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In the last decade, a better understanding of the molecular pathogenesis of B-cell non-Hodgkin lymphomas has resulted in the development of novel targeted therapies, such as small molecule inhibitors of select kinases in the B-cell receptor pathway, antibody–drug conjugates, and small molecules that target a variety of proteins (eg, CD-19, EZH2, and XPO-1–mediated nuclear export). Anti-CD19 CAR T-cell therapy, first approved for relapsed/refractory (R/R) diffuse large B-cell lymphoma, has also emerged as a novel treatment option for R/R follicular lymphoma and mantle cell lymphoma. These NCCN Guideline Insights highlight the new targeted therapy options included in the NCCN Guidelines for B-Cell Lymphomas for the treatment of R/R disease.

Ibrutinib ist ein bekannter Inhibitor der Bruton-Tyrosinkinase (BTK) und der Interleukin-2-induzierbaren T-Zell-Kinase (ITK), der zur Behandlung von B-Zell-Erkrankungen (chronische lymphatische Leukämie [CLL] und verschiedene andere Lymphome) und der chronischen Graft-versus-Host-Erkrankung nach allogener Transplantation von hämatopoetischen Zellen eingesetzt wird. Da es als immunsuppressiv gilt, stellt sich bei Patienten mit einer aktiven Infektion häufig die Frage nach einer Fortführung der Ibrutinib-Therapie, und im Zusammenhang mit der Coronavirus-Erkrankung 2019 (COVID-19) ist diese Entscheidung besonders schwierig. In der vorliegenden Arbeit beschreiben wir einen Patienten mit CLL, der mit Ibrutinib behandelt wurde und im weiteren Verlauf eine schwere COVID-19-Infektion entwickelte, die eine mechanische Beatmung erforderlich machte. Wir beschlossen, die Gabe von Ibrutinib noch am Tag der Intubation fortzusetzen, mit der Argumentation, dass die BTK-Inhibition in myeloischen Immunzellen nachgewiesenermaßen die influenza-vermittelte akute Lungenschädigung verringert oder sogar umkehrt und dass die ITK-Inhibition in T-Zellen mit einer Reduzierung der Virusreplikation korreliert und daher in diesem Setting von Nutzen sein könnte. Darüber hinaus hat sich gezeigt, dass Ibrutinib auch Kinasen der Src-Familie blockiert, was möglicherweise ein verringertes Eindringen der Viren zur Folge hat und zu einer verminderten inflammatorischen Zytokinreaktion in der Lunge führt. Der Patient wurde nach 9 Tagen und einem komplizierten stationären Verlauf extubiert und schließlich unter Raumluftatmung entlassen. Die einzige Möglichkeit, solche Entscheidungen rational zu untermauern und ähnliche potenziell vielversprechende Hinweise in dieser Pandemie zu untersuchen, sind sorgfältig durchgeführte klinische Studien.

Background: The rapid global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains the international public health concern of the decade. Early clinical data suggest that patients (pts) with hematologic malignancies are vulnerable to severe forms of SARS-CoV-2 and have higher mortality rates than the general population. Greater understanding of risk factors and outcomes associated with SARS-CoV-2 in pts with hematologic malignancies is crucial in order to develop individualized risk-benefit analyses to guide care. Herein, we report a cohort study from a Comprehensive Cancer Center evaluating outcomes in pts with hematologic malignancies who developed SARS-CoV-2. Methods: Adult pts at Northwestern Memorial Hospital with a current/prior hematologic malignancy and laboratory-confirmed SARS-CoV-2 infection confirmed by quantitative RT-PCR from nasopharyngeal swabs between March-July, 2020 were identified using electronic health records. Data were collected and analyzed based on epidemiologic, laboratory, and clinical characteristics. Severity of illness was defined by level of care (ambulatory, inpatient), need for advanced respiratory support (high flow nasal cannula, BiPAP, mechanical ventilation), incidence of thrombotic events, incidence of acute kidney injury (AKI), and/or death. Statistical analyses of risk factors, severity, and outcomes were performed. Subgroup analyses based on antineoplastic treatment status and receipt of SARS-CoV-2 -directed therapy were made. Active cancer treatment was defined as antineoplastic therapy within 12 months of SARS-CoV-2 diagnosis. Results: Demographic (Table 1) and clinical (Table 2) data were recorded from 73 SARS-CoV-2 infected pts. Sixty (80%) pts had lymphoid and 15 (20%) had myeloid neoplasms, 2 with concurrent lymphoid and myeloid neoplasms. Thirty-seven (51%) pts were undergoing active treatment for their malignancy. Twenty-one pts (29%) were managed in the ambulatory setting while 52 (71%) required hospital admission. Twenty-five (34%) pts required advanced respiratory support including 14 (19%) who required mechanical ventilation. Four pts (6%) had thrombotic events and 31 (42%) received SARS-CoV-2-directed therapies. Sixteen pts (22%) died during the study period. Pts on active cancer treatment had higher rates of hospital admission (81% v 60%; p=0.05) and AKI (51% v 29%; p=0.04) but similar rates of death compared with pts not on active treatment (24% v 20%; p=0.66) (Table 3). Comparing pts who received SARS-CoV-2 -directed therapy versus no therapy: pts on therapy had longer median lengths of stay (11 v 7 days; p=0.04) and higher rates of hospital admission (94% v 55%; p=0.0003) but similar rates of death (23% v 21%; p=0.91); pts in the ICU on SARS-COV-2 -directed therapy had lower rates of death (38% v 88% p=0.02) than pts who did not receive such therapy (Table 4). Twenty-six pts (36%) were tested for viral clearance, defined as two serial negative swabs ≥24 hours apart. Of these, 17 (65%) achieved clearance with a median time of 51 days (range 15-119 days). Thirteen pts (18%) had antibody (Ab) testing. Ten (77%) had detectable Abs: 8 were positive for IgG, 1 for IgG and IgM, and 1 had unspecified positivity. Notably, all 3 pts with undetectable Abs were on active cancer treatment. Conclusion: We demonstrate that pts with hematologic malignancies are exceptionally vulnerable to severe forms of SARS-CoV-2 with high mortality rates. The incidence of thrombotic events was low, an unexpected finding in the setting of a hyperinflammatory syndrome. Prolonged time to viral clearance was observed, a finding which may cause potential delays in the resumption of cancer-directed therapies. Notably, the majority of pts who received antibody testing had detectable antibodies suggesting that pts with hematologic malignancies may be able to mount an immune response to early vaccination. Accordingly, close monitoring, aggressive therapy, and early vaccination, when available, may be warranted for this population. Larger studies are needed to confirm our findings and help guide management of pts with hematologic malignancies during the SARS-CoV-2 pandemic. Disclosures Altman: Bristol-Myers Squibb: Consultancy; Janssen: Consultancy; Immune Pharmaceuticals: Consultancy; Syros: Consultancy; Genentech: Research Funding; Novartis: Consultancy; Amphivena: Research Funding; Amgen: Research Funding; Aprea: Research Funding; ImmunoGen: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; Fujifilm: Research Funding; Kartos: Research Funding; AbbVie: Other: advisory board, Research Funding; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Agios: Other: advisory board, Research Funding; Glycomimetics: Other: Data safety and monitoring committee; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Theradex: Other: Advisory Board; ASH: Consultancy; Cancer Expert Now: Consultancy; France Foundation: Consultancy; PeerView: Consultancy; PrIME Oncology: Consultancy. Winter:Delta Fly Pharma: Consultancy; Amgen: Consultancy; Epizyme: Other: DSMB; CVS/Caremark: Consultancy; Ariad/Takeda: Consultancy; Norvartis: Consultancy, Other: DSMB; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Pro:Verastem Oncology: Research Funding. Ma:TG Therapeutics: Research Funding; Juno: Research Funding; Novartis: Research Funding; Kite: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria, Research Funding, Speakers Bureau; Bioverativ: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau. Karmali:BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Takeda: Research Funding; Karyopharm: Honoraria; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau.

Ibrutinib, a known Burton's tyrosine kinase (BTK) and interleukin‐2 inducible T‐cell kinase (ITK) inhibitor, is used for the treatment of B‐cell disorders (chronic lymphocytic leukemia [CLL] and various other lymphomas) and chronic graft versus host disease following allogeneic hematopoietic cell transplantation. Because it is considered an immunosuppressant, continuation of ibrutinib is often debated when patients have an active infection, and this becomes an especially difficult decision in the setting of coronavirus disease 2019 (COVID‐19). Here, we describe a patient with CLL who was on ibrutinib then developed severe COVID‐19 infection requiring mechanical ventilation. We elected to continue ibrutinib the same day he was intubated, reasoning that BTK inhibition in myeloid immune cells has been shown to reduce or even reverse influenza‐mediated acute lung injury and that ITK inhibition in T cells has correlated with reduction in viral replication, and therefore may have an advantage in this setting. Ibrutinib also has been shown to block Src family kinases, which potentially could result in reduction of viral entry and the inflammatory cytokine response in the lungs. The patient was extubated after 9 days with a complex hospital course and eventually discharged on room air. The only way to rationally inform these decisions and explore similar potentially promising leads in this pandemic is to conduct carefully done clinical trials.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

Treatment strategies for post-transplant lymphoproliferative disorders (PTLD) consist of response-adapted risk-stratified methods using immunosuppression reduction, immunotherapy, and chemotherapy. We investigated the efficacy of Brentuximab vedotin given concurrently with Rituximab (BV + R) once weekly for four weeks, followed by optional consolidation, and up to one year of maintenance. Among 20 assessable patients, BV + R therapy resulted in an overall response rate of 75% (95% CI 51 to 91, p = 0.044) with 60% achieving a complete response. Median time to best response was 28 days. Two-year progression-free survival and overall survival rates were 75 and 90%, respectively. Most common severe grade 3/4 treatment-related toxicities included neutropenia (40%), hypertension (30%), infection (25%), and peripheral neuropathy (15%). BV + R is a novel and effective therapeutic strategy that achieved rapid and durable remissions in previously untreated PTLD patients; however, this treatment platform requires further modification due to the high rates of treatment-related toxicity.Key pointsBrentuximab vedotin + Rituximab showed ORR and CR rates of 75 and 60% in patients with immunosuppression-associated lymphoid malignanciesHigh rates of treatment delay were attributed to treatment-related toxicity; further dosing optimization of this regimen is required.

Diffuse large B-cell lymphoma (DLBCL) transformed from follicular lymphoma (FL) (tDLBCL) has been traditionally associated with an aggressive course, but more recent studies have shown longer survivals. The clinical significance of concurrent FL at the time of diagnosis of DLBCL (cDLBCL/FL) is less clear. We compared outcomes of tDLBCL, cDLBCL/FL, and

Diffuse large B-cell lymphomas (DLBCLs) and follicular lymphoma (FL) are the most common subtypes of B-cell non-Hodgkin’s lymphomas in adults. Histologic transformation of FL to DLBCL (TFL) occurs in approximately 15% of patients and is generally associated with a poor clinical outcome. Phosphatidylinositol 3-kinase (PI3K) inhibitors have shown promising results in the treatment of relapsed/refractory FL. CAR T-cell therapy (axicabtagene ciloleucel and tisagenlecleucel) has emerged as a novel treatment option for relapsed/refractory DLBCL and TFL. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines for B-Cell Lymphomas regarding the treatment of TFL and relapsed/refractory FL and DLBCL.

Purpose: To evaluate safety and efficacy outcomes for subjects on the ECHELON-1 study treated in North America (NA). Patients and Methods: ECHELON-1 is a global, open-label, randomized phase III study comparing doxorubicin, vinblastine, and dacarbazine in combination with brentuximab vedotin (A+AVD) versus ABVD (AVD + bleomycin) as first-line therapy in subjects with stage III or IV classical Hodgkin lymphoma (cHL; NCT01712490). Subjects were randomized 1:1 to receive A+AVD or ABVD intravenously on days 1 and 15 of each 28-day cycle for up to 6 cycles. Results: The NA subgroup consisted of 497 subjects in the A+AVD (n = 250) and ABVD (n = 247) arms. Similar to the primary analysis based on the intent-to-treat population, the primary endpoint [modified progression-free survival (PFS) per independent review] demonstrated an improvement among subjects who received A+AVD compared with ABVD (HR = 0.60; P = 0.012). For PFS, the risk of progression or death was also reduced (HR = 0.50; P = 0.002). Subsequent anticancer therapies were lower in the A+AVD arm. Grade 3 or 4 adverse events (AEs) were more common, but there were fewer study discontinuations due to AEs in the A+AVD arm as compared with ABVD. Noted differences between arms included higher rates of febrile neutropenia (20% vs. 9%) and peripheral neuropathy (80% vs. 56%), but lower rates of pulmonary toxicity (3% vs. 10%) in subjects treated with A+AVD versus ABVD. Conclusions: The efficacy benefit and manageable toxicity profile observed in the NA subgroup of ECHELON-1 support A+AVD as a frontline treatment option for patients with stage III or IV cHL.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma characterized by the t(11;14) chromosomal translocation. This translocation most often results in overexpression of cyclin D1. MCL is clinically heterogeneous, outcomes are generally poor, and no standard treatment has been established. The recent approvals of ibrutinib and acalabrutinib have provided an additional therapeutic option; however, resistance has emerged as a significant issue and presents the need for more detailed studies of resistance mechanisms. Recent clinical trials have provided new perspectives on the relative efficacy and safety of various approaches for both transplant-eligible and transplant-ineligible patients. Multiple novel strategies are being evaluated in the treatment of MCL, including both targeted agents and cellular immunotherapies. At the Lymphoma Research Foundation's 13th MCL Workshop, researchers gathered to discuss research findings, clinical trial results, and future directions related to MCL, its biology, and its treatment. This report, which includes a summary of each presentation, aims to review recent findings in MCL research and highlight potential areas for future study.

Pembrolizumab, a humanized IgG4 monoclonal antibody targeting programmed death-1 protein, has demonstrated efficacy in relapsed/refractory classical Hodgkin lymphoma (cHL). To assess the complete metabolic response (CMR) rate and safety of pembrolizumab monotherapy in newly diagnosed cHL, we conducted a multicenter, single-arm, phase 2 investigator-initiated trial of sequential pembrolizumab and doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy. Patients ≥18 years of age with untreated, early, unfavorable, or advanced-stage disease were eligible for treatment. Thirty patients (early unfavorable stage, n = 12; advanced stage, n = 18) were treated with 3 cycles of pembrolizumab monotherapy followed by AVD for 4 to 6 cycles, depending on stage and bulk. Twelve had either large mediastinal masses or bulky disease (>10 cm). After pembrolizumab monotherapy, 11 patients (37%) demonstrated CMRs, and an additional 7 of 28 (25%) patients with quantifiable positron emission tomography computed tomography scans had >90% reduction in metabolic tumor volume. All patients achieved CMR after 2 cycles of AVD and maintained their responses at the end of treatment. With a median follow-up of 22.5 months (range, 14.2-30.6) there were no changes in therapy, progressions, or deaths. No patients received consolidation radiotherapy, including those with bulky disease. Therapy was well tolerated. The most common immune-related adverse events were grade 1 rash (n = 6) and grade 2 infusion reactions (n = 4). One patient had reversible grade 4 transaminitis and a second had reversible Bell’s palsy. Brief pembrolizumab monotherapy followed by AVD was both highly effective and safe in patients with newly diagnosed cHL, including those with bulky disease. This trial was registered at www.clinicaltrials.gov as #NCT03226249.

This Viewpoint reviews data demonstrating worse risk and outcomes for non-White patients with coronavirus disease 2019 (COVID-19) and makes policy proposals to mitigate the disparities, including expansion of Medicaid eligibility to expand health care access, multilingual and culturally appropriate communication and outreach, and easing accessibility to social services through health care contacts to address housing, food, legal, and economic stressors

// Kaylin M. McMahon 1, * , Cristina Scielzo 2, 3, * , Nicholas L. Angeloni 1 , Elad Deiss-Yehiely 1 , Lydia Scarfo 2, 3 , Pamela Ranghetti 2, 3 , Shuo Ma 4 , Jason Kaplan 4, 5 , Federica Barbaglio 3 , Leo I. Gordon 4 , Francis J. Giles 4, 5 , C. Shad Thaxton 1, 4, 6, 7 , Paolo Ghia 2, 3 1 Department of Urology, Feinberg School of Medicine, Northwestern University, Tarry, Chicago, IL, USA 2 Universita Vita-Salute San Raffaele, Milan, Italy 3 Strategic Research Program On CLL and Unit of B cell Neoplasia, Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy 4 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 5 Developmental Therapeutics Program of The Division of Hematology Oncology, Feinberg School of Medicine, Chicago, IL, USA 6 Simpson Querrey Institute (SQI) for BioNanotechnology, Chicago, IL, USA 7 International Institute for Nanotechnology, Evanston, IL, USA * These authors equally contributed to this work Correspondence to: C. Shad Thaxton, email: cthaxton003@md.northwestern.edu Paolo Ghia, email: ghia.paolo@hsr.it Keywords: lipoprotein, leukemia, scavenger receptor type B-I, nanoparticle, biomaterials Received: June 29, 2016 Accepted: December 26, 2016 Published: January 04, 2017 ABSTRACT Chronic lymphocytic leukemia (CLL) remains incurable despite the introduction of new drugs. Therapies targeting receptors and pathways active specifically in malignant B cells might provide better treatment options. For instance, in B cell lymphoma, our group has previously shown that scavenger receptor type B-1 (SR-B1), the high-affinity receptor for cholesterol-rich high-density lipoproteins (HDL), is a therapeutic target. As evidence suggests that targeting cholesterol metabolism in CLL cells may have therapeutic benefit, we examined SR-B1 expression in primary CLL cells from patients. Unlike normal B cells that do not express SR-B1, CLL cells express the receptor. As a result, we evaluated cholesterol-poor synthetic HDL nanoparticles (HDL NP), known for targeting SR-B1, as a therapy for CLL. HDL NPs potently and selectively induce apoptotic cell death in primary CLL cells. HDL NPs had no effect on normal peripheral blood mononuclear cells from healthy individuals or patients with CLL. These data implicate SR-B1 as a target in CLL and HDL NPs as targeted monotherapy for CLL.

Purpose: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. Patients and Methods: Patients received continuous, once-daily oral TAK-659, 60–120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD. Results: Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast (Tmax ∼2 hours) with a long terminal half-life (∼37 hours). Exposure generally increased with dose (60–120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). Conclusions: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.

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.

Background: Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Targeted therapy is available in the form of recombinant human leptin (metreleptin). Previous case series have reported dramatic weight loss and metabolic improvements with treatment, but metreleptin’s only FDA-approved indication is acquired generalized lipodystrophy (AGL). Metreleptin has a black box warning for risk of T-cell lymphoma, which has been reported in AGL patients, both treated and untreated with metreleptin. Clinical Case: Two sisters ages 18 yrs (sister A; BMI 45.2 kg/m2) and 20 yrs (sister B; 45.0 kg/m2) were referred for evaluation of obesity. They are of Pakistani origin with a family history of consanguinity. Birth weight was normal, but hyperphagia and excessive weight gain developed by age 3 months. They had been seen by endocrinologists, obesity specialists, and a geneticist during childhood but work-up for monogenic obesity was not pursued. They were treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. Sister A was diagnosed with type 2 diabetes at age 15 years. Sister B had comorbidities of hydrocephalus s/p VP shunt, developmental delay, hyponatremia, autoimmune thyroid disease, growth hormone deficiency, and prediabetes. At the time of their present evaluation, serum leptin levels were obtained and were undetectable in both sisters. After discontinuing OCPs, testing confirmed hypogonadotropic hypogonadism. Both patients were homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. On MR elastography performed for hepatic steatosis, sister B had an incidental finding of axillary lymphadenopathy. Surgical biopsy and staging work-up confirmed diagnosis of nodular lymphocyte predominant Hodgkin lymphoma (a B cell lymphoma), Stage II disease. She was treated with R-ABVD with adjuvant radiation and achieved clinical remission, prior to treatment with metreleptin. The patients were enrolled in an observational treatment protocol, and responses to metreleptin therapy will be reported in future. Conclusion: To our knowledge, these are the first cases of CLD diagnosed in the U. S. In previous reports, CLD and other monogenic obesity disorders were prevalent among children with severe obesity in a consanguineous Pakistani population. Leptin deficiency should be considered in all patients with early onset obesity and hypothalamic amenorrhea. Furthermore, to our knowledge, this is the first report of lymphoma in a patient with CLD, occurring prior to any treatment with metreleptin. The risk for lymphoma associated with metreleptin may relate to preexisting autoimmune disease or immunologic abnormalities related to leptin deficiency rather than medication adverse effect.

Pain is a serious adverse event which frequently accompanies hematopoietic stem cell transplantation (HSCT). The safety and efficacy of NSAIDS during HSCT is currently unknown. Salsalate is a platelet-sparing NSAID with a favorable toxicity profile compared with other NSAIDS. We report the safety and efficacy of salsalate for different types of pain during SCT.We conducted a retrospective study of SCT recipients empirically treated with salsalate for 48 h. Pain scores were assessed using the verbal rating scale for pain. A subset analysis of patients who received 7 days of salsalate during periods of pancytopenia, mucositis, and other end-organ toxicities is included.Sixty-four patients, 42 auto- and 22 allografts, were identified. Reason for use: vertebral-related pain (30%), musculoskeletal (30%), and cytokine inflammatory pain syndromes (24%). Median dose 1500 mg/day, number of treatment days = 5, started on day+5 post-HSCT. Pain resolved/improved to pain score 4 in 76% and stable in 15%. Forty-four patients (28-auto and 16 allografts) received 7-day salsalate. Median WBC and platelet nadir were 0.1 and 10,000 cells/ml respectively.pain was improved or eradicated in 64% and stable in 32%.LFT elevation (n = 2), elevated serum creatinine (n = 2), and minor bleed (n = 5-nose, gums, and urine). Salsalate discontinuation (n = 6): ineffective (n = 1), the liver (n = 1), the kidney (n = 1), 5 platelet transfusions (n = 1), and vomiting (n = 2). There was no treatment related mortality. Salsalate was well tolerated, safe, and beneficial for several different types of pain during HSCT.

Purpose To improve the curability of older patients with newly diagnosed Hodgkin lymphoma. Patients and Methods We conducted a multicenter phase II study that administered brentuximab vedotin (Bv) sequentially before and after standard doxorubicin, vinblastine, and dacarbazine (AVD) for untreated patients with Hodgkin lymphoma age 60 years or older. After two lead-in doses of single-agent Bv (1.8 mg/kg once every 3 weeks), patients received six cycles of AVD chemotherapy followed by four consolidative doses of Bv in responding patients. Results Patient characteristics included median age of 69 years (range, 60 to 88 years), 63% male, median Eastern Cooperative Oncology Group performance status 1, 81% stage III to IV disease, 60% International Prognostic Score 3 to 7, median Cumulative Illness Rating Scale-Geriatric comorbidity score of 7 (52% grade 3 to 4); and 12% had loss of instrumental activities of daily living at diagnosis. Thirty-seven (77%) of 48 patients completed six cycles of AVD, and 35 patients (73%) received at least one Bv consolidation. Overall response and complete remission rates after initial Bv lead-in dose were 18 (82%) of 22 and 8 (36%) of 22, respectively, and 40 (95%) of 42 and 34 (90%) of 42, respectively, after six cycles of AVD among 42 response-evaluable patients. Twenty (42%) of 48 patients experienced a grade 3 to 4 adverse event, most commonly neutropenia (44%), febrile neutropenia and pneumonia (8%), or diarrhea (6%); 33% had grade 2 peripheral neuropathy, which was reversible in a majority of patients. By intent-to-treat, the 2-year event-free survival, progression-free survival, and overall survival rates were 80%, 84%, and 93%, respectively. Furthermore, 2-year progression-free survival rates for patients with a Cumulative Illness Rating Scale-Geriatric comorbidity score of ≥ 10 versus < 10 were 45% versus 100%, respectively ( P < .001), and with baseline loss versus no loss of instrumental activities of daily living were 25% versus 94% ( P < .001), respectively, the latter persisting on multivariable analyses. Conclusion Altogether, sequential Bv-AVD was well tolerated and was associated with robust outcomes. Furthermore, geriatric-based measures were strongly associated with patient survival.

Glucocorticoids are widely used for therapy of hematologic malignancies. Unfortunately, chronic treatment with glucocorticoids commonly leads to adverse effects including skin and muscle atrophy and osteoporosis. We found recently that REDD1 (regulated in development and DNA damage 1) plays central role in steroid atrophy. Here, we tested whether REDD1 suppression makes glucocorticoid-based therapy of blood cancer safer. Unexpectedly, approximately 50% of top putative REDD1 inhibitors selected by bioinformatics screening of Library of Integrated Network-Based Cellular Signatures database (LINCS) were PI3K/Akt/mTOR inhibitors. We selected Wortmannin, LY294002, and AZD8055 for our studies and showed that they blocked basal and glucocorticoid-induced REDD1 expression. Moreover, all PI3K/mTOR/Akt inhibitors modified glucocorticoid receptor function shifting it toward therapeutically important transrepression. PI3K/Akt/mTOR inhibitors enhanced anti-lymphoma effects of Dexamethasone in vitro and in vivo, in lymphoma xenograft model. The therapeutic effects of PI3K inhibitor+Dexamethasone combinations ranged from cooperative to synergistic, especially in case of LY294002 and Rapamycin, used as a previously characterized reference REDD1 inhibitor. We found that coadministration of LY294002 or Rapamycin with Dexamethasone protected skin against Dexamethasone-induced atrophy, and normalized RANKL/OPG ratio indicating a reduction of Dexamethasone-induced osteoporosis. Together, our results provide foundation for further development of safer and more effective glucocorticoid-based combination therapy of hematologic malignancies using PI3K/Akt/mTOR inhibitors.

Immune-based treatment strategies, such as checkpoint inhibition and chimeric antigen receptor (CAR) T cells, have started a new frontier for treatment in non-Hodgkin lymphoma (NHL). Checkpoint inhibition has been most successful in Hodgkin lymphoma, where higher expression of PD-L1 is correlated with better overall response rate. Combinations of checkpoint inhibition with various chemotherapy or biologics are in clinical trials, with initially promising results and manageable safety profiles. CAR T-cell therapies that target CD19 are a promising and attractive therapy for B-cell NHLs, with a product approved by the US Food and Drug Administration in 2017. Changes in the target, hinge, or costimulatory domain can dramatically alter the persistence and efficacy of the CAR T cells. The ZUMA trials from Kite used CD19-(CD28z) CAR T cells, whereas the TRANSCEND studies from Juno and the JULIET studies from Novartis used CD19-(4-1BBz) CARs. Despite the recent successes with CAR T-cell clinical trials, major concerns associated with this therapy include cytokine release syndrome, potential neurotoxicities, B-cell aplasia, loss of tumor antigen leading to relapse, and cost and accessibility of the treatment. Although first-generation CAR T-cell therapies have failed in solid malignancies, newer second- and third-generation CAR T cells that target antigens other than CD19 (such as mesothelin or B-cell maturation antigen) are being studied in clinical trials for treatment of lung cancer or multiple myeloma. Overall, immune-based treatment strategies have given oncologists and patients hope when there used to be none, as well as a new basket of tools yet to come with further research and development.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN Guidelines Panel meets at least annually to review comments from reviewers within the NCCN Member Institutions, examine relevant data, and reevaluate and update the recommendations. These NCCN Guidelines Insights summarize recent updates centered on treatment considerations for relapsed/refractory classic HL.

Background With the introduction of the anti-CD20 antibody rituximab, the outcome of patients with follicular lymphoma (FL) has greatly improved over the last two decades. First-line prolonged rituximab monotherapy is effective, achieving long-term remission and prolonged failure-free survival in some patients. Additionally, rituximab has been shown to synergize with chemotherapeutic and novel targeted agents alike with measurable gains in duration of response. As such, rituximab has made its mark in the treatment of FL and remains a valid agent despite the availability of newer monoclonal antibodies. This review summarizes the evolving role of rituximab as the first available anti-CD20 monoclonal antibody, emphasizing its clear activity as a single agent and in combination with chemotherapy or molecular targeted agents, and setting the standard for the development of new anti-CD20 monoclonal antibodies. Conclusion We provide data that support the ongoing use of rituximab as a therapeutic partner for novel agents in future clinical trials exploring chemotherapy-free alternatives.

Introduction The treatment of aggressive B-cell NHL has evolved rapidly over the last 5 years, owing to the FDA approval of 3 CD19 CAR T-cell constructs (CARTs) along with other novel targeted therapies. Real world practice data suggest that CARTs have been successfully administered in populations typically excluded from clinical trials. However, data on how to best utilize novel targeted agents as a pathway to CARTs and feasibility of CARTs in rare histologies remains limited. This retrospective multicenter study describes patient (pt) selection and practice patterns in pts treated with CD19 CARTs and provides insight on feasibility of CARTs in special populations. Methods Adult pts with R/R aggressive B-cell NHL treated with CD19 CARTs between 2015- 2020 across 12 US academic centers were identified. Data on demographic and clinical characteristics, disease and toxicity outcomes were collected. Univariate analyses (UVA) were performed to determine impact of demographic/clinical variables on survival. Survival curves were calculated using Kaplan-Meier method. Subgroup analysis was performed for pts with secondary central nervous system lymphoma (sCNSL). Results Clinical and demographic features were recorded from 400 pts (Table 1). Median age was 59 years (range 18-84). Of 271 pts with immunohistochemistry data, 79 (29%) had double-expressor lymphoma. Of 178 pts with FISH data captured, 62 (35%) had double/triple-hit lymphoma. Most common histological subtypes included 271 (68%) pts with de novo DLBCL, 81 (20%) with transformed FL, 13 (3%) with Richter's syndrome, and 8 (2%) with PMBCL. Rare histologies included 7 (2%) with transformed MZL, 5 (1%) with PTLD and 2 (0.5%) with grey zone lymphoma. 24 (6%) pts had sCNSL at time of CART apheresis. Two (0.5%) pts were HIV-positive. Median number of lines of therapy prior to CART was 2 (range 1-8); 182 (46%) pts received ≥ 3 lines. 114 (28%) pts previously had an autologous stem cell transplant. Targeted therapies used as salvage regimens at any point prior to CART are listed in Table 2: commonly used salvage targeted therapies included lenalidomide based therapy (imids, n=37, 9%), BTK inhibitors (BTKis, n=30, 8%), checkpoint inhibitors (CBIs, n=17, 4%) and polatuzumab-containing regimens (n=10, 3%). 2 (1%) pts received loncastuximab, and no pts received tafasitamab. Six (1.5%) pts proceeded to CART despite complete response to most recent pre-CART therapy. 191 (48%) pts received bridging between apheresis and CART infusion, choice of bridging noted in Table 2: the majority received chemotherapy (n=103, 54%); 28 (15%) received radiation (XRT); 25 (13%), 24 (13%) and 18 (9%) pts received imids, polatuzumab-containing regimens, or BTKis, respectively. With median follow-up of 22.4 months (mo) for the overall group, median (m) PFS was 11 mo (n=363); mOS, was 27 mo (n=397; Fig 1). Pts with sCNSL had a mPFS and mOS of 2 and 4 mo, respectively (Fig 1). On UVA, factors predicting poorer PFS and OS in the overall group included ≥3 pre-CART lines (p For outcomes according to bridging regimens: mPFS after CART for most commonly used systemic bridging therapies was 86 days (d) for platinum-based chemotherapy, 77 d for imids, 90 d for BTKis, 98 d for polatuzumab-bendamustine/rituximab, and 274 d for XRT. Median PFS for XRT bridging (274 d) was statistically better when compared to mPFS for listed systemic therapies combined (p Conclusion Survival outcomes with CARTs in our data set are consistent with those reported in clinical trial settings. CARTs are utilized in real world practice in rare subsets of aggressive R/R B-cell NHL not routinely included in clinical trials. Despite early data suggesting pts with sCNSL benefit from CART, our data suggest outcomes with CART are dismal in this group. Targeted therapies including imids, polatuzumab, BTKis and CBIs are feasible choices for salvage and/or bridging as a pathway to CARTs. Bridging with XRT resulted in improved mPFS post CART as compared to bridging with systemic therapies and suggests differences in pt selection for each with systemic therapies likely favored in those with more widespread disease burden. Minimal use of CD19-targeted agents pre-CART is attributed to later approval of these agents and concern for potential loss of CD19 antigen leading to CART resistance. Figure 1 Figure 1. Disclosures Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Shouse: Kite Pharma: Speakers Bureau; Beigene: Honoraria. Hess: ADC Therapeutics: Consultancy; BMS: Speakers Bureau. Stephens: Beigene: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Epizyme: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive: Membership on an entity's Board of Directors or advisory committees; Arqule: Research Funding; Mingsight: Research Funding; JUNO: Research Funding; Celgene: Consultancy; CSL Behring: Consultancy; AstraZeneca: Consultancy; Abbvie: Consultancy; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ma: Loxo: Research Funding; AstraZeneca: Honoraria, Research Funding, Speakers Bureau; Juno: Research Funding; Beigene: Research Funding, Speakers Bureau; Abbvie: Honoraria, Research Funding; Janssen: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau. Winter: BMS: Other: Husband: Data and Safety Monitoring Board; Actinium Pharma: Consultancy; Janssen: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Agios: Other: Husband: Consultancy; Epizyme: Other: Husband: Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Danilov: Astra Zeneca: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Gilead Sciences: Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Rigel Pharm: Honoraria; Bayer Oncology: Consultancy, Honoraria, Research Funding; SecuraBio: Research Funding. Shah: Umoja: Consultancy; Legend: Consultancy; Kite: Consultancy; Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Lily: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy; Incyte: Consultancy. Barta: Seagen: Honoraria; Daiichi Sankyo: Honoraria; Acrotech: Honoraria; Kyowa Kirin: Honoraria. Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Karmali: Epizyme: Consultancy; BeiGene: Consultancy, Speakers Bureau; EUSA: Consultancy; Roche: Consultancy; AstraZeneca: Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Karyopharm: Consultancy; Takeda: Research Funding; BMS/Celgene/Juno: Consultancy, Research Funding; Janssen/Pharmacyclics: Consultancy; Genentech: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau.

Introduction: Treatment of relapsed and refractory aggressive B cell lymphomas is challenging, especially after autologous stem cell transplant or chimeric antigen receptor T cell therapy. CpG oligodeoxynucleotides (CpGs) mimic bacterial DNA and bind to toll-like receptor 9 (TLR9). TLR9 is expressed in the endosomes of innate immune cells and B lymphocytes as well as B cell lymphomas. CpG binding to TLR9 in these cells leads to a pro-inflammatory response and induces apoptosis of lymphoma cells by altering NF-kB activation. However, clinical utility of CpGs is limited due to difficulties delivering the DNA directly to the innate immune cells and lymphoma cells, and these DNA strands are easily degraded in biological fluids. Therefore, we designed a nano-carrier to deliver two classes of CpGs to improve clinical efficacy of CpGs in treating lymphoma. Class B CpGs (B-CpGs) mainly stimulate B cells while class C CpGs (C-CpGs) act on both B cells and plasmacytoid dendritic cells. Though C-CpGs are the focus of current clinical trials, B-CpGs may have a special a role in the treatment of lymphoma due to their more potent, direct cytotoxic effect on the malignant lymphoma cells. Here, we evaluated the anti-lymphoma effect of the combination of B-CpG nanoparticles (BNP) and C-CpG nanoparticles (CNP) by optimizing lymphoma cell death and immune stimulation. Methods: BNP and CNP were synthesized by surface-functionalizing gold nanoparticles with modified B-CpGs and C-CpGs, followed by purification via centrifugation. We used a dual flank tumor murine lymphoma model to evaluate the local and systemic anti-lymphoma efficacy of the CpG NPs and screen for the most effective formulation. A20 lymphoma tumors were implanted on both flanks of Balb/c mice. When the tumors were 5-7mm in diameter, various treatments were injected intratumorally on days 1, 4, and 8 on the side with the larger tumor. Treatment groups include PBS, B-CpG, C-CpG, B+C-CpG, BNP, CNP, BNP+CNP. Free CpGs were injected at 50ug/ml in 50ul (2.5ug CpG per injection) and nanoparticles at 100nM (equivalent to 50ug/ml CpGs) in 50ul. Tumor growth were measured every other day. Event is defined as tumor volume > 3cm 3. Second, we used an advanced disease lymphoma model to evaluate intravenous delivery of combination NPs. We implanted A20 lymphoma cells on a flank tumor (on day -14), then we injected A20 cells intravenously to mimic advanced disease (on day -7). We treated the mice with intravenous (tail vein) injections of PBS, B+C-CpG, or BNP+CNP on days 1, 4, and 8. Results: We found that the combination of BNP and CNPs had the most significant reduction in total tumor volume (TTV) (treated + untreated tumor size) (393mm 3 on day 22). The PBS group demonstrated rapid tumor growth (TTV 3516mm 3). The experimental treatment groups, B-CpG (TTV 949mm 3),, C-CpG (TTV 2230mm 3), B+C-CpGs (TTV 1680mm 3), BNP (TTV 1224mm 3), and CNP (1894mm 3) had similar TTV growth curves. Separating the treated tumor and untreated tumor growth curves, we found that B-CpG and BNP along with combination of BNP+CNP had the best tumor suppression on the treated side. This is not surprising as B-CpG sequences are more directly cytotoxic to lymphoma cells versus C-CpGs. Interestingly, combination nanoparticle treatment (BNP+CNP) was the only group that had significantly reduced tumor growth of the untreated tumor compared with all other conditions (p Conclusions: Overall, the combination of class B and class C CpG nanoparticles can generate a strong in situ anti-lymphoma vaccination response, presumably through the combination of by combining the superior cytotoxicity of BNPs with the enhanced immune stimulation effect of the CNPs. Further evaluation of the combined mechanism of action of this dual CpG nanoparticle approach and toxicity studies are in progress. Disclosures Thaxton: Zylem biosciences: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding.

Dosing with duvelisib 25 mg BID has been shown to be efficacious in iNHL, most notably the pivotal phase 2 DYNAMO study (NCT01882803) in follicular lymphoma (FL). The TEMPO study (NCT04038359) was designed to examine the effects of prespecified 2-week dose holidays on tumor responses and safety/tolerability in patients with iNHL (FL, MZL), based on data from a phase 3 trial (DUO) in CLL/SLL which demonstrated no negative impacts of (unscheduled) dose interruptions on response. In TEMPO, patients were randomized to receive duvelisib 25 mg BID for one 10-week cycle followed by 25 mg BID on Weeks 3 and 4 of each subsequent 4-week cycles (Arm 1) or duvelisib 25 mg BID on Weeks 1, 2, 5, 6, 9 and 10 of one 10-week cycle, then on Weeks 3 and 4 of each subsequent 4-week cycles (Arm 2). Patients continued treatment until disease progression, unacceptable toxicity, or withdrawal. As of May 5, 2021 data cutoff, a total of 65 treated pts had at least 4 months of follow up on or after study drug treatment. Across both arms, the median age was 63 years (range 34-85), and 47 (72.3%) of the patients remained on study treatment at the time of this analysis (table 1). 18 of 65 pts (27.7%) discontinued therapy; 13 of 65 pts (19.7%) discontinued due to PD: 7 out of 33 (21.2%) in arm 1 and 6 out of 32 (18.8%) in arm 2. Of the remaining 5 pts (out of 65 patients) that discontinued, all were in arm 1: 4 out of 33 pts (12.1%) due to adverse events and 1 out of 33 (3%) due to study drug interruption > 42 days. Across both arms, the ORR was 60% (39 of 65 pts), and the CR rate was 12.3% (8 of 65 pts). See table 2 for responses by arm. Grade > 3 AEs were higher in Arm 1 vs Arm 2, with the exception of neutropenia: elevated ALT/AST was 30.3%/27.3% vs 3.1%/3.1%; neutropenia 9.1% vs 18.8%; GI disorders 9.1% vs 0; infections 9.1% vs 3.1%; rash 6.1% vs 3.1%; and drug reaction with eosinophilia 3% vs 0 -- respectively. Discontinuation of study drug due to AEs only occurred in arm 1, in 5 out of 33 patients (15.2%), and were due to ALT/AST elevations (2 of 33 pts, 6.1%); skin and subcutaneous tissue disorders (2 of 33 pts, 6.1%); and pneumonia (1 of 33 pts, 3.0%). In summary, based on this interim analysis, continuous dosing followed by intermittent dosing (arm 1) and intermittent dosing (arm 2) are both efficacious in patients with iNHL. The ORR and CR are similar to those seen in DYNAMO. The study confirms the overall safety profile of duvelisib, demonstrating that intermittent dosing may well decrease the incidence of side effects without compromising efficacy. Figure 1 Figure 1. Disclosures Vorobyev: Janssen, Roche, Sanofi, Takeda, Biocad, Abbvie: Other: Advisory Boards, Speakers Bureau; Astellas, Novartis, AstraZeneca: Speakers Bureau. Tarella: ADC-THERAPEUTICS: Other: ADVISORY BOARD; Abbvie: Other: ADVISORY BOARD. Litwak: Secura Bio: Current Employment. Cohan: Secura Bio: Current Employment. Flinn: Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Zinzani: CELLTRION: Other: Advisory board, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; Incyte: Other, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; ROCHE: Other, Speakers Bureau; SANDOZ: Other: Advisory board; NOVARTIS: Consultancy, Other, Speakers Bureau; ADC Therap.: Other; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. OffLabel Disclosure: duvelisib is a PI3K inhibitor indicated for the treatment of relapsed/refractory CLL/SLL and FL. The approved dose of duvelisib is 25mg BID. A cycle consists of every 28 days.

Introduction: Radioimmunotherapy is a targeted approach to cancer care. It has been shown to improve progression-free survival and quality of life in people with specific types of non-Hodgkin's lymphoma, including CD20- and CD37-positive B-cell lymphoma (Barr et al., 2018 NCT00770224; Green & Press, 2017; Kolstad et al., 2018 NCT01796171; Witzig et al., 2002). It has also been shown to increase the proportion of people who achieve complete response to therapy (Green & Press, 2017). Although CD20-targeted therapy has been approved in the US and Europe for nearly two decades, its use remains limited. At its peak in the UK in 2007, only 57 people with lymphoma were treated with the therapy (Rojas et al., 2019). However, research is ongoing; a PubMed search for 'radioimmunotherapy' and 'lymphoma' produces 1,097 articles in the past 20 years, including over 300 articles in the past ten years. With novel applications (CD37- and CD22-targeted) currently under investigation, it is increasingly important to understand potential system and policy barriers to uptake, such that existing roadblocks are overcome. Tackling these challenges is essential to ensuring that radioimmunotherapy is appropriately integrated into relevant clinical guidelines and care pathways. Aim: To better understand the policy and system barriers to integration of existing and novel radioimmunotherapy into lymphoma care in the US and the UK. Methodology: We conducted a structured literature review, taking a systems approach, to explore each of the five domains of the health system as outlined in the Radioligand Therapy Readiness Assessment Framework (Figure 1. Five core domains of the health system, with subdomains; The Health Policy Partnership, 2021). This approach allowed us to gain a holistic understanding of what integration of radioimmunotherapy involves and identify potential barriers, from clinical development through to patient care. We also conducted semi-structured interviews with lymphoma experts in the US (N=5) and UK (N=6), including clinicians and nurses ('clinical experts', N=8) and patient advocates ('advocates', N=3). Our work was guided by national expert advisory groups in each country. Results: While the US and UK health systems are organized and funded very differently, the literature and expert interviews revealed many common strategic challenges to the integration of radioimmunotherapy. These were: 1) low awareness and understanding of radioimmunotherapy among newly licensed healthcare professionals (an issue raised by n=8 clinical experts); 2) limited awareness by patient advocates, patients and policymakers (n=3 advocates); 3) caution around uptake of new radioimmunotherapy agents based on limited access to and use of older treatments (n=7 clinical experts); 4) nonexistent referral pathways and unclear models of working which discourage shared care and hinder multidisciplinary coordination (n=4 clinical experts); 5) lack of recent clinical data and research to support evidence-based use (n=5 clinical experts); 6) reimbursement concerns (n=5 clinical experts). Policy implications: Taking a systems approach to explore potential barriers to integration of radioimmunotherapy has allowed us to explore potential adaptations needed to achieve multisectoral and multidisciplinary working. Our findings reveal that professional societies, policymakers and patient advocacy groups will need to work together to overcome these barriers by: 1) reaching consensus on timing and eligibility criteria for use of radioimmunotherapy; 2) creating accurate and consistent patient-friendly information; 3) efficiently updating clinical training and treatment guidelines to include approved radioimmunotherapy; 4) developing evidence-based and personalized referral and treatment pathways which ensure consistency of care; and 5) investing in data collection and analysis to continually inform practice. Figure 1 Figure 1. Disclosures Morgan: Nordic Nanovector: Consultancy; Advanced Accelerator Applications: Consultancy. Merkel: Advanced Accelerator Applications: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Bayer: Consultancy; Bristol-Myers Squibb: Consultancy; Curium: Consultancy; Johnson & Johnson: Consultancy; MSD: Consultancy; Nordic Nanovector: Consultancy; Novartis: Consultancy. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Buscombe: Advanced Accelerator Applications Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wait: Bayer: Consultancy; Curium: Consultancy; Johnson & Johnson: Consultancy; MSD: Consultancy; Advanced Accelerator Applications: Consultancy; Nordic Nanovector: Consultancy; Shionogi: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy. Dreyling: Genmab: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Amgen: Speakers Bureau; Astra Zeneca: Consultancy, Speakers Bureau; Bayer HealthCare Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy; Gilead/Kite: Consultancy, Research Funding, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Roche: Consultancy, Research Funding, Speakers Bureau; Abbvie: Research Funding. Mittra: Advanced Accelerator Applications Novartis: Consultancy, Honoraria, Research Funding; Curium: Consultancy, Honoraria; Nordic Nanovector: Research Funding. Gopal: Janssen: Consultancy, Honoraria, Research Funding; Cellectar: Consultancy, Honoraria; Bristol Meyers Squibb: Research Funding; SeaGen: Consultancy, Honoraria, Research Funding; I-Mab bio: Consultancy, Honoraria, Research Funding; Incyte: Honoraria; MorphoSys: Honoraria; Servier: Consultancy, Honoraria; Genetech: Consultancy, Honoraria, Research Funding; IGM Biosciences: Research Funding; Astra-Zeneca: Research Funding; Karyopharm: Consultancy, Honoraria; Takeda: Research Funding; Teva: Research Funding; Agios: Research Funding; Kite: Consultancy, Honoraria; ADC Therapeutics: Consultancy, Honoraria; Acrotech: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria; Nurix Inc: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding.

Background: The standard of care (SOC) treatment (Tx) in the curative setting for patients (pts) with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) after 1st-line (1L) chemoimmunotherapy (CIT) is high-dose therapy with autologous stem cell rescue (HDT-ASCT) if responsive to 2L CIT; however, as many pts do not respond to or cannot tolerate 2L CIT, or are not intended for HDT-ASCT, outcomes remain poor. Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for R/R LBCL after ≥2 prior systemic therapies. Since CAR T-cell therapy may benefit pts in earlier lines of therapy, we conducted ZUMA-7 (NCT03391466), a global, randomized, Phase 3 trial of axi-cel vs SOC in pts with 2L R/R LBCL, and report here the results of the primary analysis (PA). Methods: Eligible pts were ≥18 y with LBCL, ECOG PS 0-1, R/R disease ≤12 mo of adequate 1L CIT (including anti-CD20 monoclonal antibody and an anthracycline), and intended to proceed to HDT-ASCT. Pts were randomized 1:1 to axi-cel or SOC, stratified by 1L Tx response and 2L age-adjusted IPI (sAAIPI). In the axi-cel arm, pts received a single infusion of 2×10 6 CAR T cells/kg after conditioning (3 d; cyclophosphamide 500 mg/m 2/day and fludarabine 30 mg/m 2/day). Optional bridging Tx was limited to corticosteroids (CIT was not allowed). In the SOC arm, pts received 2-3 cycles of an investigator-selected, protocol defined, platinum-based CIT regimen; pts with partial response or complete response (CR) proceeded to HDT-ASCT. Disease assessments by PET-CT per Lugano Classification occurred at timepoints specified from randomization. Although there was no planned trial crossover between arms, pts not responding to SOC could receive CAR T-cell therapy off protocol. Axi-cel was hypothesized to result in a 50% improvement in event-free survival (EFS: time to earliest date of disease progression, death from any cause, or new lymphoma Tx) vs SOC. The PA was event-driven, and the primary endpoint was EFS by blinded central review. Key secondary endpoints, tested hierarchically, were objective response rate (ORR) and overall survival (OS; interim analysis); safety was also a secondary endpoint. Level of CAR T cells was an exploratory endpoint. Results: As of 3/18/21, 359 pts were enrolled globally. The median age was 59 y (range, 21-81; 30% ≥65 y). Overall, 74% of pts had primary refractory disease and 46% had high sAAIPI (2-3). Of 180 pts randomized to axi-cel, 170 (94%) were infused; of 179 pts randomized to SOC, 64 (36%) reached HDT-ASCT after 2L CIT. The primary endpoint of EFS was met (HR: 0.398; P Conclusions: ZUMA-7, the first randomized, global, multicenter Phase 3 study of axi-cel vs 2L SOC in R/R LBCL, demonstrated a statistically significant and clinically meaningful improvement in EFS. Axi-cel showed superiority over SOC with >4-fold greater median EFS, 2.5-fold greater EFS at 2 y, double the CR rate, and more than double the percentage of pts receiving definitive Tx. Safety of axi-cel was manageable and at least consistent with 3L axi-cel therapy. Axi-cel may replace CIT/HDT-ASCT as the SOC for 2L R/R LBCL. These data are reported on behalf of all ZUMA-7 investigators and contributing Kite members. Disclosures Locke: Novartis: Consultancy, Other, Research Funding; Janssen: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Umoja: Consultancy, Other; Wugen: Consultancy, Other; Takeda: Consultancy, Other; Legend Biotech: Consultancy, Other; EcoR1: Consultancy; Emerging Therapy Solutions: Consultancy; Gerson Lehrman Group: Consultancy; Cowen: Consultancy; Calibr: Consultancy, Other: Scientific Advisory Role; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding. Miklos: Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy; Pharmacyclics: Patents & Royalties. Jacobson: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Perales: Cidara: Honoraria; Omeros: Honoraria; Merck: Honoraria; Servier: Honoraria; Medigene: Honoraria; Takeda: Honoraria; Miltenyi Biotec: Honoraria, Other; Sellas Life Sciences: Honoraria; Kite/Gilead: Honoraria, Other; Novartis: Honoraria, Other; Incyte: Honoraria, Other; Equilium: Honoraria; Karyopharm: Honoraria; NexImmune: Honoraria; Celgene: Honoraria; Nektar Therapeutics: Honoraria, Other; MorphoSys: Honoraria; Bristol-Myers Squibb: Honoraria. Kersten: Novartis: Consultancy, Honoraria, Other: Travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding; Roche: Consultancy, Honoraria, Other: Travel support, Research Funding; BMS/Celgene: Consultancy, Honoraria; Takeda: Research Funding; Celgene: Research Funding; Miltenyi Biotec: Consultancy, Honoraria, Other: Travel support. Oluwole: Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Pfizer: Consultancy; Curio Science: Consultancy. Ghobadi: Amgen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Atara Biotherapeutics: Consultancy; Wugen: Consultancy; Celgene: Consultancy. McGuirk: Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; Novartis: Research Funding; Gamida Cell: Research Funding; Pluristem Therapeutics: Research Funding; Bellicum Pharmaceuticals: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Magenta Therapeutics: Consultancy, Honoraria, Research Funding; EcoR1 Capital: Consultancy; Novartis: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding. Pagel: Incyte/MorphoSys: Consultancy; Gilead: Consultancy; AstraZeneca: Consultancy; Actinium Pharmaceuticals: Consultancy; Pharmacyclics/AbbVie: Consultancy; BeiGene: Consultancy; Epizyme: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy. Muñoz: Targeted Oncology, OncView, Kyowa, Physicians' Education Resource, and Seagen: Honoraria; Pharmacyclics, Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa, Alexion, Beigene, Fosun Kite, Innovent, Seagen, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, and Servier: Consultancy; Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics, Janssen, Seagen, Acrotech, Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/Bristol Myers Squibb, Genentech, and Roche: Speakers Bureau; Bayer, Kite, a Gilead Company, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seagen, and Janssen, Millennium: Research Funding; OncView: Honoraria; Kyowa Kirin: Honoraria; Physicians' Education Resource: Honoraria. Farooq: Kite, a Gilead Company: Honoraria. Van Meerten: Kite, a Gilead Company: Honoraria; Janssen: Consultancy. Reagan: Genentech: Research Funding; Kite, a Gilead Company: Consultancy; Curis: Consultancy; Seagen: Research Funding. Sureda: Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau. Flinn: Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Vandenberghe: Bristol Myers Squibb/Celgene: Consultancy; Pfizer: Research Funding; Gilead Sciences: Consultancy, Other: Travel support; Miltenyi Biotec: Consultancy; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy. Song: GlaxoSmithKline: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria; Kite, a Gilead Company: Honoraria; Sanofi: Honoraria. Dickinson: Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Research Funding; Amgen: Honoraria; Roche: Consultancy, Honoraria, Other: travel, accommodation, expenses, Research Funding, Speakers Bureau; Gilead Sciences: Consultancy, Honoraria, Speakers Bureau; MSD: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria. Minnema: Janssen: Consultancy; Alnylam: Consultancy; Kite/Gilead: Consultancy; Cilag: Consultancy; Celgene: Other: Travel expenses; BMS: Consultancy. Riedell: Kite/Gilead: Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Calibr: Research Funding; Tessa Therapeutics: Research Funding; Xencor: Research Funding; MorphoSys: Research Funding. Leslie: Karyopharm Therapeutics: Honoraria, Speakers Bureau; BeiGene: Consultancy, Honoraria, Speakers Bureau; Celgene/BMS: Consultancy, Honoraria, Speakers Bureau; Merck: Consultancy; Abbvie: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Pharmacyclics: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy; Epizyme: Consultancy, Honoraria, Speakers Bureau; PCYC/Janssen: Consultancy, Honoraria, Speakers Bureau; Seagen: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Speakers Bureau. Chaganti: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Travel support, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: travel support, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Honoraria, Other: Travel support; Atara Bio: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding; Incyte: Honoraria, Speakers Bureau. Yang: Kite, a Gilead Company: Current Employment. Filosto: Tusk Therapeutics: Patents & Royalties: or other intellecular property; Gilead Sciences: Other: stock or other ownership ; Kite, a Gilead Company: Current Employment. Schupp: Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support. To: NantWorks: Ended employment in the past 24 months; Kite, a Gilead Company: Current Employment, Other: stock or other ownership . Cheng: Kite, a Gilead Company: Current Employment, Other: Travel support; Gilead Sciences: Other: stock or other ownership . Gordon: Bristol Myers Squibb: Honoraria, Research Funding; Zylem Biosciences: Patents & Royalties: Patents, No royalties. Westin: Genentech: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Curis: Research Funding; Iksuda Therapeutics: Consultancy; Umoja: Consultancy; ADC Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding.

Background: Genomic copy number alterations (CNAs) of chromosome 9p24.1 characterize classic Hodgkin lymphoma (cHL) leading to increased expression of programmed cell death ligands -1 and -2 (PD-L1 and PD-L2). Amplifications and high level copy number gains (CNG) have been associated with advanced stage cHL and inferior treatment outcomes with standard chemotherapy. Few studies have assessed 9p24.1 genomic alterations in the frontline setting in the context of PD-1 blockade monotherapy. We conducted a phase 2 clinical trial of sequential pembrolizumab (PEM) x 3 followed by doxorubicin, vinblastine, and dacarbazine (AVD) chemotherapy (4-6 cycles) in newly diagnosed cHL. Interim response to single agent PEM was assessed by PET-CT and by decline in metabolic tumor volume (MTV). Herein, we report updates after extended follow-up of patients (median 33.1 months), and results of correlative studies analyzing 9p24.1 CNAs and PD-1 pathway expression. Methods: Pre-treatment diagnostic biopsy specimens were double stained for PD-L1 (E1L3N, XP Cell Signaling) and PAX5, single stained for PD-L2 and pSTAT3, and scored by two expert hematopathologists (QC, LBS) for percentage positive cells and intensity of staining. A modified H score was calculated as the product of staining intensity (0-3) and percentage of positive tumor cells (0-100%), ranging from 0 - 300 was calculated for PD-L1, PD-L2, and pSTAT3. Fluorescence in situ hybridization (FISH) to assess chromosome 9p24.1 CNAs was performed by co-hybridizing PD-L1/PD-L2 probes (target) with the centromeric 9 probe (control). In each case, the percentage and magnitude of 9p24.1 CNAs were evaluated. Four FISH categories were defined based on the target:control ratio and total copy numbers (CNs) of the target per Hodgkin Reed-Sternberg (HRS) cell to include: amplification (ratio≥3), copy number gain (CNGs) (1≤ratio The relationships between PD-1 pathway markers, genomic alterations, and response to single agent PEM by MTV were assessed statistically using Fisher's Exact test, Kruskal-Wallis test, or Spearman's rank correlation as appropriate. PD-L1 H Scores were grouped into terciles of approximately equal size for categorical analysis. Response was defined as a complete metabolic response (CMR), ≥ 90% reduction in MTV (near CMR), or partial response with < 90% reduction by MTV (PR). Kaplan-Meier curves were used to analyze progression-free survival (PFS) and overall survival (OS). Results: Thirty patients were enrolled from September 2017 through August 1, 2019; 28 had tissue available for FISH analysis and 29 for immunohistochemistry. Patient responses to single agent PEM were PMR in 11 (36.7%), near-CMR in 8 (26.7%), and CMR in 11 (36.7%). CMR rate following AVD x 2 was 100%. With the extended follow-up (median 33.1 months, range 26.0-43.0), PFS and OS both remained at 100% (Figures 1a, 1b). Among 28 cases with available FISH analysis, all patients demonstrated genomic alterations in 9p24.1. The highest level alteration was amplification in 14 patients (50%) and copy number gain in 14 (50.0%) Six of 22 examined cases were EBER-positive. Forty-one percent (n=7) of patients with a CMR or near CMR had amplifications in 9p24.1, compared to 64% (n=7) with a PMR following PEM monotherapy (p=0.2). The median PD-L1 H score was 215 (range 20-300). Of 29 patients assessed, 28% had PD-L1 H scores in the first tercile (H-score 1-190), 34% in the second tercile (190-240), and 38% in the third tercile (240-300). There was no association between response to single agent PEM and 9p24.1 alteration, PD-L1, PD-L2 or STAT3 H-scores, % residual disomy, or EBER status (see Figure 1c for PD-L1 results). Conclusions: We found that after extended follow-up, sequential pembrolizumab and AVD chemotherapy remains a highly effective strategy with 100% of patients remaining alive without relapse. The high response rates observed at all PD-L1/PD-L2 levels in this clinical study suggest that even low levels of PD ligand expression may be sufficient for response to PD-1 blockade in previously untreated cHL. We gratefully acknowledge support from Merck & Co. Figure 1 Figure 1. Disclosures Allen: Kyowa Kirin: Consultancy; Secure Bio: Consultancy; ADC Therapeutics: Consultancy; MorphoSys: Consultancy; Epizyme: Consultancy. Advani: Astellas/Agensys: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Bayer: Membership on an entity's Board of Directors or advisory committees; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees; Cell Medica: Membership on an entity's Board of Directors or advisory committees; Forty Seven: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genetech Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceutical: Research Funding; Juno: Membership on an entity's Board of Directors or advisory committees; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Kura: Research Funding; Kyowa: Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding; Millenium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Portola Pharmaceuticals: Consultancy; Regeneron: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Winter: Actinium Pharma: Consultancy; BMS: Other: Husband: Data and Safety Monitoring Board; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Epizyme: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Janssen: Other: Husband: Consultancy; Karyopharm (Curio Science): Honoraria; Merck: Consultancy, Honoraria, Research Funding.

Introduction: Approximately 30-35% of patients with classic Hodgkin Lymphoma will prove refractory to frontline therapy or relapse subsequently. Traditional second-line chemotherapy regimens including ifosfamide, carboplatin, and etoposide (ICE) result in complete response rates of ~50%. Achievement of complete metabolic response (CMR) assessed by PET/CT imaging prior to autologous hematopoietic stem cell transplant (AHSCT) predicts favorable progression free survival (PFS) and overall survival (OS). PD-1 blockade is a well-established therapeutic strategy for the treatment of cHL. Pembrolizumab (PEM) is a checkpoint inhibitor targeting PD-1 currently FDA approved as monotherapy in relapsed cHL. We hypothesized that PEM in combination with ICE (PEM-ICE) chemotherapy would be a safe and effective regimen that would yield high CMR rates prior to AHSCT. Methods: This single arm, phase II, multi-institutional clinical trial evaluated the addition of PEM to ICE chemotherapy in AHSCT eligible patients with relapsed and refractory cHL (NCT03077828). The regimen consisted of 21 day cycles of PEM 200 mg IV on day 1 with standard ICE including ifosfamide 5 g/m2 with MESNA as a 24hr continuous infusion on day 2, carboplatin AUC 5 IV (max 800 mg) on day 2, and etoposide 100 mg/m2/day IV on days 1 to 3. Two cycles of PEM-ICE were followed by stem cell mobilization/collection. One cycle of PEM 200 mg IV monotherapy was then administered. Our primary endpoint was the rate of CMR on PET/CT (PET2) imaging defined as a Deauville score of ≤ 3. Images were reviewed centrally. An optional third cycle of PEM-ICE was permitted for patients achieving CMR to allow for appropriate timing of AHSCT. Secondary objectives included clinical outcomes (PFS and OS), safety and tolerability, and transplantation related metrics including ability to collect stem cells and time to engraftment. Results: A total of 42 patients were enrolled with 37 patients evaluable for the primary endpoint. Median age was 34 (19-70) with female predominance (n=27, 64%). 16 patients had primary refractory disease. The CMR rate assessed by PET/CT imaging following 2 cycles of PEM-ICE was 86.5% (95% CI, 71.2-95%), meeting our primary endpoint of improvement over historical outcomes to 70%. The PET2 ORR was 97.3% with 11% PR and 2.7% PD. PET2 scores were Deauville 1 in 45% (n=17), Deauville 2 in 27.0% (n=10), Deauville 3 in 8.1% (n=3), Deauville 4 in 13.5% (n=5), and Deauville 5 in 5.4% (n=2). New areas of PET-positivity in two cases were biopsied showing noncaseating granuloma in one case and EBV but no cHL in another. Five patients received the optional third cycle of PEM-ICE chemotherapy with 35 of the 37 evaluable patients proceeding to AHSCT. Seven patients had radiation as part of the conditioning regimen with an additional 4 patients receiving consolidative radiation following transplant. After a median follow up of 27 months, the median PFS was 26.9 months with survival probability at 24 months of 88.2% (Figure 1). Median OS was not reached with too few events but remained 95.1% at 27 months. The addition of PEM to ICE did not impair stem cell mobilization and all patients successfully collected, with 35 (87%) within 2 apheresis sessions (range 1-7). No patients had engraftment delays or failure. Of the 42 patients, all received at least one dose of PEM and were therefore eligible for toxicity analyses. 34 patients (81%) experienced adverse events (AEs) attributed to PEM and 22 patients (52.3%) had grade 3-4 AEs comprised of cytopenias, elevated AST/ALT, hyponatremia, hypophosphatemia, and fatigue. Five patients had severe AEs attributed to PEM which included anemia, back pain, decreased EF, fever, and thrombocytopenia. There were no significant PEM-related autoimmune events that delayed a patient's treatment on protocol. There were two grade 5 toxicities on the protocol including a patient with cardiac arrest during stem cell collection and a patient with acute respiratory distress syndrome attributed to engraftment syndrome. Both were judged "possibly" related to PEM. Conclusions: Pembrolizumab with ICE chemotherapy is a tolerable and efficacious regimen with high CMR rate as assessed by PET/CT. Despite short follow up, patients had excellent PFS and OS in the post-transplant setting. The results support further investigation of PEM-ICE as second-line treatment for AHSCT eligible patients with relapsed and refractory classical Hodgkin lymphoma. Figure 1 Figure 1. Disclosures Casulo: BMS: Research Funding; Verastem: Research Funding; Genentech: Research Funding; Gilead: Research Funding. Allen: Kyowa Kirin: Consultancy, Honoraria, Research Funding; Daichii Sankyo: Consultancy, Honoraria; Secure Bio: Consultancy, Honoraria. Karmali: Epizyme: Consultancy; AstraZeneca: Speakers Bureau; Roche: Consultancy; Genentech: Consultancy; EUSA: Consultancy; Janssen/Pharmacyclics: Consultancy; Karyopharm: Consultancy; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; Takeda: Research Funding. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Winter: Actinium Pharma: Consultancy; BMS: Other: Husband: Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Epizyme: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Gilead: Other: Husband: Consultancy; Janssen: Other: Husband: Consultancy. OffLabel Disclosure: new combination of study agent with standard of care chemotherapy regimen

BACKGROUND: Maintenance rituximab in MCL has improved survival and supports the exploration of maintenance with novel targeted agents. Ibrutinib is a BTK inhibitor approved for relapsed/refractory MCL. We report the final analysis of safety and efficacy of Ibrutinib maintenance (I-M) as monotherapy following chemo-immunotherapy induction for treatment-naive MCL in a multicenter phase II trial. METHODS: Pts with CR/PR to frontline chemo-immunotherapy (+/- autologous stem cell transplant (autoSCT)) received I-M 560 mg daily for up to 4 years. The primary endpoint was 3-year PFS rate. Secondary endpoints were to determine PR to CR conversions, median OS and the safety profile of I-M. Minimal residual disease (MRD) was measured using an NGS-MRD assay on peripheral blood (detection resolution of 1 cell per million; clonoSEQ®; Adaptive Biotechnologies) prior to and 1, 6 and 18-24 mo(s) after initiation of I-M. RESULTS: 36 pts were enrolled to complete accrual. Median age was 60 years (range 46-90). For induction, most pts were treated with BR (n=17, 47%) or a cytarabine-containing regimen (n=18, 50%). Eighteen (50%) pts underwent autoSCT. Thirty-four (94%) and 2 (6%) had CR and PR as best response to induction respectively, with 1 PR to CR conversion on I-M. At a median follow-up of 47 months, 10 (28%) pts completed a full I-M course, 7 (19%) remain on I-M, 15 (42%) discontinued I-M for treatment related adverse events (TRAEs) and 4 (11%) discontinued I-M for other reasons (PD x 1, secondary malignancies requiring treatment x 2, death cause unknown x 1). Three pts died during I-M, 2 deaths deemed unrelated to I-M (aspiration pneumonia, 2 nd malignancy) and 1 from unknown cause; 1 pt was lost to follow-up. Four pts were treated with rituximab maintenance after stopping I-M prematurely for toxicity without evidence of disease progression prior to or after change in therapy. At the time of data cut-off, MRD was assessed in 22 of 36 pts (available samples) at varying time points (Fig 1) with a dominant clone identified in all 22 pts. Pts were deemed MRD (-) if no sequences were detected at a threshold of 10 -6. Seventeen pts were MRD (-), 4 MRD indeterminate and 1 MRD (+) with radiographic CR after induction; the latter remained MRD (+) at 18 months with CR. All MRD indeterminate pts were MRD (-) when checked after 1 month on I-M. Six pts MRD (-) post-induction became MRD (+) during their I-M course. Of these pts, 2 reverted to MRD (-) with continued I-M; of the remaining 4 pts, 1 had PD and the others maintain stable clinical responses with ongoing I-M though MRD has not been rechecked. 3-year PFS and OS rates were 91% and 94% respectively (Figure 2A, B). PFS was improved in pts who received autoSCT prior to enrollment (Fig 2C, p=0.03) with a trend for improved OS (Figure 2D, p=0.057). MRD did not correlate with PFS (p=0.65) and OS (p=0.45) given few events. Atrial fibrillation/flutter occurred in 10 pts (28%; G1-2 n=7, 19%, G≥3 n = 3, 8%), 8 (22%) with new onset and 2 (6%) with worsening grade. HTN occurred in 20 pts (55%; G1-2 n=13, 33%, G≥3 n = 7, 22%), 15 (42%) with new onset and 5 (14%) with worsening grade. Incidences of both atrial fibrillation/flutter and HTN increased over time with ongoing I-M exposure (Table). Four pts had a 2 nd solid malignancy, 2 while on treatment and 2 after stopping I-M. TRAEs led to permanent dose reductions in 8 (22%) pts, 2 for neutropenia, 2 for fatigue, 2 for myalgias, 1 each for diarrhea and mucositis. Fifteen (42%) pts permanently discontinued I-M, most commonly for atrial fibrillation/flutter (n=8, 22%; n=5, 14% for G1-2). CONCLUSION: I-M 560 mg daily after response to frontline chemo-immunotherapy is feasible in MCL and results in durable PFS and OS. Toxicities including rates of high-grade atrial fibrillation/flutter and HTN are consistent with ibrutinib's known safety profile with increased incidence with longer exposure; discontinuation of I-M for atrial fibrillation/flutter in 22% of pts is higher than expected. Changes in NGS-MRD were noted in a small number of pts during maintenance. Extended follow-up and correlation of changes in MRD with PFS and OS are needed to determine clinical relevance of I-M and MRD status. Further studies evaluating maintenance with next generation BTK inhibitors as alternatives to ibrutinib should be explored to mitigate toxicity. Figure 1 Figure 1. Disclosures Karmali: Takeda: Research Funding; Genentech: Consultancy; Roche: Consultancy; Epizyme: Consultancy; Morphosys: Consultancy, Speakers Bureau; BeiGene: Consultancy, Speakers Bureau; Janssen/Pharmacyclics: Consultancy; BMS/Celgene/Juno: Consultancy, Research Funding; AstraZeneca: Speakers Bureau; Karyopharm: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; EUSA: Consultancy. Abramson: Seagen Inc.: Research Funding; Allogene Therapeutics: Consultancy; Astra-Zeneca: Consultancy; Incyte Corporation: Consultancy; BeiGene: Consultancy; Kymera: Consultancy; Bluebird Bio: Consultancy; Genmab: Consultancy; EMD Serono: Consultancy; Bristol-Myers Squibb Company: Consultancy, Research Funding; Novartis: Consultancy; Kite Pharma: Consultancy; Morphosys: Consultancy; C4 Therapeutics: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Stephens: JUNO: Research Funding; Abbvie: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; AstraZeneca: Consultancy; CSL Behring: Consultancy; Celgene: Consultancy; Mingsight: Research Funding; Arqule: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Winter: Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Actinium Pharma: Consultancy; BMS: Other: Husband: Data and Safety Monitoring Board; Gilead: Other: Husband: Consultancy; Janssen: Other: Husband: Consultancy; Epizyme: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Karyopharm (Curio Science): Honoraria. Ma: Juno: Research Funding; Beigene: Research Funding, Speakers Bureau; AstraZeneca: Honoraria, Research Funding, Speakers Bureau; Loxo: Research Funding; Janssen: Research Funding, Speakers Bureau; Abbvie: Honoraria, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau. Petrich: Daiichi-Sankyo: Current Employment; Abbvie: Ended employment in the past 24 months. Hochberg: Leuko: Consultancy; Trapelo Health: Consultancy. Kuhr: Adaptive Biotechnologies: Current Employment. Lee: Adaptive Biotechnologies: Current Employment. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. OffLabel Disclosure: We will report on the use of ibrutinib maintenance after front-line induction therapy in MCL.

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.

Background: Anti-CD19 chimeric antigen receptor T-cell therapy (CART) is a highly active therapy for relapsed/refractory (R/R) aggressive B-cell lymphoma. Nonetheless, most patients (pts) ultimately develop progressive disease (PD). There is little guidance on the optimal treatment approach(es) for these pts. We performed a multicenter retrospective analysis with a primary objective to assess treatment patterns and outcomes in pts with R/R aggressive B-cell lymphoma who develop PD after anti-CD19 CARTs. Methods: Pts with aggressive B-cell lymphoma treated with anti-CD19 CART between 2015 and 2020 across 12 US academic medical centers were included. Demographic and clinical characteristics were collected along with CART toxicities and response. Regimens administered as salvage post CART were assessed. Univariate analyses (UVA) were performed to determine impact of demographic and clinical variables on survival outcomes. All p-values were two-tailed. Survival curves were calculated using the Kaplan-Meier method. Results: A total of 400 pts received anti-CD19 CARTs and were included for analysis. For the entire cohort: median PFS and OS from time of CART infusion were 11 months [mo] and 27 mo respectively. On log-rank testing, pts who received ≥3 lines of pre-CART therapy and those with refractory disease pre-CART had significantly worse PFS (p=0.004 & 0.001) and OS (both p With median follow-up 22.4 mo, 190 pts (48%) had PD after CART; demographic and clinical variables of pts with and without PD are detailed in Table 1. Biopsy to confirm PD and assess CD19 status was done in 69 pts (36%) with CD19 negative relapse seen in 11 (16%). Of pts with PD, median PFS and OS from time of PD was 83 days (in pts who received salvage) and 174 days (for all PD pts) respectively. Pts with PD were more likely to have elevated LDH (p=0.001) and extranodal disease (p=0.003) at apheresis. For pts with PD after CART: 125 (65.5%) received further therapies. Pts were more likely to receive salvage therapies if their best response to CART was CR (p=0.026) or PR (p=0.015). Response rates of select first- and second-line therapies and PFS of first line therapies received after CART failure are detailed in figure 1. ORR and CRs were highest for polatuzumab, bendamustine, & rituximab (pola-BR; 73% & 40%), followed by BTK inhibitors (BTKi; 50% & 38%), and bispecific antibodies (bsAb) (50% & 25%). Five of 7 pts who received a BTKi had non-germinal center (GC) cell of origin (COO; 1 unknown COO). On log-rank testing, pts with elevated LDH (p=0.003) at time of apheresis and those with intermediate/high IPI (p=0.013) had inferior PFS with first salvage regimens. Median PFS was highest for pola-BR (4.5 mo, n=14), followed by bsAb (2.5 mo, n=8), lenalidomide +/- anti-CD20 antibody (1.8 mo, n=13), checkpoint inhibitors (CPI; 1.6 mo, n=10), BTKi (1.2 mo, n=8), radiation alone (1.2 mo; n=17), chemotherapy (1.1 mo, n=12), and tafasitamab + lenalidomide (0.9 mo, n=5). Median PFS for all treated pts was 1.8 mo. OS from start of first salvage regimen was highest for CPI (OS 12.4 mo, n=10), followed by pola-BR (8.9 mo, n=14), BTKi (8.8 mo, n=8), lenalidomide +/- anti-CD20 (8.7 mo, n=13), radiation alone (7.1 mo, n =17), bsAb (5.9 mo, n=8), chemotherapy (5.4 mo, n=12), and tafasitamab + lenalidomide (1.2 mo, n=5). 12 pts (6.3%) later received an allogeneic hematopoietic cell transplant (alloHCT). In alloHCT pts at last follow-up, 10 were evaluable for response: 7 had CR and 5 remain in CR. Clinical characteristics of pts who received alloHCT are detailed in table 2. Notably, median age was 59 years (41-68), 1 (8.3%) had a prior alloHCT, and 6 (50%) had prior autologous HCT. The majority had CR or PR as best response to CART (CR n=6, 50%; PR n=3, 25%), and only 1 pt (8.3%) with PD as best response to CART was salvaged with alloHCT. Conclusions: This is the largest reported analysis to date of pts with aggressive B-cell lymphoma who develop PD post-CART. The highest ORRs were with pola-BR, bsAb, and BTKi as first line of salvage. High response rates with BTKi may be attributed to non-GC COO in the majority of treated pts and perhaps a beneficial immunomodulatory effect on previously administered CARTs. AlloHCT remains a potential curative therapy for select pts with over half with durable remission; however, few ultimately received alloHCT. Despite increased use of novel therapies, survival in pts who progress after CART is still dismal warranting more effective therapies. Figure 1 Figure 1. Disclosures Epperla: Genzyme: Honoraria; Karyopharm: Other: Ad Board; Beigene: Speakers Bureau; Verastem: Speakers Bureau. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Hess: ADC Therapeutics: Consultancy; BMS: Speakers Bureau. Cohen: Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo, BeiGene, Adaptive: Consultancy; Genentech, BMS/Celgene, LAM, BioINvent, LOXO, Astra Zeneca, Novartis, M2Gen, Takeda: Research Funding. Ma: Abbvie: Honoraria, Research Funding; Beigene: Research Funding, Speakers Bureau; Loxo: Research Funding; Juno: Research Funding; AstraZeneca: Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau. Winter: Gilead: Other: Husband: Consultancy; Janssen: Other: Husband: Consultancy; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Epizyme: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Actinium Pharma: Consultancy; BMS: Other: Husband: Data and Safety Monitoring Board; Merck: Consultancy, Honoraria, Research Funding; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. Danilov: Bayer Oncology: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Rigel Pharm: Honoraria; Takeda Oncology: Research Funding; TG Therapeutics: Consultancy, Research Funding; Abbvie: Consultancy, Honoraria; Beigene: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; SecuraBio: Research Funding; Astra Zeneca: Consultancy, Honoraria, Research Funding; Bristol-Meyers-Squibb: Honoraria, Research Funding; Gilead Sciences: Research Funding. Stephens: Adaptive: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees; Epizyme: Membership on an entity's Board of Directors or advisory committees; JUNO: Research Funding; Mingsight: Research Funding; CSL Behring: Consultancy; Novartis: Research Funding; Abbvie: Consultancy; AstraZeneca: Consultancy; Arqule: Research Funding; Celgene: Consultancy; Innate Pharma: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding. Shah: Miltenyi Biotec: Consultancy, Honoraria, Research Funding; Umoja: Consultancy; Incyte: Consultancy; Kite: Consultancy; Legend: Consultancy; Epizyme: Consultancy; Lily: Consultancy, Honoraria, Research Funding. Shouse: Beigene Pharmaceuticals: Honoraria; Kite Pharmaceuticals: Speakers Bureau. Barta: Acrotech: Honoraria; Daiichi Sankyo: Honoraria; Seagen: Honoraria; Kyowa Kirin: Honoraria. Karmali: Karyopharm: Consultancy; EUSA: Consultancy; Roche: Consultancy; Janssen/Pharmacyclics: Consultancy; Genentech: Consultancy; Morphosys: Consultancy, Speakers Bureau; Epizyme: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; AstraZeneca: Speakers Bureau; Takeda: Research Funding; BeiGene: Consultancy, Speakers Bureau.

Staging in lymphoma has changed significantly over time, from the Ann Arbor criteria (1971) to the Cotswolds criteria (1989) to the Lugano Classification (2011). The evolution of imaging technology has played a major role in these changes, and PET/CT is now standard for certain lymphomas, whereas chest radiographs are no longer routine. More recently, response criteria have been refined to account for possible flare reactions of immunomodulatory therapy with a provisional term called “indeterminate response.” The latest RECIL criteria use single-dimension measurements to assess response to therapy in patients with lymphoma. Finally, clinical data can be represented graphically in many ways, including the Kaplan-Meir plot, forest plot, waterfall plot, and swimmers plot. Each representation has its own strengths and limitations.

BACKGROUND There is no clear consensus between pediatric and adult providers about the treatment of adolescents and young adults (AYAs) with Hodgkin lymphoma (HL). METHODS Failure-free survival (FFS) and overall survival (OS) were compared between 114 patients ages 17 to 21 years with HL who were treated on the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network Intergroup adult E2496 study and 391 similarly patients ages 17 to 21 years with HL who were treated on the pediatric Children's Oncology Group (COG) AHOD0031 study. RESULTS Comparing AYAs from the COG and E2496 studies, there were no significant differences in extralymphatic disease, anemia, or hypoalbuminemia. More AYAs in the E2496 trial had stage III and IV disease (63% vs 29%; P < .001) and B symptoms (63% vs 27%; P < .001), and fewer had bulk disease (33% vs 77%; P < .001). More AYAs on the COG trial received radiotherapy (76% vs 66%; P = .03), although in smaller doses. E2496 AYA The 5-year FFS and OS rates were 68% and 89%, respectively in the E2496 AYAs and 81% and 97%, respectively, in the COG AYAs, indicating a statistically superior compared in the COG AYAs (P = .001). In stratified multivariable analyses, E2496 AYAs had worse FFS than COG AYAs in all strata except patients who had stage I and II HL without anemia. Propensity score analysis (based on stage, anemia, and bulk disease) confirmed inferior FFS for E2496 AYAs compared with COG AYAs (P = .004). On the E2496 study, FFS was significantly divergent across age groups (P = .005), with inferior outcomes for those ages 17 to 21 years versus 22-44 years. There was no difference across age on the COG study. CONCLUSIONS Younger AYA patients with HL appear to have better outcomes when treated on a pediatric trial than patients of similar age on an adult trial. Prospective studies examining these differences are warranted. Cancer 2017. © 2017 American Cancer Society.

Introduction Traumatic pancreatic injuries are rare, and morbidity and mortality information are often conflicting. To determine the frequency and outcomes of patients presenting with trauma to the pancreas, we reviewed data from a large multi-institutional healthcare system for mechanism of injury, intervention, subsequent complications, in-hospital morbidity rates, and mortality. Methods We performed a retrospective analysis of records of all pancreatic injury cases seen at four healthcare centers from 1990 to 2014. Descriptive measures are presented for continuous and categorical data. Mortality rates were obtained using the publicly accessible Social Security Death Master File. Results Of 69 patients with pancreatic injuries, median age was 24 years (range 1–88). Mechanisms of injury were blunt in 87% and penetrating in 11.8%. The median injury grade was 1. Most injuries involved the pancreatic head (24.6%). Median Injury Severity Score at presentation was 9. Thirty-seven (53.6%) patients required surgery. Twenty-five patients (36.2%) required total parenteral nutrition, 34 patients (49.3%) developed intra-abdominal fluid collections, 24 patients (34.8%) developed acute pancreatitis, and three (4.4%) developed endocrine insufficiency requiring insulin. Ten (14.5%) patients died. There were four (5.8%) readmissions and one re-operation (1.4%) within 30 days of discharge. Conclusion Traumatic pancreatic injuries occur most frequently in young healthy males with little or no comorbidities, and are generally associated with other acute injuries. Contrary to past reports, our results revealed a low mortality rate but significant morbidity, with the most common complications being intra-abdominal fluid collections, acute pancreatitis, and a need for total parenteral nutrition.

This portion of the NCCN Guidelines for Hodgkin lymphoma (HL) focuses on the management of classical HL. Current management of classical HL involves initial treatment with chemotherapy or combined modality therapy followed by restaging with PET/CT to assess treatment response using the Deauville criteria (5-point scale). The introduction of less toxic and more effective regimens has significantly advanced HL cure rates. However, long-term follow-up after completion of treatment is essential to determine potential long-term effects.

Cancer cachexia is defined as a state of involuntary weight loss, attributed to altered body composition with muscle mass loss and/or loss of adiposity. Identifying the association between cancer cachexia and outcomes may pave the way for novel agents that target the cancer cachexia process. Clinical parameters for measurement of cancer cachexia are needed. We conducted a single-institution retrospective analysis that included 86 NHL patients with the aim of identifying an association between cancer cachexia and outcomes in aggressive lymphomas using the cachexia index (CXI) suggested by Jafri et al. (Clin Med Insights Oncol 9:87–93, 15). Impact of cachexia factors on progression-free survival (PFS) and overall survival (OS) were assessed using log-rank test and Cox proportional hazards regression. Patients were dichotomized around the median CXI into “non-cachectic” (CXI ≥49.8, n = 41) and “cachectic” (CXI

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma typically associated with the t(11;14) chromosomal translocation, resulting in overexpression of cyclin D1. Although MCL is associated with clinical heterogeneity, outcomes are generally poor and no standard treatment has been established. However, the recent approval of ibrutinib provides a new therapeutic option. Moreover, recent clinical trials have provided new perspectives on the relative efficacy and safety of various approaches for both transplant-eligible and transplant-ineligible patients. Multiple novel strategies are being evaluated in the treatment of MCL, including both targeted agents and cellular immunotherapies. At the Lymphoma Research Foundation's 12th MCL Workshop, researchers gathered to discuss research findings, clinical trial results, and future directions related to MCL, its biology, and its treatment. This manuscript, which includes a summary of each presentation, aims to review recent findings in MCL research and highlight potential areas for future study.

Background Patients treated with chronic immunosuppression face a six-fold increase in their cumulative lifetime risk of lymphoma relative to age-matched immunocompetent counterparts. These malignances represent a spectrum of lymphoid and plasmacytic histologies collectively referred to as post-transplant lymphoproliferative disorders (PTLD). Accurate risk-stratification and optimal treatment strategies are unclear given wide histologic and clinical heterogeneity. Current standard-of-care models include immunosuppression reduction and sequential, response-adapted chemoimmunotherapy platforms, however 80% of patients will require chemotherapy exposure. Overall response rates (ORR) are >90%, however relapse is common and serious treatment-related toxicities including infection and allograft rejection pose significant challenges. Several risk-stratification schemes have been proposed to direct initial therapy and predict clinical outcomes, however their external validity has been inconsistent across patient populations. We report here the results of a single-center retrospective study assessing the treatment patterns and outcomes of patients diagnosed with PTLD and provide a risk-assessment profile that may help improve clinical outcomes. Methods Patients with a diagnosis of PTLD were identified by Electronic Medical Records database query. Inclusion criteria were: age ≥ 18 years at the time of diagnosis, confirmation of PTLD by internal pathology review, primary diagnosis from 2008-2018, and receipt of therapy and surveillance care at Northwestern University in Chicago, Illinois, USA. Exploratory univariate analyses were performed using Kaplan-Meier estimates with 95% confidence intervals and log-rank p-values for time-to-event outcomes; significance was set at p < 0.05. Response to treatment and disease progression were classified per provider-specific interpretations of clinical data as assessed by patient chart review. ORR is defined as complete or partial response. Progression-free survival (PFS) is defined as time from diagnosis to disease progression; patients who died before restaging or who were lost to follow-up were censored. Overall survival (OS) is defined as time from diagnosis to death from any cause; patients who were alive at last follow-up were censored. Results A total of 182 patients were identified by database query and 111 patients met our inclusion criteria. Demographics data are provided (Figure 1A). Five-year PFS and OS were 55.7% and 87.2%, respectively (Figure 1B). 92.6% of patients treated with immunosuppression agents underwent dose reduction and 16.8% experienced graft rejection, of which 27.8% required re-transplantation. Exploratory univariate analyses were performed on the following clinical factors: age, LDH, Ann-Arbor Stage, presence of extranodal disease, histologic EBER positivity, ECOG PS, comorbid conditions (type II diabetes, obesity, and coronary artery disease), CNS involvement, transplant type, presence of EBV viremia, and PTLD subtype. Established risk stratification models, including the IPI, R-IPI, Leblond score, Ghobrial score, and PTLD prognostic index, were applied to this cohort. We identified elevated LDH (p=0.04) and IPI score >3 (p=0.015) as predictors of PFS (Figure 1C); elevated LDH (p=0.02) and thoracic allograft transplantation (p=0.03) were predictors of OS (Figure 1D). The PTLD prognostic index significantly predicted PFS (p=0.03) and OS (p=0.013) (Figure 1E). 50.4% received Rituximab monotherapy prior to risk-stratification for combination chemoimmunotherapy; ORR and CR rates with Rituximab monotherapy were 67.9% and 41.1%, respectively. Overall response to Rituximab monotherapy was found to be a significant predictor of PFS (p Conclusions This study represents one of the largest retrospective cohorts of PTLD patients to date. We show that the PTLD prognostic index is the most accurate risk stratification tool in predicting PFS and OS in this patient population and may have utility in guiding therapeutic approaches in PTLD patients. LDH, IPI score, and type of allograft transplantation are significant clinical variables in predicting clinical outcomes. Furthermore, response to Rituximab monotherapy was a significant predictor of PFS; improving frontline outcomes to high-risk patients remains a critical unmet need. Figure Disclosures Winter: Epizyme: Other: DSMB; Delta Fly Pharma: Consultancy; Amgen: Consultancy; CVS/Caremark: Consultancy; Ariad/Takeda: Consultancy; Norvartis: Consultancy, Other: DSMB; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Karmali:BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau. Ma:AbbVie: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria, Research Funding, Speakers Bureau; Bioverativ: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Juno: Research Funding; Novartis: Research Funding; TG Therapeutics: Research Funding. Ganger:Mallinkrodt: Consultancy; Gilead: Speakers Bureau. Pro:Verastem Oncology: Research Funding.

Introduction: Although radiation therapy (RT) has limited clinical efficacy for advanced stage lymphoma, RT has been used as a method for in situ vaccination to generate an abscopal effect. Frank et al. combined low dose RT with class C CpG deoxynucleotides (CpGs) for the treatment of advanced stage indolent lymphoma (Cancer Discovery, 2018). CpGs are toll-like receptor 9 agonists and activates the innate immune system. The overall response rate was high (89.6%) in this trial but only 7 of 29 patients (pts) (24%) had partial response and 1 had a complete response (3%). Unlike external beam RT, photothermal therapy (PTT) using gold nanoparticles (AuNPs) can generate a strong in situ vaccination effect by heat ablation of tumors (Bear et al. PLOS One, 2013). (Figure 1A) The ablation induced increased CD8 T cell infiltration in non-treated tumors and dendritic cell maturation in the draining lymph nodes, but it also increased systemic immune suppression via increased myeloid suppressor cells (MDSCs) in a melanoma model. MDSCs differentiate into active macrophages when stimulated by CpGs. Other PTT methods have been evaluated in combination with check-point inhibitors with success in solid tumor murine models (Liu et al. Immunotherapy 2018; Chen et al. Nature Comm. 2016). Therefore, we hypothesized that PTT in combination with CpG can elicit a stronger the in situ vaccination effect compared with RT with CpG in a murine lymphoma model. Methods: PTT is achieved by exciting branched AuNP (BNP) with a near infrared (NIR) laser (808nm). For the dual lymphoma model, A20 lymphoma cells in Matrigel were injected into the right flank of BALB/c mice to establish a primary tumor. Three days later, a secondary tumor was established in the left flank. When the tumor reached 5 mm in diameter, PTT with CpG (sequence 2395) or RT (10Gy) with CpG of the primary tumor were performed. Control groups included PTT without CpG, CpG only, BNP with CpG without PTT, and PBS. Sixteen days after PTT or RT, mice are euthanized and flow cytometry was performed on the primary tumor, secondary tumor, spleen, and draining lymph nodes and analyzed for T cells and dendritic cells (DC). Results: Within 5 minutes after PTT, the temperature of the treated primary tumor reached almost 60°C. The primary tumor growth was inhibited for both RT/CpG and PTT/CpG treatment groups compared with the PBS control group. RT/CpGs treated primary tumors demonstrated re-growth 14 days (D14) after treatment while PTT/CpG treated tumors did not (p Conclusion: Overall, we demonstrated as a proof-of-concept that PTT/CpG generated a stronger in situ vaccination effect when compared with RT/CpG therapy in lymphoma. In addition, we have described the immune responses after PTT in combination with CpG in a lymphoma model, showing increased dendritic cell maturation and T cell mediated immune response. Further studies including dosing schedule, combination therapy with check-point inhibitors or other immune based treatments will move this technology closer to clinical practice. Disclosures Gordon: Zylem Biosciences: Patents & Royalties: Patents, No Royalties.

Background: Chromosome 9p24.1/PD-L1/PD-L2 genomic copy number alterations (CNAs) including amplifications and copy number gains (CNGs) are predominant features of classic Hodgkin lymphoma (cHL) and lead to overexpression of the programmed death-1 (PD-1) ligands 1 and 2 (PD-L1 and PD-L2). Amplifications and high level CNGs have been associated with advanced stage cHL and inferior treatment outcomes with standard chemotherapy. There are few studies that correlate 9p24.1/PD-L1/PD-L2 amplifications or CNGs with response to PD-1 blockade monotherapy in the frontline setting. We conducted a phase 2 clinical trial of sequential pembrolizumab (PEM) x 3 followed by doxorubicin, vinblastine, dacarbazine (AVD) chemotherapy (4-6 cycles) for newly diagnosed cHL. Interim response to single agent PEM was assessed by PET-CT and by decline in metabolic tumor volume (MTV). Herein, we report the results of correlative studies analyzing 9p24.1 CNAs, PD-1 pathway expression and response to PD-1 blockade. Methods: Pre-treatment diagnostic biopsy specimens were double stained for PD-L1 (E1L3N, XP Cell Signaling) and PAX5, single stained for PD-L2 and pSTAT3, and scored by two expert hematopathologists (QC, LBS) for percentage positive cells and intensity of staining. A modified H score was calculated as the product of staining intensity (0-3) and percentage of positive tumor cells (0-100%), ranging from 0 - 300. Fluorescence in situ hybridization to assess (FISH) chromosome 9p24.1 CNAs was performed by co-hybridizing PD-L1/PD-L2 probes (target) with the centromeric 9 probe (control). In each case, the percentage and magnitude of 9p24.1 CNAs were evaluated. Four FISH categories were defined based on the target: control ratio and the total copy numbers (CNs) of the target per Hodgkin Reed-Sternberg (HRS) cell to include: amplification (ratio≥3, CNs≥ 6), copy number gain (CNGs) (1≤ratio Results: Thirty patients were enrolled from September 2017, through August 1, 2019; 28 had tissue available for FISH analysis and 29 for immunohistochemistry. Response to single agent PEM was PR in 11 (36.7%), near-CMR in 8 (26.7%), and CMR in 11 (36.7%). CMR rate following AVD x 2 was 100%. All patients in this analysis had genomic alterations, although 5 patients did not reach the cut off of 10%. The highest level alteration was amplification in 11 patients (36.7%), copy gain in 7 (23.3%), polysomy in 5 (16.7%) and disomy in 5 (16.7%) (Table 1). The average 9p24.1 copy number per HRS cell was 3.1 (range 2-8.1). Six of 22 examined cases were EBER-positive. There was no evidence of a statistical relationship between response to single agent PEM and 9p24.1 alteration, PD-L1, PD-L2 or STAT3 H-scores, or EBER status. We found PD-L1 H Score tercile differed statistically by FISH category (P=.024, Fisher's Exact Test). Notably, there were no patients with amplification in the lowest tercile. More compelling, we found a positive association between PD-L1 H Score and average 9p24.1 locus copy number (Spearman's ρ=.36, P=.063, Fig 1a) and a negative association between PD-L1 H Score and percent disomic cells (Spearman's ρ= -0.21, P=0.29, Fig 1b) although the statistical significance of these results was limited by the small sample size. Conclusions: Our data is consistent with prior reports indicating a positive association between 9p24.1 genetic alterations and PD-L1 expression. The high response rates observed at all PD ligand levels seen in this clinical study suggests that even low levels of PD ligand expression may be sufficient for response to PD-1 blockade in previously untreated cHL. Disclosures Allen: Bayer:Consultancy, Other;Imbrium:Consultancy, Other;Research to Practice:Speakers Bureau;Clinical Care Options:Speakers Bureau;Curio Sciences:Honoraria.Evens:Merck:Consultancy, Honoraria, Research Funding;Pharmacyclics:Consultancy, Honoraria;Novartis:Consultancy, Honoraria;MorphoSys:Consultancy, Honoraria;Research To Practice:Honoraria, Speakers Bureau;Abbvie:Consultancy, Honoraria;Mylteni:Consultancy, Honoraria;Seattle Genetics:Consultancy, Honoraria, Research Funding;Epizyme:Consultancy, Honoraria, Research Funding.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.Pro:Verastem Oncology:Research Funding.Karmali:Takeda:Research Funding;BeiGene:Speakers Bureau;BMS/Celgene/Juno:Honoraria, Other, Research Funding, Speakers Bureau;Karyopharm:Honoraria;AstraZeneca:Speakers Bureau;Gilead/Kite:Honoraria, Other, Research Funding, Speakers Bureau.Gordon:Zylem Biosciences:Patents & Royalties: Patents, No Royalties.Winter:Amgen:Consultancy;Epizyme:Other: DSMB;Norvartis:Consultancy, Other: DSMB;CVS/Caremark:Consultancy;Ariad/Takeda:Consultancy;Delta Fly Pharma:Consultancy;Merck:Membership on an entity's Board of Directors or advisory committees, Other: advisory board;Karyopharm:Membership on an entity's Board of Directors or advisory committees, Other: advisory board.

BACKGROUND: Ibrutinib is a BTK inhibitor approved for relapsed/refractory MCL. We evaluated the safety and efficacy of single-agent ibrutinib maintenance (I-M) following frontline chemo-immunotherapy for MCL in a multicenter phase II trial. Herein, we report preliminary results. METHODS: Patients (Pts) received I-M 560 mg daily for up to 4 years after complete/partial response (CR/PR) to frontline chemo-immunotherapy (+/- autoSCT). The 3-year PFS rate was the primary endpoint. Secondary endpoints were PR to CR conversions, median OS and toxicity. After identifying a trackable clone using archived tissue obtained at diagnosis, minimal residual disease (MRD) was measured using NGS (detection resolution of 1 cell per million; clonoSEQ®; Adaptive Biotechnologies) on peripheral blood at 4 time-points: baseline (after induction but prior to starting I-M) and then at 1, 6 and 18-24 mo(s) after initiation of I-M. RESULTS: 36 pts were enrolled between 7/2014-7/2018. Median age was 60 years (range 46-90). For induction, 17 (47%) received BR, 18 (50%) a cytarabine-containing regimen and 1 (3%) R-CHOP. Eighteen (50%) had autoSCT in CR1. Post-induction +/- autoSCT, 33 (92%) had a CR and 3 (8%) had a PR as best response respectively. One patient converted from PR to CR on I-M. Median f/u was 34.6 months. 5 (14%) pts completed the 4-year I-M course and 15 (42%) remain on I-M (median 31 cycles, range 2-52). Sixteen (44%) pts discontinued I-M early due to: treatment related adverse events (TRAEs; n=12), second malignancies considered unrelated to I-M (n=2), PD (n=1) and death of unknown cause (n=1). Three pts died, 2 deaths deemed unrelated to I-M (aspiration pneumonia, 2nd malignancy) and 1 from unknown cause; 1 pt was lost to follow-up. The most common grade ≥ 3 TRAEs during I-M were neutropenia, HTN, infection, bleeding and atrial fibrillation/flutter (Table 1). TRAEs led to permanent dose reductions in 9 (25%) pts, most commonly for neutropenia (n=3), and I-M discontinuation in 12 (33%), 6 for new onset atrial fibrillation/flutter, 1 each for myalgias, rash, pericardial effusion, mucositis, TIA, subdural hematoma/bleed. Notably, I-M was discontinued in the majority of pts with new onset atrial fibrillation/flutter though not typical of current practice. At the time of data cut-off, MRD was assessed in 21 of 36 pts at varying time points (Figure 1) with remaining samples not yet collected/analyzed. After induction but prior to I-M, 16 pts were confirmed MRD (-), 4 were MRD indeterminate and 1 was MRD (+). Four pts MRD (-) prior to I-M became MRD (+) with follow-up, 2 induced with hyperCVAD, 1 with BR and 1 with R-CHOP + autoSCT prior to I-M; 2 of these pts reverted back to MRD (-) status with ongoing I-M. Of the 2 pts with persistent MRD (+) disease, 1 had clinical progression and the other maintains radiographic CR. Post induction, all MRD indeterminate pts were MRD (-) when checked after 1 month on I-M. The pt who was MRD (+) after front-line treatment (Nordic regimen + autoSCT) remains MRD (+) after 30 cycles of I-M without clinical relapse. MRD correlations with PFS and OS have not yet been performed. CONCLUSION: I-M 560 mg daily is feasible in pts with MCL after response to frontline chemo-immunotherapy. Grade ≥ 3 rates of atrial fibrillation/flutter are consistent with ibrutinib's known safety profile. NGS-based assessments demonstrate that most pts are MRD negative after intensive induction. Longer follow-up and correlation of MRD with PFS and OS are needed to determine the clinical relevance of I-M and MRD status. Disclosures Karmali: BeiGene: Speakers Bureau; AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; Takeda: Research Funding; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Stephens:Arqule: Research Funding; Innate: Consultancy; Juno: Research Funding; Acerta: Research Funding; MingSight: Research Funding; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Beigene: Consultancy; Pharmacyclics: Consultancy; Gilead: Research Funding; Verastem: Research Funding. Winter:Norvartis: Consultancy, Other: DSMB; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Epizyme: Other: DSMB; Delta Fly Pharma: Consultancy; Amgen: Consultancy; CVS/Caremark: Consultancy; Ariad/Takeda: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Ma:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Bioverativ: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Juno: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; TG Therapeutics: Research Funding. Petrich:AbbVie: Current equity holder in publicly-traded company; Daiichi-Sankyo: Current Employment. Hochberg:Intervention Insights: Consultancy; Leuko: Consultancy. Kuhr:Adaptive Biotechnologies: Current Employment. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Pro:Verastem Oncology: Research Funding. OffLabel Disclosure: maintenance ibrutinib after frontline therapy in MCL

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: The human c-MYC oncogene is rearranged or overexpressed in approximately 12% or 37% of aggressive B-cell non-Hodgkin lymphomas (NHL), respectively. Relapses within 18-24 months are observed in more than 50% of these patients when treated with standard chemoimmunotherapy. Ixazomib is an orally bioavailable proteasome inhibitor that is FDA approved for multiple myeloma and has been shown to down-regulate MYC in lymphoma models (Ravi et al., 2016). It has also demonstrated preclinical activity in aggressive NHL, including double-hit (DH) lymphoma. Herein, we report results of a multicenter phase I/II study evaluating the safety and efficacy of induction chemotherapy with DA-EPOCH-R in combination with ixazomib followed by ixazomib maintenance in aggressive MYC-aberrant NHL. METHODS: Adult patients with aggressive MYC-aberrant NHL defined as MYC-overexpression (> 40%) by IHC, MYC-amplification (>4 copies) by FISH, and/or MYC-rearrangement by FISH were eligible. Ixazomib was administered in conjunction with 6 cycles of DA-EPOCH-R. Intrathecal methotrexate prophylaxis was administered using institutional guidelines. Ixazomib was continued as maintenance for up to one year in responders. During phase I, an accelerated titration design was employed to determine the MTD of ixazomib (doses of 2.3 mg, 3 mg or 4 mg) in combination with DA-EPOCH-R. During induction, ixazomib was administered twice per cycle (1 cycle = 21 day), day 1 and day 8 or 15 based on blood counts. For maintenance, ixazomib was dosed at 4 mg weekly. Based on phase I results, 3mg of ixazomib was chosen as the RP2D for phase II. The primary objective was to determine MTD in phase I and to evaluate the efficacy of ixazomib given with DA-EPOCH-R as measured by 12-month PFS rate in phase II. Secondary objectives were to evaluate safety and assess ORR post-induction and OS in all phase I/II patients. RESULTS: Thirty-eight patients were enrolled between 10/2015 and 9/2019 and 36 were evaluable for response. Median age was 63 years (range 31-77) and 27 were male (71%), 86% had advanced stage, 46% had DH or triple hit lymphoma (28% and 18%, respectively), and 89% had an IPI of 2 or higher (Table 1). Twenty-nine (76.3%) patients completed all 6 cycles of induction therapy with DA-EPOCH-R and 25 (65.8%) patients were able to undergo dose escalation of DA-EPOCH-R. Two (5.3%) patients had ixazomib dose reductions during induction and 10 (26.3%) patients had discontinuation of ixazomib during induction. Reasons for early discontinuation during induction included peripheral neuropathy, concomitant comorbidities, progressive disease, and death. Of the 21 (55.3%) patients who received maintenance therapy, 5 (23.8%) had ixazomib dose reductions, and 9 (42.9%) had discontinuation of ixazomib during maintenance. Reasons for early discontinuation during maintenance included peripheral neuropathy, patient preference, and progressive disease. Treatment-related adverse events (TRAEs) of interest occurring in b % 10 % of patients are noted in Table 2. The ORR after induction was 89% with an associated CR rate was 61%. One patient received autologous transplant as consolidation and did not pursue maintenance as a result. Estimated 24-months PFS and OS were 66.9% (95% CI, 50.7% to 88.4%) and 78.7% (95% CI, 65.10% to 95.52%), respectively. Of the 21 patients who received maintenance, sixteen had a CR while 5 had a PR. In those who achieved a PR and went on to receive maintenance, 1 patient converted to CR and 1 maintained a PR with ongoing response at last follow-up. Two patients progressed and 1 has not yet been re-evaluated for response. At a median follow up of 17.6 months (range: 14-19 months), 7 patients had PD. Six patients died, 3 from PD, 1 from respiratory failure, 1 from sepsis, and 1 from natural causes considered unrelated to study drug. CONCLUSION: In this older population with aggressive MYC-aberrant NHL, DA-EPOCH-R induction with adjunctive ixazomib followed by maintenance ixazomib appears to be safe and effective. It is notable that 31% of patients had ixazomib dose reduction or discontinuation during induction and only 55% of patients initiated maintenance, which may have compromised the efficacy of this approach. Exploratory analysis of clinical and histological variables is ongoing and will be presented at the meeting. Improving frontline outcomes for this subset of patients remains a critical unmet need. Disclosures Karmali: Karyopharm: Honoraria; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; Takeda: Research Funding; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Hamadani:Takeda Pharmaceutical Company; Spectrum Pharmaceuticals; Astellas Pharma: Research Funding; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi Genzyme, AstraZeneca: Speakers Bureau; Janssen R&D; Incyte Corporation; ADC Therapeutics; Celgene Corporation; Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio: Consultancy. Gordon:Zylem Biosciences: Patents & Royalties: Patents, No Royalties. Winter:Norvartis: Consultancy, Other: DSMB; Ariad/Takeda: Consultancy; CVS/Caremark: Consultancy; Delta Fly Pharma: Consultancy; Amgen: Consultancy; Epizyme: Other: DSMB; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Ma:TG Therapeutics: Research Funding; Novartis: Research Funding; Juno: Research Funding; Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kite: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Bioverativ: Consultancy, Honoraria; BeiGene: Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Research Funding. Fenske:Medical College of Wisconsin: Current Employment. Shah:Cell Vault: Research Funding; Miltenyi Biotec: Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Incyte: Consultancy; TG Therapeutics: Consultancy; Verastim: Consultancy; Lily: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria. Jagadeesh:Verastem: Membership on an entity's Board of Directors or advisory committees; Debiopharm Group: Research Funding; MEI Pharma: Research Funding; Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Klein:Takeda: Membership on an entity's Board of Directors or advisory committees. Petrich:AbbVie: Current equity holder in publicly-traded company; Daiichi-Sankyo: Current Employment. Evens:Epizyme: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Abbvie: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Pro:Verastem Oncology: Research Funding. OffLabel Disclosure: Ixazomib is an orally bioavailable proteasome inhibitor that is FDA approved for multiple myeloma. It has also demonstrated preclinical activity in aggressive NHL, including double-hit (DH) lymphoma.

Context: Few first-line chemotherapy-free treatment options are available for patients with follicular lymphoma (FL) who are elderly or have comorbid conditions. Single-agent rituximab has been used to treat previously untreated elderly, frail patients or those with low tumor burden. Ibrutinib, a once-daily Bruton's tyrosine kinase inhibitor, is approved in the US and EU for the treatment of various B-cell malignancies. The combination of once-daily ibrutinib with 4 weekly doses of intravenous rituximab was evaluated in a phase 2 study as a first-line treatment option for patients with FL. At a median follow-up of 34 months, an overall response rate of 85% and complete response of 40% were reported. At 30 months, the progression-free survival (PFS) and overall survival rates were 67% and 97%, respectively (Fowler, BJH. 2020). Based on these promising results, the phase 3 PERSPECTIVE study was designed to further evaluate ibrutinib-rituximab combination therapy in previously untreated patients with FL. Objective: To compare PFS outcomes between: (1) ibrutinib-rituximab and placebo-rituximab, and (2) continuous versus fixed-duration ibrutinib treatment. Design: Phase 3, multicenter, randomized, double-blind, placebo-controlled study (PCYC-1141-CA, NCT02947347 ). Patients or other participants: Eligible patients are enrolled if they meet ≥1 Groupe d'Etude des Lymphomes Folliculaires (GELF) criterion, and are aged ≥70 years or 60–69 years with ≥1 comorbidities (creatinine clearance 30–59 mL/min or ECOG performance status of 2). Patients who received any prior treatment for FL or showed evidence of CNS involvement or transformed lymphoma are excluded. Enrollment of approximately 440 patients is planned. Interventions: In Part 1, patients will be randomized to receive either: (1) once-daily oral ibrutinib-rituximab, or (2) once-daily oral placebo-rituximab. Patients in both arms will receive rituximab in 4 weekly doses, followed by rituximab maintenance therapy. In Part 2, patients receiving ibrutinib-rituximab and remaining on ibrutinib treatment for ≥2 years will be randomized again to either receive once-daily oral ibrutinib or switch to once-daily oral placebo. Main outcome measures: The primary endpoint is PFS for both parts. Conclusions: The study is currently enrolling patients at participating sites in the US, EU, and Asia Pacific. Funding: Pharmacyclics LLC, an AbbVie Company.

In this issue of Blood , LaCasce et al present data on the incorporation of brentuximab vedotin (BV) with bendamustine (BVB) in patients with recurrent/refractory classical Hodgkin lymphoma (HL) that might be practice-changing. 1