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Background: Tumor-intrinsic molecular features informing risk and resistance mechanisms in large-B-cell lymphoma (LBCL) treated with CD19-directed chimeric antigen receptor T-cells (CAR-T) are lacking. TP53 has been implicated in aberrant apoptosis signaling and immune evasion. We hypothesized that TP53-alterations are detrimental in LBCL treated with CD19-CAR-T. Methods: Patients with relapsed/refractory LBCL treated with CD19-CAR-T were included. Targeted next-generation sequencing (NGS) encompassing protein-coding exons of over 400 genes (MSK-IMPACT) was performed on pre-CAR-T tumor samples in a subset of patients. Response and survival rates by tumor-intrinsic histological, cytogenetic, and molecular markers were assessed. Interactions between genomic aberrations and cellular pathways that could contribute to CAR-T resistance were studied using publicly available datasets with genomic and transcriptomic profiling. Results: We included 136 adults with LBCL treated with CD19-CAR-T. (axicabtagene-ciloleucel [70, 51%], tisagenlecleucel [38, 28%], lisocabtagene-maraleucel [28. 21%]). Patients were heavily pre-treated (≥4 treatment lines [58%]) and primarily categorized as diffuse large B-cell lymphoma (DLBCL)-NOS (79%) followed by double/triple hit high-grade lymphoma (12%). DLBCL transformed from follicular lymphoma, high KI67-index, germinal center B-cell cell of origin, and double expressor phenotype were highly represented (43%, 47%, 50%, and 40%, respectively). Outcomes in the complete cohort echoed pivotal trials: best overall response rate 78% (Fig. A), median overall survival (OS) 22.7 months (95%CI 14.8-NR), median progression-free survival 6.2 months (3.3-12.3). A subset of 76 patients had tumor NGS profiling. Clinical features and CR and OS rates were similar across patients with and without NGS. TP53 genomic alterations were common (28, 37%). A total of 26 TP53 mutations (22 missense; 2 in-frame deletions; 2 splice sites) were identified in 23 patients. An additional five patients had TP53 homozygous deletions (i.e., copy number alterations). Two patients had concurrent TP53 mutations and homozygous deletions. Among tumor-intrinsic factors, only TP53-alterations were predictive of complete response (CR) in univariable and multivariable logistic regression; no association was observed with histological and cytogenetic features (Fig. B). TP53-alterations were also predictive of OS in univariable and multivariable Cox regression (Fig. C-D; 1-year OS in TP53-altered (48% [95% CI 32 - 71]) vs. wild-type (75% [64 - 89]), p = 0.039). Notably, in TP53-altered LBCL, axicabtagene-ciloleucel therapy was associated with superior OS compared to aggregated 41BB products (HR 3.40 [1.19-9.66]) in multivariable Cox regression adjusted for age, performance status, and primary refractory disease (Fig. E). Transcriptomic analysis of publicly available samples from newly diagnosed LBCL patients (n=562) demonstrated that TP53-alterations are associated with dysregulation of pathways related to CAR-T cell cytotoxicity, including downregulation of interferon and death receptor pathway genes, and reduced CD8 T-cell tumor infiltration (Fig. F-H). Conclusions: We show, for the first time, that TP53 alterations are a valuable prognostic and potentially predictive marker in LGBL CD19-CAR-T recipients. Gene expression profiling suggests that TP53 alterations result in an immunosuppressive tumor-microenvironment and impaired apoptosis signaling, which could lead to decreased CAR-T efficacy. Figure 1 Figure 1. Disclosures Shouval: Medexus: Consultancy. Batlevi: Life Sciences: Consultancy; Kite Pharma: Consultancy; Juno/Celgene: Consultancy; GLG Pharma: Consultancy; Pfizer: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Seattle Genetics: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Moderna: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Dava Oncology: Honoraria; Bayer: Research Funding; TouchIME: Honoraria; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Dahi: Kite / Gilead: Membership on an entity's Board of Directors or advisory committees. Giralt: AMGEN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Salles: Janssen: Consultancy; Novartis: Consultancy; Epizyme: Consultancy, Honoraria; Miltneiy: Consultancy; Regeneron: Consultancy, Honoraria; Incyte: Consultancy; Ipsen: Consultancy; Kite/Gilead: Consultancy; Morphosys: Consultancy, Honoraria; Velosbio: Consultancy; Takeda: Consultancy; Loxo: Consultancy; Genentech/Roche: Consultancy; Rapt: Consultancy; Genmab: Consultancy; Allogene: Consultancy; Debiopharm: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Sauter: Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Genmab: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Scordo: i3 Health: Other: Speaker; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; Angiocrine Bioscience: Consultancy, Research Funding; Omeros Corporation: Consultancy; McKinsey & Company: Consultancy. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. van den Brink: Seres: Other: Honorarium, Intellectual Property Rights, Research Fundingand Stock Options; Ceramedix: Other: has consulted, received honorarium from or participated in advisory boards ; Merck & Co, Inc: Honoraria; WindMILTherapeutics: Honoraria; MagentaTherapeutics: Honoraria; Da Volterra: Other: has consulted, received honorarium from or participated in advisory boards; Pluto Therapeutics: Current holder of stock options in a privately-held company, Other: has consulted, received honorarium from or participated in advisory boards ; GlaskoSmithKline: Other: has consulted, received honorarium from or participated in advisory boards; Forty-Seven, Inc.: Honoraria; Lygenesis: Other: has consulted, received honorarium from or participated in advisory boards ; Rheos: Honoraria; Pharmacyclics: Other; Kite Pharmaceuticals: Other; Frazier Healthcare Partners: Honoraria; Priothera: Research Funding; Wolters Kluwer: Patents & Royalties; Juno Therapeutics: Other; DKMS (nonprofit): Other; Notch Therapeutics: Honoraria; Nektar Therapeutics: Honoraria; Synthekine (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Novartis (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Jazz Pharmaceuticals: Honoraria; Therakos: Honoraria; Amgen: Honoraria. Perales: Nektar Therapeutics: Honoraria, Other; MorphoSys: Honoraria; Miltenyi Biotec: Honoraria, Other; Merck: Honoraria; Medigene: Honoraria; Kite/Gilead: Honoraria, Other; Karyopharm: Honoraria; Incyte: Honoraria, Other; Equilium: Honoraria; Cidara: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; NexImmune: Honoraria; Novartis: Honoraria, Other; Omeros: Honoraria; Sellas Life Sciences: Honoraria; Servier: Honoraria; Takeda: Honoraria. Palomba: Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.

Introduction: North American-ATLL (NA-ATLL) is a distinct genomic and clinical entity when compared with Japanese ATLL. Despite the frequent CNS involvement by this entity there are no prognostication tools to identify variables associated with higher risk. We studied one of the largest NA-ATLL cohorts in the United States at a minority rich ethnically diverse New York City based tertiary care center to identify discrete variables that may be associated with CNS involvement. Additionally, we examined the predictive power of the previously validated International Prognostic Index (IPI) developed for Diffuse Large B-cell Lymphoma (DLBCL) in terms of CNS involvement as well as overall survival in our cohort. In our previous work, we assigned CNS involvement of ATLL if: 1) cerebrospinal fluid (CSF) cytology or flow cytometry was positive; 2) CNS imaging was positive for disease involvement or 3) physical exam was compatible with neurologic involvement. Methods and results: Of 65 NA-ATLL patients (pts), 20 (30.77%) had CNS involvement by ATLL meeting above mentioned criteria. The median age of all pts in our dataset was 59 years. Pts were divided into non- CNS involved NA-ATLL (non-CNS NA-ATLL) and CNS involved NA-ATLL (CNS NA-ATLL) groups. Parameters to predict CNS involvement were outlined as leukocytosis (>11000 per microliter [μL]), elevated acute lymphocytic count (>4000/ μL), elevated lactate dehydrogenase (LDH) (>190 units/liter [u/l]), generalized lymphadenopathy (LAD) defined as involvement of 2 or more non-contiguous nodal sites, elevated corrected serum calcium levels (>10.5 mg/deciliter), bone marrow (bm) involvement and serosal involvement defined as pleural or peritoneal involvement. These variables were chosen given our prior work identifying them as critical to predict OS in our general NA-ATLL population. We then performed the Fisher test of proportions to determine if the variables above mentioned were different between the CNS NA-ATLL and the non-CNS NA-ATLL. We did not find significant associations when analyzing gender (p=0.0535), leukocytosis (p= 0.4001), lymphocytosis (p =0.57), hypercalcemia (p= 0.7661), elevated LDH (p= 0.4898), generalized LAD (p=0.271), serosal involvement (p= 0.05088) or bone marrow involvement (p=1). We only found a strong association when examining ATLL subtypes, being the acute/lymphomatous variant strongly associated with CNS involvement (p=2.226e10 -5). To identify variables that can have an impact in OS in CNS NA-ATLL vs non-CNS NA-ATLL we calculated Kaplan Meier survival curves. We did not find any difference based on age (p=0.23), gender (p=0.95), leukocytosis (p= 0.074), lymphocytosis (p =0.21), hypercalcemia (p= 0.094), elevated LDH (p= 0.37), generalized LAD (p=0.28), and serosal involvement (p= 0.1) in the overall survival. The only significant association we found was bone marrow involvement in predicting poor OS in CNS NA-ATLL group (p= 0.038). Next, we determined IPI scores (age>60, ECOG performance status>2, Ann Arbor stage III/IV, serum LDH score >190 u/L and more than 1 extra-nodal site) in our CNS NA ATLL and non-CNS NA ATLL cohorts. We sought to determine if: 1) this prognostication tool is predictive in NA-ATLL and 2) if these variables can be used to identify CNS involvement in our cohort. CNS pts with a higher IPI score (>3) showed tendency towards a lower survival rate (p=0.089) than non-CNS pts (p=0.3). IPI score of 3 or more was not predictive of CNS involvement in our sample (p=1). Conclusions: NA-ATLL is a rare and protean disease with poor prognosis and CNS involvement is prevalent. With the variables used we did not find clear predictors of CNS associated disease other than patients presented with the lymphomatous and acute subtypes. We also observed than bone marrow involvement portends a dismal prognosis for individuals with CNS involvement. Future studies with a larger cohort could provider further insight on discovering predictors for CNS involvement in NA ATLL. Figure 1 Figure 1. Disclosures Shah: Celgene/BMS: Research Funding; Janssen: Research Funding. Gritsman: iOnctura: Research Funding. Shastri: GLC: Consultancy; Kymera Therapeutics: Research Funding; Guidepoint: Consultancy; Onclive: Honoraria. Verma: BMS: Research Funding; GSK: Research Funding; Incyte: Research Funding; Medpacto: Research Funding; Curis: Research Funding; Eli Lilly: Research Funding; Stelexis: Consultancy, Current equity holder in publicly-traded company; Novartis: Consultancy; Acceleron: Consultancy; Celgene: Consultancy; Stelexis: Current equity holder in publicly-traded company; Throws Exception: Current equity holder in publicly-traded company. Janakiram: Amgen: Honoraria.

Up to 70% of large B-cell lymphoma (LBCL) patients will eventually experience relapse or progress following CD19-CAR-T therapy. Data guiding management of this challenging population are lacking. Therefore, we aimed to study the relationship between treatment strategies and outcomes following CD19-CAR-T failure. We included 273 adults, from two centers, treated with CD19-CAR-T (axicabtagene-ciloleucel [98, 36%], tisagenlecleucel [76, 28%], lisocabtagene-maraleucel [28, 10%], and an academic CD28-product [71, 26%]) for relapsed/refractory LBCL Cumulative incidence of relapse or progression was 40% (95% CI: 34%, 46%). Of 176 patients with residual or relapsed disease post-CAR-T (Fig. A), 133 received subsequent first-line anti-cancer therapy for active or residual disease (primary cohort) at a median of 79 days (interquartile range 49-124) after CAR-T infusion. Within the primary cohort, 65% of patients had stage III-IV disease at time of subsequent therapy. Most lymphomas remained CD19-positive after CAR-T therapy (45 biopsies, 91% positive by flow cytometry [58% normal, 33% dim expression]). At time of first treatment post-CAR-T, nearly all patients had either relapsed disease or stable/progressive disease (SD/PD), with eight patients in ongoing partial response (PR). With a median follow-up of 14.5 months (95% CI: 11.5-21.4), the median overall survival (OS) from time of first subsequent therapy was 8.6 months (IQR 6.9-12.0). We sought to identify determinants of survival among patients receiving initial post-CAR-T treatment. Variables measured pre- and post-CAR-T therapy and significantly associated (p < 0.1) with OS in univariable Cox regression were introduced into a multivariable model. Age ≥ 65y (HR 2.01 [95% CI: 1.23-3.29], p 0.005), bulky disease at apheresis (HR 2.05 [1.07-3.95], p 0.031), and disease refractory to CAR-T therapy (HR 1.89 [1.19-2.98], p 0.007) were associated with inferior OS in the multivariable analysis. Based on the cumulative burden of OS determinants, we propose a prognostic tool allowing risk stratification of patients receiving treatment post-CAR-T. Increasing number of these three risk factors was associated with greater mortality (HR 1.86 [1.32-2.62], p Therapy strategies post-CAR-T varied. Polatuzumab (n=25), anthracycline or platinum ("chemotherapy"; n=17), BTK inhibitors (n=13) and lenalidomide (n=12) based treatment were most frequently administered for non-localized disease (stage ≥2). Involved site radiation therapy (ISRT; n=20) was primarily given for stage I disease (Fig. C). Overall response rate (ORR) in the entire cohort was 47% (25% CR; 22% PR). Fig. D shows response rates by treatment. Remarkably, novel agents, including polatuzumab and lenalidomide-based therapies, had ORR of 52% (CR 35%) and 33% (CR 33%), respectively. In contrast, traditional chemotherapy-based approaches did not result in CR, and only 50% achieved PR. Survival was poorest with chemotherapy (6 month OS: 25% [95% CI: [11-59]), while rates with lenalidomide and polatuzumab-based therapies were 65% (42-100) and 67% (50-89). Patients and disease characteristics across treatment groups were unbalanced. However, the three prognostic factors comprising the OS prognostic tool: age ≥ 65y, bulky disease at apheresis and disease refractoriness to CAR-T, were similar across lenalidomide, polatuzumab, checkpoint inhibitors, and chemotherapy-based treatment groups. Patients who underwent alloHCT were significantly younger but achieved high rates of response. In conclusion, we present the most extensive and detailed experience of treatment outcomes post-CAR-T therapy. Our data suggest that novel agents may be preferable to traditional chemotherapies as the first post-CAR-T treatment. However, survival is still poor, and investigation of curative approaches is needed. We provide a tool to inform mortality risk in this difficult-to-treat population. Figure 1 Figure 1. Disclosures Scordo: i3 Health: Other: Speaker; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; McKinsey & Company: Consultancy; Omeros Corporation: Consultancy; Angiocrine Bioscience: Consultancy, Research Funding. Batlevi: ADC Therapeutics: Consultancy; Juno/Celgene: Consultancy; Life Sciences: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; Viatris: Current holder of individual stocks in a privately-held company; GLG Pharma: Consultancy; Xynomic: Research Funding; Seattle Genetics: Consultancy; Kite Pharma: Consultancy; TG Therapeutics: Consultancy; TouchIME: Honoraria; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Research Funding; BMS: Current holder of individual stocks in a privately-held company; Medscape: Honoraria; Pfizer: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; Dava Oncology: Honoraria; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Dahi: Gilead sciences: Membership on an entity's Board of Directors or advisory committees; Kite pharma: Membership on an entity's Board of Directors or advisory committees. Giralt: PFIZER: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; JANSENN: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees. Palomba: Pluto: Honoraria; Lygenesis: Honoraria; Magenta: Honoraria; Juno: Patents & Royalties; Wolters Kluwer: Patents & Royalties; WindMIL: Honoraria; Priothera: Honoraria; Nektar: Honoraria; Rheos: Honoraria; BeiGene: Consultancy; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Kite: Consultancy; Ceramedix: Honoraria; Notch: Honoraria, Other: Stock; Novartis: Consultancy; PCYC: Consultancy. Salles: Ipsen: Consultancy; Regeneron: Consultancy, Honoraria; Genentech/Roche: Consultancy; Genmab: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Incyte: Consultancy; Morphosys: Consultancy, Honoraria; Janssen: Consultancy; Epizyme: Consultancy, Honoraria; Allogene: Consultancy; Kite/Gilead: Consultancy; Loxo: Consultancy; Miltneiy: Consultancy; Debiopharm: Consultancy; Velosbio: Consultancy; Rapt: Consultancy; BMS/Celgene: Consultancy; Beigene: Consultancy; Abbvie: Consultancy, Honoraria; Bayer: Honoraria. Sauter: Genmab: Consultancy; Celgene: Consultancy, Research Funding; Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Kite/Gilead: Consultancy; Precision Biosciences: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Avigdor: Gilead: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Research Funding; Janssen: Research Funding; Takeda: Consultancy, Honoraria. Perales: Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Equilium: Honoraria; Cidara: Honoraria; MorphoSys: Honoraria; Incyte: Honoraria, Other; Servier: Honoraria; Celgene: Honoraria; Medigene: Honoraria; Kite/Gilead: Honoraria, Other; Karyopharm: Honoraria; Nektar Therapeutics: Honoraria, Other; Merck: Honoraria; Novartis: Honoraria, Other; NexImmune: Honoraria; Miltenyi Biotec: Honoraria, Other; Omeros: Honoraria; Sellas Life Sciences: Honoraria. Shouval: Medexus: Consultancy.

Background: Adoptive immunotherapy using CD19-targeted Chimeric Antigen Receptor T-cells (CAR-T) has revolutionized the treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL). We have demonstrated the efficacy of FDA-approved axicabtagene ciloleucel (Yescarta) in a multiethnic New York City underserved population with 80% complete response (CR) rate in the first ten patients treated at our institution (Abbasi et al., 2020). There is limited data on the propensity of infections and lymphohematopoietic reconstitution after Day 30 (D30) following CAR-T cell therapy. In this study, we evaluated the prevalence and nature of infectious complications in an expanded cohort of DLBCL patients treated with CD19 CAR-T therapy and its association with the dynamics of leukocyte subpopulation reconstitution post-CAR-T cell therapy. Methods: We conducted a retrospective study of patients who received CAR-T therapy at our institution between 2018-2020. Variables collected include patient demographics, absolute neutrophil (ANC), lymphocyte (ALC) and monocyte counts (AMC) at Day 30, hematologic reconstitution (ANC≥ 1500/µL) at Day 90 (D90), presence or absence of infections after D30 by clinical and/or microbiological parameters. Associations between presence of infection and D30 ANC, ALC, AMC, ANC/ALC ratio, AMC/ALC ratio were assessed using Kruskal-Wallis test. Association between infection and hematologic reconstitution at D90 was done using Chi-square test. Kaplan-Meier curves with log-rank test were used to evaluate overall survival (OS) and progression-free survival (PFS). Results: Nineteen patients were evaluated in our study, consisting of 42% (8) Hispanic, 32% (6) Caucasian, 21% (4) African-American, and 5% (1) Asian subjects. Based on clinical and microbiologic data, 47% (9) developed an infection after D30 (infection group) while 53% (10) of subjects remained infection-free after D30 (non-infection group). The most common infection type observed was viral (11 patients) followed by bacterial (8 patients) and fungal (3 patients) (Table 1). Of 25 total infectious events, 44% (11) were grade 1 or 2 and 48% (12) were grade 3 with 10 being viral in etiology. Two deaths occurred due to an infectious process. Three patients tested SARS-CoV-2 positive and were hospitalized with COVID-19 pneumonia. Median OS and PFS has not been reached in either group. To determine the kinetics of lymphohematopoietic reconstitution and its association with infection risk, we evaluated the relationship between cytopenias and rates of infection after D30. Notably, compared to non-infection group, infection group had a higher median ALC (1000/µL vs 600/µL p=0.04), a lower median ANC/ALC ratio (1.4 vs 4.5 p1500/µL) at D90. We observed that only 22% (2) of patients had recovered ANC > 1500/µLin the infection group as opposed to 80% (8) in the non-infection group at D90 (p= 0.038). Rates of cytokine release syndrome (CRS) were comparable between the two groups (55.6% vs 70% p=0.52). Surprisingly, rates of immune-effector cell associated neurotoxicity syndrome (ICANS) was lower (55.6%) in the infection group compared to (90%) non-infection group (p=0.09). Fourteen of 19 patients had follow-up over one year, of which 8 (57%) remained in complete remission (CR). Conclusions: We demonstrate an infection rate of 47% (9) beyond D30 in patients undergoing CD19 CAR-T. Increased ALC, lower ANC/ALC and AMC/ALC ratios at D30 may be predictive of infectious complications. Median OS has not been reached in our cohort. Given the potential clinical impact, our observations should be corroborated using larger datasets. Disclosures Steidl: Pieris Pharmaceuticals: Consultancy; Bayer Healthcare: Research Funding; Stelexis Therapeutics: Consultancy, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Aileron Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Janakiram:ADC Therapeutics, FATE therapeutics, TAKEDA pharmaceuticals: Research Funding. Verma:BMS: Consultancy, Research Funding; acceleron: Consultancy, Honoraria; Janssen: Research Funding; stelexis: Current equity holder in private company; Medpacto: Research Funding.

Prior studies have evaluated incidence and survival trends for B-Acute Lymphoblastic Leukemia (B-ALL) in children and adults. However, there have been no recent studies evaluating the difference in survival between different race and ethnicities in the era of tyrosine kinase inhibitors and novel combination therapy. We wanted to determine 5-year observed survival for adult patients with B-ALL diagnosed in recent years and assess for any difference in survival by race-ethnicity. Methods: We used Surveillance Epidemiology End Results (SEER) 18 registry to identify B-ALL patients using ICD-O-3 codes 9811-9818 and 9836. SEER 18 covers ~28% of US population. The year of diagnosis was limited to 2010-2016 in order to capture a patient population most likely treated with modern therapies. We limited our study to adults aged 20 years (yrs) or more, which were then divided into the following age groups: 20-29, 30-39, 40-49, 50-59, 60-69,70-79,80+ yrs of age. Gender, race-ethnicity, median family income and observed overall survival (OS) were obtained from SEER. For multivariate survival analysis, Cox proportional hazard model was used to adjust for clinically important and other relevant variables (age, gender, race-ethnicity, median income). We included median family income, a county level characteristic in our analysis as a surrogate for access to care. We divided these counties into quintiles based on median family income and included that variable in the multivariate model. We did not adjust for genetic risk or patient insurance status, as the information provided in SEER was inadequate and would likely lead to misclassification bias. SEER Stat 8.3.5 and SAS student edition were used for analysis. Results: 4244 cases of B-ALL were identified with an age adjusted incidence rate of 0.92 per 100,000. B-ALL occurred at all ages, but incidence was higher in young adults ( Age adjusted incidence was the highest among Hispanics (1.61{1.53-1.71}), followed by Non-Hispanic Whites (NHW)(0.77{0.73-0.8}, Non-Hispanic Asian Pacific Islander (NHAPI)(0.7{0.63-0.78}) and Non-Hispanic Blacks (NHB)(0.54{0.47-0.61}); this difference was statistically significant (p-value About 52% of population died during the study period from any cause. We limited our survival analysis to patients without second malignancy to avoid the confounding effect of another cancer associated mortality. We evaluated OS differences between race-ethnicity in a multivariate model that adjusted for age, sex and income. We found that when compared to NHW, Hispanics (Hazard Ratio (HR) 1.3{1.16-1.46}; p Conclusion: Our study showed a significant survival disparity in adult B-ALL by race and ethnicity in the modern era. This can partly be attributed to differences in access to care as shown in our study. Interestingly, Hispanic and NHB have a significantly worse overall survival compared to NHW and NHAPI even after accounting for income differences, as a surrogate for access to care. This could be due to other unaccounted measure of health disparity, availability of allogeneic transplantation and/or difference in disease biology. Further studies are needed to evaluate such differences, identify barriers to care in minority populations and characterize potential differences in the genetic make-up of B-ALL in the various ethnic/racial groups. Disclosures Sica: Physician's Education Resources (PER): Honoraria. Verma:Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria; BMS: Research Funding; Janssen: Research Funding.

Adult T cell leukemia / lymphoma is a rare neoplasm with dismal cure rates and poor response to chemotherapy. The genetic basis of refractoriness against conventional agents is not known. We follow one of the largest cohorts of ATLL in the US and recently showed that North American ATLL (NA-ATLL) has a distinct mutational profile from Japanese ATLL (J-ATLL) with a higher incidence of epigenetic mutations (Shah et al, Blood, 2018; 132(14):1507-1518). Here, we analyze the mutational landscape of ATLL clones at diagnosis and at relapse in a pilot study of 7 NA-ATLL patients using deep targeted sequencing of 236 recurrently mutated genes. Our goal was to examine clonal evolution patterns that may result as a consequence of the selective pressure of chemotherapy by determining changes in mutational profiles as well as clonal abundance on patients with aggressive ATLL [acute and lymphomatous] (Table 1). All patients were treated with EPOCH (Etoposide, Prednisone, Vincristine, Cyclophosphamide and Doxorubicin) chemotherapy after initial diagnosis except one patient who received interferon therapy. Distinct patterns of clonal evolution were observed in patients with primary refractory disease when compared to those who relapsed after an initial remission. Group 1 has 3 cases (Pts 1 to 3), all of which experienced early relapse and showed mutation patterns suggestive of clonal replacement by a new emerging clone at relapse. Group 2 has 3 patients (Pts 4-6) that are characterized by worsening of primary refractory disease. Mutation patterns in the before-and-after sample pairs suggest linear progression from a previously existing clone during therapy. The clonal evolution status was not resolved in our third group (Pt#7) indicating that mutations outside the 236 genes evaluated might have been present. Frequent epigenetic mutations were found in both diagnostic and refractory/relapsed samples. Surprisingly, 4 epigenetic mutations (KMT2D, EP300, SPEN, SETBP1) identified in 4 cases were confirmed or suspected of germline origin. This suggests that ancestral genomic differences between the Caribbean and Japanese populations could contribute to the mutational and clinical disparities between NA- and J-ATLL. Multiple mutations with similar variant allele frequencies (VAF) at the time of relapse were identified, suggesting simultaneous acquisition of several mutations during clonal evolution. Clonal replacement by an emerging clone (Group 1) such as GATA3 (Pt#3) or KMT2D (Pt#1) (either germline or founding mutation) was observed in patients who achieved an initial response. On the other hand, in primary refractory disease (Group 2), relapse was driven by dominant TBL1XR1 mutations in 2 out of the 3 cases either alone (Pt#6) or in combination with mutated SMARCB1 (Pt#5). The protein encoded by TBL1XR1 is a negative regulator of the nuclear receptor corepressor (NCoR) /histone deacetylase 3 (HDAC3) complex. Therefore, TBL1XR1 inactivation is expected to result in hyper-activity of NCoR/HDAC3, an epigenetic abnormality targetable by HDAC inhibitors. SMARCB1 is also an epigenetic regulator associated with several malignancies and has been targeted with alisertib. A subclonal expansion of EP300 (a histone acetyltransferase) appears to drive relapse in the other case of this group (Pt#4). Therefore, our primary refractory cases show that epigenetic mutations seem to be of utmost importance not only at diagnosis as we have previously shown, but as the driving force behind chemotherapy refractoriness and subsequent relapse. Conclusion: To our knowledge, this is the first mutation-based clonal evolution study aimed to examine dynamic changes induced by chemotherapy among NA-ATLL patients. Early relapse appears to be driven by the emergence of new mutant clones. On the other hand, primary refractory disease appears to have epigenetic drivers that convey chemotherapy refractoriness and evolve from linear progression of a previously existing clone. Serial mutational testing can provide critical information on clonal architecture and identify actionable molecular vulnerabilities in a cohort without effective therapeutic options and a dismal prognosis. Disclosures Sica: Physician's Education Resource (PER): Honoraria. Shah:Physicians' Education Resource: Honoraria. Steidl:Aileron Therapeutics: Consultancy, Research Funding; Stelexis Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Co-Founder; Pieries Pharmaceuticals: Consultancy; BayerHealthcare: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Consultancy. Verma:Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria; Celgene: Honoraria; BMS: Research Funding; Janssen: Research Funding.

SF3B1 mutations are the most frequently occurring splicing factor mutations in MDS and AML, however the misspliced genes that contribute the malignant state in SF3B mutant MDS or AML remains unclear. We determined that SF3B1 mutant cases of MDS express a longer, active isoform of interleukin 1 receptor associated kinase (IRAK4). IRAK4 is a serine/threonine kinase that is downstream of toll-like receptor (TLR) signaling and leads to activation of oncogenic signaling states, including NF-kB and MAPK. Examination of IRAK4 by RNA sequencing showed that normal cells predominantly express small IRAK4 isoforms resulting from exclusion of the part of exon 6. These isoforms are targeted for proteosomal degradation leading to diminished IRAK4 expression and activation in normal cells. In contrast, a large proportion of MDS/AML samples with SF3B1 mutation show increased expression of an IRAK4 isoform that retains full exon 6, encoding the full-length protein (IRAK4-Long). Consequently, we show that expression of mutant SF3B1-K700E in leukemic cells is associated with increased NF-kB activity, suggesting that mutations in SF3B1 instruct expression of IRAK4 RNA isoforms with maximal functional potential. Furthermore, SF3B1 mutant MDS and AML cells exhibited a block in hematopoietic differentiation in clonogenic assays. This differentiation block was ameliorated with pharmacologic inhibition of IRAK4 with CA-4948, a potent oral clinically useful small-molecule inhibitor of IRAK4. CA-4948 blocked TLR-stimulated cytokine release in various cell models and also led to decreased leukemic burden in mice xenografted with SF3B1 mutant MDS/AML cells. Finally, we determined that SF3B1 mutation induced IRAK4 activation led to TRAF6 mediated K63 ubiquitination of critical cell cycle and regulatory proteins directly implicated in oncogenesis. We had recently shown that U2AF1 mutations can lead to IRAK4 activation via retention of exon 4 (Smith et al, Nat Cell Bio, 2019). Our data now demonstrate that SF3B1 leads to overactivation of IRAK4 via retention of a different exon (exon 6), thus reinforcing that IRAK/TRAF6 activation is a common downstream oncogenic pathway in splicing factor mutated MDS/AML. Taken together, in this study, we find that mutations in SF3B1 induce expression of therapeutically targetable "active" IRAK4 isoforms and provide a genetic link between a spliceosome mutation and oncogenic innate immune signaling in MDS and AML. Disclosures Booher: Curis: Employment. Ramachandra:Aurigene: Employment. Samson:Curis: Employment. Will:Novartis Pharmaceuticals: Research Funding. Steidl:BayerHealthcare: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; GlaxoSmithKline: Research Funding; Celgene: Consultancy; Stelexis Therapeutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Other: Scientific Co-Founder; Pieries Pharmaceuticals: Consultancy; Aileron Therapeutics: Consultancy, Research Funding. Starczynowski:Kurome Therapeutics: Consultancy. Verma:Janssen: Research Funding; BMS: Research Funding; Celgene: Honoraria; Stelexis: Equity Ownership, Honoraria; Acceleron: Honoraria.

Introduction: As people with HIV live longer, the epidemiology of plasma cell disorders (PCD) including MGUS, smoldering myeloma and Multiple myeloma (MM) becomes relevant and remains unknown. Moreover, patients with HIV have a higher incidence of monoclonal proteins which may not be related to an underlying lymphoproliferative disorder[1, 2] . There are mostly anecdotal reports and very few studies in HIV myeloma[3]. A retrospective study of 10 patients with HIV+ve symptomatic MM reported possible therapeutic benefit of ART and reported better overall survival of HIV+ve MM on ART as compared to HIV -ve MM. There is a paucity of data in PCD in this population whose incidence can be expected to increase globally. We conducted a single-institution retrospective study to look at the incidence of PCD. Methodology:We reviewed an electronic database of patients with HIV related PCD treated at Montefiore Medical Center between 2001 and 2018. All patients with a new diagnosis of PCD between January 1 2001 to July 15 2018 were identified. Data on patient demographics, HIV status, clinical outcomes (including mortality) and therapy was collected. Results: Between 2001 and 2018, 14438 patients were identified with HIV and 1986 patients had a monoclonal band in SPEP (13.8%). Based on our previous study, patients who had a definitive monoclonal band or suspected MM underwent a BM biopsy. 34 patients were diagnosed with PCD --MGUS 16 (47.05%), Smoldering MM 1 (2.94%), MM 16 (47.05%) and Primary plasma cell leukemia (PCL) 1 (2.94%). The majority of the patients were AA consistent with demographics of the Bronx. Interestingly HCV co-infection was identified in 50% (n=17) of patients and HBV co-infection was present in 15% (n=5) patients. The median CD4 count was 381 (12-1080), median viral load 237 (0-501534) and 53% patients were on ART at the time of diagnosis. The median time from HIV diagnosis was 13.9 (-2.8 to 29) years. In patients with MGUS the predominant heavy chain involvement was IgG, the median protein on SPEP was 1.1 g (0.7-1.9 g) and percentage of BM involvement was 5% (2-10%). In patients with MM IgG was the predominant heavy chain involved. On presentation, ISS Stage was Stage I in 2 patients (15.4%), 4 (30.7%) had at least Stage 2, 7 patients (53.9%) had stage 3. On presentation, 10 (58.8%) patients presented with anemia, 10 (58.8%) presented with renal impairment (Cr>=1.3), 16 (94.1%) presented with bone lesions, 6 (37.5%) presented with hypercalcemia. 5 patients (34.6%) had extramedullary presentation including 1 patient (2.9%) with PCL, 2 (5.8%) with anaplastic plasmacytoma. All patients were treated with an imid or bortezomib based regimen and there were no unusual side effects in these patients. 5 patients (29.4%) underwent autologous stem cell transplant with successful outcomes. Discussion: The prevalence of a positive SPEP is 13.8% in patients with HIV and the prevalence of plasma cell dyscrasias (PCD) in our population is 0.02%. A previous study from this cohort[2] showed that approximately 6.4% of patients with a positive SPEP developed hematological malignancy and all patients with a faint monoclonal band had lymphoma (70.5%) and those with a definite monoclonal band had myeloma (29.5%). Even though prevalence is less than the general population rate of 3%, as patients with HIV live longer this number may increase. In our study there was a high rate of co-infection with HCV in patients who had a PCD and this needs further investigation to determine causality. PCD developed at a median of 13.9 years after HIV diagnosis. The ISS staging distribution in patients presenting with myeloma is consistent with non HIV myeloma. People with HIV tolerate standard imid or proteasome inhibitor based triple drug therapy and have successful outcomes with autologous transplantation. This is the largest cohort and report describing PCD in HIV population. References:Jou, E., et al., Viral co-infections and paraproteins in HIV: effect on development of hematological malignancies. Ann Hematol, 2016. 95(4): p. 575-80.Jou, E., et al., Retrospective study of the prevalence and progression of monoclonal gammopathy in HIV positive versus HIV negative patients. Hematol Oncol, 2017. 35(1): p. 64-68.Li, G., et al., A retrospective analysis of ten symptomatic multiple myeloma patients with HIV infection: A potential therapeutic effect of HAART in multiple myeloma. Leukemia Research, 2014. 38(9): p. 1079-1084. Disclosures Janakiram: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Background: Multiple Myeloma (MM) represents 1.8% of all new cancers in the United States and is the second most common hematologic malignancy in the US with 30,000 new cases/year. The highest incidence is amongst African Americans (AA) (SEER, 2018). Increased use of autologous stem cell transplant (AHSCT) as well as introduction of proteasome inhibitors (PIs) and immunomodulatory agents (iMiDs) have led to an improvement in overall survival (OS) from 35.6% between 1998-2001 to 50.7% in 2008-2014 (Child et al. 2003; Pulte et al. 2014). Despite these improvements, outcomes in MM are heterogeneous and are influenced by sociodemographic factors like race and ethnicity, disease biology (laboratory markers, cytogenetics) and access to transplantation (Al-Hamadani, Hashmi, and Go 2014; Ailawadhi et al. 2016). Several large population-based studies report that Hispanics have low stem cell utilization rates, limited access to novel therapeutics and clinical trials as well (Ailawadhi et al. 2018; Costa et al. 2015; Schriber et al. 2017; Pulte et al. 2014). Hence, outcomes for Hispanics and AA lag behind non-Hispanic Whites as well (Pulte et al. 2014). We wanted to evaluate outcomes of MM patients at Montefiore Medical Center where AA and Hispanics have access to novel agents and therapeutics, and most of whom hail from a poor socio-economic status. Methods: We obtained a cohort of patients diagnosed with MM between 1/1/2000-12/31/2017 from the Montefiore Medical Center Cancer Registry database via Clinical Looking Glass software. Socio-demographic characteristics including self-reported ethnicity, date of diagnosis, histology, laboratory parameters (hemoglobin (Hgb), creatinine (Cr), albumin (Alb), serum lactate dehydrogenase (LDH)) within 30 days of diagnosis were obtained. Ethnicity and race variables were condensed to Hispanics, Non-Hispanic Whites (NHW) and Non-Hispanic African Americans (NHAA). Charlson comorbidity score and its age-adjusted version were calculated. Primary payor (Medicaid, Medicare, private insurance or self-pay) was identified for each patient. Descriptive statistical analysis was performed using STATA 15.1 statistical software. OS was estimated using the Kaplan-Meier method and HR and corresponding 95% confidence intervals (CI) were estimated using the cox proportional hazard model. All the variables in the Cox proportional hazard ratio model fulfill the proportional hazard assumption. Results: We identified 1630 patients during the study period; 1502 patients were available for analysis (Table 1) The mean age of diagnosis was 66 years, and NWH were diagnosed at older age when compared to Hispanics or NHAA (71 vs 64 vs 66, p=0.001) respectively. Hispanics had a higher proportion of Medicaid affiliation. The baseline mean Hb (p=0.02), Cr (p=0.02) and LDH (p=0.09) were different; however this difference is unlikely to be clinically relevant (Table 1). Median survival for the cohort was 63 months (95% CI: 59-69). Hispanics had better mean OS (118 months, (95% CI 96-128) as compared to NHW (49 months, 95% CI 40-68)) and NHAA (60 months, 95% CI 53-66) and others (32 months, 95% CI 21-46) (Figure 1). After controlling for age at diagnosis, gender, socioeconomic status, modified Charlson age score, race had a statistically significant impact on the outcome, with NHW (HR-2.01) and NHAA (HR 1.77) having poorer survival when compared to Hispanics (P Conclusion The study cohort is significantly different to prior reports, with a higher rate of NHAA and Hispanics. Hispanics had a higher percentage of Medicaid as primary payor. Contrary to prior reports, we show that with access to novel agents and transplantation, MM in Hispanics has a better OS than AA and NHW. We also show that NHAA (41%) despite being diagnosed at a younger age than NHW continue to have poorer outcomes than Hispanics. Further characterization including risk stratification and cytogenetics is underway to identify factors leading to better and worse outcome in Hispanics and AA respectively. Disclosures Janakiram: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Introduction Adult T-cell leukemia/lymphoma (ATLL) is a rare, aggressive T cell neoplasm associated with a retrovirus human T cell lymphotropic virus (HTLV-1) and carries a dismal prognosis. Within the United States, New York, and Florida see the majority of cases due to the concentration of Caribbean immigrants (Zell, Assal et al. 2016, Malpica, Pimentel et al. 2018). SEER data does not include states like New York and Florida where most cases are seen and therefore a true estimate of the disease burden in this country is not known (Chihara, Ito et al. 2012, Adams, Newcomb et al. 2016). Aim We aim to study the epidemiology and clinical outcomes of ATLL in the United States particularly in the state of New York. Methods Data for New York was obtained from the New York State Cancer Registry (NYSCR). Data were also retrieved from 18 Surveillance, Epidemiology, and End Results (SEER) registries in the United States. Patients with ATLL (HTLV-1 positive) (includes all variants) were categorized using the International Classification of Diseases for Oncology, Third Edition codes ICD-O-3 as 9827/3. Race/ethnicity was categorized as non-Hispanic white, non-Hispanic black, all Hispanic and other/unknown in the NYSCR whereas it was categorized as non-Hispanic white, non-Hispanic black, all Hispanic, non-Hispanic American Indian/Alaska Native, non-Hispanic Asian or Pacific Islander, and non-Hispanic unknown race in SEER. ATLL patients ≥ 15 years of age were identified from 1995 to 2014 in SEER and all ages were included in NYSCR. Survival was estimated from SEER follow-up data with Kaplan Meier survival analysis. For NYSCR mean and median survival time (month) for deceased patients - cases diagnosed through death certificate only were removed. NYSCR does not conduct active patient follow-up and assumes patients are still alive if we didn't find a deathmatch through vital record or National Death Index linkages. Results Five hundred and eleven patients with ATLL were identified in SEER. These patients had a median survival of 8 months (m) which was worse than all other subtypes of peripheral T cell lymphoma. (Figure 1) Four hundred and twenty-nine patients with ATLL were identified in NYSCR and these patients had a median survival of 4.5 m. (Figure 2) Over the years from 2000 until 2014 the number of cases diagnosed within SEER registry coverage areas has not changed. In New York state however there has been a doubling in the number of cases diagnosed from 1995 to 2014. (Figure 3A, B) The non-Hispanic black population was diagnosed at a median age of 52.5 in SEER and 54 in NYSCR while the non-Hispanic whites were diagnosed at a median age of 71 in SEER and 64.5 in NYSCR. The Hispanic patients were diagnosed at a median age of 58.5 in NYSCR and 52.5 in SEER. (Figure 4A, B) There was no gender predominance with 50% males in both registries. ATLL patients in SEER were 47.2% non-Hispanic white, 31.7% non-Hispanic black, 9.8% Hispanic and 11.4% other/unknown. There were 5.5% Japanese patients (n=28) diagnosed in SEER. NYSCR had 22.4% non-Hispanic white, 59.4% non-Hispanic black, 15.9% Hispanic and 2.3% other/unknown. (Figure 5A, B) Within SEER registries most cases occurred in New Jersey, California, Connecticut and Georgia. (Figure 6) New York state had a significantly higher number of cases than these states. Seventy four percent cases diagnosed within New York state are diagnosed in New York city and only 26% of cases are diagnosed in upstate New York. Based on reported country of birth within New York state, only 27% of the ATLL cases diagnosed are born in the US whereas 49% are born in the Caribbean (most likely to be from Jamaica, Dominican Republic and Haiti). (Figure 7A, B, C) For SEER and NYSCR the age-adjusted cancer incidence rate by race year and other factors will be presented at the meeting. Conclusions ATLL has a worse prognosis than all other PTCL subtypes. New York State has a high endemicity for ATLL with a rising number of cases. The higher percentage of non-Hispanic black patients in New York compared to the rest of the country is consistent with the diverse racial demographics in this state. Survival varied significantly by race/ethnicity and disparities were evident especially for non-Hispanic blacks who were diagnosed at a younger median age and had a shorter survival. Further research into this aggressive disease is needed to improve outcomes for these patients. Disclosures No relevant conflicts of interest to declare.

Introduction: Human T-cell lymphotropic virus (HTLV) is a retrovirus that has been associated with adult-T cell leukemia/lymphoma (ATLL) and other inflammatory conditions. Pulmonary involvement has not been widely associated to HTLV infection; however, high rates of imaging abnormalities in patients with and without ATLL have been reported. Okada reported 30%, 69% and 94% of abnormalities in HTLV1 carriers, ATLL and patients that transformed into ATLL. Whether these abnormalities follow a pattern related to each condition individually has not been defined. Hence, we undertook a retrospective study in ATLL and HTLV infected patients to determine the lung abnormalities which could be due to ATLL involvement rather than HTLV infection. Objectives: To compare the CT pulmonary findings among patients with HTLV infection with and without ATLL diagnosed at Montefiore Medical Center between 2004 and 2017. Methods: Patients diagnosed with HTLV infection by ICD9 were identified using the software Clinical Looking Glass and those with an available chest CT scan were selected. Data regarding demographics, smoking history, prior pulmonary conditions, HTLV and ATLL-associated characteristics was collected by chart review. CT chest was reviewed by an expert radiologist who was unaware of the patient diagnosis (ATLL versus non-ATLL) and findings were compared among groups. The staging CT scan was used to determine baseline pulmonary findings in patients with ATLL and the first CT chest around HTLV diagnosis was used for HTLV patients. Results: A total of 97 patients (72 with ATLL and 25 with HTLV alone) were identified. Mean age at HTLV diagnosis was 58.4 years (range: 33-88), 54.6% were females, 72.2% were Black Non-Hispanics while 27.8% were Hispanic. 88.3% were from Caribbean origin. Smoking history was similar between ATLL and non-ATLL groups (12% vs 8%, p=0.07) with no cases of prior active TB infection. Abnormal CT chest findings were present in 92.8%, 94.4% and 88% for the total cohort, ATLL and non-ATLL patients. Among patients with ATLL, 52.1% had acute and 43.7% had lymphomatous types; while only 1.4% and 2.8% had smoldering and chronic type. The most common CT chest findings were lymphadenopathy (50, 69.4%); followed by 3-10 mm nodules (32, 44.4%), ground-glass opacity, pleural effusion (31, 43.1% each), centrilobular nodules (28, 39.4%), thickening of interlobular septum (23, 31.9%) and bronchiectasis (18, 25%). Compared to the acute subtype, patients with lymphomatous subtype had higher rates of lymphadenopathy (83.9% vs 64.9, p=0.07) and lower rates of bronchiectasis (16.1% vs 35.1%, p=0.07). Among patients with non-ATLL, HTLV infection was diagnosed at an older age (63.8 vs. 56.6 years, p=0.03); HTLV-associated comorbidities were found in 16 cases (64%). Of these, myelopathy was the most frequent (10, 40%), followed by strongyloides (4, 16%). After HTLV diagnosis, CT chest was indicated in 28% patients for otherwise unexplained respiratory symptoms and to evaluate lung nodules or other chest X-ray abnormalities in 24% of cases. Bronchiectasis was the most common finding (12, 48%) followed by pleural thickening (11, 44%), ground-glass opacity and thickening of interlobular septum (10, 40%, each). Persistent abnormalities on follow-up imaging were present in 86.7% of the cases. Among patients with HTLV infection, those with ATLL were more likely to have nodules and lymphadenopathy (41.7% vs 20%, p=0.05 and 69.4% vs 24%, p Conclusions: Pulmonary findings are highly prevalent in CT chest of patients with HTLV infection with and without ATLL. Bronchiectasis and pleural thickening was more frequently encountered in non-ATLL patients while lymphadenopathy and nodules were common finding in patients with ATLL. Pulmonary involvement in lymphoma is usually characterized by nodules and lymphadenopathy but patients with ATLL had a higher incidence of findings including ground glass opacities, bronchiectasis and interlobular septal thickening possibly due to their underlying HTLV infection. Based on this data, nodules and lymphadenopathy should be classified as ATLL involvement of the lung while other findings described here could be due to HTLV infection. These findings are important in staging and response criteria for ATLL. Disclosures Janakiram: Seatle Genetics: Membership on an entity's Board of Directors or advisory committees.

Introduction: World Health Organization (WHO) classifies therapy-related myeloid neoplasms (t-MN) into therapy related acute myeloid leukemia (t-AML), therapy related myelodysplastic syndrome (t-MDS), and therapy related myelodysplastic syndrome/myeloproliferative neoplasms (t-MDS/MPN). These diseases are aggressive hematological malignancies and only allogeneic transplant offers the possibility of long-term remission. We performed retrospective analyses of Surveillance, Epidemiology, and End-Results (SEER) database to examine differences in incidence and survival outcomes of t-MN across different races and ethnicities in United States (US). Methods: Patients who developed t-MN following previous hematological or solid organ malignancies were included in the analyses. SEER registries classify race, ethnicity using 2000 US Census categories based on self- identification, medical records, death certificates and though linkage to Indian Health Service records. The race/ethnicity was categorized as non-Hispanic white (nHW), Hispanic white (HW), non-Hispanic Black (nHB), non-Hispanic Asian/Pacific islander (nHA/P), non- Hispanic American Indian/ Alaskan natives (nHI/A) and unknown groups (U). The patients were divided into various age group categories: 80 years. The statistical analyses were performed using SAS 9.4 software. Results: 13990 patients were reported to SEER database during 2000-2012 period with the diagnosis of t-MN. The total number of newly diagnosed t-MN in various racial groups was: nHW-11307, HW-900, nHB-1018, nHA/P-708, nHI/A -51 and U-6. There was higher reporting of non-Hodgkin lymphoma in females and lung/bronchial malignancies in males across all racial groups. Comparing different age groups, 50 months OS rates were: 2%, 6%, 13%,22% and 26% for groups >80 years, 70-79 years, 60-69 years, 50-59 years and Conclusion: In summary, the analyses of SEER database for t-MN revealed that t-MN developed in small proportion of patients exposed to cytotoxic agents or radiotherapy. nHWs non-had the highest incidence of reported t-MN, probably due to better access to healthcare and resources. There was statistically significant difference in the observed OS of HWs versus other ethnic groups. It appeared that the median age of diagnosis of t-MN in HW was 65 yrs, which made this racial group more likely to get definitive management for t-MN(allogeneic transplant). This might have contributed towards better overall survival in HW population. nHB group had statistically significant poor OS when compared with nHW or HW groups. The possible explanation could be, lack of access to healthcare, unable to get allogeneic transplant due to lack of donor availability or genetic variations such as polymorphisms in DNA repair enzymes and nucleotide excision repair pathways. The cancer survivors are living longer with novel treatment and are more likely to develop subsequent malignancies and population based studies are essential for identifying cohorts of at risk patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background Waldenstrom Macroglobulinemia (WM) is a hematological malignancy that affects 1500 people each year in the United States. Due to lack of literature on era comparative population-based analysis, we have analyzed Surveillance Epidemiology and End Results (SEER) data to evaluate the changes in incidence and survival patterns in the new millennium where modern therapeutic agents such as rituximab, immunomodulatory drugs and proteasome inhibitors were offered to WM patients; in contrast to the earlier period when they were non-existent. Methods The SEER 18 registry which includes data from 1973-2010 from 18 geographic areas including 28% of US representative population was used in analysis. ICD-O-3 code 9761 was used for identifying patients for this analysis. SEER* Stat 8.0.4 is used to calculate age-adjusted incidence and mortality rates based on race, gender, and age for patients. Age adjusted rates were used in this anlaysis to avoid confounding variables when comparing rates over time. Results We have included 4304 patients in the analysis (1244 patients diagnosed before 2000 and 3060 patients after 2000). The incidence rate of WM increased with age. The 10 year cumulative incidence rate per 100,000 by age stratification (80) are 0.02%, 0.40%, 1.01%, 2.14% and 2.98% respectively. Over the last decade the trend of incidence rate in WM has been steadily decreasing across all age groups (Figure 1). Median survival for all WM patients is 74 months (m) (70.2-77.8). Significant survival improvement was seen in the current era (median survival ≥2000 vs. 80: 36 vs. 31 m; p=0.05). Younger patients Conclusion The incidence rates of Waldenstrom's macroglobulinemia are trending down over the last decade for reasons unclear. The survival rates have significantly improved across most stratifications of age, sex, gender in the new millennium. These results could be secondary to the favorable impact of new drugs used in treating patients with Waldenstrom's macroglobulinemia. Also should be taken into consideration, that the current classification for WM took place in the new millennium which is a limitation for interpretation of this survival benefit observed. Disclosures: Boise: Onyx Pharmaceuticals: Consultancy. Kaufman:Onyx: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Millenium: Consultancy; Merck: Research Funding. Heffner:Genentech: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Biotest: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

Introduction A recent Spanish study suggested an impact of the type of hospital (teaching versus non-teaching) on survival of multiple myeloma (MM) patients. Such data, as well as other hospitalization parameters such as indications, length of stay (LOS), in-hospital mortality (IHM) in MM patients admitted to hospitals in the U.S are lacking. We have explored the National Inpatient sample (NIS) data to address the indications for hospitalization in MM patients and their survival outcomes of the hospitalization. Methods We obtained the National Inpatient Sample (NIS) data for the years 01/2001 until 12/2010 from Healthcare Cost and Utilization Project database (HCUP) database. The 2010 NIS contains all discharge data located in 45 States, approximating a 20% stratified sample of the U.S hospitals. Teaching hospital was defined as a hospital supported by AMA-approved residency program, is a member of the council of teaching hospitals or has a ratio of full-time equivalent interns and residents to beds of ≥0.25. Results A total of 178354 admissions reported to NIS were analyzed. Majority of admissions were to teaching hospitals (61.7% admissions: 45.8% for non-SCT and 15.9% for SCT indications) (Table 1). Among the patients that were admitted for non-SCT indications, significantly younger patients were admitted to teaching hospitals. Complicated procedures such as cancer chemotherapy were admitted to teaching hospitals (teaching vs. non-teaching: 8.3% vs. 3.4%; p= Conclusions This analysis suggests inferior survival outcomes in MM patients admitted to non-teaching hospitals. Despite the difference in severity of admissions, IHM is significantly increased in non-teaching hospitals. This effect is at least partially attributable to older patient admissions. IHM in SCT admissions is similar to published literature, validating our findings. Disclosures: Kaufman: Onyx: Consultancy; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy; Millenium: Consultancy; Merck: Research Funding. Boise:Onyx Pharmaceuticals: Consultancy. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

Introduction Myeloma patients that experience a pathological fracture have 44% increased risk of mortality compared to their counterparts without pathological fractures. Given the negative impact of pathological fractures on survival, we have explored if access to obtain a therapeutic procedure influences the survival. We analyzed the nationwide inpatient cohort to evaluate for access to procedures and other hospitalization variables for myeloma patients admitted to the hospital for the diagnosis of pathologic fractures. Methodology Myeloma patients admitted in the hospital for the primary diagnosis of pathologic fractures from 2001-2010 were analyzed from the Nationwide Inpatient Sample (NIS). Procedures and diagnoses were identified using ICD-9-CM and NIS CCS codes. Variables of therapeutic procedures, length of stay (LOS), in-hospital mortality (IHM) and hospital charges were explored using multivariate logistic regression. Costs are derived from total hospital charges using cost-to-charge ratios based on hospital accounting reports from the Centers for Medicare and Medicaid Services and reflect the actual costs to produce hospital services. Results Of the 5154 myeloma patient admitted for pathological fractures, 2422 patients (47%) underwent a therapeutic procedure. The mean LOS for the primary diagnosis was 7.23 days (SE 0.14); cost for the hospitalization was $19344 and the IHM is 2.32%. The probability of getting a therapeutic surgical procedure and the cost of hospitalization is lower in patients >65, but had similar LOS and IHM compared to patients Conclusions This analysis addresses the question that older myeloma patients (age >65) and those that have the payer status of medicare and medicaid are significantly associated with the probability of not getting a therapeutic surgical procedure when they are admitted with pathological fracture. However, this did not result in increased in-hospital mortality suggesting that probably pathological fractures may reflect the biology of the underlying disease with negative impact on survival or the morbidity associated with a pathological fracture may impede the long term survival in myeloma patients. Disclosures: Lonial: Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.