Objective  To study adverse drug events (ADEs) of busulfan the U. S. Food and Drug Administration Adverse Event Reporting System (FAERS), and to mine the potential ADE signals, so as to provide reference for the safe drug use in clinical practice.

Methods  Data from the first quarter of 2004 to the first quarter of 2023 were retrieved from the FAERS database, and ADE records for busulfan as a primary suspect drug were obtained through data cleaning and standardization of target drug names. Risk signals for busulfan ADEs were mined based on the reporting odds ratio method, the proportional reporting ratio method, and Medicines and Healthcare Products Regulatory Agency method. The information component  method was used to assess the intense of the risk signals. The ADEs were systematically classified according to Medical Dictionary for Regulatory Activities (MedDRA), and two ranking sequence of busulfan ADEs were generated by signal occurrence frequency and signal intense, respectively.

Results  A total of 20 326 ADE records were collected, involving 5 615 patients with 556 related ADE signals, of which 117 were newly reported as compared to those in the drug instruction of busulfan. Male patients accounted for a higher proportion than female patients (40.71% vs. 30.74%). The main population of patients were younger than 18 years old (31.56%). The reports were most reported by physicians (33.71%) and other health professionals (24.35%) as well as pharmacists (23.86%), mainly from the United States (29.69%), Japan (15.78%), and France (11.79%). The top five ADEs in terms of occurrence frequency were busulfan use in unapproved indications, hepatic veno-occlusive disease (HVOD), mucosal inflammation, cytomegalovirus infection, and graft versus host disease. The top five ADEs in terms of signal intense were HVOD, acute graft versus host disease, veno-occlusive disease, graft versus host disease, and chronic graft versus host disease. The ADE signals involves 23 system organ classes. The top three SOCs in terms of the number of ADE signals were infections/infestations, investigations and neoplasms benign/malignant/unspecified (include cysts and polyps).

Conclusion  When busulfan is used in clinic, attention should be paid to its adverse events in hepatic veno-occlusive disease, infections, graft versus host disease, neurotoxicity, and venous thromboembolism, which are likely to cause serious consequences. The clinical pharmacists can assist clinicians to make prevention plans in case of busulfan ADEs, so as to improve the safety of busulfan use in clinic.

1.Palmer J, McCune JS, Perales MA, et al. Personalizing busulfan-based conditioning: considerations from the American Society for Blood and Marrow Transplantation Practice Guidelines Committee[J]. Biol Blood Marrow Transplantn, 2016, 22(11): 1915-1925. DOI: 10.1016/j.bbmt.2016.07.013.

2.Geddes M, Kangarloo SB, Naveed F, et al. High busulfan exposure is associated with worse outcomes in a daily i.v. busulfan and fludarabine allogeneic transplant regimen[J]. Biol Blood Marrow Transplantn, 2008, 14(2): 220-228. DOI: 10.1016/j.bbmt.2007.10.028.

3.Grochow LB, Jones RJ, Brundrett RB, et al. Pharmacokinetics of busulfan: correlation with veno-occlusive disease in patients undergoing bone marrow transplantation[J]. Cancer Chemother Pharmacol, 1989, 25(1): 55-61. DOI: 10.1007/bf00694339.

4.宋敏, 张子雨, 张宏伟, 等. 基于FAERS数据库的伊布替尼不良事件信号挖掘研究[J]. 肿瘤药学, 2021, 11(4): 406-412. [Song M, Zhang ZY, Zhang HW, et al. Data mining for adverse events signals of ibrutinib based on FAERS database[J]. Anti-tumor Pharmacy, 2021, 11(4): 406-412.] DOI: 10.3969/j.issn.2095-1264.2021.04.04.

5.王华玲, 胡巧织, 徐珽. 基于FAERS的小剂量甲氨蝶呤药品不良事件信号挖掘研究[J]. 中国药业, 2021, 30(8): 88-91. [Wang HL, Hu QZ, Xu T. Data-mining of adverse drug event signals induced by low-dose methotrexate based on FAERS[J]. China Pharmaceuticals, 2021, 30(8): 88-91.] DOI: 10.3969/j.issn. 1006-4931.2021.08.027.

6.张婧媛, 白羽霞, 韩晟, 等. 数据挖掘方法检测药品不良反应信号的应用研究[J]. 药物不良反应杂志, 2016, 18(6): 412-416. [Zhang JY, Bai YX, Han S, et al. Application of data mining algorithm to detect adverse drug reaction signal[J]. Adverse Drug Reactions Journal, 2016, 18(6): 412-416.] DOI: 10.3760/cma.j.issn.1008-5734. 2016.06.003.

7.陈友生, 缪健, 梁义敏, 等. 常用药品不良反应信号检测方法研究进展[J]. 中国药物依赖性杂志, 2014, 23(2): 89-92. [Chen YS, Miao J, Liang YM, et al. Research progress on detection methods of common adverse drug reaction signals[J]. Chinese Journal of Drug Dependence, 2014, 23(2): 89-92.] DOI: 10.13936/j.cnki.cjdd1992. 2014.02.015.

8.谈军涛. 基于FAERS数据库的ACEI类药品不良反应信号挖掘与分析[D]. 重庆: 重庆医科大学, 2021.https://d.wanfangdata.com.cn/thesis/D02446570.

9.Bate A, Lindquist M, Edwards IR, et al. A Bayesian neural network method for adverse drug reaction signal generation[J]. Eur J Clin Pharmacol, 1998, 54(4): 315-321. DOI: 10.1007/s002280050466.

10.Feng X, Wu Y, Zhang J, et al. Busulfan systemic exposure and its relationship with efficacy and safety in hematopoietic stem cell transplantation in children: a meta-analysis[J]. BMC Pediatr, 2020, 20(1): 176. DOI: 10.1186/s12887-020-02028-6.

11.Bartelink IH, Lalmohamed A, van Reij EM, et al. Association of busulfan exposure with survival and toxicity after haemopoietic cell transplantation in children and young adults: a multicentre, retrospective cohort analysis[J]. Lancet Haematol, 2016, 3(11): e526-e536. DOI: 10.1016/s2352-3026(16)30114-4.

12.肖浩文, 肖扬, 蒋祖军, 等. 不同剂型白消安联合环磷酰胺预处理方案在异基因造血干细胞移植中严重毒副反应观察[J]. 临床血液学杂志, 2009, 22(5): 493-494. [Xiao HW, Xiao Y, Jiang ZJ, et al. Observe the severe adverse drug reactions of different dosage forms of busulfan combined with cyclophosphamide regimen in allogeneic hematopoietic stem cell transplantation[J]. Journal of Clinical Hematology, 2009, 22(5): 493-494.] DOI: 10.3969/j.issn.1004-2806.2009.05.016.

13.冀冰心, 苏力, 赵弘, 等. 异基因造血干细胞移植患者白消安每日一次静脉滴注联合环磷酰胺预处理方案的疗效及安全性[J]. 药物不良反应杂志, 2013, 15(3): 132-135. [Ji BX, Su L, Zhao H, et al. Efficacy and safety of pretransplant conditioning regimens with intravenous infusion of busulfan once daily and cyclophosphamide in patients undergoing allogeneic stem cell transplantation[J]. Adverse Drug Reactions Journal, 2013, 15(3): 132-135.] DOI: 10.3760/cma.j.issn.1008-5734.2013.03.004.

14.Jiang HL, Cao LQ, Chen HY. Protective effects ROS up-regulation on premature ovarian failure by suppressing ROS-TERT signal pathway[J]. Eur Rev Med Pharmacol Sci, 2018, 22(19): 6198-6204. DOI: 10.26355/eurrev_ 201810_16025.

15.潘焕玉, 朱康儿, 张涛, 等. 白消安-氟达拉滨预处理方案对异基因造血干细胞移植后肝静脉闭塞症的影响[J]. 暨南大学学报(自然科学与医学版), 2013, 34(2): 195-197. [Pan HY, Zhu KE, Zhang T, et al. Impact of busulfan-fludarabine conditioning regimen on hepatic veno-occlusive disease (HVOD) following allogeneic hematopoietic stem cell transplantation[J]. Journal of Jinan University (Natural Science & Medicine Edition), 2013, 34(2): 195-197.] DOI: 10.3969/j.issn.1000-9965. 2013.02.015.

16.DeLeve LD, Wang X Role of oxidative stress and glutathione in busulfan toxicity in cultured murine hepatocytes[J]. Pharmacology, 2000, 60(3): 143-154. DOI: 10.1159/000028359.

17.Nava T, Rezgui MA, Uppugunduri CRS, et al. GSTA1 genetic variants and conditioning regimen: missing key factors in dosing guidelines of busulfan in pediatric hematopoietic stem cell transplantation[J]. Biol Blood Marrow Transplantn, 2017, 23(11): 1918-1924. DOI: 10.1016/j.bbmt.2017.07.022.

18.Chen S, Osborn JD, Chen X, et al. Subacute hepatic necrosis mimicking veno-occlusive disease in a patient with HFE H63D homozygosity after allogeneic hematopoietic cell transplantation with busulfan conditioning[J]. Int J Hematol, 2015, 102(6): 729-731. DOI: 10.1007/s12185-015-1878-x.

19.中华医学会血液学分会. 造血干细胞移植后肝窦隙阻塞综合征诊断与治疗中国专家共识(2022年版)[J]. 中华血液学杂志, 2022, 43(3): 177-183. DOI: 10.3760/cma.j.issn.0253-2727.2022.03.001.

20.De Ramón Ortiz C, Justo Sanz R, Beauverd Y, et al. Low plasma levels of hyaluronic acid might rule out sinusoidal obstruction syndrome after hematopoietic stem cell transplantation[J]. Dis Markers, 2023, 2023: 7589017. DOI: 10.1155/2023/7589017.

21.Strouse C, Zhang Y, Zhang MJ, et al. Risk score for the development of veno-occlusive disease after allogeneic hematopoietic cell transplant[J]. Biol Blood Marrow Transplantn, 2018, 24(10): 2072-2080. DOI: 10.1016/j.bbmt.2018.06.013.

22.Brice K, Valerie B, Claire G, et al. Risk-adjusted monitoring of veno-occlusive disease following Bayesian individualization of busulfan dosage for bone marrow transplantation in paediatrics[J]. Pharmacoepidemiol Drug Saf, 2008, 17(2): 135-143. DOI: 10.1002/pds.1504.

23.杨漾, 张义成. 异基因造血干细胞移植后病毒感染的防治进展[J]. 内科急危重症杂志, 2023, 29(2): 101-105. [Yang Y, Zhang YC. Progress of prevention and treatment for viral infection following allogeneic hematopoietic stem cell transplantation[J]. Journal of Internal Intensive Medicine, 2023, 29(2): 101-105.] DOI: 10.11768/nkjwzzzz20230203.

24.Einsele H, Ljungman P, Boeckh M. How I treat CMV reactivation after allogeneic hematopoietic stem cell transplantation[J]. Blood, 2020, 135(19): 1619-1629. DOI: 10.1182/blood.2019000956.

25.秦菁, 张素平, 李丽, 等. 异基因造血干细胞移植后带状疱疹病毒感染的危险因素分析[J]. 中国组织工程研究, 2023, 27(33): 5292-5297. [Qin J, Zhang SP, Li L, et al. Analysis of risk factors for varicella-zoster virus infection after allogeneic hematopoietic stem cell transplantation[J]. Chinese Journal of Tissue Engineering Research, 2023, 27(33): 5292-5297.] DOI: 10.12307/2023.728.

26.Hakki M, Aitken SL, Danziger-Isakov L, et al. American Society for Transplantation and Cellular Therapy Series: #3-prevention of cytomegalovirus infection and disease after hematopoietic cell transplantation[J]. Transplant Cell Ther, 2021, 27(9): 707-719. DOI: 10.1016/j.jtct.2021.05.001.

27.Qu Y, Ding W, Liu S, et al. Metagenomic next-generation sequencing vs. traditional pathogen detection in the diagnosis of infection after allogeneic hematopoietic stem cell transplantation in children[J]. Front Microbiol, 2022, 13: 868160. DOI: 10.3389/fmicb.2022.868160.

28.Inazawa N, Hori T, Hatakeyama N, et al. Large-scale multiplex polymerase chain reaction assay for diagnosis of viral reactivations after allogeneic hematopoietic stem cell transplantation[J]. J Med Virol, 2015, 87(8): 1427-1435. DOI: 10.1002/jmv.24161.

29.Gooptu M, Antin JH. GVHD Prophylaxis 2020[J]. Front Immunol, 2021, 12: 605726. DOI: 10.3389/fimmu.2021. 605726.

30.Barba P, Piñana JL, Valcárcel D, et al. Early and late neurological complications after reduced-intensity conditioning allogeneic stem cell transplantation[J]. Biol Blood Marrow Transplant, 2009, 15(11): 1439-1446. DOI: 10.1016/j.bbmt.2009.07.013.

31.夏凡, 刘明红, 于迪, 等. 静脉滴注白消安致急性精神异常[J]. 中国医院药学杂志, 2020, 40(17): 1902-1903. [Xia F, Liu MH, Yu D, et al. Acute mental disorder caused by intravenous busulfan[J]. Chinese Journal of Hospital Pharmacy, 2020, 40(17): 1902-1903.] DOI: 10.13286/j. 1001-5213.2020.17.21.

32.中华医学会血液学分会造血干细胞应用学组. 造血干细胞移植相关血栓性微血管病诊断和治疗中国专家共识(2021年版)[J]. 中华血液学杂志, 2021, 42(3): 177-184. DOI: 10.3760/cma.j.issn.0253-2727.2021.03.001.