bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety of asparaginase Erwinia chrysanthemi in a compassionate-use trial: Subanalysis of the adolescent/young adult (AYA) and adult patient (Pt) population.
Authors: Plourde Paul V. , Jeha Sima , Hijiya Nobuko , Keller Frank G. , Rheingold Susan R. , Dreyer Zoann , Dahl Gary V. H. , Mercedes Taheri , Corn Tim 
Published: March 2020

7097 Background: The AYA population is usually defined as pts aged 16 to 39 years. NCCN guidelines recommend that AYA patients with acute lymphoblastic leukemia (ALL) be treated with ‘pediatric-inspired’ protocols that includeL-asparaginase (L-ASP) as an integral component of their multiagent chemotherapy regimen. Hypersensitivity reaction is the most common toxicity associated with L-ASP treatment, occurring in 10%–30% of pts treated with E coli–derived L-ASP, necessitating its discontinuation. In those pts, it is recommended that L-ASP derived from Erwinia chrysanthemi (Erw) be initiated since it is immunologically distinct from E coli–derived L-ASP. Methods: A large compassionate-use trial in pts with ALL or lymphoblastic lymphoma who developed a hypersensitivity reaction (ie, grade ≥2) to an E coli–derived L-ASP was conducted to evaluate the safety of Erw. Pts were excluded if they had a history of pancreatitis, previous allergic reaction to Erw, or were pregnant. Adverse events (AEs) and/or case report forms were completed for 940 pts. The Erw safety information for the full study population was previously reported. Here, we report a safety analysis of pts aged ≥16 years with the majority being AYA (94%), a population in which little Erw safety information has been presented. Results: In this compassionate-use trial, 156 pts were aged ≥16 years. These pts were primarily male (67.9%), had nonrelapsed disease (70.5%), B-lineage ALL (71.2%), and received intramuscular Erw (85.9%). 71.8% completed their planned Erw course. Reasons for discontinuation included allergic reaction (3.2%), other AEs (9.6%), other reasons (6.4%), and unknown reasons (9%). Hypersensitivity occurred in 20 (12.8%); hyperglycemia, 9 (5.8%); pancreatitis, 6 (3.8%); thrombosis, 5 (3.2%); bleeding, 1 (1%). Grade 3/4 AEs with a >5% incidence included hyperglycemia (5.8%). There were 10 deaths: 4 disease progression, 3 infection, 1 coma, 1 renal impairment, 1 unknown. Conclusions: The safety profile of Erw in pts ≥16 years was consistent with the profile in the entire study population. This compassionate-use trial permitted the completion of L-ASP in 71.8% of AYA and adult pts. Clinical trial information: NCT00693602.
The effect of BMI on systemic toxicity in AML patients receiving chemotherapy.
Authors: Dave Manish J. , Burhani Mansoor , Venugopal Parameswaran , Larson Melissa L. 
Published: March 2020

7108 Background: There are about 15,000 new cases of acute myeloid leukemia (AML) every year in the US, and about 9,000 will die annually from this disease. Because approximately 69.2% of adults in the US are overweight or obese, it is important to examine whether body mass index (BMI) can affect treatment outcomes. While there has been a study of survival based on BMI, there have been no studies to examine the effect of BMI on systemic toxicity with induction chemotherapy. Methods: 91 patients with AML were treated with a high-dose cytarabine and mitoxantrone regimen from 2008-2012. Prior to receiving induction chemotherapy, each patient’s BMI was recorded. All patients in this study were treated with doses based on actual weight. Two doses of cytarabine 3 gm/m2 were given 12 hours apart followed by one dose of mitoxantrone 30 mg/m2on days 1 and 5. The lowest platelet and hemoglobin after each induction treatment was recorded, along with the number of red blood cell (RBC) and platelet transfusions. Systemic toxicity was further examined by presence of infection and/or bleeding. Results: The BMI groups are based on the World Health Organization classifications. Of the 91 AML patients in this study, 2 were underweight, 35 were normal weight, 29 were overweight, 16 were obese, and 9 were morbidly obese. The mean number of platelet transfusions for the underweight group was 8.5, 10.6 for normal weight, 13.8 for overweight, 12.1 for obese, and 5.0 for the morbidly obese group. The mean number of RBC transfusions for the underweight group was 6.0, 9.1 for normal weight, 11.2 for overweight, 9.1 for obese, and 9.2 for the morbidly obese group. The rates of infection by positive cultures were the following: 51% of normal, 58% of overweight, and 68% of obese patients. Rates of infection by imaging were 37% of normal, 31% of overweight, and 26% of morbidly obese patients. The percentage of patients bleeding after induction was 20% in the normal weight group, 31% for overweight, 12.5% of obese, and 33% of morbidly obese patients. Conclusions: The results of this study show that there is no difference in toxicity amongst the different BMI groups. The data demonstrates the importance of dosing chemotherapy on actual, rather than ideal, body weight.
Clinical implications of discrepancy in the diagnosis of primary myelofibrosis between referral and tertiary center.
Authors: Jeyakumar Ghayathri , Arana Yi Cecilia Ysabel , Medina Pedro , Cortes Jorge E. , Pierce Sherry , Brandt Mark , Kantarjian Hagop M. , Verstovsek Srdan 
Published: March 2020

7115 Background: Primary Myelofibrosis (PMF) is a stem cell-derived clonal disorder with broad disease spectrum and the diagnosis is based on a combination of clinicopathological criteria. The aim of the study is to evaluate the frequency of diagnostic discrepancies between the referring center and a tertiary center and the impact in clinical outcomes in patients with PMF. Methods: 560 patients (pts) with Primary Myelofibrosis (PMF) referred to MD Anderson Cancer Center from January 2007 to December 2011 were evaluated. Results: 70 (12.5%) pts were discordant and 490 (87.5%) were non-discordant. The median age was 67 years (range, 32-88): 39 (56%) discordant versus 326 (67%) non-discordant pts were older than 65 years (p<0.075). Cytogenetics in the discordant group were favorable in 40 (57%) and unfavorable in 27 (39%) and in the non-discordant group 309 (63%) and 162 (33%) respectively (p<0.36). The DIPSS-plus score in the discordant group was low in 3 (4%), intermediate-1 in 11(16%), intermediate-2 in 27 (39%), and high in 26 (37%), and in the non-discordant group 12 (2%), 63(13%), 251 (51%) and 161 (33%) respectively (p < 0.33). JAK2V617F was positive in 46 (66%) cases of discordant group and in 381 (78%) of the non-discordant group (p<0.027). Peripheral blasts >1% were present in 378 (77%) non-discordant and in 36 (51%) discordant cases (p<0.001). The referring diagnosis for discordant cases were MPN unclassified in 18(26%), PV in 12 (17%), ET in 7 (10%), CML in 5 (7%), MDS/MPN unclassified in 15 (21%), BCR-ABL negative CML in 2 (32%), CMML in 2 (3%) and MDS in 8 (11%) cases. The median OS in the non-discordant group versus discordant group after the appropriate diagnosis were 44.6 and 36.6 months respectively (p<0.069). Conclusions: The results confirm that the diagnosis of PMF is complex. The rate of discrepancy is high confirming the need for complete evaluation in a tertiary center. The presence of peripheral blasts and JAK2 mutation appear to helped in making proper diagnosis before referral.
A phase II study of mocetinostat, an oral isotype-selective histone deacetylase (HDAC) inhibitor, in combination with 5-azacitidine in patients with myelodysplastic syndrome (MDS).
Authors: Luger Selina M. , O'Connell Casey Lee , Klimek Virginia , Cooper Maureen A. , Besa Emmanuel C. , Rossetti James M. , Reid Gregory K. , Humphrey Rachel , Martell Robert E. , Garcia-Manero Guillermo 
Published: March 2020

7116 Background: Mocetinostat (MGCD0103) is an orally available, isotype-selective, non-hydroxamate HDAC inhibitor targeting HDACs 1,2, 3 and 11 with single agent activity in AML and both Hodgkin’s and non-Hodgkin’s lymphomas. Preclinical evaluation demonstrating in vitro and in vivo synergy and antileukemic activity with demethylating agents, including 5-azacitidine (AZA), prompted clinical evaluation of mocetinostat + AZA in MDS and AML. Methods: This open-label, Phase II trial enrolled patients with MDS or AML. Patients received AZA (75 mg/m2SC; days 1-7 every 28 days) and mocetinostat (90-110 mg 3x/wk starting on AZA day 5). Anticancer activity, safety and pharmacokinetics and pharmacodynamics were evaluated. We report here on the MDS cohort. Results: Twenty patients with MDS were enrolled. Eight patients had received prior therapy for MDS including decitabine (n=1), lenalidomide (n=3), tipifarnib (n=2) and cytarabine (n=2). Median age was 70.5 yrs (range 41-81). Disease control rate (defined as CR + marrow-CR + PR + SD) was 80% (16/20). Ten patients (50%) had baseline marrow blast counts ≥10% (protocol-defined high risk). Responses in high-risk patients included 5 (50%) with CR + marrow-CR and 2 (20%) with SD. Six patients (30%) had an on-treatment marrow blast count of 0. These included 3 patients in the high-risk category, with baseline blast counts of 11%-15%. CR was observed in one patient, a 74-yr-old male with previously untreated RAEB. In this patient, marrow blasts fell from a baseline of 11% to 0% following 1 cycle of treatment; CR with normalization of all cell lines was achieved by late Cycle 3. He remained on study for 1 yr. Most drug-related AEs in the study were grade 1 or 2. The most common drug-related grade 3/4 events were nausea (15%), vomiting, fatigue, anemia, thrombocytopenia and febrile neutropenia (10% each). There was one death (5%), due to pneumonia that was not felt by the investigator to be drug related. Conclusions: The combination of mocetinostat and 5-azacitidine in patients with MDS demonstrated an acceptable safety profile and encouraging evidence of clinical benefit. Further clinical studies are warranted. Clinical trial information: NCT00324220.
Neoadjuvant chemotherapy with or without preoperative irradiation in stage IIIA/N2 non-small cell lung cancer (NSCLC): A randomized phase III trial by the Swiss Group for Clinical Cancer Research (SAKK trial 16/00).
Authors: Pless Miklos , Stupp Roger , Ris Hans-Beat , Stahel Rolf A. , Weder Walter , Thierstein Sandra , Xyrafas Alexandros , Frueh Martin , Cathomas Richard , Zippelius Alfred , Roth Arnaud , Bijelovic Milorad , Ochsenbein Adrian , Meier Urs R. , Mamot Christoph , Rauch Daniel , Gautschi Oliver , Betticher Daniel C. , Mirimanoff Rene-Olivier , Peters Solange ,   on behalf of the SAKK Lung Cancer Project Group
Published: March 2020

7503 Background: For stage III/N2 NSCLC neoadjuvant chemotherapy (NCT) followed by radical surgery is one standard treatment approach. In our previous trial, this strategy led to a median survival of 33 months (Betticher et al. JCO 2003). We now investigated whether the addition of preoperative radiotherapy (RT) would improve outcome. We report the results of a planned interim analysis on data of the first 219 patients (pts). The trial was closed to accrual in December 2012 due to futility after enrollment of 232 of 240 planned pts. Methods: Pts with pathologically proven, resectable stage IIIA/N2 NSCLC, performance status 0-1, adequate heart, kidney, liver and bone marrow function were randomized 1:1 to receive 3 cycles of NCT (cisplatin 100 mg/m2 and docetaxel 85 mg/m2 d1, q3weeks) followed by accelerated concomitant boost RT (44 Gy/22 fractions in 3 weeks) or NCT alone, with subsequent surgery for all pts. The primary endpoint was event-free survival (EFS). Results: 23 centers included 219 pts. Median age was 60 years. Pts characteristics were well balanced. Toxicity to CT was substantial, but 91% completed 3 cycles of NCT. RT-induced grade 3 esophagitis was seen in 5 pts, grade 3 skin toxicity in 2 pts. One pt in each treatment arm died during NCT, there was one postoperative death (arm NCT alone). The efficacy results are summarized below, all comparisons are statistically non-significant. Conclusions: This is the first completed phase III trial to investigate the value of the addition of neoadjuvant radiotherapy to CT and surgery. RT did not improve EFS or survival, nor did it reduce the local failure rate. Nevertheless, the overall survival rates of our neoadjuvant chemotherapy strategy confirm our previous report, and are among the best results reported to date in a multicenter setting. Clinical trial information: NCT00030771. [Table: see text]
Custom (Molecular Profiling and Targeted Therapy for Advanced Non-Small Cell Lung Cancer, Small Cell Lung Cancer, and Thymic Malignancies) trial.
Authors: Giaccone Giuseppe , Lopez-Chavez Ariel , Thomas Anish , Rajan Arun , Raffeld Mark , Duffy Regan M. , Morrow Betsy , Wang Yisong , Carter Corey Allan , Guha Udayan , Killian Keith , Lau Christopher Y. , Abdullaev Zied , Xi Liqiang , Pack Svetlana , Meltzer Paul S. , Corless Christopher L. , Beadling Carol , Warrick Andrea , Szabo Eva 
Published: March 2020

7513 Background: CUSTOM is the first completed prospective clinical trial using molecular selection for treatment assignments into multiple targeted therapy arms and in multiple cancer histological subtypes concurrently. Methods: All patients with advanced NSCLC, SCLC or TM were eligible to participate in the study. Oncogenic mutations, amplifications or translocations in 12 genes detected in CLIA-certified laboratories were used to assign patients to 1 of 5 biomarker/treatment groups per histological subtype: EGFR mutations/erlotinib; KRAS, NRAS, HRAS or BRAF mutations/AZD6244; PIK3CA, AKT or PTEN mutations/MK2206; ERBB2 mutations or amplifications/lapatinib; and KIT or PDGFRA mutations/sunitinib; or to standard-of-care therapy. For each arm, the study was conducted as an optimal two-stage phase II trial in favor of a response rate of 40% or more. Results: 668 patients were enrolled at two academic institutions. The most frequent genetic alterations in NSCLC were KRAS and EGFR mutations (25.2 and 19.7% respectively), ALK rearrangements 7.8%, HER2 amplifications 2.7% and mutations in PIK3CA 2.5%, BRAF 1.9%, HRAS 1.5%, ERBB2 1.7%, AKT1 0.4%, and NRAS 0.7%. PTEN mutation analysis was only feasible in 13 patients with NSCLC of which 3 were positive (23%). The most frequent genetic alterations in SCLC were mutations in PIK3CA 6.5%, ERBB2 amplifications 5.3% and mutations in HRAS 3.4%, AKT1 2.2%, BRAF 2% and KRAS 2%. The most frequent genetic alterations in TMs were HER2 amplifications 7.7% and mutations in HRAS 4.7%, PIK3CA 1.4% and EGFR 1.4%. Only 6.2% (n=42) of patients met criteria for enrollment into the treatment arms of the study. Efficacy analyses including response rates will be presented. Conclusions: CUSTOM is the first completed prospective clinical trial demonstrating the feasibility of conducting efficacy analyses of multiple biomarker-matched therapies in multiple cancer histological subtypes concurrently. CUSTOM is also the largest prospective molecular profiling study of patients with SCLC and TMs. Clinical trial information: NCT01306045.
A DNA-repair prognostic signature for early-stage NSCLC patients, in IFCT-0002 trial of neoadjuvant chemotherapy.
Authors: Zalcman Gerard , Levallet Guenaelle , Fouret Pierre , Antoine Martine , Brambilla Elisabeth , Bergot Emmanuel , Galateau-Salle Francoise , Lavole Armelle , Quoix Elisabeth A. , Debieuvre Didier , Mazieres Julien , Moro-Sibilot Denis , Pujol Jean-Louis , Braun Denis , Beau-Faller Michele , Baudrin Laurence , Morin Franck , Westeel Virginie ,   Intergroupe Francophone de Cancérologie Thoracique (IFCT)
Published: March 2020

7515 Background: IFCT-0002 trial compared two perioperative CT regimens, CDDP-Gemcitabine vs.CBDCA-Paclitaxel in 528 stage I-II NSCLC patients. Paraffin-embedded post-chemo specimens were collected in the 490 non-complete responder patients for tissue expression studies of DNA-repair proteins. Methods: Surgical specimens were processed for immunohistochemistry as previously published. Variables were studied as continuous variables. Cut-off values were validated by bootstrap. Multivariate backward Cox regressions were used to adjust for patients’ characteristics associated with the corresponding outcome at p<0.20 in univariate analysis. Discrimination of the proposed Cox models was estimated using the c-indexes corrected for over-optimism by a resampling procedure. Median follow-up was 72.0 months, 95%CI [69.7-73.5]. Results: ERCC1, MSH2, XRCC5/Ku80 and BRCA1 immunostainings were available in 413, 356, 396 and 221 specimens. Expressed as a continuous variable, only MSH2 staining score correlated with overall survival. XRCC5 showed no influence on survival. When dichotomised, low BRCA1 (under median value) and ERCC1 (ERCC1=0), while high MSH2 protein expression (over median value), adversely affected overall survival with respective adj. HRs of 1.56, 95%CI [1.05-2.32], p=0.028 ; 1.37 95%CI [1.01-1.86], p=0.042 and 1.53, 95%CI [1.12-2.09], p=0.007. No interaction was found between the attributed treatment and any of the 4 markers. High MSH2 and low ERCC1 variables were tested in 200 bootstrap multivariate Cox models and correlated with OS in respectively 87% and 78.5% (c-index=0.570), whereas stage predicted survival in only 49% of those theoretical samples. A prognostic score led to the definition of three groups of high-, intermediate- and low-risk of death with respective HRs of 2.83, 1.60 and 1. Median OS were respectively 28.3 months, 71.5 and not reached, 5-y survival rates were 34.2%, 54.8% and 66.3% (Log-Rank p<0.0001). Conclusions: With a 6-year median follow-up, a prognostic score derived from multivariate Cox regression, validated by bootstraping, accurately discriminates a sub-group with high risk of death according to tumor expression of MSH2 and ERCC1.
RTOG 0618: Stereotactic body radiation therapy (SBRT) to treat operable early-stage lung cancer patients.
Authors: Timmerman Robert D. , Paulus Rebecca , Pass Harvey I. , Gore Elizabeth , Edelman Martin J. , Galvin James M. , Choy Hak , Straube William , Nedzi Lucien Alexander , McGarry Ronald , Robinson Cliff Grant , Schiff Peter B. , Bradley Jeffrey D. 
Published: March 2020

7523 Background: The Radiation Therapy Oncology Group (RTOG) protocol 0618 was a phase II trial utilizing SBRT to treat early stage non-small cell lung cancer in operable patients (pts). Methods: All pts were deemed operable by a thoracic surgeon utilizing specific criteria. Pts with biopsy proven peripheral T1-T3, N0, M0 tumors were eligible. The prescription dose was 18 Gy X 3 fractions delivered in 1½-2 weeks. The primary endpoint was 2-year primary tumor control (PTC, avoidance of in-field (INF) and marginal failure (MF)) with overall and progression free survival (OS, PFS), adverse events (AE), local (LF), regional (RF), and distant failure (DF) as secondary endpoints. Early surgical salvage was directed as part of protocol design in the event of LF after SBRT. Results: The study opened December 2007 and closed May 2010 after accruing a total of 33 pts. Of 26 evaluable pts, 23 had T1, and 3 had T2 tumors. Median age was 72 years. Median FEV1, DLCO at enrollment were 72%, 68% predicted, respectively. 4 pts (16%) had SBRT related grade 3 AEs while 0 had grade 4-5 AEs. Median follow-up was 25 months. 2 pts have been scored with INF (11.7 and 12.4 months post SBRT) and 1 with MF (32.5 months post SBRT) giving an estimated 2-year primary tumor failure rate of 7.7% (95% CI: 0.0%, 18.1%). 2-year estimates of LF (primary tumor plus involved lobe failure), RF, and DF are 19.2% (95% CI: 3.7%, 34.7%), 11.7% (95% CI: 0.0%, 24.5%), and 15.4% (95% CI: 1.2%, 29.6%), respectively. Only one patient was eligible for attempted surgical salvage and underwent lobectomy 1.2 years post SBRT complicated by a grade 4 cardiac arrhythmia. 2-year estimates of PFS and OS are 65.4% (95% CI: 44.0%, 80.3%) and 84.4% (95% CI: 63.7%, 93.9%), respectively. Conclusions: SBRT given appears to be associated with a high rate of PTC, moderate treatment related morbidity, and infrequent need for surgical salvage in operable early stage lung cancer pts with peripheral lesions. These results support ongoing enrollment into the ACOSOG Z4099-RTOG 1021 trial comparing SBRT to sublobar resection in high risk operable pts. The project was supported by RTOG grant U10 CA21661, CCOP grant U10 CA37422, and ATC U24 CA81647 from the National Cancer Institute. Clinical trial information: NCT00551369.
The effects of physician-delivered brief smoking cessation on ACRIN/NLST participants’ smoking behaviors.
Authors: Gareen Ilana F , Park Elyse R. , Gorelick Jeremy , Japuntich Sandra , Lennes Inga Tolin , Baum Sarah , Sicks JoRean , Rigotti Nancy 
Published: March 2020

7525 Background: The National Lung Screening Trial (NLST) demonstrated a 20% relative reduction in lung cancer mortality for current and former heavy smokers screened with low-dose CT vs. radiography. The NCCN and ACS recently released lung screening guidelines which promote smoking cessation counseling, but there is no information about the prevalence or effectiveness of brief physician-delivered smoking cessation interventions, such as the 5As (Ask, Advise, Assess, Assist, and Arrange follow-up) among lung screening patients. Methods: Among 8,878 NLST participants from 23 ACRIN sites who were smoking at enrollment, we conducted a longitudinal examination of the 1) rates and patterns of each reported 5A receipt and 2) association between each A and quitting. Using a case-control logistic regression, which matched participants according to trial arm; sociodemographic; medical; and smoking characteristics, we compared self-reported point-prevalence abstinence following 5A receipt. Results: Participants were 54% male, 90.6% white, and mean age 60.8 years. Receipt of 5As was consistent for the first 3 study years; rates of Ask (75%) and Advise (74%), exceeded rates of Assess (64%), Assist (58%), and Arrange follow-up (13%). Receipt of Ask, Advise, and Assess did not significantly increase the odds of a participant quitting smoking. Assist (cessation counseling, medication) increased the odds of quitting smoking by 22% (p=0.0002), and Arrange follow-up increased the odds of quitting by 20% (p=0.002). Older age and lower nicotine dependence were significantly associated with quitting, after accounting for the effectiveness of Assist (OR=1.34, CI: 1.16-1.55; OR== 0.95, CI: .93-.97) and Arrange follow-up (OR=1.34, CI: 1.16, 1.54; OR=.95, CI: .93-.97). Conclusions: Among high risk patients undergoing lung screening, Advice to quit was not associated with improved odds of smokers’ quitting. Assist and Arrange follow-up were associated with improved odds of smokers’ quitting, but unfortunately, rates of receipt of these As were low. Physician-delivered smoking cessation assistance and follow-up has the potential to enhance the effectiveness and cost effectiveness of lung screening. Clinical trial information: CDR0000257938.