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Autologous stem cell transplantation (ASCT) is standard of care for patients with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline chemotherapy. Achievement of complete remission (CR) with pre-ASCT salvage chemotherapy predicts favorable outcomes post-ASCT. This phase 1/2 study evaluated the combination of brentuximab vedotin (BV) plus bendamustine as a first salvage regimen in relapsed/refractory HL. A total of 55 patients (28 primary refractory and 27 relapsed) were enrolled. Patients received BV (1.8 mg/kg) on day 1 and bendamustine (90 mg/m 2 ) on days 1 and 2 of a 21-day cycle for up to 6 cycles. Patients could undergo ASCT any time after cycle 2. Following ASCT or completion of combination therapy if not proceeding to ASCT, patients could receive BV monotherapy for up to 16 cycles of total therapy. After a median of 2 cycles of combination therapy (range, 1-6), the objective response rate among 53 efficacy-evaluable patients was 92.5%, with 39 patients (73.6%) achieving CR. Forty patients underwent ASCT. Thirty-one patients (25 of whom underwent ASCT) received BV monotherapy (median, 10 cycles; range, 1-14). After a median of 20.9 months of follow-up, the estimated 2-year progression-free survival was 69.8% and 62.6% for patients who received ASCT and all patients, respectively. Thirty-one patients (56.4%) experienced infusion-related reactions (IRRs), with a majority occurring during cycle 2 of combination therapy. A protocol amendment requiring premedication reduced IRR severity. BV plus bendamustine as first salvage therapy in relapsed/refractory HL is highly active with a manageable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT01874054.

Summary Once-weekly administration of bortezomib has reduced bortezomib-induced peripheral neuropathy without affecting response rates, but this has only been demonstrated prospectively in three- and four- drug combinations. We report a phase II trial of alternate dosing and schedule of bortezomib and dexamethasone in newly diagnosed multiple myeloma patients who are not eligible for or refused autologous stem cell transplantation. Bortezomib 1·6 mg/m2 intravenously was given once-weekly for six cycles, together with dexamethasone 40 mg on the day of and day after bortezomib. Fifty patients were enrolled; 58% did not require any dose modification. The majority of patients had multiple co-morbidities, including cardiovascular (76%) and renal insufficiency (54%), and the median number of medications prior to enrollment was 13. Of all evaluable patients, the overall response rate was 79% and at least 45% had at least a very good partial response. The median time to first response was 1·3 months (range, 0·25–2·4 months). The progression-free and overall survivals were 8 months and 46·5 months, respectively. Twenty-four percent developed worsening neuropathy. We conclude that alternate dosing and scheduling of bortezomib and dexamethasone is both safe and effective for management of newly diagnosed multiple myeloma in frail patients. (ClinicalTrials.gov number, NCT01090921).

Off-label prescribing in oncology is common and unregulated. The aim of this study was to describe the off-label use of rituximab, a novel anti-CD20 antibody, among patients from a large proprietary insurance database to understand how frequently and appropriately off-label prescribing occurs for this medication.In this descriptive study, 11,232,642 patients were enrolled in the D2 Hawkeye commercial insurance database between 2001 and 2007, and 2,782 patients received rituximab. The main outcome measures were quantity and type of off-label usage, and expenditures for off-label usage.Seven hundred five (25.3%) patients received rituximab for off-label indications, and of those, 332 (47.1%) received rituximab for uncertain or inadequate evidence-based diagnoses. Expenditures for off-label indications were 17.1% of expenditures for rituximab usage.The frequent use of rituximab for off-label indications should lead to improved postapproval surveillance of biologics by the US Food and Drug Administration, so that use can be adequately studied. This will also facilitate improved regulatory mechanisms to ensure evidence-based use.

PURPOSE OF REVIEW: Human immunodeficiency virus infection is associated with an increased risk of non-Hodgkin lymphoma. Even with a decrease in AIDS-defining illnesses after the advent of highly active antiretroviral therapy, HIV-associated non-Hodgkin lymphoma remains an important problem. RECENT FINDINGS: Low CD4+ T-lymphocyte count, disease stage, performance status, serum lactate dehydrogenase, and number of extranodal sites of disease are all important prognostic factors for HIV-non-Hodgkin lymphoma. Recent studies have examined the role of infusional chemotherapy, as well as immunotherapy, in the treatment of aggressive HIV-non-Hodgkin lymphoma, and autologous stem cell transplantation for relapsed or refractory HIV-non-Hodgkin lymphoma. New developments in the association of viral infection and pathogenesis of certain subtypes of HIV-non-Hodgkin lymphoma have also recently been reported. SUMMARY: Outcomes of HIV-non-Hodgkin lymphoma are improving with the routine use of highly active antiretroviral therapy and combination chemotherapy. For aggressive HIV-non-Hodgkin lymphoma, infusional chemotherapy regimens are well tolerated and lead to complete response in about 50-75% of cases and a 2-3 years overall survival of 40-60%. The potential benefit of adding rituximab to combination chemotherapy may be offset by infectious complications in severely immunosuppressed patients. HIV-associated Burkitt lymphoma should be treated with an intensive regimen rather than standard cyclophosphamide, doxorubicin, vincristine, prednisone-like chemotherapy. Autologous stem cell transplantation should be considered for selected patients with relapsed or refractory HIV-non-Hodgkin lymphoma.

BACKGROUND: Anemia remains the most common hematologic disorder in human immunodeficiency virus (HIV) infection despite the use of effective antiretroviral therapy, and is associated with decreased quality of life and survival. Hypogonadism is prevalent in advanced HIV disease, however low testosterone levels have not been customarily implicated in HIV-associated anemia. This study was undertaken to determine whether there is a relationship between testosterone levels and androgen use with anemia in HIV, and to characterize other clinical correlates of HIV-associated anemia. METHODS: This cross-sectional study examined the clinical characteristics of 200 HIV positive patients at a public hospital HIV clinic and clinical features associated with anemia. A written questionnaire detailed previous and current medication use, opportunistic infections and malignancies. Hematologic and virologic parameters, testosterone and erythropoietin levels were measured; CD4 count and viral load nadir and peak levels were obtained from the computerized medical record. Anemia was defined as hemoglobin RESULTS: Anemia was present in 24% of women and 28% of men. Anemia was negatively associated with female sex (adjusted OR 0.30, 95% CI 0.11–0.85), current antiretroviral therapy (adjusted OR 0.43, 95% CI 0.20–0.95), current androgen use (adjusted OR 0.20, 95% CI 0.05–0.84) and macrocytosis (adjusted OR 0.23, 95% CI 0.09–0.61). Anemia was positively associated with lymphopenia (adjusted OR 4.0, 95% CI 1.36–11.80), high erythropoieitin levels (adjusted OR 7.73, 95% CI 2.92–20.48) and low testosterone levels (adjusted OR 3.27, 95% CI 1.01–10.60). CONCLUSIONS: Low testosterone levels may have a positive association, and supplemental androgens a negative association with anemia in HIV disease. Predictors of Anemia Unadjusted odds ratios and 95% confidence intervals obtained by logistic regression. Variables that achieved a p-value of N % Anemic Unadjusted OR (95% CI) Adjusted OR (95% CI) Female 38 23.7 0.78 (0.34, 1.78) 0.30 (0.11, 0.85) Male/MTF Transgender 162 28.4 Lymphopenia (100fL) 71 14.1 0.34 (0.16, 0.74) 0.23 (0.09, 0.61) Normal MCV 117 32.5 Microcytosis (MCV

Purpose: We evaluated a novel therapy for primary central nervous system lymphoma (PCNSL) with induction immunochemotherapy with high-dose methotrexate, temozolomide, and rituximab (MT-R) followed by intensive consolidation with infusional etoposide and high-dose cytarabine (EA). In addition, we evaluated the prognostic value of the minimum apparent diffusion coefficient (ADCmin) derived from diffusion-weighted MRI (DW-MRI) in patients treated with this regimen. Experimental Design: Thirty-one patients (median age, 61 years; median Karnofsky performance score, 60) received induction with methotrexate every 14 days for 8 planned cycles. Rituximab was administered the first 6 cycles and temozolomide administered on odd-numbered cycles. Patients with responsive or stable central nervous system (CNS) disease received EA consolidation. Pretreatment DW-MRI was used to calculate the ADCmin of contrast-enhancing lesions. Results: The complete response rate for MT-R induction was 52%. At a median follow-up of 79 months, the 2-year progression-free and overall survival were 45% and 58%, respectively. For patients receiving EA consolidation, the 2-year progression-free and overall survival were 78% and 93%, respectively. EA consolidation was also effective in an additional 3 patients who presented with synchronous CNS and systemic lymphoma. Tumor ADCmin less than 384 × 10–6 mm2/s was significantly associated with shorter progression-free and overall survival. Conclusions: MT-R induction was effective and well tolerated. MT-R followed by EA consolidation yielded progression-free and overall survival outcomes comparable to regimens with chemotherapy followed by whole-brain radiotherapy consolidation but without evidence of neurotoxicity. Tumor ADCmin derived from DW-MRI provided better prognostic information for PCNSL patients treated with the MTR-EA regimen than established clinical risk scores. Clin Cancer Res; 18(4); 1146–55. ©2012 AACR.

Chronic hepatitis C virus (HCV) infection is common among individuals infected with HIV. In the United States, 15%–33% of people with HIV infection are coinfected with HCV [1–4], and up to 60% of people who acquired HIV infection via injection drug use have chronic HCV infection [4, 5]. As a result of patients’ increased longevity with the emergence of combination antiretroviral therapy, complications of HCV-related disease are becoming increasingly more important causes of morbidity and mortality in HIV-HCV–coinfected individuals [1, 6, 7]. Individuals with HIV infection have a higher HCV load [8–11], more rapid progression of fibrosis and cirrhosis [11–13], and a more rapid development of hepatocellular carcinoma [14], leading to increased mortality, compared with patients with HCV infection alone. The risk of cirrhosis or decompensated liver disease in patients with HIV-HCV coinfection is estimated to be 3 times that in patients infected with HCV alone [15]. The efficacy of IFN or pegylated IFN (plus ribavirin) as treatment for HCV infection has been established in HCV-monoinfected patients and those with HCV-HIV coinfection, with sustained virologic responses of 47%–66% [16–18] and 12%–44% [19–22], respectively. Response rates among patients infected with HCV genotype 1 are significantly lower than among those with non–genotype 1 HCV infection. Hematologic toxicity may be more pronounced in HIV-infected individuals than in those without HIV infection, especially for patients with underlying hematologic disorders. People with chronic HIV infection are at risk for multiple hematologic abnormalities [23–25]. Chronic HCV infection can lead to leukopenia, anemia, and thrombocytopenia resulting from splenic sequestration in patients with cirrhosis and portal hypertension, as well as to anemia resulting from chronic inflammation and autoimmune hemolytic anemia [26]. Use of antiretrovirals and prophylactic medications, opportunistic infections, and malignancies, also contribute to cytopenia in people with HIV-HCV coinfection. Both IFN and, to a greater degree, pegylated IFN can lead to bone marrow suppression [17, 18, 28]. Ribavirin is associated with a dose-dependent hemolytic anemia. Although combination therapy with IFN and ribavirin can occasionally lead to severe neutropenia and thrombocytopenia, an increase in infectious complications has not been noted, and spontaneous bleeding is rare [26, 27]. However, these adverse effects commonly lead health care providers to reduce the dose or discontinue therapy, which may negatively impact the outcome of therapy [29]. To date, the effect of dose modifications for hematologic toxicity on outcomes of therapy for HCV infection in individuals coinfected with HIV has not yet been described. In randomized, controlled trials comparing IFN plus ribavirin with pegylated IFN plus ribavirin for the treatment of HIV-HCV–coinfected individuals, withdrawal from therapy occurred in up to 39% of subjects (12%–17% for adverse events) [19–21]. The rate of dose modification for hematologic toxicities varies. Most trials report the percentage of patients who require dose modification for anemia in the range of 8%–15%, 3%–12% for anemia, and only 2%–5% for thrombocytopenia [19–21]. The Adult AIDS Clinical Trials Group A5071 study was a prospective, phase II/III, open-label, randomized, controlled trial designed to compare the efficacy, safety, and tolerability of IFN-alfa-2a plus ribavirin versus pegylated IFN-alfa-2a plus ribavirin for chronic HCV infection as treatment for chronic HCV infection in individuals coinfected with HIV-1. As has previously been reported, adverse events led to premature withdrawal from treatment for 8 subjects in each arm (12% overall); all withdrawals occurred within the first 20 weeks of treatment. Grade 4 anemia occurred in 3 subjects and was managed with dose modifications. Of the subjects who developed grade 4 neutropenia, 2 discontinued treatment, and 4 underwent dose modifications, some of which involved the addition of a hematopoietic growth factor. Only 1 subject experienced grade 4 thrombocytopenia [22]. Because of the concern that overlapping hematologic complications of HIV and HCV coinfection and toxicity associated with IFN-alfa-2a and ribavirin therapy may have affected treatment outcomes, this analysis was undertaken to examine the effect of hematologic toxicity on the treatment outcome in the Adult AIDS Clinical Trials Group A5071 study.

Background Long-term outcomes from autologous stem cell transplant (ASCT) in patients (pts) with relapsed/refractory (R/R) Hodgkin lymphoma (HL) are significantly better in patients who achieve a complete remission (CR) from salvage chemotherapy prior to ASCT. However, standard salvage therapy produces variable CR rates (19%-60%) and is associated with significant toxicity. Brentuximab vedotin and bendamustine are highly active when administered as single agents to pts with R/R HL (34% and 33% CR rates, respectively) and have manageable safety profiles. This phase 1/2, single-arm, 2-stage, open-label study was designed to evaluate the safety and efficacy of brentuximab vedotin in combination with bendamustine for the treatment of pts with primary refractory disease or in first relapse (ClinicalTrials.gov #NCT01874054). Methods Pts received an outpatient IV infusion of 1.8 mg/kg brentuximab vedotin on Day 1 with bendamustine on Days 1 and 2 of 3-week cycles for up to 6 cycles. Pts could undergo ASCT any time after Cycle 2 and post-transplant resume treatment with brentuximab vedotin as monotherapy for up to 16 total doses. Phase 1 was designed to determine the recommended dose of bendamustine, with an initial dose of 90 mg/m2 and a de-escalation scheme to be implemented if it exceeded the maximum tolerated dose. During phase 2, bendamustine was administered at the recommended dose in order to assess the CR rate of the combination. Response was assessed by the investigator per Cheson 2007. Enrollment is complete and long-term follow-up for PFS and OS continues. Results Fifty-five pts (56% female) with a median age of 36 yrs (range, 19-79) were enrolled. Fifty-one percent of pts had relapsed disease and 49% of pts had primary refractory disease after frontline therapy. A median of 13.8 mos (range, 3-98) had elapsed since initial diagnosis. No dose-limiting toxicities were observed in the safety cohort, thus the recommended dose of bendamustine in combination with brentuximab vedotin was 90 mg/m2. Pts received a median of 2 cycles (range, 1-6) of the combination and a median of 9 cycles (range, 1-14) of single-agent brentuximab vedotin. The main toxicity observed with the combination was infusion-related reactions (56% overall). The most common symptoms (≥10%) were pyrexia (26%), chills (20%), dyspnea and nausea (15% each), flushing (13%), and hypotension (11%). Premedication with corticosteroids and antihistamines was instituted with a protocol amendment and appeared effective. Before the amendment, 6 pts (24% of treated pts) discontinued treatment prematurely because of IRRs; post-amendment, IRRs led to treatment discontinuation for 2 pts (7%). The CR rate of the combination was 74% (39/53 pts evaluable for response) and the overall objective response rate (CR and partial remission) was 93% (49/53 pts). The CR rate was 64% and 84% for refractory and relapsed pts, respectively. Stem cell collection after first-line mobilization (G-CSF± plerixafor) was successful in 93% of pts (37/40). Median number of CD34+ cells collected was 4.1 x106 (Q1, Q3: 3.0, 5.4) in a median of 2 (range, 1-5) apheresis sessions. Median time to neutrophil and platelet engraftment was 11 days (range, 9-21) and 13 days (range, 9-39), respectively. Pts have been followed for a median of approximately 1 year from first dose (median = 418 days; range, 118-635) and approximately 10 mos (314 days; range, 13-553) from ASCT. To date, 12 progression events have been observed: 7 in the 40 pts who underwent transplant and 5 in the 13 pts who did not undergo transplant. The estimated 12-mos PFS is 80% for both the transplanted population (95% CI: 70%, 90%) and the overall population (95% CI: 60%, 90%). Three of the 12 progression events were deaths; 2 pts died from progression of their HL and 1 pt died from septic shock after transplant. Conclusions The outpatient regimen of brentuximab vedotin 1.8 mg/kg on Day 1 in combination with bendamustine 90 mg/m2 on Days 1 and 2 of 3-week cycles induced a very high CR rate that compares favorably with historical data. The regimen has a manageable safety profile, with the most significant side effect being IRRs that can be successfully managed by premedication. The estimated 12-mos PFS rate of 80% demonstrates response durability, making the combination a promising salvage regimen for pts with HL in the first relapse setting. Progression-Free Survival Figure 1. Figure 1. Disclosures Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. This study evaluates brentuximab vedotin in HL patients with primary refractory disease or in first relapse. . Sawas:Seattle Genetics, Inc.: Research Funding. Agura:Seattle Genetics, Inc.: Research Funding. Matous:Takeda Pharmaceuticals International Co.: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Crosswell:KIYATEC (employment); Gilead (common stock ownership and research funding): Employment, Equity Ownership, Research Funding. Islas-Ohlmayer:Seattle Genetics, Inc.: Research Funding. Behler:Seattle Genetics, Inc.: Research Funding; Onyx Pharmaceuticals: Speakers Bureau. Cheung:Seattle Genetics, Inc.: Research Funding. Forero-Torres:Seattle Genetics, Inc.: Research Funding. Vose:Seattle Genetics, Inc.: Honoraria, Research Funding. Josephson:Seattle Genetics, Inc.: Employment, Equity Ownership. Advani:Seattle Genetics, Inc.: Research Funding; Genetech: Consultancy.

Background Patients (pts) with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline therapy typically undergo salvage chemotherapy followed by high-dose conditioning and autologous stem cell transplant (ASCT). Improved outcomes have been reported for pts who achieve complete remission (CR) with salvage chemotherapy prior to ASCT. Variable CR rates (19%-60%) and significant toxicities are associated with standard salvage therapy in the first relapse setting. Brentuximab vedotin and bendamustine have independent mechanisms of action and are highly active with manageable safety profiles when administered as single agents to pts with HL who relapse after ASCT (brentuximab vedotin: 34% CR [Younes, 2012]; bendamustine: 33% CR [Moskowitz, 2013]). This phase 1/2, single-arm, 2-stage, open-label study was designed to evaluate the safety and efficacy of brentuximab vedotin in combination with bendamustine for the treatment of pts with HL in first relapse (ClinicalTrials.gov #NCT01874054). Methods Pts received an outpatient IV infusion of 1.8 mg/kg brentuximab vedotin on Day 1 with 90 mg/m2 bendamustine on Days 1 and 2 of 3-week cycles for up to 6 cycles. Pts could undergo ASCT any time after Cycle (C) 2 and post-transplant resume treatment with brentuximab vedotin as monotherapy for up to16 total doses. Phase 1 was designed to determine the recommended dose of bendamustine in combination with brentuximab vedotin. During this phase, the dose of bendamustine was to be de-escalated if ≥4/10 pts experienced dose-limiting toxicity (DLT), defined as any C1 toxicity requiring a dose delay of ≥14 days. During phase 2, bendamustine was administered at the recommended dose in order to assess the CR rate of the combination. Response was assessed by the investigator per Cheson 2007. Results Forty-five pts (58% female) with a median age of 35 yrs (range, 19-79) have been enrolled. Fifty-eight percent of pts had relapsed disease and 42% of pts primary refractory disease after frontline therapy. A median of 13.1 mos (range, 3- 98) had elapsed since initial diagnosis. No DLTs were observed in the safety cohort, thus the recommended dose of bendamustine in combination with brentuximab vedotin was 90 mg/m2. Pts received a median of 2 cycles (range, 1-6) of the combination. The main toxicity observed with the combination was infusion-related reactions. The most common symptoms (≥10%) were dyspnea (13%), flushing (13%), and chills (11%). The majority of reactions occurred within 24 hours of C2 infusion and were considered related to both agents. Premedication with corticosteroids and antihistamines was instituted with a protocol amendment and appeared effective. Prior to the amendment, 36% (9/25 unique pts) of treated pts had reactions that were either serious adverse events (SAEs) (n=6), Grade 3 in severity (n=8), and/or led to treatment discontinuation (n=6). Following premedication implementation, 15% (3/20 unique pts) of treated pts had such events (0 SAEs, 1 treatment discontinuation, and 2 Grade 3 toxicities). The CR rate of the combination was 82% (28/34 pts evaluable for response) and the overall objective response rate (CR and partial remission) 94% (32/34 pts). The majority of CRs (24/28 pts) were achieved after 2 cycles of combination therapy. Stem cell mobilization and collection was considered adequate in all 24 pts who underwent the procedure. The median number of CD34+ cells collected was 4.3 x106 (range, 1.7- 16.0 x106) in a median of 2 apheresis sessions (range, 1-5). To date, 20 pts have undergone ASCT, the majority after C2 (12 pts) or C3 (6 pts), and 13 pts have resumed brentuximab vedotin as monotherapy. One patient with CR developed progressive disease 3 cycles post-transplant. The median duration of remission for pts who obtained a CR has not been reached (95% CI: 8.7,– [range, 0.03+-10.4+ months]). Conclusions The outpatient regimen of brentuximab vedotin 1.8 mg/kg on Day 1 in combination with bendamustine 90 mg/m2 on Days 1 and 2 of 3-week cycles has a manageable safety profile with premedication. The very high CR rate observed on combination treatment compares favorably with historical data. The durability of responses observed to date and the success of stem cell mobilization and collection suggest that the regimen may represent a promising approach for maximizing responses prior to ASCT in pts with HL who are either relapsed or are refractory after frontline therapy. Disclosures LaCasce: Seattle Genetics, Inc.: Research Funding. Off Label Use: Brentuximab vedotin is indicated in the US for treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates and for the treatment of patients with systemic anaplastic large cell lymphoma after failure of at least one prior multi-agent chemotherapy regimen. Bociek:Seattle Genetics, Inc.: Research Funding. Matous:Celgene: Consultancy, Speakers Bureau; Onyx: Speakers Bureau; Takeda Pharmaceuticals International Co.: Speakers Bureau; Seattle Genetics, Inc.: Research Funding, Speakers Bureau. Sawas:Seattle Genetics, Inc.: Research Funding. Caimi:Seattle Genetics, Inc.: Equity Ownership, Research Funding. Ansell:Seattle Genetics, Inc.: Research Funding. Islas-Ohlmayer:Seattle Genetics, Inc.: Research Funding. Cheung:Seattle Genetics, Inc.: Research Funding. Agura:Seattle Genetics, Inc.: Research Funding. Behler:Onyx Pharmaceuticals: Speakers Bureau; Seattle Genetics, Inc.: Research Funding. Crosswell:Seattle Genetics, Inc.: Consultancy, Equity Ownership, Research Funding, Travel expenses Other. Vose:Seattle Genetics, Inc.: Honoraria, Research Funding. Josephson:Seattle Genetics, Inc.: Employment, Equity Ownership. Advani:Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding; Seattle Genetics, Inc.: Research Funding, Travel expenses Other.

Abstract 3964 Background: Bortezomib in combination with dexamethsone is administered twice a week for 2 weeks with excellent therapeutic outcome. However, in a proportion of patients it is associated with toxicities such as neuropathy and twice a week regimen is inconvenient especially in older patients. To improve convenience and compliance, we have investigated the efficacy and safety of a weekly bortezomib regimen. Methods: We conducted a phase II multi-center single-arm study in participating Veterans Hospitals (VA) nationwide evaluating bortezomib administered at 1.6 mg/m2 IV weekly for 4 weeks with 1 week off with dexamethasone 40mg PO on the day of and day after bortezomib for upto 6 cycles in newly diagnosed multiple myeloma patients not considered for autologous stem cell transplant. The objective is to evaluate overall response rate (ORR) and toxicity of this regimen. Results: We have enrolled all planned 50 patients (median age-71; range 50–89) at 12 VA Hospitals. Patients had significant co-morbidities including 86% with cardiovascular problems, 67% with diabetes and/or hyperlipidemia, 54% with renal dysfunction, 37% with respiratory problems, and 18% with history of cancer. All patients were on at least 5 daily medications. Of the 50 patients enrolled, 42 patients have received at least 1 cycle of therapy and were evaluable for toxicity and efficacy. With a median of 4 cycles administered, this regimen was very well tolerated. Ten patients experienced neuropathy: 6 patients experienced grade 1, two patients developed grade 2 neuropathy, while two patients who had grade 1 neuropathy at diagnosis increased to grade 2 neuropathy with pain, and the other patient increased to grade 3 neuropathy with pain, with an overall Grade 3 neuropathy rate of 2.4%.Dexamethasone dose was reduced in 30% while bortezomib dose was reduced in 10% of the patients. Additionally, grade ≥1 asthenia was observed in 52%, constipation in 38%, diarrhea in 34%, anemia in 64%, vomiting/nausea in 26%, and thrombocytopenia in 54%. Four patients have died of co-morbidities which were considered unrelated or probably unrelated to the treatment with bortezomib. Of the patients who received at least 1 cycle of therapy, 62% patients achieved ≥PR; 12% CR/nCR and an additional 14% achieved VGPR. Including MR in the analysis, ORR was observed in 90% of the evaluable patients. On intent to treat analysis including all 50 patients, ORR was observed in 76% patients and ≥ PR in 52% patients. Conclusions: Once a week bortezomib with dexamethasone regimen is effective and well tolerated even in older patients with significant co-morbidities and should be considered as an important option in multiple myeloma. Disclosures: Munshi: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees. Yellapragada:Celgene: Research Funding; BMS: Research Funding. Roodman:Amgen: Consultancy; Millennium: Consultancy.

Abstract 3219 Background: Macrophages are an important component of the tumor microenvironment and the immune response to malignancy. Classically activated (M1-polarized) macrophages exhibit anti-tumor effect, while alternatively activated (M2-polarized) macrophages promote tissue repair, angiogenesis, immunosuppression and tumor progression. To date, the vast majority of studies on macrophage phenotype and polarization have been based upon in vitro studies or murine model systems. We tested the hypothesis that distinct macrophage subsets can be identified within the microenvironment of lymphoid tumors and that the relative proportion of M1:M2 macrophages correlates with therapeutic response and/or resistance. In addition, we postulated that transcriptional analysis of distinct macrophage subpopulations would provide insights into mechanisms by which M2 macrophages promote tumor progression and reveal novel mechanisms which direct the interconversion of activated macrophages between classical and alternative activation states. Our focus has been on the evaluation of the tumor microenvironment in CNS lymphomas, the cerebrospinal fluid (CSF), which is enriched in inflammatory cells including activated CD14+ macrophages that we hypothesized would exhibit phenotypic features consistent with M1 and M2 polarization. Methods: We developed a novel 9-parameter flow-cytometric method to isolate distinct subpopulations of activated macrophages from CSF and peripheral blood. The method identifies macrophages with M1 features based upon expression of nitric oxide synthase (iNOS) and M2 macrophages on the basis of low-expression of iNOS and high expression of scavenger receptors CD206, CD209 and CD36. Subpopulations of macrophages were quantified and analyzed by FACS and transcriptional profiling (Affymetrix Gene Chip 1.0 ST). Serial analysis of CSF was performed in CNS lymphoma patients to correlate macrophage polarization states with response and/or progression. Parallel analyses were performed in blood in patients with non-Hodgkin lymphoma (NHL) to control conditions including infections and/or sarcoid. Results: At least four distinct subpopulations of activated macrophages were identified in CSF in association with CNS lymphoma (N=30) and controls (N=28). A greater than six-fold increase in the proportion of M2 macrophages was detected in CSF of CNS lymphoma patients compared to control subjects (p Conclusions: We believe this to be the first application of flow-cytometry to define the phenotypes and dynamic interconversion of intratumoral macrophages within the lymphoma microenvironment and the first correlation of M2 macrophages with the evolution of resistance to therapy. In addition, this dataset provides the first in-depth transcriptional profiling analysis of in vivo human macrophage subpopulations and suggests novel mechanisms by which tumor-associated macrophages may facilitate lymphoma progression via the regulation of the metabolic microenvironment, angiogenesis, tumor invasion and immunosuppression. Based upon our additional preliminary data, we hypothesize that these results may be relevant to a variety of lymphoid tumors. Disclosures: Off Label Use: We will discuss the use of rituximab within the leptomeningeal compartment to treat recurrent/refractory CNS lymphomas.

8074^ Background: The current BZ regimen administered twice a week for 2 weeks with one week off is effective, however is inconvenient and associated with toxicities such as neuropathy. To improve ...

Abstract 3061 The current bortezomib schedule involves administration of the drug twice a week at 1.3 mg/m2 for 2 weeks every 21 days. This regimen although effective is inconvenient and associated with side effects including neuropathy and gastrointestinal toxicities that limits its use in a proportion of patients. Therefore, to improve convenience and compliance, we have investigated efficacy and safety of a weekly regimen of bortezomib. In this one-stage phase II multi-center, open-label single-arm study bortezomib is administered once a week at 1.6 mg/m2 in combination with dexamethasone in newly-diagnosed multiple myeloma patients not considered for autologous stem cell transplant in participating Veterans Hospitals nationwide. The objective is to evaluate overall response rate and toxicity of this regimen. Patients received bortezomib at 1.6 mg/m2 IV weekly for 4 weeks followed by 1 week off and dexamethasone 40mg PO on the day of and day after each dose of bortezomib. Patients may receive 6 such 5-week cycles. At the current time 32 patients (median age - 73; range 50–88) have been enrolled at 11 Veterans Administration Hospital across the U.S. Patients had significant co-morbidities including 61% with cardiovascular problems, 58% with diabetes and/or hyperlipidemia, 58% with elevation of serum creatinine, 26% with respiratory problems and 23% with previous history of cancer. All patients were at least on 5 daily medications. Of the 32 patients enrolled, 25 patients have received at least one cycle of therapy and were evaluable for toxicity and efficacy, while 6 patients have received less than one cycle of therapy and one patient has inadequate data. With a median of 4 cycles administered, this regimen was well tolerated. None of the patients have developed grade 3 neuropathy, while grade 1 neuropathy was observed only in 2 patients and one patient with grade 1 neuropathy at diagnosis had increase to grade 2. Dexamethasone dose was reduced in 29% patients while 6% required reduction in bortezomib dose to 1.3 mg/m2. Additionally, Grade ≥1 asthenia was observed in 42%, diarrhea in 35%, and thrombocytopenia in 26%. Four patients have died of co-morbidities which were considered unrelated or probably unrelated to the treatment with bortezomib. The partial response or better was achieved in 68% patients receiving at least 1 cycle of therapy; 20% patients achieved CR/nCR and additional 12% achieved VGPR. Including MR in the analysis, overall response was observed in all evaluable patients. On intent to treat analysis including all 32 patients, overall response rate (≥ MR) was observed in 78% patients and PR or better in 53% patients. These preliminary results suggest that the once a week bortezomib regimen is effective and tolerable with reduced toxicity even in this older patient population with significant co-morbidities. Disclosures: Munshi: Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees. Roodman:Millennium: Consultancy; Amgen: Consultancy, Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria.

TPS307 Background: BZ is proteasome inhibitor with demonstrated efficacy in NDMM when given on twice a week (wk) schedule. However, neuropathy is one of the side effects that limit its use in a proportion of pts. Therefore, there is a need to investigate efficacy and safety of a weekly regimen of BZ. Methods: We are conducting a one-stage phase II multicenter, open-label single-arm noninferiority study of once a wk BZ in combination with dex, for the treatment of NDMM in Veterans Hospitals nationwide. The purpose is to show that the study regimen is not inferior to the standard BZ therapy with respect to objective response (OR) rate in pts with NDMM not undergoing transplant. Previously untreated MM pts who are not considered for autologous stem cell transplant (ASCT) due to age > 65 and/or comorbidities, or who are age ≥60 and have declined ASCT are eligible.Pts receive 1.6 mg/m2 IV BZ weekly, for 4 weeks followed by 1 week off. They also receive 40 mg dex PO the day of and day after each dose of BZ. Pat...

Introduction Pure red cell aplasia due to anti-epoetin antibodies is a known complication of epoetin therapy for anemia due to chronic kidney disease. This disease has not previously been well described in the setting of therapy for chronic hepatitis C virus infection. While treatment for pure red cell aplasia due to anti-epoetin antibodies is usually with immunosuppressive therapy such as calcineurin inhibition, the safety of this treatment in chronic hepatitis C virus infection is unknown. To date, little has been published on the efficacy of rituximab on pure red cell aplasia due to anti-epoetin antibodies. Case presentation This report describes a 65-year-old Asian-American woman who developed pure red cell aplasia from high titer neutralizing anti-epoetin antibodies after epoetin-alfa therapy during ribavirin and peg-interferon treatment for chronic hepatitis C virus infection. We describe the outcome of her treatment with rituximab. The reticulocyte count increased, and anti-epoetin antibody titer decreased with a loss of neutralizing activity in vitro, leading to a reduction in blood transfusions, and eventual resolution of anemia, without reactivation of hepatitis C virus. Conclusion The diagnosis of pure red cell aplasia from anti-epoetin antibodies should be considered in patients undergoing therapy for chronic hepatitis C virus infection who develop severe anemia after administration of erythropoietin or darbepoetin. Though it is currently an off-label indication, rituximab is a therapeutic option for patients with pure red cell aplasia due to anti-epoetin antibodies.