The Kresge Hearing Research Institute-3 (KHRI-3) antibody binds to a guinea pig inner ear supporting cell antigen (IESCA) and causes hearing loss. To gain insight into the mechanism of antibody-induced hearing loss, we used antibody immunoaffinity purification to isolate the IESCA, which was then sequenced by mass spectroscopy, revealing 10 guinea pig peptides identical to sequences in human choline transporter-like protein 2 (CTL2). Full-length CTL2 cDNA sequenced from guinea pig inner ear has 85.9% identity with the human cDNA. Consistent with its expression on the surface of supporting cells in the inner ear, CTL2 contains 10 predicted membrane-spanning regions with multiple N-glycosylation sites. The 68 and 72 kDa molecular forms of inner ear CTL2 are distinguished by sialic acid modification of the carbohydrate. The KHRI-3 antibody binds to an N-linked carbohydrate on CTL2 and presumably damages the organ of Corti by blocking the transporter function of this molecule. CTL2 mRNA and protein are abundantly expressed in human inner ear. Sera from patients with autoimmune hearing loss bind to guinea pig inner ear with the same pattern as CTL2 antibodies. Thus, CTL2 is a possible target of autoimmune hearing loss in humans.

Bevacizumab (BV) is a humanized monoclonal antibody that inhibits angiogenesis by targeting vascular endothelial growth factor (VEGF). The addition of BV to combination chemotherapy has been shown to improve the outcomes in several malignancies, including colorectal carcinoma (CRC). However, the use of BV has been associated with adverse effects, including hypertension, hemorrhage, proteinuria, delayed wound healing and bowel perforation. Pneumothorax (PTX) as an adverse event associated with BV use has rarely been reported. We herein report the case of a 68-year-old female patient with a history of metastatic CRC treated with combination chemotherapy, including BV, who presented with complaints of shortness of breath and was found to have a right-sided PTX.

e14117 Background: Cytotoxic T-lymphocyte activator-4 immune checkpoint inhibitors (CTLA-4-ICPI) is believed to cause more toxicity than programmed cell death/Ligand-1 (PD-1/PD-L1) ICPIs. We conducted a meta-analysis to outline the gastrointestinal (GI), pancreatic, and hepatic toxicity of CTLA-4 ICPIs when used alone and in combination with PD-1/PD-L1 ICPIs (C-ICPI). Methods: Ovid MEDLINE, EMBASE, Cochrane Library, SCOPUS, Web of Science, ClinicalTrials.gov, and WHO ICTRP were queried from January 2007-October 2018. Clinical trials reporting ICPI associated adverse events (AEs) were included. Colitis was defined as the development of diarrhea or documented colitis of any grade. Pancreatitis was defined as an elevation of amylase or lipase. Hepatitis was defined as elevation of ALT, AST, or transaminitis of any grade. A meta-analysis of proportions was conducted to report pooled AEs rate with 95% confidence intervals (CI) using a random effects model. Results: Overall, 30 study arms (20 CTLA-4, 10 C-ICPI) enrolling 3721 patients were included. There were a total of 3944 and 3317 AEs with CTLA-4 and C-ICPI use, respectively, with a pooled incidence of high grade AEs (grade 3-5; HAEs) of 23% (95% CI 16-33%) with CTLA-4 use and 52% (95% CI 37-67%) with C-ICPI use ( Table). The incidence of high-grade colitis was higher among patients treated with CTLA-4 ICPI. The proportion of high-grade pancreatitis was higher among patient who received C-ICPI. Two GI perforations were reported with CTLA-4 use. Pooled incidence of treatment related mortality was 1% in both groups. Conclusions: Though the overall GI, hepatic and pancreatic safety profile of CTLA-4 is comparable to C-ICPI, a higher incidence of high-grade colitis was found with CTLA-4. Two GI perforations were reported with CTLA-4 and warrant further investigation. No difference in treatment related mortality was found among the two groups. [Table: see text]

e15141 Background: The clinical utility and safety of immune-checkpoint inhibitors (ICIs) in HIV infected cancer patients has not been well studied. Methods: We conducted a systematic search of Medline and Embase from inception to December 2019 to identify case reports and case series of ICI use in HIV infected cancer patients. Data were pooled utilizing a pre-specified protocol, and descriptive statistics were employed to report findings. Results: We identified 79 cases with a mean age of 52.5 (SD 11.65), 50 of whom were males. The most common cancers were NSCLC followed by Melanoma. Nivolumab was used in 54 patients whereas Pembrolizumab was used in 15 patients, with a mean of 25.7 months to ICI initiation from cancer diagnosis, and with a mean of 1.6 prior systemic lines of chemotherapy. 72 patients were on antiretroviral therapy. The mean baseline CD4 count was 385 (227.03), with a median baseline viral load of 40 (IQR 10.75-95.39). Mean CD4 count and median viral load during ICI therapy were 344.87 (SD 209.7) and 20 (0-400), respectively. 28 patients experienced and irAE; 63.2% and 63.6% of patients who experienced a decreased or increased CD4 count while on ICI therapy experienced an irAE, respectively. 27 patients experienced progressive disease (PD); 50% of patients who experienced a decrease in their CD4 count while on ICI therapy had PD. 13 patients experienced a complete response to ICI therapy; none of the patients who had a decreased CD4 count while on ICI therapy achieved complete response to ICI therapy, whereas 25% and 33% of patients who had an increased and stable CD4 count while ICI therapy experienced a complete response to therapy. The mortality rate was 24; 75% of patients who had a decreased CD4 count on ICI therapy suffered mortality, as opposed to 37.5% and 20% of patients with increased or stable CD4 count while on ICI therapy, respectively. Conclusions: Patients with a declining CD4 count while on ICI therapy may have poor outcomes with ICI therapy. The current body of evidence is weak, and further studies are needed to reach to a strong conclusion.

e19098 Background: Tumor lysis syndrome (TLS) is a life-threatening oncological emergency. Spontaneous TLS (STLS) in solid tumors occurring prior to initiation of therapy is a rarely reported entity and has poor outcomes. Little is known about the prognostic factors influencing STLS in solid tumors. Methods: A systematic search of Medline, PubMed, and Embase was conducted to identify reports of patients ≥18 years diagnosed with STLS in solid tumors. Individual case reports and case series were summarized, and descriptive statistics were employed to report clinical outcomes. Fischer exact t test was used for statistical analysis. Results: 63 patients from 61 case reports and one patient from our institution resulted in a total of 64 patients. 53.1% were males with a median age of 56.1 years. The most common solid tumors were of pulmonary origin. 85.9% patients had stage 4 malignancy, 75.0% had hepatic involvement. The most common presenting symptom was abdominal discomfort. The mean serum potassium, phosphorus, uric acid, calcium, lactate dehydrogenase, and creatinine upon presentation were 6.1 mmol/l, 7.5 mg/dl, 16.4 mg/dl, 7.5 mg/dl, 4421.2 IU/L and 3.7 mg/dl, respectively. In addition to intravenous hydration, allopurinol and rasburicase were administered in 48.4% and 42.2% patients. Urinary alkalization and sodium bicarbonate administration were reported in 6.3% and 15.6% patients. 43.8% patients required hemodialysis and 39 patients died (mortality of 60.9%). Patients who underwent hemodialysis had a similar mortality of 60.4%. We assessed liver involvement (primary hepatocellular carcinoma and hepatic metastasis) as a potential prognostic factor. Compared to patients without liver involvement, patients with liver involvement had a higher unadjusted all-cause mortality (70.83% vs 25%; OR 7.29 [95% CI 1.71 - 30.98]; p = 0.006). Conclusions: Hepatic involvement is a potential prognostic factor for STLS in solid tumors and is associated with a grave prognosis. Future large prospective studies are needed to probe into the role of early hemodialysis and to identify other prognostic factors of STLS in solid tumors.

e14131 Background: The safety of programmed death receptor and ligand-1 (PD-1/PDL-1) inhibitors in hematologic cancers is not well-defined. We conducted a meta-analysis to investigate their safety. Methods: Pubmed & Cochrane databases were searched from 1968-2018. Full-text articles of clinical trials reporting treatment-related adverse events (AE) of PD-1/PDL-1 inhibitors in hematologic cancers were included. Incidences of all-grade and high-grade (≥grade 3) AEs were pooled and generated with a 95% confidence interval (CI) using a random effect model on STATA. Results: Eight studies (5 nivolumab & 3 pembrolizumab) were identified, with 703 patients and the median age of 34. Six studies were done in patients with relapsed/refractory (R/R) classical Hodgkin Lymphoma, one in R/R diffuse large B-cell lymphoma and one in combined hematologic cancers. There were 1092 total AEs, with a pooled high grade AEs rate of 13% (95% CI 9-17%). High-grade AEs (HAE) are summarized in the Table. Lipase elevation was the most common HAE for nivolumab (pooled incidence of 13%; 95% CI 6-23%), whereas leukopenia was the most common HAE reported with pembrolizumab use (pooled incidence of 36%; 95% CI 10-65%) There were 47 treatment discontinuation due to treatment-related AE. For Nivolumab, there was one treatment-related death (of a heavily pretreated patient) due to fatal pneumonitis. Conclusions: PD-1/PDL-1 inhibitors are well-tolerated in hematologic malignancies with a favorable risk of adverse events and very low treatment-related mortality. The HAE profile of Nivolumab differs from Pembrolizumab, and future studies should assess this heterogeneity further. [Table: see text]

Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

e23543 Background: Alveolar soft part sarcoma (ASPS) is a rare subtype of soft tissue sarcoma, characterized by a specific unbalanced translocation leading to the fusion of the TFE3 gene on chromosome-X to the ASPSCR1 gene on chromosome-17. Despite its indolent course, ASPS presents a challenge in treatment due to its resistance to conventional anthracycline-based chemotherapy and lack of large scale trial data for this rare sarcoma. This review aimed to assess the efficacy of tyrosine kinase inhibitors (TKI) and immune checkpoint inhibitors (ICI) in metastatic alveolar soft part sarcoma. Methods: A systematic search was performed on Embase and Medline databases for studies that assessed best response of patients with unresectable or metastatic ASPS to TKI and ICI therapy, according to the Response Evaluation Criteria in Solid Tumors (RECIST) edition 1.0 or 1.1. This study followed the Preferred Reporting Items for Systematic Reviews (PRISMA) protocol. Four independent reviewers screened abstracts and extracted the data; any discrepancy was resolved by discussion among reviewers. Pooled objective response rate (ORR) and disease control rate (DCR) were obtained using the Freeman-Tukey double-arcsine transformation using random effects model on STATA software (version. 16.1, StataCorp). Results: 27 articles and abstracts published between 2011 and 2020 were included in the review, resulting in 2 randomized clinical trials (104 participants), 14 single arm prospective trials (214 participants), and 11 retrospective studies (120 patients). Among clinical trials, the pooled ORR and DCR were 18% (95% confidence interval [CI] 8 - 30%; I2 = 72.25%; p < 0.01) and 87% (95% CI 97 - 93%; I2 = 43.2%; p = 0.03) respectively. Conclusions: The response rate to targeted therapy in metastatic ASPS is not only clinically meaningful, but also comparable to that of first-line chemotherapy. The majority of patients receiving targeted therapy achieved disease control. Patients who had refractory or progressive disease to one targeted agent demonstrated response to other agents. More randomized trials are warranted to expand treatment options and compare to standard of care regimens.