The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

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

  • prevention recognition and management of adverse events associated with Gemtuzumab ozogamicin use in acute myeloid leukemia
    Journal of Hematology & Oncology, 2020
    Co-Authors: Jorge E. Cortes, Elihu H Estey, Herve Dombret, Marcos De Lima, Sergio Giralt, Pau Montesinos, Christoph Rollig, Adriano Venditti, Eunice S. Wang
    Abstract:

    Gemtuzumab ozogamicin (GO), a humanized anti-CD33 monoclonal antibody conjugated to the cytotoxic antibiotic agent calicheamicin, is approved for the treatment of newly-diagnosed CD33 + AML in adults and children ≥ 1 month old, and relapsed or refractory CD33 + AML in adults and children ≥ 2 years old. GO treatment has been associated with an increased risk of hepatotoxicity and hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS), especially following hematopoietic stem cell transplantation. Other non-specific serious adverse events (SAEs) associated with GO treatment are myelosuppression, bleeding/thrombocytopenia, infusion-related reaction, and tumor lysis syndrome. This report summarizes an expert panel of physicians' recommendations for the evaluation and management of SAEs following GO, emphasizing the prevention and management of VOD/SOS.

  • cure of apl without chemotherapy
    2018
    Co-Authors: Elihu H Estey, Maryelizabeth M Percival
    Abstract:

    The chemotherapy-free treatment of acute promyelocytic leukemia (APL) is a modern success story. Early clinical trials in China during the 1980s suggested the potent activity of all-trans retinoic acid (ATRA) in APL, leading to differentiation of the malignant cells and complete remission. In the 1990s, arsenic trioxide (ATO) was also shown to lead to differentiation of the promyelocytes. Thus, the current treatment for newly diagnosed standard-risk APL (white blood cell count <10 × 109 cells/L) in adults is ATRA and ATO without chemotherapy, which leads to a remarkable cure rate of over 90%. In newly diagnosed patients with high-risk APL (white blood cell count ≥10 × 109 cells/L), cytoreduction with Gemtuzumab ozogamicin or anthracyclines is recommended in addition to combination ATRA and ATO. A once highly fatal disease has now become the most highly curable subtype of acute myeloid leukemia, in most cases without the need for chemotherapy.

  • CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
    2016
    Co-Authors: Elihu H Estey, Francis J. Giles, Jorge E. Cortes, Deborah A. Thomas, Xuemei Wang, Peter F. Thall, Miloslav Beran, Sherry A. Pierce, Hagop M. Kantarjian
    Abstract:

    Gemtuzumab ozogamicin with or without interleukin 11 in patients 65 years of age or older with untreated acute myeloid leukemia and high-risk myelodysplastic syndrome: comparison with idarubicin plus continuous-infusion, high-dose cytosine arabinosid

  • 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, Elihu H Estey, Farhad Ravandi, Hagop M. Kantarjian, 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, Frederick R Appelbaum, Elihu H Estey, Sylvie Castaigne, 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.

Susan Obrien - 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, Elihu H Estey, Farhad Ravandi, Hagop M. Kantarjian, 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

  • Gemtuzumab ozogamicin with fludarabine cytarabine and granulocyte colony stimulating factor flag go as front line regimen in patients with core binding factor acute myelogenous leukemia
    American Journal of Hematology, 2014
    Co-Authors: Gautam Borthakur, Jorge E. Cortes, Xuemei Wang, Guillermo Garciamanero, Elias Jabbour, Susan Obrien, Elihu E Estey, Stefan Faderl, Tapan M Kadia, Keyur P Patel
    Abstract:

    Despite being considered "good-risk" acute myelogenous leukemia (AML), long term outcomes in core binding factor (CBF) AML suggest room for improvement. We report on a regimen consisting of fludarabine, cytarabine, granulocyte colony stimulating factor, and low dose Gemtuzumab ozogamicin (FLAG-GO) as front-line therapy of patients with CBF AML. Forty-five patients were enrolled (median age 48 years). Remission rate was 95% with 5% induction deaths. The overall survival (OS) and relapse free survival (RFS) probability at 3 years are 78% and 85%, respectively. FLAG-GO regimen results in high rates of RFS and OS in CBF AML. Our data along with recent data from several large groups strongly argues in favor of incorporation of Gemtuzumab ozogamicin in frontline regimens for CBF AML.

  • effect of fludarabine cytarabine filgrastim and Gemtuzumab ozogamicin flag go on relapse free survival in patients with newly diagnosed core binding factor acute myelogenous leukemia
    Journal of Clinical Oncology, 2012
    Co-Authors: Gautam Borthakur, Farhad Ravandi, Jorge E. Cortes, Susan Obrien, Stefan Faderl, Tapan M Kadia, Varsha Gandhi, Zeev Estrov, William Plunkett, Joyce Bass
    Abstract:

    6528 Background: Prior modulation with fludarabine increases cytarabine-triphosphate (ara-CTP) accumulation and granulocyte-colony-stimulating factor (G-CSF) increases the fludarabine-triphosphate (F-ara-ATP) levels in leukemic blasts. Our front-line regimen of fludarabine, cytarabine and filgrastim (FLAG) based on this rationale showed improved event-free survival compared to anthracycline and cytarabine based regimens in patients (pts) with core-binding factor acute myelogenous leukemia (CBF-AML). Medical Research Council AML 15 trial reported survival benefit from addition of Gemtuzumab ozogamicin (GO) to chemotherapy regimens in patients with favorable-risk cytogenetics AML. Methods: In a clinical trial combining GO (3 mg/m2 IV) with FLAG (FLAG-GO) in newly diagnosed CBF-AML, pts received GO on day 1 of induction and of post-remission cycles 2 or 3 and 5 or 6 in addition to FLAG. FLAG regimen was comprised of fludarabine 30 mg/m2 and cytarabine 2 gm/m2 IV daily (both for 5 days in induction and 3-4 da...

  • clinical and molecular response in core binding factor acute myelogenous leukemia with fludarabine cytarabine g csf and Gemtuzumab ozogamicin
    Blood, 2008
    Co-Authors: Gautam Borthakur, Farhad Ravandi, Srdan Verstovsek, Susan Obrien, Stefan Faderl, Dan Jones, Varsha Gandhi, Zeev Estrov, Joyce Bass, Mark Brandt
    Abstract:

    Abstract 2056 Poster Board II-33 Background: Core binding factor associated acute myelogenous leukemias (CBF AML) are characterized by sensitivity to high dose cytarabine (ara-C). Attempts to modulate intra-cellular ara-C tri phosphate (ara-CTP) by induction/consolidation therapy with fludarabine, cytarabine and granulocyte colony stimulating factor (GCSF) (FLAG) has resulted in improved event free survival (EFS) (median EFS not reached after median follow-up of 118 weeks) in patients with CBF AML (Borthakur et al. 2008, Cancer 113:3181). Addition of Gemtuzumab ozogamicin (GO) to induction and consolidation has resulted in improved disease free survival (DFS) in patients with AML and “favorable cytogenetics” (Burnett,A. et al. ASH 2006#13). Method: In an attempt to improve upon these results we have initiated a study incorporating GO with FLAG (GO-FLAG) in induction/consolidation for treating patients with newly diagnosed CBF AML. Patients with CBF AML, untreated or who received one cytarabine based induction regimen are eligible. Induction regimen comprises of fludarabine 30 mg/m 2 IV days 1- 5, cytarabine 2 g/m 2 IV days 1- 5 (3.5 h after completion of that day9s fludarabine infusion, Gemtuzumab ozogamicin 3 mg/m 2 IV on Day 1, filgrastim (G-CSF) 5 mcg/kg body weight starting day-1 till recovery of absolute neutrophil count (ANC) to 1.0 × 10 9 /L or above (filgrastim is started on day 2 for patients with presenting WBC count > 10 × 10 9 /L). We report on clinical and molecular responses in patients enrolled in this study. Extracted RNA is reverse transcribed and analyzed by real-time quantitative PCR for the fusion transcript associated with CBF leukemias. Values are expressed as a percentage of fusion transcript to normalizing ABL transcripts. The sensitivity of detection is approximately 1 in 100,000 for AML1-ETO and 1 in 10,000 for CBFb-MYH11. Results: Thirty-four (Inv 16=10/t 8;21=24) patients (male=20)[median age 48 years (range, 29-73)]have been treated to date with a median follow-up of 11 months (range,1-24). Patient characteristics at presentation include median WBC 12.3 (range, 1.3-97.2) x 10 9 /L, hemoglobin 9.1 (range, 7.8-11.9) gm/dL, platelet count 22 (range, 6-365) x 10 9 /L. Additional cytogenetic abnormalities were present in 18 patients; +8 and –Y being most frequent. Three patients had kit mutations. Five patients were in complete remission at start (from other ara-C based induction) and except two deaths in induction all others achieved CR or CR with incomplete platelet recovery (CRp). Two patients died in CR from infectious complications. One patient has relapsed (initially resistant to “3=7” regimen). Median pre-treatment value for fusion transcript to Abl ratio by Q-PCR is 100 (range, 100-857). More than 3 log reduction in this median value has sustained post induction/consolidation in follow up evaluations extending up to 9 months at the time of this report. Grade≥3/4 induction toxicities included liver dysfunction (N=3, 9%), atrial fibrillation, pancreatitis, respiratory failure 1 patient each and 2 deaths in induction (one from pulmonary hemorrhage and other from intra-cranial bleed). Conclusion: Induction/consolidation therapy with GO-FLAG regimen in CBF AML results in excellent clinical and molecular response. Accrual and multi-variate comparison with historical regimens used to treat patients with CBF AML at MDACC are ongoing. Disclosures: Off Label Use: Use of Gemtuzumab Ozogamicin in frontline therapy of AML.

  • the role of Gemtuzumab ozogamicin in acute leukaemia therapy
    British Journal of Haematology, 2005
    Co-Authors: Apostolia Maria Tsimberidou, Elihu H Estey, Francis J. Giles, Susan Obrien, Michael J Keating, Hagop M. Kantarjian
    Abstract:

    Gemtuzumab ozogamicin (GO) is an immunoconjugate that binds to CD33 on the surface of acute myeloid leukaemia (AML) blasts and, after internalisation, releases a cytotoxic drug, calicheamicin. GO is approved by the US Food and Drug Administration for the treatment of CD33-positive AML at first relapse in patients 60 years and older who are not candidates for other cytotoxic therapy. GO as a single agent has low antileukaemic activity. When given to patients meeting the criteria noted above, it produces a complete response (CR) rate of only 12%, with another 12% achieving CR with inadequate platelet recovery (CRp). The median survival of patients treated with GO monotherapy is 11·2 months. GO therapy at 9 mg/m2 is complicated with hepatic veno-occlusive disease in 5–10% of patients, particularly prior to or following stem cell transplantation. GO at lower doses combined with chemotherapy as induction or postremission therapy is promising, however, and phase III trials are ongoing. GO is probably most active in acute promyelocytic leukaemia (APL). It is used for induction regimens in high-risk APL and for the elimination of minimal residual APL. Case reports suggest that GO also has activity in CD33-positive acute lymphoblastic leukaemia. In conclusion, single agent GO can induce responses in patients with CD33-positive AML in first recurrence. The future of GO is its use in combination with other cytotoxic agents. Ongoing clinical trials may better define the role of GO combinations, particularly in untreated AML.

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

  • CD33_PGx6_Score Predicts Gemtuzumab Ozogamicin Response in Childhood Acute Myeloid Leukemia: A Report From the Children's Oncology Group.
    JCO precision oncology, 2019
    Co-Authors: Lata Chauhan, Richard Aplenc, Miyoung Shin, Yi-cheng Wang, Michael R. Loken, Jessica A. Pollard, Betsy A. Hirsch, Susana C. Raimondi, Rhonda E. Ries, Irwin D. Bernstein
    Abstract:

    PURPOSEThe US Food and Drug Administration recently announced reapproval of Gemtuzumab ozogamicin (GO) for treatment of CD33-positive acute myeloid leukemia (AML), thus opening up opportunities to ...

  • Gemtuzumab ozogamicin for acute myeloid leukemia
    Blood, 2017
    Co-Authors: Frederick R Appelbaum, Irwin D. Bernstein
    Abstract:

    On 1 September 2017, the US Food and Drug Administration (FDA) approved Gemtuzumab ozogamicin (GO) for the treatment of adults with newly diagnosed CD33+ acute myeloid leukemia and for patients aged ≥2 years with CD33+ acute myeloid leukemia who have experienced a relapse or who have not responded to initial treatment. This signals a new chapter in the long and unusual story of GO, which was the first antibody-drug conjugate approved for human use by the FDA.

  • 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

  • NEOPLASIA
    2016
    Co-Authors: B. Walter, Kelli M Boyle, Irwin D. Bernstein
    Abstract:

    Simultaneously targeting CD45 significantly increases cytotoxicity of the anti-CD33 immunoconjugate, Gemtuzumab ozogamicin, against acute myeloid leukemia (AML) cells and improves survival of mice bearing human AML xenograft

  • cd33 expression and its association with Gemtuzumab ozogamicin response results from the randomized phase iii children s oncology group trial aaml0531
    Journal of Clinical Oncology, 2016
    Co-Authors: Irwin D. Bernstein, Richard Aplenc, Michael R. Loken, Jessica A. Pollard, Betsy A. Hirsch, Susana C. Raimondi, Robert B. Gerbing, Alan S Gamis, Todd A. Alonzo
    Abstract:

    PurposeCD33 is variably expressed on acute myeloid leukemia (AML) blasts and is targeted by Gemtuzumab ozogamicin (GO). GO has shown benefit in both adult and pediatric AML trials, yet limited data exist about whether GO response correlates with CD33 expression level.Patients and MethodsCD33 expression levels were prospectively quantified by multidimensional flow cytometry in 825 patients enrolled in Children’s Oncology Group AAML0531 and correlated with response to GO.ResultsPatients with low CD33 expression (lowest quartile of expression [Q1]) had no benefit with the addition of GO to conventional chemotherapy (relapse risk [RR]: GO 36% v No-GO 34%, P = .731; event-free survival [EFS]: GO 53% v No-GO 58%, P = .456). However, patients with higher CD33 expression (Q2 to Q4) had significantly reduced RR (GO 32% v No-GO 49%, P < .001) and improved EFS (GO 53% v No-GO 41%, P = .005). This differential effect was observed in all risk groups. Specifically, low-risk (LR), intermediate-risk (IR), and high-risk (...

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

  • Gemtuzumab ozogamicin in acute myeloid leukemia
    Leukemia, 2017
    Co-Authors: Colin D Godwin, Roland B Walter, Robert Peter Gale
    Abstract:

    CD33 is variably expressed on leukemia blasts in almost all patients with acute myeloid leukemia (AML) and possibly leukemia stem cells in some. Efforts to target CD33 therapeutically have focused on Gemtuzumab ozogamicin (GO; Mylotarg), an antibody-drug conjugate delivering a DNA-damaging calicheamicin derivative. GO is most effective in acute promyelocytic leukemia but induces remissions in other AML types and received accelerated approval in the US in 2000. However, because a large follow-up study showed no survival improvement and increased early deaths the drug manufacturer voluntarily withdrew the US New Drug Application in 2010. More recently, a meta-analysis of data from several trials reported better survival in adults with favorable- and intermediate-risk cytogenetics but not adverse-risk AML randomized to receive GO along with intensive induction chemotherapy. As a result, GO is being re-evaluated by regulatory agencies. Responses to GO are diverse and predictive biological response markers are needed. Besides cytogenetic risk, ATP-binding cassette transporter activity and possibly CD33 display on AML blasts may predict response, but established clinical assays and prospective validation are lacking. Single-nucleotide polymorphisms in CD33 may also be predictive, most notably rs12459419 where the minor T-allele leads to decreased display of full-length CD33 and preferential translation of a splice variant not recognized by GO. Data from retrospective analyses suggest only patients with the rs12459419 CC genotype may benefit from GO therapy but confirmation is needed. Most important may be markers for AML cell sensitivity to calicheamicin, which varies over 100 000-fold, but useful assays are unavailable. Novel CD33-targeted drugs may overcome some of GO’s limitations but it is currently unknown whether such drugs will be more effective in patients benefitting from GO and/or improve outcomes in patients not benefitting from GO, and what the supportive care requirements will be to enable their safe use.

  • Mcl-1 dependence predicts response to vorinostat and Gemtuzumab ozogamicin in acute myeloid leukemia.
    Leukemia Research, 2014
    Co-Authors: William E. Pierceall, Ryan Lena, Bruno C. Medeiros, Noel Blake, Camille Doykan, Michael Elashoff, Michael H. Cardone, Roland B Walter
    Abstract:

    Abstract Older adults with acute myeloid leukemia (AML) are commonly considered for investigational therapies, which often only benefit subsets of patients. In this study, we assessed whether BH3 profiling of apoptotic functionality could predict outcomes following treatment with vorinostat (histone deacetylase inhibitor) and Gemtuzumab ozogamicin (GO; CD33-targeted immunoconjugate). Flow cytometry of BH3 peptide priming with Noxa (anti-apoptotic protein Mcl-1 modulator) correlated with remission induction ( p  = .026; AUC = 0.83 [CI: 0.65–1.00; p  = .00042]: AUC = 0.88 [CI:0.75–1.00] with age adjustment) and overall survival ( p  = .027 logistic regression; AUC = 0.87 [0.64–1.00; p  = .0017]). This Mcl-1-dependence suggests a pivotal role of Bcl-2 family protein-mediated apoptosis to vorinostat/GO in AML patients.

  • 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).

  • sgn cd33a a novel cd33 targeting antibody drug conjugate using a pyrrolobenzodiazepine dimer is active in models of drug resistant aml
    Blood, 2013
    Co-Authors: May Kung Sutherland, Roland B Walter, Scott C Jeffrey, Patrick J Burke, Changpu Yu, Heather Kostner, Ivan Stone, Maureen Ryan, Django Sussman, Robert P Lyon
    Abstract:

    Outcomes in acute myeloid leukemia (AML) remain unsatisfactory, and novel treatments are urgently needed. One strategy explores antibodies and their drug conjugates, particularly those targeting CD33. Emerging data with Gemtuzumab ozogamicin (GO) demonstrate target validity and activity in some

  • 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, Bruno C. Medeiros, Charles A. Schiffer, 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.

Todd A. Alonzo - One of the best experts on this subject based on the ideXlab platform.

  • Gemtuzumab ozogamicin improves event free survival and reduces relapse in pediatric kmt2a rearranged aml results from the phase iii children s oncology group trial aaml0531
    Journal of Clinical Oncology, 2021
    Co-Authors: Jessica A. Pollard, Richard Aplenc, Michael R. Loken, Robert B. Gerbing, Todd A. Alonzo, Erin M Guest, Lisa Eidenschink Brodersen, Anders E Kolb, Soheil Meshinchi
    Abstract:

    PURPOSEWe investigated the impact of the CD33-targeted agent Gemtuzumab ozogamicin (GO) on survival in pediatric patients with KMT2A-rearranged (KMT2A-r) acute myeloid leukemia (AML) enrolled in th...

  • functional properties of kit mutations are associated with differential clinical outcomes and response to targeted therapeutics in cbf acute myeloid leukemia
    Clinical Cancer Research, 2019
    Co-Authors: Yi-cheng Wang, Michael R. Loken, Rhonda E. Ries, Robert B. Gerbing, Todd A. Alonzo, Katherine Tarlock, Laura Pardo, Tiffany Hylkema
    Abstract:

    Purpose:KIT mutations (KIT+) are common in core binding factor (CBF) AML and have been associated with varying prognostic significance. We sought to define the functional and clinical significance of distinct KIT mutations in CBF pediatric AML. Patients and Methods: Following transfection of exon 17 (E17) and exon 8 (E8) mutations into HEK293 and Ba/F3 cells, KIT phosphorylation, cytokine-independent growth, and response to tyrosine kinase inhibitors (TKI) were evaluated. Clinical outcomes of patients treated on COG AAML0531 (NCT01407757), a phase III study of Gemtuzumab ozogamicin (GO), were analyzed according to mutation status [KIT+ vs. wild-type KIT (KIT−)] and mutation location (E8 vs. E17). Results:KIT mutations were detected in 63 of 205 patients (31%); 22 (35%) involved only E8, 32 (51%) only E17, 6 (10%) both exons, and 3 (5%) alternative exons. Functional studies demonstrated that E17, but not E8, mutations result in aberrant KIT phosphorylation and growth. TKI exposure significantly affected growth of E17, but not E8, transfected cells. Patients with KIT+ CBF AML had overall survival similar to those with KIT− (78% vs. 81%, P = 0.905) but higher relapse rates (RR = 43% vs. 21%; P = 0.005). E17 KIT+ outcomes were inferior to KIT− patients [disease-free survival (DFS), 51% vs. 73%, P = 0.027; RR = 21% vs. 46%, P = 0.007)], although Gemtuzumab ozogamicin abrogated this negative prognostic impact. E8 mutations lacked significant prognostic effect, and GO failed to significantly improve outcome. Conclusions: E17 mutations affect prognosis in CBF AML, as well as response to GO and TKIs; thus, clinical trials using both agents should be considered for KIT+ patients.

  • cd33 expression and its association with Gemtuzumab ozogamicin response results from the randomized phase iii children s oncology group trial aaml0531
    Journal of Clinical Oncology, 2016
    Co-Authors: Irwin D. Bernstein, Richard Aplenc, Michael R. Loken, Jessica A. Pollard, Betsy A. Hirsch, Susana C. Raimondi, Robert B. Gerbing, Alan S Gamis, Todd A. Alonzo
    Abstract:

    PurposeCD33 is variably expressed on acute myeloid leukemia (AML) blasts and is targeted by Gemtuzumab ozogamicin (GO). GO has shown benefit in both adult and pediatric AML trials, yet limited data exist about whether GO response correlates with CD33 expression level.Patients and MethodsCD33 expression levels were prospectively quantified by multidimensional flow cytometry in 825 patients enrolled in Children’s Oncology Group AAML0531 and correlated with response to GO.ResultsPatients with low CD33 expression (lowest quartile of expression [Q1]) had no benefit with the addition of GO to conventional chemotherapy (relapse risk [RR]: GO 36% v No-GO 34%, P = .731; event-free survival [EFS]: GO 53% v No-GO 58%, P = .456). However, patients with higher CD33 expression (Q2 to Q4) had significantly reduced RR (GO 32% v No-GO 49%, P < .001) and improved EFS (GO 53% v No-GO 41%, P = .005). This differential effect was observed in all risk groups. Specifically, low-risk (LR), intermediate-risk (IR), and high-risk (...

  • tet2 mutations are highly associated with runx1 runx1t1 translocations and npmc in childhood aml a report from children s oncology group aaml03p1 aaml0531 and nci cog target aml initiative
    Blood, 2015
    Co-Authors: Matthew A Kutny, Yi-cheng Wang, Rhonda E. Ries, Todd A. Alonzo, Jason E Farrar, Jaime Guidry M Auvil, Malcolm A Smith, Daniela S Gerhard, Tanja M Davidsen, Patee Gesuwan
    Abstract:

    Abnormalities of epigenetic regulatory genes including DNMT3A , IDH1 , IDH2 and TET2 are common in adults with AML. The prevalence of these abnormalities appears to increase with older age, but their impact in pediatric AML is less certain. The Children9s Oncology Group (COG) has previously reported that mutations of DNMT3A , IDH1 and IDH2 are very rare in pediatric patients (Ho et al Leukemia 2010; Ho et al Pediatric Blood and Cancer 2011). In the current study we examined the prevalence and prognostic significance of TET2 gene mutations in a large cohort of pediatric patients with AML. We screened for genomic mutations in the TET2 gene using DNA extracted from diagnostic specimens of 949 pediatric de novo AML patients treated on the COG studies AAML03P1 (N=226) and AAML0531 (N=723). The COG trial AAML03P1 was a phase III pilot study with non-random assignment to Gemtuzumab ozogamicin in combination with multi-agent chemotherapy. AAML0531 was a phase III trial with randomization to Gemtuzumab ozogamicin. The entire coding sequence of TET2 and was amplified and sequenced. Mutational data was correlated with clinical characteristics and outcome data in both univariable and multivariable analyses. Mutations of the TET2 gene were found in 26 of 949 samples (2.7%). Mutations were found across TET2 gene exons 3-11 from amino acid 121 to 1920. There were 14 missense mutations, 8 nonsense mutations, 2 insertion/deletion (in/del) resulting in frame shift and 2 samples with multiple mutations (1 with missense mutation and in/del frameshift; 1 with nonsense mutation and in/del frameshift). There was no significant difference in the age, gender, race or ethnicity of patients with or without TET2 mutations. Patients with TET2 mutations had a higher prevalence of normal cytogenetics than those without a TET2 mutation (44% vs. 22%, P=0.011). There was also a significant association of TET2 mutations with core binding factor leukemia, although the direction of the association differed between t(8;21) and inv(16). Patients with TET2 mutations compared to those without these mutations were more likely to have t(8;21) (53% vs. 17%, P= 0.021) but less likely to have inv(16) (0% vs. 21%, P=0.039). Molecular mutations currently used in risk stratification of pediatric AML were evaluated. There was no association with FLT3/ITD or mutations of CEBPA , but there was a strong association with NPMc+ which is known to confer a favorable prognosis. TET2 mutant patients had a 32% prevalence of NPMc+ compared to only 7% NPMc+ among TET2 non-mutant (P= TET2 mutant patients among the 3 genetic risk groups utilized by the COG (Low Risk= t(8;21), inv(16), NPMc+, or CEBPA mutant; High Risk= Monosomy 7, Monosomy 5/del 5q, or FLT3/ITD; Standard Risk= all others). Comparing patients with and without TET2 mutations, there was no significant difference in overall survival (OS) (5 yr: 77% vs. 65%, P=0.194), event free survival (EFS) (5 yr: 58% vs. 50%, P=0.411) or relapse risk (40% vs. 37%, P=0.772). We performed multivariable analysis of OS and EFS for TET2 mutation status, risk grouping, NPMc+ status and treatment exposure to Gemtuzumab ozogamicin. TET2 mutation status was not predictive of outcome in this multivariable analysis. However, genetic risk group was significantly associated with both OS and EFS and treatment with Gemtuzumab ozogamicin was associated only with EFS (HR 0.824 for patients treated with Gemtuzumab ozogamicin). Due to the strong association of TET2 mutation and NPMc+, we further evaluated Kaplan Meier estimates of EFS of the 4 groups of patients stratified by both TET2 mutation and NPMc+ status and determined that co-occurrence of TET2 mutation does not modify the clinical significance of NPMc+. (Figure 1) This study demonstrates that TET2 gene mutations are not common events in childhood AML but are highly associated with NPMc+ and may hint at potential cooperation of genetic and epigenetic factors that mediate myeloid leukemogenesis. The authors would like to gratefully acknowledge the important contributions of the late Dr. Robert Arceci to the AML TARGET initiative. Disclosures Off Label Use: Arsenic Trioxide in pediatric patients with newly diagnosed APL. Gemtuzumab Ozogamicin in Pediatric AML..

  • Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event free survival by reducing relapse risk results from the randomized phase iii children s oncology group trial aaml0531
    Journal of Clinical Oncology, 2014
    Co-Authors: Alan S Gamis, Betsy A. Hirsch, Susana C. Raimondi, Robert B. Gerbing, Todd A. Alonzo, Soheil Meshinchi, Lillian Sung, Samir B Kahwash, Amy Heeremamckenney, Laura Winter
    Abstract:

    Purpose To improve survival rates in children with acute myeloid leukemia (AML), we evaluated Gemtuzumab-ozogamicin (GO), a humanized immunoconjugate targeted against CD33, as an alternative to further chemotherapy dose escalation. Our primary objective was to determine whether adding GO to standard chemotherapy improved event-free survival (EFS) and overall survival (OS) in children with newly diagnosed AML. Our secondary objectives examined outcomes by risk group and method of intensification. Patients and Methods Children, adolescents, and young adults ages 0 to 29 years with newly diagnosed AML were enrolled onto Children's Oncology Group trial AAML0531 and then were randomly assigned to either standard five-course chemotherapy alone or to the same chemotherapy with two doses of GO (3 mg/m2/dose) administered once in induction course 1 and once in intensification course 2 (two of three). Results There were 1,022 evaluable patients enrolled. GO significantly improved EFS (3 years: 53.1% v 46.9%; hazard...