bluuebunny/crossref_metadata_2025_split huggingface dataset:
Developmental subtypes assessed by DNA methylation-iPLEX forecast the natural history of chronic lymphocytic leukemia
Authors: Giacopelli Brian , Zhao Qiuhong , Ruppert Amy S. , Agyeman Akwasi , Weigel Christoph , Wu Yue-Zhong , Gerber Madelyn M. , Rabe Kari G. , Larson Melissa C. , Lu Junyan , Blachly James S. , Rogers Kerry A. , Wierda William G. , Brown Jennifer R. , Rai Kanti R. , Keating Michael , Rassenti Laura Z. , Kipps Thomas J. , Zenz Thorsten , Shanafelt Tait D. , Kay Neil E. , Abruzzo Lynne V. , Coombes Kevin R. , Woyach Jennifer A. , Byrd John C. , Oakes Christopher C. 
Published: July 2019

AbstractAlterations in global DNA methylation patterns are a major hallmark of cancer and represent attractive biomarkers for personalized risk stratification. Chronic lymphocytic leukemia (CLL) risk stratification studies typically focus on time to first treatment (TTFT), time to progression (TTP) after treatment, and overall survival (OS). Whereas TTFT risk stratification remains similar over time, TTP and OS have changed dramatically with the introduction of targeted therapies, such as the Bruton tyrosine kinase inhibitor ibrutinib. We have shown that genome-wide DNA methylation patterns in CLL are strongly associated with phenotypic differentiation and patient outcomes. Here, we developed a novel assay, termed methylation-iPLEX (Me-iPLEX), for high-throughput quantification of targeted panels of single cytosine guanine dinucleotides from multiple independent loci. Me-iPLEX was used to classify CLL samples into 1 of 3 known epigenetic subtypes (epitypes). We examined the impact of epitype in 1286 CLL patients from 4 independent cohorts representing a comprehensive view of CLL disease course and therapies. We found that epitype significantly predicted TTFT and OS among newly diagnosed CLL patients. Additionally, epitype predicted TTP and OS with 2 common CLL therapies: chemoimmunotherapy and ibrutinib. Epitype retained significance after stratifying by biologically related biomarkers, immunoglobulin heavy chain mutational status, and ZAP70 expression, as well as other common prognostic markers. Furthermore, among several biological traits enriched between epitypes, we found highly biased immunogenetic features, including IGLV3-21 usage in the poorly characterized intermediate-programmed CLL epitype. In summary, Me-iPLEX is an elegant method to assess epigenetic signatures, including robust classification of CLL epitypes that independently stratify patient risk at diagnosis and time of treatment.
Selection of unrelated donors and cord blood units for hematopoietic cell transplantation: guidelines from the NMDP/CIBMTR
Authors: Dehn Jason , Spellman Stephen , Hurley Carolyn K. , Shaw Bronwen E. , Barker Juliet N. , Burns Linda J. , Confer Dennis L. , Eapen Mary , Fernandez-Vina Marcelo , Hartzman Robert , Maiers Martin , Marino Susana R. , Mueller Carlheinz , Perales Miguel-Angel , Rajalingam Raja , Pidala Joseph 
Published: July 2019

Abstract
This Special Report, this month’s CME article, details evidence-based guidelines for the selection of optimal unrelated donors and cord blood units for allogeneic hematopoietic cell transplantation.
Targeted sequencing of plasma cell-free DNA to predict response to PD1 inhibitors in advanced non-small cell lung cancer.
Authors: Guibert Nicolas , Jones Greg , Beeler John F. , Morris Clive D. , Plagnol Vincent , Mourlanette Jean , Delaunay Myriam , Rouquette Isabelle , Favre Gilles , Pradines Anne , Mazieres Julien 
Published: July 2019

103 Background: Tumor mutational burden is an emerging biomarker of response to immune checkpoint inhibitors (ICI), whose clinical adoption is challenging, especially in liquid biopsies. We hypothesized that targeting limited but relevant genetic alterations in plasma cell-free DNA with next generation sequencing (NGS) along with early monitoring may represent a non-invasive approach to predict response to ICI. Methods: Plasma samples from responders (PFS > 6 months) and non-responders (progressive disease at first evaluation) patients collected before nivolumab (second line) initiation and at 1 month were tested using tagged amplicon sequencing of hotspots and coding regions from 36 genes, blinded to clinical outcomes and tumor genotype. Molecular profile of ctDNA, and its early kinetics (1 month) were analyzed as potential early indicators of response. Results: 98 patients were analyzed, of which 86 (39 responders, 47 non-responders) were evaluable for response. Alterations in ctDNA were detectable in 67/86 baseline samples (78%). The detection of a targetable oncogenic driver (5 EGFR, 1 ALK) was associated with progressive disease on the first CT-scan The presence of a PTEN and/or STK11 mutations (b-PS(+)) was correlated with poor outcomes (median PFS 1.5 months vs. 8 months in b-PS(-)) patients, p = 0.0007), while the presence of transversion mutations in KRAS and/or TP53 (b-KP-Tv(+)) predicted good outcomes (median PFS 11 months vs. 2 months in b-KP-Tv(-) patients, p = 0.0088). Combining these results, patients with a low “immune score” (driver and/or b-PS(+) and/or b-KP-Tv(-)) derived poor outcomes (PFS 2 months), compared with patients with a high immune score (no driver, b-PS(-) and b-KP-Tv(+), PFS 14 months, p = 0.0001, HR 2.96). Studying early changes in 65 specimens, molecular response was correlated with clinical outcomes (14 months PFS in patients with early ctDNA decrease compared to 2 months in patients with increase, p < 0.0001; HR 2.7). Using cut-off of 30% and 50% of plasma response increased the ability of ctDNA to predict response (HR 4 and 4.17, respectively). Conclusions: Targeted sequencing of plasma ctDNA and its early variations can predict response to anti-PD-1. Clinical trial information: NCT02827344.
Preclinical CAR-T cell target safety, biodistribution, and tumor infiltration analysis using in situ hybridization technology.
Authors: Pimentel Helly , Jarnagin Helen , Zong Hailing , Todorov Courtney , Anderson Courtney M. , Zhang Bingqing , Bunker Christopher , Ma Xiao-Jun 
Published: July 2019

112 Background: Chimeric antigen receptor (CAR) T cell therapy is highly effective in treating hematologic malignancies, and major efforts are being made to achieve similar efficacy in solid tumors. The greater potency of CAR-T cells compared to antibody therapeutics demands a more stringent CAR-T target safety assessment to avoid adverse events resulting from “on-target/off-tumor” activity. Furthermore, it is critical to track and monitor CAR+ T cells within intact tissue and tumor to understand the mechanisms underlying off-tumor toxicity and efficacy in tumor killing. Methods: We employed the RNAscope in situ hybridization (ISH) technology to assess target expression specificity and to track CAR-T cell distribution and activation in xenograft and host tissues using the RPMI-8226 xenograft mouse model. Results: For the CAR-T target candidates, Target X and Target Y, RNA ISH revealed that Target X was only expressed in the xenograft tumor and in no mouse organs, while Target Y was found to be expressed at low levels in mouse lung and liver, as well as in the xenograft tumor. Duplex RNA ISH assays with probes targeting the CAR 3’ UTR and either IFNG or GZMB allowed for highly sensitive and specific detection of CAR-T cells and their activation state in both tumor and normal tissues from vehicle, Target X CAR-T cell, or Target Y CAR-T cell treated mice. Activated Target X CAR-T cells expressing GZMB and IFNG were found only in the xenograft tumor, where Target X was expressed. In contrast, activated Target Y CAR-T cells were found almost exclusively in mouse lung and liver, with very few Target Y CAR-T cells being found in the xenograft tumor. Lastly, a multiplex ISH-IHC approach confirmed the presence of activated Target X CAR-T cells in the xenograft tumor through simultaneous detection of the Target X CAR 3’ UTR, IFNG, GZMB, and CD3. Conclusions: These data demonstrate how the RNAscope assay can be utilized for CAR-T cell efficacy and safety/toxicity assessment in preclinical models by detecting very low levels of target antigen expression in off-tumor tissues and monitoring CAR-T cell pharmacodynamics and activation in tumor models and can also be applied for assessing TCR-T cell activity in tumors.
Tolerability and antitumor activity of cemiplimab, a human monoclonal anti-PD-1, in patients with non-small cell lung cancer (NSCLC): Interim data from a phase I dose escalation and NSCLC expansion cohort.
Authors: Moreno Victor , Calvo Emiliano , Olmedo Garcia Maria Eugenia , Gil-Martin Marta , Aljumaily Raid , Papadopoulos Kyriakos P. , Rosen Lee S. , Rietschel Petra , Mohan Kosalai Kal , Li Jingjin , Stankevich Elizabeth , Rowlands Tracey , Feng Minjie , Fury Matthew G. 
Published: July 2019

116 Background: NSCLC accounts for ~85% of lung cancers; most patients (pts) are at an advanced stage at the time of diagnosis. Cemiplimab (REGN2810) is being investigated for the treatment of NSCLC, in addition to other indications (NCT02383212). Methods: In the dose escalation (DE) phase, enrolled pts with advanced malignancies with no alternative standard-of-care therapeutic option received cemiplimab 1, 3 or 10 mg/kg every 2 weeks (Q2W) intravenously (IV) for up to 48 weeks. In the NSCLC expansion cohort (EC 1), enrolled pts with advanced disease who had relapsed after, or were refractory to at least first-line therapy received cemiplimab 200 mg Q2W IV for up to 48 weeks. Tumor biopsies were performed at baseline (EC 1 only), Day 29 and progression, if possible. Tumor measurements were performed every 8 weeks according to RECIST 1.1. Results: As of Sept 1, 2017, 21 pts with NSCLC (1 in DE at 1 mg/kg; 20 in EC 1) were enrolled; median age was 65.0 years (range, 50–82; 14 M/ 7 F); 81.0% had a ECOG performance status of 1, 19.0% of 0; 13/21 (61.9%) had a histology of adenocarcinoma. The most common treatment-related adverse events (TRAEs) were asthenia, pneumonitis, and rash (each n = 3, 14.3%). Each of the following ≥Grade 3 TRAEs occurred once: pneumonitis, diabetic ketoacidosis, and nephritis. By central independent review, 6 pts had partial response (PR), 6 had stable disease (SD) or non-complete response (CR)/non-progressive disease (PD), and 9 had PD. Overall response rate (ORR; CR + PR) was 28.6%. Duration of response exceeded 8 months in 5 of the 6 responders. Disease control rate (ORR + SD) was 57.1%. Disease control has been maintained for 7 pts after a planned treatment completion at 48 weeks. Of the 17 pts who had tissue available for PD-L1 expression evaluation, 11 (64.7%) had a tumor proportion score (TPS) of < 1%, and 3 (17.6) had a TPS of > 50%. Conclusions: Cemiplimab showed an acceptable safety profile and demonstrated antitumor activity in pretreated pts with NSCLC. Pivotal trials of cemiplimab as monotherapy or in combination with other treatments in pts with advanced NSCLC are currently enrolling (NCT03088540; NCT03409614). Clinical trial information: NCT02383212.
Immune pneumonitis-related treatment discontinuations and outcomes in metastatic non-small cell lung cancer treated with nivolumab: A pooled analysis from a multi-institutional international collaboration.
Authors: Naqash Abdul Rafeh , Owen Dwight Hall , Ricciuti Biagio , Toi Yukihiro , Chiari Rita , Sharma Nitika , Patel Sandip H. , Sugawara Shunichi , Cherry Cynthia R. , Burkart Jarred Thomas , De Giglio Andrea , Sugisaka Jun , Bowling Mark , Otterson Gregory Alan , Walker Paul R. 
Published: July 2019

118 Background: Immune-related adverse events (irAEs) due to immune-checkpoint inhibitors (ICI) can lead to significant morbidity. Immune pneumonitis (IP) constitutes one of the common irAEs in non-small cell lung cancer (NSCLC) with a reported incidence of 3-5%. However outside of clinical trials there is a paucity of data regarding incidence/outcomes of IP in nivolumab (N) treated metastatic-NSCLC (m-NSCLC). Methods: We retrospectively pooled data of 381 m-NSCLC patients (pts) from four cohorts treated with N within different treatment time periods: East Carolina University, USA: 4/2015- 2/2018; Ohio State University, USA: 6/2013-6/2016; University of Perugia, Italy: 10/2013-9/2017, and Sendai Kousei Hospital, Japan: 1/2016-1/2018. IP identification was based on clinical diagnosis of treating team. Grade (G) was based on Common Terminology Criteria for Adverse Events (CTCAE v 4.03). Time to immune pneumonitis (TTIP) was the time from starting N to diagnosis of IP. Results: The rate of IP was 13.1% (n=50) with 68% of IP presenting as the index irAE. Median TTIP was 9.75 weeks (range: 0.25-73.7) with G1 (24.0%), G2 (36.0%), G3 (36.0%), G4 (4.0%). 57.9% of IP ≥G2 had TTIP ≤ 3 months (m). For all-G (IP), 22.0% pts had stopped N before IP either due to non-IP irAEs or progression. Excluding these, treatment discontinuations (d/c) attributed to IP ≥ G2 were 66.6%. IP ≥G2 had higher treatment d/c when TTIP was ≤ 3m vs. > 3m (51.8% vs. 14.8%; P=0.09). Median overall survival (OS) by log rank test for pts with any grade IP vs. no IP was not statistically significant (13.7 vs. 7.5m; P =0.14). IP ≥G2 occurring at > 3m had longer median OS vs. IP ≥G2 occurring in ≤3m (16.7 vs. 3.6m, P=0.008), which was not significant at a 3m landmark analysis when accounting for time on N (P= 0.31). Conclusions: Our real-world multi-institutional data shows a higher incidence of IP in m-NSCLC. We also see a trend for frequent ICI d/c in IP ≥ G2 occurring within 3 months that may ultimately influence OS per our landmark analysis. Thus aggressive and early symptom management specifically directed at allowing reinitiation of ICI after IP needs to be considered.
Outcomes of nivolumab (NIVO)-treated patients (pts) with advanced non-small cell lung cancer (aNSCLC) in United States community oncology practice.
Authors: Nadler Eric , Espirito Janet , Wilson Thomas , Gupte-Singh Komal , Rao Sumati , Korytowsky Beata 
Published: July 2019

119 Background: The phase 3 Checkmate 017 and 057 trials demonstrated improved survival of NIVO vs. chemotherapy in pts who progressed on or after platinum-based chemotherapy for aNSCLC, regardless of histology (squamous [SQ]/non-squamous [NSQ]) and PD-L1 expression. Real-world (RW) long-term effectiveness data with PD-1 inhibitors are limited. This study evaluated RW adoption of I-O and outcomes of NIVO-treated pts with aNSCLC in community practices, overall and by histology. Methods: This retrospective observational study of US Oncology Network electronic health records and supplemental chart abstraction followed a cohort of pts with aNSCLC receiving PD-1 inhibitors for ≥17 months, from initial FDA approval, 03/2015 through 10/2017. Pts in clinical trials or receiving treatment for other malignancies were excluded. Demographic and clinical features were characterized. Duration of therapy (DOT) and overall survival (OS) were assessed by the Kaplan-Meier method. Results: Of 217 included pts, 203 received NIVO; outcomes for 14 receiving pembrolizumab are not presented. NIVO was administered as first-line (1L) therapy in 15 pts, 2L+ therapy in 188 pts (n = 134 LOT2, n = 54 LOT3-4). For all 2L+ pts treated with a PD-1 inhibitor, median age was 70 years, 57% were male, 73% had NSQ histology, and 82% had ECOG performance status of 0-1. All pts with biomarker data were ALK negative and 5% were EGFR positive. Approximately 13% of pts had PD-L1 testing, of whom 6% were positive (expression > 1%). For 2L+, DOT (median months [mos], 95% CI) was 3.5 (3.0, 4.1) in the overall population, 3.3 (1.9, 4.2) with SQ, and 3.6 (2.3, 4.6) with NSQ histology. Of all 2L+ pts, 30.3% (95% CI 23.9%, 37.0%) remained on treatment at 6 mos. For 2L+, OS (median mos, 95% CI) was 8.7 (7.6, 11.0) overall, 7.0 (3.8, 9.1) with SQ, and 10.5 (8.4, 13.3) with NSQ histology; 1-year OS was 35%. Conclusions: RW DOT and OS for 2L+ NIVO treatment of aNSCLC were similar to outcomes reported in the phase 3 Checkmate 017 and 057 trials, with longer DOT and greater OS in patients with NSQ histology. Few RW pts had PD-L1 testing in this 2L+setting. Future analyses are needed to assess the uptake of PD-1 inhibitors for 1L treatment of aNSCLC.
Hematological profile: A prognosis tool in melanoma patients treated with immunotherapy.
Authors: Lobo Martins Soraia , Miguel-Semedo Patrícia , Martins-Branco Diogo Alexandre , Monteiro Ana Maria , Moreira Cecilia Melo Alvim , Pais Helena , Vendrell Ines , Mansinho Andre , Gouveia Emanuel Jose , Passos Maria-Jose Saramago , Costa Luis , Sousa Ana Rita Teixeira 
Published: July 2019

135 Background: Immunotherapy (IO) has changed the disease course of metastatic malignant melanoma (mMM). Prognostic biomarkers are lacking, but high neutrophil-lymphocyte ratio (NLR) has been correlated with poor outcome. Lymphocyte-monocyte ratio (LMR) and platelet-lymphocyte ratio (PLR) are also readily available. This study aimed to investigate the prognostic value of NLR, LMR and PLR. Methods: Retrospective cohort of mMM patients (pts) treated with anti PD-1 blockade in 2 centers, between Jan ’13-Aug ’18. Baseline and 6-week (6 w) blood counts were collected. Cut-offs for NLR, LMR and PLR were defined based on literature and ROC curve method. Progression free survival (PFS; primary outcome) and overall survival (OS) were calculated using log rank test. Uni and multivariate analysis were performed using cox-regression model. Results: Baseline characteristics: 83 pts with median age 65.5 years (range 21-90), 77% BRAFwt, 98% PS-ECOG 0-1, 51% LDH >ULN, 5% on steroids. Median NLR 2.7 (IQR 2.1-3.8), LMR 3.1 (2.1-4.3) and PLR 160.8 (98.3-216.4). The majority of pts (65%) were treated with pembrolizumab. With a median follow-up of 6.2 months (m), median PFS was 7.3 m (CI 5.5-9.2) and median OS was 15.9 m (13.4-18.4). In the multivariate model, baseline NLRhigh (≥3.0) and PLRhigh (≥180.0) were associated with worse PFS (HR 2.04, CI 1.11-3.77; p=0.02; and HR 2.50, CI 1.37-4.57; p=0.003). Baseline LMRhigh (≤2.1) was associated with worse PFS (HR 1.886, CI 1.019-3.488; p=0.043) only on the univariate analysis. At 6 w, 16 out of 39 pts with baseline NLRhigh presented a decrease in NLR. This was associated with better PFS (HR 0.24, CI 0.09-0.62; p=0.003). Inversely, an increase ≥20% in NLR or PLR was associated with progression (HR 3.65, CI 1.99-6.72, p < 0.001; and HR 3.99, CI 2.01-7.91, p < 0.001). Conclusions: Our data showed that NLR and PLR, as surrogates for systemic inflammation, might be used as prognostic biomarkers for melanoma patients treated with IO. Decreasing NLR in pts with previously high NLR, has a 76% risk reduction of progression. In clinically challenging situations, these biomarkers may help the clinician in an earlier therapeutic orientation.
Healthcare resource utilization in first-line immunotherapies for patients with metastatic melanoma.
Authors: Liu Frank Xiaoqing , Klink Andrew , Feinberg Bruce A. , Ahsan Sama , Nero Damion , Chmielowski Bartosz 
Published: July 2019

137 Background: Immunotherapies (I/Os) have demonstrated improved overall survival vs. chemotherapy for patients (pts) with metastatic melanoma (MM). However, little is known about the comparative health care resource utilization (HCRU) among different I/Os. This study examined the real world HCRU across different I/Os: PD-1 inhibitors (pembrolizumab (PEM) or nivolumab (NIVO), PD-1), CTLA-4 inhibitor (ipilimumab, IPI), and combination of I/Os (IPI+NIVO). Methods: A retrospective observational study was conducted using a large US payer claims data. Adults with ≥2 claims for MM and ≥1 claim for metastasis were identified between 1/1/2012 and 6/30/2017 and followed through 9/30/2017. All pts had pharmacy and medical claims and ≥6 months pre-index enrollment. HCRU was calculated per pt per month (PPPM) and by percentages across PD-1, IPI, IPI+NIVO from Index date until the first occurrence of: change in regimen, end of continuous enrollment, or end of study period. Adjusted odds ratios (OR) for HCRU were estimated using logistic regressions to control for baseline patient characteristics. Results: On average, pts in the PD-1 cohort (n = 255) were older than those in IPI (n = 555) and IPI+NIVO (n = 88) cohorts (mean 68 vs 63 and 63, both p < 0.05) and had less brain metastasis (22% vs 34% and 31%, p < 0.05 and p = 0.11, respectively). During 1L therapy, fewer PD-1 pts had any hospitalization (HOSP, 25.9% vs 39.8% and 45.5%, both p < 0.05), fewer HOSPs PPPM (mean 0.06 vs 0.10 and 0.14, both p < 0.05), and fewer ER visits PPPM (mean 0.09 vs 0.13 and 0.18, both p < 0.05) compared to IPI and IPI+NIVO, respectively. Any 30-day re-HOSP and ER visits were numerically lower with PD-1 compared with IPI and IPI+NIVO, but not statistically significant (13.7% vs 19.1% and 18.2%; 40.0% vs 47.0% and 50.0% respectively). Adjusting for baseline characteristics, pts treated with IPI and IPI+NIVO were more likely to have a HOSP than PD-1s (OR = 2.10, 95% CI, 1.44-3.07; and 2.35; 95% CI, 1.32-4.12, both p < 0.01). Conclusions: Pts treated with IPI or IPI+NIVO had significantly increased odds of being hospitalized and higher HOSP and ER visits PPPM compared to PD-1s. Further studies are warranted to confirm these findings.
Emerging treatment patterns and checkpoint inhibitor (CPI) use among newly diagnosed Merkel cell carcinoma (MCC) patients in the United States veteran population.
Authors: Zheng Ying , Pandya Shivani , Yu Ting , Kearney Mairead , Shrestha Sulena , Wang Li , Kim Ruth , Phatak Hemant 
Published: July 2019

139 Background: MCC is a rare and aggressive skin cancer with annual incidence of 2,500 in the U.S. Checkpoint inhibitors (CPIs) demonstrated durable disease response historically not seen with chemotherapy among MCC patients in clinical trials. Avelumab, a PD-L1 antibody, became the first and only approved treatment for metastatic MCC by the U.S. FDA in March 2017. This study evaluated emerging treatment patterns among MCC patients using the US Veterans Health Administration (VHA) database. Methods: This retrospective study identified newly-diagnosed MCC patients who initiated ≥1 systemic therapy from Oct. 2013 to Jan. 2018 and had continuous enrollment from ≥6 months pre-initial MCC diagnosis date until ≥2 months post-index date with follow-up until the earliest of death, disenrollment, or study end. The index date was defined as the start date of first-line (1L) systemic therapy. A subsequent line of therapy (2L) was defined by the earliest of new therapy addition, regimen switch, or a new/existing regimen after a >60-day gap from the prior cycle end. Duration of 1L therapy was evaluated among patients treated with CPIs, National Cancer Comprehensive Network (NCCN)-recommended chemotherapy (recCTs), and other chemotherapy (oCTs). The median duration of therapy was estimated using the Kaplan Meier method. Results: Of the 120 MCC patients (72% pre-2017) with 1L systemic therapy, 17%, 45%, and 38% were treated with CPIs, recCTs and oCTs, respectively. More than 75% were white men aged ≥65 years with mean baseline Charlson comorbidity index scores ≥5. Carboplatin-etoposide (56%) and cisplatin-etoposide (26%) were the most commonly-used recCTs. The median duration of 1L therapy in patients treated with CPI, recCTs and oCTs was 300, 91, and 21 days, respectively. 2L therapy was initiated in 33% of all 1L patients. Conclusions: Among 1L MCC patients, CPIs treated patients appear to be on treatment longer than both recCTs and oCTs patients. These descriptive findings provide important insights into the emerging real-world treatment patterns amongst MCC patients in the VHA population.