Suero‐Abreu, Giselle Alexandra

Importance The introduction of immune checkpoint inhibitor (ICI) therapy has improved cancer outcomes but at the cost of adverse events, mainly related to the immune system. Cardiovascular (CV) toxic effects, and especially myocarditis, are of particular concern and are the subject of this position statement by the International Cardio-Oncology Society with representation of experts from oncology, hematology, and cardiology. Observations CV toxic effects of ICI therapies include inflammation-associated diseases, such as myocarditis, pericarditis, and vasculitis, as well as the aggravation of chronic inflammatory conditions, such as atherosclerosis with acute ischemic complications (myocardial infarction and stroke). Patients taking ICI therapies can also develop cardiac dysfunction, stress-induced cardiomyopathy (Takotsubo or apical ballooning syndrome), and heart failure without inflammatory cell infiltration of the myocardium. Atrial and ventricular arrhythmias can emerge in the setting of a systemic inflammatory milieu, myocarditis, or ischemia. Of all potential CV adverse effects, myocarditis remains of highest concern, although fatality rates have declined over time with a broadening spectrum of presentations ranging from troponin elevation of uncertain significance to smoldering, nonsevere, and severe or fulminant myocarditis. Conclusions and Relevance Concerns for myocarditis continue to dominate the spectrum of CV toxic effects in patients receiving ICI therapy. Recommendations for management vary according to severity. Multidisciplinary collaborations remain key for managing acute toxic effects and future cancer treatment decisions, including ICI rechallenge. Ischemic heart disease constitutes the main differential diagnosis in these patients, while pericarditis can be concomitantly present, and atrial and ventricular arrhythmias can also complicate the clinical picture. Several gaps in knowledge are identified and require further research.

e20518 Background: Gut microbiome dysbiosis is correlated with graft-versus-host disease (GVHD) in allogeneic stem cell transplant (allo-SCT) patients. In the allo-SCT population, antibiotics have been associated with increased risk for GVHD mortality and relapse due to loss of gut obligate anaerobes . It has been shown that antibiotics may negatively impact the efficacy of checkpoint inhibitors for patients with solid tumors. Based on these studies, we performed a retrospective analysis to determine if antibiotic treatment affects outcomes of multiple myeloma (MM) patients after autologous SCT (ASCT). Methods: This is a single institution retrospective study at Hackensack University Medical Center. A list of consecutive MM patients treated from 1/2012 to 12/2015 was obtained and an electronic medical record review of the first 217 who received ASCT was performed. Baseline characteristics, treatment history, transplant course and antibiotic treatment (including β-lactams, fluoroquinolones, macrolides, metronidazole, and vancomycin) were reviewed. Prophylactic antibiotics were excluded. Response was defined using the IMWG criteria. Median progression free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method. Log rank tests were used to compare the difference in survival between stratified groups. The LASSO cox regression analysis method was used for multivariate analyses of PFS and OS. Results: Of the 217 patients, 205 patients were available for analysis. Median age at ASCT was 61. β-lactams were associated with decreased median PFS (1.95 vs 4.77 years (yrs), p < 0.01) and decreased median OS (7.51 vs 13.45 yrs, p = 0.01). Multivariate analysis adjusting for lasso-selected age, gender, complete remission (CR) after ASCT, and ISS demonstrated independent progression risk associated with β-lactam use (HR = 2.00, 95% CI, 1.28–3.12, p < 0.01). β-lactams were associated with worse OS in multivariate analysis adjusting for lasso-selected age, gender, CR after ASCT and high risk cytogenetics (HR = 1.89, 95% CI, 1.07–3.40, p = 0.03). Conclusions: In this preliminary study, β-lactams predicted for decreased PFS and OS compared to patients who did not receive β-lactams in MM patients undergoing ASCT. The study was limited by its retrospective nature but demonstrates one of the first evaluations of antibiotic effect on the ASCT population in MM. Prospective studies evaluating the impact of antimicrobials on patient outcomes and the gut microbiome are ongoing.

Abstract Introduction: In the ASPIRE and ENDEAVOR trials, multiple myeloma (MM) patients treated with carfilzomib (K) had significantly improved progression‐free survival and overall survival compared with standard of care. The incidence of all-grade adverse cardiovascular events (ACVE) was 26.6% and 24.5% in the K treated groups in ASPIRE and ENDEAVOR respectively. The atherosclerotic cardiovascular disease (ASCVD) score is a risk stratification tool used by cardiologists to classify patients with a score ≥7.5% as high risk for the incidence of ASCVD events. To date, there are no clinically relevant models that predict the likelihood of ACVE in MM patients treated with K nor are we aware of any protective factors against ACVE. Our study aims to identify factors which can predict and mitigate the incidence of ACVE. Methods: A retrospective chart review of 372 MM patients who were treated with K between 2011 and 2018 at our institution was performed.Data were summarized using descriptive statistics; Chi-square tests of association and Kruskal-Wallis tests were employed to test for differences across groups, where appropriate. Logistic regression was performed to examine the risk factors associated with ACVE. Results: Of the 372 patients, 243 (65%) were Durie-Salmon Stage (DSS) III, 70 (19%) were International Staging System (ISS) III; 186 (50%) were men. There were a total of 102 (27%) ACVE and 33 (9%) ≥grade 3 events. The most common ACVE were congestive heart failure (29%), asymptomatic elevations in pulmonary arterial systolic pressure (PASP) (27%), and hypertension (HTN) (16%). Sixty-eight (66%) Caucasians, 14 (14%) African Americans and 17 (17%) Hispanics developed ACVE. Aspirin (ASA) (64%), beta blockers (BB) (51%), calcium channel blockers (CCB) (43%) and statins (37%) were the most common cardiac medications patients were taking at the time of K initiation. Regardless of cardiac history, patients who were taking a CCB had higher odds of experiencing an ACVE compared to patients who were not taking a CCB (CCB + Cardiac history: OR=1.9; CI=1.0-3.7; CCB, no Cardiac history: OR=6.3; CI= 2.1-18.4) (Table 1). Patients with an ASCVD score ≥7.5% did not have an increased incidence of ACVE but did have an increased incidence of ≥grade 3 vs. grade 1-2 ACVE (100% vs. 78%, p=0.092). Prior cardiac history, including history of HTN, was common (59%) but not associated with incidence or severity of ACVE. Those with type 2 diabetes had a higher rate of ≥grade 3 vs. grade 1-2 ACVE (33% vs. 10%, p=0.004). Patients on certain CV medications while receiving K-based treatment had a higher incidence of ACVE compared to those not on these medications, including BB (51% vs. 34%, p=0.002), CCB (43% vs. 26%, p=0.002), aldosterone antagonists (AA) (8% vs. 3%, p=0.024) and statins (37% vs. 25%, p=0.022). Patients on ASA were more likely to experience ≥grade 3 compared to grade 1-2 ACVE (78% vs. 53%, p=0.016). ACE inhibitors or angiotensin receptor blockers (ACE/ARB) were not associated with increased incidence or severity of ACVE. The use of K in relapsed, as opposed to induction setting, was associated with a higher incidence of ACVE (31% vs. 20%, p=0.035). Maximum dose and number of K doses were not associated with ACVE. There was no relationship between PASP elevation and age >75, use of BB, CCB, AA, ACE/ARB, number of K treatments or maximum dose of K. Factors that were associated with increased odds of ACVE in multivariate analysis included patients who received K in the relapsed setting (OR= 1.7; CI=0.94-3.0) and use of an AA (OR= 4.5; CI=1.4-14.1) (Table 1). Conclusion: In line with prior studies, 28% of MM patients treated with K at our institution developed an ACVE, with 9% grade 3 or above. Use of CCB and AA were particularly associated with increased risk of ACVE, while use of ACE/ARB were not. ASCVD score ≥7.5% was associated with an increased incidence of ≥grade 3 ACVE in K-treated patients and should perhaps be evaluated as a predictive tool in prospective studies. Disclosures Siegel: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Speakers Bureau. Biran:Merck: Research Funding; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; BMS: Research Funding.

e14132 Background: The use of PD-1 inhibitors (PD1) has been limited due to the lack of prognostic markers of response. Previous studies have suggested that indirect inflammatory markers such as neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) may correlate with response to treatment and improved survival. We sought to evaluate the impact NLR and PLR in a real world cohort of patients (pts) with advanced solid tumors treated with PD1. Methods: Records of all pts treated with PD1 between 2011-2017 at the John Theurer Cancer Center were reviewed. NLR and PLR were registered at baseline and longitudinally. We dichotomized as low (lNLR/lPLR), and high (hNLR ≥5/hPLR ≥160). Univariate logistic regression and Cox proportional hazards were used for progression free survival (PFS), and overall survival (OS). Landmark analyses were performed at cycles 2 (C2), and 5 (C5). Results: 178 pts received 1131 cycles of PD1. Median age was 65 (range 24-93); 43% were female. ECOG was ≥1 for 85%. 142 pts (80%), and 89 (50%) received ≥2C and ≥5C respectively. In univariate analyses, baseline hNLR and hPLR were independently associated with inferior OS (median 7.8 vs 18.3 months; HR 1.77, 95% CI 1.21-2.43; p = 0.004), ) and (median 6.4 vs 15.6 months; HR 1.42, 95% CI 1.09-2; p = 0.04) respectively. On landmark analyses, lNLR and lPLR were associated with longer PFS and OS at 2C, and 5C. Longitudinally, lNLR and lPLR correlated with response rate; NLR decreased by 0.08 (95% CI: -0.19 to -0.04; p = 0.03) and PLR by 17 (95% CI: -29 to -14; p = 0.07) per month in responders compared with non-responders. hNLR or hPLR did not correlate with increase in autoimmune toxicities. Conclusions: hNLR, hPLR are adversely prognostic markers in pts receiving PD1 inhibitors in a “real world cohort”. These markers correlate with a longitudinal response and may help predict response. Further prospective studies are needed to determine their utility in decision making during treatment.

594 Background: Given the heterogeneity of gastrointestinal cancers (GICs), molecular profiling is becoming part of the standard of care for many solid tumors. The aim of this study was to evaluate the molecular profile of patients (pts) with GICs using a multiplatform profiling tool and to assess how the pattern of detected molecular alterations could guide clinical decision-making in these tumors. Methods: We retrospectively analyzed samples of 85 pts with GICs via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) in order to evaluate clinically relevant genomic alterations (CRGAs) and clinically relevant biomarker expression (CRBs) in GICs. Results: A total of 85 pts with GICs were analyzed. 45 (53 %) were males and 40 (47%) were females. Tumors were colorectal 43 (51%), pancreatic 11 (13%) esophageal 11 (13%) gastric 8 (9%), hepatobiliary 8 (11%), anal canal 3 (4%), and small intestine 1 (1%). 80 cases (94%) had adequate sample for profiling. CRGAs were identified in 71 cases (89%) with a median of 3 CRGAs in the cohort. The most commonly detected CRGAs were TP53 45 (56%), APC 35 (44%), KRAS 32 (40%), ATM 14 (18%) and PTEN 5 (6%). The median number of CRBs was 9 and high expression levels were seen of mismatch repair biomarkers (MLH1, MSH2, MSH6, PMS2) in 45 (56%), TOPO1 in 44 (55%), PTEN in 27 (34%), TOP2A in 20 (25%), ERCC1 in 19 (24%), and both TS and TUBB3 in 17 (21%). Based on actionable CRGAs and CRBs, 94% of pts matched at least one FDA approved treatment with proven clinical benefit, with a median of 4 available therapies per pt. In addition, there was a median of 189 chemotherapy and 64 targeted therapy clinical trial opportunities available for these pts given the molecular blueprint of their GICs. Conclusions: Multiplatform molecular profiling identified a high frequency of actionable CRGAs and CRBs in GIC pts. This approach has the potential to aid in clinical decision-making by providing a stratification of beneficial therapeutic alternatives individualized to the molecular framework of tumor. Larger prospective studies are warranted to further investigate the impact of profiling guided treatment decisions on patient outcomes.

93 Background: Tumor mutational load (TML) has been proposed as a biomarker of responsiveness to novel immune checkpoint inhibitors (ICIs) due its association with increased neoantigen formation and tumor immunogenicity. Gastrointestinal cancers (GICs) are generally insensitive to ICIs; therefore the aim of this study was to evaluate the TML, clinically relevant genomic alterations (CRGAs), and PDL-1 status of GIC patients (pts). Methods: We analyzed samples of pts with GICs using a multiplatform profiling tool (Caris Life Sciences, Phoenix, AZ). TML and CRGAs were calculated based on next generation sequencing and mutational load was stratified as high (≥17 mut/Mb), intermediate (8-16 mut/Mb), and low (≤ 7 mut/Mb). PD-L1 status was determined by IHC. Descriptive statistics and simple linear regression were used for analysis. Results: A total of 85 pts with GICs were analyzed. The median pt age was 65. 53% were males and 47% were females. Tumors were colorectal 51%, pancreatic 13%, esophageal 13%, gastric 9%, hepatobiliary 11%, anal canal 4%, and small intestine 1%. 80 cases (94%) had an adequate sample for profiling and TML was available in 59 cases (74%). Cases were 5% TML-high, 56% TML-intermediate, and 39% TML-low. The median TML was 9 mut/Mb and median CRGAs was 3. The most commonly detected CRGAs were TP53 (56%), APC (44%), KRAS (40%), ATM (18%) and PTEN (6%). A positive but very weak correlation was found between TML and number of CRGAs (R2 = 0.3). PD-L1 status was available in 74 cases (93%) with 86% being PD-L1 negative and 14% PD-L1 positive. PD-L1 expression was most commonly seen in esophageal (50%) and anal canal (30%) cancers. Among 57 tumors tested for both biomarkers, no correlation was found between a high TML and PD-L1 expression. Conclusions: TML varies among GICs, and higher TML scores were not associated with PD-L1 expression, but there was a weak correlation between TML and the number of CRGAs. Further analysis by stratification of GIC type and prognostic analysis to assess the correlation between TMB and response to ICIs is warranted.