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Originally published as JCO Early Release 10.1200/JCO.2008.21.0567 on March 23 2009 © 2009 American Society of Clinical Oncology.
Reply to C.A. Dasanu et alRoswell Park Cancer Institute, Buffalo, NY
Erasmus Medical Center, University Hospital, Rotterdam, the Netherlands
Hotel Dieu Hospital, Nantes, France
Dana-Farber Cancer Institute, Boston, MA We thank Drs Dasanu and Alezandrescu1 for their thoughtful comments regarding our study. In our trial, we demonstrated an increased incidence of varicella zoster virus (VZV) reactivation in patients with relapsed multiple myeloma (MM) receiving bortezomib treatment (13%), compared with those receiving high-dose dexamethasone (5%).2 In their letter, Dasanu and Alezandrescu raise the concern that a causative link between VZV reactivation and bortezomib treatment has not yet been established and that the benefit to risk ratio of routine antiviral prophylaxis in this patient population needs more careful assessment. We agree that the authors have highlighted an important need for more research to follow-up on our clinical observations, but we do believe that the evidence for the link between bortezomib exposure and VZV reactivation is now clear. Patients with MM are known to have an increased inherent risk of VZV reactivation, likely due to disease and treatment-related immune suppression. The enhanced incidence of herpes zoster infection observed with bortezomib treatment is unlikely due solely to immune suppression, as the absolute lymphocyte count tended to be lower in the dexamethasone control group compared with the bortezomib group, yet bortezomib-treated patients still had a higher rate of VZV reactivation. Patient-to-patient transmission of herpes zoster is unlikely, as the associated symptoms generally result from reactivation of latent VZV. The study by Schutt et al3 cited by Dasanu and Alezandrescu1 reported a VZV reactivation rate of 4%. Several other studies have demonstrated that the incidence of herpes zoster in patients with relapsed/refractory MM is notably lower than the 12% reported by Dasanu and Alezandrescu for their cohort of patients with MM (N = 40). In a phase III study of lenalidomide-dexamethasone in relapsed myeloma, conducted in a patient population comparable to that in our study, the rate of herpes zoster was not reported; however, only 1% of the patients in this study required treatment with antiviral medications, suggesting the rate was low.4 Similarly, in other clinical trials conducted in previously untreated MM, VZV reactivation was reported in 0% to 4%5–7 of patients treated with non–bortezomib-containing regimens. Large randomized trials that include safety reporting (including all types of infection) as a prospectively defined end point, have consistently and repeatedly demonstrated a higher incidence of VZV reactivation in patients treated with bortezomib in the absence of antiviral prophylaxis compared with patients receiving non–bortezomib-based therapies. In the relapsed setting, Kropff et al8 reported herpes zoster infection in 15% of patients treated with bortezomib-cyclophosphamide-dexamethasone, consistent with other phase II clinical trials.9,10 Use of bortezomib in the frontline setting, where patients may be less immune compromised due to the absence of prior therapies, have consistently demonstrated an increased VZV reactivation rate (Table 1). In the VISTA trial, herpes zoster infection occurred in 13% of newly diagnosed patients treated with bortezomib-melphalan-prednisone compared with 4% in patients treated with melphalan-prednisone alone.7 This trial was then amended to require antiviral prophylaxis after these early observations of increased VZV reactivation. On the addition of antiviral prophylaxis, the rate of herpes zoster decreased to 3% for the bortezomib containing cohort. Similar trends were seen across additional phase III randomized trials.11,12 Similarly, at Roswell Park Cancer Institute, 65 patients with MM (54 previously untreated and 11 relapsed/refractory) receiving bortezomib-based antimyeloma therapies were treated with acyclovir for prophylaxis of herpes zoster. None of these patients had reactivation of VZV (unpublished data).
A recent retrospective study by Vickrey et al13 clearly demonstrates the safety and efficacy of prophylactic acyclovir treatment in patients with MM receiving bortezomib therapy. This study examined 125 consecutive patients who received acyclovir prophylaxis in addition to bortezomib treatment. Compliance with acyclovir treatment was 100%, and no cases of VZV reactivation were reported. Additionally, acyclovir treatment was well tolerated with no adverse events attributed to this treatment. In the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma: Assessment With Melphalan and Prednisone) trial, adverse event profiles were similar for patients receiving antiviral prophylaxis compared with those not receiving these agents. In our own clinical experience, we have also noted that antiviral prophylaxis is highly effective and well tolerated in patients with MM,14 and most ongoing clinical studies utilizing bortezomib now mandate routine use of antiviral prophylaxis. Moreover, the National Comprehensive Cancer Network guidelines recommend that herpes zoster prophylaxis be considered for patients receiving bortezomib or bortezomib-based therapies.15 We recognize that the retrospective nature of our study does have weaknesses with regards to assessing the value of an intervention such as prophylaxis with acyclovir. However, several large prospective trials have clearly demonstrated the increased risk of VZV reactivation in patients receiving bortezomib-based therapies and confirmed that antiviral prophylaxis seems to be effective in ameliorating this risk. A large, randomized, double-blind prospective trial comparing antiviral prophylaxis with 0 placebo would be required to definitively determine the safety and efficacy of acyclovir prophylaxis in patients with myeloma receiving bortezomib-based therapies. However, we do not feel that at this time, with the preponderance of existing clinical evidence, that it would be reasonable or ethical to conduct a trial utilizing bortezomib but restricting access to antiviral prophylaxis. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Consultant or Advisory Role: Asher A. Chanan-Khan, Millenium (C), Celgene (C), Immunogen (C); Pieter Sonneveld, Jansen-Cilag (C); Paul G. Richardson, Millenium (C), Celgene (C), Johnson & Johnson (C); Jean-Luc Harousseau, Orthobiotech, Celgene, Pharmion (C) Stock Ownership: None Honoraria: Asher A. Chanan-Khan, Millenium, Celgene, Immunogen; Jean-Luc Harousseau, Ortho Biotech, Janssen-Cilag Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. Dasanu CA, Alexandrescu DT: Does bortezomib induce de facto varicella zoster virus reactivation in patients with multiple myeloma? J Clin Oncol doi: 10.1200/JCO.2008.21.0138. 2. Chanan-Khan A, Sonneveld P, Schuster MW, et al: Analysis of herpes zoster events among bortezomib-treated patients in the phase III APEX study. J Clin Oncol 26:4784–4790, 2008. 3. Schütt P, Brandhorst D, Stellberg W, et al: Immune parameters in multiple myeloma patients: Influence of treatment and correlation with opportunistic infections. Leuk Lymphoma 47:1570–1582, 2006.[CrossRef][Medline] 4. Weber DM, Chen C, Niesvizky R, et al: Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med 357:2133–2142, 2007. 5. Cavo M, Tacchetti P, Patriarca F, et al: Superior complete response rate and progression-free survival after autologous transplantation with up-front velcade-thalidomide-dexamethasone compared with thalidomide-dexamethasone in newly diagnosed multiple myeloma. Blood 112: 2008 abstr 158. 6. Palumbo A, Bringhen S, Caravita T, et al: Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: Randomised controlled trial. Lancet 367:825–831, 2006.[CrossRef][Medline] 7. San Miguel JF, Schlag R, Khuageva NK, et al: Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 359:906–917, 2008. 8. 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 138:330–337, 2007.[CrossRef][Medline] 9. Jagannath S, Richardson PG, Barlogie B, et al: Bortezomib in combination with dexamethasone for the treatment of patients with relapsed and/or refractory multiple myeloma with less than optimal response to bortezomib alone. Haematologica 91:929–934, 2006. 10. Richardson PG, Barlogie B, Berenson J, et al: A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med 348:2609–2617, 2003. 11. Harousseau JL, Mathiot C, Attal M, et al: Bortezomib/dexamethasone versus VAD as induction prior to autologous stem cell transplantion (ASCT) in previously untreated multiple myeloma (MM): Updated data from IFM 2005/01 trial. J Clin Oncol 26:455s; 2008 (suppl) abstr 8505.[CrossRef] 12. Sonneveld P, van der Holt B, Schmidt-Wolf IGH, et al: First analysis of HOVON-65/GMMG-HD4 randomized phase III trial comparing bortezomib, adriamycine, dexamethasone (PAD) vs VAD as induction treatment prior to high-dose melphalan (HDM) in patients with newly diagnosed multiple myeloma (MM): American Society of Hematology. Blood 112: 2008 abstr 653. 13. Vickrey E, Allen S, Mehta J, et al: Acyclovir to prevent reactivation of varicella zoster virus (herpes zoster) in multiple myeloma patients receiving bortezomib therapy. Cancer 115:229–232, 2008.[CrossRef] 14. DePaolo D, Miller KC, Whitworth A, et al: Oral acyclovir is an effective in decreasing the incidence of bortezomib associated herpes zoster in patients with multiple myeloma. Blood 110: 2007 abstr 3614. 15. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Multiple Myeloma 2009. http://www.nccn.org.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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