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Originally published as JCO Early Release 10.1200/JCO.2008.21.0138 on March 23 2009 © 2009 American Society of Clinical Oncology.
Does Bortezomib Induce De Facto Varicella Zoster Virus Reactivation in Patients With Multiple Myeloma?Department of Hematology and Medical Oncology, St Francis Hospital and Medical Center, Hartford, CT
Georgetown Dermatology, Washington, DC To the Editor: In a subset analysis of the APEX (Assessment of Proteasome Inhibition for Extending Remissions) study, Chanan-Khan et al1 concluded that the use of bortezomib was associated with a significantly higher incidence of herpes zoster infections when compared with dexamethasone treatment for multiple myeloma (MM). The authors additionally call for consideration of prophylactic antivirals during treatment with bortezomib. We are making the point that it cannot be concluded with certainty whether bortezomib by itself contributed to the herpes zoster reactivation in the setting described. It appears to us premature and potentially toxic to recommend routine antiviral prophylaxis in this situation. Based on a publication from 1974,2 Chanan-Khan et al1 advocate that MM by itself is not a risk factor for recurrent herpetic infections, including zoster, because humoral rather than cell-mediated immune defects are present in this disease. However, recent work by Schütt et al3 demonstrated both cellular and humoral immunodeficiencies in patients with MM. Their analysis of 480 samples from 77 patients demonstrated significantly reduced CD4+/45RO+, CD19+, CD3+/HLA-DR+, and natural killer (NK) cells, as well as nonmyeloma immunoglobulin (Ig) A, IgG, and IgM in patients with untreated myeloma. Conventional-dose chemotherapy resulted in a significantly reduced CD4+ and an even further decline of CD4+/CD45RO+ cells in relapsed patients with MM. Moreover, prolonged immunosuppression was observed in the same group of patients after high-dose chemotherapy. Although CD8+, NK, CD19+ and CD4+/CD45RO+ cells recovered to normal values within 60 to 720 days; reduced levels of CD4+ counts persisted even longer thereafter. Occurrence of opportunistic infections, such as cytomegalovirus, pneumocystis pneumonia, and varicella zoster virus (VZV), was associated with severely reduced CD4+, CD4+/CD45RO+ and CD19+ counts. The mechanism of action of bortezomib, a reversible proteasome inhibitor, is partly mediated through the nuclear factor-kappa B (NF-kB) inhibition, leading to myeloma cell apoptosis, decreased angiogenic cytokine expression, and inhibition of tumor cell adhesion to stroma.4 However, bortezomib barely affected the unstimulated T cells in vitro5 and had little, if any, impact on the function or number of the mature lymphocytes in animal models.6 Similar studies in humans failed to show consistent alterations in CD4+, CD8+ or CD56+ NK cell populations with the use of bortezomib. In addition, elevated levels of NF-kB have been demonstrated to mediate immune suppression, while targeting NF-kB was shown to improve immune responses in tumor models. This effect occurs through a decrease in NK and T-cell death rate and a consequent augmentation of NK cell activation and cytotoxic antitumor activity.7 The suppressive effects of bortezomib seem to be largely confined to the interference with the immature dendritic cells, while mature monocyte-derived dendritic cells remain unaffected, maintaining their phenotype and allostimulatory capacity. Therefore, self-immunity processes rather than the adaptive immune responses are expected to be affected as a result of NF-kB inhibition with bortezomib.8 Direct data on viral replication during proteasome inhibition have been generated by Neznanov et al,9 who found that proteasome blockade stimulates stress-related processes, such as accumulation of chaperone heat shock protein and phosphorylation of elongation inhibitory factor. This process leads to an overall inhibition of translation, which in turn results in an inhibition of viruses such as the vesicular stomatitis virus and a delay in poliovirus replication.9 The patient cohort of Chanan-Khan et al1 is, in fact, heavily pretreated with such agents as steroids, alkylating drugs, anthracyclines, vinca alkaloids, and/or high-dose chemotherapy followed by stem-cell rescue. The likelihood of harboring severely reduced CD4+ cell counts in such patients is, evidently, high, in opposition to the authors' statement that "the degree of immunosuppression was not severe."1 A "below-normal absolute lymphocyte count during the days leading to the onset of zoster infection" likely signifies a pre-existing cell-mediated immunodeficiency in their cohort. However, the absence of a CD4+/CD8+ lymphocyte subpopulation analysis, as well as a humoral immune parameter assessment, makes it almost impossible to evaluate the pre-existing immune damage in these heavily pretreated patients. Therefore, it becomes difficult to determine whether the number of increased herpes zoster infections in this cohort could be attributed to the pre-existing immunosuppression in patients with MM, their heavy chemical pretreatment, or the proteasome inhibition itself. In addition, the primary end points of the APEX study were designed to assess treatment outcomes (overall survival, time to progression) in MM,10 and not the incidence of zoster events. The retrospective nature of this analysis is inherently a limitation, and prospective clinical trials have not been yet conducted in this regard. Other possibilities to be considered include that of a patient-to-patient transmission of VZV during the frequent clinic visits required by the administration of bortezomib for MM. Notwithstanding, the overall incidence (7% to 13%) of herpesvirus infections during the treatment with bortezomib appears to be similar to the incidence of those infections in myeloma, especially in the setting of advanced disease and in patients treated with steroids. To our knowledge, to date, no rigorous analysis has been conducted to prove with statistical power an increased incidence of VZV infections during treatment with bortezomib. Furthermore, the possibility of confounding bias is real. Our personal observation of the incidence of VZV in over 40 patients with MM revealed only 7% occurrence during the treatment with bortezomib versus 12% during other treatments, including systemic steroids. Renal injury associated with antiviral drugs, including acyclovir, involves direct renal tubular damage, as well as other processes affecting the renal transporters.11 Severe acyclovir-associated kidney impairment was shown to occur in immunocompromised patients.12 The resulting nephrotoxicity correlates well with the impaired baseline glomerular filtration rate. One would expect renal toxicity to be even higher in patients with myeloma who, in addition to immunosuppression, present an intrinsic tubular dysfunction produced by the disease process itself. Postmarketing surveys following the recent US Food and Drug Administration approval of bortezomib in first-line myeloma therapy will bring a more accurate estimate of the incidence of VZV events related to this agent. Assessing a previously untreated myeloma population is preferable, because the progressively impaired immunity as a result of the natural progression of MM and its therapy may explain the apparently increased incidence of VZV at the time bortezomib is administered. And, if bortezomib is shown to truly increase the incidence of VZV reactivation, this will have important implications for the clinical management of patients with MM. As of today, a careful assessment of the true causation of this phenomenon, and the associated risk-benefit ratio of prophylactic antivirals, is therefore required. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. 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. 2. Morison WL: Letter: Herpes simplex and herpes zoster in neoplasia. Lancet 1:1293; 1974.[Medline] 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. Rajkumar SV, Richardson PG, Hideshima T, et al: Proteasome inhibition as a novel therapeutic target in human cancer. J Clin Oncol 23:630–639, 2005. 5. Blanco B, Pérez-Simón JA, Sánchez-Abarca LI, et al: Bortezomib induces selective depletion of alloreactive T lymphocytes and decreases the production of Th1 cytokines. Blood 107:3575–3583, 2006. 6. Maseda D, Meister S, Neubert K, et al: Proteasome inhibition drastically but reversibly impairs murine lymphocyte development. Cell Death Differ 15:600–612, 2008.[CrossRef][Medline] 7. Jewett A, Head C, Cacalano NA: Emerging mechanisms of immunosuppression in oral cancers. J Dent Res 85:1061–1073, 2006. 8. Subklewe M, Sebelin-Wulf K, Beier C, et al: Dendritic cell maturation stage determines susceptibility to the proteasome inhibitor bortezomib. Hum Immunol 68:147–155, 2007.[CrossRef][Medline] 9. Neznanov N, Dragunsky EM, Chumakov KM, et al: Different effect of proteasome inhibition on vesicular stomatitis virus and poliovirus replication. PLoS ONE 3:e1887; 2008.[CrossRef][Medline] 10. Niesvizky R, Richardson PG, Rajkumar SV, et al: The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma. Br J Haematol 143:46–53, 2008.[CrossRef][Medline] 11. Izzedine H, Launay-Vacher V, Deray G: Antiviral drug-induced nephrotoxicity. Am J Kidney Dis 45:804–817, 2005.[CrossRef][Medline] 12. Schreiber R, Wolpin J, Koren G: Determinants of aciclovir-induced nephrotoxicity in children. Paediatr Drugs 10:135–139, 2008.[CrossRef][Medline]
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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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