ALBERT

Description: 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.

Description: 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.

Description: 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.

Description: 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.

Description: 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.

Description: Background Financial conflicts of interests in clinical studies have been a perennial subject of investigation because of their potential to harm the public’s health. In 2010, we reported the first systematic analysis examining such conflicts in preclinical research, identifying that academic researchers without financial conflicts of interest significantly differed from academic researchers with financial conflicts of interest as well as scientists employed by manufacturers of erythropoiesis stimulating agents (ESAs). Those with no conflict of interest identified functional erythropoietin (Epo) receptors on tumor cells and that these receptors when activated carried out detrimental cell signaling and tumor promotion effects. The analysis was based on published studies from 1993 to 2008. In 2008, an NCI-sponsored conference with 14 academic scientists and 6 manufacturer employed-scientists restated these findings. We now review the status of the peer-reviewed published literature that has been disseminated following the NCI conference. Methods Articles identified in MEDLINE and EMBASE databases (2008-2012) investigating preclinical findings were reviewed for information on Epo receptors, signaling events, cellular function, and study conclusions. Study findings were classified into 3 groups according to funding source. (1) Academic-based studies authored by investigators without manufacturer funding [13 studies], (2) academic-based studies authored by investigators with funding from ESA manufacturers [8 studies], and (3) industry-based studies authored by more than 75% of investigators employed by ESA manufacturers [2 studies]. Results Studies authored by investigators in groups 1 and 2 report: Epo-induced signaling events in tumor cells (84.6% and 100.0%, respectively) and conclude that ESAs could be clinically harmful (83.3% and 57.2%, respectively); while no investigators in group 3 report Epo-induced signaling events in tumor cells or conclude that ESAs could be clinically harmful. Using univariate optimal discriminate analysis, 6/9 studies authored by investigators in groups 2 and 3 found no harmful changes in cellular function and is statistically different from investigators in group 1 who found harmful changes in cellular function in 11/12 studies (p

Description: 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.

Description: Abstract 2203 Background: Thrombotic thrombocytopenic purpura (TTP) is frequently characterized by severe ADAMTS13 deficiency, the cause of which is unknown. An important exception is ticlopidine-associated TTP (tc-TTP), the most common drug-induced TTP syndrome. In 1998, a possible association of TTP with ticlopidine was reported. In 1999, two additional series reported this association. In 2000, a fourth study reported severe A DAMTS13 deficiency among six of seven tc-TTP persons- suggesting a causal pathway. All of these reports were from the United States. Recently, we reported characteristics of 186 acquired idiopathic (ai)- TTP patients in Japan with severe ADAMTS13 deficiency, noting that clinical and laboratory findings for ai-TTP patients in Japan differed from those for cohorts of ai-TTP patients in Europe and North America- raising concern that TTP findings vary by region of the world. (PLOS One 2011) We now on report clinical and laboratory characteristics of a cohort of TTP patients from Japan with tc-TTP, and compare these findings to three cohorts of tc-TTP in the United States and one cohort of ai-TTP patients from Japan. Methods: We queried a database of thrombotic microangiopathy patients identified from a national TTP referral laboratory in Japan of cases identified between 1998 and 2008. Severe ADAMTS13 deficiency was characterized by activity levels 〈 5%. All tc-TTP patients and 186 of 911 ai-TTP patients in the database had severe ADAMTS13 deficiency and first onset of TTP. Comparisons were made to tc-TTP patients reported previously from the United States. Results: Characteristics of ai- TTP with severe ADAMTS13 deficiency in Japan and tc-TTP in Japan and US Conclusions: These data from Japan validate insights about tc-TTP initially proposed in 1998, 1999, and 2000 in the United States. Ticlopidine is a likely cause of TTP, the mechanism is via a cross-reactive antibody to ADAMTS13:AC resulting in formation of an ADAMTS13:INH, and therapeutic plasma exchange is necessary for treatment. Disclosures: Ortel: Eisai: Research Funding; Glaxo SmithKline: Research Funding; Pfizer: Research Funding; Instrumentation Laboratory, Inc: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Fujimura:Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; Alexion Pharma: Membership on an entity's Board of Directors or advisory committees.