et al. Phase II, randomized, open-label study of pegfilgrastim-supported VDC/IE chemotherapy in pediatric sarcoma patients. J Clin Oncol 2010; 28: 1329-36
14. Wendelin G, Lackner H, Schwinger W, Sovinz P, Urban C. Once-per-cycle pegfilgrastim versus daily filgrastim in pediatric patients with Ewing sarcoma. J Pediatr Hematol Oncol 2005; 27: 449-51
15. te Poele EM, Kamps WA, Tamminga RY, Leeuw JA, Postma A, de Bont ES. Pegfilgrastim in pediatric cancer patients. J Pediatr Hematol Oncol 2005; 27: 627-9
16. Milano-Bausset E, Gaudart J, Rome A, Coze C, Gentet JC, Padovani L. et al. Retrospective comparison of neutropenia in children with Ewing sarcoma treated with chemotherapy and granulocyte colony-stimulating factor (G-CSF) or pegylated G-CSF. Clin Ther 2009; 31 Pt 2: 2388-95
17. Fritsch P, Schwinger W, Schwantzer G, Lackner H, Sovinz P, Wendelin G. et al. Peripheral blood stem cell mobilization with pegfilgrastim compared to filgrastim in children and young adults with malignancies. Pediatr Blood Cancer 2010; 54: 134-7
18. Fox E, Widemann BC, Hawkins DS, Jayaprakash N, Dagher R, Aikin AA. et al. Randomized trial and pharmacokinetic study of pegfilgrastim versus filgrastim after dose-intensive chemotherapy in young adults and children with sarcomas. Clin Cancer Res 2009; 15: 7361-7
19. Andre N, Kababri ME, Bertrand P, Rome A, Coze C, Gentet JC. et al. Safety and efficacy of pegfilgrastim in children with cancer receiving myelosuppressive chemotherapy. Anticancer Drugs 2007; 18: 277-81
20. Shi YK, Chen Q, Zhu YZ, He XH, Wang HQ, Jiang ZF. et al. Pegylated filgrastim is comparable with filgrastim as support for commonly used chemotherapy regimens: A multicenter, randomized, crossover phase 3 study. Anticancer Drugs 2013; 24: 641-7

| Figure 1  Differences between pre- and post-treatment absolute neutrophil count|

1. Hoekman K, van der Vijgh WJ, Vermorken JB. Clinical and preclinical modulation of chemotherapy-induced toxicity in patients with cancer. Drugs 1999; 57: 133-55
2. Lowenthal RKM, Eaton K. Toxicity of chemotherapy. Hematol Oncol Clin North Am 1996; 10: 967-90
3. Bodey GP, Buckley M, Sathe YS, Freireich EJ. Quantitative relationships between circulating leukocytes and infection in patients with acute leukemia. Ann Intern Med 1966; 64: 328-40
4. Smith TJ, Khatcheressian J, Lyman GH, Ozer H, Armitage JO, Balducci L. 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; 24: 3187
5. Pizzo PA, Poplack DG. Principles and practice of pediatric oncology. 6th ed., Vol. 2. Lippincott Williams & Wilkins (LWW): Philadelphia 2011; 2: p.1177
6. Beveridge RA, Miller JA, Kales AN, Binder RA, Robert NJ, Harvey JH. 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: 366-73
7. Morstyn G, Campbell L, Souza LM, Alton NK, Keech J, Green M. et al. Effect of granulocyte colony stimulating factor on neutropenia induced by cytotoxic chemotherapy. Lancet 1988; 1: 667-72
8. Pui CH, Boyett JM, Hughes WT, Rivera GK, Hancock ML, Sandlund JT. et al. Human granulocyte colony-stimulating factor after induction chemotherapy in children with acute lymphoblastic leukemia. N Engl J Med 1997; 336: 1781-7
9. Bunn PAJr, Crowley J, Kelly K, Hazuka MB, Beasley K, Upchurch C. et al. Chemoradiotherapy with or without granulocyte-macrophage colony-stimulating factor in the treatment of limited-stage small-cell lung cancer: A prospective phase III randomized study of the Southwest oncology group. J Clin Oncol 1995; 13: 1632-41
10. Staar S, Rudat V, Stuetzer H, Dietz A, Volling P, Schroeder M. et al. Intensified hyperfractionated accelerated radiotherapy limits the additional benefit of simultaneous chemotherapy--results of a multicentric randomized German trial in advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 2001; 50: 1161-71
11. Molineux G. The design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta). Curr Pharm Des 2004; 10: 1235-44
12. Zamboni WC. Pharmacokinetics of pegfilgrastim. Pharmacotherapy 2003; 23: 9S-14S
13. Spunt SL, Irving H, Frost J, Sender L, Guo M, Yang BB. et al. Phase II, randomized, open-label study of pegfilgrastim-supported VDC/IE chemotherapy in pediatric sarcoma patients. J Clin Oncol 2010; 28: 1329-36
14. Wendelin G, Lackner H, Schwinger W, Sovinz P, Urban C. Once-per-cycle pegfilgrastim versus daily filgrastim in pediatric patients with Ewing sarcoma. J Pediatr Hematol Oncol 2005; 27: 449-51
15. te Poele EM, Kamps WA, Tamminga RY, Leeuw JA, Postma A, de Bont ES. Pegfilgrastim in pediatric cancer patients. J Pediatr Hematol Oncol 2005; 27: 627-9
16. Milano-Bausset E, Gaudart J, Rome A, Coze C, Gentet JC, Padovani L. et al. Retrospective comparison of neutropenia in children with Ewing sarcoma treated with chemotherapy and granulocyte colony-stimulating factor (G-CSF) or pegylated G-CSF. Clin Ther 2009; 31 Pt 2: 2388-95
17. Fritsch P, Schwinger W, Schwantzer G, Lackner H, Sovinz P, Wendelin G. et al. Peripheral blood stem cell mobilization with pegfilgrastim compared to filgrastim in children and young adults with malignancies. Pediatr Blood Cancer 2010; 54: 134-7
18. Fox E, Widemann BC, Hawkins DS, Jayaprakash N, Dagher R, Aikin AA. et al. Randomized trial and pharmacokinetic study of pegfilgrastim versus filgrastim after dose-intensive chemotherapy in young adults and children with sarcomas. Clin Cancer Res 2009; 15: 7361-7
19. Andre N, Kababri ME, Bertrand P, Rome A, Coze C, Gentet JC. et al. Safety and efficacy of pegfilgrastim in children with cancer receiving myelosuppressive chemotherapy. Anticancer Drugs 2007; 18: 277-81
20. Shi YK, Chen Q, Zhu YZ, He XH, Wang HQ, Jiang ZF. et al. Pegylated filgrastim is comparable with filgrastim as support for commonly used chemotherapy regimens: A multicenter, randomized, crossover phase 3 study. Anticancer Drugs 2013; 24: 641-7