TPS7091 Background: Bispecific CD20 x CD3 TCEs are changing the treatment landscape for pts with r/r non-Hodgkin lymphomas (NHL); however, they are associated with immune-related toxicities, namely cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which limit their use. AZD5492 is a first-in-class, humanized, asymmetric, subcutaneously-administered, trispecific monoclonal IgG1 antibody that harbors two Fab binding domains to CD20, one VHH binding domain to T-cell receptor and one VHH binding domain to a CD8 co-receptor. Preclinical data have shown that AZD5492 drives B-cell killing through preferential engagement of CD8+ T cells, with reduced CD4+ T-cell activation and associated cytokine production. Thus, AZD5492 may have a wider therapeutic index and safety advantage compared with first generation CD20 x CD3 TCEs which equally engage and activate CD4+ and CD8+ T cells. In an in vivo NHL model, AZD5492 showed potent antitumor activity with reduced cytokine release compared with a CD20 x CD3 comparator. TITANium is a global Phase 1/2 multicenter dose escalation (Part A) and expansion (Part B) study (NCT06542250) of AZD5492 in pts with r/r B-cell malignancies. Methods: We present the study design of Part A. Eligible pts are aged ≥18 years with histologically documented CD20+ mature B-cell neoplasm, specifically large B-cell lymphoma (LBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), chronic lymphocytic leukemia (CLL), and small lymphocytic lymphoma (SLL), with ≥1 measurable lesion (except for CLL) and r/r disease after ≥2 prior lines of therapy. Pts with history of Grade ≥3 CRS or ICANS, post-transplant lymphoproliferative disease, Ritcher’s transformation, Burkitt’s lymphoma or Burkitt-like lymphoma are excluded. Part A will consist of two independent dose escalation groups: Part A1 will enroll pts with MCL or CLL/SLL; Part A2 will enroll pts with LBCL or FL. Dose escalation will start with pts receiving AZD5492 subcutaneously at a fixed dose per dose-level. An immune-related toxicity during Part A will trigger a double step-up strategy. Thereafter, treatment will continue for a limited duration. Each part will continue dose escalation independently, using fixed or step-up dosing. Part A will initially follow an accelerated titration design and will switch to a modified toxicity probability interval-2 design when triggered by emerging data. The primary objective is to assess safety and tolerability of AZD5492. Key secondary objectives are to evaluate preliminary efficacy, pharmacokinetics and immunogenicity of AZD5492. Enrollment began in September 2024 and is currently ongoing. Clinical trial information: NCT06542250 .

Relapse following CD19-directed chimeric antigen receptor T-cells (CAR-T) for relapsed/refractory large B-cell lymphoma (r/r LBCL) is commonly ascribed to antigen loss or CAR-T exhaustion. Multi-antigen targeting and PD-1 blockade are rational approaches to prevent relapse. Here, we test CD19/22 dual-targeting CAR-T (AUTO3) plus pembrolizumab in r/r LBCL as inpatient or outpatient therapy (NCT03289455, https://clinicaltrials.gov/ct2/show/NCT03289455). Endpoints include toxicity (primary) and response rates (secondary). AUTO3 was manufactured for 62 patients using autologous leukapheresis, modified with a bicistronic transgene. 52 patients received AUTO3 (7/52,50x106; 45/52,150-450x106) and 48/52 received pembrolizumab. Median age was 59 years (range,27-83) and 46/52 had stage III/IV disease. Median follow-up was 21.6 months (range,15.1-51.3) at last data cut (Feb 28, 2022). AUTO3 was safe: grade 1-2 and grade 3 CRS affected 18/52 (34.6%) and 1/52 (1.9%) patients, neurotoxicity arose in 4 patients (2/4, grade 3-4), HLH affected 2 patients, and no Pembrolizumab-associated autoimmune sequalae were observed. On this basis, outpatient administration was tested in 20 patients, saving a median of 14 hospital days/patient. AUTO3 was effective: overall response rates were 66% (48.9%, CR; 17%, PR). For patients with CR, median DOR was not reached, with 54.4% (CI: 32.8, 71.7) projected to remain progression-free beyond 12 months after onset of remission. DOR for all responding patients was 8.3 months (95% CI: 3.0, NE) with 42.6% projected to remain progression-free beyond 12 months after onset of remission. Overall, AUTO3 +/- pembrolizumab for r/r LBCL was safe, lending itself to outpatient administration, and delivered durable remissions in 54.4% of complete responders, associated with robust CAR-T expansion. Neither dual-targeting CAR-T nor pembrolizumab prevented relapse in a significant proportion of patients, and future developments include next-generation-AUTO3, engineered for superior expansion/persistence in vivo, and selection of CAR binders active at low antigen densities.

Abstract Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 “don't eat me” signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. Patients and Methods: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). Results: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing. Conclusions: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.

Mutations in IDH1 occur in 6–10% of pts with AML and are associated with a poor prognosis. Ivosidenib is a first-in-class, potent, oral, targeted, small-molecule inhibitor of mutant IDH1 (mIDH1), which has been approved by the US FDA to treat mIDH1 R/R AML based on the clinical efficacy results from the global pivotal AG120-C-001 study. In China, however, there is still no standard of care therapy for this rare pt population. Here we report for the first time the clinical data from the bridging registrational study of ivosidenib in Chinese pts with mIDH1 R/R AML.

8001 Background: CD19 directed CAR T cells are effective in patients with r/r DLBCL, however relapses due to CD19 loss or PDL1 upregulation are common. In this study, we evaluate the safety and efficacy of AUTO3, a CAR T targeting CD19/22 with limited duration of PD-1 blockade. Methods: We constructed a bicistronic retroviral vector encoding both an anti-CD19 (OX40 co-stim) and an anti-CD22 (41BB co-stim) CAR with humanized binders. The cell product was manufactured in a semi-automated and closed process using CliniMACS Prodigy. Patients (≥ 18 years) with r/r DLBCL (NOS) or transformed (tDLBCL); ECOG <2, adequate organ function are eligible. Lymphodepletion was Flu/Cy prior to AUTO3. Bridging therapy was allowed. The three dose levels explored are 50, 150, and 450 x 10^6 CAR T cells. Patients received AUTO3 alone, or with 3 doses of pembrolizumab (pem) 200 mg q 3 wks starting on D14 (regimen A), or with a single dose of pem 200 mg on D-1 (regimen B). The primary endpoint is frequency of DLTs and grade (G) 3-5 adverse events (AE) and secondary endpoints included ORR, CRR, and biomarkers. Results: As of Jan 21, 2020, 28 patients underwent leukapheresis, 27 successfully manufactured, 1 being manufactured, and 19 patients treated with AUTO3. The median age was 57 (28 - 71) and median number of prior therapies was 3 (2 - 10). 89% had refractory disease, 74% were DLBCL NOS, and 26% were tDLBCL. Dose escalation from 50 to 450 x 106 cells with pem regimen A and B have been completed without DLTs. G > 3 treatment emergent AEs that occurred > 15% were neutropenia (89%), thrombocytopenia (58%), anemia (47%), febrile neutropenia (16%), and hypophosphataemia (16%). Across all dose levels, there were 0% sCRS with primary infusion and 5% severe neurotoxicity (sNT) (1/19), which resolved. There were no cases of sCRS and no neurotoxicity of any grade at > 50 x 106 cells. Eighteen patients were evaluable for efficacy. Among the 11 treated at dose > 50 x 106, the ORR and CRR were 64% and 55%, and all CRs are ongoing (1-12 mth). Two out of 3 patients achieved CR at 450 x 106 cells on pem regimen B. Additional patients and longer follow up, as well as biomarkers, will be presented. Conclusions: AUTO3 at > 50 x 106 CAR T cells with pembrolizumab induces CRs without severe CRS or neurotoxicities of any grade. Clinical trial information: NCT03287817 .

CD19 directed CAR T cells are effective in patients with r/r DLBCL, however relapses due to CD19 loss or PDL1 upregulation are common. In this study, we evaluate the safety and efficacy of AUTO3, a CAR T targeting CD19/22 with limited duration of PD-1 blockade. We constructed a bicistronic retroviral vector encoding both an anti-CD19 (OX40 co-stim) and an anti-CD22 (41BB co-stim) CAR with humanized binders. The cell product was manufactured in a semi-automated and closed process using CliniMACS Prodigy. Patients (≥ 18 years) with r/r DLBCL (NOS) or transformed (tDLBCL); ECOG < 2, adequate organ function are eligible. Lymphodepletion was Flu/Cy prior to AUTO3. Bridging therapy was allowed. The three dose levels explored are 50, 150, and 450 x 106 CAR T-cells. Patients received AUTO3 alone, or with 3 doses of pembrolizumab (pem) 200 mg q 3 wks starting on D14 (regimen A), or with a single dose of pem 200 mg on D-1 (regimen B). The primary endpoint is frequency of DLTs and grade (G) 3-5 adverse events (AE) and secondary endpoints included ORR, CRR, and biomarkers. As of April 27, 2020, 23 patients were treated with AUTO3 in the ongoing phase I study. The median age was 57 (28 - 83) and median number of prior therapies was 3 (2 - 10). 87% had refractory disease, 74% were DLBCL NOS, and 26% were tDLBCL. Dose escalation from 50 to 450 x 106 cells with pem regimen A and B have been completed without DLTs. G ≥ 3 treatment emergent AEs that occurred ≥ 25% were neutropenia (87%), thrombocytopenia (57%), and anemia (48%). Majority of Serious AE were hematological related and reversible. There were 0 cases of severe cytokine release syndrome (sCRS) or neurotoxicity (NT) of any grade at > 50 x 106 cells. Among the 16 patients treated at dose > 50 x 106, the ORR was 69% and CRR was 56%, and all CRs are ongoing at a median f/u 3 months (1-12 months). Among the 8 patients treated at a dose > 50 x 106 with D-1 pem, the ORR was 75% and CRR was 63%. Additional data from patients treated at the recommended phase II dose as well as patients treated in an out-patient setting and longer follow up, as well as relevant biomarkers will be presented. AUTO3 at > 50 x 106 CAR T cells with pembrolizumab induces CRs without severe CRS or NT of any grade.

Introduction: CD 19 CAR T cell therapies have shown significant activity in patients with r/r DLBCL, however relapses due to CD19 loss or PDL1 upregulation are common. In this study, we are evaluating the safety and efficacy of AUTO3, a CAR T cell therapy designed to target CD19 and CD22 simultaneously followed by 3 doses of anti-PD1 monoclonal antibody pembrolizumab (Pem) treatment. The incorporation of dual targeting and anti-PD1 to target relapses due to antigen loss and PDL1 upregulation is novel and first in its kind. Methods & Patients: We constructed a novel bicistronic retroviral vector encoding both an anti-CD19 CAR and an anti-CD22 CAR. Antigen binding domains were humanized incorporating an OX40 co-stimulatory domain for the CD19 CAR and a 41BB co-stimulatory domain for the CD22 CAR. The CD22 CAR was enhanced by incorporating a novel pentameric spacer. The cell product was manufactured in a semi-automated and closed process. Patients (≥ 18 years) with r/r DLBCL not otherwise specified (NOS), high grade, or transformed from indolent histology; Eastern Cooperative Oncology Group Performance Status <2, adequate renal, hepatic, cardiac function and an absolute lymphocyte count ≥0.5 x 10e9/L are eligible. Patients with CNS disease, prior allogeneic stem cell transplant, prior CD19 or CD22 directed therapy are excluded, as well as patients with any contraindication to receiving Pem. All patients received lymphodepletion with 30 mg/m2/day fludarabine and 300 mg/m2/day cyclophosphamide for 3 days prior to AUTO3 infusion. Patients in cohort 1 received 50 x 10e6 and patients in cohort 2 received 150 x 10e6 transduced CAR T-cells. The first 3 patients in lowest dose cohort received AUTO3 alone, subsequently all patients should receive AUTO3 followed by 3 doses of Pem 200 mg given every 3 weeks starting day 14. The primary endpoints of phase 1 are frequency of dose-limiting toxicities (DLTs) and grade (G) 3-5 toxicity. Key secondary endpoints include overall response rate, complete response rate, duration of response, disease free survival, overall survival, and biomarker endpoints such as the level of AUTO3 cells in blood and duration of B cell aplasia. Results: As of the data cut-off date (05-July, 2019), 24 patients have been enrolled, 4 patients were screen failures, 1 patient is in screening, and 19 patients underwent leukapheresis. 16/16 patients had product successfully manufactured and 3 patient products in the manufacturing process. 5/16 patients discontinued before dosing and 11 patients were dosed with AUTO3 in cohort 1 and 2. Four with AUTO3 alone, and 7 with AUTO3 followed by Pem. Seven patients received 50x10e6 AUTO3, and 4 patients received 150 x 10e6 AUTO3. Median age was 49, median 3 prior lines of treatment, and 27% had prior autologous transplant. Seven patients had DLBCL NOS and 4 patients had transformed DLBCL from marginal zone or follicular lymphoma. Eleven patients in cohort 1 and 2 had a minimum of 4 week follow up and were evaluable for safety and efficacy analysis. No AUTO3 related deaths and no DLTs were observed. G > 3 treatment emergent adverse events > 10 % were neutropenia (73%), thrombocytopenia (64%), anemia (64%), and infection (18%). Treatment emergent adverse events > 25% regardless of grades were pyrexia (82%), thrombocytopenia (82%), neutropenia (73%), anemia (64%), nausea (36%), vomiting (36%), fatigue (36%), headache (36%), constipation (36%), dyspnea (27%), and cough (27%). 27% experienced cytokine release syndrome (CRS), all were grade 1, no ≥ G2 CRS were noted. Only one case (9%) of neurotoxicity was noted which was grade 3 and treated with steroids and tocilizumab. Dose levels 50 and 150 x 10e6 have been cleared without DLTs. At the lowest dose level of 50 x 10e6 cells, the objective response rate (ORR) was 57% and complete remission rate (CRR) was 29%. The ORR and CRR at dose 150 x 10e6 cells was 50%. Updated follow up and additional patient data at higher dose levels as well as cellular kinetics, product characteristics and relevant biomarkers will be presented. Conclusions: AUTO3, a novel bicistronic anti CD19/CD22 CAR T therapy, has a manageable safety profile in combination with Pem. Notable is the lack of severe CRS (0%). The efficacy data with 2/4 patients achieving CR at dose 150 x 10e6 cells is promising. The study continues to enroll patients at higher dose levels of AUTO3 followed by Pem. Disclosures Al-Hajj: Autolus Therapeutics: Employment, Equity Ownership. Thomas:Autolus: Employment, Equity Ownership. Faulkner:Autolus Therapeutics: Employment, Equity Ownership. Kotsopoulou:Autolus Therapeutics: Employment, Equity Ownership. Pule:Autolus: Employment, Equity Ownership, Patents & Royalties. Peddareddigari:Autolus Therapeutics: Employment, Equity Ownership. Khokhar:Autolus Therapeutics: Employment, Equity Ownership. Jonnaert:Autolus Therapeutics: Employment. Chen:Autolus Therapeutics: Employment. Osborne:Novartis: Other: Travel; Roche: Consultancy, Honoraria, Other: Travel, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; MSD: Consultancy; Servier: Consultancy; Gilead: Consultancy; Takeda: Consultancy, Honoraria, Other: Travel, Speakers Bureau.

Introduction: Up to 20-40% of patients (pts) with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL) and most treated pts with follicular lymphoma (FL) will have relapsed or refractory (RR) disease. Despite recent therapeutic advances, a minority of pts with transplant-ineligible RR HL or DLBCL, or RR FL will achieve durable remission with currently available treatments (tx). Effective novel therapies for pts with RR HL, DLBCL, or FL remain an unmet need. Although responses to PD1 blockade have been observed in pts with RR HL, DLBCL, and FL, there is room for improvement. Despite a high overall response rate (ORR) to anti-PD1 monotherapy in RR HL, the complete response (CR) is low and most patients with RR DLBCL or FL will not respond. Histone deacetylase inhibitors (HDACi) have immunomodulatory effects, including enhancing antigen presentation, recruiting T-cells into tumors, and promoting T-cell function. Preclinical models in melanoma and lung cancer demonstrated enhanced anti-tumor activity when HDACi were combined with PD1 blockade. We conducted a phase I study to determine the safety and efficacy of pembrolizumab plus vorinostat in RR DLBCL, FL, and HL. Methods: Adult pts with RR HL, DLBCL, or FL who had failed ≥ 1 prior line of tx and were transplant-ineligible were enrolled to receive IV pembrolizumab and oral vorinostat in 21-day cycles. Pts were treated in a dose-escalation cohort with 2 dose levels (DL) using a Rolling 6 design and then onto an expansion cohort with tx at the recommended phase 2 dose (RP2D). In DL1, vorinostat was administered at 100mg BID on days 1-5 and 8-12 and in DL2, vorinostat was administered at 200mg BID on days 1-5 and 8-12. Pembrolizumab dose was 200mg every 3 weeks in all DLs. Tx could continue for a maximum of 2 years. The primary endpoint was safety and determination of the RP2D. Responses were assessed using PET-CT (DLBCL, HL, FL) or CT (FL) by investigators according to the 2014 Lugano Classification. Results: 30 pts were enrolled, including 12 in the dose escalation and 18 in the expansion cohort. At baseline, 67% were male, 73% were Caucasian, the median age was 44 years (range 19-79), the median number of prior tx was 4 (range 1-7), 9 pts had DLBCL, 9 had FL, and 12 had HL. Among DLBCL pts, 4 had primary mediastinal large B-cell lymphoma (PMBL), 4 were non-GCB by Hans criteria, 3 had double-expressor lymphoma, and 3 had prior CAR T-cells. Among HL pts, 11 had prior BV, 7 had prior PD1 blockade, and 3 were refractory to prior PD1 blockade. Additional baseline characteristics are shown in Table 1. In 28 pts with tx data, the median number of cycles was 5 (range 1-16). Of 6 pts treated at DL1, 1 had a DLT (Grade 4 Stevens-Johnson syndrome, SJS) and 1 out of 6 pts had a DLT in DL2 (Grade 3 pulmonary embolism, PE); therefore, DL2 was chosen as the RP2D. In all pts, including the expansion cohort, the most common adverse events (AEs) were nausea (61%), fatigue (57%), hypertension (54%), anemia (50%), leukopenia (50%), hyponatremia (43%), diarrhea (43%), neutropenia (39%), and thrombocytopenia (39%). Grade (gr) 3-4 AEs included 2 pts with gr 3 neutropenia, 1 pt had Gr 4 SJS, and 1 pt each with gr 3 hypertension, anemia, thrombocytopenia, hyperkalemia, lymphopenia, or PE. Immune-related AEs included the Gr 3 SJS and 5 (18%) pts with thyroiditis. 2 patients had vorinostat dose reduction - 1 for neutropenia, 1 for GI toxicity. 12 pts remain on tx; tx was discontinued for toxicity in 3 pts (SJS, PE, elevated creatinine), stem cell transplant in 3 pts, patient preference in 2 pts, and insufficient response in 10 pts. Among 27 evaluable pts, the ORR was 59% and the CR rate was 30% (Table 2). The 9 pts with DLBCL had an ORR of 56% with a CR of 33%, including 2 CR, 1 PR, 1 PD in the 4 PMBL pts (1 had been refractory to CAR T-cells). The 9 pts with FL had an ORR of 22% and CR rate of 11%, and the 9 pts with HL had an ORR of 100% with a CR rate of 44% - both evaluable HL pts who were previously refractory to PD1 blockade responded (2 PR). The median follow-up time in all pts was 4 months (mo, range 1-11). The median duration of response, progression-free survival (PFS), and overall survival (OS) in all patients were 6 mo, 8 mo, and not reached. The overall 6 mo PFS and OS were 59% and 76%, including 67%/71% in DLBCL, 33%/40% in FL, and 80%/100% in HL. Conclusions: Pembrolizumab and vorinostat was tolerable and produced objective responses in pts with RR DLBCL, FL, and HL. A majority of DLBCL pts and all HL pts responded, including pts who had progressed on prior anti-PD1 tx. Disclosures Herrera: AstraZeneca: Research Funding; Kite Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Research Funding; Immune Design: Research Funding; Merck: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding. Popplewell:City of Hope: Employment. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Mei:Seattle Genetics, Inc.: Research Funding. Chen:Autolus Therapeutics: Employment. Kwak:Pepromene Bio: Consultancy, Equity Ownership, Research Funding; InnoLifes: Consultancy, Equity Ownership; Xeme BioPharma, Inc: Consultancy, Equity Ownership; Enzychem LifeSciences: Consultancy; Celltrion Healthcare: Consultancy; Celltrion, Inc.: Consultancy.

The neural transcription factor SOX11 is usually highly expressed in typical mantle cell lymphoma (MCL), but it is absent in the more indolent form of MCL. Despite being an important diagnostic marker for this hard-to-treat malignancy, the mechanisms of aberrant SOX11 expression are largely unknown. Herein, we describe 2 modes of SOX11 regulation by the cell-cycle regulator cyclin D1 (CCND1) and the signal transducer and activator of transcription 3 (STAT3). We found that ectopic expression of CCND1 in multiple human MCL cell lines resulted in increased SOX11 transcription, which correlated with increased acetylated histones H3K9 and H3K14 (H3K9/14Ac). Increased H3K9/14Ac and SOX11 expression was also observed after histone deacetylase 1 (HDAC1) or HDAC2 was depleted by RNA interference or inhibited by the HDAC inhibitor vorinostat. Mechanistically, we showed that CCND1 interacted with and sequestered HDAC1 and HDAC2 from the SOX11 locus, leading to SOX11 upregulation. Interestingly, our data revealed a potential inverse relationship between phosphorylated Y705 STAT3 and SOX11 expression in MCL cell lines, primary tumors, and patient-derived xenografts. Functionally, inactivation of STAT3 by inhibiting the upstream Janus kinase (JAK) 1 or JAK2 or by STAT3 knockdown was found to increase SOX11 expression, whereas interleukin-21 (IL-21)-induced STAT3 activation or overexpression of the constitutively active form of STAT3 decreased SOX11 expression. In addition, targeting SOX11 directly by RNA interference or indirectly by IL-21 treatment induced toxicity in SOX11+ MCL cells. Collectively, we demonstrate the involvement of CCND1 and STAT3 in the regulation of SOX11 expression, providing new insights and therapeutic implications in MCL.

Background: ME-401, a potent and selective oral PI3kδ inhibitor, is being evaluated in a Phase 1b study in patients (pts) with R/R B-cell malignancies (NCT02914938).70 pts were treated as of January 2019 and we report here results in pts with FL and CLL/SLL.Methods: Adult pts with ECOG performance status ≤2, no prior PI3K therapy, and progression of disease (POD) after ≥1 prior therapy were initially enrolled in a dose escalation phase (60-180 mg) then in 60 mg expansion cohorts as monotherapy or in combination with rituximab (375 mg/m² x 8 doses in 6 months).ME-401 was given initially on a daily continuous schedule (CS) until POD or unacceptable toxicity.Patients on CS were switched to an intermittent schedule (IS) on days 1-7 of a 28-day cycle in Cycle 3 (n = 20) or in Cycles ≥4 (n = 18) of CS.Toxicity on CS was managed by switch to IS and POD on IS was managed by switch to CS. Results: 61 pts, 48 with FL and 13 with CLL/SLL received ME-401 alone (n = 48) or with rituximab (n = 13).Median age 65 yrs.(range:38-81), median prior therapies 2 (range: 1-10), 33 pts had ≥2 prior therapies, and 25 FL pts were POD24.In CLL/SLL pts, IgVH was unmutated in 7, mutated in 2, and not evaluated in 4. 39 pts (64%) remain on therapy with a median follow-up of 12.3 months (range: 1.6-25.1)and 22 pts discontinued: 9 POD, 5 adverse events (AEs), 5 withdrew consent, and 3 were referred to stem cell transplant in CR.Delayed (i.e., Cycle >2) grade 3 immune related AEs (irAEs), primarily diarrhea/colitis and rash, were reported in 13/41 pts (31.7%) on CS and 2/20 pts (10%) who had switched to IS in Cycle 3, with irAEs noted 15 and 18 days after switch to IS. 6 pts with grade 3 irAEs had a drug holiday and corticosteroid therapy then resumed ME-401 on IS without recurrence of the irAE.Objective responses were achieved in 33/43 evaluable FL pts (77%) and 11/11 evaluable CLL/SLL pts (100%).In FL, response rate was 77% with ME-401 alone (including 29% CR by Lugano criteria), 78% with ME-401 plus rituximab, 91% in POD24, and 75% in pts who had ≥2 prior therapies.Of 38 pts switched to IS, 33 (87%) remain on therapy (median: 14.5 months), 26 on IS and 7 who switched back to CS due to POD on IS, 3 pts discontinued due to persistent POD after switch to CS, and 2 pts withdrew.Conclusions: ME-401 achieves a high rate of durable responses in R/R FL and CLL/SLL.IS appears to reduce the incidence of irAEs and maintain responses.POD on IS can be successfully retreated by reverting to CS.A global study is enrolling pts with R/R FL randomized to ME-401 by IS or CS after 2 cycles of CS, with switch to IS for irAEs and switch to CS if POD on IS (NCT03768505).

Alisertib, an Aurora kinase A inhibitor, was evaluated in a Phase 1 study in combination with the histone deacetylase inhibitor vorinostat, in patients with relapsed/refractory lymphoid malignancies (N?=?34; NCT01567709). Patients received alisertib plus vorinostat in 21-day treatment cycles with escalating doses of alisertib following a continuous or an intermittent schedule. All dose-limiting toxicities (DLTs) were hematologic and there were no study-related deaths. The recommended phase 2 dose (RP2D) of the combination was 20?mg bid of alisertib and 200?mg bid of vorinostat on the intermittent schedule. A 13-patient expansion cohort was treated for a total of 18 patients at the RP2D. There were no DLTs at the RP2D, and toxicities were mainly hematologic. Two patients with DLBCL achieved a durable complete response, and two patients with HL achieved partial response. Alisertib plus vorinostat showed encouraging clinical activity with a manageable safety profile in heavily pretreated patients with advanced disease.

Introduction: MCL outcomes have improved with the use of IBR; however, 33% of patients do not respond to IBR and duration of response is about 1.5 yrs (Wang ML Blood 2015). Synergy of IBR with VEN has been demonstrated (Jayappa KD Blood Advances 2017; Axelrod M Leukemia 2014). As both drugs are metabolized by CYP3A, a dose finding study, supported by a grant from AbbVie Inc., was conducted utilizing a continual re-assessment method for toxicity and efficacy in 6 dosing cohorts (see table) (NCT02419560). Here we report the optimal dose and outcomes. Methods: IBR-naïve MCL patients, relapsed or refractory to at least one line of therapy, were eligible if they had adequate organ function and were not at high risk for tumor lysis syndrome (TLS). Subjects were enrolled in two phases of the study. Each subject was sequentially placed into escalating dose levels. Then, subjects were allocated to a dose arm based on best response among the arms that were estimated safe based on DLT data from prior subjects. The cohort with the best response and acceptable toxicity was considered optimal (Wages NA et al, CCR 2017). DLTs were defined as any related Grade 3-5 non-hematologic or Grade 4-5 hematologic event lasting more than 2 weeks and occurring within 8 weeks of starting both VEN and IBR. VEN was given alone for 1 week at a dose of 100mg daily. IBR was added on week 2 at the allocated dose. VEN was further titrated to its allocated dose. After one of 15 subjects experienced TLS with one 100mg dose (Davids MS JCO 2018), the study was amended to titrate VEN from 20mg to 100mg over 2 weeks before adding IBR (see figure). After amendment, the optimal dose was defined as the cohort that had 10 subjects allocated or the cohort with the max subjects allocated after 38 total subjects enrolled. Study treatment with IBR and VEN continued for 6 months; subsequent treatment was per investigator discretion. Results: Enrollment began 9/2015. A total of 35 subjects were treated (15 prior to amendment and 20 after). Subjects were predominantly male (29/35) and had an average age of 62.5 yrs (range 49-81 yrs). 51.4% (n=18) were refractory to their last therapy and 42.8% (n=15) had a prior autologous transplant. After amendment, 10 subjects were allocated to Arm B as of 2/2019, making Arm B (IBR 420mg/VEN 200mg) the optimal dose identified. No subjects were treated at the maximum dose combination as 2 DLTs occurred at dose level E (persistent Grade 4 neutropenia and Grade 3 diarrhea). At the time of submission, ORR (CR+PR) on Arm B was 15/16 (93.8%, 90% CI:[74, 100]) with CR rate (best response) of 6/16 (37.5%, 90% CI:[18, 61]). Two subjects on Arm B are still undergoing therapy and results will be updated. No DLTs were identified in this cohort. Best ORR for all 34 evaluable subjects is 28/34 (82.4%, 90% CI:[68, 92]) with best CR rate of 14/34 (41.2%, 90% CI:[27, 57]). Five of 34 (14.7%, 90% CI:[6, 28]) subjects progressed without response and 3 additional subjects progressed after a response (all PR) (Table 1). Non-response or progression during the 6-months of study was not dependent on dose of either drug. Survival assessments are not currently mature. The most common adverse events (AE) were neutropenia (Gr >3 n=10), thrombocytopenia (Gr>3 n=2), nausea (all Gr1 n=13), diarrhea (Gr 1 n=12; Gr>2 n=2), infections (Gr 2 n=11; Gr 3 n=3), cardiac (afib Gr 3 n=3; heart failure Gr 3 n=1) and arthralgia (Gr 1 n=9, Gr2 n=2). There were no deaths due to AEs. Five subjects had dose modifications (IBR n=1; VEN n=4, Both n=0), and 3 stopped treatment early due to AE (22.8%). Conclusions: In this phase I/Ib study, the combination of IBR 420mg and VEN 200mg is considered the optimal dose for relapsed MCL. Response at this level is favorable compared to historical cohorts of single agent IBR and toxicity is manageable. Two other studies have been reported using IBR 560mg and VEN 400mg in MCL, though with different dosing strategies (Tam CS NEJM 2018; Wang ML Lugano 2019). Both showed similar ORR to the current study and both had approximately 60% of subjects requiring dose reduction in at least one drug. In our study, higher dose combinations showed toxicity without an improvement in response. Progressions during the 6-months of IBR/VEN treatment occurred at all dose levels, suggesting that failure of the combination is not dose dependent but biologically driven. Dose reductions are not predicted to alter response; though survival outcomes are immature. Correlative studies are planned. Disclosures Portell: AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Roche/Genentech: Research Funding; Infinity: Research Funding. Kahl:TG Therapeutics: Consultancy; BeiGene: Consultancy; ADC Therapeutics: Consultancy, Research Funding; Seattle Genetics: Consultancy. Budde:F. Hoffmann-La Roche Ltd: Consultancy. Chen:Autolus Therapeutics: Employment. Cohen:Astra Zeneca: Research Funding; Lymphoma Research Foundation: Research Funding; ASH: Research Funding; LAM Therapeutics: Research Funding; Takeda Pharmaceuticals North America, Inc.: Research Funding; Gilead/Kite: Consultancy; Bristol-Meyers Squibb Company: Research Funding; Janssen Pharmaceuticals: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding; Genentech, Inc.: Consultancy, Research Funding; UNUM: Research Funding; Hutchison: Research Funding. Williams:Seattle Genetics: Consultancy; Sandoz: Consultancy; Pharmacyclics: Research Funding; TG Therapeutics: Consultancy, Research Funding; Allos: Research Funding; AbbVie: Consultancy; Astra-Zeneca: Consultancy; Kite: Consultancy; Juno: Consultancy; Verastem: Consultancy; Celgene: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Venetoclax is not approved in MCL; the combination of venetoclax and ibrutinib is not approved in MCL.

Key Points Five-year follow-up of S1106 demonstrates similar efficacy, MRD negativity, and 5-year survival with RH or RB, but RH was more toxic than RB. RB showed excellent efficacy and survival and less toxicity compared with a cytarabine-based regimen in transplant-eligible MCL patients.

7539 Background: The ECHELON-1 trial demonstrated improved outcomes for patients (pts) with advanced HL who received frontline A+AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine) vs ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine), with 2-year mPFS rates of 82% and 77%, respectively. Here we report a post-hoc analysis of mPFS outcomes and clinical characteristics by Cycle 2 PET (PET2) status per independent review facility (IRF). Methods: Pts were randomized 1:1 to A+AVD or ABVD on Days 1 and 15 for up to six 28-day cycles. PET scans were conducted at the end of Cycle 2 and end of treatment. PET2 results guided an optional switch to alternative therapy at the treating physician’s discretion for pts with a Deauville score of 5. A switch to alternate therapy was not considered an event. The primary endpoint, mPFS, was defined as time to progression, death, or absence of a complete response with subsequent anticancer therapy, per IRF. Results: PET2 negativity rates (Deauville ≤3) were 89% (588/664 pts) in the A+AVD arm and 86% (577/670) with ABVD. Baseline characteristics were well-balanced across arms, with no significant differences in PET2– vs PET2+ pts in either arm. PET2 positivity rates (Deauville ≥4) were 7% (47/644) in the A+AVD arm and 9% (58/670) with ABVD; 5 total pts with a Deauville score of 5 switched to alternative frontline therapy. Subgroup analyses showed a favorable treatment effect for both subgroups in favor of A+AVD (Table 1), with 2-year mPFS (PET2– vs PET2+) of 85.2 vs 57.5% in the A+AVD arm, and 80.9 vs 42.0% in the ABVD arm. Outcomes for PET2+ pts were relatively poor in both arms, as previously reported. Conclusions: Overall, ECHELON-1 demonstrated a treatment effect in favor of A+AVD over ABVD. This post-hoc analysis showed a similar treatment effect on mPFS consistently in favor of A+AVD regardless of PET2 status. Clinical trial information: NCT01712490.Summary of mPFS by PET2 Status. 2-year mPFS (per IRF), % HR P-value A+AVD ABVD Overall 82.1 77.2 0.77 0.035 95% CI 78.8–85.0 73.7–80.4 0.603–0.983 N 664 670 PET2– 85.2 80.9 0.774 0.070 95% CI 81.9–88.0 77.3–84.0 0.586–1.022 N 588 577 PET2+ 57.5 42.0 0.609 0.089 95% CI 41.0–70.9 28.6–54.8 0.341–1.088 N 47 58

7541Background: ECHELON-1 is a global, phase 3 study of BV plus doxorubicin, vinblastine, and dacarbazine (A+AVD) vs ABVD as frontline therapy in patients with advanced HL (NCT01712490). The primar...

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

Abstract Background: Brentuximab vedotin (BV), an antibody drug conjugate (ADC), selectively delivers anti-tubulin agent monomethyl auristatin E (MMAE) to CD 30+ cells. In a multi-center phase II trial in patients with relapsed/refractory Hodgkin lymphoma (HL), BV showed an overall response rate (ORR) of 75%, a complete response (CR) rate of 34%, and a median duration of response (DOR) of 6.7 months (Younes A et al, JCO 2012). Although this drug has high response rates in HL, many patients will eventually develop resistance. We have shown that resistance to BV is associated with upregulation of MDR1 (multidrug resistance pump), and BV resistance cells have a decreased intracellular concentration of MMAE as a result of overexpression of drug export pump (Chen et al, MCT 2015). Cyclosporine (CsA), an immunosuppressant, can inhibit drug export pump by competitive binding. It has been combined with non-targeted chemotherapy to overcome drug resistance in the past without significant benefits. However, it has never been combined with targeted therapies such as antibody drug conjugates. We found that addition of CsA to BV restores intracellular MMAE concentration in BV resistant cell lines and restores the IC50 to BV (Chen ASH 2017). In BV resistant mouse xenograft models, addition of CsA also restores BV sensitivity (Chen ASH 2017). We hypothesize that the combination of CsA and BV is safe and efficacious, thus we designed and conducted a phase I trial using the combination of CsA plus brentuximab vedotin in patients with R/R HL. Patients and Methods: This is a prospective, phase I trial with a 3 + 3 design in patients with relapsed/refractory HL. All patients had biopsy proven relapsed/refractory HL. Three dose levels are planned: 1) 1.2 mg/kg BV every 21 days and 5 mg/kg CsA PO BID on D 1-5, 2) 1.8 mg/kg BV every 21 days and 5 mg/kg CsA PO BID on D 1-5. 3) 1.8 mg/kg BV every 21 days and 7.5 mg/kg of CsA PO BID on D 1-5. DLT period is 21 days. Patients who were relapsed/refractory to BV were allowed. The primary endpoint was MTD. Secondary endpoints were safety, ORR, duration of response, and correlative analysis. Imaging studies were performed every two cycles with alternating CT and CT/PET scans. Response criteria were per Lugano 2014. Results: Thirteen patients were accrued, and all were evaluable for toxicity and 12/13 for efficacy. The baseline characteristics are shown in table 1 and include: previous BV (100%), previous PD1 inhibitor (92%), previous HCT (62%), male predominance (54%), Caucasian predominance (85%), median age of 37, stage III/IV (69%), refractory to previous BV (92%), progressed after PD1 blockade (92%). There was 0 DLT at dose level 1 (0/3), 1 DLT of abdominal pain (grade 3) and neutropenia at dose level 2 in the same patient (1/6 patients), and 4 DLT in 2 out of 3 patients treated at dose level 3. The DLTs were grade 3 hyperglycemia (1), grade 3 bone pain (1), grade 3 constipation (1), and grade 4 lymphopenia (1). Thus dose level 2 is the MTD. Grade 3 or higher possibly-related toxicities (excluding DLT) included neturopenia (6) anemia (4), lymphopenia (3), hyponatremia (3), hypophosphatemia (3), acidosis (1), pneumonitis (1), abdominal pain (1), colitis (1), AST elevation (1), weight loss (1), and hypokalemia (1). Grade II possibly related toxicities >20% included hypertension (46%), peripheral sensory neuropathy (31%), hypophosphatemia (31%), hypokalemia (31%), fatigue (31%), ALT increase (23%), elevated bili (23%), and myalgia (23%). Patients treated at the MTD experienced grade 3/4 possibly-related toxicities that were mainly laboratory based which included: neutropenia (4), anemia (2), hypophosphatemia (2), hypophosphatemia (1), hyponatremia (1), AST elevation (1), lymphopenia (1), abdominal pain (1), and colitis (1). The best overall response (CR+PR) rate was 67%, CR rate was 33%, PR 33%, stable disease rate was 25%, 1 patient was inevaluable. The best overall response rate for patients treated at dose level 1 and 2 was 67% with a CR of 44%. Median number of cycles was 4 (1-14). 2 patients went to autoHCT and 2 patients went to alloHCT after protocol. Conclusion: Addition of CsA to BV is safe and feasible at the MTD. The MTD was determined to be 1.8 mg/kg BV every 21 days plus 5 mg/kg of CsA PO BID on D 1-5. The ORR of 67% and CR of 33 % is very encouraging in a primary BV refractory population. The study has opened the expansion phase. Table 1. Table 1. Disclosures Chen: Millennium Pharmaceuticals: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Genentech Inc.: Consultancy; Affimed: Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding. Herrera:Seattle Genetics: Research Funding; Merck, Inc.: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Research Funding; Genentech: Consultancy, Research Funding; Gilead Sciences: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; KiTE Pharma: Consultancy, Research Funding; Immune Design: Research Funding. Siddiqi:Juno Therapeutics: Other: Steering committee. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

Introduction: High intensity treatments such as autologous hematopoietic cell transplantation (HCT) can be curative for patients with relapsed/refractory lymphoma (Hodgkin [HL], non-Hodgkin [NHL]), but this needs to be balanced by the risk of non-relapse mortality (NRM) associated with HCT and potentially sub-optimal disease response with less intensive treatments. Measures of pre-treatment body composition such as quantity and quality of muscle are prognostic in patients with solid tumors, but their association with post-HCT outcomes is unknown. We examined the prognostic significance of muscle depletion prior to HCT, defined by having both low muscle quantity (lumbar skeletal muscle index [SMI]) and quality (muscle attenuation [MA]) on computed tomography (CT) imaging, in a population-based cohort of patients undergoing autologous HCT for lymphoma. Next, we examined the prognostic significance of muscle depletion after HCT in a subset of patients with normal muscle composition prior to HCT, allowing us to examine the impact of change in body composition over time. Methods: 440 consecutive patients with lymphoma, age ≥18y, who underwent a first HCT between 2009 and 2014 at a single institution were included in the study. Measures of muscle quantity (SMI) and quality (MA) were ascertained from pre- and post-HCT abdominal CT scans using image analysis software (SliceOmatic; Tomovision, Quebec, Canada). SMI was calculated as the ratio of skeletal muscle area (cm2) divided by height (m)2. Sex and body mass index (BMI)-specific cutoff values of low SMI and MA were used to identify patients with muscle depletion (J Clin Oncol 2013 31:1539). Measurements were made by trained researchers blinded to patient demographics and HCT outcome (Figure 1); 3rd lumbar vertebra was used as a landmark because of its high correlation with whole-body muscle mass (J Clin Oncol 2016 34:1339). This report is limited to 321 (73%) patients with CT scans performed ≤90 days from HCT. Cumulative incidence of NRM was calculated taking into consideration competing risk of disease-related mortality. Kaplan-Meier method was used to examine overall survival (OS). Multivariable Cox regression analysis was used to calculate the hazard ratio (HR) estimates and 95% confidence intervals (CI), adjusted for relevant covariates (demographics, diagnosis, pre-HCT Karnofsky performance score [KPS] and comorbidity index [HCT-CI]). Results: Sixty-two (19.3%) patients had muscle depletion pre-HCT. Median age at HCT was 53y (range: 18-78); 62.0% were male; 54.0% were non-Hispanic white; Diagnoses: HL (N=84 [26.2%]), NHL (N=237 [73.8%]); KPS ≤80 (N=87 [27.1%]); HCT-CI ≥3 (N=52 [16.2%]). Impact of pre-HCT muscle depletion: Patients with pre-HCT muscle depletion had significantly worse 5-y OS (56.4% vs. 77.8%, p<0.001; Figure 2) and higher NRM (11.4% vs. 5.1%, p=0.05) when compared to those with normal body composition. OS was especially poor for patients who were obese (BMI ≥30 kg/m2) and had muscle depletion (20.0% vs. 77.1%, p<0.001) pre-HCT. Median length of hospitalization was also significantly longer (27d vs. 23d; p=0.03) among patients with muscle depletion. Muscle depletion was associated with a 2.2-fold (HR=2.2 [CI: 1.0-4.5]) risk of NRM and 1.8-fold (HR=1.8 [CI: 1.1-3.1]) risk of all-cause mortality when compared to those with normal body composition. Impact of post-HCT muscle depletion: Among 223 patients with normal body composition prior to HCT, 24 (9.3%) developed muscle depletion after HCT, detected at a median 63d (range 27-165) from HCT. In these patients, there was a 3-fold (HR=3.1 [CI: 1.5-6.4]) risk of all-cause mortality compared to those who maintained normal muscle composition throughout HCT. Conclusion: Muscle depletion is an important and independent predictor of outcomes after HCT, with potential additional downstream impacts on health-economic outcomes such as length of hospitalization and the burden of chronic morbidity in long-term survivors. Taken together, these data form the basis for real-time decision making prior to HCT (e.g. pre-habilitation, less intensive treatment approaches), or during HCT (e.g. dietary optimization, increased supportive care services, resistance training), setting the stage for innovative strategies to improve outcomes after HCT. Chen: Affimed: Research Funding; Merck & Co., Inc.: Consultancy, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech Inc.: Consultancy; Millennium Pharmaceuticals: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.