Witzig, Thomas E.

Abstract Background. Recent clinical trials based on immunotherapies targeting the PD-1/PD-L1 pathway have shown striking durable responses in a subset of patients with solid cancers. The Programmed death 1 (PD-1) protein is a key immune checkpoint inhibitor expressed by activated T cells. Its ligand, PD-L1, was reported highly expressed by tumor cells in some diffuse large B-cell lymphomas (DLBCL) of non-Germinal Center phenotype. We recently reported on the French multicenter GOELAMS075 trial that pre-treatment soluble PD-L1 (sPD-L1) in plasma was elevated in DLBCL patients compared to controls, and that elevated sPD-L1 was associated with inferior overall survival (OS), independent of the International Prognostic Index (IPI) and other clinical factors (Rossille et al., Leukemia 2014). Here, we replicate and extend these findings in two independent studies from Australia and the US. Methods. The protein expression of sPD-L1 was evaluated using a commercial ELISA kit. The French discovery cohort consisted of 288 adults with newly diagnosed aggressive DLBCL, age 18 to 60 years, and treated with R-CHOP or high dose chemotherapy plus rituximab followed by autologous stem cell support (clinicaltrials.gov: NCT00561379); there were also 60 controls. The Australian study consisted of 51 DLBCL patients age 18 to 71 years, all stages, treated with R-CHOP14, along with 57 controls. The US study was an observational cohort from the Iowa/Mayo Lymphoma SPORE and consisted of 225 DLBCLs, age 19 to 92 years, all stages, treated with immunochemotherapy, along with 98 controls. Plasma samples were collected pre-treatment using EDTA tubes for the Australian and the US cohorts, BDª P100 tubes for the French cohort. sPD-L1 expression was measured in Rennes, France (French & US samples) and in Brisbane, Australia (Australian samples).The Kaplan-Meier method and Cox regression were used to model the association of sPD-L1 with OS. The 95th percentile of the sPD-L1 levels in each matched control group was used as the cutoff point to define elevated sPD-L1 levels. Results. Replicating the French findings, sPD-L1 levels were significantly higher for DLBCL patients compared to controls in both the US (P<0.0001) and Australian (P<0.0001) studies (Figure 1). The odds ratios for elevated sPD-L1 among patients compared to controls were 10.7 (95% CI 3.3-22.0), 8.9 (95% CI 3.1-25.3) and 12.6 (95% CI 2.7-28.0) for the French, US and Australian studies, respectively. In the French cohort, elevated sPD-L1 levels were associated with inferior OS (Hazard Ratio (HR)=2.05; 95% CI 1.18-3.57), and this was replicated in the US cohort (HR=1.71; 95% CI 0.97-3.01) (Figure 2). Due to the similarity of the results, we next pooled the French and US cohorts to increase power for multivariate and subset analyses. The median age at diagnosis of the 513 patients was 54 years; 29% were more than 60 years old; 69% of the patients had stage III-IV disease; 56% were IPI intermediate-risk and 9% were IPI high-risk patients. The median follow-up was 48 months (range, 0.5-126) overall, and 66 months for the patients still alive; there were 102 deaths. Using a cutpoint of 1729 pg/mL from the combined studies, patients with elevated sPD-L1 had inferior OS compared to patients without elevated sPD-L1, with 3-year OS rates estimated at 78% (95% CI 71.8-84.9) vs. 87.8% (95%CI 84.5-91.4) (P<0.01). In multivariate analysis, elevated sPD-L1 (HR=1.75; 95%CI 1.16-2.64), age (HR=1.03; 95%CI 1.02-1.05), high-risk IPI score (HR=3.71; 95%CI 1.91-7.21) and ALC ² 1 G/L (HR=2.19; 95%CI 1.44-3.33) were all significant at P<0.01. In analyses stratified by IPI, the 3-year OS rates among high-risk patients (IPI 4-5) was 40.9% (95% CI 23.6-71.0) for elevated sPD-L1 vs. 82.1% (95% CI 69.1-97.6) for not elevated sPD-L1 (P<0.01). There was no association of sPD-L1 with 3-year OS among low risk (IPI 0-1) or intermediate-risk (IPI 2-3) patients. Conclusion. We confirmed that sPD-L1 levels are higher in pre-treatment plasma samples of newly diagnosed DLBCL patients compared to controls, and that elevated levels of sPD-L1 are associated with inferior OS in DLBCL patients treated with immunochemotherapy, and this is independent of IPI and other clinical factors. Among high risk patients, we identified a subgroup with less than 50% survival. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract Background: EBV+ DLBCL not otherwise specified (EBV+ DLBCL NOS) is defined by the 2016 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues as EBV+ DLBCL in patients without a history of known immunosuppression. Among Asian patients, adverse outcomes have been associated with EBV+ vs EBV- DLBCL, and circulating EBV has been found in the majority of patients. Outcome studies of unselected North American patients are few and non-confirmatory. No formal assessment of immunosuppression status has been incorporated into these analyses, leading to the variable inclusion of patients with a history of immunocompromised states. We sought to determine the prevalence, presenting clinical and pathology characteristics, and outcomes of DLBCL by EBV and immunosuppression status in an unselected prospective cohort study of North American patients. Methods: From 2002-2012, we enrolled consecutive, newly diagnosed patients with lymphoma who were ≥ 18 years and HIV negative into the Molecular Epidemiology Resource (MER). Clinical, laboratory, and treatment data were abstracted from medical records. All DLBCL patients with available tissue microarrays (TMAs), excluding primary mediastinal DLBCL and post-transplant lymphoproliferative disorders, were included. Medical records were reviewed using a standard protocol to classify patients as immunocompromised based on a documented history of primary immunodeficiency or iatrogenic immunosuppression. DLBCL cell of origin was classified as germinal center (GCB) vs non-GCB using the Hans algorithm. CD30 was determined using immunohistochemistry; positivity cutoff was 20% of neoplastic cells. EBV testing was performed by in-situ hybridization for EBV encoded small RNAs (EBERs), and scored by an expert hematopathologist. Event free survival (EFS) was defined as time from diagnosis until recurrence, retreatment, or death due to any cause. Associations with EFS and Overall Survival (OS) were obtained using the methods of Kaplan-Meier (KM). Hazard Ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox regression models. Results: 1,100 patients with DLBCL were enrolled into the MER; 362 had TMAs available for this analysis. Median age was 63 years (range 20-89) and 59% were male. 89.5% of patients were treated with immunochemotherapy. 16 cases (4.4%) were EBV+, and 39 cases (10.8%) were considered immunocompromised. EBV positivity was more common in immunocompromised vs immunocompetent patients, with a trend towards significance (10.3% vs 3.7%; P = 0.08). The non-GCB subtype was more frequent in EBV+ vs EBV- DLBCL (62.5% vs 34.1%; P < 0.01), but similar between immunocompromised vs immunocompetent patients (48.7% vs 33.7%; P = 0.10). CD30 positivity was also more frequent in EBV+ vs. EBV- DLBCL (25.0% vs 8.1%; P < 0.01), but similar between immunocompromised vs immunocompetent patients (12.8% vs 8.4%, respectively; P = 0.45). With a median follow-up of 59 months (range 0.7-155.2) there were 151 events and 119 deaths. KM curves by EBV and immunosuppression status are shown in the figure. There was no association of EBV positivity with EFS (HR = 0.76; 95% CI 0.34-1.72) or OS (HR = 0.99; 95% CI 0.43-2.25). A history of immunosuppression was not associated with EFS (HR = 1.17; 95% CI 0.72-1.89) or OS (HR = 1.02; 95% CI 0.58-1.78). In the subset of immunocompetent patients, there was no association of EBV positivity with EFS (HR = 0.54; 95% CI 0.17-1.70) or OS (HR = 0.71; 95% CI 0.23-2.25). Similar results were obtained after adjustment for the International Prognostic Index. Circulating viral DNA was detected in 2/5 EBV+ and 4/49 EBV- DLBCL patients. Conclusions: The prevalence of EBV+ DLBCL NOS is <5% among patients in a large North American cohort, similar to other western populations. There was no evidence of an association of EBV or immunosuppression status with EFS or OS, with low power for detecting associations with EBV. Circulating viral DNA was infrequent among either EBV+ or EBV- DLBCL patients. While immunosuppression has been previously shown to be a risk factor for DLBCL, it was not found to be associated with EFS or OS. Overall, these results suggest divergent outcomes among EBV+ DLBCL patients between western and non-western populations, underscoring differences in host factors or circulating viral strains. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding.

Abstract Introduction New treatment strategies are improving outcomes for patients with Hodgkin (HL) and non-Hodgkin lymphoma (NHL) but achieving durable responses and cure in the relapsed patient remain a challenge. Both the mTORC1 inhibitor everolimus (RAD001) and the IMiD, lenalidomide (LEN) have efficacy as single agents in patients with relapsed and refractory (R/R) HL and NHL. Individually, LEN and RAD present a low toxicity profile and in combination may offer synergistic therapeutic efficacy by unique mechanisms of action. A phase I/II clinical trial of RAD and LEN was designed to explore the tolerability, toxicity and to determine the maximum tolerated dose (MTD) of this combination for the Phase II study. The results of phase I/II data are reported here. Methods MC0981 was activated on January 10, 2011. In phase I, the study enrolled a total of 25 patients and RAD 5 mg daily + LEN 10 mg/d X 21d in a 28-day cycle was defined as the MTD. The phase II opened on May 14, 2013, and closed on Feb 19, 2014, during which 33 patients were enrolled and were treated until progression of disease. Eligibility required age ≥18, biopsy proven relapsed or refractory NHL or HL, ECOG PS 0- 2, measurable disease, Hb >9g/dl, ANC ≥1200/uL, platelet ≥ 50,000/uL, creatinine ≤1.5xULN and willingness to sign informed consent. Women of child bearing potential had pregnancy testing and all patients followed recommendations for contraception. Follow up data was analyzed as of July 2014. Results A total of 58 patients were enrolled to this study and fifty five are evaluable for analysis (2 never started therapy, 1 deemed ineligible). The median age was 62 years (21-82) and 38 (69.1%) were male. Sixty-five percent had stage IV disease and 42% had 4 or more prior treatments including stem cell transplantation in 49%. Histologies included HL (n=10) and NHL (n=45 with 23 DLBCL, 2 FL-III, 5 LPL, 3 MCL, 2 MF, and 3 other). At least 1 Gr≥3 adverse event was seen in 74.5% of patients. The most common Gr≥3 toxicities were hematologic - neutropenia (30.9%), and thrombocytopenia (21.8%), and anemia (10.9%). Nine of 55 patients (16%) had Gr≥3 infection; 2 with skin infection, 1 with cholecystitis, 1 with lung infection, 1 with pharyngitis 1 with otitis externa, 1 with otitis media, and 1 with pleural infection and 1 with upper respiratory tract infection. Seven patients discontinued treatment due to adverse events. At this time, 44% (25/55) remain progression-free. A documented tumor response, as overall response rate (ORR) was seen in 20% (11/55) with 1CR, 8PR, and 2MR; 17 remain on therapy; and 22 deaths have occurred with a median survival of 15.0 months (95% CI 7.5-NR). Median follow up time was 5.5 (range, 0.7- 41.0) months. The median duration of response (DOR) in those responding is 19.4 months. Conclusions In a heavily pretreated population with baseline compromised bone marrow function, the combination of everolimus and lenalidomide is feasible with a modest ORR and a surprisingly long DOR. Future studies in more defined groups of NHL or HL are necessary to better predict which patients will be long-term responders. This trial is sponsored by Novartis and Celgene Disclosures Off Label Use: mTORC1 inhibitor (Everolimus) and the Immunomodulatory (IMiD) drug Lenalidomide for patients with Heavily Pretreated Relapsed Lymphoma . Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Nowakowski:Celgene, Morphosis: Consultancy. Witzig:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding. Reeder:Millennium, Celgene, Novartis: Research Funding.

Abstract Background: Vitamin D insufficiency (VDI) has been associated with inferior outcomes in patients with follicular lymphoma (FL) treated with chemotherapy and an anti-CD20 monoclonal antibody (immunochemotherapy; IC), but whether this association holds for other FL treatment strategies is not known. Furthermore, the subset of FL patients who experience clinical failure (progression, treatment failure) within 12 months of diagnosis have an inferior outcome compared to those achieving event-free status at 12 months (EFS12). We tested the hypothesis that VDI is predictive of early clinical failure (failure to achieve EFS12), overall survival (OS), and lymphoma-specific survival (LSS) among FL patients overall and in subgroups who were initially observed, treated with IC, rituximab monotherapy, or other therapies. Methods: We evaluated this hypothesis in a prospective cohort study of 642 newly diagnosed patients with grade 1-3a FL enrolled from 2002-2012 in the Molecular Epidemiology Resource of the Iowa/Mayo Lymphoma SPORE. Serum 25-hydroxyvitamin D [25(OH)D] was measured by liquid chromatography-tandem mass spectroscopy, and VDI was defined as serum total 25(OH)D <20 ng/mL (per Institute of Medicine criteria) determined within 120 days of diagnosis. We used logistic regression to estimate Odds Ratios (ORs) and 95% confidence intervals (CIs) and Cox regression to estimate hazard ratios (HRs) and 95% CIs. We adjusted for FLIPI, body mass index, and month of blood draw; for the full cohort, we additionally adjusted for treatment. Results: The mean age at diagnosis was 60 years (range 23-93); 19% of patients had VDI. The median follow-up period was 59 months (range 1-144), with 297 events and 78 deaths (42 due to lymphoma). Treatment included IC (N=252), observation (N=218), rituximab monotherapy (N=76), or other (N=96). OS and EFS curves are shown in figures 1 and 2. In the full cohort, VDI was associated with inferior EFS12 (OR=2.05; 95% CI 1.18-3.54), OS (HR=2.35; 95% CI 1.37-4.02), and LSS (HR=2.97; 95% CI 1.52-5.80). In the IC subset, VDI was associated with inferior EFS12 (OR=3.00; 95% CI 1.26-7.13), OS (HR=2.86; 95% CI 1.39-5.85), and LSS (HR=2.96; 95% CI 1.29-6.79). VDI was associated with inferior OS in patients who were observed (HR=2.25; 95% CI 1.20-6.76) or received other therapies (HR=3.06; 95% CI 1.01-9.24). VDI was positively but not statistically significantly associated with inferior EFS12 in the patients who were observed (OR=1.71; 95% CI 0.70-4.17) or received other therapies (OR=2.31; 95% CI 0.41-13.07), with low power for these associations; LSS could not be estimated due to lack of deaths. There were too few events (N=10) and deaths (N=5) in the R-monotherapy group for analysis. Conclusions: We confirm previous findings that vitamin D insufficiency is associated with adverse long-term prognosis among patients with FL treated with IC, and extend these findings to patients who are initially observed or treated with other therapies. For the first time, we observed an association of vitamin D insufficiency with early clinical failure, suggesting a potentially modifiable factor to address in this subset of patients with poor outcomes. Whether treating VDI improves outcomes in FL warrants assessment. Disclosures Ansell: BMS, Seattle Genetics, Merck, Celldex and Affimed: Research Funding. Nowakowski:Celgene: Research Funding; Morphosys: Research Funding; Bayer: Consultancy, Research Funding.

Abstract Waldenström macroglobulinemia (WM) is a B-cell malignancy that is characterized by the production of a monoclonal IgM protein, a lymphoplasmacytic infiltrate in the bone marrow, and associated symptoms including anemia, lymphadenopathy and hyperviscosity. The aberrant production of a monoclonal IgM in the serum is a major factor causing significant morbidity in patients with this disease, yet little is known about the mechanisms that regulate monoclonal protein synthesis. While recent gene array studies and serum analysis have shown that IL-6 is elevated in WM patients suggesting an important role for this cytokine in this disease, the precise role played by IL-6 in WM is unknown. Using a multiplex ELISA approach to screen sera from WM patients, we confirmed that IL-6 was significantly elevated (p<0.0019) in patients (n=20) compared to controls (n=20). Serum levels of IL-6 in WM patients correlated with elevated levels of β2-microglobulin (p<0.0019). Additionally, we also found that serum levels of CCL5 (Rantes) were significantly elevated in WM patients (p<0.0001). CCL5 has been shown to regulate IL-6 secretion, and we therefore wanted to determine if CCL5 influenced IL-6 expression in WM and what the subsequent consequence of IL-6 stimulation was on WM cells. To define the source of IL-6 in the tumor microenvironment, we used stromal cells from the bone marrow of healthy donors, malignant cells from patients with WM, and the BCWM.1 WM cell line, and tested their ability to secrete IL-6 by ELISA. All cell types secreted IL-6, with stromal cells secreting the most. We then tested the ability of CCL5 to induce IL-6 secretion by WM and stromal cells. CCL5 significantly increased IL-6 secretion by stromal cells (p<0.03) and also increased IL-6 secretion by fresh CD19+ CD138+ cells from WM patients (p<0.02). Using fresh patient WM cells and the BCWM.1 WM cell line as a model, we then determined the effect of IL-6 on growth of WM cells. We found that IL-6 had a modest effect (mean=20% increase, range=5–41%) on cell proliferation (p<0.0039) but had no effect on cell viability. In contrast, when we addressed the role of IL-6 on IgM secretion, we found that IL-6 increased IgM secretion by BCWM.1 cells in a dose-dependent manner. The IL-6 mediated increase in IgM secretion was abolished in the presence of neutralizing antibodies to IL-6. When we analyzed the downstream signaling events activated by IL-6 in WM cells we found that stimulation of BCWM.1 cells, which express the IL-6R, resulted in phosphorylation of Stat1, Stat3 and Erk1/2, but not Akt. Using a mitogen activated protein kinase (MAPK) inhibitor, we could inhibit the IL-6-mediated phosphorylation of Erk1/2. Similarly, using a JAK1 Inhibitor, we could inhibit IL-6 mediated signaling through Stat1 and Stat3. In summary, we have clearly shown that IL-6 significantly upregulates IgM secretion by WM cells and increases their proliferation. We have also demonstrated the ability of both the malignant cells and the stromal cells to secrete IL-6, and that this secretion is regulated in part by CCL5. We have found that WM cells express IL-6R, and that IL-6 induced signaling is through both the MAPK and Jak/Stat pathways. Therapies targeting IL-6 secretion or the IL-6 signaling pathways may therefore provide clinical benefit to patients with WM; not just by inhibiting the malignant cells but by down regulating the production of the monoclonal protein.

Abstract INTRODUCTION: mTOR inhibitors have been associated with responses in Mantle cell lymphoma and other lymphomas (J Clin Oncol23; 5347, 2005). Phase I and II trials with the oral everolimus (RAD001, Novartis Pharmaceuticals) have demonstrated a favorable side effect profile. This phase II study tested everolimus in patients with relapsed/refractory Waldenstrom Macroglobulinemia (WM). METHODS: Patients who had at least one previous therapy for WM and who had relapsed or refractory disease were eligible. Other eligibility criteria included symptomatic disease, > 2 weeks from last therapeutic agent used, >10% involvement with lymphoplasmacytic cells in the bone marrow, IgM paraprotein > 2x upper limit of normal, absolute neutrophil count >1000/mm3 and platelet count >75,000/mm3, serum creatinine of < 2 x upper limit of normal. NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by criteria established at the second consensus panel for WM. All patients received 10mg RAD001 daily for 28 days per cycle for 6 cycles; response was assessed after 2 cycles. RESULTS: 10pts (8 men and 2 women, median age is 62 years, range 52–71) have been treated to date. The median number of lines of prior treatment was 3 (range 1 – 5). The median IgM at baseline was 3970 mg/dL (range 3120– 7410); median M-spike at baseline was 2.07 gm/dL (range 1.41 – 4.02); and median hemoglobin was 11.3 g/dL (9.4–13.3). The median follow up was 4 months (range 1 – 7 months). Prior therapy included rituximab, nucleoside analogues (fludarabine and 2-CDA), combination chemotherapy (e.g CHOP, CVP), chlorambucil. and bortezomib. Seven patients are currently evaluable for response. The best response to single agent RAD001 after 2 cycles is presented in Table 1. Median duration of response has not been reached. Patients tolerated RAD001 well without significant toxicities. The main toxicities observed were apthous ulcers in 4 patients. One patient required dose reduction due to mucositis. One patient stopped therapy within the first month of treatment and went on to hospice care before succumbing to his disease after one month. Attributable toxicities otherwise proved manageable with appropriate supportive care and RAD001 was generally well tolerated, with no peripheral neuropathy. CONCLUSIONS: Oral RAD001 as monotherapy has been well tolerated and demonstrates exciting activity achieving PR + MR in 57%, and/or stabilization of disease in 43% of evaluable patients with relapsed WM. Accrual of a total of 30 patients is rapidly ongoing. Updated data will be presented at the meeting. Table 1 Response N=7; ORR (CR+PR+MR)= 57% Median time to best response (months) Partial Response 1 (14%) 5 Minimal Response 3 (43%) 4 (3–6) Stable Disease (SD) 3 (43%) NA Progressive Disease 0

Background MZL is a low-grade non-Hodgkin's lymphoma (NHL) which involves lymph nodes, extranodal sites, or spleen. It is sensitive to radiation therapy, which is used in localized disease with curative intent. Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) that targets CD20. It is approved for relapsed/refractory low grade and follicular NHL. The data on its use in MZL is limited. We present long-term outcome of the largest reported cohort of MZL patients who received (90)Y-IT. Methods Medical records of patients who received treatment with (90)Y-IT at Mayo Clinic Cancer Center between January 2004 and December 2018 were analyzed. We selected patients with MZL and reviewed clinical data including age, gender, MZL type, clinical stage (Ann Arbor Staging System), treatment response, (90)Y-IT related adverse effects (AEs), as well as lymphoma and treatment related events. All patients received (90)Y-IT according to the standard treatment guidelines. Overall response rate (ORR) and complete response rate (CR) were calculated. Progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS) were analyzed using the Kaplan-Meier method. Results Twenty-one patients were identified (Table 1). The median age at diagnosis was 60 years (range, 11-81) and 71% (15/21) were female. 52% (11/21) were previously-untreated (UMZL) while 48% (10/21) were relapsed (RMZL). The median number of pretreatments in RMZL patients was 2 (range, 1-3). ECOG performance status at the time of treatment was 0 in 90% (19/21) and 1 in 10% (2/21). 62% (13/21) were stage III/IV disease at the time of (90)Y-IT therapy. The median follow-up was 8.5 years (95% CI; 4.5, 12.4); 17 (81%) patients remain alive. The ORR was 91% (19/21) with the two non-responders being in the RMZL group. The CR rate was 81% (17/21) and 65% (11/17) remain in CR at a median follow-up of 5.7 years (95% CI; 1.4, 11). Nine (43%) patients had a relapse during the study period. More relapses occurred in the RMZL group (7/10; 70%) compared to (2/11; 18%) in the UMZL group. Median PFS (whole cohort) was 10 years (95% CI; 2.1, NR) and TTNT (whole cohort) was not reached (NR) (95% CI; 2.1 years, NR). Median PFS was significantly higher in UMZL group compared to RMZL group NR (95% CI; 2.5 years, NR) vs 2.1 years (95% CI; 0.17, 9.9), respectively (Figure 1-A).Median OS (whole cohort) was 19.3 years (95% CI; 8.9, 19.3) without statistical difference in between UMZL group and RMZL group NR (95% CI; NR, NR) vs 16.6 years (95% CI; 9, 19.4), respectively (Figure 1-B). None of the 11 UMZL patients died at median follow up of 4.7 years (95% CI; 1.6, 9.2). All 4 deaths were in the RMZL group with 3 dying of transformation to high-grade lymphoma at 8, 22, and 25 months post-(90)Y-IT treatment. One patient died of myelodysplastic syndrome 7.3 years post-(90)Y-IT treatment while in CR. Toxicities were primarily hematologic. Grade ³3 neutropenia was observed in 6/21 (29%) patients with median time to nadir of 48.5 days (range, 19-70) and median time to recovery to normal absolute neutrophil count of 39.5 days (range, 7-476). Grade ³3 thrombocytopenia was observed in 3 (14%) patients with median time to nadir of 35 days (range, 19-357) and median time to recovery of 21 days (range, 2-538). Grade ³3 anemia was observed in only one patient. Only two patients required transfusions and growth factor support. Non-hematologic AEs included mild to severe fatigue in 4 patients. Conclusion RIC with (90)Y-IT is efficacious and well-tolerated in patients with previously untreated as well as relapsed MZL. As expected it appears to be more efficacious in previously untreated patients. Long-term complete remission (&gt;5 years) was observed in 52% of the study population (43% of UMZL and 9% of RMZL). Combination of efficacy, tolerability, and treatment schedule most convenient for patients makes (90)Y-IT a reasonable alternative to systemic therapy with immunotherapy, chemotherapy, or chemo-immunotherapy in management of MZL. Figure 1: (A) Progression-free survival; comparing time to progression or death after (90)Y-IT treatment between previously untreated patients (UMZL) and patients with relapsed MZL (RMZL), (B) Overall survival; comparing time to death from all causes after (90)Y-IT treatment between UMZL patients and RMZL patients. Disclosures Tun: Curis: Research Funding; TG Therapeutics: Research Funding; BMS: Research Funding; DTRM Biopharma: Research Funding; Celgene: Research Funding; Mundi-pharma: Research Funding. OffLabel Disclosure: The use of Yttrium-90 ibritumomab tiuxetan as a first line treatment for marginal zone lymphoma

Background Burkitt NHL (BL) is a rare hematologic malignancy that occurs in younger adults and is highly curable with aggressive chemoimmunotherapy induction regimens. Unfortunately, patients that are refractory or relapse after these regimens fare poorly and treatment guidelines are not well established. The typical approach is with standard platinum-based salvage regimens; those who obtain a complete remission (CR) become eligible for autologous or allogeneic stem cell transplantation (SCT). Chimeric antigen receptor T (CAR-T) cell therapy and bispecific antibodies offer potential novel approaches for these patients, especially those who are unable to achieve remission in order to proceed with SCT; however, CAR-T therapy is not approved nor even tested in BL other than promising single case reports (Avigdor A, Bone Marrow Transplant. 2018 May 24). The goal of this study was to learn the clinical features and outcome of R/R BL in order to design a prospective strategy for novel therapy use in relapsed/refractory (R/R) BL patients. Methods We reviewed the Mayo Clinic Lymphoma database to find cases of BL diagnosed and treated between 1/1/2000 - 9/30/2018. Forty-two cases were identified and 32 (76%) entered CR and never relapsed; 10 (24%) did not respond or relapsed and are the focus of this report. Demographic, clinical response to treatment regimens, and long-term outcomes were extracted from the Mayo Clinic electronic medical record. Results The 10 patients with R/R BL had a median age of 41 years (range, 28-59); all had received aggressive chemoimmunotherapy induction regimens; 7 were primary refractory and 3 relapsed within 3 months (2-4) of achieving first CR. All 3 patients that relapsed did so in the central nervous system (CNS) despite receiving CNS prophylaxis with their induction therapy regimen. The response to salvage therapy was 30% (3/10) with 10% CR and 30% (3/10) proceeded to autologous SCT (no patients made it to allogenic SCT). The median progression free survival (PFS) and overall survival (OS) from diagnosis of all 10 patients was 4 months (1-9) and 70% (7/10) died within 6±4 months from date of relapse. The 3 patients with relapsed BL survived 7, 10, and17 months from date of relapse. The 3 patients who did survive to receive a SCT lived 2, 4, and 13 months from date of SCT. None of the 10 patients survived past 26 months from date of diagnosis. Conclusions Patients with R/R BL represent an uncommon and unique subset of aggressive NHL that require a new therapeutic approach such as CAR-T. Our study demonstrates the very poor outcome with traditional salvage therapies and the very short OS of these young, otherwise healthy patients. We recommend that these patients be considered as emergencies and referred promptly for novel therapies such as CAR-T trials at the very first sign of treatment failure. Waiting with the intent of attaining response to traditional therapies is futile. Insurance approval initiation and harvesting of T-cells should be rapidly performed, preferably prior to initiating salvage therapy, given the rapid clinical deterioration and demise of these patients. Disclosures Kenderian: Lentigen: Research Funding; Novartis: Patents & Royalties, Research Funding; Tolero: Research Funding; Humanigen: Other: Scientific advisory board , Patents & Royalties, Research Funding; Morphosys: Research Funding; Kite/Gilead: Research Funding. Bennani:Kite Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Adicet Bio: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Purdue Pharma: Other: Advisory board; Purdue Pharma: Other: Advisory board; Bristol-Myers Squibb: Research Funding; Adicet Bio: Other: Advisory board; Kite Pharma: Other: Advisory board; Kite Pharma: Other: Advisory board; Seattle Genetics: Other: Advisory board; Bristol-Myers Squibb: Research Funding. Nowakowski:Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding; Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Background Follicular lymphoma (FL) is the second most common lymphoma accounting for approximately 15% of all non-Hodgkin's lymphoma (NHL). Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) which targets CD20. It is approved in relapsed/refractory low-grade NHL and as consolidation after upfront induction chemoimmunotherapy for FL. This study analyzed patients with previously untreated (UFL) or relapsed/refractory low-grade FL (RFL) treated at our institution with (90)Y-IT. It represents the largest reported cohort for therapeutic use of (90)Y-IT in low-grade FL. Methods Medical records of patients with low-grade FL (WHO grade 1-2) who received treatment with (90)Y-IT at Mayo Clinic Cancer Center between January 2003 and December 2018 were analyzed. Overall response rate (ORR) and complete response rate (CR) were calculated. Progression-free survival (PFS), time to next therapy (TTNT), and overall survival (OS) were analyzed using the Kaplan-Meier method. Results Our cohort consists of 137 patients - 29% (40/137) with UFL and 71% (97/137) with RFL. The median age at diagnosis was 60 years (range, 18-86) with 54% (74/137) males. The median number of previous treatments in RFL patients was 1 (range, 1-5). ECOG performance status at the time of treatment was 0 in 90% and 1 in 10% of patients. 87% (119/137) had stage III/IV disease at the time of (90)Y-IT therapy. The median follow up from the time of (90)Y-IT therapy was 10.2 years (95% CI; 8.8, 11.6); 69% (95/137) of patients are alive. The ORR was 100% in UFL with 93% (37/40) CR while ORR in UFL was 93% (90/97) with 73% (71/97) CR. 45% (48/108) of the CR patients remain in continuous CR (CCR) with a median follow-up of 7 years (95% CI; 5.2, 9.9). CCR was observed in 55% (22/40) of UFL patients compared to 27% (26/97) of RFL patients. 63% (86/137) of patients had relapsed. More relapses occurred in the RFL group (69/97; 71%) compared to the UFL group (17/40; 43%), (p=0.002). In the entire cohort, the median PFS was 2.5 years (95% CI; 2.1, 3.5) and TTNT was 3.6 years (95% CI; 2.5, 4.7). Median PFS was significantly higher in UFL group compared to RFL group- 4.1 years (95% CI; 2.3, NR) vs 2.2 years (95% CI; 1.6, 3.1), respectively (Figure 1-A). Median TTNT was higher in UFL group compared to RFL group- NR (95% CI; 4.1 years, NR) vs 2.4 years (95% CI; 2, 3.6), respectively (Figure 1-B). Median OS (entire cohort) was 18 years (95% CI; 15.8, NR) with no statistically significant difference between UFL group and RFL group; NR (95% CI; NR, NR) vs 18 years (95% CI; 12.3, 20.5), respectively (Figure 1-C). Transformation to high grade lymphoma was seen in 19% (18/97) in RFL group compared to 2.5% (1/40) in UFL group, (p=0.005). Median time to transformation was 4.3 years (range, 1-11). More patients developed therapy-related myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) in the RFL group 14% (14/97) compared to 2.5% (1/40) in the UFL group (p= 0.02). Median time to develop MDS/AML was 3.3 years (range, 0-9.7). Grade ³3 neutropenia was observed in 46% of patients with median time to recovery of 21 days (range, 2-706). Grade ³3 thrombocytopenia was observed in 47% of patients with median time to recovery of 23 days (range, 7-548). Eighteen patients required growth factors support and 14 required transfusions. Non-hematologic AEs included mild to severe fatigue in 35 patients. Conclusion Radio-immunoconjugate therapy with (90)Y-IT is an effective single-agent regimen for low-grade FL. The response and survival data in this large real-world cohort is superior to the pivotal trials of this agent conducted nearly 20 years ago. The data in untreated FL is also of interest and provides the rationale for our current randomized phase 2 trial in untreated FL (https://clinicaltrials.gov/show/NCT02320292). Long-term complete remission (>7 years) was seen in 35% of the study population. Based on these promising results, clinical trials combining RIC with novel agents that could potentiate its effects are warranted. Figure 1 (A) Progression-free survival; comparing time to progression or death after (90)Y-IT treatment between previously untreated patients (UFL) and patients with relapsed/refractory FL (RFL), (B) Time to next therapy; comparing time to starting next line of treatment after (90)Y-IT treatment between UFL and RFL, (C) Overall survival; comparing time to death from all causes after (90)Y-IT treatment between UFL and RFL. Figure 1 Disclosures Tun: DTRM Biopharma: Research Funding; TG Therapeutics: Research Funding; BMS: Research Funding; Curis: Research Funding; Celgene: Research Funding; Mundi-pharma: Research Funding. OffLabel Disclosure: Yttrium-90 ibritumomab tiuxetan [(90)Y-IT; Zevalin] is a radio-immunoconjugate (RIC) which targets CD20. It is approved in relapsed/refractory low-grade NHL and as consolidation after upfront induction chemoimmunotherapy for FL. We are discussing its use as a frontline therapy in low grade FL.