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AbstractBackgroundSeveral registry-based analyses suggested a survival advantage for married versus single patients with pancreatic cancer. The mechanisms underlying the association of marital status and survival are likely multiple and complex and, therefore, may be obscured in analyses generated from large population-based databases. The goal of this research was to characterize this potential association of marital status with outcomes in patients with resected pancreatic cancer who underwent combined modality adjuvant therapy on a prospective clinical trial.Materials and MethodsThis is an ancillary analysis of 367 patients with known marital status treated on NRG Oncology/RTOG 97-04. Survival analysis was performed using the Kaplan-Meier method and compared using the log-rank test. Multivariate analysis was performed using the Cox proportional hazards regression model.ResultsOf 367 patients, 271 (74%) were married or partnered and 96 (26%) were single. Married or partnered patients were more likely to be male. There was no association between marital status and overall survival (OS) or disease-free survival (DFS) on univariate (hazard ratio [HR], 1.09 and 1.01, respectively) or multivariate analyses (HR, 1.05 and 0.98, respectively). Married or partnered male patients did not have improved survival compared with female or single patients.ConclusionAncillary analysis of data from NRG Oncology/RTOG 97-04 demonstrated no association between marital and/or partner status and OS or DFS in patients with resected pancreatic cancer who received adjuvant postoperative chemotherapy followed by concurrent external beam radiation therapy and chemotherapy. Clinical trial identification number. NCT00003216.

Background/Objective The great auricular nerve (GAN) arises from C2‐C3 and provides innervation over the skin in the pre‐auricular region, jaw angle, posteroinferior pinna, and mastoid. Although damage to the GAN has been reported following trauma or procedures nearby this nerve course, neuralgia of this nerve is uncommon with knowledge based on a handful of case reports in literature. The objective of this study is to describe the presentation, treatment, and outcome of 13 cases of GAN neuralgia. Methods Case series . Retrospecive review of charts from 1994 to 2018 with diagnoses: “auricular neuralgia,” “auricular neuritis,” or “auricular neuropathy.” We included subjects with neuralgic pain within the distribution of the GAN, and excluded patients with atypical facial pain, GAN neuropathy, or unclear etiology. Results Of 79 charts, 13 patients met criteria (age at onset 11‐59; 11 women, 2 men). Pain was most often described as paroxysmal stabbing provoked by: turning the head (n = 7), touching the neck (n = 5), neck position during sleep (n = 2), jaw movement (n = 2), and other (n = 2). Seven patients received GAN blocks: all noted dramatic improvement in pain, including 3 who continued to receive serial blocks at our institution successfully for the next 2 to 5 years. Two patients successfully transitioned from GAN blocks to GAN stimulators. One patient with GAN lymphoma had resolution of pain following GAN resection. Conclusion GAN neuralgia should be considered in the differential for periauricular pain. GAN blocks or stimulators may be helpful for pain management.

Abstract Pediatric large B-cell lymphomas (LBCLs) share morphological and phenotypic features with adult types but have better prognosis. The higher frequency of some subtypes such as LBCL with IRF4 rearrangement (LBCL-IRF4) in children suggests that some age-related biological differences may exist. To characterize the genetic and molecular heterogeneity of these tumors, we studied 31 diffuse LBCLs (DLBCLs), not otherwise specified (NOS); 20 LBCL-IRF4 cases; and 12 cases of high-grade B-cell lymphoma (HGBCL), NOS in patients ≤25 years using an integrated approach, including targeted gene sequencing, copy-number arrays, and gene expression profiling. Each subgroup displayed different molecular profiles. LBCL-IRF4 had frequent mutations in IRF4 and NF-κB pathway genes (CARD11, CD79B, and MYD88), losses of 17p13 and gains of chromosome 7, 11q12.3-q25, whereas DLBCL, NOS was predominantly of germinal center B-cell (GCB) subtype and carried gene mutations similar to the adult counterpart (eg, SOCS1 and KMT2D), gains of 2p16/REL, and losses of 19p13/CD70. A subset of HGBCL, NOS displayed recurrent alterations of Burkitt lymphoma–related genes such as MYC, ID3, and DDX3X and homozygous deletions of 9p21/CDKN2A, whereas other cases were genetically closer to GCB DLBCL. Factors related to unfavorable outcome were age >18 years; activated B-cell (ABC) DLBCL profile, HGBCL, NOS, high genetic complexity, 1q21-q44 gains, 2p16/REL gains/amplifications, 19p13/CD70 homozygous deletions, and TP53 and MYC mutations. In conclusion, these findings further unravel the molecular heterogeneity of pediatric and young adult LBCL, improve the classification of this group of tumors, and provide new parameters for risk stratification.

Abstract Background : Carfilzomib is an innovative second generation proteasome inhibitor (PI) that binds irreversibly and selectively to the proteasome. Carfilzomib exhibits sustained inhibition of the proteasome with minimal off-target activity. Kd was approved in 2016 as a treatment (Tx) option for R/RMM patients who have received one to three prior lines of therapy.In the ENDEAVOR phase 3, open label, multicenter randomized controlled trial assessing Kd vs Vd, median progression-free survival (PFS) was 18.7 months (95% CI:15.6 - could not be estimated) in the Kd group vs 9.4 months (8.4 - 10.4) in the Vd group at an a priori, pre-specified interim analysis (hazard ratio [HR]: 0.53 [95% CI: 0.44 - 0.65]; p<0.0001). OS data at the 1st interim analysis were immature. In the current study, we assessed the cost-effectiveness (CE) of Kd vs Vd from a US payer perspective using data from ENDEAVOR and long-term overall survival (OS) data from the Surveillance, Epidemiology, and End Results Program (SEER). Methods: A partitioned-survival model with a progression-free (PF), a post-progression (PP) and a death state was built with a 30 year horizon. PFS was modelled using separately fitted log-logistic parametric curves. In order to estimate measures of efficacy for OS and to incorporate treatment effect into the model, time-dependent multiple semiparametric Cox regression analyses were implemented for OS outcomes, which controlled for baseline covariates. OS for Vd in the base case was modelled with a separately fitted Weibull parametric curve, which was fitted to the Vd data. The time-dependent multiple Cox model generated a HR for 0 to 12 months and a HR beyond 12 months for Kd vs Vd, which were applied to model the Kd OS curve. The OS curves beyond 36 months were extrapolated with SEER data. A Weibull distribution was used for the extrapolation by matching the SEER registry data to the ENDEAVOR population, which was assumed to represent the Vd survival rate. To this extrapolated survival curve beyond 36 months, the OS treatment effect was applied in order to model the Kd curve. Grade ≥ 3 adverse events (AEs) with ≥ 2% incidence in any ENDEAVOR arm were included. Utilities were derived from the literature and adjusted for the treatment specific improvement in QoL observed when patients were PF in ENDEAVOR. Costs related to drug (WAC prices), administration, monitoring, AE management, and subsequent Tx were considered. The base case utilized OS results from an updated OS dataset (March 2016) that resulted in an ad hoc OS analysis. A 3% discount rate was applied to costs and health outcomes. Results: In the base-case, results from the model showed thatKd was more effective compared to Vd, providing 1.874 PfLY, 1.854 LY, and 1.654 QALY gains over the modelled horizon. Kd incurred $227,703 in total additional costs and the ICER vs Vd was 137,660$/QALY. Conclusions: The model predicts that Kd delivers 1.85 additional life years over the the comparator Vd. Per the base case, Kd is cost-effective vs Vd at generally accepted willingness-to-pay thresholds of $150,000/QALY and $300,000/QALY in the US. Based on the ENDEAVOR data, Kd is a superior PI-based doublet compared to Vd, and should be preferred whenever doublets are appropriate for the patient, Furthermore, this CE analysis shows that Kd delivers considerable incremental value to patients with relapsed or refractory MM and to payers who must allocate budgets for the treatment of patients. Table Table. Disclosures Jakubowiak: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; SkylineDx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Majer:Amgen Inc: Employment, Equity Ownership. Houisse:Amgen Inc: Consultancy. Benedict:Amgen Inc: Consultancy. Campioni:Amgen: Employment, Other: Holds Amgen Stock. Panjabi:Amgen Inc: Employment, Equity Ownership. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy.

Abstract Introduction: Classical Hodgkin lymphoma (cHL) is characterized by Reed Sternberg (RS) cells surrounded by an extensive but ineffective inflammatory/immune cell infiltrate. Recent studies suggest that Hodgkin RS cells have developed mechanisms that exploit the programmed cell death-1 (PD-1) pathway to evade immune detection. In cHL, chromosome 9p24.1 gain is a frequent structural alteration that increases the gene dosage of the PD-1 ligands, PD-L1 and PD-L2, and their induction via JAK/STAT signaling. Epstein-Barr Virus (EBV) infection also increases the expression of the PD-1 ligands in EBV-positive cHL. Ligand binding to PD-1 receptor-positive activated T cells induces “T cell exhaustion,” a reversible inhibition of T cell activation and proliferation. Nivolumab (BMS-936558, Bristol-Myers Squibb) is a fully human IgG4 monoclonal PD-1 blocking antibody that potentiates anti-tumor T cell activity, and exhibits clinical efficacy in several solid tumors. We hypothesized that nivolumab may augment anti-tumor activity in patients with relapsed or refractory (R/R) cHL, including those who had failed brentuximab vedotin (BV), and evaluated the PD-1 blocking antibody. These are the first analyses being reported with PD-1 antibody for the treatment of cHL. Methods: Patients with R/R cHL were included as an independent cohort in a dose escalation and cohort expansion phase I study of nivolumab in lymphoma and multiple myeloma (MM). Results for patients with non-Hodgkin lymphoma and MM are reported separately. Patients with cHL received nivolumab 3 mg/kg every 2 weeks until confirmed tumor progression or excessive toxicity. Responses were evaluated using standard criteria. The primary endpoint was safety; key secondary endpoints included anti-tumor activity and expression of immunomodulatory proteins in tumor biopsies. Results: Twenty-three patients were enrolled with R/R cHL. Patients were heavily pre-treated, 87% had received ≥ 3 prior treatment regimens, 78% had prior autologous stem cell transplant (ASCT), and 78% had prior BV treatment. Drug-related adverse events (AEs) of any grade occurred in 78% of patients, the most common of which were rash (22%), decreased platelet count (17%), diarrhea, nausea, pruritus, fatigue, and pyrexia (each at 13%). Drug-related grade 3/4 AEs occurred in 22% of patients. Three patients experienced 1 serious AE each (grade 3 myelodysplastic syndrome [MDS], grade 3 pancreatitis, and grade 2 lymph node pain). The objective response rate (ORR) was 87% (20/23), with 4 patients (17%) achieving a complete response (CR) and 16 (70%) obtaining a partial response (PR). The remaining 3 patients (13%) had stable disease (SD). All 23 patients had a reduction in tumor burden at 1 or more efficacy assessments during treatment with nivolumab (Figure). Among the 18 patients who had previously failed BV, the ORR was 89% (16/18), with 6% (1/18) achieving CR and 83% (15/18) PR. Progression-free survival (PFS) rate at 24 weeks was 86% (95% CI, 62-95%). The median overall survival (OS) has not been reached (range, 21+ to 75+ weeks). Six of 23 patients elected to discontinue study treatment to undergo stem cell transplantation, 2 patients discontinued due to toxicities (MDS and thrombocytopenia in 1 patient; pancreatitis in 1 patient), 4 patients discontinued due to disease progression, and 11 patients continue on study as of June 16, 2014. In a subset of study patients (10/23), PD-L1 and PD-L2 copy numbers in RS cells were assessed using fixed tumor biopsy specimens and a 3-probe fluorescence in situ assay (PD-L1,PD-L2, and control centromeric probe). In all tumors, RS cells had copy gains of PD-L1 and PD-L2, as a result of either polysomy or amplification; these tumors also exhibited increased protein expression of PD-L1. RS cells were also largely positive for pSTAT3, indicative of active JAK/STAT signaling. Conclusions In patients with R/R cHL, nivolumab-mediated PD-1 blockade is safe and tolerable with a safety profile similar to that in solid tumors. The frequent and long-lasting responses in heavily pretreated, R/R patients, including those who have failed BV, highlight the importance of the PD-1 pathway in cHL, and the genetically defined sensitivity to PD-1 blockade in this disease. Based on these results, the FDA granted nivolumab breakthrough status in relapsed cHL and a large, multinational, phase II trial of this therapy is underway. Figure 1 Figure 1. Disclosures Armand: Merck: Consultancy. Off Label Use: Nivolumab was tested for the treatment of hematologic malignancies.. Ansell:Bristol-Myers Squibb: Research Funding. Lesokhin:Bristol-Myers Squibb: Consultancy, Research Funding. Timmerman:Bristol-Myers Squibb: Research Funding. Borrello:Bristol-Myers Squibb: Research Funding. Rodig:Bristol-Myers Squibb: Research Funding. Zhu:Bristol-Myers Squibb: Employment. Grosso:Bristol-Myers Squibb: Employment, Equity Ownership. Kim:Bristol-Myers Squibb: Employment. Shipp:Merck: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Janssen R&D: Membership on an entity's Board of Directors or advisory committees.

Abstract Panobinostat (PBST) is a histone deacetylase inhibitor with biologic rationale in the treatment of gliomas harboring H3 K27M mutation. METHODS We performed a retrospective medical record review of adult patients with H3 K27M mutant diffuse midline glioma treated with PBST at Mayo Clinic (Rochester, MN). RESULTS Four patients were identified with a mean age 40 years (range 22–62 years). Tumor location was: spinal cord (thoracic n=1, cervical n=1), brainstem (n=1), and thalamus (n=1).Two patients underwent biopsy alone while two underwent a partial resection. Three patients were treated with radiation (36–54 Gy) immediately prior to PBST monotherapy, and one patient was treated with PBST monotherapy without preceding radiation. All patients were otherwise chemotherapy naïve and did not receive any concurrent chemotherapy with PBST. PBST was dosed at either 10 mg (n=1) or 20mg (n=3) administered on days 1, 3, 5, 8, 10 and 12 of 21 day cycles. The mean duration of PBST therapy was 5 months (range 2–11 months). PBST was well tolerated overall. One patient experienced an objective response per RANO criteria. Two patients continue on therapy (5 cycles, 12 cycles) with stable disease. One patient rapidly progressed after 2 cycles of PBST therapy. In contrast with the patients who derived benefit from PBST, this patient was younger (22) and had multifocal disease with leptomeningeal involvement at treatment onset. The average progression free survival post PBST initiation was 8 months. CONCLUSION This single institution case series shows promise that PBST may have therapeutic benefit in adult patients with H3 K27M mutant diffuse midline glioma.

Abstract BACKGROUND The Tumor Treating Fields (TTF) mechanism of action is hypothesized act upon mitosis by disrupting the cell spindle apparatus. However, biomarkers and human tissue correlation of the effect of the TTF device are lacking. CASE: A 41 year-old previously healthy woman was found to have a right frontoparietal glioblastoma after she developed subacute onset of left hemiparesis and headache. The tumor was IDH wild type MGMT promoter unmethylated and TERT mutated. Chromosomal Microarray (CMA) was performed and demonstrated genome wide aneuploidy primarily characterized by hyperdiploidy. She underwent a gross total resection of the enhancing portion of the tumor and subsequent standard chemoradiotherapy (60 Gy IMRT with concomitant temozolomide) followed by initiation of the TTF device and adjuvant temozolomide. Six months after diagnosis, after 72 days of using the TTF device with 75% compliance and completion of the third cycle of temozolomide the patient had radiographic recurrence. She underwent a repeat resection. Pathology demonstrated recurrent tumor. Genetic analysis no longer demonstrated chromosomal losses or gains: the tumor was diploid. DISCUSSION This case may be a demonstration of effect of the TTF device applying a selective pressure to cells with multiple chromosomal gains and losses as the efficiency of mitosis in these cells may already be severely compromised. We are currently performing CMA on all patients with available tissue treated with the TTF device at our institution, with a planned retrospective analysis to explore this hypothesis further. CONCLUSION Repeat resection with detailed genetic analysis of GBM recurrence after therapies may help generate hypotheses regarding mechanisms of resistance, and in this case, mechanisms of action of the TTF.

Abstract Background Langerhans cell histiocytosis (LCH) is a heterogeneous disease whose myriad manifestations result from accumulation of Langerhans cells in a variety of organs most commonly including skin, bone, central nervous system, liver, lymph nodes, and bone marrow. The disease can affect people of any age. Treatment is primarily driven by disease extent and organ involvement and can range from focused radiation or surgery to multi-agent chemotherapy. There is a relatively high recurrence rate following complete remissions with conventional chemotherapy. In the first-time-in-human (FTIH) study of the oral pan-AKT inhibitor afuresertib (GSK2110183), in patients with hematologic malignancies, a patient with refractory multi-system LCH experienced a prolonged period (> 3 years) of clinical benefit on 125mg oral once daily afuresertib. This observation led to the evaluation of the use of afuresertib in patients with LCH. Methods This single-arm, open-label trial was designed to evaluate the efficacy and safety of afuresertib, administered at 125 mg once daily, in adults and adolescents with relapsed/refractory LCH and adults with treatment-naïve LCH. Secondary objectives included pharmacokinetics. Diagnosis of LCH was confirmed by pathology review of archival tissue. The Histiocyte Society criteria were used for response evaluation at three and six months with safety and pharmacokinetic assessments performed at pre-specified intervals. BRAF status from archival tissue was evaluated by Sanger sequencing. Results 17 patients (16 adults, 10 females) were enrolled; median age was 38 years (15-75). 3/17 patients had isolated pulmonary disease, 1/17 had single-system multifocal-bone disease, 1/17 had single-system skin disease, and 12/17 had multi-system disease. Seven patients were treatment-naïve; 10 had relapsed/refractory disease, including the one adolescent. The most frequent (>20% of patients) adverse events (AEs), regardless of causality, were nausea (59%), fatigue (59%), upper respiratory infection (47%), diarrhea (47%), dyspepsia (35%), bone pain (39%), asthenia (24%), memory impairment (24%), decreased appetite (24%) and vomiting (24%). Most AEs were Grade 1 or 2 in severity; no Grade 4 AEs were reported and no Grade 3 AEs occurring in more than 1 subject were reported. 6/17 (35%) had afuresertib dose modifications (interruption or reduction). Afuresertib plasma concentrations in the adult patients were similar to values seen in adult patients with other hematologic malignancies in the FTIH study. Following a single dose, the concentration-time profile in the adolescent patient was similar to adults in the FTIH study (Tmax = 3h: Cmax 229 ng/ml: AUC24 = 3893 ng*h/mL). 15 patients had archival tissues collected for BRAF testing; 13 had DNA suitable for analysis. 2/13 was BRAF V600E mutant and 11/13 were BRAF wild type. Upon evaluation of the all-treated patient population, 5/17 (29%) patients were reported as better at the three and/or six month disease assessment. Among the 5 responders, three were treatment-naïve and two had relapsed/refractory disease. The median duration on study for all patients was 214 (44-426) days. For the 5 patients who responded, the median duration on study was 372 (255-426) days. Conclusion The pharmacokinetic and safety profile of afuresertib in patients with LCH was consistent with that observed in patients with other hematologic malignancies evaluated in the FTIH study. Afuresertib was active in patients with both treatment-naïve and relapsed/refractory disease. Additional evaluation, including molecular profiling, may be warranted alone or in combination with BRAF inhibitors or established therapies for LCH to determine the optimal population of patients with LCH who might benefit from afuresertib Disclosures: Vassallo: GlaxoSmithKline: Research Funding. Oliff:GlaxoSmithKline: Employment. Morris:GlaxoSMithKline: Employment. Reedy:GlaxoSmithKline: Employment. Portnoy:GlaxoSmithKline: Stock, prior employee Other. Smith:GlaxoSmithKline: Employment, Equity Ownership. Noble:GlaxoSmithKline: Employment, stock Other. Murnane:GlaxoSmithKline: Employment, stock Other. Szabo:GlaxoSmithKline: Employment. Heaney:Novartis: Research Funding; Sanofi-Aventis: Consultancy, Research Funding; Onconova: Research Funding; Incyte: Consultancy, Research Funding.