ALBERT

Description: Abstract 2174 Introduction: The prognosis for patients with primary induction failure (PIF) or relapsed acute myeloid (Rel-AML) is poor. Mitoxantrone (M) plus etoposide (E)- based salvage regimens (ME), in particular, either alone or with intermediate dose cytarabine (MEC) are effective in these high risk patients; However, these regimens have not been directly compared. Heterogeneity in chemotherapy dose, dose escalation and age have been important limitations in the evaluation of previous studies. Also problematic, historically patients were classified according to FAB criteria. Since then, karyotype has been shown to be a main determinant of prognosis. The influence of karyotype on response to ME or MEC is currently unknown. Herein, we report the response to treatment with a fixed dosing schedule of ME or MEC in 66 patients treated for PIF or Rel-AML with intermediate(intermed-) or unfavorable(unfav-) risk cytogenetics. Differences in CR between ME and MEC subsets were analyzed to determine the effect of adding of C to ME. Methods: 66 consecutive patients with PIF or Rel-AML treated with either ME(n=37)or MEC(n=29) between 10/2004-12/2008 were evaluated. All patients had received initial induction therapy with daunorubicin 45–60mg/m2 IV bolus d1-3 and cytarabine 100mg/m2 CI d1-7(7+3), and consolidation with HIDAC if CR was achieved. ME and MEC were dosed according to previously published studies. The decision to use a given salvage was left to the discretion of the treating physician. Chi-Square test was used for statistical analysis. Results: Table1 shows there was no difference between the ME and MEC groups with regards to age, sex, % blasts at initial diagnosis, and %CR after initial induction with 7+3, or % patients who received inter- to high dose C prior to ME or MEC. Length of CR (after 7+ 3 and consolidation) was significantly longer in the MEC group. A significantly higher number of CR's was observed in the MEC group compared to ME(p=0.05). Within the MEC group, no difference in CR was observed between patients with intermed- and unfav-risk cytogenetics(p=0.96). The same was true within the ME group(p=0.13). When MEC was compared to ME, a significant difference in CR was observed in patients with unfav-risk cytogenetics(p=0.044) and patients

Description: Abstract 1351 Purpose Rasburicase (recombinant urate oxidase) is used to rapidly metabolize uric acid in patients with hyperuricemia. Rasburicase is considered immunogenic given that it is produced by a genetically modified Saccharomyces cerevisiae. Rasburicase labeling indicates that anaphylaxis rarely occurs (

Description: Abstract 4314 The prognosis for patients with primary induction failure (PIF) or relapsed acute myeloid leukemia (rel-AML) is poor. Dose intense etoposide (E) and cyclophosphamide (C) used alone or in combination therapy, without stem cell transplantation (HSCT) have been successfully used as salvage therapy for hematological malignancies. Difference in chemotherapy dose and schedule has been a limitation in the evaluation of previous E and C studies. Additionally, previous EC studies were conducted before karyotype was found to be a major determinant of prognosis. Currently the influence of karyotype on response to dose-intense EC is unknown. We report the response to treatment with dose intense EC combination therapy in 34 heavily pretreated PIF or rel-AML patients, most with intermediate or unfavorable cytogenetics. Methods: 34 consecutive patients with PIF or Rel-AML treated with dose-intense EC between 10/2004-12/2011 were evaluated. All patients received initial induction therapy with daunorubicin 45–90mg/m2 IV bolus d1–3 and cytarabine 100mg/m2 CI d1–7, and consolidation with HIDAC for 1–3 courses if CR was achieved. Treatment: 27 patients (79%) received etoposide 3gm/m2 by continuous infusion over 48–72hours followed by cyclophosphamide 50mg/kg iv infusion daily for 3 or 4 days. The remaining 7 patients received reduced etoposide 1.8–2.4gm/m2. The decision to use a given dose of EC was left to the discretion of the treating physician. Chi-Square, Fischers Exact Test and Cox regression analysis were bused for statistical analysis. Results: Patient demographics can be seen in Table 1. Most patients had rel-AML (62%), previous exposure to high or intermediate-dose cytarabine (75%), were 〈 60 years old (70%), had intermediate or unfavorable cytogenetics (92%), and received at least 1 salvage regimen (in addition to induction and consolidation) prior to dose-intense EC (65%). Patient outcomes are seen in Table 2. Overall, CR was achieved in 32% of patients. Median duration of CR after DI-EC treatment was 5 months. Figure 1 shows overall survival curve. No significant difference in response was found for patient's age 〉60years (p

Description: Abstract 2479 Poster Board II-456 Hyperuricemia(HU) is a frequent complication following therapy for hematologolical malignancies(HM). Conventional therpy with alkalinization, hydration and allopurinol may not be sufficient to lower pre-existingly high uric acid levels(UA). Rasburicase, recombinant urate oxidase, when given at pediatric doses(0.15-.2mg/kg/d x 3-5d)is very effective in lowering UA levels 7 mg/dL) in 247 adult patients with hematologic malignancies. 28% had renal failure (serum creatinine 〉2.5 mg/dL) and 29% had tumor lysis syndrome. The median dose of 36 μg/kg (range 18-65) was a fraction of the recommended pediatric dose of 0.75-1.0 mg/kg over 5 days. The median change in the uric acid levels at 24 hours was -4.1 mg/dL (range -12 to +1) and -45% (range -95 to +9). The uric acid levels normalized at 24 hours in 78% of patients. There was no relationship between the weight-adjusted dose and uric acid decline. The only predictor of resolution of hyperuricemia was baseline uric acid; the failure rate was 84% with baseline uric acid of 〉12 mg/dL compared to 18% if the baseline level was '12. The level continued to decline beyond 24 hours in the majority of patients in the absence of additional doses. Serum creatinine remained stable over 24 hours and declined over 48 hours and 7 days. There was no relationship between the extent of reduction in uric acid levels and serum creatinine. The approach We conclude that a single 3 mg dose of rasburicase, used with close clinical and laboratory monitoring, is sufficient in most adults with elevated serum uric acid levels up to 12 mg/dL. The best approach to patients with higher levels remains unclear. Table 2: Serum uric acid and creatinine levels and changes (median, range) Serum uric acid (Median, range) Baseline level (mg/dL) 9.3 (7.1–27.3) 24-hour level (mg/dL) 5.3 (0.5–23.0) 24-hour direction of change Any increase 9 (3%) No change 1 (5 mg/dL 150 (52%) Serum creatinine (Median, range) Baseline level (mg/dL) 1.7 (0.6–9.7) 24-hour level (mg/dL) 1.6 (0.6–8.7) 24-hour direction of change Any increase 88 (31%) No change 54 (19%) Any decrease 145 (50%) ≥10% increase 52 (18%)

Description: Background Brentuximab vedotin (BV) is a novel antibody drug conjugate consisting of an anti- CD30 IgG1 antibody, cAC10, linked to monomethylauristatin E, a potent inhibitor of microtubule polymerization. It is approved for treatment of relapsed classical Hodgkin lymphoma (cHL) and anaplastic large cell lymphoma (ALCL) in the US (FDA; 8/2011) and Europe (EMA; 10/2012). Peripheral neuropathy was the most frequent treatment-related adverse event (AE) in phase II trials, and the most common Grade 3 or higher toxicity apart from cytopenias. Although abdominal pain has been observed in up to 25% of all patients, pancreatitis is a previously unrecognized AE. We now report 8 cases of BV-associated pancreatitis, 2 of them fatal. Methods Following a grade 5 AE from pancreatitis in a patient receiving single-agent BV on an ongoing clinical trial (NCT01476410), collaborating investigators examined their collective cases of pancreatitis associated with BV. Lymphoma specialists at other centers were solicited for additional events. IRB or Ethics Committee approval as required was obtained in all cases. AE's reported to the FDA Adverse Event Report Systems (FAERS) from 6/2011-7/2013 were also examined. Data was collected and analyzed through the Research on Adverse Drug Events and Reports Project. Immunohistochemical staining with the anti-CD30 antibody BER-H2 (DAKO) was performed on residual normal pancreas from one of the fatal cases and normal control pancreas. Results Eight cases of BV-associated pancreatitis were identified by collaborators, and one additional report with limited information was listed in FAERS. Demographic, treatment and AE information for the eight complete cases is detailed in Table 1. In all cases, BV was administered as a single agent. In seven cases, the dosing was 1.8 mg/kg every 21 days with a maximum of 180 mg; in one case, BV was administered weekly at 1.2 mg/kg (days 1,8,15, q 28). Two patients were retreated with BV after resolution of pancreatitis; one had no further evidence of pancreatitis and proceeded to a stem cell transplant, whereas the other patient, having recovered from Grade 4 pancreatitis, experienced a second episode (Grade 3). All patients demonstrated clinical evidence of pancreatitis as manifested by severe abdominal pain and nausea. In addition, all patients had biochemical and radiologic evidence of pancreatitis. Notably, no patient had an antecedent history of excess alcohol use or radiologic evidence of biliary pathology. Two patients developed progressive and fatal multiorgan dysfunction as a consequence of acute pancreatitis. An autopsy performed on one of the two fatalities showed evidence of acute necrotizing pancreatitis as the cause of death; diffuse pancreatic parenchymal necrosis and fat necrosis were seen but no cholelithiasis. Although the anti-CD30 antibody BER-H2 was previously reported to stain normal pancreas (BLOOD 1989 74:1678), routine immunohistochemical staining for CD30 on both the patient pancreas and normal pancreas controls were negative. Conclusion This is the first series describing pancreatitis as a rare, but serious and potentially fatal toxicity related to BV. Pancreatitis has been previously reported with other microtubule inhibitors such as taxanes and vinca alkaloids, but the mechanism, as with BV, remains unclear. Genetic factors that predispose to both acute and chronic pancreatitis have been reported and may underlie a susceptibility to this uncommon complication of treatment with BV. Clinicians prescribing BV should evaluate patients who present with abdominal pain for pancreatitis, and should consider pre-treatment biochemical assessments with serum lipase and/or amylase. Disclosures: Off Label Use: Brentuximab Vedotin is approved for relapsed, refractory Hodgkin Lymphoma in patients who have already had a transplant or are ineligible for one, or for patients with relapsed, refractory anaplastic large cell lymphoma. Patients treated on clinical trials or off label will be included in this presentation. Evens:Seattle Genetics : Consultancy, Honoraria. Fenske:Seattle Genetics: Consultancy. Hamlin:Seattle Genetics : Consultancy, Honoraria. Coiffier:Millennium Pharmaceuticals : Consultancy. Engert:Millennium Pharmaceuticals : Consultancy. Moskowitz:Seattle Genetics : Research Funding. Ghosh:Millennium Pharmaceuticals : Membership on an entity’s Board of Directors or advisory committees. Petrich:Seattle Genetics : Consultancy, Honoraria, Research Funding. Gordon:Seattle Genetics : Research Funding. Winter:Seattle Genetics : Research Funding.

Description: Background: The accelerated approval (AA) regulation (21CFR314.510 Subpart H) is granted by the Food and Drug Administration (FDA) when drugs for serious medical illnesses are shown to be an improvement over available therapy. AA provides an option to use surrogate outcomes considered likely to predict clinical benefit. AA was initially developed to hasten access to HIV drugs, then, in 1995, AA was extended to cancer indications. Sponsors receiving AA are required to confirm clinical benefit (termed subpart H trials). Policy makers have several raised concerns: AA is no longer relevant today as the approval bar via this mechanism has been raised too high; many drugs that received AA did not complete subpart H trials; and some drugs approved by AA were subsequently found to be unsafe or ineffective. Methods: Using publicly available databases, we compared safety, efficacy, clinical development times, and subpart H completion rates for FDA-approved new molecular entities (NMEs) for hematologic and solid tumor cancers from 1995–2008. Results: 37% of all oncology NMEs received AA versus regular approval (64% during 1995–2003 and 33% during 2004–2008). Twenty oncology NMEs received FDA approval for hematologic malignancies (lymphomas, leukemias, Kaposi’s sarcoma, and myelodysplastic syndromes), accounting for 34% of regular approvals and 53% of AAs for oncology NMEs. Compared to NMEs approved for solid tumors, NMEs approved for hematologic malignancies were more likely to involve Orphan Drug indications (95% vs. 32%); to have shorter development times, defined as the interval between investigational new drug filing and marketing approval, (median 5.6 vs. 7.8 years); and to be approved based on phase II studies (65% vs. 29%). Prior to 2004, development times were similar for solid tumor and hematologic malignancy NMEs. Since 2004, development times have decreased by more than 2 years for hematologic malignancy NMEs, but not for solid tumor NMEs. 50% of NMEs approved for hematologic malignancies versus 71% of NMEs for solid tumor diagnoses are included in first-line cancer regimens in current National Comprehensive Cancer Network guidelines. Drugs approved for solid tumor and hematologic indications have similar safety profiles and efficacy; respectively, 30% and 38% carried black box warnings at initial approval, and 15% and 10% had black box warnings added post-approval. Studies confirming efficacy were completed for 89% of NMEs receiving AA for solid tumor indications versus 30% for NMEs receiving AA for hematologic malignancy indications. Concern that sponsors are not completing subpart H commitments has led the FDA to move from basing AA on final results of single-arm phase II trials to interim results of phase III trials. Conclusions: AAs for hematologic malignancy indications are less likely to complete Subpart H commitments. In the current era, development times for NMEs are shorter for hematologic malignancy versus solid tumor indications, principally related to the approval based on Phase II versus Phase III studies. Establishing a global policy that AA approval for cancer drugs should be based on interim results of phase III analyses rather than on final analyses of phase II trials may hamper development of novel therapies for hematologic malignancies. Solide tumor indications Hematologic malignancy indications 1995–2003 (n=21) 2004–2008 (n=10) 1995–2003 (n=11) 2004–2008 (n=9) Drugs receivving AA (%) 29 30 64 33 Orphan drugs (%) 24 40 100 78 Of AAs, Subpart H completion (%) 100 66 27 0 Approval based on phase II trial (%) 33 0 73 78 Median development time (years) 8.4 7.8 8.8 5.2

Description: Tacrolimus is an effective immunosuppressive agent for allogeneic HSCT. It is primarily metabolized by the CYP450 3A4 isoenzyme. Voriconazole is often used to prevent fungal infections after allogeneic HSCT. It is metabolized by the CYP450 3A4, 2C9 and 2C19 isosenzymes. Studies in healthy volunteers and case reports in HSCT recipients have shown significant drug interaction between the two requiring reduction of tacrolimus dose. Ordinarily, tacrolimus prophylaxis is initiated at the dose of 0.03 mg/kg IV daily on day -1. After starting tacrolimus at this dose and having to reduce the dose substantially within 2–3 days in all patients receiving concomitant voriconazole 200 mg twice daily orally from day 0, we implemented a simple, pre-emptive tacrolimus dose reduction strategy to maintain steady-state levels between 5 and 15 ng/mL in patients on IV tacrolimus. As a first step, IV tacrolimus was initiated at the reduced dose of 0.022 mg/kg adjusted body weight per day. As a second step, tacrolimus dose was reduced by 30–40% if the steady-state level 48 h after initiation of tacrolimus (day +1) was between 7 and 10 ng/mL, and by 40–50% if the level was between 10 and 15 ng/mL. No change was made if the level was

Description: Abstract 942 Background: Early death in APL, most often due to bleeding, has emerged as the major cause of treatment failure now that curative strategies exist. Despite the routine use of ATRA, EDR remains high (Lehmann et al Leukemia 2011, Park et al Blood 2011). Although the optimal strategy to prevent early death is not clear, the recommendation is to initiate ATRA immediately at first suspicion of the disease without waiting for genetic confirmation. Therefore, we examined the timing of ATRA administration. Methods: To determine time interval from initial presentation to ATRA administration, we retrospectively collected data on all newly diagnosed APL pts presenting between 1992–2009 to 4 institutions: Northwestern University, Chicago, IL (university medical center); Memorial Sloan-Kettering Cancer Center, New York, NY (free standing cancer center); John J. Stroger Hospital of Cook County, Chicago, IL (public hospital); and Rambam Medical Center, Haifa, Israel, (Northern Israel's largest hospital; a tertiary referral center). We also examined 3 other time intervals: presentation to suspicion of APL, suspicion of APL to ordering ATRA, and ordering ATRA to its administration. Results: We identified 205 newly diagnosed APL pts: 46% men, median 48 years (range 1.5–85). Median white blood cell (WBC) count at presentation was 2,100/uL (range 300/uL-222,500/uL); 25% had high risk (HR) disease (WBC 〉10,000/uL). Median time interval from initial presentation to suspicion of APL was 1 day and median time from suspicion of APL to ordering ATRA was an additional day (table 1). ATRA was ordered on the day APL was suspected in 32% pts, the next day in 31%; 2 days after suspicion in 17%; and after 3 or more days in 16%. 89% received ATRA on the day ordered. At least 1 bleeding episode was identified in 34% of 185 pts with bleeding data available. Bleeding was associated with higher WBC count (p=0.0003) and lower hemoglobin (p=0.027) at presentation. 46 of 186 pts with complete information on time from presentation to administration of ATRA died. 23 (12%) died within 30 days of presentation; comprising half of all fatalities. Causes of death were: hemorrhage −15, sepsis −4, suspected MI −2, pneumonia −1, and sepsis plus differentiation syndrome -1. Among deaths within 30 days, 48%, 22%, 26% and 7% were in 1st through 4th weeks, respectively. 4 (18%) of these 23 pts died before ATRA was administered, all day 1 or 2 after presentation and all from bleeding. Only 15/182 pts received ATRA on day of presentation. Two of these 15 (13%) died within 30 days (none from bleeding). In comparison, 7/40 (18%) who received ATRA on day after presentation died within 30 days (71% from bleeding). 10/127 (8%) who received ATRA on day 2 or after died within 30 days (6 from bleeding). 20% in each group who received ATRA on either day of presentation or day 1 after presentation had HR disease. For this subgroup, if ATRA was administered on the day APL was suspected or one of the following 2 days, EDR was 19% (7/37). However, if ATRA was initiated on day 3 or 4, EDR was 80% (4/5); (p=0.013). 59% received ATRA prior to confirmation and 41% received ATRA on the day APL was confirmed or later. Conclusions: (1) APL was suspected rapidly upon presentation, usually within 1 day and ATRA was almost always administered on the day ordered. (2) However, ATRA was not given to most pts the day APL was suspected and for some 2 or more days elapsed. This time interval contributed to the delay in ATRA administration, suggesting physicians waited for marrow morphology or genetic confirmation before ordering ATRA. (3) Although at these centers a lower EDR (12%) than reported from the SEER database (17.3%) was observed, the current recommendation to give ATRA at first suspicion of APL was often not practiced. (4) There appears to be an association between EDR and timing of ATRA administration; other factors contribute to the EDR including variability in blood product support. (5) Our study argues that educating health care professionals who are the first to encounter APL pts as to the urgency of ATRA administration will reduce early deaths that occur even in the ATRA era. Disclosures: No relevant conflicts of interest to declare.

Description: Background: The incidence of Zygomycete infection has been increasing, almost exclusively in patients with hematologic malignancy with or without history of stem cell transplantation. In a single institution case control study, voriconazole was identified as an independent risk factor for the development of Zygomycete infections. A small number of single institution case reports have also been noted. Methods: Investigators for The Research on Adverse Drug Events and Reports (RADAR) project requested collaboration from cancer centers regarding the identification and characterization of Zygomycete infections in patients with prior exposure to voriconazole. 12 centers participated in this study project. Medical records were reviewed and data collected on a standard case report form including diagnosis, transplant type, concomitant risk factors, exposure times, concurrent infection and outcomes. A minimum of 5 days exposure was noted between clinical diagnosis and confirmation with either tissue or histology. Results: 54 cases were identified from 12 centers and with notably almost 75% mortality rate in individuals who were diagnosed with Zygomycoses with prior exposure to voriconazole.Of interest 31/54 cases received voriconazole for prophylaxis. Presenting characteristics were similar to those reported previously with lung as major site of infection. Concomitant risk factors included steroid use, immunosupression, GVH, neutropenia and diabetes. Simultaneous co-infections from diverse bacterial, viral and fungal infections were noted in 60% of patients signifying a compromised immune status. Drug therapy with an amphotericin product used to treat the identified Zygomycosis was highly ineffective with failure in 26/32 patients with resultant mortality. Conclusion: Rates of breakthrough zygomycoses with high mortality rates with prior voriconazole therapy are on the increase. Appropriateness of prophylactic use as well as early diagnosis and institution of antifungal therapy in these patients with Zygomycoses is essential to combat this devastating infection.