bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morbidity and mortality in a national cohort of pediatric patients with hemophagocytic lymphohistiocytosis.
Authors: Allen Steven William , McCormick Meghan , Kalpatthi Ram , Rapkin Louis 
Published: May 2019

10062 Background: Despite significant advances in diagnosing and treating hemophagocytic lymphohistiocytosis (HLH) in the pediatric population, survival remains low and the extent of disease morbidity and health care utilization is poorly characterized. Thus, we sought to investigate morbidity, mortality, and the health care burden of HLH in a pediatric population. Methods: We queried the Pediatric Health Information System (PHIS) for children admitted with HLH and treated with etoposide and dexamethasone between 1/1/2004 – 9/30/2018. Collected data included demographics and clinical variables associated with morbidity and mortality. Results: A total of 493 patients (10.5 per 100,000 patients admitted) met inclusion criteria during the study period. The majority of patients (n = 284, 58%) were less than 5 years of age. A total of 331 patients were readmitted after the initial hospitalization, with 29% of readmissions complicated by infections. Median cost for initial hospitalization was $101,906 (IQR: $47,552 – $271,822). A significant number of patients required ICU care during both the initial admission (60%) and readmission (57%). Hematopoietic stem cell transplant (HSCT) was performed in 136 patients (28%) with a median time to HSCT of 126 days (IQR: 75-193 days). Overall mortality was 32% (n = 158), half occurring during the initial admission. There was a trend towards increased mortality in younger age groups. Median time to death during and after the initial admission was 45 days (IQR: 20-84 days) and 198 days (IQR: 108-368 days), respectively. Post-HSCT mortality rate was 35%. Conclusions: This represents the largest cohort of pediatric patients treated for HLH. Overall and post-HSCT mortality was consistent with prior publications. We observed significant morbidity and increased health care resource utilization in our cohort. These findings emphasize the need for novel therapeutic approaches to improve not only patient survival but also long-term quality of life. Planned future analysis of the PHIS data will be aimed at assessing treatment variability, morbidity and mortality depending on treatment, and risk factors associated with mortality in pediatric patients with HLH.
A randomized phase II study of palbociclib plus exemestane with GNRH agonist versus capecitabine in premenopausal women with hormone receptor-positive metastatic breast cancer (KCSG-BR 15-10, NCT02592746).
Authors: Park Yeon Hee , Kim Tae Yong , Kim Gun Min , Jung Kyung Hae , Kang Seok Yun , Park In Hae , Kim Jee Hyun , Lee Kyoung Eun , Ahn Hee Kyung , Lee Moon Hee , Kim Hee Jun , Kim Han Jo , Lee Jong In , Koh Su-Jin , Kim Ji-Yeon , Lee Kyung-Hun , Sohn Joohyuk , Kim Sung-Bae , Im Young-Hyuck , Im Seock-Ah 
Published: May 2019

1007 Background: Endocrine treatment is preferred recommendation by clinical guidelines in premenopausal as well as postmenopausal women with hormone receptor(HR)-positive, HER2-negative metastatic breast cancer(MBC). In real-world clinical practice, however, substantial numbers of patients are treated with chemotherapy in earlier lines based on endocrine resistance and/or on physician’s concern of worse prognosis associated with aggressive tumor behavior and younger age. In terms of the chemotherapy regimens, capecitabine seems one of the most popular options. The purpose of this phase II study is to assess the safety and the clinical anti-tumor activity of exemestane plus GNRH agonist in combination with palbociclib versus capecitabine in premenopausal HR-positive MBC patients. Methods: This is a prospective, two-arm, randomized, multi-center open-label phase II study of the Korean Cancer Study Group. Patients were allowed with previous 1 line of chemotherapy for MBC. De Novo metastatic patients should have been treated with tamoxifen before enrollment. Patients were randomized to chemotherapy (capecitabine 1250 ㎎/㎡twice a day from day 1 to 14 every 3 weeks) or endocrine therapy combination (exemestane 25 mg for 28 days and palbociclib 125 mg for 21 days every 4 weeks with GNRH agoinst). Primary endpoint was Progression-Free Survival (PFS). Results: Among 189 patients enrolled between 2016 and 2018 from 14 centers, 184 patients were randomly assigned to chemotherapy (n = 92) or endocrine therapy with palbociclib (n = 92). Median age was 44 (range 28-58). De Novo MBC was found equally in both arm (30%). During median 14 months of follow-up, median PFS was superior in endocrine with palbociclib than in capecitabine arm [19.0 vs. 11.3 months, p = 0.0493 by log-rank test; Hazard Ratio (HR) 0.643 (0.415-0.999), p = 0.0493]. Approximately half of the patients (51%) were treatment naïve in the advanced setting (49% for palbociclib vs. 51% for capecitabine). Grade III or more hematologic toxicities were more common in palbociclib than in capecitabine with statistical significance (60.9% vs. 19.2%, p < 0.0001). Diarrhea (11% vs. 38%) and Hand-Foot syndromes (1% vs. 76%) were more common in capecitabine arm. Conclusions: Exemestane plus palbociclib with ovarian suppression showed clinical benefit in terms of PFS compared with capecitabine in patients with premenopausal ER-positive MBC. Clinical trial information: NCT02592746.
Real-world treatment patterns and outcomes in ER+/PR+/HER2+ metastatic breast cancer (MBC) patients: A National Cancer Database analysis.
Authors: Statler Abby , Nahleh Zeina A. , Hobbs Brian , Wei Wei (Auston) , Gupta Annie , Blake Cassann N. 
Published: May 2019

1033 Background: Treatment patterns and clinical outcomes are unclear for MBC patients diagnosed with estrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+) human epidermal growth factor 2 positive (HER2+) disease (i.e. triple positive). This study aimed to: 1) examine the utilization of first-line therapy among ER+/PR+/HER2+ MBC patients and 2) compare overall survival (OS) between the identified regimens. Methods: We analyzed triple positive MBC patients included in the National Cancer Database who were treated with endocrine therapy (ET) or chemotherapy (chemo) between 2010 and 2015. Kaplan-Meier method was used to estimate distributions of OS, which were compared among patient cohorts using the log-rank test. Results: A total of 6,234 patients were included in the analysis; of these, 3770 (60%) received ET and 2464 (40%) received chemo. Of those with complete survival data, there was no difference in median OS between patients treated with chemo vs. ET; however, those who received anti-HER2 therapy had significantly better OS than those who did not (median OS 49.4 vs. 41.0 months, p < 0.0001). Median OS stratified by ET or chemo with and without anti-HER2 further supported these findings, revealing the addition of anit-HER2 therapy to chemotherapy and ET resulted in superior median OS (Table). Conclusions: This is the first study to evaluate treatment utilization and OS among real-world triple positive MBC patients treated with ET or chemo. Our results suggest the majority of patients in the United States are treated with first-line ET; furthermore, the reported OS outcomes support the consideration of ET plus anti-HER2 therapy as a first-line treatment option for ER+/PR+/HER2+ MBC. Prospective trials evaluating de-escalation of systemic therapy in this subgroup of patients and future research to identify biomarkers to determine which patients can avoid chemotherapy are warranted. [Table: see text]
Interim results from the full population of the phase 3b CompLEEment-1 study of ribociclib (RIBO) plus letrozole (LET) in the treatment of HR+/HER2– advanced breast cancer (ABC).
Authors: DeLaurentiis Michelino , Borstnar Simona , Campone Mario , Warner Ellen , Bofill Salvador , Jacot William , Dent Susan Faye , Martin Miguel , Ring Alistair E. , Cottu Paul H. , Lu Janice M. , Ciruelos Eva , Azim Hamdy A. , Chatterjee Sanjoy , Zhou Katie , Wu Jiwen , Ankrah Nii , Zamagni Claudio 
Published: May 2019

1041 Background: RIBO, an oral, selective inhibitor of CDK4/6 (CDK4/6i), is approved for use in combination with endocrine therapy (ET) in women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) ABC in multiple countries worldwide. Here we report interim safety and efficacy results from CompLEEment-1, a phase 3b trial evaluating RIBO+LET in an expanded patient (pt) population and the largest CDK4/6i trial in ABC to date. Methods: Pts with HR+, HER2– ABC, ≤1 line of prior chemotherapy (CT), and no prior ET for ABC received RIBO+LET. Treatment regimens and study endpoints have been reported previously (De Laurentiis, et al. ASCO 2018. Poster 1056). Results: Overall, 3,246 pts, who received ≥1 dose of study treatment, were evaluated (cut-off date, August 8, 2018). Median duration of RIBO exposure was 8.1 months (min, 0.0; max, 22.4). Demographic and baseline characteristics indicated a diverse population including men (1.2%), premenopausal women (22.2%), and patients aged ≥70 years (19.5%). Pts were well represented in terms of age, race, and disease history; 5.9% of pts received prior CT for ABC. The only non-hematologic any-cause grade ≥3 AEs ≥5% were increased alanine (7.3%) and aspartate (5.3%) aminotransferase. Treatment-related AEs (any grade) led to discontinuation in 11.4% of pts. Of the 51 (1.6%) on-treatment deaths, 26 were due to study indication and 25 to other reasons. The median time to progression was not estimable (NE) (95% confidence interval [CI], 17.1-NE). Overall response rate was 20.5% (95% CI, 19.1%-21.9%) and clinical benefit rate was 66.1% (95% CI, 64.4%-67.7%). Consistent mean change from baseline in Functional Assessment of Cancer Therapy – Breast Cancer questionnaire scores indicated that pts maintained their quality of life throughout treatment. Conclusions: This interim analysis demonstrates the safety, tolerability, and efficacy of RIBO+LET in a large, diverse cohort of pts with HR+, HER2– ABC who had not previously received ET for ABC. Safety results were consistent with those observed in RIBO pivotal studies and no new safety signals were observed. Clinical trial information: NCT02941926.
A GINECO randomized phase II assessing addition of an aromatase inhibitor to oral vinorelbine in pretreated metastatic breast cancer patients.
Authors: Heudel Pierre , Arnaud Antoine , Frenel Jean-Sebastien , Chabaud Sylvie , You Benoit , Stefani Laetitia , Garnier-Tixidre Claire , Simon Helene , Beal-Ardisson Dominique , Jacquin Jean-Philippe , Del Piano Francesco , Lortholary Alain , Cornea Claudiu , Lharidon Tifenn , Largillier Remy , Brocard Fabien , Legouffe Eric , Atlassi Mustapha , Hardy-Bessard Anne-Claire , Bachelot Thomas Denis 
Published: May 2019

1043 Background: For ER+/HER2- metastatic breast cancer (mBC), efficacy of endocrine therapy + chemotherapy combination remain an open question. We hypothesized that continuing ER targeted therapy after progression in combination with chemotherapy may improve disease control. The objective of the CHEOPS trial was to assess the benefit of adding aromatase inhibitor (AI) to metronomic chemotherapy,oral vinorelbine, 50mg/3 time a week (OV) for AI pre-treated, ER+/HER2- mBC patients. Methods: Eligible patients had to have progressed on endocrine therapy and one or two lines of chemotherapy. They were randomized between vinorelbine (OV) and vinorelbine + AI (OV+AI). Primary end point was progression-free survival (PFS). To show an increase of median PFS (from 3.5 to 5.5 month, HR 0.636), with alpha = 5% and power = 80%, 130 evaluable patients were needed. Results: 121 patients were Included (OV = 61; OV+AI = 60). Median age was 68 (range: 49-87), Median time from metastatic diagnosis was 3.2 years (range 0 - 16.9). 109 patients (90%) had visceral metastases. They all had previously received an AI and had been treated with one line (N = 66, 54.5%), or 2 lines (N = 55, 45.5%) of chemotherapy. Median PFS was increased from 2.3 months with OV to 3.7 months with OV+AI, but this difference was not significant (HR 0.73 [95 % CI 0.50-1.06], log-rank test: P = 0.09) 81 patients (67%) had at least one adverse event (AE) of grade ≥ 3 (40 (66%) for OV vs 41 (68%) for OV+AI). The most common grade ≥ 3 AE were: GT gammas (23%), neutropenia (18%), arterial hypertension and lymphopenia (17%). The occurrence of 3 toxic deaths (OV = 1; OV+AI = 2) secondary to febrile aplasia motivated the early cessation of this clinical trial. 9 patients (5 OV (10%) and 4 OV+AI (8%) presented an objective complete or partial response. Conclusions: The addition of AI to OV over OV alone in AI resistant mBC was associated with a non-significant improvement of PFS, but both PFS are lower than expected. Metronomic OV schedule, at 50 mg three times a week, requires close biological monitoring. The question of hormonal treatment and chemotherapy combination remains open. Clinical trial information: EudraCT Number: 2015-000401-39.
A phase Ib/II trial of lenvatinib (len) and letrozole (let) incorporating pharmacodynamics studies in postmenopausal women with hormone receptor positive (HR+) locally advanced/metastatic breast cancer (LABC/MBC).
Authors: Lim Joline Si Jing , Wong Andrea Li Ann , Ow Samuel Guan Wei , Eng Lim Siew , Sundar Raghav , Chan Gloria HJ , Yadav Kritika , Heong Valerie , Tan David Shao Peng , Soo Ross A. , Chee Cheng Ean , Yong Wei-Peng , Goh Boon C. , Lee Soo-Chin 
Published: May 2019

1045 Background: Endocrine blockade (EB) is standard of care for patients (pts) with HR+ LABC/MBC. RET over-expression (RET+) occurs in up to 75% of HR+ breast cancers and is a postulated mechanism of endocrine resistance. Preclinical studies show cross talk between RET and estrogen receptor, and at least additive treatment (Tx) effect of Len+EB. Methods: We performed a phase Ib trial (3+3 dose escalation) to study safety, tolerability, pharmacodynamics and efficacy of Len+Let. Both drugs were given as continuous daily dosing with 2 weeks (wks) of Len alone, followed by Len+Let for 12 wks then surgery (LABC), or till disease progression (PD) (MBC). Serial tumor biopsies (n = 15) were done at baseline, after Len alone, 4 wks post Len+Let, and at surgery [LABC] / upon PD [MBC]. Results: 16 pts were treated (4 LABC, 12 MBC); Among MBC pts, median lines of prior Tx was 3 (range 0-10); 84.6%, 66.7%, and 58.3% had prior EB, EB+CDK4/6 inhibitor (i), and chemotherapy (CT) respectively. At dose level (DL) 1, 2/4 pts had dose-limiting toxicities (DLT). There was no DLT at DL-1, but 6/6 pts needed dose reductions (DR), with 4/6 DR within 6 wks of Len+Let (3 G3 hypertension [HTN], 1 G3 wound pain), deeming DL-1 intolerable. At DL-2, 0/6 pts had DLT; this was declared recommended phase 2 dose (RP2D). Most frequent G3 toxicities (tox) were HTN (6/16), proteinuria (2/16) and palmar-plantar erythrodysesthesia (PPE) (2/16), with no G4/5 tox. Len+Let was active with 93.8% overall disease control rate (DCR) (50.0% partial response [PR], 43.8% stable disease [SD]). Among MBCts (8/12 had prior EB+CDK4/6i), DCR ≥12 wks was 91.7%; 1 pt had sustained PR for 48 wks and 1 ongoing PR at 40 wks. 9/16 pts had RET+ tumors on immunohistochemistry at baseline, and 66.7% showed down-regulation with Tx (RECIST: 4 PR, 2 SD). Conclusions: Len+Let showed significant anti-tumor activity, even in pts who failed prior CT or EB+CDK4/6i. RP2D of 14mg Len and 2.5mg Let is tolerated with efficacy; dose expansion is currently underway. Clinical trial information: NCT02562118. [Table: see text]
Real-world evidence of male breast cancer (BC) patients treated with palbociclib (PAL) in combination with endocrine therapy (ET).
Authors: Bartlett Cynthia Huang , Mardekian Jack , Yu-Kite Michelle , Cotter Matthew James , Kim Sindy , Decembrino Jaclyn , Snow Tamara , Carson Kenneth R. , Motyl Rockland Jillian , Kraus Albert L. , Wilner Keith D. , Oharu Norihiko , Schnell Patrick , Lu Dongrui (Ray) , Tursi Jennifer 
Published: May 2019

1055 Background: The rarity of BC in men limits the feasibility of randomized clinical studies in this population. Treatment guidelines recommend that men with BC be treated similarly to postmenopausal women. PAL, a cyclin-dependent kinase 4/6 inhibitor, is used in men with metastatic BC (mBC) in real-world clinical practice, presenting an opportunity to utilize real-world evidence to enable healthcare providers to assess novel agents in this space. Methods: Two parallel approaches were taken. In the first approach, pharmacy and medical claims data from IQVIA Inc were retrospectively analyzed to describe the treatment patterns and duration of PAL + ET (aromatase inhibitor or fulvestrant) compared to ET in men with mBC. The second approach was a retrospective analysis of data derived from electronic health records in the Flatiron Health database to understand real-world clinical response to PAL + ET vs ET alone. Median duration of treatment (mDOT) was estimated by the Kaplan-Meier method. Results: Between Feb 2015 and Apr 2017, 12.9% (147/1139 [IQVIA dataset]) of men receiving treatment for mBC were prescribed PAL + ET for any line of therapy. The mDOT in the first-line setting was numerically longer in the PAL cohort (n=37) compared with the non-PAL cohort (n=214; 8.5 vs 4.3 mo, respectively). In particular, mDOT in the first-line setting was longer with PAL + letrozole (LET; n=26) than with LET alone (n=63; 9.4 vs 3.0 mo, respectively). In the Flatiron Health dataset between Feb 2015 and July 2017, the real-world maximum response rate in the PAL + ET cohort across all lines of therapy in the mBC setting (n=12) was 33.3% (2 complete responses [CR], 2 partial responses [PR]) vs 12.5% (0 CR, 1 PR) for the ET alone cohort (n=8). Conclusions: The real-world data sources used in this study support that men with mBC derive clinical benefit from the addition of PAL to ET. Given the challenges of conducting randomized clinical trials in men with mBC, noninterventional, real-world evidence data appear to be useful to delineate the benefit of such therapies in this setting. Funding: Pfizer.
The clinical utility of strict laboratory monitoring of CDK 4/6 inhibitors in metastatic breast cancer patients.
Authors: Patel Urvi , Meisel Jane Lowe , Barbee Meagan Spencer , Frinzi Kristina , Sakach Elizabeth , Chen Zhengjia 
Published: May 2019

1062 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK 4/6i) are widely used in the treatment of hormone receptor positive, metastatic breast cancer (MBC). CDK 4/6is are well-tolerated and highly effective, but can cause neutropenia. Therefore, the FDA mandates assessment of the absolute neutrophil count (ANC) every 2 weeks for the first 2 cycles of therapy and monthly thereafter. Strict ANC monitoring is optimal in theory, but presents a challenge in the real world, impacting quality of life for patients (pts) and adding financial burden to the healthcare system. This study aims to evaluate whether strict monitoring of ANC significantly impacts treatment decisions, pt safety, and disease outcomes. Methods: A retrospective chart review of 160 pts with MBC was conducted at the Winship Cancer Institute in pts prescribed CDK 4/6is from Feb 2015 to Jan 2019. The pt’s ANC at C1D1, C1D14, C2D1, C2D14 were recorded along with various pt outcomes. Pts were divided into strict monitoring (SM) or relaxed monitoring (RM) groups. SM is defined as pts who received ANC testing within 72h of C1D14, C2D1, and C2D14. RM was defined as not meeting those criteria. Results: Palbociclib was used in 152 pts; abemaciclib was used in 8. Average age was 58. Study population was 55% Caucasian; 38% African American; 6% Asian. Pts had an average of 3 lines of prior therapy and average of 9 cycles on a CDK 4/6i. 71% of pts suffered neutropenia (40% grade 3, 4% grade 4, 2.5% febrile neutropenia). PFS and OS did not statistically differ between groups (Table), but OS data is immature. Conclusions: This study analyzed a more diverse and heavily pre-treated MBC population than previous CDK 4/6 studies. The prevalence of neutropenia (grade 3/4) aligns with results described in the PALOMA trial. PFS was higher in the RM group than in the SM group, suggesting strict monitoring for neutropenia does not improve PFS. If ANC monitoring parameters could be safely relaxed for CDK 4/6i, it could improve quality of life and decrease financial toxicity across the system. This is a topic worthy of further study. [Table: see text]
AL101 mediated tumor inhibition in notch-altered TNBC PDX models.
Authors: Broner Esther Channah , Alpert Genia , Gluschnaider Udi , Mondshine Adi , Solomon Oz , Sloma Ido , Rauch Rami , Izumchenko Evgeny , Aster Jon Christopher , Davis Matti 
Published: May 2019

1064 Background: The Notch pathway is activated during mammary gland development and has been implicated as a key driver in breast cancer. There is an urgent need to identify new therapeutic strategies for triple-negative breast cancer (TNBC), a sub-type associated with poor prognosis and no available targeted therapies. Notch gain of function (GOF) genetic alterations are potential tumor drivers found in ~10% of TNBC. This motivated the development of Notch inhibitors, including AL101 a pan-Notch, gamma secretase inhibitor (J Clin Oncol 36, 2018 abstract 2515). AL101 is currently being evaluated in Adenoid Cystic Carcinoma patients with activating Notch mutations (NCT03691207, ACCURACY trial). Here, we aim to test the activity of AL101 in TNBC patient derived xenograft (PDX) models with Notch activating genetic alterations. Methods: Gene expression cluster analysis was performed for 38 TNBC PDX tumors using a list of 21 Notch target genes. Seven tumors, bearing a “Notch-on” signature, were enriched with mutated/fusion (M/F) Notch genes and clustered separately from all other tumors. Of 9 models selected for study, 4 had a Notch-on signature and were expected to respond to AL101. Tumors were implanted into female athymic nude mice. Once tumors reached an average size of 150-300 mm3, mice (n = 5/group) were randomized to Vehicle or AL101 treatment arms (3 mg/kg, PO, 4on/3off) until tumors reached 1500 mm3 or day 60. Results: As measured by tumor growth inhibition (TGI), AL101 was more potent in tumors with a putative Notch-on signature. Within these 4 models, M/F genes were present in Notch1-NRR GOF (103% TGI p = 0.0004); Notch2-fusion (62%TGI p = 0.036); Notch3-fusion (75% TGI p = 0.032); or Notch4-fusion (147% TGI p < 0.00001). Tumors lacking the Notch signature did not respond significantly to AL101: WT Notch (43% TGI p = 0.0104; 64% TGI p = 0.13); Notch1 with a predicted loss of function mutation (12% TGI p = 0.53), Notch1 Variant of Unknown Significance (VUS) (30% TGI p = 0.44), Notch2 VUS (41% TGI p = 0.44). Conclusions: We demonstrate that in TNBC PDX models, the presence of a Notch-on signature and Notch GOF mutations/fusions correlates with potent response to AL101. These data support the clinical development of AL101 as a targeted therapy for TNBC with Notch GOF alterations.