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Introduction: Mantle cell lymphoma (MCL) is a rare form of lymphoma with no current standard of care. As a result, clinical trials are critical to improving our understanding of the disease and its management. However, clinical trial participation is often limited due to lack of access to studies, restrictive eligibility criteria, and decisions by treating physicians or patients not to participate. We evaluated the rate of enrollment and outcomes associated with clinical trial participation of patients with MCL at 12 US Medical Centers. Methods: We included patients from 12 medical centers in the United States with MCL diagnosed between January 1, 2000, and January 1, 2018, who were ≥ 18 years old, received any induction therapy, and for whom it was known whether initial treatment was on a clinical trial (CT) or not. We compared differences between the two groups (CT vs not) using Fisher's Exact and Chi-square tests as appropriate. We defined overall survival (OS) as time from diagnosis to death. Patients not experiencing an event were censored at their last known follow-up. OS was determined using the Kaplan-Meier method, and univariate and multivariable models were developed to identify predictors of OS. Results: Eight hundred twelve patients were included in this analysis, including 164 (20%) patients who participated in a clinical trial during initial therapy. Rate of participation ranged from 4% to 36% across contributing sites. Median age for the entire cohort was 62 years, 572 (74%) of patients were male, and 95% of patients had ECOG 0-1. MCL International Prognostic Index (MIPI) risk score was high in 163 patients (31%), and 84% of patients had stage IV disease. Ki67 was >30% in 169/225 (43%) patients with available data, and 19% of patients (65/271) had a complex karyotype with > 3 chromosomal abnormalities. Four hundred sixteen (53%) of patients received an intensive induction regimen (defined as initial treatment with a high-dose cytarabine-containing regimen and/or receipt of autologous hematopoietic cell transplantation as consolidation), including 333 patients (43%) who underwent transplant consolidation. Patients with an increased lactate dehydrogenase (LDH) level (p 3 cytogenetic abnormalities (p=0.015) were less likely to participate in clinical trials, but there was no significant difference in rates of participation based on MIPI (p=0.49) or ECOG performance status (p=0.22; Table). Patients treated on study were less likely to receive an intensive regimen compared to those treated off study (p=0.002). Median time to treatment from diagnosis was 35 days for patients enrolled on trial and 31 days for patients not enrolled on trial (p=0.83). With a median follow-up of 3.8 years, the median OS was 13.6 years (95% CI: 11.5-21.1) for patients not treated on a trial and not reached (95% CI: 9.9 - Not Reached) for patients treated on trial (Figure; p=0.036). In a multivariable model including clinical trial participation, MIPI, time to initial treatment, and receipt of an intensive induction regimen, only clinical trial participation (HR 0.54, 95%CI: 0.31-0.93; p=0.028) and high risk MIPI score (HR 4.24, 95% CI: 2.37-7.56; p Conclusions: Participation in a clinical trial is associated with improved OS among patients with untreated MCL, even when accounting for time to initial treatment and MIPI score. This study is unable to account for other factors that may predict trial participation including baseline comorbidities, socioeconomic status, social support, and distance to the treating center that are frequently factors that limit trial participation. However, these findings do suggest that enrollment on a clinical trial frequently leads to a successful outcome for patients in addition to providing answers to key clinical questions and should be considered for all eligible patients. Disclosures Cohen: Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; UNUM: Research Funding; LAM Therapeutics: Research Funding; Hutchison: Research Funding; Genentech, Inc.: Consultancy, Research Funding; ASH: Research Funding; Lymphoma Research Foundation: Research Funding; Astra Zeneca: Research Funding. Calzada:Seattle Genetics: Research Funding. Kolla:Amgen: Equity Ownership. Bachanova:Incyte: Research Funding; Novartis: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Gamida Cell: Research Funding; GT Biopharma: Research Funding; Celgene: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Barta:Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding. Danilov:MEI: Research Funding; Seattle Genetics: Consultancy; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Curis: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Celgene: Consultancy; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; Bayer Oncology: Consultancy, Research Funding; Bristol-Meyers Squibb: Research Funding; Abbvie: Consultancy; Pharmacyclics: Consultancy. Grover:Seattle Genetics: Consultancy. Karmali:Astrazeneca: Speakers Bureau; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution. Hill:TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding. Ghosh:Spectrum: Consultancy, Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; Astra Zeneca: Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Forty Seven Inc: Research Funding; Genentech: Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; T G Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Speakers Bureau. Park:BMS: Consultancy, Research Funding; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Hamadani:Otsuka: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau; Janssen: Consultancy; Merck: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy; Medimmune: Consultancy, Research Funding; Pharmacyclics: Consultancy. Martin:Karyopharm: Consultancy; I-MAB: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; Teneobio: Consultancy. Flowers:Pharmacyclics/Janssen: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Millenium/Takeda: Research Funding; Karyopharm: Consultancy; AstraZeneca: Consultancy; Gilead: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; V Foundation: Research Funding; Optimum Rx: Consultancy; BeiGene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Spectrum: Consultancy; Celgene: Consultancy, Research Funding. Kahl:BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy.

INTRODUCTION The optimal frontline treatment for mantle cell lymphoma (MCL) is not clearly defined. Bendamustine + rituximab (BR) is commonly used as initial therapy. The role of maintenance rituximab (MR) after BR is not agreed upon due to limited data supporting this practice, whereas MR improves overall survival (OS) after autologous stem cell transplant (ASCT) and after R-CHOP for elderly patients who do not receive ASCT. Preliminary results from a subgroup analysis of the randomized phase 3 MAINTAIN study revealed neither a progression-free survival (PFS) nor OS benefit for MR as compared to observation for MCL pts (Rummel, ASCO 2016). In follicular lymphoma patients, however, there does appear to be a PFS benefit to rituximab maintenance following BR. Given these disparate results, we sought additional data to evaluate the role of rituximab maintenance following BR in MCL METHODS MCL pts treated at 12 U.S. medical centers with frontline BR who achieved a complete response (CR) or partial response (PR) and who did not receive consolidative ASCT from 2011 - 2017 were included. Use of MR was based on individual physician/patient preferences. Baseline pt characteristics were compared using chi-squared test, Fisher's exact tests, or ANOVA. Descriptive statistics, comparisons, and OS using the Kaplan-Meier method were stratified by response status as determined by the treating site (complete response (CR) only, partial response (PR) only, and CR/PR). RESULTS Among 135 pts responding to frontline BR who did not complete subsequent ASCT, 80% achieved complete remission (CR) and 20% had a partial remission (PR). Median age was 70 (range 45 - 93) years and 66% were male. Baseline MIPI score was low (13%), intermediate (38%), or high (49%) among patients with available data (n = 92) and did not differ between treatment cohorts. Among responding patients, 78 (58%) received MR and 57 (40%) were observed. With a median follow up of 3.1 years, median OS was not reached for pts responding to BR (with CR or PR) who received MR vs. 6 years for those who received no maintenance (Figure Panel A, P = 0.0013). Use of MR vs. observation was associated with a significant improvement in OS for pts in PR at the end of induction therapy (Figure Panel B, median not reached vs. 1.7 years, P = 0.006), but there was no statistically significant OS difference for pts in CR (Figure Panel C, median not reached vs. 9.6 years, P = 0.2575). In multivariable analysis, MIPI score CONCLUSIONS Whereas the MAINTAIN trial showed no PFS advantage to MR after BR for MCL pts, in this multi-center outcomes analysis across multiple US centers, the use of MR was associated with an improvement in OS in pts receiving frontline BR without consolidative ASCT. The survival benefit was only observed for pts in PR after induction therapy. Because of the potential for selection bias in the application of MR, further validation cohorts and prospective study are needed to clarify if there is benefit to maintenance therapy after BR-treated patients not undergoing ASCT as well as the potential for differential benefit of maintenance based on remission status Disclosures Hill: Takeda: Research Funding; Amgen: Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding. Martin:Janssen: Consultancy; I-MAB: Consultancy; Celgene: Consultancy; Sandoz: Consultancy; Karyopharm: Consultancy; Teneobio: Consultancy. Calzada:Seattle Genetics: Research Funding. Kolla:Amgen: Equity Ownership. Bachanova:Gamida Cell: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; GT Biopharma: Research Funding; Novartis: Research Funding. Gerson:Abbvie: Consultancy; Seattle Genetics: Consultancy; Pharmacyclics: Consultancy. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Celgene: Research Funding; Merck: Research Funding; Mundipharma: Honoraria; Seattle Genetics: Honoraria, Research Funding; Celgene: Research Funding; Mundipharma: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Research Funding. Danilov:Curis: Consultancy; Bristol-Meyers Squibb: Research Funding; TG Therapeutics: Consultancy; Abbvie: Consultancy; Genentech: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; MEI: Research Funding; Pharmacyclics: Consultancy; Aptose Biosciences: Research Funding; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Seattle Genetics: Consultancy; AstraZeneca: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Celgene: Consultancy; Janssen: Consultancy. Grover:Seattle Genetics: Consultancy. Karmali:Takeda, BMS: Other: Research Funding to Institution; Astrazeneca: Speakers Bureau; Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau. Ghosh:Celgene: Consultancy, Research Funding, Speakers Bureau; T G Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Speakers Bureau; Spectrum: Consultancy, Speakers Bureau; Astra Zeneca: Speakers Bureau; Forty Seven Inc: Research Funding; Genentech: Research Funding; Gilead/Kite: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau. Park:G1 Therapeutics: Consultancy; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Hamadani:Otsuka: Research Funding; Merck: Research Funding; Celgene: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Janssen: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau; Pharmacyclics: Consultancy; Medimmune: Consultancy, Research Funding; Takeda: Research Funding. Kahl:Seattle Genetics: Consultancy; BeiGene: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy, Research Funding. Flowers:Optimum Rx: Consultancy; Acerta: Research Funding; Gilead: Consultancy, Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; National Cancer Institute: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy, Research Funding; Bayer: Consultancy; Eastern Cooperative Oncology Group: Research Funding; Millenium/Takeda: Research Funding; V Foundation: Research Funding; Karyopharm: Consultancy; BeiGene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; AstraZeneca: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; Spectrum: Consultancy; Denovo Biopharma: Consultancy. Cohen:Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Genentech, Inc.: Consultancy, Research Funding.

Introduction: Time to treatment (TTT) is an important prognostic factor in patients with newly diagnosed diffuse large B-cell lymphoma (Maurer et al JCO 2018) where patients who initiate therapy quickly after diagnosis have an inferior event free survival compared to those who do not require such immediate treatment initiation. More recently, TTT has shown to be associated with adverse clinical factors and inferior outcomes in mantle cell lymphoma (MCL; Maurer, et al ASH, 2018). However, there is a paucity of data on the impact of TTT on overall survival (OS). We sought to validate these findings and to evaluate the impact of TTT on survival outcomes in newly diagnosed patients with MCL. Methods: We included patients from 12 medical centers in the United States with MCL diagnosed between January 1, 2000, and January 1, 2018, who had information on the TTT and initiated treatment within 60 days of diagnosis (to exclude patients whose treatment was purposefully deferred). TTT was defined as the time in days from first lymphoma diagnosis to initiation of therapy. Patients who received treatment within 14 days were categorized into short TTT group. We compared differences between the two groups (TTT 14 days and ≤ 60 days, longer TTT group) using chi-squared test, Fisher's exact tests, or ANOVA tests as appropriate. OS was defined as the time from diagnosis to death or last follow-up. Patients not experiencing an event were censored at their last known follow-up. OS was determined using the Kaplan-Meier method, and univariable and multivariable models were developed to identify predictors of OS. Results: Of 1,168 patients with newly diagnosed MCL, seven hundred fifty-five patients met the inclusion criteria and were included in this analysis, including 205 (27%) with short TTT and 550 (73%) with longer TTT. Median time to treatment was 7 days (range, 0-14) for the short TTT group vs 31 days for the longer TTT group (range, 15-60 days). The median age for the entire cohort was 63 years, 75% of patients were male, and 93% of patients had ECOG 0-1. The proportion of patients with stage 4 disease (93 vs 86%, p=0.015), elevated LDH (58 vs 39%, p3 cytogenetic abnormalities (29 vs 14%, p=0.005), B symptoms (47 vs 29%, p On univariable analysis, factors associated with inferior OS included, TTT=2 (p10k (p=0.002), BM involvement (p=2 (HR=2.25, 95%CI=1.22-4.14; p=0.009), elevated LDH (HR=1.81, 95%CI=1.16-2.85; p=0.01), and receipt of non-intensive regimen (HR=1.61, 95%CI=1.04-2.50; p=0.03) were significant predictors of OS while B symptoms was not. Conclusions: Short TTT for patients with newly diagnosed MCL is associated with aggressive disease features and inferior OS despite an increased likelihood of receiving intensive induction regimens. Further studies are needed to identify molecular determinants of such aggressive disease behavior that can be assessed quickly and utilized to initiate appropriate therapy in a timely manner. Ongoing front-line clinical trials in MCL should be developed in a way to facilitate enrollment of patients requiring urgent therapy, including potentially permitting a cycle of off-study treatment to manage symptoms while a patient is screened and enrolled. Disclosures Epperla: Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Kolla:Amgen: Equity Ownership. Bachanova:GT Biopharma: Research Funding; Incyte: Research Funding; Novartis: Research Funding; Gamida Cell: Research Funding; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Gerson:Seattle Genetics: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy. Barta:Mundipharma: Honoraria; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Seattle Genetics: Honoraria, Research Funding; Bayer: Consultancy, Research Funding; Mundipharma: Honoraria; Merck: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Danilov:Bristol-Meyers Squibb: Research Funding; Aptose Biosciences: Research Funding; Takeda Oncology: Research Funding; AstraZeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding; Celgene: Consultancy; Curis: Consultancy; Seattle Genetics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; MEI: Research Funding; Janssen: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy. Grover:Seattle Genetics: Consultancy. Karmali:Gilead/Kite; Juno/Celgene: Consultancy, Speakers Bureau; Takeda, BMS: Other: Research Funding to Institution; Astrazeneca: Speakers Bureau. Hill:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria; Celegene: Consultancy, Honoraria, Research Funding; Kite: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Amgen: Research Funding; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Consultancy, Research Funding. Ghosh:Forty Seven Inc: Research Funding; AbbVie: Consultancy, Speakers Bureau; Celgene: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; Gilead/Kite: Consultancy, Speakers Bureau; T G Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Astra Zeneca: Speakers Bureau; Genentech: Research Funding; Spectrum: Consultancy, Speakers Bureau. Park:Teva: Consultancy, Research Funding; Gilead: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Rafael Pharma: Membership on an entity's Board of Directors or advisory committees; G1 Therapeutics: Consultancy; BMS: Consultancy, Research Funding. Hamadani:Pharmacyclics: Consultancy; Medimmune: Consultancy, Research Funding; Janssen: Consultancy; Sanofi Genzyme: Research Funding, Speakers Bureau; Celgene: Consultancy; Otsuka: Research Funding; Merck: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Takeda: Research Funding. Martin:I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Teneobio: Consultancy. Kahl:AbbVie Inc, Acerta Pharma - A member of the AstraZeneca Group, AstraZeneca Pharmaceuticals LP, BeiGene, Celgene Corporation, Genentech, Pharmacyclics LLC, an AbbVie Company, Roche Laboratories Inc.: Consultancy. Flowers:V Foundation: Research Funding; National Cancer Institute: Research Funding; Millenium/Takeda: Research Funding; Gilead: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Burroughs Wellcome Fund: Research Funding; Karyopharm: Consultancy; Spectrum: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Optimum Rx: Consultancy; Pharmacyclics/Janssen: Consultancy, Research Funding; TG Therapeutics: Research Funding; Acerta: Research Funding; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Eastern Cooperative Oncology Group: Research Funding; Bayer: Consultancy. Cohen:Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; Bristol-Meyers Squibb Company: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; LAM Therapeutics: Research Funding; UNUM: Research Funding; Hutchison: Research Funding; Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; Janssen Pharmaceuticals: Consultancy.

Introduction: CAR T-cell therapy has revolutionized treatment for patients with relapsed/refractory (r/r) diffuse large b-cell lymphoma (DLBCL). Although impressive durable responses can be achieved, this is weighted by adverse events including neurotoxicity and cytokine release syndrome (CRS). Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) is a validated score that utilizes comorbidities to predict outcomes in patients receiving allogeneic stem cells transplants, but it not validated in CAR T-cell recipients. Meanwhile, the Cumulative Illness Rating Scale (CIRS) is a comprehensive tool which has been incorporated into clinical research in lymphoma. Here we report the impact of comorbidities, as measured by the HCT-CI and CIRS, on survival and tolerance of CAR T-cell therapy in patients with r/r DLBCL treated off clinical protocols. Methods: We conducted a retrospective analysis of patients with r/r DLBCL treated with commercial CART product at 4 academic medical centers after approval by the respective institutional review boards. Comorbidity data was assessed at the time of T-cell collection, and outcome data was assessed per last known follow-up. CIRS score was calculated as in Salvi et al, 2008. HCT-CI score was calculated as in Sorror et al, 2005. High comorbidity burden was defined as CIRS score ≥7, presence of severe impairment (CIRS score of 3 or 4 in ≥1 organ system; CIRS-3+), or HCT-CI ≥3. Cox proportional hazards models adjusted for age, ECOG performance status, number of prior therapies, type of product, cell of origin, MYC positivity on FISH, and comorbidities were used to assess effect on progression free survival (PFS) and overall survival (OS). Results: We analyzed 59 patients, with a median age of 63 years (range, 25-82). 80% of patients had an ECOG PS of 0 or 1. Median number of prior therapies was 3 (range, 2-6). 15 patients received tisagenlecleucel, and 44 patients received axicabtagene ciloleucel. 30 patients had germinal center B-cell (GCB) subtype DLBCL, and 29 were non-GCB as determined by Hahn's algorithm. 13 patients exhibited a MYC rearrangement by FISH, of which 9 also had BCL2 or BCL6 chromosomal translocation. Four patients did not receive CAR T-cells (3 died of disease progression; 1 died of an unrelated event). All patients (N=59) were used in the analysis. Median total CIRS was 10 (range, 1-20). 40 patients had score ≥7 and 29 had a CIRS-3+. 16 patients had neither total CIRS score ≥7 or CIRS-3+. The most common comorbidities were seen in the upper GI, endocrine and vascular/hematopoietic systems. Median HCT-CI was 2 (range, 0-13). Median follow-up was 154 days. Significant comorbidities assessed by CIRS (either total score ≥7 or CIRS-3+) were associated with inferior PFS (HR 3.65, p=0.037) and OS (OS; HR 5.31, p=0.025) compared to patients without significant comorbidities in univariate analyses. Median PFS was not reached, and OS was 305 days for patients without significant comorbidities, and was 170 and 237 for patients with significant comorbidities respectively (Figure 1,2). HCT-CI ≥3 was not predictive of PFS (HR 0.85, p=0.70) or OS (HR 1.06, p=0.90). MYC positivity was associated with inferior OS (HR 2.64, p=0.033). Presence of comorbidities assessed by CIRS and HCT-CI, were not associated with incidence of neurotoxicity or CRS. Presence of comorbidities by CIRS retained independent significance in multivariate models of PFS (HR 8.64, p=0.002) and OS (HR 15.44, p=0.042) when adjusted for all covariates. MYC also retained independent significance regarding OS (HR 3.23, p=0.032). Interestingly, older age was associated with superior PFS (HR 0.54, p=0.001) and OS (HR 0.59, p=0.007). Conclusions: In this multicenter retrospective analysis we show that CIRS has prognostic significance in patients with r/r DLBCL treated with commercial CAR T-cell therapy, as increased comorbidities, defined by presence of total CIRS score ≥7 or CIRS-3+, were associated with both a shorter PFS and OS. We did not find an association between the HCT-CI score and survival, nor did we see an association between comorbidities and incidence of neurotoxicity or CRS, however numbers were small. These findings show that evaluating comorbidities in patients eligible to receive CAR T-cell therapy should be considered. Further validation is needed to determine the extent that patient comorbidities predict survival in DLBCL patients undergoing CAR-T therapy. Disclosures Bishop: Novartis Pharmaceuticals: Consultancy. Stephens:Karyopharm: Research Funding; Gilead: Research Funding; Acerta: Research Funding. Hill:Amgen: Research Funding; TG therapeutics: Research Funding; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celegene: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria; Takeda: Research Funding; Kite: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Consultancy, Honoraria. Danilov:Seattle Genetics: Consultancy; MEI: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Verastem Oncology: Consultancy, Other: Travel Reimbursement , Research Funding; Bayer Oncology: Consultancy, Research Funding; Pharmacyclics: Consultancy; Aptose Biosciences: Research Funding; Janssen: Consultancy; Celgene: Consultancy; Curis: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Takeda Oncology: Research Funding; Bristol-Meyers Squibb: Research Funding.

Background Most patients with chronic lymphocytic leukemia (CLL) present with multiple comorbidities. Although comorbidities negatively affect outcomes for patients treated with chemoimmunotherapy, their impact on patients who receive targeted therapies is unknown. Methods This multicenter, retrospective analysis evaluated the significance of comorbidities, as assessed by the Cumulative Illness Rating Scale (CIRS), among patients with CLL treated with ibrutinib. Results One hundred forty-five patients received ibrutinib (80% in a relapsed/refractory setting). A high burden of comorbidities (CIRS score ≥ 7) was associated with inferior median event-free survival (EFS; 24 vs 37 months; P = .003) and 2-year overall survival (OS; 79% vs 100%; P = .005). In an adjusted Cox model, both EFS and OS worsened with an incremental increase in the CIRS score. Furthermore, comorbidities were associated with an increased risk of ibrutinib dose reduction and therapy discontinuation. CIRS was predictive in both frontline and relapsed CLL, regardless of patient age. Conclusions Comorbidities portend a poor prognosis among patients with CLL treated with ibrutinib. Prospective studies are needed to optimize the treatment of patients with CLL who have comorbidities. Cancer 2018. © 2018 American Cancer Society.

Background Autologous stem cell transplant (ASCT) is frequently used as a consolidative therapy option after induction treatment in fit patients with mantle cell lymphoma (MCL) with the goal of prolonging the initial response duration. Despite recent advances there remains a subset of patients who experience early disease relapse after ASCT. We examined predictors of shortened progression-free survival (PFS) and post-relapse overall survival (OS) in a cohort of patients completing ASCT in first remission. Methods We evaluated MCL patients treated at 10 US academic medical centers. Eligible patients were treated from 2000 through 2017, and we collected information on demographic, clinical, and treatment-related variables of interest. Patients were then categorized into three post-ASCT PFS groups: 0-2 years, 2-5 years, and > 5 years, with PFS determined from the date of ASCT until progression or death from any cause. Patients followed for at least 5 years post-ASCT who were relapse free were included in the > 5 sub group. Associations were examined between groups and collected characteristics using chi-squared tests for categorical patient characteristics and ANOVA for numeric patient characteristics. The Kaplan-Meier method was used to estimate overall survival (OS) for each group, using time of relapse after ASCT as the starting point. Results Of 968 total MCL patients, 242 patients completed ASCT in first remission and either had a PFS event or were relapse-free for at least 5 years post-ASCT. Patients were 80% male, and the median age was 59 (Range: 29-83). The patients were divided into groups of post-ASCT PFS 0-2 years (n=74), 2-5 years (n=75), and more than 5 years (n=93). Post-ASCT PFS was shorter in patients with stage 4 disease (p=0.022), splenomegaly at baseline (p=0.005), and a lymph node size > 5 centimeters at baseline (p=0.043). Other variables were not significantly associated with PFS, including time to transplant and use of intensive therapy. Patients with 0-2 year PFS had a shorter median OS (22.1 months, 95% CI: 13.1- 38.1 months) in comparison to 2-5 year PFS (132 months, 95% CI: 36-132 months) and 5+ year PFS not reached (95% CI: 41.2 – N.A; Figure). Conclusion Patients with higher tumor burden at baseline have a shorter post-ASCT PFS and are more likely to relapse within 2 years. As has been seen in other lymphoma subtypes, early relapse is associated with shorter OS. This represents a patient group requiring improved therapies and perhaps are the best candidates for post-ASCT maintenance or consolidation approaches. Further studies integrating minimal residual disease and molecular risk-stratification may better identify patients at high risk for early progression.

Enzalutamide (MDV3100) is a second-generation androgen receptor antagonist that improves survival in metastatic, castration-resistant prostate cancer (mCRPC). Alternatives include chemotherapy, radiation, immunotherapy and abiraterone.The Phase I/II study showed early evidence of efficacy and determined that fatigue is the dose-limiting toxicity. Two randomized, placebo-controlled trials have demonstrated superiority of enzalutamide 160 mg by mouth daily over placebo in terms of overall survival, radiographic progression-free survival as well as a broad range of secondary and exploratory end points in men who had received previous chemotherapy (AFFIRM) and in those who were chemotherapy naive (PREVAIL). Common side effects include fatigue, arthralgias and constipation. A post hoc analysis from AFFIRM found that enzalutamide is safe and effective in men aged ≥ 75 years. The Phase I/II studies as well as AFFIRM and PREVAIL are described in this review.Enzalutamide extends overall and progression-free survival and is associated with robust response rates and quality of life benefits in men with mCRPC. Enzalutamide has not been proven to be effective in biochemically relapsed disease or in castration-sensitive prostate cancer. It should not be used in men at high risk for seizure, and patients should be counseled about the increased risk of falls.

Introduction: Chronic lymphocytic leukemia (CLL) is a common leukemia which tends to occur late in life. Comorbidities are common, and the iwCLL guidelines recommend their assessment in patients (pts) enrolled on clinical trials. The Cumulative Illness Rating Scale (CIRS) is a rigorous tool designed to evaluate the burden of comorbidities, which has been employed in therapeutic studies. Our group and others demonstrated that CIRS score predicts survival in pts with CLL treated with either chemo-immunotherapy (CIT) or novel kinase inhibitors (KI; ibrutinib) (Manda et al, 2016 & Gordon et al, 2018). However, CIRS has not become part of common clinical practice, in part due to complexities in scoring. It is also unknown whether all of the 14 organ systems included in the score carry equal weight to determine prognosis. Here we report the impact of specific comorbidities from a multicenter retrospective cohort of CLL pts treated with either CIT or KI. Methods: We conducted a retrospective analysis of pts with CLL treated at five US academic medical centers between 2000 and 2017. CIRS score was calculated as in Salvi et al, 2008. Random forest (RF) was used to assess specific comorbidities' impact on overall survival (OS) and event-free survival (EFS, defined as time to new therapy, disease progression or death). We adapted two separate approaches to investigate the RF variable selection process: variable Importance (VIMP), a property related to variable misspecification, and Minimal Depth (MD), a property derived from the construction of trees within the forest. Best variables were those selected consistently as top 3 in both VIMP and MD on the 500 RF repetitions. Because hepatic and renal comorbidities were rare they were excluded. OS and EFS were assessed by Kaplan-Meier estimates and Cox proportional hazard model adjusted for performance status and age. Significance was assessed with log-rank test. Results: 398 pts were included in the final analysis. The median age was 63 years (range, 30-93). 50% of pts (n=198) had a high CIRS score (≥7). 184 pts (46%) had comorbidities assessed in relapsed setting. For all pts, the most common treatments included ibrutinib (n=145; 37%), fludarabine-containing regimens (n=104; 26%) and bendamustine (n=39; 10%). Complex karyotype was observed in 3.5% (n=14) and 10.6% (n=42) of pts had del(17p). Pts with comorbidities (CIRS ≥7) demonstrated shortened survival following therapy, with 5-year OS of 64% vs 89% (p Random forest variable selections identified vascular comorbidities (e.g. DVT/PE) as the most influential risk factor for OS with CIT treatment, while HEENT and cardiac comorbidities were most impactful to OS for patients treated with KI. For EFS, the most influential comorbidities were cardiac and vascular for the CIT treatment group and endocrine and HEENT for patients treated with KI. Across EFS and OS, the most frequently selected variables in CIT were cardiac, hypertension, vascular and neurologic. We constructed a simplified scoring system assigning 1 point for each category. Comparing scores of 0, 1 and 2-4 (n=100, n=82, n=60), 5-year OS was 87%, 82% and 66%, respectively (p Conclusion: Comorbidities impact survival in CLL whether treated with CIT or KI. Which comorbidities are most prognostic may vary by treatment type. Vascular and cardiac comorbidities appear to be the most relevant in CLL pts treated with CIT. Meanwhile, cardiac, endocrine and HEENT had greater impact when pts were treated with KI. A simplified CIRS score is predictive of outcomes in both treatment subgroups. Disclosures Choi: Gilead: Speakers Bureau; AbbVie, Inc: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Rigel: Consultancy; Genentech: Speakers Bureau. Cohen:Takeda: Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioInvent: Consultancy. Persky:Genentech: Honoraria; Morphosys (IDMC): Consultancy; Spectrum: Research Funding; Merck: Research Funding. Danilov:Aptose Biosciences: Research Funding; Verastem: Consultancy, Research Funding; Astra Zeneca: Consultancy; Gilead Sciences: Consultancy, Research Funding; Takeda Oncology: Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Bayer Oncology: Consultancy, Research Funding.

Background: The identification of effective therapies based on targeted interventions for human cancers faces the challenges of genetic and epigenetic heterogeneity underlying the disease. Large-scale sequencing efforts have uncovered a spectrum of mutations in many hematologic malignancies, suggesting that combinations of agents will be required to treat these diseases effectively. Combinatorial approaches will also be critical for combating the emergence of genetically heterogeneous subclones, rescue signals in the microenvironment, and tumor-intrinsic feedback pathways that all contribute to disease relapse. Methods: We used a functional ex vivo screening assay to identify small-molecule targeted inhibitors and inhibitor combinations demonstrating selective efficacy across broad categories of leukemia. Primary mononuclear cells isolated from leukemia patients (n=588) were plated in the presence of a panel of graded concentrations of over 120 single-agent inhibitors or combinations spanning multiple drug classes. Leukemia specimens from 5 diagnosis subgroups included acute myeloid leukemia (AML; n=293), acute lymphoblastic leukemia (ALL; n=83), chronic lymphocytic leukemia (CLL; n=140), chronic myeloid leukemia (CML; n=26) and myeloproliferative neoplasms/myelodysplastic syndrome (MPN or MDS/MPN; n=46) patients. The combinations were designed as drug pairs that target non-overlapping biological pathways and comprise drugs from different classes, preferably with Food and Drug Administration approval. IC50 and AUC values were derived from probit-based regression for each response curve. Mutational status for FLT3-ITD and NPM1 were compiled from clinical labs or by capillary electrophoresis using a QiaXcel instrument. Disease status was obtained from clinical chart review. Single and combination drug treatment IC50 and AUC values were compared within groups by Friedman test, across groups by Kruskal-Wallis test, and with continuous variables by Spearman rank correlation. Results: Among 588 unique leukemia patients evaluated, we observed that the combination of venetoclax (a BCL2 inhibitor) with ibrutinib(a BTK inhibitor) showed enhanced benefit above that for either single agent in both myeloid and lymphoid malignancies, including AML, ALL, and CLL. Expanded analyses of combination sensitivity in AML patients showed no significant associations with age, gender, or ELN prognostic risk. Comparison of AML samples by disease treatment status indicated a slightly greater sensitivity in relapsed/refractory (n=42) versus newly diagnosed (n=115) AML samples by both AUC and IC50 (p=0.028 and 0.026, respectively). Among AML samples, FLT3-ITD and NPM1 mutation status was available for 204 and 188 patients, respectively. Venetoclax + ibrutinib was significantly more effective in patient samples harboring FLT3-ITD or NPM1 mutations by both AUC (p=0.0002 and p=0.0032, respectively) and IC50 (p=0.0002 and p=0.021, respectively). Furthermore, among 112 AML samples with RNAseq data available, sensitivity to the combination (AUC) was significantly correlated with gene expression for BCL2 and BTK (Spearman r: -0.48 and -0.21, respectively). Evaluation of the combination using an expanded 7x7 concentration matrix on AML cell lines revealed synergy for the majority of drug-pair concentrations by the Bliss independence model. Analysis to align additional clinical and genetic features for leukemia patient samples with drug sensitivities is in progress and results with be presented at the meeting. Conclusion: Both myeloid and lymphoid-derived primary leukemia cells show sensitivity to combined inhibition of BCL2 and BTK with the combination of venetoclax and ibrutinib, suggesting this drug pair may have broad therapeutic indications. Disclosures Tyner: Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Constellation: Research Funding; Janssen: Research Funding; AstraZeneca: Research Funding; Incyte: Research Funding; Array: Research Funding; Aptose: Research Funding. Danilov:TG Therapeutics: Consultancy; Takeda Oncology: Research Funding; Aptose Biosciences: Research Funding; Genentech: Consultancy, Research Funding; Astra Zeneca: Consultancy; Gilead Sciences: Consultancy, Research Funding; Bayer Oncology: Consultancy, Research Funding; Verastem: Consultancy, Research Funding. Druker:Aileron Therapeutics: Consultancy; Third Coast Therapeutics: Membership on an entity's Board of Directors or advisory committees; Aptose Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Patient True Talk: Consultancy; Vivid Biosciences: Membership on an entity's Board of Directors or advisory committees; GRAIL: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARIAD: Research Funding; Oregon Health & Science University: Patents & Royalties; Fred Hutchinson Cancer Research Center: Research Funding; Cepheid: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millipore: Patents & Royalties; Leukemia & Lymphoma Society: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Sciences: Consultancy, Membership on an entity's Board of Directors or advisory committees; McGraw Hill: Patents & Royalties; Henry Stewart Talks: Patents & Royalties; Novartis Pharmaceuticals: Research Funding; Monojul: Consultancy; ALLCRON: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Beta Cat: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Research Funding; MolecularMD: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Purpose Identify AML patients most likely to respond to CPX-351, a nano-scale liposome formulation containing cytarabine and daunorubicin co-encapsulated at a 5:1 molar ratio. Methods We examined the ex vivo cytotoxic activity of CPX-351 against leukemic cells isolated from 53 AML patients and an additional 127 samples including acute lymphoblastic leukemia, myelodysplastic syndrome/myeloproliferative neoplasms, or chronic lymphocytic leukemia/lymphoma. We assessed activity with respect to common molecular lesions and used flow cytometry to assess CPX-351 cellular uptake. Results AML specimen sensitivity to CPX-351 was similar across conventional risk groups. FLT3-ITD cases were five-fold more sensitive to CPX-351. CPX-351 was active across other indications with nearly all cases exhibiting IC 50 values markedly lower than reported 72-h plasma drug concentration in patients receiving CPX-351. The range and distribution of CPX-351 IC 50 values were comparable for AML, CLL, and ALL, whereas MDS/MPN cases were less sensitive. CPX-351 uptake analysis revealed a correlation between uptake of CPX-351 and cytotoxic potency. Conclusions Our findings are consistent with clinical data, in which CPX-351 activity is retained in high-risk AML patients. Ex vivo analysis of cytotoxic potency may provide a means to identify specific AML subsets, such as FLT3-ITD, that benefit most from CPX-351 and warrant additional clinical evaluation.

Objectives The purpose of this study was to describe the clinical characteristics and outcomes in cardiac non-Hodgkin's lymphoma (NHL). Methods A retrospective analysis of 94 cases of NHL with biopsy-proven cardiac involvement in PubMed between 1990 and 2015. Results Among cases with cardiac involvement, diffuse large B-cell lymphoma was the most common histologic subtype (58%), followed by T-cell lymphoma (16%), Burkitt's lymphoma (9%), and small lymphocytic lymphoma (6%). Symptomatic heart failure was the most common clinical presentation (34%), and 20% of patients had no cardiac symptoms. Median survival was 3 months (range, 0-72) among all patients. Patients who presented with heart failure had inferior outcomes. Patients with primary, vs. secondary, cardiac involvement had a trend toward superior outcomes. Importantly, chemotherapy treatment was associated with a prolongation in median survival (18 vs. 1 month, HR 0.16, 95% CI, 0.47-0.54, P = 0.0003), and patients diagnosed in the chemo-immunotherapy era demonstrated a trend toward better outcomes. Median survival was not reached among patients with B-cell malignancies who were alive for 1 month after the diagnosis. Conclusion Pathologic lymphomatous involvement of cardiac tissue should be considered in the evaluation of patients with NHL. Durable remissions can be achieved in B-cell NHL with cardiac involvement, and thus, therapy should be considered in such cases.

e19514Background: Concurrent use of strong CYP3A4 inhibitors increases ibrutinib exposure 20-fold. Hence, use of strong CYP3A4 inhibitors/inducers is not recommended, and moderate inhibitors warran...

Introduction: The majority of patients with chronic lymphocytic leukemia (CLL) present with comorbidities, commensurate with the median age at diagnosis of 71 years. The Cumulative Illness Rating Scale (CIRS) is a widely used index which has been incorporated into clinical research in CLL. CIRS consists of 14 categories related to different body systems and scores the severity of each condition from 0-4. We have previously reported in a single-center study that CIRS predicted outcomes in patients with CLL treated with chemo-immunotherapy (CIT). However, to date it is not yet known how comorbidities impact outcomes in the era of novel agents. We tested a hypothesis that CIRS and severe organ dysfunction would retain prognostic significance. Methods: We conducted a retrospective analysis of patients with CLL who underwent treatment at three academic medical centers between 2000 and 2016. CIRS score was calculated as in Salvi et al, 2008. Overall survival (OS) and progression-free survival (PFS) were assessed by Cox proportional hazards models adjusting for performance status (PS), age group, and chemotherapy regimen. Survival analysis in patients treated with ibrutinib was adjusted for age, PS, Rai stage, del17p and prior treatment. In addition, the impact of severe organ dysfunction (CIRS-3+, i.e. CIRS score ≥3 in single organ system) was assessed. Results: Median age in patients receiving CIT was 65 years (N=233). The most common comorbidities were hypertension, endocrine (e.g. diabetes mellitus) and vascular (e.g. deep vein thrombosis). Fludarabine-Rituximab (N=61), Fludarabine-Cyclophosphamide-Rituximab (N=67), Rituximab-Cyclophosphamide-Vincristine-Prednisone (N=35), Bendamustine-Rituximab (N=38) and chlorambucil (N=47) were the most commonly used regimens. 79.5% of treatments were administered in a frontline setting. Average total CIRS was 6.6 and 47% had CIRS-3+. Median OS among all patients receiving CIT was 112 months (95% CI: 105 - 128 months). CIRS≥7 and CIRS3+ were associated with inferior OS compared to patients without significant comorbidities (87, 92 and 129 months, respectively, p In patients treated with ibrutinib the median age was 71 years (N=83), which was significantly older than in the CIT cohort (p Conclusion: In this multicenter retrospective analysis we show that CIRS has prognostic significance in patients with CLL treated with either CIT or ibrutinib, where increased comorbidities correlate with shortened progression-free and overall survival. CIRS appears to carry prognostic value in both upfront and relapsed settings, including patients whose disease can be salvaged with ibrutinib. Larger prospective studies of patients with lymphoid malignancies who have comorbidities are necessary to better define the prognostic value of CIRS in the era of targeted agents and determine the optimal approach to therapy of such patients. Figure 1 Figure 1. Disclosures Persky: Genentech: Consultancy; MorphoSys: Other: Independent Data Monitoring Committee member ; Verastem: Consultancy; Spectrum Pharmaceuticals: Research Funding.

Introduction: CPX-351 (Vyxeos) is a liposomal combination of cytarabine and daunorubicin at a synergistic 5:1 molar ratio. Recently, CPX-351 has been shown to be significantly more effective than the 7+3 standard of care chemotherapy in treating high-risk AML patients, including patients with the FLT3-ITD mutation. We previously treated primary patient samples with CPX-351 ex vivo and found that FLT3-ITD+ samples were significantly more sensitive to CPX-351 and showed enhanced drug uptake. We hypothesized that dysregulated FLT3 signaling results in an activation of liposome uptake pathways, leading to increased sensitivity to CPX-351 and ultimately cell death. Furthermore, we examined the effect of combining CPX-351 with existing FLT3 inhibitors (e.g. quizartinib and midostaurin). Methods: To examine drug uptake dynamics, we exposed AML cell lines (including MOLM-13 and MOLM14 that contain FLT3-ITD, and ME1 that contains an activating FLT3 mutation) to varying concentrations of CPX-351, with or without pre-treatment of quizartinib and midostaurin. We evaluated cell viability using a colorimetric assay and measured intracellular daunorubicin fluorescence, an indicator of drug uptake, by flow cytometry. Additionally, we analyzed the synergy of exposing these cell lines to CPX-351 and FLT3 inhibitors in combination and at different dose schedules, followed by measuring cell viability and daunorubicin fluorescence. Results: We observed that cell lines containing FLT3-ITD or FLT3-activating mutation were more sensitive to CPX-351 and exhibited increased drug uptake compared to cell lines with other genetic abnormalities. Interestingly, we observed that pre-treatment with quizartinib for 16 hrs produced a population of cells (approximately 50% of the total population) that exhibited decreased daunorubicin fluorescence, suggesting that prolonged FLT3 inhibition may decrease CPX-351 uptake. Consistent with this, we observed robust synergy when combining CPX-351 with FLT3 inhibitors simultaneously or with CPX-351 exposure scheduled 24 hours prior to FLT3 inhibitor exposure. However, exposure to FLT3 inhibitors 24 hours prior to CPX-351 administration was less synergistic and even antagonistic at certain doses. Conclusions: These data provide additional supportive evidence that FLT3 activation results in increased uptake of CPX-351. This is consistent with results from the CPX-351 Phase III trial in which FLT3-ITD+ patients survived significantly longer when treated with CPX-351 compared to 7+3 chemotherapy. We also show that combining CPX-351 with existing FLT3 inhibitors can elicit a synergistic response when administered in dosing regimens where FLT3 inhibition does not precede CPX-351 treatment. Cumulatively, our data support further testing of CPX-351 in combination with FLT3 inhibitors for treating AML patients with genetic dysregulation of FLT3 signaling. Citation Format: David K. Edwards, Nathalie Javidi-Sharifi, Angela Rofelty, Max Gordon, Riley Roth-Carter, Paul Tardi, Lawrence Mayer, Jeffrey W. Tyner. CPX-351 works synergistically in combination with FLT3 inhibitors against AML with FLT3-ITD [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1087. doi:10.1158/1538-7445.AM2017-1087

Background:There are multiple prognostic markers used to risk stratify pts with mantle cell lymphoma (MCL) including the MCL International Prognostic Index (MIPI) which divides newly diagnosed patients into three groups based on available clinical and laboratory data.Complex karyotype (CK) defined as equal to or greater than 3 chromosomal abnormalities has also been associated with inferior outcomes in MCL although its association with MIPI is lesswell-described. We conducted a multicenter analysis of MCL pts to assess the relative contributions of MIPI, CK and Ki67 as predictors of progression-free (PFS) and overall survival (OS). Methods:Untreated pts atleast18 years of age with MCL from 5 academic centers diagnosed between 1993 and 2015 who had available data describing MIPI, Ki67, and cytogenetics were included. Patients with 3 or more chromosomal abnormalities were defined as having CK. High Ki67 was defined as immunohistochemistry staining >30%. We described the associations between MIPI risk group, CK, Ki67, and other clinical factors of interest as predictors of PFS and OS in univariate and multivariable models. Results:Of 92 eligible MCL patients, 30 (32.6%) had low-risk, 36 pts (39.1%) had intermediate-risk, and 26 pts (28.3%) had high-risk MIPI scores. Ki67 index was >30% in 44.6% of patients, and 17.4% had CK. Neither Ki67 > 30% (p=0.548) norpresence of CK (p=0.409) wereassociated with MIPI risk category. In the low-risk MIPI subgroup, 37% of patients had Ki67 > 30% and 10% had CK. Induction regimens included: R-HyperCVAD (n=15), R-CHOP/R-DHAP (n=7), Nordic regimen (n=13), R-CHOP (n=10), B-R (n=19), and others (n=28). Thirty-two patients (39%) had an autologous stem cell transplant (ASCT) in first remission. Median PFS for the entire cohort was 3.8 years, and median OS has not yet been reached. Median PFS for was 2.2 years, 2.5 years, and 7.9 years for patients with high-, intermediate-, and low- risk MIPI scores, respectively, at diagnosis. Median PFS was 2.4 years for patients with Ki67 > 30% and 7.9 years for patients with Ki67 < 30%. Median PFS was 1.3 years for patients with CK and 4.3 years for patients without CK. High risk MIPI (p=0.042), CK (p=0.002), and Ki67 index > 30% (p=0.002) were all associated with inferior PFS in a univariable analyses (See Figure). In a multivariable analysis (See Table) Ki67 >30% (HR=3.66, p Conclusions:Our findings suggest that Ki67> 30% and CK are independently associated with inferior outcomes in MCL. In this analysis, MIPI risk score was not independently associated with PFS or OS when considering these additional prognostic markers, which needs to be confirmed in other retrospective and prospective cohort studies. Our high-risk MIPI patients, in general, have an improved outcome compared to prior reports. (Hoster2008, 2014;Lex2014), suggesting that alternative markers may play an important role in MCL risk-assessment. Efforts to incorporate additional patients and develop a new prognostic model in MCL are underway. Figure Figure. Figure Figure. Disclosures Danilov: Pharmacyclics: Consultancy; Astra Zeneca: Research Funding; Takeda: Research Funding; GIlead Sciences: Research Funding; ImmunoGen: Consultancy; Dava Oncology: Honoraria; Prime Oncology: Honoraria. Hamadani:Janssen: Consultancy; Celgene: Honoraria, Research Funding; Takeda Pharmaceuticals: Research Funding. Flowers:TG Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Infinity: Research Funding; Millenium/Takeda: Research Funding; Mayo Clinic: Research Funding; NIH: Research Funding; Roche: Consultancy, Research Funding; Pharmacyclics, LLC, an AbbVie Company: Research Funding; ECOG: Research Funding; AbbVie: Research Funding; Acerta: Research Funding; Gilead: Consultancy, Research Funding. Cohen:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium/Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding.

The correlation of rheumatoid arthritis and lymphoma—and more generally, autoimmune disease and malignancy—has long been observed. Here, we present the case of a woman with rheumatoid arthritis who developed lymphoma limited to her hands.

Background: CPX-351, a synergistic ratio of cytarabine (Cyt) and daunorubicin (Daun) co-encapsulated in a nano-scale carrier, has demonstrated improved complete remission and overall survival rates compared to conventional Cyt + anthracycline treatments in two randomized clinical trials and is currently being evaluated in a Phase 3 trial vs 7+3 Cyt:Daun. To determine whether these effects are attributable to liposome-mediated altered drug PK or specific AML blast genotypes/phenotypes, we investigated the ex vivo cytotoxic potency of CPX-351 against fresh AML blast samples. Cytotoxicity results were correlated with patient characteristics as well as CPX-351 cellular uptake and molecular phenotype status including FLT3-ITD, NPM1 and CEBPα. Methods: Peripheral blood was obtained at diagnosis from patients with AML. White blood cells were isolated on Ficoll gradients. Cells were incubated over graded concentrations of CPX-351 for 72 hr at which time cell viability was assessed by MTS assay. Cell viability values were normalized to patient-matched untreated cells. Patient-specific IC50 values were calculated and correlated with clinically-relevant disease features. Uptake of intact CPX-351 liposomes by AML cells was determined by monitoring cells for daunorubicin fluorescence by flow cytometry. Results: CPX-351 cytotoxicity was evaluated in 53 AML patient specimens. CPX-351 IC50 values ranged from 0.03:0.006 uM to 10:2 uM (Cyt:Daun), and all values were significantly lower than the 72 hour plasma drug concentration of 60:12 uM Cyt:Daun observed in patients receiving CPX-351. Sensitivity to CPX-351 was similar regardless of cytogentic risk, NPM1 and CEBPα status as well as whether the patients went on to achieve a CR or PD upon receiving standard 7+3 Cyt:Daun after blast samples were taken. Surprisingly, AML blasts exhibiting the FLT3-ITD phenotype exhibited some of the lowest IC50 values and as a group were 5-fold more sensitive to CPX-351 than those with wild type FLT3. Flow cytometric analysis revealed a correlation between uptake of CPX-351 into AML blasts and its cytotoxic potency. Taken together, the data are consistent with clinical observations where CPX-351 retains significant anti-leukemic activity in AML patients exhibiting high-risk characteristics that are typically associated with poor outcomes when treated with conventional regimens. Conclusions: The profile of ex vivo AML blast sensitivity to CPX-351 mirrors the efficacy profile observed clinically and may provide a means to identify specific AML patient genotypes/phenotypes that could benefit most from CPX-351 treatment. The increased sensitivity of FLT3-ITD+ blasts to CPX-351 is an example of how such analyses may identify additional AML patient populations warranting further clinical investigation. Citation Format: Max Gordon, Paul Tardi, Lawrence D. Mayer, Jeffrey Tyner. CPX-351 cytotoxicity against fresh AML blasts is increased for FLT3-ITD+ cells and correlates with drug uptake and clinical outcomes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 287.

7567Background: While mantle cell lymphoma (MCL) has historically been treated at the time of diagnosis, we recently reported a national cohort analysis which identified a subset of patients who can safely defer therapy (Cohen et. al, ASH 2015), validating previously reported single-center findings (Martin et al, JCO 2009). We conducted a multicenter analysis of MCL patients with additional clinical data to better describe the role of deferred therapy in MCL. Methods: Patients ≥ 18 years old who received initial treatment for newly diagnosed MCL between 1995-2015 at one of four academic sites were included. Deferred therapy was defined as receipt of first treatment > 90 days following diagnosis. We identified variables associated with receipt of deferred therapy and evaluated the impact of deferred therapy, demographic factors and MIPI components on progression-free (PFS) and overall survival (OS) in multivariable regression models. Results: Of 356 patients, 71 (20%) received deferred therapy with a media...

7565Background: Complex karyotype (CK) has been associated with inferior outcomes in mantle cell lymphoma (MCL) and other hematologic malignancies, including, but has only been evaluated in small M...

Introduction: Cardiac involvement by Non-Hodgkin lymphoma (NHL) occurs by several distinct mechanisms: primary extra-nodal disease, direct extension, hematogenous or lymphatic spread. While it is not an uncommon autopsy finding, it is rarely deemed to be clinically significant. By contrast, extranodal involvement by NHL is associted with inferior outcomes. Here we performed a retrospective review of 91 published cases of NHL with biopsy-proven cardiac disease to evaluate its clinical significance and impact on outcomes. Methods: A literature search using Pubmed was performed between 1990 and 2015. Inclusion criteria were biopsy proven lymphoma, age greater than or equal to 18, no history of bone marrow transplant and direct involvement of the pericardium and or myocardium. Survival data was only analyzed from patients without HIV/AIDS. Log-rank (Mantel-Cox) test was used to calculate survival. Age comparisons were calculated using an unpaired t-test with a two-tailed p-value and one-way ANOVA. Results: Ninety-one cases met inclusion criteria for the review. The mean age was 55 years (range 19-90 years). Patients with Burkitt lymphoma and HIV/AIDS were younger (p=0.016). Of patients with pathological evidence of cardiac involvement, diffuse large B-cell lymphoma (DLBCL) was the most common NHL subtype (52% of cases), followed by T-cell lymphoma (16%), Burkitt Lymphoma (8%) and small lymphocytic lymphoma (SLL, 6%). Chest pain was the most frequent presenting symptom (Table). Table. N=91 (%) Age: 18-60 >60 (60-90) 48 (53) 43 (47) Sex: Male Female 60 (66) 31 (34) Lymphoma type: Burkitt SLL DLBCL Follicular T-Cell Not specified 8 (9) 6 (7) 52 (57) 2 (2) 15 (16) 8 (9) Treatment: Chemotherapy Chemo and radiation Radiation Surgery None Unreported 25 (28) 6 (6) 1 (1) 4 (4) 11 (12) 44 (49) HIV/AIDS: Infected Non-infected 17 (19) 74 (81) Presenting clinical syndrome: Arrhythmia Chest pain CHF/Dyspnea Constitutional symptoms SVC syndrome Heart Block Stroke Sudden Death Other Unreported 2 (2) 10 (12) 31 (34) 6 (7) 4 (4) 4 (4) 3 (3) 3 (3) 8 (9) 20 (22) Forty-eight patients had primary cardiac lymphoma, which was defined as de novo lymphomatous involvement confined to the myocardium and/or pericardium, 41 patients had secondary disease and two were indeterminate. Patients with primary cardiac lymphoma were older (60 years, 95% CI, 55-59 years, versus 50 years, 95% CI, 47-53 years, p=0.006). Survival data were available for 54 patients. Of note, ~50% of patients did not receive therapy. Median survival was 3 months for all patients. The median survival of patients with T-cell lymphoma was 2 months, versus 4 months in the B-cell lymphoma subgroup (p=0.20). The median survival of patients with indolent B-cell lymphoma (SLL) was 37.5 months versus 4 months in patients with aggressive lymphoma (DLBCL and Burkitt, p=0.77). We found that female sex was associated with a trend towards improved outcome (median survival of 12 versus 3 months, p=0.63). Furthermore, patients diagnosed with primary (de novo) cardiac lymphomas also had better survival, 4 versus 2 months (p=0.23), possibly reflecting the more aggresive nature of relapsed disease. On further analysis, patients who were alive one month after diagnosis had a median survival of 18 months versus 3 months for all patients in this cohort (p=0.032). Furthermore, patients with primary B-cell lymphoma had superior survival to patients with T-cell lymphoma and/or secondary disease (median survival not reached vs 2.5 months, p=0.027). We also found that patients who received chemotherapy had a median survival of 18 months versus 1 month for those who did not (p=0.003). Discussion: Symptomatic cardiac involvement by NHL is rare. While it appears to be more common in DLBCL, it is seen across multiple indolent and aggressive NHL subtypes and is more common in men, typically presenting in the 6th decade of life. The outcomes of patients with NHL with cardiac involvement are poor, particularly among those with aggressive subtypes. However, patients who are candidates for chemotherapy and who survive beyond one month, particularly those with de novo (primary) cardiac B-cell lymphoma, are more likely to achieve long-term survival. Pathological lymphomatous involvement of cardiac tissue needs to be considered as part of differential diagnosis during work-up of patients with NHL. Disclosures No relevant conflicts of interest to declare.

Ewing sarcoma (EWS) is a primary bone tumor that most often occurs in the long bones of young patients. EWS is typically an aggressive tumor that is highly sensitive to radiation therapy; recurrences often occur, usually within a year of treatment. We present a case of EWS that first presented in a patient at the age of 40 with extraosseous disease. The patient was treated initially with radiation and surgery. Over the following 36-year period, the tumor recurred once and metastasized twice. The morphologic, immunohistochemical, and cytogenetic features of this tumor were typical of EWS, and the tumor was highly responsive to radiation therapy. The unusually prolonged course in this patient demonstrates significant heterogeneity in the biological behavior of EWS, and the importance of randomized trials in cancer therapy.