Villasboas, José C.

Clinical success with intravenous (IV) oncolytic virotherapy (OV) has to date been anecdotal. Here, we conducted a phase 1 clinical trial of systemic OV therapy and investigated the mechanisms of action in responding T-cell lymphoma (TCL) patients. A single IV dose of VSV-IFNβ-NIS was administered to patients with relapsed refractory hematologic malignancies to determine safety and efficacy across 4 dose levels (DL). Correlative studies were undertaken to evaluate viremia, virus shedding, virus replication and immune responses. Fifteen patients received VSV-IFNβ-NIS (7 multiple myeloma, 7 TCL, 1 acute myeloid leukemia); 3 patients were treated at each DL1 through DL3 (0.05, 0.17, and 0.5 x 1011 TCID50), and 6 at DL4 (1.7 x 1011 TCID50). There were no dose limiting toxicities. 3 of 7 patients with TCL had RECIST responses: a 3-month PR at DL2, a 6-month PR and a durable CR ongoing at 20 months at DL4. Viremia peaked at the end of infusion and no infectious virus shedding was detected. Plasma interferon-β levels, a biomarker of VSV-IFNβ-NIS replication, peaked between 4h and 48h post infusion. The patient with CR had robust viral replication with increased ell free DNA in her plasma, a very high peak IFNβ level of 18,213 pg/ml, a strong anti-VSV neutralizing antibody response, and increased numbers of tumor reactive T-cells. VSV-IFNβ-NIS as a single agent was effective in patients with TCL resulting in durable disease remissions in heavily pretreated patients. Correlative analyses suggest that responses may be due to a combination of direct oncolytic tumor destruction and immune-mediated tumor control. Further clinical testing is warranted. (This trial is registered at www.clinicaltrials.gov as NCT03017820).

Abstract Background: While extranodal involvement by mantle cell lymphoma (MCL) is relatively common, involvement of the central nervous system (CNS) is rare (<5% of cases), with limited treatment options. We report the outcomes of 36 patients (pts) with CNS involvement compared to 72 matched control MCL pts without CNS involvement. Methods: MCL pts with CNS involvement seen at Mayo Clinic between 1/1995-9/2020 were identified using the Mayo Data Explorer tool. CNS involvement was defined by tissue biopsy confirmed CNS MCL, CSF analysis demonstrating lymphoma cells, and/or neuroimaging findings compatible with CNS involvement. A 2:1 control group of MCL pts without CNS involvement, matched by age (+/- 2 years) and year of diagnosis (+/- 1 year), was selected among all MCL cases. Medical records were reviewed for baseline characteristics, treatment modalities, and outcomes. Kaplan-Meier method was used for time to event analysis. Wilcoxon test was used to compare continuous variables and Chi square test was used for categorical variables. Results: Out of 1,753 pts with MCL, 36 (2%) had evidence of CNS involvement, including 4 pts with CNS involvement at initial MCL diagnosis. Baseline characteristics of pts with CNS involvement (CNS MCL group) and those without CNS involvement (control group) are shown in Table 1. At MCL diagnosis, non-CNS extranodal involvement was seen in 30 (83%) pts in the CNS MCL group (24 pts with 1 site and 6 pts with ≥ 2 sites), with bone marrow being the most common extranodal site of involvement (n=24, 67%). For the control group, 54 (75%) pts had extranodal involvement (44 pts with 1 site and 10 pts with ≥ 2 sites), and bone marrow was also the most common extranodal site of involvement (n=50, 69%). Notably, advanced stage disease (stage 3-4) was more commonly seen in the CNS MCL group (n=32, 97%) than in the control group (n=59, 83%) (p=0.04) at MCL diagnosis. Blastoid variant was present in a higher proportion of pts in the CNS MCL group (n=11, 31%) compared to the control group (n=8, 11%) (p=0.02). The CNS MCL group also presented with a higher median serum LDH at diagnosis (239 U/L [range 153-1901] vs. 187 U/L [range 124-588], p=0.02), and higher Ki-67 (40% [range 15-100] vs. 30% [range 10-90], p=0.04) compared to the control group. The most common frontline treatment regimen was anthracycline-based therapies (i.e. R-CHOP, Nordic regimen, R-hyperCVAD) for both groups (58% in CNS MCL group and 56% in control group). 14 (39%) pts in the CNS MCL group underwent autologous stem cell transplant in CR1 vs. 31 pts (43%) in the control group. Similar use of rituximab maintenance was seen in both groups (31% in CNS MCL group and 25% in control group). Median total lines of therapy from initial MCL diagnosis was 3 (range 1-9) in CNS MCL group and 2 (range 1-9) in the control group. The median follow-up from MCL diagnosis was 134 months (95% CI:119-163) for the entire cohort. Median OS from MCL diagnosis was 50.3 months (95% CI: 20.9-71.1) for the CNS MCL group compared to 97.1 months (95% CI: 82.6-192.7; p=<0.001) for the control group (Figure 1). Median time from MCL diagnosis to CNS involvement was 25 months (range 0-167). Median OS from CNS involvement was 4.7 months (95% CI: 2.3-6.7). At last follow up, 31 (86%) pts were deceased from the CNS MCL group, compared to 38 (52%) pts in the control group. For the CNS MCL group, the causes of death were CNS lymphoma in 10 (32%) pts, systemic lymphoma in 9 (29%) pts, treatment-related complication in 7 (23%) pts, and other/unknown in 5 (16%) pts. For the control group, the causes of death were systemic lymphoma in 15 (39%) pts, treatment-related in 2 (5%) pts, and other/unknown in 21 (55%) pts. Conclusion: In pts with MCL, CNS involvement is associated with worse outcomes as evident by a shorter median OS from initial MCL diagnosis (50 months vs. 97 months). Involvement of the CNS by lymphoma is an important contributor for the shorter OS as suggested by the median OS of only 5 months from CNS involvement. Advanced stage, blastoid variant, elevated LDH, and elevated Ki67 at MCL diagnosis were features more commonly seen in the CNS MCL cohort. Validation of risk factors at initial MCL diagnosis associated with CNS involvement and exploring the role of CNS prophylaxis are important topics for further investigation. Figure 1 Figure 1. Disclosures Paludo: Karyopharm: Research Funding. Wang: Novartis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Research Funding; InnoCare: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding. Bennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board. Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Habermann: Seagen: Other: Data Monitoring Committee; Tess Therapeutics: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding.

Abstract Backgrounds: Autologous stem cell transplant (ASCT) has been the standard treatment approach for patients with relapsed or high-risk lymphoma for several decades. Despite the improvement in supportive care, age has remained one of the critical factors that determines transplant eligibility and outcomes. Herein, we explored the transplant-related outcomes of patients with lymphoma aged 70 years or older at our institution and compared to those with younger ages. Methods: In this retrospective single center study, we include all patients with diagnosis of lymphoma who underwent ASCT between January 2000 and February 2021 at Mayo Clinic, Rochester, Minnesota. In addition to data obtained from the transplant database, we abstracted data from electronic medical record. We described relevant clinical characteristics and transplant associated outcomes including engraftment, transplant related mortality, relapse incidence, and survival outcomes. We compared the key transplant related outcomes with patients at the younger age group between 65 and 70 years old. Results: A total of 196 patients with lymphoma aged 70 years or older underwent ASCT between January 2000 and February 2021. The median age of patients at the time of ASCT was 72.4 (70.0-78.7) years with 24 patients (12.2%) being older than 75 years old. Of 196 patients, 76 (38.8%) had Charlson comorbidity index of 3 or higher and 10 (5.1%) had performance status of 2 or higher at the time of ASCT. Table 1 summarizes the relevant baseline clinical characteristics of 196 patients in this cohort including the comparison with younger patients (age 65-70 years old, n=296). The most common transplant indication in this cohort was relapsed diffuse large B cell lymphoma. The majority of patients (91.3%) received peripheral blood graft with a median CD34+ cell dose of 5.14x10 6 cells/kg which was significantly lower than younger patients (P=0.01). The rate of neutrophil and platelet engraftment was 99.0% and 98.8% with corresponding median time to engraftment of 13 days for both cell lineages. The 30- and 100-day non-relapse mortality (NRM) of the entire cohort was 1.5% (95%CI 0-3.2%) and 4.6% (95%CI 1.6-7.5%) not statistically different between 70-75 years old and 75 years or older cohorts. With the median follow-up duration of 48 months, the 2-year event free survival (EFS) and overall survival (OS) was 55.9% (95%CI 49.2-63.5%) and 67.4% (95%CI 61.0-74.5%), respectively. Patients from the 70 years old or older cohort had similar EFS but inferior OS compared to the 65-70 years old cohort. However, there was no difference in EFS and OS between 70-75 and >75 years old cohorts. There was overall an improved trend of 30-day NRM, 2-year EFS and 2-year OS over the 3 different transplant periods (Figures). Although not statistically significant, patients who underwent ASCT between 2000 and 2006 had a trend towards higher 30-day NRM compared to patients who were transplanted at later time points (7.3% vs 0%, P=0.06). The major causes of death included progressive lymphoma, infection, and conditioning regimen related organ toxicities. Conclusion: Outcomes of ASCT in older patients with lymphoma have improved over time with an excellent 30-day NRM (0%) in the past recent years. The major cause of treatment failure after ASCT was progressive disease. With appropriate patient selection, ASCT in older patients is feasible and provides acceptable outcomes comparable to the patients from younger age group. Figure 1 Figure 1. Disclosures Paludo: Karyopharm: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding.

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy is an effective treatment that has transformed hematologic malignancy management. However, its significant short-term toxicities, mainly cytokine release syndrome (CRS) and neurotoxicity, require frequent monitoring almost universally achieved via prolonged inpatient admissions. We have reported our institution's specialized, multi-disciplinary hospital-based outpatient (HBO) CAR-T service and experience (Bansal et.al, ASCO 2021). To enhance the HBO practice, we implemented a remote patient monitoring (RPM) program, comprised of in-home, electronic health record-integrated technology to monitor vital signs and neurologic symptoms for 30 days post CAR-T infusion. The RPM program's triaging algorithm generates alerts based on predetermined parameters to guide escalation of care if needed. In this report, we describe the characteristics of RPM program patients (pts), focusing on the alerts received within 48 hours (h) of first hospitalization in the post-CAR-T setting. Methods: Pts undergoing commercial CAR-T cell therapy at Mayo Clinic Rochester were enrolled in the RPM program as part of our standard of care from 06/2020 to 05/2021. Pts with detailed RPM data available were included in this analysis. Patient characteristics, health care utilization, inpatient interventions, and RPM alert data were reviewed. Wilcoxon test was used for continuous variables, chi-squared test was used for categorical variables. Results: Baseline characteristics are summarized in Table 1. Of 20 pts in this analysis, 13 had RPM alerts in the 48h preceding the first hospitalization post CAR-T. For the remaining 7 pts without RPM alerts, 3 were hospitalized within 24h of CAR-T infusion without significant RPM data, 1 patient hospitalized with acute pancreatitis (day +8 post CAR-T infusion), 1 for doubling of CRP (day +10), 1 for acute pain crisis (day +5), and 1 with neutropenic fever (day +5) with not reporting RPM data. The median RPM program duration was 18 days (range 3-32) which accounts for interruptions in the RPM monitoring while pts are hospitalized. The median number of data points per patient was 231 (range 22-532), with a median of 20 alerts per patient (range 2-81). The median missing data points per patient were 20 (10%) (range 0-95). Of the 13 pts with RPM alerts within 48h of first hospitalization, alerts met our definition of urgent criteria in 6 pts [temperature (temp) > 100F (n=3), temp > 100F + tachycardia (n=1), temp > 100F + hypoxia (n=1), and hypoxia (n=1)]. In the remaining 7 pts, the RPM alerts met our routine criteria definition [temp 99-100 (n=2), tachycardia + hypertension + weight loss (n=2), hypertension (n=2), new incontinence (n=1)]. CRS was reported in 12 pts [grade 1-2 (n=11), grade 3-4 (n=1)] and neurotoxicity in 8 pts [grade 1-2 (n=7), grade 3-4 (n=1)]. The median post CAR-T first hospitalization day was day +4 (range day +2-10), Figure 1. The median time from the last RPM alert to hospitalization was 5.8h for pts meeting urgent criteria vs 10.8h for those meeting routine criteria (p=0.13). Tocilizumab was used in 5 pts during the first hospitalization [3 (50%) in the urgent criteria group and 2 (28%) in the routine criteria group], with a median time from admission to tocilizumab of 12h in the urgent criteria group vs 43h in the routine criteria group (p=0.05). Early hospitalization (≤ 3 days) post CAR-T infusion was associated with later need for tocilizumab [median 51h (range 30-57) vs. 11.5h (range 6-33) from admission, p=0.03] than late hospitalization (> 4 days post CAR-T). Upon admission, oxygen supplementation was started on both pts with hypoxia noted in the RPM alerts. Only 1 patient (routine criteria group) required use of vasopressors while hospitalized, initiated more than 48h after admission. Conclusion: A CAR-T RPM program can identify adverse symptoms and vital sign changes in CAR-T pts managed in the outpatient setting. In this pilot implementation, the CAR-T RPM triaging algorithm identified pts requiring expedited hospitalization and facilitated early initiation of tocilizumab. The intermittent monitoring and proportion of missing data are the main limitations of the RPM in the acute care setting post-CAR-T infusion. Incorporation of wearable devices for continuous remote monitoring is being explored as a mitigating strategy to these limitations. Figure 1 Figure 1. Disclosures Paludo: Karyopharm: Research Funding. Dingli: Apellis: Consultancy; Janssen: Consultancy; GSK: Consultancy; Novartis: Research Funding; Sanofi: Consultancy; Alexion: Consultancy. Kapoor: Glaxo SmithKline: Research Funding; Sanofi: Consultancy; Amgen: Research Funding; AbbVie: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Ichnos Sciences: Research Funding; Pharmacyclics: Consultancy; Takeda: Research Funding; Regeneron Pharmaceuticals: Research Funding; Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy. Gertz: Aurora Biopharma: Other: Stock option; Ionis Pharmaceuticals: Other: Advisory Board; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria. Wang: InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kenderian: Humanigen, Inc.: Consultancy, Honoraria, Research Funding. Kumar: Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Oncopeptides: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche-Genentech: Consultancy, Research Funding; Carsgen: Research Funding; Antengene: Consultancy, Honoraria; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Bluebird Bio: Consultancy; Beigene: Consultancy; Tenebio: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Bennani: Purdue Pharma: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Vividion: Other: Advisory Board; Kymera: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Lin: Merck: Research Funding; Vineti: Consultancy; Gamida Cell: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Legend: Consultancy; Celgene: Consultancy, Research Funding; Sorrento: Consultancy; Takeda: Research Funding; Janssen: Consultancy, Research Funding; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding.

Abstract Introduction: Novel therapeutic agents such as immune checkpoint inhibitor (ICI) and brentuximab vedotin (BV) are active in classic Hodgkin lymphoma (cHL), including in patients that relapse after autologous stem cell transplant (ASCT). However, optimal management strategy is unclear for patients with relapsed or refractory (RR) cHL post-ASCT. The aim of the study is to determine the impact of novel agents relative to conventional therapy and allogeneic stem cell transplant (allo-SCT) on survival outcomes of patients with cHL who relapsed after ASCT. Methods: Patients with RR cHL who underwent ASCT between 06/1993 and 10/2017 at 3 Mayo Clinic sites were included. Clinical characteristics, treatment information, and outcome data were abstracted. For patients who relapsed after ASCT, the post-relapse progression free survival (PFS) and overall survival (OS) were analyzed using the Kaplan-Meier method and Cox proportional hazards models. Statistical analyses were done in JMP v15.2.1 and EZR v1.54. Results: A total of 332 patients with RR cHL who underwent salvage therapy and ASCT were identified. After a median post-ASCT follow-up of 8.6 years (range 6.8-9.7), 136 (41%) patients had a relapse or disease progression after ASCT. Patient characteristics of the 136 cases are summarized in the Table. The median age at post-ASCT relapse was 34 years (range 20-73), and 77 (57%) were male. 59 (43%) relapsed within 6 months and 77 (57%) relapsed after 6 months following ASCT. 59 (45%) had an extranodal site involvement at relapse. 14 (10%) had therapy with ICI or BV as salvage therapy prior to ASCT or maintenance therapy post-ASCT. The median post-relapse PFS and OS was 0.8 (95% CI 0.6-1.1) and 3.2 years (95% CI 2.2-5.5) years, respectively. Compared to patients who relapse after 6 months, patients who relapsed within 6 months of ASCT had worse post-relapse PFS (median 0.5 [0.3-0.7] vs 1.3 [0.9-1.9] years, p=0.0003) and OS (median 1.3 [0.5-2.2] vs 6.4 [3.7-10.4] years, p=0.0003). Extranodal site involvement at relapse was not associated with post-relapse PFS (median 0.7 [0.5-1.2] vs 0.9 [0.6-1.3] years, p=0.28) but was associated with worse post-relapse OS (median 2.7 [1.5-4.2] vs 6.4 [2.6-NA] years, p=0.006). Prior therapy with ICI or BV was not associated with post-relapse PFS (median 0.6 [0.3-NA] vs 0.8 [0.6-1.1] year, p=0.8) and OS (median NR [1.0-NA] vs 3.2 [2.2-5.5] years, p=0.5). After post-ASCT relapse, the median lines of subsequent therapy were 2 (range 1-12). For first post-ASCT salvage therapy, novel agents (ICI or BV), compared to other therapies, were associated with superior post-relapse PFS (median 1.7 [0.7-3.6] vs 0.7 [0.5-1.0] years, p=0.004) and OS (median 7.6 [4.7-NA] vs 3.2 [2.2-5.6], p=0.02). Allo-SCT following first post-ASCT relapse (n=9) was not associated with improvement in post-relapse PFS (median 2.2 years [0.3-NA] vs 0.8 [0.6-1.1] years, p=0.1) or OS (median NR [0.5-NA] vs 5.1 [3.2-7.3] years, p=0.7). Patients who received ICI or BV at any point post-ASCT relapse had significantly better post-relapse OS (median 7.6 [4.3-16.7] vs 2.2 [1.4-3.7] years, p=0.004) compared to those who never received any novel agent (Figure 1A). In contrast, allo-SCT at any point post-ASCT relapse (n=27) did not improve post-relapse OS (median 5.6 [2.7-NA] vs 4.7 [2.7-7.3] years, p=0.3) (Figure 1B). In multivariate Cox regression models adjusted for age and sex, exposure to ICI and/or BV was associated with superior post-relapse OS (HR 0.5, 95% CI 0.3-0.8, p=0.007); however, allo-SCT was not associated with improvement in post-relapse OS (HR 0.8, 95% CI 0.4-1.5, p=0.5). Conclusions: Patients relapsing within 6 months of ASCT and those with extranodal involvement at relapse had inferior OS after post-ASCT relapse. Prior therapy with novel agents did not impact post-relapse survival outcomes. In the setting of post-ASCT relapse, novel therapeutic agents significantly improved survival outcomes while allo-SCT did not. Future multicenter studies are needed to explore the role of novel agents and allo-SCT in patients with RR cHL post-ASCT relapse. Figure 1 Figure 1. Disclosures Wang: Eli Lilly: Membership on an entity's Board of Directors or advisory committees; InnoCare: Research Funding; MorphoSys: Research Funding; Genentech: Research Funding; Novartis: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Paludo: Karyopharm: Research Funding. Tun: Gossamer Bio, Acrotech: Consultancy; Mundipharma, Celgene, BMS, Acrotech, TG therapeutics, Curis, DTRM: Research Funding. Cerhan: Regeneron Genetics Center: Other: Research Collaboration; Genentech: Research Funding; Celgene/BMS: Other: Connect Lymphoma Scientific Steering Committee, Research Funding; NanoString: Research Funding. Habermann: Tess Therapeutics: Other: Data Monitoring Committee; Morphosys: Other: Scientific Advisory Board; Incyte: Other: Scientific Advisory Board; Seagen: Other: Data Monitoring Committee; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Nowakowski: Celgene, MorphoSys, Genentech, Selvita, Debiopharm Group, Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene, NanoString Technologies, MorphoSys: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding.

Abstract INTRODUCTION: Luxeptinib (CG-806) is a potent, non-covalent oral inhibitor of BTK and FLT3. It suppresses BCR signaling pathways (LYN, SYK, BTK, AKT, ERK) and other oncogenic pathways in cell lines and primary CLL cells, kills malignant B-cells insensitive to ibrutinib or venetoclax at low nM concentrations, and shows enhanced activity in combination with venetoclax. Luxeptinib is currently being evaluated in a Phase 1a/b trial in patients with relapsed or refractory B-cell malignancies (NCT03893682). AIMS: Primary objectives are to assess the safety and tolerability of luxeptinib and determine the recommended expansion dose for future clinical trials in patients with R/R CLL/SLL or B-NHL. Key secondary objectives include elucidation of the pharmacokinetic (PK) and pharmacodynamic (PD) characteristics, and evidence of antitumor activity. METHODS: Luxeptinib is administered continuously as oral capsules BID in 28-day cycles, in ascending cohorts of 3 patients. Treatment emergent adverse events (TEAEs) and tumor responses are evaluated per disease specific guidelines. RESULTS: As of June 7, 2021, a total of 23 patients (median age 64.0 years, 11 CLL/SLL, 4 follicular lymphoma (FL), 1 Richter's transformation lymphoma, 2 Waldenstrom's macroglobulinemia (WM), 2 mantle cell lymphoma, 3 diffuse large B cell lymphoma (DLBCL)) with a median of 3 prior systemic regimens (range of 1 - 12) have been treated with luxeptinib at doses of 150 mg (n=1), 300 mg (n=1), 450 mg (n=9), 600 mg (n=4) and 750 mg (n=8). Drug related grade ≥ 3 TEAEs included neutropenia (n=5, 21.7%), leukocytosis (n=2, 8.7%), decreased white blood cell count, decreased platelet count, anemia, increased alanine aminotransferase, diarrhea, hypertension, and headache (n=1, 4.3 % each). One patient, who experienced progressive hypertension before receiving luxeptinib, developed grade 1 hypertension during screening evolving to grade 2 prior to dosing on C1D1, experienced grade 4 hypertension after luxeptinib treatment at 750 mg BID for 5 days. While this was considered a DLT per protocol, luxeptinib plasma levels in this patient were lower than those observed in patients at this and lower dose levels, and no drug-related hypertension has been observed in any other patient treated to date. The average steady-state (C min) plasma levels of luxeptinib in patients treated with 750 mg BID were > 1µM and were sustained over multiple cycles. PD analysis demonstrated that C min of luxeptinib in the plasma of patients treated with doses of 300 mg or higher significantly reduced levels of phosphorylated BTK, SYK, ERK and FLT3 in EOL-1 reporter cells in a plasma inhibitor activity assay, demonstrating multi-target engagement. Response evaluations were available for 12 patients who had at least one imaging study or IgM measurements (WM patients) after starting treatment. Eight out of these 12 patients had various reductions of lesion size or IgM measurements compared to baseline (3 SLL, 2 FL, 1 CLL, 1 WM and 1 DLBCL), demonstrating anti-tumor activity. FDG PET-CT scans in one FL patient, who had 2 prior regimens, revealed lesion growth during treatment with luxeptinib at 450 mg BID for 7 cycles. After dose-escalation to 600 mg BID in Cycle 8, lesion measurements demonstrated continuous reduction. By C15D1, target lesions decreased by 42.5% and 11.3% when compared with peak tumor size and baseline measurements, respectively. One WM patient in Cohort 5 (750 mg BID), who had 2 prior regimens including ibrutinib, has had a 24.9% reduction in IgM level by C3D1 compared with baseline as her best response so far. CONCLUSIONS: Luxeptinib has a favorable safety profile in patients treated with 150 mg to 600 mg BID over multiple cycles. A single apparent DLT (grade 4 hypertension in one patient with pre-existing hypertension) led to expansion of the 750 mg dose level to 6 patients. Pharmacodynamic studies documented inhibition of SYK, BTK and ERK in the BCR signaling pathway. Anti-tumor activity was observed in multiple B-NHL subtypes and CLL/SLL patients. Enrollment of patients with R/R CLL/SLL and B-NHL at dose level 5 (750 mg) is ongoing and updated clinical data will be presented at the meeting. Disclosures Samaniego: Arog: Research Funding; Imbrium: Membership on an entity's Board of Directors or advisory committees. Burke: AstraZeneca: Consultancy; Verastem: Consultancy; Bristol Myers Squibb: Consultancy; Epizyme: Consultancy; Kura: Consultancy; Kymera: Consultancy; SeaGen: Consultancy, Speakers Bureau; X4 Pharmaceuticals: Consultancy; Adaptive Biotechnologies: Consultancy; Beigene: Consultancy, Speakers Bureau; AbbVie: Consultancy; MorphoSys: Consultancy; Roche/Genentech: Consultancy. Mahadevan: caris: Speakers Bureau; Guardanthealt: Speakers Bureau; PFIZER: Other: Clinical trial Adverse events committee; TG Therapeuticals: Other: Clinical trial Adverse events committee. Cherry: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sadiq: Dava Oncology: Honoraria. Reid: ADC Therapeutics: Other: Serves as Principle Investigator, Research Funding; Aptose Biosciences: Other: Serves as Principle Investigator, Research Funding; Millennium Pharmaceuticals: Other: Serves as Principle Investigator, Research Funding; Xencor: Other: Serves as Principle Investigator, Research Funding. Roeker: TG Therapeutics: Consultancy; Pfizer: Consultancy, Research Funding; AbbVie, AstraZeneca, Janssen, LOXO, Pharmacyclics, TG Therapeutics, Vaniam Group, Verastem: Consultancy; Loxo Oncology: Consultancy; Abbot Laboratories: Current equity holder in publicly-traded company; Pharmacyclics: Consultancy. Melear: Astrazeneca: Speakers Bureau; TG Therapeutics: Speakers Bureau; Janssen: Speakers Bureau. Zhang: Aptose Biosciences, Inc.: Current Employment. Rastgoo: Aptose Biosciences, Inc.: Current Employment. Benbatoul: Aptose Biosciences, Inc.: Current Employment. Haney: Aptose Biosciences, Inc.: Current Employment. Jin: Aptose Biosciences, Inc.: Current Employment. Marango: Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company. Howell: Aptose Biosciences, Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Research Funding. Rice: Oncolytics Biotech Inc.: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Bejar: Astex: Consultancy; Silence Therapeutics: Consultancy; Aptose Biosciences, Inc.: Current Employment, Current equity holder in publicly-traded company; Epizyme: Consultancy, Honoraria; Takeda: Research Funding; Gilead: Consultancy, Honoraria; BMS: Consultancy, Research Funding.

Abstract Introduction: Factors contributing to the antitumor activity of systemic oncolytic virotherapy (OV) include (i) generalized innate immune activation due to virus infusion; (ii) direct oncolytic and/or immune-mediated destruction of OV infected tumor cells due to intratumoral spread of the virus infection; (iii) collateral boosting of tumor antigen-specific T cell responses that target uninfected tumor cells. We investigated the relative contributions of these 3 factors T cell lymphoma (TCL) patients (pts) responding to a single intravenous infusion of Voyager-V1, an oncolytic vesicular stomatitis virus (VSV) encoding IFNβ and sodium iodide symporter (NIS) on NCT03017820. Of relevance, the virally encoded IFNβ enhances tumor specificity, boosts proinflammatory activity & serves as a convenient serum biomarker of infection. Methods: In a first in human trial, a single infusion of Voyager-V1 was administered to 15 pts with relapsed refractory hematologic cancers; 4 dose levels (DL) were tested (5x10 9, 1.7x10 10, 5x10 10, 1.7x10 11 TCID50); 7 pts had TCL. Cytokine levels and CRS symptoms were determined as a measure of generalized immune activation; serum IFNβ levels were monitored as a pharmacodynamic biomarker of virus infection; antitumor T cell responses were measured using ELISPOT assays. Results: Of 8 TCL pts, 3 had RECIST responses: PR at DL 2, a CR & PR at DL 4. Most pts experience short lived CRS typically resolving within 24 hours of virus infusion. Serum IFNβ levels increased post-therapy in all pts, typically peaking by 24 hours post virus infusion and returning to baseline by median day 10. T cell responses could not be accurately determined in most cases due to suboptimal T cell viability and/or function after thawing of frozen PBMC. Factors contributing to tumor regression in each of the responding pts appeared to differ significantly, as exemplified by the case reports below. Pt (I) with CTCL experienced grade 1 CRS followed by brisk regression of multiple cutaneous lesions. The PR lasted 3 mo, after relapse of an eye lesion, but responses at other sites deepened after the relapsed lesion was irradiated; pt remained off active therapy for the next 2 yrs. Peak serum IFNβ 4 hours post infusion was only 182 pg/ml suggesting that disease response may have been driven by nonspecific innate immune activation associated with the virus infusion. Pt (IV) (CD30+ PTCL/ cutaneous relapse) had short lived grade 2 CRS, then developed signs of IFNβ toxicity with AST elevation and thrombocytopenia. Oral ruxolitinib was administered for 5 days as IFNβ toxicity mitigation leading to normalization of AST and platelets. All PET-avid tumors regressed completely. This CR continues 16 months post virus infusion. Peak serum IFNβ was 18,213 pg/ml strongly suggesting that response was driven by extensive intratumoral amplification of the virus and oncolytic tumor destruction. Robust CTL responses to tumor neoantigens were detected in this pt at baseline indicating that collateral boosting of tumor-specific T cells may have been responsible for the long term maintenance of this CR Pt (V) (CD30+ PTCL) had short lived grade 2 CRS followed by response at all disease sites (including complete normalization of an enlarged FDG-avid spleen). Her PR ended after 6 months due to relapse in cervical lymph nodes. Peak serum IFNβ level was modest, 600 pg/ml & sustained over 48 hours suggesting slower intratumoral spread of the virus infection. The deepening of the response long after resolution of the oncolytic phase points strongly to a contribution from antitumor CTL but the assay was technically unsatisfactory in this pt. Conclusion: Analysis of the correlative data supports that intravenous Voyager-V1 therapy can recruit diverse antitumor effector mechanisms to impact tumor response in pts with heavily pretreated TCL. Importantly, intratumoral virus amplification, which results in high circulating concentrations of IFNβ, does not necessarily lead to tumor regression perhaps because of defective immune cell recruitment and/or activation in some tumors but not in others. This will be further evaluated in future study participants by performing CTL assays on fresh, rather than frozen PBMC. In conclusion, a single IV infusion of Voyager-V1 shows highly promising activity against treatment refractory TCL and should be further advanced as a new single-shot or combination therapy for this therapeutically challenging indication. Figure 1 Figure 1. Disclosures Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Paludo: Karyopharm: Research Funding. Patnaik: StemLine: Research Funding; Kura Oncology: Research Funding. Dispenzieri: Takeda: Research Funding; Alnylam: Research Funding; Pfizer: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Bennani: Kymera: Other: Advisory Board; Vividion: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Verastem: Other: Advisory Board. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding. Gertz: Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board. Dingli: Janssen: Consultancy; Sanofi: Consultancy; GSK: Consultancy; Apellis: Consultancy; Novartis: Research Funding; Alexion: Consultancy. Kumar: Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Beigene: Consultancy; Carsgen: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Merck: Research Funding; Oncopeptides: Consultancy; Roche-Genentech: Consultancy, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Honoraria; Tenebio: Research Funding; Novartis: Research Funding; Bluebird Bio: Consultancy; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, 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; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Bergsagel: Oncopeptides: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genetech: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Patents & Royalties: human CRBN mouse; Janssen: Consultancy, Honoraria. Kapoor: Karyopharm: Consultancy; Cellectar: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Ichnos Sciences: Research Funding; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Lin: Sorrento: Consultancy; Vineti: Consultancy; Legend: Consultancy; Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Merck: Research Funding; Juno: Consultancy; Celgene: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Gamida Cell: Consultancy; Janssen: Consultancy, Research Funding; Takeda: Research Funding. OffLabel Disclosure: VSV-IFNβ-NIS is an oncolytic virus in clinical trial for systemic administration in hematologic malignancies

Abstract The tumor microenvironment plays a crucial role in mediating the tumor immune response, thereby affecting patient outcomes in follicular lymphoma (FL). Using CyTOF, we analyzed single cell suspensions created from pre-treatment biopsies in a cohort of 82 FL patients and retrospectively extracted patient clinical parameters. Hierarchical analysis of the tumor microenvironment composition stratified these patients into 4 groups: group 1 represents patients with high percentage of monocyte/macrophages/NK cells; patients from group 2 and 3 are rich of intratumoral T and B cells, respectively. Patients with intermediate number of T and B cells are classed into group 4. Intratumoral T cells from these 4 groups exhibited distinct phenotypical characteristics. Group 1 was enriched with KLRG1 +CD8 + T cells, while group 4 showed increased number of CXCR3 - T EM and CD4 + T N cells. Patients from group 2 and 3 featured with increased number of ICOS + T reg cells and CD57 + T FH cells, respectively. We observed that higher numbers of T cells significantly correlated with early disease stage, lack of B-symptoms, event-free survival at 24 months (EFS24) and a favorable overall and EFS survival in patients with histological grade 1 and 2. However, this association was not seen in patients with histological grade 3a and b, suggesting that T cell-mediated anti-tumor immunity is preserved in low grade patients, but overridden in higher grade patients. CITRUS analysis revealed that a cluster that is CD57 + and PD-1 high was significantly more abundant in patients who had disease progression than patients who had a complete response to therapy, suggesting a role of CD57 + T FH cells in promoting malignant cell growth in FL. Consistent with this finding, we observed that higher number of CD57 + T FH cells correlated with an inferior survival in FL. Using CITE-seq technology, we found that CD57 + T FH cells exhibited a substantially different transcriptome when compared to CD57 - T FH cells. Genes that were differentially upregulated in CD57 + T FH cells when compared to CD57 - T FH cells included genes involved in cell survival, compromised inflammatory response, and metabolism activation including GZMK, CCL4, CST7, DUSP2, LGALS3, CYTOR, CHI3L2, SYNE2, CXCL13, CD27 and FABP5. Taken together, our results indicate different tumor microenvironments among FL patient groups that is associated with variable T-cell phenotype. We found that CD57 + T FH cells play an important role in predicting disease progression and patient prognosis in FL. Figure 1 Figure 1. Disclosures Novak: Celgene/BMS: Research Funding. Ansell: Bristol Myers Squibb, ADC Therapeutics, Seattle Genetics, Regeneron, Affimed, AI Therapeutics, Pfizer, Trillium and Takeda: Research Funding.

Abstract Introduction: Central nervous system (CNS) relapse is an uncommon but devastating complication occurring in about 2-10% of patients with diffuse large B-cell lymphoma (DLBCL). The CNS-IPI is a validated prognostic tool used to identify patients at high risk of CNS relapse. MYC and BCL2/BCL6 rearrangements (double-hit lymphoma- DHL) and non-GCB (NGCB) cell of origin may be at higher risk of CNS relapse. However, the ability of these molecular data to refine CNS-IPI risk prediction has not been assessed. In this study, we aimed to describe the impact of DHL and NGCB cell of origin in the incidence of CNS relapse in patients with newly diagnosed DLBCL. Methods: A retrospective review was conducted to identify patients with newly diagnosed DLBCL from 01/01/2002 - 06/30/2015 using the University of Iowa/Mayo Clinic Lymphoma Molecular Epidemiology Resource database. Patients with primary CNS lymphoma or with CNS involvement at diagnosis were excluded. All patients received chemoimmunotherapy. Clinical, biological, laboratory and radiological data were abstracted including the occurrence of CNS relapse. CNS IPI risk score categories were defined as low- (≤1) intermediate- (2-3) and high-risk (≥4) as originally described (Schmitz et al, JCO 2016). Cell of origin (COO) classification into GCB and non-GCB subtypes was performed using Hans algorithm and/or NanoString data. Characteristics between groups were compared using Kruskal-Wallis or Chi-squared test as appropriate. Survival analysis was performed using Cox proportional hazards model and the Kaplan Meier method. Statistical analysis was performed using SAS version 9.4M5 and R version 4.0.3. Results: We identified a total of 1,360 patients with newly diagnosed DLBCL. Patients had a median age of 62 years (range 18-93 years), were predominantly male (56%), had a performance status <2 (84%), had stage III/IV disease (61%) and an elevated LDH (56%) at diagnosis. Fluorescent in situ hybridization data was present for 65% of patients. Among patients with available data, DHL and NGCG COO represented 2.8% and 36% of the cohort, respectively. CNS IPI high- and intermediate-risk categories were present in 12.4% and 52% of the patients, respectively. R-CHOP was the most common upfront chemotherapy (n=980, 72%). The median follow-up for the entire cohort was 84.9 months (IQR: 58.9-120.9). Overall, 50 patients (3.6%) had a CNS relapse during the study period. Lymphoma relapsed in the CNS in 3.0% (95% CI:2.1-4.4), 4.7% (95% CI: 3.4-6.3) and 4.9% (95% CI: 3.7-6.6)% of patients with CNS-IPI score of intermediate/high risk at 1, 3 and 5 years following the diagnosis of DLBCL. In patients with low risk CNS-IPI, 1.1% (95% CI: 0.4-2.5), 1.7% (95% CI: 0.9-3.4) and 1.7% (95% CI: 0.9-3.4) had a CNS relapse at 1, 3 and 5 years following DLBC diagnosis. Patients with CNS relapse were more likely to have elevated LDH (76% vs 56%, p=0.008), advanced stage (78% vs 61%, p=0.01), adrenal involvement (8% vs 2.4%, p=0.014) and have a CNS IPI intermediate risk (68% vs 51%), and high risk (16% vs 12.3%, p=0.014) at the time of initial diagnosis compared to patients without CNS relapse. Patients with CNS relapse had similar rates of DHL (4% vs 2.7%, p=0.17) and NGCB cell of origin (42% vs 36.2%, p=0.52) compared to patients without CNS relapse. In the multivariable analysis, the strongest predictors for CNS relapse were CNS IPI high risk (Hazard Ratio [HR]= 3.6, 95%CI= 1.4-9.7) and CNS IPI intermediate risk (HR= 3.15, 95%CI= 1.46-6.81). DHL and NGCB cell of origin were not associated with a significantly higher risk of CNS relapse (HR= 1.79, [95%CI=0.42-7.59] and HR= 1.26, [95%CI=0.62-2.57], respectively). Conclusion: CNS relapse was an uncommon occurrence in patients with DLBCL who were treated with chemoimmunotherapy. CNS IPI intermediate- and high-risk scores remain the strongest predictors of CNS relapse in patients with DLBCL after adjusting to biological high-risk variables including DHL and NGCB cell of origin. Larger studies are required to validate our findings due to the low incidence of CNS relapse in our cohort. Figure 1 Figure 1. Disclosures Farooq: Kite, a Gilead Company: Honoraria. Maurer: Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Genentech: Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Witzig: Karyopharm Therapeutics, Celgene/BMS, Incyte, Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene/BMS, Acerta Pharma, Kura Oncology, Acrotech Biopharma, Karyopharm Therapeutics: Research Funding. Habermann: Tess Therapeutics: Other: Data Monitoring Committee; Seagen: Other: Data Monitoring Committee; Incyte: Other: Scientific Advisory Board; Morphosys: Other: Scientific Advisory Board; Loxo Oncology: Other: Scientific Advisory Board; Eli Lilly & Co.,: Other: Scientific Advisor. Novak: Celgene/BMS: Research Funding.