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Michael L Linenberger - One of the best experts on this subject based on the ideXlab platform.

  • CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Multidrug-resistance phenotype and clinical responses to Gemtuzumab Ozogamicin
    2016
    Co-Authors: Michael L Linenberger, Eric L. Sievers, Tom Hong, Ted Gooley, John M Bennett, Mark S Berger, Lance H. Leopold, David Flowers, Irwin D. Bernstein
    Abstract:

    features by acute myeloid leukemia (AML) cells predicts a poor response to many treatments. The MDR phenotype often correlates with expression of P-glycopro-tein (Pgp), and Pgp antagonists such as cyclosporine (CSA) have been used as chemosensitizing agents in AML. Gemtu-zumab Ozogamicin, an immunoconjugate of an anti-CD33 antibody linked to cali-cheamicin, is effective monotherapy for CD331 relapsed AML. However, the contri-bution of Pgp to Gemtuzumab Ozogamicin resistance is poorly defined. In this study, blast cell samples from relapsed AML patients eligible for Gemtuzumab ozo-gamicin clinical trials were assayed for Pgp surface expression and Pgp function using a dye efflux assay. In most cases, surface expression of Pgp correlated with Pgp function, as indicated by elevated dye efflux that was inhibited by CSA. Among samples from patients who either failed to clear marrow blasts or failed to achieve remission, 72 % or 52%, respec-tively, exhibited CSA-sensitive dye efflux compared with 29 % (P 5.003) or 24% (P <.001) among samples from respond-ers. In vitro Gemtuzumab Ozogamicin– induced apoptosis was also evaluated using an annexin V–based assay. Low levels of drug-induced apoptosis were associated with CSA-sensitive dye efflux, whereas higher levels correlated strongly with achievement of remission and mar-row blast clearance. In vitro drug-induced apoptosis could be increased by CSA in 14 (29%) of 49 samples exhibiting low apoptosis in the absence of CSA. To-gether, these findings indicate that Pgp plays a role in clinical resistance to gem-tuzumab Ozogamicin and suggest that treatment trials combining Gemtuzumab Ozogamicin with MDR reversal agents are warranted. (Blood. 2001;98:988-994) © 2001 by The American Society of Hematolog

  • cd33 directed therapy with Gemtuzumab Ozogamicin in acute myeloid leukemia progress in understanding cytotoxicity and potential mechanisms of drug resistance
    Leukemia, 2005
    Co-Authors: Michael L Linenberger
    Abstract:

    CD33-directed therapy with Gemtuzumab Ozogamicin in acute myeloid leukemia: progress in understanding cytotoxicity and potential mechanisms of drug resistance

  • breast cancer resistance protein bcrp abcg2 does not confer resistance to Gemtuzumab Ozogamicin and calicheamicin gamma1 in acute myeloid leukemia cells
    Leukemia, 2004
    Co-Authors: Roland B Walter, Michael L Linenberger, David A Flowers, Brian W Raden, Hans Peter Kiem, Irwin D. Bernstein, J. Thompson
    Abstract:

    Breast cancer resistance protein (BCRP/ABCG2) does not confer resistance to Gemtuzumab Ozogamicin and calicheamicin- γ 1 in acute myeloid leukemia cells

  • Breast cancer resistance protein (BCRP/ABCG2) does not confer resistance to Gemtuzumab Ozogamicin and calicheamicin-gamma1 in acute myeloid leukemia cells.
    Leukemia, 2004
    Co-Authors: Roland B Walter, David A Flowers, Brian W Raden, Hans Peter Kiem, Irwin D. Bernstein, Thompson J, Michael L Linenberger
    Abstract:

    Breast cancer resistance protein (BCRP/ABCG2) does not confer resistance to Gemtuzumab Ozogamicin and calicheamicin- γ 1 in acute myeloid leukemia cells

  • multidrug resistance phenotype and clinical responses to Gemtuzumab Ozogamicin
    Blood, 2001
    Co-Authors: Michael L Linenberger, David A Flowers, Eric L. Sievers, Tom Hong, Ted Gooley, John M Bennett, Mark S Berger, Lance Leopold, Frederick R Appelbaum, Irwin D. Bernstein
    Abstract:

    Expression of multidrug resistance (MDR) features by acute myeloid leukemia (AML) cells predicts a poor response to many treatments. The MDR phenotype often correlates with expression of P-glycoprotein (Pgp), and Pgp antagonists such as cyclosporine (CSA) have been used as chemosensitizing agents in AML. Gemtuzumab Ozogamicin, an immunoconjugate of an anti-CD33 antibody linked to calicheamicin, is effective monotherapy for CD33+ relapsed AML. However, the contribution of Pgp to Gemtuzumab Ozogamicin resistance is poorly defined. In this study, blast cell samples from relapsed AML patients eligible for Gemtuzumab Ozogamicin clinical trials were assayed for Pgp surface expression and Pgp function using a dye efflux assay. In most cases, surface expression of Pgp correlated with Pgp function, as indicated by elevated dye efflux that was inhibited by CSA. Among samples from patients who either failed to clear marrow blasts or failed to achieve remission, 72% or 52%, respectively, exhibited CSA-sensitive dye efflux compared with 29% ( P  = .003) or 24% ( P  < .001) among samples from responders. In vitro Gemtuzumab Ozogamicin–induced apoptosis was also evaluated using an annexin V–based assay. Low levels of drug-induced apoptosis were associated with CSA-sensitive dye efflux, whereas higher levels correlated strongly with achievement of remission and marrow blast clearance. In vitro drug-induced apoptosis could be increased by CSA in 14 (29%) of 49 samples exhibiting low apoptosis in the absence of CSA. Together, these findings indicate that Pgp plays a role in clinical resistance to Gemtuzumab Ozogamicin and suggest that treatment trials combining Gemtuzumab Ozogamicin with MDR reversal agents are warranted.

Roland B Walter - One of the best experts on this subject based on the ideXlab platform.

Irwin D. Bernstein - One of the best experts on this subject based on the ideXlab platform.

Elihu H. Estey - One of the best experts on this subject based on the ideXlab platform.

  • a phase ii study of decitabine and Gemtuzumab Ozogamicin in newly diagnosed and relapsed acute myeloid leukemia and high risk myelodysplastic syndrome
    Leukemia, 2016
    Co-Authors: Naval Daver, Farhad Ravandi, Hagop M. Kantarjian, Elihu H. Estey, Xuemei Wang, Guillermo Garciamanero, Elias Jabbour, Marina Konopleva, Susan Obrien, Srdan Verstovsek
    Abstract:

    A phase II study of decitabine and Gemtuzumab Ozogamicin in newly diagnosed and relapsed acute myeloid leukemia and high-risk myelodysplastic syndrome

  • addition of Gemtuzumab Ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia a meta analysis of individual patient data from randomised controlled trials
    Lancet Oncology, 2014
    Co-Authors: Robert Kerrin Hills, Sylvie Castaigne, Frederick R Appelbaum, Elihu H. Estey, Jacques Delaunay, Stephen H Petersdorf, Megan Othus, Herve Dombret, Sylvie Chevret, Norbert Ifrah
    Abstract:

    Summary Background Gemtuzumab Ozogamicin was the first example of antibody-directed chemotherapy in cancer, and was developed for acute myeloid leukaemia. However, randomised trials in which it was combined with standard induction chemotherapy in adults have produced conflicting results. We did a meta-analysis of individual patient data to assess the efficacy of adding Gemtuzumab Ozogamicin to induction chemotherapy in adult patients with acute myeloid leukaemia. Methods We searched PubMed for reports of randomised controlled trials published in any language up to May 1, 2013, that included an assessment of Gemtuzumab Ozogamicin given to adults (aged 15 years and older) in conjunction with the first course of intensive induction chemotherapy for acute myeloid leukaemia (excluding acute promyelocytic leukaemia) compared with chemotherapy alone. Published data were supplemented with additional data obtained by contacting individual trialists. The primary endpoint of interest was overall survival. We used standard meta-analytic techniques, with an assumption-free (or fixed-effect) method. We also did exploratory stratified analyses to investigate whether any baseline features predicted a greater or lesser benefit from Gemtuzumab Ozogamicin. Findings We obtained data from five randomised controlled trials (3325 patients); all trials were centrally randomised and open label, with overall survival as the primary endpoint. The addition of Gemtuzumab Ozogamicin did not increase the proportion of patients achieving complete remission with or without complete peripheral count recovery (odds ratio [OR] 0·91, 95% CI 0·77–1·07; p=0·3). However, the addition of Gemtuzumab Ozogamicin significantly reduced the risk of relapse (OR 0·81, 0·73–0·90; p=0·0001), and improved overall survival at 5 years (OR 0·90, 0·82–0·98; p=0·01). At 6 years, the absolute survival benefit was especially apparent in patients with favourable cytogenetic characteristics (20·7%; OR 0·47, 0·31–0·73; p=0·0006), but was also seen in those with intermediate characteristics (5·7%; OR 0·84, 0·75–0·95; p=0·005). Patients with adverse cytogenetic characteristics did not benefit (2·2%; OR 0·99, 0·83–1·18; p=0·9). Doses of 3 mg/m 2 were associated with fewer early deaths than doses of 6 mg/m 2 , with equal efficacy. Interpretation Gemtuzumab Ozogamicin can be safely added to conventional induction therapy and provides a significant survival benefit for patients without adverse cytogenetic characteristics. These data suggest that the use of Gemtuzumab Ozogamicin should be reassessed and its licence status might need to be reviewed. Funding None.

  • Gemtuzumab Ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study
    Haematologica, 2013
    Co-Authors: Roland B Walter, Bruno C. Medeiros, Kelda M. Gardner, Kaysey F. Orlowski, Leonel Gallegos, Bart L. Scott, Paul C. Hendrie, Elihu H. Estey
    Abstract:

    Epigenetic therapeutics such as the histone deacetylase inhibitor, vorinostat, and the DNA methyltransferase I inhibitor, azacitidine, enhance Gemtuzumab Ozogamicin efficacy in vitro. We therefore investigated vorinostat/azacitidine/Gemtuzumab Ozogamicin in 52 adults aged 50 years or over with acute myeloid leukemia requiring therapy for first relapse (remission duration ≤12 months) or primary refractory disease in a phase I/II trial. Vorinostat and Gemtuzumab Ozogamicin were escalated step-wise during the phase I portion of the trial. Vorinostat (400 mg/day orally from Days 1–9), azacitidine (75 mg/m2/day intravenously or subcutaneously from Days 1–7), and Gemtuzumab Ozogamicin (3 mg/m2/day intravenously on Days 4 and 8) were identified as the maximum tolerated dose. Among the 43 patients treated at this dose, 10 achieved a complete remission and 8 achieved a complete remission with incomplete blood count recovery, for an overall response rate of 41.9% (exact 95% confidence interval (CI): 27.0–57.9%). Four of these 18 patients (2 with complete remission and 2 with complete remission with incomplete blood count recovery) had persistence of minimal residual disease by flow cytometry at the time of best response. Four patients died within 28 days of treatment initiation. Median overall survival for the 18 patients achieving complete remission/complete remission with incomplete blood count recovery was significantly longer than for those 21 patients who failed therapy but lived at least 29 days after treatment initiation (224.5 days (range 70–798) vs. 95 days (range 36–900); P=0.0023). These data indicate that vorinostat/azacitidine/Gemtuzumab Ozogamicin has activity in this difficult-to-treat acute myeloid leukemia patient subset. (ClinicalTrials.gov: identifier 00895934).

  • Gemtuzumab Ozogamicin: Time to Resurrect?
    Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 2012
    Co-Authors: Farhad Ravandi, Frederick R Appelbaum, Richard A. Larson, Elihu H. Estey, Francesco Lo-coco, Charles A. Schiffer, Alan Kenneth Burnett, Hagop M. Kantarjian
    Abstract:

    On May 17, 2000, the US Food and Drug Administration (FDA) granted accelerated approval for the use of Gemtuzumab Ozogamicin (GO) in older patients (age ≥ 60 years) with acute myeloid leukemia (AML) in first relapse who were not considered candidates for standard cytotoxic chemotherapy.1 Approval for this novel anti-CD33 immunoconjugate was based on a phase II trial demonstrating a 30% response rate (including complete response [CR] and CR with incomplete platelet recovery)2 and was conditional on future demonstration of benefit in treatment of AML. Over the past 10 years, several phase II and III trials have addressed this issue.

  • Phase II trial of vorinostat and Gemtuzumab Ozogamicin as induction and post-remission therapy in older adults with previously untreated acute myeloid leukemia
    Haematologica, 2011
    Co-Authors: Roland B Walter, Frederick R Appelbaum, Charles A. Schiffer, Bruno C. Medeiros, Bayard L. Powell, Elihu H. Estey
    Abstract:

    Histone deacetylase inhibitors such as vorinostat enhance Gemtuzumab Ozogamicin efficacy in vitro. We, therefore, investigated vorinostat+Gemtuzumab Ozogamicin for adults aged 60 years and over with untreated acute myeloid leukemia. We stratified patients into 2 groups (group 1: patients aged ≥70 years and performance status 2–3; group 2: aged 60–69 years with performance status 0–3 or aged ≥70 years and performance status 0–1). Responses were monitored separately in group 2 patients with normal or favorable cytogenetics (group 2A) and other cytogenetics (group 2B). Among 31 patients, 6 (19.4%) achieved complete remission, and one (3.2%) achieved complete remission with incomplete platelet recovery; these patients had a higher median overall survival than non-responders (553 vs. 131 days, P=0.0026). Response rates were: group 1, one of 10 (10.0%); group 2A, 6 of 13 (46.2%); and group 2B, none of 8 (0%). These data indicate that vorinostat+Gemtuzumab Ozogamicin has activity that is mostly confined to patients with normal karyotype disease. ClinicalTrial.gov: NCT00673153.

Hans Peter Kiem - One of the best experts on this subject based on the ideXlab platform.