Search

Background: T cell lymphomas (TCL) have been known to exhibit epigenetic dysregulation and aberrant cell signaling. Tenalisib (RP6530), a highly selective PI3K δ/γ+SIK3 inhibitor has shown clinically promising activity as a single agent in TCL with a differentiated and favorable safety profile. In vitro studies in TCL cell lines showed increased apoptosis when tenalisib was combined with romidepsin (Rhizen data on file). A Phase I/II study of tenalisib in combination with romidepsin was designed to assess safety, pharmacokinetics and efficacy in relapsed/refractory TCL (NCT03770000). Methods: This is a multi-center, open label, Phase I/II study in patients with T cell lymphoma (PTCL and CTCL). The Phase I is a 3+3 dose escalation study to determine the MTD/optimal dose. The Phase II is an expansion cohort at the MTD/optimal dose of the combination. Tenalisib was administered orally at doses of 400, 600 and 800 mg BID in combination with romidepsin (12 &14 mg/m2, Q3W). The objectives of the study are to establish safety, MTD/optimal dose, pharmacokinetics and anti-tumor activity of the combination. We report the dose escalation results and preliminary data from the expansion cohorts. Results: A total 15 patients were enrolled between July 24, 2019 and July 20, 2020. Baseline demographics are presented in Table 1. Patients had a median of 3 (range; 1-17) prior treatments and 11 (73%) were refractory to their last therapy. About 67% (6/9) of CTCL patients had prior mogamulizumab therapy. No DLT was reported in the dose escalation phase and Tenalisib 800 mg BID+ Romidepsin 14 mg/m2, Q3W was considered as the optimal dose for expansion cohorts. PK analysis showed linear and dose-dependent kinetics for tenalisib. Co-administration of romidepsin along with tenalisib did not significantly alter the mutual PK of either agents. Fifteen patients were assessed for safety. Most common treatment emergent adverse events of any grade were nausea (33%), thrombocytopenia (33%) and fatigue (27%). Related ≥ Grade 3 AEs were seen in 5 (33%) patients. These included thrombocytopenia (7%), atrial fibrillation (7%) and pyrexia (7%) which were related to romidepsin while anemia (7%) neutropenia (7%) and rash (7%) were considered related to the combination. There were no instances of transaminitis or colitis. None of the TEAEs led to study discontinuation. Patients from the dose escalation cohorts (n=9) were evaluated for response. Three patients (3/9) showed complete response (CR), 4 patients (4/9) showed stable disease (SD) while 2 patients (2/9) had progressive disease (PD). Out of the three responders, two were PTCL (AITL) patients, one of which is planned for transplantation, while the third patient was a CTCL (Sezary syndrome) patient who had progressed on prior mogamulizumab therapy. This patient showed rapid reduction of Sezary cell count after 2 cycles of treatment. Three patients (2 CR, 1 SD) are currently ongoing with a median duration of response being 9.0 (range; 7.6-10.5+) months. The expansion cohort has 6 patients and is currently enrolling. Conclusions: The combination of tenalisib and romidepsin demonstrates a favorable safety profile and promising indicators of combined anti-tumour activity in patients with R/R TCL. The expansion cohort in CTCL and PTCL is currently underway to validate these encouraging early results. Updated results will be presented during the ASH meeting. Disclosures Iyer: Afffimed: Research Funding; Rhizen: Research Funding; Seattle Genetics, Inc.: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Target Oncology: Honoraria; Spectrum: Research Funding; Merck: Research Funding; CRISPR: Research Funding. Huen:Seattle Genetics: Consultancy, Research Funding; Kyowa Kirin: Consultancy, Research Funding; Rhizen: Research Funding; Glaxo Smith Kline: Research Funding; Galderma: Research Funding; Miragen: Research Funding; Helsinn: Consultancy; Medivir: Research Funding. Haverkos:Viracta THerapeutics: Consultancy. Ai:ADC Therapeutics, Kymera: Membership on an entity's Board of Directors or advisory committees; Nurix Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kuzel:Eselixis, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genomic Health: Honoraria; Sanofi/Genzyme: Honoraria; Bioarray: 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; Amgen: Membership on an entity's Board of Directors or advisory committees; Marck: Membership on an entity's Board of Directors or advisory committees; Tyme: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Alderuccio:ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Inovio Pharmaceuticals: Other: Family member; Foundation Medicine: Other: Family member; Puma Biotechnology: Other: Family member; Forma Therapeutics: Other: Family member; Agios Pharmaceuticals: Other: Family member; Oncinfo: Honoraria; OncLive: Honoraria. Stevens:Amgen, MorphoSys: Consultancy. Feldman:Viracta: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy; Trillium: Research Funding; Amgen: Research Funding; Pfizer: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Cell Medica: Research Funding; Rhizen: Research Funding; Corvus: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Celgene: Honoraria, Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Takeda: Honoraria, Other: Travel expenses; Pharmacyclics: Honoraria, Other, Speakers Bureau; Abbvie: Honoraria; Bayer: Consultancy, Honoraria; Eisai: Research Funding. Jagadeesh:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; Debiopharm Group: Research Funding; MEI Pharma: Research Funding. Reddy:KITE Pharma, Abbvie, BMS, Celgene: Consultancy; Genentech, BMS: Research Funding. Routhu:Rhizen Pharmaceuticals S.A>.: Current Employment. Barde:Rhizen Pharmaceuticals S.A: Current Employment. Nair:Rhizen Pharmaceuticals S.A.: Current Employment.

Introduction The phase 3 ECHELON-2 study (NCT01777152) demonstrated that frontline treatment with brentuximab vedotin (BV) plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) is superior to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) for patients (pts) with systemic anaplastic large cell lymphoma (sALCL) or other CD30-expressing peripheral T-cell lymphomas (PTCL) (Horowitz S, et al. Lancet 2019). With a median follow-up of 36.2 months for progression-free survival (PFS), the hazard ratio (HR) (0.71 [95% confidence interval {CI}: 0.54, 0.93], P=0.01) favored A+CHP over CHOP. The median PFS was 48.2 months (95% CI: 35.2, not evaluable) versus 20.8 months (95% CI: 12.7, 47.6) for A+CHP and CHOP, respectively. With a median follow-up of 42.1 months for overall survival (OS), the HR (0.66 [95% CI: 0.46, 0.95], P=0.02) also favored A+CHP over CHOP. Median OS was not reached for either arm. With these results, A+CHP was the first treatment regimen to show an OS benefit over CHOP in this pt population. Herein, we report results with a median follow-up of 44.3 months for PFS and 55.5 months for OS. Methods ECHELON-2 is a phase 3, randomized, double-blind, double-dummy, placebo-controlled, active-comparator, multicenter study. Eligible adult pts with previously untreated CD30-positive PTCL (targeting 75% ± 5% with sALCL) were randomized to A+CHP or CHOP for six or eight cycles. Randomization was stratified by histological subtype and international prognostic index score. The primary endpoint of PFS was assessed per blinded independent central review in the primary analysis and per investigator in this updated analysis. Key secondary endpoints were OS, PFS in sALCL, complete remission (CR) rate, and objective response rate (ORR). Subsequent therapies, including BV or BV-containing regimens, were permitted. Results A total of 452 pts were enrolled and randomized 1:1 with 226 pts in each arm. The study included pts with advanced disease (Stage III [27%] and Stage IV [53%]; IPI ≥2 [78%]); given target enrollment, most pts (316 [70%]) had sALCL (218 [48%] anaplastic lymphoma kinase [ALK]-negative and 98 pts [22%] ALK-positive). With additional follow-up, the HRs for PFS per investigator (0.70 [95% CI: 0.53, 0.91], P=0.0075) (Figure 1) and OS (0.74 [95% CI: 0.54, 1.02], P=0.0688) continue to favor A+CHP over CHOP. The median PFS was 63.5 months (95% CI: 42.0, not evaluable) versus 23.8 months (95% CI: 13.6, 55.9) for A+CHP and CHOP, respectively. The estimated 5-year PFS was 50.9% (95% CI: 42.1, 59.1) for the A+CHP arm versus 42.7% (95% CI: 35.3, 49.8) for the CHOP arm. Median OS was not reached for either arm. The estimated 5-year OS was 68.7% (95% CI: 61.3, 75.0) for the A+CHP arm versus 60.3% (95% CI: 52.8, 67.0) for the CHOP arm. The PFS analyses for key prespecified subgroups were generally consistent with the overall study results (Figure 2). In the subset of pts with sALCL, the HR for PFS (0.55 [95% CI: 0.39, 0.78]) also favors A+CHP over CHOP, with an estimated 5-year PFS of 59.8% (95% CI: 48.0, 69.7) for the A+CHP arm versus 48.1% (95% CI: 39.1, 56.6) for the CHOP arm. A total of 23 pts (10%) in the A+CHP arm (16 pts with sALCL, 4 pts with PTCL not otherwise specified, and 3 pts with angioimmunoblastic T-cell lymphoma) and 51 pts (23%) in the CHOP arm received subsequent systemic therapy with BV. In the A+CHP arm, the median time to retreatment was 12.3 months (range, 3, 51); 15 pts (ORR: 65%) had CR (9 pts) or partial remission (6 pts) after retreatment with BV monotherapy (21 pts) or BV-containing regimen (2 pts). With additional follow-up in pts with treatment-emergent peripheral neuropathy (PN) (117 pts A+CHP and 124 pts CHOP), 68% of pts in the A+CHP arm had either resolution or improvement of these events compared with 77% of pts in the CHOP arm. Of the pts with ongoing PN events at last follow-up, 73% in A+CHP arm and 74% in the CHOP arm had grade 1 events, 25% and 23% of pts, respectively, had grade 2 events, and 2% of pts in each arm had grade 3 events. Conclusions At 5 years, frontline treatment with A+CHP continues to provide clinically meaningful improvement in PFS and OS versus CHOP, including ongoing remission in ~60% of pts with sALCL, with a manageable safety profile, including continued resolution or improvement of PN. Additional 5-year results, including data from prespecified subgroups, will be presented. Disclosures Horwitz: C4 Therapeutics: Consultancy; Daiichi Sankyo: Research Funding; Affirmed: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Kura Oncology: Consultancy; Miragen: Consultancy; Myeloid Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; ASTEX: Consultancy; Vividion Therapeutics: Consultancy; Beigene: Consultancy; ADCT Therapeutics: Consultancy, Research Funding; Aileron: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Research Funding; Kyowa Hakka Kirin: Consultancy, Research Funding; Millenium/Takeda: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Corvus: Consultancy; Innate Pharma: Consultancy; Mundipharma: Consultancy; Portola: Consultancy, Research Funding. Pro:Verastem Oncology: Research Funding. Illidge:Takeda: Current Employment, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Iyer:Legend Biotech: Consultancy; Rhizen: Research Funding; Spectrum: Research Funding; CRISPR: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Target Oncology: Honoraria; Afffimed: Research Funding; Daiichi Sankyo: Consultancy; Merck: Research Funding; Seattle Genetics, Inc.: Research Funding. Advani:Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy; Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding. Bartlett:BTG: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Consultancy; Forty Seven: Research Funding; Autolus: Research Funding; Acerta: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Immune Design: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Affimed Therapeutics: Research Funding; BMS/Celgene: Research Funding; Roche/Genentech: Consultancy, Research Funding. Christensen:Odense University Hospital: Current Employment; Seattle Genetics, Inc.: Research Funding. Morschhauser:Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy. Domingo-Domenech:Takeda: Consultancy, Other: Travel, accomodations and expenses , Research Funding; Bristol-Myers Squibb: Other: Travel, Research Funding; Roche: Other: Travel, accomodations and expenses ; Janssen: Other: Travel, accomodations and expenses ; Seattle Genetics, Inc.: Research Funding. Rossi:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Advisory board; Astellas: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; Sanofi: Honoraria; Jazz: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Kim:Donga: Research Funding; Joihnson & Johnson: Research Funding; Kyowa Kirin: Research Funding; Mundipharma: Research Funding; Pfizer: Research Funding; Roche: Research Funding; Takeda: Research Funding; Celltrion: Research Funding. Feldman:Celgene: Honoraria, Research Funding; Cell Medica: Research Funding; Amgen: Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; Rhizen: Research Funding; Janssen: Speakers Bureau; Pharmacyclics: Honoraria, Other, Speakers Bureau; AstraZeneca: Consultancy; Bayer: Consultancy, Honoraria; Abbvie: Honoraria; Takeda: Honoraria, Other: Travel expenses; Pfizer: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Trillium: Research Funding; Portola: Research Funding; Corvus: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Eisai: Research Funding; Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Viracta: Research Funding. Menne:Daiichi Sankyo: Honoraria; Kyowa Kirin: Other: Travel expenses; Pfizer: Honoraria, Other; Roche: Honoraria; Bayer: Other: Travel expenses; Kite/Gilead: Honoraria, Other: Travel expenses; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel expenses; Takeda: Honoraria; Atara: Honoraria; AstraZeneca: Research Funding; Amgen: Honoraria, Other: Travel expenses; Janssen: Honoraria, Research Funding. Belada:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel expenses, Research Funding; Janssen: 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, Other: Travel expenses, Research Funding; Celgene: Research Funding. Illés:Celgene, Janssen, Novartis,Roche, Takeda: Consultancy; Novartis, Janssen, Pfizer, Roche;: Other: Travel, Accommodations, Expenses; Janssen, Celgene, Takeda, Novartis Pharma SAS, Pfizer Pharmaceuticals Israel, Roche;: Consultancy, Honoraria; Takeda, Seattle Genetics: Research Funding. Tobinai:Daiichi Sankyo: Consultancy, Honoraria; Kyowa Kirin: Consultancy, Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Consultancy, Honoraria; Mundipharma: Consultancy, Honoraria; Ono Pharma: Consultancy, Honoraria; Solasia: Honoraria; SymBio: Consultancy; Takeda: Consultancy, Honoraria; HUYA Bioscience: Consultancy, Honoraria; Eisai: Honoraria; Yakult: Consultancy, Honoraria; Zenyaku Kogyo: Consultancy, Honoraria; Chugai Pharma: Consultancy, Honoraria. Tsukasaki:Ono Pharma: Consultancy; Mundy Pharma: Honoraria; HUYA: Consultancy, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Daiichi Sankyo: Consultancy; Eizai: Research Funding; Seattle Genetics: Research Funding. Yeh:AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees. Shustov:Seattle Genetics: Research Funding. Hüttmann:Lead Discovery Center GmbH: Consultancy; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Gilead: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Roche: Other: Travel expenses; Seattle Genetics: Research Funding; University Hospital Essen, University of Duisburg-Essen, Essen, Germany: Current Employment. Savage:Verastem: Honoraria; Takeda: Honoraria; Servier: Consultancy; Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria. Zinzani:Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics, Inc.: Honoraria, Speakers Bureau; EUSA Pharma: Consultancy, 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, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kirin Kyowa: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Speakers Bureau; Eusapharma: Consultancy, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Miao:Takeda: Current equity holder in publicly-traded company. Bunn:Seattle Genetics: Research Funding; Takeda: Current Employment. Fenton:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Fanale:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Puhlmann:Seattle Genetics: Current Employment, Current equity holder in publicly-traded company. Truemper:Janssen: Consultancy; Mundipharma: Research Funding; Nordic Nanovector: Consultancy; Roche: Research Funding; Seattle Genetics: Research Funding; Takeda Europe: Consultancy, Research Funding.

Background: Relapse is the major cause of failure after autologous stem cell transplantation (autoSCT) for patients (pts) with lymphoma. Targeting immune checkpoints with ipilimumab (Ipi) could result in lasting responses but only in few pts. We have previously reported that combination strategies of Ipi with lenalidomide (LEN) 10 mg (Ipi+LEN) resulted in enhanced immune activity manifested by a significant increase in the numbers of ICOS+CD4+FoxP3- T cells (Khouri I et al. Clin Cancer Res 2018:1011-1018). We have demonstrated proof-of-principle of this activity in one pt with refractory double hit lymphoma (DHL) (failed an autoSCT then relapsed after an allogeneic SCT) and another pt with CLL (failed ibrutinib, CART cell, and allogeneic SCT). Both pts then achieved complete remission with Ipi+LEN that has lasted 5+ and 4+ years, respectively. Hence, we have used Ipi+LEN to prevent relapse after autoSCT in pts with high-risk lymphoma, including double-expressor (DEL)/DHL who have been reported to have a 0% progression-free survival (PFS) rate at 4-years after autoSCT (Herrera et al. J Clin Oncol. 2017; 35:24-33). Patients andMethods: In this prospective trial, pts with lymphoma were enrolled within 6 months post-autoSCT. Inclusion criteria included: age 18 to 80 years; an ECOG PS 0-2; adequate liver (bilirubin and liver enzyme concentrations up to two times the upper limit of normal), renal (serum creatinine < 1.6 mg/dl) , cardiac (ejection fraction 45%), and pulmonary (diffusing capacity of the lung for carbon monoxide 40% of predictive value) function; no active infections; ANC ≥ 1.5x109/L and a platelet count ≥ 75x109/L. Treatment consisted of LEN 10 mg PO daily for 21 days (cycles 1) alternating with Ipi 3 mg/kg IV on day 1 (Cycle 2) for up to 8 cycles. LEN dose reduction was permitted to 5 mg based on standard clinical practice. Results: Twenty-three pts were enrolled in the study. The median age at autoSCT was 56 years (range, 33-74). Fifteen (65%) were males and 5 (22%) pts had an HCT-CI ≥ 3. The median # of prior chemotherapies excluding their SCT was 2 (range, 1-5). Two pts had failed a prior autoSCT and were enrolled after a second transplant. Histologies included [DEL/DHL (n=8, 35%), DLBCL nonDEL/nonDHL (n=6, 23%), mantle cell lymphoma (MCL) (n=4, 17%; including 2 with 2 prior transplants, 1 with CNS involvement, 2 had blastoid histology, 1 in partial response to induction chemotherapy), follicular lymphoma (n=1; 4%; 3 prior therapies) Hodgkin's disease (n=2, 9%; including 1 with persistent PET+ post-transplant), angioimmunoblastic t-cell lymphoma (n=2, 9%). Most pts received R-BEAM (n=17, 74%) or BEAM (n=3, 13%) conditioning for their autoSCT. Median # of cycles of immunotherapy received after autoSCT was 5 (range, 2-8). Two pts are continuing their pre-planned treatment. Median follow-up duration was 35 months (range, 4-78 months). The 3-year rates of overall survival (OS) and PFS were 92% and 73%, respectively (Figure 1). Only 1 death was observed: this occurred in a pt with MCL who received 2 prior autoSCT and then developed post-transplant lymphoproliferative disorder without any evidence of MCL recurrence. The most common other grade 3-4 AEs were 10 events of neutropenia, anemia (1), perianal infection (1), and one developed pulmonary embolism on therapy. All AEs resolved. An immune-related AE occurred in one patient (dermatitis, gr 3) after the second ipilimumab dose and resolved with steroids. DEL/DHL group (n=8): This group was heavily pre-treated. The median # of prior chemotherapies excluding their SCT was 3 (range, 1-5). Five have failed DA-REPOCH, one had failed R-Hyper-CVAD and one was induced with R-CHOP. With a median follow-up of 35 months (range, 4-78months), all pts remain alive. One patient with DEL/DHL who was transplanted during second remission relapsed at 1.6 months after initiating therapy (just after finishing the cycle 2). All others remain in complete remission (Figure 2). Conclusions: Maintenance therapy with Ipi+LEN after autoSCT for high-risk lymphoma shows encouraging survival rates, including pts with DEL/DHL who usually have dismal outcomes. The treatment has favorable toxicity profile. These results warrant a randomized trial for confirmation. Disclosures Khouri: Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Jabbour:Genentech: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. Lee:Seattle Genetics: Research Funding; Oncternal Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau; Guidepoint Blogal: Consultancy; Celgene: Research Funding; Takeda: Research Funding. Nastoupil:Pfizer: Honoraria, Research Funding; Gilead/KITE: Honoraria; Merck: Research Funding; Genentech, Inc.: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; TG Therapeutics: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Gamida Cell: Honoraria; Bayer: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karus Therapeutics: Research Funding. Iyer:Merck: Research Funding; Afffimed: Research Funding; Spectrum: Research Funding; Target Oncology: Honoraria; Legend Biotech: Consultancy; CRISPR: Research Funding; Curio Biosciences: Honoraria; Rhizen: Research Funding; Seattle Genetics, Inc.: Research Funding; Trillium: Research Funding; Daiichi Sankyo: Consultancy. Flowers:TG Therapeutics: Research Funding; Millennium/Takeda: Consultancy, Research Funding; Leukemia and Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; Burroughs Wellcome Fund: Research Funding; V Foundation: Research Funding; National Cancer Institute: Research Funding; Bayer: Consultancy; Kite: Research Funding; Eastern Cooperative Oncology Group: Research Funding; AbbVie: Consultancy, Research Funding; Cancer Prevention and Research Institute of Texas: Research Funding; Celgene: Consultancy, Research Funding; Acerta: Research Funding; BeiGene: Consultancy; Spectrum: Consultancy; Pharmacyclics/Janssen: Consultancy; Karyopharm: Consultancy; OptumRx: Consultancy; Gilead: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Genentech, Inc./F. Hoffmann-La Roche Ltd: Consultancy, Research Funding. Champlin:Genzyme: Speakers Bureau; Johnson and Johnson: Consultancy; Omeros: Consultancy; Actinium: Consultancy; Takeda: Patents & Royalties; DKMS America: Membership on an entity's Board of Directors or advisory committees; Cytonus: Consultancy. Sharma:BioAlta: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Achelois: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Apricity Health: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Constellation: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Dragonfly Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Forty-Seven Inc.: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Hummingbird: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lava Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Lytix Biopharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Marker Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Oncolytics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Glympse: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Polaris: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Jounce Therapeutics: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; BioNTech: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Codiak BioSciences: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; ImaginAb: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Infinity Pharma: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Maintenance therapy with Ipilimumab and Lenalidomide after transplantation

Follicular lymphoma (FL) is a B-cell lymphoma with a complex tumor microenvironment that is rich in non-malignant immune cells. We applied single-cell RNA-sequencing to characterize the diverse tumor and immune cell populations of FL and identified major phenotypic subsets of FL T-cells including a novel cytotoxic CD4 T-cell population. Their relative proportions of T-cells defined four major FL subtypes, characterized by differential representation or relative depletion of distinct T-cell subsets. By integrating exome sequencing, we observed that somatic mutations are associated with, but not definitive for, reduced antigen presentation on FL cells. In turn, expression of MHC class II genes by FL cells was associated with significant differences in the proportions and targetable immunophenotypic characteristics. This provides a classification framework of the FL microenvironment, their association with FL genotypes and antigen presentation, and informs different potential immunotherapeutic strategies based upon tumor cell MHC class II expression.Statement of significanceWe have characterized the FL-infiltrating T-cells, identified cytotoxic CD4 T-cells as an important component, showed that the abundance of these T-cell populations is associated with tumor-cell-intrinsic characteristics, and identified sets of targetable immune checkpoints on T-cells that differed between FLs with normal versus low antigen presentation.

Introduction Central nervous system (CNS) relapse (CNSr) in patients with aggressive non-Hodgkin lymphoma (NHL) occurs uncommonly (estimated incidence 5%) but carries a high morbidity and mortality. Studies have identified risk factors for CNSr such as high tumor burden and extranodal (EN) disease. However, most focus on B-cell NHL with minimal data in T-cell lymphomas (TCL), which are significantly less common and more heterogenous. The few small series of CNSr in TCL report a median overall survival (OS) less than 3 months (mo) with incidence ranging from 2.6-9%. To better define CNSr in TCL, we performed a multi-institutional retrospective analysis of TCL patients with CNSr and herein describe clinicopathologic characteristics and treatment of CNSr. Methods We performed a retrospective observational study using data from 9 US academic centers with IRB approval at individual sites. We included adult patients diagnosed with a mature T-cell neoplasm as per the 2016 WHO classification between 1/1/2009-1/1/2019, who were found to have CNSr at any time after initial diagnosis, and collected patient, disease, and treatment characteristics at time of initial diagnosis as well as at CNSr. Patients with a diagnosis of a precursor T-cell malignancy or with CNS disease identified at initial TCL diagnosis (TCLd) and/or prior to first-line systemic treatment were excluded. Results In this analysis, we report the outcomes of 75 patients (male n=45, female n=30). At TCLd, the median age was 59 years (range 20-81), and 61% of patients (n=46) had an IPI score of at least 3, 92% (n=69) had EN involvement with 37% (n=28) involving at least 2 EN sites, and 59% (n=44) had BM involvement. The most common pathologic diagnoses were peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS; 24%, n=18), angioimmunoblastic T-cell lymphoma (AITL; 17%, n=13), adult T-cell leukemia/lymphoma (ATLL; 17%, n=13), and mycosis fungoides (MF; 12%, n=9) (Figure 1A). First-line systemic therapy for TCL included anthracyclines for 72% (n=54). Autologous and allogenic transplants were performed prior to CNSr in 12% (n=9) and 8% (n=6) of patients, respectively. Prior to CNSr, 48% (n=36) had non-CNS relapse. Some form of CNS prophylaxis was used during initial systemic lymphoma therapy in 24% of patients (n=18), predominantly intrathecal methotrexate (IT MTX; n=16). Median time from TCLd to CNSr was 8.5mo, though this was significantly longer in MF (46.8mo [range 17.5-187.7]) versus PTCL, NOS (7.6mo [range 1.1-58.4], P=0.0002), AITL (21.2mo [range 2.0-61.6, P=0.008), and ATLL (7.3mo [range 0.7-46.4], P=0.0005) (Figure 1B). CNSr developed within 6mo of TCLd in 31% of patients (n=23) and within 12mo in 57% (n=43). Symptoms related to CNSr occurred in 71% of patients (n=53). CNSr patterns were 61% leptomeningeal (n=46), 21% parenchymal (n=16), and 17% both (n=13) with no significant survival difference between leptomeningeal or parenchymal disease alone (HR 1.45, 95% CI 0.78-2.70, P=0.28). Concomitant systemic relapse was observed in 59% of patients (n=44). The most common CNS-directed therapy for CNSr was IT MTX (56%; n=42), though multiple different IT and/or systemic regimens were used. Patients received a median of 1 line of CNS-directed treatment (range 0-5). The overall response rate to initial CNS directed treatment was 32% (16% CR, 16% PR). Median follow up after CNSr was 40.7mo. At last follow up, 83% had died (n=62). Median OS after CNSr was 4.6mo (range 0.1-68.7) (Figure 1C). Those with ATLL had the shortest median OS after CNSr (2.7mo) versus 6.3mo in MF (HR 3.69, 95% CI 1.44-9.42, P=0.005), 6.5mo in AITL (HR 2.16, 95% CI 0.92-5.06, P=0.054), and 4.8mo in PTCL, NOS (HR 1.49, 95% CI 0.70-3.19, P=0.27) (Figure 1D). The most common cause of death was progressive lymphoma (77%; n=48). Conclusions This is to our knowledge the largest series of CNSr in TCL to date. Most CNSr occurred within 12mo, though CNSr occurred later in patients with MF. Although the prognosis after CNSr was generally poor, we found that median OS in CNSr was longer than previously reported, perhaps reflecting more effective treatments for CNS and systemic relapse, inclusion of MF, or lead time bias. Further analysis of the impact of different treatment strategies and outcomes in CNSr was limited by the small sample size and heterogeneity within our cohort, and future analyses in a larger cohort should focus on factors associated with outcomes. Figure 1 Figure 1. Disclosures Horwitz: ADC Therapeutics, Affimed, Aileron, Celgene, Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium /Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/SecuraBio.: Consultancy, Research Funding; Affimed: Research Funding; Aileron: Research Funding; Acrotech Biopharma, Affimed, ADC Therapeutics, Astex, Merck, Portola Pharma, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle Genetics, Shoreline Biosciences, Inc, Takeda, Trillium Th: Consultancy; Celgene: Research Funding; C4 Therapeutics: Consultancy; Crispr Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; Forty Seven, Inc.: Research Funding; Kura Oncology: Consultancy; Kyowa Hakko Kirin: Consultancy, Research Funding; Millennium/Takeda: Research Funding; Myeloid Therapeutics: Consultancy; ONO Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Secura Bio: Consultancy; Shoreline Biosciences, Inc.: Consultancy; Takeda: Consultancy; Trillium Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Verastem/Securabio: 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. Chavez: AstraZeneca: Research Funding; ADC Therapeutics: Consultancy, Research Funding; Merk: Research Funding; MorphoSys, AstraZeneca, BeiGene, Genentech, Kite, a Gilead Company, and Epizyme: Speakers Bureau; MorphoSys, Bayer, Karyopharm, Kite, a Gilead Company, Novartis, Janssen, AbbVie, TeneoBio, and Pfizer: Consultancy; BMS: Speakers Bureau. Sokol: Dren Bio: Membership on an entity's Board of Directors or advisory committees; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees. Saeed: Nektar Therapeutics: Consultancy, Other: research investigator; MEI Pharma Inc: Consultancy, Other: investigator; Celgene Corporation: Consultancy, Other: investigator; MorphoSys AG: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb Company: Consultancy; sano-aventis U.S.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutica Products, LP: Consultancy, Other: investigator; Kite Pharma: Consultancy, Other: investigator; Other-TG therapeutics: Consultancy, Other: investigator; Other-Epizyme, Inc.: Consultancy; Other-Secura Bio, Inc.: Consultancy; Seattle Genetics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees. Mehta-Shah: Kiowa Hakko Kirin: Consultancy; C4 Therapeutics: Consultancy; Verastem: Research Funding; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding. Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding. Allen: Epizyme: Consultancy; MorphoSys: Consultancy; ADC Therapeutics: Consultancy; Secure Bio: Consultancy; Kyowa Kirin: Consultancy. Gerson: Abbvie: Consultancy; Kite: Consultancy; TG Therapeutics: Consultancy; Pharmacyclics: Consultancy. Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; ADCT: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Incyte: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees. Schuster: Adaptive Biotechnologies: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Genentech/Roche: Consultancy, Research Funding; Tessa Theraputics: Consultancy; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; BeiGene: Consultancy; Alimera Sciences: Consultancy; Acerta Pharma/AstraZeneca: Consultancy; Abbvie: Consultancy, Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Svoboda: Atara: Consultancy; Adaptive: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Imbrium: Consultancy; Pharmacyclics: Consultancy, Research Funding; Genmab: Consultancy; Merck: Research Funding; Incyte: Research Funding; BMS: Consultancy, Research Funding; TG: Research Funding; Seattle Genetics: Consultancy, Research Funding. Barta: Kyowa Kirin: Honoraria; Acrotech: Honoraria; Daiichi Sankyo: Honoraria; Seagen: Honoraria.

PURPOSE/OBJECTIVE(S) Brentuximab vedotin (BV) and polatuzumab vedotin (PV) are antibody-drug conjugates targeting CD30 and CD79B, respectively, approved for the treatment of select T- and B-cell lymphomas. Safety data to inform the use of concurrent radiation therapy (CRT) with BV or PV is lacking. MATERIALS/METHODS We retrospectively reviewed 31 patients (pts) who received CRT with BV or PV from 5/2018 to 1/2021. We defined CRT as infusion within 3 weeks prior to or concurrent with RT. Timing of toxicity (CTCAE v5.0) was classified as pre-RT (within 1 month prior to RT), acute (start to 1 month post-RT), and subacute (2-3 months following RT), censored at subsequent systemic therapy. Statistics were performed using Mann-Whitney U and Chi-squared tests. RESULTS Of 31 pts, 20 (65%) received BV and 11 (35%) received PV. Median age at CRT was 55 (range 27-88), and 14 pts were female (45%). 26 pts (84%) had stage III-IV disease at the time of CRT. The most common diagnoses were mycosis fungoides (12 pts, 39%; 7 with large cell transformation) and diffuse large B cell lymphoma (10 pts, 32%). Pts received a median of 4 lines of prior systemic therapy (range 0-8). 22 pts received prior RT courses (median 1, range 1-6). Fourteen pts received combination regimens with BV or PV: bendamustine and rituximab (R) (5, 16%); cyclophosphamide (C) (± R) (3, 10%); R alone (5, 16%); and C with doxorubicin (1, 3%). Eleven pts (35%) were treated with electrons targeting skin, with a median dose of 12 Gy (range 4-32). Twenty pts (65%) were treated with photons to 32 sites, with a median dose of 25 Gy (range 9-44); treatment sites included the spine (14 pts, 45%), abdomen/pelvis (9 pts, 29%), and brain (3 pts, 10%). Median percent bone marrow (BM) treated was 6.6 (range 0-18.3). The rate of grade 2 or higher (G2+) hematologic toxicity (HT) was 45% (14/31) pre-CRT vs. 79% (23/29) in the acute setting (P = 0.044) and 71% (10/14) in the subacute setting (P = 0.29). There was no significant change in acute or subacute pain, fatigue, diarrhea, neuropathy, or hepatotoxicity following CRT. Acute G2+ HT was associated with pre-RT G2+ HT (P = 0.019) and more lines of prior systemic therapy (P = 0.011). Percentage of BM irradiated was not significantly associated with acute G2+ HT (P = 0.09). Age, concurrent chemotherapy with BV or PV, prior RT courses, RT dose, and RT modality were not associated with G2+ HT. Six pts (19%) were bridged to stem cell transplant at a median of 26 days (IQR 16-52). 12 patients (39%) received subsequent systemic therapy for progression at a median of 81 days (IQR 25-87). Median time to progression or last follow-up was 72 days (IQR 20-113). At last follow-up, 18 pts (58%) were deceased; median overall survival from CRT was 177 days (95% CI 92-263). CONCLUSION CRT with BV or PV was overall well tolerated. We observed HT, particularly in patients with cytopenias prior to RT. Care should be taken during RT planning to reduce this risk if possible.

Introduction Classic Hodgkin's lymphoma (cHL) is a highly curable lymphoid malignancy. Epstein-Barr virus (EBV) is associated with cHL, with a variable rate of detection in Hodgkin and Reed-Sternberg (HRS) cells among different histologic types and geographic areas.Although most adults worldwide are EBV seropositive, only a minority of patients infected with EBV will develop cHL. EBV is thought to be one of the causative agents for the development of cHL with an important pathobiology role. The goal of this study was to compare the presentation and the outcomes of patients with EBV+ HRS cells at the time of initial diagnosis of cHL. Methods This single-center study included patients with a diagnosis of cHL who were first seen at The University of Texas MD Anderson Cancer Center between January 1,2016 and May 28, 2020 for either newly diagnosed cHL or relapsed/refractory (R/R) cHL. Pathology was confirmed and analyzed for positivity of EBV (EBV +ve) in all patients by immunohistochemical (IHC) staining for by Epstein-Barr virus-encoded small RNA (EBER) with available paraffin blocks. The primary aims were to assess overall survival (OS), progression-free survival (PFS) and frequency of advanced disease. Descriptive statistics for categorical and continues variables were analyzed. Kaplan-Meier method was used for time-to-event analysis, including PFS and OS. Median time to event in months with 95% confidence interval (CI) was calculated. The Log-rank test was used to evaluate the difference in time-to-event endpoints between patient groups. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used for statistical analyses. Results Between 2016 and 2020, 644 patients met the inclusion criteria. Three hundred and fifty six patients (55%) had enough/available tissue to undergo testing for EBV at the time of initial diagnosis. The median age at diagnosis was 36 years with 51.4% males. Eighty-eight patients had positive EBV (25%) at diagnosis. The median age of +ve EBV was 37 years (Range: 18-83 years) compared to 33 years (Range: 18-85 years) for patients with -ve EBV. Mixed cellularity histology was more frequent in patients with +ve EBV when compared to the whole group of patients (32% vs. 7%; p-value: 0.03). Human immunodeficiency virus (HIV) was positive in a minority of the patients (8 patients out of 498 patients with available results) (1.6%) however 50% of the patients with HIV had +ve EBV at the time of diagnosis. Baseline demographics are summarized in Table 1. EBV was associated with the initial stage (stage II 38% in EBV +ve vs. 53% in EBV -ve, stage III 25% in EBV +ve vs. 14% in EBV -ve, stage IV 24% in EBV +ve vs. 31% in EBV -ve; p-value 0.0001). Most of the patients were treated with doxorubicin, bleomycin, vinblastine and decarbazine (ABVD) based therapy (77%). Other therapies included brentuximab vedotin (BV) (13%) and checkpoint inhibitors (CPIs) (6%). Median follow up was 1.97 years (range: 0.047- 44.09 years). PFS rate difference at 5 years was not statistically significant (64% in EBV +ve vs. 52% in EBV -ve; p-value 0.14). OS rate at 5 years was significantly lower in patients with +ve EBV (89% vs. 98%, p-value: 0.0014). OS rates at 10 years were similar (89% in EBV +ve vs. 88% in EBV -ve). Conclusions EBV at the time of diagnosis was associated with lower prevalence of localized cHL and inferior survival rates at 5 years of follow up (9% lower OS rate at 5 years). Implementation of different frontline therapy treatment algorithms specific to EBV +ve patients may help in improving the survival outcomes. Further research is needed to understand the biological significance of +ve EBV in cHL to help in developing novel agents targeting EBV positive cHL population with the ultimate goal of improving outcome. Disclosures Parmar: Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Iyer:Rhizen: Research Funding; CRISPR: Research Funding; Seattle Genetics, Inc.: Research Funding; Merck: Research Funding; Legend Biotech: Consultancy; Daiichi Sankyo: Consultancy; Trillium: Research Funding; Curio Biosciences: Honoraria; Target Oncology: Honoraria; Afffimed: Research Funding; Spectrum: Research Funding. Nieto:Novartis: Other: Grant Support; Astra Zeneca: Other: Grant Support; Affimed: Consultancy, Other: Grant Support; Secura Bio: Other: Grant Support. Chuang:Sage-Evidence=Based Medicine & Practice: Consultancy. Wang:Beijing Medical Award Foundation: Honoraria; Loxo Oncology: Consultancy, Research Funding; Pulse Biosciences: Consultancy; Nobel Insights: Consultancy; Verastem: Research Funding; Dava Oncology: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Molecular Templates: Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OMI: Honoraria, Other: Travel, accommodation, expenses; Targeted Oncology: Honoraria; Lu Daopei Medical Group: Honoraria; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; VelosBio: Research Funding; Acerta Pharma: Research Funding; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Juno: Consultancy, Research Funding; OncLive: Honoraria; Guidepoint Global: Consultancy. Lee:Celgene: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau; Seattle Genetics: Research Funding; Oncternal Therapeutics: Research Funding; Guidepoint Blogal: Consultancy.

Background: Anti-CD38 monoclonal antibodies (mAb) like daratumumab (dara) have become integral in managing relapsed/refractory (RR) and newly diagnosed (ND) multiple myeloma (MM). Isatuximab (isa), a newer CD38 mAb, induces direct rather than indirect apoptosis of MM cells. However, little is known about whether the use of one prior CD38 mAb will alter the efficacy of another in subsequent lines of therapy. Methods: All patients (pts) with MM treated at MD Anderson with isa after receiving dara in prior lines of therapy were identified. We conducted a retrospective analysis with data points including patient and disease characteristics, responses to dara, response to isa, the presence of high risk features, and the presence of t(11,14). Results: 9 pts were identified, ages 56-72. 5 pts (55%) were male. 5 pts (55%) were alive at the time of data cutoff. 5 pts were Hispanic, 3 White, and 1 Black. 8 pts (89%) had high risk features as represented by the presence of del17p, t(4,14), t(14,16), t(14,20), p53 mutations, gain 1q, extramedullary disease (EMD), CNS disease, early relapse (within 1 year) after autologous transplant, or an increased (>5%) peripheral blood plasma cells (PBPC). 2 (22%) had t(11,14). 4 (44%) had IgG MM. 2 (22%) with light chain disease, 2 (22%) with IgA MM, and 1 (11%) with IgD MM. Dara was initially used in lines 2-7. Dara combinations with pomalidomide (pom), bortezomib (bor), thalidomide (thal), lenalidomide (len), or carfilzomib (car); and pom combinations that also included elotuzumab (elo) or Cytoxan (cytox) are noted in table 1. Dara was discontinued (dc'd) in 8 pts due to progressive disease (PD) and in 1 pt due to toxicity. 8 pts (89%) experienced a best overall response (ORR) of partial response (PR) to dara; 1 pt had stable disease (SD). All pts received prior len and 8 pts received prior pom at some time during the treatment of MM. All pts received isa in combination with pom/dexamethasone (dex). Best ORR to isa/pom/dex: 5 pt (55%) had PR, 2 pt with minimal response (MR), 1 SD, 1 PD. Median treatment duration of isa/pom/dex was 5 weeks (2-14 weeks) at data cutoff. 3 pts dc'd isa/pom/dex due to infections, and 2 due to later progression. 2 pts remain on therapy. 1 pt chose to dc all MM therapy for quality of life purposes despite PR with isa/pom/dex. 1 pt died from cardiac disease unrelated to MM or treatment. Conclusions: Our current study of heavily pretreated pts with RRMM demonstrates that despite prior anti-CD38 therapy with dara, most patients (77%) experienced a response of MR or better with treatment with another anti-CD38 therapy isa. To our knowledge, this is the first report of outcomes to isa in patients with prior dara therapy. Further long term follow up will be needed to determine the length of response. Additional studies are planned to further evaluate this patient population. Table 1 Disclosures Thomas: Pharmacyclics: Other: Advisory Boards; BMS: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; X4 Pharma: Research Funding; Xencor: Research Funding; Genentech: Research Funding. Iyer:Rhizen: Research Funding; CRISPR: Research Funding; Spectrum: Research Funding; Merck: Research Funding; Curio Biosciences: Honoraria; Target Oncology: Honoraria; Afffimed: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Trillium: Research Funding; Seattle Genetics, Inc.: Research Funding. Patel:Celgene: Consultancy, Research Funding; Cellectis: Research Funding; Nektar: Consultancy, Research Funding; Oncopeptides: Consultancy; Poseida: Research Funding; Precision Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Manasanch:Adaptive Biotechnologies: Honoraria; GSK: Honoraria; Sanofi: Honoraria; BMS: Honoraria; Takeda: Honoraria; Quest Diagnostics: Research Funding; Merck: Research Funding; JW Pharma: Research Funding; Novartis: Research Funding; Sanofi: Research Funding. Kaufman:Janssen: Research Funding; Bristol Myers Squibb: Research Funding; Karyopharm: Honoraria. Lee:Genentech: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Sanofi: Consultancy; Daiichi Sankyo: Research Funding; Regeneron: Research Funding; Genentech: Consultancy. Orlowski:Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; STATinMED Research: Consultancy; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding.

Purpose: Dual expression of MYC and BCL2 proteins (Double Expressor Lymphoma-[DEL]) is an important prognostic factor in patients (pts) with diffuse large B-cell lymphoma (DLBCL) who are treated with standard chemo-immunotherapy. Studies have suggested that pts with these biomarkers have inferior survival compared to pts who were non-DEL after autologous stem cell transplantation (autoSCT). For this reason, allogeneic stem cell transplantation (alloSCT) has been advocated for its potential graft-versus-lymphoma effect. Data are limited however regarding the outcomes in pts with relapsed DEL who were treated with autoSCT vs. alloSCT. Methods: Data from pts with relapsed DEL/DLBCL who underwent auto- and alloSCT as their first transplant at our center and in whom archived tumor material was available were analyzed. Cutoff values of 40% for MYC and 70% for BCL2 were established by immunohistochemistry (IHC). The majority of autoSCT pts (84%) underwent chemo-mobilization of stem cells with rituximab (R) for in-vivo purging; rituximab was also given on days+1 and +8 with BEAM conditioning (J Clin Oncol 2005; 23:2240-7; Clin Cancer Res 2018; 24:2304-11). Conditioning for the alloSCT was myeloablative (n=16, 50%), reduced-intensity (n=6, 19%), and nonmyelablative (n=10,31%). The study was IRB-approved at our center. Kaplan-Meier analysis and corresponding log-rank/Gray's tests were used to estimate and compare overall survival (OS), progression-free survival (PFS), and cumulative incidence (CI) of non-relapse mortality and relapse by SCT group. Standard multivariable Cox regression was used to evaluate associations between SCT type and OS/PFS after controlling for differences in baseline characteristics and cause-specific multivariable Cox regression was used for competing-risk outcomes [non-relapse mortality (NRM) and relapse]. Results: The study included 161 autoSCT and 32 alloSCT pts treated between 2000-2018. Median age was 59 (range,18-80) and 55 years (range, 21-66), respectively (P=0.009). Male gender was 62.7 vs 50.0%, respectively (P= 0.234). Fifty-one (32.5%) autoSCT pts and 9 (28.1%) alloSCT pts had an elevated serum LDH (P= 0.683) and 41/148 (27.7%) autoSCT and 11/25 (44.0%) alloSCT pts were PET-positive at study entry (P=0.106). The time from diagnosis to transplant was 20.0 and 25.2 months, respectively, (P=0.068), and the distribution of the years of transplant was similar between both groups (P=0.317). Significant differences between treatment groups were observed for prior number of chemotherapies, disease status, stage, and HCT-CI score at transplant. Pts. receiving alloSCT were more heavily pretreated [median 3 prior therapies, (range 1-8) vs. a median of 2, (range 1-6); P=0.0001], had more advanced stage III-IV disease (P=0.035), and more refractory disease (P=0.010) at transplant. In addition, a higher percentage of alloSCT pts had an HCT-CI of >4 (28.1% vs. 10.2%, P=0.018) at study entry. Allogeneic transplant characteristics included matched siblings (n=18; 56.3%), matched unrelated (n=13, 40.6%) and haplo-identical (n=1, 3.1%) donors. With a median follow-up for autoSCT surviving pts of 65 months (range, 5-217 months) and 93 months (range, 34--124 months) for alloSCT pts, the OS at 5-years were 59% and 34%, respectively (P= 0.0001) (Figure1). The PFS rates at 5-years were 49% and 31%, respectively (P = 0.002). AutoSCT had a similar rate of relapse to alloSCT but a lower rate of NRM. The 5-year CI of relapse was 37% vs 28%, respectively (P = 0.611) and the 5-year NRM rates were 14% vs 41 % (P=0.0001), respectively (Figure 2). The associations between SCT group and outcomes persisted after adjusting for differences between groups (alloSCT vs. autoSCT HR= 3.46/p=0.0004 for OS; HR=2.67/p=0.005 for PFS; HR=4.74/p=0.009 for NRM; HR=2.22/p=0.080 for relapse). The 100-day CI of grade II-IV and III-IV acute GVHD in the alloSCT group was 37.5 and 9.4%, respectively. The 1-year CI of chronic GVHD was 25.0%. C onclusions: This study is the first to show that autoSCT confers a superior survival in pts with relapsed DEL/DLBCL compared to alloSCT. Our conclusions are supported by long-term follow-up. The use of novel nonmyeloablative regimens in a larger number of pts receiving an alloSCT and ongoing studies at our center with targeted investigational agents after autoSCT may improve results. Disclosures Khouri: Pfizer: Research Funding; Bristol Myers Squibb: Research Funding. Iyer:CRISPR: Research Funding; Spectrum: Research Funding; Daiichi Sankyo: Consultancy; Trillium: Research Funding; Curio Biosciences: Honoraria; Target Oncology: Honoraria; Afffimed: Research Funding; Merck: Research Funding; Legend Biotech: Consultancy; Rhizen: Research Funding; Seattle Genetics, Inc.: Research Funding. Popat:Bayer: Research Funding; Novartis: Research Funding. Qazilbash:Angiocrine: Research Funding; Amgen: Research Funding; Bioclinica: Consultancy; Janssen: Research Funding; Bioline: Research Funding. Champlin:DKMS America: Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy; Johnson and Johnson: Consultancy; Omeros: Consultancy; Cytonus: Consultancy; Takeda: Patents & Royalties; Genzyme: Speakers Bureau.

Background: Lenalidomide (LEN) monotherapy has been effective in extending progression free survival (PFS) after AuSCT in pts with MM. Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against signaling lymphocytic activation molecule F7 (SLAM F7), is FDA approved in combination with LEN and dexamethasone (DEX) for treatment of MM pts who have received 1-3 prior therapies. We report updated results of this phase 2 trial evaluating the efficacy and safety of adding ELO to LEN as maintenance therapy post- AuSCT. Patients and Methods: Between 4/15/2015-1/27/2016, 27 evaluable pts were treated on 28 day cycles with ELO, 10 mg/kg iv weekly for cycles 1-2, q2weeks for cycles 3-6, then 20 mg/kg once monthly for cycles 7+. Pts enrolled after 1/28/2016 (n=73 pts) have received ELO, 10 mg/kg IV weekly for cycles 1-2, and 20 mg/kg on day 1 from cycle 3 until disease progression (PD). LEN has been dosed at 10 mg/day for cycles 1-3, with a dose increase to 15 mg/day at physician discretion starting with cycle 4, in the absence of non-hematologic toxicity > grade 1 and significant cytopenias (ANC < 1000/mL, platelet count < 100,000/ml). For the 1st 8 weeks, pts The study's primary endpoint is PFS, defined as time from AuSCT to PD or death (whichever occurs first), or censored at date of last contact. Secondary objectives are best response, OS, incidence of second primary malignancies (SPMs) and adverse event (AE) profile. Total enrollment of 100 evaluable pts was completed on 6/5/2019. Patients are followed until death, withdrawal of consent or removal from study. Eligible pts received ≤2 lines of induction therapy, and were 60-210 days post-AuSCT. Results: Pts (n=100) have been treated for a median of 27.5 cycles (4-67). At study entry, 37 (37%) had complete response (CR), 40 (40%) very good partial response (VGPR), 22 (22%) partial response (PR) and 1 (1%) minor response (MR). Best response achieved to date on study is CR in 61 pts (61%), VGPR in 29 pts (29%) and PR in 10 pts (10%). Median time for conversion to CR on study is 1 month. Of pts in CR and tested for minimal residual disease (MRD) to date, 42/48 are negative (flow cytometry on ≥ 2 x106 cells). Eleven of 42 have converted from VGPR to MRD negative CR while on study. With a median follow up of 41 months, 90% of pts (n=90) remain alive. Eighteen pts have had PD; of these, 10 had high-risk cytogenetics. Three died of PD while receiving salvage therapy, 1 of pneumonia, 4 of second malignancies and 1 of unknown cause at another facility. One additional pt died on study in VGPR, after developing acute cerebral encephalopathy with refractory status epilepticus of unclear etiology. Estimated 4 year PFS is 75%. High-risk cytogenetics (n =31) adversely affected PFS (p=0.01); 14/31 pts remain on study. Of 23 pts transitioned to another therapy, median 2nd PFS has not been reached. Grade 3-4 Hematologic AEs (no. of pts/102 pts) were: neutropenia 32% (33), febrile neutropenia 15% (15), thrombocytopenia 7% (7), and anemia 10% (10). Grade 3-4 non-Hematologic AEs (no. of pts): hypophosphatemia 29% (30), respiratory infections 21% (21), diarrhea 15% (15), fatigue 12% (12), peripheral neuropathy 8% (8), other infections 7% (7), myalgias 5% (5), dyspnea 5% (5). SPMs include cutaneous basal and squamous cell carcinomas (8), AML (1), B-cell ALL (1), t-MDS (4), osteosarcoma (1), intra-epidermal adenocarcinoma of the neck (1), mucinous appendiceal neoplasm (1), mucinous epidermoid carcinoma of parotid (1), prostate cancer (1). Renal cell carcinoma was diagnosed in 1 pt, 15 months after removal from study for PD. Conclusions: Lenalidomide-elotuzumab is a well-tolerated maintenance therapy on which 38% of pts have had improvement in quality of response while on therapy, including 27% who converted to CR. SPM rates seem consistent with those observed in CALGB 100104 and IFM 2005-02 trials of lenalidomide alone. Longer follow up is required to determine how median PFS and OS will compare with those from lenalidomide monotherapy trials, and how SPM rates will continue to evolve. Table 1 Disclosures Thomas: X4 Pharma: Research Funding; Ascentage: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Xencor: Research Funding; Pharmacyclics: Other: Advisory Boards; Genentech: Research Funding. Shah:Karyopharm: Current Employment, Current equity holder in publicly-traded company. Lee:Regeneron: Research Funding; Daiichi Sankyo: Research Funding; Sanofi: Consultancy; GlaxoSmithKline: Consultancy, Research Funding; Genentech: Consultancy; Takeda: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech: Consultancy. Manasanch:JW Pharma: Research Funding; Merck: Research Funding; Quest Diagnostics: Research Funding; Takeda: Honoraria; BMS: Honoraria; Glaxo Smith Kline: Honoraria; Adaptive Biotechnologies: Honoraria; Novartis: Research Funding; Sanofi: Honoraria, Research Funding. Patel:Oncopeptides: Consultancy; Takeda: Consultancy, Research Funding; Cellectis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Nektar: Consultancy, Research Funding; Precision Biosciences: Research Funding; Poseida: Research Funding. Kaufman:Bristol Myers Squibb: Research Funding; Karyopharm: Honoraria; Janssen: Research Funding. Iyer:Trillium: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Merck: Research Funding; Rhizen: Research Funding; Seattle Genetics, Inc.: Research Funding; Target Oncology: Honoraria; Afffimed: Research Funding; CRISPR: Research Funding; Spectrum: Research Funding; Curio Biosciences: Honoraria. Qazilbash:Angiocrine: Research Funding; Bioclinica: Consultancy; Janssen: Research Funding; Bioline: Research Funding; Amgen: Research Funding. Bashir:Amgen: Other: Advisory Board; Purdue: Other: Advisory Board; Takeda: Other: Advisory Board, Research Funding; Acrotech: Research Funding; StemLine: Research Funding; Celgene: Research Funding; KITE: Other: Advisory Board. Orlowski:Laboratory research funding from BioTheryX, and clinical research funding from CARsgen Therapeutics, Celgene, Exelixis, Janssen Biotech, Sanofi-Aventis, Takeda Pharmaceuticals North America, Inc.: Research Funding; Amgen, Inc., AstraZeneca, BMS, Celgene, EcoR1 Capital LLC, Forma Therapeutics, Genzyme, GSK Biologicals, Ionis Pharmaceuticals, Inc., Janssen Biotech, Juno Therapeutics, Kite Pharma, Legend Biotech USA, Molecular Partners, Regeneron Pharmaceuticals, Inc.,: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis, Servier, Takeda Pharmaceuticals North America, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Founder of Asylia Therapeutics, Inc., with associated patents and an equity interest, though this technology does not bear on the current submission.: Current equity holder in private company, Patents & Royalties; STATinMED Research: Consultancy. OffLabel Disclosure: Elotuzumab (ELO), a humanized IgG1 immunostimulatory monoclonal antibody against SLAM F7. It is FDA approved in combination with Lenalidomide and dexamethasone (DEX) for treatment of MM pts who have received 1-3 prior therapies. This is a phase 2 trial evaluating the efficacy and safety of adding ELO to LEN as maintenance therapy post-autologous stem cell transplant.

Introduction. The efficacy of CAR T-cell therapy in relapsed/refractory (r/r) LBCL has been associated with peak CAR T-cell expansion post-infusion. One of the critical factors that drives CAR T-cell expansion is the availability of homeostatic cytokines, such as IL-15, at the time of infusion. Consistent with this hypothesis, serum IL-15 levels have been associated with CAR T-cell therapy expansion and efficacy, higher levels favoring improved outcomes. Since induction of lymphodepleting conditioning (LDC) therapy results in decreased consumption of homeostatic cytokines and thereby increases their serum levels, we aimed to determine whether the magnitude of change in absolute lymphocyte count (ALC) pre- and post-conditioning, referred to as delta lymphocyte index (DLIx), impacts outcomes after CAR T-cell therapy in r/r LBCL. Methods. This is a retrospective study of all patients with r/r LBCL treated with standard of care (SOC) axicabtagene ciloleucel (axi-cel) at MD Anderson Cancer Center between 01/2018 and 04/2020 (data cut-off 06/30/2020). DLIx was defined as the difference in ALC between day of initiation of LDC and day of axi-cel infusion. All patients received LDC therapy with cyclophosphamide and fludarabine. CRS and ICANS were prospectively graded according to CARTOX criteria from 01/2018 to 04/2019, and ASTCT criteria from 05/2019 onward. Response to treatment and progression were defined according to 2014 Lugano criteria. Results. All 171 LBCL patients treated with SOC axi-cel were included in the analysis. At time of initiation of LDC, median age was 59 years (range, 18-85 years), 120 (70%) were male, 151 (88%) had an ECOG performance status of 0-1; 96 (56%) had an IPI > 3, median number of prior systemic therapies was 4 (range, 2-15), 45 (26%) had received an autologous SCT, 3 (2%) an allogeneic SCT; 86 (50%) patients received bridging therapy, including chemotherapy in 52 (30%), radiotherapy in 21 (12%), and biological therapy or corticosteroids in 13 (8%). Median ALC at time of LDC was 0.6 X 109/L (range, 0-2.8 X 109/L) and < lower limit of normal (LLN) in 131 (77%) patient; at time of axi-cel infusion it was 0.03 X109/L (range, 0-1.9 X109/L), and median DLIx was 0.5 X 109/L (range, 0.01-2.75 X 109/L). Ten (6%) patients experienced a delay between LDC and axi-cel infusion, with a median time of 13 days (range, 7-19 days), but no association between delay and DLIx was observed (p=0.79). On univariate analysis, the baseline characteristics associated with low DLIx were ALC < LLN (p Overall, 13 (8%) patients had grade (Gr) 3-4 CRS, and 61 (36%) had Gr 3-4 ICANS. There was no association between DLIx and incidence of Gr 3-4 CRS (p=0.28) or Gr 3-4 ICANS (0.43). Of 164 patients evaluable for response, complete responses (CR) was achieved in 89 (54%) patients, and DLIx was significantly higher in patients who achieved CR vs. non-CR (p=0.04)(Figure). After a median follow-up of 9 months (95% CI, 7-11 months), 94 patients progressed and/or died, and median progression-free survival (PFS) was 6 months (95% CI, 4-8 months). Median PFS was significantly shorter in patients with low DLIx (Q1 vs. Q2-4): 3 months vs 9 months (p=0.002). The association was maintained also after adjusting for bridging therapy use (Hazard Ratio (HR) 0.6, 95% CI 0.4-0.9; p=0.02)(Figure). At data cut-off, 56 (33%) patients died and median OS was not reached. Median OS was significantly shorter among patients with low DLIx (Q1 vs Q2-4) (7 months vs not reached, p Discussion. DLIx has prognostic value in patients with r/r LBCL treated with axi-cel, with low DLIx independently associating with worse outcome. Additional studies are planned and will be presented to determine whether the pharmacokinetics of cyclophosphamide and fludarabine or other host factors impact DLIx, and whether levels of homeostatic cytokines correlate with DLIx. Such studies could lead to optimization of conditioning therapy and development of future combination strategies, aimed at improving CAR T-cell efficacy in these patients. Figure 1 Disclosures Lee: Takeda: Research Funding; Celgene: Research Funding; Guidepoint Blogal: Consultancy; Oncternal Therapeutics: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Aptitude Health: Speakers Bureau; Seattle Genetics: Research Funding. Iyer:Legend Biotech: Consultancy; Daiichi Sankyo: Consultancy; Seattle Genetics, Inc.: Research Funding; Merck: Research Funding; Afffimed: Research Funding; Trillium: Research Funding; Curio Biosciences: Honoraria; CRISPR: Research Funding; Spectrum: Research Funding; Rhizen: Research Funding; Target Oncology: Honoraria. Nastoupil:Pfizer: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Merck: Research Funding; Karus Therapeutics: Research Funding; TG Therapeutics: Honoraria, Research Funding; LAM Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Gilead/KITE: Honoraria; Gamida Cell: Honoraria; Genentech, Inc.: Honoraria, Research Funding; Bayer: Honoraria. Parmar:Cellenkos Inc.: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Wang:Juno: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pulse Biosciences: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Dava Oncology: Honoraria; InnoCare: Consultancy; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; Guidepoint Global: Consultancy; Targeted Oncology: Honoraria; Molecular Templates: Research Funding; OncLive: Honoraria; VelosBio: Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria; MoreHealth: Consultancy; Acerta Pharma: Research Funding; Verastem: Research Funding; Loxo Oncology: Consultancy, Research Funding. Shpall:Takeda: Other: Licensing Agreement; Magenta: Membership on an entity's Board of Directors or advisory committees; Adaptimmune: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Zelluna: Membership on an entity's Board of Directors or advisory committees. Kebriaei:Pfizer: Other: Served on advisory board; Ziopharm: Other: Research Support; Amgen: Other: Research Support; Jazz: Consultancy; Novartis: Other: Served on advisory board; Kite: Other: Served on advisory board. Westin:Genentech: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Curis: Consultancy; 47 Inc: Consultancy; Kite: Consultancy; Juno: Consultancy; MorphoSys: Consultancy; Unum: Consultancy. Neelapu:N/A: Other; Takeda Pharmaceuticals: Patents & Royalties; Karus Therapeutics: Research Funding; Pfizer: Other: personal fees; Novartis: Other: personal fees; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Kite, a Gilead Company: Other: personal fees, Research Funding; Precision Biosciences: Other: personal fees, Research Funding; Legend Biotech: Other; Unum Therapeutics: Other, Research Funding; Acerta: Research Funding; Adicet Bio: Other; Allogene Therapeutics: Other: personal fees, Research Funding; Cell Medica/Kuur: Other: personal fees; Incyte: Other: personal fees; Poseida: Research Funding; Cellectis: Research Funding; Calibr: Other; Celgene: Other: personal fees, Research Funding.

Background CD47 is an innate immune checkpoint that binds signal regulatory protein alpha (SIRPα) and delivers a "do not eat" signal to suppress macrophage phagocytosis. Overexpression of CD47 serves as a mechanism of immune surveillance evasion, and is found to be associated with poor prognosis in both hematologic and solid malignancies. TTI-622 is a fusion protein consisting of the CD47-binding domain of human SIRPα linked to the Fc region of human IgG4. It is designed to enhance phagocytosis and antitumor activity by preventing CD47 from delivering its inhibitory signal as well as generating a moderate pro-phagocytic signal via IgG4 Fc. Importantly, unlike many CD47-blocking agents, TTI-622 does not bind to human red blood cells. Methods TTI-622-01 is an ongoing multicenter, Phase 1 study of the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary antitumor activity of TTI-622 in adult patients with relapsed/refractory (R/R) lymphoma (NCT03530683). Based on a modified 3+3 scheme, weekly doses are escalated through pre-planned dose levels ranging from 0.05 to 8 mg/kg. The observation period for dose limiting toxicity (DLT) is the initial 3 weeks of treatment. Safety monitoring includes weekly clinical laboratories and assessments of adverse events (AEs) based on CTCAE v 4.03. Blood samples are collected for PK analysis and assessment of receptor occupancy on normal peripheral T cells. Disease assessments are performed per Lugano criteria every 8 weeks within the first 6 months, every 3 months up to two years, and every 6 months thereafter until the end of treatment. Results As of the July 16, 2020 cutoff, 25 patients (12M/13F) with a median age of 68 years (range 24-86) have received dose levels of 0.05−8 mg/kg with testing at 8 mg/kg ongoing. Patients with the following histologies have been enrolled: diffuse large B-cell lymphoma (DLBCL; n=13), Hodgkin lymphoma (n=5), follicular lymphoma (FL; n=2), peripheral T-cell lymphoma (PTCL; n=2), cutaneous T-cell lymphoma with CD30 negative large cell transformation (CTCL-LCT, n=2), and mantle cell lymphoma (n=1). Disease stages at entry have been III or IV in 23 patients; patients had received a median of 3 (range 1-9) prior systemic therapies including CAR-T in 5 patients and HSCT in 6 patients. Treatment-related AEs have been reported in 12 (48%) patients. Most AEs have been grade 1 or 2. The most frequent treatment-related AEs include thrombocytopenia (n=4; 1 grade ≥3), neutropenia (n=3; 3 grade ≥3) and fatigue (n=3; 0 grade ≥3). Grade 4 thrombocytopenia occurred in 1 patient in the 8 mg/kg cohort and accounted for the only DLT and treatment-related serious AE reported to date. This event that occurred on Day 8 was not associated with bleeding and resolved within 1 day after prophylactic platelet transfusion. Mild to moderate platelet decreases seen in the majority of patients generally occurred on dosing days and recovered quickly to baseline levels. No other grade ≥3 thrombocytopenia have been observed in the 4 other DLT evaluable patients dosed with 8 mg/kg to date. Preliminary PK results suggest dose-dependent increases in exposure following both single and repeated TTI-622 infusions. PD results indicate that end-of-infusion CD47 receptor occupancy (RO) is above 60% at doses ≥2 mg/kg and that RO is more sustained with TTI-622 doses ≥1 mg/kg compared to lower doses. Objective responses have been achieved in 5 patients, including 1 complete response (CR) in DLBCL (0.8 mg/kg) and 4 partial responses (PR) in PTCL (2 mg/kg), DLBCL (4 mg/kg), CTCL-LCT and FL (8 mg/kg). Initial responses were achieved at the first disease assessment (week 8) in all 5 responders including initial PR in the patient who subsequently achieved CR at week 36 (See Figure 1). In the dose range of 0.8-8 mg/kg, objective responses occurred in 31% (5/16) of patients with ≥1 post-treatment response assessment (See Table 1). Two of 4 response evaluable patients in the ongoing 8 mg/kg cohort achieved a PR, and 2 other patients have been on treatment for Conclusions Results to date from this ongoing Phase 1 study in patients with R/R lymphomas indicate that weekly doses of TTI-622 up to 4 mg/kg are well tolerated with dose-dependent increases in exposure and RO. TTI-622 has shown activity in R/R lymphoma with objective responses across a broad dose range (0.8-8 mg/kg) and in multiple histologies. The study is currently evaluating the 8 mg/kg dose level. Disclosures Patel: Pharmacyclics: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; Janssen: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Kite: Consultancy; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy. Ramchandren:Seattle Genetics, Sandoz-Novartis, Pharmacyclics/Janssen, Bristol-Myers Squibb: Consultancy; Merck, Seattle Genetics, Janssen, Genentech: Research Funding. Lesokhin:Juno: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Janssen: Research Funding; GenMab: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties; Takeda: Consultancy, Honoraria. von Keudell:Pharmacyclics: Research Funding; Genentech: Research Funding; Bayer: Research Funding. Cheson:Symbio: Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Consultancy; Pharmacyclics: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; TG Therapeutics: Speakers Bureau; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Research Funding; Kite: Consultancy; Parexel: Consultancy. Zonder:Intellia, Amgen, Takeda, Janssen, Regeneron, Alnylam, Caelum, Oncopeptides: Consultancy; BMS, Celgene: Research Funding. Seymour:Seattle Genetics: Research Funding; Merck: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding. Catalano:Trillium Therapeutics Inc.: Current Employment. Lin:Trillium Therapeutics Inc.: Current Employment. Uger:Trillium Therapeutics Inc.: Current Employment. Petrova:Trillium Therapeutics Inc.: Current Employment. Roberge:Trillium Therapeutics Inc.: Current Employment. Shou:Trillium Therapeutics Inc.: Current Employment. Iyer:Target Oncology: Honoraria; Seattle Genetics, Inc.: Research Funding; Rhizen: Research Funding; CRISPR: Research Funding; Curio Biosciences: Honoraria; Trillium: Research Funding; Daiichi Sankyo: Consultancy; Legend Biotech: Consultancy; Spectrum: Research Funding; Merck: Research Funding; Afffimed: Research Funding.

Introduction The pathogenesis of classic Hodgkin's lymphoma (cHL) is largely unsettled. Previous studies have provided limited support to the possible association between tobacco smoking and outcome in cHL with inadequate evidence of a dose-outcome relationship. Smoking can result in a multitude of preventable malignancies, thus we studied the association between smoking, the initial stage of cHL and survival outcomes. Methods This single-center study included patients with a diagnosis of cHL who were first seen at The University of Texas MD Anderson Cancer Center between January 1,2016 and May 28, 2020 for either newly diagnosed cHL or relapsed/refractory (R/R) cHL. Patients' charts were reviewed to assess the history of active smoking, former smoking and the amount of smoking (measured as pack-year). Former smoking was defined as history of smoking prior to the diagnosis of cHL and no active smoking at the time of diagnosis. The primary aims were to assess overall survival (OS), progression-free survival (PFS) and frequency of advanced disease at the time of diagnosis. Descriptive statistics including mean, standard deviation, median, and range for continuous variables such as age, amount of smoking and lab measurements, and frequency counts and percentages for categorical variables such as race, gender, history of current/prior smoking and response were analyzed. Kaplan-Meier method was used for time-to-event analysis including PFS and OS. Median time to event in months with 95% confidence interval (CI) was calculated. The Log-rank test was used to evaluate the difference in time-to-event endpoints between patient groups. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used for statistical analyses. Results Between 2016 and 2020, 644 patients met the inclusion criteria. The median age at diagnosis was 33 years (range: 9-85 years) with 52% males. Advanced stage (stages III and IV) occurred in 45% of patients. Ninety-seven percent of patients had 0-1 Eastern Cooperative Oncology Group (ECOG) performance status. Histological subtype was predominately nodular sclerosis (83%). International Prognostic Index was =>4 in 13% of patients. Most of the patients received doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) based therapy (77%), brentuximab vedotin (BV) based therapy (13%)and checkpoint inhibitors (CPIs) based therapy (6%). Patient's demographics are outlined in Table.1. The percentage of active smoking was low at 6% (median age of active smokers: 33.5). History of prior smoking occurred in 21% of patients. The mean amount of smoking was 1.87 pack-year (rang :0. 05-54 pack-year). Active smoking was associated with advanced stage (9.5% vs. 4.9%, p-value: 0.033). PFS rate at 5 years was similar in smokers and non smokers (52% vs. 54%, p-value 0.9). OS rate at 10 years was better in never smokers when compared to former smokers (95% vs. 77%, p-value: 0.017). Univariable Cox proportional hazards model for OS showed a significant association between amount of smoking and OS with hazard ratio of 1.04 (95% CI: 1.005 1.07, p-value: 0.025). Conclusions We report the largest analysis of smoking status and impact on advanced stage and cHL clinical outcomes. Smoking history is associated with inferior 10 year OS (18% lower OS in patients with history of former smoking). Active smoking was associated with advanced stage however the frequency of active smoking in our patient database was low at 6% compared to previous reports of higher incidence of up to 20%. Patients should be counseled against smoking to avoid worse outcome associated with smoking in many clinical conditions including cHL. Disclosures Parmar: Cellenkos Inc.:Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.Iyer:Legend Biotech:Consultancy;CRISPR:Research Funding;Rhizen:Research Funding;Curio Biosciences:Honoraria;Target Oncology:Honoraria;Afffimed:Research Funding;Merck:Research Funding;Spectrum:Research Funding;Trillium:Research Funding;Daiichi Sankyo:Consultancy;Seattle Genetics, Inc.:Research Funding.Nieto:Astra Zeneca:Other: Grant Support;Secura Bio:Other: Grant Support;Affimed:Consultancy, Other: Grant Support;Novartis:Other: Grant Support.Chuang:Sage-Evidence=Based Medicine & Practice:Consultancy.Wang:Guidepoint Global:Consultancy;Dava Oncology:Honoraria;Loxo Oncology:Consultancy, Research Funding;Verastem:Research Funding;Beijing Medical Award Foundation:Honoraria;Targeted Oncology:Honoraria;OMI:Honoraria, Other: Travel, accommodation, expenses;AstraZeneca:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;OncLive:Honoraria;Molecular Templates:Research Funding;Celgene:Consultancy, Other: Travel, accommodation, expenses, Research Funding;Kite Pharma:Consultancy, Other: Travel, accommodation, expenses, Research Funding;Pulse Biosciences:Consultancy;MoreHealth:Consultancy;Janssen:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Pharmacyclics:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;BioInvent:Research Funding;Lu Daopei Medical Group:Honoraria;Juno:Consultancy, Research Funding;VelosBio:Research Funding;Acerta Pharma:Research Funding;InnoCare:Consultancy;Oncternal:Consultancy, Research Funding;Nobel Insights:Consultancy.Lee:Celgene:Research Funding;Seattle Genetics:Research Funding;Bristol-Myers Squibb:Consultancy, Research Funding;Aptitude Health:Speakers Bureau;Guidepoint Blogal:Consultancy;Takeda:Research Funding;Oncternal Therapeutics:Research Funding.

Introduction Classic Hodgkin's lymphoma (cHL) is a highly curable lymphoid malignancy. Most of the patients receive either bleomycin or brentuximab vedotin (BV) based therapies as a frontline treatment. Treatment alterations are common and can be related to toxicity, patient's preference, and/or clinical evidence of response. The aim of our study is to explore the frequency and characteristics of treatment alterations, especially bleomycin and BV, in frontline therapies used in newly diagnosed cHL. Methods This single center study included patients with a diagnosis of cHL who were first seen at The University of Texas MD Anderson Cancer Center between January 1,2016 and May 28, 2020 for either newly diagnosed cHL or relapsed/refractory (R/R) cHL. Patients' charts were reviewed to assess frequency of treatment discontinuation at the time of frontline therapy and underlying reasons for any treatment alterations. The primary aims were to assess the frequency of treatment alterations and its effects on overall survival (OS), and progression-free survival (PFS). Descriptive statistics including mean, standard deviation, median, and range for continuous variables such as age, and lab measurements, and frequency counts and percentages for categorical variables such as race, gender, and response were analyzed. The Kaplan-Meier method was used for time-to-event analysis including PFS and OS. Median time to event in months with 95% confidence interval (CI) was calculated. The Log-rank test was used to evaluate the difference in time-to-event endpoints between patient groups. Statistical software SAS 9.4 (SAS, Cary, NC) and S-Plus 8.2 (TIBCO Software Inc., Palo Alto, CA) were used for statistical analyses. Results In the studied period, 644 patients met the inclusion criteria. The median age at diagnosis was 33 years (range:9-85) with 52% males. Advanced stage (stages III and IV) occurred in 45% of patients. Ninety-seven percent of patients had 0-1 Eastern Cooperative Oncology Group (ECOG) performance status. Histological subtype was predominately nodular sclerosis (83%). International prognostic index at the time of diagnosis was ≥4 in 13% of patients. Most of the patients received doxorubicin, bleomycin, vinblastine and dacarbazine (ABVD) based therapy (77%). Other therapies included brentuximab vedotin (BV)(13%) and checkpoint inhibitors (CPIs) (6%, as a part of clinical trial). Patient's demographics are outlined in Table.1. Treatment alteration, which included either addition or omission of drug/s, occurred in 26% of patients. The most common discontinued drugs were bleomycin (79%), and BV (15%). Of the patients who were started on ABVD based therapy, the frequency of bleomycin discontinuation was 26% (116 of 455 patients). The most common reasons for bleomycin discontinuation were: treatment response as per the RATHL study (49%), pulmonary toxicity (27%) and other treatment-related toxicity (9%). Of the patients who were started on frontline BV based therapy, the frequency of BV discontinuation was 26% (20 of 78 patients). The most common reasons for BV discontinuation were: peripheral neuropathy (65%), skin rash (10%) and other treatment-related toxicity (25%). Patients who discontinued bleomycin due to adverse events (AEs) had a higher chance of primary refractory disease at the end of frontline treatment (19% vs. 15%, p-value: 0.005) while patients who discontinued bleomycin due to treatment response had similar rates of primary refractory disease (13% vs. 15%, p-value: 0.57). The median cycles number of bleomycin based therapy were the same (6 cycles) among all the groups (those who continued bleomycin without AEs or discontinuation, patients who discontinued bleomycin for treatment response and patients who discontinued bleomycin for AEs) . Patients who discontinued BV due to AEs had similar outcome to the patients who continued the treatment without alterations. Conclusions Frontline treatment alterations in cHL are common. Positron emission tomography treatment response based bleomycin discontinuation was not associated with worse PFS or OS. However bleomycin discontinuation secondary to AEs was associated with a statistically significant higher rate of primary refractory disease and subsequent worse PFS and OS. BV discontinuation secondary to AEs didn't result in worse outcomes. Disclosures Parmar: Cellenkos Inc.:Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.Iyer:CRISPR:Research Funding;Spectrum:Research Funding;Merck:Research Funding;Afffimed:Research Funding;Rhizen:Research Funding;Seattle Genetics, Inc.:Research Funding;Legend Biotech:Consultancy;Daiichi Sankyo:Consultancy;Trillium:Research Funding;Curio Biosciences:Honoraria;Target Oncology:Honoraria.Nieto:Affimed:Consultancy, Other: Grant Support;Novartis:Other: Grant Support;Secura Bio:Other: Grant Support;Astra Zeneca:Other: Grant Support.Chuang:Sage-Evidence=Based Medicine & Practice:Consultancy.Wang:Lu Daopei Medical Group:Honoraria;Pulse Biosciences:Consultancy;Molecular Templates:Research Funding;BioInvent:Research Funding;VelosBio:Research Funding;Beijing Medical Award Foundation:Honoraria;Juno:Consultancy, Research Funding;Oncternal:Consultancy, Research Funding;AstraZeneca:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Celgene:Consultancy, Other: Travel, accommodation, expenses, Research Funding;InnoCare:Consultancy;Loxo Oncology:Consultancy, Research Funding;Verastem:Research Funding;Acerta Pharma:Research Funding;Pharmacyclics:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;Janssen:Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding;MoreHealth:Consultancy;OncLive:Honoraria;Kite Pharma:Consultancy, Other: Travel, accommodation, expenses, Research Funding;Nobel Insights:Consultancy;Guidepoint Global:Consultancy;Dava Oncology:Honoraria;OMI:Honoraria, Other: Travel, accommodation, expenses;Targeted Oncology:Honoraria.Lee:Celgene:Research Funding;Guidepoint Blogal:Consultancy;Bristol-Myers Squibb:Consultancy, Research Funding;Aptitude Health:Speakers Bureau;Oncternal Therapeutics:Research Funding;Seattle Genetics:Research Funding;Takeda:Research Funding.

Background Population-based screening for the common non-communicable diseases (NCD) is recommended but is difficult to implement in the hard-to-reach areas of low resourced countries. The objective of our pilot study was to evaluate the feasibility and the efficacy of delivering NCD screening services at home by trained community health workers (CHWs). Men and women aged 30-60 years residing in rural areas of India were targeted for screening. Methods The CHWs made home visits to educate the participants about healthy lifestyles and symptoms of common cancers and counsel the tobacco/alcohol users to quit. They measured height, weight, blood pressure (BP) and random blood sugar for all and performed oral visual examination (OVE) to screen the tobacco/alcohol users for oral cancer. For cervical cancer screening, the women themselves provided self-collected vaginal samples that the CHWs delivered to the laboratory for high-risk Human Papillomavirus (HPV) detection. The women were not screened for breast cancer but were made aware of the common symptoms and the importance of early diagnosis. Further assessment of the screen-positive individuals and the women with breast symptoms was arranged at the nearest primary health center (PHC). Results The CHWs screened 1998 men and 4997 women from 20 villages within 6 months; the refusal rate was less than 10%. High BP and sugar were detected in 32.6% and 7.5% participants respectively; hypertension and diabetes were confirmed in 42.3% and 35% respectively among those undergoing follow-up. Obesity prevalence was only 2.4%. More than 50% men were tobacco chewers. Of the total participants, 2.6% were positive on OVE, though no oral cancer was detected among them. HPV test was positive in 8.6% women and they were triaged with visual inspection after application of acetic acid (VIA) test for treatment either by thermal ablation (same visit) or by loop excision. VIA was positive in 14% of the HPV-positive women and 56.5% of them received same day ablative treatment. The VIA-negative women were advised follow up after 1 year. No breast cancer was detected among the 0.6% women complaining of breast symptoms. Conclusions Delivery of NCD screening services at home by trained CHWs is feasible and well-accepted by our study population.

The biology of acute myelogenous leukemia (AML) is characterized by a block in differentiation, increase in proliferation and inhibition of apoptosis, all of which when combined lead to an expansion of leukemic blasts.1 AML therapy cures ~20% of those affected,2 highlighting the need for a better understanding of leukemia biology in order to identify novel therapeutic targets. The Wilms’ tumor 1 (WT1) gene has an oncogenic role in leukemogenesis and its overexpression correlates with a poor prognosis.3 WTAP is a highly conserved protein that partners with WT14,5 to function as a switch gene, regulating the balance between quiescence and proliferation.6 WTAP-null mice exhibit embryonic lethality.7 WTAP has been recently described as an oncogenic factor in gliomas.8 We hypothesized that alterations in WTAP, whose role in leukemogenesis is unknown, might provide an alternate means of modulating the WT1 pathway in AML. We performed a series of experiments to test this possibility. First, we examined WTAP expression in several primary AML samples observing increased levels of WTAP in AML compared with normal peripheral blood mononuclear cells (Figure 1a) as well as in AML cell lines (data not shown). Next, the WTAP expression levels were determined in 511 newly diagnosed AML patients using the reverse-phase protein array (RPPA) technique. In comparison with normal bone marrow CD34+ cells, WTAP expression in bulk AML cells was above normal levels in 32% of patients (Figure 1b). Although WTAP levels were not associated with individual cytogenetic abnormalities, some specific molecular mutations such as NPM1 and FLT3-ITD were found to have significant correlation (P ≤ 0.05) with WTAP expression (Supplementary Figure 1A). In addition, RPPA analysis showed that WTAP levels were positively correlated (R > |0.2|) with levels of various cell proliferation-related proteins (cyclins and Hsp90), antiapoptotic proteins (Bcl-2 and Bax), oncoproteins (FLI1) and proteins important for stem cell functions such as Myc and Ash2L (Supplementary Figure 1B). To assess the functional significance of increased WTAP expression, its expression was silenced in K562 and HL-60 cells, leading to a significant reduction (P ≤ 0.05) in proliferation (Figure 1c), and clonogenic survival (P ≤ 0.01) (Figure 1d). Similar effects on proliferation were observed in the AML cell line OCI-AML3 and in primary AML cells (Supplementary Figure 1C), suggesting a pro-proliferative role for WTAP in AML. WTAP knockdown alone did not induce apoptosis but markedly increased (P ≤ 0.01) the extent of apoptosis following etoposide treatment (Figure 1e). These results provide evidence for an association between the increased expression of WTAP and chemoresistance in AML. Figure 1 Expression of WTAP in AML and effect of WTAP silencing on AML cell behavior. (a) Peripheral blood mononuclear cells from normal donors (NL) and AML patients (AML) were obtained by Ficoll–Paque density centrifugation, and protein extracts were ... To examine the role of WTAP in AML progression in vivo, we performed tumor xenograft experiments in nude mice. As shown in Figure 1f, the growth rates and masses of tumors derived from WTAP-knockdown cells were significantly reduced (P ≤ 0.01) compared with control. To complement this analysis, the in vitro transforming activity of WTAP was examined by investigating its effects on growth of the Ba/F3 cell line. This line depends on interleukin 3 (IL-3) for survival and proliferation, but this dependence can be released by the transgenic expression of suitable oncogenes.9 Whereas control Ba/F3 cells were not viable in the absence of IL-3 at 72 h, WTAP-expressing Ba/F3 cells were able to maintain growth factor-independent proliferation, as demonstrated by significantly higher (P ≤ 0.01) number of viable cells (Figure 1g), suggesting that WTAP harbors oncogenic activity. The aberrant cellular proliferation and terminal differentiation block of myeloid cells are two hallmarks of AML.10 Having shown that WTAP regulates growth and survival, we investigated whether WTAP has a role in myeloid cell differentiation. As shown in Figure 1h, knockdown of WTAP promoted phorbol 12-myristate 13-acetate (PMA)-induced myeloid differentiation, as revealed by an increase in the expression of myeloid differentiation markers CD11b and CD14 compared with control cells. These results suggest that increased expression of WTAP in AML not only supports cell proliferation but also induces the differentiation block. Our RPPA analysis suggested a link between WTAP and mammalian target of rapamycin (mTOR) expression; and given that the mTOR pathway is deregulated in a number of cancers including AML,11 we hypothesized a putative regulatory role of WTAP on mTOR activity in AML. As shown in Figure 1i, WTAP knockdown induced a decrease in the phosphorylation levels of mTOR and its downstream effector p70 ribosomal subunit 6 kinase (pS6K) compared with control shRNA. To further understand the participation of WTAP in leukemogenesis, we performed transcriptomic analysis with RNA-Seq on WTAP knockdown in K562 cells. Gene ontology analysis indicated that cell adhesion and regulation of cell proliferation are the most enriched functionalities (Supplementary Figure 1D and Supplementary Table 2). Among the most relevant genes affected by WTAP with recognized roles in leukemia are CD4, CD44, CEBPA, CSF1R, MPO, ABCG2, TCL1A, CYP1A1, CYP3A4, FGFR1, PTPRC (CD45), CD83, CD86, CD9 and CCR4. Consistent with its described role in RNA processing, we determined that WTAP knockdown affected exon usage of 93 genes, including important factors such as MLL and MSI2. Interestingly, we also observed that WTAP affects the processing of its own transcript, very likely via polyA site selection. Complete analysis can be accessed in GEO ({"type":"entrez-geo","attrs":{"text":"GSE46718","term_id":"46718"}}GSE46718—http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=jbkjjswaqscegjsa Fisher’s exact test) in their mRNA levels as determined by RNA-Seq. Mutations of WTAP were not observed in the TCGA analysis of AML.12 Therefore, the etiology of increased WTAP expression in AML remains unexplained. We next sought to determine the potential mechanism that may contribute to an increase in WTAP expression in AML. The molecular chaperone Hsp90 maintains the stability of many tumor-promoting oncoproteins,13 including WT1.14 Keeping in mind the connection between WT1 and WTAP, we investigated the potential interaction between Hsp90 and WTAP. First, we determined that WTAP co-immunoprecipitates with Hsp90 (Figure 2a), whereas treatment with the Hsp90 inhibitor ganetespib significantly reduced the binding of Hsp90 to WTAP. Therefore, formation of the WTAP–Hsp90 complex is dependent on the chaperoning activity of Hsp90. Studies have shown that Hsp90 client proteins shift the primary chaperone association from Hsp90 to Hsp70 following inhibition of Hsp90 activity.15 Accordingly, our results showed that ganetespib treatment increased WTAP association with Hsp70 (Figure 2a). Furthermore, the GST pull-down assay showed a direct interaction between WTAP and Hsp90 (Figure 2b). To understand the functional significance of the association of Hsp90 with WTAP, we investigated the effects of Hsp90 inhibitors on WTAP protein stability. Ganetespib treatment promoted the degradation of WTAP in K562 (CML), MV4-11 (AML) and Kasumi-1 (AML) cell lines, previously shown to be highly sensitive to ganetespib (Figure 2c).16 Marked reduction in WTAP expression was similarly observed in blasts exposed to ganetespib (Figure 2d). Furthermore, ganetespib inhibited AML tumor growth in nude mice, as we reported previously,14 and WTAP expression in xenograft tumors (Figure 2e). Inhibition of Hsp90 induces polyubiquitination and proteasomal degradation of Hsp90 client proteins.17 We confirmed that pretreatment with proteasomal inhibitor bortezomib largely prevented ganetespib-induced degradation of WTAP (Figure 2f), and higher levels of ubiquitinated WTAP were observed in the presence of the combination of bortezomib and ganetespib compared with either agent alone (Figure 2g). Together, these data show that ganetespib-mediated degradation of WTAP is dependent on the ubiquitin-proteasome pathway, very similar to other bonafide Hsp90 client proteins. Figure 2 Hsp90 associates with WTAP and is necessary for its stability. (a) The K562 cells were treated with vehicle (−) or Hsp90 inhibitor, ganetespib (1 µm for 6 h) followed by immunoprecipitation (IP) with IgG and WTAP antibody. The immunoprecipitates ... In summary, our study shows that WTAP has an important role in abnormal proliferation and arrested differentiation of leukemia cells, and WTAP is a novel client protein of Hsp90. Therefore, WTAP may be a promising novel therapeutic target in AML. Further investigation aimed to elucidate the mechanism of action of WTAP is warranted.

Background: Aplastic anemia is an autoimmune disease of the bone marrow (BM) characterized by defective and decreased regulatory T cells (Tregs) which results in unchecked cytotoxic T cell mediated bone marrow suppression [1]. In a xenogeneic model of induce BM aplasia, adoptive therapy with cord blood (CB) Tregs reverses such a defect (Fig 1A). Furthermore, as compared to peripheral blood (PB), CB Tregs show a higher expression of Helios, a marker of thymic derived Tregs (Fig 1B) and CB Tregs exert a superior suppression of proliferating conventional T-cells in CFSE assay (Fig 1C). In a xenogeneic mouse model of GVHD, CB Tregs can exert suppression across HLA barrier resulting in survival benefit (Fig 1D); and in another xenogenic lupus model, a single dose of CB Tregs results in significant decrease in circulating effector T cells (Fig 1E) up to 8 weeks. Furthermore, under stressful conditions of continued culture in the presence of inflammatory cytokines including IL15 and IL23, CB Tregs do not secrete IL-17 or express RORγt, a concern of plasticity that plagues PB Tregs (Fig 1F). In fact, CB Tregs increase their secretion of the suppressor cytokine, IL-10 in response to inflammatory stress, which supports our hypothesis, that CB Tregs based adoptive therapy can have wide application and can be used to treat inflammatory disorders. Therefore, we hypothesized that adoptive therapy with CB Tregs can be utilized as treatment for the inflammatory bone marrow failure (BMF) disorders including aplastic anemia, hypoplastic myelodysplasia and primary myelofibrosis. Study Design and Methods: We have now launched a phase I clinical trial examining the role of single infusion of CK0801, an allogeneic, fresh CB Treg product, utilizing novel process development that consist of well-defined qualification criteria for the starting material (cord blood units), parameters for manufacturing and culture-expansion; and well-defined analytic testing and lot release criteria, for the treatment of BMF, where 3 doses are examined: i) dose level I: 1x106 cells/kg; ii) dose level II: 3x106 cells/kg and iii) dose level III: 10x106 cells/kg (NCT03773393). The study follows 3+3 phase I design where 3 patients will be treated at dose level I. If no DLT is observed, then the dose will be escalated to dose level II and if no DLT is observed, then the dose will be escalated to dose level III. If 1 DLT is observed at a dose level, then 3 additional patients will be treated at that level. If no additional DLTs, then that dose level will be defined as MTD. If ≥2DLTs are observed at dose level II or III, then prior dose level is defined as MTD. If ≥2DLTs at dose level I, then DSMB will review and evaluate for study continuation. MTD will be decided when 6 patients are treated at a dose level with < 2 DLTs. The eligibility criteria include: i) diagnosis of aplastic anemia, myelodysplastic syndrome or myelofibrosis, ii) Age > 18 years, iii) cord blood unit matched at HLA 3 out of 6 with the patient for generation of CK0801. The primary endpoint includes dose limiting toxicity (DLT) as defined by i) severe (grade 3 or 4) infusion toxicity within 24 hours; ii) regimen related death within 30 days or iii) severe (grade 3 or 4) cytokine release syndrome within 30 days. The secondary endpoints include i) disease-specific response including complete remission, transfusion independence and hematologic improvement and ii) duration of response. The exploratory endpoints include assessment of PB and BM immune reconstitution and inflammatory cytokines at baseline and scheduled follow ups of Days 0, +1, +3, +7, +14, +21, +30, +60, +90, +180 and +365 in the post-treatment setting. These studies will include T cell compartment analysis: Treg, Effector T cells, T-cell anti-viral activity. Serum will be analyzed for inflammatory cytokines: IL1, IL2, IL4, IL6, IL7, IL8, IL10, IL17, IFN-gamma, ST2, REG3a, OPN, Follistatin, Elafin, TGF-beta. Optional exploratory cytokines: SCF, G-CSF, GM-CSF, HGF, VEGF, SDF1a, MCP1, MCP2, TARC, MIP3a, TECK, CTACK, CCL28, FGF, PDGF, EGF, TGF-α, TLR. The first patient is already consented with a planned total of 9 patients. References: 1. Kordasti S, Costantini B, Seidl T, et al., Deep phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment. 2016 Sep 1;128(9):1193-205 Figure 1 Disclosures Kadia: AbbVie: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. DiNardo:abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; jazz: Honoraria; medimmune: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Iyer:Rhizen: Research Funding; Seattle Genetics: Research Funding; Trillium Therapeutics: Research Funding; Merck: Research Funding; Spectrum: Research Funding. Hari:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria. Jabbour:BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Borthakur:Novartis: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Agensys: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; BMS: Research Funding; AstraZeneca: Research Funding; Bayer Healthcare AG: Research Funding; Eisai: Research Funding; Strategia Therapeutics: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Argenx: Membership on an entity's Board of Directors or advisory committees; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tetralogic Pharmaceuticals: Research Funding; PTC Therapeutics: Consultancy; Oncoceutics, Inc.: Research Funding; Eli Lilly and Co.: Research Funding; GSK: Research Funding; NKarta: Consultancy; Cantargia AB: Research Funding; Cyclacel: Research Funding. Verstovsek:Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Pharma Essentia: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy.

Background High risk smoldering multiple myeloma (HRSMM), defined as having immunoparesis and at least 95% abnormal plasma cells/all plasma cells by advanced flow cytometry, has a risk of progression to multiple myeloma of about 75% after 5 years of diagnosis. These patient have no symptoms and current standard is to follow them without treatment. Isatuximab is an IgG1 monoclonal antibody that binds to CD38 highly expressed in myeloma cells. Isatuximab has activity as monotherapy (overall response rate (ORR) 35%), with lenalidomide/dexamethasone (ORR 56%) and pomalidomide/dexamethasone (ORR 62%) in relapsed MM. We designed a phase II study to test the efficacy of isatuximab in high risk smoldering myeloma. Our study is registered in clinicaltrials.gov as NCT02960555. Methods The primary endpoint of the study is the ORR of isatuximab 20 mg/kg IV days 1, 8, 15, 22 cycle 1; days 1, 15 cycles 2-6 and day 1 cycles 7-30 in high risk smoldering myeloma. 24 patients were accrued in the first stage (of maximum 61 patients). Secondary endpoints are PFS, OS, clinical benefit rate (CBR). Exploratory endpoints are quality of life analysis (QoL), MRD, molecular/immune characterization using DNA/RNA sequencing of myeloma cells and the microenvironment before and after treatment. Results 24 patients with HRSMM were accrued from 02/08/2017 until 12/21/2018 (Table 1). All patients are evaluable for response. Best responses: ORR (≥PR) 15(62.5%), CR MRD- flow at 10-5 1 (5%), VGPR 4 (17%), PR 10 (42%), minor response (MR) 4 (18%), stable disease 5 (21%); CBR (≥MR) 79%. Median number of cycles received were 11.5 (range 6-30). Five patients have stopped treatment (one has completed the study, one with heavy history of smoking was diagnosed with squamous cell cancer of the tongue, one could no longer travel to treatments due to relocation, two progressed to active multiple myeloma after 16 and 6 cycles of treatment, respectively). There have been no deaths. DNA/RNA seq is ongoing for biomarkers of response. There were 5 grade 3 severe treatment-related adverse events (RAE) which resolved to baseline: dyspnea -related to infusion reaction (n=2), headache (n=1), ANC decrease (n=1), urinary tract infection (n=1). Most common grade 1-2 related adverse events (n): nausea (7), vomit (5), WBC decrease (3), diarrhea (3), fatigue (6), headache (4), mucositis (4), myalgia (4) and infusion reaction (3). In patients with available QoL functional scores (n=9 at baseline and n=7 after 6 months of therapy), isatuximab was effective in reducing their anxiety and worry of progression to multiple myeloma. Isatuximab also improved general QoL scores by the end of cycle 6 of treatment which were now comparable to those in the general population (Figure 1). Conclusion Isatuximab is very well tolerated, results in high response rates in HRSMM and has the potential to change the natural history of this disease. In ongoing QoL analysis, initial data shows improvement in QoL and decreased cancer worry after isatuximab treatment. Immune-genomic analysis is ongoing and may identify patients that benefit the most from treatment. Disclosures Manasanch: celgene: Honoraria; merck: Research Funding; quest diagnostics: Research Funding; sanofi: Research Funding; BMS: Honoraria; Sanofi: Honoraria. Jagannath:Multiple Myeloma Research Foundation: Speakers Bureau; BMS: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Medicom: Speakers Bureau; Merck: Consultancy. Lee:Daiichi Sankyo: Research Funding; Celgene: Consultancy, Research Funding; GlaxoSmithKline plc: Research Funding; Sanofi: Consultancy; Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Patel:Poseida Therapeutics, Cellectis, Abbvie: Research Funding; Oncopeptides, Nektar, Precision Biosciences, BMS: Consultancy; Takeda, Celgene, Janssen: Consultancy, Research Funding. Kaufman:Janssen: Other: travel/lodging, Research Funding. Thomas:Xencor: Research Funding; BMS: Research Funding; Celgene: Research Funding; Amgen: Research Funding. Mailankody:Takeda Oncology: Research Funding; Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; CME activity by Physician Education Resource: Honoraria. Lendvai:Janssen: Employment. Neelapu:Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Incyte: Consultancy; Merck: Consultancy, Research Funding; Allogene: Consultancy; Cellectis: Research Funding; Poseida: Research Funding; Karus: Research Funding; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Precision Biosciences: Consultancy; Cell Medica: Consultancy. Orlowski:Poseida Therapeutics, Inc.: Research Funding. Landgren:Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Merck: Other: IDMC. OffLabel Disclosure: Isatuximab for the treatment of smoldering myeloma

Background: There is a large unmet need for relapsed/refractory T cell lymphoma. For patients (pts) with recurrent disease, the efficacy of salvage and autologous stem cell transplant (if feasible) is moderate and the 3-year overall survival is less than 30%. Romidepsin is a histone deacetylase inhibitor (HDACi) that is FDA approved for the treatment of relapsed or refractory peripheral T-cell lymphoma (PTCL) and cutaneous T-cell lymphoma. Immune checkpoint blockade (CPB) of PD1/PDL-1 has been successful in many malignancies. In a recent report, PDL1 expression was observed 5-17% of tumor cells and 43%-57% in stromal histiocytes in PTCL-NOS or AITL. A phase II single agent study of the PD1 monoclonal antibody (mAB) pembrolizumab in PTCL demonstrated modest responses (Barta et.al). In addition, PTCL often carries multiple gene mutations in epigenetic modifier genes (TET2, IDH2, DNMT3A) and others (RHOA, FYN) that may impair immunogenicity and promote immune escape. This was the rationale for combining HDACi and CPB. We report this single center, single arm, nonrandomized trial of pembrolizumab in combination with romidepsin in subjects with relapsed or refractory PTCL that have failed to achieve a complete response or progressed after at least one systemic treatment regimen (NCT03278782). METHODS: This is a phase I/II study to examine the safety and efficacy of pembrolizumab 200 mg fixed dose administered every 3 weeks (Q3W) in combination with romidepsin. The safety of the combination was tested in the lead-in phase I study with a strategy of dose de-escalation, keeping the starting dose of romidepsin 14 mg/m2 on days 1 and 8. This eventually became the dosing for the phase II study. Adverse events were monitored throughout the trial and graded in severity according to the guidelines outlined in the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary objectives of the trial are to determine safety, tolerability, and overall response rate (ORR) of the combination. Secondary objectives include further analysis of various efficacy parameters [complete remission rate (CRR), progression free survival (PFS), overall survival(OS) and duration of response (DOR)]. Response assessment was performed utilizing Lugano Revised Response Criteria, and PD-L1 expression assessed by immunohistochemistry and exploratory analysis of targeted Next Generation Sequencing in the primary lymphoma tissue. Changes in peripheral blood T-cell repertoire were assessed primarily by flow cytometry. RESULTS: 15 pts were evaluable for the primary endpoint (demographics in figure 1). The phase I part was expanded from 3 to 6 pts, because of a dose limiting toxicity (DLT) of hypotension and renal insufficiency which resolved. The phase II is ongoing with 9 pts enrolled. The overall response rate was 44%; 3 pts. achieved a complete response and 2 achieved PR. The median follow-up was 6 months (3 weeks- 12 months). The 3 complete responders remain in remission > 10 months. One patient with refractory ALCL who achieved CR after 3 cycles is now 6 months post Haplo-identical transplant. Nausea and vomiting was the most common adverse event (Grade 1/2-). The most common ≥ grade 3 treatment-emergent adverse events were Nausea/vomiting and fatigue ( n =1 and n= 2). Two patients experienced hyperprogression within the first 10 days after the treatment. Correlative studies including NGS, expression of PD-L1, CD4+ T lymphocytes counts are in progress. CONCLUSIONS: The combination of Romidepsin and Pembrolizumab has demonstrated acceptable safety and early encouraging results. Table. Disclosures Iyer: Spectrum: Research Funding; Seattle Genetics: Research Funding; Merck: Research Funding; Trillium Therapeutics: Research Funding; Rhizen: Research Funding. Neelapu:BMS: Research Funding; Allogene: Consultancy; Acerta: Research Funding; Incyte: Consultancy; Cell Medica: Consultancy; Pfizer: Consultancy; Unum Therapeutics: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Merck: Consultancy, Research Funding; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Karus: Research Funding; Cellectis: Research Funding; Poseida: Research Funding. Nieto:Affimed: Research Funding; Novartis: Research Funding; Astra-Zeneca: Research Funding; Affimed: Consultancy. Westin:Genentech: Other: Advisory Board, Research Funding; Novartis: Other: Advisory Board, Research Funding; MorphoSys: Other: Advisory Board; Juno: Other: Advisory Board; Janssen: Other: Advisory Board, Research Funding; Celgene: Other: Advisory Board, Research Funding; Unum: Research Funding; 47 Inc: Research Funding; Kite: Other: Advisory Board, Research Funding; Curis: Other: Advisory Board, Research Funding. Parmar:Cellenkos Inc.: Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Research Funding. Fowler:TG Therapeutics: 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; Roche: 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. Nastoupil:Bayer: Honoraria; Gilead: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genentech, Inc.: Honoraria, Research Funding; Spectrum: Honoraria; Novartis: Honoraria; TG Therapeutics: Honoraria, Research Funding. Duvic:Janssen Pharmaceuticals (div of Johnson & Johnson): Speakers Bureau; PleXus Communications: Speakers Bureau; Therakos: Speakers Bureau; Eisai: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Jonathan Wood & Assoc.: Speakers Bureau; Mallinckrodt Pharmaceuticals (formeraly Therakos, Inc): Research Funding; Soligenetics: Research Funding; Evidera, Inc.: Consultancy; Guidepoint Global: Consultancy; Cell Medica Inc.: Consultancy; UT MD Anderson Cancer Center: Employment; Shape: Research Funding; USCLC Registry: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Secretary/treasurer of Item h; Hawaiian Dermatology Society: Speakers Bureau; Hemedicus: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Spatz Foundation: Research Funding; Oncoceuticals: Research Funding; Millennium (formerly Takeda): Research Funding; Allos: Research Funding; Rhizen Pharma: Research Funding; Cutaneous Lymphoma Foundation: Membership on an entity's Board of Directors or advisory committees; Cell Medica Ltd.: Honoraria; Forty Seven Inc: Membership on an entity's Board of Directors or advisory committees; Tetralogic: Research Funding. Huen:Galderma Inc: Research Funding; Glaxo Smith Kline Inc: Research Funding; Rhizen Pharmaceuticals: Research Funding; Innate Pharmaceuticals: Research Funding. OffLabel Disclosure: Pembrolizumab in T cell lymphoma

Introduction Tenalisib (RP6530) is a next generation, oral, selective, PI3Kδ/g inhibitor with nanomolar inhibitory potency. Besides its apoptotic and anti-proliferative activity, Tenalisib modulates the tumor microenvironment resulting in reprogramming of tumor associated-macrophages (TAMs) from a protumor M2 phenotype to an antitumor M1 phenotype and a marked reduction of angiogenesis in pre-clinical models. Tenalisib has demonstrated activity in patients with relapsed/refractory lymphoid malignancies (Carmelo, ASH 2016 and Oki, ASCO 2018). Since there are concerns over long-term safety of PI3K δ or PI3K dual δ/g inhibitors with respect to immune-mediated toxicities (e.g. transaminitis, colitis and pneumonitis), cytopenias, and infections, a pooled safety analysis across two Phase I studies in patients treated with Tenalisib was performed. Methods Safety data was pooled from two Phase I Tenalisib monotherapy trials (NCT02017613 and NCT02567656) with similar key eligibility criteria. Patients had R/R lymphoid malignancies with ≥1 prior therapy. Responses were evaluated in lymphoid malignancies using IWG criteria (Cheson et al., 2007) and in CTCL using the modified Severity Weighted Assessment Tool (mSWAT). Adverse events were graded according to CTCAE v4.03. Results A total of 93 patients were included in the analysis. Among these patients, 34% were PTCL, 32% CTCL, 16% HL, 6% DLBCL and 12% were other lymphomas. Patients received a median of 5 prior therapies. 53 % of patients received Tenalisib for ≤ 3 months, 21% for 3-6 months and 26% for > 6 months. The overall incidence of related AEs and ≥G3 AEs were 58% and 29% respectively (Table 1). Very few AEs were seen with exposures >6 months and mainly included single cases of diarrhea, anemia, edema, and abdominal pain. There were no incidences of late onset toxicities such as colitis and pneumonitis and most of the AEs happened during the initial three months of therapy. No treatment discontinuations due to AE's were seen in patients exposed to > 6 months of treatment. Efficacy response assessments of the 66 evaluable patients demonstrated an ORR of 45% in TCL (44% in PTCL (8/18, 3 CR, 4 PR) & 45% in CTCL (9/20, 9 PR)), 29% (4/14; 1CR; 3PR) in HL, and 13% (1/6; 1CR) in DLBCL. Conclusion In this pooled safety analysis with long term follow-up, Tenalisib exhibited an improved safety profile when compared to other investigational/marketed PI3K inhibitors. The incidence of transaminitis was low and occurred within the first two to three cycles of therapy. In particular, there were no occurrences of pneumonitis or colitis in patients that had been on treatment for > 3 months and beyond. Incidence of neutropenia/thrombocytopenia and infections was limited. Tenalisib can therefore be safely combined with a diverse array of other agents active in lymphoid malignancies. Tenalisib is currently being studied in combination with Pembrolizumab and Romidepsin and as a monotherapy in a Phase II trial in indolent NHL. Disclosures Haverkos: Viracta Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ramchandren:Pharmacyclics LLC an AbbVie Company: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding. Devata:Affimed: Research Funding. Routhu:Rhizen Pharmaceuticals SA: Employment. Barde:Rhizen Pharmaceuticals SA: Employment. Nair:Rhizen Pharmaceuticals SA: Employment. Carlo-Stella:Boehringher Ingelheim Italia: Consultancy; Sanofi: Consultancy; MSD Italia: Speakers Bureau; Rhizen Pharmaceuticals: Research Funding; AstraZeneca: Speakers Bureau; ADC Therapeutics: Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Genenta Science: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Amgen: Speakers Bureau.