bluuebunny/crossref_metadata_2025_split huggingface dataset:
Innovative approach to determine overall survival (OS) benefit for orphan diseases using case match control analyses (CMCA): The PROPEL experience of pralatrexate in patients with relapsed/refractory (R/R) peripheral T-cell lymphoma (PTCL).
Authors: O'Connor Owen A. 
Published: September 2018

7521 Background: The challenges in conducting randomized studies in orphan diseases poses limitations on our ability to identify the most promising treatments. Randomized studies in this setting can take protracted periods of time to complete, can be very expensive while not offering the promise of significant commercial return, and could become irrelevant as the pace of scientific advancement continues. The majority of drugs approved in this setting are often approved on surrogate end-points like progression free survival (PFS) or complete response (CR) rates in single arm studies. CMCA are statistically stronger than single arm studies, and can be highly informative in this setting. Methods: We established an integrated international database of patients with R/R PTCL to clarify the OS advantage of pralatrexate using original data from the PROPEL study, an international, multicenter phase II study in patients with R/R PTCL. The propensity score was used to match cases and controls. Cases were matched based on histology, number of previous treatments received, age at diagnosis and sex. Results: With 1:1 ratio match, we identified 83 cases and 83 controls. In total, 83 patients out of 109 treated on the PROPEL study were successfully matched. OS was plotted for each of the two study populations. The survival curves for the control population were found to be nearly identical to that reported for this population from other datasets. The overall survival was 4.04 months (95% CI 2.83, 5.78), which is consistent with historical controls describing this population. The median OS in for the pralatrexate treated cohort in this analysis was 16.6 months (95% CI: 11.99-25.56). The OS was a highly statistically significant difference between these two populations, with a hazard ratio of 0.426 (95% CI: 0.296-0/61). This difference held up for each of the major histologic subsets, including PTCL-NO and angioimmunoblastic PTCL. Conclusions: This approach can be used to better understand how new drugs in orphan diseases perform in heterogeneous patient populations. Clinical trial information: NCT00364923.
Digital sorting and copy number profiling of purified, PD-L1 positive, Reed Sternberg cells in classical Hodgkin lymphoma.
Authors: Mangano Chiara , Lanzellotto Rossana , Bolognesi Chiara , Forcato Claudio , Ferrarini Alberto , Del Monaco Valentina , Petrini Edoardo , Tononi Paola , Buson Genny , Medoro Gianni , Fontana Francesca , Manaresi Nicolò 
Published: September 2018

7528 Background: Classical Hodgkin Lymphoma (cHL) is one of the disease in which the check-point inhibitors have been demonstrated to be more successful. Lately, it has been reported that in malignant Reed-Sternberg Cells (RSCs), PD-1 ligands (PD-Ls) are overexpressed and that chr.9 amplification correlates with advanced stages of the disease, when the standard therapy have already failed. Unfortunately, the detection of the genetic alterations in RSCs is challenging, as one of the hallmark of cHL is the presence of a small number of malignant cells sparse in an abundant and heterogeneous immune infiltrate. Here we present a method for the isolation and the genetic characterization of purified RSCs, which overcomes the limitations posed by the low-cellularity of cHL biopsies, and could be helpful for earlier detection of genetic alterations and adoption of immunotherapy. Methods: FFPE tissue sections from cHL patients were dissociated down to single-cell suspension and stained using anti-CD30 and anti-PD-L1 antibodies. Beyond the positivity to CD30 and PD-L1, RSCs were selected according to morphological criteria such as cell size and the presence of polylobate nuclei compared to surrounding lymphocytes. Target cells were isolated using the DEPArray™ cell sorter, as single cells or in small pools of cells. Recovered cells were whole genome amplified ( Ampli1™ WGA), and genome-wide copy-number aberrations (CNAs) profiles were obtained using Ampli1™ LowPass kit on IonTorrent platform. Results: After the dissociation, RSCs maintained cell morphology and therefore, we were able to discriminate them from the heterogeneous immune infiltrate. RSCs appeared as large multinucleated cells with a big central nucleolus surrounded by a clear halo; cell diameter and ploidy were computed from the images. Pools of lymphocytes and pools of CD30+/ PD-L1+ RSCs were isolated. Sequencing results confirmed the expected flat profile for lymphocytes, while RSCs showed an aberrant profile with multiple losses and gains. Conclusions: The analysis of purified RSCs, could offer a valuable tool to uncover genetic alterations hidden by cHL immune infiltrate, for earlier adoption of more effective treatment regimens.
Activity of the immunologic doublet of lenalidomide plus obinutuzumab in relapsed follicular lymphoma: Results of a phase I/II study.
Authors: Fowler Nathan Hale , Neelapu Sattva Swarup , Samaniego Felipe , Forbes Sheryl , Hagemeister Fredrick B. , Fayad Luis , Feng Lei , Turturro Francesco , Westin Jason R. , Arafat Janine , Neal Eleanor , Nastoupil Loretta J. 
Published: September 2018

7531 Background: Relapsed follicular lymphoma (FL) remains a challenge and salvage regimens are associated with toxicity and limited control. Outcomes are linked to the immune microenvironment and lenalidomide and rituximab are highly active in FL. Obinutuzumab has increased ADCC compared to rituximab in preclinical models and is approved for relapsed FL. We hypothesized that the immunologic properties of obinutuzumab and lenalidomide would be synergistic. The study objective was to determine the MTD of lenalidomide with obinutuzumab in relapsed FL and describe the efficacy of the combination. Methods: This open label phase I/II study enrolled Gr 1-3a FL. Transformation was excluded. Lenalidomide was given on D 2-22 with 1000mg obinutuzumab on D1, 8, 15, and 22 of cycle 1 and on D1 for up to 12 cycles (28 days/cycle). Obinutuzumab was given every 2 months thereafter for up to 30 months in pts who responded following doublet therapy. During dose escalation, 3 cohorts were planned with 10, 15 and 20mg of lenalidomide. Phase II planned to enroll 30 pts at MTD with efficacy and safety as primary endpoints. Results: All 36 pts with FL enrolled (6 in dose escalation and 30 at MTD), and are eligible for efficacy and safety analysis. The median age was 65 with a median of 2 prior therapies. No DLTs were observed in phase I, and 20 mg of lenalidomide was used for phase II. To date, the most common all grade non-heme toxicities were fatigue(83%), diarrhea(67%) and rash(53%). Grade 3+ toxicities included neutropenia (23%), infection (11%) and fatigue (8%). The overall response rate was 100% with 78% (95%CI 60.85-89.88%) of pts attaining complete response (CR/Cru). All pts with rituximab refractory FL (13) responded. At a median follow up of 14 months, 10 pts progressed. The estimated 24 month PFS is 61% (95% CI 43-87%). Conclusions: Lenalidomide and obinutuzumab is highly active with durable remissions in relapsed FL, with all pts responding and 78% achieving CR. The majority of pts remain on therapy and the combination appeared safe. Correlatives are ongoing to identify biomarkers of response and frontline studies of the combination are currently enrolling. Clinical trial information: NCT01995669.
Elucidation of distinct mutational patterns between diffuse large B cell lymphoma subtypes utilizing circulating tumor DNA.
Authors: Soo Joanne , Kurtz David Matthew , Scherer Florian , Craig Alexander F.M. , Jin Michael C. , Westin Jason R. , Rossi Davide , Gaidano Gianluca , Advani Ranjana H. , Diehn Maximilian , Alizadeh Ash A. 
Published: September 2018

7538 Background: Patients with diffuse large B cell lymphoma (DLBCL) exhibit significant differences in clinical outcome based on cell-of-origin (COO). Patients are categorized as having germinal-center-like (GCB) or activated-B-cell-like (ABC) disease based on RNA microarray and histopathological analyses of tumor biopsies. We recently described an accurate sequencing-based method for determination of COO in DLBCL utilizing stereotyped differences in mutations (Scherer et al., 2016). Here, we further explore the mutational patterns in patients with differing molecular subtypes of DLBCL based on sequencing of circulating tumor DNA. Methods: We applied cancer personalized profiling by deep sequencing (CAPP-Seq) to pretreatment plasma samples and matched germline from a cohort of 115 patients with DLBCL. We then identified somatic alterations, which were used to determine COO molecular subtypes as previously described. Finally, we compared mutational patterns in patients with GCB and non-GCB DLBCL. Results: We detected a significantly greater number of total mutations (GCB: 1766 ± 160 mutations per Mb of targeted sequencing; non-GCB: 1364 ± 150 mutations per Mb of targeted sequencing; p < 0.05) and coding mutations (GCB: 145 ± 21 mutations per Mb of targeted sequencing; non-GCB: 28 ± 8.5 mutations per Mb of targeted sequencing; p < 0.001), particularly in immunoglobulin (Ig) regions (p < 0.05). In addition, GCB and non-GCB samples exhibited distinct mutational patterns within Ig regions. GCB samples were enriched for mutations in regions of switch mu (Sμ) (p < 0.01) and IGHV2-70 (p < 0.01), while non-GCB samples were enriched for mutations in regions of IGHG3 (p < 0.03), IGHV4-34 (p < 0.03), and IGLL5 (p < 0.05). GCB samples were also significantly enriched for coding mutations in SOCS1 (p < 0.01), a gene not included in our original COO classifier. Conclusions: Patients with GCB and non-GCB DLBCL exhibit distinct mutational patterns across both Ig and non-Ig loci of the genome. These differences in mutational patterns can be used to classify molecular subtypes noninvasively, potentially providing further utility to noninvasive genotyping and liquid biopsies.
Anti-infective prophylaxis with aciclovir and cotrimoxazole to reduce the rate of infections and therapy-associated deaths in elderly patients with DLBCL undergoing R-CHOP immunochemotherapy.
Authors: Murawski Niels , Amam Josif , Altmann Bettina , Ziepert Marita , Haenel Mathias , Viardot Andreas , Neubauer Andreas , Held Gerhard , Truemper Lorenz , Schmidt Christian , Kanz Lothar , Hallek Michael , Schmitz Norbert , Heintges Tobias , Koelbel Christian , Poeschel Viola , Pfreundschuh Michael 
Published: September 2018

7539 Background: To study if anti-infective prophylaxis with aciclovir and cotrimoxazole is effective in preventing infections in pts. receiving R-CHOP, we compared infections and treatment-related deaths in two prospective DSHNHL trials with different anti-infective strategies. Methods: 61-80-yo. pts. in RICOVER-60 study [Lancet Oncol 2008; 9:105-116] received 6 or 8 cycles of CHOP-14 with or without 8 applications of rituximab. Anti-infective prophylaxis consisted of ciprofloxazine (500 mg/d) during days of severe leukocytopenia ( < 1000 / mm3). In OPTIMAL > 60, pts. were randomized to 6xCHOP-14 or 6xCHLIP-14 (conventional substituted by liposomal vincristine) in combination with rituximab, 8 applications q 2 wks. or 12 applications between days -4 and 238 /2x2 factorial design). In OPTIMAL > 60, anti-infective prophylaxis consisted of cotrimoxazole (2 double strength doses twice every week p. o.) and aciclovir (4 x 400 mg/d p.o.) in addition to ciprofloxazine. Results: In RICOVER-60, grade 3&4 infections in 232 patients (IPI = 1 and bulky disease or IPI > 1) receiving 6xCHOP-14+8R were 6% (76/1200) per cycle and 28% (60/218) per patient. With intensified anti-infective prophylaxis in OPTIMAL > 60 there were no differences with respect to infections between the 4 treatment arms. Grade 3&4 infections were 4% (83/1987) per cycle (p = 0.007) and 18% (64/365 pts. with toxicity documentation) per patient (p = 0.004). Treatment-related deaths (defined as all non-lymphoma associated deaths during and within 2 months after the end of chemotherapy) went down from 15/232 (7%) in RICOVER-60 to 7/385 (2%; p = 0.003) in OPTIMAL > 60. Conclusions: Anti-infective prophylaxis with cotrimoxazole and aciclovir in addition to ciprofloxazine significantly reduced the rates of severe infections and treatment-related deaths in elderly patients receiving R-CHOP supporting the use of this anti-infective strategy in all DLBCL patients receiving R-CHOP. Clinical trial information: NCT01478542.
Frequency of secondary malignancies (SM) in patients with large granular lymphocytic leukemia (LGLL): A single institutional experience.
Authors: Isenalumhe Leidy Lismeri , Van den Bergh Magali , Wang Emilie , Schaible Braydon , Ma Zhenjun , Zhang Ling , Sokol Lubomir 
Published: September 2018

7542 Background: Large granular lymphocyte (LGL) disorders represent a spectrum of aberrant T-cell or natural killer cell lymphocytic proliferations. LGLL is classically associated with autoimmune conditions and bone marrow (BM) failure disorders. SM has been reported in association with LGLL in about 10%. The aim of this study is to evaluate the impact of SM on the clinical course of LGLL. Methods: This is a retrospective study of LGLL patients (pts) evaluated at Moffitt Cancer Center between January 1995 and May 2016. The diagnostic clinico-pathological criteria consisted of LGL count > 0.5 k/μL with T-cell receptor gene rearrangement. Lower absolute number of clonal circulating LGLs with characteristic immunophenotype associated with BM involvement, cytopenias, splenomegaly and/or associated symptoms were also diagnostic. Pts with myelodysplastic syndrome were excluded. Survival analysis was performed using the Kaplan-Meier method with log-rank test. Chi-square and T-test were used to analyze association among various variables. Significant P-value was considered < 0.05. Results: Out of 668 screened pts with LGL expansions in peripheral blood, 261 met criteria for LGLL. SM were present in 44% (116/261) of LGLL pts, of which 38% were hematological and 80% arose prior to onset of LGLL. Most common solid SM included skin cancer (14%), prostate cancer (12%), and breast cancer (12%), while most common hematological SM consisted of non-Hodgkin lymphoma (17%) and chronic leukemia (14%). 5-year overall survival (OS) for all LGLL pts was 75% and 10-year OS 63%. There was a statistically significant difference in 5-year OS between LGLL pts with SM compared to without (p = 0.049), but no difference between both groups in median OS or 10-year OS. Pts diagnosed with SM prior to LGLL had worse 5-year OS (p = 0.031) and 10-year OS (p = 0.05) compared to all other LGLL pts. Conclusions: This study showed that the frequency of SM is higher than previously described, especially with onset prior to diagnosis of LGLL. Even though median age of LGLL is around 60 years, it appears that age itself cannot explain this phenomenon. Our results suggest that having a SM is a poor prognostic factor in LGLL patients.
Phase I dose escalation of ibrutinib and buparlisib in relapsed/refractory diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), and follicular lymphoma (FL).
Authors: Batlevi Connie Lee , Hamlin Paul A. , Matasar Matthew J. , Horwitz Steven M. , Gerecitano John F. , Moskowitz Craig H. , Straus David J. , Zelenetz Andrew David , Drullinsky Pamela , Copeland Amanda , Ahsanuddin Salma , Callan Devin , Freidin Benjamin , Porzio Robert , Dang Thu Oanh , Ni Ai , Rademaker Jurgen , Schöder Heiko , Dogan Ahmet , Younes Anas 
Published: September 2018

7544 Background: In vitro studies of BTK and PI3K inhibitors demonstrate synergy in non-Hodgkin lymphoma (NHL). We embarked on a phase I/Ib investigator-initiated clinical trial evaluating the combination of ibrutinib (BTK inhibitor) and buparlisib (pan-PI3K inhibitor) in relapsed/refractory (R/R) NHL. The completed dose escalation is reported. Methods: Patients (pts) were eligible if they had R/R DLBCL, MCL, or FL with ECOG≤2 and adequate organ function. Ibrutinib and buparlisib were given daily by mouth on a 28-day cycle. Dose reductions were permitted after cycle 1. Tumor response was based on Lugano Classification however CR required both PET resolution and ≥ PR by CT. Results: As of Dec 16, 2016, 13 pts were enrolled and evaluated for toxicity (DLBCL 5, FL 2, MCL 6). Dose levels and DLT per table. Six pts discontinued treatment for disease progression (DLBCL 4, FL 2). Hematologic AE ≥ grade 3 are anemia (2), leukocytosis (2), and leukopenia (4). Relevant non-hematologic AEs of any grade ≥ 20% across all pts were fatigue (77%), diarrhea (62%), anorexia (54%), rash (46%), hyperbilirubinemia (46%), gastric reflux (46%), CMV reactivation (31%), mood change (31%), and hypertension (23%). Most common related grade 3/4 toxicity is rash (N = 3). No grade 5 toxicities noted. Serious adverse events (SAE) include: grade 2 pleural effusion and grade 2 nausea (N = 1), grade 1 fever with hospitalization (N = 1), grade 2 confusion and grade 4 hyponatremia (N = 1) were unrelated to therapy. Responses noted in 13 pts: MCL (N = 6: CR 4, PR 2), FL (N = 2: SD 2), DLBCL (N = 5: SD 1). One CR was a MCL pt with CR after 2 cycles on combination therapy and continues in remission on ibrutinib alone because of buparlisib toxicity. Conclusions: Combination of ibrutinib and buparlisib while generally well tolerated has predicted toxicities of both BTK and PI3K inhibitors. The recommended phase 2 dose is ibrutinib 560 mg and buparlisib 100 mg though dose reductions for tolerability may be needed for long term oral therapies. Promising efficacy is observed in MCL. Clinical trial information: NCT02756247. [Table: see text]
Rapid, real-time central pathology review for E1412: A novel and successful paradigm for future National Clinical Trials Network diffuse large B cell lymphoma studies.
Authors: King Rebecca L. , Nowakowski Grzegorz S. , Witzig Thomas E. , Scott David W. , Little Richard F. , Hong Fangxin , Gascoyne Randy D. , Kahl Brad S. , Macon William R 
Published: September 2018

7547 Background: E1412 statistical design is based on results of lenalidomide/RCHOP (R2CHOP) vs RCHOP in ABC-DLBCL as determined by NanoString gene expression profiling (GEP). Central pathology review (CPR) was conducted to confirm diagnosis and to ensure adequate tissue for GEP. Initially, CPR occurred after randomization and treatment initiation. Due to high ineligibility rate (IR), the protocol was amended to include real-time CPR to determine patient eligibility prior to study enrollment. We describe the revision and how it affected the IR. Methods: Pre-amendment, CPR was done retrospectively. Post-amendment, CPR was done prior to enrollment, in real time, on a submitted tissue block, H&E, and CD20 slides. Based on CPR, if a diagnosis of DLBCL was confirmed, and sufficient tissue remained for GEP, a patient was deemed eligible and the submitter was notified by fax. Protocol goal was notification within 2 working days (WD) of receipt of materials at the CPR site. Results: Pre-amendment, 219 patients were enrolled. Material was typically received at the CPR site 6-9 months after patient registration. The IR with CPR was 36% for all those enrolled, and 26% for patients with adequate tissue for GEP. Post-amendment, 218 patients were submitted for CPR: 145 (67%) were eligible; 73 (33%) were ineligible. Reasons for ineligibility included insufficient tissue (n=27) or a diagnosis other than de novo DLBCL (n=46). Notification of eligibility occurred in a median of 2 WD (Mean 2 WD; Range 1-5 WD). 90% were notified within the protocol goal of 2 WD. GEP for all enrolled was completed within 6 weeks of CPR. Conclusions: The success of this novel, real-time CPR serves as a model for the future of NCTN DLBCL trials. When CPR is performed rapidly prior to enrollment, study slots may more accurately reflect the target population and eliminate excess costs. In the precision medicine era, rapid collection of relevant pathology and biomarker data is essential to trial success. Study Coordinated by ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs), supported by NCI grant # CA180820, CA180794, CA180790, CA180799, CA180833.
Survival outcomes for various treatment modalities in early-stage grade 3 follicular lymphoma (FL3): a National Cancer Database (NCDB) study.
Authors: Giri Upama , Vick Eric , Lee Sophia SeoHyeon , Altahan Alaa , VanderWalde Noam Avraham , Dickson Paxton Vandiver , Deneve Jeremiah Lee , Martin Michael Gary 
Published: September 2018

7551 Background: The prognosis, response to therapy and curability of FL3 is controversial. 5-year Overall Survival (OS) in the literature ranges from 35-72% (Ganti 2006). The aim of this study was to compare the OS for patients with early-stage FL3 managed with single- and multi-agent chemotherapy (CT) with and without radiotherapy (RT). Methods: We identified patients (pts) diagnosed with stage I & II FL3 between 2004 – 2012 from the NCDB and categorized into 3 groups based on therapy – pts given single agent CT with or without RT were combined due to small sample sizes (SA±RT), multi-agent CT without RT (MA-RT), and multi-agent CT with RT (MA+RT). We calculated OS for each group using Kaplan-Meier method and compared the results using Log Rank test. Cox regression model was used to identify factors which had significant impact on OS. Results: 1,563 pts were identified – 827 (53%) with stage I and 736 (47%) with stage II FL3. Median age was 61 yrs (range 18-90yrs); 750 (48%) males, 813 (52%) females; 1423 (91%) whites, 76 (5%) blacks. 112 (7%) received SA±RT, 886 (57%) MA-RT and 565 (37%) MA+RT. 5-year OS for MA+RT (95%) was significantly more than MA-RT (87%; HR 0.33, P<0.001) or SA±RT (88%; HR 0.38, P=0.007). Cox regression indicated that age (HR 1.05, P<0.001), sex (HR 0.66 for females, P=0.02), comorbidities (HR 1.60 for Charlson Deyo Score 1, P=0.04; HR 3.07 for Score 2, P=0.001), stage (HR 1.79, P=0.001), insurance status (HR 0.22 for insured, P<0.001) and increasing year of diagnosis (HR 0.92, P=0.03) also had significant impact on OS. Median radiation dose for the MA+RT was 36Gy (interquartile range 30.6 – 36Gy), and the proportion of patients who received greater than 36Gy decreased from 55% in 2004 to 38% in 2012 and at the same time, the proportion of patients who received intensity modulated RT increased from 5% in 2004 to 15% in 2012. Use of MA CT declined (2004 95% v 2012 89%, P=0.02) but there was no significant trend in use of RT (2004 39% v 2012 34%) during the periods studied. Conclusions: For pts with early-stage FL3, there was an association of improved survival with the use of MA+RT over other treatment strategies and appear to have outcomes superior to what has been previously reported.