Roy, Vivek

Background: Ibrutinib (ibr) is a small-molecular inhibitor of Bruton's Tyrosine Kinase (BTK), active in the treatment of various B-cell malignancies. B-cell receptor signaling blockade by BTK inhibition using ibr down regulates IRF4 (survival transcription factor) which is down regulated by lenalidomide (R) as well, suggesting possible synergistic effect on cell death. Higher doses of ibr (560-840 mg daily) have been used in combination regimens for MM with no significant dose-limiting toxicities (DLTs) but the combination of ibr and len has not been previously tested. We present safety and preliminary efficacy of the combination ibr, R, and dexamethasone (d) in RRMM patients. Methods: This is a phase I dose escalation study (NCT03015792) of 28-day cycles of ibr (420 mg daily, 560 mg daily, 700 mg daily or 840 mg daily) days 1-28 in combination with R 25 mg PO days 1-21, and d 40 mg PO weekly utilizing a 3+3 dose-escalation design. Eligible RRMM patients had progression after ≥2 prior lines of treatment, measurable disease as per International Myeloma Working Group criteria, ECOG performance status ≤2, adequate bone marrow (BM) (absolute neutrophil count ≥1.0 x 109, platelets ≥50,000 cells/mm3 for patients with BM plasmacytosis <50% or ≥30,000 cells/mm3 for patients with BM plasmacytosis ≥50%), kidney (creatinine clearance ≥30 mL/min), and liver function [total bilirubin ≤1.5 x upper limit of normal (ULN), aspartate aminotransferase and alanine aminotransferase ≤3 x ULN], and PT/INR ≤1.5 X ULN. Treatment was to be continued till progressive disease (PD) or any unacceptable toxicity. The primary objective was to determine the maximum tolerated dose (MTD) of ibr+Rd in RRMM and secondary objective was to evaluate safety profile of this regimen. Results: As of July 26 2019, 18 patients had been enrolled in the trial. Three patients had to be replaced (2 at 700 mg cohort, 1 each due to withdrawal and ineligibility, and 1 at 840 mg due to withdrawal). Median age of all patients was 67 years (range 49-79) with 9 of the 15 evaluable patients being females. Evaluable patients as per ibr dose level included 3 at 420 mg, 3 at 560 mg, 3 at 700 mg, and 6 at 840 mg. Four out of 15 patients had high-risk cytogenetics. Median prior lines of treatment were 4 (range 2-13) and prior treatments included bortezomib in 87% (n=13), carfilzomib in 47% (n=7), ixazomib in 47% (n=7), lenalidomide in 87% (n=13), pomalidomide in 40% (n=6), thalidomide in 40% (n=6), daratumumab in 60% (n=9), and stem cell transplant in 53% (n=8). High risk cytogenetics [del 17p, t(4;14), t(14;16), t(14;20)] were noted in 4 of the 15 evaluable patients (27%). Median follow up for alive patients was 8.6 months (range 1.1-25.1 months) and the median number of treatment cycles was 2 (range 1-5). Most common reason for treatment discontinuation was PD (40%) followed by adverse events (AEs) (26.7%). Only 1 DLT possibly related to ibr was a grade 3 rash at the 840 mg dose. Grade 3/4 AEs at least possibly related to study treatment included anemia (n=3), thrombocytopenia (n=3), neutropenia (n=3), leucopenia (n=3), lymphopenia (n=2), febrile neutropenia (n=1), and rash (n=2). Overall, the most common all grade AEs included anemia (n=12), thrombocytopenia (n=10), fatigue (n=10), neutropenia (n=8), leucopenia (n=5), and diarrhea (n=5). (Figure 1) No treatment-related deaths were noted. Overall response rate (ORR) was 7% with partial response (PR) noted in 1 patient. Additionally, 1 patient achieved a minor response (MR) and 10 patients had stable disease (SD) for a clinical benefit rate (CBR) of 80%. (Figure 2) PD was noted in 1 patient and 2 patients did not get response assessment. Ibr 840 mg (daily) with R 25 mg (days 1-21) and d 40 mg weekly was considered the MTD of this regimen. The median progression-free survival (PFS) for the 15 evaluable patients was 4.5 months (95% CI: 1.8-not reached). Conclusions: We report the first phase 1 trial of combining a BTK inhibitor with Rd in RRMM patients. MTD of ibr was determined as 840 mg (daily) in combination with R 25 mg (days 1-21) and d 40 mg weekly. This dose of ibr is consistent with some other trials showing the benefit of a higher dose of ibr in various regimens for treatment of B-cell malignancies. We noted this regimen to be well-tolerated without much high-grade AEs. Disease stabilization was noted in majority of patients. These data lay the basis for a larger trial in a more uniform cohort of patients to better define the efficacy of this regimen. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy. Chanan-Khan:AbbVie: Research Funding; Xencor: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding. OffLabel Disclosure: Ibrutinib is not FDA-approved for the treatment of multiple myeloma. The regimen of ibrutinib with lenalidomide and dexamethasone is not FDA-approved for the treatment of multiple myeloma.

Background: Chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment of relapsed/refractory B-cell lymphoid malignancies. Axicabtagene ciloleucel (axi-cel), an anti-CD19 CAR-T not only targets the malignant B-cell, but can potentially also target and eliminate normal B-cells. This can interfere with the normal B-cell repertoire, compromising host humoral immunity such as decreased titers of common vaccines (DTaP, MMR). To assess if this was a clinically significant problem, we evaluated all recipients of axi-cel at our center between 6/2018 through 7/2019. Patients and methods: For patients who received commercial axi-cel, humoral immunity was evaluated both quantitatively [absolute lymphocyte count (ALC)] as well as qualitatively by serology titers [IgG antibodies (Abs)] for diphtheria, tetanus, pertussis, measles, mumps, and rubella, and total Immunoglobulin G (IgG) levels. Data was collected within 30 days prior to CAR-T infusion, then at day +30 and between days +60 and +100 after CAR-T infusion. Results: We identified 10 patients (males = 5, 50%), with a median age of 49.9 years (range 30-65) who received commercial axi-cel during the study period. Patient characteristics and indications for CAR-T therapy are shown in Table 1; the cohort represented a heavily pre-treated aggressive B-cell lymphoma patient population. Baseline information on antibody (Ab) titers was available in 8 patients. At baseline, all patients had positive tetanus IgG Abs (≥0.01 IU/mL), 7 had positive diphtheria IgG Abs (≥0.01 IU/mL), 6 had positive measles IgG Abs (≥ 1.1 AI), 5 had positive rubella IgG Abs (≥ 1.0 AI), 3 had positive mumps IgG Abs (≥ 1.1 AI). None of the patients had a positive pertussis IgG Abs (≥100 IU/mL). At follow-up, all patients with positive Ab at baseline maintained titers in the positive range at day +30 and between days +60 and +100 (Figure 1). None of the patients demonstrated a clinically meaningful decrease in Abs titers, despite a drop in ALC and IgG levels (table 2). Conclusions: Albeit a small sample size, IgG Ab titers for diphtheria, tetanus, measles, mumps, and rubella did not appear to be affected by axi-cel at a short interval follow-up after infusion (up to day +100). We plan to extend this analysis in a larger cohort with a longer-term prospective follow-up to validate our findings, especially in light of dropping absolute lymphocyte counts and IgG levels. Disclosures Ailawadhi: Celgene: Consultancy; Amgen: Consultancy, Research Funding; Cellectar: Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy; Pharmacyclics: Research Funding. Foran:Agios: Honoraria, Research Funding. Tun:Celgene: Research Funding; Curis: Research Funding; TG Therapeutics: Research Funding; Mundi-pharma: Research Funding; DTRM Biopharma: Research Funding; BMS: Research Funding. Chanan-Khan:Pharmacyclics: Research Funding; Merck: Research Funding; Jansen: Research Funding; Mayo Clinic: Employment; Ascentage: Research Funding; Millennium: Research Funding; AbbVie: Research Funding; Xencor: Research Funding. Kharfan-Dabaja:Daiichi Sankyo: Consultancy; Pharmacyclics: Consultancy.

Abstract BACKGROUND Respiratory failure syndromes are common after allogeneic hematopoietic cell transplantation (allo-HCT), and are associated with substantial morbidity and mortality. These syndromes are incompletely understood, and may be associated with histopathologic evidence of acute lung injury (ALI). The role of biopsy in this setting is controversial, with uncertain benefits and considerable procedural risk. We report the clinical, radiologic and histopathologic features of patients with biopsy-proven ALI following allo-HCT in a large multi-site retrospective series. METHODS The medical records of 1,864 consecutive adults who underwent allo-HCT at Mayo Clinic, Minnesota (n = 916), Arizona (n = 694), and Florida (n = 254) (Jan 2005-Dec 2017) were reviewed. A total of 152 patients underwent a lung biopsy: 126 bronchoscopic, 22 surgical, and 4 CT-guided biopsies (Figure 1). Patients with a histopathologic diagnosis of ALI were included in the study, and were classified into clinicopathologic subgroups per published American Thoracic Society guidelines (Am J Resp Crit Care Med, 2011). Patients whose diagnosis remained uncertain after a detailed review of the medical records were included in a separate subgroup as undifferentiated ALI. Transplant characteristics, radiologic features, pulmonary function test (PFT) results, treatments, and outcomes were compared between groups. RESULTS Clinicopathologic diagnoses in 62 patients with biopsy-proven ALI consisted of an infectious etiology in 15 (24%), cryptogenic organizing pneumonia (COP) in 15 (24%), idiopathic pneumonia syndrome (IPS) in 9 (15%), bronchiolitis obliterans syndrome (BOS) in 9 (15%), diffuse alveolar hemorrhage in 3 (5%), periengraftment respiratory distress syndrome in 2 (3%), and undifferentiated ALI in 9 (15%) patients (Figure 2). Transplant characteristics were comparable between groups. Infectious pneumonia and IPS were the most common diagnoses during the first 100 days post HCT (50% and 36%, respectively). Between 100 and 365 days, a range of diagnoses were seen including infectious pneumonia (20%), COP (23%), IPS (14%), BOS (23%), and undifferentiated ALI (20%) (Table 1). In 14/15 (93%) infectious pneumonia cases, biopsy did not change management and diagnosis was concurrently established by bronchoalveolar lavage (BAL) or non-invasive testing. Patients with IPS, BOS, and undifferentiated ALI more commonly had a pleural effusion (66%, 44%, and 44%, respectively). Nodular infiltrates were most commonly seen in patients with infectious pneumonia (55%). Other radiographic findings were not clearly discriminative. BOS and infectious pneumonia were more commonly associated with an obstructive PFT (78% and 33%, respectively), whereas restrictive pattern was more frequently seen in COP and IPS (50% and 57%, respectively) (Table 2). Despite a histopathologic diagnosis of ALI, 9 (15%) patients had clear clinical and radiographic evidence of BOS. Steroids were used commonly in noninfectious syndromes: 93% of patients with COP and in 100% of IPS patients. Of 4 patients with IPS who received Etanercept, 2 (50%) showed complete recovery, whereas the remaining 5 patients who did not receive Etanercept died from fulminant respiratory failure. Most common treatment response was complete recovery in COP (73%), fulminant respiratory failure leading to death in IPS (78%), and chronic respiratory failure in BOS (78%). Estimated OS was shortest in the group with IPS and undifferentiated ALI (median 5 and 17 mons, respectively), whereas patients with COP had the best prognosis (mOS not reached) followed by the infectious pneumonia and the BOS groups (mOS of 59 and 55 mons, respectively). Pulmonary complications were the most common cause of death in patients with non-infectious ALI. Lung biopsy was associated with post-procedural pneumothorax in 17 (27%) patients; 12 of whom required a chest tube. CONCLUSIONS In this largest case series to date of histopathologic ALI after allo-HCT, biopsy does not appear to meaningfully change management in the majority of patients, and is associated with substantial procedural risk. Histopathologic findings do not clearly correlate with the clinical and radiographic picture in a sizeable proportion of the patients. PFT results, BAL findings, the timing of the onset of respiratory failure after HCT, and the response to steroids seem to be of greater diagnostic and/or prognostic value. Disclosures No relevant conflicts of interest to declare.

Abstract Background: Multiple myeloma (MM) is characterized by the invasion of malignant plasma cells into the bone marrow. While first line treatment options result in significant clinical benefit to patients, spatiotemporal clonal evolution results in disease relapse and mortality. Advances in genomics have armed clinicians with unprecedented insight into the molecular architecture of MM cells, however, the clinical benefit derived by genomics-guided intervention has been limited. We present a novel computational biology modelling (CBM) tool, which takes into account the combined effect of individual mutations, gene copy number abnormalities and large scale chromosomal changes in order to predict the salient molecular pathways utilized by the MM cell for survival. By reverse-engineering MM cell architecture in silico, the CBM tool is able to predict drug response and resistance mechanisms. Thus, our aim was to determine the accuracy of the CBM tool in predicting treatment response of relapsed/refractory MM patients for future management of their disease, in a more individualized manner. Methods: Cytogenetics and somatic mutations (by targeted NGS) for 15 MM patients were input into the CBM model to predict responses to different therapeutic combinations. All patients were relapsed to prior treatment. CBM uses PubMed and other online resources to generate patient-specific protein network maps of activated and inactivated disease pathways. We simulated the specific combinations of the drugs per patient and measured the quantitative drug effect on a composite MM disease inhibition score (i.e., cell proliferation, viability, apoptosis and paraproteins). The actual clinical outcome of the treatments was compared with predicted outcomes. Results: Fifteen patients were analysed using CBM for prediction of treatment response after NGS was performed. 13/15 were clinically evaluable, of which 1 was a responder and 12 were non-responder. 6/13 patients were treated on clinical trial and 7/13 were on drug combinations per physician decision. CBM correctly predicted 1 responder and 11 non-responder with a PPV of 50%, NPV 100%, specificity 91.67%, sensitivity 100%. The accuracy of CBM prediction was 92.30%. CBM also predicted the response of prior drug therapies for its non-response at relapse. For prior drug treatment options, 14 patients were evaluable. All the 14 patients were clinically non-responders and CBM correctly predicted for 13 patients with NPV 100%, Specificity 92.85% and overall accuracy of 92.85%. The majority of patients did not respond to therapies recommended at relapse. As an example, the operative molecular pathways from 2 patients who did not respond to combination treatment, either pre-NGS or post-NGS profiling, are shown in Fig. 1 and Table 1. CBM identified amplification (AMP) of chromosome (chr) 1 (WNT3A, IL6R, CKS1B, MCL1, PIK3C2B, USF1), chr 3 (HES1, PIK3CA, CTNNB1, WNT7A, FANCD2), chr 5 (IL6ST, IRF1, GLRX, SKP2), chr 7 (CDK5, EZH2, IL6, CAV1, ABCB1), chr 9 (NOTCH1, HSPA5, FANCC, FANCG), chr 15 (DLL4, FANCI, ALDH1A2), chr 19 (ERCC1, ERCC2, USF2); deletion(DEL) of chr 13 (CUL4A) , chr 16 (AXIN1, CDH1) and TP53 mutation in different combinations, which confer resistance to therapies at relapse. Conclusions: The CBM technology represents a potential means to identify therapeutic options for MM patients based on the patients individual tumor-genome profile and which can also be deployed for uncovering drug resistance mechanisms. This tool may aid clinicians in decision making for recommending the most appropriate therapy based on standard of care agents or clinical trials; thus improving patient outcomes and reducing unnecessary costs or drug-related toxicities. Disclosures Singh: Cellworks Research India Private Limited: Employment. Sauban:Cellworks Research India Private Limited: Employment. Husain:Cellworks Research India Private Limited: Employment. Kumar:Cellworks Research India Private Limited: Employment. Kumari:Cellworks Research India Private Limited: Employment. Tyagi:Cellworks Research India Private Limited: Employment. Abbasi:Cell Works Group Inc.: Employment. Vali:Cell Works Group Inc.: Employment. Ailawadhi:Pharmacyclics: Research Funding; Takeda: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Janssen: Consultancy.

Abstract Background: Therapeutic advancements have led to significant improvement in outcomes for MM patients. Revised diagnostic criteria from International Myeloma Working Group focus on initiating treatment before the onset of end-organ damage. Thus, timeliness of initial therapy can significantly improve patient morbidity and outcomes. Such an analysis has not been reported for MM. Methods: We analyzed patients diagnosed with MM between 2004-2015 from the National Cancer Database (NCDB). Patients who received systemic treatment any time within the first year of diagnosis were included; those treated later than one year were considered possibly initially diagnosed with smoldering myeloma and hence, excluded. Time to initial treatment was divided into centiles with the 4 centiles analyzed being 0-7 days, 8-18 days, 19-37 days and >37 days. We performed univariate and multivariate analyses to compare sociodemographic and clinical factors influencing patient distribution across these timeliness categories and trends over time. Results: A total of 53,665 patients were included with 15,282 in 0-7 days, 12,462 in 8-18 days, 12,723 in 19-37 days and 13,198 in the >37 days treatment categories. Distribution across these centiles over time is shown in Figure. Univariate analyses showed a significant difference in distribution across the timeliness categories by year of diagnosis, patient age, gender, race/ethnicity, education level, insurance type, comorbidity score, treatment facility type, geographical location and distance to treating facility (all p<0.001) but no effect of income level. Multivariate analysis showed that there was a significantly higher likelihood of being in 4th centile (>37 days to treatment) for women (p<0.001), African Americans (p<0.001) or Hispanics (p=0.03; reference: Whites) or diagnosed in more recent years (p<0.001). Patients were less likely to be in the 4th centile if they were ≥80 years (HR 0.89, 95% CI 0.81-0.98, p=0.02), had >0 Charlson comorbidity score (p<0.001), were uninsured (p=0.02) or had Medicaid (p=0.03) as compared to having private insurance, were in non-community treatment facilities or geographical location other than Northeast (p<0.001). Patient education, income level or distance from treating facility was no longer significant. Conclusions: Several factors were found to affect timeliness of treatment in MM. We noted relatively faster time to initial treatment in elderly, uninsured or those who were treated in academic/comprehensive cancer programs but a delay in treatment for women and racial/ethnic minorities among other factors. These factors need to be addressed for equitable access and treatment practices and to realize improved outcomes for all. Figure. Figure. Disclosures Ailawadhi: Amgen: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding.

Abstract INTRODUCTION: Significant burden of pain syndromes are reported in patients with hematological malignancies undergoing HSCT mostly due to underlying disease and associated treatments. Opioid analgesics and benzodiazepines are routinely used for symptomatic management in this patient population. The use of narcotic analgesics and benzodiazepines in non-transplant hospitalized patients has been shown to adversely affect health related outcomes such as length-of-stay (LOS), falls and other complications. However, there is a significant knowledge gap regarding the patterns of opioid and benzodiazepine use and their impact on health outcomes in HSCT patients. METHODS: We identified 275 patients from the year 2015-2018 who underwent HSCT (allogeneic and autologous transplants) at our center for a variety of hematological malignancies. Opioid exposure was defined in three groups of patients 1) Opioid naïve: those did not report prior use of opioid at admission and who were not prescribed opioid during hospitalization, 2) Previous Opioid users: those who reported active use of opioid at admission and continued during hospitalization 3) New Opioid users: Patients who did not report opioid use at admission but were prescribed opioid during hospitalization. Multivariable analysis was performed to identify differences in opioid status, opioid use, benzodiazepine use, disease diagnosis, Karnofsky score, gender, age, race, and marital status with associated complications (Poisson regression), emergency department visits (Logistic Regression) and length of stay (Ordinal Logistic Regression) Figure 1 and Figure 2. RESULTS: The median age of patients was 59 (range: 25-74 ) years with slight male predominance (57%). Patients undergoing autologous transplants for multiple myeloma (MM) comprised 48% of the population. The majority (72 %) were exposed to opioid during hospitalization. Ninety two percent of the opioid naïve population (28% of the total population) underwent autologous transplant. Conversely, 36% of patients undergoing autologous transplants never received opiates during hospitalization as compared to 7% of those who received an allogeneic transplant. Median morphine milligram equivalent daily dose was 3.1 mg. Median diazepam equivalent daily dosage in patients that were opiate exposed was 2.07 milligram. Of the total transplant population, 55% received benzodiazepine concurrently with opiates during hospitalization. 76 % of the population was exposed to both opioid and benzodiazepine. Twenty five percent of those who were exposed to opioid did not receive benzodiazepines. Sixty four percent of the MM patients were exposed to opioid of which majority (59%) were previous opioid users. Of the non-MM patients undergoing HSCT, 80% were exposed to opioid of which 36% were previous opioid users and 64% were new users. A wide range of complications from neutropenic fever to death, were seen in 89% of all patients (opioid users and non-users) but all the falls occurred in patients who were on opioid medications. Autologous transplant recipients had higher odds of having a greater number of complications compared to Allogeneic transplant patients (OR 1.25, 95% CI: 1.01 - 1.55, p=0.04), as well as a reduced odds of having a medium or high length of stay (OR 0.03, 95% CI: 0.02 - 0.07). Of the opioid naïve patients, 6% presented to the ED within 30 days of discharge versus 15% of those that were exposed to opiates during hospitalization. Benzodiazepine use at admission for HSCT was associated with greater odd of presenting to ED within 30 days of discharge (OR 3.94, 95% CI: 1.55-10.04) and this was more significant in patients with MM (OR 4.08, 95% CI: 1.01-16.44). Finally, we also saw a trend towards longer stay in patients who were exposed to opioids as compared to opioid naïve (40% vs. 17%). CONCLUSION: Our study, albeit limited due to its retrospective design, is among the first to report the patterns of use and the impact of opioids and benzodiazepines in patients undergoing HSCT. Our results indicate that the use of these medications is frequent in this population and as in the non-transplant hospitalized patients and is associated with more emergency room visits post discharge, along with other potentially adverse outcomes. Disclosures Kharfan-Dabaja: Incyte Corp: Speakers Bureau; Seattle Genetics: Speakers Bureau; Alexion Pharmaceuticals: Speakers Bureau. Ailawadhi:Amgen: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy.

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: 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: 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.