18 results on '"Baldus, Claudia D."'
Search Results
2. Impact of IDH1 and IDH2 mutational subgroups in AML patients after allogeneic stem cell transplantation
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Kunadt, Desiree, Stasik, Sebastian, Metzeler, Klaus H., Röllig, Christoph, Schliemann, Christoph, Greif, Philipp A., Spiekermann, Karsten, Rothenberg-Thurley, Maja, Krug, Utz, Braess, Jan, Krämer, Alwin, Hochhaus, Andreas, Scholl, Sebastian, Hilgendorf, Inken, Brümmendorf, Tim H., Jost, Edgar, Steffen, Björn, Bug, Gesine, Einsele, Hermann, Görlich, Dennis, Sauerland, Cristina, Schäfer-Eckart, Kerstin, Krause, Stefan W., Hänel, Mathias, Hanoun, Maher, Kaufmann, Martin, Wörmann, Bernhard, Kramer, Michael, Sockel, Katja, Egger-Heidrich, Katharina, Herold, Tobias, Ehninger, Gerhard, Burchert, Andreas, Platzbecker, Uwe, Berdel, Wolfgang E., Müller-Tidow, Carsten, Hiddemann, Wolfgang, Serve, Hubert, Stelljes, Matthias, Baldus, Claudia D., Neubauer, Andreas, Schetelig, Johannes, Thiede, Christian, Bornhäuser, Martin, Middeke, Jan M., and Stölzel, Friedrich
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- 2022
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3. Molecular profiling and clinical implications of patients with acute myeloid leukemia and extramedullary manifestations
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Eckardt, Jan-Niklas, Stölzel, Friedrich, Kunadt, Desiree, Röllig, Christoph, Stasik, Sebastian, Wagenführ, Lisa, Jöhrens, Korinna, Kuithan, Friederike, Krämer, Alwin, Scholl, Sebastian, Hochhaus, Andreas, Crysandt, Martina, Brümmendorf, Tim H., Naumann, Ralph, Steffen, Björn, Kunzmann, Volker, Einsele, Hermann, Schaich, Markus, Burchert, Andreas, Neubauer, Andreas, Schäfer-Eckart, Kerstin, Schliemann, Christoph, Krause, Stefan W., Herbst, Regina, Hänel, Mathias, Hanoun, Maher, Kaiser, Ulrich, Kaufmann, Martin, Rácil, Zdenek, Mayer, Jiri, Kroschinsky, Frank, Berdel, Wolfgang E., Ehninger, Gerhard, Serve, Hubert, Müller-Tidow, Carsten, Platzbecker, Uwe, Baldus, Claudia D., Schetelig, Johannes, Bornhäuser, Martin, Thiede, Christian, and Middeke, Jan Moritz
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- 2022
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4. Safety and tolerability of AMG 330 in adults with relapsed/refractory AML: a phase 1a dose-escalation study.
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Ravandi, Farhad, Subklewe, Marion, Walter, Roland B., Vachhani, Pankit, Ossenkoppele, Gert, Buecklein, Veit, Döhner, Hartmut, Jongen-Lavrencic, Mojca, Baldus, Claudia D., Fransecky, Lars, Pardee, Timothy S., Kantarjian, Hagop, Yen, Priscilla K., Mukundan, Lata, Panwar, Bharat, Yago, Marc R., Agarwal, Suresh, Khaldoyanidi, Sophia K., and Stein, Anthony
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CYTOKINE release syndrome ,ACUTE myeloid leukemia ,ADVERSE health care events ,CANCER remission ,CYTOTOXINS - Abstract
AMG 330, a bispecific T-cell engager (BiTE®) that binds CD33 and CD3 on T cells facilitates T-cell–mediated cytotoxicity against CD33+ cells. This first-in-human, open-label, dose-escalation study evaluated the safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of AMG 330 in adults with relapsed/refractory acute myeloid leukemia (R/R AML). Amongst 77 patients treated with AMG 330 (0.5 µg/day–1.6 mg/day) on 14-day or 28-day cycles, maximum tolerated dose was not reached; median duration of treatment was 29 days. The most frequent treatment-related adverse events were cytokine release syndrome (CRS; 78%) and rash (30%); 10% of patients experienced grade 3/4 CRS. CRS was mitigated with stepwise dosing of AMG 330, prophylactic dexamethasone, and early treatment with tocilizumab. Among 60 evaluable patients, eight achieved complete remission or morphologic leukemia-free state; of the 52 non-responders, 37% had ≥50% reduction in AML bone marrow blasts. AMG 330 is a promising CD33-targeted therapeutic strategy for R/R AML. [ABSTRACT FROM AUTHOR]
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- 2024
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5. Gemtuzumab ozogamicin plus midostaurin in combination with standard '7 + 3' induction therapy in newly diagnosed AML: Results from the SAL‐MODULE phase I study.
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Röllig, Christoph, Schliemann, Christoph, Ruhnke, Leo, Fransecky, Lars, Heydrich, Björn‐Niklas, Hanoun, Maher, Noppeney, Richard, Schäfer‐Eckart, Kerstin, Wendelin, Knut, Mikesch, Jan‐Henrik, Middeke, Jan Moritz, Reimann, Manja, Fiebig, Frank, Zukunft, Sven, Wermke, Martin, Serve, Hubert, Platzbecker, Uwe, Müller‐Tidow, Carsten, Baldus, Claudia D., and Bornhäuser, Martin
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ACUTE myeloid leukemia ,LEUKEMIA - Abstract
Summary: We conducted a phase I trial in newly diagnosed acute myeloid leukaemia (AML) to investigate the combination of two novel targeted agents, gemtuzumab ozogamicin (GO) and midostaurin, with intensive chemotherapy in FLT3‐mutated AML and CBF leukaemia. Three dose levels of midostaurin and one to three sequential doses of 3 mg/m2 GO in combination with '7 + 3' induction were evaluated. Based on safety findings in 12 patients, our results show that 3 mg/m2 GO on Days 1 + 4 and 100 mg midostaurin on Days 8–21 can be safely combined with IC in newly diagnosed AML. [ABSTRACT FROM AUTHOR]
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- 2024
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6. Rationale and design of the 2 by 2 factorial design GnG-trial: a randomized phase-III study to compare two schedules of gemtuzumab ozogamicin as adjunct to intensive induction therapy and to compare double-blinded intensive postremission therapy with or without glasdegib in older patients with newly diagnosed AML
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Jaramillo, Sonia, Krisam, Johannes, Le Cornet, Lucian, Kratzmann, Markus, Baumann, Lukas, Sauer, Tim, Crysandt, Martina, Rank, Andreas, Behringer, Dirk, Teichmann, Lino, Görner, Martin, Trappe, Ralf-Ulrich, Röllig, Christoph, Krause, Stefan, Hanoun, Maher, Hopfer, Olaf, Held, Gerhard, Buske, Sebastian, Fransecky, Lars, Kayser, Sabine, Schliemann, Christoph, Schaefer-Eckart, Kerstin, Al-Fareh, Yousef, Schubert, Jörg, Geer, Thomas, Kaufmann, Martin, Brecht, Arne, Niemann, Dirk, Kieser, Meinhard, Bornhäuser, Martin, Platzbecker, Uwe, Serve, Hubert, Baldus, Claudia D., Müller-Tidow, Carsten, and Schlenk, Richard F.
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- 2021
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7. Loss-of-function mutations of bcor are an independent marker of adverse outcomes in intensively treated patients with acute myeloid leukemia
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Eckardt, Jan-Niklas, Stasik, Sebastian, Kramer, Michael, Röllig, Christoph, Krämer, Alwin, Scholl, Sebastian, Hochhaus, Andreas, Crysandt, Martina, Brümmendorf, Tim H., Naumann, Ralph, Steffen, Björn, Kunzmann, Volker, Einsele, Hermann, Schaich, Markus, Burchert, Andreas, Neubauer, Andreas, Schäfer-Eckart, Kerstin, Schliemann, Christoph, Krause, Stefan W., Herbst, Regina, Hänel, Mathias, Frickhofen, Norbert, Noppeney, Richard, Kaiser, Ulrich, Baldus, Claudia D., Kaufmann, Martin, Rácil, Zdenek, Platzbecker, Uwe, Berdel, Wolfgang E., Mayer, Jiří, Serve, Hubert, Müller-Tidow, Carsten, Ehninger, Gerhard, Stölzel, Friedrich, Kroschinsky, Frank, Schetelig, Johannes, Bornhäuser, Martin, Thiede, Christian, and Middeke, Jan Moritz
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Medizin ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,risk stratification ,acute myeloid leukemia ,BCOR ,survival ,Article ,loss-of-function ,hemic and lymphatic diseases ,ddc:610 ,BCORL1 ,RC254-282 - Abstract
Cancers 13(9), 2095 (2021). doi:10.3390/cancers13092095, Published by MDPI, Basel
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- 2021
8. Point Mutations in the FLT3 -ITD Region Are Rare but Recurrent Alterations in Adult AML and Associated With Concomitant KMT2A -PTD.
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Stasik, Sebastian, Kramer, Michael, Zukunft, Sven, Röllig, Christoph, Baldus, Claudia D., Platzbecker, Uwe, Serve, Hubert, Müller-Tidow, Carsten, Schäfer-Eckart, Kerstin, Kaufmann, Martin, Krause, Stefan, Sauer, Tim, Hänel, Mathias, Neubauer, Andreas, Ehninger, Gerhard, Bornhäuser, Martin, Schetelig, Johannes, Middeke, Jan M., and Thiede, Christian
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ACUTE myeloid leukemia ,DELETION mutation ,BONE marrow cells ,MOLECULAR association ,NUCLEOTIDE sequencing - Abstract
FLT3 -ITD mutations are common druggable alterations in patients with acute myeloid leukemia (AML) and associated with poor prognosis. Beside typical ITD mutations, point mutations and deletions in the juxtamembrane domain (JMD) have been observed. However, due to the low frequency of these alterations, there is only limited information on molecular and clinical associations. To evaluate the prognostic impact of non-ITD mutations in the FLT3 JMD region, we analyzed a large cohort of 1,539 adult AML patients treated in different protocols of the Study Alliance Leukemia, using next-generation sequencing. Non-ITD point mutations and deletions within the FLT3 JMD were identified with a prevalence of ~1.23% (n = 19). Both FLT3 -ITD and non-ITD mutations were associated with a higher rate of NPM1 (42%–61%; p < 0.001) and DNMT3A mutations (37%–43%; p < 0.001), as well as an increased percentage of peripheral blood (54%–65%) and bone marrow blast cells (74%; p < 0.001), compared to FLT3 -wild-type patients. Most significantly, AML patients with FLT3 non-ITD mutations had a higher rate of concomitant KMT2A -PTD mutations (37.5%; p < 0.001) as compared to FLT3 -ITD (7%) or FLT3 -wild-type cases (4.5%). In a multivariable analysis, FLT3 non-ITD mutations were not an independent prognostic factor. However, patients with dual FLT3 non-ITD and KMT2A -PTD mutations showed a trend for inferior outcome, which points at a functional interaction in this subset of AML. [ABSTRACT FROM AUTHOR]
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- 2022
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9. TP53 mutation in patients with high-risk acute myeloid leukaemia treated with allogeneic haematopoietic stem cell transplantation.
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Middeke, Jan M., Herold, Sylvia, Rücker‐Braun, Elke, Berdel, Wolfgang E., Stelljes, Matthias, Kaufmann, Martin, Schäfer‐Eckart, Kerstin, Baldus, Claudia D., Stuhlmann, Reingard, Ho, Anthony D., Einsele, Hermann, Rösler, Wolf, Serve, Hubert, Hänel, Mathias, Sohlbach, Kristina, Klesse, Christian, Mohr, Brigitte, Heidenreich, Falk, Stölzel, Friedrich, and Röllig, Christoph
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ACUTE myeloid leukemia ,HEMATOPOIETIC stem cells ,CYTOGENETICS ,PROGNOSIS ,GENETIC mutation ,PATIENTS - Abstract
Treatment success in patients with acute myeloid leukaemia ( AML) is heterogeneous. Cytogenetic and molecular alterations are strong prognostic factors, which have been used to individualize treatment. Here, we studied the impact of TP53 mutations on the outcome of AML patients with adverse cytogenetic risk treated with allogeneic haematopoietic stem cell transplantation ( HSCT). Samples of 97 patients with AML and adverse-risk cytogenetics who had received a HSCT within three randomized trials were analysed. Complete sequencing of the TP53 coding region was performed using next generation sequencing. The median age was 51 years. Overall, TP53 mutations were found in 40 patients (41%). With a median follow up of 67 months, the three-year probabilities of overall survival ( OS) and event-free survival for patients with TP53 wild type were 33% [95% confidence interval ( CI), 21% to 45%] and 24% (95% CI, 13% to 35%) compared to 10% (95% CI, 0% to 19%) and 8% (95% CI, 0% to 16%) ( P = 0·002 and P = 0·007) for those with mutated TP53, respectively. In multivariate analysis, the TP53-mutation status had a negative impact on OS (Hazard Ratio = 1·7; P = 0·066). Mutational analysis of TP53 might be an important additional tool to predict outcome after HSCT in patients with adverse karyotype AML. [ABSTRACT FROM AUTHOR]
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- 2016
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10. ERG Transcriptional Networks in Primary Acute Leukemia Cells Implicate a Role for ERG in Deregulated Kinase Signaling.
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Bock, Juliane, Mochmann, Liliana H., Schlee, Cornelia, Farhadi-Sartangi, Nasrin, Göllner, Stefanie, Müller-Tidow, Carsten, and Baldus, Claudia D.
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GENES ,LEUKEMIA ,ACUTE myeloid leukemia ,IMMUNOPRECIPITATION ,DEPHOSPHORYLATION ,KINASES ,PATIENTS - Abstract
High expression of the E26 transforming sequence related gene (ERG) is associated with poor prognosis in a subgroup of leukemia patients with acute myeloid (AML) and acute T-lymphoblastic leukemia (T-ALL). In a previous study we proposed that ERG overexpression may deregulate several signaling cascades in acute leukemia. Herein, we further expand those studies by identifying a consensus of biological targets in primary blasts of newly diagnosed acute leukemia patients. Our findings of chromatin immunoprecipitation-on-chip of primary samples revealed 48 significantly enriched single genes including DAAM1 and NUMB. Significantly enriched signaling pathways included WNT/b-catenin, p53, and PI3K/AKT with ERG overexpression inducing dephosphorylation of AKT(Ser473) relative to non ERG expressing K562 cells. Cell based ERG overexpression studies also revealed drug resistance to multi-kinase inhibitor, BAY 43-9006 (Sorafenib) and to the tyrosine kinase inhibitor TKI258. Thus in primary leukemic cells, ERG may contribute to the dysregulation of kinase signaling, which results in resistance to kinase inhibitors. [ABSTRACT FROM AUTHOR]
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- 2013
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11. BAALC, a novel marker of human hematopoietic progenitor cells
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Baldus, Claudia D., Tanner, Stephan M., Kusewitt, Donna F., Liyanarachchi, Sandya, Choi, Changsun, Caligiuri, Michael A., Bloomfield, Clara D., and Chapelle, Albert de la
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ACUTE myeloid leukemia , *BLOOD cells , *CLINICAL pathology , *HEMATOPOIESIS - Abstract
: ObjectiveThe gene BAALC (Brain And Acute Leukemia, Cytoplasmic), a novel molecular marker involved in leukemia, is highly expressed in a subset of patients with acute leukemia and predictive of clinical outcome in patients with acute myeloid leukemia and normal karyotype. The role of BAALC in hematopoiesis and leukemogenesis is unknown.: Material and methodsWe used real-time RT-PCR to show that BAALC is strongly expressed in CD34+ cells from the bone marrow and blood and only weakly expressed in total normal bone marrow and blood cells.: ResultsExpression analyses of FACSorted cells revealed high BAALC transcript levels in CD34+ bone marrow cells including CD34+/CD38−, CD34+/CD33+, as well as CD34+/CD19+/CD10+, CD34+/CD7+, and CD34+/CD71+/CD45− cell fractions. Expression was significantly lower in all CD34− fractions. In vitro differentiation of CD34+ bone marrow cells showed downregulation of BAALC and CD34 transcripts as early as day 4 in suspension cultures supplemented with lineage-specific cytokines (G-CSF, M-CSF, or EPO). In cultures with only lineage-unspecific cytokines (IL-3, SCF, GM-CSF), BAALC transcripts persisted up to day 20, while CD34 transcripts disappeared earlier. These observations suggest that expression of BAALC is stage specific.: ConclusionsBAALC expression is restricted to progenitor cells, and downregulation of BAALC occurs with cell differentiation. We postulate that BAALC represents a novel marker of an early progenitor cell common to the myeloid, lymphoid, and erythroid pathways. [Copyright &y& Elsevier]
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- 2003
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12. Measurable residual disease-guided treatment with azacitidine to prevent haematological relapse in patients with myelodysplastic syndrome and acute myeloid leukaemia (RELAZA2): an open-label, multicentre, phase 2 trial.
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Platzbecker, Uwe, Middeke, Jan Moritz, Sockel, Katja, Herbst, Regina, Wolf, Dominik, Baldus, Claudia D, Oelschlägel, Uta, Mütherig, Anke, Fransecky, Lars, Noppeney, Richard, Bug, Gesine, Götze, Katharina S, Krämer, Alwin, Bochtler, Tilmann, Stelljes, Matthias, Groth, Christoph, Schubert, Antje, Mende, Marika, Stölzel, Friedrich, and Borkmann, Christine
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MYELODYSPLASTIC syndromes , *CYCLOPHOSPHAMIDE , *AZACITIDINE , *LEUKEMIA , *CANCER chemotherapy , *CARCINOGENESIS , *ANTIMETABOLITES , *ANTINEOPLASTIC agents , *COMPARATIVE studies , *DRUG administration , *LONGITUDINAL method , *RESEARCH methodology , *MEDICAL cooperation , *RESEARCH , *RISK assessment , *TIME , *DISEASE relapse , *EVALUATION research , *ACUTE myeloid leukemia - Abstract
Background: Monitoring of measurable residual disease (MRD) in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukaemia (AML) who achieve a morphological complete remission can predict haematological relapse. In this prospective study, we aimed to determine whether MRD-guided pre-emptive treatment with azacitidine could prevent relapse in these patients.Methods: The relapse prevention with azacitidine (RELAZA2) study is an open-label, multicentre, phase 2 trial done at nine university health centres in Germany. Patients aged 18 years or older with advanced MDS or AML, who had achieved a complete remission after conventional chemotherapy or allogeneic haemopoietic stem-cell transplantation, were prospectively screened for MRD during 24 months from baseline by either quantitative PCR for mutant NPM1, leukaemia-specific fusion genes (DEK-NUP214, RUNX1-RUNX1T1, CBFb-MYH11), or analysis of donor-chimaerism in flow cytometry-sorted CD34-positive cells in patients who received allogeneic haemopoietic stem-cell transplantation. MRD-positive patients in confirmed complete remission received azacitidine 75 mg/m2 per day subcutaneously on days 1-7 of a 29-day cycle for 24 cycles. After six cycles, MRD status was reassessed and patients with major responses (MRD negativity) were eligible for a treatment de-escalation. The primary endpoint was the proportion of patients who were relapse-free and alive 6 months after the start of pre-emptive treatment. Analyses were done per protocol. This trial is registered with ClincialTrials.gov, number NCT01462578, and finished recruitment on Aug 21, 2018.Findings: Between Oct 10, 2011, and Aug 20, 2015, we screened 198 patients with advanced MDS (n=26) or AML (n=172), of whom 60 (30%) developed MRD during the 24-month screening period and 53 (88%) were eligible to start study treatment. 6 months after initiation of azacitidine, 31 (58%, 95% CI 44-72) of 53 patients were relapse-free and alive (p<0·0001; one-sided binomial test for null hypothesis pexp≤0·3). With a median follow-up of 13 months (IQR 8·5-22·8) after the start of MRD-guided treatment, relapse-free survival at 12 months was 46% (95% CI 32-59) in the 53 patients who were MRD-positive and received azacitidine. In MRD-negative patients, 12-month relapse-free survival was 88% (95% CI 82-94; hazard ratio 6·6 [95% CI 3·7-11·8], p<0·0001). The most common (grade 3-4) adverse event was neutropenia, occurring in 45 (85%) of 53 patients. One patient with neutropenia died because of an infection considered possibly related to study treatment.Interpretation: Pre-emptive therapy with azacitidine can prevent or substantially delay haematological relapse in MRD-positive patients with MDS or AML who are at high risk of relapse. Our study also suggests that continuous MRD negativity during regular MRD monitoring might be prognostic for patient outcomes.Funding: Celgene Pharma, José Carreras Leukaemia Foundation, National Center for Tumor Diseases (NCT), and German Cancer Consortium (DKTK) Foundation. [ABSTRACT FROM AUTHOR]- Published
- 2018
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13. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial.
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Cortes, Jorge, Perl, Alexander E, Döhner, Hartmut, Kantarjian, Hagop, Martinelli, Giovanni, Kovacsovics, Tibor, Rousselot, Philippe, Steffen, Björn, Dombret, Hervé, Estey, Elihu, Strickland, Stephen, Altman, Jessica K, Baldus, Claudia D, Burnett, Alan, Krämer, Alwin, Russell, Nigel, Shah, Neil P, Smith, Catherine C, Wang, Eunice S, and Ifrah, Norbert
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PROTEIN-tyrosine kinases , *ACUTE myeloid leukemia , *GENETIC mutation , *PLATELET count , *PNEUMONIA , *ACUTE myeloid leukemia diagnosis , *THIAZOLES , *UREA , *CANCER relapse , *CLINICAL trials , *COMPARATIVE studies , *DRUG administration , *DRUG dosage , *DOSE-effect relationship in pharmacology , *DRUG toxicity , *INTERNATIONAL relations , *RESEARCH methodology , *MEDICAL cooperation , *ORAL drug administration , *PROGNOSIS , *RESEARCH , *RESEARCH funding , *SURVIVAL , *TRANSFERASES , *EVALUATION research , *TREATMENT effectiveness , *THERAPEUTICS - Abstract
Background: Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia.Methods: We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed.Findings: Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia's formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [<1%]) and hepatic failure (two [1%]). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten [6%] of 157 patients in cohort 1 and eight [5%] of 176 in cohort 2.Interpretation: Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses.Funding: Ambit Biosciences/Daiichi Sankyo. [ABSTRACT FROM AUTHOR]- Published
- 2018
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14. Allogeneic Stem Cell Transplantation Improves Survival in Patients with Acute Myeloid Leukemia Characterized by a High Allelic Ratio of Mutant FLT3-ITD.
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Ho, Anthony D., Schetelig, Johannes, Bochtler, Tilmann, Schaich, Markus, Schäfer-Eckart, Kerstin, Hänel, Mathias, Rösler, Wolf, Einsele, Hermann, Kaufmann, Martin, Serve, Hubert, Berdel, Wolfgang E., Stelljes, Matthias, Mayer, Jiri, Reichle, Albrecht, Baldus, Claudia D., Schmitz, Norbert, Kramer, Michael, Röllig, Christoph, Bornhäuser, Martin, and Thiede, Christian
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STEM cell transplantation , *GRAFT versus host disease , *ACUTE myeloid leukemia , *ALLELES , *GENETIC mutation , *PATIENTS - Abstract
Allogeneic hematopoietic cell transplantation (alloHCT) as a postremission therapy in patients with FLT3-ITD –positive intermediate-risk acute myeloid leukemia (AML) remains controversial. FLT3-ITD mutations are heterogeneous with respect to allelic ratio, location, and length of the insertion, with a high mutant-to-wild-type ratio consistently associated with inferior prognosis. We retrospectively analyzed the role of alloHCT in first remission in relationship to the allelic ratio and presence or absence of nucleophosmin 1 mutations ( NPM1 ) in the Study Alliance Leukemia AML2003 trial. FLT3-ITD mutations were detected in 209 patients and concomitant NPM1 mutations in 148 patients. Applying a predefined cutoff ratio of .8, AML was grouped into high- and low-ratio FLT3-ITD AML (HR FLT3-ITD and LR FLT3-ITD ). Sixty-one patients (29%) were transplanted in first remission. Overall survival (OS) (HR, .3; 95% CI, .16 to .7; P = .004) and event-free survival (EFS) (HR, .4; 95% CI, .16 to .9; P = .02) were significantly increased in patients with HR FLT3-ITD AML who received alloHCT as consolidation treatment compared with patients who received consolidation chemotherapy. Patients with LR FLT3-ITD AML and wild-type NPM1 who received alloHCT in first remission had increased OS (HR, .3; 95% CI, .1 to .8; P = .02) and EFS (HR, .2; 95% CI, .1 to .8; P = .02), whereas alloHCT in first remission did not have a significant impact on OS and EFS in patients with LR FLT3-ITD AML and concomitant NPM1 mutation. In conclusion, our results provide additional evidence that alloHCT in first remission improves EFS and OS in patients with HR FLT3-ITD AML and in patients with LR FLT3-ITD AML and wild-type NPM1 . [ABSTRACT FROM AUTHOR]
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- 2016
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15. Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial.
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Röllig, Christoph, Serve, Hubert, Hüttmann, Andreas, Noppeney, Richard, Müller-Tidow, Carsten, Krug, Utz, Baldus, Claudia D, Brandts, Christian H, Kunzmann, Volker, Einsele, Hermann, Krämer, Alwin, Schäfer-Eckart, Kerstin, Neubauer, Andreas, Burchert, Andreas, Giagounidis, Aristoteles, Krause, Stefan W, Mackensen, Andreas, Aulitzky, Walter, Herbst, Regina, and Hänel, Mathias
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ACUTE myeloid leukemia treatment , *ACUTE myeloid leukemia diagnosis , *SORAFENIB , *AGE factors in disease , *PLACEBOS , *RANDOMIZED controlled trials , *ANTINEOPLASTIC antibiotics , *DAUNOMYCIN , *THERAPEUTIC use of antimetabolites , *CYTARABINE , *AGE distribution , *ANTINEOPLASTIC agents , *COMBINED modality therapy , *COMPARATIVE studies , *HEMATOPOIETIC stem cell transplantation , *HOMOGRAFTS , *RESEARCH methodology , *MEDICAL cooperation , *PROGNOSIS , *RESEARCH , *TIME , *UREA , *VITAMIN B complex , *DISEASE relapse , *EVALUATION research , *ACUTE myeloid leukemia , *TREATMENT effectiveness , *PROPORTIONAL hazards models , *BLIND experiment , *DISEASE progression , *KAPLAN-Meier estimator , *PROTEIN kinase inhibitors , *VITAMIN therapy , *THERAPEUTICS - Abstract
Background: Preclinical data and results from non-randomised trials suggest that the multikinase inhibitor sorafenib might be an effective drug for the treatment of acute myeloid leukaemia. We investigated the efficacy and tolerability of sorafenib versus placebo in addition to standard chemotherapy in patients with acute myeloid leukaemia aged 60 years or younger.Methods: This randomised, double-blind, placebo-controlled, phase 2 trial was done at 25 sites in Germany. We enrolled patients aged 18-60 years with newly diagnosed, previously untreated acute myeloid leukaemia who had a WHO clinical performance score 0-2, adequate renal and liver function, no cardiac comorbidities, and no recent trauma or operation. Patients were randomly assigned (1:1) to receive two cycles of induction therapy with daunorubicin (60 mg/m(2) on days 3-5) plus cytarabine (100 mg/m(2) on days 1-7), followed by three cycles of high-dose cytarabine consolidation therapy (3 g/m(2) twice daily on days 1, 3, and 5) plus either sorafenib (400 mg twice daily) or placebo on days 10-19 of induction cycles 1 and 2, from day 8 of each consolidation, and as maintenance for 12 months. Allogeneic stem-cell transplantation was scheduled for all intermediate-risk patients with a sibling donor and for all high-risk patients with a matched donor in first remission. Computer-generated randomisation was done in blocks. The primary endpoint was event-free survival, with an event defined as either primary treatment failure or relapse or death, assessed in all randomised patients who received at least one dose of study treatment. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00893373, and the EU Clinical Trials Register (2008-004968-40).Findings: Between March 27, 2009, and Nov 28, 2011, 276 patients were enrolled and randomised, of whom nine did not receive study medication. 267 patients were included in the primary analysis (placebo, n=133; sorafenib, n=134). With a median follow-up of 36 months (IQR 35·5-38·1), median event-free survival was 9 months (95% CI 4-15) in the placebo group versus 21 months (9-32) in the sorafenib group, corresponding to a 3-year event-free survival of 22% (95% CI 13-32) in the placebo group versus 40% (29-51) in the sorafenib group (hazard ratio [HR] 0·64, 95% CI; 0·45-0·91; p=0·013). The most common grade 3-4 adverse events in both groups were fever (71 [53%] in the placebo group vs 73 [54%] in the sorafenib group), infections (55 [41%] vs 46 [34%]), pneumonia (21 [16%] vs 20 [14%]), and pain (13 [10%] vs 15 [11%]). Grade 3 or worse adverse events that were significantly more common in the sorafenib group than the placebo group were fever (relative risk [RR] 1·54, 95% CI 1·04-2·28), diarrhoea (RR 7·89, 2·94-25·2), bleeding (RR 3·75, 1·5-10·0), cardiac events (RR 3·46, 1·15-11·8), hand-foot-skin reaction (only in sorafenib group), and rash (RR 4·06, 1·25-15·7).Interpretation: In patients with acute myeloid leukaemia aged 60 years or younger, the addition of sorafenib to standard chemotherapy has antileukaemic efficacy but also increased toxicity. Our findings suggest that kinase inhibitors could be a useful addition to curative treatment for acute myeloid leukaemia. Overall survival after long-term follow-up and strategies to reduce toxicity are needed to determine the future role of sorafenib in treatment of this disease.Funding: Bayer HealthCare. [ABSTRACT FROM AUTHOR]- Published
- 2015
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16. High expression of IGFBP2 is associated with chemoresistance in adult acute myeloid leukemia
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Kühnl, Andrea, Kaiser, Martin, Neumann, Martin, Fransecky, Lars, Heesch, Sandra, Radmacher, Michael, Marcucci, Guido, Bloomfield, Clara D., Hofmann, Wolf-Karsten, Thiel, Eckhard, and Baldus, Claudia D.
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ACUTE myeloid leukemia treatment , *GENE expression , *DRUG resistance , *INSULIN-like growth factor-binding proteins , *MESSENGER RNA , *MULTIVARIATE analysis , *LEUKEMIA etiology , *CANCER chemotherapy - Abstract
Abstract: Insulin-like growth factor (IGF) signaling plays an important role in many tumors and overexpression of IGF Binding Protein (IGFBP) 2 has been associated with adverse outcome in childhood leukemia. Here, we evaluated IGFBP2 mRNA expression and its prognostic implications in 99 adult acute myeloid leukemia (AML) patients by quantitative real-time RT-PCR. High IGFBP2 was associated with a high incidence of primary resistant disease (IGFBP2 high 65%, IGFBP2 low 32%; P =0.02) and was independently predictive for therapy resistance [OR 3.6 (95% CI 1.2–11); P =0.02] in multivariate analyses. Gene-expression profiling revealed an up-regulation of genes implicated in leukemogenesis (MYB, MEIS1, HOXB3, HOXA9) and genes associated with adverse outcome (ERG, WT1) in patients with high IGFBP2 expression. Thus, our data suggest a role of IGFBP2 and IGF signaling in chemoresistance of AML. Patients with high IGFBP2 expression might benefit from molecular therapies targeting the IGF pathway. [Copyright &y& Elsevier]
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- 2011
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17. The role of microRNA-196a and microRNA-196b as ERG regulators in acute myeloid leukemia and acute T-lymphoblastic leukemia
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Coskun, Ebru, von der Heide, Eva Kristin, Schlee, Cornelia, Kühnl, Andrea, Gökbuget, Nicola, Hoelzer, Dieter, Hofmann, Wolf-Karsten, Thiel, Eckhard, and Baldus, Claudia D.
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MYELOID leukemia genetics , *LYMPHOBLASTIC leukemia , *HEMATOPOIESIS , *GENE transfection , *GENE expression , *NON-coding RNA , *GENETICS - Abstract
Abstract: Overexpression of the ETS transcription factor ERG is an adverse prognostic factor in adult patients with acute myeloid leukemia (AML) and T-cell acute lymphoblastic leukemia (T-ALL). We investigated the regulation of ERG by microRNAs and explored their role in hematopoiesis and leukemia. Transfection of precursor molecules of miR-196a and miR-196b induced ERG downregulation and luciferase assays confirmed binding of miR-196a and miR-196b to the ERG 3′UTR. During in vitro differentiation of CD34+ cells, miR-196b expression decreased with time, indicating a role for miR-196b in early hematopoiesis. In AML, patients with NPM1-mutations had higher levels of miR-196a and miR-196b compared to NPM1-wildtype. In T-ALL patients, miR-196a and miR-196b expression was associated with an immature immunophenotype, and expression of CD34 and CD33. In conclusion, our results identify miR-196a and miR-196b as ERG regulators and implicate a potential role for these miRNAs in acute leukemia. [ABSTRACT FROM AUTHOR]
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- 2011
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18. Epigenetic control of differential expression of specific ERG isoforms in acute T-lymphoblastic leukemia
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Bohne, Arend, Schlee, Cornelia, Mossner, Max, Thibaut, Julia, Heesch, Sandra, Thiel, Eckhard, Hofmann, Wolf-Karsten, and Baldus, Claudia D.
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GENETIC regulation , *LYMPHOBLASTIC leukemia , *ACUTE myeloid leukemia , *LEUKEMIA etiology , *METHYLATION , *GENETIC transcription , *PROMOTERS (Genetics) , *PROGNOSIS , *GENETICS - Abstract
Abstract: Expression of ERG is of prognostic significance in acute myeloid leukemia (AML) and T-lymphoblastic leukemia (T-ALL) pointing to its role in leukemogenesis. To unravel its transcriptional regulation we analyzed the expression of ERG specific isoforms. Expression of the two main isoforms ERG2 and ERG3 was found in AML and normal CD34+ cells, whereas T-ALL blasts only expressed ERG isoforms harboring exon 5 (ERG3) lacking expression of ERG2. Bisulfite sequencing revealed hypermethylation of a CpG island within the ERG2 promoter region in T-ALL. Treatment of the T-lymphoblastic cell line BE13 with decitabine led to re-expression of ERG2 and pyrosequencing showed concordant DNA hypomethylation, thus confirming a methylation regulated expression of ERG2. Moreover, the identification of a new ERG isoform (ERG3Δex12) suggests the association with different interaction partners and adds to the complexity of downstream pathways mediated by the expression of specific ERG transcripts in acute leukemia. [Copyright &y& Elsevier]
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- 2009
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