22 research outputs found
Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS
DNA methylation abnormalities have recently emerged as one of the most frequent molecular changes in hematopoietic neoplasms. Since methylation and transcriptional status are inversely correlated, the hypermethylation of genes involved in cell-cycle control and apoptosis could have a pathogenetic role in the development of cancer. In particular, high-risk myelodysplastic syndromes (MDS) and secondary leukemias show a high prevalence of tumor suppressor gene hypermethylation. The progression of chronic myeloproliferative diseases and of myelodysplastic syndromes, as well as that of lymphoproliferative diseases, is associated with an increased methylation rate, pointing to a role for hypermethylation of critical promoter regions in the transformation to more aggressive phenotypes. In the same line, a significantly worse prognosis has been shown for patients with hypermethylation of several genes compared to that of patients with unmethylated genes. For these reasons, the use of irreversible DNA methyltransferase inhibitors, such as 5-azacytidine and Decitabine, appears to be a promising option for the treatment of MDS and acute myeloid leukemia. In clinical trials, Azacytidine results in a significantly higher response rate, improved quality of life, reduced risk of leukemic transformation, and improved survival compared to supportive care. Similarly, Decitabine showed favorable results, promising response rates, a good nonhematologic toxicity profile, and a trend for better survival compared to intensive chemotherapy, particularly in older patients. The synergistic effect of histone deacetylase inhibitors, including phenylbutyrate (PB), in reactivating silenced genes encouraged clinical studies on the combination of PB and demethylating agents in hematological diseases, characterized by p15 silencing. The sequential administration of a "first generation" demethylating agent and HDAC inhibitors gave preliminary evidence of a reduced methylation of target genes, as also described with Decitabine. Clinical trials are still ongoing, and preliminary data indicate for the first time that the natural history of MDS may be changed by a non-intensive treatment, characterized by an outstanding toxicity profile
Inhibitors of DNA methylation in the treatment of hematological malignancies and MDS
DNA methylation abnormalities have recently emerged as one of the most frequent molecular changes in hematopoietic neoplasms. Since methylation and transcriptional status are inversely correlated, the hypermethylation of genes involved in cell-cycle control and apoptosis could have a pathogenetic role in the development of cancer. In particular, high-risk myelodysplastic syndromes (MDS) and secondary leukemias show a high prevalence of tumor suppressor gene hypermethylation. The progression of chronic myeloproliferative diseases and of myelodysplastic syndromes, as well as that of lymphoproliferative diseases, is associated with an increased methylation rate, pointing to a role for hypermethylation of critical promoter regions in the transformation to more aggressive phenotypes. In the same line, a significantly worse prognosis has been shown for patients with hypermethylation of several genes compared to that of patients with unmethylated genes. For these reasons, the use of irreversible DNA methyltransferase inhibitors, such as 5-azacytidine and Decitabine, appears to be a promising option for the treatment of MDS and acute myeloid leukemia. In clinical trials, Azacytidine results in a significantly higher response rate, improved quality of life, reduced risk of leukemic transformation, and improved survival compared to supportive care. Similarly, Decitabine showed favorable results, promising response rates, a good nonhematologic toxicity profile, and a trend for better survival compared to intensive chemotherapy, particularly in older patients. The synergistic effect of histone deacetylase inhibitors, including phenylbutyrate (PB), in reactivating silenced genes encouraged clinical studies on the combination of PB and demethylating agents in hematological diseases, characterized by p15 silencing. The sequential administration of a "first generation" demethylating agent and HDAC inhibitors gave preliminary evidence of a reduced methylation of target genes, as also described with Decitabine. Clinical trials are still ongoing, and preliminary data indicate for the first time that the natural history of MDS may be changed by a non-intensive treatment, characterized by an outstanding toxicity profile
DNA methylation and demethylating drugs in myelodysplastic syndromes and secondary leukemias
Methylation of DNA is a common epigenetic modification that plays an important role in the control of gene expression in mammalian cells. This process involves CpG dinucleotide sequences and is catalyzed by DNA-methyltransferase enzymes. Under physiological conditions, methylated CpG sites are only present in DNA sequences typical of bulk chromatin, where the DNA is inaccessible to transcription factors. In contrast, CpG islands of promoter regions are usually unmethylated (with few exceptions such as the genes on the inactive X-chromosome). DNA methylation abnormalities have recently emerged as the most frequent molecular changes in hematopoietic neoplasms
Green and Scalable Fractionation of Gold Nanoclusters by Anion Exchange Chromatography: Proof of Principle and Scale-Up
The chromatographic separation of atomically precise
glutathione-stabilized
gold nanocluster (AuNC) mixtures is demonstrated for purely aqueous
anion exchange chromatography (AEX) and compared to the results of
hydrophilic interaction liquid chromatography (HILIC), which requires
mixtures of water and acetonitrile. For isocratic HILIC separations,
the influence of the mobile phase composition with respect to ionic
strength and acetonitrile content is investigated. Individual AuNCs
are identified by their optical properties directly from chromatograms
and by comprehensive electrospray ionization differential mobility
mass spectrometry. Separations by AEX are performed in aqueous mobile
phases and are thus considered as a green and sustainable technique
for the efficient fractionation of AuNCs. Henry coefficients are determined,
which describe the retention behavior of single AuNCs and thus form
the basis for modeling, optimization, and scale-up of the separation.
The separation by AEX is optimized by linear salt gradient experiments.
The scalability of the separation is demonstrated by increasing the
AuNC feed concentration up to 64 g/L. Moreover, we quantify the amounts
of individual AuNCs by inductively coupled plasmaâoptical emission
spectroscopy after separation and close the mass balance demonstrating
the reversible adsorption from the stationary phase. Our AEX approach
is superior to HILIC since it offers a higher resolution, provides
access to larger clusters, is readily scalable, and is purely water-based.
AEX is considered as a sustainable, scalable, and widely applicable
technique for the isolation of all types of water-soluble single cluster
species. Therefore, we anticipate applications for instance for highly
specialized nanocatalysts, sensors, or in medicine
Acute Panmyelosis with Myelofibrosis: An Evaluation of Distinctive Clinicopathological Features Including Bone Marrow Stroma.
Acquired high-titer factor VIII inhibitor: fatal bleeding despite multimodal treatment including rituximab preceded by multiple plasmaphereses
Imatinib and Interferon-Alpha Maintenance Therapy for Patients with Philadelphia-Positive Acute Lymphoblastic Leukemia (Ph+ALL) Ineligible for Allogeneic Stem Cell Transplantation (SCT).
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Phase Ib Study of Oral Panobinostat In Combination with 5-Azacitidine (5-aza) In Patients with Myelodysplastic Syndromes (MDS), Chronic Myelomonocytic Leukemia (CMML), or Acute Myeloid Leukemia (AML)
Abstract
Abstract 4957
Background:
Panobinostat is a potent pan-deacetylase inhibitor (pan-DACi) that causes increased acetylation of target proteins such as HSP90, p53, α-tubulin and HIF-1α which are involved in cell cycle regulation, gene transcription, angiogenesis, and tumor cell survival. Preliminary evidence from phase I trials has demonstrated anti-tumor activity in patients with hematologic malignancies including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The advent of hypomethylating agents, such as 5-aza, represent a significant advancement in the treatment of MDS, chronic myelomonocytic leukemia (CMML), and AML. Although an improvement in clinical outcomes has been observed, including increased overall survival in patients with MDS, a substantial number of patients do not benefit from the therapies currently available. Preclinical studies suggest that the combination of a demethylating agent and a pan-DACi represents a rational strategy to reverse silencing of tumor suppressor genes, which contributes to the malignant phenotype, and improve outcomes in patients with MDS and AML. In this study, the combination of the pan-DACi, panobinostat, and the hypomethylating agent, 5-aza, was evaluated in patients with MDS, CMML and AML.
Methods:
This phase Ib, open-label, multicenter, dose-finding study is comprised of 2 stages: a dose-escalation stage to determine the maximum tolerated dose (MTD) of panobinostat in combination with standard dose 5-aza, and a subsequent expansion stage to evaluate safety, tolerability, and preliminary activity at the MTD dose level. The primary endpoint is incidence of dose-limiting toxicity (DLT) and secondary endpoints include type, duration, frequency, and relationship of adverse events (AEs) to the combination. Exploratory endpoints include clinical response and hematologic improvement according to IWG response criteria, and biomarker analysis of methylation status and expression of disease-associated genes in peripheral blood cells prior to and during therapy. Adult patients with IPSS INT-2 or high-risk MDS, CMML, or AML with multi-lineage dysplasia and †30% marrow blasts who are candidates for therapy with 5-aza and have not received a prior hypomethylating agent or pan-DACi are eligible for enrollment on the trial. Oral panobinostat was administered on Days (D) 3, 5, 8, 10, 12, and 15, starting at 20 mg, in combination with 5-aza (75 mg/m2 sc D 1â7) during a 28-D cycle. Patients received treatment for †6 cycles or until progression of disease, incidence of unacceptable toxicity, or withdrawal of consent.
Results:
To date, 11 patients have been enrolled including 9 patients with MDS, 1 patient with AML and 1 patient with CMML. The median age of patients enrolled on the trial was 69.0 (60-80). Patients have been evaluated at 2 panobinostat dose cohorts; 6 (20 mg) and 5 (30 mg). The AE analysis is based on 9 patients (6 from 20 mg cohort and 3 from 30 mg cohort) and the nature and incidence of AEs observed in the two cohorts were similar. Adverse events regardless of study drug relationship included nausea (4 [44%]), vomiting, fatigue (5 [55%] each) and asthenia (3 [33%]). Grade 3/4 AEs suspected to be treatment related included thrombocytopenia (2 [22%], febrile neutropenia and arthritis (1 [11%] each). Serious adverse events observed included febrile neutropenia, asthenia (2 [22%] each), atrial fibrillation and septic shock (1 [11%] each). One DLT has been observed (grade 4 febrile neutropenia) in the 20 mg panobinostat dose cohort.
Conclusions:
Panobinostat has been well tolerated up to a dose of 30 mg in combination with 5-aza (75 mg/m2) with dose escalation ongoing. Patients are currently being enrolled at the 40mg dose cohort. The most common AEs observed included febrile neutropenia, thrombocytopenia with one DLT observed (grade 4 febrile neutropenia) in the 20mg panobinostat dose cohort. The current data show that the addition of panobinostat to 5-aza is safe with no unexpected toxicities. Updated data, including safety and preliminary efficacy data will be presented at the meeting.
Disclosures:
Fenaux: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding; ROCHE: Honoraria, Research Funding; AMGEN: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Cephalon: Honoraria, Research Funding. Off Label Use: Panobinostat is an investigational agent currently being evaluated for the treatment of hematologic and solid malignancies. DeAngelo: Novartis: Membership on an entity's Board of Directors or advisory committees. Sekeres: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Winiger: Novartis Pharma AG: Employment. Squier: Novartis: Employment. Li: Novartis: Employment. Ottmann: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees
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Determination of a Phase II Dose of Panobinostat in Combination with 5-Azacitidine in Patients with Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, or Acute Myeloid Leukemia
Abstract
Abstract 459
BACKGROUND:
5-Azacitidine (AZA), a demethylating agent, is approved for treatment of myelodysplastic syndromes (MDS) and provides complete remission (CR) in 17% of patients (pts) and a median overall survival of 24.5 months, thus highlighting an unmet need in this population. Panobinostat, a potent pan-deacetylase inhibitor (pan-DACi), has demonstrated anti-tumor activity in pts with MDS and acute myeloid leukemia (AML). Preclinical studies suggest a combination of AZA and a pan-DACi may, in part through synergistic gene reactivation and apoptosis induction, improve outcomes in pts with MDS, AML, and chronic myelomonocytic leukemia (CMML) and appears to be a promising new approach in this population.
AIMS:
The primary objective of this phase I, open-label, multicenter, dose-escalation study is to determine maximum tolerated dose (MTD) of panobinostat with a fixed dose of AZA. Secondary objectives are to characterize safety and tolerability, with an exploratory objective to evaluate preliminary anti-leukemic activity of panobinostat in combination with AZA.
METHODS:
Adult pts (ECOG †2) with IPSS intermediate-2 or high-risk MDS, CMML, or AML with multi-lineage dysplasia and 20%â30% marrow blasts, not initially eligible for hematopoietic stem-cell transplantation, were treated with oral panobinostat (20 mg/day starting dose and 10-mg dose increments) during a 28-day cycle on days 3, 5, 8, 10, 12, and 15 in combination with a fixed dose of AZA (75 mg/m2 sc) on days 1â7 of each cycle. On the basis of the occurrence of dose-limiting toxicities (DLTs) during the first treatment cycle and an overall assessment of safety and tolerability data from all cycles, a phase II dose was recommended. Safety and tolerability were described as type, duration, frequency, relatedness, and severity of adverse events (AEs) according to CTCAE, v3.0. The adaptive Bayesian logistic regression model was used to guide panobinostat dose escalation with overdose control at all dose levels. Cycle extension, up to day 42, is allowed in cases of toxicity. The minimum exposure criterion for determining MTD was 6 scheduled doses of panobinostat and 7 scheduled doses of AZA during cycle 1.
RESULTS:
A total of 31 pts, with a median age of 70 years (range 34â81), in 3 cohorts were enrolled. Of these pts, 6 were treated at a dose level of 20 mg, 18 at 30 mg, and 7 at 40 mg of panobinostat; 28 pts were evaluable for MTD. Safety and efficacy data are based on 29 and 16 pts, respectively. One DLT (febrile neutropenia) was observed at 20 mg, 3 DLTs (dehydration/fatigue, colitis, a 1-day echocardiogram T-wave inversion, and an atrial fibrillation/syncope) were seen at 30 mg, and 2 DLTs (hyperbilirubinemia and nausea/vomiting) were reported in the 40-mg cohort. On the basis of the occurrence of DLTs and overall safety and tolerability data in cycle 1, dose levels at and above 40 mg were not further evaluated. Additional pts were enrolled at 30 mg. The most frequent AEs suspected to be related to the study treatment were gastrointestinal issues and fatigue. Grade 3/4 treatment-related AEs included thrombocytopenia (8 [28%]), neutropenia (5 [17%]), and febrile neutropenia (6 [21%]). Other frequent AEs of all grades, regardless of study drug relationship, included nausea (19 [67%]), fatigue (18 [62%]), diarrhea (16 [55%]), vomiting (15 [52%]), thrombocytopenia (13 [45%]), and decreased appetite (12 [41%]). The most common serious AEs (SAEs), regardless of study drug relationship, were febrile neutropenia (8 [28%]) and asthenia (5 [17%]). Based on the DLTs observed in cycle 1 and overall assessment of safety and tolerability, a phase II dose of 30 mg was recommended. Preliminary efficacy data for 8 pts with AML and 8 with MDS/CMML show 4 pts (2 at 30 mg, 2 at 40 mg) achieving CR or morphological CR (CRi) and 6 pts (4 at 30 mg, 2 at 40 mg) showing stable disease (SD). Hematologic improvement was seen in 4 pts, 2 of whom relapsed.
CONCLUSIONS:
Current data show that oral panobinostat at 30 mg/day on days 1, 3, 5, 8, 10, and 12 of a 28-day cycle can be safely combined with AZA at the registered label dose in pts with intermediate-2 or high-risk MDS, CMML, or AML. Additional pts will be evaluated in an expansion phase to further characterize the safety profile and activity at the 30-mg dose level. To date, preliminary efficacy shows that CR/CRi was achieved in 4 pts, SD was achieved in 6 pts, and HI was observed in 4 pts.
Disclosures:
Ottmann: Novartis Corporation: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding. DeAngelo:Novartis Corporation: Membership on an entity's Board of Directors or advisory committees. Sekeres:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Zahlten:Novartis AG: Employee of Novartis, Employment. Squier:Novartis Corporation: Employment. Acharyya:Novartis Corporation: Employment. Winiger:Novartis AG: Employment, Equity Ownership, Honoraria. Fenaux:Celgene Corporation: Honoraria, Research Funding; Amgen: Honoraria; Roche: Research Funding; Janssen Cilag: Research Funding