Abstract
Background/Aim: The importance of compliance with National Comprehensive Cancer Network (NCCN) guidelines for preventing varicella-zoster virus reactivation (VZVr) in multiple myeloma (MM) in a clinical setting has not been well investigated. Patients and Methods: We retrospectively studied the clinical characteristics and outcomes of 118 patients with MM treated with proteasome inhibitors. Results: Thirty-nine episodes of VZVr were observed in 37 patients (VZVr group). The proportion of prophylactic antiviral prescriptions and compliance with antiviral prophylaxis based on the NCCN Clinical Practice guidelines was 76% and 30% in the VZVr group, and 88% and 74% in the non-VZVr group, respectively. Multivariate analysis showed that compliance with the NCCN guidelines was the only independent risk factor for VZVr (p=0.0017). Conclusion: It is important that prophylactic antivirals are prescribed for an appropriate duration of time to prevent the reactivation of VZV in compliance with existing guidelines.
Multiple myeloma (MM) is an incurable refractory hematological disease, even in the era of novel anticancer agents. Bortezomib, the first proteasome inhibitor (PI), was approved in the United States (US) in May 2003 (in Japan in December 2006), followed by carfilzomib in the US in July 2012 (in Japan in August 2016) and ixazomib in the US in November 2015 (in Japan in May 2017), which has become a key drug for MM treatment. In addition, with the recent introduction of monoclonal antibodies (mAbs) such as elotuzumab, daratumumab, and isatuximab, the number of treatment options has increased dramatically (1, 2).
Several reports have shown that bortezomib increases varicella-zoster virus (VZV) reactivation (3-6), and the National Comprehensive Cancer Network (NCCN) guidelines place PI at high risk of VZV reactivation. Prophylactic oral antivirals such as acyclovir (ACV), famciclovir, and valacyclovir (VACV) should be considered during treatment and the associated neutropenic period. The risk of reactivation in autologous stem cell transplantation (ASCT), which is important in the treatment of MM, is considered moderate, and prophylactic medication should be continued for at least 6 months to 1 year after transplantation (7). Although it has been reported that prophylactic antivirals should be administered for mAbs, such as elotuzumab and daratumumab (8), the NCCN guidelines do not recommend prophylaxis for mAbs used in the treatment of MM, and a consensus has not yet been reached. A number of reports have examined the efficacy of antivirals in preventing VZV reactivation in patients with MM who have received bortezomib and conventional chemotherapy (9-15). However, these reports lacked information on the extent to which the guidelines were followed, although they did mention whether or not prophylactic antivirals were prescribed.
The aim of the study was to determine the detailed incidence of VZV reactivation and its risk factors, taking into account the prescription status of prophylactic antivirals during the past 10 years, including the treatment era of new agents.
Patients and Methods
Patients and study design. This retrospective study evaluated MM patients who had started treatment, including PIs, and had been treated for at least 3 months at the National Hospital Organization Tokyo Medical Center (Tokyo, Japan) between July 2009 and June 2019. Patient information was obtained from medical records. We collected data on patient baseline characteristics, including age, sex, International Staging System (ISS) category at diagnosis, myeloma subtype, Charlson Comorbidity Index (CCI), number of lines of myeloma therapy, medical history of herpes zoster (HZ) infection, diabetes mellitus, and collagen disease; and hematologic parameters such as neutrophil count, lymphocyte count, hemoglobin, platelet counts, C-reactive protein (CRP), and creatinine. This study was performed according to the principles set out in the 1964 Declaration of Helsinki and all subsequent revisions and was approved by the Ethics Committee at National Hospital Organization Tokyo Medical Center (R20-107). The need for informed consent was waived by the ethics committee because the data were retrieved from electronic medical records.
Myeloma treatment and antiviral prophylaxis. We investigated the use of typical drugs used in treating myeloma and the number of ASCT performed. We also surveyed the use of prophylactic antivirals since the start of PI treatment and compliance to NCCN guidelines that met the definition described below.
Characteristics of VZV reactivation. We also investigated the frequency and timing of onset of VZV reactivation, treatment for VZV, and postherpetic neuralgia (PHN) in cases that met the definition described below. The severity of VZV infection was determined using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Incidence of and risk factors for VZV reactivation. The cumulative incidence rates of VZV reactivation and reactivation-free mortality were evaluated using Gray’s method, considering both as a competing risk (16). Crude incidence rates of VZV reactivation per 100 person-years were calculated for each year since starting treatment with PIs. Person-time was censored at loss to follow-up, death, or 3 years after beginning treatment with PIs, whichever occurred first.
Definitions. VZV reactivation was defined as localized and disseminated HZ with a history of chickenpox. We could not obtain the anti-VZV immunoglobulin G serology of the patients. Localized HZ was defined in the presence of cutaneous vesicular lesions in a dermatomal distribution with or without confirmation of VZV by polymerase chain reaction. Disseminated HZ was defined as the subsequent appearance of lesions in non-contiguous dermatomes and/or visceral involvement. The occurrence of new episodes of VZV reactivation after complete resolution of a preceding episode or more than a week after adequate antiviral treatment was defined as recurrent VZV reactivation. The number of days until VZV reactivation was calculated using the date of PI initiation as the starting date. Antiviral prophylaxis was defined as patients in whom antiviral agents were prescribed for more than 4 weeks after the start of treatment with PIs. The proportion of prophylactic antiviral prescriptions covering the treatment period was calculated by dividing the total number of days from the start of prophylactic antiviral prescription to the last prescription date by the number of days from the start of PIs to the last dose (or until recovery to less than grade 3 neutropenia when there was grade 3 or greater) or 6 months from the day of transplant in ASCT recipients. Compliance with the recommended period of prophylactic antivirals in the NCCN guideline was defined as in which prophylactic antiviral prescriptions were at least 80% of the PI treatment period, including the associated neutropenic periods, or at least 6 months post-transplantation in patients with ASCT. PHN was defined as dermatomal pain that persisted for more than 3 months after VZV reactivation (17). Recent treatment history was defined as the most recent treatment that had been performed for up to 6 months before VZV reactivation.
Statistical analysis. Fischer’s exact test and Mann-Whitney U-test were used for between-group comparisons (univariate analysis) of categorical and numerical data, respectively. A multivariable model for the assessment of risk factors for VZV reactivation was constructed using logistic regression. All variables with p-values <0.15, in the univariate analyses, were included in the multivariate analysis. All p-values were two-sided, and p<0.05, was considered significant. All statistical analyses were performed using EZR version 1.40 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) (18).
Results
Patient characteristics. One hundred twenty-two patients started with PI therapy between June 2009 and July 2019, of which four were excluded due to a treatment duration <3 months, for 118 patients. VZV reactivation was observed in 37 patients with 39 episodes (including two recurrences). At the cut-off of June 30, 2020, patients were followed-up for a median of 44.3 months [interquartile range (IQR)=21.2-67.6]. Patients were divided into two groups according to the presence (VZVr) or absence (non-VZVr) of VZV reactivation. As shown in Table I, there were no significant differences in the baseline characteristics between the two groups, except for age and hemoglobin levels.
Baseline patient characteristics.
Myeloma treatment and antiviral prophylaxis. Table II shows the treatment of myeloma and the prevention of VZV reactivation with antiviral drugs. Treatment with PIs was started with bortezomib in almost all patients, and only one patient in the non-VZVr group received induction therapy with carfilzomib and then no treatment after ASCT; therefore, there was no history of treatment with bortezomib. All other 15 patients were administered carfilzomib except 1, and all 18 patients were administered ixazomib in combination with lenalidomide and dexamethasone for relapsed and/or refractory conditions. Alkylating agents indicate the therapeutic regimen, including oral cyclophosphamide (VCD) or melphalan (MP). There were 19 ASCT recipients (51%) in the VZVr group and 22 (27%) in the non-VZVr group with a statistically significant difference (p=0.019). Regarding the duration of exposure by each drug category, there was no significant difference, although immunomodulatory drugs (IMiDs) tended to be longer in the non-VZVr group. The majority of prophylactic antivirals prescribed were ACV 200 mg/day in 25 patients (68%) in the VZVr group and 65 patients (80%) in the non-VZVr group. No prophylactic antivirals were prescribed in nine patients (24%) in the VZVr group and 10 patients (12%) in the non-VZVr group. The median proportion of prophylactic antiviral prescriptions covering the treatment period was 42% (IQR=0-100) in the VZVr group and 100% (IQR=68.9-100) in the non-VZVr group. Compliance with the provisions of the NCCN guidelines for prophylactic antivirals was statistically significant in 11 patients (30%) in the VZVr group and 60 patients (74%) in the non-VZVr group (p<0.001).
Myeloma treatment and antiviral prophylaxis.
Characteristics of VZV reactivation. The median time from initiation of treatment with PIs to VZV reactivation was 353 days (IQR=106-634). Of the five patients who had been prescribed prophylactic antivirals at the time of VZV reactivation, one was more than 1 year after ASCT, and four were on bortezomib therapy, as shown in Table III. In addition, VZV reactivation was localized in 33 episodes (85%) and disseminated in six episodes (15%). According to the CTCAE version 5.0, there were no fatal infections, but there were eight grade 3 infections (20%) that required hospitalization. As for the treatment status at the time of VZV reactivation, ASCT was the most common treatment with 14 episodes (36%), followed by 11 episodes (30%) of induction therapy. The ASCT included 12 patients who were in treatment-free follow-up after ASCT and two patients on maintenance therapy. Nine of the 12 patients had their prophylactic antiviral prescriptions discontinued less than six months after ASCT. The most recent treatment at the time of VZV reactivation was no treatment for 18 episodes (46%), and these mostly occurred during the treatment-free observation period after ASCT and induction therapy. PHN as a complication after HZ was observed in 12 patients (13 episodes), 11 of whom underwent ASCT. Six of these patients continued to have neuropathic pain and were prescribed with analgesics, such as pregabalin. No grade 4 or 5 patients due to VZV reactivation were observed. All six patients diagnosed with disseminated HZ were hospitalized and required intravenous ACV treatment, and one of them had swelling and severe pain in the left auricle, which was initially suspected to be Ramsay Hunt syndrome. Since there was no obvious facial paralysis afterwards, a definitive diagnosis was not made, but it took 127 days before the planned treatment could be resumed.
Characteristics of varicella zoster virus infection episodes in patients with myeloma.
Incidence of and risk factors for VZV reactivation. The cumulative incidence of VZV reactivation after starting treatment with PIs was 16.5% [95% confidence interval (CI)=10.2-23.5] after 1 year and 36.5% (95% CI=26.4-46.6) during the observation period (Figure 1). The two cases with recurrent VZV reactivation were counted as events in the first reactivation. In addition, the incidence rate during the 3-year observation period was calculated using the person-year method to ascertain VZV reactivation status in each year of treatment with PIs. The 3-year incidence rate in 2009 was the highest at 27.5/100 person-years, and since 2010, the rates have been 14.0, 8.8, 14.3, 17.2, 10.5, 16.0, and 18.1 (Figure 2). Multivariate analysis showed that compliance with the NCCN guidelines was the only independent risk factor for VZV reactivation (odds ratio=0.17; 95% CI=0.054-0.51, p=0.0017) (Table IV).
Cumulative incidence of VZV reactivation after treatment with PIs. Censored patients are marked on the curves with a cross. VZV, Varicella zoster virus; PI, proteasome inhibitor.
The 3-year-incidence rates (per 100 person-years) of VZV reactivation after starting treatment with PIs. Crude incidence rates of VZV reactivation per 100 person-years were calculated for each year of starting treatment with PIs. Person-time was censored at loss to follow-up, death, or 3 years after starting treatment with PIs, whichever occurred first. VZV, Varicella zoster virus; PI, proteasome inhibitor.
Multivariate analysis of the risk factors for varicella zoster virus reactivation.
Discussion
To the best of our knowledge, this is the first report discussing the usefulness of compliance with the NCCN GL in preventing VZV reactivation using real-world data in Japan. In addition, this study was more detailed than previous reports, as it investigated not only the frequency of VZV reactivation after PI treatment, but also anticancer drug treatment for MM at the onset, treatment for HZ, and the frequency of PHN as a sequela, through long-term observation.
The proportion of VZV reactivation during the overall period of our study was 31.4% (37/118), which was higher than that previously reported in patients treated with bortezomib (0-16.7%), but the proportion of reactivation at one year of PI treatment was 16.1% (19/118), which was similar to that reported previously (3, 9-12). This may be due to differences in the median observation period (44.3 months in our study vs. 3.8-8.3 months in previous reports), that in the proportion of prophylactic antivirals prescribed [84% (99/118) vs. 0-100%], and the impact of ASCT and subsequent treatment in case of relapse (3, 9-12). In addition, the recommended daily dose of ACV for prophylactic use in the US and Europe is 800 mg (19); however, in our study, a lower dose of 200 mg was prescribed in 91% (90/99) of patients. In previous studies in patients treated with ASCT (14), allogeneic SCT (20), and bortezomib (21), including MM patients, 200 mg/day of ACV has been reported to be effective in preventing VZV reactivation. On the other hand, there are only few reports suggesting that 200 mg/day ACV is insufficient to prevent VZV reactivation and that a dose of 400 mg/day or higher is recommended (12). There are also reports on the prevention of VZV reactivation by VACV as an antiviral drug other than ACV (22-24), since there was no difference between the VZVr and Non-VZVr groups with regard to the type of prophylactic antivirals, as shown in Table II, we speculate that neither the type nor dose of prophylactic antivirals had a significant effect on VZV reactivation. The frequency and duration of IMiDs prescriptions are increasing, regardless of the indication for ASCT (25). Although IMiDs themselves have been reported to increase the risk of VZV reactivation (26), there were only five episodes (13%) of VZV reactivation during treatment with IMiDs, including the combination with PIs in our study.
As shown in Figure 2, a comparison of the 3-year reactivation rates for each year of PI initiation shows that 2009 was higher than in later years. The first case series of VZV reactivation by bortezomib was reported in 2005 (27), and a detailed analysis of VZV reactivation was reported in 2008 as an ancillary study to a large-scale clinical trial (APEX) (3). However, at that time, there was still a lack of evidence for the prevention of VZV reactivation, and the 2007 version of the NCCN guidelines did not include prophylactic antivirals during treatment with bortezomib, which was recommended in the 2012 version (28). As a result, we estimate that even in 2009, the frequency of prophylactic antiviral prescriptions was low and the rate of VZV reactivation was high. Out of the 11 myeloma patients who were on induction therapy at the time of VZV reactivation, five had started treatment with bortezomib in 2009, and all had VZV reactivation early in treatment without prophylactic antiviral prescriptions (Table III). One of the reasons for the subsequent decline in the rate of reactivation may be that prophylactic administration of ACV with bortezomib was approved for insurance coverage in September 2011 in Japan. Furthermore, since around 2010, pharmacists in our hospital have been actively checking individual prescriptions for both inpatients and outpatients, which may have contributed to a reduction in the number of missed prescriptions for prophylactic antivirals. More than half of the VZV reactivation occurred within 1 year of PI initiation (Figure 1), mainly during the treatment-free follow-up period after ASCT or initial treatment remission. The five guideline-compliant cases of VZV reactivation while continuing prophylactic antiviral prescriptions included two early after the start of induction therapy, one during the plateau phase after initiation of induction therapy, one during the first relapse therapy after induction therapy, and one during the first relapse therapy after tandem ASCT. Three of the patients, except for the two who reactivated early in the course of treatment with induction, reactivated after more than a year of treatment, and may have had poor adherence to prophylactic antivirals, although they had been prescribed.
PHN was the most common complication of VZV reactivation and was observed in 12 patients (13 episodes, 33%) in our study. Some of the patients had severe and persistent neuropathic pain and were prescribed analgesics such as pregabalin for more than half a year to reduce their quality of life. Although there were no fatal cases of VZV reactivation in our study, its prevention is important because there have been a small number of deaths in the general population (29), and some deaths have been reported in the absence of prophylactic medication, particularly in transplant recipients (30).
Recombinant zoster vaccine (RZV), which has already been approved in Europe and the US, was reported to have an efficacy rate of 68.2% in a prospective randomized clinical trial examining the efficacy of RZV in ASCT cases including MM (31). RZV became available in Japan in January 2020; therefore, it was not yet available during the study period, and there were no cases of routine RZV administration. In addition, some reports have already proposed measures incorporating RZV to prevent VZV reactivation after ASCT (7, 32). There were three cases of VZV reactivation after discontinuation of prophylactic antivirals more than one year after ASCT in our study, and similar cases have been reported in previous reports (30). Therefore, it is difficult to completely control reactivation by prophylactic antivirals alone, and prevention strategies combined with vaccination should be considered in the future in Japan.
Our study had several limitations. First, because it was a single-center, retrospective observational study, there was a selection bias. Second, prophylactic antivirals are only a prescribing history, and although pharmacists were interviewed in many cases during inpatient and outpatient treatment, they did not always confirm patient adherence in all cases. Finally, because our center did not have mandatory serological testing for VZV before ASCT, we could not strictly distinguish between primary and reactivated episodes of HZ.
In conclusion, we conducted a detailed analysis of VZV reactivation in MM patients with a history of PI treatment in the past 10 years, while taking into account the prescription status of prophylactic antivirals. In addition to prescribing prophylactic antivirals, it may be important that they be used for an appropriate period in accordance with the guidelines.
Footnotes
This article is freely accessible online.
Authors’ Contributions
YO and AY designed the study. YO, NM, YY, and AY prepared the manuscript. YO, MY, DN, AI, YN, KO, HU, TY, and AY collected the clinical data. YO and KH analyzed the data. All Authors have read and approved the final version of the manuscript.
Conflicts of Interest
The Authors declare that they have no competing interests.
- Received June 6, 2021.
- Revision received July 15, 2021.
- Accepted August 20, 2021.
- Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
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