Ansell, Stephen M.

Abstract Background AFM13 is a bispecific, tetravalent NK cell-engaging antibody construct binding to CD30 on CD30+ tumor cells and CD16A on NK cells. By engaging CD16A-positive NK cells, AFM13 leads to NK cell-mediated killing of CD30-positive lymphoma cells (Reusch et al., 2014) making it an attractive agent to target classical Hodgkin lymphoma (HL). Pembrolizumab is a PD-1 blocking antibody which has shown high single-agent response rates in patients (pts) with relapsed/refractory HL (RRHL; Armand et al., 2016, Chen et al., 2017). AFM13 has shown clinical activity in RRHL as a single agent in a preceding Phase 1 study (Rothe et al., 2015). Preclinical in vivo data of the combination of AFM13 with PD-1 blockade showed synergistic activity and the potential for induction of cross-talk between innate and adaptive immunity (Zhao et al., 2016). We hypothesize that the combination of the two agents could improve outcomes in pts with RRHL. Methods This Phase 1b study is evaluating the safety and tolerability of the combination of AFM13 with pembrolizumab (Keytruda) as salvage therapy after failure of standard therapies including brentuximab vedotin (BV) in HL (NCT02665650). Pts receive escalating doses of AFM13 in combination with pembrolizumab at a dose of 200 mg flat administered every 3 weeks following a classical 3+3 design, followed by enrollment into an extension cohort at the maximum tolerated dose (MTD)/maximum administered dose (MAD). Response assessment is performed every 12 weeks by PET/CT according to the Lugano Classification (Cheson et al., 2014). The main objectives of the study is to ascertain the MTD/MAD along with the preliminary efficacy of the combination. Results As of June 29, 2018, 30 pts have been enrolled into the study. The median age is 34 years (range, 18-73), with a median of 4 (range 3-7) prior lines of therapy. All pts had relapsed or refractory disease (43% relapsed, 57% refractory) and had failed standard treatments including BV and 43% of pts (13/30) had BV as their latest therapy. Thirty seven percent (11/30) had undergone prior autologous stem cell transplantation. All 30 pts have completed the 6-week dose-limiting toxicity (DLT) observation period. Twelve pts were enrolled into the dose escalation cohorts (Cohorts 1 (n=3), 2 (n=3), and 3 (n=6)) and 18 into the Extension Cohort, with a total of 24 patients treated at the MAD (dose level 3). One DLT was observed in Cohort 3 (missing ≥25% of AFM13 during the DLT period) and another observed in the Extension Cohort (G4 infusion-related reaction; IRR). The most common related adverse events (AEs) were IRRs (80%), rash (30%), pyrexia (23%), nausea (23%), diarrhea (20%), fatigue (17%), headache (17%), increased aspartate aminotransferase (13%), and increased alanine aminotransferase (10%). Treatment related G3/4 AEs included IRRs (13%), elevated AST (3%), gastritis (3%), hypotension (3%), nausea (3%), neutropenia (3%), and vomiting (3%). The majority of IRRs were manageable with standard of care measures and did not lead to treatment discontinuations. Included in the efficacy analysis were the best response from 29 evaluable pts who had at least one post-baseline disease assessment as of the data cutoff on June 29, 2018. The overall response rate (ORR) and complete response (CR) rate for evaluable pts treated at the dose and schedule chosen for expansion (n=23; Cohort 3 and Extension Cohort) were 87% and 35% by the investigator-confirmed assessment, respectively. Independent assessment resulted in an ORR of 87% and CR rate of 39% for these pts. Updated data for all 30 patients will be presented at the meeting. Conclusions The combination of AFM13 and pembrolizumab is a well-tolerated salvage therapy in pts with RRHL. IRRs were the most frequently observed adverse events; however, most of these events were of mild or moderate severity and manageable. Both the ORR and CR rate compare favorably to monotherapy pembrolizumab in a similar RRHL population (Chen et al., 2017). The combination of AFM13 and pembrolizumab could be a potential new therapeutic option for HL patients. Disclosures Bartlett: Immune Design: Research Funding; Affimed: Research Funding; Bristol-Meyers Squibb: Research Funding; Merck & Co: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Novartis: Research Funding; Millennium: Research Funding; ImaginAB: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees. Chen:Affimed: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech Inc.: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Millennium Pharmaceuticals: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Domingo-Domenech:Affimed: Research Funding. Forero-Torres:Affimed: Research Funding. Garcia-Sanz:Affimed: Research Funding. Devata:Affimed: Research Funding. Rodriguez Izquierdo:Affimed: Research Funding. Lossos:Affimed: Research Funding. Reeder:Affimed: Research Funding. Sher:Affimed: Research Funding. Choe-Juliak:Affimed: Employment. Prier:Affimed: Research Funding. Schwarz:Affimed: Employment. Strassz:Affimed: Employment. Alland:Affimed: Employment. Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Merck & Co: Research Funding; Affimed: Research Funding; Takeda: Research Funding.

Abstract Background: Relapsed/refractory (R/R) Hodgkin lymphoma (HL) remains a significant clinical challenge. We hypothesized that using immune checkpoint blockade to activate the immune cells in the tumor microenvironment, and concurrently targeting tumor cells with the CD30 targeting antibody-drug conjugate brentuximab vedotin (BV) could overcome tumor resistance. E4412 is a Phase 1/2 ECOG-ACRIN sponsored study of the combinations of BV, nivolumab (Nivo), and ipilimumab (Ipi) in patients with R/R HL. Here we present the preliminary safety and response data on the full cohort of patients treated in Phase 1 with BV + Ipi + Nivo (Arms G-I). Methods: Patients with confirmed R/R HL were treated with Nivo 3mg/kg, Ipi 1mg/kg and BV 1.2mg/kg (Arm G) or 1.8mg/kg (Arm H) with a 3+3 design, and an expansion cohort (Arm I) of 9 patients with BV at 1.8mg/kg. BV and Nivo are given every 21 days for 16 cycles; Nivo may be continued for an additional 12 months. Ipi is given every 12 weeks except for the first 2 patients in Arm G who received Ipi every 6 weeks for the first 3 cycles. Dose limiting toxicity (DLT) was defined within the first cycle of therapy. Results: As of 6/30/18 22 patients with a median of 2 prior therapies (range 1-5) have been treated; 7 in Arm G, 6 in Arm H, and 9 in Arm I. Median age was 35, range (19-60); 11 patients were male. Nine patients had prior SCT (1 alloSCT, 8 autoSCT); 1 patient had prior BV. Safety: All 22 enrolled patients are evaluable for safety. There were 3 DLTs, one in each arm. In Arm G one patient experienced grade 4 diabetic ketoacidosis and hyperglycemia, and went off treatment after cycle 1. In Arm H, one patient had transient grade 3 AST elevation; this was of no clinical significance and did not require a delay in therapy. In Arm I a post AlloSCT patient had grade 4 Steven-Johnson syndrome with grade 3 pruritis, rash, and GVHD, and came off therapy. Common toxicities considered at least possibly related to drug, are shown in Table 1, and grade 3 or greater toxicity in Table 2. There were no grade 5 AEs or additional grade 4 AEs. Significant grade 3 AEs were: rash, colitis, gastritis, pancreatitis, and arthritis each in one patient, resulting in dose delays but not discontinuation of therapy. One patient experienced grade 2 angioedema in cycle 1 and came off therapy. No significant infusion reactions were noted. Response: Nineteen of 22 patients are evaluable for response. Three patients discontinued treatment after cycle 1 and are not evaluable for response. For the full population the overall response rate (ORR) was 82% (18/22), with a complete response (CR) rate of 68% (15/22). For patients treated with at least 3 cycles of therapy who were evaluable for response, the ORR is 95% (18/19) with a CR rate of 79% (15/19). Six patients went from treatment to SCT. With a median follow-up of 0.52 years median progression free survival (PFS) has not been reached (Figure 1), and with a median follow-up of 0.82 years overall survival (OS) has not been reached (Figure 2). Conclusion: In this study of the triplet combination of BV, Ipi and Nivo for R/R HL, therapy was generally well tolerated, although more grade 3 AEs were seen than in the doublets. In a heavily pretreated patient population, with 9 patients post SCT, the ORR of 95% and CR rate of 79% in evaluable patients is extremely promising. Data will be updated to include longer term PFS and OS by the time of the meeting. Optimization of this strategy is ongoing in E4412, now a randomized phase 2 study comparing the doublet of BV-Nivo to the triplet of BV-Ipi-Nivo. Disclosures Diefenbach: Trillium: Research Funding; Incyte: Research Funding; Genentech: Consultancy; Seattle Genetics: Consultancy, Research Funding; Denovo: Research Funding; Acerta: Research Funding; Millenium/Takeda: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Hong:Merck: Consultancy. Cohen:Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding; BioInvent: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Advani:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Merck: Research Funding; Autolus: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Kura: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cell Medica: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board, Research Funding; Janssen: Research Funding; Millenium: Research Funding; Infinity: Research Funding; Regeneron: Research Funding; Agensys: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Astra Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Gilead/Kite: Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Kyowa: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Participated in an advisory board; Forty Seven: Research Funding. Barta:Janssen: Membership on an entity's Board of Directors or advisory committees; Merck, Takeda, Celgene, Seattle Genetics, Bayer: Research Funding. Svoboda:Regeneron: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Kyowa: Consultancy; TG Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; KITE: Consultancy. Karmali:AstraZeneca: Speakers Bureau; Gilead: Speakers Bureau. Kahl:Genentech: Consultancy; Abbvie: Consultancy; Acerta: Consultancy; Celgene: Consultancy; AstraZeneca: Consultancy; ADC Therapeutics: Consultancy; Seattle Genetics: Consultancy; Juno: Consultancy; CTI: Consultancy; Gilead: Consultancy. Ansell:LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding.

Abstract Background Survival rates for older pts with advanced HL (aged ≥60 yrs) were historically poor with doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD). Reasons may include decreased tolerance of therapy, increased toxicity (particularly with bleomycin), comorbidities, and disease biology. The pivotal phase 3 ECHELON-1 study demonstrated superior 2-yr modified progression-free survival (mPFS) with frontline brentuximab vedotin + doxorubicin, vinblastine and dacarbazine (A+AVD) vs ABVD in pts with stage III/IV cHL (Connors JM et al, NEJM 2018). The study allowed entry of older pts, with no upper age limit. Alternative dosing schedules of the A+AVD regimen have been studied (e.g., sequential brentuximab vedotin before and after AVD; NCT01476410, Evens AM et al, J Clin Oncol 2018). We report efficacy and safety results from ECHELON-1 for older pts with cHL and compare these with those for pts aged <60 yrs. Methods mPFS per independent review facility (IRF) for pts ≥60 years was a prespecified subgroup analysis of ECHELON-1. Additional exploratory safety and efficacy analyses were also assessed and compared with younger pts (<60 yrs). The study was not powered for age-based subgroup analyses; p-values are descriptive without multiplicity adjustment. Results 14% (186/1334) of pts in the intent-to-treat (ITT) population were aged ≥60 yrs (A+AVD, n=84; ABVD, n=102) and included in the sub analyses. Median age (range) of older pts was: A+AVD, 68.0 yrs (60-82); ABVD, 66.0 yrs (60-83). Baseline pt and disease characteristics in older pts were similar in both arms. ECOG PS scores were 0 (36% vs 36%), 1 (52% vs 54%), and 2 (12% vs 10%) in A+AVD and ABVD arms, respectively. Pts received a median of 6 cycles with mean relative dose intensities for each drug (%) in older pts of: A+AVD, 92.3, 96.6, 93.3, and 97.9; ABVD, 97.3, 88.7, 93.3, and 95.9. With median follow-up of ~25 months, 2-yr mPFS per IRF was similar in both arms for older ITT pts (A+AVD 70.3% [95% CI: 58.4, 79.4] vs ABVD 71.4% [95% CI: 60.5, 79.8]; HR=1.00 [95% CI: 0.58, 1.72]; p=0.993). An exploratory analysis of standard PFS per investigator (INV) showed HR=0.85 ([95% CI: 0.49, 1.48]; p=0.576) (Table 1). For older pts with stage IV cHL (A+AVD n=51; ABVD n=67), there was an increase in 2-yr PFS per INV with A+AVD vs ABVD (74.0% [95% CI: 59.5, 84.0] vs 59.9% [95% CI: 45.6, 71.5]; HR, 0.66 [95% CI: 0.34, 1.26]; p=0.20); mPFS per IRF improvement with A+AVD in older stage IV pts was lower (HR=0.80; [95% CI: 0.42, 1.53]). In younger stage III/IV pts (<60 yrs) 2-yr mPFS per IRF and PFS per INV were also higher compared with older pts in both arms (Table 1). 66 of 83 older A+AVD pts required ≥1 dose modification of brentuximab vedotin, reasons were: dose reduction (n=27), dose held (n=4), dose delayed (n=51), brentuximab vedotin discontinued (n=17). In older pts, grade (G) 3/4 AEs occurred in 88% of A+AVD pts vs 80% ABVD pts; for younger pts, rates were 82% (A+AVD) vs 63% (ABVD) (Table 2). In older pts there were 3 (4%) on-study deaths in the A+AVD arm (1 each: hemophagocytosis, neutropenic sepsis, and myocardial infarction) and 5 (5%) with ABVD (all pulmonary-related). In pts <60 yrs, there were 6 on-study deaths (1%) with A+AVD vs 8 (1%) with ABVD. G3 neutropenia in older pts was (70%) A+AVD pts vs (59%) ABVD pts, and febrile neutropenia (FN) in 31 (37%) vs 17 (17%) pts. In older pts who had G-CSF primary prophylaxis (PP) neutropenia was seen in 4/10 (40%) A+AVD pts vs 1/9 (11%) ABVD pts (on-study FN in 3 [30%] vs 2 [22%] pts). In older pts, treatment-emergent peripheral neuropathy (PN) was reported in 54 (65%) of A+AVD pts vs 42 (43%) of ABVD pts (G≥3 in 15 [18%] vs 3 [3%] pts), respectively. In pts <60 yrs PN was reported in 388 (67%) A+AVD pts vs 244 (43%) ABVD pts (G≥3 in 55 [9%] vs 8 [1%] pts), respectively. In older pts at last follow-up, 65% (35/54) of A+AVD pts and 60% (25/42) of ABVD pts had complete resolution (A+AVD, 39%; ABVD, 38%) or improvement (A+AVD, 26%; ABVD, 21%) of PN events. 2% older A+AVD pts had pulmonary AEs (both G1/2 pulmonary infiltration) vs 13% older ABVD pts. Conclusions For older ECHELON-1 pts, mPFS and PFS were similar in both arms. In the larger subgroup of younger pts, mPFS and PFS were improved vs older pts. As expected, incidence of treatment-emergent AEs was higher in older pts, with regimen-specific AEs seen, including fatal pulmonary events in ABVD pts. The high incidence of FN in older A+AVD pts points to the need for G-CSF PP. Disclosures Evens: Acerta: Consultancy; Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Affimed: Consultancy; Janssen: Consultancy; Abbvie: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Tesaro: Research Funding; Novartis: Consultancy. Connors:Merck: Research Funding; Amgen: Research Funding; Takeda: Research Funding; Roche Canada: Research Funding; NanoString Technologies: Patents & Royalties: Named Inventor on a patent licensed to NanoString Technologies, Research Funding; Seattle Genetics: Honoraria, Research Funding; Janssen: Research Funding; F Hoffmann-La Roche: Research Funding; Bayer Healthcare: Research Funding; Cephalon: Research Funding; Bristol Myers-Squibb: Research Funding; Lilly: Research Funding; Genentech: Research Funding. Younes:Sanofi: Honoraria; Merck: Honoraria; Astra Zeneca: Research Funding; Celgene: Honoraria; Incyte: Honoraria; Seattle Genetics: Honoraria; Bayer: Honoraria; Novartis: Research Funding; Curis: Research Funding; J&J: Research Funding; Genentech: Research Funding; Takeda: Honoraria; Roche: Honoraria, Research Funding; Abbvie: Honoraria; Janssen: Honoraria, Research Funding; Pharmacyclics: Research Funding; BMS: Honoraria, Research Funding. Ansell:Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Celldex: Research Funding; Bristol-Myers Squibb: Research Funding. Radford:Takeda: Consultancy, Research Funding, Speakers Bureau; GlaxoSmithKline: Equity Ownership; AstraZeneca: Equity Ownership; Seattle Genetics: Consultancy, Speakers Bureau; ADC Therapeutics: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau; Pfizer: Research Funding; Celgene: Research Funding; BMS: Consultancy, Speakers Bureau. Feldman:Seattle Genetics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Pharmacyclics: Speakers Bureau; Johnson and Johnson: Speakers Bureau; Celgene: Speakers Bureau; Portola: Research Funding; KITE: Speakers Bureau. Tuscano:Takeda: Research Funding; Genentech: Consultancy, Research Funding; Amgen: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Celgene: Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding. Oki:Seattle Genetics: Research Funding; Takeda Millenium: Honoraria, Research Funding; Jazz Pharmaceuticals: Employment. Grigg:Roche: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Pocock:Kent & Canterbury Hospital: Employment. Dlugosz-Danecka:Roche: Consultancy; Servier: Consultancy. Fenton:Seattle Genetics, Inc.: Employment, Equity Ownership. Engley:Seattle Genetics: Employment. Liu:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Miao:Millennium Pharmaceuticals Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Jolin:Takeda Pharmaceuticals International Co.: Employment. Gautam:Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Employment. Gallamini:Takeda: Consultancy, Speakers Bureau.

Abstract Background: Limited data exist regarding histological transformation in patients with Waldenström macroglobulinemia (WM). In this study, we present the disease characteristics, outcomes and risk factors for histological transformation in WM. Methods: Patients with WM seen at Mayo Clinic, Rochester, MN between January 1996 and December 2017 were included. Patients with aggressive non-Hodgkin lymphoma in the setting of WM were considered to have transformation. Univariate analysis for comparing baseline characteristics of transformed versus non-transformed WM was performed using Wilcoxon, Fisher's exact and Chi square tests, as appropriate. Multivariate analysis was performed using logistic regression analysis. Cox proportional hazard method was used to assess the impact on time-to-transformation. All time-to-event analyses were calculated by the Kaplan-Meier method. Results: Of 1014 patients with WM, 42 patients (4.1%) developed histological transformation. The median follow-up for the entire cohort was 9.5 years (95% CI: 8.8-10.5 years). The cumulative probability of transformation was 2.3% at 5 years, 5.3% at 10 years and 8.5% at 15 years from diagnosis of WM, respectively. There was no difference in the 5-year cumulative probability of transformation in patients with WM diagnosed between 1996-2000 (2.1%), 2001-2005 (2.9%), 2006-2010 (2.7%) and 2011-2015 (3.8%), p=0.61.The disease characteristics, laboratory parameters and histology at transformation are outlined in Table 1. In patients with DLBCL histology (n=39), Revised-International Prognostic Index was calculable in 28 patients, with 50% (n=14), 46% (n=13) and 4% (n=1) of DLBCL belonging to poor, good and very good risk groups, respectively. For DLBCL histology, 18 patients were classifiable using Hans algorithm into germinal center B-cell (GCB) type (n=3, 17%) and non-GCB type histology (n=15, 83%). The median lines of therapy received prior to transformation for the entire cohort was 2 (range 0-9), with 5 (11%) patients not having received any therapy for WM before transformation. Number of lines of alkylator-based therapy used prior to transformation [median 1 line (range 0-4)] was comparable to that used in patients in whom WM did not occur [median 1, (range 0-6); p=0.78]. The median time-to-transformation from diagnosis of WM was 4.8 years (95% CI: 2.6- 6.8 years). Overall survival (OS) from transformed disease was 3.2 years (95% CI 1.1-3.9 years). The 10-year OS of patients with WM who transformed was lower (46%) compared to patients without transformation (60%) with a trend towards statistical significance (p=0.08), Figure 1. The MYD88L265P mutation status was available in 333 patients in the entire cohort (22/42 pts in the transformed cohort and 311/972 in the non-transformed cohort. Of the 22 patients in the transformed WM cohort, 13 (59%) exhibited MYD88WT genotype and 9 (41%) exhibited MYD88L265P genotype. The risk of transformation was higher in patients with MYD88WT status [Odds ratio 6.3 (95% CI: 2.6-15.5); p<0.0001]. Additionally, serum lactate dehydrogenase (LDH) was higher at diagnosis of WM in patients who transformed, Table 2. On multivariate analysis, MYD88WT status remained an independent predictor of disease transformation [p=0.003; odds ratio 10 (95% CI: 2.1-48)]. On univariate Cox proportional hazard analysis for identifying predictors of time-to-transformation, only MYD88WT mutational status was associated with shorter time-to-transformation with a 5-year transformation rate of 15.5 % for MYD88WT versus 2.6 % with MYDL265P mutated patients [risk ratio 6.2 (95% CI: 2.5-16.4); p<0.0001]. Treatment-related details in the transformed cases were available for 37 (90%) patients; R-CHOP was the most common (41%) frontline therapy for transformation; 33% patients underwent autologous stem cell transplantation for transformed disease during their disease course. Conclusion: Histological transformation is an uncommon event in WM but confers poorer survival. MYD88WT genotype is independently associated with histological transformation a shorter time-to- transformation in patients with WM. Disclosures Ansell: Trillium: Research Funding; Pfizer: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Takeda: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Gertz:Apellis: Consultancy; Alnylam: Honoraria; spectrum: Consultancy, Honoraria; janssen: Consultancy; annexon: Consultancy; Prothena: Honoraria; Abbvie: Consultancy; Amgen: Consultancy; celgene: Consultancy; Teva: Consultancy; Medscape: Consultancy; Ionis: Honoraria; Research to Practice: Consultancy; Physicians Education Resource: Consultancy. Dingli:Millennium Takeda: Research Funding; Millennium Takeda: Research Funding; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.; Alexion Pharmaceuticals, Inc.: Other: Participates in the International PNH Registry (for Mayo Clinic, Rochester) for Alexion Pharmaceuticals, Inc.. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Dispenzieri:Celgene, Takeda, Prothena, Jannsen, Pfizer, Alnylam, GSK: Research Funding. Lacy:Celgene: Research Funding. Kumar:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kapoor:Takeda: Research Funding; Celgene: Research Funding.

Abstract Introduction: Given the established role of PD-1 in mediating immune suppression in chronic lymphocytic leukemia (CLL), we tested and reported the efficacy of PD-1 blocking antibody pembrolizumab in relapsed and transformed CLL patients. A selective response of pembrolizumab (~40%) in patients with RT, particularly after prior ibrutinib, was observed (Ding, Blood, 129:3419). Correlative analysis showed PD-1 expression in tumor B-cells of patients with RT and aggressive CLL after progression on ibrutinib. PD-1, an inhibitory receptor expressed on CLL T-cells, inhibits the immune synapse and cytotoxic T cell functions via the interactions with its ligands. However, the expression pattern and role of PD-1 in tumor B-cells is not well defined. In this study we investigated the functional implication of the PD-1 signaling axis in B-cell pathobiology in CLL and RT patients. Methods: 26 CLL-involved lymph node (LN) and 20 RT-involved LN were tested for PD-1 expression by immunohistochemistry (mouse clone NAT105, Abcam). For in vitro study, we checked PD-1 expression in 11 lymphoma cell lines and 1 CLL cell line by both flow cytometry and Western blot (WB) analysis. Effect of PD-1 knockdown using CRISPR/Cas9 system (Addgene) and over-expression of PD-1 using pLEX-lentiviral (Thermoscientific) or pRetro-retroviral (Clonetech) system were evaluated on pro-survival and apoptotic signaling pathways by Western blot analysis. Gene expression signatures in CLL and RT patients were also evaluated by Illumina-based RNA sequencing using FFPE-nodal tissue obtained by clinical biopsy (Tempus Labs; Chicago, IL). Results: The expression of PD-1 was significantly increased in RT-LN compared to CLL-LN. (mean ± SEM in RT vs. CLL, 30.6 ± 4.7 vs. 11.5 ± 2.8, p < 0.001). PD-1 expression was highest in patients with RT where the immediate prior CLL therapy was ibrutinib (Figure 1A). Among all cell lines tested for PD-1 expression, the expression of PD-1 by WB and flow was highest in Mino (mantle cell lymphoma line), followed by moderate expression in Jvm2 (B-PLL line) and Mec1 (CLL line), and very low-level expression in both Jeko-1 (B-NHL line) and lymphoma line 'Karpas299'. CRISPR/Cas9 mediated depletion of PD-1 in Mino cells inhibited constitutively active Akt, p70S6K and mTOR pathway, accompanied by significant downregulation of the anti-apoptotic proteins, Bcl-2, Mcl-1 and XIAP, but P-ERK1/2 was not affected. Constitutive lentiviral (pLEX-PD-1)-mediated overexpression of PD-1 in Jeko-1 and doxycycline regulated inducible retroviral (pRetro-PD-1) mediated overexpression of PD-1 in Karpas299 activated Akt, mTOR and p70S6K pathway. Overexpression of PD-1 in Jeko-1 significantly increased Bcl-2 and Mcl-1 and in Karpas299 increased Bcl-2, Mcl-1 and XIAP expression (Figure 1B). A parallel genetic analysis using RNA sequencing was performed on 5 nodal tissues involved by either RT or progressive CLL after these patients developed clinical progression after prior ibrutinib therapy. In all 5 patients, overexpression of PD-1 was associated with increased expression of Bcl-2 and mTOR regardless of the genetic mutations detected (including TP53, ATM, BTK, NOTCH1, XPO1, SF3B1, TET2 etc). However, in 2 patients who received prior chemoimmunotherapy, similar overexpression of gene signature was not observed by RNA sequencing analysis, alternative pathways including Met or NFkB overexpression was detected. Given these clinical and laboratory findings, we have treated 2 RT patients with a combination of BTK and Bcl-2 inhibitors (ibrutinib and venetoclax, respectively) whose CLL transformed after prior ibrutinib. Significant reduction of tumor burden was observed in both cases with one complete response and one mixed response. Conclusion: An increased expression of PD-1, Akt/mTOR and Bcl-2 gene signature was first observed in RT patients after prior ibrutinib therapy. PD-1 overexpression in the tumor B-cells of RT and progressive CLL patients likely regulate AKT/mtOR to upregulate Bcl-2. Targeting both BTK and Bcl-2 pathways in addition to PD-1 blockade appear to be a promising strategy to treat these aggressive diseases. Disclosures Parikh: Gilead: Honoraria; Janssen: Research Funding; Abbvie: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; AstraZeneca: Honoraria, Research Funding. Kenderian:Novartis: Patents & Royalties; Tolero Pharmaceuticals: Research Funding; Humanigen: Research Funding. Ansell:Takeda: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Celldex: Research Funding; Merck & Co: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Pfizer: Research Funding. Kay:Infinity Pharm: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Acerta: Research Funding; Agios Pharm: Membership on an entity's Board of Directors or advisory committees; Cytomx Therapeutics: Membership on an entity's Board of Directors or advisory committees; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees. Ding:Merck: Research Funding.

Abstract Background: PTLD is the most common malignancy, other than non-melanoma skin cancer, complicating solid organ transplantation (SOT) and has been one of the most commonly observed fatal consequences in SOT. The clinical presentations, management strategies, histologies, causes of death and outcomes are diverse (Dierickx D, Habermann TM. N Engl J Med 2018;378:549-62). The 2017 WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues has redefined the categories as non-destructive PTLDs (plasmacytic hyperplasia, infectious mononucleosis, and florid follicular hyperplasia), polymorphic PTLD, monomorphic PTLD: B-cell neoplasms (diffuse large B-cell lymphoma, Burkitt lymphoma, high-grade B-cell lymphoma, plasmablastic lymphoma, plasma cell myeloma, plasmacytoma, and other) and T-cell neoplasms (peripheral T-cell lymphoma NOS, hepatosplenic T-cell lymphoma, other), and classic Hodgkin lymphoma (CHL) PTLD. We report the outcomes and long-term follow-up of patients from a single institution based on these categories whose pathology was retrospectively reviewed and reclassified based on the WHO 2017 classification. Methods: Patients with SOT who were diagnosed with PTLD at Mayo Clinic (Rochester, MN) were identified through the Mayo Clinic Lymphoma Data base and the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER). The histology was re-reviewed in 80% of the cases (RLK) and classified according to the WHO Classification of Tumours of Haematopoietic an Lymphoid Tissues 2017. Cases were considered "PTLD, unclassified" if the histology could not be confidently classified based on pathology material available for review. Indolent small B-cell lymphomas were not included among the PTLDs except for EBV-positive marginal zone lymphoma. Cox proportional hazards models were used to assess the association of clinical factors in overall survival (OS). Results: 233 patients diagnosed with PTLD between 1987 and 2017 were identified. The median age at the time of diagnosis of PTLD was 54 years (range 16 to 84) with 85 patients (36%) over the age of 60. 156 (67%) were male. The transplanted organs were kidney (41%), kidney/pancreas (5%), liver (29%), heart (9%), lung (7%), and other (8%). PTLD occurred late (more than one year after transplantation) in 66%. There were 69 stage I, 19 stage II, 8 stage III, and 128 stage IV patients. 84% presented with extranodal disease. 21% had involvement of the engrafted organ. 64% of the patients developed a PTLD that was EBV positive by in situ hybridization. Initial approaches to management included reduction of immunosuppression (N=55), chemotherapy/immunochemotherapy (N=71), reduction in immunosuppression with rituximab (N=58), single agent rituximab (N=14), and radiation therapy (N=5). At a median follow-up of 87 months (range 9-289), 139 (60%) patients had died. All six CHL-PTLD patients are alive, two of whom had an event. The median overall survival (OS) was 85 months (95% CI: 39-144) in 177 monomorphic B-cell lymphoma PTLD, 95.5 months (95% CI: 40-not reached) in 24 polymorphic PTLD, and 60 months in 8 non-destructive PTLD cases. In contrast, the median overall survival was 12 months (95% CI: 4-200) in 8 monomorphic T cell and 3 months (95% CI: 1-unreached) in 9 unclassified PTLD cases. Conclusion: PTLD is a heterogeneous group of immunodeficiency-associated lymphoproliferative disorders. The overall survival in non-destructive, polymorphic, and monomorphic PTLD were similar. Monomorphic T/NK cell types had inferior outcomes. Figure. Figure. Disclosures Maurer: Morphosys: Research Funding; Nanostring: Research Funding; Celgene: Research Funding. Ansell:Celldex: Research Funding; Merck & Co: Research Funding; Takeda: Research Funding; LAM Therapeutics: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Bristol-Myers Squibb: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Pfizer: Research Funding. Cerhan:Celgene: Research Funding; Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board.

Abstract Introduction: Our group (Porrata et al, BBMT 2016; 22: 1017-1023) previously published that the infusion of autograft natural killer (NK) cells correlates with survival post-autologous stem cell transplantation (ASCT) in non-Hodgkin's lymphoma (NHL) patients. A limitation of our previous study was the lack of killer-immunoglobulin-like receptor (KIR) analysis. Thus, we set up to investigate if the infusion of autograft activating and inhibitory KIR affects survival in NHL. Methods: From December 2007 to October 2010, 122 NHL patients participated in our Phase III clinical trial. A total of 111 patients finished the trail and samples were available for analysis. We analyzed the content of the autograft for inhibitory and activating KIR using flow cytometry analysis of each apheresis collection. Overall survival (OS) and progression-free survival (PFS) were analyzed from the date of transplant. Results: With a median follow-up of 82.8 months (range: 2.1-122.3 months), patients infused with an activating NKp30 (CD158b-CD337+) KIR ≥ 0.09 x 109 cells/kg experienced superior OS and PFS vs < 0.09 x 109 cells/kg: [OS: median was not reached vs 39.8 months, 5 years OS rates of 95% (95%CI, 56%-98%) vs 43% (95%CI, 22%-48%), p < 0.0001, respectively; and PFS: median was not reached vs 12.7 months, 5-years PFS rates of 77% (95%CI, 65%-86%) vs 13% (95%CI, 6%-24%), p < 0.0001, respectively]. Patients infused with the inhibitory KIR2DL2 (CD158b+CD337-) KIR < 0.066 x 109 cells/kg experienced superior OS and PFS vs ≥ 0.066 x 109 cells/kg : [OS: median was not reached vs 48.2 months, 5 years OS rates of 86% (95%CI, 75%-93%) vs 44% (95%CI, 31%-88%), p < 0.0001, respectively; and PFS: median was not reached vs 25.6 months, 5-years PFS rates of 62% (95%CI, 49%-74%) vs 31% (95%CI, 20%-44%), p < 0.0002, respectively]. We combined NKp30 and KIR2DL2 into NKp30/KIR2DL2 ratio. Patients infused with an NKp30/KIR2DL2 ratio ≥ 1.8 experienced superior OS (Figure 1) and PFS (Figure 2) vs < 1.8 : [OS: median was not reached vs 33.4 months, 5 years OS rates of 95% (95%CI, 86%-98%) vs 33% (95%CI, 21%-47%), p < 0.0001, respectively; and PFS: median was not reached vs 14.9 months, 5-years PFS rates of 76% (95%CI, 63%-85%) vs 14% (95%CI, 7%-27%), p < 0.0001, respectively]. Multivariate analysis revealed that the NKp30/KIR2DL2 ratio was an independent predictor for OS [HR = 0.03, 95%CI 0f 0.01-0.07, p < 0.0001] and PFS [HR = 0.17, 95%CI 0f 0.09-0.31, p < 0.0001]. Conclusion: The NKp30/KIR2DL2 ratio provides a platform to develop an immunocompetent autograft to improve clinical outcomes in NHL patients undergoing ASCT. Figure 1. Figure 1. Disclosures Ansell: LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Celldex: Research Funding; Takeda: Research Funding; Merck & Co: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding.

Abstract Introduction: Genetic alterations at 9p24.1 resulting in overexpression of programmed death-1 (PD-1) ligands are near-universal in cHL (Roemer et al, J Clin Oncol 2016); cHL may thus be uniquely sensitive to PD-1 blockade. Nivolumab (nivo), an anti-PD-1 monoclonal antibody, was associated with an objective response rate (ORR) of 69% in relapsed/refractory (R/R) cHL after auto-HCT and irrespective of prior brentuximab vedotin (BV) in the phase 2 CheckMate 205 study (Armand et al, J Clin Oncol 2018; NCT02181738). Whether some patient (pts) can derive very long clinical benefit, whether depth of response predicts long-term outcome, whether treatment (Tx) can be interrupted in complete remission (CR), and whether the safety profile of nivo in R/R cHL changes with prolonged Tx all remain unclear. We therefore present an updated analysis of CheckMate 205, focusing on long-term efficacy and safety. Methods: This international, single-arm, multi-cohort study enrolled pts aged ≥18 y with R/R cHL after auto-HCT. Pts were BV naïve (Cohort A), had prior BV failure after auto-HCT (Cohort B), or had received BV before and/or after auto-HCT (Cohort C). Pts received nivo 3 mg/kg every 2 wk until disease progression (PD)/unacceptable toxicity. Pts in Cohort C discontinued nivo after 1 y in CR and could resume if they relapsed within 2 y of the last dose. Primary endpoint was ORR per independent radiology review committee (IRC); additional endpoints included duration of response (DOR) per IRC, progression-free survival (PFS) per IRC, overall survival (OS), and safety. Time to next Tx (TTNT: time from first dose to next systemic Tx or death) was an exploratory post-hoc analysis. Responses were assessed using International Working Group 2007 criteria. Results: In total, 243 pts were enrolled to Cohorts A (n=63), B (n=80), and C (n=100). Baseline characteristics have been previously described (Armand et al, J Clin Oncol 2018). At data cut-off, minimum follow-up was 31 mo and 49 pts (20%) were still on Tx; the most common reason for discontinuation was PD (35%). Median duration of Tx was 14 mo. ORR per IRC was 71% (65%, 71%, 75% in Cohorts A, B, C, respectively) with a best overall response (BOR) of CR in 21% (32%, 14%, 20% in Cohorts A, B, C, respectively). Among 51 pts who achieved CR, 20 had CR as the first response and 31 improved from partial remission (PR), mostly (n=28/31) within 1 year of first PR. Median time to response was 2 mo, and to CR was 4 mo. Within the first 6, 12, and 18 mo, 68%, 71%, and 71% of pts, respectively, achieved a response. Median DOR was 18 mo overall, and was 32 and 13 mo in pts with a BOR of CR and PR, respectively. Among responders, 64%, 44%, 31%, and 21% of pts had a DOR of at least 6, 12, 18, and 24 mo, respectively. Overall, 11 pts in Cohort C discontinued with persistent investigator-assessed CR; 2 reinitiated nivo due to PD. Median (95% CI) PFS per IRC among all pts was 15 (11-19) mo (Figure A), and was 17, 12 and 15 mo in Cohorts A, B, and C, respectively. Median OS was not reached in any cohort; 24-mo OS rates were 90%, 86%, and 86% in Cohorts A, B, and C, respectively, and were similar among pts in CR, PR, or with stable disease (SD; Figure B). Median TTNT was 29, 27, and 20 mo in Cohorts A, B, and C, respectively. The most common Tx-related adverse events (AEs) of any grade (G) were fatigue (24%), diarrhea (16%), and rash (12%), each <1% G3-4. Tx-related infections were reported in 15% of pts, 2% G3-4. Tx-related infusion related reactions were reported in 34 pts (14%), <1% G3-4. The most commonly reported immune-mediated AE category was rash, which was G3-4 in 4 pts (2%). In total, 26 pts (11%) experienced an AE of any cause leading to discontinuation. There were no Tx-related deaths. Conclusions: With the longest phase 2-3 study follow-up of a checkpoint inhibitor in R/R cHL to date, nivo was associated with frequent and durable responses regardless of BV Tx history. More than 1 in 5 responders remained in response ≥2 years later. With extended follow-up, additional pts achieved CR in all cohorts. Pts with CR had longer PFS than pts with PR or SD. However, pts with both PR and SD had prolonged OS, unlike pts with PD, which may suggest that clinical benefit duration is not well predicted by conventional response criteria. Nivo continued to be well tolerated, with no new safety signals. Characteristics of long-term responders will be presented. Study support: BMS. Medical writing: A Gill, Caudex, funded by BMS Figure. Figure. Disclosures Armand: Infinity: Consultancy; Affimed: Consultancy, Research Funding; Pfizer: Consultancy; Otsuka: Research Funding; Adaptive: Research Funding; Merck: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Roche: Research Funding; Tensha: Research Funding. Younes:Celgene: Honoraria; Genentech: Research Funding; Janssen: Honoraria, Research Funding; Bayer: Honoraria; Novartis: Research Funding; J&J: Research Funding; Astra Zeneca: Research Funding; BMS: Honoraria, Research Funding; Merck: Honoraria; Abbvie: Honoraria; Takeda: Honoraria; Seattle Genetics: Honoraria; Roche: Honoraria, Research Funding; Sanofi: Honoraria; Incyte: Honoraria; Curis: Research Funding; Pharmacyclics: Research Funding. Zinzani:PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Honoraria, Speakers Bureau; Celltrion: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees. Collins:ADC Therapeutics: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Celgene Corporation: Research Funding; BMS: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Amgen: Research Funding. Ramchandren:Merck: Research Funding; Bristol-Myers Squibb: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Cohen:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BioInvent: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Takeda: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Infinity Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees. De Boer:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Membership on an entity's Board of Directors or advisory committees; EISA: Membership on an entity's Board of Directors or advisory committees. Kuruvilla:Lundbeck: Honoraria; Gilead: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Princess Margaret Cancer Foundation: Research Funding; Leukemia and Lymphoma Society Canada: Research Funding; Abbvie: Consultancy; Merck: Consultancy, Honoraria; Karyopharm: Honoraria; Roche: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria; Amgen: Honoraria; Celgene: Honoraria. Trněný:F. Hoffman-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board, Research Funding; Sandoz: Honoraria; Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Abbvie: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Morphosys: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: Advisory board. Shipp:Merck: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Sacchi:Bristol-Myers Squibb: Employment, Equity Ownership. Sumbul:Bristol-Myers Squibb: Employment. Ansell:Trillium: Research Funding; Pfizer: Research Funding; Regeneron: Research Funding; Celldex: Research Funding; Seattle Genetics: Research Funding; Affimed: Research Funding; Merck & Co: Research Funding; LAM Therapeutics: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda: Research Funding.

Abstract Background Diffuse large B cell lymphoma post-transplant lymphoproliferative disorder (DLBCL-PTLD) represents a fatal complication after a solid organ transplant (SOT). Approximately 50% of DLBCL-PTLD can be related to Epstein Barr Virus (EBV) infection. However, the EBV status is not taken into account in the DLBCL-PTLD categorization, although increasing evidence suggests its critical role in biological, clinical and prognostic aspects of the disease. In this single center retrospective study, we compared clinical and histological features, as well as outcomes of DLBCL-PTLDs by EBV status. Methods This study focused on patients with SOT who were diagnosed with DLBCL-PTLD at Mayo Clinic (Rochester, MN). Patients were identified through the Mayo Clinic Lymphoma Data base and the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource (MER), between 1989 and 2017. The histology was re-reviewed (RLK) and classified according to the WHO Classification or Tumours of Haematopoietic and Lymphoid Tissues 2017. Cell of origin (COO) was performed by Hans algorithm. EBV RNA in situ hybridization (EBER) was performed. Cox proportional hazards models were used to assess the association of clinical factors in overall survival (OS). Results 148 DLBCL-PTLD were identified. The median age at SOT and at the time of PTLD diagnosis were 50 years (range: 15-71) and 56 years (range: 18-82), respectively. The median time to PTLD diagnosis from SOT was 38 months (range: 1-499). The types of SOT included renal (44%), liver (36%), cardiac (9%), renal/pancreas (5%), pancreas (8%), lung (7%) and multiorgan (4%). 62% were stage III-IV, 30% had elevated LDH and 67% had an IPI >1. 88% of patients presented with extranodal disease, and 16% had involvement of the grafted organ. Eighty-three (56%) cases were EBV positive. The COO information was available on 35 cases. The non-GCB subtype was identified in 24 cases and GCB subtype in 11 cases. The initial treatment was as follows: reduction in immunosuppression (12%), immunosuppression reduction with rituximab (26%), rituximab alone (5%), chemotherapy with or without rituximab (35%). Patients with EBV positive PTLD were more likely to have grafted organ involvement (20% vs. 8%, p=0.047) and late PTLD (occurring after 12 months from SOT - 60% vs. 8%, p<0.001) than patients with EBV negative PTLD. There was no association between EBV status and age, sex, stage, LDH, and extranodal site involvement. At a median follow-up of 80 months (range 9-269), 83 patients (56%) had died. The 5-year survival rate from PTLD diagnosis was 56% (95% CI: 48-65%). The median OS was 85 months (95% CI: 37-148). There was no difference in OS in patients with EBV positive PTLD (median OS=84.7 months, HR=1.21, 95% CI: 0.77-1.92) versus patients with EBV negative DLBCL-PTLD (median OS=85.4 months, p=0.41). Conclusion Our study assessed the impact of EBV status on the presentation and clinical outcome of DLBCL-PTLD in a 148-patient single-institution cohort. 56% of cases were EBV positive. EBV positivity was associated with grafted organ involvement and late PTLD diagnosis. Patients with EBV-negative and EBV-positive disease had similar survival from PTLD diagnosis. Disclosures Maurer: Celgene: Research Funding; Morphosys: Research Funding; Nanostring: Research Funding. Cerhan:Nanostring: Research Funding; Jannsen: Other: Scientific Advisory Board; Celgene: Research Funding.

Abstract Introduction: Lenalidomide (len) is an immunomodulatory agent with single agent activity in relapsed and refractory peripheral T-cell lymphoma (PTCL). CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) is a common initial regimen. Herein, we report the completed phase II results of the combination of len-CHOEP. Methods: Eligible patients (pts) had newly diagnosed PTCL, ANC ≥1000 cells/mm3, platelets ≥100 K/mm3, and adequate organ function. Based on phase I results [Lunning et al. T-cell Forum 2018] 10 mg of len was chosen for phase II. CHOEP was administered at standard doses with len given on days 1-10 of 21-day cycle for six planned cycles. Mandatory prophylaxis included aspirin (ASA) or alternative thromboprophylaxis and growth factor support per institutional guidelines with each cycle. A PET/CT after two cycles (PET-2) for interim response assessment was required per protocol. The primary endpoint was complete response (CR) by PET/CT after 6 cycles (PET-6) of len-CHOEP utilizing the revised Cheson 2007 criteria with secondary endpoints to include toxicity, overall response rate (ORR), progression free survival (PFS), 2-year PFS, and overall survival (OS). Pts who had CR or partial response (PR) at the end of therapy had the option of len maintenance (10 mg/day for 21 out of 28 days) for 1-year or consolidative autologous stem cell transplant (ASCT) without len maintenance. Per protocol pts dosed at 10 mg in phase I (N=8) were included in the phase II analysis. Results: Forty pts with PTCL-NOS (23), ALK negative ALCL (5) and AITL (12) enrolled into the phase II portion. Median age was 62 years (range 24-79) and 21 were male. Thirty (75%) pts completed all 6 cycles. Reasons for discontinuing len-CHOEP early were toxicity (n=6) and progressive disease (PD; n=4). PET-2 was not done in 4/40 pts (n=2 each either not performed or PD). In an intent to treat (ITT) analysis the CR rate at the end of treatment was 48% (19/40; 95CI-32-64%) with an ORR of 68%. In pts who completed 6 cycles (n=30) the CR/ORR rate was 63%/87% respectively. Seven pts (18%) experienced primary treatment failure. Of the 19 pts in CR at end of initial therapy, 14 were in a CR at PET-2 assessment. Two pts in a PET-2 CR discontinued prior to cycle 6 due to toxicity and have not progressed. Five pts converted from a PR to CR after PET-2, but 7 of 13 PRs remained PRs. Responding pts (CR/PR; n=30) proceeded either to an ASCT (n=18), len maintenance (n=10) or neither (investigator/pts preference; n=2). At a median follow up of 13 months (range: 4-23 months), the 1-year estimated PFS and OS is 68% [95% CI--50-80%] and 89% [95%CI--73-96%] respectively. There were five grade (G) 5 events including PD (n=1), secondary malignancy (n=1; AML), sepsis (n=2), and cardiac arrest (n=1). Serious or recurrent adverse events (SAEs or AEs) of interest occurring during any cycle included 38% G 3-4 febrile neutropenia despite mandated GCSF use, 43% G 3-4 anemia, 43% G 3-4 thrombocytopenia (without report of G 3-4 bleeding or bruising despite ASA use), 3% G3-4 rash (all G 23%), and 8% G 3-4 diarrhea (all G 43%). Conclusions: The phase II portion of the study in an ITT population noted an unexpectedly modest 48% CR rate and a high discontinuation rate (15%) due to AEs or SAE. The utility of response at PET-2 and post initial therapy strategy (len maintenance vs ASCT) continue to be monitored for PFS and OS in this limited cohort. Improving frontline outcomes for pts with PTCL remains an unmet need. Disclosures Lunning: Celgene: Consultancy; TG Therapeutics: Consultancy; Genentech: Consultancy; Bayer: Consultancy; AbbVie: Consultancy; Spectrum: Consultancy; Kite: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Portola: Consultancy; Seattle Genetics: Consultancy; Astra-Zeneca: Consultancy; Genzyme: Consultancy; Juno: Consultancy; Genentech: Consultancy; Verastem: Consultancy. Horwitz:Millennium/Takeda: Consultancy, Research Funding; Trillium: Consultancy; Mundipharma: Consultancy; Kyowa-Hakka-Kirin: Consultancy, Research Funding; Portola: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Corvus: Consultancy; Spectrum: Research Funding; Seattle Genetics: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Advani:Janssen Pharmaceutical: Other: Institutional Research Support; Cell Medica: Other: Consultancy/Advisory Role; Bayer Healthcare Pharmaceuticals: Other: Consultancy/Advisory Role; Merck: Other: Institutional Research Support; Forty Seven, Inc: Other: Institutional Research Support; Millenium: Other: Institutional Research Support; Roche/Genentech: Other: Consultancy/Advisory Role, Institutional Research Support; Pharmacyclics: Other: Institutional Research Support; Celgene: Other: Institutional Research Support; Regeneron Pharmaceuticals, Inc.: Other: Institutional Research Support; Kura: Other: Institutional Research Support; Infinity: Other: Institutional Research Support; Autolus: Other: Consultancy/Advisory Role; Kyowa: Other: Consulting/Advisory Role; Takeda: Other: Consultancy/Advisory Role; Bristol Myers Squibb: Other: Consultancy/Advisory role and Institutional Research Support; Agensys: Other: Institutional Research Support; Gilead/Kite: Other: Consultancy/Advisory Role; Seattle Genetics: Other: Consultancy/Advisory role, Institutional Research Support; AstraZeneca: Other: Consultancy/Advisory Role. Vose:Epizyme: Honoraria; Roche: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Research Funding; Incyte Corp.: Research Funding; Legend Pharmaceuticals: Honoraria; Bristol Myers Squibb: Research Funding; Seattle Genetics, Inc.: Research Funding; Abbvie: Honoraria; Acerta Pharma: Research Funding; Kite Pharma: Research Funding; Merck Sharp & Dohme Corp.: Research Funding. Mehta-Shah:Verastem: Research Funding; Genetech: Research Funding; Celgene: Research Funding; Bristol-Myers Squibb: Research Funding; Spectrum: Consultancy. Haverkos:Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Moskowitz:ADC Therapeutics: Research Funding; Bristol Myers-Squibb: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Takeda: Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Ansell:Merck & Co: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Seattle Genetics: Research Funding; Trillium: Research Funding; Takeda: Research Funding; LAM Therapeutics: Research Funding; Affimed: Research Funding; Celldex: Research Funding; Regeneron: Research Funding.