Original Article

Acyclovir to Prevent Reactivation of Varicella Zoster Virus (Herpes Zoster) in Multiple Myeloma Patients Receiving Bortezomib Therapy
Eric Vickrey, PA-C, Sharon Allen, RN, APN, Jayesh Mehta, MD, and Seema Singhal, MD
BACKGROUND: Humoral-mediated as well as cell-mediated immunity is compromised in myeloma patients receiving treatment. Immunocompromised patients are at risk of developing herpes zoster. There is evidence from clinical trials that bortezomib therapy is associated with a significant risk of herpes zoster. It is the authors clinical policy to administer long-term acyclovir prophylactically to all symptomatic myeloma patients. METHODS: A retrospective review of the records of 125 myeloma patients who were treated with bortezomib and who also received routine acyclovir prophylaxis at the dose of 400 mg daily in >80% of patients was undertaken. Alternatives, used in <20% of patients, were 200 mg of acyclovir, 250/500 mg of valacyclovir, or 500 mg of famciclovir administered daily. This was accompanied by patient education regarding the importance of compliance with these prophylactic medications. RESULTS: The duration of bortezomib therapy was 1 to 164 weeks (median, 16 weeks). The total duration of exposure to bortezomib was 4150 weeks (80 patient-years). Except for the occasional missed dose, the self-reported compliance with antiviral prophylaxis was 100%. Not a single episode of herpes zoster was reported during this period. No adverse effects were noted that could be definitely attributed to acyclovir, valacyclovir, or famciclovir. CONCLUSIONS: Daily acyclovir (or a suitable alternative) appears to be effective at preventing herpes zoster virus in patients with myeloma who are receiving bortezomib, with or without corticosteroids. Cancer C 2008 American Cancer Society. 2009;115:229-32. V KEY WORDS: acyclovir, herpes zoster, myeloma, bortezomib, shingles, varicella zoster.

Although myeloma is a malignancy of B cells, humoral- and cell-mediated immunity are both compromised in myeloma patients, especially when they are receiving treatment.1,2 Immunocompromised patients are at risk of developing herpes zoster (varicella zoster virus reactivation).3,4 There is evidence from clinical trials that bortezomib therapy is associated with a significant risk of herpes zos5-7 ter. In a recent clinical trial using bortezomib that was associated with a sizeable incidence of herpes zoster before universal acyclovir prophylaxis, the incidence decreased markedly after acyclovir prophylaxis was administered.8

Corresponding author: Seema Singhal, MD, Division of Hematology/Oncology, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, 676 North St. Clair Street, Suite 850, Chicago, IL 60611; Fax: (312) 695-6189; s-singhal@northwestern.edu Division of Hematology/Oncology, Feinberg School of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois Received: March 25, 2008; Revised: August 1, 2008; Accepted: August 6, 2008
C 2008 American Cancer Society Published online: December 17, 2008, V

DOI: 10.1002/cncr:24006, www.interscience/wiley.com

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It has been our clinical practice to administer acyclovir prophylactically long-term to all symptomatic myeloma patients irrespective of the therapy they are receiving.2 The standard regimen we have used is 400 mg of acyclovir daily. The drug is administered when diseasespecific therapy is initiated, and is continued indefinitely unless toxicity supervenes. Although we are not aware of any published evidence to support this practice, it has been found to be effective in our experience because we have not noted any incidence of herpes zoster infection unless patients have been noncompliant. When myeloma patients undergo autologous hematopoietic stem cell transplantation (HSCT) with high-dose melphalan or receive combination chemotherapy that can result in mucositis, a higher acyclovir dose is used (400 mg three times daily) until oral mucositis resolves, at which time the dose is reduced to once daily.9 The purpose of the higher dose is to prevent herpes simplex virus reactivation. The aim of this retrospective review was to determine the efficacy of acyclovir prophylaxis in myeloma patients receiving bortezomib therapy.

Table 1. Herpes Zoster Prophylaxis Schedules Employed

Drug
Acyclovir Acyclovir Valacyclovir Famciclovir

Dose
400 mg daily 200 mg daily 250-500 mg daily 500 mg daily

Comments
The standard regimen (n101) Used if serum creatinine level is >2 mg/dL (n15) Alternative to acyclovir (n7) Alternative to acyclovir (n2)

MATERIALS AND METHODS

The study population was comprised of 125 patients with myeloma who received bortezomib with (n 101) or without (n 24) corticosteroids and fulfilled the following criteria: all treatment was administered at Northwestern University between July 2003 and July 2007, and patients were followed at least once a month. In all, 104 patients were being treated for recurrent or refractory disease, and 21 patients were being treated for newly diagnosed disease. Patients who received only part of their bortezomib therapy at Northwestern University (ie, therapy was delivered partly there and partly elsewhere) or those who received therapy elsewhere (usually in a community practice) but were regularly followed at Northwestern University (approximately 200 patients over the same time period) were excluded because of a lack of stringent information concerning compliance with antiviral prophylaxis. Patients who received bortezomib as part of combination regimens that contained agents other than corticosteroids were also excluded. In addition to disease-specific therapy and other medications, patients were advised to take acyclovir pro230

phylaxis if they were not already receiving it. Alternative agents were valacyclovir or famciclovir in <10% of patients. Table 1 shows the drug schedules used. A detailed medication history was taken at each visit to ensure compliance with all medications. Patients received bortezomib either in the standard manner (on Days 1, 4, 8, and 11 every 21 days) or on a once-weekly schedule. A small minority of patients were receiving bortezomib as maintenance therapy once a month with bisphosphonates because of a previous history of a good response to the drug. Paper and electronic clinical records were reviewed to determine drug therapy, herpes zoster occurrence, compliance, and potential drug toxicity. This retrospective chart review was approved by the Institutional Review Board as part of a study of bortezomib therapy in patients with myeloma.

RESULTS
The duration of bortezomib therapy, measured based on the first and last drug doses, was 1 to 164 weeks (median, 16 weeks). The total duration of bortezomib therapy was 4150 weeks (80 patient-years). During the period of observation, not a single episode of varicella zoster reactivation was observed. Greater than 90% of patients received acyclovir, and the remainder received valacyclovir or famciclovir over this period of time. In the context of our clinical practice, as described earlier, the duration of antiviral prophylaxis was much longer. Except for the occasional missed dose (including forgetting to take medication or running out of medication), the self-reported compliance rate with antiviral prophylaxis was 100%.

DISCUSSION
It is believed that the most common infections at the time of presentation in myeloma patients are Streptococcus
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Acyclovir to Prevent Herpes Zoster in Myeloma / Vickrey et al

pneumoniae, Haemophilus influenzae, and herpes zoster.10 Although to our knowledge there are no systematic data regarding the incidence of herpes zoster in myeloma patients, historically we have observed an incidence of herpes zoster that is close to 10% on an annual basis in patients who are receiving myeloma-specific therapy containing high-dose corticosteroids but who are not being treated with prophylactic acyclovir (unpublished data). On the basis of this finding, we have developed a policy of administering long-term acyclovir prophylaxis to all patients with myeloma once therapy is initiated, a practice that has been reflected in other anti-infection prophylaxis recommendations for myeloma patients.2 However, it must be emphasized that we are not aware of any other evidence to support this practice. Nonetheless, in our experience, the incidence of herpes zoster in patients receiving acyclovir has been very low. Indeed, whenever zoster has developed, it has been in a patient who has been noncompliant. Because acyclovir is relatively safe and inexpensive, with no known acquired resistance when it is used to prevent varicella zoster virus reactivation, the use of this agent in prophylaxis therefore appears justified. Recently, in the context of bortezomib therapy, herpes zoster appears to have become a clinically significant problem.5-8 In a multicenter study from Spain,8 the overall incidence of herpes zoster was 13% in the first 38 patients. After prophylactic acyclovir was introduced, only 2 of 30 patients developed herpes zoster. No data were available regarding compliance.8 In a randomized study by Chanan-Khan et al comparing bortezomib with dexamethasone,5 the incidence of herpes zoster was found to be significantly higher with bortezomib (13%) than with dexamethasone (5%) (P .0002). However, the incidence of other opportunistic infections, including herpes zoster, was comparable between the 2 arms (23% vs 20%). A weakness in the way the incidence of herpes zoster was described in that study5 was that zoster occurs in a time-dependent fashion and therefore cannot be described simply in terms of percentages. The duration of bortezomib therapy was longer than that of dexamethasone therapy in the study by Chanan-Khan et al because dexamethasone-treated patients developed disease recurrence earlier.5 It is therefore possible that the number of episodes of herpes zoster per patient-years of exposure to either drug may not have
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been as different as would appear. The data would be better expressed the way we have done in the current study (no episode of herpes zoster reported during 80 patientyears of exposure). It is interesting to note that bortezomib appeared to predispose patients to develop herpes zoster more than other infections. To our knowledge, the reason for this remains unclear. Many questions relating to the development of herpes zoster during bortezomib therapy arise. What is the exact mechanism of bortezomib-induced immunosuppression that predisposes patients to zoster reactivation? Does the risk of occurrence increase when patients are treated with bortezomib in combination with other agents compared with single-agent bortezomib? Does the risk of occurrence increase when patients are treated with infrequent doses of bortezomib (once a week or once a month)? Unfortunately, the answers to these are unknown. The initial choice of 400 mg as the standard dose was empiric. To our knowledge, the only data that existed when we initiated this practice >10 years ago pertained to higher doses of acyclovir.11 However, there are recent data validating the use of the 400-mg dose for prophylaxis in the setting of HSCT.12-14 Data from the current study suggest that acyclovir or related drugs are effective at preventing varicella zoster virus reactivation in myeloma patients receiving bortezomib provided that compliance is ensured. These drugs are relatively safe and effective. Moreover, treatment appears to be cost-effective because acyclovir is very inexpensive (approximately $15 for 100 tablets of 400 mg). However, although we have confined our data presentation in this study to patients receiving bortezomib, unpublished observations suggest that acyclovir at a dose of 400 mg daily (or the equivalent) is effective at preventing herpes zoster in myeloma patients regardless of the phase of the disease and the type of therapy administered. Based on the data presented herein, we suggest using acyclovir prophylactically in patients with myeloma who are receiving bortezomib therapy to prevent herpes zoster. We would suggest that prophylaxis should be continued at least as long as patients are being treated with bortezomib based on our observations. Although to our knowledge there are no data from clinical trials to support such a practice, because of the efficacy and safety of acyclovir, consideration should be given to using the drug
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prophylactically in patients with other diseases (eg, mantle cell lymphoma or Waldenstrom macroglobulinemia) who are receiving bortezomib or myeloma patients who are receiving any kind of systemic therapy. Of course, prospective clinical studies would be helpful to evaluate such an approach critically. Conflict of Interest Disclosures
Drs. Mehta and Singhal have acted as members of the Speakers Bureau for Millennium Pharmaceuticals and Celgene Pharmaceuticals.

7.

Kropff M, Bisping G, Schuck E, et al. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 2007;138: 330-337. Mateos MV, Hernandez JM, Hernandez MT, et al. Bortezomib plus melphalan and prednisone in elderly untreated patients with multiple myeloma: results of a multicenter phase 1/2 study. Blood. 2006;108:2165-2172. Trifilio S, Verma A, Mehta J. Antimicrobial prophylaxis in hematopoietic stem cell transplant recipients: heterogeneity of current clinical practice. Bone Marrow Transplant. 2004; 33:735-739.

8.

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