Citations

Abstract Introduction: Patients with relapsed or refractory diffuse large B-cell lymphoma (RR DLBCL) who cannot tolerate or who are not eligible for autologous or chimeric antigen receptor T cell (CAR-T) therapy have limited therapeutic options and suboptimal long-term outcomes. In patients who were not eligible for HSCT, the rituximab plus gemcitabine, dexamethasone and cisplatin (R-GDP) regimen (and variations using methylprednisolone or carboplatin/oxaliplatin) have shown an overall response rates (ORR) of ~50%, a complete response (CR) rate of ~25% (Gopal, Leuk Lymphoma, 2010), and a median progression-free survival (PFS) and an overall survival (OS) of 3 and 9 months, respectively (Crump, Hematol Oncol Clin N Am. 2016; Gopal Leuk Lymphoma, 2010; Ng, Br J Cancer, 2005; Sirohi, Hematology, 2007; Barton, Eur J Haematol. 2015; Moccia Leuk Lymphoma, 2017). Selinexor is an oral small molecule selective inhibitor of exportin-1 (XPO1) mediated nuclear export (SINE) compound leading to activation of tumor suppressor proteins and reduction in oncoprotein levels. It also reduces the expression of deoxyribonucleic acid (DNA) damage repair proteins and therefore potentiates DNA damage-based therapies leading to an increased death of cancer cells. Selinexor has synergistic effects with gemcitabine and cisplatin, and enhanced anti-lymphoma effects with dexamethasone. In the SADAL study (n=134), single-agent oral selinexor 60 mg twice weekly induced an ORR of 29% and a CR rate of 13% in patients with RR DLBCL. The response rates were consistent across various subgroups including patients <70 vs ≥70 years old, those with de novo and transformed DLBCL, and GCB and non-GCB subtypes of DLBCL. The median duration of response (DOR) was 9.3 months, and 23 months for patients who achieved CR. OS was 9.0 months. In June 2020, selinexor monotherapy was approved in the US for the treatment of adult patients with RR DLBCL, not otherwise specified, including DLBCL arising from follicular lymphoma, after at least 2 lines of systemic therapy. Selinexor in combination with R-GDP was evaluated in a Phase 1 clinical trial (SELINDA), in which patients with DLBCL received either 40 or 60 mg selinexor once or twice weekly in combination with standard dose R-GDP. The recommended phase 2 dose for further exploration was 40 or 60 mg once weekly with an ORR of 60-80%. Therefore, combining selinexor with R-GDP is expected to improve response rates, and continuation of treatment with single-agent selinexor is expected to prolong the duration of responses, improve PFS (and potentially OS) in patients with RR DLBCL. Materials and methods: XPORT-DLBCL-030 is a Phase 2/3, multicenter study. The Phase 2 portion of the study is an open-label randomized study to identify the optimal dose of selinexor (40 or 60 mg) in combination with R-GDP in patients (n=120) with RR DLBCL. Patients ≥18 years with 1-3 prior lines of therapy and ECOG performance status ≤2 who are not intended for HSCT or CAR-T therapy are randomized 1:1:1 to one of 3 treatment arms: Arm 1: selinexor 40 mg+R-GDP (S40+R-GDP); Arm 2: selinexor 60 mg+R-GDP (S60 + R-GDP); Arm 3: R-GDP. Combination treatment will be given for up to 6 cycles (21 days/cycle). After completing the SR-GDP combination therapy (EoC), patients in Arms 1 and 2 who reach at least partial response (PR), will receive weekly single-agent selinexor 60 mg (28 days/cycle) as "continuous therapy" until disease progression (PD) or unacceptable toxicity. After PD, patients will be followed up for survival. Patients in the R-GDP arm will be followed up for PD and survival. Patients who are ineligible for HSCT due to an active disease, or those who have primary refractory DLBCL, defined as no response or relapse within 6 months after ending first-line treatment, will be allowed to enroll in the study (up to 15% and 25%, respectively of all patients enrolled). The primary endpoint of the study is ORR according to the Lugano 2014 criteria. Secondary endpoints include PFS, OS, ORR-EoC, DOR and incidence and severity of adverse events. Figure 1 Figure 1. Disclosures Pinto: Takeda: Consultancy; MSD: Honoraria; Incyte: Honoraria; Roche: Honoraria, Speakers Bureau; Bristol Myers Squibb-CELGENE: Honoraria. Yimer: Texas Oncology: Current Employment; Pharmacyclics: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau. Manda: Morphosys: Honoraria; Genmab: Current equity holder in publicly-traded company. Canales: Sanofi: Consultancy; Incyte: Consultancy; Novartis: Consultancy, Honoraria; Sandoz: Honoraria, Speakers Bureau; iQone: Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Gilead/Kite: Consultancy, Honoraria; Eusa Pharma: Consultancy, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria. Jurczak: European Medicines Agency, Sandoz-Novartis, Janssen China R&D, BeiGene, Epizyme, Acerta, AstraZeneca: Consultancy; AbbVie, AstraZeneca, Bayer, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics, Pharmacyclics, Affirmed, Gilead Sciences, Nordic Nanovecto: Research Funding; Jagiellonian University: Ended employment in the past 24 months; Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; AstraZeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche: Membership on an entity's Board of Directors or advisory committees. Sureda: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Ma: Karyopharm Therapeutics Inc.: Current equity holder in publicly-traded company, Ended employment in the past 24 months. Li: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Ingalls: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Arriola: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Arazy: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shah: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Shacham: Karyopharm: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: (8999996, 9079865, 9714226, PCT/US12/048319, and I574957) on hydrazide containing nuclear transport modulators and uses, and pending patents PCT/US12/048319, 499/2012, PI20102724, and 2012000928) . Kauffman: Karyopharm Therapeutics Inc.: Current Employment, Current equity holder in publicly-traded company. Nowakowski: Celgene, NanoString Technologies, MorphoSys: Research Funding; Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Context Identification of modifiable risk factors, including genetic and acquired disorders of lipid and lipoprotein metabolism, is increasingly recognized as an opportunity to prevent premature cardiovascular disease (CVD) in at-risk youth. Pediatric endocrinologists are at the forefront of this emerging public health concern and can be instrumental in beginning early interventions to prevent premature CVD-related events during adulthood. Aim In this article, we use informative case presentations to provide practical approaches to the management of pediatric dyslipidemia. Cases We present 3 scenarios that are commonly encountered in clinical practice: isolated elevation of low-density lipoprotein cholesterol (LDL-C), combined dyslipidemia, and severe hypertriglyceridemia. Treatment with statin is indicated when the LDL-C is ≥190 mg/dL (4.9 mmol/L) in children ≥10 years of age. For LDL-C levels between 130 and 189 mg/dL (3.4-4.89 mmol/L) despite dietary and lifestyle changes, the presence of additional risk factors and comorbid conditions would favor statin therapy. In the case of combined dyslipidemia, the primary treatment target is LDL-C ≤130 mg/dL (3.4 mmol/L) and the secondary target non-high-density lipoprotein cholesterol <145 mg/dL (3.7 mmol/L). If the triglyceride is ≥400 mg/dL (4.5 mmol/L), prescription omega-3 fatty acids and fibrates are considered. In the case of triglyceride >1000 mg/dL (11.3 mmol/L), dietary fat restriction remains the cornerstone of therapy, even though the landscape of medications is changing. Conclusion Gene variants, acquired conditions, or both are responsible for dyslipidemia during childhood. Extreme elevations of triglycerides can lead to pancreatitis. Early identification and management of dyslipidemia and cardiovascular risk factors is extremely important.

SummaryFimepinostat (CUDC‐907), a first‐in‐class oral small‐molecule inhibitor of histone deacetylase and phosphatidylinositol 3‐kinase, demonstrated efficacy in a phase 1 study of patients with relapsed/refractory (R/R) diffuse large and high‐grade B‐cell lymphomas (DLBCL/HGBL), particularly those with increased MYC protein expression and/orMYCgene rearrangement/copy number gain (MYC‐altered disease). Therefore, a phase 2 study of fimepinostat was conducted in this patient population with 66 eligible patients treated. The primary end‐point of overall response (OR) rate for patients with MYC‐IHC ≥40% (n = 46) was 15%. Subsequently, exploratory pooled analyses were performed including patients treated on both the phase 1 and 2 studies based upon the presence of MYC‐altered disease as well as a biomarker identified by Virtual Inference of Protein activity by Enriched Regulon analysis (VIPER). For these patients with MYC‐altered disease (n = 63), the overall response (OR) rate was 22% with seven responding patients remaining on treatment for approximately two years or longer, and VIPER yielded a three‐protein biomarker classification with positive and negative predictive values of ≥85%. Prolonged durations of response were achieved by patients with MYC‐altered R/R DLBCL/HGBL treated with single‐agent fimepinostat. Combination therapies and/or biomarker‐based patient selection strategies may lead to higher response rates in future clinical trials.

With rapid advances in our understanding of cancer, there is an expanding number of potential novel combination therapies, including novel–novel combinations. Identifying which combinations are appropriate and in which subpopulations are among the most difficult questions in medical research. We conducted a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review of trials of novel–novel combination therapies involving immunotherapies or molecular targeted therapies in advanced solid tumors. A MEDLINE search was conducted using a modified Cochrane Highly Sensitive Search Strategy for published clinical trials between July 1, 2017, and June 30, 2020, in the top-ranked medical and oncology journals. Trials were evaluated according to a criterion adapted from previously published Food and Drug Administration guidance and other key considerations in designing trials of combinations. This included the presence of a strong biological rationale, the use of a new established or emerging predictive biomarker prospectively incorporated into the clinical trial design, appropriate comparator arms of monotherapy or supportive external data sources and a primary endpoint demonstrating a clinically meaningful benefit. Of 32 identified trials, there were 11 (34%) trials of the novel–novel combination of anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) and anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) therapy, and 10 (31%) trials of anti-PD-1/PD-L1 and anti-vascular endothelial growth factor (VEGF) combination therapy. 20 (62.5%) trials were phase II trials, while 12 (37.5%) were phase III trials. Most (72%) trials lacked significant preclinical evidence supporting the development of the combination in the given indication. A majority of trials (69%) were conducted in biomarker unselected populations or used pre-existing biomarkers within the given indication for patient selection. Most studies (66%) were considered to have appropriate comparator arms or had supportive external data sources such as prior studies of monotherapy. All studies were evaluated as selecting a clinically meaningful primary endpoint. In conclusion, designing trials to evaluate novel–novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design. Designing trials to evaluate novel–novel combination therapies presents numerous challenges to demonstrate efficacy in a comprehensive manner. A greater understanding of biological rationale for combinations and incorporating predictive biomarkers may improve effective evaluation of combination therapies. Innovative statistical methods and increasing use of external data to support combination approaches are potential strategies that may improve the efficiency of trial design.

Abstract Background and study aims Current guidelines conditionally recommend performing early colonoscopy (EC) (< 24 hours) in patients admitted with acute lower gastrointestinal bleeding (LGIB). It remains unclear whether this practice is implemented widely. Therefore, we used the Nationwide Inpatient Sample to investigate trends for timing of colonoscopy in patients admitted with acute LGIB. We also assessed trend of hospitalization and mortality in patients with LGIB. Patients and methods Adult patients with LGIB admitted from 2005 to 2014 were examined. ICD-9-CM codes were used to extract LGIB discharges. Trends were assessed using Cochrane-Armitage test. Factors associated with mortality, cost of hospitalization, and length of stay (LOS) were assessed by multivariable mixed-effects and exact-matched logistic, linear regression, and accelerated-failure time models, respectively. Results A total of 814,647 patients with LGIB were included. The most common etiology of LGIB was diverticular bleeding (49 %) and 45 % of patients underwent EC. Over the study period, there was no change in the trend of colonoscopy timing. Although admission with LGIB increased over the study period, the mortality rate decreased for patients undergoing colonoscopy. Independent predictors of mortality were age, surgery (colostomy/colectomy) during admission, intensive care unit admission, acute kidney injury, and blood transfusion requirement. Timing of colonoscopy was not associated with mortality benefit. However, cost of hospitalization was $ 1,946 lower and LOS was 1.6 days shorter with EC. Conclusion Trends in colonoscopy timing in management of LGIB have not changed over the years. EC is associated with lower LOS and cost of hospitalization but it does not appear to improve inpatient mortality.

In this study we aim to examine gene–environment interactions (GxEs) between genes involved with estrogen metabolism and environmental factors related to estrogen exposure. GxE analyses were conducted with 1970 Korean breast cancer cases and 2052 controls in the case-control study, the Seoul Breast Cancer Study (SEBCS). A total of 11,555 SNPs from the 137 candidate genes were included in the GxE analyses with eight established environmental factors. A replication test was conducted by using an independent population from the Breast Cancer Association Consortium (BCAC), with 62,485 Europeans and 9047 Asians. The GxE tests were performed by using two-step methods in GxEScan software. Two interactions were found in the SEBCS. The first interaction was shown between rs13035764 of NCOA1 and age at menarche in the GE|2df model (p-2df = 1.2 × 10−3). The age at menarche before 14 years old was associated with the high risk of breast cancer, and the risk was higher when subjects had homozygous minor allele G. The second GxE was shown between rs851998 near ESR1 and height in the GE|2df model (p-2df = 1.1 × 10−4). Height taller than 160 cm was associated with a high risk of breast cancer, and the risk increased when the minor allele was added. The findings were not replicated in the BCAC. These results would suggest specificity in Koreans for breast cancer risk.