ALBERT

Description: Background: Multiple myeloma (MM) is a common hematologic malignancy for which standard therapy does not offer a cure. Incidence of MM in African-Americans is twice that of Caucasians, suggesting differences in either environmental or genetic risk factors. Historically, black patients have also had a slightly better prognosis than white patients, suggesting racial differences in prognostic factors such as cytogenetics. Since metaphase cytogenetic profiles are routinely collected in MM patients, we sought to determine if race-based differences in cytogenetics exist, using data from the Veterans Health Administration (VHA) cancer registry. Methods: Using CPT codes, 88271-88275, 88291, 88299, 88365, 83896, 88237, 88261-88264, 88280, 88283, and 88285, we identified 988 patients with MM diagnosed between 1998 and 2009, who also had standard metaphase cytogenetic analysis performed on a bone marrow specimen at the time of diagnosis (228 Black and 585 White) . Fisher’s exact test was used to assess for race-based differences in the following cytogenetic abnormalities: 13q deletion, Hypodiploidy, Hyperdiploidy, and translocations involving chromosome 14. Results: Among the 988 patients in the cohort, normal cytogenetic profiles, isolated Y chromosome deletion, or no mitotic activity were observed in 704(71%) patients. Translocations involving the immunoglobulin heavy chain (chromosome 14) (n=4) were uncommonly observed on routine cytogenetics, such that no statistical conclusions could be drawn. Hyperdiploidy was noted in 13/228(5.7%) of the black and 45/585(7.7%) of the white patients (p=0.32). Similarly 13q deletions were detected in 8/228(3.5%) black patients, and 21/585(3.6%) of the white patients (p=0.96). Hypodiploidy was also not significantly different in black 4/228(1.8%) and white patients 12/585(2.0%). Conclusion: This is the largest study of race-based differences in MM cyogenetics presented to date. We found no significant race-based differences in standard metaphase cytogenetics. Future studies should focus on determining if race-based differences can be discovered using fluorescent in situ hybridization (FISH) or molecular testing not available for this retrospective study. Our study adds to this growing body of evidence suggesting that metaphase cytogenetic differences are not a significant factor in MM outcome disparities. Disclosures Carson: Spectrum Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau.

Description: Background: At ASH 2005, we reported that 9 drugs had received accelerated approval (AA) for 11 hematologic indications since 1992, and that only 2 of these drugs had fulfilled post-marketing requirements for conversion to regular approval. Following our original report in 2004, only 1 drug had converted to regular approval by 2005. At that time, we suggested that the FDA establish stricter post-marketing milestones, a suggestion echoed in Congressman Ed Markey’s report “Conspiracy of Silence.” Two years later, we update the experience with AA for hematologic indications and reevaluate the FDA’s post-marketing approval process. Methods: Information on approval status and the clinical trials which form the basis of AA was obtained from the FDA website, product inserts, and medical literature reviews. Results: Since 1992, 11 drugs have received AA for 14 hematologic indications. Post-marketing requirements have been fulfilled for only 2 indications (14%), and none have converted to regular approval since 2005. The median time since AA for the 12 indications with pending post-marketing commitments is 5.5 years. For solid tumors and supportive oncology, by contrast, 15 drugs have received AA for 15 indications; Subpart H requirements have been fulfilled for 9 indications (56%). The median time to completion of post-marketing commitments for oncologic and supportive indications is 8 years, and the median time since AA for indications with pending commitments is 3 years. The mean number of patients in clinical trials for AA is 155 for hematologic indications and 1567 for solid tumor and supportive indications. Conclusions: The rate of conversion to regular approval for drugs with hematologic indications remains low. Our prior recommendation for stricter post-marketing milestones seems to be an untenable solution given the stagnancy of the approval process since our last report. Completion of Subpart H commitments may simply be unachievable, due to small numbers of patients and slow accrual to clinical trials following AA, in part due to violation of equipoise. We therefore revise our approach to AA. Surrogate endpoints are typically predictive of clinical benefit, while safety signals are often missed in early trials; the FDA should concentrate on preventing harm by mandating drug companies to keep safety registries after AA is granted, while still encouraging the emergence of new drugs for rare diseases through AA. Drug AA Indication/Date Years since AA # pts in trials on which AA based Date Subpart H commitment fulfilled (P=Pending) BORTEZOMIB MYELOMA-5/13/03 4.25 193 3/25/05 IMATINIB CML, INITIAL TX-5/10/01 6.25 864 12/8/03 Nelarabine T Cell ALL-10/28/05 1.8 68 P Clofarabine Pediatric ALL-12/28/04 3.33 74 P Tositumomab Rituxan-naive follicular NHL (expanded indication)-12/22/04 3.33 130 P Tositumomab Rituxan-refractory NHL-6/27/03 4.1 100 P Imatinib Pediatric CML-5/20/03 4.25 39 P Imatinib GIST-2/1/02 5.5 147 P Ibritumomab NHL-2/19/02 5.5 157 P Alemtuzumab CLL-5/7/01 6.25 93 P Gemtuzumab CD33+ AML-5/17/00 7.25 42 P Cytarabine liposomal Lymphomatous meningitis-4/1/99 8.33 14 P Denileukin Diftitox Cutaneous T cell lymphoma-2/5/99 8.5 71 P Doxorubicin liposomal AIDS-related Kaposi’s sarcoma-11/17/95 11.75 77 P AA for Hematologic Indications Drug AA Indication/Date Years since AA # pts in trials on which AA based Date Subpart H commitment fulfilled (P=Pending) BORTEZOMIB MYELOMA-5/13/03 4.25 193 3/25/05 IMATINIB CML, INITIAL TX-5/10/01 6.25 864 12/8/03 Nelarabine T Cell ALL-10/28/05 1.8 68 P Clofarabine Pediatric ALL-12/28/04 3.33 74 P Tositumomab Rituxan-naive follicular NHL (expanded indication)-12/22/04 3.33 130 P Tositumomab Rituxan-refractory NHL-6/27/03 4.1 100 P Imatinib Pediatric CML-5/20/03 4.25 39 P Imatinib GIST-2/1/02 5.5 147 P Ibritumomab NHL-2/19/02 5.5 157 P Alemtuzumab CLL-5/7/01 6.25 93 P Gemtuzumab CD33+ AML-5/17/00 7.25 42 P Cytarabine liposomal Lymphomatous meningitis-4/1/99 8.33 14 P Denileukin Diftitox Cutaneous T cell lymphoma-2/5/99 8.5 71 P Doxorubicin liposomal AIDS-related Kaposi’s sarcoma-11/17/95 11.75 77 P

Description: Introduction: In 2002 and 2003, Ortho Biotech Products, L.P. issued “Dear Health Professional” letters describing two distinct episodes with distribution of counterfeit epoetin (ProcritÒ). The first episode in 2002 occurred when counterfeit labels marked as “40,000 Unit” vials were switched onto 2,000 Unit Procrit vials (5% potency). An estimated 97,000 vials of this product were not recovered, as many as 25,000 patients may have been exposed. A second episode occurred in 2003 when bacteria-contaminated tap water was added to vials that were labeled as containing “40,000 Units” of Procrit®. The “Dear Doctor” letters describe the subtle labeling and other product packaging features that distinguish the products from authentic. In addition, specific lot numbers are identified. We reviewed all MedWatch reports from the United States’ Food and Drug Administration (FDA) for confirmed or possible cases of counterfeit epoetin. Methods: For the years 1998 to 2004, the FDA’s adverse event reporting system (AERS) was searched, using key words: “suspected product tampering,” “decreased drug effect” and related terms, and all epoetin product names. We summarized the demographic variables for the cases and identified the lot numbers reported within the cases. Results: Seven cases of “medication tampering” were identified in the FDA’s Adverse Event Reporting System (AERS) database - all 7 included Procrit® lot numbers identified in the “Dear Health Professional” Warning Letters from OrthoBiotech. The cases had been reported to the FDA by pharmacists (n=5), a consumer (n=1), and a nurse (n=1). In six of these case reports, among cancer patients, death also listed on the report, although counterfeit product was not listed as the proximate cause of death. There were no case reports identified by the diagnostic term of “pharmaceutical product counterfeit”, which was added to the FDA’s AERS in 2004. We identified an additional 643 cases of MedWatch cases that were coded with the diagnostic labels of “drug ineffective”, “therapeutic response decreased”, “drug effect decreased”, “condition aggravated”, and similar terms. The mean age equal to 59.7± 17.7 years, range 5–95 years. There were 269 females (42%) and 358 males (55%), gender not reported for 3%. All epoietin products were included. Finally, one case was found with a reported lot number corresponding to one listed in the warning letters. Death occurred in this 89 year-old patient. Conclusion: Health professionals should be alert for potential counterfeit drugs whenever drug effects are less than expected and the pharmaceutical is costly. Whenever suspected, the occurrences should be reported to the FDA and the manufacturer as possible “pharmaceutical product counterfeit.” The use of radio frequency identification (RFID), planned to be implemented in 2007 may help prevent the domestic distribution of counterfeit drugs, but increases in direct importation of drugs from international sources will potentially increase the likelihood of distribution of counterfeit drugs domestically.

Description: Background: Due to the rarity of TTP (approximately 4 cases per million), epidemiologic data and correlative laboratory samples from a prospectively identified incident cohort of TTP patients are needed. Methods: SERF TTP is a NHLBI-funded 15-site study targeted to identify 300 incident TTP patients and 600 age-/gender-matched community controls. Results: From nine IRB-approved collaborating sites, 22 incident TTP cases and 17 controls have been interviewed. Data and plasma (acute and convalescent samples) are available for 19 TTP patients (Table 1). Their mean age is 42.5 years (range, 20 – 80 years), and 90% are female. Using the Rose-Eldor TTP Scoring system based on platelets, creatinine, hemoglobin, and neurologic function, 37% would be classified as severely ill (score 〉 4 of a maximum 8 points). Mean time from symptom onset to diagnosis was 9.2 days, median 5.5 days (range, 0 to 33 days). Severity of TTP was poorer for the 5 patients whose treatment did not begin for at least 16 days (16–33 days) versus the other 14 patients (mean Rose-Eldor score of 4.6 versus 4). Medications which had been prescribed to the patients prior to TTP onset included herbal supplements (n= 5) and hormone replacement therapy or oral contraceptives (n= 6). All patients received at least daily therapeutic plasma exchange (TPE). A platelet count 〉150,000 was reached at a mean of 9.4 days following TPE initiation. At 30-days follow-up, all patients were alive, although 3 had an exacerbation requiring daily TPE reinstitution. Fourteen patients (78%) experienced an adverse event, including allergic reactions to plasma (n=9), citrate-related toxicity (n=9) and venous access complications (n=2) including one with major hemorrhage requiring transfer to the intensive care unit. Conclusion: The clinical characteristics of the SERF-TTP cohort are similar to those reported from large single-site studies, although the survival rate (100% versus 71% and 83%) is higher. Only a minority of incident TTP cases in the modern era present with renal insufficiency or neurologic findings - highlighting the importance of developing reliable diagnostic laboratory testing. Clinical Characteristics at Presentation Study Platelets

Description: The present invention includes compositions and methods for the use of an encapsulation additive having between about 0.1 to about 30 percent isolated and purified vitelline protein B to provide for mixed and extended release formulations.