Granulocyte colony-stimulating factor therapy as a bridging treatment for pediatric decompensated liver cirrhosis prior to liver transplantation: an open-label randomized clinical trial

Tri Hening Rahayatri; Alida Harahap; Aryono Hendarto; Hanifah Oswari; Rianto Setiabudy; Akmal Taher

doi:10.15562/bmj.v11i3.3527

Granulocyte colony-stimulating factor therapy as a bridging treatment for pediatric decompensated liver cirrhosis prior to liver transplantation: an open-label randomized clinical trial

Tri Hening Rahayatri ,

Alida Harahap ,

Aryono Hendarto ,

Hanifah Oswari ,

Rianto Setiabudy ,

Akmal Taher ,

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DOI: https://doi.org/10.15562/bmj.v11i3.3527 |
Published: 2022-09-23

Abstract

Background: Decompensated cirrhosis (DC) in children is the main indication of liver transplantation (LT). The lack of access to liver transplantation and impending clinical complications while awaiting transplantation affect the morbidity and mortality in pretransplant patients. Granulocyte colony-stimulating factor (G-CSF) therapy has shown promising results in adult decompensated cirrhosis as a potential bridging treatment. Our study aimed to identify the effect of G-CSF on pediatric end-stage liver disease (PELD) score, liver function, CD34+ cell mobilization, nutritional status, survival, and short-term side effects in children awaiting LT.

Methods: This study was an open-label, randomized controlled trial that included patients with decompensated liver cirrhosis between 3 months and 12 years of age. The intervention group received 12 courses of G-CSF subcutaneous injection (5 μg/kg/day) plus standard medical treatment (SMT) for liver cirrhosis. Results were obtained regarding PELD scores, liver function, CD34+ cell mobilization, changes in leukocyte and neutrophil counts, nutritional status, survival, and side effects within three months.

Results: Thirty-five pediatric patients were randomized into the intervention (17 patients) and control (18 patients) groups. During the trial, 14 (82%) in the intervention group completed the treatment. The median ages of the patients in the intervention and control groups were 18 and 14.5 months, respectively. The study's primary outcome identified no statistically significant difference in PELD scores between the intervention and control groups after G-CSF treatment. Liver function tests that showed significant changes in the intervention group compared to the control group were from improvements in alanine aminotransferase (ALT) levels. Other liver function tests, nutritional status, and survival did not. CD34+ cell mobilization was increased in the intervention group compared with the control group, but there was no significant difference. Minor side effects of G-CSF were observed in the intervention group.

Conclusion: Multiple doses of G-CSF did not improve the PELD score, nutritional status, and survival after three months but significantly showed temporary improvement in ALT level.

References

Robert H. Squires VN, Rene R, Ekong U, Hardikar W, Emre Sukru, Mazariegos GV. Evaluation of the pediatric patient for liver transplantation: 2014 practice guideline by the American Association for the Study of Liver Diseases, American Society of Transplantation and the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Hepatology. 2014;60.
Oswari H, Rahayatri TH, Soedibyo S. Pediatric living donor liver transplant in indonesia's national referral hospital. Transplantation. 2020;104:1305-7.
Zhang QK, Wang M-L. The management of perioperative nutrition in patients with end stage liver disease undergoing liver transplantation. Hepatobiliary Surg Nutr. 2015;4:336-44.
Prajapati R, Arora A, Sharma P, Bansal N, Singla V, Kumar A. Granulocyte colony-stimulating factor improves survival of patients with decompensated cirrhosis: a randomized-controlled trial. Eur J Gastroenterol Hepatol. 2017;29:448-55.
Philips C, Augustine P, Ahamed R, Rajesh S, George T, Valiathan G, et al. Role of granulocyte colony-stimulating factor therapy in cirrhosis, 'inside any deep asking is the answering'. J Clin Transl Hepatol. 2019;7:371-83.
Yang Q, Yang Y, Shi Y, Lv F, He J, Chen Z. Effects of granulocyte colony-stimulating factor on patients with liver failure: a meta-analysis. J Clin Transl Hepatol. 2016;4:90-6.
Chavez-Tapia N, Mendiola-Pastrana I, Ornelas-Arroyo V, Norena-Herrera C, Vidana-Perez D, Delgado-Sanchez G, et al. Granulocyte-colony stimulating factor for acute-on-chronic liver failure: systematic review and meta-analysis. Ann Hepatol. 2015;14:631-41.
Skokowa J, Dale DC, Touw IP, Zeidler C, Welte K. Severe congenital neutropenias. Nat Rev Dis Primers. 2017;3:17032. doi: 10.1038/nrdp.2017.32.
Rodríguez ZN, Tordecilla CJ, Campbell BM, Joannon SP, Rizzardini LC, Soto AV, et al. Usefulness of G-CSF in pediatric high risk cancer patients with fever and neutropenia. Rev Chilena Infectol. 2005;22(3):223-7.
Badr M, Hassan T, Sakr H, Karam N, Rahman D, Shahbah D, et al. Chemotherapy-induced neutropenia among pediatric cancer patients in Egypt: risks and consequences. Molecular and Clinical Oncology. 2016;5(3):300-6.
Krishnankutty B, Advani S, Achreckar S, Thomas D. Granulocyte colony-stimulating factor (filgrastim) in chemotherapy-induced febrile neutropenia. Indian J Med Paediatr Oncol. 2010;31(3):125.
Rahayatri TH. Granulocyte-colony stimulating factor (G-CSF) as optimizing therapy for pediatric liver transplantation. ClinicalTrials.gov: Fakultas Kedokteran Universitas Indonesia; 2019.
Alvarez-Larran A, Jover L, Marin P, Petriz J. A multicolor, no-lyse no-wash assay for the absolute counting of CD34+ cells by flow cytometry. Cytometry. 2002;50(5):249-53. doi: 10.1002/cyto.10129.
Simonetto DA, Shah VH, Kamath PS. Improving survival in ACLF: growing evidence for use of G-CSF. Hepatol Int. 2017;11(6):473-5. doi: 10.1007/s12072-017-9834-x.
Duan XZ, Liu FF, Tong JJ, Yang HZ, Chen J, Liu XY, et al. Granulocyte-colony stimulating factor therapy improves survival in patients with hepatitis B virus-associated acute-on-chronic liver failure. World J Gastroenterol. 2013;19(7):1104-10. doi: 10.3748/wjg.v19.i7.1104.
Newsome PN, Fox R, King AL, Barton D, Than N-N, Moore J, et al. Granulocyte colony-stimulating factor and autologous CD133-positive stem-cell therapy in liver cirrhosis (REALISTIC): an open-label, randomised, controlled phase 2 trial. The Lancet Gastroenterology & Hepatology. 2018;3(1):25-36. doi: 10.1016/s2468-1253(17)30326-6.
Philips CA, Augustine P, Rajesh S, Ahamed R, George T, Padsalgi G, et al. Granulocyte colony-stimulating Factor Use in Decompensated Cirrhosis: Lack of Survival Benefit. J Clin Exp Hepatol. 2020;10(2):124-34. doi: 10.1016/j.jceh.2019.05.003.
Sharma S, Lal SB, Sachdeva M, Bhatia A, Varma N. Role of granulocyte colony stimulating factor on the short-term outcome of children with acute on chronic liver failure. J Clin Exp Hepatol. 2020;10(3):201-10. doi: 10.1016/j.jceh.2019.10.001.
Rathi S, Hussaini T, Yoshida EM. Granulocyte colony stimulating factor: A potential therapeutic rescue in severe alcoholic hepatitis and decompensated cirrhosis. Ann Hepatol. 2020. doi: 10.1016/j.aohep.2020.04.011.
Kwo PY, Cohen SM, Lim JK. ACG linical guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112(1):18-35. doi: 10.1038/ajg.2016.517.
Sharma M, Rao PN, Sasikala M, Kuncharam MR, Reddy C, Gokak V, et al. Autologous mobilized peripheral blood CD34(+) cell infusion in non-viral decompensated liver cirrhosis. World J Gastroenterol. 2015;21(23):7264-71. doi: 10.3748/wjg.v21.i23.7264.
Burdon TJ, Paul A, Noiseux N, Prakash S, Shum-Tim D. Bone marrow stem cell derived paracrine factors for regenerative medicine: current perspectives and therapeutic potential. Bone Marrow Res. 2011;2011:207326. doi: 10.1155/2011/207326.
Gaia S, Olivero A, Smedile A, Ruella M, Abate ML, Fadda M, et al. Multiple courses of G-CSF in patients with decompensated cirrhosis: consistent mobilization of immature cells expressing hepatocyte markers and exploratory clinical evaluation. Hepatol Int. 2013;7(4):1075-83. doi: 10.1007/s12072-013-9473-9.
Verma N, Kaur A, Sharma R, Bhalla A, Sharma N, De A, et al. Outcomes after multiple courses of granulocyte colony-stimulating factor and growth hormone in decompensated cirrhosis: A randomized trial. Hepatology. 2018;68(4):1559-73. doi: 10.1002/hep.29763.
Anand L, Bihari C, Kedarisetty CK, Rooge SB, Kumar D, Shubham S, et al. Early cirrhosis and a preserved bone marrow niche favour regenerative response to growth factors in decompensated cirrhosis. Liver Int. 2019;39(1):115-26. doi: 10.1111/liv.13923.
Liu K, Wang FS, Xu R. Neutrophils in liver diseases: pathogenesis and therapeutic targets. Cell Mol Immunol. 2021;18(1):38-44. doi: 10.1038/s41423-020-00560-0.
Albillos A, Lario M, Álvarez-Mon M. Cirrhosis-associated immune dysfunction: Distinctive features and clinical relevance. Journal of Hepatology. 2014;61(6):1385-96. doi: 10.1016/j.jhep.2014.08.010.
Cameron R, Kogan-Liberman D. Nutritional considerations in pediatric liver disease. Pediatr Rev. 2014;35(11):493-6. doi: 10.1542/pir.35-11-493.
Mouzaki M, Bronsky J, Gupte G, Hojsak I, Jahnel J, Pai N, et al. Nutrition Support of Children With Chronic Liver Diseases: A Joint Position Paper of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2019;69(4):498-511. doi: 10.1097/mpg.0000000000002443.
Sveikata A, Gumbrevicius G, Sestakauskas K, Kregzdyte R, Janulionis V, Fokas V. Comparison of the pharmacokinetic and pharmacodynamic properties of two recombinant granulocyte colony-stimulating factor formulations after single subcutaneous administration to healthy volunteers. Medicina (Kaunas). 2014;50(3):144-9. doi: 10.1016/j.medici.2014.08.001.