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Objective: To generate a summative report on the most commonly diagnosed illnesses in Major League Baseball (MLB) and Minor League Baseball (MiLB) athletes with specific attention to their impact based on time out of play. Design: Retrospective analysis. Setting: Injury and illness data from the MLB Health and Injury Tracking System. Participants: All MLB and MiLB athletes active between 2011 and 2016. Assessment of Risk Factors: Illnesses were defined as atraumatic medical diagnoses that occurred during the MLB or MiLB season and resulted in at least 1 day out of play. Main Outcome Measures: Incidence of illness diagnoses and resulting time out play. Results: Eight thousand eight hundred thirty-four illnesses were reported, representing 14.7% of all diagnoses resulting in time out of play. Total days missed (DM) due to illness were 39 614, with a mean of 4.6 (SD 9.9 days) and median 2 DM per diagnosis. The annual incidence of illness per season was 20.3 per 100 athletes. The most common diagnosis was nonspecific viral illness (15.3%), followed by gastroenteritis (13.6%), other gastrointestinal illness (8.3%), influenza (7.0%), and upper respiratory infection (6.2%). Appendicitis (15.2%) and Epstein–Barr virus/cytomegalovirus (9.1%) were the most common season-ending diagnoses. Conclusions: Illnesses represent a significant cause of time out of play in MLB and MiLB. Prevention efforts should focus on limiting the spread of communicable viral, respiratory, and gastrointestinal disease among players, as the majority of diagnoses fell into these categories. This work may be used to guide future research into illness treatment and prevention in professional baseball.

AbstractBackground/objectivesSeveral epidemiologic studies have suggested that patients with celiac disease may be at an increased risk of sarcoidosis but the results were inconsistent. This systematic review and meta‐analysis was conducted with the aim to better characterize this risk by summarizing all available data.MethodsA literature review was performed using MEDLINE and EMBASE database from inception to February 2019. Studies that compared the risk of sarcoidosis among patients with celiac disease versus individuals without celiac disease were included. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a random‐effect, generic inverse variance method.ResultsOf 426 retrieved studies, four studies with 693 639 participants met the eligibility criteria and were included in meta‐analysis. The risk of sarcoidosis among patients with celiac disease was higher than individuals without celiac disease with the pooled OR of 7.16 (95% CI, 1.48‐34.56). The statistical heterogeneity of this study was high (I2 = 95%).ConclusionsThis systematic review and meta‐analysis found a significantly higher risk of sarcoidosis among patients with celiac disease.

Background:Despite recent advances, multiple myeloma (MM) remains incurable, and new treatment options are needed to continue to improve patient outcomes. This is the first randomized, phase 3 trial of an anti‐CD38 antibody in combination with pomalidomide (P) and dexamethasone (d) in RRMM.Aims:The primary objective of this phase 3 trial (NCT02990338) was to demonstrate progression free survival (PFS) improvement of isatuximab (Isa), a novel anti‐CD38 monoclonal antibody targeting a specific epitope, combined with Pd versus (vs) Pd in RRMM.Methods:Patients (pts) with RRMM who received ≥2 prior lines, including lenalidomide (len) and a proteasome inhibitor (PI), refractory to last therapy were enrolled. IsaPd arm received Isa 10 mg/kg IV weekly for first 4 weeks (wks), then every 2 wks. Both arms received approved schedules of pom and dex (4 mg PO days 1–21; 40 mg [20 mg if >75 yrs] PO or IV weekly) every 28 days until progression or unacceptable toxicity.Results:307 pts (154 IsaPd, 153 Pd) were randomized and analyzed (ITT). Patient characteristics were well balanced across arms. Median age: 67 (36–86) yrs; median prior lines of therapy: 3 (2–11); estimated GFR: <60 ml/min in 33.9% pts; 92.5% refractory to len, 75.9% to PI; and 19.5% pts had high‐risk cytogenetics. At median follow‐up of 11.6 months (mos), median PFS was 11.5 mos IsaPd vs 6.5 mos Pd; HR 0.596 (95% CI 0.44–0.81), P = 0.001. PFS benefit was consistent across all major subgroups. ORR (≥PR) was 60.4% IsaPd vs 35.3% Pd, P < 0.0001. VGPR rate or better was 31.8% IsaPd vs 8.5% Pd, and MRD negativity (NGS, 10−5) was seen in 5.2% IsaPd pts vs 0% Pd. At analysis date, overall survival (OS) was immature (99 events) but a trend to OS improvement in IsaPd (vs Pd) was observed (HR 0.687; 95% CI 0.461–1.023). Median treatment duration was 41 wks IsaPd vs 24 wks Pd; median Isa infusion (inf.) duration was 3.3 h at 1st inf. and 2.8 h at subsequent inf. Grade ≥3 AEs were observed in 86.8% IsaPd vs 70.5% Pd; 7.2% IsaPd and 12.8% Pd pts discontinued due to AEs; 7.9% IsaPd and 9.4% Pd pts died due to AEs. Inf. reactions were reported in 38.2% (2.6% grade 3–4) IsaPd. Grade ≥3 infections were seen in 42.8% IsaPd and 30.2% Pd, grade ≥3 neutropenia in 84.9% (febrile 11.8%) IsaPd and 70.1% (febrile 2.0%) Pd.Summary/Conclusion:Isatuximab in combination with pomalidomide and dexamethasone significantly improved PFS and ORR vs pomalidomide and dexamethasone, with a manageable safety profile. Isatuximab in combination with pomalidomide and dexamethasone is an important new treatment option for the management of RRMM.

Background:Autoimmune haemolytic anaemia (AIHA) is characterized by haemolysis mediated by autoantibodies directed against red blood cells (RBCs). Warm antibody (wAIHA; 60%>70%) and cold agglutinin disease (CAD; 20%>25%) subclasses are defined by the immunoglobulin (Ig) isotype involved and its thermal optimum for binding RBCs. wAIHA is mediated by IgG while 90% of CAD is mediated by IgM isotypes. CAD and wAIHA outcomes can be life‐threatening, but no therapies are approved. Complement C3b deposition on RBCs plays a central role in AIHA, accelerating phagocytosis in the liver and/or spleen (extravascular haemolysis) and forming membrane attack complexes (intravascular haemolysis). By blocking formation of C3b, APL‐2, a cyclic peptide, has potential as a novel therapeutic for AIHA.Aims:To assess whether inhibiting complement C3 with daily subcutaneous (SC) doses of APL‐2 (270 mg/day or 360 mg/day) prevents intra‐ and extravascular haemolysis in AIHA subjects, reducing anaemia associated signs and symptoms.Methods:Subjects with primary AIHA were eligible for this Ph 2 open‐label study to assess the safety, tolerability, efficacy, and pharmacokinetics of APL‐2. Subjects had haemoglobin (Hb) levels < 11 g/dL, signs of haemolysis, and a positive direct agglutinin test (DAT) for IgG and/or complement C3. Twenty‐four subjects (13 CAD, 11 wAIHA) were recruited and will be treated with APL‐2 for 48 weeks. Efficacy was assessed by change from baseline in Hb, transfusion requirements, absolute reticulocyte counts (ARC), lactate dehydrogenase (LDH), haptoglobin, indirect bilirubin (INDBIL), and Functional Assessment of Illness Therapy (FACIT) fatigue score. Data are reported after 16 weeks (Day 112).Results:Two of 13 CAD subjects withdrew; 7 of 11 remaining subjects reached Day 112. Mean Hb (standard error [SE]) increased from 8.9 (0.4) [n = 13] to 11.6 (0.5) [n = 7] g/dL, and mean LDH, ARC, and INDBIL returned within normal range. Mean FACIT scores (SE) increased 9.9 (3.4) points from baseline. Two subjects had pre‐study and 1 had on‐study transfusions (normalized to 112 days). All 13 CAD experienced ≥1 treatment‐emergent adverse event (TEAE), mainly Grade 1–2 and unrelated. Four subjects reported 10 unrelated serious adverse events (SAEs) (6 SAEs in 1 subject). Three subjects experienced 3 unrelated Grade 3 TEAEs (pneumonia, dyspnoea, hypertension); 1 subject reported 2 unrelated Grade 4 TEAEs (high calcium, high creatinine) and withdrew.Eight of 11 wAIHA subjects were DATmonoC3+ and 3 were DATmonoC3‐. Two of 3 DATmonoC3‐ withdrew for lack of response and efficacy data are reported for 8 DATmonoC3+ subjects. Six of these reached Day 112. Mean Hb (SE) increased from 9.2 (0.3) [n = 8] to 10.8 (0.5) [n = 6] g/dL, and mean ARC and INDBIL returned within normal. Mean FACIT scores (SE) increased 2.7 (2.8) points from baseline. One subject had pre‐study and 2 had on‐study transfusions (normalized to 112 days). Ten of 11 wAIHA (C3+ and C3‐) experienced ≥1 TEAE, mainly Grade 1–2 and unrelated. Five subjects reported 8 unrelated SAEs. Five subjects experienced 13 unrelated Grade 3 TEAEs (oral squamous cell carcinoma, haemolytic flare, purpura, acute kidney injury, dyspnoea, chest pain); 1 subject reported 1 unrelated Grade 4 TEAE (haemolytic flare) and withdrew. Six‐month data for 10 CAD and 6 wAIHA C3+ is planned for June 2019.Summary/Conclusion:APL‐2 increases Hb values in CAD and wAIHA C3+ within the first weeks of treatment with sustained benefit with longer exposure. APL‐2 reduces intra‐ and extravascular haemolysis shown by reductions in LDH, INDBIL, and ARC. APL‐2 appears to be safe and well‐tolerated.

e21004 Background: Pembrolizumab (PEMBRO) and combination ipilimumab + nivolumab (IPI+NIVO) are FDA-approved immunotherapies for advanced melanoma (AM). HRQoL was better maintained with PEMBRO vs IPI in KEYNOTE-006. CheckMate-067 reported no clinically meaningful HRQoL differences with IPI+NIVO vs IPI. As randomized trial data are lacking, we compared HRQoL outcomes in AM between PEMBRO and IPI+NIVO in real-world clinical settings. Methods: A prospective, observational study was conducted with sponsor blinded to sites, and sites blinded to sponsor; nine oncologists from 9 US academic centers and affiliated satellite clinics enrolled AM patients (pts) age ≥18 years initiating first-line PEMBRO or IPI+NIVO between June 2017 – March 2018. The European Organization for the Treatment of Cancer Quality of Life Questionnaire Core-30 (EORTC QLQ C30) and EQ-5D-5L were administered at baseline and weeks 6, 12, 18, and 24 following therapy. Least squared (LS) mean changes in HRQoL scores from baseline were compared using mixed-effects models for repeated measures, adjusting for baseline covariates. Results: A total of 225 PEMBRO and 187 IPI+NIVO pts were enrolled, with > 95% questionnaire completion rates through week 24. At baseline, PEMBRO pts were more likely > age 65 (49% vs 37%, p = .011), stage IV disease (92% vs 85%; p = .002), and higher comorbidity index (1.0 vs 0.6; p < .001) compared with IPI+NIVO pts. Adjusted EORTC global health status/quality of life (GHS) LS mean changes from baseline showed greater improvement with PEMBRO vs. IPI+NIVO at 12, 18 and 24 weeks. At week 24, PEMBRO pts achieved a 3.3-point improvement (95% CI = 0.8, 5.7) and IPI+NIVO pts had no significant change (1.0, 95% CI = -1.6, 3.5), with a LS mean difference of 2.3 points (p = .037; 95% CI = 0.14, 4.51). At week 24, the EQ-5D visual analogue scale increased 1.0 (95% CI, -1.2, 3.2) for PEMBRO vs IPI+NIVO which decreased 0.9 (95% CI = -3.2, 1.3), with a statistically significant LS mean difference of 2.0 (95% CI = 0.4, 3.9; p = .045). Conclusions: Results from 2 measures suggest HRQoL was maintained vs. baseline in both PEMBRO and IPI+NIVO pts, with a significant between-group difference favoring PEMBRO in GHS over 24 weeks.

9532 Background: Both pembrolizumab (PEMBRO) and combination ipilimumab + nivolumab (IPI+NIVO) are FDA-approved immunotherapies for advanced melanoma (AM). These two treatment regimens have different toxicity profiles which may impact health care resource utilization (HCRU). Our aim was to compare real-world risk of hospitalization and emergency department (ED) visits within 12 months of starting the two treatment regimens. Methods: A retrospective cohort study was conducted in patients ≥18 years old with AM initiating PEMBRO or IPI+NIVO between Jan 1, 2016 – Dec 30, 2017. Patients were identified from 12 US academic medical centers and affiliated satellite clinics. Data were abstracted through chart review. All-cause hospitalizations or ED visits and the rates per patient per month (PPPM) through 12 months of follow-up were calculated. Utilization was compared between PEMRBO and IPI+NIVO using multivariate logistic regression analysis. Results: 400 patients were included, 200 each PEMBRO and IPI+NIVO with mean (SD) follow-up time of 10 (3) and 10 (4) months, respectively. The PEMBRO cohort had poorer Eastern Cooperative Group (ECOG) performance status at treatment start, 71% ECOG 0 or 1 vs 88% (p < .001); more diabetes, 21% vs 13% (p = .045); a trend towards more heart disease, 18% vs 12% (p = .067); were more likely to be PD-L1 expression positive, 77% vs 63% (p = .011); and less likely to harbor a BRAF mutation, 35% vs 50% (p = .003). The proportion with at least one hospitalization through 12 months was 17% PEMBRO vs 24% IPI+NIVO. Less than 2% of patients had more than one admission and none had more than two, regardless of cohort. Unadjusted mean (SD) PPPM hospitalizations were .016 (.037) for PEMBRO and .020 (.038) for IPI+NIVO. The adjusted odds ratio for any hospitalization with PEMBRO was 0.55 (95% CI .31, .97; p = .039) vs. IPI+NIVO. ED visits occurred in 18% vs 21% in PEMBRO and IPI+NIVO respectively, with no difference in covariate-adjusted analysis (p = .147). Conclusions: Patients receiving PEMBRO had a significantly lower probability of hospitalization and similar probability of ER visits compared with IPI+NIVO in the real world through 12 months.

e15169 Background: In metastatic colorectal cancer with deficient DNA mismatch repair (dMMR), anti-PD-1 antibody monotherapy produced high tumor response rates and extended progression-free survival compared to lack of benefit for cancers with proficient MMR. In an ongoing phase III randomized trial, we will determine if the addition of the anti-PD-L1 antibody, atezolizumab (Genentech), to adjuvant FOLFOX can improve patient disease-free survival (DFS) vs FOLFOX alone in patients with stage III colon cancers with dMMR. By blocking the PD-1/PD-L1 interaction, atezolizumab may activate T cells, thereby, restoring their ability to detect and attack tumor cells. Limited data suggest that FOLFOX may increase intratumoral cytotoxic CD8+ T cells that could serve as ‘immune priming'. Methods: Patients with curatively resected stage III colon carcinomas with evidence of dMMR are randomized to modified FOLFOX6 for 6 months (12 cycles) alone (control arm) or combined with atezolizumab (840 mg IV q2 wk) with continuation of the antibody as monotherapy for an additional 6 months (total duration of 12 months) [experimental arm]. Patients will be stratified by T, N stage and tumor sidedness. Local testing for MMR proteins is allowed. Atezolizumab must begin by/with cycle 2. One cycle of FOLFOX is allowed pre-registration. The targeted accrual goal of 700 patients and 165 disease-free survival (DFS) events will provide 90% power to detect an effect size expressed as hazard ratio of 0.6 for the primary endpoint of DFS at two-sided alpha of 0.05. Interim analyses are planned at 50% and 75% of events. Secondary endpoints include overall survival, treatment tolerability, and quality of life. Results: This study is being conducted by the Alliance for Clinical Trials in Oncology, was approved by NCI CTEP and activated in 09/2017. The study is actively accruing and, as of 02/11/2019, 152 patients are enrolled. We are actively exploring an international collaboration. Conclusions: This is a current clinical trial in progress. Clinical trial information: NCT02912559.

3583 Background: The Microsatellite instability (MSI) or deficient mismatch repair (dMMR) phenotype is usually taken as a single biological entity whereas no data are available concerning prognosis and response to chemotherapy between sporadic and familial dMMR cases. Methods: Resected KRAS exon 2 wild-type (WT) tumor stage III colon cancers (N = 4596) from patients (pts) randomly assigned to FOLFOX +/- cetuximab in two adjuvant large phase III trials were prospectively analyzed for MSI status and dMMR mechanism (sporadic vs familial). Stratified Cox models were used to assess prognostic and predictive values of dMMR mechanism by treatment arms, adjusting for age, gender, tumor grade, ECOG PS, pT/pN stage and primary tumor location. Results: Among dMMR patients with complete data for dMMR mechanism analysis (N = 354), there were 255 (72%) sporadic ( BRAF mutated or WT with MLH1 methylation) and 99 (28%) familial (loss of MSH2 or MSH6, or loss MLH1 with BRAF WT and unmethylated MLH1) cases. A large proportion of dMMR sporadic cases were mutated for BRAF (n = 200; 80%). In pts treated with FOLFOX, the disease-free survival (DFS) was not statistically different by dMMR mechanism, while for pts treated with FOLFOX + cetuximab, the sporadic cases did worse than familial cases (DFS; adjusted (adj) HR, 2.69; 95% CI, 1.02-7.08; P= 0.04). Considering the predictive value, a deleterious effect of adding cetuximab to FOLFOX was observed in sporadic (DFS; adjHR, 1.68; 95% CI, 1.01-2.79; P= 0.04) but not in familial dMMR pts (interaction P value regarding treatment effect = 0.03). Furthermore, a non-significant trend to a deleterious effect of adding cetuximab to FOLFOX was observed in BRAF mutant (DFS; adjHR, 1.66; 95% CI, 0.95-2.92; P= 0.07) but not in BRAF WT pts. Conclusions: The addition of cetuximab to FOLFOX was associated with reduced DFS in patients with sporadic dMMR cases. Further studies including the methylator phenotype (CIMP) analysis are needed to validate these results. Clinical trial information: NCT00265811 and NCT00079274.

3532 Background: Colorectal cancer with dMMR display heterogeneity in the extent of intratumoral T-cell infiltration which may explain their variable responsiveness to PD-1 blockade. We examined the association of intratumoral CD3+ and CD8+ T-cell densities (TCD) with objective response rate (ORR) and response duration in patients with dMMR mCRCs receiving pembrolizumab (PEM). Methods: Record review was performed on 12 patients with dMMR mCRC treated with PEM (200 mg intravenously every 3 weeks) after failure of prior chemotherapy [median no. of regimens was 1 (range 1-4)] between 01/2015 and 12/2017. CD3+ and CD8+ TCDs were analyzed in the primary tumor core (CT) and at the invasive margin (IM) by immunohistochemistry and automated image analysis to determine density score (0 to 100) for each T-cell subtype and compartment (Ventana Medical Systems, Inc.). Patients were categorized as 1) responders [CR (complete response) + PR (partial response)] vs. non responders [SD (stable disease) + PD (progressive disease)] per RECIST version 1.1, and 2) by duration of response (< or > 12 months). Results: Median follow-up post PEM was 19.5 (9-41) months. Responders included 2 CR and 5 PR; non-responders included 4 SD and 1 PD. The ORR and median time to response were 58.3% (7/12) and 12 weeks (range 9-40), respectively. CD3+ and CD8+ TCD scores were higher in responders vs. in non-responders as well as in patients who had disease control for > 12 months; differences were greatest for CD8+ CT (Table). Conclusions: Among patients treated with PEM, data suggest higher intratumoral CD3+ and CD8+ TCDs in responders versus non-responders and in those with a longer duration of disease control. If confirmed, TCDs may potentially predict responsiveness to PD-1 blockade in dMMR mCRCs. [Table: see text]