Marie Sebert - Academia.edu (original) (raw)

Papers by Marie Sebert

Research paper thumbnail of Erlotinib Increases Efficacy of 5-Azacitidine (AZA) by Inhibiting Drug Efflux Via ABC-Transporters

Ash Annual Meeting Abstracts, Nov 19, 2010

Research paper thumbnail of Myelodysplastic syndromes with single neutropenia or thrombocytopenia are rarely refractory cytopenias with unilineage dysplasia by World Health Organization 2008 criteria and have favourable prognosis

British Journal of Haematology, 2016

Research paper thumbnail of Azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities

American journal of hematology, Jan 25, 2015

Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dis... more Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high-risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic sub-group. . We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI-1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non-complex cyto...

Research paper thumbnail of Combination therapy with ruxolitinib plus intensive treatment strategy is feasible in patients with blast-phase myeloproliferative neoplasms

British Journal of Haematology, 2015

Research paper thumbnail of A phase I/II trial of Erlotinib in higher risk myelodysplastic syndromes and acute myeloid leukemia after azacitidine failure

Leukemia Research, 2014

Survival after azacitidine (AZA) failure in higher-risk myelodysplastic syndromes (MDS) is poor a... more Survival after azacitidine (AZA) failure in higher-risk myelodysplastic syndromes (MDS) is poor and new treatment options are needed. Erlotinib, an oral inhibitor of the epidermal-growth-factor-receptor (EGFR), has shown in preclinical models some efficacy in higher risk MDS and acute myeloid leukemia (AML). In this phase I/II trial, 30 patients received 100mg/day (n=5) or 150mg/day (n=25) of Erlotinib orally after primary or secondary resistance to AZA treatment. Eighteen MDS and 12 AML patients were treated. This outpatient treatment was well tolerated with limited grade III-IV extra hematological toxicities (skin (n=1), and diarrhea (n=3). Response was observed in 6 patients (20%) including 1 complete remission (CR), 1 marrow CR and 4 hematological improvement (2 erythroid and 2 on platelets). Median duration of response was 5 months. Erlotinib appears to induce a significant number of responses in higher risk MDS/AML having failed AZA treatment. Given the good safety profile of Erlotinib, its combination with other drugs could be tested in the future in MDS and AML.

Research paper thumbnail of 188 The EGFR-inhibitor erlotinib sensitizes MDS derived cells to chemotherapeutic agents by increasing their intracellular retention via modulation of ABC-transporters

Research paper thumbnail of Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine

Leukemia Research, 2014

TP53 mutations are found in 5-10% of MDS and AML, where they are generally associated with comple... more TP53 mutations are found in 5-10% of MDS and AML, where they are generally associated with complex karyotype and an overall poor prognosis. However, the impact of TP53 mutations in MDS treated with azacitidine (AZA) remains unclear. We analyzed TP53 mutations in 62 patients with high risk MDS or AML treated with AZA. A TP53 mutation was found in 23 patients (37.1%), associated with complex karyotype in 18 (78.3%) of them. TP53 mutations had no significant impact on response or complete response to AZA (p=0.60 and p=0.26, respectively). By univariate analysis, OS was negatively influenced by the presence of TP53 mutation (median OS 12.4 months versus 23.7 months, p<10(-4)), abnormal cytogenetics (median OS 14.4 months vs 33 months, p=0.02) complex cytogenetics (median OS 12.7 months versus 23.7 months, p=0.0005), and a diagnosis of AML (median 14.5 months vs 21.2 months for MDS or CMML, p=0.02). By multivariate analysis, only TP53 mutational status (HR 2.89 (95% confidence interval 1.38-6.04; p=0.005) retained statistical significance for OS. Results were similar when the analysis was restricted to MDS and CMML patients, excluding AML (HR=2.46 (95% confidence interval: 1.1-6.4); p=0.04)). Thus, TP53 mutations strongly correlated with poorer survival in higher risk MDS and AML treated with AZA.

Research paper thumbnail of Treatment by Lenalidomide in lower risk myelodysplastic syndrome with 5q deletion—The GFM experience

Leukemia Research, 2011

L. Adès). low or intermediate 1 ("lower risk") groups of the International Prognostic scoring sys... more L. Adès). low or intermediate 1 ("lower risk") groups of the International Prognostic scoring system (IPSS) [1], by a female predominance (unlike other MDS), severe anemia, normal or elevated platelet counts, abnormal large monolobulated megakaryocytes, generally isolated del 5q, and are considered to have relatively rare progression to AML and prolonged survival .

Research paper thumbnail of P149 Treatment of high risk MDS and AML post-MDS with azacytidine (AZA): current results of the French ATU program

Research paper thumbnail of P114 Treatment of lower risk MDS with del 5q by lenalidomide (LEN), with or without G-CSF: current results of the French Patient Named Program (ATU)

Research paper thumbnail of 165 Synergistic effects on apoptosis in higher risk MDS by combining azacitidine (AZA) and the EGFR-tyrosine kinase inhibitor erlotinib

Research paper thumbnail of 189 Hypomethylating agents induce apoptosis and cell cycle arrest with a concomitant activation of p53-dependent signalling pathways and Foxo3a activation

Research paper thumbnail of Treatment with lenalidomide does not appear to increase the risk of progression in lower risk myelodysplastic syndromes with 5q deletion. A comparative analysis by the Groupe Francophone des Myelodysplasies

Haematologica, 2012

Although lenalidomide is very effective in the treatment of anemia of lower risk myelodysplastic ... more Although lenalidomide is very effective in the treatment of anemia of lower risk myelodysplastic syndromes with 5q deletion (del 5q), concerns have been raised over the fact that this drug could trigger progression to acute myeloid leukemia in some patients.

Research paper thumbnail of Treatment for metastatic malignant melanoma: Old drugs and new strategies

Critical Reviews in Oncology/Hematology, 2010

Research paper thumbnail of Hypomethylating agents reactivate FOXO3A in acute myeloid leukemia

Cell Cycle, 2011

the deregulation of the DNA damage response (DDR) can contribute to leukemogenesis and favor the ... more the deregulation of the DNA damage response (DDR) can contribute to leukemogenesis and favor the progression from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). Since hypomethylating agents-notably azacitidineconstitute an efficient therapy for patients with high-risk MDS, we assessed whether such compounds can activate the DDR in malignant blasts. While azacitidine and decitabine had moderate effects on apoptosis and cell cycle progression, both agents induced profound changes in the expression and functionality of DDR-related proteins. Decitabine-and to a lesser degree azacitidine-induced the activation of checkpoint kinases Chk-1 and Chk-2, and the phosphorylation of the DDR-sensor H2AX. In addition, hypomethylating agents were found to cause the dephosphorylation of the transcriptional regulator forkhead box o3, best known as FoXo3A, whose phosphorylation has been related to poor prognosis in AML. the dephosphorylation of FoXo3A induced by azacitidine or decitabine in malignant blasts was accompanied by the translocation of FoXo3A from the cytoplasm to the nucleus. Upon stimulation with azacitidine, MDS/AML-derived, azacitidine-sensitive SKM-1S cells upregulated FoXo3A and the pro-apoptotic FoXo3A targets BIM and pUMA, and this effect was attenuated or abolished in azacitidine-resistant SMK-1R cells. Altogether, our results suggest that the re-activation of FoXo3A may contribute to the effects of hypomethylating agents in malignant blasts.

Research paper thumbnail of Tyrosine kinase inhibitors for the treatment of acute myeloid leukemia: Delineation of anti-leukemic mechanisms of action

Biochemical Pharmacology, 2011

Initially, tyrosine kinase inhibitors (TKIs) were developed as targeted therapies that would sole... more Initially, tyrosine kinase inhibitors (TKIs) were developed as targeted therapies that would solely interfere with aberrant tyrosine kinase activation in malignant cells. Nevertheless, preclinical and clinical studies demonstrated that TKI also exhibit "off-target" effects, that is effects not mediated by the assumed mechanisms of action. We and others showed that the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib exert potent antineoplastic effects on EGFR-negative myeloblasts from patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Here, we undertook a side-by-side comparison of the anti-leukemic efficacy of four different TKI in MDS and AML. Besides the EGFR inhibitor erlotinib, which served as a point of reference, we employed the dual EGFR/HER2 TKI lapatinib, as well as the multikinase inhibitors dasatinib and sorafenib. All four drugs had anti-leukemic effects on cell line models of MDS/AML in vitro as well as on malignant blasts from MDS/AML patients ex vivo. We explored the biological phenomena underlying this anti-leukemic efficacy. Since it is established that a therapeutic benefit in MDS/AML can be conveyed by induction of cell cycle arrest, apoptosis and/or differentiation, we deciphered the individual contribution of these three phenomena to the anti-leukemic action of each of the four TKI. The concomitant assessment of the panel of TKI enables us thus to define (and quantify) their differential capacity to impact on the three biological phenomena, and provide further evidence that these mechanisms are not solely explained by on-target effects.

Research paper thumbnail of Risk of AML Evolution In Lower Risk MDS with Del 5q Treated with or without Lenalidomide. A Report by the Groupe Francophone Des Myelodysplasies (GFM)

Ash Annual Meeting Abstracts, Nov 19, 2010

Research paper thumbnail of Erlotinib Increases Efficacy of 5-Azacitidine (AZA) by Inhibiting Drug Efflux Via ABC-Transporters

Ash Annual Meeting Abstracts, Nov 19, 2010

Research paper thumbnail of Myelodysplastic syndromes with single neutropenia or thrombocytopenia are rarely refractory cytopenias with unilineage dysplasia by World Health Organization 2008 criteria and have favourable prognosis

British Journal of Haematology, 2016

Research paper thumbnail of Azacitidine treatment for patients with myelodysplastic syndrome and acute myeloid leukemia with chromosome 3q abnormalities

American journal of hematology, Jan 25, 2015

Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dis... more Acute Myeloid Leukemia (AML) and myelodysplasia (MDS) with chromosome 3q abnormalities have a dismal outcome either untreated or with conventional treatments. Azacitidine (AZA) is now considered as the standard of care in high-risk MDS and oligoblastic AML patients. The objective of this study was to evaluate the impact of azacitine treatment in this cytogenetic sub-group. . We report here a multicentre retrospective study of 157 patients treated with AZA for AML/MDS with chromosome 3q abnormalities and 27 patients with isolated EVI-1 overexpression. Median age was 65 years, 40 patients (25%) had inv(3)(q21q26.2) or t(3;3)(q21;q26.2), 36 patients (23%) had other balanced 3q26 rearrangements, 8 patients (5%) had balanced 3q21 rearrangements and 73 patients (46%) had other 3q abnormalities. The overall response rate was 50% (29% CR). Median overall survival was 10.6 months. By multivariate analysis, patients with lower bone marrow blast counts, higher platelet counts, non-complex cyto...

Research paper thumbnail of Combination therapy with ruxolitinib plus intensive treatment strategy is feasible in patients with blast-phase myeloproliferative neoplasms

British Journal of Haematology, 2015

Research paper thumbnail of A phase I/II trial of Erlotinib in higher risk myelodysplastic syndromes and acute myeloid leukemia after azacitidine failure

Leukemia Research, 2014

Survival after azacitidine (AZA) failure in higher-risk myelodysplastic syndromes (MDS) is poor a... more Survival after azacitidine (AZA) failure in higher-risk myelodysplastic syndromes (MDS) is poor and new treatment options are needed. Erlotinib, an oral inhibitor of the epidermal-growth-factor-receptor (EGFR), has shown in preclinical models some efficacy in higher risk MDS and acute myeloid leukemia (AML). In this phase I/II trial, 30 patients received 100mg/day (n=5) or 150mg/day (n=25) of Erlotinib orally after primary or secondary resistance to AZA treatment. Eighteen MDS and 12 AML patients were treated. This outpatient treatment was well tolerated with limited grade III-IV extra hematological toxicities (skin (n=1), and diarrhea (n=3). Response was observed in 6 patients (20%) including 1 complete remission (CR), 1 marrow CR and 4 hematological improvement (2 erythroid and 2 on platelets). Median duration of response was 5 months. Erlotinib appears to induce a significant number of responses in higher risk MDS/AML having failed AZA treatment. Given the good safety profile of Erlotinib, its combination with other drugs could be tested in the future in MDS and AML.

Research paper thumbnail of 188 The EGFR-inhibitor erlotinib sensitizes MDS derived cells to chemotherapeutic agents by increasing their intracellular retention via modulation of ABC-transporters

Research paper thumbnail of Prognostic value of TP53 gene mutations in myelodysplastic syndromes and acute myeloid leukemia treated with azacitidine

Leukemia Research, 2014

TP53 mutations are found in 5-10% of MDS and AML, where they are generally associated with comple... more TP53 mutations are found in 5-10% of MDS and AML, where they are generally associated with complex karyotype and an overall poor prognosis. However, the impact of TP53 mutations in MDS treated with azacitidine (AZA) remains unclear. We analyzed TP53 mutations in 62 patients with high risk MDS or AML treated with AZA. A TP53 mutation was found in 23 patients (37.1%), associated with complex karyotype in 18 (78.3%) of them. TP53 mutations had no significant impact on response or complete response to AZA (p=0.60 and p=0.26, respectively). By univariate analysis, OS was negatively influenced by the presence of TP53 mutation (median OS 12.4 months versus 23.7 months, p<10(-4)), abnormal cytogenetics (median OS 14.4 months vs 33 months, p=0.02) complex cytogenetics (median OS 12.7 months versus 23.7 months, p=0.0005), and a diagnosis of AML (median 14.5 months vs 21.2 months for MDS or CMML, p=0.02). By multivariate analysis, only TP53 mutational status (HR 2.89 (95% confidence interval 1.38-6.04; p=0.005) retained statistical significance for OS. Results were similar when the analysis was restricted to MDS and CMML patients, excluding AML (HR=2.46 (95% confidence interval: 1.1-6.4); p=0.04)). Thus, TP53 mutations strongly correlated with poorer survival in higher risk MDS and AML treated with AZA.

Research paper thumbnail of Treatment by Lenalidomide in lower risk myelodysplastic syndrome with 5q deletion—The GFM experience

Leukemia Research, 2011

L. Adès). low or intermediate 1 ("lower risk") groups of the International Prognostic scoring sys... more L. Adès). low or intermediate 1 ("lower risk") groups of the International Prognostic scoring system (IPSS) [1], by a female predominance (unlike other MDS), severe anemia, normal or elevated platelet counts, abnormal large monolobulated megakaryocytes, generally isolated del 5q, and are considered to have relatively rare progression to AML and prolonged survival .

Research paper thumbnail of P149 Treatment of high risk MDS and AML post-MDS with azacytidine (AZA): current results of the French ATU program

Research paper thumbnail of P114 Treatment of lower risk MDS with del 5q by lenalidomide (LEN), with or without G-CSF: current results of the French Patient Named Program (ATU)

Research paper thumbnail of 165 Synergistic effects on apoptosis in higher risk MDS by combining azacitidine (AZA) and the EGFR-tyrosine kinase inhibitor erlotinib

Research paper thumbnail of 189 Hypomethylating agents induce apoptosis and cell cycle arrest with a concomitant activation of p53-dependent signalling pathways and Foxo3a activation

Research paper thumbnail of Treatment with lenalidomide does not appear to increase the risk of progression in lower risk myelodysplastic syndromes with 5q deletion. A comparative analysis by the Groupe Francophone des Myelodysplasies

Haematologica, 2012

Although lenalidomide is very effective in the treatment of anemia of lower risk myelodysplastic ... more Although lenalidomide is very effective in the treatment of anemia of lower risk myelodysplastic syndromes with 5q deletion (del 5q), concerns have been raised over the fact that this drug could trigger progression to acute myeloid leukemia in some patients.

Research paper thumbnail of Treatment for metastatic malignant melanoma: Old drugs and new strategies

Critical Reviews in Oncology/Hematology, 2010

Research paper thumbnail of Hypomethylating agents reactivate FOXO3A in acute myeloid leukemia

Cell Cycle, 2011

the deregulation of the DNA damage response (DDR) can contribute to leukemogenesis and favor the ... more the deregulation of the DNA damage response (DDR) can contribute to leukemogenesis and favor the progression from myelodysplastic syndrome (MDS) to acute myeloid leukemia (AML). Since hypomethylating agents-notably azacitidineconstitute an efficient therapy for patients with high-risk MDS, we assessed whether such compounds can activate the DDR in malignant blasts. While azacitidine and decitabine had moderate effects on apoptosis and cell cycle progression, both agents induced profound changes in the expression and functionality of DDR-related proteins. Decitabine-and to a lesser degree azacitidine-induced the activation of checkpoint kinases Chk-1 and Chk-2, and the phosphorylation of the DDR-sensor H2AX. In addition, hypomethylating agents were found to cause the dephosphorylation of the transcriptional regulator forkhead box o3, best known as FoXo3A, whose phosphorylation has been related to poor prognosis in AML. the dephosphorylation of FoXo3A induced by azacitidine or decitabine in malignant blasts was accompanied by the translocation of FoXo3A from the cytoplasm to the nucleus. Upon stimulation with azacitidine, MDS/AML-derived, azacitidine-sensitive SKM-1S cells upregulated FoXo3A and the pro-apoptotic FoXo3A targets BIM and pUMA, and this effect was attenuated or abolished in azacitidine-resistant SMK-1R cells. Altogether, our results suggest that the re-activation of FoXo3A may contribute to the effects of hypomethylating agents in malignant blasts.

Research paper thumbnail of Tyrosine kinase inhibitors for the treatment of acute myeloid leukemia: Delineation of anti-leukemic mechanisms of action

Biochemical Pharmacology, 2011

Initially, tyrosine kinase inhibitors (TKIs) were developed as targeted therapies that would sole... more Initially, tyrosine kinase inhibitors (TKIs) were developed as targeted therapies that would solely interfere with aberrant tyrosine kinase activation in malignant cells. Nevertheless, preclinical and clinical studies demonstrated that TKI also exhibit "off-target" effects, that is effects not mediated by the assumed mechanisms of action. We and others showed that the epidermal growth factor receptor (EGFR) inhibitors erlotinib and gefitinib exert potent antineoplastic effects on EGFR-negative myeloblasts from patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Here, we undertook a side-by-side comparison of the anti-leukemic efficacy of four different TKI in MDS and AML. Besides the EGFR inhibitor erlotinib, which served as a point of reference, we employed the dual EGFR/HER2 TKI lapatinib, as well as the multikinase inhibitors dasatinib and sorafenib. All four drugs had anti-leukemic effects on cell line models of MDS/AML in vitro as well as on malignant blasts from MDS/AML patients ex vivo. We explored the biological phenomena underlying this anti-leukemic efficacy. Since it is established that a therapeutic benefit in MDS/AML can be conveyed by induction of cell cycle arrest, apoptosis and/or differentiation, we deciphered the individual contribution of these three phenomena to the anti-leukemic action of each of the four TKI. The concomitant assessment of the panel of TKI enables us thus to define (and quantify) their differential capacity to impact on the three biological phenomena, and provide further evidence that these mechanisms are not solely explained by on-target effects.

Research paper thumbnail of Risk of AML Evolution In Lower Risk MDS with Del 5q Treated with or without Lenalidomide. A Report by the Groupe Francophone Des Myelodysplasies (GFM)

Ash Annual Meeting Abstracts, Nov 19, 2010