Yarchoan, Mark

4023 Background: Biliary tract cancers (BTC) are increasingly subtyped by molecular alterations, but little is known about the relationship between gain-of-function mutations and the RNA transcript expression of immune-related pathways. Methods: A sample of retrospective, clinicogenomic and transcriptomic data from de-identified records of patients with BTC in the Tempus database was selected. We then investigated the relationship between the mutational landscape and immune-related RNA signatures of different anatomic and genomic BTC subtypes. Results: The cohort included 455 samples of intrahepatic bile duct (IH) (n=267), gallbladder (GB) (n=153), and extrahepatic bile duct (EH) (n=35) cancer subtypes. Across all subtypes, we detected alterations in TP53 (43.8%), ARID1A (19.8%), KMT2C (18.2%), BAP1 (14.6%), KRAS (12.7%), TERT (12.0%), IDH1 (11.4%), KMT2D (11.0%), LRP1B (11.0%), and PBRM1 (10.7%), along with FGFR2 fusions (2.6%). Potentially actionable biomarkers ( FGFR2 and NTRK1-3 fusions, IDH1 and BRAFV600E mutations, tumor mutational burden [TMB]>10, HER2 expression, and/or microsatellite instability) were identified in 21.1% of all BTC and 28.6% of IH samples. Mutually exclusive alterations observed between subtypes were TP53 & BAP1, KRAS & BAP1, TP53 & IDH1, KRAS & IDH1, and SMAD4 & BAP1 ( P < 0.001 for all). GB was more inflamed based on RNA signatures and classical immune biomarkers, including PD-L1 and TMB. RNA signature analyses revealed a higher expression of immune-related pathways in GB than IH ( P = 0.001) with no differences in comparison with EH. PD-L1 expression and continuous TMB were elevated in GB versus the other anatomical subtypes. Significant associations were noted between particular genetic mutations and immune profiling features (table). Conclusions: BTC subtypes are diverse in DNA alterations, RNA inflammatory signatures, and immune markers. Notably, potentially actionable biomarkers were identified in a sizable portion of the cohort and varied significantly between subtypes. These results provide guidance for targeted therapy development and support the use of multimodal immune profiling for BTC. For example, GB-specific clinical trials may be considered due to the relative increase in immune-related biomarkers observed in GB and the historically limited success of BTC trials.[Table: see text]

128 Background: Treatment for neoplastic fevers and sweating (NFS) is usually accomplished successfully with non-steroidal drugs (NSAIDs) such as naproxen, but such therapies may be contraindicated in some patients due to drug interactions, bleeding diathesis, renal disease, or cirrhosis. Options for treating NFS in such patients are limited. Methods: We report the first use of oxybutynin (OxyB), commonly used for hyperhidrosis and increasingly used for hormonally mediated hot flashes (Smith TJ, NEJM 2018; Leon-Ferre R, SABCS 2018, under review in JNCI Cancer Spectrum, for NFS in NSAID-ineligible or refractory patients. Results: Two patients with NFS were treated. The first was a 70 year old (yo) woman with cholangiocarcinoma with 3 months of NFS for whom naproxen was ineffective and who was starting chemotherapy. Within 2 hours after 2.5 mg OxyB q12h her sweating was gone, and her fever, which had been up to 100.4F, never resumed. The second was a 52 yo male with cirrhosis and hepatocellular carcinoma who was prescribed 2.5 mg q12h OxyB with lysis of his fever within hours and cessation of his sweating. To date, over one month has passed with no reduction in efficacy. Conclusions: OxyB may be a successful treatment modality for patients with NFS who cannot be treated with or are refractory to NSAIDs. Further research is warranted to ensure stability of results over time and to monitor for side effects.

Abstract Introduction: The development of immune checkpoint inhibitors (ICPis) has ushered in a new paradigm for the treatment of both solid and liquid malignancies. However, these therapies, which promote an activated T cell phenotype, can cause a unique spectrum of autoimmune toxicities known as immune-related adverse events (IRAEs), which can affect a variety of organ systems. Autoimmune hemolytic anemia (AIHA) has been described as a rare complication of ICPis, but existing data are mostly limited to isolated case reports. Further, guidelines for the diagnosis and treatment of these patients are lacking. We describe the clinical and laboratory features of 14 patients who developed ICPi-associated AIHA. Methods: We contacted hematology departments at 18 academic medical centers across the U.S. to inquire about potential cases of ICPi-associated AIHA. Nine centers contributed a total of 14 cases to the current series. We defined AIHA as an abrupt decrease in hemoglobin ≥2g/dL, the presence of at least two laboratory features of hemolysis (elevated serum lactate dehydrogenase [LDH], elevated reticulocyte percentage, low or absent serum haptoglobin, and spherocytes), and the exclusion of other causes of anemia. We collected data on demographics and comorbidities, features of AIHA, and response to treatment. We defined complete recovery (CR) and partial recovery (PR) of hemoglobin as an increase from the nadir hemoglobin to within 1 and 2 g/dL of the baseline value, respectively, in the absence of recent transfusion. Results: The clinical features of the 14 patients in our cohort with ICPi-associated AIHA are summarized in the Figure (panel A). Underlying malignancies included melanoma (n = 9), non-small cell lung cancer (n = 3), colorectal cancer (n = 1), and acute myelogenous leukemia (n = 1). Four patients had a pre-existing diagnosis of a lymphoproliferative disorder, and two of these patients were known to have a positive direct antiglobulin test (DAT) prior to initiation of ICPi. ICPis used included ipilimumab, nivolumab, a combination of ipilimumab and nivolumab, and pembrolizumab. Representative hemoglobin and LDH trends are shown in the Figure (panels B and C). The median (interquartile range [IQR]) interval from initiation of ICPis to AIHA was 55 (22-110) days. Eight patients (57%) were DAT positive: 3 were positive for both IgG and C3; 3 were positive for IgG alone; 2 were positive for C3 alone; and 1 was weakly positive on polyspecific testing. Five patients (36%) were DAT negative, and in one patient a DAT was not performed. The median (IQR) hemoglobin nadir was 6.3 (6.1-8.0) g/dL,and 11 patients (79%) required red blood cell transfusion. All patients were treated with glucocorticoids, with 3 requiring additional immunosuppressive therapy. All patients achieved a CR or PR of hemoglobin in response to treatment (CR, n = 11; PR, n =3). The median (IQR) time from the hemoglobin nadir to CR or PR was 47 (30-62) days. Seven patients (50%) experienced at least one other IRAE. Seven patients (50%) were re-challenged with ICPis, and one patient developed recurrent AIHA with re-challenge. Conclusion: ICPi-associated AIHA is a recently-described phenomenon, which will be encountered more frequently with the widespread use of ICPis. ICPi-associated AIHA shares many clinical features with other forms of AIHA; however, a unique aspect of ICPi-associated AIHA appears to be a relatively high incidence of DAT negativity (36% in our series, compared with 3-11% in other forms of AIHA). It is possible that more advanced DAT testing - i.e., "super-Coombs" - which was not performed in any of the patients in this series, would have yielded different results. Glucocorticoids appear to be an effective first-line regimen in most patients with ICPi-associated AIHA. Furthermore, we found that AIHA does not necessarily recur with ICPi re-challenge. Additional studies are needed to better understand the mechanisms underlying ICPi-associated AIHA and optimal treatment strategies. Disclosures Anagnostou: ASH Research Training Award for Fellows 2018: Research Funding; Mayo Clinic SPORE: Research Funding; Mayo Clinic Immune Monitoring Core: Research Funding; Mayo Clinic Hematology Research Division: Research Funding. Salama:BMS: Research Funding; Celldex: Research Funding; Dynavax: Research Funding; Genentech: Research Funding; Merck: Research Funding; Reata: Research Funding; Incyte: Research Funding; Immunocore: Research Funding; Array: Consultancy; Merck: Consultancy; Biocryst: Consultancy; BMS: Speakers Bureau.

Abstract Hepatocellular carcinoma (HCC) has emerged as a major cause of cancer deaths globally. The landscape of systemic therapy has recently changed, with six additional systemic agents either approved or awaiting approval for advanced stage HCC. While these agents have the potential to improve outcomes, a survival increase of 2–5 months remains poor and falls short of what has been achieved in many other solid tumor types. The roles of genomics, underlying cirrhosis, and optimal use of treatment strategies that include radiation, liver transplantation, and surgery remain unanswered. Here, we discuss new treatment opportunities, controversies, and future directions in managing HCC.

AbstractImmune checkpoint inhibitors (ICPis) are a novel class of immunotherapeutic agents that have revolutionized the treatment of cancer; however, these drugs can also cause a unique spectrum of autoimmune toxicity. Autoimmune hemolytic anemia (AIHA) is a rare, but often severe, complication of ICPis. We identified 14 patients from nine institutions across the United States who developed ICPi‐AIHA. The median interval from ICPi initiation to development of AIHA was 55 days (interquartile range [IQR], 22‐110 days). Results from the direct antiglobulin test (DAT) were available for 13 of 14 patients: 8 patients (62%) had a positive DAT and 5 (38%) had a negative DAT. The median pretreatment and nadir hemoglobin concentrations were 11.8 g/dL (IQR, 10.2‐12.9 g/dL) and 6.3 g/dL (IQR, 6.1‐8.0 g/dL), respectively. Four patients (29%) had a preexisting lymphoproliferative disorder, and two (14%) had a positive DAT prior to initiation of ICPi therapy. All patients were treated with glucocorticoids, with three requiring additional immunosuppressive therapy. Complete and partial recoveries of hemoglobin were achieved in 12 (86%) and 2 (14%) patients, respectively. Seven patients (50%) were rechallenged with ICPis, and one (14%) developed recurrent AIHA. Clinical and laboratory features of ICPi‐AIHA were similar in DAT positive and negative patients. ICPi‐AIHA shares many clinical features with primary AIHA; however, a unique aspect of ICPi‐AIHA is a high incidence of DAT negativity. Glucocorticoids are an effective first‐line treatment in the majority of patients with ICPi‐AIHA, and most patients who are rechallenged with an ICPi do not appear to develop recurrence of AIHA.