Adverse Survival Outcomes Research Articles

RAS/CBL mutations predict resistance to JAK inhibitors in myelofibrosis and are associated with poor prognostic features

AbstractThe dysregulation of the JAK/STAT pathway drives the pathogenesis of myelofibrosis (MF). Recently, several JAK inhibitors (JAKis) have been developed for treating MF. Select mutations (MTs) have been associated with impaired outcomes and are currently incorporated in molecularly annotated prognostic models. Mutations of RAS/MAPK pathway genes are frequently reported in cancer and at low frequencies in MF. In this study, we investigated the phenotypic, prognostic, and therapeutic implications of NRASMTs, KRASMTs, and CBLMTs (RAS/CBLMTs) in 464 consecutive MF patients. A total of 59 (12.7%) patients had RAS/CBLMTs: NRASMTs, n = 25 (5.4%); KRASMTs, n = 13 (2.8%); and CBLMTs, n = 26 (5.6%). Patients with RAS/CBLMTs were more likely to present with high-risk clinical and molecular features. RAS/CBLMTs were associated with inferior overall survival compared with patients without MTs and retained significance in a multivariate model, including the Mutation-Enhanced International Prognostic Score System (MIPSS70) risk factors and cytogenetics; however, inclusion of RAS/CBLMTs in molecularly annotated prognostic models did not improve the predictive power of the latter. The 5-year cumulative incidence of leukemic transformation was notably higher in the RAS/CBLMT cohort. Among 61 patients treated with JAKis and observed for a median time of 30 months, the rate of symptoms and spleen response at 6 months was significantly lower in the RAS/CBLMT cohort. Logistic regression analysis disclosed a significant inverse correlation between RAS/CBLMTs and the probability of achieving a symptom or spleen response that was retained in multivariate analysis. In summary, our study showed that RAS/CBLMTs are associated with adverse phenotypic features and survival outcomes and, more important, may predict reduced response to JAKis.

The influence of venous tumor thrombus combined with bland thrombus on the surgical treatment and prognosis of renal cell carcinoma patients.

ObjectiveTo describe the clinical characteristics of renal cell carcinoma (RCC) with venous tumor thrombus (VTT) and bland thrombus (BT), and to evaluate the influence of BT on surgical treatment and cancer‐specific survival (CSS) of RCC with VTT.MethodsWe retrospectively reviewed clinical data of 123 patients with RCC and VTT, who underwent surgical treatment in our center between February 2015 and May 2018. Patients were divided into the BT group (21 patients) and non‐BT group (102 patients). Chi‐square and Mann‐Whitney U test were used for categorical and continuous variables respectively. Univariable log‐rank tests and multivariable Cox regressions were conducted to evaluate the prognostic significance of each variable. Kaplan‐Meier plots were performed to evaluate the influence of BT.ResultsIn the delayed phase of enhanced magnetic resonance imaging (MRI), BT and VTT had difference. Patients were divided according to the relative position of BT: proximal end BT (one patients), contralateral renal vein BT (two patients), distal end BT (12 patients), and multiple BT (six patients). The average length of BT was 8.4 ± 5.8 cm (range: 0.6‐20.0 cm). Patients with BT had longer operative time (P = .001), more surgical blood loss (P = .004), higher proportion of open surgery (P = .006), more postoperative complications (P = .011). BT (hazard ratio [HR] = 3.323, P = .007) were independent risk factors for poor prognosis.ConclusionsIn the delayed phase of enhanced MRI, BT showed no obvious enhancement, while VTT usually showed enhancement. This was an important basis for preoperative imaging diagnosis of BT. The presence of BT increases the difficulty of surgery, and is correlated with adverse survival outcomes in patients with RCC and VTT.

Stromal LAG-3+cells infiltration defines poor prognosis subtype muscle-invasive bladder cancer with immunoevasive contexture

BackgroundLymphocyte activation gene 3 (LAG-3) is a promising immune checkpoint therapeutic target being evaluated in clinical trials. We assessed the LAG-3+ cells distribution, its association with clinical outcomes and immune contexture and its role in the landscape of muscle-invasive bladder cancer (MIBC) treatment.Methods141 patients with MIBC from Zhongshan Hospital were included for survival and adjuvant chemotherapy (ACT) benefit analyses. 32 fresh resected samples of MIBC were collected to detect CD8+ T cells functional state. The molecular classification analyses were based on 391 patients with MIBC from The Cancer Genome Atlas. Immunohistochemistry and flow cytometry were performed to characterize various immune cells infiltration.ResultsIn Kaplan-Meier analyses and Cox regression models, stromal LAG-3+ cells enrichment was consistently associated with inferior overall survival and disease-free survival, and indicated suboptimal responsiveness to ACT. Patents with high stromal LAG-3+ cells possessed increased protumor cells, immunosuppressive cytokines and immune checkpoint expression. The phenotypic analyses of CD8+ T cells correlated its dysfunctional state with LAG-3+ cells. Besides, LAG-3 mRNA level was linked to luminal and basal subtypes of MIBC. LAG-3-high tumors exhibited limited FGFR3 mutation and signaling signature, and displayed activated immunotherapeutic and EGFR-associated pathway.ConclusionsStromal LAG-3+ cells abundance indicated an immunoevasive contexture with dysfunctional CD8+ T cells, and represented an independent predictor for adverse survival outcome and ACT resistance in MIBC. LAG-3 expression could potentially be a novel biomarker for FGFR3-targeted and EGFR-targeted therapies and immunotherapy. The crucial role of LAG-3+ cells in the therapeutic landscape of MIBC needs further validation retrospectively and prospectively.

Type of prior genotoxic insult determines the genomic characteristics of therapy-related acute myeloid leukemia.

7515 Background: Therapy-related AML (tAML) is a long-term complication of cytotoxic cancer therapy. It is characterized by adverse genetics and inferior survival outcomes when compared to de novo AML. A proposed mechanism in tAML pathogenesis includes treatment-induced selection of clones harboring pre-existing mutations (i.e. clonal hematopoiesis, CH). We hypothesize that genotoxic therapies used to treat prior malignancy drive leukemogenesis through different mechanisms leading to unique clonal compositions. Methods: AML patients (pts) treated at The Ohio State University between 2015-2018 were included. Genetic profiling was performed using Miseq Illumina platform with a 49-gene targeted sequencing panel at our clinical laboratory. Results: We studied 337 AML pts (Table), of whom 53% had smoking history. Mutations involving ASXL1 were more common in smokers vs non-smokers (14% vs 5.8%, p= .001), while JAK2 mutations were more common in non-smokers (8% vs 1.2%, p= .003). Regarding specific genotoxic therapies and mutations in tAML, we investigated common CH-associated mutations including DNMT3A, TET2, and ASXL1 (DTA mutations). In tAML pts, those exposed to radiotherapy experienced a higher frequency of DTA (52% vs 27%, p= .05), NPM1 (21% vs 0%, p= .002), and SRSF2 (15% vs 0%, p= .01) mutations, and conversely, a lower incidence of TP53 mutations (21% vs 46%, p= .04). Pts with history of cytotoxic chemotherapy had a lower incidence of DTA mutations, including those who received platinum agents (8% vs 49%, p= .005) and taxanes (7% vs 52%, p< .001), but had a higher incidence of TP53 mutations (75% vs 25%, p< .001 for platinum; 53% vs 25%, p= .04 for taxanes). Similarly, alkylators and anthracyclines were associated with lower incidence of DNMT3A (0% vs 20%, p= .009) and ASXL1 (0% vs 12.5%, p= .04) mutations. Conclusions: Different genotoxic agents demonstrate unique effects in leukemia development. Our data suggest that CH clones with DTA mutations may be enriched with smoking and radiotherapy, while cytotoxic chemotherapy may confer a higher incidence of TP53 mutations. Given the adverse prognosis of TP53 mutated AML, identification of pre-existing CH clones might influence treatment selection in solid tumor pts receiving anticancer therapy. [Table: see text]

The expression of urokinase-type plasminogen activator system in upper tract urothelial carcinoma and its prognostic value after radical nephroureterectomy

BackgroundTo evaluate the expression pattern and prognostic role of the urokinase-type plasminogen activator (uPA) system in patients who underwent radical nephroureterectomy (RNU) for nonmetastatic upper tract urothelial carcinoma (UTUC). MethodsA total of 732 patients who were treated with RNU for clinically nonmetastatic UTUC comprised our analytical cohort. Immunohistochemical staining of uPA, uPA receptor (uPAR) and uPA inhibitor (PAI-1) was performed using Murine IgG1 monoclonal antibodies. Outcomes of interest were recurrence-free survival, cancer-specific survival, and overall survival. ResultsThe median age of the patients was 69.8 years and 56.6% of them were males. Overall, overexpression of uPA, uPAR, and PAI-1 was observed in 292 (39.9%), 346 (47.3%), and 345 (47.1%) patients, respectively. The uPA system components showed a statistically significant association with adverse clinicopathologic features such as lymphovascular invasion, multifocality, sessile tumors, and advanced pathologic stage (P < 0.01). On multivariable models, higher pathologic tumor stage, multifocality, and lymph node involvement were associated with RFS, OS, and CSS, but not the overexpression of uPA, uPAR, or PAR-1. In patients with organ-confined disease (≤pT2N0), however, uPA was significantly associated with RFS (hazard ratio [HR]: 2.04, 95% confidence interval [CI]: 1.21–3.43), OS (HR: 1.59, 95% CI:1.08–2.24) and CSS (HR: 2.55, 95% CI:1.44–4.52). uPA improved the predictive accuracy of a standard post-RNU model for all 3 endpoints, in organ-confined disease, by a prognostically significant margin. ConclusionsOverexpression of uPA system components was associated with adverse clinicopathologic characteristics and survival outcomes on the univariable, but not multivariable analyses. uPA expression was an independent predictor of survival outcomes in patients with organ-confined disease. While the clinical value of the uPA system remains limited in this cohort, further studies are needed to identify a marker or constellation of markers of high predictive value to help in counseling and treatment planning of UTUC patients.

Association between immune-related adverse events and long-term survival outcomes in patients treated with immune checkpoint inhibitors

Background: The impact of immune-related adverse events (irAE) on survival outcomes after single-agent immune checkpoint inhibitors (ICIs) remains unclear. We aimed to evaluate the association between irAEs and ICI efficacy in various malignancies.Methods: All patients treated with a single-agent ICI for any advanced cancer were included in this retrospective multicentric series. The primary objective was to assess the impact of all type grade ≥II irAEs on progression-free survival (PFS) and overall survival (OS). IrAEs were first considered as a fixed covariate and included in Cox-regression models. In addition, as irAEs are time-related events and can occur at any point during follow-up, we analysed the occurrence of irAEs as a time-varying covariate.Results: In this cohort of 410 patients, the majority of patients (70%) were treated for non-small cell lung cancer. The ICI was an anti-PD(L)1 for 356 patients (82%) and an anti-CTLA4 for 79 patients (18%). In total 126 (29%) of the patients presented at least one grade ≥II irAEs. The first occurrence of a grade ≥II irAE had a positive impact on PFS and OS when considered as a fixed or as a time-varying covariate (hazard ratio [HR] for PFS = 0.63, 95% confidence interval [CI] 0.50–0.81; P = 0.00022; HR for OS = 0.57, 95% CI 0.43–0.74, P < 0.0001). This overall finding was confirmed in patients treated with an anti-PD(L)1 and among patients with lung cancer.Conclusion: In this pooled multi-institutional cohort, the incidence of irAEs was associated with better long-term survival across different malignancies treated with ICI monotherapy.

Diffuse large B-cell lymphoma in a South African cohort with a high HIV prevalence: an analysis by cell-of-origin, Epstein–Barr virus infection and survival

Diffuse large B-cell lymphoma, not otherwise specified (DLBCL NOS) is subdivided according to the cell-of-origin (COO) classification into germinal centre B-cell (GCB) and activated B-cell (ABC) subtypes, each with different molecular profiles and clinical behaviour. This study aims to describe the pattern of the COO subtypes, the proportion of Epstein-Barr virus (EBV) co-infection, and their influence on survival outcomes in a setting of high HIV prevalence. This retrospective cohort study included patients diagnosed with de novo DLBCL NOS at our tertiary academic centre in Cape Town, South Africa over a 14-year period. Immunohistochemical stains were performed for COO classification, according to the Hans algorithm. Tumour EBV co-infection was established by EBV-encoded ribonucleic acid in situ hybridisation (EBER-ISH) staining. The effect of the COO subtypes and EBV co-infection on overall survival were described by means of univariate, bivariate and multivariate analyses. A total of 181 patients with DLBCL NOS were included, which comprised 131 HIV-uninfected and 50 HIV-infected patients. There was an equal distribution of GCB and ABC subtypes in the HIV-infected and HIV-uninfected groups. EBV co-infection was detected in 16% of the HIV-infected cases and in 7% of the HIV-uninfected cases (p=0.09). There was no significant difference in the incidence of EBV co-infection between the GCB and ABC subtypes (p=0.67). HIV-infected patients with CD4 ≥150 cells/mm3 had similar survival to HIV-uninfected patients (p=0.005). Multivariate regression analysis showed that in the HIV-infected group with marked immunosuppression (CD4 <150 cells/mm3), there was significantly poorer overall survival compared to the HIV-uninfected group (HR 2.4, 95% CI 1.3-4.1). There were no statistically significant differences in overall survival by DLBCL COO subtype. There was no difference in the proportion of DLBCL COO subtypes, regardless of HIV status. EBV co-infection was more common in the HIV-infected group, but less than described in the literature. Unexpectedly, there were no significant differences in survival outcomes between the GCB and ABC subtypes. Higher CD4 counts in the HIV-infected group had good survival outcomes, while lower CD4 counts predicted adverse survival outcomes. Further research is needed to explore the genetic mutational landscape of HIV-associated DLBCL.

Integrin ανβ6 Protein Expression and Prognosis in Solid Tumors: A Meta-Analysis.

Integrins are a family of adhesion receptor proteins that provide signaling from the extracellular matrix to the cytoplasm. They have been associated with cancer by promoting migration, invasion, metastasis, and survival. ανβ6 integrin is upregulated in several tumors. Here, we evaluate the prognostic impact of ανβ6 integrin protein expression in solid tumors. A systematic search of electronic databases identified publications exploring the effect of ανβ6 integrin on overall survival (OS). Hazard ratios (HRs) were pooled in a meta-analysis using generic inverse variance and random effects modeling. Subgroup analyses were conducted based on tumor site, tumor stage, antibody used for immunohistochemistry (IHC) and method for extraction of the HR. A meta-regression explored the influence of clinical variables on the magnitude of effect of ανβ6 integrins on OS. Seventeen studies comprising 5795 patients met the inclusion criteria. High ανβ6 integrin expression in tumors was associated with worse OS (HR 1.65, 95% confidence interval [CI] 1.32-2.06; Cochran'sQ p < 0.001, I2 = 81%). Adverse outcomes were similar in all tumor sites (subgroup difference p = 0.10), with the strongest association between ανβ6 integrins and OS in gastric cancer (HR 2.20, 95% CI 1.71-2.83) and the lowest in head and neck cancer (HR 1.21, 95% CI 0.79-1.83). There was no significant difference between early-stage and metastatic cancer, type of IHC antibodies, and analysis methods. High expression of ανβ6 integrins is associated with adverse survival outcome in several tumors. Prospective studies evaluating the prognostic impact of ανβ6 integrin and its role as a therapeutic target are warranted.

Anti-PD1-Induced Immune-Related Adverse Events and Survival Outcomes in Advanced Melanoma.

Objective response rates (ORR) appear to be higher in melanoma patients who develop immune-related adverse events (irAEs), but whether there is a similar association between irAEs and survival remains unknown. Patients with advanced melanoma treated with single-agent pembrolizumab or nivolumab in the province of Alberta from June 2014 to May 2017 were identified through the provincial pharmacy database. Chart review identified and categorized all irAEs that occurred while on anti-programmed cell death protein 1 (PD-1) checkpoint inhibitors. The primary objective was to compare overall survival (OS) with patients who developed any irAEs versus those who did not. Secondary outcomes included progression-free survival (PFS) and ORR. Among 186 patients, any-grade and grade ≥3 irAEs occurred in 88 (47%) and 27 (15%) patients, respectively; one patient died of pneumonitis. In a landmark analysis excluding patients who died within the first 12 weeks, the median follow-up was 24 months, 20 months in patients without any irAEs and 26 months in patients with irAEs (p = .006). Median OS was 39 versus 23 months (hazard ratio [HR], 0.46; p = .001) for any irAE and no irAE, respectively, and median OS not reached versus 29 months for grade ≥3 irAEs and no grade ≥3 irAEs, respectively. In multivariate analysis, elevated lactate dehydrogenase correlated with reduced OS (HR, 2.34; p = .001), whereas each additional cycle of treatment received (HR, 0.94; p < .001) and development of grade ≥3 irAEs (HR, 0.29, p = .024) were significantly associated with longer OS. Anti-PD-1-associated grade ≥3 irAEs in patients with advanced melanoma is associated with better patient outcomes, including overall survival. Previous prospective randomized clinical trials demonstrate improved response rates in patients with melanoma who develop select adverse events. The current population-based real-world study in advanced melanoma reports an association with anti-programmed cell death protein 1 (PD-1)-induced grade ≥3 immune-related adverse events (irAEs) and better patient outcomes, including overall survival. These results suggest that irAEs may be a manifestation of a patient's ability to mount a systemic immune response from PD-1-directed therapies, which may be associated with therapeutic benefit. The finding of irAEs coinciding with clinical benefit from these therapies supposes that these events are, by and large, unavoidable, and the critical management of irAEs remains essential for optimizing patient outcomes.

Prediction of Postoperative Clinical Outcomes in Resected Stage I Non-Small Cell Lung Cancer Focusing on the Preoperative Glasgow Prognostic Score.

Background: The Glasgow Prognostic Score (GPS), which consists of albumin and C-reactive protein (CRP), may predict overall survival (OS) in cancer patients. The aim of this retrospective analysis was to evaluate the clinical impact of the preoperative GPS on patients with resected early stage non-small cell lung cancer (NSCLC). Methods: 300 patients with curatively resected stage I NSCLC were followed-up for OS, recurrence-free survival (RFS), cancer-specific survival (CSS), and death from other causes. Results: 229 patients (76%) had a preoperative GPS of 0, and 71 (24%) a GPS ≥ 1. The three-year probabilities of RFS, OS, CSS, and death from other causes were 81%, 84%, 88%, and 96% in patients with GPS = 0, and 79%, 74%, 91%, and 82% in patients with a GPS ≥ 1, respectively. GPS ≥ 1 was significantly associated with a higher risk of death from other causes (p = 0.022), serving as an independent predictor of death from other causes (p = 0.034). Pathologically elevated CRP levels (CRP > 5 mg/L) were found in 91 patients (30%). The mean CRP level was 7.88 ± 15.80 mg/L (0.5–135.6 mg/L). Pre-treatment CRP level was significantly associated with coronary heart disease (p < 0.0001), histology (p = 0.013), tumor size (p = 0.018), tumor stage (p = 0.002), and vascular invasion (p = 0.017). Conclusion: The preoperative GPS predicts adverse survival outcomes in patients with resected stage I NSCLC.

Serum tumor markers and positron emission tomography-computed tomography scan as post-breast cancer treatment surveillance

Background: Post-operative surveillance is an important aspect in managing breast cancers. The primary aim is to allow early detection of metachronous breast cancers. However, post-operative breast cancer surveillance has not been standardized. Mammography has been the only evidence-based imaging modality for detecting metachronous breast cancers. The value of regular monitoring with serum carcinoembryonic antigen (CEA) and CA 15-3 has been controversial. The aim of this study is to evaluate the efficacy of using tumor markers as a surveillance tool in post-operative patients. Methods: This is a retrospective review of all post-breast cancer surgery patients monitored with tumor markers from 2005–2010. Correlation between tumor markers and subsequent detection of metachronous breast cancer was evaluated. Long-term survival data was analyzed. Results: Six hundred and forty-nine patients underwent positron emission tomography-computed tomography (PET-CT) scan, 250 patients had regular tumor markers monitoring. By using 5 ng/mL as cutoff for CEA, and 23 U/mL for CA 15.3, elevated levels are associated with development of metachronous breast cancer (P=0.004 and P Conclusions: Elevated serum CEA and CA 15-3 is associated with metachronous breast cancer and is associated with adverse long-term survival outcome.

Gene Expression Profiling of Structural and Functional High-Risk Multiple Myeloma

Introduction: High-risk multiple myeloma can be defined by the presence of specific cytogenetic abnormalities (structural) or by characteristic changes in bone marrow and peripheral blood biomarkers (functional). While both entities are characterized by therapeutic resistance, frequent disease relapses, and adverse survival outcomes, the underlying molecular mechanisms remain incompletely understood. Methods: We performed gene expression profiling (GEP) using an Affymetrix GeneChip Human Genome U133 Plus 2.0 microarray on CD138+ bone marrow cells from 137 patients diagnosed with multiple myeloma between 2004 and 2012. All patients underwent Fluorescence In-situ Hybridization (FISH) evaluation, plasma cell labeling, International Staging System (ISS) risk stratification, and GEP prior to initiating treatment with novel agents. The presence of del(17p), t(4;14), t(14;16), and t(14;20) on FISH, a plasma cell labeling index (PCLI) &gt; 2%, and ISS stage III were considered high-risk abnormalities: FISH-HR (n = 15, structural high-risk, at least one high-risk FISH lesion), PCLI-HR (n = 20; functional high-risk, PCLI &gt; 2%), and ISS-HR (n = 12; functional high-risk, ISS stage III). For each HR group we sampled standard risk (SR) controls in a 4:1 ratio. After data quality control and normalization, differential gene expression was estimated using limma. Statistical significance was adjusted for multiple comparisons using a false discovery rate-based approach for genome-wide experiments (q-value). We employed PANTHER pathway analysis for the differentially expressed genes in each HR group. We implemented a simple gene expression score (GES) by calculating the sum of quartiles of the normalized gene expression values for genes differentially expressed in more than one HR group (GES = ΣUP(quartile - 1) + ΣDN(4 - quartile)) and externally validated its prognostic significance (UAMS TT2 / TT3, GSE24080). Survival outcomes were analyzed using the methods described by Kaplan, Meier, and Cox. Computation and visualization were performed in R. Results: Median age at diagnosis was 63 years (32 - 87), 53% of the patients were male. High-risk disease was associated with inferior overall survival, regardless of the used definition (left Kaplan-Meier plots): FISH-HR (HR 4.3, 95% CI 1.9 - 9.8, p &lt; 0.001), PCLI-HR (HR 2.7, 95% CI 1.4 - 5.3, p = 0.004), and ISS-HR (HR 2.8, 95% CI 1.2 - 6.5, p = 0.015). There were 59 (FISH-HR), 424 (ISS-HR), and 507 (PCLI-HR) differentially expressed genes (q &lt; 0.050 for all genes, volcano plots). PCLI-HR and FISH-HR demonstrated a predominance of transcriptional up-regulation while ISS-HR had a balanced gene expression profile with a similar number of genes being up- and down-regulated. The involved cellular pathways were different across the HR groups except for anti-apoptotic signaling (bar graphs). All HR groups had distinct gene expression profiles with no complete overlap between all HR groups. There were 71 genes with overlap between two HR groups (69 up-regulated, 2 down-regulated, Venn diagrams). The median GES was 97 (18 - 206, higher numbers indicating higher expression of up-regulated and lower numbers of down-regulated high-risk genes) in 559 patients treated on UAMS TT2 / TT3 (GSE24080). Tertiles of the GES were associated with event-free survival (HR 1.4, 95% CI 1.2 - 1.6, p &lt; 0.001) and remained independently prognostic after adjusting for age, sex, and ISS stage (HR 1.3, 95% CI 1.1 - 1.5, p &lt; 0.001). Conclusions: High-risk multiple myeloma remains associated with inferior overall survival, regardless of the used definition (structural or functional). The subtypes of high-risk disease have distinct gene expression profiles and involve different cellular pathways, providing important clues to the underlying biology. A 71 gene signature derived from the different high-risk subtypes was of prognostic significance in a clinical trial population after adjusting for known prognostic factors. Figure Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Alnylam: Research Funding. Stewart:Takeda: Consultancy; Seattle Genetics: Consultancy; Roche: Consultancy; Ono: Consultancy; Celgene: Consultancy, Research Funding; Ionis: Consultancy; Janssen: Consultancy, Research Funding; Oncopeptides: Consultancy; Amgen: Consultancy, Research Funding; Bristol Myers-Squibb: Consultancy. Bergsagel:Celgene: Consultancy; Ionis Pharmaceuticals: Consultancy; Janssen Pharmaceuticals: Consultancy. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Daratumumab-Mediated Lymphocyte Kinetics Predict Adverse Events and Survival Outcomes in Patients with Multiple Myeloma

Background: Daratumumab, a human monoclonal antibody that binds CD38, has been recently approved to treat patients with Multiple Myeloma (MM), a disease of clonal plasma cells. Daratumumab is generally well-tolerated; however, lymphopenia and neutropenia can occur while on treatment. Hereby, we report real-world experience of rates, trends, and outcomes of patients who developed lymphopenia while being treated with Daratumumab in our institution. Methods: Patients who received Daratumumab between November 2015 and July 2019 at the Ohio State University in Columbus, Ohio were identified, retrospectively. Data pertaining to patient demographics, prior lines of therapy, MM staging, absolute lymphocyte count (at start, nadir, and end of treatment), infections, ED visits, and hospital stays were collected. Absolute Lymphocyte count (ALC) of less or equal to 500 cells/μL was considered severe lymphopenia. Results: One hundred patients who completed Daratumumab treatment in our institution between November 2015 and July 2019 were included. Fifty-nine patients (59%) developed severe lymphopenia with an absolute lymphocyte count (ALC) nadir equal to or less than 500 lymphocytes/μL. Sixty-one percent of them (36/59) recovered on therapy to ALC &gt;500 lymphocyte/μL with 16 of them recovering to normal ALC (&gt;1000 lymphocyte/μL). The median time to become severely lymphopenic was 31 days, with an average of 64 days (range 0-453). The median time to recover was 14 days (average 43 days; range 1-453). Patients with severe lymphopenia had a higher rate of infections (52.5%) compared to patients without lymphopenia (41.4%). Among the patients who had infections, patients with severe lymphopenia required hospital stays in 83.8% of the cases compared to 52.9% of the cases for the patients without severe lymphopenia (p-value= 0.03, Odd Ratio-OR: 4.6; 95% CI, 1.186 to 17.70). The most common infections were viral upper respiratory tract infections and pneumonias (22/31-71%). However, more serious infections, such as CMV/EBV reactivation, influenza A/B infection, fungal meningitis, and bacteremia occurred in our patient population. No statistically significant difference in terms of progression-free survival (PFS), overall survival (OS), or overall response rate (ORR) (58.5% versus 50.8%) was noted between patients who did or did not develop severe lymphopenia. However, when the severe lymphopenic group was stratified based on the presence of recovery, those who did not recover their ALC had worst OS (p= 0.0019) and PFS (p&lt;0.0001; median PFS 8.7 months vs 14.7 months vs 68 months), possibly due to better immune-mediated anti-tumoral effects. Average age (64.9 vs 66.1), number of prior lines of treatment (4.1 vs 3.8) or prior transplant (72.8% vs 65.8%) were not associated with development of severe lymphopenia. Patients older than 65 had similar ALC nadir values (median 425, range 0-2250 vs median 400, range 0-1940), rates of lymphopenia (55.7% vs 62.5%, OR, 1.322; 95% CI, 0.5774 to 2.845) and time to severe lymphopenia (75.3, range 7-453 vs 58.88, range 0-254) than younger patients. However, they tended to recover slower than younger patients (average: 52 days vs 24 days). Only 26 of our patients received Daratumumab as single agent, while fifty-five of them were treated in combination with immunomodulatory drugs (IMIDs- lenalidomide or pomalidomide) and sixteen in combination with proteasome inhibitors (PIs). When patients were divided by combination strategy, no statistical difference was noted in ALC nadir values; however, IMID combination caused severe lymphopenia in 38/55 patients (69%) compared to 11/26 patients (42.3%) treated with single agent regimen (p= 0.05, OR: 2.8). Patients treated with Bortezomib combination had a slower time to severe lymphopenia (p= 0.05 and p=0.01, respectively) but longer recovery time (p= 0.0081) than patients treated with single agent or IMIDs. Conclusions: In our patient population, we discovered an elevated rate of severe lymphopenia, hospital utilization and infections. IMID combination was associated with increased rates of lymphopenia, while PI-combination caused more prolonged lymphopenia. Age more than 65 was associated with longer ALC recovery time. Interestingly, patients who did not recover their ALC had worst OS and PFS compared to patients who never became severly lymphopenic or patients who recovered their ALC count. Disclosures Efebera: Takeda: Honoraria; Janssen: Speakers Bureau; Akcea: Other: Advisory board, Speakers Bureau. Rosko:Vyxeos: Other: Travel support.

Experience of Generic Imatinib As a First Line Therapy for Patients with Chronic Myeloid Leukemia in a Single Reference Institution

Background: The treatment of chronic myeloid leukemia (CML) was revolutionized by the approval of Gleevec (imatinib mesylate) by the FDA in 2001. In low-middle-income countries, due to economic issues related to the high cost of this treatment, scientific governmental entities started to produce and release a generic imatinib in 2013. High quality data about the security profile and efficacy of generic imatinib treatment are still needed. Aims: We herein aimed to evaluate the 6 years follow up of CML patients treated with generic imatinib as first line therapy. Patients and Methods: We evaluated a retrospective cohort of 39 patients diagnosed with CML at a single institution, during the period between December 2001 and July 2019, that had used only generic formulation of imatinib since diagnosis; and analyzed their rate of response to treatment as a primary goal and adverse events and survival outcomes as secondary goals. Responses were evaluated according to ELN 2013. Event-free survival and overall survival were measured from starting date of treatment until: loss of molecular response or death from any cause, and until death from any cause or last seen, respectively. Results: The cohort of 39 patients treated with generic imatinib as first line therapy was composed of 23 men (59%) and 16 women (41%), with median age at diagnosis of 52 years (16-74). The median follow up time was 24 months (8-68), and the median duration of generic imatinib therapy was 19 months (5 - 68). Most of the patients were diagnosed at chronic phase (92%), with only 2 accelerated phase and 1 myeloid blast crisis. Risk stratification according to Eutos, Sokal and Hasford score was low in 92%, 67% and 80%; intermediate in 0%, 30% and 6% and high in 8%, 3% and 14%, respectively. Six different brands of generic imatinib were used (Cristalia, Instituto Vital Brasil, FURP, EMS, Fiocruz and Eurofarma); the most frequently used were Cristalia and Instituto Vital Brasil. The median number of brands used per patient was 2 (1-5). Patients received 400 mg of generic imatinib daily; the dose was increased to 600 mg in 4 patients due to sub-optimal response during follow up. The rate of hematologic response with treatment was 97% and median time to reach it was 1 month (1-7). The rate of response at 3, 6 and 12 months was 74%, 60%, and 92% for optimal cytogenetic response, and 69%, 61%, and 26% for optimal molecular response. The probability to reach deep molecular response at each year of follow up was 41% at 1st year, 52% at 2nd year, 46% at 3rd year, 50% at 4th year, 50% at 5th year, and 50% at 6th year. The probability to reach a molecular response 4.5 at each year of follow up was 10% at 1st year, 23% at 2nd year, 30% at 3rd year, 50% at 4th year, 50% at 5th year, and 50% at 6th year. Hematologic toxicities were frequent during the first three months of therapy. Reported non-hematologic adverse events were hypophosphatemia (62%), diarrhea (30%), cramps (30%), liver toxicity (28%), nausea (18%), bone pain (18%), edema (15%), rash (8%), and hypomagnesaemia (2.5%). Eight percent of patients evolved with deterioration of renal function during the treatment period, but its relationship with generic imatinib was not well established. Two patients (5%) needed a dose reduction because of adverse events. Eight (20.5%) patients switched to second line tyrosine-kinase inhibitors, five (13%) due to resistance and three (8%) due to side effects (severe hepatotoxicity, diarrhea, and rash). Three patients progressed after switching to another tyrosine kinase inhibitor. After a median follow up of 24 months, the event free survival rate was 80% and the overall survival rate was 100%. Conclusion: The rate of complete cytogenetic response, resistance, and intolerance after use of generic imatinib was not worse than the rates described in the long-term follow up of the IRIS trial (N Engl J Med 2017; 376:917-927). Deep molecular response rates seen in the cohort of patients on generic imatinib were inferior to the ones in the IRIS trial, but overall survival was not impacted. Hypophosphatemia was observed in a high percentage of patients, although it has not been reported in other cohorts on generic imatinib. Prospective randomized studies are needed to allow better conclusions regarding the comparative efficacy and safety of generic imatinib. Disclosures Figueiredo-Pontes: Novartis: Honoraria.

7PD - Synergistic anti-cancer activity of auranofin with anti-PD-L1 therapy in triple negative breast cancer

BackgroundTriple-negative breast cancers (TNBCs) are very aggressive and lethal forms of breast cancer with no effective targeted therapy. TNBCs spontaneously metastasize to distant organs including lungs, bone, and brain. Neo-adjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25-30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. MethodsWe tested the anti-cancer activity of auranofin monotherapy on primary tumor growth and metastasis in vitro and in vivo. Further, using in vitro analysis we conceptualized the PD-L1 dependent resistance against auranofin which we validated in vivo using syngeneic TNBC model. ResultsExpression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and correlated with adverse survival outcomes. Treatment with auranofin, an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC grown as spheroids in 3D culture. Further, auranofin treatment exerted a significant in vivo anti-tumor activity in multiple TNBC models including syngeneic 4T1.2 model, human MDA-MB-231 xenograft, and PDX model by inhibiting thioredoxin redox activity. Auranofin also significantly inhibited the invasion potential of TNBC cells in vitro and significantly inhibited lung metastasis in 4T1.2 syngeneic model in vivo by reducing the expression of various EMT markers. We for the first time showed that auranofin increased CD8+Ve T-cells tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in ERK1/2-MYC-dependent manner. Moreover, combination of auranofin with anti-PD-L1 monoclonal antibody synergistically impaired the growth of 4T1.2 primary tumor. ConclusionsOur data provides a novel therapeutic strategy using auranofin in combination with anti-PD-L1 antibody for TNBCs and warrants further clinical investigation for TNBC patients. Since the success rate of anti-PD-L1 therapy is very low in TNBC patients, our data provides a novel strategy to use auranofin with anti-PD-L1 therapy to that may enhance the efficacy of immune checkpoint therapy in TNBC patients. Legal entity responsible for the studyThe authors. FundingCure Cancer Australia & Can Too Foundation Project grant [ID 1147230] to Prahlad Raninga National Health & Medical Research Council (NH&MRC) Program Grant [ID 1017028] to Kum Kum Khanna Perpetual IMPACT Philanthropy project grant [IPAP201602001] to Kum Kum Khanna and Murugan Kalimutho. DisclosureAll authors have declared no conflicts of interest.

The Value of Troponin T Level Change During Chemoradiation in Esophageal Cancer Patients

Cardiac adverse events are common in esophageal cancer patients who received chemoradiation (CRT). However, reliable marker is lacking to predict these cardiac events. Troponin T (TnT) is a marker of myocardial necrosis, which is widely used in diagnosis of acute coronary syndromes. The relationship between TnT level change during CRT and cardiac injury is unknown. We hypothesized that the TnT level change during CRT is associated with acute cardiac adverse events and long-term survival outcomes. We retrospectively reviewed 113 esophageal cancer patients who received definitive or neoadjuvant CRT from 2010-2016. All patients consented on a prospective blood collection protocol where samples are drawn at baseline before, once during, at the end of CRT, and at each follow up timepoints. Irradiation dose parameters for the whole heart and each chamber were recorded from the treatment plan. TnT levels were quantified using the Elecsys® TnT-high sensitive assay (Roche Diagnostic). TnT level change was defined as CRT end level divided by baseline level. Logistic regression was used to evaluate the correlation between TnT change and acute cardiac adverse events. Kaplan-Meier method was used to compare survival outcomes in different TnT level change groups. The median TnT level gradually increased from baseline, to mid treatment course, and at the end of CRT: 6.27, 8.56, and 10.63 pg/ml, respectively. The median TnT level change was 1.48 (IQR, 1.12-2.01). For the whole heart, left ventricle (LV), right ventricle (RV), and right atrium (RA), the dose distribution was different between IMRT and proton: IMRT mainly contributed to low dose level (<30Gy), while in high dose regions (>40Gy), proton using passive scattering approach had significantly higher dose than IMRT. The TnT level change was strongly correlated to LV and RV dose percentage from V5 to V50 in proton patients (p<0.01), but not in IMRT patients. Male, lower BMI and lower tumor location were associated with higher TnT increase, while TnT level change could not predict acute cardiac adverse events during CRT or postoperative cardiac complications. There was no significant correlation of TnT levels and survival outcomes. There was significant correlation of TnT levels and cardiac dose distribution in proton patients that was not seen in IMRT patients. Whether TnT level alterations with treatment could correlate with late cardiac events specifically in proton patients requires longer term follow up.

Prognostic significance of solid growth in endometrioid endometrial adenocarcinoma.

Endometrioid endometrial cancer is the most common histological subtype of endometrial adenocarcinoma. In the FIGO grading scheme, both architectural and nuclear grade are taken into consideration. However, the specific impact of solid growth alone on endometrioid endometrial adenocarcinoma outcome is not well documented. We sought to assess the degree of impact of solid growth on lymphovascular space invasion (LVSI), myometrial invasion, tumor size, FIGO stage, lymph node metastasis (LNM), relapse-free survival (RFS) and disease-specific survival (DSS). Paraffin blocks of 269 patients treated for endometrioid endometrial cancer were retrospectively analyzed with morphometry for solid growth percentages. A statistically significant cut-off value of 1% solid growth was found for predicting LNM and advanced stage (III or IV), myometrial invasion and LVSI (p < 0.001) and a cut-off value of 8% was found for predicting adverse survival outcome (p < 0.001). The mean DSS was significantly higher in patients with < 6% solid growth compared to patients with 6-50%, 51-75% and > 75% solid growth (p < 0.001). Although, the mean RFS and DSS were lowest in patients with 51-75% solid growth, this did not reach statistical significance in comparison to 6-50% and > 75% (p > 0.05). Although > 75% solid growth was most significantly associated with many of the adverse prognostic factors, this subset did not provide prognostic superiority in predicting adverse survival when compared to subsets within 6-75% solid growth. In conclusion, although no statistically significant difference in survival was found among subdivisions of architectural grades 2 and 3, solid growth, especially ≥ 8%, appeared to be an independent prognostic factor for survival in patients with early-stage endometrioid endometrial cancer.

Management of orbital invasion in esthesioneuroblastoma: 14\u2009years\u2019 experience

BackgroundThere is a scarcity of data about the prognostic value of orbital invasion in esthesioneuroblastoma (ENB), as well as about its management strategies. Indications for the preservation of orbital contents remain controversial, and the evaluation of orbital invasion has been ill defined.MethodsThis retrospective analysis contained 60 ENB patients with orbital invasion who underwent radiotherapy with or without surgery over the past 14 years. Orbital invasion was classified into three grades.ResultsThere were 52 patients at stage C and 8 at stage D, according to Foote classifications. Grade I, grade II and grade III orbital invasion was detected in 12, 23, and 25 patients, respectively. The median follow-up was 57 months (IQR 32–95 months). Fourteen patients received radical radiotherapy, with a 5-year overall survival (OS) of 63.5%; 46 received surgery plus radiation, with a 5-year OS of 70.7%; and the difference was not statistically significant (p = 0.847). Orbital preservation was feasible in 100% of cases, including 18 cases that extended to extraocular muscles or the eye globe. Five-year locoregional relapse-free survival was 100% in patients with prophylactic elective neck irradiation (PENI) and 58.1% in patients without PENI (p = 0.004). Univariate analysis showed that grade II/III orbital invasion was associated with poorer OS and progression-free survival. Neck metastasis (with a Foote stage of D) was independently associated with shorter OS and distant metastasis–free survival in multivariate analysis.ConclusionsOur data suggested that primary radiotherapy achieved comparable survival to surgery plus radiotherapy in advanced ENB. Invasion of either the extraocular muscles or the eye globe is not a contraindication for eye-sparing surgery. Orbital invasion in grade II/III was significantly associated with adverse survival outcomes. Prophylactic radiotherapy to the neck with N0 significantly reduces the risk of regional recurrence.

PB2091 HOST INFLAMMATORY FACTORS MIGHT PREDICT LEUKEMIC TRANSFORMATION AND OVERALL SURVIVAL IN CHRONIC MYELOMONOCYTIC LEUKEMIA

Background:Chronic myelomonocytic leukemia (CMML) is a clonal myeloid malignancy with a variable clinical course and 15‐30% risk of progression to acute myeloid leukemia. Prognosis can vary according to various pretreatment patients’ factors. Scoring systems have been developed based on clinical and cytogenetic parameters1. Among patient related factors, host inflammatory anti‐neoplastic factors, e.g. neutrophils, monocytes, platelets, can contribute significantly to disease progression by promoting cancer cell proliferation, evasion of immune‐surveillance, etc., thus playing key roles in patients’ survival.Aims:The aim of the study was to evaluate the clinical and laboratory features at the initial diagnosis and their impact on the survival outcome of the investigated cohort.MethodsWe retrospectively collected clinical and hematologic data for 75 consecutive patients with CMML diagnosed at the National Hematology Hospital, Sofia in the period 2013‐2018. The diagnosis was defined according to WHO 2016 revised criteria. Demographic, clinical and laboratory data were recorded at the initial presentation. Overall survival (OS) was calculated as the time from diagnosis until death from any cause or last contact.Results:The patients’ cohort comprised of 49 males (65%) and 26 females (35%) at a mean age of 68,6 (ranging 26‐90). According to the FAB criteria the CMML cases with myelodysplastic features (WBC &lt; 13 G/l) were 28% (n = 21) vs CMML with myeloproliferative characteristics (WBC &gt; 13 G/l) 72% (n = 54). Progression to acute myeloid leukemia occurred in 9% of the cases for a 5‐year period of time and was significantly correlated with absolute neutrophil counts (ANC) (33% in pts with ANC &lt; 1,8 × 109/l vs 67% in pts with ANC ≥1,8 × 109/l; log rank p = 0,05), female gender (29% male vs 71% female pts; log rank p = 0,04) and splenomegaly (p = 0,03). No relevant differences were found in regard to hemoglobin levels, blast cell percentage, degree of myelofibrosis, number of dysplastic lineages, lactate dehydrogenase level or the therapeutic approach. We detected JAK2 V617F activated mutation in five (9,6%) of CMML patients, all younger than 70 years (p = 0,02), however JAK2 V617F mutational status did not correlate with clinical and laboratory parameters and also did not impact either leukemia free (LFS), nor overall survival (OS). Further analysis showed that in terms of OS the presence of constitutional symptoms, monocytes ≥3 × 109/l and platelets &lt;100 × 109/l were associated with adverse survival outcome. CMML cases with absolute monocyte count &lt;3 × 109/l had longer OS (82% vs 62,5% OS in pts with ≥3 × 109/l, mean 44 vs 16 months, respectively; log rank p = 0,03). Similarly, platelet count ≥100 × 109/l correlated with better outcome in the overall cohort (94% vs 64% OS in pts with thrombocytopenia, mean 42 vs 29 months, respectively; log rank p = 0,02) (Figure 1).Figure 1. Overall survival curves for patients with CMML according to the platelet count and absolute monocyte count at the initial diagnosis.Summary/Conclusion:Conclusion: In addition to some well established factors, e.g. gender and splenomegaly, our study provided data that pre‐treatment levels of some systemic inflammatory markers such as neutrophils, monocytes and platelets could be used in addition to predict leukemia transformation and shorter overall survival in CMML. Further research is needed to elucidate the underlying pathophysiological background for predictability of combined inflammatory biomarkers.image

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti-PD-L1 antibody for treatment of triple-negative breast cancer.

Triple-negative breast cancer (TNBCs) is a very aggressive and lethal form of breast cancer with no effective targeted therapy. Neoadjuvant chemotherapies and radiotherapy remains a mainstay of treatment with only 25-30% of TNBC patients responding. Thus, there is an unmet clinical need to develop novel therapeutic strategies for TNBCs. TNBC cells have increased intracellular oxidative stress and suppressed glutathione, a major antioxidant system, but still, are protected against higher oxidative stress. We screened a panel of antioxidant genes using the TCGA and METABRIC databases and found that expression of the thioredoxin pathway genes is significantly upregulated in TNBC patients compared to non-TNBC patients and is correlated with adverse survival outcomes. Treatment with auranofin (AF), an FDA-approved thioredoxin reductase inhibitor caused specific cell death and impaired the growth of TNBC cells grown as spheroids. Furthermore, AF treatment exerted a significant in vivo antitumor activity in multiple TNBC models including the syngeneic 4T1.2 model, MDA-MB-231 xenograft and patient-derived tumor xenograft by inhibiting thioredoxin redox activity. We, for the first time, showed that AF increased CD8+Ve T-cell tumor infiltration in vivo and upregulated immune checkpoint PD-L1 expression in an ERK1/2-MYC-dependent manner. Moreover, combination of AF with anti-PD-L1 antibody synergistically impaired the growth of 4T1.2 primary tumors. Our data provide a novel therapeutic strategy using AF in combination with anti-PD-L1 antibody that warrants further clinical investigation for TNBC patients.