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PURPOSE Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

PURPOSE Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication. PATIENTS AND METHODS Data were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution’s guidelines. Responses were assessed as per Lugano 2014 classification. RESULTS Of 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel–treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis. CONCLUSION The safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.

2527 Background: Allogeneic chimeric antigen receptor (CAR) T cell therapy holds promise in addressing logistical/manufacturing challenges of autologous CAR T cell therapy. ALLO-501 (anti-CD19; uses Cellectis technologies) and ALLO-715 (anti-BCMA) are allogeneic CAR T cell products whose a) disrupted TCRα constant gene may reduce GvHD risk, and b) edited CD52 gene may permit use of ALLO-647 (a humanized anti-CD52 mAb) to selectively deplete host T cells. Methods: The ongoing ALPHA (ALLO-501) and UNIVERSAL (ALLO-715) trials include patients (pts) with relapsed/refractory large B-cell or follicular lymphoma and multiple myeloma, respectively. The lymphodepletion regimen included ALLO-647 (39 mg [low dose, LD; n = 33], 60 mg [n = 12], or 90 mg [high dose, HD; n = 27]) with Flu 30 mg/m2/d x 3d +/- Cy 300 mg/m2/d x 3d (Flu+Cy, n = 66; Cy, n = 6) (ALLO-647/Flu +/- Cy) before CAR T infusion. A mixed-effects population pharmacokinetic (PK) model was fit to ALLO-647 concentration vs. time data. Pharmacodynamic (PD) effects on host T cells, IL15, and CAR T cell expansion were also studied. Results: As of the data cut, 72 pts were treated. Common Grade ≥3 AEs were neutropenia (71%), thrombocytopenia (42%), anemia (39%), and lymphopenia (28%). Neutrophil, hemoglobin, and platelet counts did not differ by ALLO-647 dose, suggesting these dim-CD52+ cells were unaffected. Gr ≥3 infections were seen in 21% pts; 33 had infusion-related reactions (IRR; Gr 1: 13%; Gr 2: 32%; Gr 3: 1.4%). IRR incidence and severity were higher with HD ALLO-647. The optimal PK model included a saturable (concentration-dependent) elimination pathway; clearance varied as a function of baseline lymphocyte count (LC). Serum ALLO-647 levels increased with dose; median modelled Cmax was 4,224 and 14,139 ng/mL for LD and HD, respectively. With ALLO-647/Flu +/- Cy, all but 2 pts reached a LC nadir < 0.05x109 cells/L, typically by D-3. Duration of lymphodepletion was typically longer with HD ALLO-647. Median duration of T-cell suppression ( < 10 cells/µl) was ̃ 8.5 and 13.6 days from CAR T infusion, respectively, for LD and HD ALLO-647. With HD, T cell counts were < 10 through D+28 in 17 pts and > 10 in 2. In 68 evaluable pts, compared to LD, HD ALLO-647 was associated with higher D0 serum IL15 levels, which have been linked to improved clinical response (eg, Kochenderfer JCO 2017). Higher CAR T expansion was also observed post D+14 with HD ALLO-647 compared to LD, creating an opportunity for clinical response. Conclusions: ALLO-647/Flu +/- Cy had a tolerable safety profile and produced a deep and durable window of lymphocyte depletion. ALLO-647 exhibited target-mediated drug disposition; clearance increased with higher baseline LC. HD was associated with higher IL15 levels and better CAR T expansion, suggesting dose responses. Enrollment in both studies is ongoing; updated safety and PK/PD data will be presented. Clinical trial information: NCT04093596.

7548 Background: ZUMA-5 is a Phase 2 study of axi-cel anti-CD19 CAR T-cell therapy in pts with R/R iNHL (follicular lymphoma [FL]; marginal zone lymphoma [MZL]). In the primary analysis, 11 pts (9 FL; 2 MZL) were retreated with axi-cel, achieving an overall response rate (ORR) of 100% (91% complete response [CR] rate) at a median follow-up of 2.3 mo post-reTx, with no Grade ≥3 cytokine release syndrome (CRS) or neurologic events (NEs; Chavez et al. ASH 2020. #2036). Here, we report updated clinical and translational outcomes with longer follow-up in pts retreated with axi-cel in ZUMA-5. Methods: Eligible pts with FL or MZL had R/R disease after ≥2 lines of therapy. Pts were considered for reTx if they progressed after a response at mo 3, had no evidence of CD19-negative relapse in biopsy, had no axi-cel neutralizing antibodies, and had no Grade 4 CRS or NEs with 1st Tx. Retreatment was per investigator discretion. At both Txs, pts received axi-cel (2×106 CAR T cells/kg) after conditioning chemotherapy. Results: As of 9/14/2020, 13 pts with iNHL (11 FL; 2 MZL) received axi-cel reTx, with 2 pts retreated after the primary analysis. Before their 1st Tx, pts had median 4 prior lines of therapy; 85% had stage 3–4 disease; 82% had FLIPI of ≥3; 46% were POD24; 77% had refractory disease. Among the 13 retreated pts, 85% had a CR to 1st Tx. Median 1st duration of response (DOR) was 8.2 mo. Detectable CD19 was confirmed in all evaluable biopsies from retreated pts at relapse, and median time from 1st Tx to reTx was 10.6 mo. Following reTx, the ORR was 100% (77% CR rate). After a median follow-up of 11.4 mo, the median DOR had not yet been reached; 46% of retreated pts had ongoing responses at data cutoff. At 1st Tx, CRS occurred in 9 pts (5 Grade 1, 4 Grade 2); NEs occurred in 5 (3 Grade 1, 1 Grade 2, 1 Grade 3). At reTx, CRS occurred in 8 pts (6 Grade 1, 2 Grade 2); NEs occurred in 4 (3 Grade 1, 1 Grade 2). Median peak levels of biomarkers typically associated with severe CRS and NEs were similar at reTx and 1st Tx (IL-6, 7.7 vs 5.7 pg/mL; IL-2, 1.8 vs 0.9 pg/mL; IFN-γ, 62.9 vs 64.2 pg/mL). In the 11 retreated pts with FL, tumor burden (median sum of product diameters [SPD]) was lower before reTx vs 1st Tx (1416 vs 4770 mm2). Engraftment index (CAR T-cell expansion relative to SPD) is an indirect proxy for effector:target ratio and a key covariate of response to axi-cel (Locke et al. Blood Adv. 2020). Though median peak CAR T-cell levels appeared lower at reTx vs 1st Tx (5.2 vs 14.3 CAR+ cells/µL blood), engraftment index was similar (0.003 vs 0.005 cells/µL×mm2). Conclusions: Axi-cel reTx achieved deep and durable responses, with an acceptable safety profile. Tumor CD19 positivity was maintained at relapse, and engraftment index was similar at both Txs, comparing favorably to previous reports in aggressive lymphomas (Locke et al. ASCO 2020. #8012). These data suggest axi-cel reTx is a promising option for pts with R/R iNHL. Clinical trial information: NCT03105336.

7536 Background: Axi-cel is an autologous anti-CD19 CAR T-cell therapy approved for patients (pts) with relapsed/refractory LBCL after ≥2 prior systemic therapies. In the pivotal ZUMA-1 study, pts with high pretreatment (preTx) TB (estimated by sum of product diameters [SPD]) had lower peak CAR T-cell expansion normalized to TB and less frequent durable response rates vs pts with low TB ( < 30% vs > 60%, respectively; Blood Adv. 2020;4:3268). The number of CD8+ and CCR7+CD45RA+ product T cells infused and favorable immune contexture in preTx TME were also associated with axi-cel response ( Blood Adv. 2020;4:3268; Galon et al. ASCO 2020. #3022). As potential barriers to axi-cel efficacy are not fully elucidated, we systematically analyzed preTx TME characteristics, including myeloid-related biomarkers and product attributes, to identify such challenges in ZUMA-1 pts with high TB. Methods: Samples from evaluable pts in ZUMA-1 Phase (Ph) 1 and Ph2 Cohorts (C) 1–3 were analyzed (NCT02348216; Ph1 and Ph2 C1+2, ≥2-y follow-up; C3, ≥6-mo follow-up). PreTx immune TME was analyzed by multiplex immunohistochemistry (n = 18) and gene expression analysis (n = 30) as previously described (Rossi et al. AACR 2018. #LB-016; Galon et al. ASCO 2020. #3022). CAR T-cell product characteristics and other covariates were evaluated as previously described ( Blood Adv. 2020;4:3268). Correlative analyses of these covariates with clinical outcomes were performed by Wilcoxon or Kruskal-Wallis test. Median TB (by SPD) from ZUMA-1 Ph1 and Ph2 C1+2 was used as a cutoff for high ( > 3721 mm2) vs low (≤3721 mm2) TB. Durable response refers to pts in ongoing response at time of data cutoff. Results: PreTx immune TME features related to suppressive myeloid-related activity, most notably ARG2, TREM2, and IL-8 gene expression, were elevated in pts who failed to respond or relapsed without documented loss of CD19 expression. ARG2 and TREM2 levels in preTx biopsies were negatively associated with CD8+ T-cell density. Pts with high TB who achieved durable response had low preTx ARG2 and TREM2 levels in TME and enhanced CAR T-cell expansion after axi-cel compared to pts with high TB who relapsed. High ratio of T-cell to suppressive myeloid cell markers (T/M ratio) in preTx biopsies associated positively with CAR T-cell expansion (peak and peak normalized to TB) and durable response in pts with high TB. Conclusions: Axi-cel may overcome high TB in pts with a favorable immune TME alongside robust CAR T-cell expansion. Favorable immune TME is characterized by reduced suppressive myeloid cell activity (low ARG2 and TREM2 expression) and increased T/M ratio. These data suggest possible actionable strategies to overcome high TB in the context of CAR T-cell therapy. [JC and VP contributed equally] Clinical trial information: NCT02348216.

7515 Background: POD24 is an indicator of poor survival in iNHL (Casulo & Barr. Blood. 2019). In the ZUMA-5 Phase 2 study of axi-cel anti-CD19 CAR T-cell therapy in pts with R/R iNHL, overall response rates (ORR) after 17.5 months median follow-up were similarly high in those with and without POD24 (93% and 92%; Jacobson et al. ASH 2020. #700). Here, we report updated outcomes with longer follow-up in pts with POD24 in ZUMA-5. Methods: Adults with R/R follicular lymphoma (FL) or marginal zone lymphoma (MZL) after ≥2 lines of therapy underwent leukapheresis followed by conditioning therapy and axi-cel infusion (2×106 CAR T cells/kg). Axi-cel–treated pts with available data on progression after an anti-CD20 mAb + alkylating agent were included. The updated efficacy analysis occurred when ≥80 treated pts with FL had ≥18 months follow-up. Results: Of 129 pts at baseline, 81 pts (63%; 68 FL, 13 MZL) had POD24 and 48 pts (37%; 40 FL, 8 MZL) did not have POD24. Median prior lines of therapy in pts with and without POD24 were 3 and 3.5, respectively. High-risk characteristics of pts with and without POD24 included stage III/IV disease, 83% and 94%; ≥3 FLIPI, 44% and 43%; high tumor bulk (GELF), 51% and 44%; and refractory disease, 77% and 63%, respectively. With 23.3 months median follow-up, ORR among efficacy-evaluable pts with POD24 (n = 61) and without POD24 (n = 37) was 92% each (complete response rates, 75% and 86%). At data cutoff, 52% of pts with POD24 and 70% without POD24 had ongoing responses. Median duration of response, progression-free survival, and overall survival were not reached in pts with and without POD24; 18-month estimated rates were 60% and 78%, 55% and 84%, and 85% and 94%, respectively. Incidences of Grade ≥3 adverse events were similar in pts with and without POD24 (84% and 88%), including cytopenias (69% and 65%) and infections (15% and 21%). Grade ≥3 cytokine release syndrome (CRS) occurred in 9% and 2% of pts with and without POD24, respectively; Grade ≥3 neurologic events (NEs) occurred in 17% of pts each. Median times to onset were similar in pts with and without POD24 for CRS (4 days each) and NEs (8 days and 7 days); median durations of CRS (7 days and 5 days) and NEs (11 days and 13 days) were also similar between groups. In efficacy-evaluable pts with FL, median peak CAR T-cell levels were similar in pts with and without POD24 (35.8 cells/μL and 34.5 cells/μL). Peak levels of key inflammatory biomarkers and axi-cel product attributes were generally similar in pts with and without POD24. Conclusions: Axi-cel showed a high rate of durable responses in pts with POD24 iNHL, a population with high-risk disease. Efficacy results, as well as safety and pharmacological profiles, appeared largely comparable between groups, with the exception of PFS rates. Clinical trial information: NCT03105336.

2529 Background: Allogeneic CAR T cell therapy addresses logistical/manufacturing challenges inherent in autologous (auto) CAR T therapy. ALLO-501A, which uses Cellectis technologies, is an allogeneic anti-CD19 CAR T cell product whose a) disrupted TCRα gene may reduce GvHD risk, and b) edited CD52 gene may permit use of ALLO-647 (a humanized anti-CD52 mAb) to selectively deplete host T cells. Methods: The ongoing ALPHA2 study is a single-arm, open-label, 2 phase study of ALLO-501A in non-HLA matched patients (pts) with R/R LBCL and ≥2 prior lines of therapy. Prior auto CD19 CAR T therapy is allowed if tumors remain CD19+. Following lymphodepletion (LD) with ALLO-647 (60 mg or 90 mg), fludarabine 30 mg/m2/d x 3d (Flu), and cyclophosphamide 300 mg/m2/d x 3d (Cy), escalating doses of ALLO-501A (40 [DL1] or 120 [DL2] x 106 viable CAR T cells) were administered. Retreatment was allowed for PD or SD with suboptimal CAR T expansion. Pts who had ≥SD at D28 could receive a second dose in a consolidation cohort. Phase 1 assessed safety/tolerability and cell kinetics of escalating doses of ALLO-501A following LD. Results: By 1/15/21, 11/11 enrolled pts received ALLO-647 (60 mg: n=6; 90 mg: n=5). Mean duration from enrollment to start of therapy was 6 days. After LD, 1 and 9 pt(s) were treated with ALLO-501A at DL1 and DL2, respectively; 1 pt developed CNS lymphoma and was not treated. Of 10 pts treated, 1 pt received retreatment and 4 pts were enrolled in the consolidation cohort. Pts had a median age of 60 years; 8 were ≥ stage III at diagnosis, 5 had IPI scores ≥3, and 3 had baseline LDH > 2x ULN. Median number of prior therapies was 3 (range 2 – 7); 3 pts had received auto CD19 CAR T cell therapy. 4/8 evaluable pts had rapidly PD at study entry. Median FU was 1.7 months. No dose modifications were required and no pt experienced DLTs. The most common AEs were anemia, leukopenia, neutropenia and thrombocytopenia (73%); and lymphopenia (64%). No GvHD or ICANS were reported. CRS was seen in 2 (18%) pts, both Grade < 3. Infusion-related reactions, all grade

3022 Background: Axi-cel is a US and EU-approved autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for pts with relapsed/refractory large B cell lymphoma after ≥ 2 prior therapies. In ZUMA-1 (NCT02348216), the objective response rate was 83% (58% complete response rate; Locke et al. Lancet Oncol. 2019). T cell-related biology (Immunosign 21; Immunoscore) measured pretreatment in the tumor microenvironment (TME) was associated with response to axi-cel (Rossi et al. AACR 2018. #LB-016; Rossi et al. AACR 2019. #CT153). This expanded analysis characterized the pretreatment TME immune contexture and examined associations between immune cell subsets and response. Methods: In ZUMA-1, pts received axi-cel at a target dose of 2.0 × 106 CAR T cells/kg. Archival pretreatment tumor biopsy samples were analyzed by multiplex immunohistochemistry (Brightplex). Two panels were developed and applied to assess T cell (CD3, CD8, FoxP3, PD-1, LAG-3, TIM-3) and myeloid cell (CD11b, CD14, CD15, LOX1, S100A9, CD68) subsets (n = 14 total). The association between T cell and myeloid cell subset density, prespecified immune scores (Immunosign 21; Immunoscore), and objective response was evaluated. T test values were based on Brightplex analysis. Results: Pretreatment tumor biopsy samples from 18 pts were analyzed (14 objective responders and 4 nonresponders). The pretreatment TME comprised all major myeloid and T cell subsets, with diverse distribution across samples analyzed. The median TME density of monocytes (CD11b+ CD15− CD14+; 1215 cells/mm2) and macrophages (CD68+; 530 cells/mm2) was greater than that of the total CD8+ T cell subset (312 cells/mm2). The pretreatment Immunosign 21 and Immunoscore scores associated positively with the density of all major T cell subsets and some myeloid subsets. The density of activated CD8+ T cells (PD-1+ LAG-3+/− TIM-3−) was most significantly associated with clinical response versus other T cell subsets. The density of nonactivated CD8+ T cells (PD-1− LAG-3− TIM-3−) and exhausted CD8+ T cells (PD-1+ LAG-3+ TIM-3+) were not significantly associated with response. Additional characterization of the immune contexture and correlative analysis of cell subsets will be presented. Conclusions: These results suggest that a TME associated with increased density of activated PD-1+ LAG-3+/− TIM-3− CD8+ T cells, measurable pretreatment, facilitates clinical response in pts post–axi-cel.

8011 Background: Corticosteroids are commonly used for management of severe toxicities associated with chimeric antigen receptor (CAR) T-cell therapy. However, it remains unclear whether the dose, duration, and timing of corticosteroid therapy may impact clinical efficacy of CAR T-cell therapy. Methods: This is a retrospective analysis of patients with relapsed or refractory LBCL treated with standard of care axi-cel at MD Anderson Cancer Center, Houston, Texas between 01/2018 and 05/2019 (data cut-off 12/21/2019). Progression-free survival (PFS) was defined as time from axi-cel infusion to progression/death or last follow-up, and the Breslow test was used for comparisons between subgroups. Results: One hundred patients with relapsed or refractory LBCL were included in the study, and 60 (60%) received corticosteroids for management of toxicities after axi-cel infusion. There was no significant difference in baseline tumor burden, disease stage or international prognostic index between the 2 groups. The median cumulative dexamethasone-equivalent dose was 186 mg (range, 8-1803 mg) and the median duration of corticosteroid treatment was 9 days (range 1-30); 45 (45%) patients started corticosteroid treatment between day 0 and 7, and 15 (15%) beyond day 7. After a median follow-up of 10 months (95% CI 8-10 months), median PFS was 8 months (95% CI, 3-13 months), and use of corticosteroids (any dose) showed a trend for association with shorter PFS (6 vs 9 months, p = 0.13). Use of high-dose corticosteroids (Quartiles (Q) 3-4, 195-1803 mg) significantly associated with shorter PFS (2 vs 9 months, p = 0.005). A trend for shorter PFS was observed among patients receiving corticosteroids for a prolonged time (Q3-Q4, 10-30 days) (5 vs 8 months, p = 0.12) and among patients starting corticosteroids within the first 7 days after axi-cel infusion (6 vs 11 months, p = 0.07). At most recent follow-up, 36 patients died, 28 of progression. Median overall survival has not been reached, and was significantly shorter among patients who received corticosteroids (13 vs not reached, p = 0.006). Conclusions: Early and prolonged use of high-dose corticosteroids is associated with early progression and death in patients with LBCL treated with axi-cel. Additional evaluation is needed to understand the mechanism underlying this association.

8008 Background: Advanced stage iNHL, including follicular lymphoma (FL) and marginal zone lymphoma (MZL), is considered incurable as most pts experience multiple relapses (Wang, et al. Ther Adv Hematol. 2017), highlighting a need for novel therapies. Here, we present interim results from ZUMA-5, a Phase 2, multicenter study of axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, in pts with R/R iNHL. Methods: Adults with R/R FL (Grades 1-3a) or MZL (nodal or extranodal) after ≥ 2 lines of therapy (including an anti-CD20 monoclonal antibody [mAb] with an alkylating agent), and an ECOG of 0 – 1 were eligible. Pts were leukapheresed and received conditioning chemotherapy followed by axi-cel infusion at 2 × 106 CAR T cells/kg. The primary endpoint was objective response rate (ORR) by central review (Cheson, et al. J Clin Oncol. 2014). Secondary endpoints included duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and blood levels of cytokines and CAR T cells. Results: As of 8/20/19, 94 pts (80 FL; 14 MZL) received axi-cel with a median follow-up of 11.5 mo (range, 4.2 – 24.9). Median age was 63 y (range, 34 – 79), 47% of pts were male, 52% had stage IV disease, 51% had ≥ 3 FLIPI, and 59% had high tumor bulk (GELF). Pts had a median 3 prior lines of therapy, 66% progressed < 2 y after initial anti-CD20 mAb-containing therapy (POD24), and 73% were refractory to the last prior treatment. Of 87 pts evaluable for efficacy, ORR was 94% (79% complete response [CR] rate). Pts with FL (n = 80) had an ORR of 95% (80% CR rate). Pts with MZL (n = 7) had an ORR of 86% (71% CR rate). Overall, 68% of pts had ongoing responses as of the data cutoff. Updated data, including DOR, PFS, and OS with longer follow-up, will be included in the presentation. Of 94 pts evaluable for safety, 83% experienced Grade ≥ 3 adverse events (AEs), most commonly neutropenia (33%) and anemia (28%). Grade ≥ 3 cytokine release syndrome (CRS; per Lee et al, Blood 2014) and neurologic events (NEs; per CTCAE v4.03) occurred in 11% and 19% of pts, respectively. Median times to onset of CRS and NEs were 4 and 7 d, with median durations of 6 and 14.5 d. There were 2 Grade 5 AEs: multisystem organ failure in the context of CRS (related to axi-cel) and aortic dissection (unrelated to axi-cel). Median peak and AUC0-28 CAR T cell levels were 44 cells/µL and 490 cells/µL × d, respectively. Conclusions: Axi-cel demonstrated significant and durable clinical benefit, with high rates of ORR and CR, and a manageable safety profile in pts with R/R iNHL. Clinical trial information: NCT03105336 .

8021 Background: Transformation of untreated indolent B-cell lymphoma (Tr-iNHL) is associated with poor outcomes. Current practices are extrapolated from prospective studies of de novo large B-cell lymphoma (DLBCL) or small retrospective studies. High dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) is used as consolidation in first remission (CR1) in some centers but the evidence-base is weak. Methods: CLL/SLL, MCL as primary diseases and non-DLBCL transformations were excluded. Propensity score analysis (PSM) using the “greedy match” algorithm was used to match the baseline covariates to adjust for potential selection bias. Landmark analysis was performed with time zero at 3 months after completion of front line chemotherapy (FLC). Kaplan-Meier method and the Cox proportional hazards model were was used for time-to-event analysis including progression-free survival (PFS) and overall survival (OS). Results: 319 transplant eligible patients (age 45%, no severe lung disease, CR by PET or CT >3 months after FLC) who received >/= standard RCHOP intensity FLC were identified across three centers in Australia & US. 283 (89%) patients had follicular lymphoma, 30 (9%) marginal zone lymphoma, 6 (2%) other subtypes. 49 patients underwent HDC and ASCT in CR1, a matched cohort of 98 pts based on age, stage, HGBL-DH and ECOG PS at diagnosis was generated with a 1:2 ratio using PSM. After a median follow-up of 3.6 (min: 0.1, max: 18.3) years, ASCT was associated with significantly superior PFS on multivariable analysis (MVA) (HR 0.51, 0.27-0.98; P=0.043). Univariate analysis demonstrated a trend towards inferior OS in the ASCT cohort (HR 2.36; 0.87-6.42; P=0.092) with more deaths in the ASCT arm due to PD (8% v 4%). Of the 40 patients (41%) with relapsed disease in the non-ASCT cohort–15 patients underwent salvage HDC & ASCT with 7/15 (47%) ongoing CR; 10 patients underwent CAR-T therapy (5 relapse post ASCT, 4 refractory disease, 1 relapse post FLC) with 6/10 (60%) ongoing CR; 3 patients underwent allogeneic SCT (2 relapse post ASCT, 1 relapse post FLC) with 2/3 (67%) ongoing CR. Conclusions: Although ASCT in CR1 may improve initial duration of disease control in de novo Tr-iNHL, the impact on OS is less clear with effective salvage therapies in the CAR-T era.

8061 Background: Untreated transformed indolent lymphoma (unTIL) can present as a composite lymphoma (COM), 2 or more separate sites of disease with one site transformed (discordant; DIS) or following indolent lymphoma sequentially (SEQ). Current practices are guided by small retrospective studies or extrapolated from trials involving non-transformed lymphomas. Methods: 353 patients (pts) with biopsy-proven unTIL treated with curative chemoimmunotherapy between 01/2000 to 01/2019 were included (intention to treat). All indolent B-cell lymphomas (iNHL) were included except CLL/SLL. Patients with MCL and non-DLBCL transformation were excluded. Prior therapy for iNHL was not allowed except one line of non-chemotherapy-based therapy. Kaplan-Meier method was used for time-to-event analysis including progression-free (PFS) and overall survival (OS). Results: 252 (71%) pts presented with COM, 50 (14%) DIS and 51 (14%) SEQ lymphoma. The underlying iNHL was: 308 (87%) follicular lymphoma, 37 (10%) nodal MZL, 7 (2%) MALT lymphoma, and 1 (0.3%) WM. Frontline therapy (FLT) included: RCHOP for 271 (77%), DAEPOCHR for 60 (17%), clinical trial for 7 (2%), BR for 4 (1%), RHCVAD for 2 (1%), RCEOP for 2 (1%), radiation therapy for 2 (1%), RFND for (1%) 2, RCVP for 2 (1%), and rituximab only for 1 (0.3%). 9 (3%) pts had ASCT in first remission. 50 (15%) pts received maintenance rituximab (MR) with fewer cases of HGBL-DH compared to the non-MR cohort (0% v 10%). With a median follow-up of 3.4 years (range 0.1-19.1), 4-year PFS and OS rates were 59% and 88%. By univariate analysis (UVA) the underlying type of iNHL, cell-of-origin and choice of induction therapy (DAEPOCHR v RCHOP) were not associated with inferior outcomes. SEQ transformations were associated with inferior OS on UVA (P = 0.02) which was not significant on multivariable analysis (MVA) (P = 0.3). MVA identified ECOG PS > 1, B symptoms and HGBL-DH as independent prognostic factors for inferior PFS and OS. In patients who achieved PR or greater following FLT, MR was associated with improved PFS on MVA (HR 0.6, 95% CI 0.3-0.9, P = 0.04) without an OS benefit (P = 0.2). 39 (31%) pts relapsed with iNHL only (mPFS 2.4 yrs, 4-yr OS 94%) and 88 (69%) relapsed with transformed lymphoma (mPFS 1.1 yrs, 4-yr OS 69%) with no significant difference in pattern of relapse with MR (P = 0.2). Conclusions: The clinicopathologic features of unTIL are similar to those of de novo DLBCL. Escalation of therapy beyond R-CHOP may not be required in the absence of HGBL-DH. unTIL should be included in future clinical trials involving de novo DLBCL given the similar clinicopathologic features.

e20013 Background: Nivolumab and Pembrolizumab are effective immune checkpoint inhibitor (ICI) therapies targeting PD-1/ PDL-1 immune axis. The drugs are currently approved for relapsed/ refractory classical Hodgkin lymphoma (cHL)based on phase I and II trial data. Methods: We conducted a retrospective study of patients (pts) with relapsed refractory cHL treated with ICI therapy at M.D. Anderson Cancer center from 4/2013 to 5/2019 to evaluate the efficacy of this treatment. The responses were assessed using revised response criteria according to the Lugano classification Results: Ninety-two pts treated with nivolumab (66) and pembrolizumab (26) were included. Fifty six pts (63%) were advanced stage at diagnosis, most treated initially with ABVD (88%) and BV-AVD (3%). Seventy percent pts had primary refractory disease or relapsed < 12 months after frontline therapy. At the time of ICI initiation, pts had the following characteristics: median age 35 (range 18-86), extranodal disease - 28 pts (37%), prior BV exposure in 81 pts (89%) with 66% considered BV refractory. Sixty one percent patients were refractory to the last prior line of salvage therapy. Median prior lines of therapy was of 3 (range 1-13) and 53 pts (58%) had a prior HSCT. At a median follow-up time of 20.2 months (range: 1.58 - 55.98 months), median progression free survival was 12.3 months and median overall survival was not reached. Among the 39 patients with no prior transplant, 11 patients who achieved CR with ICI were consolidated with HSCT (autologous - 7 and allogeneic - 4). Of this cohort, 2 pts (1 post auto, 1 post-allo) have relapsed. Five patients in our cohort were treated with an alternative ICI for subsequent relapse; of four patients with response assessment, 3 achieved CR and 1 experienced PD. Conclusions: In this cohort of cHL pts, ICI offered high response rates before and after HSCT supporting the possibility for using ICI earlier in the treatment course for refractory or early relapsed HL.

8002 Background: Allogeneic (off the shelf) chimeric antigen receptor (CAR) T cell therapy addresses the logistical challenges and variable product quality of autologous CAR T therapy. ALLO-501 is a genetically modified anti-CD19 CAR T cell product in which the TCR alpha constant gene is disrupted to reduce the risk of graft-versus-host disease (GvHD) and the CD52 gene is disrupted to permit the use of ALLO-647, an anti-CD52 mAb, for selective and prolonged host lymphodepletion. Methods: This is an open-label, Phase 1 trial (NCT03939026) in adults with R/R LBCL/FL who have received ≥ 2 prior lines of therapy; prior anti-CD19 cell therapy is allowed. Patients (pts) receive fludarabine (flu) 90 mg/m2, cyclophosphamide (cy) 900 mg/m2, and ALLO-647 39 or 90 mg followed by ALLO-501 at 1 of 3 dose levels (DL) in a 3+3 design: 40, 120, and 360 × 106 CAR+ T cells. Results: As of 20 January 2020, 12 pts were enrolled: 9 received ALLO-501 at 3 DLs (4, 4 & 1 pts in DL1, DL2 and DL3 respectively), 1 pt discontinued due to kidney injury prior to lymphodepletion and 2 are starting treatment. Of the 9 treated pts aged 42 to 70 years: 5 had LBCL, 2 were female, 3 had primary refractory disease, and 3 had prior autologous stem cell transplants. The median number of prior lines of therapies was 3 (range 2 to 4). All treated pts received 39 mg of ALLO-647. No DLTs or GvHD have been observed to date. Most common Grade (Gr) ≥ 3 adverse events were neutropenia (55.6%), leukopenia (33.3%) and anemia (22.2%). Two pts (22.2%) developed cytokine release syndrome (1 Gr1 and 1 Gr2) that resolved within 72 hrs without steroids or tocilizumab. One pt developed Gr1 neurotoxicity that resolved without treatment. Infections included upper respiratory tract infection (Gr2), CMV (Gr3) and EBV viremia (Gr1), all reported in a single pt and resolved. One pt had a Gr2 infusion reaction to ALLO-647 which resolved with antihistamines. The overall response rate is 78% (95% exact CI: 40%, 97%): 3 complete and 4 partial responses. With a median follow up of 2.7 mos, 4 pts have ongoing responses and 3 pts progressed at 2, 4 and 6 mos. ALLO-501 cell expansion by qPCR was observed in 4 of 6 pts in varying degrees. Conclusions: These early data suggest that ALLO-501 and ALLO-647 have a manageable safety profile. ALLO-647 may be an effective and selective lymphodepleting agent with CD52 gene editing, and ALLO-501 shows evidence of clinical activity in pts with advanced NHL. Enrollment is ongoing, and updated safety, efficacy, PK/PD data will be presented including pts treated with increasing doses of ALLO-647. Clinical trial information: NCT03939026 .

8057 Background: HLH is a rare but serious complication of chimeric antigen receptor (CAR) T cell therapy, characterized by severe immune activation, and immune mediated multi-organ failure. Diagnosis is difficult in the context of cytokine release syndrome (CRS) and optimal treatment and outcomes are unclear. Methods: Retrospective, descriptive analysis of patients with relapsed/refractory LBCL treated with SOC axi-cel at MD Anderson Cancer Center between 01/2018 - 10/2019 (data cut-off 12/21/2019). Progression-free survival (PFS) defined as time from axi-cel infusion to progression/death or last follow-up. Diagnosis of HLH per HLH-2004 and CART cell therapy toxicity guidelines (Neelapu, 2018) Results: One hundred and five patients with relapsed/refractory LBCL included, 6 diagnosed with HLH. No significant difference in baseline characteristics, disease stage, international prognostic index or inflammatory markers at baseline between groups, with exception of platelet count which was lower in HLH group 116 [37-129] versus 141 [9-391] (p = 0.07). Development of HLH was early after CART cell infusion at a median 11 days [7 – 78 days] with 3 patients having bone marrow hemophagocytosis; all 6 had abnormalities in liver function tests, fibrinogen, triglycerides, and at least 1 ferritin level > 10,000. CART toxicity in HLH cohort: 4 patients experienced grade 0-1 CRS, and 1 with grade 2 CRS while 3 HLH patients experienced grade 3-4 IEC-associated neurotoxicity syndrome ( ICANS), and 2 patients had grade 0-1 ICANS. Five HLH patients treated with high dose steroids, and tocilizumab; anakinra administered in 2 patients. Four of 6 patients had resolution of HLH with treatment and didn’t require escalation to HLH specific therapy however 1 patient was treated with steroids/etoposide. PFS and overall survival (OS) were significantly shorter in HLH group, PFS 1 months vs 8 months, respectively (p < 0.001) and median OS 2 months vs not reached, respectively (p = 0.001) follow up 10 months (95% CI 8-12 months). One patient died of acute respiratory failure, 2 patients died of HLH and multi-organ failure without progressive disease (PD). Of 3 remaining patients, all had radiographic PD at day 30, 2 of whom died of PD. Conclusions: HLH is likely an underreported complication of CART cell therapy, and patients with HLH have significantly worse outcomes. In this series the majority of patients died of PD, not the syndrome itself. More information is necessary to design treatment strategies that won’t compromise CART outcomes.

8012 Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is approved in the US and EU for pts with relapsed/refractory large B cell lymphoma after ≥ 2 prior therapies. In the ZUMA-1 pivotal study (NCT02348216), the objective response rate (ORR) was 83% (58% complete response [CR] rate; Locke et al. Lancet Oncol. 2019). While axi-cel has demonstrated durable responses in a subset of pts, approximately half of all responders relapsed, and little is known on the viability of reTx with CAR T cell therapy. Here we report outcomes of pts retreated with axi-cel in ZUMA-1. Methods: Pts with progressive disease (PD) were eligible for reTx if there was no evidence of CD19 loss by local review, and if during 1st Tx they did not experience any dose-limiting toxicities, as defined in Phase 1, or comparable toxicities in Phase 2. Pts received the same regimen at reTx as at 1st Tx: 2 × 106 CAR T cells/kg after conditioning chemotherapy. Results: Thirteen pts in Cohorts 1 – 4 received axi-cel reTx. Prior to 1st Tx, most pts (69%) had an IPI score 3-4, 85% had disease stage 3-4, and the median number of prior regimens was 3 (range, 2 – 6). At first Tx, 6 pts achieved a CR, 6 achieved partial response (PR), and 1 pt had stable disease (SD) prior to PD. Median duration of first response was 96 days (range, 56 – 274). There was no Grade ≥ 3 cytokine release syndrome (CRS; 6 pts each had Grade 1 and 2). There were no Grade 4 or 5 neurologic events (NEs; 2 pts had Grade 1, 1 had Grade 2, and 7 had Grade 3). Upon reTx, 54% of pts achieved response (4 CR, 3 PR). Response to reTx was more common among pts who achieved CR at 1st Tx (83%; 4/6 CR, 1 PR, 1 SD) than in pts who achieved PR at 1st Tx (33%; 2/6 PR, 1 SD, 3 PD), and no response was observed in the pt with SD at 1st Tx. Median duration of response at reTx was 81 days (range, 1 – 225+). Response with reTx was longer than that with 1st Tx for 2 pts. One pt remains in response 255 days post-reTx. Comparable rates of CRS were observed with reTx as with 1st Tx. Compared with 1st Tx, fewer pts experienced NEs with reTx, and those that did occur were of lower grade: 23% (3 of 13 pts) had Grade 3; 23% (3 of 13 pts) had Grade 1, and 8% (1 of 13 pts) had Grade 2. Peak CAR T cell expansion was lower upon reTx vs 1st Tx (median, 4.3 vs 66.1 CAR gene-marked cells/µL blood). Conclusions: Based on this limited sample size, reTx with axi-cel may have clinical efficacy, although transient, in some pts, especially those who achieve CR with 1st Tx. CAR T cell expansion and severe CRS and NEs may be attenuated at reTx. Further studies with additional pts are needed to confirm these results. Clinical trial information: NCT02348216 .

7540 Background: Positron emission tomography (PET) is recommended in follicular lymphoma (FL) for initial staging, evaluation of potential transformation, and response assessment. The prognostic value of pre-treatment PET scan has not been adequately explored. Methods: We performed a single-institution retrospective analysis of patients with advanced stage FL, without histological evidence of transformation, treated with frontline rituximab-based therapy, and analyzed the prognostic significance of baseline maximum standardized uptake value (SUVmax). Results: The median follow-up for the cohort was 94 months. Of 346 patients, 151 (44%) received R-CHOP and 195 (56%) received non-R-CHOP regimens. Among multiple single unit increments of SUVmax, a value of >18 showed the strongest association with progression-free survival (PFS) (hazard ratio [HR] 1.5, 95% confidence interval (CI) 0.95-2.3, p=0.08), and was selected as cut-off for further analysis. Fifty-two (15%) patients had a SUVmax > 18. On univariate analysis, factors associated with SUVmax > 18 were male sex (67% vs 52%, p=0.05), elevated β2-microglobulin (65% vs 47%, p=0.02), elevated LDH (37% vs 13%, pmax > 18 (odds ratio [OR] 2.7, 95% CI 1.3-5.3, p=0.006). SUVmax > 18 significantly associated with a lower CR rate among patients treated with non-R-CHOP regimens (45% vs 92%) (pmax > 18 associated with significantly shorter PFS among patients treated with non-R-CHOP regimens (77 months vs not reached, p=0.02), but not among patients treated with R-CHOP (p=0.73). SUVmax > 18 associated with shorter overall survival (OS) both in patients treated with R-CHOP (15 year OS 70% vs 75%, p=0.02) and non-R-CHOP regimens (15 year OS 50% vs 75%, p=0.001). Conclusions: In conclusion, baseline SUVmax has prognostic value in patients with advanced stage FL receiving rituximab-based therapies. Evaluation in prospective studies is needed to further confirm these findings.

TPS7574 Background: Pts with LBCL who have persistent disease assessed by dynamic PET after rituximab-based induction therapy have an increased risk of death (Casasnovas, et al. Blood. 2017). Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of pts with relapsed/refractory LBCL with ≥ 2 prior systemic therapies. In ZUMA-1, the registrational study of axi-cel in pts with refractory LBCL, the objective response rate (ORR) was 91% (70% complete response [CR] rate) in pts with double-expressor or high-grade LBCL with ongoing responses in 48% after a median follow-up of 27.1 mos (Locke FL, et al. Lancet Oncol 2019). Furthermore, pts with fewer prior lines of therapy and lower tumor burden had higher rates of ongoing responses and manageable safety (Locke et al. ASCO 2018. 3039). ZUMA-12 will investigate the efficacy and safety of axi-cel as a first-line therapy in newly diagnosed pts with high-risk LBCL who have PET-positive disease after 2 cycles of induction therapy. Methods: This Phase 2 study has a planned enrollment of ≈40 pts aged ≥ 18 y with high-risk LBCL, defined by the presence of MYC and BCL2 and/or BCL6 translocations by FISH or an IPI score ≥ 3 any time before enrollment, and an ECOG performance status of 0 – 1. Before enrollment, pts must have a Deauville score of 4 – 5 (Barrington SF et al. J Clin Oncol. 2014) after 2 cycles of chemoimmunotherapy that includes an anti-CD20 monoclonal antibody and anthracycline. After leukapheresis, pts with bulky or rapidly progressing disease may receive optional non-chemotherapy bridging therapy. Following conditioning therapy with cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) for 3 days, pts will receive a single infusion of axi-cel at a target dose of 2 × 106 CAR T cells/kg. The primary endpoint is investigator-assessed CR rate per the Lugano classification (Cheson et al. J Clin Oncol. 2014). Key secondary endpoints include ORR, duration of response, event-free survival, progression-free survival, overall response, safety, relapse with CNS disease and levels of blood CAR T cells and serum cytokines over time. Accrual is ongoing. Clinical trial information: NCT03761056.

7545 Background: Cytopenia lasting beyond 30 days has been observed after CAR T cell therapy. Here, we describe the hematopoietic recovery and immune reconstitution following axicabtagene ciloleucel (axi-cel) in patients with relapsed/refractory large B-cell lymphoma. Methods: Patients with available complete blood counts 30 days after axi-cel infusion were eligible for the analysis. Results: Of 31 patients treated on ZUMA-1 (=24) and ZUMA-9 (=7) trials at our institution, grade ≥3 cytopenias were observed in 15 (48%) patients at day 30 (d30), represented by neutropenia in 9 (29%), anemia in 5 (16%), and thrombocytopenia in 13 (42%). Baseline (d-5) characteristics associated with d30 grade ≥3 cytopenia on univariate analysis were ECOG performance status >0 (60% vs 19%, p=0.03) and >3 prior therapies (67% vs 25%, p=0.03). While on study, patients with d30 grade ≥3 cytopenia had a significantly higher need for intravenous immunoglobulins (Ig) (67% vs 25%, p=0.03) and platelet transfusion (73% vs 25%, p=0.01). No significant association was observed between d30 grade ≥3 cytopenia and subsequent grade ≥3 infections (27% vs 31%, p=1), need for growth factor support (both 100%), red blood cell transfusions or diagnosis of myelodysplastic syndromes. At a median follow-up of 2.7 years, a trend for a higher 3-year PFS was observed for patients with d30 grade ≥3 cytopenia (63% vs 35%, p=0.18). Among patients with ongoing response at most recent follow-up, resolution of grade ≥3 cytopenia was observed in 75% of patients at 1 year and 86% at 2 years; recovery in CD4, CD8, CD56, CD19, and IgG was observed in 63%, 100%, 100%, 29%, and 58% of patients at 1 year, and 86%, 100%, 100%, 25% and 50% of patients at 2 years. Among patients with d30 cytopenia, a significant correlation was observed between platelet count and CD56 count (r=+0.64, p 3 cytopenias are common after axi-cel therapy, but resolve in most patients by 1 year. Recovery of CD4 T cells appears to be delayed beyond 1 year in 1/3 of the patients, highlighting the need for prolonged prophylaxis for opportunistic infections.

8024 Background: MRD is a standard measurement for response assessment in MM. Despite new treatments, HRM patients continue to have poor prognosis. We evaluated the impact of MRD- in high vs standard (SRM) risk patients. Methods: We retrospectively evaluated all consecutive MM/plasma cell leukemia patients who had routine MRD testing by 1-tube 8-color advanced flow cytometry with 2,000,000 events and sensitivity level 10-5 at our center from 2015-2018 after initial therapy. Kaplan-Meier and log-rank test were used to assess survival estimates and differences between study groups. Results: 136 patients with MRD testing after initial therapy/autologous transplant (ASCT) were identified. Patient and disease characteristics are included in Table. At a median follow-up of 14 months (1-36), PFS and OS were significantly worse in HRM vs SRM. During the study period, 50% of HRM had progressed (relapse and/or death) vs 20% in SRM (p=0.0006). No patients with SRM died, but 4 (14%) in the HRM group did (p=0.0007). Regardless of MRD status, HRM patients had statistically significant worse PFS than SRM; at median f/u 10% SRM MRD-; 20% SRM MRD+; 40%HRM MRD-; 45% HRM MRD+ had either relapsed or died (p=0.0041). MRD status did not impact OS in either group (p=0.0914), however longer follow up is needed to assess survival. Conclusions: Genetic abnormalities (FISH/GEP) remain a powerful prognostic indicator for myeloma regardless of MRD status. For newly diagnosed myeloma patients treated with novel triple initial therapy and frontline ASCT, achieving MRD negative status didn’t mitigate the poor prognosis outcomes of HRM. [Table: see text]

7517 Background: Axi-cel, an anti-CD19 CART cell therapy, achieved 83% ORR, 58% CR rate, with 39% PFS at 2 years in patients (pts) with relapsed refractory large B-cell lymphoma (LBCL) on the ZUMA-1 study (Locke, Lancet Oncology 2018). Data from a 17-center consortium showed response rates were similar in 274 pts treated with commercial axi-cel (Nastoupil, ASH 2018). Here, we performed retrospective analysis of outcomes in pts with progressive disease (PD) after axi-cel. Methods: Response status was determined by Cheson 2014 and reported as date of radiologic relapse. 274 pts were infused by December 26, 2018 with maximum follow-up of 14 months; 116 pts had PD as of Feb 1, 2019. Twelve sites provided additional data, detailing 85% of PD pts (n=99) with a median time to relapse of 54 days (IQR 16-120). Results: Pre axi-cel pt characteristics: median lines of therapy were 4 (range 2-11), 86% were Stage III/IV and 22% were ECOG >1. Following relapse, 60% (n=61) were biopsied and 70% (43/61) had CD19 expression measured. Thirty percent (13/43) were CD19 negative by: IHC (3/13), flow (2/13) or both (8/13). Seventy percent (n=71) received salvage therapy for PD. Median lines of salvage therapy was 1 (range 0-4). The most common therapies were Lenalidomide-based (30%), checkpoint inhibitors (30%), chemotherapy (20%) and radiation (10%). First salvage therapy ORR by regimen: checkpoint inhibitors = 24%, lenalidomide regimens = 20% and chemotherapy = 11%. One patient received allogeneic transplant. Twelve pts enrolled on clinical trial, with one receiving 2nd CAR-T. Median OS following relapse was 108 days (95% LCL 71). Nineteen pts relapsed 3 months post axi-cel and received therapy had estimated median OS >220 days (95% LCL 81). Conclusions: Patients with LBCL relapsing less than 3 months following axi-cel have extremely poor outcomes supporting the development of novel therapies. Therapy for relapse >3 months appears promising. JYS and SD contributed equally; APR, DBM and BTH contributed equally.

7508 Background: The non-germinal center (non-GCB) subtype of Diffuse Large B-cell Lymphoma (DLBCL) is associated with inferior outcomes from standard immuno-chemotherapy. The BTK inhibitor ibrutinib (I) and immunomodulatory agent lenalidomide (L) have promising activity in non-GCB DLBCL as single agents, and result in synthetic lethality in non-GCB DLBCL models when combined. In relapsed non-GCB DLBCL, rituximab (R), L and I result in overall response rate (ORR) of 55% (Ramchandren, ASH 2018). We report the final results of RLI prior to chemotherapy in newly diagnosed non-GCB DLBCL patients, an investigator initiated, single-arm, open-label, phase 2 study. Methods: Adult patients with non-GCB DLBCL, determined by the Hans method, with adequate organ function and performance status were eligible. The primary objectives were to determine (1A) the ORR of two cycles of RLI as initial therapy, and (1B) the complete response rate (CRR) after 6 cycles of chemotherapy combined with RLI. All patients were treated with rituximab 375 mg/m2 IV day 1, ibrutinib 560 mg po daily, and lenalidomide 25 mg po days 1-10 of 21 day cycles for 2 cycles, followed by 6 additional cycles of RLI with chemotherapy. Results: The protocol accrued 60 patients from May 2016 – February 2019, with 52 patients evaluable for disease response (2 withdrew consent prior to restaging, 6 pending restaging prior to abstract deadline). The median age was 64 years (range: 30-83), 28% were ≥ 70 years, and 50% were female. Half the patients had poor risk IPI, 61% had advanced stage, and 71% had a Ki-67 of ≥ 80%. One patient had a fatal fungal infection (CNS aspergillosis) attributed to high dose corticosteroids and RLI, leading to prohibition of corticosteroids during the RLI only cycles with no further fungal infections identified. The ORR for 2 cycles of RLI was 84.6% (n=44), and the CRR was 38.5% (n=20). One patient refused to proceed with the pre-planned chemotherapy after achieving a CR with 2 cycles of RLI, and remains relapse free 18 months later. Conclusions: The Smart Start trial demonstrates the chemotherapy-free combination of rituximab 375 mg/m2, ibrutinib 560 mg, and lenalidomide 25 mg is highly effective in patients with newly diagnosed non-GCB DLBCL. Additional studies evaluating more cycles of RLI with less chemotherapy consolidation are planned. Clinical trial information: NCT02636322.

2540 Background: CAR-T cells targeting CD19 positive B-cells have improved outcomes for relapsed/refractory non-Hodgkin lymphoma (NHL) and B-cell acute lymphoblastic leukemia (B-ALL). CAR-T emergent toxicities for FDA approved therapies leading to non-progression related death have been reported in the pivotal studies. However, they are underreported and there remains a need to obtain a comprehensive report of NRM emergent with anti-CD19 CAR-T. Methods: We retrospectively searched FDA adverse events reporting system (FAERS) for all adverse events (AE) related to “Tisagenlecleucel(T)” and “Axicabtagene ciloleucel(AC)” reported from 2013-2018. FAERS contains AEs from clinical trials and standard of care patients. All cases with the outcome of death were analyzed. Results: Total numbers of anti-CD19 CAR-T pts reported were 636, out of which 288 cases received “T” and 348 received “AC”. Out of total 129 total deaths, 95 died due to non-disease progression. Patient characteristics are summarized in Table. CART-NRM for entire cohort was 15%; 21% for “T” and 10% for “AC”. Major toxicities reported include CRS, hematological, cardiovascular, neurological and infectious. Difference in mortality is likely related to different patient population, diagnoses and the CAR-T construct. Conclusions: CART-NRM remains considerably high at 15%. Our analysis highlights the major toxicities and informs the potential opportunities for interventions to reduce mortality. We will present updated data with comparative analysis of published clinical studies at the upcoming ASCO Meeting in Chicago. [Table: see text]

7041 Background: Combining PD-1/PD-L1 blockade with hypomethylating agents (HMA) shows encouraging preliminary efficacy in AML, but immune features predictive of response are lacking. Methods: We treated 11 relapsed/refractory (R/R) AML patients with azacitidine (AZA) and nivolumab (Nivo) in a phase 2 clinical trial ( Daver N et al Cancer Discovery 2018). Patient characteristics: median (med) age 65 years (47-73), 63% adverse cytogenetics, 27% TP53 mutated. Pretreatment bone marrow aspirates had immune-phenotypic 17-color flow analysis and NanoString RNA quantification of 1469 immune-relevant genes. Results were correlated with clinical, pathological and molecular data. Results: The median courses of AZA+Nivo administered was 3 (range 1-17). The CR/CRi rate was 45% (including 2 CR, 1 CRi, 1 CRN and 1 CRP), with a median time to response of 1.8 months (range 0.8-4.9 months). The median overall survival was 13 months with 27% patients alive at 1 year. We found significant positive correlations between proportions of T-effector cells at baseline, and CD3+, CD8+, and T-regulatory cells at end of cycle (EOC) 1 (r > 0.75, p < 0.01 for all). At EOC2, these correlations were no longer significant. However, there was a significant positive correlation between T-effector cells at baseline and T-regulatory cells (r = 1, p < 0.001) at EOC4. Using NanoString analysis, we found 105 differentially expressed genes (fold change = 1.5, p < 0.05) between responders (5/11) and non-responders (6/11) at pretreatment. IL2-STAT5, TP53 and TNF Hallmark pathways and immune response from GO gene sets were highly enriched (q < 5x10-4) in responders. We then utilized z-score distribution analysis to quantify the degree of activation of known immunologic pathways. We found that signatures highly specific to neutrophils, NK cells, T-cells and eosinophils were significantly (p < 0.05) upregulated in patients with CR compared to non-responders at pretreatment. Conclusions: Our data demonstrates that a signature suggestive of lymphocyte activation in the pretreatment BM may be associated with augmented clinical response to PD-1 based therapies. Similar underlying pathways that have consistently predicted for responses to PD-1 inhibition in solid cancers, primarily IL2-STAT5 genes, may have predictive relevance in AML. Such pretreatment flow and NanoString signatures may help select AML patients most likely to benefit from PD-1 blockade plus HMA, further enhancing the benefit-risk ratio with such therapies.

7555 Background: Axi-cel is a US FDA-approved, autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy for the treatment of pts with relapsed or refractory LBCL with ≥ 2 prior systemic therapies. In the 2-y follow-up of ZUMA-1, the objective response rate (ORR) was 83% with a complete response (CR) rate of 58%, and 39% of pts were in ongoing response (Locke et al. Lancet Oncol. 2019). Here we report efficacy and safety outcomes by age. Methods: Eligible pts with refractory LBCL underwent leukapheresis and conditioning chemotherapy followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg. The Phase 2 primary endpoint was investigator-assessed ORR. Additional key endpoints were adverse events (AEs), overall survival (OS), and levels of CAR gene-marked cells in peripheral blood. Efficacy was evaluated for Phase 2 pts; safety was evaluated for all treated pts (Phases 1 and 2). Pts were analyzed by ≥ 65 y vs < 65 y of age. Results: As of 8/11/2018, 108 pts were treated. Pts ≥ 65 y (n = 27) vs < 65 y (n = 81) had a median age of 69 y vs 55 y, respectively, were 81% vs 63% male, 70% vs 36% had an IPI score 3-4, 59% vs 57% had ECOG 1, 67% vs 72% had ≥ 3 prior therapies, and median tumor burdens were 3790 mm2 vs 3574 mm2. Median follow-up was 27.1 mo for Phase 2 pts (n = 101). The ORR for pts ≥ 65 y (n = 24) and < 65 y (n = 77) was 92% and 81% (CR rate 75% and 53%), respectively, with ongoing responses in 42% and 38% of pts (ongoing CR 42% and 35%). The 24-mo OS rate was 54% for pts ≥ 65 y and 49% for pts < 65 y. Most pts experienced Grade ≥ 3 AEs (100% of pts ≥ 65 y; 98% of pts < 65 y), and 4% of each group (1/27 pts ≥ 65 y and 3/81 pts < 65 y) died due to AEs as previously reported. Grade ≥ 3 neurologic events and cytokine release syndrome occurred in 44% vs 28% and 7% vs 12% of pts ≥ 65 y vs < 65 y, respectively. CAR T cell expansion by peak level (43 vs 35 cells/μl) or area under the curve (562 vs 448 d × cells/μl) was similar in pts ≥ 65 y vs < 65 y, respectively. Conclusions: The 2-y follow-up of ZUMA-1 demonstrates that axi-cel can induce high rates of durable responses with a manageable safety profile for pts ≥ and < 65 y. Axi-cel offers substantial clinical benefit for older pts with refractory LBCL who otherwise have limited treatment options. Clinical trial information: NCT02348216.

Purpose The Janus kinase 2/signal transducers and activators of transcription (JAK2/STAT) pathway plays an important role in the pathogenesis of hematologic malignancies. We conducted a phase I dose-finding and pharmacokinetic/pharmacodynamic study of SB1518, a potent JAK2 inhibitor, in patients with relapsed lymphoma. Patients and Methods Patients with relapsed or refractory Hodgkin or non-Hodgkin lymphoma of any type except Burkitt's or CNS lymphoma were enrolled. Patient cohorts received escalating doses of SB1518 orally once daily for 28-day cycles. Response was evaluated after 8 weeks. Results Thirty-four patients received doses of 100 to 600 mg/d. The maximum tolerated dose was not reached. Treatment was well tolerated, with mostly grade 1 and 2 toxicities. Gastrointestinal toxicities were the most common treatment-related events. Cytopenias were infrequent and modest. Pharmacologically active concentrations were achieved at all doses. Dose-related linear increases in area under the concentration–time curve were seen on day 1, with no significant accumulation on day 15. Mean terminal half-life was 1 to 4 days, and mean time to peak concentration ranged from 5 to 9 hours. SB1518 inhibited JAK2 signaling at 4 hours postdose at all levels. Increases in fms-like tyrosine kinase-3 (FLT-3) ligand, reflecting FLT-3 inhibition, were seen in most patients. There were three partial responses (≥ 300 mg/d) and 15 patients with stable disease (SD), with most responses lasting longer than 2 months. Seven of 13 SDs had tumor reductions of 4% to 46%. Conclusion SB1518 has encouraging activity in relapsed lymphoma, providing the first proof-of-principle of the potential therapeutic value of targeting the JAK/STAT pathway in lymphoma in the clinical setting.

3039Background: In ZUMA-1 (NCT02348216), axi-cel, an anti-CD19 chimeric antigen receptor (CAR) T cell therapy, demonstrated significant benefit in patients (pts) with refractory large B cell lympho...

3003Background: Axi-cel, an anti-CD19 CAR T cell therapy, demonstrated significant clinical benefit and a manageable safety profile for pts with refractory large B cell lymphoma in ZUMA-1 (Neelapu ...

Purpose This phase II trial evaluated the safety and efficacy of yttrium-90 (90Y)–ibritumomab tiuxetan in patients with relapsed or refractory mantle cell lymphoma (MCL). Patients and Methods Patients with relapsed or refractory MCL were eligible for the study if they had adequate major organ function and performance status. Those with CNS disease, pleural effusion, circulating lymphoma cells ≥ 5,000/μL, or history of stem-cell transplant were ineligible. Patients with a platelet count ≥ 150,000/μL received a dose of 0.4 mCi/kg of 90Y–ibritumomab tiuxetan, whereas those with a platelet count less than 150,000/μL received a dose of 0.3 mCi/kg. Results Thirty-four patients with a median age of 68 years (range, 52 to 79 years) received the therapeutic dose. The patients had received a median of three prior treatment regimens (range, one to six treatment regimens), including those that contained rituximab (n = 32) and bortezomib (n = 7). Of the 32 patients with measurable disease, 10 (31%) achieved complete or partial remission. After a median follow-up of 22 months (range, 2 to 72+ months), an intent-to-treat analysis revealed a median event-free survival (EFS) duration of 6 months and an overall survival duration of 21 months. The median EFS for those who achieved partial or complete remission was 28 months, while it was 3 months for those whose disease did not respond (P < .0001); it was 9 months for patients whose tumor measured less than 5 cm in the largest diameter before treatment and 3 months for those whose tumor measured ≥ 5 cm (P = .015). Conclusion The single-agent activity of 90Y–ibritumomab tiuxetan and its favorable safety profile warrant its further development for the treatment of MCL.

Purpose To evaluate patient-specific immunotherapy with mitumprotimut-T (idiotype keyhole limpet hemocyanin [Id-KLH]) and granulocyte-macrophage colony-stimulating factor (GM-CSF) in CD20+ follicular lymphoma. Patients and Methods Patients with treatment-naive or relapsed/refractory disease achieving a complete response (CR), partial response (PR), or stable disease (SD) with four weekly rituximab infusions were randomly assigned to mitumprotimut-T/GM-CSF or placebo/GM-CSF, with doses given monthly for six doses, every 2 months for six doses, and then every 3 months until disease progression (PD). Randomization was stratified by prior therapy (treatment-naive or relapsed/refractory) and response to rituximab (CR/PR or SD). The primary end point was time to progression (TTP) from randomization. Results A total of 349 patients were randomly assigned; median age was 54 years, 79% were treatment naive, and 86% had stage III/IV disease. Median TTP was 9.0 months for mitumprotimut-T/GM-CSF and 12.6 months for placebo/GM-CSF (hazard ratio [HR] = 1.384; P = .019). TTP was comparable between the two arms in treatment-naive patients (HR = 1.196; P = .258) and shorter with mitumprotimut-T/GM-CSF in relapsed/refractory disease (HR = 2.265; P = .004). After adjusting for Follicular Lymphoma International Prognostic Index (FLIPI) scores, the difference in TTP between the two arms was no longer significant. Overall objective response rate, rate of response improvement, and duration of response were comparable between the two arms. Toxicity was similar in the two arms; 76% of adverse events were mild or moderate, and 94% of patients had injection site reactions. Conclusion TTP was shorter with mitumprotimut-T/GM-CSF compared with placebo/GM-CSF. This difference was possibly due to the imbalance in FLIPI scores.

e19040 Background: Frontline regimens for indolent lymphoma are effective, but patients still suffer from relapse. From 2005 to 2007 we enrolled previously untreated patients on a phase II trial to investigate response rate and efficacy of pentostatin combined with cyclophosphamide and rituximab (PCR). PCR is an effective frontline therapy in chronic lymphocytic leukemia. We report the final analysis with a median follow up of nearly ten years. Methods: Patients were treated with 6 cycles of therapy with additional 3 cycles in case of not attaining a CR/CRu. All patients received Pentostatin (4 mg/m2), Cyclophosphamide (600 mg/m2), and Rituximab (375 mg/m2) on day one and every 21 days. Results: Of the 83 patients, five were considered unevaluable for response, but are included as non-responders in our intent-to-treat analysis. Diagnoses included FL (43.4%), SLL (38.5%), and MZL (18.1%). 78.3% had Ann Arbor stage IV lymphoma and 63.9% had bone marrow (BM) involvement. For all 83 patients, the overall response was 92%, and most toxicity events were hematologic, with grade ≥3 neutropenia in 68 of 509 cycles of chemotherapy administered. Long term toxicity includes secondary malignancies in 14 patients. Two patients developed treatment related MDS/AML and both occurred after additional lines of therapy. PFS at 10 years for FL, MZL, and SLL was 71%, 67% and 15%, respectively. PFS was affected by clinicopathologic characteristics. 10-year PFS rates for those with pretreatment β2M < 2.2 and > 2.2 mg/l were 71 % and 21 % respectively. Patients without BM involvement had 10-year PFS of 72% versus 29% for those with BM involvement. The median OS has not been reached. The overall survival rate was 87% at 5 years and 64% at 10 years. The difference in OS rate was statistically significant based on histology, 94% for FL, 66% for MZL, and 39 % for SLL. Conclusions: Long term follow up confirms that PCR is an effective, robust and tolerable treatment regimen for indolent B-cell lymphomas with 34 of 36 patients with FL alive at 10 years with 27 remaining in remission. Clinical Trial Information NCT00496873 Clinical trial information: NCT00496873.

3025 Background: Axi-cel is an autologous anti-CD19 CAR T cell therapy. ZUMA-1 is a multicenter, registrational trial of axi-cel in patients (pts) with refractory/aggressive B-cell non-Hodgkin lymphoma (NHL). In a pre-specified interim analysis, ZUMA-1 met its primary endpoint with 76% objective response rate and 47% complete response (Blood 2016;128:LBA-6). We describe, for the first time, a tumor microenvironment immune gene signature associated with CAR T cell treatment (tx) of NHL pts. Methods: Paired biopsies, pre- and within 3 weeks post-axi-cel tx, were analyzed by digital gene expression followed by a pre-specified bioinformatics algorithm applied to IGES15 and IGES21 genes involved in immune-mediated tumor regression (Immunosign; Galon Immunity 2013). Immunosign profiles expression of a pre-defined set of effector T cell, Th1, chemokine, and cytokine genes. Expression analysis and hierarchical clustering were used to define an axi-cel-related tumor immune gene signature. Wilcoxon signed rank test with multiple test correction by FDR (Benjamini-Yekutieli) was used. Results: Gene expression profile comparisons of pre- and post-axi-cel tx biopsies from 14 pts showed profound changes in gene expression within the tumor environment after infusion. The most upregulated genes post-axi-cel tx were CCL5 (RANTES), CTLA4, and GZMA (log2 fold change > 2, P< 0.05, FDR < 0.050). Immune checkpoints PD-L1 and LAG3 were also upregulated post-axi-cel (log2 fold change > 1.6, P< 0.05, FDR < 0.055). Other genes associated with T cell proliferation, homing, and effector function were also upregulated: IL-15, GZMK, CXC3CL1 (Fractalkine), CD8A, and STAT4 (log2 fold change > 1.6; P< 0.05, FDR < 0.074). Additional baseline tumor characteristics and associative analysis will be presented. Conclusions: We define a mechanistic tumor immune gene signature in NHL pts associated with axi-cel tx. This signature comprises upregulation of T cell activation, effector, chemokine, and immune checkpoint genes. These data will potentially lead to rational optimization of T cell interventions in cancer Clinical trial information: NCT02348216.

e19019 Background: De novo CD5+ DLBCL is associated with poor prognosis. Methods: We retrospectively reviewed the MD Anderson Lymphoma Outcome Database and identified 104 patients (pts) with de novo CD5+ DLBCL diagnosed between 2001-2016. We excluded primary CNS lymphoma and Richter’s transformation. Results: Median age was 62 (range 29-96); 55% were male. Most (71%) pts had advanced stage at diagnosis, with 55% being Stage IV. Eighty percent (n = 79) had extranodal disease at presentation with bone/bone marrow being the most common site (40%); central nervous involvement was seen in 5%. Two-thirds had elevated LDH; 37% had B symptoms on presentation. ECOG PS was ≥2 in 26% of pts; beta-2 microglobulin was elevated in 68%. Of the 77 pts with IPI score, 21% (n = 16), 23% (n = 18), 26% (n = 20), and 30% (n = 23) were considered low, low-intermediate, high-intermediate, and high risk, respectively. In the diagnostic specimen, median Ki67 was 85%. Majority were non-GCB by Han’s criteria (n = 47 of 77). Two pts were double-hit lymphoma. All received R-containing regimens for primary therapy, including RCHOP (n = 64), dose-adjusted R-EPOCH (n = 24), R-HyperCVAD (n = 6), and other (n = 10). Prophylactic intrathecal chemotherapy use was 35%. Sixty-eight (65%) pts achieved complete response (CR) with primary therapy. Two pts underwent frontline autologous stem cell transplant. Median PFS duration was 28 months (mo) (95% CI: 10-27). Median OS duration was 112 mo (95% CI: 10-214). Pts with primary refractory disease had the worst OS duration of 14 mo. Pts with relapse within 1 year of achieving CR fared no better with median OS of 22 mo. PFS and OS were not significantly different by choice of primary therapy. By multivariate analysis using Cox proportional hazard model, male gender (HR = 3.0, 95% CI: 1.1-8.1, p = 0.029) and high IPI (HR = 2.5, 95% CI: 1.4-4.3, p = 0.001) were associated with shorter PFS. Only IPI score was significantly associated with worse OS (HR = 3.0, 95% CI: 1.6-5.7, p = 0.001). Conclusions: De novo CD5+ DLBCL is frequently associated with extranodal presentation and poor outcome with R-containing intensive chemotherapy. IPI remains the most significant prognostic factor for worse PFS and OS. There is clearly an unmet need for novel treatment for this disease.

7531 Background: Relapsed follicular lymphoma (FL) remains a challenge and salvage regimens are associated with toxicity and limited control. Outcomes are linked to the immune microenvironment and lenalidomide and rituximab are highly active in FL. Obinutuzumab has increased ADCC compared to rituximab in preclinical models and is approved for relapsed FL. We hypothesized that the immunologic properties of obinutuzumab and lenalidomide would be synergistic. The study objective was to determine the MTD of lenalidomide with obinutuzumab in relapsed FL and describe the efficacy of the combination. Methods: This open label phase I/II study enrolled Gr 1-3a FL. Transformation was excluded. Lenalidomide was given on D 2-22 with 1000mg obinutuzumab on D1, 8, 15, and 22 of cycle 1 and on D1 for up to 12 cycles (28 days/cycle). Obinutuzumab was given every 2 months thereafter for up to 30 months in pts who responded following doublet therapy. During dose escalation, 3 cohorts were planned with 10, 15 and 20mg of lenalidomide. Phase II planned to enroll 30 pts at MTD with efficacy and safety as primary endpoints. Results: All 36 pts with FL enrolled (6 in dose escalation and 30 at MTD), and are eligible for efficacy and safety analysis. The median age was 65 with a median of 2 prior therapies. No DLTs were observed in phase I, and 20 mg of lenalidomide was used for phase II. To date, the most common all grade non-heme toxicities were fatigue(83%), diarrhea(67%) and rash(53%). Grade 3+ toxicities included neutropenia (23%), infection (11%) and fatigue (8%). The overall response rate was 100% with 78% (95%CI 60.85-89.88%) of pts attaining complete response (CR/Cru). All pts with rituximab refractory FL (13) responded. At a median follow up of 14 months, 10 pts progressed. The estimated 24 month PFS is 61% (95% CI 43-87%). Conclusions: Lenalidomide and obinutuzumab is highly active with durable remissions in relapsed FL, with all pts responding and 78% achieving CR. The majority of pts remain on therapy and the combination appeared safe. Correlatives are ongoing to identify biomarkers of response and frontline studies of the combination are currently enrolling. Clinical trial information: NCT01995669.

7519 Background: Follicular lymphoma (FL) tumors are infiltrated with antitumor T cells, however, their function is impaired by immune checkpoints such as PD-1/PD-ligand pathway. Blocking PD-1 enhances the function of antitumor T cells in FL. In addition, blocking PD-1 on NK cells has been shown to enhance the ADCC effect of NK cells. We reasoned that the combination of pembrolizumab (P), an anti-PD-1 antibody (ab), and rituximab (R), an anti-CD20 ab that induces ADCC, is likely to be synergistic through activation of both the innate and adaptive immune systems and result in enhanced clinical activity in FL. Methods: We evaluated P and R in an open-label, non-randomized, single institution, phase II trial (N=30). Key inclusion criteria included adult (age ≥ 18 years), FL grade 1-3a, ECOG 0-1, in relapse after ≥1 prior therapy (tx) and R sensitive disease, defined as a complete (CR) or partial response lasting at least 6 months (mos) after most recent R-containing therapy. Pts received R (375 mg/m2 IV) on days 1, 8, 15, and 22 of cycle 1 and P (200mg IV) q 3 weeks for up to 16 cycles starting on day 2 of cycle 1. Primary endpoint was overall response rate (ORR). Results: 27 pts have initiated therapy, median age 65 (range 42-79), 52% male, 76% had intermediate or high risk FLIPI, 56% met GELF criteria. Median prior tx =1 (range 1-4). Adverse events (AE) regardless of causality were mild, most grade 1-2. Grade 3 AE’s included nausea (N=2), infusion reaction (N=2), aseptic meningitis (N=1), pneumonia (N=1). Immune-related AEs included grade 2 diarrhea (N=2), grade 2 pneumonitis (N=1), grade 2 skin rash (N=1). At the pre-planned interim analysis (N=15), ORR was 80%, CR rate was 60%. With a median follow up of 7 mos (range 0.5-17), median DOR, PFS, and OS has not been reached. PD-L1 expression was tested in 8 baseline tumor samples using PD-L1 22C3 IHC pharmDx and was detected in histiocytes in all 8 tumors, present in only 1-8% of tumor cells in 5 tumors. Additional biomarker analyses are ongoing. Conclusions: The combination of P and R is well tolerated in relapsed FL and is associated with high overall and CR rate. These interim results warrant further investigation of this combination in FL. Clinical trial information: NCT02446457.

7512 Background: Outcomes in activated B cell subtype diffuse large B cell lymphoma (ABC-DLBCL) and r-NHL are poor (Sehn Blood 2015, Crump ASCO 2016). ZUMA-1 is the first, multicenter trial of anti-CD19 chimeric antigen receptor (CAR) T cells, axi-cel, in r-NHL. Methods: Dosing and eligibility were per Neelapu ASH 2016. The primary endpoint was objective response rate (ORR); secondary endpoints were duration of response (DOR), overall survival (OS), and safety. Cell of origin (COO) and CD19 status were assessed centrally using Lymphoma Subtyping Test NanoString (Wallden JCO 2015) and a validated immunohistochemistry assay, respectively. Results: As of Jan 27, 2017, 111 patients (pts) were enrolled; the manufacturing success rate was 99% with an average 17-d turnaround time; 101 pts (modified intent-to-treat [mITT] population) received axi-cel. In the mITT population, the ORR was 82% (complete response [CR], 54%). With 8.7 m median follow-up, 44% remain in response and 39% in CR. The median DOR was 8.1 m and not reached (NR) for pts with CR. Median OS was NR. Results for clinical and biologic covariates are listed in the table. In pts who received tocilizumab (n = 43) and/or steroids (n = 27) for cytokine release syndrome (CRS) and/or neurologic events (NE), ORR was 84% and 78%, respectively. Most common grade ≥3 adverse events (AEs) were neutropenia (66%), leukopenia (44%), anemia (43%), febrile neutropenia (31%), thrombocytopenia (24%), and encephalopathy (21%). Rates of grade ≥3 CRS and NE were 13% and 28%, respectively. There were 3 grade 5 AEs (Neelapu ASH 2016). Conclusions: Axi-cel induced an ORR of 82% in pts with r-NHL, response is ongoing in 44% of pts at 8.7 m. Similar clinical responses were observed in pts with r-ABC-DLBCL. AEs were manageable and the use of tocilizumab/steroids did not appear to impact ORR. Drs Locke and Neelapu contributed equally. Funding source: Kite Pharma and Leukemia & Lymphoma Society Therapy Acceleration Program Clinical trial information: NCT02348216. [Table: see text]

TPS7575Background: Diffuse large B-cell Lymphoma (DLBCL), the most common lymphoid malignancy, is categorized by the putative cell of origin (COO) classification system into germinal center (GCB) a...

7563Background: Several studies on single and double protein expressing DLBCL (DPL), defined as BCL2 positive in > 70% and MYC positive in > 40%, have identified inferior clinical outcomes when tre...

4130Background: The importance of the tumor microenvironment in the biology of mPC has been increasingly recognized. However, immune checkpoint blockade has previously shown limited clinical respon...

7559This study is supported in part by The Leukemia & Lymphoma Society Therapy Acceleration Program Background: Durable remissions with CD28/CD3z anti-CD19 CAR T cells have been observed in patient...

8537 Background: CUDC-907 is an oral inhibitor of class I PI3K as well as class I and II HDAC enzymes. Anti-tumor effects of CUDC-907 have been demonstrated in B-cell lymphoma and multiple myeloma ...

8528 Background: Between 1997-2002, we conducted a randomized trial for patients (pts) with previously untreated stage IV small lymphocyctic (SLL), marginal zone (MZL), or follicular lymphoma (FL), with the primary aim to compare concurrent FND+R versus sequential FND followed by R. This is the final analysis with mature data. Methods: Patients were randomized to 6 doses of R given during the first 5 of 8 courses of FND, or monthly during IFN maintenance following FND. We now report response rates, progression free survival (PFS), overall survival (OS), and adverse events (AE) including secondary malignancy with nearly 12 years of follow up. Results: Of the 157 pts, 18% had SLL, 11% MZL, and the remaining 71% had FL. 80 pts received concurrent FND+R, 77 sequential. Pts on the 2 arms were comparable in terms of prognostic features (FLIPI components). Median age for all pts was 54 years, 54% were female, 90% had bone marrow involvement, 80% had intermediate or high FLIPI score, 68% had high tumor burden. Wi...

8536 Background: Thalidomide, and its analog, lenalidomide have shown activity in WM, when combined with rituximab. However, neuropathy and anemia respectively, have limited their use. P is a newer generation IMID® which has demonstrated efficacy and tolerability in R/R multiple myeloma. These results provided the rationale for a phase I study of P in pts with R/R WM. Methods: Eligible pts had WM that was R/R to ≥ 1 prior therapy. All pts received daily oral P (28d cycles), starting at a 1mg dose level. Following a 3+3 statistical design, the dose was increased by 1 mg increments until the MTD was reached. Overall response was assessed as per International WM Working Group Response Criteria. Results: Between 10/2010-01/2014, 9 pts (7 males, 2 females) were treated. Median age at enrollment was 64 yrs (range 51-85), median time from 1st therapy was 6.1 yrs (range 2.0-16.3), and median prior therapies was 2 (range 1-5). With a median f/u of 30 mos. (range: 6-36), 8 pts remain alive, and 1 continues to recei...

8508 Background: Preclinical models suggested synergistic antineoplastic activity of HDAC and mTOR inhibitors in Hodgkin lymphoma by reducing the activity of AKT, mTOR and HDAC. Methods: We designe...

2528 Background: Murine models show Id-vaccines induce antitumor responses, possibly through Th1/Tc1 cytokines. We report an 11-year follow-up of Id-vaccine following DA-EPOCH-Rituximab in 26 untreated MCL patients. Methods: DA-EPOCH-R was administered q3 weeks × 6, followed 12 weeks later by 5 cycles of Id-vaccine. Id protein was made by hybridoma technology, conjugated to keyhole limpet hemocyanin (KLH) and administered with GM-CSF. Pre- and post-vaccine immune responses (IR) were tested in parallel: anti-Id and anti-KLH humoral responses (ELISA); anti-KLH cellular responses (intracellular cytokine assay); and anti-tumor cellular responses (cytokine induction, IFNγ ELISPOT). Results: Characteristics: median age 57 (r 22-73), blastoid variant 15%, and MIPI (low-65%; intermediate-16%; high-19%). With 122 mo median follow-up (r 111-132), the median PFS is 24 mo and OS is 104 mo. MIPI was associated with OS (p=0.0002); median OS: low (not reached), intermediate (84 mo) and high (44 mo). We found no association between OS and anti-KLH IR, anti-Id humoral response, IFNγ ELISPOT, or antitumor TNFα or IFNγ responses. Normalized antitumor T-cell GM-CSF response (median 4.3) was associated with OS of 79 mo vs. not reached, respectively (p=0.015 (unadj.) and p=0.045 (adj.)). MIPI (p=0.02) and GM-CSF (p=0.057) were independently associated with OS. TTNT (based on disease activity), correlated with antitumor GM-CSF response (p=0.018) but not MIPI and was independent of MIPI (GM-CSF; p=0.041). Correlation of pre-and post-treatment GM-CSF production suggested a priming effect. Tumor proliferation by GEP did not correlate with OS (n=14). Conclusions: Antitumor GM-CSF response was significantly associated with OS and TTNT, suggesting antitumor cellular immune response significantly delayed tumor growth. Antitumor GM-CSF response may serve as a surrogate biomarker for vaccine efficacy. Our results are consistent with recent data that T-cell GM-CSF production is required for breaking tolerance against self-antigens. Id vaccines may prolong survival of MCL following rituximab-based chemotherapy and should be further evaluated.

8030 Background: Lenalidomide has been shown to have single-agent activity in relapsed NHL, and rituximab (R) is effective alone and in combination with chemotherapy in untreated patients. The aim of this phase II, single arm study is to evaluate the efficacy and safety of lenalidomide and rituximab in pts with untreated, advanced stage, indolent NHL. Methods: Pts with measurable (>1.5 cm) untreated indolent NHL received 20 mg/day of lenalidomide on days 1-21 and rituximab 375 mg/m2 on day 1 of each 28 day cycle. Prophylactic growth factors were not used. Response was assessed every 3 cycles using the 1999 International Working Group Response Criteria. Results: 75 pts have completed 6 cycles of treatment or are off-study, and 70 pts are evaluable for response. Histologies included: CLL/SLL n=15, FL n=41, and marginal zone lymphoma n=19. The median age was 57 (35-84) years, and 55% were male. The overall response (OR) rate for all pts was 90% with 66% attaining a complete response (CR). Seventeen pts (25%)...

8053 Background: DLBCL is a common lymphoma of older adults, and a potentially curable disorder with the regimen RCHOP (Coiffier, et.al. NEJM,2002). Doxorubicin, a key drug in the regimen, has risk for cardiotoxicity, and thus of concern in older patients (pts) with higher incidence of cardiovascular (CV) disease. In breast cancer pts pegylated liposomal doxorubicin (D) has shown greater cardiac safety and similar efficacy to doxorubicin. We thus replaced doxorubicin with D in RCHOP (DRCOP). Methods: The regimen is: rituximab 375 mg/m2 IV day (d) 1; D 40 mg/m2 IV d 1; cyclophosphamide 750 mg/m2 IV d 1; vincristine 2 mg IV d 1 total dose; prednisone 100 mg/d p.o. d 1-5. Eligibility criteria were: > 60 years of age; untreated confirmed DLBCL (no discordant histology); Ann Arbor stage II-IV; baseline LVEF 50%. CV disease was permitted, if symptoms controlled, but consult at baseline by Cardiologist and at follow-up required. Troponin and brain natriuretic peptide (BNP) levels were monitored. Granulocyte grow...

TPS305 Background: Follicular lymphoma (FL) is one of the most immune-responsive of all cancers. However, immunosuppressive mechanisms in the tumor microenvironment may impair the efficacy of antitumor immune responses. We have recently identified the programmed death (PD)- 1/PD-ligand pathway as an important immunosuppressive mechanism in the FL tumor microenvironment. Expression of the coinhibitory PD-1 receptor was markedly increased on intratumoral T cells and associated with decreased reactivity to autologous FL tumor cells. Blocking PD-1/PD-ligand pathway with CT-011 enhanced the proliferation of antitumor T cells and augmented the expression of activating receptors on human NK cells. Administration of CT-011 delayed tumor growth and improved survival of mice in lymphoma xenograft models and combination with rituximab further improved survival compared with rituximab alone (Chu et al, Blood, Nov 2009; 114: 724.). In a phase I clinical trial, CT-011 was safe, induced sustained elevations of CD4+ T ce...

8036 Background: The optimal treatment for newly diagnosed indolent non-Hodgkins lymphoma (NHL) has not been determined. While several combination chemotherapy regimens have response rates approach...