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Abstract Background: DLBCL is the most common adult NHL and despite significant advancements, outcomes in ethnic minorities remain suboptimal. Factors responsible for these disparities in ethnic minorities, especially variability in clinical and pathological features with evaluation of patient-level data have not been studied. Methods: A multi-institutional database of DLBCL patients seen at Mayo Clinic in Florida, University of Miami and University of Southern California between 1996-2016 was developed. Patient demographics, clinical disease characteristics and details of DLBCL immunophenotype [CD10, MUM1, BCL6 (Han's classification), Ki 67, MYC, BCL2) were reviewed. Comparisons between Hispanic and Non-Hispanic patients were made by Chi-square, Fischer's exact and Signed rank tests, where applicable. Patients with missing data on a certain feature were not included in the statistical analysis of that specific characteristic. Results: A total of 966 DLBCL patients with 69 Hispanics and 752 non-Hispanics were identified. These included 52% males (N=36) and 48% females (N=33) in Hispanics versus 58% males (N=436) and 42% females (N=316) in Non-Hispanics (p=0.35). Median age at diagnosis was significantly lower at 61 years (range 27-89) in Hispanics versus 66 in non-Hispanics (p=0.014). Extranodal disease was seen significantly more commonly in Hispanics (74%) than in non-Hispanics (60%) (p=0.037). There was no significant difference in disease stage at presentation between the two cohorts (p=0.189) although the proportion of patients with stage III and IV disease was higher among Hispanics (80.4%) as compared to non-Hispanics (68.5%). Similarly there was no significant difference in presence of primary CNS DLBCL at diagnosis between the two groups (p=0.74). GCB phenotype per the Hans' classification was seen in 59% (N=29) in both, Hispanics and Non-Hispanics (N=241) (p=0.99). Similarly, the median ki67 index of 80% was seen in both cohorts (p=0.48). MYC was positive in 59% in Hispanics versus only 37.5% in non-Hispanics (p=0.024). BCL2 expression by itself and also combined BCL2 and MYC double expression were not significantly different between the two groups (p=0.58 and p=0.11, respectively). Median overall survival (OS) was 22.5 months in Hispanics compared 54.9 months in Non-Hispanics (p<0.0001) (Figure 1). Conclusion: Survival outcome disparities in racial and ethnic minorities have been previously reported from population-based analyses. Lack of patient-level clinical data makes these analyses hypothesis generating, but not conclusive. We confirmed some prior findings including younger age at diagnosis for Hispanics with DLBCL. We also reported greater incidence of extranodal as well as stage III or IV disease at the time of presentation among Hispanics which may contribute to poor outcomes in this population. From DLBCL pathology standpoint, we found increased expression of MYC among Hispanics but no other significant immunohistochemical differences including double expression or non-GCB phenotype. The inferior OS despite uniform treatment practices at large Cancer Centers suggest multifactorial influences on patient outcomes which may at least in part include some of the differences we report here. Disclosures Ailawadhi: Pharmacyclics: Research Funding; Janssen: Consultancy; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy.

Abstract Background Outcomes for patients with chronic myeloid leukemia (CML) have improved in recent years. Nonetheless, survival disparities persist between various patient subgroups. There have been limited reports of ethnic variations in CML outcomes, with limited data on ethnic minorities (Hispanics and Asians), who are the fastest growing ethnic subgroups in the Unites States. We undertook a large Surveillance Epidemiology and End Results (SEER) based analysis to describe outcome disparities in different subgroups of CML patients, with a specific focus on various ethnicities. Methods SEER 17 Registry data (1973-2010) was utilized. Adult (>18 years) patients with confirmed diagnosis of CML were eligible. To avoid bias of under representation by ethnic minorities, analysis was restricted to patients with a diagnosis date of 1992 or later (SEER expansion). Cases that received a diagnosis at death certificate/autopsy, no follow-up records, or lacking age at diagnosis, sex, or race/ethnicity documentation were excluded. Cox proportional hazards models, adjusted for confounding variables, were used to evaluate association between patient characteristics and overall survival (OS). All statistical tests were two-sided with a significance level of 0.05, utilizing the SAS software (v9.2). Results The final analysis included 10,356 CML patients (5,943 males; 57.4%, 4,413 females; 42.6%). Age group cohorts included: 18-44 years (2,592; 25%), 45-54 years (1,706; 16.5%), 55-64 years (1,817; 17.6%), 65-74 years (1,876; 18.1%), and ≥75 years (2,365; 22.8%). Patients were stratified by race/ethnicity: White (7,292; 70.4%), African-American (AA) (1,143; 11%), Hispanic (1,163; 11.2%), Asian (697; 6.7%), and Native American (61; 0.6%). For survival analysis, Native Americans were excluded due to their small numbers. Patients were also stratified based on year of diagnosis (1992-1999, 2000-2004 and 2005-2010) to study the impact of evolving therapeutics on CML outcomes. Median age at diagnosis was significantly different among ethnicities (p<0.001) with Hispanics the youngest (47 years) and Whites the oldest (63 years) (Figure 1). There were more Hispanic and AA CML patients reported in recent years in the database than those in 1992-1999 or 2000-2004 (p<0.001). Survival analysis revealed that for all patients, females had a significantly better median OS than males (7.8 years vs. 6.4 years; p<0.001). Among the different age cohorts, median OS got progressively worse with increasing age at diagnosis (p<0.001), with a median OS of 15+ years in 18-44 year cohort vs. 2.3 years in patients ≥75 years. Patients diagnosed more recently had a better median OS (1992-1999: 4.5 years vs. 2000-2004: 7.7 years vs. 2005-2010: 9.8 years; p<0.001). AA had the worst median OS among all ethnicities, which was significantly worse than Whites (reference) (5.8 years vs. 7.4 years; p<0.001). Asians had a median OS of 6.4 years and Hispanics 6 years. In a multivariate model using race, age at diagnosis, year of diagnosis, sex and marital status, a significant interaction was noted between year of diagnosis and race, with all racial subgroups showing improvement in 5-year survival in more recent time periods (p=0.001) (Figure 2). A significant interaction was also noted between year of diagnosis and age, with a progressive improvement in 5-year survival noted across all age groups in more recent years (p<0.001) (Figure 3). Conclusions We present a population-based study of outcomes in CML with the largest representation of ethnic minorities reported so far. We noted a higher number of AA and Hispanic patients reported to the SEER database in recent years. Hispanic patients had a significantly younger age at diagnosis, which could mean longer treatment duration over the lifetime of a patient. AA patients had the worst median OS among all ethnicities, although all ethnicities and age groups were noted to have progressive improvement in outcomes in more recent years of diagnosis. The incremental benefit in outcomes was seen most for Asians and least for Whites. These results will help in better understanding of ethnic influences on disease biology and clinical behavior as well as optimal triaging of healthcare resources. Disclosures: Off Label Use: The abstract shows scientific information on SAR245409 which is an investigational product developed by Sanofi. This investigational product is not approved by any health authority for any indication.

Abstract Background: Racial disparities in outcomes of cancer patients have been reported. Access to comprehensive cancer centers is associated with improved overall survival (OS) but racial/ethnic minorities may have a disparate access to such care. While the impact of treatment facility volume on outcomes has been evaluated, outcomes of centers with minority-predominant patient population have not been studied. We compared demographic profiles, facility level data and OS of patients treated at minority-predominant facilities to facilities that treated predominantly non-Hispanic Whites (NHW) with non-DLBCL. Methods: The National Cancer Database (NCDB) was used to identify all non-DLBCL patients diagnosed between 2004 and 2015. "Minority-treating facilities" were defined as facilities in the top decile by proportion for initial treatment of non-Hispanic African-Americans (NHAA), Hispanics and other races. We performed univariate and multivariate analyses to compare sociodemographic and clinical factors influencing outcomes between minority treating and non-minority treating facilities. A subgroup analysis stratified by race/ethnicity was also conducted to study the effect of treating facilities on the outcome of NHWs and minorities separately. Results: Of 1339 total facilities, 123 (9.1%) qualified as minority treating. Of 207,239 eligible patients in NCDB, 18,719 (9.03%) received treatment at the minority-treating facilities and of these, 11,190 (~60%) belonged to the minority races. Overall, 4.5% (6,988/156,664) NHWs and 30% (11,190/37,639) minorities received treatment at the minority-treating facilities. Several demographic and facility level characteristics were significantly different among the patients treated at minority-treating facilities as compared to non-minority treating facilities. Overall, significantly higher number of patients in minority-treating hospitals had lower income and education, had Medicaid coverage or lack of insurance. The OS of patients in minority treating facilities was significantly worse as compared to non-minority facilities (Figures). On multivariate analysis, patients who received treatment at minority-treating facilities were at 10% (HR=1.10, 95% CI: 1.06-1.14 p<0.001) higher risk of mortality as compared to those treated at the non-minority treating facilities. On multivariate analysis, NHAA (30% increased risk) and 'other races' (9% increased risk) were at significantly higher risk of mortality as compared to the NHW (Table 2). To study the effect of treatment at minority-treating facilities on OS among the patients of same race/ethnicity group, a multivariate analysis was also run separately for NHW and racial minorities. The NHWs who received treatment at minority-treating facilities were at 13% higher risk of death (HR=1.13, 95% CI: 1.08-1.19 p<0.001) as compared to NHWs who were treated at non-minority treating facilities. Similarly, the racial minorities who received treatment at minority treating facilities were at 8% higher risk of death (HR=1.08, 95% CI: 1.03-1.19 p=0.003) as compared to those who received treatment at the nonminority treating facilities. Conclusions:Outcomes of patients who received treatment at minority treating facilities was significantly worse than those at non-minority treating facilities. This was true for NHWs and racial minorities separately as well. Several demographic and facility level characteristics were significantly different in the two groups however OS remained worse after adjusting for them. Causes of poor outcomes at minority-treating facilities must be analyzed to mitigate them and improve outcomes for all. Figure. Figure. Disclosures Ailawadhi: Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Research Funding.

Abstract Background Familial myeloid neoplasms are rare causes of myeloid malignancies. Over the last few years germline mutations involving RUNX1, JAK2, GATA1, GATA2 and CEBPA genes have been associated with myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). We carried out this study to describe the spectrum of familial myeloid neoplasms seen at our institution. Methods After due IRB approval, the myeloid neoplasms data base (1990-2012) at the Mayo Clinic in Minnesota was queried for patients presenting with, or having a strong family history of myeloid neoplasms. Selective sequencing of germline DNA was done in appropriate patients. Germline mutations that were screened for included; RUNX1, JAK2, GATA1, GATA2 and CEBPA. In one family with none of the aforementioned gene mutations, exome sequencing was performed. Families with chromosomal breakage and primary telomere disorders were excluded. All patients had bone marrow and cytogenetic studies at diagnosis. Results We identified six families with familial myeloid neoplasms (table one). There were two with germline GATA2 mutations (no.1 and 2); one with a novel c1339A>C, pS447R, non-zinc finger gene abnormality. In this family nine members have developed MDS/AML. All members had profound B/NK cell deficiency, viral warts and one member had primary lymphedema (Embergers syndrome). Three of the 6 seen at the clinic have successfully undergone allo- SCT. The second GATA2 mutated family had a less extensive history of myeloid neoplasms. There was one patient (no.5) who presented with long standing thrombocytopenia, clinically diagnosed as ITP. She eventually developed MDS with trisomy 8. She had three first degree relatives with myeloid neoplasms. Germline sequencing identified a RUNX1 mutation. Platelet electron microscopy identified characteristic ultrastructural changes. There was one family (no.4) with a germline JAK2V617F mutation. The propositus was diagnosed to have primary myelofibrosis and then demonstrated clonal evolution to a concomitant BCR-ABL1 p190 driven chronic myeloid leukemia. His sister and mother have essential thrombocytosis (ET) and his brother has a detectable JAK2 mutation (no evidence for disease). The patient has successfully undergone an allo-SCT. The patient with a GATA1 mutation (no.3) presented with congenital anemia and had craniofacial anomaly, atrial septal defect and developmental delays. Red cell and platelet ultrastructural abnormalities lead to the diagnosis with an additional family member having chronic anemia and suspected MDS. One family (no.6) presented with seven first degree relatives affected by MDS/AML. Germline sequencing for the aforementioned genes was negative. Exome sequencing has been performed and results should be available at the time of the meeting. The prepositus has successfully undergone allo-SCT. Conclusion Familial myeloid neoplasms are uncommon but warrant early recognition. Clues to diagnosis include strong family history, associated primary immunodeficiency states, morphological/skeletal abnormalities and platelet ultrastructural defects (RUNX1, GATA2, and GATA1). Exome and whole genome sequencing is an exciting prospect for further discoveries. Disclosures: No relevant conflicts of interest to declare.

Abstract Background: The treatment of NHL has witnessed a paradigm shift over time, with targeted immunotherapy, stem cell transplant (SCT) among others. Historically, XRT was used quite frequently for the management of NHL but with advent of better systemic therapy, its utilization has changed. Trends and patterns of care for XRT use have never been formally reported. Methods: We identified patients with NHL diagnosis in the National Cancer Database (NCDB) between years 2004 and 2015. Demographic, clinical, facility level, initial treatment and outcome data were collected. The utilization of XRT in diffuse large B-cell (DLBCL) and non-DLBCL NHL were analyzed separately by univariate and multivariate analyses. To analyze the trends in the rates of XRT, we applied segmented linear regression to calculate the average annual percent change (AAPC) and 95% confidence Interval (CI) with a 'p' value. AAPC and CIs were calculated using the segmented package in R studio v1.1.49. Rest of the analyses was conducted using StataCorp version 15.1. Results: A total of 133,182 DLBCL and 204,933 non-DLBCL patients were identified. Among patients with DLBCL, 27,895 (20.9%) patients received RT. The rate of XRT declined from 25% in 2004 to 18.4% in 2015 with estimated AAPC of -0.59% (95%CI: -0.70- -0.49), p= 0.03 (Figure 1). In a subgroup analysis, a similar decline in the rate of XRT was evident across all the age groups, combined stages I and II vs stages III and IV and nodal vs extra nodal DLBCL (Table 1). Among non DLBCL, 33,369 (16.3%) patients received XRT. There was a statistically significant decline in the rate of XRT from 18.03% in 2004 to 16.3% in 2014 with an AAPC of -0.26 (95%CI: -0.38- -0.14) p <0.001 (Figure 1). On the subgroup analysis, the utilization of XRT declined across all the studied subgroups except among patients aged 80 years and above (Table 1). On multivariate analysis, several demographic, clinical and facility level factors were found to be significantly associated with XRT utilization in NHL (Table 2). In particular, older age groups, racial/ethnic minorities, advanced stages, higher Charlson comorbidity scores and diagnosis in the more recent calendar years were associated with lesser chances of receiving RT. Extranodal DLBCL had lower utilization while extranodal non-DLBCL had increased XRT utilization. Conclusion: There has been a significant decline in the utilization of XRT among patients with NHL (DLBCL and non-DLBCL) in the US since 2004, likely due to introduction of practice changing systemic therapeutics. There is still significant heterogeneity noted in practice patterns regarding utilization of XRT across the US. Having more standardized guidelines will help streamline delivery of evidence-based patient care. Disclosures Ailawadhi: Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding.

Background The ubiquitin proteasome system (UPS) maintains homeostasis in eukaryotic cells by degrading and recycling proteins associated with DNA transcription and cell cycle regulation. In tumor cells with a high protein turnover rate, particularly in immunoglobulin secreting cancers such as Waldenströms Macroglobulinemia (WM), proteasomes are critical for sustained cell proliferation. Proteasome inhibitors (PI) such as bortezomib and carfilzomib target the B5 subunit of the proteasome catalytic core and disrupt its activity leading to accumulation of polyubiquitinated proteins. Although highly effective in WM, persistent use of bortezomib eventually leads to emergence of a bortezomib resistant (BR) subclone. Point mutation in the PSMB5 gene (encoding the B5 subunit) leading to altered binding kinetics is identified as a potential underlying mechanism of PI resistance. Despite these adaptive modifications that support resistance to PI resistance, the UPS as a whole remains a relevant target with vulnerable sites that can be therapeutically exploited. The 19S cap of the proteasome contains deubiquitinating enzymes (DUBS) that function to deubiquitinate proteins prior to their entry into the proteasomal core. Using a novel DUB-inhibitor b-AP15, which blocks the UCHL5 and USP14 DUBS, D’Arcy et al demonstrated that disruption of these DUBS does not alter proteasomal activity yet induces robust tumor cell death in various cancers. Aim Investigation of b-AP15 in preclinical models of BR WM and characterization of associated downstream signaling interactions. Methods For these studies, we developed and used BR variants of the most commonly used WM cell lines (variants termed BCWM.1/BR, RPCI-WM1/BR and MWCL-1/BR). Proteasomal activity was measured in these cells using synthetic fluorogenic peptide substrates and apoptosis was measured by annexin-v/PI staining. For gene expression profiling (GEP), the Nanostring nCounter mRNA quantification assay was utilized. Results We treated all BR WM clones with either single agent bortezomib (10nM), carfilzomib (10nM), b-AP15 (100nM) or all three agents in combination and assessed their effect on chymotrypsin-like, caspase-like and trypsin-like proteasomal activity. b-AP15, either alone or in combination with the other PI, did not alter proteasomal activity, nor did it abrogate the inhibition of chymotrypsin-like activity of other PI. Although proteasomal activity was not disrupted, we observed an increase in high molecular weight ubiquitinated proteins on immunoblot analysis. We hypothesized that despite the BR cells resistance to B5-targeting PI, they would remain sensitive to UPS inhibition if targeted through DUB inhibition. We treated BR cells with b-AP15 at concentrations ranging from 50nM - 1.25uM and observed that b-AP15 induced robust WM cell death in a dose and time dependent manner. Apoptosis was more pronounced in MWCL-1/BR cells and optimal cell death (55%) was observed at 500nM; however a commitment towards cellular demise was evident by PARP-1 and caspase cleavage as early as 3 hrs. Use of a pan-caspase inhibitor resulted in rescuing of the BR WM cells from b-AP15 mediated death and demonstrated a caspase-dependent death process. In order to gain further mechanistic insight into the processes that regulates response to b-AP15, we performed GEP and immunoblot of BR WM cells treated with 50nM of b-AP15. We observed an increase in phospho-p38 protein, which belongs to the MAPK family and regulates IL8 secretion. When BR WM cells were treated with a p38 inhibitor in combination with b-AP15, a significant decrease in cell viability was noted relative to b-AP15 (100nM) alone. Furthermore, GEP and network analysis identified key regulator genes associated with p53, cell cycle and MAPK signaling. Summary We provide first evidence that inhibition of the DUBS, UCHL5 and USP14 with b-AP15 results in caspase-dependent apoptosis of BR WM cells. Our investigation uncovers important molecular interactions that may dictate the BR cells responsiveness to DUB-inhibition by b-AP15. These observations validate the pervasive role of the UPS and confirm alternate therapeutics targets using our unique BR WM models. We are grateful to the Waterfall Waldenström Macroglobulinemia Research Fund, the Leukemia and Lymphoma Society and the International Waldenström Macroglobulinemia Foundation for their continued support. Disclosures: Martin: Teva: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Speakers Bureau; Millennium: Research Funding; Seattle Genetics: Consultancy, Speakers Bureau.

Abstract Background: CLL is the most common leukemia diagnosis in adults and its treatment has undergone significant change from chemotherapy, to immunotherapy and now targeted kinase inhibitors, leading to improved overall survival (OS). With improving survivorship, SPMs can occur but an in-depth analysis of risks and trends of SPMs in CLL survivors is lacking. We performed a population-based analysis to evaluate this. Methods: Patients in the Surveillance, Epidemiology and End Results (SEER) database diagnosed with CLL between 1973-2015 were included. Due to variation in management techniques over time, the cohort was divided in four time periods: 1973-1982, 1983-1992, 1993-2002 and 2003-2015. We evaluated differences in risk for SPMs among CLL survivors compared to risk of individual malignancies expected in the general population during these time periods and studied the effect of demographics and time since CLL diagnosis. Results: Over a nearly 270,000 person-year follow up, 6,467 new SPMs were diagnosed with a standardized incidence ratio (SIR) of 1.2 (95% CI 1.17-1.23), which resulted in a 39 excess cancers per 10,000 population. The CLL survivors had a 20% overall increased risk of developing SPMs (excluding non-squamous skin cancer) compared to the general population. The risks for both solid (SIR 1.15 CI 95% 1.12-1.18) and hematological malignancies (SIR 1.61 95% CI 1.5-1.73) was higher than the expected in the general population. However, the risk for individual cancers was heterogeneous. The tumors associated with the highest risk were Hodgkin lymphoma (almost 8 times higher), Kaposi Sarcoma (4 times), non-epithelial skin cancers (4 times), salivary gland cancer (3 times) and acute lymphocytic leukemia (3 times). In contrast, tumors in the hepatobiliary system, female breast and female genital system were associated with a lower risk than the general population. The highest SIR across the study periods was observed in the younger population (ages 15-49). Although the risk increased in all ethnicities, it was statistically significant only in Caucasians. There was no gender-wise difference in SIR during any of the four time periods. A statistically significant increase in SIR was observed for both men and women from 1973-1982 to 2003-2015. This was mostly due to an increase in risk of hematological malignancies from 1.08 early in the study to 2.56 in the most recent study period. The SIR in solid tumors did not change significantly over time; in absolute terms, however, lung carcinoma contributed the most to the excess risk, followed by non-epithelial skin cancers and non-Hodgkin's lymphoma. The risk of developing a SPM was higher for the CLL survivors during most of the latency periods, but it was statistically significant during the 2-5 months and 12-59 months after diagnosis. A multivariate analysis was conducted to evaluate the impact of period of diagnosis on the development of SPMs among these patients. After adjusting for gender, ethnicity, radiation therapy, chemotherapy, and age at diagnosis of CLL, patients diagnosed with CLL in the most recent time period were at 45% higher risk of developing SPMs as compared to the patient diagnosed during 1973-1982 (Hazard ratio(HR) =1.45 95%CI:1.34-1.6, p<0.001). Moreover increased HRs were also observed for 1983-1992 and 1993-2002 time periods (Fig. 1) Conclusions: With improving therapeutics for cancer treatment, survivorship is improving as well and the risk of SPMs needs to be better understood and addressed. This is truer for CLL, where majority of patients have a favorable survival. The risk of SPMs was 20% higher in CLL survivors than in the general population and was most prominent in the survivors aged 15-49 years at the time of CLL diagnosis. The risk of individual malignancies may be heterogenous but there has been an increase in risk of SPMs over time, mainly due to an increase of secondary hematological malignancies in recent years. Active survivorship plans and long-term surveillance for SPMs is crucial for improved outcomes of patients with a history of CLL. Disclosures Ailawadhi: Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding.

Abstract Background Waldenstršms macroglobulinemia (WM) is a rare and incurable indolent Non-Hodgkin's lymphoplasmacytic lymphoma. Rarity and limited availability of authentic preclinical models has been a major constraint in drug development for WM. We recently reported the establishment and characterization of a novel human WM cell line, RPCI-WM1. Thereafter we evaluated the tumorigenic potential of this unique WM cell line in a xenograft mouse model along with its ability to produce human IgM in vivo. Moreover, we assessed its potential as a possible model for enhanced understanding of WM cell biology in vivo and a mechanism to conduct functional studies and preclinical anti-WM drug evaluation. Aim The primary goal of this experiment was to develop and validate an in vivo WM model that can be used to investigate WM cell biology as well as drug evaluation. Methods The RPCI-WM1 cell line (1x106 cells) was injected both subcutaneously and via tail vein into female SCID mice. Engraftment was validated via detection of human IgM (ELISA) and tumor growth (as well as response to therapy) was monitored by weekly assessment of IgM levels and external tumor formation measurements. Results After subcutaneous injection (flank) into mice, the RPCI-WM1 cells developed localized tumors that secreted human IgM detectable in serum as early as 14 days. Progressive increase in IgM was measured in the serum and this corresponded with tumor growth in a time-dependent fashion. On average, tumor tissues grew to a median of 3 cm and IgM levels reached a median of 823 ng/mL by Day 30 post-implantation. We also assessed the practical utility of this xenograft mouse model for evaluation of therapeutics, using a compound X (propriety drug with demonstrable in vitro anti-WM effects). Eleven days post-implantation, the mice were randomized into 3 groups receiving either DMSO (n=6), 100 mg of compound X (n=7) or 200 mg/kg of compound X (n=7) every alternate day via intraperitoneal injection for 26 days. On Day 37, mice were sacrificed and tumor volume was measured. We observed a 48% reduction in tumor volume in the 100mg/kg cohort, with no additional anti-WM benefit noted in the 200mg/kg cohort. Human IgM secreted by the xenografted tumors was measured by ELISA and was significantly lower in mice treated with compound X versus the control group (Figure 1). We also conducted immunohistochemistry (IHC) analysis on tumor tissues obtained from 9 mice treated with compound X (both dose cohorts) or DMSO alone. IHC staining demonstrated changes in the known target proteins of compound X (such as BCL2, p53, Ki-67) between the treated and untreated mice. Summary Thus we demonstrate that the RPCI-WM1 cell line can be dependably used to induce tumor growth through xenotransplantation in SCID mice and this mimics the IgM secreting clinical disease model. This can then be used to serve as a platform for preclinical testing of novel anti-WM therapeutics and allow for subsequent correlative studies for pharmacodynamics purpose. Comprehensive data regarding this model its utility in evaluation of various biological questions such as those relevant to the tumor microenvironment as well therapeutic modeling will be presented. We are grateful to the Leukemia and Lymphoma Society and the International Waldenstršm Macroglobulinemia Foundation for their continued support. Disclosures: No relevant conflicts of interest to declare.

Abstract Introduction: Monoclonal gammopathy (MG) is a spectrum of conditions including monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM). MM is the second most common hematologic malignancy. Despite advances in the treatment of MM it remains an incurable disease that accounts for > 80 000 deaths annually worldwide. Many etiologies for myelomagenesis have been postulated. One theory suggests that chronic antigen stimulation from rheumatologic conditions can increase the risk of MG. Numerous studies have reported an increased risk of MG and other lymphoproliferative disorders in patients with systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). However, the association between rheumatoid arthritis (RA) and MG is controversial as conflicting results have been reported. Case control studies have described an increased risk of RA but this finding was not corroborated in a subsequent meta-analysis. We used the national inpatient sample (NIS) database to explore the association of RA with MGUS and MM. Methods: The NIS is a validated database derived from discharge billing information which provides a sample of all non-federal hospital discharges in the Unites States. We identified adult patients with discharge diagnosis codes for MGUS (ICD-9 273.1), MM (ICD-9 203.0), RA (ICD-9 714.0), SLE (ICD-9 710.0) and SS (ICD-9 710.2) from 2014. Demographic data such as age, sex and race were also obtained. Multiple logistic regressions were used to analyze data for association of RA with MGUS and MM after adjusting for age, gender, race and other rheumatic diseases. Statistical analysis was performed with STATA 14. Results: A total of 7,071,762 discharges were analyzed. There were 20,066 hospitalized adults with discharge diagnosis codes for MM and 6,433 patients with a discharge diagnosis of MGUS. The prevalence of RA in patients with MGUS is 5.1% (p<0.001) and the prevalence of RA in patients with MM is 1.6 % (p=0.92). By logistic regression MGUS was associated with RA (OR 2.04, CI 1.80 - 2.32, p<0.0001) when adjusted for age, gender, race, SLE and SS. However, logistic regression did not show a significant association between MM and RA when adjusted for the same variables (OR 1.05, CI 0.95-1.15, p=0.23). MGUS was significantly associated with SS (OR 4.4, CI 3.29-5.90, p<0.001) and SLE (OR 1.9, CI 1.44-2.43, p<0.001) when adjusted for variables. Discussion: Our review of the NIS database found a significant association between rheumatologic disorders (RA, SLE and SS) and MGUS. These results are in concordance with previous retrospective studies. However, we did not find a significant relationship between RA and MM. There is known to be a high prevalence of MGUS in the general population, the clinical significance of which is being debated. The association between RA and MGUS that our study found may be due to a selection bias as patients with rheumatic conditions such as RA are tested more frequently for MGUS than the general population. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Clinical trials are fundamental to advance therapeutics systematically and improve patient outcomes. Despite this, enrollment on clinical trials remains dismal in the United States (US) and is a constant focus of healthcare policy. We studied distribution of clinical trials for B-cell malignancies over time across the US and unique clinical trial opportunities i.e. individual clinical trials for the given diagnosis at a site that patients may have access to participate. Methods: We abstracted data from clinicaltrials.gov for all trials that had non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) as an inclusion indication between 1999-2018. Clinical trial characteristics and distribution over US geographical divisions (West, Midwest, Northeast, and South) were studied, and differences were assessed by Chi-square test. Results: A total of 1930 trials were identified (NHL: 982, MM: 948), of which 483 were recruiting at the time of data abstraction (NHL: 250, MM: 233). Over the past 2 decades, 182691 patients were enrolled on the various trials (NHL: 81592, MM: 101099). Trials by phase of study included phase 1: 629, phase 1/2: 316, phase 2: 813, phase 2/3: 11 and phase 3: 161. Number of trials by phase separated by NHL and MM are shown in Figure 1. Of these, 197 trials were randomized (NHL: 67, MM: 130). Geographical distribution of trials by diagnosis type is shown in Figure 2. A total of 31806 unique trial opportunities were noted for MM and NHL, of which 9,513 were international and 22,293 were in the US, with a geographical distribution of 5080 in West, 8198 in Midwest, 3944 in Northeast, and 5071 in South. 4,883 of the unique trial opportunities were available at NCI/NCCN accredited sites and 17,410 were at non-NCI/NCCN sites in the US. Treatment characteristics of the trials included monoclonal antibodies in 1218, other targeted agents in 2641, stem cell transplant in 526, and other agents in 517 trials with several trials utilizing more than one of these therapeutic options. There was no statistically significant difference in the distribution of clinical trials by phase of study across various US geographical regions for MM (p=0.71), NHL (p=0.98) or combined MM+NHL (p=0.16). On the other hand, unique trial opportunities were significantly different by study phase and geographical distribution for MM, NHL or MM+NHL (all p<0.001) (Figure 3). Conclusions: Widespread access to clinical trials within a cancer diagnosis is imperative for generalizability of trial results. In a comprehensive, national analysis we noted that while it may appear that clinical trials are available across the US, sites where they are open are distributed unevenly, giving rise to a disparity in access to evidence-based therapeutic advancements for patients. Disclosures Ailawadhi: Janssen: Consultancy; Amgen: Consultancy; Pharmacyclics: Research Funding; Takeda: Consultancy; Celgene: Consultancy. Sher:Affimed: Research Funding.