Abstract
Background/Aim: Bendamustine-associated skin damage occurs frequently in Japan and can have a profound impact on health-related quality of life. To our knowledge, there are no reports on the timing of skin damage caused by bendamustine. This study assessed trends in and the time to onset of skin damage caused by bendamustine using the Japanese Adverse Drug Reaction Reporting Database (JADER). Patients and Methods: Data related to skin damage with more than five reported cases from April 2004 to March 2021 were extracted from JADER, and the relative risk of adverse events was estimated using the reporting odds ratio and 95% confidence interval. The data were analyzed for time to onset of skin damage. Results: JADER included a total of 2,450 reports of adverse drug reactions from bendamustine. Of these, 170 skin ailments of 10 types were reported to be associated with bendamustine. Significant associations for skin damage were found for rash, herpes zoster, and infusion-related reactions. The reporting odds ratios (with 95% confidence interval) for rash, herpes zoster, and infusion-related reaction were 1.63 (1.19-2.21), 3.25 (2.20-4.78), and 7.25 (4.84-10.85), respectively. The median onset (interquartile range) of rash, herpes zoster, and infusion-related reactions caused by bendamustine were 13 (10-28), 60 (28-107), and 6 (1-28) days, respectively. Conclusion: A comprehensive study using a pharmacovigilance approach enabled us to identify that a rash or infusion-related reaction may be expected within 2 weeks of treatment with bendamustine and that the onset of herpes zoster occurs at a median of 2 months after treatment with bendamustine.
Bendamustine is now being used to treat a variety of hematological malignancies, including non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia, and multiple myeloma. However, a phase II study in the United States revealed that 9.2% of patients with NHL treated with bendamustine had skin damage (1). Similarly, a phase II study in Japan showed that 46.4% of patients with NHL treated with bendamustine had skin damage (2). Using e-medical records, 42 (44.2%) were found to have experienced skin toxicities after the initiation of bendamustine chemotherapy (3); this frequency was similar to that of the phase II study. Therefore, it is suggested that bendamustine-associated skin damage occurs at a high frequency in Japan. Skin damage can have profound impacts on the health-related quality of life of patients (4-6). To monitor adverse drug reactions (ADRs), it is important to determine the onset time of skin damage caused by bendamustine; however, there are no reports on the timing of skin damage.
ADR data obtained from clinical trials before the approval of a drug constitute the information obtained from a relatively small population under various limitations. However, after approval, new trends in ADRs may be discovered through the repeated use of the drug in patients with various characteristics. Therefore, pharmacovigilance, which aims to monitor drug safety, is important for the proper use of all medicines (7-9). The spontaneous reporting system has been used to evaluate pharmacovigilance, which reflects the reality of clinical practice (10). The Pharmaceuticals and Medical Devices Agency (PMDA) in Japan has established a database of ADR information (JADER) as a spontaneous reporting system. In addition, the practice of pharmacovigilance enables the prompt provision of information to healthcare professionals and patients, thereby reducing the risk of ADRs in patients.
The purpose of this study was to retrospectively analyze the JADER database to identify the time profile of the skin disorders that developed in patients treated with bendamustine.
Patients and Methods
We used data from the public releases of the JADER database (11-14). This database is available for free download from the PMDA website (http://www.pmda.go.jp) and includes ADR cases. We analyzed ADR reports recorded between April 2004 and March 2021. The data structure of the JADER consists of four datasets: Patient demographic information (DEMO), drug information (DRUG), adverse events (REAC), and medical history (HIST). The ADRs in the JADER database were coded according to the terminology preferred by the Medical Dictionary for Regulatory Activities/Japanese version 24.1 (www.pmrj.jp/jmo/php/indexj.php).
We first removed duplicate cases from the DRUG and REAC tables. We then used the identification number of each ADR case to merge corresponding case data from the DRUG, REAC, and DEMO tables. The medication contributions to ADRs were classified as “suspected medicine,” “concomitant medicine,” and “interaction.” We only extracted cases that were classified as “suspected drug.”
Data on skin damage with more than five reported cases was extracted from JADER, and the relative risk of adverse events was estimated using the reporting odds ratio (ROR). ROR is frequently used in the spontaneous reporting database as an indicator of the relative risk of ADRs. We used the analysis data table and constructed 2×2 tables based on two classifications: The presence or absence of “skin damage” and the presence or absence of suspected bendamustine use. We calculated the RORs, 95% confidence intervals (Cis), and p-values using Fisher’s exact tests. Skin damage associations were considered positive when the lower limits of the 95% CIs of the ROR exceeded a value of 1. In addition, the detected skin damage associations were analyzed for the time to onset. The scale parameter α and shape parameter β were calculated from the Weibull distribution of the histogram of time to onset. All statistical analyses were performed using JMP Pro® 16 (SAS Institute, Cary, NC, USA).
Results
We combined data from three tables, DRUG (3,875,874 reports), REAC (1,096,193 reports), and DEMO (693,295 patients), by their ID number. We removed duplicate data from the DRUG and REAC tables. Of the causes of ADRs, all data included in the category of “suspected drug”, were extracted and used as the data table (1,772,494 reports). Analyzing this data table, we obtained 2,450 reports of ADRs caused by bendamustine. Of these, 170 cases of skin disorders were reported to be associated with bendamustine (Figure 1). The patient characteristics are shown in Table I. Approximately 55.3% of the patients were men. According to the age distribution of the study population, skin damage occurred frequently in those in their 70s (35.3%).
Process of constructing a data analysis table. ADR: Adverse drug reactions; DEMO: demographic information; DRUG: drug information; REAC: adverse events.
Patient characteristics.
Among the types of skin damage caused by bendamustine, the numbers of rash, herpes zoster, infusion-related reaction, Stevens–Johnson syndrome, drug eruption, erythema multiforme, toxic epidermal necrolysis, hypersensitivity, erythema, and toxic skin eruptions related to bendamustine use reported were 41, 26, 24, 24, 13, 10, 10, 9, 8, and 5, respectively (Table II). Rash, herpes zoster, and infusion-related reaction were extracted as ADRs with a 95% CI >1, and significant associations were detected for these three (rash, herpes zoster, infusion-related reaction) out of the 10 skin damage-related ADRs.
Numbers of reported cases and reporting odds ratios (RORs) of skin damage related to bendamustine out of 2,450 reported adverse drug events from the Japanese Adverse Drug Event Report Database.
A histogram of the time to onset of the three ADRs showed that they occurred from 6 to 60 days after bendamustine administration (Figure 2). The median onset (quartiles, 25-75%) of rash, herpes zoster, and infusion-related reactions caused by bendamustine 13 (10-28), 60 (28-107), and 6 (1-28) days, respectively. The Weibull distribution of the histogram of the time to onset showed that the range of 95% CIs for the shape parameter β of the infusion-related reaction was as follows: 0<β<1 (Table III).
A histogram of ocurrence of skin damage under therapy with bendamustine for rash (A), herpes zoster (B), and infusion-related reaction (C).
Median time to onset (TTO) and Weibull parameters of skin damage as adverse events of therapy with bendamustine.
Discussion
In our analysis, skin diseases were more common among individuals in their 60s and 70s, and were slightly more common in men. This result may be attributed to the fact that the median age at which NHL is diagnosed is 67 years, and that there are more deaths among men (15, 16). The results of the present study indicated that rash and infusion-related reactions were adverse events associated with bendamustine administration. This trend was similar to that reported in a previous retrospective study (3, 13). The median number of days for the occurrence of rash and infusion-related reactions was 13 days and 6 days after treatment, respectively. In particular, infusion-related reactions showed a strong tendency to occur early. To our knowledge, no prior report has shown the trend in the time to the onset of skin damage after treatment with bendamustine.
Structurally, bendamustine consists of three parts: A mechlorethamine group, which has an alkylating effect; a butyric acid side chain, which increases water solubility; and a benzimidazole ring, which has an antimetabolic effect (17, 18). A review of the current literature reported a relationship between the use of aromatic drugs and rash (19, 20). Skin damage such as infusion-related reaction and rashes shown in this study may be cross-reactions caused by the benzimidazole moiety of bendamustine.
In addition, the results of the present study indicate that herpes zoster is an adverse event of bendamustine administration. The median number of days for the occurrence of herpes zoster was 60 days after treatment. The incidence of herpes zoster after cancer-related treatment of NHL has been reported to be 12.2% (21). In a phase II study of bendamustine in Japan, the incidence of CD4 lymphopenia was 93% (22). Patients with CD4 lymphocytopenia are susceptible to various opportunistic infections such as herpes zoster (23). The time to onset of herpes zoster after cyclophosphamide, doxorubicin, vincristine, and prednisolone plus cyclophosphamide; epirubicin, vincristine plus prednisolone; and rituximab therapy has been reported to reach a plateau within 2 years of the diagnosis of NHL (21). It has been reported that NHL, shingles, and its complications can affect patients’ quality of life and delay scheduled anti-lymphoma treatment (21). To our knowledge, this is the first study to show a trend in the time to shingles following treatment with bendamustine.
However, this study has some limitations. The adverse drug cases in the JADER database were reported voluntarily. Thus, spontaneous reporting systems such as the JADER are subject to over-reporting, under-reporting, missing data, lack of a denominator, and the presence of confounding factors (e.g. concomitant medications and comorbidities) (24). Therefore, the true incidence of skin disorders cannot be calculated. Although the JADER dataset has more clinical details than other spontaneous reporting system databases, such as the Food and Drug Administration Adverse Events Reporting System, further studies are needed to address these limitations. However, bendamustine is one of the most important drug therapies for NHL. In addition, as bendamustine is administered as an outpatient regimen, it is difficult for healthcare professionals to monitor skin conditions of the patients daily. This makes it even more important to identify trends in the occurrence of skin damage, both in clinical practice and in the monitoring of ADRs. The results of this study suggest that a rash or infusion-related reaction may be expected within 2 weeks of treatment with bendamustine, and that the time to onset of herpes zoster is 2 months after treatment with bendamustine.
Conclusion
A comprehensive study using a pharmacovigilance approach enabled us to identify that a rash or infusion-related reaction occurs within 2 weeks of treatment with bendamustine, and that the time to onset of herpes zoster is 2 months after treatment with bendamustine. These findings will facilitate an increased awareness of these reactions among physicians and potentially aid in the diagnosis of these ADRs and in their clinical management.
Acknowledgements
This study was supported by a Grant-in-Aid for Young Scientists (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (grant no. 19K16429).
Footnotes
Authors’ Contributions
Misui Kashiwagi and Tadashi Shimizu served as co-first authors and each contributed equally to this study. Tadashi Shimizu and Mayako Uchida: Conceptualization, methodology, formal analysis, writing-original draft preparation, review and editing. Misui Kashiwagi, Rika Kawai, Takehiro Kawashiri and Yoshihiro Uesawa: Review and editing. Mayako Uchida: Supervision.
Conflicts of Interest
Authors declare no conflicts of interest.
- Received March 2, 2022.
- Revision received March 24, 2022.
- Accepted March 25, 2022.
- Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
