The introduction of stem cell transplantation and the novel anti-myeloma agents, bortezomib, thalidomide, and lenalidomide, have improved the outcome of patients with multiple myeloma. In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. Herpes zoster has been reported as a possible adverse event associated with bortezomib because a major target of bortezomib, nuclear factor-kappaB, is known to be involved with T-cell immunity. Outcomes of interest were survival, disease control, response rate, response duration, quality of life and adverse effects. All patients who were included in this study were responsive to a prior salvage therapy with bortezomib and had a measurable disease. Case Report. A 73-year-old female with a history of marginal cell lymphoma was monitored without requiring therapy.
Two patients progressed to have chronic HZ ophthalmicus and postherpetic neuralgia requiring ongoing antiviral therapy and neuroepileptic medications for the neuropathic pain. Depending on how this dose is tolerated, subsequent doses may be increased or decreased. In particular, the use of Proteasome Inhibitors (PIs) such as bortezomib (initially approved by the US Food & Drug Administration [FDA] in 2003 for treatment of relapsed plasma cell myeloma, with further approval in 2008 and 2014 for additional indications) and carfilzomib (approved in 2012 for the treatment of relapsed and refractory myeloma previously treated with bortezomib and an immunomodulatory therapy) has further advanced our ability to treat this incurable disease. Brenner H, Gondos A, Pulte D. Serial monitoring for HBV displayed seroconversion one month after change in therapy. Conclusion. Bortezomib associated late HBV reactivation appears to be a unique event that requires further confirmation and brings to discussion whether hepatitis B core positive individuals would benefit from monitoring of HBV activation while on therapy.
Clinical studies suggest that bortezomib is effective for the treatment of MM and offers improved remission and better survival –. Worldwide chronic infection is an even greater problem affecting approximately 350 million individuals . 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. 2009;360:2645-2654. This can be induced by exposure to immunosuppressants or host immunodeficiency, chemotherapy with rituximab, immune modulation using prednisone, or infliximab for autoimmune conditions. Oncolytic herpes simplex virus-1 (oHSV) therapy utilizes viruses that are engineered to infect and replicate in cancer cells with minimal damage to non-neoplastic tissue. Eligibility criteria also included a serum concentration of AST or ALT less than 3× the upper limit of the normal range, a serum total bilirubin less than 2 mg/dL, a measured creatinine less than 2.5× the upper limit of the normal range, a platelet count of ≥ 75,000/mm2, and an absolute neutrophil count of at least 1,000/mm2.
Often times the start of this rash is mistaken for a spider bite, but instead of getting better, it worsens. This regimen was well tolerated, allowing dose intensity of all compounds in more than 90% of patients. A total of 98 consecutive patients diagnosed with MM and who were treated with upfront or salvage bortezomib-based treatments in the Severance Hospital between January 2006 and December 2012 were included. And tnf-related weak inducer of apoptosis. All patients provided written informed consent and received bortezomib-based combination chemotherapy as first-line treatment. These studies were simple repeats of Western studies testing the efficacy such of melphalan with prednisone (MP), multi-drug combinations such as M2 protocol [vincristine, carmustine, cyclophosphamide, melphalan, and prednisone (VBCMP)], vincristine with doxorubicin and dexamethasone(VAD) or merely reporting clinical features. The patient did not engage in tobacco, alcohol, or illicit drug use.
In 2008, she presented with back pain and was diagnosed with MM, presenting as a plasmacytoma. Peripheral neuropathy common; requires careful monitoring, neurological evaluation and possible dose/schedule modification, or change to SC route. She required vertebral decompression and focal radiation. Immunoproteasomes are hypothesized to promote the presentation of normal self-protein fragments to prevent autoimmune responses directed at uninfected lymphoid cells . She developed MM related acute renal failure with Cr of 6.2 mg/dL, which did not improve with plasmapheresis and resulted in dialysis dependence. All patients were enrolled and treated at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins between September 2004 and October 2006. BOR was administered at a dose of 1.3 mg/m2/day on days 1, 4, 8, and 11 of three weekly cycles.
Liposomal doxorubicin at 30 mg/m2 and zoledronic acid 4 mg were given on day 1 of each cycle along with ondansetron 16 mg. After a temporary response to five cycles, she progressed and was switched to LEN 5 mg taken after dialysis, thrice a week, on a 3-week-on and one-week-off regimen. She was being monitored for hepatitis serology at the dialysis center and had undergone seroconversion eight months after receiving BOR and one month after initiation of LEN therapy. Prior to BOR therapy, the patient was seropositive for hepatitis B surface antibody (anti-HBs) and hepatitis B core antibody (anti-HBc) with negative hepatitis B surface antigen (HBsAg), which was indicative of her having a resolved infection. Hepatitis C antibody was negative. Other laboratory values were as follows: WBC, 3000/μL; Hgb, 9.5 g/dL; platelets, 96,000/μL with normal electrolyte values. Her aminotransferase levels at that time were within normal limits [alanine aminotransferase level (ALT) 14 U/L and aspartate aminotransferase level (AST) 22 U/L].
After seroconversion, HBsAg was highly reactive with HBV DNA of 1.2 × 106 IU/mL (6.9 × 106 copies/mL); ALT was 19 U/L, AST 29 U/L, WBC 1900/μL, Hgb 10.8 g/dL, and platelets 142,000/μL. Ultrasound of the abdomen revealed an enlarged liver with coarse echo texture, which was deemed to be secondary to early cirrhosis or hepatitis. He also was found to have hyporeflexia throughout his extremities. Blood. During the following months, she developed cancer related complications. She was admitted to the hospital with vertebral fractures requiring surgical intervention, venous thrombosis, progressive functional decline, and sepsis. She was eventually placed under comfort care and died eleven months after seroconversion.
The median duration of follow-up for the 215 patients from diagnosis was 22.5 months (range, 2.0–64.0 months). In most instances, the hepatitis flares are asymptomatic, but icteric flares, and even hepatic decompensation and death have been observed [11, 12]. Clinical studies including two controlled trials showed that prophylactic therapy with antiviral suppression can reduce the rate of HBV reactivation, severity of associated hepatitis flares, and mortality [11, 13]. A clinical staging system for multiple myeloma. Another randomized, controlled trial of entecavir prophylaxis for rituximab associated HBV reactivation confirmed the reactivation incidence rate of individuals who did not receive prophylaxis as being 17.9%. For rescue assay with geldanamycin and 17-AAG, cells were pretreated with either agent for 1 hour before bortezomib treatment. The median hemoglobin at enrollment was 11.4 g/dL (range, 6.2 to 16.7 g/dL), with 44% (n = 16) of the patients with anemia (< 11 g/dL). We present a comparison of reported cases of HBV reactivation in . Beysel et al. Ninety-eight patients received a median of 4 treatment courses (range, 1–15) of bortezomib-based chemotherapy and a total of 427 bortezomib courses. He received four courses of VAD (vincristine, doxorubicin, and dexamethasone) regimen while on lamivudine prophylaxis. 1A, Table 3). This could be explained as selection bias. However, 18 months later, BOR associated late HBV reactivation was demonstrated by detection of 20,000 copies/mL (4000 IU/mL) of HBV DNA. The patient was lost to follow-up and had not taken the recommended lamivudine for at least a nine-month period. This raises the possibility of reactivation secondary to lack of compliance with recommended prophylaxis. Tanaka et al. In the Phase II SUMMIT and CREST study with bortezomib, more than 80% of patients had symptoms of polyneuropathy . Both were immediately discontinued and he was started on entecavir. The progression-free survival (PFS) was defined as the time that patients were alive and progression-free from initiation of treatment to the date disease progression was documented. BOR and DEXA were resumed thereafter. The serology of this patient preceding BOR therapy, with isolated positive anti-HBs, favors immunization over resolved infection. The lack of risk factors for contracting infection between onset of BOR and detection of HBV DNA demonstrates how this immunity can be lost and active infection recurs in the setting of chemotherapy. Goldberg et al.  describes a 72-year-old male with resolved HBV who underwent reactivation after four months of treatment with BOR. He failed to respond to entecavir (ETV), developed fulminant hepatic failure, and passed away within 4 weeks of onset of the acute episode. Given the isolated positive HBcAb, this case is the closest in terms of the initial serologies of our case, with reactivation of an apparently resolved hepatitis. With BOR and the ensuing immunocompromise, this infection resulted in fulminant hepatic failure. Our patient, on the other hand, had a progressive clinical decline secondary to complications of MM resulting in the family's decision to withdraw care. The role of one month of LEN remains unclear in this reactivation process. Mya et al. Einsele H, Liebisch P, Langer C, et al. Of the 273 patients with MM, one had reactivation four months after BOR and DEX salvage therapy. Although data are limited, it has been suggested that BOR may alter the number and function of specific lymphocyte subsets, in particular the CD8 T cells and CD56 natural killer cells . The consequent suppression of cellular mediated immunity (CMI) that plays an important role in the suppression of VZV reactivation may have a role in the unchecked replication of VZV during BOR therapy . As HBV is another DNA virus that remains dormant in the human host, whether HBV reactivation can be attributable to BOR's impact on CMI remains to be defined. AASLD chronic HBV guidelines 2009  () state that HBsAg and anti-HBc testing should be performed in persons who have high risk of HBV infection , prior to initiation of chemo- or immunosuppressive therapy. Prophylactic antiviral therapy should be administered to HBV carriers (regardless of baseline serum HBV DNA level) at the onset of cancer chemotherapy or a finite course of immunosuppressive therapy and maintained for 6 months afterwards. 2010;116:Abstract 40. HBsAg-positive persons with serum HBV DNA levels >2,000 IU/mL prior to undergoing cytotoxic chemotherapy should continue antiviral therapy until they reach therapeutic endpoints for chronic HBV. Effect of bortezomib and oHSV on cancer cell killing. (B) The median progression-free survival (PFS) is 15.6 months (95% CI, 11.2 to 21.1 months), with estimated 12-month and 18-month PFS of 58% (95% CI, 39% to 75%) and 45% (95% CI, 27% to 63%).
There is no enough information to recommend routine prophylaxis for these individuals. These patients should be monitored with serial laboratory testing and antiviral therapy initiated if serum HBV DNA becomes detectable . In conclusion, it has been a known fact that some chemotherapeutic agents pose a significant risk of HBV reactivation in HBV carriers. Bortezomib associated reactivation in resolved HBV is a unique phenomenon and brings to discussion whether such individuals receiving chemotherapy would benefit from antiviral prophylaxis versus serial monitoring of HBV DNA. This question should be addressed by future research studies. The defective function of DCs in patients with MM was significantly affected by loading tumor antigens, and neutralization of VEGF could overcome this DC dysfunction through the elimination of abnormal signal transduction . Syed-Mohammed R.
Jafri serves on the Advisory Board for Gilead. This case was presented at the American College of Physicians National conference, April 2013, and American College of Gastroenterology, October 2013. The abstract was published in Supplement to The American Journal of Gastroenterology Volume 108 Supplement 1, Page S118-119, October 2013.