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In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 696-696

Abstract: Introduction: Recent data from the ARROW and CHAMPION-1 study show significant activity of once weekly carfilzomib administration. Furthermore, the recent MUK5 and CARF studies show significantly increased PFS with carfilzomib maintenance therapy. Here, we compare 9 cycles of weekly KRd with weekly KTd (after 2 cycles of biweekly therapy) followed by a second randomization to 12 cycles of carfilzomib maintenance or observation only in elderly NDMM. Methods: 75 of 146 planned pts (median age: 75 years, range 55-84) with NDMM have been enrolled so far in this randomized phase 2 study. Treatment regimen: Carfilzomib 20mg/m2 on day 1+2, 27mg/m2 on day 8, 9, 15 and 16; cycle 2: 27mg/m2 on day 1,2,8,9,15 and 16; Carfilzomib was switched to once weekly dosing (56mg/m2, d1, 8, 15) from cycle 3 on until cycle 9. Patients received dexamethasone weekly (20mg in pts ≥75 years) and either lenalidomide 25mg d 1-21, or thalidomide 100mg/day, day 1-28 (50mg in pts ≥75 years). Patients with ≥SD after 9 cycles were randomized to carfilzomib 56mg/m2 (or last tolerated dose) on day 1 and 15 q 4 weeks, or to control for one year. FISH testing was done according recommended standards. NGF MRD testing was done in pts reaching CR or VGPR. Survival estimates were calculated according to Kaplan-Meier. Differences in response rate were assessed using Fisher's exact test, while the Log-Rank test was used for evaluating differences in survival. This trial is registered on clinicaltrials.gov (NCT02891811). Results: Median follow up was 11.7 months. 58 of the 75 pts completed ≥2 cycles (per protocol population (PP)), 12 pts discontinued therapy within the first 2 cycles due to AE/unacceptable toxicity [4 (5.3%)], death [3 (4%)] , investigator decision [2 (2.7%)], patient's decision [2 (2.7%)] , or other reason [1 (1.3%)]. As the trial is still ongoing, response rates and survival data are given for both groups (KRd and KTd) combined. Overall response was noted in 56 of the 58 pts (96.6%) with response data available, CR in 21 (36.2%), VGPR in 22 (37.9%), PR in 13 (22.4%), and MR in 2 (3.4%) pts. Of the 17 pts with MRD testing available, 47.1% achieved MRD negativity. PFS was 22.3 months in both the PP and ITT pts. Overall survival at 24 months was 78% in the ITT and 79% in the PP group, respectively. Between very elderly pts 75 years of age or older and pts below 75 years, no difference in ORR (96.8% vs. 96.3%, p=1), ≥VGPR (67.7% vs. 81.5%, p=0.3678) and PFS was found (ITT group: 22.3 months vs. not reached, p=0.926; PP group: 22.3 months vs. not reached, p=0.895). Likewise, OS did not differ in both age groups (data not shown). Outcome was also similar between pts with and without high-risk cytogenetics: ORR 100% vs.97.1%, p=1; ≥VGPR 80% vs. 71.4%, p=1; PFS not reached vs. 22.3 months, p=0.342; OS at 24 months was 85% for high-risk and 67% for standard-risk pts. In a safety evaluation with 66 patients, the most frequent grade 3/4 hematologic adverse events were anemia (4.5%), leukopenia (1.5%), and thrombocytopenia (6.0%). The non-hematologic grade 3/4 AEs were infections (21.2%), cardiac failure, gastrointestinal disorders, and renal impairment (6.0% each), neurologic disorders, hypertension, and rash (3.0% each), and hepatic failure, SPM, VTE, and psychiatric disorders (1.5% each). Conclusion: Once weekly carfilzomib 56mg/m² in combination with either lenalidomide or thalidomide resulted in high response rate and deep responses including MRDneg status in 47.1% of tested elderly patients with NDMM. Results were similar in very elderly pts (³75 years) and in those aged & lt;75 years. Treatment was associated with an acceptable tolerance profile. Adverse events (mostly infections, and less frequently GI-toxicities, cardiac failure, and renal impairment) resulting in treatment discontinuations occurred mostly during cycle 1 or 2, when the twice weekly regimen was administered as run in phase. Disclosures Ludwig: Janssen: Speakers Bureau; BMS: Speakers Bureau; Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; PharmaMar: Consultancy; Celgene: Speakers Bureau. Zojer:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hartmann:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: sponsoring of educational seminars; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of educational seminars. Gunsilius:Amgen: Honoraria. Podar:Janssen Pharmaceuticals: Consultancy, Honoraria; Roche Pharmaceuticals: Research Funding; Takeda: Consultancy; Celgene: Consultancy, Honoraria; Amgen Inc.: Honoraria. Egle:Celgene: Honoraria, Other: Advisory board and Travel support. Willenbacher:Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commission: Research Funding; Abbvie: Consultancy, Honoraria; Tirol Program: Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Fujimoto: Consultancy, Honoraria; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Petzer:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Other: Personal fees; Takeda: Membership on an entity's Board of Directors or advisory committees. Machherndl-Spandl:Celgene: Other: Advisory board. Paiva:Amgen, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Roche, and Sanofi; unrestricted grants from Celgene, EngMab, Sanofi, and Takeda; and consultancy for Celgene, Janssen, and Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau. Greil:Eisai: Honoraria; Boehringer Ingelheim: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; GSK: Research Funding; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Cephalon: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Honoraria; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Mundipharma: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sandoz: Honoraria; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Bristol-Myers-Squibb: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Honoraria. OffLabel Disclosure: Carfilomib 56mg/m2 in weekly dosing in combination with either Lenalidomide and low dose dexamethasone (KRd), or with thalidomide and low dose dexamethasone (KTd) was evaluated for first line treatment in TNE NDMM patients. After 9 cycles pts were randomized to K biweekly maintenance therapy for 12 months or to observation.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2019-127954

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 822-822

Abstract: Acute myelogenous leukemia (AML) is characterized by multiple genetic and epigenetic abnormalities including a profound dysregulation of microRNA expression. Specific expression signatures of miRNA are associated with disease behavior and clinical outcome. Effective clinical treatment of AML has largely depended on a class of antimetabolites – the nucleoside analogs. Of these, sapacitabine is a nucleoside analog prodrug that is in development for the therapy of AML. It is converted to its active metabolite 2-C-cyano-2-deoxy-1-β(-D-arabino-pentafuranosyl) cytosine (CNDAC), which interferes with DNA synthesis by initially causing a single stranded DNA break that is converted into a double strand break in the subsequent replicative cycle. Such double strand breaks are primarily repaired by the homologous recombination repair (HR) pathway. Consequently, efficient HR may offer a potential resistance mechanism to therapy with sapacitabine. Panobinostat and vorinostat are pan HDAC inhibitors (HDACi) that modulate gene expression, induce apoptosis, and are clinically active against specific leukemias and lymphomas. In pilot experiments, we identified that exposure of AML cell lines to a combination of panobinostat or vorinostat and sapacitabine had a greater than additive effect on cell viability. Loss of cell survival was preceded by a rapid and marked decline in the levels of Rad51, a protein that is critical in repairing CNDAC-induced damage via the HR repair pathway, both in AML cell lines and primary tumor cells that were exposed to either panobinostat or vorinostat. Therefore, we hypothesized that exposure of AML cells to HDACi would activate the expression of a set microRNAs, that would target Rad51. Loss of Rad51 protein, would in turn impede the successful completion of HR rendering the cells incapable of repairing the damage caused by CNDAC and thus sensitizing them to the nucleoside analog. Our preliminary data using microRNA arrays indicated that exposure of AML cells to panobinostat resulted in the induction of nine microRNA that putatively target Rad51. We then ectopically expressed three of the nine Rad51- directed miRNA and found that miR-182 efficiently targeted the Rad51 protein. Using real time-PCR we found that the levels of miR-182 were significantly lower in primary AML cells when compared to hematopoietic cells from normal donors. Using chromatin immunoprecipitation (ChIP) assays we identified that HDAC1 and HDAC2 were recruited to the miR182 promoter in AML cell lines as well as in primary AML cells, which was probably linked to loss of gene expression. Correspondingly, HDAC inhibition led to the accumulation of activating chromatin modifications at the miR-182 promoter, which was followed by the induction of miR-182 levels in both AML cells lines and primary AML cells. To determine whether HDAC inhibition targets Rad51 via miR-182, we expressed antagomiRs that interfere with the binding of miR-182 to Rad51, and found that the levels of Rad51 were preserved in cells expressing anti-miR182 before being exposed to panobinostat. Finally, we identified that exposure to panobinostat suppressed ongoing HR as measured by the absence of Rad51 foci in cells exposed to this agent, whereas cells exposed to CNDAC alone exhibited robust Rad51 foci formation, indicating an active HR pathway. In conclusion, HDAC inhibition results in the induction of miR-182 which targets Rad51 and attenuates HR to sensitize cells to sapacitabine in AML. This therapeutic strategy may be effective in circumventing potential resistance mechanisms to nucleoside analog therapy in AML. Disclosures: Ewald: Novartis: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V122.21.822.822

Language: English

Publisher: American Society of Hematology

Publication Date: 2013

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3702-3702

Abstract: Abstract 3702 Introduction. Patients with chronic lymphocytic leukemia (CLL), multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma (HL) together accounted for 7% of new cancers and 6% of cancer deaths in 2010. Despite therapeutic advances, many of these patients develop relapsed or refractory disease and have poor survival thereafter. CLL, MM, NHL, and HL highly express the CD40 receptor, which is activated by the CD40 ligand (CD40L, CD154) and stimulates downstream proliferation and survival. Lucatumumab is a fully antagonistic human anti-CD40 monoclonal antibody that has demonstrated activity in preclinical and clinical studies and is hypothesized to act through dual mechanisms of action by inhibiting CD40L-CD40 signaling and inducing antibody-dependent cell-mediated cytotoxicity. Here, we present a full safety analysis from 2 phase I trials in patients with relapsed or refractory CLL (NCT00108108) or MM (NCT00231166) and from an ongoing phase I/II study in patients with NHL and HL (NCT00670592). Methods. These early-phase trials of lucatumumab were designed to determine the maximum tolerated dose (MTD), safety profile, pharmacokinetics, and pharmacodynamics of lucatumumab, and to evaluate early signals of clinical efficacy in CLL, MM, NHL, and HL. Patients with relapsed or refractory CLL, MM, NHL, and HL were enrolled and received 4 intravenous infusions of lucatumumab 0.3, 1.0, 3.0, 4.0, 4.5, or 6.0 mg/kg once weekly per treatment cycle. Dose-limiting toxicities (DLTs), MTD, and adverse events (AEs) were assessed. Results. A total of 164 patients with relapsed or refractory CLL (n=26), MM (n=28), or lymphoma (NHL or HL; n=110) were enrolled in 3 trials. Lucatumumab was well tolerated; the most frequent AEs were primarily grade 1/2 events. Infusion-related reactions typically occurred during or within 1 day of the first infusion and decreased in frequency for subsequent infusions. Any-grade AEs included chills (42%), nausea (32%), pyrexia (32%), and fatigue (25%). Non-laboratory grade 3/4 AEs due to any cause included dyspnea (5%), chills (2%), fatigue (2%), and hypotension (2%). Hematologic grade 3/4 abnormalities, regardless of drug relationship, included neutropenia (14%), anemia (14%), and thrombocytopenia (9%). Cytopenia was manageable, was reversible, and led to treatment discontinuation in 3% of patients. The most common grade 3/4 biochemical laboratory abnormalities included asymptomatic elevations of lipase (25%), amylase (10%), ALT (7%), or AST (5%). The most common AE leading to study discontinuation was increased lipase (n=18; 11%). These elevations resolved per investigators after a median of 16 days (range 1–99 days). A total of 14 DLTs were reported during dose escalation phases of the studies; all DLTs occurred at doses ≥3.0 mg/kg and most commonly included grade 3/4 laboratory elevations lasting 〉 7 days. The lucatumumab MTDs for patients with CLL, MM, or NHL/HL were 3.0, 4.5, and 4.0 mg/kg once weekly, respectively. A total of 14 deaths due to any cause occurred on study or within 28 days of discontinuation, 1 of which (due to sepsis) was considered possibly related to the study drug by the investigator. No antibodies to lucatumumab were detected in any patients. Conclusions. The tolerability profile of lucatumumab reported here supports further study in relapsed or refractory CLL, MM, NHL, and HL as a single agent or in combination with other agents that are established for the treatment of these conditions. A combination study of lucatumumab and bendamustine in follicular lymphoma is ongoing. Disclosures: Fanale: Novartis Pharmaceuticals Corporation: Honoraria, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; MedImmune: Research Funding; Millenium: Research Funding. Bensinger:Novartis Corporation: Research Funding. Ewald:Novartis Pharmaceuticals Corporation: Employment. Carreon:Novartis Pharmaceuticals Corporation: Fellow for Rutgers University Sponsored by Novartis Pharmaceuticals Corporation. Baeck:Novartis Pharmaceuticals Corporation: Employment. Freedman:Pfizer: Data safety monitoring committee member; GlaxoSmithKline: Data safety monitoring committee member; Novartis Pharmaceuticals Corporation: Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V118.21.3702.3702

Language: English

Publisher: American Society of Hematology

Publication Date: 2011

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In: Blood, American Society of Hematology, Vol. 98, No. 4 ( 2001-08-15), p. 940-944

Abstract: In follicular lymphoma, the t(14;18) status of the peripheral blood and bone marrow analyzed by polymerase chain reaction (PCR) is assumed to correlate with disease activity in patients with relapsed disease. The clinical significance of quantitating circulating lymphoma cells by real-time PCR is reported in patients on first-line treatment. Thirty-four consecutive patients with previously untreated follicular lymphoma and detectable t(14;18)-positive cells in pretreatment peripheral blood samples were monitored. All patients were treated with standard chemotherapy in combination with interferon alfa-2b. Before and after induction therapy, blood samples were taken for quantitative analysis of t(14;18). At presentation, a median of 262 t(14;18)-positive cells per 75 000 normal cells was found (range, 1-75 000). Patients with lower numbers of circulating tumor cells more frequently had bulky disease (P = .02). Seventy-nine percent of the patients responded clinically to treatment. In 22 of 28 patients, including 4 patients in whom treatment had failed clinically, the number of circulating t(14;18)-positive cells decreased to undetectable or low levels after therapy. In the remaining responding patients, circulating tumor cells persisted after therapy. These quantitative data on circulating t(14;18)-positive cells call into question the usefulness of molecular monitoring of the blood in a group of patients with follicular lymphoma uniformly treated with a noncurative first-line regimen. T(14;18)-positive cells decreased in peripheral blood after treatment, irrespective of the clinical response. Therefore, the significance of so-called molecular remission should be reconsidered in follicular lymphoma.

Type of Medium: Online Resource

ISSN: 1528-0020 , 0006-4971

URL: Article

DOI: 10.1182/blood.V98.4.940

Language: English

Publisher: American Society of Hematology

Publication Date: 2001

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 49, No. 5 ( 1977-05-01), p. 799-806

Abstract: A circulating anticoagulant against factor VIII activity was demonstrated in the plasma of a boy from a family with both factor VIII deficiency and prolonged bleeding time. However, the factor VIII- related antigen, ristocetin-induced platelet aggregation activity, platelet retention in glass bead columns, platelet aggregation with adenosine 5′-diphosphate, collagen and epinephrine, and clot retraction among affected members were normal. The electrophoretic mobility of factor VIII-related antigen on crossed immunoelectrophoresis was normal. The inactivation of factor VIII activity by the inhibitor was time dependent and was nonlinear as the concentration of the inhibitor was increased. Immunotyping showed that the inhibitor was IgG with k light chains.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V49.5.799.799

Language: English

Publisher: American Society of Hematology

Publication Date: 1977

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 32, No. 6 ( 1968-12-01), p. 884-894

Abstract: Red blood cell survival time as measured with 32DFP and 51Cr was studied in subjects with iron deficiency anemia associated and nonassociated with hook-worm infection. 51Cr T ½ was definitely shorter in all cases in which 32DFP showed marked excess hemolysis, but a normal 51Cr T ½ was found in some cases in which 32DFP survival was slightly reduced. There was a high correlation between survival measured with 32DFP and the rate of abnormal red cells in the peripheral blood. Less correlation was found between the proportion of hypochromic microcytic red cells and 32DFP, and even less correlation, although significant, was observed when 51Cr T ½ was compared with the red cell parameters. Results of the red cell survival studies with erythrocytes from subjects with iron deficiency anemia injected into the donor subject, normal recipients, and splenectomized subjects, as well as body 51Cr surface countings, indicated that excess hemolysis in this type of anemia is due to an intrinsic defect of the red blood cells and that the spleen is the principal sites of destruction of these cells.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V32.6.884.884

Language: English

Publisher: American Society of Hematology

Publication Date: 1968

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 49, No. 5 ( 1977-05-01), p. 799-806

Abstract: A circulating anticoagulant against factor VIII activity was demonstrated in the plasma of a boy from a family with both factor VIII deficiency and prolonged bleeding time. However, the factor VIII- related antigen, ristocetin-induced platelet aggregation activity, platelet retention in glass bead columns, platelet aggregation with adenosine 5′-diphosphate, collagen and epinephrine, and clot retraction among affected members were normal. The electrophoretic mobility of factor VIII-related antigen on crossed immunoelectrophoresis was normal. The inactivation of factor VIII activity by the inhibitor was time dependent and was nonlinear as the concentration of the inhibitor was increased. Immunotyping showed that the inhibitor was IgG with k light chains.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V49.5.799.bloodjournal495799

Language: English

Publisher: American Society of Hematology

Publication Date: 1977

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 284-284

Abstract: Abstract 284 Background: Lucatumumab (LUC) is a pure antagonistic CD40 monoclonal antibody to the transmembrane receptor CD40. In preclinical testing, micromolar concentrations of LUC decrease proliferation of B cells in vitro and LUC shows anti-lymphoma activity in in vivo models. LUC has been clinically evaluated in chronic lymphocytic leukemia and multiple myeloma, and now is under evaluation in pts with follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), marginal zone lymphoma/mucosal associated lymphoid tissue (MZL/MALT), or Hodgkin's lymphoma (HL) who had progressed after at least two prior therapies. Methods: LUC was given IV once weekly for 4 weeks, followed by a 4 week rest period. Pts with stable disease or whose disease responded are eligible for additional cycles of LUC. Objectives were: (1) determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) dose (dose escalation, phase Ia), (2) assess the clinical response rate at the MTD (dose expansion, phase II), (3) exploratory: pharmacodynamics and correlative humoral biomarkers. Bayesian logistic regression modeling was used to escalate LUC. To estimate the response rate to LUC of each of the subtypes under study, a hierarchical Bayesian model has been used. Results: During phase Ia, 32 pts received LUC at dose levels of 3.0 mg/kg (15 pts), 4.0 mg/kg (12 pts), or 6.0 mg/kg (5 pts). The MTD and DLT dose were identified as 4.0 mg/kg and 6.0 mg/kg, respectively. DLTs were limited to clinically asymptomatic and reversible grade 3/4 elevations of amylase and/or lipase and grade 3/4 elevations of ALT and/or AST. As of June 14, 2010, 99 patients had received at least 1 infusion of LUC (32 from phase Ia, 67 from phase II). Of these patients, preliminary efficacy data is available for 79 patients (30 from phase Ia, 49 from phase II). A 40% response rate to LUC was observed in patients who were refractory to rituximab. Peripheral blood CD40 receptor occupancy analyses demonstrated greater than 90% occupancy of circulating B-cells at 4 mg/kg (MTD). The half-life of LUC at 4 mg/kg was calculated as 13 ± 11 days. No immunogenicity was observed in any samples. Conclusions: Preliminary results for LUC show anti-lymphoma activity on patients who failed at least two lines of therapy at an acceptable safety profile. Enrollment is continuing to further evaluate efficacy in all subtypes. The data warrants further development at least in the refractory setting of FL. Disclosures: Freedman: Novartis Pharmaceuticals, Inc: Consultancy. Kuruvilla:Hoffman LaRoche: Honoraria, Research Funding; Celgene: Research Funding; Amgen: Honoraria; Genzyme: Honoraria; Otsuka: Honoraria. Engert:Novartis Pharmaceuticals, Inc: Honoraria, Research Funding. Corradini:Novartis Pharmaceuticals, Inc: Consultancy; Genezyme: Consultancy; Roche: Speakers Bureau; Celegene: Speakers Bureau. Fanale:Novartis Pharmaceuticals, Inc: Honoraria, Research Funding. Bendiske:Novartis Pharmaceuticals, Inc: Employment. Ewald:Novartis Pharmaceuticals, Inc: Employment. Dey:Novartis Pharmaceuticals, Inc: Employment. Baeck:Novartis Pharmaceuticals, Inc: Employment. Younes:Novartis Pharmaceuticals, Inc: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Seattle Genetics: Honoraria, Research Funding; SBIO: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.284.284

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

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In: Blood, American Society of Hematology, Vol. 91, No. 8 ( 1998-04-15), p. 2991-2997

Abstract: The BCL-2 gene family regulates the susceptibility to apoptotic cell death in many cell types during embryonic development and normal tissue homeostasis. Deregulated expression of anti-apoptotic BCL-2 can be a primary aberration that promotes malignancy and also confers resistance to chemotherapeutic agents. Recently, studies ofBax-deficient mice have indicated that the pro-apoptotic BAX molecule can function as a tumor suppressor. Consequently, we examined human hematopoietic malignancies and found that approximately 21% of lines possessed mutations in BAX, perhaps most commonly in the acute lymphoblastic leukemia subset. Approximately half were nucleotide insertions or deletions within a deoxyguanosine (G8) tract, resulting in a proximal frame shift and loss of immunodetectable BAX protein. Other BAX mutants bore single amino acid substitutions within BH1 or BH3 domains, demonstrated altered patterns of protein dimerization, and had lost death-promoting activity. Thus, mutations in the pro-apoptotic molecule BAX that confer resistance to apoptosis are also found in malignancies.

Type of Medium: Online Resource

ISSN: 1528-0020 , 0006-4971

URL: Article

DOI: 10.1182/blood.V91.8.2991.2991_2991_2997

Language: English

Publisher: American Society of Hematology

Publication Date: 1998

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In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 3639-3639

Abstract: Acute myelogenous leukemia (AML) is characterized by multiple genetic and epigenetic abnormalities including a profound dysregulation of microRNA expression. Effective clinical treatment of AML has largely depended on a class of antimetabolites - the nucleoside analogs. Of these, sapacitabine is a nucleoside analog prodrug that is in development for the therapy of AML. It is converted to its active metabolite 2-C-cyano-2-deoxy-1-β(-D-arabino-pentafuranosyl) cytosine (CNDAC), which interferes with DNA synthesis by initially causing a single stranded DNA break that is converted into a double strand break in the subsequent replicative cycle. Such double strand breaks are primarily repaired by the homologous recombination repair (HR) pathway. Consequently, efficient HR may offer a potential resistance mechanism to therapy with sapacitabine. Rad51 is a protein plays a critical role in HR, and high levels of Rad51 are linked to resistance to DNA damaging therapies. Histone deacetylases (HDACs) are chromatin modulating agents that decrease levels of acetylation of histones, repress gene expression. HDAC inhibitors (HDACis) function by modifying chromatin to epigenetically reverse gene silencing of coding and non-coding genes such as the microRNAs (miRs). miRs are endogenous noncoding RNAs 19-25 nucleotides in length that bind to complimentary sequences in target RNA to either destabilize it or prevent its transcription. In this study, we determined that determined primary AML blasts and cell lines express low levels of microRNA-182. Recruitment of HDAC1 and its co-repressors were linked to the epigenetic silencing of miR-182 in AML. Conversely, HDAC inhibition led to accumulation of activating chromatin modifications followed by the upregulation of miR-182 in AML blasts and cell lines. The HDACi-induced increases in miR-182 were linked to decreases in the levels of Rad51, an inhibition in the ability of cells to conduct homologous recombination repair as measured by the Homologous recombination directed repair (HDR) assay, persistent levels of DNA damage as measured by the levels of Ɣ-H2AX and sensitization to sapacitabine. We then mechanistically defined the relation between miR-182 and Rad51. Ectopic expression of miR-182 in AML cell lines identified that Rad51 was a target of miR-182. An assay with luciferase constructs bearing full length or mutated Rad51 3'UTR indentified that Rad51 was a direct target of miR-182. We also determined that ectopic expression of miR-182 attenuated the ability of AML cells to conduct homologus repair as measured by the Homologous recombination directed repair (HDR) assay which resulted in sensitizing AML cells to the cytotoxic action of CNDAC as measured by colony forming assays. In conclusion, our data show that HDAC inhibitors target Rad51 via miR-182 to compromise HR repair to result in higher levels of residual DNA damage and sensitize AML cells to double strand damaging agents such as CNDAC. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.3639.3639

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7