Experience with use of Zostavax® in patients with hematologic malignancy and hematopoietic cell transplant recipients
Authors: Elliot Naidus, Lloyd Damon, Brian S. Schwartz, Cheryl Breed, Catherine Liu
Journal: American Journal of Hematology (2011)

Compared with immunocompetent hosts, patients with hematologic malignancy and hematopoietic cell transplant (HCT) recipients have increased rates of herpes zoster (HZ) and are at higher risk for disseminated disease, complications such as bacterial superinfection, post-herpetic neuralgia, and death (Cohen, J Infect Dis 2008;197 Suppl 2:S237-241; Locksley, et al., J Infect Dis 1985;152:1172-1181; Mazur and Dolin, Am J Med 1978;65:738-744; Schimpffer, et al., Ann Intern Med 1972;76:241-254; Schuchter, et al., Blood 1989;74:1424-1427). Improved strategies for prevention are needed to reduce the morbidity associated with HZ in these patients. While Zostavax® is FDA-approved for healthy adults ≥50-years-old, there are no published data on its safety and efficacy among immunocompromised patients. We retrospectively assessed our experience with the use of Zostavax® among 62 patients with hematologic malignancy, of whom 26 (41.9%) and 5 (8.1%) received an autologous and allogeneic HCT, respectively. The median time to vaccination post-transplant was 482 days (range, 173–4,334 days) and 1,323 days (range, 703–2,406 days) for autologous and allogeneic HCT recipients, respectively. The median duration of patient follow-up post-vaccination was 268.5 days (range, 51–947 days). There were no documented adverse reactions. A single patient developed HZ during the study period. Although further research is clearly needed, these data suggest that Zostavax® may be received safely in select patients with hematologic malignancy on minimal or no immunosuppressive therapy. Current options for prevention of HZ in this population are primarily limited to antiviral prophylaxis. Acyclovir is recommended for the prevention of HZ for the first year post-hematopoietic cell transplant (HCT) although HZ can occur later, particularly among those requiring ongoing immunosuppressive therapy [1-5]. There is limited experience with the use of live-attenuated varicella vaccine (Varivax®) in pediatric HCT recipients [6, 7], and an investigational inactivated varicella vaccine appears promising although is currently available for research use only [8]. The herpes zoster (HZ) vaccine (Zostavax®, Merck) contains a live, attenuated virus that is about 14 times more potent than the varicella vaccine (Varivax®, Merck) and is not licensed for use in immunocompromised patients. The 2008 Advisory Committee on Immunization Practices (ACIP) guidelines indicate that if the vaccine is to be used, that it be administered no earlier than 24 months after transplantation on a case-by-case basis depending on the patient's immune status [9]. The 2009 ASBMT Guidelines considers Varivax® "optional" among those patients who are >24 months post-transplant without active GVHD or on immunosuppression, with Zostavax® being contraindicated in HCT recipients given the significantly higher viral titers [10]. For patients with hematologic malignancy who have not undergone HCT, the 2008 ACIP guidelines indicate that the vaccine may be given to those patients whose leukemia is in remission and who have not received chemotherapy (e.g., alkylating drugs or antimetabolites) or radiation for at least 3 months and recommends that immunosuppressive therapy such as high-dose corticosteroids be discontinued for at least a month prior to vaccination. Since 2007, the University of California, San Francisco (UCSF), Hematology and Blood and Marrow Transplant (BMT) group has used the vaccine among patients with hematologic malignancy and HCT recipients who were selected at the provider's discretion based on the clinical impression of having intact immunity and in the absence of data to suggest harm of the vaccine in such patients. Given the paucity of data on safety and efficacy of Zostavax® in patients with hematologic malignancy and HCT recipients, we elected to review our institution's experience with this vaccine in this population. Between November 2007 and May 2010, we identified 62 patients with hematologic malignancy and/or HCT who received the Zostavax® vaccine. The median duration of patient follow-up was 268.5 days (range, 51–947 days) post-vaccination. Thirty-one (50%) patients received a HCT; 26 underwent autologous HCT while five had an allogeneic HCT. The median duration to vaccination post-transplant was 482 days (range, 173–4,334 days) and 1,323 days (range, 703–2,406 days) for autologous and allogeneic HCT recipients, respectively. Seventeen (54.8%) HCT recipients (all autologous HCT) received the vaccine <24 months after transplant. Two patients had a distant history (>1 year) of graft-vs.-host disease (GVHD); they had absolute lymphocyte counts (ALC) of 2,080 and 1,230 cells/μL, respectively, and were not on immunosuppression or antiviral therapy at the time of vaccination. Detailed patient characteristics regarding demographics, underlying hematological disease and associated therapy, as well as immunological markers at the time of vaccination are provided in the Table I. Of the 31 patients with hematologic malignancy who had not received a HCT, 16 (51.6%) were in complete remission at the time of vaccination. Of these 16 patients, three received rituximab within 3 months of vaccination, one received concurrent maintenance bortezomib, and one patient received a combination of bortezomib, lenalidomide, and dexamethasone within 3 months of vaccination, but was only receiving lenalidomide at the date of vaccination (bortezomib was discontinued >8 weeks prior). Of the 15 patients with hematologic malignancy who were not in remission, none received chemotherapy within 3 months of vaccination and included: eight patients with chronic lymphocytic leukemia (CLL; one patient received rituximab and chlorambucil 4 months prior to vaccination and the remaining seven patients did not receive any chemotherapy), four with Non-Hodgkin's lymphoma (NHL; one patient received rituximab 2 years prior; one received 5-FU, oxaliplatin, cetuximab 2 years prior; and two patients did not receive any treatment), two patients with Waldenstrom macroglobulinemia (one received rituximab 16 months prior to vaccination; one did not receive any chemotherapy), and one patient with multiple myeloma who received no chemotherapy. Of the 31 HCT recipients, 23 were in complete remission with four receiving concurrent maintenance lenalidomide for multiple myeloma at the time of vaccination and one receiving imatinib until the vaccination date for cKit-positive AML after autologous HCT. Of the other 18 patients in complete remission, none received chemotherapy within 3 months of vaccination. The eight HCT recipients who were not in complete remission had myeloma; one patient was on bortezomib and dexamethasone (20 mg daily), five were receiving maintenance lenalidomide with two of these patients receiving concurrent dexamethasone (20 and 40 mg weekly, respectively) while the remaining two did not receive any concurrent therapy at the time of vaccination. Antiviral prophylaxis (e.g., acyclovir or valacyclovir) was administered to patients at the provider's discretion. Twenty-three (37.1%) patients had antiviral prophylaxis discontinued for >24 hr prior to receipt of Zostavax®. Sixteen (25.8%) patients concurrently received antiviral prophylaxis at the time of and/or beyond the date of vaccination, with one patient starting acyclovir on the vaccination date and continuing for 11 months. The median ALC was 760 cells/μL and median IgG was 923 mg/dL among these 16 patients who were on antiviral drugs on the day of vaccination. Of these 16 patients on concurrent antiviral drugs, 11 were autologous HCT recipients (median, 9.1 months post-transplant) and two were allogeneic HCT recipients (median, 40.8 months post-transplant). One patient received the vaccine with subsequent initiation of antiviral prophylaxis 3 months post vaccination for a total duration of 2 months. The 23 (37.1%) patients who did not receive antiviral prophylaxis were generally lower risk patients with indolent disease; 8 (34.8%) required chemotherapy at some point, 5 (21.8%) received only rituximab, and 10 (43.5%) did not receive any pharmacotherapy for their malignancy. Thirteen (21.0%) patients had documented episodes of HZ prior to receiving the vaccine with a median time between HZ episode and vaccination of 515 days (range, 211–1,215 days). Nine of the 13 patients with HZ episodes prior to vaccination were HCT recipients; four developed HZ prior to transplant and HZ occurred in 5 after HCT at a median time of 350 days (range, 211–507 days) post-transplant. One patient developed HZ after vaccination. This patient was a 63-year-old woman who received Zostavax® 5 months and 27 days after autologous HCT for multiple myeloma. She was receiving maintenance lenalidomide at the time of vaccination and had no other comorbidities. The patient's ALC and IgG levels obtained on the day of vaccination were 1,320 cells/μL and 812 mg/dL, respectively. Three weeks after vaccination, she presented to the hematology-oncology clinic with an episode of trigeminal HZ and was treated with 10 days of high dose acyclovir followed by reinstatement of prophylaxis, recovering without sequelae. As the vesicles were not cultured, we were unable to distinguish between wildtype varicella zoster virus (VZV) and the Oka/Merck strain present in Zostavax®. Of note, the patient was receiving acyclovir prophylaxis, which was discontinued on the day of vaccination. Therefore, it is possible that vaccine efficacy was reduced but in the absence of culture data, it is unclear whether the episode of HZ represented reactivation of latent VZV or infection due to the vaccine strain. Of the 62 patients who received the vaccine, there were no documented adverse reactions associated with administration of Zostavax®. To our knowledge, this is the first study to examine the use of Zostavax® in patients with hematologic malignancy and/or HCT. Due to the significant morbidity and risk of complicated disease in such patients, new strategies for prevention of HZ are needed. Although further study is clearly needed, this study suggests that Zostavax® may be safely given to selected patients with hematologic malignancy without significant immunosuppression. Notably, none of these patients had active GVHD and none were receiving immunosuppressive therapy with the exception of two patients who received dexamethasone along with maintenance lenalidomide. No patients received cytotoxic chemotherapy within 3 months of vaccination although three patients received bortezomib which has been associated with an increased risk of HZ when compared to high-dose dexamethasone [11, 12]. This study had several limitations, including a small sample size, retrospective, descriptive study design, and a heterogeneous population selected for a clinical impression of intact immunity. In addition, a quarter of patients had been on acyclovir therapy the day of Zostavax® administration and may have been perceived as higher risk by their clinicians. Although safety concerns preclude the use of Zostavax® in severely immunosuppressed patients, this study may help move forward a discussion on whether Zostavax® may be received safely in select patients with hematologic malignancy and HCT recipients without significant immunosuppression. Larger, prospective, controlled studies are warranted to further define the safety and efficacy of Zostavax® in this patient population. Since November 2007, Zostavax® was administered by the hematology/BMT group at UCSF at the provider's discretion. Through review of pharmacy records, we identified UCSF Hematology Clinic patients >18 years who received the Zostavax® vaccine. In June 2010, a standardized form was used to capture date of immunization, demographics, details of underlying hematologic malignancy, transplant history, prior chemotherapy, immunosuppressive therapy, antiviral therapy, selected laboratory tests and other relevant clinical data, evidence of vaccine associated adverse events, and clinical or laboratory evidence of subsequent VZV infection. The study protocol was approved by the UCSF Committee on Human Research. Elliot Naidus*, Lloyd Damon , Brian S. Schwartz , Cheryl Breed , Catherine Liu , * Oregon Health and Sciences University School of Medicine, Division of Hematology-Oncology, Department of Medicine, The Helen Diller Family Comprehensive Cancer, the University of California, San Francisco, California, Division of Infectious Diseases, Department of Medicine, the University of California, San Francisco, California.