bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase II Study of the Safety and Efficacy of a Novel Oral fXa Inhibitor (LY517717) for the Prevention of Venous Thromboembolism Following TKR or THR.
Authors: Agnelli Giancarlo , Haas Sylvia K. , Krueger Kathryn A. , Bedding Alun W. , Brandt John T. 
Published: April 2020

Abstract
Background: There is a continuing need for safe, effective and convenient therapies for prophylaxis of venous thromboembolism (VTE) after major orthopedic surgery. LY517717 (LY), an oral direct inhibitor of activated factor X (fXa), has been well tolerated in healthy subjects and is being developed to address these needs.
Objective: To assess the safety and efficacy of LY and to determine whether one or more doses of LY is non-inferior to enoxaparin in preventing VTE in patients undergoing total knee replacement (TKR) or total hip replacement (THR).
Methods: In a double-blind, double-dummy, dose-escalation study, patients undergoing TKR or THR were randomized to receive one of six oral doses of LY (25, 50, 75, 100, 125 or 150mg) or enoxaparin, 40 mg SC once daily. LY was administered fasting 6–8 hours after wound closure and then each morning. Enoxaparin was administered the night before surgery and then every evening. Both treatments were continued for a total of 6–10 doses. Patients underwent mandatory bilateral venography within 12 hours of the last dose of oral study drug and were assessed for symptomatic deep vein thrombosis (DVT), pulmonary embolism (PE) and bleeding events through day 30 (±7). All VTE and bleeding events were adjudicated by a blinded independent central adjudication committee. DVT detected by mandatory venography and symptomatic DVT and PE events were included in the combined VTE endpoint. Non-inferiority would be declared if the upper limit of the 90% confidence interval (CI) for the absolute difference in VTE incidence between an LY dose and enoxaparin was less than 0.14.
Results: 511 subjects were randomized. 507 patients received at least one dose of LY or enoxaparin and were included in the safety analyses. 391 patients had an evaluable bilateral venogram or experienced an objectively confirmed clinical VTE and were included in the efficacy analyses. The 3 lowest doses were stopped early due to lack of efficacy, and the study was completed with the 3 highest doses. VTE and bleed event data through the treatment and follow-up periods are summarized in the table. The 100, 125 and 150 mg doses of LY were non-inferior to enoxaparin in the incidence of symptomatic or venographic DVT or PE (upper limits for the 90% CI of the absolute differences are 0.13, 0.05 and 0.01, respectively). Adjudicated bleed events were uncommon in both LY and enoxaparin patients.
Conclusion: The 100, 125 and 150 mg doses of LY517717 were as efficacious as enoxaparin 40 mg for the prevention of VTE following TKR or THR in this study. LY was safe and well tolerated by study patients, with no significant difference in bleeding risk compared with enoxaparin.
Incidence of VTE and Bleed Events (%) (preliminary results)*
RHAMM/CD168-R3 Peptide Vaccination of HLA-A2+ Patients with Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS) and Multiple Myeloma (MM).
Authors: Greiner Jochen , Giannopoulos Krzysztof , Li Li , Liebisch Peter , Wendl Christiane , Chen Jinfei , Ringhoffer Mark , Guillaume Phillipe , Ritter Gerd , Doehner Hartmut , Schmitt Michael 
Published: April 2020

Abstract
The receptor for hyaluronic acid mediated motility (RHAMM/CD168) has been described as a leukemia-associated antigen (LAA) eliciting both humoral and cellular immune responses in patients with hematological malignancies. RHAMM/CD168 is expressed in more than 80% of patients with acute myeloid leukemia (AML) or multiple myeloma (MM). Recently, we characterized the RHAMM/CD168-derived peptide R3 (ILSLELMKL) as a CD8+ T cell epitope. R3-primed CD8+ T lymphocytes were able to lyse autologous RHAMM/CD168+ AML blasts in a MHC class I-restricted and epitope-specific manner. Therefore, we initiated a phase I/II R3 peptide vaccination trial for patients with AML, MDS or MM overexpressing RHAMM/CD168. Patients were included with positive RHAMM/CD168 expression but with a limited tumor load. 300 mcg RHAMM R3 peptide emulsified with the incomplete Freund’s adjuvant (ISA-51, Montanide; day 3) and GM-CSF (Leukine, days 1–5) was administrated four times subcutaneously at a biweekly interval. The primary aim of the study is safety and feasibility of this peptide vaccination, secondary aims the evaluation of a specific T cell immune response to RHAMM/CD168 R3 peptide and the assessment of the influence of the R3 peptide vaccination on the remission status. Since January 2005, ten patients were enrolled in this study. The first eight patients (2 AML, 3 MDS, 3 MM) have completed the course of four vaccinations and four patients have been evaluated. The only side effects observed under R3-peptide vaccination were erythema and induration of the skin at the site of injection (CTC I°). In 2/4 patients, we found in the peripheral blood a significant increase of specific CD8+ T cells (from 0.01% to 0.8%) recognizing the R3 peptide in ELISPOT analysis and tetramer staining, one patient showed already initially a high number of HLA-A2/R3 tetramer+CCR7-CD27-CD45RA+ effector T cells and maintained this level of T cell response. Clinical responses have been assessed by the examination of peripheral blood and bone-marrow samples before and after vaccination. Patients showed a reduction of the tumor-specific expressed antigen RHAMM/CD168 in real-time RT-PCR analysis after vaccination. 2/4 patients with myeloid disorders (1 AML, 1 MDS RAEB1) showed a reduction of CD33+ cells in FACS analysis of the bone-marrow after 4 vaccinations from 10 and 7 % to 1–2 and &lt;1%, respectively. One patient with MM showed a reduction of plasma cells in bone-marrow and a stable quantity of light chains in peripheral blood, one patient with AML showed a progressive disease. In summary, RHAMM/CD168 is a promising target antigen for immunotherapies in patients with hematological malignancies.
Gene Expression Profiling Predictive of Tipifarnib (ZARNESTRA®, R115777) Response in Patients with Newly Diagnosed Acute Myeloid Leukemia.
Authors: Raponi Mitch , Zhang Yi , Jatkoe Tim , Yu Jack , Lee Grace , Lancet Jeffrey E. , Karp Judith E. , Thibault Alain , Wang Yixin 
Published: April 2020

Abstract
The farnesyltransferase inhibitor (FTI), tipifarnib (ZARNESTRA®, R115777), has demonstrated clinical response in patients with hematological disease. While the inhibition of protein farnesylation is the primary mechanism of action (MOA), the level of farnesyl inhibition is not a reliable pharmacodynamic marker of response, nor is it clear what genetic markers can be employed to predict response. This prospectively designed study was conducted to identify potential genetic markers and expression signatures that may be surrogate predictors of response for tipifarnib in patients with acute myeloid leukemia (AML). Bone marrow samples were collected and gene expression profiles analyzed from a single arm phase 2 clinical study of tipifarnib in poor-risk patients with newly diagnosed AML (Lancet, et al. Blood. 2004;104:249a). In total, 79 samples were obtained before (n = 25), during (n = 30), and after (n = 24) tipifarnib treatment. Bone marrow samples were analyzed using the Affymetrix U133A GeneChip® array. Global gene expression signatures revealed that tipifarnib treatment resulted in gene expression changes that were maintained for up to 120 days following treatment termination. Pretreatment vs posttreatment samples identified approximately 500 genes that had significant changes (False Discovery Rate [FDR] &lt;0.005) in gene expression following farnesyltransferase inhibition, including several genes associated with farnesylation (eg, K-ras, FNTA). Many of the modulated genes were identified as those significantly involved in protein biosynthesis, DNA replication, intracellular signaling, and cell cycle pathways, thus, reflective of inhibition of cellular proliferation. A subset of 27 genes (including genes associated with signal transduction and cell cycle) was also identified as being differentially modulated between responders and nonresponders (P &lt;0.01). Gene expression signatures previously identified from a phase 2 clinical trial in relapsed and refractory AML were also tested in pretreatment samples to examine their ability to predict response (Raponi, et al. Blood. 2004;104:246a). A combination of 6 genes was found to have significant predictive accuracy in this independent set of samples (P = 0.05). The genes identified from these studies might be used as surrogate biomarkers of tipifarnib activity.
Use of a Disease-Specific Comorbidity Index To Describe Elderly Patients with Acute Myelogenous Leukemia (AML) and High Risk Myelodysplasia (MDS) Enrolled in a Phase II Study of CLORETAZINE™ (VNP40101M).
Authors: Giles Francis , Rizzieri David , Karp Judith , Vey Norbert , Khan Khuda , Mufti Ghulam , Hudak Diana , Karsten Verena , O’Brien Susan 
Published: April 2020

Abstract
Background: Elderly patients (pts) with AML generally have an unfavorable clinical course and are under-represented in clinical studies. Comorbid conditions are common in the elderly and, for older pts with AML, may have a major influence on choice of treatment. The ability to objectively measure comorbidity in this population may help predict patients’ risk for unacceptable toxicity. Comorbidity indices developed from a general medical population may underestimate the risks of cytotoxic treatment. An index developed specifically for pts with hematologic malignancies may be useful in categorizing pts by risk before selection of leukemia induction therapy. The Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) is an index which captures comorbidities that predict non-relapse mortality (NRM) in pts with hematologic malignancies considered for allogeneic transplant (Sorror; Blood; 2005). The HCT-CI defines low risk with a score = 0, intermediate = 1–2 and high = ≥3. We used the HCT-CI to assess baseline comorbidity in an elderly pt population (median age 72) with untreated AML or high risk MDS enrolled in a single agent phase II study of CLORETAZINE.
Methods: Case report forms of 105 pts ≥ 60 years of age containing information about baseline medical history, concomitant medications, physical examination, and serum chemistries were reviewed. Using the HCT-CI definitions, pts were given scores representing the weighted sum of conditions that were active or required treatment at study entry.
Results: A total of 232 comorbid conditions were scored. In order of frequency, the most common were: cardiac (28%), including congestive heart failure, myocardial infarction, arrythmias, coronary artery stenosis requiring treatment, and valve disease; psychiatric disturbances (12%); hepatic dysfunction (11%); infection (11%); and ≥ grade 2 pulmonary disease (8%). Most pts (64%) had multiple comorbid conditions. Cardiac conditions were observed in 46% of all pts, psychiatric disturbances in 27%, hepatic disease in 25%, ongoing but controlled infections in 24%, and pulmonary disease in 18%. The response rate within each risk category is similar to the overall response rate, as summarized in the table below. The 19 early deaths (≤ 30 days) occurred in pts from the intermediate and high risk categories.
Risk Category N (%) # CR/CRp (%) # Early Deaths (%) Low (0) 11 (10) 4 (36) 0 Intermediate (1–2) 32 (30) 11 (34) 7 High (≥3) 62 (59) 18 (29) 12 Total 105 33 (31) 19 (18)
Conclusions: The HCT-CI is a helpful tool for defining comorbid conditions in elderly untreated AML pts. The majority of pts enrolled in the single agent Phase II CLORETAZINE study is at high risk for NRM as measured by HCT-CI score. Pts respond to CLORETAZINE across the HCT-CI scored risk groups.
Predictors of Clinical Response in Patients with High Risk Acute Myeloid Leukemia Receiving Treatment with the Histone Deacetylase Inhibitor Sodium Valproate.
Authors: Craddock Charles , Bradbury Charlotte , Narayanan Sujaatha , Rye Adam , Basu Supratik , MacWhannell Alan , Sawers Alistair , Cook Mark , Griffiths Michael , Grimwade David , Bunce Christopher , Turner Bryan 
Published: April 2020

Abstract
There is increasing evidence that perturbations in chromatin structure contribute to the pathogenesis of AML raising the possibility that modulators of chromatin structure may be of therapeutic benefit. Sodium valproate (VPA) is a potent histone deacetylase inhibitor (HDI) and in conjunction with ATRA induces apoptosis of primary AML blasts in vitro. It has been postulated that induction of pro-apoptotic genes including p21 and TRAIL play a critical role in determining the tumor selectivity of HDIs. We have therefore conducted a Phase I/II study of combined VPA/ATRA therapy in patients with high risk AML ineligible for chemotherapy and correlated clinical response with alterations in chromatin structure, induction of pro-apoptotic genes and in vitro sensitivity to VPA. In light of evidence that modulating cAMP levels may increase rexinoid responsiveness theophylline was added in patients who had failed to respond to 28 days combined VPA/ATRA therapy. A total of 20 patients (median age 72 yrs) have been treated to date including 12 patients with relapsed AML, 6 with previously untreated disease and 2 with primary refractory disease. Nine patients completed treatment for at least 8 weeks. Four patients (all with relapsed AML) demonstrated a haematological response. One patient achieved a complete remission and two a partial remission. Myeloblasts isolated from trial patients prior to the commencement of therapy demonstrated varying sensitivity to VPA and ATRA in vitro which correlated with clinical response. Combined treatment with VPA and ATRA resulted in increased levels of histone acetylation and methylation and induced expression of p15, p16 and p21 in myeloblasts from treated patients. Induction of TRAIL was documented in three patients-two of whom demonstrated a clinical response. p21 induction was documented in all responding patients. Induction of p21 and TRAIL was most marked in the patient who achieved a CR. There was no apparent correlation between induction of p15 or p16 and response. We have previously documented that exposure of AML cell lines to HDIs results in specific changes in HDAC expression patterns with selective up-regulation of HDAC11 and to a lesser extent HDAC9 and SIRT4. Similar changes in HDAC expression were documented in myeloblasts from patients after 28 days treatment with VPA/ATRA. This study demonstrates that VPA, in combination with ATRA and theophylline, has significant clinical and biological activity and identifies possible mechanisms underlying the tumor-specific activity of VPA in AML in vivo.
A Phase I Trial of CHIR-258, a Multitargeted RTK Inhibitor, in Acute Myeloid Leukemia (AML).
Authors: Morgan Gareth J. , Parker A. , Cavet J. , Cavenaugh J. , Heise C. , Garzon F. 
Published: April 2020

Abstract
Background: CHIR-258 is an orally active small molecule receptor tyrosine kinase (RTK) inhibitor which exhibits potent single digit nanomolar inhibitory activity against multiple RTKs involved in tumor growth and angiogenesis (IC50 &lt;=10 for VEGFR, PDGFR, FGFR, C-KIT, and FLT-3). Approximately 30% of AML patients have a FLT-3 mutation (ITD-internal tandem duplication or catalytic domain) which drives the malignant process and confers a worse prognosis. Additionally, the inhibition of the angiogenesis component of the disease could be beneficial in all cases. Preclinical data have shown FLT3 ITD models to be ~25 fold more sensitive than FLT3 WT (Menezes, et al, Blood 2005). Our hypothesis was that AML blasts carrying FLT-3 mutations would be exquisitely sensitive to CHIR-258, but that there may also be activity against patients with wild type (wt) FLT-3.
Methods: CHIR-258 was administered orally to adult patients with relapsed/refractory AML on a 7 on/7 off schedule followed by continuous daily dosing for 28 days (1 cycle). Subsequent 28-day cycles of continuous dosing were permitted. Pharmacokinetic (PK) and pharmacodynamic (PD) assessments were serially performed and drug tolerability assessed.
Results: As of May 2005 8 patients have been treated in 2 (50mg and 100 mg) cohorts of 3–6 patients [median age: 62 years (range: 46–72), sex: 4M/4F, median prior relapses = 1 (range: 1–3), FAB subtypes: M1–1, M2–2, M5–1, M6–2, unclassifiable-1, no information-1] Five patients remain on study with a median number of treatment cycles=3 (range=1–11). There have been no DLTs to date. Dose escalation to 200 mg has been tolerated and accrual continues. Drug related adverse events include fatigue, anorexia, nausea/vomiting, and headache and were generally mild (CTC G1-2). Of the 8 patients treated, 1 had FLT-3 ITD mutation and 7 were wt for ITD and D835. A patient with AML-M6 with wt FLT-3 continues with stable disease after 11 cycles of therapy and was dose escalated from 50mg to 100mg after 8 cycles. The patient with FLT-3 ITD mutation treated at the 100mg dose had near complete clearing of blasts from marrow and peripheral blood. This patient later died due to a presumed fungal infection, not attributed to CHIR-258. Plasma exposure and Cmax increase proportionally across the dose range, and Cmax at the 100mg dose level is in the range where antitumor activity was seen in a preclinical oncogene addicted tumor models for FLT-3 ITD AML (MV4;11).
Conclusions: CHIR-258 has demonstrated activity in relapsed refractory patients with AML, both with a FLT-3 mutation and wt FLT-3. Accrual continues at the 200mg dose cohort and updated data will be presented at the meeting.
The Anti-Tumor Effects of SU11248, a Class III Receptor Tyrosine Kinase Inhibitor, Against a Variety of Human Hematological Malignancies.
Authors: Ikezoe Takayuki , Bandobashi Kentaro , Yang Yang , Saito Tsuyako , Togitani Kazuto , Tasaka Taizo , Koeffler H. Phillip , Taguchi Hirokuni 
Published: April 2020

Abstract
We studied anti-tumor effects of the class III receptor tyrosine kinase inhibitor SU11248 against a wide variety of hematological malignancies including the following leukemias: acute myeloid (THP-1, U937, Kasumi-1, MV4-11), acute lymphoblastic (NALL-1, Jurkat, BALL-2, PALL-1, -2), blast crisis of chronic myeloid (KU812, Kcl-22, K562) and adult T-cell (MT-1, -2, -4), as well as, non-Hodgkin’s lymphoma (KS-1, Dauji, Akata) and multiple myeloma (U266). Thymidine-uptake studies showed that SU11248 was active against MV4-11 and Kasumi-1 cells which possessed activating mutations of the FLT-3 and the c-Kit gene, respectively, with IC50s of approximately 30 nM. In addition, SU11248 inhibited the proliferation of Bcr/Abl-expressing KU812, Kcl-22, K562, PALL-1, and -2 cells with IC50s ranging from 2 to 5 uM. SU11248 induced apoptosis of these cells via activation of caspase 3 as measured by Annexin V staining and caspase assay. SU11248 inhibited phosphorylation of c-Abl and its downstream effectors Akt and STAT5 in these cells. Interestingly, mTOR inhibitor rapamycin enhanced the ability of SU11248 to inhibit the proliferation of Bcr/Abl-expressing cells. For example, SU11248 (2 uM, 48 h) or rapamycin (100 nM, 48 h) alone inhibited the proliferation of KU812 cells by 47 ± 6 % or 8 ± 6 %, respectively. When both were combined, their proliferation was inhibited by approximately 90 %. Furthermore, SU11248 (10 nM to 1 uM, 48 h) inhibited the proliferation of freshly-isolated leukemia cells from individuals with AML (15 cases) as well as Ph-positive ALL (1 case), who relapsed after treatment with conventional chemotherapy with imatinib. Profound growth inhibition by SU11248 (IC50s &lt;10 nM) occurred in leukemia cells (4 cases) having an in-frame tandem duplications within the juxtamembrane region of FLT3 gene. Furthermore, rapamycin potentiated the anti-proliferative effects of SU11248 in the freshly-isolated leukemia cells. Taken together, SU11248 may be useful for treatment of individuals with variety of leukemias and the combination of SU11248 and rapamycin represents a promising novel treatment strategy.
Sequential Treatment with 5-Azacytidine, Valproic Acid (VPA), and All-Trans Retinoic Acid (ATRA) in Patients with High-Risk Acute Myeloid Leukemia (AML).
Authors: Raffoux Emmanuel , de Labarthe Adrienne , Gardin Claude , Daniel Marie-Therese , Chomienne Christine , Fenaux Pierre , Degos Laurent , Dombret Herve 
Published: April 2020

Abstract
Probably through inhibition of histone deacetylases, VPA ± ATRA has been associated with clinical responses in patients with myelodysplastic syndrome (MDS) or AML (Kuendgen, Blood 2004; Raffoux, Haematologica 2005). Interestingly, VPA/ATRA-induced differentiation of AML cells has been documented in vivo (Nervi, ASH 2004 #1805). On the other hand, the combination of VPA with a demethylating agent synergistically enhances its antileukemia activity in vitro (Yang, Leukemia Res 2005). In a pilot phase, we treated 5 high-risk AML patients with a sequential combination of 5-azacytidine, VPA, and ATRA. Each treatment cycle comprised 75 mg/m2/d 5-azacytidine SC from day 1 to 7, 20 mg/kg/d VPA (then adapted on serum concentration) from day 1 to 28, and 45 mg/m2/d ATRA from day 8 to 28. Six cycles were planned, each starting at day 29 of the previous one whatever the hematological status. High-risk AML (AML-M3 excluded) was defined as:
previously untreated de novo or post-MDS AML in patients aged 65+ unfit for intensive chemotherapy; or post-MDS AML in first relapse or AML in second or subsequent relapse.
Eligibility criteria also comprised WBC&lt;30 G/L, PS&lt;2, no severe infection, liver enzyme levels ≤ 2xULN, and serum creatinine ≤ 1.5xULN. Main patient characteristics and response are indicated in the Table below:
Patient Age AML Prior Tx BM blasts Cycles Response Time to response #1 71y post-MDS 4 41% 6 CRp 4 cycles #2 73y post-MDS 0 28% 6 CR 4 cycles #3 76y de novo 2 62% 2 Progression – #4 68y post-MDS 0 26% 2 Stable – #5 55y de novo 2 20% 4+ AML-free 3 cycles
Patient #3 progressed after the 2nd cycle. Treatment was also discontinued after the 2nd cycle in patient #4, because of ovarian carcinoma diagnosis. Response was observed after at least 3 cycles in the 3 remaining patients (1 CR, 1 CRp, 1 AML-free state with platelet count normalization), all treated as out-patients. Safety profile was excellent (no significant treatment-induced cytopenia). Main side effects were pain at 5-azacytidine injection sites and constipation. This treatment approach appearing promising in terms of efficacy versus toxicity, a formal multicenter Phase 2 study has been initiated.