12 research outputs found
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).
Recommended from our members
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 1–7) 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
Recommended from our members
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%–30% 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 1–7 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 34–81), 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
Continued Low-Dose Decitabine (DAC) Is an Active First-Line Treatment of Older AML Patients: First Results of a Multicenter Phase II Study.
Recommended from our members
Survival, Prognostic Factors, and Rates of Leukemic Transformation in a Multicenter Study of 303 Untreated Patients with MDS and Del(5q)
Abstract
Abstract 945
In 2001, the WHO defined the category MDS with del(5q) due to unique cytogenetic, morphologic, hematologic, clinical, prognostic and therapeutic features. The survival of these patients, as well as patients with refractory cytopenia with unilineage dysplasia (RCUD) and refractory anemia with ring sideroblasts is favorable in comparison to other MDS types. Data on disease progression to a more advanced MDS category or to acute leukemia (AML) are sparse and have not been examined in detail. In order to address this issue we collated data of all patients with MDS and del(5q) characterized by low or intermediate-1 IPSS risk score that had been included into various collaborating MDS registries. Patients were followed from diagnosis and data on cell counts, transfusion dependency, and MDS progression were documented. No patients received treatment other than best supportive care. The status of 62 patients was censored at the time of the initiation of Lenalidomide therapy. AML progression was defined as >20% marrow blasts. Estimates of survival probability were calculated with the Kaplan-Meier method. The cumulative incidence of progression to AML was calculated both with the Kaplan-Meier method and with the competing risk method where “death without progression to AML” is considered as competing event, not as censoring. For both events the cumulative incidences are estimated simultaneously. This method has the advantage that it takes into account that there is a difference between end of follow-up and death. Depending on the number of competing events, the curves are lower than those calculated with the Kaplan-Meier estimator.
We identified 303 patients, median age at diagnosis 65 years (28-91), 71% were females. Median follow up time was 3 years. Median survival was 71.5 months. Patients with del(5q) as a sole chromosomal aberration had a median survival of 73 months as compared to 19.3 months in patients with more than 1 additional aberrations. Patients who had red cell transfusion need at diagnosis had a median survival of 39 months vs. 97 months in transfusion independent patients (p=0.00005). Transfusion need at diagnosis was the most important parameter for survival. Patients in the WPSS very low risk group had a median survival of 107 months, as compared to 73 and 56 months in the low and intermediate risk group and 37 months in the high risk group.
44 of the 303 patients (15%) progressed to AML (>20% marrow blasts). The cumulative AML progression rate calculated with the Kaplan-Meier method was 7% at 2 years and 18.2% at 5 years. The cumulative risk of AML progression calculated with the competing risk method was 6.6% at 2 years and 15.1% at 5 years. Factors associated with the risk of AML transformation were intermediate-I IPSS risk and high risk WPSS score, marrow blast count >5%, and red-cell transfusion need at diagnosis. Survival and progression rates did not differ among the participating centers.
In conclusion, survival of patients with MDS and del(5q) is high and is comparable to patients with RCUD and RARS, but is associated with a risk of AML-transformation similar to RCMD without del(5q). Further cytogenetic and molecular studies are warranted in order to identify patients at greater risk of progression.
Disclosures:
Germing: Novartis, Celgene: Honoraria, Research Funding. Lauseker:Celgene: Research Funding. Hildebrandt:Celgene: Research Funding. Symeonidis:Celgene: Research Funding. Cermak:Celgene: Research Funding. Pfeilstöcker:Celgene: Research Funding. Nösslinger:Celgene: Research Funding. Sekeres:Celgene: Research Funding. Maciejewski:Celgene: Research Funding. Haase:Celgene: Research Funding. Schanz:Celgene: Research Funding. Seymour:Celgene: Research Funding. Weide:Celgene: Research Funding. Lübbert:Celgene: Research Funding. Platzbecker:Celgene: Research Funding. Valent:Celgene: Research Funding. Götze:Celgene: Research Funding. Stauder:Celgene: Research Funding. Blum:Celgene: Research Funding. Kreuzer:Celgene: Research Funding. Schlenk:Celgene: Research Funding. Aul:Celgene: Research Funding. Kündgen:Celgene: Research Funding. Hasford:Celgene: Research Funding. Giagounidis:Celgene: Research Funding