bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I/II Study of Escalating Doses of Idarubicin Orally Given with Oral Cyclophosphamide, Etoposide, Prednisolone and Intravenous Rituximab in Elderly Patients with Disseminated High Grade Non Hodgkin Lymphoma.
Authors: Fauveau Amélie , Lacotte-Thierry Laurence , Fleck Emmanuel , Colin Jean Yves , Guilhot François , Chabin Michèle , Langlois Alice , Guilhot Joëlle , Delwail Vincent 
Published: October 2019

Abstract
Abstract 3695
Poster Board III-631

Introduction
This study was performed to determine the maximum-tolerated dose (MTD) of oral idarubicin in combination with oral cyclophosphamide (CY), etoposide (ET), prednisolone (PRED) and intravenous (IV) rituximab (RI) administrated to previously untreated patients (pts) (60-80 years-old) with high grade stage III or IV non Hodgkin lymphoma. Secondary objectives were evaluation of toxicity and efficacy.

Patients and Methods
Idarubicin was administrated per os on day 1 with doses starting at 20 mg/m2 and escalated by 10 mg/m2 increments. Each idarubicin dose level included 3 to 6 pts. No intrapatient dose escalatation was allowed. Dose-limiting toxicity (DLT) was defined as grade 4 neutropenia lasting at least 4 days or grade 4 thrombopenia or more than grade 2 extra haematological toxicity. The MTD was defined as the dose level at which at least 2 of 3 or 3 of 6 pts experienced a DLT. CY and ET were given per os on day 1 to 3 at the fixed dose of 150 mg/m2 and 100 mg/m2 respectively. PRED was given at the fixed dose of 50 mg/m2 per os on day 1 to 5. RI was administrated IV on day 1 at the fixed dose of 375 mg/m2. G-CSF was systematically used from day 6 to haematological reconstitution. Eight cycles were planned at 3 week-intervals.

Results
Between October 2003 and August 2008, 19 immunocompetent pts [median age 70 (range 62-80)] with a new diagnosis of high grade non Hodgkin lymphoma received 128 cycles at 3 different idarubicin dose levels. No DLT was observed at dose level 1 (20 mg/m2), whereas 2 of 6 patients developed a DLT at dose level 2 (30 mg/m2). All 3 pts developed a DLT at level 3 (40 mg/m2) which was considered as MTD. Seven pts were enrolled at level 2 to confirm the results. Main toxicity results are summarized in the table below. No toxicity related mortality was observed. Two pts stopped treatment because of toxicity and 8 pts received a decreased dose. Overall response rate and complete response rate were 79% and 68% respectively. With a median follow-up of 22 months, the 2-year survival rates were 75% (95% CI: 45-90) for all pts and 58 % (95% CI: 21-83) for dose level 2 pts.

Conclusion
This first analysis clearly shows that the MTD of oral idarubicin administrated with CY, ET, PRED and RI, is 40 mg/ m2 on day 1 every 21-day cycle. The recommended dose study is ongoing. Overall survival data seems to be similar to previous publications. (Coiffier et al, NEJM 2002). Future development of subcutaneous anti-CD20 antibody could represent a special interest for this new oral chemotherapeutic protocol in order to improve the quality of life of elderly pts.

Disclosures:
No relevant conflicts of interest to declare.
The Histone Deacetylase Inhibitor MGCD0103 Down Regulates CD30, Activates NF-Kb, and Synergizes with Proteasome Inhibitors by HDAC6 Independent Mechanism in Hodgkin Lymphoma.
Authors: Buglio Daniela , Mamidipudi Vidya , Khaskhely Noor M , Gloghini Annunziata , Carbone Antonino , Heise Carla , Besterman Jeffrey M. , Martell Robert E , MacBeth Kyle J , Younes Anas 
Published: October 2019

Abstract
Abstract 3735
Poster Board III-671
Recent clinical trials demonstrated a promising clinical activity of the HDAC inhibitor MGCD0103 in heavily pretreated patients with relapsed HL. However, the mechanisms underlying MGCD0103 activity in HL remains unclear. Here we show that MGCD0103 preferentially inhibited HDACs1, 2 with no effect on HDAC6. Using three HL-derived cell lines, the IC50 for MGCD0103 after 72 hour of incubation was in the submicromolar concentrations, and was more effective than vorinostat in inducing cell death. Using gene expression profiling (GEP) studies, pathway PCR array, and western blot analysis, we identified several pathways that are modulated by MGCD0103. MGCD0103 downregulated the X-linked inhibitor of apoptosis (XIAP) protein, activated the intrinsic caspase pathway, and synergized with TRAIL agonistic antibodies. MGCD0103 downregulated CD30 mRNA and surface protein expression in a dose dependent manner, but had no significant effect on B cell-associated proteins, including CD19 and CD20, or on the costimulatory receptors CD40 and CD80. MGCD0103 induced TNF-alfa expression and secretion, which was associated with NF-kB activation, upregulation of the silencer of cytokine signaling (SOCS)-3, downregulated STAT6, and upregulation of STAT1 and 2. Selective inhibition of TNF-alfa expression by short interfering mRNA enhanced MGCD0103-induced cell death. Similarly, inhibition of NF-kB by proteasome inhibitors also potentiated the effect of MGCD0103, thus demonstrating synergy independent of HDAC6 inhibition. These findings demonstrate that MGCD0103 has a potent anti lymphoma activity by modulating the expression of a variety of survival proteins, and provides mechanistic rationale for combining class-I HDAC inhibitors with proteasome inhibitors and TRAIL.

Disclosures:
Mamidipudi: Celgene: Employment. Heise:Celgene Corporation: Employment, Equity Ownership. Besterman:Methylgene: Employment. Martell:Methylgene: Employment. MacBeth:Celgene Corporation: Employment, Equity Ownership. Younes:MethylGene: Honoraria, Research Funding.
Rituximab Does Not Improve Progression Free (PFS) or Overall Survival (OS) in Patients with Limited Stage Diffuse Large B Cell Lymphoma (DLBCL).
Authors: Hochberg Ephraim P. , Birrer Nicole , Toomey Christiana E. , Barnes Jeffrey A. , Lee Alfred Ian , LaCasce Ann , Abramson Jeremy S. 
Published: October 2019

Abstract
Abstract 3755
Poster Board III-691

Introduction
Diffuse Large B Cell Lymphoma (DLBCL) is the most common lymphoid malignancy accounting for approximately 33% of all newly diagnosed NHLs. Three randomized trials and multiple retrospective analyses have demonstrated both progression-free (PFS) and overall survival (OS) benefit to the addition of the anti-CD20 monoclonal antibody rituximab to anthracycline-containing chemotherapy in older advanced-stage patients, and in young low-risk patients with DLBCL. Approximately half of newly diagnosed patients with DLBCL present in limited stage and the benefit of rituximab containing chemotherapy regimens for these patients remains uncertain.

Methods
We used an IRB-approved clinicopathologic database, derived from comprehensive tumor registry data at the Massachusetts General Hospital, Dana Farber Cancer Institute and Brigham and Women's Hospital, to identify all patients 18 years or older diagnosed with limited stage DLBCL between 2000 and 2006. We included all patients treated with 3 or more cycles of anthracycline containing chemotherapy with curative intent. We excluded primary DLBCL of the CNS. We determined the impact of the use of rituximab on OS and PFS. PFS and OS were calculated from the date of initial diagnosis.

Results
A total of 138 patients met eligibility criteria and are included in the analysis. Median age was 51 years (range 18-89 years). 30% of patients were above 60 years of age, and less than 3% had an IPI score of 3 or higher. One hundred and six patients received CHOP + rituximab (RCHOP) and 32 received CHOP alone. Of the 106 patients receiving RCHOP, 48 were irradiated and 58 were not. Of the 32 patients receiving CHOP, 20 received radiation and 12 did not. At a median follow-up of 35 months (range 3-109 months), PFS and OS for the entire cohort are 86.2% and 90.6%, respectively. On univariate analysis of outcome, the addition of rituximab to CHOP did not improve PFS (81.3% vs. 87.7%,p=0.817, Logrank Test) or OS (84.4% vs. 92.5%, p=0.411, Logrank Test).

Conclusion
The outcome of an unselected series of patients with limited stage DLBCL is excellent. In this retrospective cohort of patients with limited stage DLBCL, the use of rituximab in conjunction with standard chemotherapy did not improve PFS or OS. The results we obtained are very similar to those reported by SWOG (Persky et al. JCO 2008). The overlapping confidence intervals for PFS and OS between SWOG 0014 and 8736 patients and our data suggest that a large multicenter trial will be needed to show a benefit of rituxan in this extremely good prognosis population.

Disclosures:
Hochberg: Genentech: Speakers Bureau; Biogen-Idec: Speakers Bureau; Enzon: Speakers Bureau; Amgen: Speakers Bureau.
Modulation of Cell Surface Protein Free Thiols; A Potential Novel Mechanism of Action of the Sesquiterpene Lactone Parthenolide in Non-Hodgkin's Lymphoma.
Authors: Skalska Jolanta , Brookes Paul S , Nadtochy S. M , Hilchey Shannon , Jordan Craig T. , Guzman Monica L. , Maggirwar Sanjay , Briehl Margaret M , Bernstein Steven H. 
Published: October 2019

Abstract
Abstract 3774
Poster Board III-710
Recent data supports the concept that redox regulation of cell surface protein thiols (i.e., exofacial thiols) effects critical cellular functions. We therefore hypothesized that redox-active anti-cancer therapeutics would modulate exofacial thiols, and that such modulation could be related to cell death mechanisms. To test this hypothesis, we used the sesquiterpene lactone parthenolide, a known anti-cancer agent. Parthenolide treatment results in a dose dependent decrease in mantle cell (MCL) and diffuse large cell lymphoma cell viability. Indeed, parthenolide decreases the level of free (ie. reduced) exofacial thiols on Granta MCL cells as assessed by flow cytometry. Parthenolide specifically modifies free thiols of surface proteins having molecular weights of ∼12 kd and ∼22 kd, as determined using a biotinylated thiol reactive reagent N-(biotinoyl)-N-(iodoacetyl) ethylendiamine (BIAM), which binds to free thiol groups and is detected by streptavidin-peroxidase staining of western blots. We further show that the central redox regulator thioredoxin is one of the surface protein thiol targets modified by parthenolide; specifically; (a) thioredoxin is detected on the Granta cell surface; (b) parthenolide directly interacts with free thiol groups on purified human thioredoxin, and; (c) parthenolide directly modifies Granta membrane associated thioredoxin, as determined with BIAM and neutravidin pull-down. To examine the functional consequences of parthenolide induced surface protein thiol modification, Granta cells were pretreated with the cell impermeable thiol antioxidant glutathione (GSH). Pretreatment with GSH inhibits the parthenolide induced; (a) decrease in exofacial free thiols; (b) modification of surface thioredoxin and; (c) Granta cell death. Pretreatment of Granta cells with GSH also inhibits parthenolide-mediated activation of JNK and inhibition of NFkB, two activities previously associated with the drug's anti-cancer activity. Based on these data, we postulate that at least one component of parthenolide's anti-lymphoma activity derives from its ability to modify the redox state of critical exofacial thiols. Indeed, to our knowledge, our data is the first to suggest that cancer cell exofacial thiols may be novel and important targets for cancer therapy.
Supported by an NCI SPORE grant in lymphoma 1P50 CA130805.

Disclosures:
Bernstein: millenium: Consultancy; genentech: Consultancy, Speakers Bureau; enzon: Consultancy.
Population Pharmacokinetics of Panobinostat (LBH589) in Patients with Advanced Solid Tumors and Hematologic Malignancies Following Intravenous and Oral Administration.
Authors: Savelieva Marina , Woo Margaret M. , Weber Harald A. , Hirawat Samit , Paul Sofia , Schindler Joanne , Fisch Roland 
Published: October 2019

Abstract
Abstract 3780
Poster Board III-716

Introduction
Panobinostat (LBH589), a hydroxamic acid derivative, is one of the most potent deacetylase inhibitors (DACi), with anti-tumor activity in a wide variety of preclinical xenograft models, and has shown promising clinical activity in patients with Hodgkin lymphoma and multiple myeloma. A population pharmacokinetic (PopPK) analysis was performed to characterize the extent and variability of panobinostat exposure in patients with advanced cancer and to evaluate the influence of selected covariates on exposure.

Patients and methods
Panobinostat concentrations in plasma were evaluated in 500 patients enrolled in five Phase I studies and four Phase II studies as asingle-agent administration. Patients received oral panobinostat at doses of 10–80 mg on Days 1, 3, and 5, weekly [QW], or every other week [QOW], or on Days 1 and 4 QW in three Phase I oral studies. Intravenous (i.v.) panobinostat was delivered at doses from 1.2 to 20 mg/m2 in 4 schedules (Days 1–7; or Days 1–3 QW or QOW; or once weekly for 3 weeks) in two Phase I i.v. studies. Panobinostat was also orally administered at 20 mg, on Days 1, 3 and 5 QW, in patients with cutaneous T-cell lymphoma, chronic myelogenous leukemia, and multiple myeloma in four Phase II oral studies. Panobinostat PopPK was characterized by a compartmental non-linear mixed-effects model.

Results
Panobinostat concentration–time data were well described by a linear 3-compartment model with first-order absorption. The model estimated the population median (CV%) of the total clearance (CL) to be 28.6 L/h (78%) and the volume of distribution (V) 27.2 L (54.8%). Absolute oral bioavailability is 30%. The relative bioavailabilities of oral formulations 1 (Phase II formulation) and 2 (Phase I formulation) are 17% and 23%, respectively. The analysis showed no effect on panobinostat clearance by gender, race, co-medications, disease state, or renal function as measured by plasma creatinine clearance. Body surface area (BSA 1.4–3.4 m2) and age (16–88 years) in the ranges studied were non-linear covariates for panobinostat clearance and volume.

Conclusions
The pharmacokinetics of panobinostat are linear and time independent. BSA may have clinical utility in predicting panobinostat clearance. The PopPK model generated from this study allows for future pharmacokinetic–pharmacodynamic correlation and application in optimizing the use of panobinostat.

Disclosures:
Savelieva Praz: Novartis: Employment. Woo:Novartis: Employment. Weber:Novartis Pharma AG: Employment. Hirawat:Novartis: Employment. Paul:Novartis: Employment. Schindler:Novartis: Employment. Fisch:Novartis : Employment.
The JNK Pathway Is a Significant Determinant of Sensitivity to DNA Damaging Agents in Pre-B ALL.
Authors: Saunders Philip O. , Bradstock Kenneth F , Bendall Linda J. 
Published: October 2019

Abstract
Abstract 3786
Poster Board III-722
The JNK pathway is reported to facilitate AP1 binding and promote apoptosis depending on cell type and environmental conditions. We have previously reported RAD001 (16μM) induces JNK pathway activation in pre-B ALL cells. We sought to evaluate the impact of changes in JNK pathway activation on pre-B ALL viability in vitro. Using JNK inhibitor SP600125 titrated to inhibit c-Jun activation, we determined that cell death in pre-B ALL cells treated with RAD001 (16μM) alone was not JNK dependent. In contrast, combining RAD001 (16μM) with DNA damaging agents significantly enhanced JNK dependent death. This difference indicates that additional factors, including genotoxic stress, are required for JNK activation to induce pre-B ALL cell death. The JNK pathway is reported to suppress transcriptional activation of key mediators of the DNA damage response. We observed that JNK activation in cells treated with RAD001 (16μM) and DNA damaging agents was associated with suppression of p53 and p21 relative to DNA damage alone. This result was supported by the observation of enhanced p53 and p21 expression in pre-B ALL cells treated with DNA damaging agents in the presence of the JNK inhibitor SP600125. Analysis of DNA content and proliferation antigen expression in pre-B ALL cells treated with RAD001 (16μM) and DNA damaging agents revealed JNK activation was associated with a significant increase in the proportion of cells in S phase, relative to DNA damage alone, which caused a G1 and G2 cell cycle arrest. Further evidence that the JNK pathway impacts on the DNA damage response was provided by the observation that pre-B ALL cells treated with DNA damaging agents and JNK inhibitor SP600125 demonstrated reduced PCNA expression at G1 and G2 and reduced expression of mitotic antigen phospho-Histone–H3. This is consistent with enhanced regulation at G1-S and G2-M checkpoints. The results indicate changes in JNK pathway activation impact on the cell cycle response to DNA damage. In conclusion we have identified that the JNK pathway has a significant impact on the sensitivity of pre-B ALL cells to DNA damaging agents. JNK activation in the presence of genotoxic stress significantly enhanced pre-B ALL cell death, associated with suppression of key mediators of the DNA damage response, p53 and p21. We found that changes in JNK activation altered the cell cycle response to DNA damage. Further study is required to determine if changes in cell cycle regulation in the presence of DNA damage is causal to JNK dependent cell death. Additional studies to identify intracellular signal pathways which facilitate JNK dependent cell death are warranted. Our observations suggest combining agents which induce JNK activation with conventional chemotherapy or selected novel agents has the potential to enhance clinical responses in pre-B ALL.

Disclosures:
No relevant conflicts of interest to declare.
The PI3K Inhibitor GDC-0941 Induces Growth Arrest and Apoptosis of Acute Myeloid Leukemia Cells.
Authors: Sun Laura , Berry Leanne , Du Changchun , Ma Xiaoju Max , Shi Lily , Medeiros Bruno C. , Ebens Allen J. 
Published: October 2019

Abstract
Abstract 3787
Poster Board III-723
Acute myeloid leukemia (AML) is a biologically and molecularly heterogeneous malignancy characterized by an accumulation of myeloid-lineage cells in the blood and bone marrow. Phosphatidylinositol 3' kinase (PI3K) -mediated signaling is frequently dysregulated in cancer and controls fundamental cellular functions such as cell migration, growth, survival and development of drug resistance in many cancers, including AML, and therefore represents an attractive therapeutic target, even against the backdrop of AML disease heterogeneity. In AML, for example, activating mutations in Ras and Flt3 are common and a number of autocrine and paracrine signaling mechanisms have been proposed as important disease mediators; all converge on PI3K as an important signal transduction node to provide growth- and survival-promoting effects. Here, we demonstrate that PI3K p110-a,b,d catalytic subunits are all prevalent across a panel of ∼30 cell lines and that the majority of cell lines as well as primary patient samples show evidence of PI3K pathway activation. We demonstrate in vitro with both cell lines and patient cell isolates, that a potent and selective pan-isoform PI3K inhibitor, GDC-0941, modulates pharmacodynamic markers such as p-Akt, p-4E-BP1, and p-FOXO-3a, and that treated cells show a G0/G1 cell-cycle arrest. A strong induction of apoptosis is observed by annexin/PI staining with upregulation of cleaved caspases and PARP. Preliminary observations suggest significant induction of p27 and Bim as direct transcriptional targets of FOXO-3a, as well as downregulation of c-Myc levels; these targets may represent key mediators of observed cellular effects and are the subject of ongoing work. Additional studies are currently underway to identify clinical standard-of-care agents and new molecular entities (pipeline NMEs) that combine favorably with PI3k-inhibition in vitro, and the results of several in-vivo xenograft studies will also be presented.

Disclosures:
Sun: Genentech Inc.: Employment. Berry:Genentech: Employment, Patents & Royalties. Du:Genentech, Inc.: Employment, Equity Ownership. Ma:Genentech: Employment, Patents & Royalties. Shi:Genentech: Employment, Patents & Royalties. Medeiros:Genentech: Research Funding. Ebens:Genentech, Inc.: Employment, Equity Ownership, Patents & Royalties.
Significant Association Between Promoter Polymorphism of the Erythropoietin Gene and Myelodysplastic Syndrome.
Authors: Ma Wanlong , Kantarjian Hagop , Zhang Ke , Zhang XI , Wang Xiuqiang , Zhang Zhong , Yeh Chen-Hsiung , Sferruzza Anthony , O'Brien Susan , Estey Elihu , Albitar Maher 
Published: October 2019

Abstract
Abstract 3825
Poster Board III-761
The risk of developing myelodysplastic syndrome (MDS) increases in the presence of a combination of genetic susceptibility factors and environmental carcinogenic factors. While numerous toxic agents have been described, genetic susceptibility factors for MDS are not well defined. A recent study showed that the TT genotype of the SNP rs1617640, located in the promoter of the eosinophile peroxidase (EPO) gene, is significantly associated with diabetic retinopathy and end-stage renal disease in patients with diabetes. Experimental models showed that the GG genotype is associated with several-fold lower erythropoietin expression than is the TT genotype. Since EPO plays a major role in the growth and differentiation of hematopoietic cells, we explored the association of the rs1617640 SNP genotype with MDS. We compared the EPO promoter SNP genotype in 187 MDS patients, 256 AML patients, and 95 normal control individuals. The GG genotype was significantly more common in patients with MDS (25.1%) than in normal control subjects (6.3%) and AML patients (12.5%) (P=0.0003); the GT genotype was present in 38.4% of MDS patients, 43.2% of AML patients, and 46.2% of normal control subjects. Combined analysis of data from MDS and control subjects indicated an elevated risk of MDS in individuals with the GG genotype relative to those with a non-GG genotype (odd ratio [OR] =4.98; 95% confidence interval [CI]=2.04-12.13). The GG (vs non-GG) genotype was also associated with elevated MDS risk when analysis was limited to the MDS and AML groups (OR =2.35; 95% CI=1.43-3.86). In contrast, analysis of AML and control group data showed a statistically insignificant elevated risk for AML in individuals with the GG genotype (OR=2.12; 95% CI=0.86-5.24). The odds of MDS and AML did not differ significantly with respect to GT (vs non-GT) or TT (vs non-TT) genotypes when compared with control subjects. Clinical and follow up data were available for 112 MDS patients and 186 AML patients. There was no correlation between EPO promoter genotype and response to therapy or overall survival in MDS or AML. In the MDS group, the GG genotype was significantly associated with shorter complete remission duration, as compared with the TT genotype (P=0.03). We found no correlation between EPO genotype and cytogenetic abnormalities, performance status, or other laboratory variables. In conclusion, the EPO promoter GG genotype shows strong association with MDS. Since MDS is well documented to develop after exposure to toxic agents, the clinical value of screening for the EPO promoter GG genotype in individuals at high risk due to exposure to toxic agents, then storing hematopoietic stem cells from those with the GG genotype for possible future use, should be investigated.

Disclosures:
No relevant conflicts of interest to declare.