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Purpose To assess veteran-specific prostate cancer (PrCA) mortality-to-incidence ratios (MIR) in South Carolina's (SC) veteran population. Methods U.S. Veterans Health Administration electronic medical records from January 1999 to December 2015 identified 3,073 PrCA patients residing in 345 ZIP code tabulation areas (ZCTA) within SC. MIRs were calculated for all SC ZCTAs and by key patient- and neighborhood-level risk factors for PrCA. Comparisons between ZCTAs identified as part of a spatial cluster were compared with non-significant ZCTAs using t tests. Results The MIR was 0.17 overall, ranging from a low of 0.15 among Black men to 0.20 among White men. Among metropolitan ZCTAs, the MIR was 0.18 compared to 0.16 in non-metropolitan ZCTAs. Two clusters of higher-than-expected MIRs were found in the Upstate region. Conclusions Identification of spatial clusters of higher- or lower-than-expected MIRs allows for further testing of possible explanatory factors, and the capacity to target resources and policies according to greatest need.

A 43‐year‐old female with multiple sclerosis developed urethral melanoma. The only potential risk factor was treatment with natalizumab, a humanized monoclonal antibody against α4 integrins. To investigate the risk‐exposure relationship, we reviewed this case, all other published cases, and cases of natalizumab‐associated melanoma reported to regulatory agencies. Data sources included the Food and Drug Administration's (FDA) Adverse Event Reporting System (FAERS) (2004–2014), a FDA Advisory Committee Meeting Report, and peer‐reviewed publications. In the United States, the manufacturer maintains an FDA‐mandated Tysabri Safety Surveillance Program (part of the Tysabri Outcomes Unified Commitment to Health (TOUCH)) of natalizumab‐treated patients. We statistically compared reporting completeness for natalizumab‐associated melanoma cases in FAERs for which information was obtained entirely from the TOUCH program versus cases where FAERS information was supplemented by TOUCH program information. FAERS included 137 natalizumab‐associated melanoma reports in patients with multiple sclerosis. Median age at melanoma diagnosis was 45 years (range: 21–74 years). Changes in preexisting nevi occurred in 16%, history of cutaneous nevi occurred in 22%, diagnosis within 2 years of beginning natalizumab occurred in 34%, and 74% had primary surgical treatment. Among seven natalizumab‐treated MS patients who developed biopsy‐confirmed melanoma on treatment and reported in the literature, median age at diagnosis was 41 years (range: 38–48 years); and the melanoma diagnosis occurred following a median of 12 natalizumab doses (range: 1–77 doses). A history of mole or nevi was noted in four patients and a history of prior melanoma was noted in one patient. Completeness scores for reports were significantly lower for FAERS cases reported from the TOUCH program versus FAERS cases supplemented by TOUCH information (median score of 2 vs. 4 items out of 8‐possible items, P

Although the availability of generic oncology drugs allows access to contemporary care and reduces costs, there is international variability in the safety of this class of drugs. In this Series paper, we review clinical, policy, safety, and regulatory considerations for generic oncology drugs focusing on the USA, Canada, the European Union (EU), Japan, China, and India. Safety information about generic formulations is reviewed from one agent in each class, for heavy metal drugs (cisplatin), targeted agents (imatinib), and cytotoxic agents (docetaxel). We also review regulatory reports from Japan and the USA, countries with the largest pharmaceutical expenditures. Empirical studies did not identify safety concerns in the USA, Canada, the EU, and Japan, where regulations and enforcement are strong. Although manufacturing problems for generic pharmaceuticals exist in India, where 40% of all generic pharmaceuticals used in the USA are manufactured, increased inspections and communication by the US Food and Drug Administration are occurring, facilitating oversight and enforcement. No safety outbreaks among generic oncology drugs were reported in developed countries. For developing countries, oversight is less intensive, and concerns around drug safety still exist. Regulatory agencies should collaboratively develop procedures to monitor the production, shipment, storage, and post-marketing safety of generic oncology drugs. Regulatory agencies for each country should also aim towards identical definitions of bioequivalence, the cornerstone of regulatory approval.

Background The 3 fluoroquinolone (FQ) antibiotics - ciprofoxacin, levofoxacin, and moxifoxacin - are commonly administered to oncology patients. Although these oral antibiotics are approved by the US Food and Drug Administration (FDA) for treatment of urinary tract infections, acute bacterial sinusitis, or bacterial infection in patients with chronic obstructive pulmonary disease, they are commonly prescribed off-label to neutropenic cancer patients for the prevention and treatment of infections associated with febrile neutropenia. New serious FQ-associated safety concerns have been identified through novel collaborations between FQ-treated persons who have developed long-term neuropsychiatric (NP) toxicity, pharmacovigilance experts, and basic scientists. Objective To conduct basic science and clinical investigations of a newly identified adverse drug reaction, termed FQ-associated disability. Methods 5 groups of C57BL/6 mice receiving the antibiotic ciprofoxacin in 10-mg increments (10 mg/kg-50 mg/kg) and 1 group of control mice were evaluated. The Southern Network on Adverse Reactions (SONAR) and a social network of FQ-treated persons with long-term NP toxicity (the Floxed Network) conducted a web-based survey. The clinical toxicity manifestations reported by 94 respondents to the web-based survey of persons who had received 1 or more doses of an FQ prescribed for any indication (generally at FDA-approved dosages) and who subsequently experienced possible adverse drug reactions were compared with adverse event information included on the product label for levofoxacin and with FQ-associated adverse events reported to the FDA's MedWatch program. Results Mice treated with ciprofoxacin had lower grip strengths, reduced balance, and depressive behavior compared with the controls. For the survey, 93 of 94 respondents reported FQ-associated events including anxiety, depression, insomnia, panic attacks, clouded thinking, depersonalization, suicidal thoughts, psychosis, nightmares, and impaired memory beginning within days of FQ initiation or days to months of FQ discontinuation. The FDA Adverse Event Reporting System (FAERS) included 210,705 adverse events and 2,991 fatalities for FQs. Levofoxacin and ciprofoxacin toxicities were neurologic (30% and 26%, respectively), tendon damage (8% and 6%), and psychiatric (10% and 2%). In 2013, an FDA safety review reported that FQs affect mammalian topoisomerase II, especially in mitochondria. In 2013 and 2014, SONAR fled citizen petitions requesting black box revisions identifying neuropsychiatric toxicities and mitochrondrial toxicity as serious levofoxacin-associated adverse drug reactions. In 2015, FDA advisors recommended that FQ product labels be revised to include information about this newly identified disability syndrome termed "FQ-associated disability" (FQAD). Limitations Basic science studies evaluated NP toxicity for only 1 FQ, ciprofoxacin. Conclusion Pharmacovigilance investigators, a social network, and basic scientists can collaborate on pharmacovigilance investigations. Revised product labels describing a new serious adverse drug reaction, levofoxacin-associated long-term disability, as recommended by an FDA advisory committee, are advised.

This was a prospective cohort study evaluating 126,805 individuals with diabetes and periodontal disease receiving care at all Veterans Administration medical centers and clinics in the United States from 2005 through 2012. The exposures were periodontal treatment at baseline (PT0) and at follow-up (PT2). The outcomes were change in HbA1c following initial treatment (ΔHbA1c1) and follow-up treatment (ΔHbA1c2), and diabetes control was defined as HbA1c at 2= −0.25%) among individuals with higher baseline HbA1c. Long-term periodontal care provided in a clinical setting improved long-term glycemic control among individuals with type 2 diabetes and periodontal disease.

Racial and socio-economic status (SES) disparities exist in prostate cancer (PrCA) incidence and mortality. Less is known regarding how geographical factors, including neighborhood social vulnerability and distance traveled to receive care, affect PrCA risk. The purpose of this research was to use the Veterans Administration Medical System, which provides a unique means for studying PrCA epidemiology among diverse individuals with ostensibly equal access to healthcare, to determine whether area-level characteristics influence PrCA incidence while accounting for individual-level risk factors. From the US Veteran’s Health Administration (VHA) electronic medical records (EMR) database from January 1999 to December 2015, we identified 3,736 PrCA patients and 104,017 cancer-free controls from South Carolina (SC). The VHA EMRs were linked to the US census which provided area-level factors. US census data were used to construct the Social Vulnerability Index which is a continuous composite measure of area-level vulnerability and was divided into tertiles for modeling purposes. Data were analyzed using a Bayesian multivariate conditional autoregressive model (CAR) which accounted for individual-level factors, area-level factors, spatial random effects, and autocorrelation, which were used to identify areas of higher- or lower-than-expected PrCA incidence after controlling for risk factors. As expected, after accounting for age (sixfold and 13-fold increases in men 40–50 years and > 50 years, respectively), race was an important risk factor, with threefold higher odds among Blacks in the fully adjusted model [ORadj 2.98 (2.77, 3.20)]. After accounting for all other factors, residing in a ZIP code tabulated areas (ZCTA) with the greatest level social vulnerability versus the lowest, least vulnerable ZCTA’s, increased PrCA risk by 39% [ORadj 1.39 (1.11, 1.75)]. While accounting for known risk factors for PrCA, including age, race, and marital status, we found geographic areas in SC characterized by higher than average social vulnerability with higher rates of incident PrCA among veterans. Outreach for screening, education, and care coordination may be needed for veterans in these areas.

Summary Biological oncology products are integral to cancer treatment, but their high costs pose challenges to patients, families, providers, and insurers. The introduction of biosimilar agents—molecules that are similar in structure, function, activity, immunogenicity, and safety to the original biological drugs—provide opportunities both to improve health-care access and outcomes, and to reduce costs. Several international regulatory pathways have been developed to expedite entry of biosimilars into global marketplaces. The first wave of oncology biosimilar use was in Europe and India in 2007. Oncology biosimilars are now widely marketed in several countries in Europe, and in Australia, Japan, China, Russia, India, and South Korea. Their use is emerging worldwide, with the notable exception of the USA, where several regulatory and cost barriers to biosimilar approval exist. In this Review, we discuss oncology biosimilars and summarise their regulatory frameworks, clinical experiences, and safety concerns.

Background : Patients with Chronic Lymphocytic Leukemia (CLL) are susceptible to infections due to impaired immunity, from both complications of disease and treatments. Specific treatments such as fludarabine or rituximab are incorporated in chemotherapy regimens for CLL and cause lymphocyte depletion and impaired humoral immunity, resulting in increased risk of fungal infections. The aim of this study is to explore the incidence rates of fungal infections in patients before and after treatment for CLL. Methods : We identified patients diagnosed with CLL using ICD9 code 204.1X within the Veterans Health Affairs (VHA) between 1999 and 2013, before the availability of novel agents for CLL. Pharmacy records were used to identify treatment of CLL (alemtuzumab, bendamustine, chlorambucil, fludarabine, ofatumumab, pentostatin, and rituximab) as well as anti-fungal agents (amphotericin, caspofungin,fluconazole, flucytosine, itraconazole, ketoconazole, micafungin, posaconazole, and voriconazole). Fungal infections were identified with two strategies, using ICD9 codes alone (candida 112.X; pneumocystis 136.3; coccidiomycosis 114.x; histoplasmosis 115.X; blastomycosis 116.X; aspergillus 117.3; cryptococcus 117.5; opportunistic mycoses 118.X) as well as using ICD9 codes combined with evidence of treatment with an anti-fungal (ICD9+antifungal). Number of infections and incidence rates were categorized as occurring in patients prior to first treatment (pre-treat), or after first treatment (post-treat), or in patients who had never received treatment within the VHA (no-treat). Incidence rate ratio between pre- and post-treatment period was calculated to quantify the magnitude of risk increase in patients who received CLL treatment. Results : A cohort of 20,023 patients were identified with CLL and followed for a mean of 5.33 years for a total surveillance of 106,772 person-years. Of these patients, 3,726 (18.6%) received treatment for CLL within the VHA. Using ICD9 codes alone, 970 fungal infections were identified and with ICD9+anti-fungal, 415 patients had an infection. With ICD9, the most common infection was candida with 765 infections, followed by aspergillus with 58 and pneumocystis with 39 infections. Rates of infections based on ICD9 were highest in the post-treat group with 2.98 infections per 100 person-years, followed by 1.08 infections per 100 person-years in the pre-treat group and 0.58 infections per 100 person-years in the no-treat group. The most common first treatment was rituximab alone, used in 35.9% of patients, followed by chlorambucil in 31.9%, fludarabine in 20.4%, and bendamustine in 9.9%. In comparison to pre-treat patients, post-treat patients had 2.91 times increased risk of fungal infection (95% confidence interval (CI) 2.24-3.81) determined by ICD9 code and 4.74 times increased risk (95% CI 3.09-7.57) determined by ICD9+antifungal. The rate of candida infection increased 2.9 fold (95% CI 2.24-3.81) with ICD9 and 4.7 fold (95% CI 3.09-7.57) with ICD9+antifungal while aspergillus infections increased 8.7 fold (95% CI 3.01-35.4) with ICD9 and 10.2 fold (95% CI 2.88-63.1) with ICD9+antifungal between post-treat and pre-treat groups. Conclusions: In this retrospective analysis of CLL patients, treatment for CLL significantly increased the rate of fungal infections, primarily candida and aspergillus. Further study is needed to understand the effect of modern treatments on fungal infections in CLL. Disclosures Schoen: Pharmacyclics: Research Funding. Georgantopoulos:Pharmacyclics: Research Funding. Bennett:Pharmacyclics: Research Funding.

This community's utilization of their Medical Reserve Corps (MRC) unit proved to be a valuable resource in their vaccination clinics as part of their response to the novel influenza A (H1N1) virus. Early planning, mock vaccination drills, and use of a strategic analysis process aided in the formulation and development of an efficient vaccination campaign.

Objective.To describe a pseudo-outbreak ofClostridium difficileinfection (CDI) caused by a faulty toxin assay lot and to determine the effect of sensitivity, specificity, and repeated testing forC. difficileon perceived CDI burden, positive predictive value, and false-positive results.Design.Outbreak investigation and criterion standard.Patients.Patients hospitalized at a tertiary care hospital who had at least 1 toxin assay for detection ofC. difficileperformed during the period from July 1, 2004, through June 30, 2006.Methods.The run control chart method and thex2test were used to compare CDI rates and the proportion of positive test results before, during, and after the pseudo-outbreak. The effect of repeated testing was evaluated by using 3 hypothetical models with a sample of 10,000 patients and various assay sensitivity and specificity estimates.Results.In November of 2005, the CDI rate at the hospital increased from 1.5 to 2.6 cases per 1,000 patient-days (P< .01), and the proportion of positive test results increased from 13.6% to 22.1% (P< .01). An investigation revealed a pseudo-outbreak caused by a faulty toxin assay lot. A decrease of only 1.2% in the specificity of the toxin assay would result in a 32% increase in perceived incidence of CDI at this institution. When calculated by use of the manufacturer's stated specificity and sensitivity and this institution's testing practices, the positive predictive value of the test decreased from 80.6% to 4.1% for patients who received 3 tests.Conclusion.Specificity is as important as sensitivity when testing for CDI. False-positive CDI cases can drain hospital resources and adversely affect patients. Repeated testing forC. difficileshould be performed with caution.

Seasonal influenza causes excess morbidity and mortality at the extremes of age: It disproportionately affects the very young and the very old, typically resulting in "U"-shaped age-distributed curves. By means of a well-established public health department surveillance system using positive influenza tests submitted from sentinel sites, the authors generated annual influenza-specific morbidity curves over a 10-year period (1998-2008) for St. Louis County, Missouri. The authors detected an unusually high incidence of cases of medically attended test-positive influenza, particularly in young adults, during the 2007-2008 season, resulting in an unexpected "W"-shaped age-distributed morbidity curve that was distinctly unique in comparison with the prior 9 influenza seasons. Public health influenza surveillance programs are useful tools for detecting emerging epidemiologic trends that may have clinical importance.

Objectives.To compare Clostridium difficile infection (CDI) rates determined with use of a traditional definition (ie, with healthcare-onset CDI defined as diagnosis of CDI more than 48 hours after hospital admission) with rates determined with use of expanded definitions, including both healthcare-onset CDI and community-onset CDI, diagnosed within 48 hours after hospital admission in patients who were hospitalized in the previous 30 or 60 days, and to determine whether differences exist between patients with CDI onset in the community and those with CDI onset in a healthcare setting.Design.Prospective cohortSetting.Tertiary acute care facility.Patients.General medicine patients who received a diagnosis of CDI during the period January 1, 2004, through December 31, 2005.Methods.CDI was classified as healthcare-onset CDI, healthcare facility–associated CDI after hospitalization within the previous 30 days, and/or healthcare facility-associated CDI after hospitalization within the previous 60 days. Patient demographic characteristics and medication exposures were obtained. The CDI incidence with use of each definition, CDI rate variability, patient demographic characteristics, and medication exposures were compared.Results.The healthcare-onset CDI rate (1.6 cases per 1,000 patient-days) was significantly lower than the 30-day healthcare facility–associated CDI rate (2.4 cases per 1,000 patient-days; PPPPP = .02) or intravenous vancomycin (P = .01) during hospitalization.Conclusions.Compared with the traditional definition, expanded definitions identify more patients with CDI. There is good correlation between traditional and expanded CDI definitions; therefore, it is unclear whether expanded surveillance is necessary to identify an abnormal change in CDI rates. Cases that met the expanded definitions were less likely to have occurred in patients with fourth-generation cephalosporin and vancomycin exposure.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder. The classic TTP ‘pentad’ is thrombocytopenia, microangiopathic hemolytic anemia (MAHA), renal impairment, neurological symptoms, and fever (Amorosi & Ultmann, 1966). Laboratory studies identified deficiency of plasma ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type 1 motifs 13) activity (ADAMTS13:AC) among some TTP patients (Furlan et al, 1998; Tsai & Lian, 1998). ADAMTS13 cleaves the peptide bond between Thy1605 and Met1606 in the A2 domain of von Willebrand factor (VWF) subunit. VWF is released into the plasma as unusually large VWF multimers (UL-VWFMs), which are degraded into smaller size VWF multimers by ADAMTS13. In the late 1990's, studies in the United States identified 117 cases of TTP that developed after initiation of the thienopyridine, ticlopidine; although at that time, ADAMTS13 activity levels were not widely available (Bennett et al, 1999; Steinhubl et al, 1999). A study of seven patients in the United States with ticlopidine-associated TTP found that all seven had severe deficiency of ADAMTS13 activity and five had detectable antibodies to ADAMTS13 activity (Tsai et al, 2000). We now report on 22 individuals from Japan with ticlopidine-induced TTP and compare these findings to those from the United States. Ticlopidine was the primary anti-platelet agent in Japan from 1989 to 2006. Since 1998, our laboratory at Nara Medical University has been a nationwide referral centre in Japan for thrombotic microangiopathies (TMAs), including TTP (Fujimura & Matsumoto, 2010). The study protocol was approved by the Ethics Committee of Nara Medical University Hospital. TTP diagnostic criteria were: microangiopathic haemolytic anaemia (haemoglobin ≤ 120 g/l), Coombs test negative, undetectable serum haptoglobin (

As of 2013, the Southern Network on Adverse Reactions (SONAR) team described 50 significant adverse drug reactions (sADRs) associated with FDA approved drugs. The team also investigates policy issues surrounding pharmacovigilance. Herein we describe the systematic approach to pharmacovigilance taken by the Southern Network on Adverse Reactions and discuss major findings from the group. By 2015, the team hopes to have identified 20 additional sADRs focusing on biologics, biosimilars, and biobetters. The ultimate goal of SONAR is to decrease the timescale between ADR detection and the dissemination of information regarding the sADR

e17623 Background: Clinical trials have identified increased risks of venous thromboembolism and mortality with ESA administration to cancer patients and increased risks of arterial thrombosis with...

e18033 Background: PML is a rare, fatal disease that results from reactivation of the JC virus during immunosuppressed states. Previously we reported that rituximab is associated with a 5-fold incr...

e18035 Background: In 2000, the Food and Drug Administration (FDA) approved Gemtuzumab ozogamycin (GO) for monotherapy treatment of patients age 60 and older with relapsed acute myeloid leukemia. A...

Patients with hematologic malignancies and hematopoietic stem cell transplant (HSCT) recipients are at high risk for bacterial bloodstream infections (BSI) owing to resistant organisms. Data describing the outcomes of vancomycin-resistant enterococcal (VRE) BSI in this patient population are limited. We performed a retrospective cohort study of all cases of VRE BSI that occurred between February 1996 and December 2002 on the Leukemia/HSCT unit at Barnes-Jewish Hospital. There were 68 episodes of VRE BSI in 60 patients with acute (53%) or chronic (8%) leukemia, non-Hodgkin's lymphoma (22%) or other malignant hematologic disorders (17%). A total of 13, 32 and 32% were recipients of autologous, related and matched-unrelated transplants, respectively. Forty-two of allograft recipients had active acute graft-versus-host disease (GVHD) and 32% chronic GVHD. Only 57% were neutropenic, 52% had refractory/relapsed malignancy and 60% had end organ dysfunction with a median APACHE II score of 17. Median survival after VRE BSI was 19 days. Pneumonia, receipt of anti-fungal drugs and low APACHE II score at the time of the VRE BSI remained significant risk factors for death on multivariable analysis. Our analysis suggests that in patients with hematological malignancies or HSCT, VRE may not have the behavior of a virulent pathogen. VRE BSI may simply be a marker of these patients' already existing critical medical condition.

Background: Thirty eight anaphylaxis cases were reported to the FDA during the first year of peginesatide marketing in 2012. Marketing was discontinued as a result. We compare 28 reports from a pilot peginesatide introduction conducted by the largest dialysis organization (LDO) in North America versus the 10 reports of anaphylaxis from usual care settings. The pilot introduction was conducted at 10 LDO centers, a nurse was assigned to each center, and staff were educated on peginesatide dosing, safety, pharmacokinetics, and handling. Methods: Reports in the FDA of anaphylaxis occurring within 30 minutes of peginesatide administration were reviewed for information on administration site, patient characteristics, time to report to FDA, and patient outcome. Findings: In comparison to 28 anaphylaxis events reported to the FDA from the pilot introduction (as described in Bennett CL et al NEJM 2014), 10 anaphylaxis reports to the FDA from the usual care settings were less often reported as fatal (0% versus 22%) or grade IV severity (10% versus 22%) associated with hypotension (20% versus 57%), or cardiorespiratory arrest (0% versus 29%), and were reported to the FDA later (median of 81 days (range, 14- 172) versus 46 days (range, 4 – 136 days). They were more often associated with clinical findings of diaphoresis (40% versus 18%), syncope (30% versus 18%), or angioedema (20% versus 11%). Onset was a median of four to five minutes after peginesatide infusion in either setting. Among 25,000 peginesatide-treated patients (19,430 in the pilot introduction), anaphylaxis rates were 1.4 per 1,000 persons in either setting. Conclusion: Clinical characteristics of anaphylaxis events were more serious and FDA reporting more timely for peginesatide-associated anaphylaxis reported to the FDA from the pilot introduction versus usual care settings. With the anticipation of biosimiars in the United States, consideration should be given to requiring pilot introductions of these agents to facilitate safety assessment. Disclosures No relevant conflicts of interest to declare.

Background: PML is an often fatal demyelinating disease of the brain due to reactivation of latent JC polyoma virus. Rituximab is an anti-CD20 monoclonal antibody associated with PML, as outlined briefly in a revised Black Box warning in 2007 and a series of Dear Healthcare Professional Letters sent by the manufacturer between 2006 and 2008. In 2009, we described 57 HIV-negative patients who developed PML after rituximab treatment [Blood. 2009; 113(20):4834–40]. Since then, the use of rituximab has continued to increase as has awareness of this association. Methods: A Freedom of Information (FOI) Act request was submitted to the U.S. Food and Drug Administration (FDA) for reports of PML cases occurring in rituximab-treated patients. These reports were obtained from the FDA in September 2013, and by definition of the FOI request, were at least 6 months old at the time obtained. Of the 483 total reports received, 173 duplicate cases were identified based on similar dates, ages, and other clinical information, resulting in 310 unique cases. An additional 14 cases were added from our 2009 publication that were not included in the original 310 cases, totaling 324 unique cases. Our case definition included HIV-negative patients in whom rituximab was administered prior to the onset of PML symptoms, with PML confirmed via brain biopsy, autopsy, or having JC virus in cerebrospinal fluid (CSF) plus brain MRI findings of PML. Results: Of the 324 unique cases, there were 231 confirmed cases of rituximab-associated PML in HIV-negative patients, from 23 countries. The majority of excluded cases lacked the necessary details in the reports to confirm the diagnosis of PML. Among the confirmed cases, case mortality rate was 89.1%. PML diagnosis was made by brain MRI AND positive JC virus CSF PCR (67.5%), brain biopsy (34.6%), or autopsy (7.8%). Indications for rituximab use included non-Hodgkin lymphoma (58.8%), chronic lymphocytic leukemia (28.4%), rheumatoid arthritis (3.1%), systemic lupus erythematosus (2.6%), autoimmune hemolytic anemia/idiopathic thrombocytopenic purpura (2.6%), and other rheumatologic conditions (3.5%). The non-Hodgkin lymphomas were subdivided into follicular (13.5%), diffuse large B-cell (9.2%), unspecified non-Hodgkin (22.7%), mantle cell (7%), Waldenstrom (4.4%), and marginal zone (1.7%). Median age was 64.5 years (range 19-90), 53% female and 47% male, with 25 patients (10.8%) having undergone prior transplantation (12 autologous stem cell, 8 allogeneic stem cell, and 5 solid organ). The median number of rituximab doses received was 6 (range 1-24), with a median of 15 months (range 0.5-128) from first dose of rituximab to PML diagnosis, and median of 4 months (range 0-65) from last rituximab dose to PML. The median time from PML diagnosis to death was 2 months (range 0-14). It is noteworthy that of the cases diagnosed by brain biopsy or autopsy, 17 had a negative JC virus CSF PCR, and of the cases diagnosed with a positive JC virus CSF PCR, 8 had at least one negative test before the diagnosis was made. Less than 10 cases per year were diagnosed until 2006 when there were 22, peaking at 40 in 2010 (figure). Figure 1 Figure 1. Conclusions: PML continues to be increasingly reported by clinicians who administer rituximab with or without concomitant chemotherapy. The temporal increase in the number of reports suggests that either the incidence may be higher than initially thought or increased awareness has led to more reporting. Furthermore, the lower number of reports in 2012 likely illustrates the delay between incident cases, reporting, and availability through FOI requests. Our findings highlight the importance of detailed adverse event reporting (as is characteristic of SONAR) to enhance clinician awareness of rare but serious toxicities, as well as the need for faster public availability of adverse event reports. Disclosures Off Label Use: Rituximab is used for a variety of indications. Our abstract describes the indications with percentages that rituximab was used from our analysis. These FDA-approved indications include chronic lymphocytic leukemia, lymphomas as listed, and rheumatoid arthritis. Indications listed that are not FDA-approved (the minority) include systemic lupus erythematosus, autoimmune hemolytic anemia/idiopathic thrombocytopenic purpura, and other rheumatologic conditions.. Carson:Genentech: Consultancy, Honoraria, Speakers Bureau.

Gemtuzumab ozogamycin (GO) received initial approval in 2000 from the Food and Drug Administration (FDA) for patients age 60 and older suffering with relapsed acute myeloid leukemia. After 10 years of administering GO-containing combination chemotherapy regimens, the drug was voluntarily removed from the commercial market in 2010 amid reports of unexpected development of sinusoidal obstructive syndrome (SOS); which has the potential to be fatal. Four months after the initial approval for marketing in 2000, SONAR initiated an investigation of GO-associated SOS. SONAR reported an incidence rate of 38% among allogeneic stem-cell transplants and 16% among autologous stem-cell transplant (SCT) patients. Ultimately, there was an overall incidence rate of 3% when single-agent GO was administered as directed by the FDA. In 2007, as a result of the examination of the reports from clinical trials and observational studies; data mining of interim reports from the manufacturer’s Prospective Observational Registry and the FDA’s Adverse Event Reporting System was undertaken. In 2013, the pharmaceutical manufacturer reported results from its FDA-mandated prospective observational study. Major differences between the SONAR report and the mnaufacturer’s report include: timing of publication (2007 versus 2013); inclusion of information on allogeneic stem cell versus autologous stem cell transplantation prior to GO administration (in our reports only) and identification of risk factors associated with higher rates of SOS (SCT within 3 months of GO administration, off-label administration of high doses of GO, and concomitant administration of 6-TG in our analysis versus no identified risk factors in the manufacturer’s analysis). The incidence of SOS was 9.1% among 482 patients at 54 centers in the manufacturer’s registry. Table 1: Comparison of gemtuzumab ozogamycin (GO) safety reports analyses between SONAR and manufacturer SONAR Pharmaceutical Investigation # of pts who received GO 1071 482 # of pts with SOS 99 44 DATA METHODS # of centers involved 50 centers (US and UK) 54 centers (US only) Interim analysis Not done Yes (2002 and 2005) Concomitant chemo given 67% 41% # of pts with concomitant HCT 26% 0% % with prior alloSCT 2.6% Not reported % with prior autoSCT 3.9% Not reported % with prior HSCT 6.5% 18.3% % with subsequent alloSCT 1.2% 0% % with subsequent autoSCT 2.0% 0% Publication Date* 2007 2013 * Gemtuzumab ozogamycin voluntarily removed from market in 2010 by the pharmaceutical manufacturer Disclosures No relevant conflicts of interest to declare.

e19540 Background: Progressive multifocal leukoencephalopathy (PML) is a rare, fatal disease that results from activation of a highly prevalent, dormant JC virus during immunosuppressed states. Rit...

Background In March 2012, the Food and Drug Administration (FDA) approved peginesatide as anemia therapy for chronic kidney disease patients. In December, the manufacturer warned that a large dialysis organization identified eight patients with peginesatide-associated anaphylaxis. In February 2013, the organization again reported five anaphylaxis events, including three deaths, and discontinued administering peginesatide. After a manufacturer’s review identified five peginesatide-associated anaphylaxis deaths, the manufacturer discontinued marketing the drug. Methods We reviewed peginesatide-associated anaphylaxis in FDA’s Adverse Event Reporting System (FAERS). Clinical findings and product lot numbers were analyzed. Inclusion criteria included peginesatide administration and toxicity within thirty minutes of administration. Results Between July 2012 and February 2013, 38 CKD patients developed anaphylaxis within a median of five minutes following peginesatide administration (range, zero to 20 minutes). Findings included dyspnea (25 patients), chest pain (10), hypotension (18), diaphoresis (9), pruritis (11), rash (3), angioedema (5), and vomiting (9). Five deaths from cardio-respiratory arrests occurred. Exposure-adjusted incidence was 1.5 cases of anaphylaxis per 1,000 peginesatide-treated patients. Of five FAERS reports for anaphylaxis occurring in February 2013, three included the product lot number C18881 while two did not have lot numbers. Of 33 FAERS anaphylaxis events reported prior to December 4, 2012; 18 included the lot number C18685, two reports included the lot number C18696, one included the lot number C18881, and lot numbers were not identified for the remaining 12 reports. Conclusion Anaphylaxis can occur within minutes of initiating peginesatide therapy. Production or supply chain management problems may be the underlying etiology. Disclosures: Macdougall: Affymax and Takeda: Consultancy, Research Funding. Mikhail: Affymax and Takeda: Consultancy, Research Funding. Goldsmith: Affymax and Takeda: Consultancy, Research Funding.

Abstract 2752 Introduction: Progressive multifocal leukoencephalopathy (PML) is a rare but fatal disease that is the result of activation of a highly prevalent dormant JC virus during immunosuppressed states such as advanced HIV, malignancy or immune-modulating medications. Rituximab, an immunomodulator, has been approved for both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). We previously reported 57-non-HIV patients developed PML after rituximab (1). This report identified the need for epidemiological cohort studies to further evaluate incidence rates and risk factors for PML by comparing Rituximab treated patients with suitable non-treated patients. Of note, natilzumab-associated PML is now well-characterized, with a reported incidence of 21 PML cases per 10,000 natilizumab-treated persons (2). Methods: In this first such epidemiological study we identified from the national data of the Department of Veteran's Affairs (VA), 61,132 patients with a primary International Classification of Diseases version 9 (ICD-9) code for either HL or NHL between 1999 to 2011 and reported the use of Rituximab among patients with and without PML. This project was conducted inside the Veterans Affairs Informatics and Computing Infrastructure (VINCI) after obtaining approvals from the VA Institutional Review Board and other oversight groups. Results: We identified 62,642 with a primary diagnosis of HL or NHL and excluded 1,510 (2.4%) patients with VA lab confirmed HIV. Our final cohort had 61,132 patients, 10,459 (17.1%) received Rituximab. A total of 12 (0.020%) patients had developed PML, 5 (0.008%) belonged to the Rituximab group and 7 (0.011%) to non-rituximab group; which results in a statistically significant unadjusted relative risk of 3.46 (95% confidence interval 1.1, 10.9). Univariate analyses of outcomes other than rate-estimates are not statistically significant between PML patients who received rituximab and those that did not receive rituximab, primarily due to extremely small sample sizes (5 and 7 patients, respectively) (Table 1). Overall, compared to non-rituximab PML patients, rituximab PML patients were younger at PML diagnosis and age of death by more than 6-years; although they did appear to live slightly longer post PML diagnosis by about 4-months. Conclusions: These results show that among lymphoma patients, the use of Rituximab is associated with a statistically significant relative risk for documented PML of 3.46. We now report a baseline rate among Veterans of 4.78 PML cases per 10,000 rituximab treated Veterans with lymphoma (25% of the rate reported among natilizumab-treated multiple sclerosis patients). As with hepatitis B, measurement of JC virus might be considered prior to initiation of rituximab therapy. Acknowledgment: This project was supported through the resources of the Wiliam JB Dorn Veterans Affairs Medical Center. Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the United States government. Disclosures: No relevant conflicts of interest to declare.