University Of Texas MD Anderson Cancer Center Research Articles

Clinical and prognostic differences in oropharyngeal squamous cell carcinoma in USA and Denmark, two HPV high-prevalence areas

BackgroundUncertainty persists regarding clinical and treatment variations crucial to consider when comparing high human papillomavirus (HPV)-prevalence oropharyngeal squamous cell carcinoma (OPSCC) cohorts for accurate patient stratification and replicability of clinical trials across different geographical areas. MethodsOPSCC patients were included from The University of Texas MD Anderson Cancer Center (UTMDACC), USA and from The University Hospital of Copenhagen, Denmark from 2015–2020, (n = 2484). Outcomes were 3-year overall survival (OS) and recurrence-free interval (RFI). Subgroup analyses were made for low-risk OPSCC patients (T1–2N0M0) and high-risk patients (UICC8 III-IV). ResultsThere were significantly more HPV-positive (88.2 % vs. 63.1 %), males (89.4 % vs. 74.1 %), never-smokers (52.1 % vs. 23.7 %), lower UICC8-stage (I/II: 79.3 % vs. 68 %), and fewer patients treated with radiotherapy (RT) alone (14.8 % vs. 30.3 %) in the UTMDACC cohort. No difference in the adjusted OS was observed (hazard ratio [HR] 1.21, p = 0.23), but a significantly increased RFI HR was observed for the Copenhagen cohort (HR: 1.74, p = 0.003). Subgroup analyses of low- and high-risk patients revealed significant clinical and treatment differences. No difference in prognosis was observed for low-risk patients, but the prognosis for high-risk patients in the Copenhagen cohort was worse (OS HR 2.20, p = 0.004, RFI HR 2.80, p = 0.002). ConclusionsWe identified significant differences in clinical characteristics, treatment modalities, and prognosis between a Northern European and Northern American OPSCC population. These differences are important to consider when comparing outcomes and for patient stratification in clinical trials, as reproducibility might be challenging.

Survival improvement for patients with metastatic colorectal cancer over twenty years

Over the past two decades of successive clinical trials in metastatic colorectal cancer (CRC), the median overall survival of both control and experimental arms has steadily improved. However, the incremental change in survival for metastatic CRC patients not treated on trial has not yet been quantified. We performed a retrospective review of 1420 patients with de novo metastatic CRC who received their primary treatment at the University of Texas M.D. Anderson Cancer Center (UTMDACC) from 2004 through 2019. Median OS was roughly stable for patients diagnosed between 2004 and 2012 (22.6 months) but since has steadily improved for those diagnosed in 2013 to 2015 (28.8 months), and 2016 to 2019 (32.4 months). Likewise, 5-year survival rate has increased from 15.7% for patients diagnosed from 2004 to 2006 to 26% for those diagnosed from 2013 to 2015. Notably, survival improved for patients with BRAFV600E mutant as well as microsatellite unstable (MSI-H) tumors. Multivariate regression analysis identified surgical resection of liver metastasis (HR = 0.26, 95% CI, 0.19–0.37), use of immunotherapy (HR = 0.44, 95% CI, 0.29–0.67) and use of third line chemotherapy (regorafenib or trifluridine/tipiracil, HR = 0.74, 95% CI, 0.58–0.95), but not year of diagnosis (HR = 0.99, 95% CI, 0.98–1), as associated with better survival, suggesting that increased use of these therapies are the drivers of the observed improvement in survival.

OTME-23. Single-cell transcriptomic and epigenomic immune landscape of isocitrate dehydrogenase stratified human gliomas

The brain tumor immune microenvironment (TIME) continuously evolves during glioma progression, but a comprehensive characterization of the glioma-centric immune cell repertoire beyond a priori cell states is uncharted. In this study, we performed single-cell RNA-sequencing (scRNA-seq) and single cell- Assay for Transposase-Accessible Chromatin using sequencing (sc-ATAC-seq) on ~100,000 tumor-associated immune cells from seventeen isocitrate dehydrogenase (IDH) mutation classified primary and recurrent human gliomas and non-glioma brains (NGBs). Our analyses revealed sixty-two transcriptionally distinct myeloid and lymphoid cell states within and across glioma subtypes and we noted microglial attrition with increasing disease severity concomitant with invading monocyte-derived cells and lymphocytes. Specifically, certain microglial and monocyte-derived subpopulations were associated with antigen presentation gene modules, akin to cross-presenting dendritic cells (DCs). We identified cytotoxic T cells with poly-functional cytolytic states mostly in recurrent IDH-wt gliomas. Furthermore, ligand-receptor interactome analyses showed a preponderance of antigen presentation and phagocytosis over the checkpoint axis in IDH-wt compared to IDH-mut gliomas.Additionally, our sc-ATAC-seq analyses revealed differences in regulatory networks in NGBs, IDH-mut and IDH-wt glioma associated immune cells. In particular, we noted abundant usage of inflammatory transcription factors (TFs) as exemplified by Nuclear factor kappa B and Activator Protein-1 TF family in IDH-wt microglia when compared with microglia from IDH-mut and NGBs. Unique features such as amplification of 11- Zinc Finger Protein accessibility were restricted to monocyte derived cells and were not observed in microglia. Finally, sc-ATAC-seq profiles of CD8+ exhausted T cells from IDH-wt showed strong enhancer accessibility on Cytotoxic T-lymphocyte-associated protein 4, Layilin and Hepatitis A Virus Cellular Receptor 2 but no enrichment on PDCD1 (gene encoding Programmed cell death protein 1) was seen. In summary, our study provides unprecedented granular detail of transcriptionally defined glioma- specific immune contexture that can be exploited for immunotherapy applications.This study in K.B. laboratory was supported by the generous philanthropic contributions to The University of Texas (UT) MD Anderson Cancer Center (MDACC) Moon Shots Program™, Marnie Rose Foundation, NIH grants: R21 CA222992 and R01CA225963. This study was partly supported by the UT MDACC start-up research fund to L.W. and CPRIT Single Core grant RP180684 to N. E. N.

Time driven activity-based costing methods used in radiation oncology clinics.

79 Background: Since 2010 The University of Texas MD Anderson Cancer Center (UTMDACC) has been using Time Driven Activity Based Costing (TDABC) to assist in tracking and quantifying changes made to clinical processes to improve efficiency of patient care delivery. Radiation Oncology (RO) providers have recently utilized this method to assist in the growing clinical patient volumes and increasing enrollment in clinical trials. UTMDACC contains disease specific multi-disciplinary centers with separate clinics for different disciplines. Resources are limited which can affect clinical providers’ ability to meet the needs of increasing patient volumes. Implementing efficient clinic work flow models will allow clinicians to provide excellent quality of clinical care even with limited resources. Methods: Standard disease-site specific note templates were created and implemented throughout the entire RO department. Additionally, standardized roles for medical assistants, residents, physician assistants (PAs), attending physicians and nurses were implemented to minimize duplication of responsibilities. Using TDABC methodology, process maps for pre and post implementation pathways were created to illustrate areas of change and possible benefit. Results: Process maps were compared for new consult and follow up and on treatment patient visits. Process times for these patient care visits were compared pre- and post-implementation of templates and clinical roles. Time savings of 110, 18 and 34 minutes were observed for consult visits, follow up visits and on-treatment visits when comparing current to baseline process maps. Conclusions: Standardization of note templates and roles for all members of the care team has led to improvements in process flow and efficiency in the RO clinic setting. Our findings suggest that further implementation of TDABC methodology by having all providers work at the top of their license could can improve clinical efficiency and patient care. Further metrics with a larger sample size is recommended to validate our results. [Table: see text]

2099. Catheter-related Staphylococcus aureus Bacteremia and Septic Thrombosis: The Role of Anticoagulation and Duration of Intravenous Antibiotic Therapy

BackgroundCatheter-related septic thrombosis is suspected in patients with persistent Central Line-associated Blood Stream Infection (CLABSI) after 72 hours of appropriate antimicrobial therapy. There are limited data outlining the characteristics of the disease and the adequate duration of antimicrobials. In addition, the role of anticoagulation in the management of septic thrombosis remains unclear. We herein studied the clinical characteristics of staphylococcus aureus catheter-related septic thrombosis as well as the appropriate management and duration of treatment.MethodsWe conducted this retrospective study where we included patients with CLABSI due to Staphylococcus aureus who had a concomitant radiographic evidence of thrombosis at the level of catheter placement between the years 2005 and 2017. We collected data pertaining to patients’ medical history, clinical presentation, management, treatment and outcome within 3 months of bacteremia onset. Failure was defined as persistence of signs and symptoms at 72 hours, persistence bacteremia at 48–96 hours, relapse, complications or overall mortality.ResultsA total of 128 patients were included. The median age was 55 years. Total relapse/recurrence rate was 8% and all-cause mortality within 3 months was 16%. We found no significant difference in overall outcome between patients who had deep vs. superficial thrombosis. Patients with superficial thrombosis were found to have higher rate of pulmonary complications (25% vs. 6%; P = 0.01) compared with those with deep thrombosis. Patients who received less than 28 days of intravascular antibiotic therapy had higher all-cause mortality (31 vs. 5% P = 0.001). A multivariate logistic regression analysis identified two independent predictors of treatment failure: presence in the ICU at any point during their illness (odds ratio (OR) = 2.74, 95% confidence interval (CI) = 1.08–6.99, P = 0.034) and not receiving anticoagulation (OR = 0.24, 95% CI = 0.11–0.54, P < 0.001).ConclusionIntravenous antimicrobial therapy for 28 days or longer carries a survival advantage over shorter duration of therapy and anticoagulation as an adjunctive treatment is an independent predictor of successful antimicrobial therapy.Disclosures I. Raad, The University of Texas MD Anderson Cancer Center: Shareholder, Licensing agreement or royalty. The Unversity of Texas MD Anderson Cancer Center: Shareholder, Dr. Raad is a co-inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed to Novel Anti-Infective Technologies LLC, in which UTMDACC and Licensing agreement or royalty.

1036. Whole Genome Sequencing Analysis of a Large Cohort of Staphylococcus epidermidis Blood Culture Positive Isolates From a Multicenter Clinical Trial

Background Staphylococcus epidermidis is a leading cause of healthcare-associated bacteremia, but the clinical course of S. epidermidis isolated from blood cultures ranges from contamination to serious deep seated infections. We tested the hypothesis that the genetic characteristics of S. epidermidis isolated from blood cultures are significantly associated with disease severity using whole genome sequencing (WGS).MethodsWe performed WGS of 163 S. epidermidis isolates from a large prospective multicenter, randomized control trial that assessed the safety and efficacy of algorithm-based treatment of patients with staphylococcal bacteremia (ClinicalTrials.gov #NCT01191840). Patient’s infection types were divided into simple (including possible contamination), uncomplicated and complicated bacteremia. Failure was defined as persistent signs and symptoms of infection at 72 hours, persistent bacteremia at 7 days, relapse, complications or overall mortality within 28 days of therapy. WGS was performed using Illumina Miseq, followed by in silico multi-locus sequence type identification and phylogenomic analysis using kSNP.ResultsOf the 163 isolates analyzed, 39 sequence types (STs) were identified with ST2 and ST5 isolates being most frequently identified (21% and 20%, respectively). ST2 and ST5 isolates were significantly more likely associated with uncomplicated and complicated infections rather than simple bacteremia (P = 0.01 by χ2 test). By multivariate regression analysis, having an ST2 or ST5 S. epidermidis bacteremia was an independent predictor of a complicated infection (odds ratio 4.28, 95% CI 1.36–13.42). Using WGS based branching points rather than sequence typing allowed for additional strengthening of the association of S. epidermidis genetic clustering and clinical infection types (figure). Although there was no significant difference in failure rates among patients infected with different STs, ST2/ST5 strains were significantly more likely to cause relapsing infections (85.7%, P = 0.02).ConclusionWGS could offer a prognostic tool in the management of S. epidermidis bacteremia. ST2 and ST5 strains may help predict a complicated bacteremia course which would warrant appropriate antimicrobial therapy. Disclosures T. L. Holland, Basilea: Consultant, Consulting fee. Motif Bio: Consultant and Scientific Advisor, Consulting fee. Theravance: Consultant, Speaker honorarium. Genentech: Consultant, Consulting fee. V. G. Fowler Jr., Debiopharm: Consultant, Consulting fee. Durata: Consultant, Consulting fee. Merck: Consultant and Scientific Advisor, Consulting fee. Cerexa/Actavis/Allergan: Grant Investigator, Grant recipient. Pfizer: Consultant and Grant Investigator, Consulting fee and Grant recipient. Advanced Liquid Logics: Grant Investigator, Grant recipient. NIH: Grant Investigator, Grant recipient. MedImmune: Consultant and Grant Investigator, Consulting fee and Grant recipient. Basilea: Consultant and Grant Investigator, Consulting fee and Grant recipient. Karius: Grant Investigator, Grant recipient. Contrafect: Consultant and Grant Investigator, Consulting fee and Grant recipient. Regeneron: Grant Investigator, Grant recipient. Genentech: Consultant and Grant Investigator, Consulting fee and Grant recipient. Affinergy: Consultant and Grant Investigator, Consulting fee and Grant recipient. Locus: Grant Investigator, Grant recipient. Medical Surface, Inc.: Grant Investigator, Grant recipient. Theravance: Consultant, Consulting fee and Speaker honorarium. Green Cross: Consultant, Speaker honorarium. Grifols: Consultant, Consulting fee. xBiotech: Consultant, Consulting fee. Achaogen: Consultant, Consulting fee. Medicines Co: Consultant, Consulting fee. Novartis: Consultant, Consulting fee. Novadigm: Consultant, Consulting fee. Bayer: Consultant, Consulting fee. Cubist: Consultant, Consulting fee. Debiopharm: Consultant, Consulting fee. Durata: Consultant, Consulting fee. I. Raad, The University of Texas MD Anderson Cancer Center: Shareholder, Licensing agreement or royalty. The Unversity of Texas MD Anderson Cancer Center: Shareholder, Dr. Raad is a co-inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed to Novel Anti-Infective Technologies LLC, in which UTMDACC and Licensing agreement or royalty.

2453. Repeated Exposures to Minocycline/Rifampin and + Chlorhexidine Combination Used to Coat Catheters Fails to Induce Antimicrobial Resistance

BackgroundCentral venous catheters (CVC) impregnated with minocycline and rifampin (M/R) are recommended for use in high-risk patients to reduce catheter related bloodstream infections (CRBSI). We developed a second generation antimicrobial CVC with addition of chlorhexidine (CHD) for extended spectrum activity against virulent Gram-positive and Gram-negative bacteria as well as yeast. In this study we examined the potential for induced resistance with repeated exposure to M/R+CHD.MethodsPotential to induce resistance was evaluated by exposing a broad-spectrum of CRBSI pathogens to serial passages of sub-inhibitory concentrations of M/R+CHD and retesting MICs following each passage. Susceptibility to individual agents in the combination were assessed, to identify organisms that were originally resistant to the individual agents in the combination. A total of 24 Gram-positive, Gram-negative, and yeast pathogens were evaluated for baseline MICs following standard CLSI procedures. Subsequently, organisms that were exposed to one half the MIC were cultured and MICs retested. This process was carried out for a total of 21 passages to assess trends in MICs and potential for induction of resistance. Any organism with ≥4 fold increase in MIC were then passed in broth alone to assess phenotypic adaptation.ResultsSynergy in the triple combination of M/R + CHD was detected for several resistant organisms that had low susceptibilities to the individual components but were highly susceptible to the combination. After a series of 21 passages, the organisms maintained the same MIC values as baseline with no clinically significant increases. One strain of Enterobacter showed a 4-fold MIC increase; however, the MIC returned to baseline after culturing in broth alone.ConclusionRepeated exposure of M/R + CHD failed to show induced antimicrobial resistance among a large number of pathogens with both low and high susceptibilities. Furthermore, any increase in MIC returned to baseline with the removal of the stressor (M/R + CHD), indicating that the increase in MIC was a phenotypic adaptation rather than induced resistance. Surveillance studies assessing development of resistance will need to be conducted in a clinical setting.Disclosures I. Raad, The University of Texas MD Anderson Cancer Center: Shareholder, Licensing agreement or royalty. The University of Texas MD Anderson Cancer Center: Shareholder, Dr. Raad is a co-inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed to Novel Anti-Infective Technologies LLC, in which UTMDACC and Licensing agreement or royalty.

1488. Invasive Pulmonary Aspergillosis in Patients with Solid Tumors: Risk Factors and Predictors of Clinical Outcomes

BackgroundThe clinical features and management of invasive pulmonary aspergillosis (IPA) in patients with hematologic malignancies are well known. In contrast, IPA is not well described in solid tumor patients.MethodsWe retrospectively reviewed all Aspergillus-positive cultures at MD Anderson Cancer Center from March 2004 to September 2017. We included all adult patients with underlying solid tumor and Aspergillus-positive respiratory cultures. The clinical algorithm for IPA diagnosis in critically-ill patients was used to separate colonization from proven or probable infection. We analyzed the association between host factors, clinical findings, and treatment modalities and 12-week overall survival, and response to antifungal therapy.ResultsOut of 1,121 Aspergillus-positive cultures, 669 cases did not meet the inclusion criteria and 351 were classified as colonization. We included 101 patients with IPA and solid tumor; 10% proven and 90% probable IPA. The median age was 63 years. The most common underlying solid tumor was lung cancer (51%), 76% of the patients had an underlying lung disease, 47% had received radiation therapy to the chest, and 33% had chronic obstructive pulmonary disease. Neutropenia and diabetes were not common risk factors. Most patients presented with respiratory symptoms (81%). A. fumigatus was the most common type isolated (69%). Most common chest imaging findings were nodular (41%) and cavitary lesions (14%); 70% of the patients were treated with voriconazole monotherapy. Independent risk factors for 12-week mortality were receiving steroids within 30 days of IPA diagnosis (hazard ratio 2.2, 95% CI, 1.1–4.6; P = 0.03) and radiation therapy to the chest (hazard ratio 2.6, 95% CI, 1.2–5.5; P = 0.01). In multivariate analysis, a positive calcofluor fungal stain was associated with lower odds of a successful outcome (odds ratio 0.2; 95% CI, 0.05–0.75; P = 0.02) whereas treatment with voriconazole was associated with higher odds (odds ratio 10.1; 95% CI, 2.1–48.5; P < 0.01).ConclusionIPA should be considered in solid tumor patients, particularly those with underlying lung disease. Radiation therapy to the chest, steroid intake, and positive fungal stain were associated with poor outcomes, while voriconazole therapy was associated with improved outcomes.Disclosures I. Raad, The University of Texas MD Anderson Cancer Center: Shareholder, Licensing agreement or royalty. The Unversity of Texas MD Anderson Cancer Center: Shareholder, Dr. Raad is a co-inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed to Novel Anti-Infective Technologies LLC, in which UTMDACC and Licensing agreement or royalty.

2100. Nitroglycerin-Citrate-Ethanol Catheter Lock Solution Is Highly Effective in Eradicating Candida auris Biofilms

BackgroundBlood stream infections due to Candida auris is a significant public health concern due to increased patient mortality, frequent misidentification, and high rates of antifungal resistance. C. auris is known to be azole resistant, however several strains have been identified with elevated MICs to all classes of antifungals. Current treatment options for a pan-resistant strain of C. auris would be extremely challenging. Previously we have shown that non-antibiotic, Nitroglycerine + Citrate + Ethanol (NiCE) lock solution was highly efficacious in eradicating various species of multi-drug-resistant Candida. In this study we compared the efficacy of NiCE with standard of care antifungals commonly used in lock solutions in eradicating C. auris biofilms.MethodsBiofilm eradication of C. auris was evaluated in 10 strains. Candida auris biofilm was grown on silicone discs for 24 hours. Discs were then washed to remove any non-adherent organisms and exposed for 2 hours to various antifungal lock solutions including NiCE, Echinocandins, Azoles, and Amphotericin B. Discs were exposed to Muller–Hinton broth as a control. Subsequently discs were sonicated for 15 minutes in 5 mL of saline and quantitatively cultured onto sabouraud dextrose agar. Plates were incubated at 37°C for 48 hours and counted for growth. All testing was conducted with 6 replicates.ResultsNiCE and Caspofungin were significantly more effective in eradicating C. auris biofilms compared with control (P = 0.002 and 0.008, respectively). However, Caspofungin failed to eradicate a few strains of C. auris biofilm while NiCE completely eradicated all 10 strains. Micafungin, Anidulafungin, Fluconazole, and Voriconazole were not significantly different than control (P > 0.05) for all strains.ConclusionNiCE catheter lock solution was capable of completely eradicating all C. auris biofilms within 2 hours indicating high potential for preventing CRBSI caused by C. auris. Caspofungin eradicated some strains of C. auris biofilm, but failed to eradicate all. Other commonly used antifungals were no different than control. Future clinical studies to verify these findings need to be conducted.Disclosures D. P. Kontoyiannis, Merck: Consultant, Research support and Speaker honorarium; Pfizer: Consultant, Research support; Astellas: Consultant, Research support and Speaker honorarium; Gilead: Speaker’s Bureau, Speaker honorarium; F2G Inc: Speaker’s Bureau, Speaker honorarium; Cidara Inc.: Speaker’s Bureau, Speaker honorarium; Jazz Pharmaceuticals: Speaker’s Bureau, Speaker honorarium. I. Raad, The University of Texas MD Anderson Cancer Center: Shareholder, Licensing agreement or royalty; The Unversity of Texas MD Anderson Cancer Center: Shareholder, Dr. Raad is a co-inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed to Novel Anti-Infective Technologies LLC, in which UTMDACC and Licensing agreement or royalty.

Comparing Diagnostic-Driven Approaches to Empiric Therapy in the Treatment of Invasive Aspergillosis in Patients with Hematologic Malignancy

Background Early antifungal therapy of invasive aspergillosis (IA) has been shown to be associated with improved outcome. Given the difficulty to establish the diagnosis of IA based on conventional methods, early initiation of empiric antifungal therapy has been used in patients with clinically suspected IA. Diagnostic-driven approach (DDA) relies on using novel diagnostic methods (e.g., early galactomannan testing). In this current study, we compared the outcomes of hematological malignancy (HM) patients with IA who were treated with Voriconazole using the DDA (DDA-Vori) vs. empiric therapy with a non-Voriconazole containing regimen (EMP-non-Vori) or empiric therapy with Voriconazole (EMP-Vori).Methods We retrospectively reviewed the medical records of 604 HM patients with documented, proven or probable IA (according to EORTC/MSG criteria) diagnosed between July, 1993 and February, 2016 at our center. We included 346 patients with underlying host factors, a suggestive CT findings of IA, and positive biopsy, fungal culture or galactomannan indicative of IA, and who received at least 7 days of DDA-Vori, EMP-Vori, or EMP-non-Vori. Outcome assessment included response to therapy (clinical and radiographic), all causing mortality and IA attributable mortality.ResultsThe patients’ median age was 54 years and 59% were males. By multivariate analysis, factors that were predictive of a favorable response included: localized/sinus IA vs. disseminated/pulmonary IA (P < 0.0001), not receiving WBC transfusion (P < 0.01), and DDA-VORI vs. EMP-non-Vori (P < 0.0001). On the other hand, predictors of mortality within 6 weeks of initiation of IA therapy included disseminated/pulmonary infection vs. localized/sinus IA (P < 0.01), not having stem-cell transplant within 1 year prior of IA (P = 0.01) and EMP-non-Vori vs. DDA-Vori (P < 0.001).Conclusion DDA-Vori is associated with a better outcome (response and survival) when compared with EMP-non-Vori and equivalent outcome to EMP-Vori. The superior to equivalent outcome associated with the DDA approach could also reduce unnecessary costs and adverse events associated with widespread use of empiric therapy.Disclosures I. Raad, Merck: Grant Investigator, Research grant. Allergan: Grant Investigator, Research grant. Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Raad is a s and Shareholder, Licensing agreement or royalty

Catheter-related Complications and Potential Risk Factors Among Catheterized Cancer Patients Receiving Parenteral Nutrition at The University of Texas MD Anderson Cancer Center: A 26,000 Parenteral Nutrition-day Experience

BackgroundParenteral nutrition (PN) is used as nutritional support in patients that are malnourished, critically ill, and/or have a nonfunctional gut. Patients receiving PN are at increased risk for both infectious and noninfectious catheter complications often leading to increased morbidity and mortality. Risk factors for catheter complications in patients receiving PN are often variable and poorly understood.MethodsWe conducted retrospective study among cancer patients who received PN between January 1, 2013 and December 31, 2015 at the University of Texas MD Anderson Cancer Center. Rate and prevalence of central line associated blood stream infection (CLABSI) and noninfectious catheter complications were assessed. Additionally, prevalence and time-to-infection of causative pathogens were evaluated. Multivariate logistic regression analyses were conducted in a sample of the PN population to identify risk factors for both infectious and noninfectious catheter complications.ResultsWe identified 46 CLABSI cases in 38 patients of the 1,762 patients receiving PN (1.73 episodes of CLABSI per 1000 PN days). Gram-positives (37.84%) and yeast (29.73%) were the most common pathogens, with catheter-related Candidemias occurring earlier than gram-positive or gram-negative CLABSI. Noninfectious catheter complications occurred in 56 patients (38.6%). Multivariate analysis identified age, GVHD, and history of occlusion in the same catheter, as well as intestinal failure and long-term PN use as significant risk factors for CLABSI and noninfectious catheter complications, respectively.ConclusionPatients receiving PN are at higher risk for both infectious and noninfectious catheter complications. Compared with national averages of CLABSI, the prevalence of catheter-related Candidemias in the PN cancer patient population was increased. This study highlights the need for development of more effective targeted preventative interventions.Disclosures J. Rosenblatt, Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Rosenblatt is a and Shareholder, Licensing agreement or royalty; UT MD Anderson Cancer Center: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Rosenblatt is a s and Scientific Advisor, Licensing agreement or royalty; I. Raad, Merck: Grant Investigator, Research grant; Allergan: Grant Investigator, Research grant; Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Raad is a s and Shareholder, Licensing agreement or royalty.

Comparative efficacies of Antimicrobial Catheter Lock Solutions for Fungal Biofilm Eradication in an in vitro model of Catheter-Related Fungemia

Fungal catheter-related bloodstream infections (CRBSIs), primarily due to Candidaspecies, account for over 12% of all CRBSIs and have been progressively increasing in prevalence. They present significant health and economic burdens and high rates of mortality. Antimicrobial catheter lock solutions are an important prophylactic option for preventing fungal CRBSIs. In this study we compared the effectiveness of two FDA-approved catheter lock solutions (heparin and saline) and three experimental antimicrobial catheter lock solutions, 30% Citrate, Taurolidine-Citrate-Heparin (TCH), and Nitroglycerin-Citrate-Ethanol (NiCE). All solutions were tested in an in vitro model of yeast biofilm eradication. The yeast tested were five different strains of Candidaclinical isolates from cancer patients who contracted CRBSIs. Time-to-biofilm-eradication was assessed in the model with 15, 30 and 60 minute exposures to the lock solutions. Only the NiCE lock solution was able to fully eradicate all fungal biofilms within 60 minutes. Neither 30% citrate nor TCH was able to fully eradicate any of the Candida biofilms in this time frame. The NiCE lock solution was significantly superior to TCH in eradicating biofilms of five different Candidaspecies (P = 0.002 for all). NiCE lock showed significant efficacy compared with all solutions tested indicating NiCE has the potential to be used as an antifungal lock solution in high-risk settings where CRBSI caused by Candida is predominant. J. Rosenblatt, Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Rosenblatt is a and Shareholder, Licensing agreement or royalty; UT MD Anderson Cancer Center: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Rosenblatt is a s and Scientific Advisor, Licensing agreement or royalty; I. Raad, Merck: Grant Investigator, Research grant; Allergan: Grant Investigator, Research grant; Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Raad is a s and Shareholder, Licensing agreement or royalty

Foley Catheter with Peri-Urethral Antimicrobial Irrigation for the Prevention of Catheter Associated Urinary Tract Infections – Assessment in an In Vitro Model

BackgroundCatheter associated urinary tract infections (CAUTIs) are a significant medical issue with substantial morbidities and costs. CAUTIs are primarily caused by colonization of the external surface of Foley catheters which serve as conduits for colonizing microbes to access the bladder. In order to prevent these CAUTIs, we developed a double-cuff Foley catheter with a novel irrigation cuff for daily irrigation of the periurethral space with a biocompatible antimicrobial disinfecting solution. This study assessed the efficacy of this system for reducing external-surface microbial colonization of catheters in an in vitro model.MethodsThe novel double cuff Foley and disinfectant solutions were evaluated in an established in vitro CAUTI model (Gaonkar, et al 2003) where a Foley catheter indwelled in a simulated urethra. 5.5 × 105 CFU of common uropathogens (MRSA, E. coli, C. albicans) were allowed to attach to the external catheter surface at meatal end of the catheter for 2 hours at 37°C. Subsequently, 3 mL of disinfectant solutions were instilled through the irrigation cuff and covered the periurethral catheter surfaces. Catheters were then incubated an additional 24–48 hours at 37°C, removed, cut into segments, and adherent organisms were quantified by sonication. Disinfectant solutions evaluated included various combinations of 1% polygalacturonic acid (PG), 0.4% caprylic acid (CAP) and (dilute) 0.3% H2O2.ResultsFor all organisms tested only the triple combination periurtehral flush (PG+CAP+H2O2) completely prevented biofilm colonization of catheters indicating antimicrobial synergy of the component agents. Control catheters grew >104 CFU/segment. Single agent or double agents combinations were only partially effective in preventing colonization by all three pathogens.ConclusionThe PG + CAP + H2O2 periurethral disinfectant flush instilled through an irrigation cuff in a novel double-cuff Foley catheter was able to completely prevent microbial colonization of the external catheter surface by MRSA, E. coli and C. albicans in an in vitro CAUTI model. In vivo studies are needed to further evaluate this technology for prevention of CAUTI.Disclosures J. Rosenblatt, Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Rosenblatt is a and Shareholder, Licensing agreement or royalty; UT MD Anderson Cancer Center: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Rosenblatt is a s and Scientific Advisor, Licensing agreement or royalty; I. Raad, Merck: Grant Investigator, Research grant; Allergan: Grant Investigator, Research grant; Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Raad is a s and Shareholder, Licensing agreement or royalty

Unnecessary Removal of Central Venous Catheters in Cancer Patients with Bloodstream Infections: Impact on Symptom Burden

BackgroundCurrent IDSA guidelines mandate removal and re-insertion of Central Venous Catheters (CVCs) in the setting of central line associated bloodstream infections (CLABSI) caused by virulent pathogens. However, CVC may be retained in the setting of non-CLABSI. There has been little if any quantitative assessment of the symptom burden associated with CVC removal and insertion.MethodsBetween 2013 and 2014, we evaluated the rate of CVC removal in 283 cancer patients who presented at our institution with a bloodstream infection (BSI) in the presence of a CVC whereby the positive blood cultures were drawn from the CVC and peripheral vein. In 2015, we collected symptom burden related to CVC removal and insertion procedures in 60 consecutive cancer patients using the MD Anderson Symptom Inventory.ResultsThe rate of CVC removal in patients with BSI and other non-CVC source was 57% which was identical to that in patients with CLABSI. (P = 0.94). In the 60 patients evaluated for symptom burden, symptoms (such as pain, pressure, distress) were present in up to 57% to 67% of patients undergoing CVC insertion and removal respectively. In 32% of patients, moderate to severe symptoms were reported with a symptom burden level of 4/10 or more.ConclusionCVC removal occurred unnecessarily in 57% of non-CLABSI patients which was equivalent to that in patients with CLABSI. Catheter removal and insertion produced moderate to severe symptom burden in cancer patients. Physician education need to be reinforced and safe interventions to salvage the vascular access should be explored.Disclosures J. Rosenblatt, Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Rosenblatt is a and Shareholder, Licensing agreement or royalty; UT MD Anderson Cancer Center: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Rosenblatt is a s and Scientific Advisor, Licensing agreement or royalty; I. Raad, Merck: Grant Investigator, Research grant; Allergan: Grant Investigator, Research grant; Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol catheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Raad is a s and Shareholder, Licensing agreement or royalty.

Catheter Lock with Minocycline, EDTA and Ethanol for Salvaging of Central Venous Catheters in the Setting of Catheter-related Bloodstream Infections

BackgroundLong-term central venous catheters are essential in delivering care for critically ill and cancer patients. These catheters could lead to central line associated bloodstream infections (CLABSI). Removal and reinsertion of a new catheter may not always be feasible due to unavailability of vascular access in the setting of thrombocytopenia. A pilot open label study conducted at our institution showed promising results when Minocycline, EDTA, Ethanol (M-EDTA-EtOH) lock was used to salvage the catheter.MethodsBetween October 2013 and August 2014, we prospectively enrolled 20 patients with catheter-related bloodstream infections (CRBSI) or CLABSI in three of our sister institutions in three countries including Brazil, Lebanon, and Japan. These patients received (M-EDTA-EtOH) lock therapy and were compared with 24 historical control patients who were matched based on organisms, underlying diseases and neutropenia status. The control patients had their CVCs removed and a new CVC inserted.ResultsThe two groups had comparable clinical characteristics. In the lock therapy group 95% of the patients had microbiological eradication within 96 hours after starting lock therapy vs. 83% of the patients in the control group (P = 0.36). In the lock group, the CVC was salvaged and retained for a median of 21 days (range 7–51) from the onset of bacteremia whereas the CVC was removed after a median of 2 days in the control group (range 0–8 days. P < 0.0001).ConclusionOur study suggests that M- EDTA-EtOH lock therapy seems to be an effective intervention to salvage long-term CVCs in the setting of CLABSI/CRBSI in cancer and dialysis patients with limited vascular access.Disclosures I. Raad, Merck: Grant Investigator, Research grant; Allergan: Grant Investigator, Research grant; Infective Technologies, LLC: Co-Inventor of the Nitroglycerin-Citrate-Ethanol atheter lock solution technology which is owned by the University of Texas MD Anderson Cancer Center (UTMDACC) and has been licensed by Novel Anti-Infective Technologies, LLC in which Dr. Raad is a s and Shareholder, Licensing agreement or royalty.

Mortality from Cancer-Associated Venous Thromboembolism

Determining the death rate due to venous thromboembolism (VTE) among cancer patients is a daunting task, suffering from methodological constraints associated with death certificates, administrative data bases, surveillance methods and disease recognition. While it is clear that VTE is a clinical marker of a high risk of dying from cancer and that cancer patients are at relatively higher risk of dying from pulmonary embolism (PE), there are large variations in mortality directly attributable to VTE. To examine mortality from venous thromboembolism (VTE) associated with cancer, we reviewed the medical records of patients from the University of Texas MD Anderson Cancer Center (UTMDACC) suffering from cancer plus VTE who died during the time period 3/1/2000 and 10/31/2010. A list of all cancer patients at UTMDACC who died during the time period 3/1/2000 through 10/31/2010 and carried one of 18 ICD-9 coded diagnoses of VTE (encompassing deep venous thrombosis, pulmonary embolism, inferior vena cava thrombosis and renal vein thrombosis) was provided by the institutional Enterprise Information Warehouse. Among 99,288 patients who died at MD Anderson over the ~ 10 year period, 11,032 had a diagnosis of VTE. The electronic health records (EHR) of 9,000 of these patients were reviewed to determine if death was attributed to VTE. A cause-of-death could be assigned to 1,459 patients and could not be determined for the remaining 7,541. The distribution of malignancies among patients with a defined cause-of-death was 19.8 % - acute leukemia or myelodysplastic syndrome (8.3% with acute myelogenous leukemia); 14.2% - lymphoma; 12.5% - genitourinary; 12.5% - lung; 12.4% - gastrointestinal; 7.3% - breast; 4.4% - myeloma; and 17% - other. The attributed cause-of-death for these 1,459 patients was disease progression in 52.8%; infection in 19.7%; VTE in 13.9%; respiratory failure (not due to disease progression or PE) in 7.6%; arterial thrombosis (myocardial infarction, sudden death, stroke or congestive heart failure) in 3.5%; hemorrhage in 1.2%; and other (stem cell transplant-related multiorgan failure, graft-versus-host disease, liver failure, diffuse alveolar hemorrhage, thrombotic microangiopathy, hepatic veno-occlusive disease, fall, or suicide) in the remaining 1.3%. Among the 203 patients whose cause-of-death was attributed to VTE, 51 had hematological malignancies (16 acute leukemia, 15 lymphoma, 14 myelodysplastic syndrome or a myeloproliferative neoplasm, 6 myeloma) and 152 were solid tumor patients (39 lung, 34 genitourinary, 26 gastrointestinal, 15 breast, and 37 miscellaneous [melanoma, sarcomas, germ cell and others]). 162 out of 203 patients with death attributed to VTE were receiving anticoagulation and 40 were treated with an inferior vena caval filter. 109/203 had thrombocytopenia (platelet count < 150,000/μl), 81 of whom received anticoagulation. 6/81 of the thrombocytopenic patients who died of VTE had bleeding; 3 of these patients had WHO grade 4 bleeding contributing to death. Fatal VTE was documented by objective measures in 83.3% (169 out of 203) and by clinical measures in 16.7% (34 out of 203). Assuming that all clinical diagnoses were wrong, objectively documented VTE directly caused 11.6% of the deaths (169/1459). These results indicate that VTE is a major cause of death among patients with heterogeneous malignancies and suggest that improved treatment of malignancy-associated VTE will have an immediate and significant favorable impact on the survival of cancer patients. Better data are needed to determine the therapeutic index of prophylactic and therapeutic anticoagulation in cancer patients, particularly those considered to be at high risk for bleeding. DisclosuresKroll:Boerhinger-Ingelheim: Membership on an entity’s Board of Directors or advisory committees; Aplagon Therapeutics: Membership on an entity’s Board of Directors or advisory committees.

Peripheral Absolute Neutrophil, Mmonocyte and Lymphocyte Counts and Clinical Ooutcome in Diffuse Large B-Cell Lymphoma

BackgroundBaseline levels of peripheral absolute neutrophil (ANC), lymphocyte (ALC) and monocyte (AMC) counts have prognostic value in solid tumors. There are limited data on their impact on outcomes in patients with diffuse large B-cell lymphoma (DLBCL). The present study is to confirm whether the baseline levels of peripheral ANC, ALC and AMC can predict outcomes in patients with newly diagnosed DLBCL.Patients and MethodsData from lymphoma database at the University of Texas MD Anderson Cancer Center (UTMDACC) were used. The correlation of baseline ANC, AMC and ALC with progression-free survival (PFS) and overall survival (OS) were analyzed in 817 newly diagnosed previously untreated patients with DLBCL who received frontline treatments at UTMDACC between 2000-2011. Kaplan-Meier method was used for time-to event analysis including PFS and OS. Multi Cox proportional hazards model were fitted to evaluate important patient characteristics on the time-to event endpoints.ResultsMedian ages at diagnoses were 58 years (range, 18 to 91 years). Seventy-nine percent of patients received conventional immunochemotherapy(CHOP-R) while 21 % of patients had intensive immunochemotherapy (HyperCVAD-R or R-EPOCH) or intensive chemotherapy(n=5; HyperCVAD or R-EPOCH) due to CD 20 negative; two patients received radiation therapy only. IPI low, intermediate and high were 38%, 46% and 16%, respectively. Overall response rate was 98% with a complete remission rate of 73%. Patients with abnormal ANC (> 7.3 X109/L) had an inferior PFS (P<0.001) and OS (P<0.001) compared to patients with ANC ≤ 7.3 X109/L; patients with abnormal ALC (< 1.0 X109/L) had significant short PFS (P<0.001) and OS (P<0.001) compared to patients with ALC ≥ 1.0 X109/L; similarly, patients with abnormal AMC (> 0.7X109/L) had inferior PFS (P< 0.001) and OS (P< 0.001) compared to patients with AMC≤ 0.7 X109/L. Multivariate analysis identified abnormal ALC and AMC as an independent adverse prognostic factors for PFS (hazard ratio [HR] 1.39 and 1.49, respectively; P<0.016 and P=0.004, respectively) and abnormal ANC and AMC as an independent adverse prognostic factors for OS (P=0.017 and P=0.024, respectively; HR 1.56 and 1.42, respectively).ConclusionsAn abnormal Neutrophil, lymphocyte and monocyte counts in peripheral blood are independent, poor prognostic factor for PFS and OS in patients with DLBCL. Incorporation of these immunological markers into IPI prognostic model may improve outcome prediction. DisclosuresNo relevant conflicts of interest to declare.

Abstract P6-12-04: Risk factors for inflammatory breast cancer

Abstract Background: The 5-year survival rates for inflammatory breast cancer (IBC) are significantly lower than non-IBC, highlighting the importance of cancer prevention in IBC. We investigated the risk factors for IBC subtypes based on estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor 2 (HER2neu) status to determine distinct etiological pathways. The Morgan Welch Inflammatory Breast Cancer Research Program and Clinic at University of Texas MD Anderson Cancer Center (UTMDACC) treats the largest number of IBC patients in a single center. The center maintains a prospective, comprehensive epidemiology registry, through which we were able to conduct the largest single center case-control study on IBC. Methods: We identified 246 patients diagnosed with IBC using strict consensus criteria and 397 cancer free patients seen at the UTMDACC Dan L. Duncan Cancer prevention clinic. We used logistic regression to estimate the odds ratios (OR) and 95% confidence intervals (CI) for the associations between breast cancer reproductive and lifestyle risk factors and IBC tumor subtypes. The tumor subtypes of IBC patients were classified as ER-positive (ER+/PR+/Her2neu-), Her2neu-positive (Her2neu+) and triple negative (ER-/PR-/Her2neu-). Results: In age-adjusted univariate analysis, body mass index (BMI), history of smoking, number of children, age at first pregnancy, breastfeeding, menopausal status, and first degree family history of breast cancer were statistically significant associated with risk of IBC (p&amp;lt;0.05). In multivariable analysis of IBC tumor subtypes, compared to cancer free controls, patients with triple negative (OR = 3.73, 95% CI = 1.52 – 9.13) and Her2neu-positive (OR = 19.27, CI = 4.14 – 89.62) tumors were significantly more likely to have ≥ 2 vs 0-1 children. Patients with triple negative (OR = 0.19, 95% CI = 0.09 – 0.45) and ER-positive (OR = 0.42, CI = 0.19 – 0.88) tumors were significantly less likely to have a history of breastfeeding. Patients with ER-positive (OR = 5.02, CI = 2.29 – 10.99) tumors were also significantly more likely to have a history of smoking. Patients with triple negative (OR = 6.07, CI = 2.62 – 17.07), ER-positive (OR = 7.22, CI = 2.94 – 17.78) and Her2neu-positive (OR = 12.81, CI = 4.59 – 35.78) were more likely to be overweight or obese (BMI ≥ 25kg/m2). Conclusion: The associations identified suggest that overweight or obese status is an important modifiable risk factor for all IBC subtypes. Triple negative IBC share similar risk factors as non-IBC triple negative tumors with increasing number of children and lack of breastfeeding associated with increased risk. Interestingly lack of breastfeeding was also associated with ER-positive IBC tumors, and Her2neu-positive IBC tumors were associated with increasing number of children; two associations that have not been previously reported. Impact: These results highlight the importance of evaluating epidemiologic risk factors of IBC, which could lead to the identification of subtype specific prevention strategies. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-12-04.

Plasmablastic Lymphoma: 28 Patient Single Institution Experience

IntroductionPlasmablastic lymphoma (PBL) is a rare, aggressive subtype of non-Hodgkin lymphoma. Published data are predominantly in the form of case reports and small retrospective case series. Initial reports of PBL were described in HIV positive patients (pts) with disease in the oral cavity, and in pts after organ transplantation on immunosuppressive therapy. The natural history may have evolved recently, with case reports of PBL in immunocompetent patients. There is no established standard of care therapy, though HIV positive pts benefit from initiation of anti-retroviral therapy, tend to respond to chemotherapy, have historically been associated with CD20 expression, and have increased overall survival rates compared with HIV negative pts with PBL. We now describe our experience in pts with PBL who received treatment at the University of Texas MD Anderson Cancer Center (UTMDACC). MethodsWe conducted a retrospective analysis of pts diagnosed with PBL between August 2000 and August 2012. We evaluated the baseline demographics, stage, therapy, response rate, progression-free survival (PFS) and overall survival (OS). Results28 pts (males n=23) with PBL were identified, with a median age of 51 (range 26-81). 10 patients had a diagnosis of HIV, and 15 were EBV positive. 7 pts had stage I disease, 2 had stage II, 1 had stage III and 18 had stage IV disease. The primary site of disease in the 7 pts with stage I disease was: 2 in the maxillary sinus, 2 in the nasal cavity, and 1 each in the colon, testicle, and lower jaw. 2 pts with stage II disease had primary sites in bowel and tonsils. 7/17 (41%) of HIV negative pts and 2/10 (20%) of HIV positive pts had stage I/II disease.The median LDH was 492 IU/L (313-618), median Ki-67 proliferation index was 85%, and all pathological samples were CD20 negative. Median follow up was 16 months (1-120). 27 pts received systemic therapy (1 pt elected hospice care). PBL was an initial cancer diagnosis for 25 pts who received the following as first line therapy: Hyper-CVAD (cyclophosphamide, vincristine, Adriamycin, dexamethasone alternating with methotrexate and cytarabine) (n=10), CHOP (cyclophosphamide, Adriamycin, vincristine, prednisone) (n=7), modified CVAD, 2 with EPOCH (etoposide, vincristine, cyclophosphamide, Adriamycin, prednisone) (n=4), bortezomib/dexamethasone (n=1), and the DeAngelis protocol (methotrexate, vincristine, procarbazine, with intrathecal methotrexate) (n=1) for CNS involvement. 2 pts had prior therapy for diagnosis of diffuse large B-cell lymphoma (DLBCL) and chronic lymphocytic leukemia (CLL) prior to diagnosis of PBL. The first pt with DLBCL was treated with Rituximab-hyper-CVAD 6 years earlier, and gemcitabine/oxaliplatin for the diagnosis of PBL. The second pt had CLL which underwent Richter's transformation to PBL, and was treated with hyper-CVXD (cyclophosphamide, vincristine, liposomal daunorubicin and dexamethasone). 1 pt underwent auto-stem cell transplant, while 8 pts received localized radiation (5 for consolidation and 3 for palliative therapy); 5/7 pts with stage I disease received consolidation with involved field radiation. After first line therapy, 20/27 patients (74%) achieved complete response, 5/27 (19%) partial response, and 2/27 (7%) stable disease. Median PFS and OS were 24.1 and 28.8 months, respectively. 5 year PFS and OS were 40% and 38%, respectively. Early stage disease (stage I or II) and younger age at diagnosis (less than 40 years old) were associated with improved survival. 5 year PFS for stage I/II pts was 90%. Conclusion41% of HIV negative pts had stage I/II disease. Early stage PBL pts who received combined chemotherapy followed by radiotherapy achieved a good PFS of 90% at 5 years. PBL consistently lacked CD20 expression irrespective of HIV status. PBL can be seen in both HIV+ and HIV– patients with overall 40% long term survival. [Display omitted] [Display omitted] Disclosures:Qazilbash:Otsuka Pharmaceuticals: Research Funding. Fanale:Seattle Genetics, Inc.: Advisory/scientific board membership and travel expenses Other, Consultancy, Honoraria, Research Funding. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Array Biopharma: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees.

Antagonizing IAPs by SMAC Mimetic Birinapant Induces Apoptosis in AML Cells Including AML Stem/Progenitor Cells Alone and in Combination With Chemotherapy in vitro and in vivo

S376 Background: Individuals with congenital Trisomy 21 (+21) have an increased risk of developing acutemyeloid leukemia (AML). AMLwith +21 has traditionally been regarded as an intermediate risk prognosis. This study focuses on the biological and clinical features of patients (pts) with +21 AML. Methods: We analyzed pts treated at University of Texas MD Anderson Cancer Center (UTMDACC) between 1995 and 2011. Only pts that presented to UTMDACC at initial diagnosis with no prior therapy were included. Four cytogenetic groups were defined: +21 alone, +21 plus favorable cytogenetics, +21 plus intermediate cytogenetics and +21 plus unfavorable cytogenetics. Time to Progression (TTP) was defined as time from diagnosis to relapse or last follow up. Survival curves were calculated using Kaplan-Meier estimates. Results: A total of 90 pts harboring +21 aberrations at diagnosis were identified. Median age was 59 years (range, 18-88), 58% were male and 72 (80%) were of white race. At diagnosis, median white cell count was 4.6 (0.6-190) x 10/L, neutrophils 14 (0-86)%, hemoglobin 8.6 (3.3-13.4) g/dL, platelets 53 (4-395) x 10/L , peripheral blasts 17% (0-96), and bone marrow blasts 48% (0-97). FAB classification: M0-2 64%, M3 1%, M4-5 20%, M6 10%, M7 4%. Cytogenetics: +21 alone 11 (12%), plus favourable 7 (8%), plus intermediate 7 (85), plus unfavourable 65 (72%). Molecular mutations: NPM1 1/25 (4%), NRAS 4/53 (7%), CKIT 0/26 (0%), FLT3 4/49 (8%). Induction regimens included: Idarubicin+AraC-based 36%, fludarabine-based 24%, clofarabine-based 11%, topotecan-based 10%, hypomethylating-based 11%, and miscellaneous 8%. Overall Response Rate was 54%. Median TTP was 11 (2-130) months. Conclusions: Pts with AML harboring +21 have unique biological and clinical features. It rarely presents as a solely aberration and mostrly associates with complex cytoenetics. Further investigation is needed to determine its specific prognostic role.