Citations

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 INTRODUCTION: Treatment of chronic lymphocytic leukemia (CLL) has expanded significantly with the approval of multiple small molecule inhibitors. This is of great significance for patients with adverse cytogenetic features who tend to respond poorly to standard chemo-immunotherapy (CIT). While single agent ibrutinib and venetoclax (V) have shown high rates of overall response, complete remission and minimal residual disease (MRD) eradication rates remain low. This argues for further testing and development of various combination strategies. The MURANO trial compared venetoclax and rituximab (VR) versus bendamustine and rituximab (BR) in patients with relapsed/refractory CLL reporting clear superiority of VR over BR. MRD rates in the bone marrow were reported to be 27.3% for VR versus 1.5% for BR. Given much higher rates of MRD eradication with combination of small molecule inhibitors and monoclonal antibodies (mAb) compared to standard CIT, we performed a comparative investigation into the direct and immune-mediated cytolytic effects of VR versus V + Obinutuzumab (O, type II anti-CD20 mAb) in primary CLL cells and B-lymphoid cell lines. METHODS: CD19+ B-cells were isolated from PBMCs of CLL patients (N=3). For all experiments using primary CLL cells, concentration of VR and VO was 3nM (V) and 10ug /ml (R, O), respectively. For cell lines, VR and VO was used at 5uM (V) and 10ug /ml (R, O), respectively. Apoptosis was determined by annexin-V/PI staining followed by flow cytometry. Antibody-dependent cell-mediated cytotoxicity (ADCC) induced by VR and VO was assessed in Calcein AM labeled CLL cells or cell lines co-cultured with healthy donor PBMCs (E:T ratio, 40:1); complement-dependent cytotoxicity (CDC) was measured using 10% serum from a healthy human donor. RESULTS: We assessed the ability of V+/-O or V+/-R to induce apoptotic cell death in the CD20+ BCWM.1 cell line (Waldenström's macroglobulinemia [WM] phenotype) and the MEC-1 cell line (B-PLL phenotype); with CD20- RPCI-WM1 (WM cells, negative control). Notably, Bcl-2 protein is expressed in all the aforementioned cell lines. We observed that single agent V, O and R induced ~30%, 61% and 13.64% annexin V/PI positivity in BCWM.1 cells, respectively. However, a significant degree of cell death was noted in VO-treated cells (~74%) compared to VR-treated cells (~40%) (p<0.01). Next, we examined for apoptosis in MEC1 cells and noted a similar trend; where the VO combination induced markedly more cell death (~71%) than VR (~57%). Contrastingly, in RPCI-WM1 cells neither single agent O or R could elicit >12% annexin V/PI positivity and where the addition of V increased apoptosis by only 3 - 4%. We also examined the apoptotic potential of VO or VR in tumor cells from low, intermediate and high-risk CLL patients. In low and intermediate-risk CLL cells from low and intermediate-risk patients, V alone induced ~30% cell death, which increased significantly with the addition of O (VO) to between 48 - 52%. Contrastingly, the combination of VR did not induce more than 29 - 32% apoptosis. In CLL cells from high-risk patient, we noted that exposure to single agent V induced ~ 28% cell death and in VO-treated cells, this number increased to 47%. We also examined for ADCC and CDC in the same cell lines and primary CLL cells. Despite considerable variability, single agent O and VO treatment of tumor cells resulted in greater ADCC than VR treatment. By contrast, in single agent R or VR-treated cells, more CDC was observed. CONCLUSION: Our preliminary investigation in VR- and VO-treated cell lines and primary CLL cells suggests the VO combination may be superior to VR in induction of direct tumor cell death. Mechanistic experiments underway will provide further insight and can aid in design of future VO-based clinical studies in CLL. Disclosures Ailawadhi: Pharmacyclics: Research Funding; Takeda: Consultancy; Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy.

Abstract Background : Treatment for relapsed multiple myeloma (MM) has evolved with the availability of many novel agents; outcomes in patients with newly diagnosed MM have improved with IMiD® agents (lenalidomide [R] or pomalidomide) and proteasome inhibitor (PI) use. Regardless of autologous stem cell transplant, many patients receive R maintenance therapy (Jagannath, Blood Adv 2018; Palumbo, N Engl J Med 2012). However, there is a lack of data describing the nature of relapse and treatment choices for patients progressing on R maintenance therapy. Recent phase III data do not evaluate these patients who are relapsed or refractory to R; current treatment guidelines do not specifically recommend second-line (2L) treatment options for these patients (Laubach, Leukemia 2016). However, phase III data show that pomalidomide in combination with bortezomib and dexamethasone improves progression-free survival (PFS) (HR 0.54; P = 0.0027) in R-exposed and refractory patients, including those with 1 prior line (Richardson, J Clin Oncol 2018). The Connect MM Registry is a US, multicenter, prospective observational cohort study designed to examine diagnostic and treatment patterns, clinical outcomes and quality of life in patients with MM. For patients who received R maintenance therapy, we describe patterns of relapse, 2L treatment choice, and outcomes. Methods : From 250 sites, transplant eligible and ineligible adult patients ≤ 60 days from MM diagnosis were enrolled (N = 3011). Patients were treated at physicians' discretion and followed up for treatment and outcomes until early discontinuation or study end. Patients who relapsed during R maintenance therapy (≤ 15 mg; assessed by treating physician), were analyzed for baseline (BL) characteristics, nature of relapse, and 2L treatment. Patients with symptoms at time of relapse were defined as the presence of ≥ 1 CRAB (hyperCalcemia, Renal failure, Anemia, and Bone disease) criterion ± 60 d from PD; absence of CRAB criteria at PD in this window was considered nonsymptomatic relapse. Primary endpoint was PFS from start of 2L; safety (serious adverse events; SAE) from start of 2L was also assessed. Logistic regression analyses on all BL factors and factors before start of 2L treatment were performed to determine covariates differentiating comparator groups. Survival outcomes were analyzed using a Cox regression after adjusting for covariates. Results : Data cutoff: 1/15/18. Of 2938 treated patients, 1102 entered 2L, 236 having received R maintenance therapy in 1L. Of those patients, 52% (n = 123) and 47% (n = 112) experienced symptoms at time of relapse and nonsymptomatic relapse, respectively (data not available for 1 patient). The top ten 2L regimens are presented in the Table. Median duration of prior maintenance therapy (367 d [IQR: 577] vs 489 d [IQR: 599]) and time from first progression to start of 2L treatment (0.3 vs 0.3 mo) did not notably differ between nature of relapse groups. Prolonged median PFS from start of 2L was observed for patients receiving triplet+ (≥ 3 agents) vs doublet (≤ 2 agents) regimens (HR: 0.72; Figure 1). PFS was better for IMiD agent + PI group compared with PI (without IMiD agents) group (HR, 0.68; Figure 2). Results of sensitivity analyses and overall survival will be presented. SAEs occurred similarly among treatment groups: 42.6% with IMiD agent + PI, 34.5% with IMiD agent (without PI), and 35.8% with PI. Conclusions: This is the first description of relapse patterns, 2L treatment choice and survival outcomes after PD on R maintenance therapy in community-based patients. Nearly equal numbers of patients had symptoms at time of relapse and nonsymptomatic relapse on R maintenance therapy. After PD on R maintenance, approximately 50% of patients switched to PI regimens without IMiD agents, 25% continued with IMiD agent + PI regimens, and 25% continued in the IMiD agents group. Our data show PFS benefit for triplet+ over doublet treatment in 2L. Patients in the IMiD agent + PI group gained survival benefits over patients in the PI group. Further characterization of the patients continuing with IMiD treatment in 2L after R maintenance therapy relapse (~ 25% of patients) are ongoing. Follow-up with recently approved agents (elotuzumab, daratumumab) and their use in 2L is limited in this analysis. These data may be used to better inform treatment choices after relapse on R maintenance therapy. Disclosures Jagannath: Celgene: Consultancy; Merck: Consultancy; Multiple Myeloma Research Foundation: Speakers Bureau; Medicom: Speakers Bureau; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Narang:Janssen: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Ailawadhi:Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy. Rifkin:Celgene: Consultancy; Boehringer Ingelheim: Consultancy; McKesson: Equity Ownership; EMD Serono: Consultancy; Amgen: Consultancy; Takeda: Consultancy; Sandoz: Consultancy. Terebelo:Celgene: Consultancy; Janssen: Speakers Bureau; Takeda: Speakers Bureau; Pharmacyclics: Speakers Bureau. Toomey:Celgene: Consultancy; Myriad Genetics: Speakers Bureau; Dava Oncology: Other: Travel. Durie:Takeda: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Hardin:Celgene: Consultancy. Gasparetto:Janssen: Consultancy, Honoraria, Other: Travel; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel; Takeda: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel, Research Funding. Wagner:EveryFit: Consultancy; Gilead: Consultancy; Janssen: Consultancy. Omel:Takeda Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene: Employment. Kitali:Celgene: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Abonour:Prothena: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

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 Introduction The 2-3 fold excess risk of multiple myeloma (MM) among family members of cases suggests a heritable contribution to risk. Recently, a genome-wide association study (GWAS) identified two genome-wide significant and one promising novel loci associated with multiple myeloma risk. To confirm these associations and identify additional novel risk loci, we performed a four-center, genome-wide association meta-analysis. Methods A fixed effects model was used for the meta-analysis which included a total of 1248 cases and 1485 controls, all of European descent, genotyped and analyzed at four separate centers with samples contributed by 10 studies. After quality control and imputation using the 1000 Genomes Project, the analysis included ∼9.5 million variants (λ=1.024). Associations between (single nucleotide polymorphisms) SNP genotypes and MM risk were evaluated under a log-additive model of inheritance, with each study adjusting for age, sex, and up to 10 principal components to control for population stratification. Promising results were replicated in an independent set of 1587 cases and 1770 controls using TaqMan, for a total of 2835 and 3255 cases and controls, respectively, in a combined meta-analysis. Results The discovery meta-analysis did not reveal any genome-wide significant associations (defined as p<5 x 10-8). We used a novel pruning algorithm to identify the top 35 most promising single nucleotide polymorphisms (SNPs) to advance to replication. We successfully genotyped 22 SNPs in the replication set. In the combined discovery and replication meta-analysis, rs1345359 at 12q23.1 was the most strongly associated SNP (P=9 x 10-8, Table 1). The variant allele C was associated with reduced risk (odds ratio discovery set [OR]= 0.69, OR replication set = 0.78, OR combined = 0.74). A second locus at 20q13.2 (rs150220835), was associated with a two-fold increased risk (P=1.22 x 10-6), a borderline increased risk (P=0.0900) and 45% increased risk (P=2.44 X 10-5) in the discovery, replication, and combined analysis sets respectively (Table 1). We also confirmed the association between MM risk and two previously published SNPs (rs4487645, p=0.0007and rs105251, p=0.0044) (Broderick et al., Nat. Genet., 2011). The third previously suggested SNP (rs6746082) was of nominal significance (p=0.0517) in the meta-analysis. Discussion We confirmed the association between MM risk and two previously published SNPs and identified a possible association with a novel SNP in chromosome 12q23.1 (rs1345359). This SNP is not located in a gene nor associated with biofeatures in ENCODE, thus further examination of correlated SNPs is necessary to identify a functional SNP linked to this locus. We also found suggestive evidence for a second locus at 20q13.2 requiring additional replication. Larger studies would improve risk variant discovery for this rare hematologic malignancy. Disclosures: Wolf: Celgene: Honoraria, Research Funding; Millenium: Honoraria; Onyx: Honoraria. Anderson:Celgene, Millennium, BMS, Onyx: Membership on an entity’s Board of Directors or advisory committees; Acetylon, Oncopep: Scientific Founder , Scientific Founder Other.

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 Introduction Recent advances in the understanding of the WM pathobiology led to the expansion of our therapeutic options in this disease. A number of targeted drugs are either available or under investigation and are poised to change the chemo-immunotherapy paradigm in the treatment of WM. Now more than ever, an individualized treatment approach for patients with WM is possible, where patient characteristics and preferences can be matched by different treatment goals and side effect profiles. While deep responses have been associated with longer disease-free survival in other hematologic malignancies, data on patients with WM are sparse. We report the impact of depth of response in disease-free and overall survival (OS) in WM. Methods WM patients consecutively seen at Mayo Clinic between 01/1998 and 12/2016 were reviewed for response to therapy and disease burden. The best response achieved after the treatment of interest (TOI) was classified using the IWWM-7 Response Criteria. The included TOI were: BR, DRC, BDR and high-dose chemotherapy followed by ASCT. All time-to-event analyses were performed from the TOI initiation date using the Kaplan-Meier method and the log-rank test. A landmark analysis from the date-of-best response was also performed for OS to prevent immortal-time bias. Univariate and multivariate analyses of progression-free survival (PFS) and time-to-next therapy (TTNT) were performed using the Cox regression method. Results A total of 181 patients had disease response assessed after the TOI. Baseline characteristics at time of diagnosis are summarized in table 1. The median follow up from TOI was 3.8 years (95% CI: 3-4), the majority of patients received TOI as salvage therapy [n=112 (63%); median 2nd line (rage 1-11)]. Best response rates with the corresponding 5-year PFS and TTNT are summarized in table 2. The median OS from TOI was longer in patients who achieved at least a PR [median 7.2 years (95% CI: 5-NR) vs 3.7 years (95% CI: 1.6-NR), p=0.01]. A trend towards a longer OS was also seen with deeper responses (PR or better) achieved with frontline therapy [median 5.8 years (95% CI: 5.8-NR) vs 3.4 years (95% CI: 1.6-NR), p=0.24]. Figure 1 shows the correlation between deeper responses with PFS and TTNT. Among patients achieving a PR or VGPR, those with a normal FLC ratio post TOI demonstrated a longer PFS and TTNT [PFS: median NR (95% CI: 3.4-NR) vs 4.9 years (95% CI: 2.8-8.7), p=0.01; TTNT: median NR (95% CI: 3.5-NR) vs 5.2 years (95% CI: 4.2-9.4), p=0.04], figure 2. In a multivariate analysis including normal FLC ratio, normal IgM level and minimal BM involvement (<5%) post TOI, normal FLC ratio remained an independent prognostic factor for longer PFS and TTNT. Similar trends were seen when considering treatment naïve and relapsed/refractory patients independently (data not shown). Discussion Our results not only suggest an association between depth of response with PFS and TTNT, but also with OS in patients with WM. A normal FLC ratio (not part of the IWWM-7 response criteria) seems to predict a longer disease-free interval in patients achieving a PR or VGPR. Disclosures Gertz: Ionis: Honoraria; Apellis: Consultancy; annexon: Consultancy; Prothena: Honoraria; janssen: Consultancy; Physicians Education Resource: Consultancy; Alnylam: Honoraria; Teva: Consultancy; spectrum: Consultancy, Honoraria; Medscape: Consultancy; celgene: Consultancy; Research to Practice: Consultancy; Amgen: Consultancy; Abbvie: Consultancy. Kapoor:Takeda: Research Funding; Celgene: Research Funding. Ailawadhi:Amgen: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pharmacyclics: Research Funding; Celgene: Consultancy. Reeder:Affimed: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Seattle Genetics: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Regeneron: Research Funding.

Abstract Introduction Immunoglobulin M monoclonal gammopathy of undetermined significance (IgM MGUS) is a relatively common pre-malignant condition that may progress to Waldenstrom macroglobulinemia (WM), an incurable low-grade non-Hodgkin lymphoma. The acquisition of genomic alterations in a multistep process of progression is likely a central mechanism responsible for the progression of IgM MGUS to WM, leading to increased tumor burden and end-organ damage. The exact role of the immune system in this process is still poorly characterized. The modulation of the immune system by malignant cells leading to anti-lymphoma immunity or immune evasion is a well-stablished principle associated with lymphoma survival and progression, respectively. The understanding of the pathobiology of IgM MGUS and WM has grown significantly over the last few years; however, most of the past research has focused on genetics and flow cytometric analysis of malignant cells. The introduction of CyTOF, a novel platform coupling mass spectometry with single-cell flow cytometry using antibody-metal isotope pairs, has allowed a broader single-cell analysis and the study of functional profiles. We here report the use of CyTOF technology to comprehensively profile the immune system of patients with IgM MGUS and WM. Methods Viably-cryopreserved (DMSO 10%) single-cell suspensions containing peripheral blood mononuclear cells from 15 patients (WM n=9 and IgM MGUS n=6) were used in this study. Recovered cells (1-3 x 106 per sample) were stained with a 30-parameter surface protein CyTOF panel designed to characterize multiple cell types and profile the immune system. Nucleated cellular events were identified using a DNA intercalator conjugated to natural abundance iridium (191Ir and 193Ir). Cisplatin (195Pt) was used for dead-live cell discrimination and calibration beads containing natural abundance cerium (140/142Ce), europium (151/153Eu), holmium (165Ho), and lutetium (175/176Lu) were used for normalization of the instrument signal. CyTOF analysis of normalized files was carried out using the Astrolabe Diagnostics platform. Cell clusters were assigned using the FlowSOM package and differential abundance analysis was performed using the edgeR package. Analysis is adjusted for multiple comparisons. Results The median live single-cell count for the entire cohort was 573,300 (range 50,681 to 869,727), representing a median of 81% (range 39% to 87%) of the total event counts [median 820,800 (range 130,452 to 1,000,000]. The cell count and the proportion of event count was similar in patients with WM or IgM MGUS. T cells represented 45.8% of the total events; granulocytes represented 31.3%; NK cells represented 8.6%; monocytes represented 8.1%; B cells represented 2.4% of the total events for the entire cohort. Figure 1 shows a heat map of different immune cell sub-types proportion per patient sample. A difference was noted in the proportion of monocytes (CD14+, CD16+) and B-cells when comparing patients with IgM MGUS and WM (figure 2). Patients with WM had a higher proportion of monocytes compared to IgM MGUS patients (p=0.05). A higher proportion of B-cells was noted in patients with IgM MGUS when compared to WM (4.2% vs 0.6%, p=0.01). When B-cells were sub-classified as naïve, transitional, non-switched memory, switched memory, and plasmablasts, the proportion of non-switched memory B-cells was higher in IgM MGUS compared to WM (p=0.05). While the results of this pilot study suggest important differences between IgM MGUS and WM as regards the immune repertoire, confirmatory studies are in progress in a larger cohort of patients. Conclusion To our knowledge, this is the first study of mass cytometry in patients with WM and IgM MGUS patients. A higher proportion of monocytes and lower proportion of memory B-cells was noted in patients with WM compared to IgM MGUS. CyTOF study of the immune profile in these patients is feasible and can potentially uncover relationships between cell types not typically associated with the disease progression continuum (IgM MGUS to WM). While definitive conclusion cannot be made using this dataset due to the small sample size, CyTOF is a powerful tool in the study of the immune profile of WM patients. Disclosures Gertz: Amgen: Consultancy; Abbvie: Consultancy; Apellis: Consultancy; annexon: Consultancy; spectrum: Consultancy, Honoraria; Teva: Consultancy; Alnylam: Honoraria; Physicians Education Resource: Consultancy; Ionis: Honoraria; janssen: Consultancy; celgene: Consultancy; Prothena: Honoraria; Research to Practice: Consultancy; Medscape: Consultancy. Kapoor:Celgene: Research Funding; Takeda: Research Funding. Ailawadhi:Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Pharmacyclics: Research Funding. Reeder:Affimed: Research Funding. Ansell:Seattle Genetics: Research Funding; Regeneron: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Merck & Co: Research Funding; Trillium: Research Funding; Affimed: Research Funding; LAM Therapeutics: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding.