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Abstract 2910 Introduction: MDS is characterized by defects in hematopoietic cell growth, differentiation and apoptosis. Ezatiostat, a glutathione S-transferase inhibitor, activates Jun kinase, promoting the growth and maturation of hematopoietic progenitors while inducing apoptosis in leukemic blasts. The purpose of this Phase 2 study was to determine the efficacy and safety of ezatiostat on extended dose schedules in MDS. Methods: Patients (pts) with International Prognostic Scoring System Low or Int-1 risk MDS were enrolled. After initial dose-ranging in 14 pts, subsequent pts were randomized to 2 selected dose schedules: 37 pts at 3 gm daily for 2 weeks followed by a 1-week rest period and 36 pts at 2 gm daily for 3 weeks followed by a 1-week rest period. Treatment was given until lack of MDS response or unacceptable toxicity. A logistic regression analysis was conducted to identify significant MDS disease factors associated with hematologic improvement-erythroid (HI-E) rates as determined by the MDS International Working Group (2006) criteria. Results: Seventy-three pts were median age 73 years (range 48–89) 70% male, and with World Health Organization classification as follows: 11 refractory anemia (RA), 15 RA with ring sideroblasts, 5 RA with excess blasts-1, 24 refractory cytopenia with multilineage dysplasia, 9 MDS-unclassified, 3 MDS/Myeloproliferative disorder-U, 4 MDS-del 5q, and 2 Unknown. Fifty pts (68%) were INT-1 risk, 23 (32%) were Low risk; 27 pts (37%) had abnormal karyotypes with 23 (85%) complex/poor prognostic types. RBC transfusion-dependent pts required a median of 6 (range 4–19) U/8 weeks prior to study entry. Prior treatments included: 34 (47%) DNA methyltransferase (DMTI), 28 (38%) lenalidomide, 56 (77%) erythropoietin, and 32 (44%) growth factors. The HI-E response rate was similar for evaluable pts on the 2 schedules, therefore the data were pooled. The overall HI-E rate was 22% (13/60) [95% CI, 12.1%–34.2%]. The median duration of response was 34 weeks. Eleven of 38 (29%) RBC transfusion-dependent pts had transfusion reductions (reduction of 4U/8weeks) with 4 pts (11%) achieving transfusion independence. A 40% HI-E rate (6/15 pts) [95% CI, 16.3%–67.7%], was observed in pts who had prior lenalidomide, but no prior DMTI, with 5/11 pts (45%) achieving significant RBC transfusion reduction and 3/11 pts (27%) achieving transfusion independence. A 28% HI-E rate (5/18 pts) [95% CI, 9.7%–53.5%] was observed in pts who were lenalidomide and DMTI naive, with 4/8 pts (50%) achieving clinically significant RBC transfusion reduction. Sixteen pts had received prior DMTI but no prior lenalidomide treatment, a 0% HI-E rate (95%CI: 0%-20.6%) was reported. Prior DMTI treatment predicts a 6-fold decrease in the odds for HI-E response to ezatiostat (p=0.027). A 19% HI-Neutrophil (HI-N) rate was observed in 4/21 pts with neutropenia (95% CI, 5.4%–41.9%) and a bilineage (HI-E and HI-N) rate of 20% (95% CI, 5.7%–43.7%) in 4/20 pts with anemia and neutropenia. A 3.7% (95% CI, 0.1%–19%) HI-P rate was observed in 1/27 thrombocytopenic pts and a trilineage (HI-E, HI-N, HI-P) rate of 9.1% (95% CI, 0.2%–41.3%) in 1/11 pts with trilineage cytopenia. There were 2 cytogenetic complete responses, 1 with 45X,-Y[4], 46, XY [16] and 1 with del5q. A total of 431 ezatiostat cycles were given, median 4.0 (range 1–14). Only 15 cycles (3.5%) required dose reduction and 37 cycles (8.6%) dose delays. Most common ezatiostat-related adverse events (AEs) were non-hematologic Grade 1 and 2 gastrointestinal (GI) including: nausea (45%, 17%), diarrhea (25%, 8%), and vomiting (30%, 12%). Grade 3 events were: nausea (1%), diarrhea (3%), and vomiting (2%). Prior DMTI treatment was associated with an increased incidence of GI AEs. Pts with prior DMTI use had GI AEs (Grades 1, 2, 3): nausea (51%, 20%, 2%), vomiting (34%, 7%, 2%), diarrhea (22%, 10%, 5%). DMTI-naive pts had fewer GI AEs (Grades 1, 2, 3): nausea (39%, 15%, 0%), vomiting (26%, 15%, 2%), diarrhea (28%, 7%, 2%). Conclusions: Ezatiostat is the first GSTP1-1 inhibitor shown to cause clinically significant reduction in RBC transfusions, including transfusion independence, as well as HI-N and HI-P. Ezatiostat has shown clinically significant efficacy in lenalidomide naive and lenaliomide treated pts. The tolerability and activity profile of ezatiostat may offer an important treatment option for pts with low to INT-1 risk MDS. Disclosures: Raza: Telik, Inc.: Research Funding. Galili:Telik, Inc.: Research Funding. Godwin:Scripps Health: Honoraria. Boccia:Telik, Inc.: Research Funding. Rarick:Telik, Inc.: Research Funding. Meng:Telik, Inc.: Employment, Equity Ownership. Jones:Telik, Inc.: Employment, Equity Ownership. Brown:Telik, Inc.: Employment, Equity Ownership, Patents & Royalties. Young:Telik, Inc.: Employment, Equity Ownership. Sekeres:Celgene Corp: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Abstract 3057 Background: Multiple myeloma (MM) is an aggressive and incurable disorder with an eventual fatal outcome bringing urgency to the identification of effective treatments for patients who have exhausted standard chemotherapy. New agents, such as lenalidomide and bortezomib have led to a rapid increase in therapeutic options as single agents and in combination with other agents. However, despite this progress nearly all patients will relapse and require additional therapeutic options. Bendamustine is a unique chemotherapeutic agent that combines an alkylating group with a purine-like benzimidazole ring that is approved in the US for the treatment of CLL and refractory indolent B-cell NHL. Bendamustine is approved in Europe for the treatment of MM. Bortezomib is a proteasome inhibitor (PI) that is approved for the treatment of MM and the combination of this PI with alkylating agents including melphalan and cyclophosphamide has proven highly effective in the treatment of MM. Thus, the combination of bortezomib with bendamustine which also possesses alkylating agent properties may enable patients that were previously treated with bortezomib to have additional therapeutic options. In addition, this combination may allow use of lower doses of bortezomib to be used potentially reducing the incidence of peripheral neuropathy as has been observed in other combinations involving bortezomib with other alkylating agents. This study is being conducted to assess the safety and efficacy of bendamustine in combination with bortezomib for the treatment of relapsed/refractory MM. Methods: This open-label, Phase 1/2 study, will enroll up to 40 patients (pts), age ≥18 years, with measurable MM that has relapsed following or is refractory to at least 1 previous treatment. Patients received bendamustine infused intravenously over 1 hour on days 1 & 4 in 3-dose cohorts of 50, 70, or 90 mg/m2 and bortezomib on days 1, 4, 8, & 11 at a fixed dose of 1.0 mg/m2 for up to eight 28-day cycles. Three pts were initially enrolled at each dose cohort. Up to 5 pts were allowed to enroll in each initial cohort if they were all in screening prior to the 3rd pt being enrolled. After the first 3 pts completed cycle 1 of each dose, the cohort was assessed for dose-limiting toxicities (DLT). In this study, a DLT was defined as any study drug related grade 3 or grade 4 non-hematologic toxicity, grade 4 hematologic toxicity, grade 3 thrombocytopenia with grade 3 or 4 hemorrhage, grade 3 febrile neutropenia, grade 3 or grade 4 nausea and vomiting refractory to anti-emetic therapy, or any drug-related deaths. A standard 3+3 approach was used for determining the MTD. The MTD cohort will be expanded so that up to 40 total pts are enrolled. Results: Twenty-five pts with a median age of 62 (44-91) have been enrolled on the study and received at least 1 dose of study drug, and 52% of the pts are male. Patients had received a median of 4 (1-17) prior therapies. Notably, 80% (20/25) of pts had received at least one prior bortezomib-containing regimen. For the Phase 1 portion, 5 pts were enrolled into the 50 mg/m2 cohort, 4 pts were enrolled into the 70 mg/m2 cohort and 5 pts were enrolled into the 90 mg/m2 cohort. No DLTs were observed in the phase 1 portion of the study. The maximum dose (90 mg/m2) was well tolerated. Patients are currently enrolling into the Phase 2 portion of the study and receiving this dose of bendamustine in the combination treatment. To date, the most common grade 3 or 4 adverse events, occurring in more than 10% of pts, were neutropenia (36%), anemia, (24%), thrombocytopenia (24%), and renal failure (12%). A worsening of baseline peripheral neuropathy was reported in 20% of pts. Two (8%) pts were reported to have grade 1, treatment emergent peripheral neuropathy. To date, nearly one-third (8/25) of pts have achieved an MR or PR. To date, 16 pts have been enrolled at the 90 mg/m2 dose of bendamustine and 5 (31%) have achieved an MR or PR. Conclusions: The combination of bendamustine 90 mg/m2 on days 1 and 4 and bortezomib 1.0 mg/m2 on days 1, 4, 8, & 11 appears to be safe and effective in this heavily pre-treated patient population. The phase 2 portion of this study is ongoing. Disclosures: Berenson: Cephalon: Consultancy, Research Funding; Millennium: Consultancy, Honoraria, Research Funding, Speakers Bureau. Off Label Use: Bendamustine is approved for CLL and refractory NHL. It is being studied in combiantion with bortezomib for multiple myeloma. Siegel:Cephalon: Research Funding; Amgen: Research Funding; Incyte: Research Funding; Marmatech: Research Funding; Medivation: Research Funding; Caremark/CVS: Consultancy. Swift:Millennium: Speakers Bureau. Ehrman:Cephalon Inc.: Employment. Bensen-Kennedy:Cephalon Inc.: Employment.

Abstract 4015 Background: MDS represents a heterogeneous group of clonal myeloid stem cell disorders with a propensity for clonal evolution with resultant progressive bone marrow failure and transformation to acute myeloid leukemia. These disorders are incurable with conventional therapy and are usually treated with hypomethylating agents and supportive care. Panobinostat (PAN, LBH589) is a pan deacetylase (DAC) inhibitor that targets a variety of tumor types, including acute and chronic leukemia, by inhibiting differentiation and inducing apoptosis. Method: This single-arm multicenter Phase II study was designed with the primary objective of assessing the overall response rate (CR, marrow CR + PR) of PAN in patients (pts) with relapsed or refractory MDS. Secondary endpoints include time-to-progression, hematologic improvement, duration of response, time-to-treatment failure, and survival. Eligible pts had histologically documented MDS, previous failure on hypomethylating (azacitidine or decitabine) therapy, no prior treatment with DAC inhibitors, no active CNS disease, and adequate organ function. Pts with up to and including 30% blasts were eligible to enroll; pts with 5q- abnormalities must have failed lenalidomide. PAN (30mg PO) was administered three times a week on Monday, Wednesday and Friday. Pts were treated for the first 21 days of a 28 day cycle. If no grade 3/4 toxicity occurred in the first 2 cycles, dose escalation (40mg PO M/W/F) would proceed. Results: The original protocol for this trial specified a dose of 20mg PAN M/W/F, which was generally well-tolerated. Accumulating data from other studies suggested that higher doses of PAN were more efficacious without a significant increase in toxicity. The dose of PAN was thus increased to 30mg M/W/F in the amended protocol. To date, 16 pts have been enrolled at 30mg; this analysis is based on 10 pts enrolled from October 2008 through December 2009; all pts in this group are ECOG PS 0 white males (median age 77years [range 62–86]). The most common non hematologic adverse events were: anorexia (5 G1/2) fatigue (8 G1/2 and 1 G3) and nausea (3 G1/2). Hematologic toxicity was assessed on an ongoing basis: 5 pts experienced G3/4 anemia; 8 G3/4 thrombocytopenia; 6 G3/4 leukopenia, and 7 G3/4 neutropenia. Response was assessed after 2 cycles. Seven of 10 pts had stable disease; 2 pts had progressive disease; 1 pt was unevaluable due to coming off study prior to evaluation. 2 of the 10pts were escalated to the 40mg dose level. There were 6 SAEs (among 3 pts) for: G3 febrile neutropenia (2), G3 neutropenia (1), G3 pain (1), G4 pneumonia (1) and G4 thrombocytopenia (1). Nine pts are currently alive with a median follow-up of 69 weeks (range 28–90). Conclusions: Collectively, these data suggest that PAN is generally well-tolerated in pts with refractory MDS. Continued investigation of this novel agent is warranted, and future studies should evaluate its safety and efficacy when used as part of a combination regimen. Disclosures: Flinn: Novartis: Research Funding.

8134 Background: PLD and bortezomib (BORT) are FDA-approved for MM patients who have received one prior therapy. We have previously demonstrated in laboratory studies that lower doses of PLD administered more frequently are better tolerated than higher doses given less often. The combination of BORT and dexamethasone (DEX) is effective for previously untreated MM patients. Prior studies by our group have shown that intravenous administration of DEX 40 mg, BORT 1.0 mg/m2 and PLD 5 mg/m2 (DVD) on days 1, 4, 8, and 11 of a 28-day cycle is effective for relapsed/refractory MM patients and well tolerated. Methods: We conducted a single-arm multi-center phase II study for previously untreated MM patients to evaluate the DVD regimen. Patients were treated to a maximum response plus two additional cycles or completed a maximum of eight cycles of therapy without disease progression. Results: Thirty-five patients were enrolled with a median age of 65 years (range, 42-82 years). Thirty and 33 patients are currently ...

Abstract 1855 Poster Board I-881 We and others have shown that LBH589, a potent histone deacetylase inhibitor (HDACi), significantly inhibits the growth of MM cells in vitro and enhances the cytotoxicity triggered by chemotherapeutic agents. Using our SCID-hu models of MM, we have also shown a striking inhibition of MM cell growth in vivo when LBH589 was combined with low doses of melphalan compared to treatment with either drug alone. Thus, these preclinical studies provided the rationale for evaluating the combination of oral melphalan with oral LBH589 for the treatment of MM patients with relapsed or refractory disease. We present the results of an ongoing phase I, open-label, multicenter, dose-escalation study. The initial treatment schedule involved administering patients oral LBH589 every Monday, Wednesday and Friday (MWF) combined with oral melphalan on days 1–5 of a 28-day cycle. Patients were to be treated to maximum response plus 2 additional cycles or complete 8 cycles of therapy without disease progression. To date, 15 patients have been enrolled. At study entry, eleven patients (73%) had International Staging System II or III MM. Fourteen patients were previously treated with melphalan. Three subjects were enrolled into the first cohort (oral LBH589 10 mg; melphalan 0.05 mg/kg) and all experienced significant hematological adverse events. During cycle 1, 2 of 3 subjects had grade 3 thrombocytopenia and all 3 patients developed grade 3 neutropenia. As a result, the melphalan dosing schedule was changed from being administered on days 1-5 to only on days 1, 3 and 5. Three subjects were enrolled into this modified first cohort using the same doses of both drugs. One subject in this cohort experienced both a grade 3 neutropenia and thrombocytopenia. However, there were no DLTs in this cohort and so enrollment into the next cohort (LBH589 at 20 mg and melphalan at 0.05 mg/kg) was initiated. In this cohort, one subject experienced a DLT (grade 4 thrombocytopenia) while the other two developed grade 3 thrombocytopenia. One patient achieved a immunofixation (IF)+ CR but withdrew consent due to intolerable fatigue. As a result, three additional patients were evaluated at this dose level, and two patients have responded including one active patient who is now in PR and another one also achieved a PR but had to be taken off study due to persistent grade 3 neutropenia. Based on the ongoing significant fatigue among patients treated with LBH89 throughout the treatment cycle, the protocol was revised so that the HDACi was administered only during the first two weeks (days 1, 3, 5, 8, 10, and 12) of the 28-day schedule. To date, 3 patients have recently started treatment with this modified schedule of LBH589 at 20 mg and melphalan at 0.05 mg/kg again administered on days 1, 3 and 5 of each 28-day cycle but are not yet evaluable for response. Thus, 12 patients are currently evaluable for response and 4 (33 %) who had previously received melphalan at higher doses have achieved a response including 1 complete response (IF+ CR) and 3 partial responses. Another 4 patients showed stable disease so that disease control was achieved overall in 8 (67%) patients. Overall, the most common ≥ grade 3 adverse events included reversible neutropenia and thrombocytopenia. Specifically, there were 6 cases of grade 3 neutropenia, 6 with grade 3 thrombocytopenia and 1 with grade 4 thrombocytopenia. All of these cytopenias were reversible. Because of the encouraging response rate (33%) that has already been observed in this relapsed and refractory population of heavily pretreated MM patients previously treated with melphalan, an expanded Phase II trial will be conducted using this combination once the MTD has been determined and schedule of dosing has been optimized. Disclosures: Berenson: Novartis Pharmaceuticals Corporation: Consultancy, Research Funding, Speakers Bureau. Off Label Use: LBH589 is a histone deacetylase inhibitor that is used for the treament of multiple myeloma. Rothstein:Novartis Pharmaceuticals Corporation: Employment.

Abstract 679 Chronic ITP is an autoimmune disease characterized by low platelet counts due to both increased platelet destruction and suboptimal platelet production. Immunosuppressive ITP therapies have variable response rates and may be associated with substantial side effects, limiting their use for long-term treatment. Romiplostim is a novel peptibody that increases platelet counts by a mechanism similar to thrombopoietin, and is approved for the treatment of chronic ITP. We present final results from a phase 3b, randomized, open-label study, comparing the incidence of splenectomy and treatment failure in adult nonsplenectomized ITP patients receiving either romiplostim or medical standard of care (SOC). Patients were randomized (2:1) to romiplostim or SOC. Eligible patients had a platelet count A total of 234 patients were randomized (romiplostim, 157; SOC, 77); 83% of romiplostim and 66% of SOC patients completed the study. Patients had been diagnosed with ITP for a median of 2 years (range 0.01 to 44 years) and 73% had received ≥2 prior ITP therapies. Patient characteristics were similar between treatment groups. The efficacy of romiplostim was significantly greater than that of SOC in both primary endpoint analyses. The incidence of splenectomy was 9% (14/157) in the romiplostim group compared to 36% (28/77) in the SOC group (OR, 0.17; 0.08, 0.35; p Disclosures: Kuter: Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria, Research Funding, Speakers Bureau; Esehi: Consultancy; Shionagi: Consultancy, Honoraria, Speakers Bureau; ONO: Consultancy, Honoraria, Speakers Bureau; MGI Pharma: Consultancy, Research Funding; Ligand: Honoraria, Speakers Bureau. Rummel:Amgen Inc.: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Boccia:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Macik:Amgen Inc.: Research Funding; Eisai Inc.: Research Funding. Pabinger:Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees. Selleslag:Amgen Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rodeghiero:Amgen Inc.: Consultancy, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau; Shionogi: Speakers Bureau. Chong:Commonwealth Serum Laboratory (CSL): Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees. Müller-Beiβenhirtz:Amgen Inc.: Consultancy. Gehl:Amgen Inc.: Employment, Equity Ownership. Wang:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

Abstract 4936 Despite recent advances in the treatment of MM, the disease remains incurable and many of the most effective, newer combination therapies are accompanied by significant side effects that have a major negative impact on the patient's quality of life. Pegylated liposomal doxorubicin (PLD) and bortezomib have shown anti-MM efficacy in the laboratory and for the treatment of previously treated MM patients, leading to FDA approval for patients who have failed one prior therapy. Using our severe combined immunodeficiency-hu murine models of human MM, we have previously demonstrated that lower doses of PLD administered daily are more effective and better tolerated than higher amounts given weekly. Moreover, the combination of bortezomib and dexamethasone has been shown to be effective for previously untreated MM patients. Prior studies by our group have shown that combining chemotherapy including PLD with bortezomib administered at 1.0 mg/m2 on days 1, 4, 8, and 11 of a 28-day cycle rather than the standard 1.3 mg/m2 on the same days of a 21-day schedule is effective for MM patients with relapsed or refractory disease and associated with a reduction in the incidence and severity of peripheral neuropathy. Thus, we conducted a single-arm multi-center phase II study for previously untreated MM patients to evaluate the combination of intravenously administered dexamethasone, bortezomib and PLD (DVD). The treatment consisted of intravenous administration of 40 mg dexamethasone followed by 1.0 mg/m2 bortezomib and finally 5.0 mg/m2 PLD on days 1, 4, 8, and 11 of a 28-day cycle. Patients were treated to a maximum response plus two additional cycles or completed a maximum of eight cycles of therapy without disease progression. To date, 22 (of 35 planned) patients have been enrolled with a median age of 64 years (range, 42-79 years). The majority of those on study (68 %) were diagnosed with International Staging System II or III MM. Four patients are too early to assess for response. To date, among the 18 evaluable patients, 16 (89%) have shown objective responses to the DVD regimen, including 2 complete responses (11%), 8 partial responses (44%) and 6 minimal responses (33%). The other 2 patients (11%) had stable disease, with one of these subjects showing a continuing reduction in M-protein after 2 cycles of therapy to date. Thus, disease control was achieved in all patients. To date, no patient has shown progressive disease after 2+ - 12+ months of follow-up. Six patients experienced grade 3 adverse events and one patient with a prior history of pulmonary interstitial fibrosis developed a grade 4 toxicity (shortness of breath). Grade 3 adverse events in three of the six patients were judged not to be related to the study treatment. The most common grade 3 adverse event was reversible neutropenia (n=2). To date, only 2 patients (9%) have developed peripheral neuropathy (grade 1). Notably, there have been no cases of stomatitis or hand-foot syndrome. Thus, these results suggest that the DVD regimen using a modified schedule and doses of the combination of intravenous dexamethasone, bortezomib and PLD is a well tolerated treatment that produces high response rates for previously untreated patients with multiple myeloma. Disclosures Berenson: Millennium Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Speakers Bureau. Hilger:Millennium Pharmaceutcals: Employment.

Abstract 3510 Poster Board III-447 Introduction Romiplostim is a peptibody protein designed to increase platelet production by binding to and activating the thrombopoietin receptor; it is approved for the treatment of thrombocytopenia in patients with chronic ITP. Home administration of romiplostim may offer a desirable treatment option for some patients. We evaluated the safety and efficacy of romiplostim home administration during a 52-week study in adult ITP patients. Patients and Methods This was a phase 3b, multi-center, randomized, standard of care (SOC) controlled, open-label study comparing the incidence of splenectomy and treatment failure in ITP patients receiving either romiplostim or medical SOC for ITP. Eligible patients were nonsplenectomized adult ITP patients who had received at least 1 prior therapy for ITP, with a baseline platelet count < 50 × 109/L. Romiplostim was administered by weekly subcutaneous injections with dose adjustments to target a platelet count of 50 to 200 × 109/L. After study week 8, patients who achieved platelet counts within the target range and a stable dose of romiplostim for at least 3 consecutive weeks were offered the opportunity to receive romiplostim outside the physician's office. Eligible patients were trained to self-inject and were required to return to the study center for platelet count evaluation and to obtain romiplostim for subsequent treatment every 4 weeks. We report data from romiplostim-treated patients, comparing the time 3 weeks before initiating home administration to the time after initiating home administration (either until the end of the treatment or until a 6-week interruption of home administration). Since the observation periods before and after initiation of home administration were not equal, exposure-adjusted data were calculated. Results The 157 patients who were randomized to romiplostim had a median age of 58 (range 18 to 90) years and 85 (54%) were female. Home administration was initiated by 69% (109/157) of the patients who received romiplostim, and home administration was continued for a median of 36 weeks (Interquartile range, 14). Home administration was interrupted for 6 consecutive weeks or more in 24/109 (22%) patients. Of the109 patients who started home administration, 93 (85%) continued to home administer until the end of the study. For each patient, their most frequently used dose of romiplostim was determined. The median of patients' most frequently used dose remained stable after home administration was initiated (Table). There was no difference in the percentage of weeks with a platelet response (defined as a platelet count > 50 × 109/L, excluding those within 8 weeks of rescue medication use) during the time before (83%) and the time after (88%) the start of home administration (p=0.147). The rate of adverse events appeared lower after patients began home administration, and did not appear to increase with longer duration of treatment (Table). No deaths occurred either before or after home administration. Conclusions The safety and efficacy profile of romiplostim was not impaired when patients changed from in-office administration to home administration. Home administration of romiplostim appears to be a convenient treatment option for some ITP patients. Disclosures: Lyons: Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy; Johnson&Johnson: Consultancy, Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy, Speakers Bureau. Boccia:Amgen Inc.: Consultancy, Honoraria, Research Funding, Speakers Bureau. Macik:Amgen Inc.: Research Funding; Eisai Inc.: Research Funding. Mandanas:Genzyme: Membership on an entity's Board of Directors or advisory committees; Novartis: Speakers Bureau; Pfizer: Speakers Bureau. Wang:Amgen Inc.: Employment, Equity Ownership. Lizambri:Amgen Inc.: Employment, Equity Ownership. Berger:Amgen Inc.: Employment, Equity Ownership.

ATN-224 (bis-choline tetrathiomolybdate) is an orally-available small molecule that is currently being studied in several phase II oncology clinical trials. ATN-224 inhibits copper-zinc superoxide dismutase (Cu/Zn-SOD; SOD1) in endothelial and tumor cells. SOD1 is an enzyme that mediates signaling by a number of mitogens including VEGF, FGF-2, EGF, IGF-1 and PDGF. The inhibition of SOD1 by ATN-224 leads to the inhibition of proliferation in endothelial cells and the induction of apoptosis in tumor cells. In a preclinical mouse model using multiple myeloma (MM) cells obtained from a patient that was refractory to bortezomib, the combination of ATN-224 and bortezomib was more effective than either agent alone and led to tumor regression. Based on this data, a phase I/II clinical study evaluating the combination of ATN-224 and bortezomib for MM patients that had previously failed bortezomib was initiated. The phase I portion of this study evaluated the safety of several doses of both ATN-224 and bortezomib and established a recommended dose and schedule of this combination for the phase II portion of the study. The phase I study has completed enrollment and results are presented here. Patients with recurrent or refractory MM that had previously failed bortezomib and currently showing evidence of disease progression were enrolled. Patients had adequate ECOG performance status (PS 0–2) and hematologic and organ function. Patients were monitored for safety and preliminary evidence of efficacy. Blood samples were collected at specific intervals for pharmacokinetic and pharmacodynamic analyses. Twenty-one patients (62% male), aged 46–80 (mean 66) with PS 0–1 were enrolled into 6 cohorts. Dose Limiting Toxicity (DLT) was defined as grade 3 or 4 neutropenia with neutropenic fever, grade 4 neutropenia, grade 3 or 4 thrombocytopenia, grade 2 peripheral neuropathy with pain, grade 3 or 4 neuropathic pain and/or peripheral sensory neuropathy, grade 4 anemia or a fall in hemoglobin by >3 g/dL when day 1 hemoglobin is ≥11 g/dL or >2 g/dL when day 1 hemoglobin is 2g/dL from baseline (n=3) and grade 3 fatigue (n=1)] were observed within the first three cohorts. After review of this data, it was determined that the more appropriate dosing schedule included a 7 day drug holiday. In cohorts 4 through 6 (n=11), ATN-224 was administered at doses of either 180 or 210 mg daily for 21 days in combination with bortezomib at a dose of either 1.0 or 1.3 mg/m2/dose on days 8,11, 15 and 18 of a 28 day cycle. One DLT (grade 4 thrombocytopenia) was observed and occurred in the 180 mg ATN-224 plus 1.3mg/m2/dose bortezomib cohort. By incrementally increasing each dose of ATN-224 and bortezomib individually and modifying the treatment schedule, treatment-related toxicities have been minimized while maximizing the treatment doses. One patient experienced a complete response that was durable for over 10 months. The other 20 patients experienced disease progression within 90 days. A daily dose of 210 mg of ATN-224 for 21 days and a dose of bortezomib at 1.0 mg/m2 on days 8, 11, 15, and 18 of a 28 day cycle was well tolerated and recommended for the phase II portion of this trial, which is now enrolling patients. The phase I portion of the study demonstrates that the combination of ATN-224 and bortezomib can be safely administered and may be an effective treatment for MM patients that are relapsed from or refractory to bortezomib.

8550 Background: MGUS patients have increased rates of bone resorption with a higher prevalence of osteopenia/osteoporosis than in the normal population. These pts also have an increased risk of fr...

MGUS occurs in 5% of individuals over 70 yrs of age and these pts have been found to have increased rates of bone resorption. Osteoporosis associated with MGUS have higher bone resorption compared to sex and aged-matched pts with osteoporosis but without evidence of MGUS. Not only do pts with MGUS have a higher prevalence of osteopenia/osteoporosis than the normal population but they also have an increased risk of fractures (fx). ZOL has been shown to increase BMD in the treatment of gonadotropin agonist-induced osteoporosis in men with prostate cancer without metastatic bone disease when administered every 3 mos at 4 mg. The rationale for the use of ZOL for pts with osteopenia/osteoporosis in the setting of MGUS is based on these studies coupled with the knowledge that pts with this disorder have a higher prevalence of bone loss and fx risk. To date, no agents have been formally studied in the treatment of osteopenia/osteoporosis associated with MGUS. A schedule of 4 mg every 6 mos has been shown to be safe and effective in increasing BMD for other cancer pts without metastatic bone disease but with significant bone loss. This open-label study was designed to evaluate the efficacy and safety of this dose and schedule of ZOL for MGUS pts with significant loss of bone. Pts had to have osteopenia/osteoporosis (T-score worse than -1) as verified by a DEXA scan and a diagnosis of MGUS. Pts with prior use of oral bisphosphonates (BIS) or fluorides for more than three mos within the last two yrs or prior use of intravenous (IV) BIS within the last two yrs were excluded. ZOL at 4 mg was administered IV at 0, 6, and 12 mos. To assess the efficacy of ZOL therapy, DEXA scans and skeletal surveys were conducted at screening and one mo after the final ZOL infusion (13 mos). Fifty-four pts were enrolled on this trial with an average age of 68 (range, 50 to 91 yrs). The starting L-spine T-scores ranged from −3.97 to −1.10 (mean = −2.16). After one year of ZOL therapy, T-scores improved by a mean of +0.55 (range, −0.40 to +3.90; P = 0.0042). This corresponded to a mean increase in BMD of +25.5% (range, −19.0% to +134%). Similar evaluation in the hip showed baseline T-scores of −3.50 to −1.00 (mean = −1.88). The mean change in T-score was +0.27 (range, −0.60 to +2.00; P = 0.0046) corresponding to a mean increase of +14.4% (range, −54.5% to +163%). One pt developed chronic lymphocytic leukemia while on study whereas no other pt showed progression to myeloma or a related B-cell disorder. No pt developed osteonecrosis of the jaw or a significant adverse renal event. During the study, no pt developed a new fx. This trial suggests that ZOL administered at 4 mg every 6 mos significantly improves BMD in MGUS pts with bone loss (osteopenia/osteoporosis); and, thus, suggests that this is a safe and effective treatment to prevent the development of new fxs in this high risk population.

8109 Background: ZIO-101(S-dimethylarsino-glutathione), a novel organic arsenic, is active against multiple cancers including myeloma in vitro and in animal models. In vitro, it is active at low concentrations in cancers resistant to arsenic trioxide. Anti-cancer activity is multifaceted and is mediated by disrupted mitochondrial function, increased reactive oxygen species (ROS) production, modified signal transduction and anti-angiogenesis. Methods: (1) Phase I/II study to determine maximum tolerated dose (MTD), dose- limiting toxicity (DLT), safety-profile and preliminary efficacy in patients with advanced/progressive myeloma receiving ZIO-101 daily for 5 consecutive d every 4 w; (2) comparison of this schedule at MTD with a schedule of 420 mg/me2/d twice/w for 3 w every 4 w. Results: (1) phase I/ II: 19 patients have been treated so far. Median age is 61 y (range, 41–84 y). Median N prior therapies was 8 (range, 4–10). ZIO-101 was well-tolerated; MTD was 420 mg/me2/d for the 5 d schedule, and DLT was transient confusion /ataxia. No clinically- important biochemical, bone marrow, or cardiac toxicities were seen and there was neither neuropathy nor QTc-prolongation. Pain during peripheral infusion was reported in some patients. Anemia was the only adverse event = grade-3 in 25% of subjects. 6 of 14 evaluable subjects had stable disease (SD) =8 w and 2, SD > 6 mo. Accrual to the phase II portion continues. Conclusions: ZIO-101 was well- tolerated. In the daily for 5 consecutive d every 4 w schedule, the MTD is 420 mg/me2/d and DLT, transient confusion /ataxia. There was SD in 43% of patients with advanced/progressive myeloma, of whom half are beyond 6 months. Accrual into the phase II part of this study continues. No significant financial relationships to disclose.

Background: Although arsenic trioxide (As2O3) is active in vitro against diverse hematological cancers, clinical data show activity only in acute progranulocytic leukemia (APL); there is little if any single-agent activity in multiple myeloma and other hematological cancers. This discordance may be because relatively little As2O3 can be given consequent to its substantial toxicity (especially QTc-prolongation) or because the mode of action (MOA) in APL (differentiation) is inoperative in other hematological cancers (or both). ZIO-101 (S-dimethylarsino-glutathione), a new organic arsenic, is active against diverse cancers in vitro and in animal models including AML and MM. Cell-killing by ZIO-101 is mediated by mitochondrial-disruption and apoptosis-induction rather than the differentiation MOA of As2O3. ZIO-101 can be given at doses ≥ 50-fold higher than As2O3 and achieves 5–10-fold higher intracellular concentrations at equimolar extracellular As concentrations. Gene-expression profiling data suggest different cellular responses to ZIO-101 and As2O3. These features make ZIO-101 attractive for evaluation in AML and MM. Methods: 2 phase-1 studies evaluating safety, activity and pharmacokinetic (PK) profile of ZIO-101 in 21 subjects with advanced AML (N=8) or MM (N=13). Median age is 58 y (range, 41–85 y). Median N of prior therapies is 5 (range, 2–12) including 4 subjects failing prior As2O3 therapy. Starting dose was 78 mg/me2/d IV for 5 consecutive d every 4 w. Results: Subjects received a median of 2 cycles (range, 1–6). Therapy was well-tolerated; adverse events ≥ grade-2 occurring in > 25% of subjects included neutropenia, hypokalemia and hyperglycemia. There was no clinically-important renal, liver or heart toxicity nor QTc-prolongation. Maximum tolerated dose (MTD) was 420 mg/me2/d. Pharmacokinetic (PK) studies at this dose showed a tmax=1 h (SD±0.9), Cmax=1.06 μg/mL (SD±0.07 μg/mL), t1/2=17.8 h (SD±1.4 h) and AUC0-∞=25.9 μg·h/mL (SD±0.8 μg·h/mL). 4 subjects with AML had stable disease (SD) after 1 cycle and received 2–4 more cycles before progressing. Blood myeloblasts decreased substantially in 1 subject and completely resolved in 2. Bone marrow myeloblasts decreased in 1. 1 subject with prior myelodysplastic syndrome (MDS) stopped requiring frequent RBC transfusions. 1 subject with rapidly-progressing As2O3- and bortezumib-resistant MM has stable disease (SD) >6 mo. Conclusions: These early data suggest activity of ZIO-101 in advanced AML and MM. The MTD is 420 mg/me2/d, ≥ 50-fold higher than As2O3. Plasma levels exceed the IC50 for AML and MM cell in vitro and animal models. Clinically-important QTc-prolongation was not seen. Some subjects failing As2O3 responded to ZIO-101 indicating efficacy of a higher dose, different MOA or both. Because of these favorable results phase-2 studies in hematological cancers are in progress.

Background: Lenalidomide (Revlimid®) in combination with dexamethasone was approved in the US on June 29, 2006 for the treatment of subjects with multiple myeloma who had received at least one prior therapy. On February 28, 2005 based upon a positive interim analysis of two pivotal placebo-controlled Phase III studies, an independent Data Safety Monitoring Board recommended the studies be unblinded and all subjects in both studies be given access to lenalidomide. In April 2005, the FDA in association with myeloma patient advocacy groups requested Celgene establish an expanded access program to make lenalidomide plus dexamethasone available to subjects with relapsed or refractory multiple myeloma while the treatment was awaiting approval. Aim: To provide lenalidomide to multiple myeloma subjects with a high likelihood of benefit and to obtain additional safety data. Methods: Subjects with relapsed or refractory multiple myeloma that received at least 1 prior therapy were eligible. Subjects received 25 mg lenalidomide plus high-dose dexamethasone in 4-week cycles until disease progression was documented, study drug was discontinued, or lenalidomide became commercially available for this indication. Results: Between September 8, 2005 and July 25, 2006, approximately 1400 subjects in the US and Canada were enrolled into the study. A data snapshot taken March 17, 2006 demonstrated that 746 subjects had been enrolled, median age was 63 years, 60% were male, and 66.5% had Stage III disease. Median time on study was 7.1 weeks (0.1–24.4) and median daily dose was 20.5 mg. At least one Grade 3 or 4 adverse event was reported in 261 (35%) of the 746 subjects. Most commonly reported Grade 3–4 events were neutropenia (7.9% of subjects), thrombocytopenia (6.0%), fatigue (3.6%), anemia (3.5%), pneumonia (3.1%) and hyperglycemia (2.0%). These most commonly reported Grade 3–4 adverse events were the same as those found in the previous pivotal studies, however, their frequencies of occurrence were lower in the current study probably due to ongoing data collection and differences in study maturity. Likewise, the most commonly reported adverse events (all grades) were the same as those reported in the two previous pivotal studies. Conclusion: Preliminary data from this expanded access program in over 1400 subjects with multiple myeloma are consistent with results from two earlier Phase III pivotal studies. The EAP of lenalidomide plus dexamethasone in multiple myeloma represents a model of how government, advocacy groups, healthcare providers and industry can work together to quickly provide treatment to subjects in need while a clearly active treatment regimen is awaiting approval.

BACKGROUND: ATN-224 is an orally available, small molecule containing molybdenum (Mo) that specifically binds copper. ATN-224 inhibits multiple signaling pathways important to angiogenesis and tumor growth such as pathways mediated by growth factors, including vascular endothelial growth and epidermal growth factors and signaling molecules such as protein kinase B (PKB/Akt) and nuclear factor kappa B. ATN-224 exerts these effects through the inhibition of the enzyme copper-zinc superoxide dismutase (SOD1) in endothelial and tumor cells. Activity has been seen in a variety of animal tumor models including bortezomib-resistant myeloma. METHODS: Adult pts with recurrent or refractory hematologic malignanies or for which no standard therapy exists were enrolled. Pts had to have adequate performance status (PS 0–2) and have adequate hematologic and organ function. Pts were monitored for safety and efficacy and blood samples for pharmacokinetic and biomarker determinations were taken at specified intervals. At least 3 pts were to be enrolled at each dose level starting at 120 mg/day. Pts who left the study prior to 28 days for reasons other than toxicity were to be replaced. If 1 pt developed dose-limiting toxicity (DLT) as defined by the protocol, the cohort was to be expanded to up to 6 pts. Maximum tolerated dose (MTD) was defined as the highest dose where no more than 1 of 6 pts had DLT. Dose adjustments were made on the basis of toxicity and serum ceruloplasmin (Cp), a surrogate marker for total body copper. Pts received a loading dose for 2 weeks and then doses were titrated to keep Cp between 5 and 15 mg/dL. RESULTS: 17 pts (53% female), ages 43–79 (mean 63), with PS 0 or 1 were entered. 8 pts had myeloma, 5 leukemia, 3 lymphoma, and 1 myelodysplastic syndrome. Because of rapid progression in 5 pts who were replaced and 1 DLT (Grade [Gr] 4 neutropenia, Gr 3 anemia), 11 pts were entered in the 1st cohort. With information from a companion study in pts with solid tumors, the dose for the next cohort was increased to 300 mg. 1 of 6 pts had DLT (Gr 4 neutropenia). No further cohorts were entered as 300 mg/day was determined as MTD from the companion study. Pts who received long-acting antacids were found to have higher Mo concentrations than those without, so the protocol was amended to require all pts to receive daily antacid. Dose-dependent inhibition of SOD in red blood cells (a surrogate tissue for tumor) was observed. Major adverse events included reversible Gr 4 neutropenia, Gr 3 anemia, and Gr 3 thrombocytopenia. Gr 3 fatigue, which was DLT in the solid tumor study, was not observed in this trial. Mild to moderate symptoms such as gastrointestinal disorders, headache and lightheadedness were also observed. There were no responses but 1 pt with leukemia had stable disease for 5 months and a pt with myeloma had stable disease for 4.5 months. CONCLUSION: ATN-224, an antiangiogenesis and antitumor agent with a novel mechanism of action, has manageable, reversible toxicity. The dose recommended for Phase II studies is 300 mg/day with dose adjustment starting at 2 weeks to maintain Cp at 5–15 mg/dL.

18511 Background: Chemotherapy-induced anemia (CIA) is common in patients (pts) receiving chemotherapy, and reduces health-related quality of life. The primary objective of this exploratory analysis was to describe the effectiveness of darbepoetin alfa administered at 300 mcg every 3 weeks (Q3W) in elderly (≥ 65 years old) and younger pts (< 65 years old) with CIA. Methods: We analyzed data on 1493 pts, enrolled in a multicenter, open-label, 16-week study and who received ≥ 1 dose of darbepoetin alfa. Eligible pts were ≥ 18 years old, had a non-myeloid malignancy, and were anemic (hemoglobin [Hb] < 11 g/dL). Pts were analyzed stratified by age (≥ 65 and < 65 years old) and baseline (BL) Hb (< 10 or ≥ 10 g/dL). Hb-based endpoints were analyzed using 2 approaches: the last value carried forward (LVCF) method, where missing Hb values or values within 28 days of a red blood cell (RBC) transfusion were imputed, or an available data approach, where missing Hb values were not imputed. Pt-reported outcomes were assessed using the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) scale. Results: Pt demographics and disease characteristics varied between the age strata: in the ≥ 65-stratum (mean age = 73.7, n = 724), 52% of pts were women and the most common cancer was gastrointestinal (27%); in the < 65-stratum (mean age = 52.1, n = 769), 69% of pts were women and the most common cancer was breast (41%). Mean (SD) BL FACT-F scores for pts ≥ 65 and < 65 were 27.5 (12.8) vs 27.2 (12.1) for the < 10-g/dL strata and 29.0 (12.5) vs 27.5 (12.0) for the ≥ 10-g/dL strata. Study endpoints are shown in the table. The safety profile was as expected for each age group. Conclusions: Darbepoetin alfa 300 mcg Q3W appears to be as effective in achieving and maintaining Hb between 11 to 13 g/dL in elderly pts as in younger pts with CIA. Since chemotherapy is often administered Q3W, synchronizing darbepoetin alfa treatment with pts’ chemotherapy schedules may simplify the treatment of CIA in this pt population. [Table: see text] [Table: see text]

Patients (pts) with cancer receiving chemotherapy commonly have chemotherapy-induced anemia (CIA), often resulting in reduced quality of life. The primary objective of this analysis was to summarize the effectiveness of darbepoetin alfa (DA) administered at 300mcg every 3 weeks (Q3W), in achieving and maintaining a hemoglobin (Hb) target range of 11–13g/dL in pts with hematologic malignancies and CIA, versus pts with solid tumors and CIA. Data for all 1493 pts enrolled in this multicenter, open-label, 16-week study who received at least one dose of DA are included in this exploratory analysis stratified by tumor type. Pts ≥18 years of age receiving multicycle chemotherapy and with Hb

8129 Background: Darbepoetin alfa (DA) 200 mcg Q2W has been shown to be as effective as epoetin alfa (EA) 40000 U QW for the treatment of chemotherapy-induced anemia (CIA; Schwartzberg 2004). In this controlled study, 82% of pts treated with DA 200 mcg Q2W achieved the target Hb (≥ 11g/dL) in a median time of 5 weeks (wks), compared with 86% of pts treated with EA in a median time of 4 wks. In addition, 16% of pts treated with DA and 17% treated with EA required transfusions. Administration of DA Q3W could offer the possibility to synchronize anemia therapy with chemotherapy. Methods: This 16-wk, single-arm, open-label study is designed to assess the effectiveness of DA 300 mcg Q3W in achieving and maintaining a target Hb consistent with evidence-based guidelines (11–12g/dL) in patients (pts) with CIA. Secondary endpoints include transfusion incidence, change in Hb from baseline (BL) and Pt-reported outcomes (assessed by the FACT-F). DA could be increased after 6 wks (2 doses) based on pt response. At any...

2510 Background: Infusion of activated & expanded autologous T lymphocytes (Xcellerated T Cells [XTC]) leads to reduction in lymphadenopathy and splenomegaly in chronic lymphocytic leukemia (Castro...

2582 Background: T cells from MM pts can be activated & expanded ex vivo using the Xcellerate Process, in which peripheral blood mononuclear cells (PBMC) are incubated with anti-CD3 & anti-CD28 ant...

2511 Background: T cells from CLL pts can be activated & expanded ex vivo using the Xcellerate Process, in which peripheral blood mononuclear cells (PBMC) are incubated with anti-CD3 & anti-CD28 an...

Background: T cells from myeloma subjects can be activated and expanded ex vivo using the Xcellerate™ Process, in which peripheral blood mononuclear cells are incubated with anti-CD3 and anti-CD28 antibody-coated magnetic beads (Xcyte™-Dynabeads®). In a previous study (Borrello et al., ASCO 2004), Xcellerated T Cells administered to myeloma subjects following high dose chemotherapy and autologous stem cell transplantation led to accelerated lymphocyte recovery and restoration of the T cell receptor repertoire. In the current study, subjects with relapsed or refractory myeloma were randomized to Xcellerated T Cells with or without one cycle of fludarabine prior to Xcellerated T Cells. Fludarabine is being used to assess the influence of lymphoablation on the anti-tumor and immune reconstitution effects of T cell therapy; it has previously been reported to have no significant activty in myeloma (Kraut et al., Invest. New Drugs, 1990). Methods: Approximately 30 subjects are planned to receive treatment. Each receives a single dose of 60–100 x 109 Xcellerated T Cells. Subjects on the fludarabine arm receive a single cycle (5 days at 25 mg/m2), completed 4 days prior to the Xcellerated T Cell infusion. Results: 17 subjects have been enrolled and 13 treated to date, with median last f/u visit of 28 days (range 0–140). Xcellerated T Cells were successfully manufactured in all subjects, with T cell expansion 136 ± 61 fold (mean ± SD), with 79.2 ± 13.8 x 109 cells infused, and final product 98.0 ± 2.0% T cells (n=13). There have been no reported serious adverse events related to Xcellerated T Cells. In the fludarabine arm, lymphocytes decreased from 1,228 ± 290/mm3 (mean ± SEM) to 402 ± 164 following fludarabine, and then increased to 1,772 ± 278 on Day 14 following T cell infusion (n=7). In the non-fludarabine arm, lymphocyte counts increased from 1,186 ± 252 to 3,204 ± 545 on Day 14 (n=4). Lymphocytes were comprised of both CD4+ and CD8+ T cells. Increases were observed in NK cells from 77 ± 26 to 121 ± 25, monocytes from 166 ± 44 to 220 ± 30 and platelets from 218 ± 16 to 235 ± 24 by Day 14 (n=11). In the non-fludarabine arm, neutrophils increased from 3.6 ± 0.9 to 4.8 ± 0.6 on Day 1. On the fludarabine arm, 3 of 6 subjects developed Grade 4 neutropenia and one developed Grade 3 thrombocytopenia. Seven subjects were evaluable for serum M-protein measurements to Day 28. One of three fludarabine treated subjects had an M-protein decrease of 38%. Conclusions: Xcellerated T Cells were well-tolerated and led to increased lymphocytes, including T cells and NK cells. Increases in other hematologic parameters, including neutrophils and platelets were also observed. In this patient population, fludarabine is lymphoablative and also can cause neutropenia and thrombocytopenia. The fludarabine schedule has been decreased from 5 to 3 days. A decrease in M-protein has been observed in one of three fludarabine-treated subjects; data on additional subjects will be presented.

Darbepoetin alfa (Aranesp®) administered at 300 mcg Q3W appears to be an effective dose in patients with hemoglobin (Hb) 10–12 g/dL to maintain Hb, and in patients with Hb 8–10 g/dL to elevate Hb to within the National Comprehensive Cancer Network (NCCN)-recommended target range of 11–12 g/dL. The objective of this multicenter, open-label study of cancer patients with chemotherapy-induced anemia was to evaluate the effectiveness of darbepoetin alfa 300 mcg Q3W, administered over a 16 week treatment period, in achieving and maintaining the therapeutic objectives of anemia treatment consistent with NCCN guidelines. This objective was assessed by determining the percentage of patients who achieved a post baseline target Hb level ≥11.0 g/dL in the absence of a transfusion within the previous 28 days, and the percentage of patients maintaining an average Hb within the NCCN target range. Secondary hematologic endpoints included the incidence of transfusion and the proportion of patients achieving a hematopoietic response (increase in Hb ≥2 g/dL from baseline or achieving a Hb ≥12 g/dL). Patient-reported outcomes were assessed using the FACT-Fatigue subscale with four additional questions relating to fatigue, energy, activity, and overall health. The relationship between clinical endpoints and the ability to achieve and maintain Hb within the NCCN target range were also assessed. Anemic patients (baseline Hb levels < 11 g/dL) with nonmyeloid malignancies receiving chemotherapy were eligible for enrollment in this study. Doses could be escalated after 6 weeks (2 doses) to 500 mcg Q3W if Hb levels remained < 10 g/dL and the increase in Hb from baseline was < 1 g/dL, or, based on physician discretion if Hb levels were > 10g/dL. To date, 539 patients have been enrolled. The majority of patients were female (59%), white (82%) with a median age of 64 years. The predominant cancers in these patients were lung (24%), gastrointestinal (22%), and breast (21%). The majority of patients had stage IV disease (45%) and a Karnofsky performance status score of 80 to 90 (65%). The mean (SD) baseline Hb level was 10.1 g/dL (0.7); 32% of patients had a baseline Hb of < 10.0 g/dL [mean (SD) Hb 9.3 (0.6) g/dL] while 66% had baseline Hb levels ≥10.0 g/dL [10.6 (0.3) g/dL]; 2% of patients (n = 12) received a transfusion within 28 days of baseline Hb measurement and were excluded from analysis. Since the majority of chemotherapy regimens are delivered on a Q3W basis, the ability to administer darbepoetin alfa at a fixed dose, synchronized with the chemotherapy schedule may reduce the number of injection-centric visits. This provides important benefits for patients and their caregivers, and represents a simplification in the treatment of chemotherapy-induced anemia in oncology practice.

Background: T cells can be activated and expanded ex vivo using the Xcellerate™ Process, in which peripheral blood mononuclear cells (PBMC) are incubated with anti-CD3 and anti-CD28 antibody-coated magnetic beads (Xcyte™-Dynabeads®). In an ongoing trial of Xcellerated T Cells in subjects with chronic lymphocytic leukemia, marked and sustained reductions in lymphadenopathy and splenomegaly were observed (Wierda et al., ASCO 2004). Increases in neutrophil, platelet and NK cell counts were also documented. This study is designed to determine if similar effects can be observed in subjects with indolent non-Hodgkin’s lymphoma (NHL). Methods: Subjects must have indolent NHL (follicular, small lymphocytic, marginal zone, or mantle cell lymphoma), have relapsed or refractory disease, and have received at least 1 but not more than 4 prior treatment regimens. PBMC are collected by leukapheresis for the Xcellerate Process, and subjects subsequently receive two infusions of 20–60 x 109 Xcellerated T Cells separated by 6–8 weeks. Approximately 40 subjects will be treated. Results: Seven subjects have been enrolled and Xcellerated T Cells have been manufactured in 5 subjects to date. T cells expanded 181.8 ± 88.5 fold and the final product was >99.0 ± 0.0% T cells (mean + SD). One subject with small lymphocytic lymphoma has been treated with two infusions of 38.6 x 109 Xcellerated T Cells. There have been no serious adverse events to date. Following the first treatment, the lymphocyte count increased from 1.8 x 109/L to 2.9 x 109/L on Day 28. The neutrophil count also increased from 2.9 x 109/L to 5.5 x 109/L six weeks following infusion. The subject had a significant reduction in cervical lymphadenopathy and a slight decrease in bulky mesenteric lymphadenopathy six weeks following the first infusion. Conclusions: Xcellerated T Cells can be manufactured in subjects with indolent NHL. Treatment leads to significant increases in T cell and neutrophil counts. Preliminary data suggest a reduction in peripheral lymphadenopathy. Data on additional subjects will be presented.

Purpose A novel transdermal formulation of granisetron (the granisetron transdermal delivery system (GTDS)) has been developed to deliver granisetron continuously over 7 days. This double-blind, phase III, non-inferiority study compared the efficacy and tolerability of the GTDS to daily oral granisetron for the control of chemotherapy-induced nausea and vomiting (CINV). Patients and methods Six hundred forty-one patients were randomized to oral (2 mg/day, 3–5 days) or transdermal granisetron (one GTDS patch, 7 days), before receiving multi-day chemotherapy. The primary endpoint was complete control of CINV (no vomiting/retching, no more than mild nausea, no rescue medication) from chemotherapy initiation until 24 h after final administration. The prespecified non-inferiority margin was 15%. Results Five hundred eighty-two patients were included in the per protocol analysis. The GTDS displayed non-inferiority to oral granisetron: complete control was achieved by 60% of patients in the GTDS group, and 65% in the oral granisetron group (treatment difference, −5%; 95% confidence interval, −13–3). Both treatments were well tolerated, the most common adverse event being constipation. Conclusions The GTDS provides effective, well-tolerated control of CINV associated with moderately or highly emetogenic multi-day chemotherapy. It offers a convenient alternative route for delivering granisetron for up to 7 days that is as effective as oral granisetron. Electronic supplementary material The online version of this article (doi:10.1007/s00520-010-0990-y) contains supplementary material, which is available to authorized users.

46 adults with previously untreated acute myelogenous leukaemia who achieved complete remission with 6-thioguanine, cytarabine, and daunorubicin (TAD) received two courses of intensive consolidation chemotherapy. The first cycle consisted of 5-azacytidine and doxorubicin followed by a second consolidation cycle with TAD. Maintenance chemotherapy was not administered. Median remission duration was 14 months and 26% (95% confidence interval, 11%-41%) remained in continuous remission at 5 years. Actuarial 5 year survival was 31% (+/- 15%). Results were most favourable in patients who achieved complete remission within 60 days of chemotherapy being initiated. These data indicate that prolonged disease-free survival can be achieved in patients treated with intensive induction and consolidation treatment alone without maintenance chemotherapy.

Acute tumor lysis syndrome (ATLS) is an entity consisting of combinations of hyperuricemia, lactic acidosis, hyperkalemia, hyperphosphatemia, and hypocalcemia and occurring generally in aggressive, rapidly proliferating lymphoproliferative disorders with high tumor burdens. A patient is described with a diffuse intermediately differentiated lymphocytic lymphoma, considered by most an indolent B-cell non-Hodgkin's lymphoma, in whom developed multiple recurrences of ATLS after treatment when tumor regrowth occurred between cycles of therapy. The mitotic rate of this lymphoma was relatively high (30-80 mitoses/ten high-power fields). Lymph proliferative disorders with a high mitotic rate, and large tumor burden, regardless of histologic features, should be treated prophylactically against tumor lysis if regrowth between cycles occurs.

Excerpt The Acquired Immunodeficiency syndrome is characterized by the presence of profound immunosuppression and the development of multiple opportunistic infections and unusual neoplasms, particu...

Background Gallbladder toxicity, including cholecystitis, has been reported with motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function. Methods Patients with advanced metastatic solid tumors ineligible for or progressing on standard-of-care therapies with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14-days-on/7-days-off (Arm B); or 75 mg BID, 5-days-on/2-days-off (Arm C). Primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound; independent review) and function (ejection fraction by CCK-HIDA; investigator assessment). Results Forty-nine patients received ≥1 dose of motesanib (Arms A/B/C, n = 25/12/12). Across all patients, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and ejection fraction decreased by a mean 19.2% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. Three patients had cholecystitis (grades 1, 2, 3, n = 1 each) that resolved after treatment discontinuation, one patient developed grade 3 acute cholecystitis requiring cholecystectomy, and two patients had other notable grade 1 gallbladder disorders (gallbladder wall thickening, gallbladder dysfunction) (all in Arm A). Two patients developed de novo gallstones during treatment. Twelve patients had right upper quadrant pain (Arms A/B/C, n = 8/1/3). The incidence of biliary “sludge” in Arms A/B/C was 39%/36%/27%. Conclusions Motesanib treatment was associated with increased gallbladder volume, decreased ejection fraction, biliary sludge, gallstone formation, and infrequent cholecystitis. Trial registration ClinicalTrials.gov NCT00448786

Excerpt To the editor: The hemolytic-uremic syndrome is a form of microangiopathic hemolytic anemia not previously reported in patients with the acquired immunodeficiency syndrome. We report the ca...