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Daniel J Deangelo - One of the best experts on this subject based on the ideXlab platform.
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A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts
Leukemia, 2017Co-Authors: Guillermo Garcia-manero, H Salman, Carlos Graux, J D Cavenagh, Arpad Illes, Miklos Egyed, Mikkael A Sekeres, Pierre Fenaux, Massimo Breccia, Daniel J DeangeloAbstract:Treatment with azacitidine (AZA), a Demethylating Agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is
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a phase 1b 2b multicenter study of oral panobinostat plus azacitidine in adults with mds cmml or aml with 30 blasts
Leukemia, 2017Co-Authors: G Garciamanero, H Salman, Carlos Graux, J D Cavenagh, Arpad Illes, Miklos Egyed, Mikkael A Sekeres, Pierre Fenaux, Massimo Breccia, Daniel J DeangeloAbstract:Treatment with azacitidine (AZA), a Demethylating Agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel Agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6–43.9%)) vs AZA (14.3% (5.4–28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50–80%); AZA, 70% (50–80%)) or time to progression (PAN+AZA, 70% (40–90%); AZA, 70% (40–80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.
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a phase ib study of oral panobinostat lbh589 administered with 5 azacitidine 5 aza in patients with myelodysplastic syndromes mds chronic myelomonocytic leukemia cmml or acute myeloid leukemia aml
Journal of Clinical Oncology, 2010Co-Authors: Oliver G Ottmann, Daniel J Deangelo, Mikkael A Sekeres, Pierre Fenaux, Michael Lubbert, G Garciamanero, Kapil N Bhalla, F Ludicke, Hansjochen Weber, I J WinigerAbstract:TPS282 Background: The Demethylating Agent 5-Aza is an integral therapy in MDS and AML, in which epigenetic modifications contributing to disease are well-documented. Despite an overall survival benefit, better and earlier responses are needed. Combination of a Demethylating Agent and a deacetylase inhibitor (DACi) is a rational strategy to reverse aberrant epigenetic alterations and the malignant phenotype. Preclinical data indicate that sequential treatment with Demethylating Agents and DACi targets multiple mechanisms to synergistically de-repress silenced genes and exert antileukemic activity. Panobinostat (PAN; LBH589) is a potent pan-DACi that has demonstrated antileukemic activity in patients (pts) with AML and MDS. This phase Ib, open-label, multicenter, dose-finding study comprises 2 phases: a dose-escalation phase to determine the maximum tolerated dose (MTD) of PAN in combination with standard dose 5-Aza, and a subsequent expansion phase to further evaluate safety, tolerability, and antileukemi...
Pierre Fenaux - One of the best experts on this subject based on the ideXlab platform.
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A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts
Leukemia, 2017Co-Authors: Guillermo Garcia-manero, H Salman, Carlos Graux, J D Cavenagh, Arpad Illes, Miklos Egyed, Mikkael A Sekeres, Pierre Fenaux, Massimo Breccia, Daniel J DeangeloAbstract:Treatment with azacitidine (AZA), a Demethylating Agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is
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a phase 1b 2b multicenter study of oral panobinostat plus azacitidine in adults with mds cmml or aml with 30 blasts
Leukemia, 2017Co-Authors: G Garciamanero, H Salman, Carlos Graux, J D Cavenagh, Arpad Illes, Miklos Egyed, Mikkael A Sekeres, Pierre Fenaux, Massimo Breccia, Daniel J DeangeloAbstract:Treatment with azacitidine (AZA), a Demethylating Agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel Agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6–43.9%)) vs AZA (14.3% (5.4–28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50–80%); AZA, 70% (50–80%)) or time to progression (PAN+AZA, 70% (40–90%); AZA, 70% (40–80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.
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transcription intermediary factor 1γ is a tumor suppressor in mouse and human chronic myelomonocytic leukemia
Journal of Clinical Investigation, 2011Co-Authors: Romain Aucagne, Nathalie Droin, Jerome Paggetti, Brice Lagrange, Anne Largeot, Arlette Hammann, Amandine Bataille, Laurent Martin, Kaiping Yan, Pierre FenauxAbstract:Transcription intermediary factor 1γ (TIF1γ) was suggested to play a role in erythropoiesis. However, how TIF1γ regulates the development of different blood cell lineages and whether TIF1γ is involved in human hematological malignancies remain to be determined. Here we have shown that TIF1γ was a tumor suppressor in mouse and human chronic myelomonocytic leukemia (CMML). Loss of Tif1g in mouse HSCs favored the expansion of the granulo-monocytic progenitor compartment. Furthermore, Tif1g deletion induced the age-dependent appearance of a cell-autonomous myeloproliferative disorder in mice that recapitulated essential characteristics of human CMML. TIF1γ was almost undetectable in leukemic cells of 35% of CMML patients. This downregulation was related to the hypermethylation of CpG sequences and specific histone modifications in the gene promoter. A Demethylating Agent restored the normal epigenetic status of the TIF1G promoter in human cells, which correlated with a reestablishment of TIF1γ expression. Together, these results demonstrate that TIF1G is an epigenetically regulated tumor suppressor gene in hematopoietic cells and suggest that changes in TIF1γ expression may be a biomarker of response to Demethylating Agents in CMML.
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a phase ib study of oral panobinostat lbh589 administered with 5 azacitidine 5 aza in patients with myelodysplastic syndromes mds chronic myelomonocytic leukemia cmml or acute myeloid leukemia aml
Journal of Clinical Oncology, 2010Co-Authors: Oliver G Ottmann, Daniel J Deangelo, Mikkael A Sekeres, Pierre Fenaux, Michael Lubbert, G Garciamanero, Kapil N Bhalla, F Ludicke, Hansjochen Weber, I J WinigerAbstract:TPS282 Background: The Demethylating Agent 5-Aza is an integral therapy in MDS and AML, in which epigenetic modifications contributing to disease are well-documented. Despite an overall survival benefit, better and earlier responses are needed. Combination of a Demethylating Agent and a deacetylase inhibitor (DACi) is a rational strategy to reverse aberrant epigenetic alterations and the malignant phenotype. Preclinical data indicate that sequential treatment with Demethylating Agents and DACi targets multiple mechanisms to synergistically de-repress silenced genes and exert antileukemic activity. Panobinostat (PAN; LBH589) is a potent pan-DACi that has demonstrated antileukemic activity in patients (pts) with AML and MDS. This phase Ib, open-label, multicenter, dose-finding study comprises 2 phases: a dose-escalation phase to determine the maximum tolerated dose (MTD) of PAN in combination with standard dose 5-Aza, and a subsequent expansion phase to further evaluate safety, tolerability, and antileukemi...
Mikkael A Sekeres - One of the best experts on this subject based on the ideXlab platform.
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A phase 1b/2b multicenter study of oral panobinostat plus azacitidine in adults with MDS, CMML or AML with ⩽30% blasts
Leukemia, 2017Co-Authors: Guillermo Garcia-manero, H Salman, Carlos Graux, J D Cavenagh, Arpad Illes, Miklos Egyed, Mikkael A Sekeres, Pierre Fenaux, Massimo Breccia, Daniel J DeangeloAbstract:Treatment with azacitidine (AZA), a Demethylating Agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is
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a phase 1b 2b multicenter study of oral panobinostat plus azacitidine in adults with mds cmml or aml with 30 blasts
Leukemia, 2017Co-Authors: G Garciamanero, H Salman, Carlos Graux, J D Cavenagh, Arpad Illes, Miklos Egyed, Mikkael A Sekeres, Pierre Fenaux, Massimo Breccia, Daniel J DeangeloAbstract:Treatment with azacitidine (AZA), a Demethylating Agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel Agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6–43.9%)) vs AZA (14.3% (5.4–28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50–80%); AZA, 70% (50–80%)) or time to progression (PAN+AZA, 70% (40–90%); AZA, 70% (40–80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.
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a phase ib study of oral panobinostat lbh589 administered with 5 azacitidine 5 aza in patients with myelodysplastic syndromes mds chronic myelomonocytic leukemia cmml or acute myeloid leukemia aml
Journal of Clinical Oncology, 2010Co-Authors: Oliver G Ottmann, Daniel J Deangelo, Mikkael A Sekeres, Pierre Fenaux, Michael Lubbert, G Garciamanero, Kapil N Bhalla, F Ludicke, Hansjochen Weber, I J WinigerAbstract:TPS282 Background: The Demethylating Agent 5-Aza is an integral therapy in MDS and AML, in which epigenetic modifications contributing to disease are well-documented. Despite an overall survival benefit, better and earlier responses are needed. Combination of a Demethylating Agent and a deacetylase inhibitor (DACi) is a rational strategy to reverse aberrant epigenetic alterations and the malignant phenotype. Preclinical data indicate that sequential treatment with Demethylating Agents and DACi targets multiple mechanisms to synergistically de-repress silenced genes and exert antileukemic activity. Panobinostat (PAN; LBH589) is a potent pan-DACi that has demonstrated antileukemic activity in patients (pts) with AML and MDS. This phase Ib, open-label, multicenter, dose-finding study comprises 2 phases: a dose-escalation phase to determine the maximum tolerated dose (MTD) of PAN in combination with standard dose 5-Aza, and a subsequent expansion phase to further evaluate safety, tolerability, and antileukemi...
G Garciamanero - One of the best experts on this subject based on the ideXlab platform.
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a phase 1b 2b multicenter study of oral panobinostat plus azacitidine in adults with mds cmml or aml with 30 blasts
Leukemia, 2017Co-Authors: G Garciamanero, H Salman, Carlos Graux, J D Cavenagh, Arpad Illes, Miklos Egyed, Mikkael A Sekeres, Pierre Fenaux, Massimo Breccia, Daniel J DeangeloAbstract:Treatment with azacitidine (AZA), a Demethylating Agent, prolonged overall survival (OS) vs conventional care in patients with higher-risk myelodysplastic syndromes (MDS). As median survival with monotherapy is <2 years, novel Agents are needed to improve outcomes. This phase 1b/2b trial (n=113) was designed to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of panobinostat (PAN)+AZA (phase 1b) and evaluate the early efficacy and safety of PAN+AZA vs AZA monotherapy (phase 2b) in patients with higher-risk MDS, chronic myelomonocytic leukemia or oligoblastic acute myeloid leukemia with <30% blasts. The MTD was not reached; the RP2D was PAN 30 mg plus AZA 75 mg/m2. More patients receiving PAN+AZA achieved a composite complete response ([CR)+morphologic CR with incomplete blood count+bone marrow CR (27.5% (95% CI, 14.6–43.9%)) vs AZA (14.3% (5.4–28.5%)). However, no significant difference was observed in the 1-year OS rate (PAN+AZA, 60% (50–80%); AZA, 70% (50–80%)) or time to progression (PAN+AZA, 70% (40–90%); AZA, 70% (40–80%)). More grade 3/4 adverse events (97.4 vs 81.0%) and on-treatment deaths (13.2 vs 4.8%) occurred with PAN+AZA. Further dose or schedule optimization may improve the risk/benefit profile of this regimen.
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a phase ib study of oral panobinostat lbh589 administered with 5 azacitidine 5 aza in patients with myelodysplastic syndromes mds chronic myelomonocytic leukemia cmml or acute myeloid leukemia aml
Journal of Clinical Oncology, 2010Co-Authors: Oliver G Ottmann, Daniel J Deangelo, Mikkael A Sekeres, Pierre Fenaux, Michael Lubbert, G Garciamanero, Kapil N Bhalla, F Ludicke, Hansjochen Weber, I J WinigerAbstract:TPS282 Background: The Demethylating Agent 5-Aza is an integral therapy in MDS and AML, in which epigenetic modifications contributing to disease are well-documented. Despite an overall survival benefit, better and earlier responses are needed. Combination of a Demethylating Agent and a deacetylase inhibitor (DACi) is a rational strategy to reverse aberrant epigenetic alterations and the malignant phenotype. Preclinical data indicate that sequential treatment with Demethylating Agents and DACi targets multiple mechanisms to synergistically de-repress silenced genes and exert antileukemic activity. Panobinostat (PAN; LBH589) is a potent pan-DACi that has demonstrated antileukemic activity in patients (pts) with AML and MDS. This phase Ib, open-label, multicenter, dose-finding study comprises 2 phases: a dose-escalation phase to determine the maximum tolerated dose (MTD) of PAN in combination with standard dose 5-Aza, and a subsequent expansion phase to further evaluate safety, tolerability, and antileukemi...
Michael Lubbert - One of the best experts on this subject based on the ideXlab platform.
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the dna Demethylating Agent 5 aza 2 deoxycytidine induces expression of ny eso 1 and other cancer testis antigens in myeloid leukemia cells
Leukemia Research, 2010Co-Authors: Maika Almstedt, Nadja Blagitkodorfs, Jesus Duqueafonso, Julia Karbach, Dietmar Pfeifer, Elke Jager, Michael LubbertAbstract:Abstract Azanucleoside DNA-hypomethylating Agents have remarkable clinical activity in myelodysplastic syndromes and acute myeloid leukemia (AML), particularly at low, non-cytotoxic doses favoring hypomethylation over cytotoxicity. Cancer/testis antigens (CTAs) encoding immunogenic proteins are not expressed in almost all normal tissues and many tumor types, but are consistently derepressed by epigenetically active Agents in various cancer cell lines. Since the expression of CTA genes is usually very low or absent in myeloid leukemias, we treated various AML cell lines with 5-aza-2′-deoxycytidine (DAC) and quantified mRNA expression of the CTAs NY-ESO-1, MAGEA1, MAGEA3 and MAGEB2. Consistent time- and dose-dependent reactivation of all 4 CTA genes was observed, with maximum mRNA levels 72–144 h after treatment start. As determined by RNA microarray analyses, numerous other CTA genes (all located on the X-chromosome) were also derepressed in a time-dependent fashion by DAC. NY-ESO-1 derepression was confirmed at the protein level. By Elispot and chromium release assays we showed that the de novo expressed NY-ESO-1 protein was naturally processed and presented in a time- and dose-dependent fashion up to 8 days after the start of DAC treatment, and converted the cell lines susceptible to antigen-specific recognition by CD8+ T-cell clones. In conclusion, NY-ESO-1 and numerous other CTAs localized on the X-chromosome are readily and transiently derepressed in AML cell lines treated with DAC. The susceptibility of DAC-treated AML cell lines to antigen-specific T-cell recognition has clear implications for future clinical trials combining DAC and specific immunotherapy in AML.
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a phase ib study of oral panobinostat lbh589 administered with 5 azacitidine 5 aza in patients with myelodysplastic syndromes mds chronic myelomonocytic leukemia cmml or acute myeloid leukemia aml
Journal of Clinical Oncology, 2010Co-Authors: Oliver G Ottmann, Daniel J Deangelo, Mikkael A Sekeres, Pierre Fenaux, Michael Lubbert, G Garciamanero, Kapil N Bhalla, F Ludicke, Hansjochen Weber, I J WinigerAbstract:TPS282 Background: The Demethylating Agent 5-Aza is an integral therapy in MDS and AML, in which epigenetic modifications contributing to disease are well-documented. Despite an overall survival benefit, better and earlier responses are needed. Combination of a Demethylating Agent and a deacetylase inhibitor (DACi) is a rational strategy to reverse aberrant epigenetic alterations and the malignant phenotype. Preclinical data indicate that sequential treatment with Demethylating Agents and DACi targets multiple mechanisms to synergistically de-repress silenced genes and exert antileukemic activity. Panobinostat (PAN; LBH589) is a potent pan-DACi that has demonstrated antileukemic activity in patients (pts) with AML and MDS. This phase Ib, open-label, multicenter, dose-finding study comprises 2 phases: a dose-escalation phase to determine the maximum tolerated dose (MTD) of PAN in combination with standard dose 5-Aza, and a subsequent expansion phase to further evaluate safety, tolerability, and antileukemi...
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treatment of myelodysplastic syndrome with a dna methyltransferase inhibitor lack of evidence for induction of chromosomal instability
Leukemia Research, 2006Co-Authors: Peter Haas, Pierre W Wijermans, Gregor Verhoef, Michael LubbertAbstract:In several large phase II trials, low-dose treatment with the azanucleoside 5-aza-2'-deoxycytidine (decitabine, DAC) resulted in complete hematologic and cytogenetic responses in 23 and 31% of MDS patients, respectively. The question of induction of chromosomal instability by this Demethylating Agent was addressed by serial karyotypic analyses. 53/122 DAC-treated patients had all normal metaphases at time of treatment start. In 46/53 patients, sequential cytogenetic analyses were performed. 9/46 patients (20%) acquired clonal chromosomal abnormalities during follow-up (4/9 transient). 8/9 abnormalities were gains or losses of entire chromosomes. The rate and pattern of cytogenetic evolution are thus not higher than in historical MDS cohorts not receiving specific treatment.
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an epigenetic approach to the treatment of advanced mds the experience with the dna Demethylating Agent 5 aza 2 deoxycytidine decitabine in 177 patients
Annals of Hematology, 2005Co-Authors: Pierre W Wijermans, Michael Lubbert, Gregor Verhoef, Andre BoslyAbstract:During the last 10 years, three European phase II studies were performed to investigate the treatment of elderly patients with myelodysplastic syndrome (MDS) with low-dose 5-aza-2′-deoxycytidine (decitabine, DAC). All these European trial data were reviewed on the basis of the International Prognostic Scoring System (IPSS) risk criteria and the response criteria as recently published by an international working group. To investigate the results in a larger cohort of patients and to determine risk factors, all data were pooled with some observations from the PCH 95-06 US phase II study. The response rate in the 177 patients evaluated (median age 70 years) was 49%. The median response duration was 36 weeks, and the median survival was 15 months. Analysis of the data according to sex, age, French–American–British classification, percentage of blasts in the bone marrow, IPSS risk group, lactate dehydrogenase and cytogenetics did not reveal any factor predictive of response. Overall, 69% of patients benefited, including those with stable disease during therapy. Response duration was significantly shorter with increasing risk (according to the IPSS classification). Haemoglobin level and neutrophil count showed an inverse correlation to the IPSS classification. Univariate analysis showed a significantly inferior survival for elderly patients (>75 years of age) and for those with high levels of serum lactate dehydrogenase (LDH) (more than two times the normal values). Patients with high-risk cytogenetic abnormalities according to the IPSS risk criteria showed better overall survival than those with intermediate-risk abnormalities. When analysed according to the IPSS risk classification, high-risk patients had worse survival prospects following decitabine therapy than those with intermediate risk; however, compared to the originally reported IPPS outcomes for high-risk patients, they probably showed better survival. During the treatment period, 18% of the patients progressed towards acute leukaemia. Decitabine showed a rather low toxicity profile in this elderly patient group. In conclusion, low-dose decitabine is an active drug for the treatment of MDS patients, even for those older than 75 years with bad prognostic characteristics.