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Steroid-refractory chronic graft versus host disease (cGVHD) remains a significant cause of morbidity and mortality following allogeneic transplantation. Abatacept is a selective co-stimulation modulator, used for the treatment of rheumatologic disease, and was recently the first drug to be approved by the FDA for the prophylaxis of acute graft versus host disease. We conducted a Phase II study to evaluate the efficacy of Abatacept in steroid-refractory cGVHD (clinicaltrials.gov #NCT01954979). The overall response rate was 58%, with all responders achieving a partial response. Abatacept was well-tolerated with few serious infectious complications. Immune correlative studies showed a decrease in IL-1-alpha, IL-21, and TNF-alpha as well as decreased PD-1 expression by CD4+ T cells in all patients after treatment with Abatacept, demonstrating the effect of this drug on the immune microenvironment. The results demonstrate that Abatacept is a promising therapeutic strategy for the treatment of cGVHD.

Odronextamab is a hinge-stabilised, fully human IgG4-based CD20 × CD3 bispecific antibody that binds CD3 on T cells and CD20 on B cells. We aimed to evaluate the safety and antitumour activity of odronextamab in patients with relapsed or refractory B-cell non-Hodgkin lymphoma.This single-arm, multicentre, phase 1, dose-escalation and dose-expansion (ELM-1) trial was conducted at ten academic sites across the USA and Germany. Patients aged 18 years or older with CD20-positive relapsed or refractory B-cell malignancies who previously received CD20-directed antibody therapy and who had at least one measurable lesion, and an ECOG performance status of 0 or 1 were included. Patients received intravenous odronextamab, according to a step-up dosing schedule in cycle 1, followed by treatment once per week at target doses ranging from 0·1 mg to 320 mg during cycles 2-4 (each cycle was 21 days). After cycle 4, maintenance treatment occurred every 2 weeks until disease progression or unacceptable toxicity. The primary endpoint of safety was assessed by the incidence of adverse events and dose-limiting toxicities to determine the maximum tolerated dose or phase 2 dose of odronextamab, or both. Preliminary antitumour activity, as measured by objective response rate, was a secondary endpoint. This study is registered with ClinicalTrials.gov, NCT02290951.From Feb 4, 2015, to Sept 25, 2021, 145 heavily pretreated patients (median of 3 (IQR 2-5] previous therapies) were enrolled (94 to the dose-escalation and 51 to the dose-expansion part of the study). The median age of patients was 67·0 years (IQR 57·0-73·0); 101 (70%) were male and 44 (30%) were female; most participants were White (119 [82%]) and not Hispanic or Latino (132 [91%]). 42 (29%) patients received previous CAR T therapy and 119 (82%) were refractory to the last line of therapy. Median duration of follow-up was 4·2 months (IQR 1·5-11·5). During dose escalation, odronextamab was administered up to the maximum dose of 320 mg once per week and no dose-limiting toxicities were observed. The recommended dose for expansion in patients with follicular lymphoma grade 1-3a was 80 mg and was 160 mg for patients with diffuse large B-cell lymphoma. Cytokine release syndrome and neurological treatment-emergent adverse events were predominantly low grade and did not result in treatment discontinuation. The most common grade 3 or worse treatment-emergent adverse events were anaemia (36 [25%]), lymphopenia (28 [19%]), hypophosphataemia (27 [19%]), neutropenia (27 [19%]), and thrombocytopenia (20 [14%]). Serious treatment-emergent adverse events occurred in 89 (61%) of 145 patients; the most frequent were cytokine release syndrome (41 [28%]), pyrexia (11 [8%]), pneumonia (nine [6%]), and infusion-related reaction (six [4%]). Four deaths were considered related to treatment (gastric perforation in a patient with gastric involvement by lymphoma, lung infection, pneumonia, and tumour-lysis syndrome). Objective response rate was 51% (95% CI 42-59; 72 of 142). In patients with follicular lymphoma who received odronextamab doses of 5 mg or higher, the objective response rate was 91% (95% CI 75-98; 29 of 32) and the complete response rate was 72% (95% CI 53-86; 23 of 32). In patients with diffuse large B-cell lymphoma without previous CAR T-cell therapy who received doses of 80 mg or higher, the objective response rate was 53% (eight of 15) and all responses were complete responses. In patients with diffuse large B-cell lymphoma who had previous CAR T-cell therapy and received doses of 80 mg or higher, the objective response rate was 33% (ten of 30) and complete response rate was 27% (eight of 30).Odronextamab monotherapy showed a manageable safety profile and encouraging preliminary activity, including durable responses in heavily pretreated patients with B-cell non-Hodgkin lymphoma, supporting further clinical investigation in phase 2 and 3 trials.Regeneron Pharmaceuticals.

Several PI3Kδ inhibitors are approved for the therapy of B cell malignancies, but their clinical use has been limited by unpredictable autoimmune toxicity. We have recently reported promising efficacy results in treating chronic lymphocytic leukemia (CLL) patients with combination therapy with the PI3Kδγ inhibitor duvelisib and fludarabine cyclophosphamide rituximab (FCR) chemoimmunotherapy, but approximately one-third of patients develop autoimmune toxicity. We show here that duvelisib FCR treatment in an upfront setting modulates both CD4 and CD8 T cell subsets as well as pro-inflammatory cytokines. Decreases in naive and central memory CD4 T cells and naive CD8 T cells occur with treatment, while activated CD8 T cells, granzyme positive Tregs, and Th17 CD4 and CD8 T cells all increase with treatment, particularly in patients with toxicity. Cytokines associated with Th17 activation (IL-17A and IL-21) are also relatively elevated in patients with toxicity. The only CLL feature associated with toxicity was increased priming for apoptosis at baseline, with a significant decrease during the first week of duvelisib. We conclude that an increase in activated CD8 T cells with activation of Th17 T cells, in the context of lower baseline Tregs and greater CLL resistance to duvelisib, is associated with duvelisib-related autoimmune toxicity.

Both continuous therapy with acalabrutinib and fixed-duration therapy with venetoclax-obinutuzumab are effective for previously untreated chronic lymphocytic leukaemia. We hypothesised that frontline time-limited, minimal residual disease (MRD)-guided triplet therapy with acalabrutinib, venetoclax, and obinutuzumab would induce deep (ie, more patients with undetectable MRD) and durable remissions.In this open-label, single-arm, investigator-sponsored, phase 2 study, patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma were recruited from two academic hospitals in Boston, MA, USA. Eligible patients were aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0-2, and were treatment naive. Patients were treated in 28 day cycles. Acalabrutinib monotherapy was given orally at 100 mg twice daily for cycle 1, then combined for six cycles with intravenous obinutuzumab (100 mg on cycle 2 day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 and on day 1 of cycles 3-7); and from the beginning of cycle 4, oral venetoclax was dosed daily using an accelerated ramp-up from 20 mg on day 1 to 400 mg by day 22 and continued at this dose thereafter. Patients continued on acalabrutinib 100 mg twice daily and venetoclax 400 mg once daily until day 1 of cycle 16 or day 1 of cycle 25. If the patient had undetectable MRD in the bone marrow they were given the option to discontinue therapy at the start of cycle 16 (if also in complete remission) or at the start of cycle 25 (if at least in partial remission). The primary endpoint was complete remission with undetectable MRD in the bone marrow (defined as1 chronic lymphocytic leukaemia cell per 10 000 leucocytes as measured by four-colour flow cytometry), at cycle 16 day 1. Safety and activity endpoints were assessed in all patients who received at least one dose of any study drug. This study is registered with ClinicalTrials.gov, NCT03580928, and is ongoing.Between Aug 2, 2018, and May 23, 2019, 37 patients with chronic lymphocytic leukaemia were enrolled and all received at least one dose of any study drug. The median age of patients was 63 years (IQR 57-70), and ten (27%) were female and 27 (73%) were male. Median follow-up was 27·6 months (IQR 25·1-28·2). At cycle 16 day 1, 14 (38% [95% CI 22-55]) of 37 participants had a complete remission with undetectable MRD in the bone marrow. The most common grade 3 or 4 haematological adverse event was neutropenia (16 [43%] of 37 patients). The most common grade 3-4 non-haematological adverse events were hyperglycaemia (three [8%]) and hypophosphataemia (three [8%]). Serious adverse events occurred in nine (24%) patients; the most common was neutropenia in three (8%) patients. There have been no deaths on study.Acalabrutinib, venetoclax, and obinutuzumab is a highly active and well tolerated frontline therapy for chronic lymphocytic leukaemia. Although the primary endpoint of this study was not met, the high proportion of patients who had undetectable MRD in the bone marrow supports further investigation of this regimen, which is being tested against acalabrutinib-venetoclax and chemoimmunotherapy in an ongoing phase 3 study (NCT03836261).AstraZeneca and a Dana-Farber Cancer Institute Collaborative Award.

Chimeric antigen receptor (CAR) T-cell therapy targeting cluster of differentiation (CD)19 has had a transformative impact on patient outcomes in a subset of patients with relapsed/refractory non-Hodgkin lymphoma. We present a patient with refractory large B-cell lymphoma in complete remission for 2 years following treatment with CD19-targeted CAR T-cell therapy, who presented with 2 weeks of progressive aphasia. Imaging revealed a left occipital brain lesion and biopsy demonstrated features diagnostic of progressive multifocal leukoencephalopathy. Further evaluation revealed severe hypogammaglobulinemia and a low CD4 count. She was treated with pembrolizumab and intravenous immunoglobulin resulting in decreased cerebrospinal fluid viral load without clinical improvement and died 8 weeks after presentation. This case highlights that there is potential for severe opportunistic infections after CAR T-cell therapy, including fatal progressive multifocal leukoencephalopathy. Strategies to enhance post-treatment immune reconstitution are essential to further harness the unique potency of CAR T-cell therapy.

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) treatments have been rapidly evolving for patients treated in later lines of therapy (LoT). Country-specific cancer registry data for the US and Western Europe (WE) were combined with physician survey results to project the incidence, prevalence, and number of DLBCL and FL patients eligible for and treated by LoT between 2020 and 2025. The total number of incidents and prevalent cases of DLBCL and FL is expected to increase between 2020 and 2025 in the US and WE. 56% and 53% of the third line plus (3L+) eligible DLBCL patients and 60% and 55% of eligible FL patients initiated treatment in the US and WE, respectively. Further research is warranted to understand the reasons behind the high proportion of treatment eligible patients who do not initiate treatment, and potential differences between countries, especially in the 3L + settings.

CD19-directed chimeric antigen receptor T cells (CAR T) are approved for treatment of adults with relapsed/refractory diffuse large B cell lymphoma (DLBCL) following at least two lines of therapy.This study describes real-world treatment patterns after CAR T in adults with DLBCL. It includes adults diagnosed with DLBCL in IBM MarketScan Commercial and Medicare Supplemental healthcare claims databases administered CAR T between 2017 and 2019 (index event) and at least 6 months of continuous health plan enrollment pre-index. Kaplan-Meier methods were used to estimate risk and time to first subsequent treatment after CAR T, as a proxy for CAR T failure.Among 129 patients meeting study criteria, most (123; 95.4%) were hospitalized during CAR T therapy. Median length of stay was 17 (25th-75th percentile, 13-22) days. Estimated 6-month risk of subsequent treatment was 36.2% (95% confidence interval [CI] 27.1-45.8%). During median follow-up of 195 (25th-75th percentile, 102-362) days, median time to the first line of therapy after CAR T, accounting for censoring, was 378 days (95% CI 226, not reached). Among 48 patients who received another therapy after CAR T, 58.3% received immunotherapy, 50.0% radiation therapy, 25.0% chemotherapy, 25.0% targeted therapy, and 12.5% hematopoietic stem cell transplant.Among real-world patients with DLBCL treated with CAR T, the risk of not achieving a durable response is considerable; additional, effective options for DLBCL salvage treatment are needed.

Cryptosporidial diarrhea is uncommon in immunocompetent individuals, more often seen in severely immunocompromised patients. Severe refractory cases have been described in patients with HIV/AIDS before the advent of modern antiretroviral therapy due to an inability to mount an adequate cellular immune response. We describe an 85-year-old patient post–chimeric antigen receptor T-cell therapy relapsed lymphoma who developed refractory Cryptosporidium spp. diarrhea in the setting of persistent CD4+ cytopenia. Despite receiving multiple antiparasitic agents, including failure of a prolonged course of nitazoxanide, the patient experienced persistent symptoms for 9 months with repeatedly positivity stool Cryptosporidium spp. direct fluorescent antibody (DFA) test. We highlight this case of refractory Cryptosporidium spp. and the importance of recognizing the pathogen in a non–HIV-infected immunosuppressed host.

PI3 kinase (PI3K) activity is critical for survival of neoplastic B cells in patients with chronic lymphocytic leukemia (CLL). Blockade of PI3K signaling with idelalisib is effective for the treatment of relapsed CLL in combination with the anti-CD20 antibody ofatumumab. In this single-arm, open-label, nonrandomized phase 2 study, we investigated the efficacy and safety of idelalisib with ofatumumab in 27 patients with treatment-naïve CLL in need of therapy. Patients were planned to receive idelalisib for 2 monthly cycles, then idelalisib and ofatumumab for 6 cycles, followed by idelalisib indefinitely. The study was closed early and all patients ceased therapy when an increased rate of death as a result of infection was observed on other first-line idelalisib trials. Median time on therapy was 8.1 months, and median duration of follow-up was 39.7 months. We previously reported high rates of hepatotoxicity in a smaller cohort of patients in this trial; toxicities necessitated therapy discontinuation in 15 patients after a median of 7.7 months. The most frequent grade ≥3 adverse events were transaminitis (52% of patients), neutropenia (33%), and colitis/diarrhea (15%). The best overall response rate (ORR) was 88.9%, including 1 complete response. Median progression-free survival (PFS) was 23 months (95% confidence interval [CI], 18-36 months); 11 patients have not yet required second-line therapy. Idelalisib and ofatumumab demonstrated an unacceptable safety profile in the first-line setting, which resulted in a short PFS despite a high ORR. Future development of PI3K inhibitors for use in treatment-naïve CLL will require novel approaches to mitigate toxicities. This trial was registered at www.clinicaltrials.gov as #NCT02135133.

Summary Background Patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or mantle cell lymphoma often do not derive durable benefit from ibrutinib monotherapy. We hypothesised that dual B-cell receptor pathway blockade would be tolerable and efficacious. We investigated a next-generation phosphoinositide-3-kinase-δ inhibitor (PI3K-δi), umbralisib, plus a Bruton tyrosine kinase inhibitor (BTKi), ibrutinib, in relapsed or refractory chronic lymphocytic leukaemia and mantle cell lymphoma. Methods We did an investigator-initiated, multicentre, phase 1–1b study of patients from five sites in the USA (academic and community sites). Patients were 18 years and older with relapsed or refractory chronic lymphocytic leukaemia or mantle cell lymphoma, with an Eastern Cooperative Oncology Group performance status of 2 or less, and were given umbralisib orally once daily (400 mg, 600 mg, or 800 mg) and ibrutinib orally once daily (420 mg for chronic lymphocytic leukaemia or 560 mg for mantle cell lymphoma) until disease progression or unacceptable toxicity. The phase 1 dose-escalation cohorts for each histology escalated independently in a standard 3 × 3 design. The primary endpoints were intention-to-treat assessment of maximum-tolerated dose, safety, and dose-limiting toxicities. This trial is ongoing and is registered with ClinicalTrials.gov , number NCT02268851 . Findings Between Dec 5, 2014, and March 7, 2018, we enrolled 44 patients, of which 42 were given at least one dose of study drug (chronic lymphocytic leukaemia, n=21; mantle cell lymphoma, n=21). Patients had a median age of 68 years (range 48–85) and had a median of two (IQR 1–3) previous therapies. No dose-limiting toxicities were observed and the maximum-tolerated dose of umbralisib was not reached. The recommended phase 2 dose of umbralisib when given in combination with ibrutinib was 800 mg once daily. The most frequent adverse events included diarrhoea (22 [52%] patients, 10% of whom had grade 3), infection (21 [50%], 17% grade 3–4), and transaminitis (ten [24%], 2% grade 3). Serious adverse events occurred in 12 (29%) patients and included lipase elevation, atrial fibrillation, hypophosphataemia, adrenal insufficiency, transaminitis, and infections. Interpretation Umbralisib plus ibrutinib is well tolerated and active in relapsed or refractory chronic lymphocytic leukaemia and mantle cell lymphoma, with a recommended phase 2 dose of umbralisib 800 mg once daily. To the best of our knowledge, these are the first clinical data on a BTKi and PI3K-δi doublet in B-cell malignancies, and the results suggest that this approach is feasible and worthy of further study. Funding TG Therapeutics, Leukemia and Lymphoma Society Therapy Accelerator Program.

Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198.

Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Although numerous precipitating etiologies have been identified, the reason that HLH occurs in only a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH. In a highly annotated cohort of older adults with HLH we found that CH was more prevalent than in control cohorts. Using the adult-onset HLH mouse model in which repeated treatments of the TLR9 agonist, ODN1826, was delivered to the mouse, we observed that macrophages carrying mutations in Tet2, one of the most commonly mutated genes in CH, have an enhanced inflammatory response to TLR9 agonism. Finally, mice carrying Tet2 mutations in the hematopoietic compartment (a common model for CH) displayed an exaggerated response to TLR9 agonism, including worse splenomegaly and anemia. Our data suggest that CH is more common in individuals with adult-onset HLH and can contribute to the pathophysiology of this disease.

Summary Background Lisocabtagene maraleucel (liso-cel) is an autologous, CD19-directed, chimeric antigen receptor (CAR) T-cell product. We aimed to assess the activity and safety of liso-cel in patients with relapsed or refractory large B-cell lymphomas. Methods We did a seamless design study at 14 cancer centres in the USA. We enrolled adult patients (aged ≥18 years) with relapsed or refractory large B-cell lymphomas. Eligible histological subgroups included diffuse large B-cell lymphoma, high-grade B-cell lymphoma with rearrangements of MYC and either BCL2, BCL6, or both (double-hit or triple-hit lymphoma), diffuse large B-cell lymphoma transformed from any indolent lymphoma, primary mediastinal B-cell lymphoma, and follicular lymphoma grade 3B. Patients were assigned to one of three target dose levels of liso-cel as they were sequentially tested in the trial (50 × 106 CAR+ T cells [one or two doses], 100 × 106 CAR+ T cells, and 150 × 106 CAR+ T cells), which were administered as a sequential infusion of two components (CD8+ and CD4+ CAR+ T cells) at equal target doses. Primary endpoints were adverse events, dose-limiting toxicities, and the objective response rate (assessed per Lugano criteria); endpoints were assessed by an independent review committee in the efficacy-evaluable set (comprising all patients who had confirmed PET-positive disease and received at least one dose of liso-cel). This trial is registered with ClinicalTrials.gov, NCT02631044. Findings Between Jan 11, 2016, and July 5, 2019, 344 patients underwent leukapheresis for manufacture of CAR+ T cells (liso-cel), of whom 269 patients received at least one dose of liso-cel. Patients had received a median of three (range 1–8) previous lines of systemic treatment, with 260 (97%) patients having had at least two lines. 112 (42%) patients were aged 65 years or older, 181 (67%) had chemotherapy-refractory disease, and seven (3%) had secondary CNS involvement. Median follow-up for overall survival for all 344 patients who had leukapheresis was 18·8 months (95% CI 15·0–19·3). Overall safety and activity of liso-cel did not differ by dose level. The recommended target dose was 100 × 106 CAR+ T cells (50 × 106 CD8+ and 50 × 106 CD4+ CAR+ T cells). Of 256 patients included in the efficacy-evaluable set, an objective response was achieved by 186 (73%, 95% CI 66·8–78·0) patients and a complete response by 136 (53%, 46·8–59·4). The most common grade 3 or worse adverse events were neutropenia in 161 (60%) patients, anaemia in 101 (37%), and thrombocytopenia in 72 (27%). Cytokine release syndrome and neurological events occurred in 113 (42%) and 80 (30%) patients, respectively; grade 3 or worse cytokine release syndrome and neurological events occurred in six (2%) and 27 (10%) patients, respectively. Nine (6%) patients had a dose-limiting toxicity, including one patient who died from diffuse alveolar damage following a dose of 50 × 106 CAR+ T cells. Interpretation Use of liso-cel resulted in a high objective response rate, with a low incidence of grade 3 or worse cytokine release syndrome and neurological events in patients with relapsed or refractory large B-cell lymphomas, including those with diverse histological subtypes and high-risk features. Liso-cel is under further evaluation at first relapse in large B-cell lymphomas and as a treatment for other relapsed or refractory B-cell malignancies. Funding Juno Therapeutics, a Bristol-Myers Squibb Company.

Fludarabine, cyclophosphamide, and rituximab (FCR) is highly effective initial therapy for younger patients with chronic lymphocytic leukemia (CLL); however, most eventually relapse. Duvelisib is a delta/gamma PI3K inhibitor approved for relapsed/refractory CLL. We conducted an investigator-initiated, phase 1b/2 study of duvelisib + FCR (DFCR) as initial treatment for CLL patients aged ≤65. A standard 3 + 3 design included two dose levels of duvelisib (25 mg qd and 25 mg bid). Duvelisib was given for 1 week, then with standard FCR added for up to six 28-day cycles, then up to 2 years of duvelisib maintenance. Thirty-two patients were enrolled. The phase 2 dose of duvelisib was identified as 25 mg bid. Hematologic toxicity was common, and all-grade non-hematologic toxicities included transaminitis (28%), febrile neutropenia (22%), pneumonia (19%), and colitis (6%). The best overall response rate by ITT was 88% (56% CR/CRi and 32% PR). The best rate of bone marrow undetectable minimal residual disease (BM-uMRD) by ITT was 66%. The rate of CR with BM-uMRD at end of combination treatment (primary endpoint) was 25%. Three-year PFS and OS are 73 and 93%, respectively. DFCR is active as initial therapy of younger CLL patients. Immune-mediated and infectious toxicities occurred and required active management.

Introduction FCR remains the only therapy other than allo transplant proven to provide a significant chance of functional cure with very long term follow-up for young, fit patients with mutated IGHV CLL. Given the excellent efficacy and tolerability of ibrutinib in a broad population of young, fit CLL patients, we designed the frontline iFCR study to investigate whether time-limited novel agent plus chemoimmunotherapy could provide durable remission for CLL patients irrespective of IGHV status. We previously reported that with a median follow-up of 16.5 months, the rate of CR with bone marrow undetectable minimal residual disease (BM-uMRD) 2 months post-FCR (primary endpoint) was 33%, and that 84% of patients achieved BM-uMRD as best response (Davids et al., Lancet Haem, 2019). Here, we report updated data with longer follow-up, with all patients having had the opportunity to complete 2 years of ibrutinib maintenance following iFCR. Methods This is a multicenter, single arm, phase 2 investigator sponsored trial (NCT02251548) which enrolled CLL patients age ≤65 years without restriction by IGHV mutation status, all of whom met iwCLL treatment criteria. Ibrutinib 420 mg daily was given for 7 days, then combination ibrutinib with FCR for up to 6 cycles. Responders continued on ibrutinib maintenance, and patients with BM-uMRD after 2 years of maintenance discontinued therapy. Response was assessed by 2008 iwCLL criteria, and toxicity by CTCAE v4.03 and iwCLL criteria. The primary objective was to determine the rate of CR/CRi with BM-uMRD 2 months after iFCR combination. Secondary objectives were to assess response rates, PFS/OS, rates of BM-uMRD after 2 years of ibrutinib maintenance, and safety/tolerability. Results Between October, 2014, and April, 2018, 85 patients were enrolled at 9 US sites.As previously reported, the median age was 55 years (range 38-65). IGHV was unmutated in 46/79 patients (58.2%). Deletion of 17p and TP53 mutation were present in 4/83 (4.8%) and 3/81 (3.7%) patients, respectively; 2 of these patients had both. The median number of FCR cycles completed was 6 (range 1-6). Median follow-up is now 40.3 months (range 3.1-76). Median number of ibrutinib maintenance cycles is 24 (range 0-81). By ITT analysis, the rate of CR with BM-uMRD at any point on study is now 55% (47/85 patients), and best rate of BM-uMRD remained 84% (71/85). After 2 years of ibrutinib maintenance, the rates of CR/CRi, BM-uMRD, and PB-uMRD in patients with available data were 77% (44/57), 81% (50/62), and 81% (55/68), respectively, with no differences based on IGHV status. At the median follow-up time of 40 months, PFS and OS for all patients were 97% and 99%, respectively (see Figure, below). Thirteen of 61 patients (21.3%) who completed iFCR and started ibrutinib maintenance in a BM-uMRD state have had recurrent BM-MRD, with median time to MRD recurrence not yet reached. Seven patients underwent retreatment with ibrutinib monotherapy (5 due to clinical progression and 2 due to recurrent BM-MRD without clinical progression), and all 7 achieved PR with re-treatment. Median time on re-treatment is 12.8 months (range 4.2-26.2), and none of these 7 patients have progressed on re-treatment. One patient died 17 months into ibrutinib maintenance due to presumed sudden cardiac death. In the updated safety analysis, the most common treatment-emergent Gr 3/4 adverse events were hematologic, including neutropenia 40% (up from 35%), thrombocytopenia 32% (unchanged), and anemia 11% (unchanged). Ten patients (12%, up from 9%) experienced Gr ≥3 febrile neutropenia, and 20 patients (24%, up from 11%) had Gr ≥3 infection. Any Gr atrial fibrillation was observed in 8%, and ventricular arrhythmia in 1 patient. No major bleeding events occurred. Two patients developed MDS, and both are now in CR for CLL and MDS after undergoing allo transplant. No patients developed Richter's syndrome. Conclusions With longer term follow-up (median of 40.3 months), most patients treated with iFCR have continued to maintain deep responses, including patients with unmutated IGHV. The safety profile remains consistent with the individual toxicities of ibrutinib and FCR. Among the few patients with recurrence after this time-limited therapy, all have responded to re-treatment with ibrutinib monotherapy. iFCR is worthy of exploring in comparative studies in younger, fit CLL patients who desire the possibility of functional cure with time-limited therapy. Figure 1 Figure 1. Disclosures Davids: Ascentage Pharma: Consultancy, Research Funding; Celgene: Consultancy; Eli Lilly and Company: Consultancy; Janssen: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy; Novartis: Consultancy, Research Funding; BeiGene: Consultancy; Adaptive Biotechnologies: Consultancy; Astra-Zeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Surface Oncology: Research Funding; AbbVie: Consultancy. Brander: NCCN: Other: panel member; Verastem: Consultancy; MEI Pharma: Research Funding; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; ArQule: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Pfizer: Consultancy, Other: Biosimilars outcomes research panel; DTRM: Research Funding; ArQule/Merck: Consultancy; LOXO: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Genentech: Consultancy, Research Funding; Ascentage: Research Funding; BeiGene: Research Funding. Montegaard: AbbVie: Consultancy; AstraZeneca*-: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy. Alencar: Seattle Genetics: Consultancy; Kite Pharma: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy; Incyte: Consultancy; Epizyme: Consultancy; Celgene: Consultancy; BeiGene: Consultancy; Amgen: Consultancy. Jacobson: Humanigen: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Axis: Speakers Bureau; Lonza: Consultancy, Honoraria, Other: Travel support; Clinical Care Options: Speakers Bureau; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria. Armand: Infinity: Consultancy; Pfizer: Consultancy; Kite: Research Funding; Tensha: Research Funding; IGM: Research Funding; Roche: Research Funding; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Epizyme: Consultancy; Enterome: Consultancy; Regeneron: Consultancy; C4: Consultancy; GenMab: Consultancy; Tessa Therapeutics: Consultancy; Miltenyi: Consultancy; Morphosys: Consultancy; Daiichi Sankyo: Consultancy; Otsuka: Research Funding; Sigma Tau: Research Funding; Celgene: Consultancy; ADC Therapeutics: Consultancy; Adaptive: Consultancy, Research Funding; Affimed: Consultancy, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding. Crombie: Roche: Research Funding; Merck: Research Funding; Abbvie: Research Funding; Bayer: Research Funding; Karyopharm: Consultancy; Incyte: Consultancy. LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Arnason: Juno/BMS: Honoraria. Hochberg: Trapelo Health: Consultancy; Leuko: Consultancy. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; Kite Pharma: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; C4 Therapeutics: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding; Invectys: Other: Data Safety Monitoring Committee Service; Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy. OffLabel Disclosure: Ibrutinib being used to enhance the efficacy of FCR

Background: Pts with previously treated R/R aggressive LBCL have compromised health-related QOL (HRQOL). Liso-cel is an autologous, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In a prespecified interim analysis of TRANSFORM (NCT03575351), a randomized, open-label, pivotal trial, liso-cel demonstrated statistically significant and clinically meaningful improvement in the primary endpoint of event-free survival and key secondary endpoints (complete response rate and progression-free survival) in adults with R/R LBCL after failure of first-line (1L) immunochemotherapy compared with SOC, with no new safety signals. Here we present results of the pt-reported outcomes (PRO) analysis from TRANSFORM. Methods: Adults (age ≤ 75 yrs) with R/R LBCL (≤ 12 mo after 1L therapy), who were eligible for autologous stem cell transplantation (ASCT), were randomized to receive either SOC (3 cycles of salvage chemotherapy [CT] and BEAM + ASCT for responding pts) or liso-cel after lymphodepletion. Crossover to receive liso-cel was allowed in the SOC arm for pts who failed treatment. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire - 30 items (EORTC QLQ-C30) and the Functional Assessment of Cancer Therapy - Lymphoma Subscale (FACT-LymS) were administered at randomization (baseline) and on Days 29 (infusion of liso-cel or 2 cycles of salvage CT), 64 (1 mo post liso-cel or completion of CT), 126 (3 mos post liso-cel or 2 mos post ASCT), and Mo 6 and other prespecified timepoints up to Mo 36 or end of study. No PRO data were collected after crossover. The analysis was based on the PRO-evaluable population (pts with a baseline and ≥ 1 post-baseline assessment). Predefined thresholds determined clinically meaningful changes. Global health/QOL (GH/QOL), physical functioning, cognitive functioning, fatigue, pain, and FACT-LymS were the primary domains of interest based on their relevance to the study population and treatment. A linear mixed model for repeated measures (MMRM) analysis was performed to assess the between-treatment difference in overall least squares (LS) mean change from baseline for each primary domain, using data collected up to Day 126 for visits with a sample size per arm ≥ 10. Proportions of pts with meaningful change from baseline were assessed for each primary domain up to Mo 6. All analyses were descriptive only. Results: Of 184 randomized pts, 90 (49%) and 85 (46%), respectively, were included in the PRO-evaluable population for the EORTC QLQ-C30 (SOC vs liso-cel n=43 vs 47) and FACT-LymS (n=40 vs 45, respectively). The PRO assessment completion rate from baseline up to Mo 6 was ≥ 45%, which was lower than expected primarily due to operational challenges during the COVID-19 pandemic but was comparable for both arms. In the MMRM analysis, the liso-cel arm had more favorable overall LS mean changes from baseline to Day 126 than the SOC arm in most of the EORTC QLQ-C30 domains and FACT-LymS. In particular, the between-treatment differences for cognitive functioning (−2.09 vs 2.21) and fatigue (3.75 vs −1.95) for SOC versus liso-cel, respectively, exceeded the prespecified minimal important difference threshold (Table); in those domains, the SOC arm deteriorated while the liso-cel arm improved. In individual-level analyses, the proportion of pts with meaningful improvement for fatigue and GH/QOL was higher, while deterioration was lower, in the liso-cel arm versus SOC arm from baseline up to Mo 6 (Figure). At Mo 6, a higher proportion of pts experienced worsened fatigue (71% vs 18%) and a lower proportion experienced improved fatigue (29% vs 47%) in the SOC arm compared with the liso-cel arm; for GH/QOL, a higher proportion of pts worsened (57% vs 18%) and lower proportion improved (14% vs 53%), respectively. For the other primary domains, the proportions of pts with improvement or deterioration favored liso-cel or were similar between arms. Conclusions: Compared with SOC, liso-cel showed favorable improvement in most primary PRO domains, particularly EORTC QLQ-C30 cognitive functioning and fatigue and more pts showed PRO improvements and fewer showed deterioration by Mo 6 with liso-cel. The results were achieved despite only responders remaining in the SOC arm after salvage CT. HRQOL was either improved or maintained after liso-cel treatment in pts with R/R LBCL after failure of 1L therapy. Figure 1 Figure 1. Disclosures Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; Morphosys: Consultancy; C4 Therapeutics: Consultancy; Kite Pharma: Consultancy; Kymera: Consultancy; Incyte Corporation: Consultancy; Bluebird Bio: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy; BeiGene: Consultancy. Arnason: Juno/BMS: Honoraria. Glass: BMS: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Riemser: Research Funding; Kite: Consultancy; Novartis: Consultancy; Helios Klinik Berlin-Buch: Current Employment. Crotta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Montheard: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Previtali: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Liu: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Braverman: BMS: Current Employment, Current equity holder in publicly-traded company. Guo: Daiichi Sankyo: Consultancy; UCB: Consultancy; Janssen: Consultancy; Gilead: Consultancy; Bristol Myers Squibb: Consultancy; EMD Serono: Consultancy; Evidera: Current Employment. Shi: Bristol Myers Squibb: Consultancy. Kamdar: ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; TG Therapeutics: Research Funding; Genentech: Research Funding; AbbVie: Consultancy; KaryoPharm: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy; SeaGen: Speakers Bureau; Celgene: Other; Genetech: Other; Celgene (BMS): Consultancy.

Background: Chronic graft versus host disease (cGVHD) remains a significant cause of morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HCT), with a cumulative incidence of 50% (Arora et al, Biol Blood Marrow Transplant 2016). Systemic corticosteroids are considered first-line therapy, and best approach to managing steroid-refractory cGVHD is lacking. Abatacept is a recombinant fusion protein consisting of the extracellular domain of human cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) linked to the modified Fc portion of human immunoglobulin G1 (IgG1) to prevent complement fixation and antibody-dependent cellular cytotoxicity. Abatacept is a selective costimulation modulator that binds specifically to CD80 and CD86 on antigen presenting cells, thus attenuating CD28-mediated T cell activation. We previously reported results from a Phase I clinical trial evaluating the safety and clinical efficacy of abatacept in patients with steroid-refractory cGVHD (Nahas et al, Blood 2018 #NCT01954979). Here we report results of the phase II study evaluating the overall clinical response rate of abatacept in patients with steroid-refractory cGVHD. Methods: Allogeneic bone marrow or stem cell transplantation recipients were eligible if they developed cGVHD as defined by NIH consensus criteria and were treated with prednisone ≥ 0.25 mg/kg/day for at least 4 weeks without complete resolution of signs and symptoms. Peripheral blood was drawn prior to each dose of abatacept and following completion of therapy to assess the effect of treatment on circulating T cells. Abatacept was administered at 10mg/kg for a total of 6 doses. Doses 1-3 were administered at two-week intervals. One month after administration of Dose 3, abatacept was given at four-week intervals for Doses 4-6. Patients who completed 6 doses of abatacept and continued to demonstrate response were eligible to receive extended duration therapy with monthly abatacept at a dose of 10mg/kg for up to a total of 12 additional doses. Primary study endpoint was overall response rate (ORR) of using abatacept in treating cGVHD. Complete response (CR) was defined as resolution of all manifestations in each organ or site, and partial response (PR) was defined as improvement in at least one organ or site without progression in any other organ or site as per the 2014 NIH Chronic GVHD Consensus Response Criteria (Lee et al Biol Blood Marrow Transplant 2015). Results: 39 subjects with median age of 62 years (range 25-77 years) had undergone HCT a median of 43 months (range 6-173 months) prior to study entry. Patients were treated with abatacept and received a median of 8 doses (range 2-18). 17 patients had moderate cGVHD and 22 patients had severe cGVHD at baseline. Baseline cGVHD assessment of the 39 evaluable patients showed involvement of the skin in 85% (n=33), mouth in 44% (n=17), eyes in 69% (n=27), gastrointestinal tract (GI) in 18% (n=7), liver in 23% (n=9), lung in 54% (n=21), joints in 82% (n=32), and genital tract in 8% (n=3). The ORR was 49% (19/39 patients) with CR 0% and PR 49%. The organ sites with greatest improvement included lung (33%), eyes (23%), mouth (21%), and joints (21%). Progression of disease occurred in 26% of patients (n=10), with sites of involvement including skin (8%), mouth (10%), eyes (5%), lung (3%), and joints (5%). Baseline median daily dose of prednisone was 20mg with a 27.5% reduction at 1-month follow-up to 14.5mg (p Conclusions: Abatacept is associated with a 49% ORR in steroid refractory cGVHD and leads to durable reduction in prednisone dosing over time. Severe infections are uncommon and the infusions are well tolerated. Abatacept represents a promising novel therapeutic agent for patients with steroid-refractory cGVHD. Disclosures Stroopinsky: The Blackstone Group: Consultancy. Arnason: Juno/BMS: Honoraria. Cutler: Cimeio: Consultancy; Editas: Consultancy; Kadmon: Consultancy; Pfizer: Consultancy; Mallinckrodt: Consultancy; CareDx: Consultancy; Incyte: Consultancy; Omeros: Consultancy; Syndax: Consultancy; Mesoblast: Consultancy; Deciphera: Consultancy; Jazz: Consultancy. Nikiforow: Kite/Gilead: Other: ad HOC Advisory Boards; Novartis: Other: ad Hoc Advisory Boards; Iovance: Other: ad Hoc Advisory Boards; Glaxo Smith Kline (GSK): Other: ad Hoc Advisory Boards. Avigan: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy, Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Aviv MedTech Ltd: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Legend Biotech: Membership on an entity's Board of Directors or advisory committees; Chugai: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy; Parexcel: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. Soiffer: Rheos Therapeutics, USA: Consultancy; Kiadis, Netherlands: Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics, USA: Other: Data Safety Monitoring Board; Precision Biosciences, USA: Consultancy; Jazz Pharmaceuticals, USA: Consultancy; Takeda: Consultancy; Jasper: Consultancy; Gilead, USA: Other: Career Development Award Committee; NMPD - Be the Match, USA: Membership on an entity's Board of Directors or advisory committees. Rosenblatt: Attivare Therapeutics: Consultancy; Parexel: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Wolters Kluwer Health: Consultancy, Patents & Royalties; Bristol-Myers Squibb: Research Funding.

Background: Pts with LBCL primary refractory to or relapsed ≤ 12 mo after first-line (1L) therapy may have poor outcomes with SOC, including salvage CT and ASCT, which underscores a critical unmet need. Liso-cel is an autologous CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In the TRANSCEND NHL 001 study (NCT02631044) in pts with R/R LBCL (≥ 2 prior lines of therapy), liso-cel treatment resulted in an ORR of 73% (CR rate, 53%), 2% grade ≥ 3 cytokine release syndrome (CRS), and 10% grade ≥ 3 neurological events (NE) (Abramson et al. Lancet 2020). Here we present a prespecified interim analysis of TRANSFORM (NCT03575351; SOC vs liso-cel as 2L therapy in pts with R/R LBCL). Methods: TRANSFORM is a pivotal, global, randomized, multicenter, phase 3 study comparing efficacy and safety of SOC (Arm A; R-DHAP, R-ICE, or R-GDP per investigator choice followed by BEAM + ASCT) vs liso-cel (Arm B). Pts were adults (aged ≤ 75 years), eligible for ASCT, and with LBCL primary refractory to or relapsed ≤ 12 mo after 1L therapy. Key inclusion criteria were ECOG PS ≤ 1 and adequate organ function (LVEF ≥ 40%; serum CrCl > 45 mL/min); pts with secondary CNS lymphoma were allowed. Key exclusion criteria were prior gene or anti-CD19-targeted therapy, and active infection. Pts in Arm A were to receive 3 cycles of CT. Responding pts (CR or PR) were to proceed to BEAM + ASCT. Pts in Arm B were to undergo lymphodepletion with fludarabine/cyclophosphamide followed by liso-cel at a target dose of 100 × 10 6 CAR + T cells. Bridging therapy with an Arm A CT regimen was allowed. Crossover to receive liso-cel was allowed in Arm A for pts not achieving CR or PR after 3 cycles of CT or not in CR after ASCT, or demonstrating PD at any time. Primary endpoint is event-free survival (EFS) based on independent review committee per Lugano 2014 criteria, defined as time from randomization to death from any cause, PD, failure to achieve CR or PR by 9 weeks after randomization, or start of new antineoplastic therapy, whichever occurred first. Key secondary endpoints included in the testing strategy are CR rate, PFS, and OS. P value significance threshold for endpoints to reject the null hypothesis was ≤ 0.012. Results: A total of 184 pts were randomized, with 92 pts in each arm. Baseline characteristics were well balanced between both arms (Table). Of 91 treated pts in Arm A (1 pt withdrew consent), 43 received BEAM + ASCT, of which 28 achieved CR with CT. Fifty pts crossed over to receive liso-cel. In Arm B, 90 pts received liso-cel infusion; 58 pts (63%) received bridging therapy. Two Arm B pts were not infused (1 each due to manufacturing failure and rapid progression). Median EFS and PFS were significantly longer, and CR rate was significantly improved for Arm B vs Arm A. For Arms A and B, respectively, median EFS was 2.3 vs 10.1 mo (HR, 0.349; P < 0.0001), median PFS was 5.7 vs 14.8 mo (HR, 0.406; P = 0.0001), and CR rate was 39% vs 66% (P < 0.0001). OS data were immature at the time of this analysis with a median follow-up of 6.2 mo (range, 0.9-20.0), but a numerical trend favored Arm B (HR, 0.509; 95% CI, 0.258-1.004; P = 0.0257). Cellular kinetics in Arm B showed a median t max of 10 d (range, 6‒22). No new liso-cel safety signals were detected in the 2L setting. In Arm B, any-grade CRS was reported in 49% of pts, with grade 1 in 37% and grade 2 in 11%. Only 1 pt had grade 3 CRS (onset at Day 9, which resolved in 2 days). Any-grade NEs were reported in 12% of pts and were also primarily low grade (grade 3, 4%). No grade 4 or 5 CRS or NEs were reported. In Arm B, 24% of pts received tocilizumab, 17% received corticosteroids, and none received vasopressors. The most common TEAEs in both arms were cytopenias. Prolonged cytopenias in Arm B (ie, grade ≥ 3 at 35 d after infusion) were reported in 43% of pts; the majority recovered within 2 mo after infusion. Conclusions: In the TRANSFORM study, liso-cel demonstrated statistically significant and clinically meaningful improvement in the primary endpoint, EFS, as well as in key secondary efficacy endpoints (CR rate and PFS) compared with SOC as 2L therapy in pts with LBCL primary refractory to or relapsed ≤ 12 mo after 1L therapy. Safety results in the 2L setting were consistent with the liso-cel safety profile in 3L or later LBCL, and no new safety concerns were identified. Liso-cel improved outcomes vs SOC and exhibited a favorable safety profile, providing support for liso-cel as a potential new SOC for 2L treatment in pts with R/R LBCL. Figure 1 Figure 1. Disclosures Kamdar: SeaGen: Speakers Bureau; ADC Therapeutics: Consultancy; Celgene: Other; TG Therapeutics: Research Funding; KaryoPharm: Consultancy; Celgene (BMS): Consultancy; Genetech: Other; Genentech: Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; Kite: Consultancy; AstraZeneca: Consultancy. Arnason: Juno/BMS: Honoraria. Glass: BMS: Consultancy; Roche: Consultancy, Research Funding, Speakers Bureau; Riemser: Research Funding; Kite: Consultancy; Novartis: Consultancy; Helios Klinik Berlin-Buch: Current Employment. Bachanova: KaryoPharma: Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; FATE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ibrahimi: Karyopharm Theraputics: Divested equity in a private or publicly-traded company in the past 24 months. Mielke: Immunicum: Other: Data safety monitoring board; Novartis: Speakers Bureau; Miltenyi: Other: Data safety monitoring board; DNA Prime SA: Speakers Bureau; Gilead/KITE: Other: Travel support, Expert panel ; Celgene/BMS: Speakers Bureau. Mutsaers: BMS: Consultancy; AstraZeneca: Research Funding. Hernandez-Ilizaliturri: Kite: Other: Advisory Boards; Amgen: Other: Advisory Boards; Pharmacyclics: Other: Advisory Boards; BMS: Other: Advisory Boards; Celgene: Other: Advisory Boards; Incyte: Other: Advisory Boards; AbbVie: Other: Advisory Boards; Gilead: Other: Advisory Boards; Epyzime: Other: Advisory Boards. Izutsu: Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Solasia: Research Funding; Symbio: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Morschhauser: Celgene: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Janssen: Honoraria; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Speakers Bureau; Chugai: Honoraria; Servier: Consultancy; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lunning: Karyopharm: Consultancy; AstraZeneca: Consultancy; Legend: Consultancy; Verastem: Consultancy; Janssen: Consultancy; Myeloid Therapeutics: Consultancy; Daiichi-Sankyo: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AbbVie: Consultancy; Acrotech: Consultancy; Beigene: Consultancy; ADC Therapeutics: Consultancy; TG Therapeutics: Consultancy; Morphosys: Consultancy; Kite, a Gilead Company: Consultancy; Kyowa Kirin: Consultancy. Maloney: Amgen: Honoraria; Celgene: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; A2 Biotherapeutics: Honoraria, Other: Stock options; BMS: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Celgene: Other: Research funding was paid to my institution, Research Funding; Umoja: Honoraria; Janssen: Honoraria; Legend Biotech: Honoraria; Genentech: Honoraria; Novartis: Honoraria; MorphoSys: Honoraria; Juno therapeutics: Other: Research funding was paid to my institution, Research Funding; Navan Technologies: Honoraria, Other: Stock options; Kite Pharma: Honoraria, Other: Research funding was paid to my institution, Research Funding; Juno Therapeutics: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb. Crotta: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Montheard: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Previtali: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Stepan: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ogasawara: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Mack: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Abramson: Bluebird Bio: Consultancy; EMD Serono: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Morphosys: Consultancy; C4 Therapeutics: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Genmab: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. OffLabel Disclosure: Liso-cel is a CAR T cell therapy approved for use in the third line for R/R LBCL. This trial reports data from the pivotal trial in the second line.

Background : LBCLs are prevalent and aggressive subtypes of NHL, with limited treatment options and historically poor outcomes in the third- or later-line setting. Liso-cel is an autologous, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. TRANSCEND NHL 001 (NCT02631044) is a seamless design, pivotal, phase 1 study evaluating liso-cel in patients (pts) with R/R LBCLs (Abramson et al. Lancet 2020). We present 2-year follow-up data from the LBCL cohort. Methods: Pts ≥ 18 years of age with R/R DLBCL not otherwise specified (NOS, including de novo and transformed from any indolent lymphoma), high-grade B-cell lymphoma (HGBCL) with MYC and BCL2 and/or BCL6 rearrangements, primary mediastinal B-cell lymphoma (PMBCL), or follicular lymphoma grade 3B (FL3B) after ≥ 2 lines of therapy and with ECOG PS 0-2 were eligible. Pts with grade 3 or 4 cytopenias, mild to moderate organ dysfunction, and secondary CNS lymphoma were allowed. Bridging therapy was allowed at clinician discretion but reconfirmation of PET-positive disease was required before lymphodepletion with fludarabine and cyclophosphamide. Primary endpoints were treatment-emergent AEs (TEAE) and ORR. Key secondary endpoints were CR rate, duration of response (DOR), PFS, and OS. TEAEs, including investigator-identified neurological events (NE) related to liso-cel, were graded using NCI CTCAE v4.03; cytokine release syndrome (CRS) was graded per Lee 2014 criteria in the liso-cel-treated set (all pts who received ≥ 1 dose of liso-cel). ORR was assessed by an independent review committee (IRC) per Lugano 2014 criteria in the efficacy-evaluable set (all pts with confirmed PET-positive disease who received ≥ 1 dose of liso-cel). Pts were followed for 2 years after the last dose of liso-cel and were then asked to enroll in a separate long-term follow-up study for up to 15 years (NCT03435796). Results: A total of 345 pts underwent leukapheresis. In the liso-cel-treated set (N = 270), median age was 63 years (range, 18-86); 41% of pts were ≥ 65 years of age. Histologies included DLBCL NOS (de novo, 51%; transformed from indolent lymphoma, 29%), HGBCL (13%), PMBCL (6%), and FL3B (1%). Seven pts (3%) had secondary CNS lymphoma. Pts received a median of 3 prior lines of systemic therapy (range, 1-8) and 33% had prior autologous HSCT (prior allogeneic HSCT, 3%). Of all pts, 67% were chemotherapy refractory, 45% had never achieved CR, and 59% received bridging therapy. As of the Jan 4, 2021 data cut, study is ongoing; 268 pts had ≥ 24 months (mo) of follow-up, died, or withdrew from the study. Responses per IRC (ORR, 73%; CR rate, 53%) in the efficacy-evaluable set (N = 257) were durable with a median (95% CI) DOR of 23.1 mo (8.6-not reached), median PFS of 6.8 mo (3.3-12.7), and median OS of 27.3 mo (16.2-45.6) (Table). At 24 mo, the probabilities (95% CI) of continued response, PFS, and OS were 49.5% (41.4%-57.0%), 40.6% (34.0%-47.2%), and 50.5% (44.1%-56.5%), respectively. During the 90-day treatment-emergent (TE) reporting period, 79% of pts in the liso-cel-treated set (N = 270) had grade ≥ 3 TEAEs; 45% had serious TEAEs. CRS and NE of any grade occurred in 42% and 30% of pts, respectively (grade 3-4 CRS, 2%; grade 3-4 NE, 10%). Median (range) time to onset of CRS and NE was 5 (1-14) and 9 (1-66) days, respectively. Grade ≥ 3 infections and laboratory-based prolonged cytopenia at Day 29 occurred in 12% and 37% of pts, respectively. In the post-TE (Day 91 to end of study) reporting period, which included 17 pts who received liso-cel re-treatment, 23% of pts in the liso-cel-treated set (N = 249) had grade ≥ 3 AEs and 17% had serious AEs. The most common grade ≥ 3 AEs in the post-TE period were neutropenia (7%), anemia (6%), thrombocytopenia (4%), and febrile neutropenia (4%). Grade ≥ 3 infections occurred in 5% of pts. In the post-TE period, 100 pts (37% of all pts) died, mostly due to disease progression (86% of all post-TE deaths; 32% of all pts). CAR T cells were present in peripheral blood for up to 4 years. Conclusions: Liso-cel demonstrated durable remissions with estimated 2-year DOR and PFS rates of 49.5% and 40.6%, respectively, and a favorable safety profile in the extended follow-up analysis of this large CAR T cell study in R/R LBCLs. Most CAR T cell-associated AEs occurred within the initial 90-day TE reporting period. No new safety signals were observed during long-term follow-up. Figure 1 Figure 1. Disclosures Abramson: Genmab: Consultancy; Kite Pharma: Consultancy; C4 Therapeutics: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Kymera: Consultancy; Bluebird Bio: Consultancy; EMD Serono: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; BeiGene: Consultancy; Allogene Therapeutics: Consultancy; Astra-Zeneca: Consultancy; Incyte Corporation: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Palomba: Rheos: Honoraria; Novartis: Consultancy; Lygenesis: Honoraria; Priothera: Honoraria; Juno: Patents & Royalties; Notch: Honoraria, Other: Stock; Pluto: Honoraria; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Magenta: Honoraria; WindMIL: Honoraria; Kite: Consultancy; Ceramedix: Honoraria; Nektar: Honoraria; Wolters Kluwer: Patents & Royalties; PCYC: Consultancy; BeiGene: Consultancy. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Lunning: Myeloid Therapeutics: Consultancy; Spectrum: Consultancy; TG Therapeutics: Consultancy; AbbVie: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy; Beigene: Consultancy; Daiichi-Sankyo: Consultancy; Novartis: Consultancy; Kyowa Kirin: Consultancy; Legend: Consultancy; Janssen: Consultancy; ADC Therapeutics: Consultancy; Acrotech: Consultancy; Verastem: Consultancy; Celgene, a Bristol Myers Squibb Co.: Consultancy; AstraZeneca: Consultancy; Kite, a Gilead Company: Consultancy. Wang: Molecular Templates: Research Funding; BGICS: Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Oncternal: Consultancy, Research Funding; Bayer Healthcare: Consultancy; Physicians Education Resources (PER): Honoraria; InnoCare: Consultancy, Research Funding; CAHON: Honoraria; OMI: Honoraria; Loxo Oncology: Consultancy, Research Funding; The First Afflicted Hospital of Zhejiang University: Honoraria; Lilly: Research Funding; Scripps: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; Clinical Care Options: Honoraria; Celgene: Research Funding; Imedex: Honoraria; Pharmacyclics: Consultancy, Research Funding; Chinese Medical Association: Honoraria; Mumbai Hematology Group: Honoraria; Dava Oncology: Honoraria; Moffit Cancer Center: Honoraria; Epizyme: Consultancy, Honoraria; DTRM Biopharma (Cayman) Limited: Consultancy; Genentech: Consultancy; CStone: Consultancy; Kite Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Hebei Cancer Prevention Federation: Honoraria; Newbridge Pharmaceuticals: Honoraria; Juno: Consultancy, Research Funding; BioInvent: Research Funding; VelosBio: Consultancy, Research Funding; Acerta Pharma: Consultancy, Honoraria, Research Funding. Arnason: Juno/BMS: Honoraria. Maloney: Janssen: Honoraria; MorphoSys: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; BMS: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb; Amgen: Honoraria; Celgene: Other: Research funding was paid to my institution, Research Funding; Juno therapeutics: Other: Research funding was paid to my institution, Research Funding; Kite Pharma: Honoraria, Other: Research funding was paid to my institution, Research Funding; Navan Technologies: Honoraria, Other: Stock options; A2 Biotherapeutics: Honoraria, Other: Stock options; Umoja: Honoraria; Genentech: Honoraria; Legend Biotech: Honoraria; Juno Therapeutics: Honoraria, Other: Rights to royalties from Fred Hutchinson Cancer Research Center for patents licensed to Juno Therapeutics/Bristol Myers Squibb. Andreadis: Merck: Research Funding; BMS: Research Funding; CRISPR Therapeutics: Research Funding; GenMAB: Research Funding; Novartis: Research Funding; Roche: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Epizyme: Honoraria; Incyte: Honoraria; TG Therapeutics: Honoraria; Kite: Honoraria; Karyopharm: Honoraria; Atara: Consultancy, Honoraria. Sehgal: Juno/Celgene: Research Funding; Kite/Gilead: Research Funding. Ghosh: Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; Karyopharma: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genmab: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria; TG Therapeutics: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau. Kostic: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Kim: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ogasawara: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Dehner: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Siddiqi: BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno 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; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Speakers Bureau; Oncternal: Research Funding.

Multiple myeloma (MM) is characterized by progressive immune dysregulation, loss of myeloma-specific immunity, and an immunosuppressive milieu that fosters disease growth and immune escape. Accordingly, cancer vaccines that reverse tumor-associated immune suppression represent a promising therapeutic avenue of investigation. We examined the potential of an allogeneic cellular vaccine to generate immune responses against MM tumor cells. The DCOne vaccine is comprised of a human myeloid leukemia cell line differentiated into a fully functional dendritic cell, expressing a range of tumor-associated antigens that are also known targets in MM. We found that the myeloma-specific antigens expressed by the DCOne vaccine can traffic via extracellular vesicles to surrounding antigen-presenting cells, thus stimulating autologous T-cell responses. Indeed, coculture of peripheral blood mononuclear cells from patients with MM with the DCOne vaccine resulted in the expansion of activated CD8 T cells expressing interferon-γ and perforin, with no significant change in the percentage of CD4 T cells producing interleukin-10. Further, coculture of patient's tumor cells with peripheral blood mononuclear cells and DCOne induced cytotoxic T-lymphocyte-mediated killing of autologous MM cells. These findings demonstrate that the allogeneic DCOne vaccine can induce T-cell activation and myeloma-specific immunity via cross presentation of antigens by native antigen-presenting cells.

The PD-L1/PD-1 pathway is a critical component of the immunosuppressive tumor microenvironment in acute myeloid leukemia (AML), but little is known about its regulation. We investigated the role of the MUC1 oncoprotein in modulating PD-L1 expression in AML. Silencing of MUC1 in AML cell lines suppressed PD-L1 expression without a decrease in PD-L1 mRNA levels, suggesting a post-transcriptional mechanism of regulation. We identified the microRNAs miR-200c and miR-34a as key regulators of PD-L1 expression in AML. Silencing of MUC1 in AML cells led to a marked increase in miR-200c and miR-34a levels, without changes in precursor microRNA, suggesting that MUC1 might regulate microRNA-processing. MUC1 signaling decreased the expression of the microRNA-processing protein DICER, via the suppression of c-Jun activity. NanoString (Seattle, WA, USA) array of MUC1-silenced AML cells demonstrated an increase in the majority of probed microRNAs. In an immunocompetent murine AML model, targeting of MUC1 led to a significant increase in leukemia-specific T cells. In concert, targeting MUC1 signaling in human AML cells resulted in enhanced sensitivity to T-cell-mediated lysis. These findings suggest MUC1 is a critical regulator of PD-L1 expression via its effects on microRNA levels and represents a potential therapeutic target to enhance anti-tumor immunity.

Myeloid-derived suppressor cells (MDSCs) play a critical role in promoting immune tolerance and disease growth. The mechanism by which tumor cells evoke the expansion of MDSCs in acute myeloid leukemia (AML) has not been well described. We have demonstrated that patients with AML exhibit increased presence of MDSCs in their peripheral blood, in comparison with normal controls. Cytogenetic studies demonstrated that MDSCs in patients with AML may be derived from leukemic or apparently normal progenitors. Engraftment of C57BL/6 mice with TIB-49 AML led to an expansion of CD11b+ Gr1+ MDSCs in bone marrow and spleen. Coculture of the AML cell lines MOLM-4, THP-1 or primary AML cells with donor peripheral blood mononuclear cells elicited a cell contact-dependent expansion of MDSCs. MDSCs were suppressive of autologous T-cell responses as evidenced by reduced T-cell proliferation and a switch from a Th1 to a Th2 phenotype. We hypothesized that the expansion of MDSCs in AML is accomplished by tumor-derived extracellular vesicles (EVs). Using tracking studies, we demonstrated that AML EVs are taken-up myeloid progenitor cells, resulting in the selective proliferation of MDSCs in comparison with functionally competent antigen-presenting cells. The MUC1 oncoprotein was subsequently identified as the critical driver of EV-mediated MDSC expansion. MUC1 induces increased expression of c-myc in EVs that induces proliferation in the target MDSC population via downstream effects on cell cycle proteins. Moreover, we demonstrate that the microRNA miR34a acts as the regulatory mechanism by which MUC1 drives c-myc expression in AML cells and EVs.

Background: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma (NHL). Most patients with MCL relapse after first-line immunochemotherapy, with poor responses to salvage therapy. Chimeric antigen receptor (CAR) T cell therapy has shown clinical efficacy in patients with relapsed/refractory (R/R) NHL. We report the results of the dose-finding and dose-expansion parts of the ongoing phase 1 TRANSCEND NHL 001 study (NCT02631044) in patients with R/R MCL (MCL cohort) who received lisocabtagene maraleucel (liso-cel), an investigational, CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. Methods: Eligible patients had confirmed MCL (cyclin D1 expression, t[11;14]) with R/R disease after ≥1 prior line of therapy. After lymphodepleting chemotherapy, patients received liso-cel infusion at 1 of 2 dose levels (DLs): DL1 (50 × 106 CAR+ T cells) or DL2 (100 × 106 CAR+ T cells). Bridging therapy was allowed between leukapheresis and initiation of lymphodepleting chemotherapy. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included complete response (CR) rate, duration of response, progression-free survival, overall survival, and pharmacokinetics (PK). Results: At data cutoff, 41 patients had undergone leukapheresis and 32 had received liso-cel (DL1, n = 6; DL2, n = 26). Among the 32 patients who received liso-cel, the median (range) age was 67 (36‒80) years and 27 patients (84%) were male. Twelve patients (37.5%) had blastoid morphology, 23 (72%) had documented Ki67 ≥30%, 7 (22%) had a TP53 mutation, and 11 (34%) had a complex karyotype. Patients had a median (range) sum of the product of perpendicular diameters before lymphodepleting chemotherapy of 28.7 (0-209.6) cm2 and median lactate dehydrogenase of 251.5 (117-811) U/L. Patients had received a median (range) of 3 (1-7) prior systemic therapies, and most (72%) were refractory to their last prior therapy. Of 28 patients (87.5%) who had received a prior Bruton tyrosine kinase inhibitor, 11 (34%) were refractory to the therapy. Seventeen patients (53%) received bridging therapy. Eighteen patients (56%) had serious treatment-emergent adverse events (TEAEs), and 27 (84%) had grade ≥3 TEAEs, primarily neutropenia (41%), anemia (34%), and thrombocytopenia (31%). Grade ≥3 thrombocytopenia was more frequent at DL2 (n = 9/26 [35%]) than at DL1 (n = 1/6 [17%]). Prolonged grade ≥3 cytopenias (present at study Day 29) occurred in 11 patients (34%). Sixteen patients (50%; DL1, n = 2/6 [33%]; DL2, n = 14/26 [54%]) had cytokine release syndrome (CRS), including 1 grade 4 event at DL2. There were no grade 3 or 5 CRS events. Median (range) time to CRS onset and resolution was 6 (2‒10) days and 4 (2‒9) days, respectively. Nine patients (28%) had neurological events (NEs), all at DL2, including 3 grade 3 NEs. No grade 4 or 5 NEs were reported. Median (range) time to NE onset and resolution was 8 (2‒25) days and 3 (1‒51) days, respectively. Ten patients (31%) received tocilizumab and/or corticosteroids for treatment of CRS and/or NEs. Grade 5 TEAEs occurred in 2 patients (at DL2): one patient with high tumor burden had tumor lysis syndrome and 1 patient had cryptococcal meningoencephalitis. DL2 was selected for dose expansion. Of 32 patients, 27 responded to liso-cel (ORR, 84%: DL1, n = 4/6 [67%]; DL2, n = 23/26 [88%]), and 19 (59%) achieved a CR (DL1, n = 2/6 [33%]; DL2, n = 17/26 [65%]). Among the 12 patients with blastoid morphology, 9 patients had a response (ORR, 75%), including 7 (58%) who achieved a CR. Overall, the median (range) time to first CR was 1 (1-6) month. At data cutoff, 20 (74%) of 27 responders were censored with an ongoing response or had completed the study. Median (range) follow-up duration was 10.9 (1.2-24.8) months for DL1 and 3.1 (0.4-23.0) months for DL2. Preliminary PK analysis indicated that median maximum expansion was higher among patients at DL2 than at DL1. Conclusions: In this phase 1 study of patients with R/R MCL, treatment with liso-cel was associated with a low incidence of grade ≥3 CRS and NEs, late onset of CRS/NEs, and promising clinical activity. Dose confirmation is ongoing at DL2 in the MCL cohort. Disclosures Palomba: Pharmacyclics: Honoraria; Juno: Honoraria; Celgene: Honoraria; Merck: Honoraria; Novartis: Honoraria; Regeneron: Research Funding; Juno: Research Funding; Genentech: Research Funding. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Siddiqi:Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DMC member; Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding; AstraZeneca: Other: Travel/accommodations/expenses; Astrazenca: Membership on an entity's Board of Directors or advisory committees; PCYC: Membership on an entity's Board of Directors or advisory committees. Abramson:Celgene: Honoraria, Other: Scientific Advisory Board; Juno Therapeutics: Other: Scientific Advisory Board; AbbVie: Other: Scientific Advisory Board; EMD Serono: Other: Scientific Advisory Board; Genentech/Roche: Other: Scientific Advisory Board; Janssen: Other: Scientific Advisory Board; Karyopharm: Other: Scientific Advisory Board; Gilead: Other: Scientific Advisory Board; Verastem: Other: Scientific Advisory Board; Bayer: Other: Scientific Advisory Board; Merck: Other; KIte Pharma: Other; Novartis: Other; Amgen: Other; Seattle Genetics: Other; Allogene: Other; Morphosys: Other; C4 Therapeutics: Other; BeiGene: Other; AstraZeneca: Honoraria; Incyte: Honoraria. Kamdar:Seattle Genetics: Speakers Bureau; Karyopharm: Consultancy; BMS: Consultancy; Abbvie: Consultancy; AstraZeneca: Consultancy; Pharmacyclics: Consultancy. Lunning:Acrotech: Consultancy; ADC Therapeutics: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Research Funding; Curis: Research Funding; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; TG Therapeutics: Research Funding; Verastem: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Legend: Consultancy; Beigene: Consultancy, Honoraria; Aeratech: Consultancy, Honoraria. Maloney:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; A2 Biotherapeutics: Consultancy, Current equity holder in publicly-traded company, Honoraria; Juno Therapeutics: Consultancy, Honoraria, Patents & Royalties: Patents are pending, but not issued, licensed, no royalties, no licensees., Research Funding; Bioline Rx: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Andreadis:Genentech: Other: Spouse Employee (salary and stock); Novartis: Research Funding; Celgene/Juno: Research Funding; Amgen: Research Funding; Merck: Research Funding; Gilead/Kite: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Astellas: Other: Advisor; Seattle Genetics: Other: Advisor; Karyopharm: Other: Advisor; Incyte: Other. Arnason:Regeneron: Consultancy; Juno: Consultancy. Ghosh:Forty Seven Inc: Consultancy, Other: Research Bureau, Research Funding; Genmab: Consultancy, Speakers Bureau; AbbVie: Speakers Bureau; Karyopharm: Consultancy; Juno/Celgene/Bristol-Myers Squibb: Consultancy, Research Funding; Kite/Gilead: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Roche/Genentech: Research Funding; SGN: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Consultancy, Research Funding; Celgene/Bristol-Myers Squibb: Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding, Speakers Bureau. Mehta:Innate Pharmaceuticals: Research Funding; Kite/Gilead: Research Funding; Merck: Research Funding; Gelgene/BMS: Research Funding; Oncotartis: Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Juno Parmaceuticals/BMS: Research Funding; fortyseven Inc/Gilead: Research Funding; Takeda: Research Funding; Roche-Genentech: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Affimed: Research Funding. Farazi:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Garcia:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb Company: Current equity holder in publicly-traded company. Dehner:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Ogasawara:Bristol-Myers Squibb: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Gao:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current Employment. Wang:Juno: Consultancy, Research Funding; Acerta Pharma: Research Funding; Loxo Oncology: Consultancy, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; InnoCare: Consultancy; Kite Pharma: 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; MoreHealth: Consultancy; Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Molecular Templates: Research Funding; Verastem: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Pulse Biosciences: Consultancy; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Oncternal: Consultancy, Research Funding; Nobel Insights: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Targeted Oncology: Honoraria; BioInvent: Research Funding; VelosBio: Research Funding.

BACKGROUND: Odronextamab (REGN1979) is a first-in-class, hinge-stabilized, fully human IgG4-based CD3 x CD20 bispecific antibody (bsAb) that has demonstrated encouraging safety, tolerability and preliminary efficacy in a first-in-human study of patients (pts) with relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL). We report updated safety and efficacy data from the dose escalation and early dose expansion phase of the ongoing Phase (P)1 study (NCT02290951). METHODS: Odronextamab was administered using a step-up dose schedule consisting of an initial dose at Week (W)1, an intermediate dose at W2, and thereafter, a fixed weekly dose until W12 followed by maintenance Q2W dosing. Dexamethasone premedication was used to mitigate the risk for cytokine release syndrome (CRS). Key primary objectives were to assess safety and dose-limiting toxicities (DLTs), and to establish a maximum tolerated dose (MTD) and recommended P2 dosing regimen (RP2DR). Secondary objectives included a preliminary assessment of anti-tumor activity. RESULTS: As of Jun 25, 2020, 127 pts with R/R B-NHL have been treated at doses ranging from 0.03-320 mg. The study included pts with diffuse large B-cell lymphoma (DLBCL; n=71), follicular lymphoma (FL) Grade (Gr) 1-3a (n=37), mantle cell lymphoma (MCL; n=11), marginal zone lymphoma (n=6), and other B-NHLs (n=2). Pts were highly refractory (80.3%) and had received a median of 3 (range: 1‒11) prior lines of therapy; 29 pts (22.8%) received prior CAR T therapy (FL: 2; DLBCL: 25; MCL: 2) and 85 pts (66.9%) were double refractory to alkylator and anti-CD20 antibody, in any line of therapy. Median follow-up was 3.9 (0.4‒37.6) months (mo). No DLTs were reported during dose escalation and MTD was not reached with odronextamab doses up to 320 mg weekly. The most frequent treatment-related adverse events (AEs) of any grade were pyrexia (76.4%), CRS (62.2%), and chills (48.0%). Gr 3 CRS occurred in 8 pts (6.3%) and a Gr 4 CRS occurred in 1 pt (0.8%). Most of the CRS events occurred during the first 2 weeks of step-up dosing and resolved within a median of 2 days (range 1-41) with supportive care measures. No pts discontinued odronextamab treatment due to CRS. Gr 3 neurologic AEs were noted in 5 pts, of which only 3 (2.3%) were considered treatment-related: somnolence, syncope, and encephalopathy. None of these events required treatment discontinuation. There were no Gr 4 or higher neurologic AEs. Overall, 7 pts (5.5%) discontinued treatment due to treatment-related AEs. In pts with R/R FL Gr 1-3a, odronextamab demonstrated a broad window of therapeutic activity. In pts treated at doses of ≥5 mg (n=28), objective response rate (ORR) was 92.9%, and complete response (CR) rate was 75.0%; median duration of response (DoR) was 7.7 mo (range 0+-20.9+), with 13 of 21 CRs ongoing at last tumor assessment. The median duration of complete response (DoCR) was 8.1 mo (range 0+-19.9+) and follow-up is ongoing (Table). In pts with R/R DLBCL, encouraging activity was observed at higher odronextamab dose levels. In DLBCL pts who had not received prior CAR T therapy, treated at doses ≥80 mg (n=10), ORR and CR rate were 60%; median observed DoR was 10.3 mo (range 2.9-18.6+), with 4 of 6 CRs ongoing at last tumor assessment. The median DoCR was 9.5 mo (range 2.9-18.6+) and follow-up is ongoing. In DLBCL pts who were refractory to prior CAR T therapy, treated at doses ≥80 mg (n=21), ORR was 33.3%, and CR rate was 23.8%; median observed DoR was 2.8 mo (range 0+-18.9+), with 5 of 5 CRs ongoing at last tumor assessment. The median DoCR was 4.4 mo (range 0+-18.9+) and follow-up is ongoing. Based on an evaluation of preliminary antitumor activity and PK, RP2DR was identified for dose expansion cohorts. CONCLUSIONS: Odronextamab has demonstrated encouraging single agent antitumor activity in highly refractory pts with B-NHLs. Durable CRs have been observed in both indolent and aggressive B-NHL pts, including in pts refractory to CAR T therapy. Most CRs are ongoing at time of data cutoff, and updated data will be presented. Odronextamab has an acceptable safety and tolerability profile. Dexamethasone premedication and step-up dosing mitigates the risk for CRS and allows odronextamab administration up to 320 mg weekly without DLTs. A global P2 trial investigating odronextamab in R/R B-NHL is ongoing. Disclosures Bannerji: Regeneron Pharmaceuticals: Research Funding; AbbVie: Research Funding; Sanofi-Pasteur: Other: Spouse is employee; F. Hoffmann-La Roche Ltd/Genentech, Inc and Pharmacyclics LLC, an AbbVie Company: Research Funding. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding. Arnason:Regeneron: Consultancy; Juno: Consultancy. Brown:Catapult: Consultancy; Sun: Research Funding; Loxo: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; TG Therapeutics: Consultancy; Sunesis: Consultancy; Rigel Pharmaceuticals: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novartis: Consultancy; Nextcea: Consultancy; MEI Pharma: Consultancy; Kite: Consultancy; Juno/Celgene: Consultancy; Eli Lilly and Company: Consultancy; Dynamo Therapeutics: Consultancy; BeiGene: Consultancy; Gilead: Consultancy, Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Acerta: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy. Advani:Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding; Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy. Ansell:Bristol Myers Squibb: Research Funding; Takeda: Research Funding; Trillium: Research Funding; ADC Therapeutics: Research Funding; Affimed: Research Funding; Seattle Genetics: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding. O'Brien:Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Kite, Regeneron, Acerta: Research Funding; Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy. Duell:Morphosys: Research Funding. Martin:Sandoz: Consultancy; Karyopharm: Consultancy, Research Funding; Celgene: Consultancy; Teneobio: Consultancy; I-MAB: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Janssen: Consultancy. Li:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Flink:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Zhu:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Weinreich:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Yancopoulos:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Sirulnik:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Chaudhry:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Ambati:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. OffLabel Disclosure: The data described in the abstract will report on use of odronextamab in a Phase 1 clinical trial of patients with B-NHL

Introduction: The MURANO study demonstrated that venetoclax (VEN) plus rituximab is an effective regimen for pts with relapsed/refractory (R/R) CLL, but included 2 years of treatment and an infusional component (Seymour et al., NEJM, 2018). Duvelisib (DUV) is an oral inhibitor of PI3K-δ/γ approved for R/R CLL/SLL after two prior therapies. We hypothesized that DUV + VEN would lead to deep remissions that allow for oral, time-limited therapy. DUV + VEN is also promising for Richter's Syndrome (RS), as this combination was synergistic in preclinical models (Iannello et al., ASH, 2019). Here we report the safety and preliminary efficacy of DUV + VEN in pts with R/R CLL/SLL and RS. Methods: This is an ongoing investigator-initiated phase I/II trial (NCT03534323) with primary endpoints: DLTs, MTD, and RP2D (phase I) and CR rate (phase II). Secondary endpoints: PK, preliminary efficacy. Pts are treated with a 7-day lead in of DUV 25 mg BID. In the phase I trial, on day 8, DUV was continued and VEN initiated at 10 mg or 20 mg (inpt) with weekly ramp-up to 20/50/100 (dose level (DL)1), 200 mg (DL2), and 400 mg (DL3) using a 3+3 design. In phase II VEN is started at 10 mg (outpt) or 20 mg (inpt) on day 8 and ramped up to 400 mg on a weekly basis. Pts with RS have the option of an accelerated VEN ramp-up to 400 mg over 5 days (inpt). Pts are treated with DUV + VEN for 12 cycles. If undetectable for minimal residual disease (uMRD), pts can discontinue therapy and reinitiate VEN with recurrence. Pts with persistent MRD after 12 cycles continue VEN. Eligibility criteria for CLL pts: ≥1 prior therapy, requiring therapy by 2008 iwCLL criteria, ECOG PS ≤2, adequate hematologic/organ function, no prior VEN/DUV. For RS, no prior therapy and prior VEN > 1 yr ago was allowed. CTCAE v5 and 2008 iwCLL were used to evaluate toxicity and efficacy. MRD was assessed by 8-color flow at 10-4 in the peripheral blood (PB) and bone marrow (BM) (Mayo Laboratories). Results: As of July 19, 2020, 22 pts were treated (phase I (n=12), phase II (CLL n=7, RS n=3)). Median age: 69 yrs (range 50-78). Del(17p): 7/22 (32%), TP53 mutation: 10/22 (45%), del(11q): 2/22 (9%), unmutated IGHV: 20/22 (91%), mutation in NOTCH1: 10/22 (45%). Median prior treatments was 3 (range 1-6), including 2 pts who relapsed after alloSCT. 15/22 (68%) pts had prior BTKi, including 7 progressors. No DLTs occurred in phase I, and PK data showed only modest increase in VEN exposure in the presence of DUV. The RP2D of VEN in combination with DUV was the approved dose of 400 mg. Heme toxicities and all grade non-heme toxicities in >25% of pts are shown in Table 1. SAEs included: gr3 febrile neutropenia and lung infection (n=2), gr3 amylase/lipase, gastritis, arthralgia (n=1), gr2 colitis (n=1), and g5 hepatic failure (n=1). All SAEs were reversible with the exception of the gr5 hepatic failure in a pt with RS involvement of the liver. Eleven pts held, 9 pts dose-reduced, and 6 pts discontinued DUV for toxicity. No laboratory or clinical tumor lysis syndrome (TLS) was observed per Cairo-Bishop criteria. VEN was briefly held during ramp-up in 2 pts for elevated LDH and K, then later in 2 pts for neutropenia and thrombocytopenia. At data cutoff, the median number of cycles was 7.5 (range 1-22) and 21 pts were evaluable after at least cycle 4 restaging (CLL n=18, RS n=3). The ORR for CLL/SLL pts was 94% (17/18), with 56% CR (primary endpt) and 39% PR. 61% (11/18) pts had uMRD in the PB, first occurring after cycle 3 (n=4), cycle 6 (n=5), or cycle 10 or 12 (n=1 each). 56% (10/18) pts have thus far achieved BM-uMRD and 4 pts have not yet reached the point of evaluation. 58% (7/12) pts who have to date completed 1 year of DUV + VEN had CR with uMRD in the PB and BM and discontinued therapy, including 2 pts with del(17p). All 4 CLL pts who had progressed on BTKi have responded thus far. Three CLL pts have come off study. One pt with minimal nodal disease achieved uMRD in PB and BM and proceeded to alloSCT. Two pts at DL1 came off study for PD (1 CLL and 1 RS). Of the 3 pts with RS, 1 had disease reduction but was in SD after 3 cycles and started new therapy, and 2 pts had early PD and came off study. 3 pts have died, all with RS. Conclusions: DUV + VEN has a manageable safety profile to date and is active for pts with R/R CLL/SLL, including those who have relapsed after BTKi. High rates of CR and uMRD for this 1-year MRD-guided, time-limited, all oral regimen have already been observed despite short follow-up. Updated results of this actively accruing study will be presented at the meeting. Disclosures Crombie: Bayer: Research Funding; Abbvie: Research Funding. Francoeur:Verastem: Current Employment, Other. Montegaard:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: KOL lecture seires guest lecturer. Soumerai:BostonGene: Research Funding; Verastem: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; TG Therapeutics: Research Funding; GlaxoSmithKine: Research Funding; Genentech/Roche: Research Funding; Beigene: Consultancy, Research Funding. Arnason:Regeneron: Consultancy; Juno: Consultancy. Brown:Janssen, Teva: Speakers Bureau; Abbvie, Acerta, AstraZeneca, Beigene, Invectys, Juno/Celgene, Kite, Morphosys, Novartis, Octapharma, Pharmacyclics, Sunesis, TG Therapeutics, Verastem: Consultancy; Gilead, Loxo, Sun, Verastem: Research Funding. Davids:Eli Lilly: Consultancy; Verastem: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy; AstraZeneca: Consultancy, Research Funding; BeiGene: Consultancy; Ascentage Pharma: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Surface Oncology: Research Funding; Novartis: Consultancy, Research Funding; Gilead Sciences: Consultancy; Zentalis: Consultancy; Sunesis: Consultancy; Syros Pharmaceuticals: Consultancy; Research to Practice: Honoraria; Merck: Consultancy; Bristol Myers Squibb: Research Funding; Janssen: Consultancy; MEI Pharma: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Celgene: Consultancy. OffLabel Disclosure: Duvelisib and venetoclax are not approved in combination for CLL.

Background Despite active frontline regimens including venetoclax (V) plus obinutuzumab (O) and continuous BTK inhibitors (BTKi), the outcomes for some CLL patients (pts) remain suboptimal. The ibrutinib (I) plus V doublet and IVO triplet are active (Jain et al., NEJM, 2019, Huber et al., EHA, 2020), but are associated with cardiac and infectious toxicities. We hypothesized that a time-limited triplet with a more specific BTKi acalabrutinib (A) with V and O (AVO) would be well-tolerated and active. We report updated data from a phase 2 trial of AVO in previously untreated CLL pts enriched for high risk disease. Methods This ongoing phase 2 investigator-initiated study (NCT03580928) initially enrolled unselected pts with previously untreated CLL. A recent protocol amendment restricted additional enrollment to pts with TP53 aberrant CLL. Additional eligibility: treatment required per iwCLL criteria, ECOG PS ≤ 2, CrCl ≥50ml/min, ANC ≥500/mm3, and platelets ≥30,000/mm3. A, V, and O are started sequentially, with a 28-day lead-in with A at 100 mg bid, then 2 cycles of AO (with O at standard dosing), then AO plus a 4-week V ramp-up beginning C4D1 with 20 mg, then 50 mg on C4D2, then weekly ramp-up to 400 mg qd. After 3 more AVO cycles (6 total cycles of O), AV continues from C8-C15; pts with bone marrow undetectable MRD (BM-uMRD) CR after C15 may discontinue therapy, while all others continue AV until completing C24, with the option to discontinue if BM-uMRD then. Response by 2018 iwCLL criteria, with central MRD testing by 8-color flow cytometry in peripheral blood (PB) and BM at 10-4. Primary endpoint: rate of BM-uMRD CR at C16D1. Non-heme AEs by CTCAE v5.0, and heme toxicity by iwCLL criteria. Results As of July 24, 2020, 44 pts were accrued. Median age: 63 yrs (range: 41-78), 68% male. Baseline prognostics: TP53 aberrant (either del(17p) and/or TP53 mutation) in 17 (39%) pts, del(11q) in 12 (27%) pts, complex karyotype (3 or more changes) in 9 (20%) pts, unmutated IGHV in 29 (66%) pts. With a median follow-up of 19 mo. (range 6-26), 43 pts remain on study (1 withdrew consent after 6 mo. due to GI symptoms). Of 36 pts with at least 16 mo. of follow-up, the overall response rate is 100% (43% CR/CRi, 57% PR [in most cases due to small residual lymph nodes]), with 31% BM-uMRD CR at C16 (primary endpoint). By ITT at C16, 84% PB-uMRD and 78% BM-uMRD. In the 10 pts with TP53-aberrant disease who have reached C16 to date, 4 had CR and 6 had PR, with 9/10 pts PB-uMRD and 7/10 pts BM-uMRD. Response and uMRD did not differ based on IGHV status. Eleven pts in BM-uMRD CR discontinued therapy as allowed per protocol after 15 cycles. Median time off therapy for these pts is 4 mos (range: 1-10). No pts have progressed to date. The most frequent non-heme AEs have been headache (80%, 61% gr1, 16% gr2, 2% gr3), fatigue (77%, 75% gr 1+2, 2% gr3), bruising (57%, 55% gr1, 2% gr2), nausea (45%, all gr 1/2), hypocalcemia (34%, 32% gr 1+2, 2% gr3), rash 32% (30% gr1, 2% gr2), and diarrhea (27%, 18% gr1, 9% gr2). Gr 3/4 heme toxicities: neutropenia (34%), thrombocytopenia (23%), and anemia (4.5%). G-CSF was used in 5 pts (11%). Infusion-related reactions occurred in 11 pts (25%, 23% gr1+2, 2% gr3). One case of gr3 afib (2%) and no cases of major bleeding or febrile neutropenia were observed. 6 pts required dose reductions, including 4 who reduced both A and V, and 1 pt each who reduced A or V alone. SAEs: gr4 neutropenia (n=4), and 1 pt each with gr3 lung infection, cardiac troponin increase, thrombocytopenia, and hyperkalemia. Gr≥3 infection occurred in 1 pt (2.3%). Transient lab TLS occurred in 2 pts (4.5%), both gr3 just after starting O (prior to any V). 41/44 pts (93%) were medium or high risk for TLS at baseline, but only 3 pts (7%) were medium risk at V initiation on C4D1. Five low or medium risk pts were admitted at investigator discretion for V initiation. Conclusion The AVO triplet is highly active, with 78% achieving BM-uMRD after 15 months of time-limited therapy in a frontline CLL population that included nearly 40% pts with TP53 aberrant disease. No pts have progressed, with a median of 19 months follow-up. The safety profile is favorable, with a 2% rate of ≥Gr3 infection and afib, and no TLS due to V, which was given with a more convenient 4-week ramp-up. AVO is now being studied in a registrational phase 3 trial CL-311 (NCT03836261) with the potential to define a new standard frontline therapy option for CLL pts. Disclosures Davids: TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Sunesis: Consultancy; Research to Practice: Honoraria; Janssen: Consultancy; Merck: Consultancy; Surface Oncology: Research Funding; AbbVie: Consultancy; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; Zentalis: Consultancy; Gilead Sciences: Consultancy; Novartis: Consultancy, Research Funding; BeiGene: Consultancy; AstraZeneca: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; Eli Lilly: Consultancy; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Syros Pharmaceuticals: Consultancy; Bristol Myers Squibb: Research Funding. Crombie:Bayer: Research Funding; Abbvie: Research Funding. Montegaard:AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: KOL lecture seires guest lecturer. LaCasce:Research to Practice: Speakers Bureau; BMS: Consultancy; UptoDate: Patents & Royalties. Armand:Adaptive: Consultancy, Research Funding; ADC Therapeutics: Consultancy; Merck: Consultancy, Honoraria, Research Funding; Affimed: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy; Genentech: Research Funding; IGM: Research Funding; Infinity: Consultancy; Otsuka: Research Funding; Pfizer: Consultancy; Roche: Research Funding; Sigma Tau: Research Funding; Tensha: Research Funding. Arnason:Regeneron: Consultancy; Juno: Consultancy. Fisher:Kyowa Kirin: Membership on an entity's Board of Directors or advisory committees. Brown:BeiGene: Consultancy; Catapult: Consultancy; Dynamo Therapeutics: Consultancy; Eli Lilly and Company: Consultancy; Juno/Celgene: Consultancy; Kite: Consultancy; MEI Pharma: Consultancy; Nextcea: Consultancy; Novartis: Consultancy; Octapharma: Consultancy; Pfizer: Consultancy; Rigel Pharmaceuticals: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Sun: Research Funding; Acerta: Consultancy; Genentech: Consultancy; Pharmacyclics: Consultancy; Morphosys: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other; Gilead: Consultancy, Research Funding; Invectys: Membership on an entity's Board of Directors or advisory committees, Other: DSMC; Astra-Zeneca: Consultancy; Janssen: Honoraria; AbbVie: Consultancy. OffLabel Disclosure: Although acalabrutinib, venetoclax, and obinutuzumab are each approved for frontline CLL, the AVO combination is not approved and therefore considered off-label.

Background: Lisocabtagene maraleucel (liso-cel) is an investigational, CD19-directed, defined composition, 4-1BB chimeric antigen receptor (CAR) T cell product administered at equal target doses of CD8+ and CD4+ CAR+ T cells. Liso-cel is being studied in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in the ongoing, open-label, phase 1/2 TRANSCEND CLL 004 study (NCT03331198). Here, we report outcomes of patients in the phase 1 monotherapy cohort after a median follow-up of 18 months (mo). Methods: Eligible patients had received ≥3 (standard-risk disease) or ≥2 (high-risk disease: del[17p], TP53 mutation, unmutated IGHV, or complex karyotype) lines of prior therapy, including a Bruton tyrosine kinase inhibitor (BTKi) unless contraindicated. Patients with active untreated central nervous system disease, Eastern Cooperative Oncology Group performance status >1, or Richter transformation were excluded. After 3 days of lymphodepletion with fludarabine and cyclophosphamide, patients received liso-cel infusion at 1 of 2 dose levels (DLs): 50 × 106 (DL1) or 100 × 106 (DL2) CAR+ T cells. Dose-limiting toxicities were evaluated for 28 days postinfusion. Responses were assessed using 2018 International Workshop on CLL criteria. Minimal residual disease (MRD) was assessed in blood by flow cytometry and/or in bone marrow (BM) by next-generation sequencing (both with a sensitivity of ≤10-4). Persistence of liso-cel was monitored by quantitative polymerase chain reaction. Results: Overall, 23 and 22 patients were evaluable for safety and efficacy, respectively. Median age was 66 (range, 49‒79) years, median number of prior therapies was 6 (range, 3‒13), and 83% of patients (n=19/23) had high-risk disease. All patients (N=23) had received prior ibrutinib, with 91% (n=21) refractory to, or who relapsed on, ibrutinib and 9% (n=2) who were intolerant to ibrutinib; overall, 48% (n=11) were refractory to both a prior BTKi and venetoclax. The safety profile was similar to that previously reported; no late or delayed adverse events of concern have emerged with the longer follow-up (Table). Among the 22 efficacy-evaluable patients, overall response rate (ORR; complete response [CR]/CR with incomplete blood count recovery [CRi] + partial response) was 82% (n=18); the CR/CRi rate was 45% (n=10). By Day 30, 68% of patients (n=15) achieved an overall response. At 15 mo and 18 mo, 53% (n=10/19; 6 CRs) and 50% (n=7/14; 5 CRs) of patients maintained their responses, respectively. At a median follow-up of 18 mo, the median duration of response was not reached (NR) in patients who had achieved a response to liso-cel (n=18), and median progression-free survival was 18 mo (95% CI, 3.0-NR) in all efficacy-evaluable patients. Two patients who completed the study maintained their response through 24 mo on study and have enrolled in a long-term follow-up study. Five of 8 patients who progressed had Richter transformation. The subgroup of patients refractory to both a prior BTKi and venetoclax had a similar ORR compared with the total evaluable population, with a CR rate of 60% (n=6/10; Table). Of 20 MRD-evaluable patients, 15 (75%) had undetectable MRD (uMRD) in the blood, 13 (87%) of whom also had uMRD in the BM, with most (60%) achieving uMRD in the BM by Day 30. Preliminary data show that liso-cel was detectable in the blood for up to 18 mo postinfusion in 4 (36%) of 11 patients. Conclusions: Liso-cel treatment resulted in a high rate of uMRD in this heavily pretreated, high-risk population of patients with R/R CLL/SLL, including those refractory to both a BTKi and venetoclax. Responses were rapid and durable, with liso-cel detectable for up to 18 mo postinfusion. No late or delayed adverse events of concern emerged with longer follow-up. The phase 2 monotherapy expansion of the study is currently enrolling at DL2. Disclosures Siddiqi: AstraZeneca: Other: Travel/accommodations/expenses; Pharmacyclics LLC, an AbbVie Company, Seattle Genetics, Janssen, and AstraZeneca: Speakers Bureau; Juno: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics LLC, an AbbVie Company, Juno Therapeutics, KITE Pharma, AstraZeneca, TG Therapeutics, Celgene, Oncternal, and BeiGene: Research Funding; PCYC: Membership on an entity's Board of Directors or advisory committees; Astrazenca: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; BeiGene: Other: DMC member; Juno Therapeutics, Pharmacyclics LLC, an AbbVie Company, AstraZeneca, Celgene, Kite Pharma, and BeiGene: Consultancy. Soumerai:Genentech/Roche: Research Funding; BostonGene: Research Funding; Beigene: Consultancy, Research Funding; GlaxoSmithKine: Research Funding; TG Therapeutics: Research Funding; AbbVie: Consultancy; AstraZeneca: Consultancy; Verastem: Consultancy. Dorritie:Kite-Gilead: Research Funding; Juno Therapeutics: Research Funding. Stephens:Beigene: Consultancy; Acerta: Research Funding; MingSight: Research Funding; Arqule: Research Funding; Verastem: Research Funding; Janssen: Consultancy; Juno: Research Funding; Gilead: Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Consultancy; Innate: Consultancy. Riedell:Karyopharm Therapeutics: Honoraria; Bayer: Honoraria; Kite Pharmaceuticals/Gilead: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Verastem Oncology: Honoraria; Celgene/Bristol-Myers Squibb Company: Honoraria, Research Funding; Morphosys: Research Funding. Arnason:Juno: Consultancy; Regeneron: Consultancy. Kipps:Pharmacyclics/ AbbVie, Breast Cancer Research Foundation, MD Anderson Cancer Center, Oncternal Therapeutics, Inc., Specialized Center of Research (SCOR) - The Leukemia and Lymphoma Society (LLS), California Institute for Regenerative Medicine (CIRM): Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Ascerta/AstraZeneca, Celgene, Genentech/F. Hoffmann-La Roche, Gilead, Janssen, Loxo Oncology, Octernal Therapeutics, Pharmacyclics/AbbVie, TG Therapeutics, VelosBio, and Verastem: Membership on an entity's Board of Directors or advisory committees; Oncternal Therapeutics, Inc.: Other: Cirmtuzumab was developed by Thomas J. Kipps in the Thomas J. Kipps laboratory and licensed by the University of California to Oncternal Therapeutics, Inc., which provided stock options and research funding to the Thomas J. Kipps laboratory, Research Funding; Genentech/Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; VelosBio: Research Funding; Celgene: Honoraria, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gillenwater:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment. Gong:Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment; Bristol-Myers Squibb: Current equity holder in publicly-traded company. Yang:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Juno Therapeutics, a Bristol-Myers Squibb Company: Current Employment. Ogasawara:Bristol-Myers Squibb: Current equity holder in publicly-traded company; Bristol-Myers Squibb: Current Employment.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder of immune system overactivation that occurs as familial and acquired forms.1 HLH is characterized by excessive cytokine production and inflammation, mediated by multiple immune cells including persistently activated macrophages. Familial HLH (FHL) is typically diagnosed in childhood and is often caused by inherited biallelic, deletion, or truncating variants in genes regulating the cytotoxic function of T lymphocytes and natural killer cells.2,3 By contrast, acquired HLH usually occurs in the setting of malignancy, infection, or autoimmune disease, and may be diagnosed at any age. Prior studies using in silico prediction algorithms have concluded that germline HLH-associated variants are enriched in adult patients with HLH but have been limited in the number of genes analyzed, incomplete clinical annotation to confirm true HLH diagnoses, and the relatively small size of the adult cohorts. Finally, the comparatively young ages at the time of HLH onset have made distinguishing FHL that occurs in early adulthood from true adult-onset HLH difficult.4-6 To overcome these issues, we sought to identify potential pathogenic germline variants in 17 genes implicated in FHL or other inherited immune disorders in a highly annotated cohort of patients diagnosed with HLH in adulthood.7

Introduction: Ibrutinib, an irreversible inhibitor of Bruton's tyrosine kinase, is an established therapeutic agent in a variety of B-cell lymphoproliferative disorders. Ibrutinib induces platelet dysfunction and concurrent treatment with ibrutinib and warfarin was shown to significantly increase the risk of bleeding. The current study was designed to investigate the safety of direct oral anticoagulants (DOACs) in patients receiving ibrutinib, considering their expanding employment together with the lack of data regarding their safety in patients receiving ibrutinib. Methods: We conducted a retrospective cohort study to evaluate risks of major bleeding in patients with B-cell lymphoproliferative disorders (CLL, MCL, DLBCL, MZL or WM) that were treated with ibrutinib and DOACs but without concurrent antiplatelet therapy, between January 2010 and October 2018 in 5 participating centers. Patient medical charts were reviewed for demographic parameters, comorbidities, ibrutinib dosage, DOACs dosage (including the adjustment for renal function), blood count and chemistry tests, bleeding site and grade. Results: The study included 30 patients, median age at starting concurrent administration of ibrutinib and DOACs was 71.58 years (range 50.9-88.2). Most patients were treated for CLL (n=18, 60%) and MCL (n=8, 26%). The most common daily doses of ibrutinib were 420 mg and 560 mg in 63.3% and 30% of patients respectively. None of the patients received an additional antiplatelet agent. Twenty-three patients were treated with apixaban (76.7%), 4 with rivaroxaban (13.3%) and 3 (10%) with dabigatran. The main indications for DOACs were atrial fibrillation and VTE (venous thromboembolism). The median follow-up after initiation of the ibrutinib-DOAC combination was 13.4 months (range 1.8-47.9 months). Bleeding was reported in 22 patients (73.3%), mostly mucocutaneous (n=12, 40%) and gastrointestinal tract (n=7, 23.3%), followed by CNS bleeding (n=4, 13.3%). Mucocutaneous bleedings were all grade 1-2 and gastrointestinal tract and CNS bleeding events were grade 1-4. Major bleeding events, defined as grade 3 or 4, occurred in 5 patients (16.6%) and did not result in death of any of the patients. The median time for bleeding following ibrutinib-DOAC initiation was 5.6 months. Over a follow-up period of 21 months of combined treatment, the incidence of bleeding events (of all grades) increased to 75% (Figure 1). Incidence of bleeding events (including all grades) was quite similar between all DOAC subtypes (73.9% with apixaban, 75% with rivaroxaban and 66.7% with dabigatran). No statistically significant predictors for increased risk of bleeding in patients receiving ibrutinib combined with DOACs were detected. Ibrutinib was stopped in 8 patients (26.7%) due to grade 1 to 4 bleeding events and was re-initiated in 6 patients, resulting in recurrent grade 3 and 4 bleeding events in 2 patients. Conclusions: Concurrent administration of DOACs and ibrutinib appears to be feasible. However, risk of bleeding is not neglectable, and treatment resumption in patients that experienced a significant bleeding event should be considered with caution. Disclosures Arnason: Celgene/Juno: Consultancy; Regeneron Pharmaceuticals, Inc.: Consultancy. Herishanu:Roche: Honoraria; AbbVie: Honoraria; Janssen: Honoraria.

Summary Background Fludarabine, cyclophosphamide, and rituximab (FCR) can improve disease-free survival for younger (age ≤65 years) fit patients with chronic lymphocytic leukaemia with mutated IGHV. However, patients with unmutated IGHV rarely have durable responses. Ibrutinib is active for patients with chronic lymphocytic leukaemia irrespective of IGHV mutation status but requires continuous treatment. We postulated that time-limited ibrutinib plus FCR would induce durable responses in younger fit patients with chronic lymphocytic leukaemia. Methods We did a multicentre, open-label, non-randomised, single-arm phase 2 trial at seven sites in the USA. We enrolled patients aged 65 years or younger with previously untreated chronic lymphocytic leukaemia. Our initial cohort (original cohort) was not restricted by prognostic marker status and included patients who had del(17p) or TP53 aberrations. After a protocol amendment (on March 21, 2017), we enrolled an additional cohort (expansion cohort) that included patients without del(17p). Ibrutinib was given orally (420 mg/day) for 7 days, then up to six 28-day cycles were administered intravenously of fludarabine (25 mg/m2, days 1–3), cyclophosphamide (250 mg/m2, days 1–3), and rituximab (375 mg/m2 day 1 of cycle 1; 500 mg/m2 day 1 of cycles 2–6) with continuous oral ibrutinib (420 mg/day). Responders continued on ibrutinib maintenance for up to 2 years, and patients with undetectable minimal residual disease in bone marrow after 2 years were able to discontinue treatment. The primary endpoint was the proportion of patients who achieved a complete response with undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR. Analyses were done per-protocol in all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov ( NCT02251548 ) and is ongoing. Findings Between Oct 23, 2014, and April 23, 2018, 85 patients with chronic lymphocytic leukaemia were enrolled. del(17p) was detected in four (5%) of 83 patients and TP53 mutations were noted in three (4%) of 81 patients; two patients had both del(17p) and TP53 mutations. Median patients' age was 55 years (IQR 50–58). At data cutoff, median follow-up was 16·5 months (IQR 10·6–34·1). A complete response and undetectable minimal residual disease in bone marrow 2 months after the last cycle of ibrutinib plus FCR was achieved by 28 (33%, 95% CI 0·23–0·44) of 85 patients (p=0·0035 compared with a 20% historical value with FCR alone). A best response of undetectable minimal residual disease in bone marrow was achieved by 71 (84%) of 85 patients during the study. One patient had disease progression and one patient died (sudden cardiac death after 17 months of ibrutinib maintenance, assessed as possibly related to ibrutinib). The most common all-grade toxic effects were haematological, including thrombocytopenia in 63 (74%) patients, neutropenia in 53 (62%), and anaemia in 41 (49%). Grade 3 or 4 non-haematological serious adverse events included grade 3 atrial fibrillation in three (4%) patients and grade 3 Pneumocystis jirovecii pneumonia in two (2%). Interpretation The proportion of patients who achieved undetectable minimal residual disease in bone marrow with ibrutinib plus FCR is, to our knowledge, the highest ever published in patients with chronic lymphocytic leukaemia unrestricted by prognostic marker status. Ibrutinib plus FCR is promising as a time-limited combination regimen for frontline chronic lymphocytic leukaemia treatment in younger fit patients. Funding Pharmacyclics and the Leukemia & Lymphoma Society.

Doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with or without radiation is standard therapy for limited-stage Hodgkin lymphoma (HL) but carries risks of bleomycin-induced lung injury and radiation toxicity. Brentuximab vedotin is highly active in relapsed HL and was recently approved with doxorubicin, vinblastine, and dacarbazine (AVD) for previously untreated stage III/IV HL. We evaluated brentuximab-AVD for nonbulky stage I/II HL in a multicenter phase 2 study. Patients received a lead-in cycle of brentuximab vedotin monotherapy on days 1 and 15, followed by an exploratory positron emission tomography/computed tomography scan. Patients then received brentuximab-AVD for 4 to 6 cycles based on interim positron emission tomography/computed tomography scanning after cycle 2. Thirty-four patients were enrolled with a median age of 36 years (range, 20-75 years). Risk was early favorable in 62% and unfavorable in 38%. The best complete response rate was 100%. At a median follow-up of 38 months, the progression-free survival and overall survival were 94% and 97%, respectively. The most common adverse events were peripheral sensory neuropathy (79%), neutropenia (76%), fatigue (74%), and nausea (71%). The most common grade 3/4 toxicities were neutropenia (62%), febrile neutropenia (35%), and peripheral sensory neuropathy (24%). One elderly patient died of neutropenic sepsis in the first brentuximab-AVD cycle. Brentuximab dose reductions were required in 38% of patients, most for peripheral neuropathy. In conclusion, brentuximab-AVD without bleomycin or radiation produced a high complete response rate, with most patients requiring only 4 total cycles of therapy. Because toxicity was higher than would be expected from AVD alone, this method may not be appropriate for early-stage patients with a highly favorable prognosis. This trial was registered at www.clinicaltrials.gov as #NCT01534078.

// Burcu Yigit 1 , Peter J. Halibozek 1 , Shih-Shih Chen 2 , Michael S. O’Keeffe 1 , Jon Arnason 3 , David Avigan 3 , Valter Gattei 4 , Atul Bhan 5 , Osman Cen 6 , Richard Longnecker 6 , Nicholas Chiorazzi 2 , Ninghai Wang 1 , Pablo Engel 7 , Cox Terhorst 1 1 Division of Immunology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 2 Karches Center for Chronic Lymphocytic Leukemia Research, The Feinstein Institute for Medical Research, Manhasset, NY, USA 3 Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA 4 Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano, Italy 5 Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA 6 Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA 7 Immunology Unit, Department of Cell Biology, Immunology and Neurosciences, Medical School, University of Barcelona, Barcelona, Spain Correspondence to: Burcu Yigit, email: byigit@bidmc.harvard.edu Cox Terhorst, email: cterhors@bidmc.harvard.edu Keywords: CLL, TCL1-192, SLAMF6, BCR, ibrutinib Received: January 29, 2016 Accepted: March 07, 2016 Published: March 25, 2016 ABSTRACT The signaling lymphocyte activation molecule family [SLAMF] of cell surface receptors partakes in both the development of several immunocyte lineages and innate and adaptive immune responses in humans and mice. For instance, the homophilic molecule SLAMF6 (CD352) is in part involved in natural killer T cell development, but also modulates T follicular helper cell and germinal B cell interactions. Here we report that upon transplantation of a well-defined aggressive murine B220 + CD5 + Chronic Lymphocytic Leukemia (CLL) cell clone, TCL1-192, into SCID mice one injection of a monoclonal antibody directed against SLAMF6 (αSlamf6) abrogates tumor progression in the spleen, bone marrow and blood. Similarly, progression of a murine B cell lymphoma, LMP2A/λMyc, was also eliminated by αSlamf6. But, surprisingly, αSLAMF6 neither eliminated TCL1-192 nor LMP2A/λMyc cells, which resided in the peritoneal cavity or omentum. This appeared to be dependent upon the tumor environment, which affected the frequency of sub-populations of the TCL1-192 clone or the inability of peritoneal macrophages to induce Antibody Dependent Cellular Cytotoxicity (ADCC). However, co-administering αSlamf6 with the Bruton tyrosine kinase (Btk) inhibitor, ibrutinib, synergized to efficiently eliminate the tumor cells in the spleen, bone marrow, liver and the peritoneal cavity. Because an anti-human SLAMF6 mAb efficiently killed human CLL cells in vitro and in vivo , we propose that a combination of αSlamf6 with ibrutinib should be considered as a novel therapeutic approach for CLL and other B cell tumors.

e20046 Background: Clinical studies of liso-cel show low incidences of severe CRS and NEs. Pts with high tumor burden and inflammation are at higher risk of CRS and NEs (Borrega, Hemasphere 2019). Here, we characterize the presenting symptoms, timing, and management of CRS and NEs in pts with R/R LBCL treated with liso-cel in TRANSCEND NHL 001 (NCT02631044). A deeper understanding of CRS/NEs after liso-cel treatment may help clinicians identify and manage these toxicities. Methods: Pts with R/R LBCL and ≥2 lines of therapy received liso-cel after lymphodepletion (LD) with fludarabine and cyclophosphamide. Bridging therapy was allowed for pts with PET-positive disease before LD (Abramson, ASH 2019 #241). Investigators were educated on prospectively identifying liso-cel–related NEs and CRS, which were collected and graded per NCI CTCAE v4.03 (NEs) or 2014 Lee criteria (CRS). Timing and severity of individual CRS/NE symptoms and interventions were also collected. Results: The analysis included 269 pts (median age, 63 y): 38% had sum of perpendicular diameters ≥50 cm2 or lactate dehydrogenase ≥500 U/L, and 59% received bridging therapy. CRS and NEs had delayed onset (median, 5 and 9 d, respectively) and a low incidence of grade (Gr) ≥3 events (CRS 2%; NE 10%). CRS occurred before NEs in most pts and was Gr 1/2 at onset in all but 2 pts (Table). The most common CRS symptoms were pyrexia (40%), hypotension (20%), and tachycardia (18%). Overall, 20% of pts received tocilizumab and/or corticosteroids for CRS (10% tocilizumab only; 2% corticosteroids only; 8% both); 3% received vasopressors. The most common NE symptoms were confusional state (11%), tremor (9%), and aphasia (8%); most were low grade. A total of 17% of pts received tocilizumab and/or corticosteroids for NEs (13% corticosteroids only; < 1% tocilizumab only; 3% both); < 1% received vasopressors. Overall, 4% of pts were admitted to the ICU for CRS and/or NEs. Additional analyses on timing of intervention and type/severity of initial symptoms will be presented. Conclusions: In pts with high-risk, aggressive R/R LBCL, liso-cel treatment was associated with a low incidence of severe CRS/NEs, late onset of mostly low-grade events at presentation, and low use of tocilizumab/corticosteroids. Clinical trial information: NCT02631044 . [Table: see text]

e19351 Background: CAR T, approved in the US as of October 2017, impacted the treatment landscape for patients with relapsed or refractory (R/R) DLBCL after ≥2 lines of therapy, but there is little known about real-world (RW) treatment patterns in patients who fail or do not respond to CAR T. No treatments of proven benefits are available after CAR T treatment failure. The objective of this study was to describe RW treatment patterns after CAR T. Methods: From MarketScan Commercial/Medicare claims databases (2017‒2018) we identified adult DLBCL patients who received approved CD19-directed CAR T (treatment date = index date). Eligible patients had ≥6 months continuous health plan enrollment prior to index date (i.e. baseline period) and were followed until plan disenrollment or December 31, 2018. Patients with a diagnosis of acute lymphoblastic leukemia over the baseline period were excluded. We identified the first and second treatments after CAR T with systemic chemotherapy, targeted therapy, immunotherapy, hematopoietic stem cell transplant (SCT), radiation therapy (RT), or a second round of CAR T therapy. Kaplan–Meier estimators were used to estimate risk of subsequent treatment and time to next treatment. Results: We identified 56 patients with DLBCL treated with CAR T (mean age [SD]: 57.3 years [9.9]; 23.2% female; 80.4% commercially insured). All patients received CAR T in the inpatient setting, median (Q1‒Q3) length of stay was 15 days (12‒19). Out of 56 patients, 19 initiated a treatment following CAR T; risk of subsequent treatment at 6 months post index was 45.6% (95% CI: 25.4‒60.4%) and median days from CAR T to next treatment was 233 days (95% CI: 139‒NA). Out of 19 patients, 3 initiated a second treatment following CAR T, within 8‒69 days of the first treatment. Over a median (Q1‒Q3) follow-up of 139.5 days (90.5‒194) following CAR T, of the 19 patients treated after CAR T, 57.9% were treated with immunotherapy, 36.8% with RT, 26.3% with targeted therapy, 21.1% with SCT, 15.8% with chemotherapy, and 0% with a second round of CAR T. Conclusions: There are few multicenter studies reporting RW treatment patterns in patients who received CAR T. In this study, risk of subsequent treatment at 6 months following CAR T in a RW setting was almost 50%. Although limited by duration of follow-up, our results suggest that additional, effective salvage treatment strategies are needed for patients who do not respond to CAR T or do not achieve a durable response to CAR T. Updated results using 2019 data will be presented.

Our personalized cancer vaccine comprises patient tumor cells fused with autologous dendritic cells (DCs) and limits the risk of antigen escape by presenting a broad array of tumor antigens in the context of DC mediated co-stimulation. In clinical trials of hematologic malignancies patients, vaccination induced expansion of tumor-specific T cells (Tc) and led to prolonged remission in a subset of patients. Currently, we are developing a novel second-generation (2G) vaccine. Fusions are presented in the context of a unique biomatrix expressing high levels of 41BB ligand (41BBL), to further accentuate Tc activation. In this study, we show the efficacy of vaccination in a preclinical lymphoma model and enhanced potency of the 2G vaccine. We first showed the fusions potency in generating anti-tumor immunity in the A20 lymphoma murine model. Bone marrow derived mononuclear cells cultured with GM-CSF and IL-4 were fused to A20 cells. Fusions effectively induced tumor specific immunity as manifested by potent lysis of A20 Tc in vitro as compared to unstimulated Tc in a CTL assay. Consistently, vaccine effectively induced tumor specific immunity in an immunocompetent murine model. Balb/C mice (30) underwent IV inoculation with 750,000, luciferase transduced, A20 cells. 24h post inoculation, 15 mice were vaccinated with 105 fusions. 10 days post inoculation, in the untreated cohort all mice had detectable tumor whereas in the treated group, 5 mice didn't show disease and 5 mice showed minimal disease as detected by BLI imaging. We further showed that patient autologous vaccine stimulated Tc mediated lysis of primary lymphoma cells. DC, generated from patient's peripheral blood mononuclear cells cultured with GM-CSF and IL-4 and matured with TNFa were fused to primary lymphoma cells isolated from resected tumor. In a standard CTL assay, fusion stimulated Tc potently lysed autologous tumor cells as compared to unstimulated Tc (25.7% as compared to 12.66%). To enhance vaccine potency, we developed a biomatrix expressing 41BBL. By carbodiimide chemistry we covalently bonded 41BBL protein to an alginate (Alg)-based scaffold, promoting a supporting microenvironment for Tc and fusions co-culture. We cultured syngeneic Tc with fusions within a scaffold with or without bound 41BBL and examined Tc cytotoxicity by a CTL assay. Tc stimulated by vaccine within the Alg/41BBL scaffold showed higher levels of tumor lysis compared to the percent killed by Tc cultured within an Alg scaffold (22.95% and 13.95 respectively). In this study we succeeded in demonstrating the fusions capacity to generate tumor specific Tc cytotoxicity. We presented patient derived tumor results supporting the applicable nature of the vaccine. In addition, we developed a 2G vaccine comprised of the original vaccine presented to the Tc in an Alg/41BBL scaffold acting as a nurturing microenvironment for Tc tumor specific immune response.

We hypothesized that ofatumumab with sequential methylprednisolone - alemtuzumab would be an effective and tolerable regimen for patients with high-risk chronic lymphocytic leukemia (CLL) with TP53 dysfunction. Thirty CLL patients with TP53 dysfunction (15 treatment naive (TN), 15 relapsed/refractory (R/R)) were enrolled in this phase II study. Therapy included ofatumumab with methylprednisolone for 2-4 monthly cycles, then ofatumumab with alemtuzumab for 4-24 weeks, then allogeneic transplantation or maintenance. The rate of overall response, complete response, marrow minimal residual disease (MRD) negativity, 3-year progression-free survival and overall survival were 80, 13, 80, 53, and 66%, respectively, in TN patients and 68, 0, 54, 25, and 53%, respectively, in R/R patients. Notable grade 3/4 toxicities included neutropenia and infection in 43 and 40% of patients, respectively. At median follow-up of 45 months, 13 patients died, and 10 patients are alive posttransplant. Overall, we observed high rates of MRD-negativity and acceptable tolerability in high-risk CLL.

Haemophagocytic lymphohistiocytosis (HLH) is a syndrome of uncontrolled immune activation that has gained increasing attention over the past decade. Although classically known as a familial disorder of children caused by mutations that affect cytotoxic T-cell function, an acquired form of HLH in adults is now widely recognized. This is often seen in the setting of malignancy, infection or rheumatological disorders. We performed a retrospective review across 3 tertiary care centres and identified 68 adults with HLH. The average age was 53 years (range 18-77 years) and 43 were male (63%). Underlying disorders included malignancy in 33 patients (49%), infection in 22 (33%), autoimmune disease in 19 (28%) and idiopathic HLH in 15 (22%). Patients were treated with disease-specific therapy and immunomodulatory agents. After a median follow-up of 32·2 months, 46 patients had died (69%). The median overall survival was 4 months (95% CI: 0·0-10·2 months). Patients with malignancy had a worse prognosis compared to those without (median survival 2·8 months versus 10·7 months, P = 0·007). HLH is a devastating disorder with a high mortality. Further research is needed to improve treatment and outcomes.