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Purpose: Lenalidomide, an immunomodulatory agent that enhances antibody-dependent cell-mediated cytotoxicity, has the potential to synergize with rituximab, an anti-CD20 mAb. We hypothesized that the addition of lenalidomide to rituximab would improve clinical outcomes in patients with B-cell lymphomas who were previously rituximab resistant, defined as no response to or progression of lymphoma within 6 months of rituximab-based therapy.Experimental Design: We conducted a single-center, phase II trial in patients with indolent B-cell or mantle cell lymphomas who were previously rituximab resistant. Patients received 10 mg lenalidomide daily for 8 weeks, and then received four weekly doses of 375 mg/m2 rituximab; lenalidomide continued during and after rituximab. Response to therapy was assessed after 8 weeks of lenalidomide and 12 weeks after first dose of rituximab. The primary endpoint was overall response rate (ORR) after lenalidomide and rituximab.Results: Fifty patients were enrolled and 43 patients completed both response assessments. ORR after 8 weeks of lenalidomide was 30.2%; 12 weeks after the addition of rituximab to lenalidomide, ORR increased to 62.8% (N = 43). For all patients (N = 50), median progression-free survival (PFS) is 22.2 months (median follow-up, 39.2 months). PFS after lenalidomide–rituximab was significantly longer than the PFS for the antecedent regimen used to define rituximab resistance (22.2 vs. 9.13 months, P = 0.0004).Conclusions: This trial is the first to show that the combination of lenalidomide and rituximab overcomes prior rituximab resistance in patients with indolent B-cell and mantle cell lymphomas. Clin Cancer Res; 21(8); 1835–42. ©2015 AACR.

CD19-directed chimeric antigen receptor–modified (CAR T) T cells achieve durable remissions in about 30% to 40% of relapsed/refractory large B-cell lymphomas. T-cell exhaustion and/or an immunosuppressive tumor microenvironment may contribute to CAR T-cell failure. Pembrolizumab, an anti-PD1 immune checkpoint inhibitor, may reverse T-cell exhaustion after CAR T-cell therapy. We treated 12 patients with B-cell lymphomas who were either refractory to (n = 9) or relapsed after (n = 3) CD19-directed CAR T-cell (4-1BB–costimulated) therapy with pembrolizumab 200 mg IV every 3 weeks. Median time from CAR T-cell infusion to first pembrolizumab dose was 3.3 months (range, 0.4-42.8 months). Pembrolizumab was well tolerated, and the only grade ≥3 adverse events related to pembrolizumab were neutropenia (n = 3; 25%). Best overall response rate after pembrolizumab was 25% (3 of 12 patients; 1 complete response; 2 partial responses). One (8%) patient had stable disease; thus, 4 of 12 (33%) patients had clinical benefit. After pembrolizumab, 4 patients with clinical benefit had an increase in percentage of CAR T cells by mass cytometry by time of flight (CyTOF); 3 of 4 of these patients also had increases in CAR19 transgene levels by quantitative polymerase chain reaction. Deep immune profiling using CyTOF revealed increased CAR T-cell activation and proliferation and less T-cell exhaustion in clinical responders. Together, PD1 blockade with pembrolizumab after CD19-directed CAR T-cell therapy appears safe and may achieve clinical responses in some patients with B-cell lymphomas refractory to or relapsed after CAR T-cell therapy. This trial was registered at www.clinicaltrials.gove as #NCT02650999.

Comprehensive genomic analyses of tumor biopsies from patients with newly-diagnosed germinal center B cell (GCB) diffuse large B cell/high grade B cell lymphoma (DLBCL/HGBL) have identified molecular subtypes predictive of inferior survival, which are characterized by somatic mutations that can be detected through clinical laboratory mutation analysis (CLMA). To determine the frequency and predictive value of individual genetic mutations associated with these experimentally-defined poor-risk subgroups, we reviewed the findings from CLMA performed on tumors from patients with newly-diagnosed GCB DLBCL/HGBL who were previously treated at our institution. CLMA was successfully performed on 58/59 patient tumor biopsies with a median turnaround time of 16 days, and 51 on which CLMA was routinely performed with adequate clinical follow-up were analyzed. Patients whose tumors demonstrated CREBBP mutation experienced a lower estimated rate of 2-year disease free survival (DFS) as compared to those whose tumors did not (45% [95% CI 18-68%] vs. 67% [95% CI 44-83%]

Non-Hodgkin lymphoma is a disease spectrum of multiple subtypes with many potential targets. Given the heterogeneity and evolving landscape for targeted therapy, incorporation of therapeutics in th...

Polatuzumab vedotin (PV), an anti-CD79b antibody drug conjugate, was approved by the United States (US) Food and Drug Administration in June 2019 for relapsed/refractory diffuse large B cell lympho...

PURPOSE: (18) F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a well-established imaging modality to assess responses in patients with B-cell neoplasms. However, there is limited information about the utility of FDG PET/CT after chimeric antigen receptor T-cell (CART) therapies for large B-cell lymphomas. In this retrospective analysis, we aimed to evaluate how FDG PET/CT performs in patients receiving commercially available anti-CD19 CART therapies for relapsed/refractory (r/r) large B-cell lymphomas. In addition, we examined the time to repeat scan and the rate of pseudoprogression within this population. Lastly, the rates of radiographic response to CART therapy using FDG PET/CT are reported. PROCEDURES: The pre-treatment and post-treatment scans were analyzed from a selected cohort of 43 patients from a single institution. Patients were stratified by diagnosis of either a first occurrence of diffuse large B-cell lymphoma: de novo diffuse large B-cell lymphoma (DLBCL); or a transformed diffuse large B-cell lymphoma arising from indolent non-Hodgkin lymphoma (t-iNHL). RESULTS: More patients received CART therapy for DLBCL than t-iNHL (65% vs 35%). FDG PET/CT had a 99% sensitivity and 100% specificity for detecting recurrent disease in this group. The median time to initial response assessment was 86 days (IQR 79-91; full range 24-146) after infusion. There were no biopsy-proven cases of pseudoprogression identified. In this selected group of patients, the overall response rate by Lugano 2014 criteria was 56%. All patients with a partial response (N = 6) eventually progressed despite additional therapy. CONCLUSIONS: Due to its excellent test characteristics and ability to detect asymptomatic disease, routine surveillance with PET/CT at 3 months after CART infusion is supported by our data. Earlier PET/CT may be of value in select situations as we did not find any cases of pseudoprogression.

Castleman disease (CD) includes a group of rare and heterogeneous disorders with characteristic lymph node histopathological abnormalities. CD can occur in a single lymph node station, which is referred to as unicentric CD (UCD). CD can also involve multicentric lymphadenopathy and inflammatory symptoms (multicentric CD [MCD]). MCD includes human herpesvirus-8 (HHV-8)–associated MCD, POEMS-associated MCD, and HHV-8−/idiopathic MCD (iMCD). The first-ever diagnostic and treatment guidelines were recently developed for iMCD by an international expert consortium convened by the Castleman Disease Collaborative Network (CDCN). The focus of this report is to establish similar guidelines for the management of UCD. To this purpose, an international working group of 42 experts from 10 countries was convened to establish consensus recommendations based on review of treatment in published cases of UCD, the CDCN ACCELERATE registry, and expert opinion. Complete surgical resection is often curative and is therefore the preferred first-line therapy, if possible. The management of unresectable UCD is more challenging. Existing evidence supports that asymptomatic unresectable UCD may be observed. The anti–interleukin-6 monoclonal antibody siltuximab should be considered for unresectable UCD patients with an inflammatory syndrome. Unresectable UCD that is symptomatic as a result of compression of vital neighboring structures may be rendered amenable to resection by medical therapy (eg, rituximab, steroids), radiotherapy, or embolization. Further research is needed in UCD patients with persisting constitutional symptoms despite complete excision and normal laboratory markers. We hope that these guidelines will improve outcomes in UCD and help treating physicians decide the best therapeutic approach for their patients.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative treatment option for patients with refractory cutaneous T-cell lymphoma (CTCL) through replacement of the bone marrow responsible for lymphoma cells and possibly induction of a graft-versus-lymphoma effect. However, allo-HSCT is not always curative; relapse of CTCL occurs in about half of patients post-transplant. Treatment of relapsed CTCL after allo-HSCT is challenging because post-transplant patients are at high risk of graft-versus-host disease, and this condition may be precipitated or exacerbated by standard CTCL therapies. The benefit of each potential therapy must therefore be weighed against its risk of graft versus host disease (GVHD). In this article, we review the management of relapsed CTCL after allo-HSCT. We begin with an exemplative patient whose relapsed Sezary syndrome was successfully treated without development of GVHD. We also report high-throughput T-cell receptor sequencing data obtained during the patient's disease relapse and remission. We then review general guidelines for management of relapsed CTCL and summarize all reported cases and outcomes of relapsed CTCL after transplant. We conclude by reviewing the current CTCL therapies and their risk of GVHD.

PURPOSE To describe long-term outcomes of anti-CD19 chimeric antigen receptor T (CART) cells in patients with relapsed or refractory chronic lymphocytic leukemia (CLL). METHODS Between January 2013 and June 2016, 42 patients with relapsed or refractory CLL were enrolled in this study and 38 were infused with anti-CD19 CART cells (CART-19). Of these, 28 patients were initially randomly assigned to receive a low (5 × 107) or high (5 × 108) dose of CART-19, and 24 were evaluable for response assessment. After an interim analysis, 10 additional patients received the selected (high) dose and of these, eight were evaluable for response. Patients were followed for a median 31.5 months (range, 2 to 75 months). RESULTS At 4 weeks, the complete and overall responses for the 32 evaluable patients were 28% (90% CI, 16% to 44%) and 44% (90% CI, 29% to 60%), respectively. The median overall survival (OS) for all patients was 64 months; there was no statistically significant difference between low- and high-dose groups ( P = .84). Regardless of dose, prolonged survival was observed in patients who achieved a CR versus those who did not ( P = .035), with median OS not reached in patients with CR versus 64 months in those without CR. The median progression-free survival was 40.2 months in patients with CR and 1 month in those without a CR ( P < .0001). Toxicity was comparable in both dose groups. CONCLUSION In patients with advanced CLL, a 5 × 108 dose of CART-19 may be more effective than 5 × 107 CART-19 at inducing CR without excessive toxicity. Attainment of a CR after CART-19 infusion, regardless of cell dose, is associated with longer OS and progression-free survival in patients with relapsed CLL.

Given the poor prognosis of MYC-overexpressing diffuse large B cell lymphoma (DLBCL) and B cell lymphoma unclassifiable with features intermediate between DLBCL and Burkitt lymphoma/high grade B cell lymphoma (BCLU/HGBL), and preclinical data suggesting that MYC may regulate the antitumor immune response, we sought to characterize expression of immune checkpoint proteins on tumor tissue from patients diagnosed with these lymphomas. Immunohistochemical staining for immune checkpoint protein expression was applied to 56 cases of MYC-overexpressing DLBCL and BCLU/HGBL, 35 of which also harbored MYC rearrangement (MYC-R). Analysis revealed both frequent overexpression of immune checkpoint proteins as well as differences in overexpression patterns based upon MYC-R status, with MYC-R cases more likely to overexpress PD-L1 and PD-1 in the tumor microenvironment (50 vs. 15%, p = 0.02 and 32 vs. 5%, p = 0.02, respectively) but less likely to overexpress CTLA-4 and CD80 on tumor cells (34 vs. 71%, p = 0.01 and 34 vs. 81%, p = 0.001, respectively), as compared to cases without MYC-R. These data may suggest a biologic rationale for investigation of the effect of checkpoint inhibitor therapies in these subgroups of MYC-overexpressing DLBCL and BCLU/HGBL.

We conducted a phase I/II multicenter trial using six cycles of brentuximab vedotin (BV) in combination with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHP) for treatment of patients with CD30-positive B-cell lymphomas. Thirty-one patients were evaluable for toxicity and 29 for efficacy including 22 with primary mediastinal B-cell lymphoma, five with diffuse large B-cell lymphoma, and two with gray zone lymphoma. There were no treatmentrelated deaths; 32% of patients had non-hematologic grade 3/4 toxicities. The overall response rate was 100% (95% confidence interval [95% CI]: 88-100) with 86% (95% CI: 68-96) of patients achieving complete response at the end of systemic treatment. Consolidative radiation following end-of-treatment response assessment was permissible and used in 52% of all patients including 59% of the patients with primary mediastinal B-cell lymphoma. With a median follow-up of 30 months, the 2- year progression-free survival and overall survival rates were 85% (95% CI: 66-94) and 100%, respectively. In the cohort with primary mediastinal B-cell lymphoma, the 2-year progression-free survival rate was 86% (95% CI: 62-95). In summary, BV-R-CHP with or without consolidative radiation is a feasible and active frontline regimen for CD30-positive Bcell lymphomas (ClinicalTrials.gov identifier: NCT01994850).

Sinus histiocytosis with massive lymphadenopathy (Rosai Dorfman Disease [RDD]), is a rare, benign but clinically heterogeneous histiocytic disorder. Our aims were to analyze the clinical characteristics of the disease and explore the outcomes of patients with RDD followed at our institution. Between January 2000 and February 2019, there were 15 patients with a pathologically confirmed diagnosis of RDD. Median age at diagnosis was 48 years old (range 26-78). The majority (87%

Introduction Venetoclax is a highly effective agent in chronic lymphocytic leukemia and acute myeloid leukemia. Phase I/II clinical trials have shown it to be safe and effective in non-Hodgkin lymphoma (NHL). Adverse events were consistent with package labeling despite escalation to high doses. To the best of our knowledge, venetoclax use outside the setting of a clinical trial of NHL has not been reported. Patients and Methods We conducted a single-center, retrospective study of 34 adult patients who had been treated off-label with venetoclax-containing regimens from 2016 to 2018. Results Of the 34 patients with NHL treated with venetoclax therapy, 13 had had high-grade B-cell lymphoma/diffuse large B-cell lymphoma, 10 mantle cell lymphoma, 5 transformed follicular lymphoma, 2 Richter transformation, 2 marginal zone lymphoma, 1 follicular lymphoma, and 1 post-transplant lymphoproliferative disorder. The patients had received a median of 4 previous therapies. The overall response rate was 26% (3% with a complete response and 35% with stable disease). The median venetoclax dose achieved was 400 mg. Of those receiving combination therapy, 18% had undergone radiation and 62% had received other systemic antineoplastic therapy. The median progression-free and overall survival for the cohort was 2 and 4.5 months, respectively. Adverse events occurred in 76% of the patients during venetoclax therapy. The adverse events included neutropenia, thrombocytopenia, tumor lysis syndrome, infection, neutropenic fever, diarrhea, and 1 opportunistic infection. Conclusion Venetoclax therapy in a real-world cohort offered modest benefits in heavily pretreated patients. Adverse events were observed at a greater incidence than in the clinical trials. A wide heterogeneity of venetoclax dose escalation, multiagent combinations, and timing of initiation were identified and require investigation in subsequent clinical trials.

PURPOSE: Patients weigh competing priorities when deciding whether to travel to a cellular therapy center for treatment. We conducted a choice-based conjoint analysis to determine the relative value they place on clinical factors, oncologist continuity, and travel time under different post-treatment follow-up arrangements. We also evaluated for differences in preferences by sociodemographic factors. METHODS: We administered a survey in which patients with diffuse large B-cell lymphoma selected treatment plans between pairs of hypothetical options that varied in travel time, follow-up arrangement, oncologist continuity, 2-year overall survival, and intensive care unit admission rate. We determined importance weights (which represent attributes' value to participants) using generalized estimating equations. RESULTS: Three hundred and two patients (62%) responded. When all follow-up care was at the center providing treatment, plans requiring longer travel times were less attractive ( v 30 minutes, importance weights [95% CI] of –0.54 [–0.80 to –0.27], –0.57 [–0.84 to –0.29], and –0.17 [–0.49 to 0.14] for 60, 90, and 120 minutes). However, the negative impact of travel on treatment plan choice was mitigated by offering shared follow-up (importance weights [95% CI] of 0.63 [0.33 to 0.93], 0.32 [0.08 to 0.57], and 0.26 [0.04 to 0.47] at 60, 90, and 120 minutes). Black participants were less likely to choose plans requiring longer travel, regardless of follow-up arrangement, as indicated by lower value importance weights for longer travel times. CONCLUSION: Reducing travel burden through shared follow-up may increase patients' willingness to travel to receive cellular therapies, but additional measures are required to facilitate equitable access.

Background Peripheral T-cell lymphomas (PTCLs) are generally aggressive non-Hodgkin lymphomas that portend poor prognosis with currently available therapies. Bexarotene, a retinoic acid derivative, has efficacy in cutaneous T-cell lymphomas, but its activity in PTCL is unknown. Patients and Methods We conducted a retrospective, single-institution, review of off-label bexarotene therapy in patients with PTCL between 2005 and 2016. Results Twelve patients were treated with bexarotene as monotherapy: 3 patients with PTCL, not otherwise specified, and 9 patients with angioimmunoblastic T-cell lymphoma. Bexarotene doses of 300 mg/m2 daily or 150 mg/m2 were used for all patients. The treatment was well-tolerated. The most common toxicities included hypothyroidism and hyperlipidemia, which were effectively managed. The overall response rate for all patients was 58% with a median duration of response of 11 months (95% confidence interval [CI], 1.3 months to not estimable). Among patients with angioimmunoblastic T-cell lymphoma, there was a 44% overall response rate. The median progression-free survival for all patients was 2.1 months (95% CI, 1.1 months to not estimable), and the median overall survival was 14.9 months (95% CI, 2.1-73.1 months). Conclusion Bexarotene monotherapy is well-tolerated and has encouraging activity in PTCL that warrants further investigation in prospective clinical trials.

Molecular imaging with 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) is an established modality for response assessment in patients with lymphoma undergoing treatment. However, patients treated with novel immunotherapies may have false-positive PET/CT findings due to tumor site and systemic inflammation. In particular, treatment with autologous chimeric antigen receptor modified T-cells redirected at CD19 (CTL019 CAR-T cells) is often complicated by "cytokine release syndrome" (CRS) due to a severe systemic inflammatory reaction. Infiltration of tumors by activated CTL019 cells may impact radiographic and functional imaging findings. The role of PET/CT in patients treated with CTL019 has not previously been described. We performed a pilot, single-arm, prospective study to explore the utility of early PET/CT in patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) undergoing treatment with CTL019 CAR-T cells. Patients had PET/CT prior to CTL019 infusion and then early PET/CT at 1 month after treatment. The primary outcome was the amount/change in metabolically active tumor volume (MTV) and FDG uptake. We enrolled seven patients (DLBCL, three; FL, four). Six of 7 had baseline PET/CT with active disease. On post-treatment PET/CT, three patients had no residual MTV, two patients had a decrease in MTV and two patients had an increase in MTV. The three patients with no residual MTV all remain in remission >2 years post-treatment. The patients with less than complete response all subsequently relapsed. Development of CRS did not confound PET/CT findings. In patients with DLBCL and FL receiving CTL019 CAR-T cells, early PET/CT may predict response to this novel immunotherapy.

BackgroundOlder patients are at risk of increased morbidity and mortality from COVID-19 disease due to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). There are few effective treatments for outpatients with COVID-19.ObjectiveTo evaluate the efficacy of hydroxychloroquine to reduce time in quarantine for symptomatic ≥40 years-old COVID-19 patients.DesignA randomized, double-blind, placebo-controlled clinical trial.SettingOutpatients with polymerase chain reaction confirmed COVID-19 at a University of Pennsylvania affiliated testing center between April 15, 2020 and, July 14, 2020.ParticipantsOut of 5511 SARS-CoV-2 positive patients, 1072 met initial eligibility criteria for telephone-based recruitment, but only 34 subjects were able to be randomized.InterventionsHydroxychloroquine 400 mg per twice daily (n=17) or matching placebo (n=17), taken orally for up to 14 days.MeasurementsThe primary outcome was the time to release from quarantine. Secondary outcomes included the participant-reported secondary infection of co-inhabitants, hospitalization, treatment-related adverse events, time to symptom improvement, and incidence of cardiac arrhythmia.ResultsThe median time to release from quarantine for HCQ-treated vs. placebo-treated participants was 8 days (range 4-19 days) vs. 11 days (4-18 days); z-score +0.58, p=n.s. This did not meet the pre-specified criteria for early termination, however, this study was terminated early due to lack of feasibility. There was no mortality in either study arm.LimitationSince this study was terminated early due to a lack of feasibility, no conclusion can be made about the efficacy of hydroxychloroquine as a treatment for COVID-19 patients 40 years of age or older quarantined at home.ConclusionThe design of this remotely conducted study could guide testing of other more promising agents during the COVID-19 pandemic.Trial registrationClinicaltrials.gov identifier: NCT04329923

Importance Treatment options for Sezary syndrome (SS) are limited and associated with low response rates. Brentuximab vedotin is a CD30-directed antibody-drug conjugate approved for refractory CD30-positive cutaneous T-cell lymphoma. However, limited data exist on its efficacy in SS, including in the pivotal phase 3 ALCANZA (A Phase 3 Trial of Brentuximab Vedotin (SGN-35) Versus Physician’s Choice [Methotrexate or Bexarotene] in Participants With CD30-Positive Cutaneous T-Cell Lymphoma) trial. Objective To assess the preliminary efficacy and tolerability of brentuximab vedotin for SS. Design, Setting, and Participants From January 1, 2017, to July 31, 2020, a total of 13 patients with SS received brentuximab vedotin and were analyzed as part of a retrospective case series. Median follow-up was 10.4 months (range, 1.4-34.6 months). All patients were 18 years or older with a diagnosis of SS and with B2 blood involvement at the time brentuximab vedotin therapy was initiated. This single-center study was conducted at a major academic referral center. Interventions Intravenous brentuximab vedotin administration approximately every 3 weeks. Main Outcomes and Measures The primary end point was the global response rate. Outcomes were assessed in the skin and lymph nodes per the 2011 European Organization for Research and Treatment of Cancer–International Society of Cutaneous Lymphoma response criteria and in the blood per the 2018 Prospective Cutaneous Lymphoma International Prognostic Index revised blood response criteria. Results The study included 13 patients (8 [62%] male; mean [SD] age, 68.2 [8.6] years). Of these 13 patients, 5 (38%) achieved a global response after a median of 6 cycles, including 1 complete response. Response rates by disease compartment were 38% in the skin, 63% in the blood, and 50% in the lymph nodes. Three of 11 patients (27%) with pruritus reported improvement. Skin CD30 positivity (>10%) was detected in 9 patients but was not associated with responses. Among responders, the median time to response was 6 weeks (range, 6-9 weeks), and the median duration of response was 5.5 months (range, 2.5-28.9 months). The median time to next treatment was 3.2 months (range, 1.5-36.7 months). Peripheral neuropathy occurred in 4 patients but resolved in 2 patients. Grade 2 adverse events were neuropathy (n = 2), constipation (n = 1), and hand-foot syndrome (n = 1). Conclusions and Relevance In this case series, brentuximab vedotin use was associated with some efficacy in SS across multiple disease compartments and in the setting of refractory disease or low CD30 skin expression. Brentuximab vedotin may offer a manageable treatment schedule and low incidence of significant toxic effects.

Purpose CD19-targeting chimeric antigen receptor T-cell (CART) therapy has emerged as a promising treatment for relapsed/refractory aggressive B-cell lymphoma (r/rABL), culminating in 2 US Food and Drug Administration–approved therapies: tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Following leukapheresis and in preparation for CART infusion, contemporary bridging and lymphodepletion regimens rely mostly on cytotoxic chemotherapy. Here, in a cohort of patients treated with commercial tisa-cel and axi-cel, we show that bridging-RT may offer a supplemental approach. Methods and Materials Thirty-one patients receiving commercial tisa-cel (n = 13) or axi-cel (n = 18) between August 2018 and February 2019 for r/rABL were retrospectively reviewed. Patients were categorized into 2 groups: (1) bridging-RT within 30 days of CART infusion or (2) nonbridging-RT (NBRT), in which patients received either remote RT greater than 30 days before CART infusion or no prior RT. Results Five patients received bridging-RT within 30 days of CART infusion. Median bridging-RT dose was 37.5 Gy and was completed a median of 13 days before infusion. No grade 3 (G3) or higher RT-toxicities occurred. No patients in the bridging-RT group experienced G3 or higher CART-related toxicities (CRS or neurotoxicity), and 23% (n = 6) and 15% (n = 4) experienced G3-5 CRS and G3-5 neurotoxicity in the NBRT group, respectively. Overall treatment response in the bridging-RT and NBRT groups was 80% and 64%, respectively. The axi-cel CART product was associated with CRS (odds ratio [OR] = 26.67, P = .001) and CRS correlated with neurotoxicity (OR = 12.22, P = .028). There was a trend toward an association for CRS with metabolic tumor volume (OR = 1.06/mL, P = .141) and TLG (OR = 1.01/mL x standard uptake value, P = .099). Conclusions Bridging-RT before commercial CART does not appear to increase the risk for CART-related toxicities or negatively affect outcomes in r/rABL patients. No G3 or higher RT-toxicities occurred in this series. Pretreatment metabolic tumor burden may be associated with CART-associated CRS; however, larger patient numbers are required to elucidate significant associations. Future work to prospectively assess the value of bridging-RT is warranted.

Idiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular (HyperV) more recently), plasmacytic, or "mixed." Though the etiology is unknown, a pro-inflammatory cytokine storm, often involving interleukin-6 (IL-6), contributes to pathogenesis. Anti-IL-6 therapy with siltuximab is the only FDA- or EMA-approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first-line for iMCD except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real-world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18/79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real-world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype. This article is protected by copyright. All rights reserved.

The optimal treatment for the monoclonal gammopathies of renal significance is not known, but there is consensus among experts that treatment should be specific for the underlying clone. The majority of patients with proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) do not have an identifiable clone, and prior studies have found poor renal outcomes for patients with PGNMID treated with a variety of regimens. Here we present a retrospective case series of 19 patients with PGNMID with a more uniform, clone-directed approach. A circulating paraprotein was detected in 37% of patients, and the overall clone detection rate was 32%. Treatment was directed at the underlying clone or, for patients without a detectable clone, empirically prescribed to target the hypothesized underlying clone. Of the 16 patients who underwent treatment, the overall renal response rate was 88%, and 38% of patients experienced complete renal response (proteinuria reduction to under 0.5 gm/24 hours) with initial treatment. All patients were End Stage Renal Disease-free at last follow-up (median 693 days after diagnosis), and treatment was well tolerated. Thus, a clone-directed approach may lead to novel, targeted treatment strategies that could significantly improve outcomes for patients with PGNMID.

Aim: To describe the long-term outcomes of patients with lymphoma in the CNS treated with rituximab, temozolomide and high-dose methotrexate without consolidation therapy. Patients & methods: A retrospective cohort study of 46 consecutive patients with primary CNS lymphoma (PCNSL, 27 patients) or secondary CNS involvement of diffuse large B-cell lymphoma (DLBCL, 19 patients) who were treated with rituximab on day 1 in combination with high-dose methotrexate (days 1 and 15) and temozolomide (days 1–5) in 28-day cycles without further consolidation. Results: Median follow-up was 21.2 months. Patients received a median of five cycles (range 1–15). Median overall survival (OS) was 26 months and median progression-free survival was 8.6 months. At 3 years, 37% of patients were alive and without evidence of disease. The patients with PCNSL had a significantly higher response rates (ORR 81 vs 47%; p = 0.015) and longer median OS (55.3 vs 4.8 months; p

Background . Anti-CD19 chimeric antigen receptor T cells (CART19) are now a standard treatment for patients (pts) with relapsed/refractory (r/r) large B-cell lymphomas (LBCL). Lymphodepleting chemotherapy (LD) is administered before CART19 to optimize CAR T cell engraftment, expansion, and function. The most widely used LD regimen is the combination of fludarabine (25-30mg/m 2) and cyclophosphamide (250-500mg/m 2) administered daily over 3 days (Flu/Cy). However, Flu/Cy is associated with a significant risk of hematologic toxicity that may preclude administration or result in prolonged cytopenias in pts with pre-existing cytopenias. Bendamustine (Benda) combines both alkylating-agent and purine-analog activities, and has potent anti-tumor efficacy in lymphoid malignancies. Importantly, compared to Flu/Cy, Benda typically has less hematologic toxicity, which may reduce the risk of infections. Therefore, because of its safety profile and lymphocytotoxic activity, Benda has been used as an alternative LD regimen for some pts receiving tisagenlecleucel (tisa-cel). In this study, we compare outcomes for Benda 90mg/m 2 for 2 days with Flu/Cy as the LD regimen before tisa-cel in pts with r/rLBCL treated at 3 different institutions. Methods : We retrospectively evaluated the outcomes of 133 consecutive r/r LBCL pts treated with commercial tisa-cel at the Hospital of the University of Pennsylvania, Oregon Health and Science University, and the Medical University of Vienna between 2018 and 2021. Patients with complete response (CR) at the time of infusion (n=20) were excluded from this analysis as this study aimed at evaluating the role of the LD regimen not only as related to the LD ability but also its effect against the tumor. Therefore, the analysis included 113 adult r/rLBCL pts treated with Flu/Cy or Benda as LD and with measurable disease on the last PET/CT scan before tisa-cel infusion. LD choice was based on physician's preference. Pts were evaluated for response (Lugano criteria), progression (PFS) and overall survival (OS), as well as hematological and CART-specific toxicities (ASTCT criteria). Pts demographics, response rates, and adverse events were compared using chi-squared and t-student tests as appropriate; log rank test was used for survival analysis. Results: Of 113 pts, 68 (60%) had diffuse large BCL not otherwise specified (NOS), 3 (3%) high-grade BCL NOS, 32 (28%) transformed follicular lymphoma, 9 (8%) high-grade BCL with MYC and BCL2 and/or BCL6 translocations, and 1 (1%) primary mediastinal BCL. Forty-one pts (36%) received Flu/Cy and 72 (64%) received Benda LD. Characteristics of Flu/Cy pts were comparable to Benda in terms of sex (female: 37% vs. 32%, p=0.616), age (68 vs. 65 years, p=0.143), performance status (ECOG ≤1: 93% vs. 94%, p=0.709), number of previous lines of therapy (3 vs. 3, p=0.707), previous autologous hematopoietic cell transplant (27% vs. 14%, p=0.089), bridging therapy (73% vs 85% p=0.136), LDH at infusion (elevated: 54% vs. 51%, p=0.708), and bulky disease (>10 cm) (15% vs. 10%, p=0.431). In whole cohort, no difference in obtaining a CR at any point after CART was observed between groups (Flu/Cy: 22% vs. Benda: 33%, p=0.201) (Fig 1A). At a median follow-up of 20.4 months, no difference in PFS was observed between Flu/Cy and Benda pts with 12-month PFS of 22% and 27%, respectively (p=0.512, Fig 1B). OS was also similar between Flu/Cy and Benda groups (2-year OS 41% vs. 49%, respectively, p=0.108). Both cytokine-release syndrome (CRS) and neurotoxicity (ICANS) were more frequent in the Flu/Cy group compared to Benda (any grade CRS: 68% vs. 40%, respectively, p=0.004; any grade ICANS: 22% vs. 7%, respectively, p=0.020). Of note, pts receiving Flu/Cy developed more severe cytopenias compared to Benda. In particular, the median absolute neutrophil count nadir 30 days after tisa-cel was significantly lower in Flu/Cy group (0.20x10 9/L) compared to Benda (2.15x10 9/L) (p Conclusions: This retrospective study of r/r LBCL pts receiving tisagenlecleucel suggests that Benda is as effective as Flu/Cy and validates a safer adverse event profile with reduced CRS, ICANS, and hematological toxicities. Figure 1 Figure 1. Disclosures Svoboda: Pharmacyclics: Consultancy, Research Funding; TG: Research Funding; Seattle Genetics: Consultancy, Research Funding; Imbrium: Consultancy; Merck: Research Funding; Incyte: Research Funding; Genmab: Consultancy; Atara: Consultancy; BMS: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. Dwivedy Nasta: Merck: Other: Data safety monitoring board; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; ATARA: Research Funding; Millenium: Research Funding; Pharmacyclics: Research Funding; Roche: Research Funding; Rafael: Research Funding; Debiopharm: Research Funding. Landsburg: Incyte: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Takeda: Research Funding; Triphase: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Morphosys: Membership on an entity's Board of Directors or advisory committees. Gerson: Kite: Consultancy; TG Therapeutics: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy. Barta: Daiichi Sankyo: Honoraria; Seagen: Honoraria; Acrotech: Honoraria; Kyowa Kirin: Honoraria. Garfall: Amgen: Honoraria; Tmunity Therapeutics: Research Funding; Janssen: Honoraria, Research Funding; GSK: Honoraria; Novartis: Research Funding. Porter: National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; American Society for Transplantation and Cellular Therapy: Honoraria; Incyte: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Jaeger: BMS/Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Norvartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maziarz: Novartis: Consultancy, Other: Data and Safety Monitoring board, Research Funding; Bristol-Myers, Squibb/Celgene,, Intellia, Kite: Honoraria; Incyte Corporation: Consultancy, Honoraria; Allovir: Consultancy, Research Funding; Artiva Therapeutics: Consultancy; CRISPR Therapeutics: Consultancy; Intellia: Honoraria; Omeros: Research Funding; Athersys: Other: Data and Safety Monitoring Board, Patents & Royalties; Vor Pharma: Other: Data and Safety Monitoring Board. Ruella: AbClon: Consultancy, Research Funding; viTToria biotherapeutics: Research Funding; Tmunity: Patents & Royalties; BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties. Schuster: Abbvie: Consultancy, Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Genetech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Incyte: Research Funding; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Merck: Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmaclcyclics: Research Funding; Tessa Theraputics: Consultancy; TG Theraputics: Research Funding.

Background: Naratuximab emtansine (nara, Debio 1562, formerly IMGN529) is an antibody-drug conjugate (ADC) consisting of a humanized anti-CD37 antibody, K7153A, conjugated via a thioether-based linker to a cytotoxic maytansinoid, DM1. CD37, a lymphocyte surface marker, is highly expressed in B-NHL. A Phase 1 monotherapy study of nara revealed a good safety profile and promising efficacy (22% overall response rate [ORR] in DLBCL at all doses). In preclinical models of B-NHL, nara demonstrated synergistic antitumor activity when combined with rituximab (RTX). Aim: The aim of thisopen-label Phase 2 study was to evaluate the safety and efficacy of nara + RTX and to characterize pharmacokinetics (PK) and pharmacodynamics (PDy) in patients (pts) with relapsed and/or refractory (R/R) B-NHL. Methods: R/R B-NHL pts who were not candidates for stem cell transplant, with 1-6 prior lines of treatment, were recruited to two study parts. In Part 1, which included a safety run-in followed by an expansion, pts received 0.7 mg/kg nara in combination with 375 mg/m 2 RTX every 3 weeks (Q3W). In Part 2, only R/R DLBCL pts were included. Pts were assigned either to the Q3W regimen (cohort A), or to a weekly regimen of 0.4, 0.2, and 0.2 mg/kg nara administered on days 1, 8 and 15 of 21-day cycles combined with 375 mg/m 2 RTX on day 1 (cohort B). Six cycles of treatment were administered with possible extension. Primary endpoints were safety and ORR. PK and PDy evaluations included ADC and DM1 catabolites' systemic levels and receptor occupancy on peripheral blood mononuclear cells (PBMCs), to investigate CD37 target engagement. Pts from cohorts A and B were requested to fill in the FACTLym quality of life questionnaire (QoL). Pts with double/triple hit lymphoma, bulky disease, and up to 6 prior lines of treatment for DLBCL were allowed. There was no limit on life expectancy. Pts were considered efficacy evaluable (EE) if they had one baseline and at least one post-baseline tumor assessment or an assessment of clinical progression. Tumor assessment by CT was acceptable. The follow-up period was up to 1 year after last pt first dose (NCT02564744). Results: 100 pts were enrolled in the study: 80 DLBCL, 14 follicular lymphoma (FL) and 6 mantle cell lymphoma (MCL) pts; 81 pts (81%) experienced grade ≥ 3 treatment emergent adverse events, the most common being neutropenia 54 (54%), leukopenia 19 (19%), lymphopenia 17 (17%), and thrombocytopenia 12 (12%). Of the 80 DLBCL pts, 10 (12.5%) were primary refractory, 24 (30%) were refractory to last line, 62 (78%) had Ann Arbor stage III/IV, and 35 (44%) had received at least 2 prior systemic cancer therapies. The ORR in the 76 EE DLBCL pts was 44.7%, with 24 (31.6%) complete responses (CR) and 10 (13.2%) partial responses (PR). In addition, 9 (11.8%) stable disease (SD) and 33 (43.4%) progressive disease (PD) were observed. 30 pts were efficacy evaluable in each of the two major cohorts (A and B) of Part 2, enrolling mainly relapsed pts. ORR was 50% in each cohort (CR rate: 43.3% in cohort A; 33.3% in cohort B). In Part 1, 16 DLBCL pts were EE, of which 6 were primary refractory and 10 were refractory to last line. ORR in this group was 25%. Median duration of response (mDoR) in the 76 evaluable DLBCL pts was not reached (lower 95% confidence interval [CI] 12 months). Median duration of follow-up in responders was 15 months (95% CI 9-18 months). In the 14 FL pts, the ORR was 57%: 5 CR, 3 PR, 3 SD, and 3 PD; the mDoR in this population was not reached (lower 95% CI: 19 months), with a median duration of follow-up of 21.8 months (95% CI 19.1 - not reached). Of the 6 MCL pts, 4 were efficacy evaluable: 2 CR and 2 PD. Due to the low number of pts, the DoR curves are not presented. PK levels were sufficient to fully engage the CD37 target on PBMCs. A relationship between PK exposure and efficacy was identified. Data showed acceptable systemic release of cytotoxic DM1 and catabolites. DLBCL responders in cohorts A and B demonstrated on average a clinically meaningful improvement of 3 points (standard deviation: 6.6) in the Lymphoma Subscale of the FACT-Lym QoL. Summary/Conclusion: The combination of nara + RTX resulted in good OR and CR rates, durable responses, a manageable safety profile, and full CD37 target engagement. Consequently, nara + RTX could be considered an attractive option for the treatment of R/R B-NHL. The treatment was well tolerated and contributed to the pts' well-being, as demonstrated by the QoL results. Figure 1 Figure 1. Disclosures Levy: Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; GSK: Consultancy, Other: Promotional speaker; Karyopharm: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Amgen Inc.: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Gilead Sciences, Inc.: Consultancy, Honoraria, Speakers Bureau; Beigene: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Other: Promotional speaker; Morphosys: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Epizyme: Consultancy, Other: Promotional speaker; Dova: Consultancy, Other: Promotional speaker; TG Therapeutics: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Other: Promotional speaker, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau. Grudeva-Popova: University Hospital St George: Current Employment; Roche: Speakers Bureau; Abbvie: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Speakers Bureau; Takeda: Speakers Bureau. Trněný: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; MorphoSys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Celgene: Consultancy; 1st Faculty of Medicine, Charles University, General Hospital in Prague: Current Employment; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Jurczak: Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debbiopharm: Research Funding; Celgene: Research Funding; Celtrion: Research Funding; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Sandoz: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Epizyme: Research Funding; Incyte: Research Funding; Merck: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding. Pylypenko: Communal nonprofit enterprise "Cherkasy regional oncology dispensary of Cherkasy oblast council: Current Employment. André: Johnson & Johnson: Research Funding; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Incyte: Consultancy; Roche: Other: Travel/accomodation/expenses, Research Funding; Celgene: Other: Travel/accomodation/expenses; AbbVie: Other: Travel/accomodation/expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Research Funding. Dwivedy Nasta: Roche: Research Funding; Pharmacyclics: Research Funding; Millenium: Research Funding; ATARA: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Merck: Other: Data safety monitoring board; Rafael: Research Funding; Debiopharm: Research Funding. Rechavi-Robinson: Debiopharm International SA: Current Employment. Toffanin: Debiopharm International SA: Current Employment. Micallef: F. Hoffmann La Roche: Ended employment in the past 24 months; Debiopharm International SA: Current Employment. Attinger: Debiopharm International SA: Current Employment. Rouits: Debiopharm International SA: Current Employment, Patents & Royalties. Roubaudi-Fraschini: Debiopharm International SA: Current Employment. Orfanos: Debiopharm International SA: Current Employment; F. Hoffmann La Roche: Ended employment in the past 24 months. Dymkowska: CANTARGIA AB: Consultancy; AUREALIS OY: Consultancy; Debiopharm International SA: Consultancy; Morphosys AG: Consultancy. Nauwelaerts: Novartis Pharmaceuticals AG, Basel: Current equity holder in publicly-traded company, Ended employment in the past 24 months; Debiopharm International SA: Current Employment. Woei-a-Jin: University Hospitals Leuven, Belgium: Current Employment; Recordati: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Kyowa Kirin: Research Funding.

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

Introduction: Cellular immunotherapy with CD19-targeted chimeric antigen receptor (CAR) T cells has provided new therapeutic options for patients with high-risk hematologic malignancies. Following this therapy, patients may experience disease relapse or CAR-mediated toxicity due to cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS). Recent studies have confirmed that the intestinal microbiome can modulate the anti-tumor immune response to chemotherapy, immune checkpoint blockade, graft-versus-host disease after allogeneic hematopoietic cell transplantation, and adoptive cellular therapy. The contribution of the intestinal microbiome on the function of CAR T cells in vivo both with respect to their anti-tumor function and their propensity to induce toxicities is not known. Hence, in a multi-center study we analyzed the association between clinical outcomes and (1) antibiotic exposure prior to CAR T cell infusion and (2) the composition and diversity of the fecal microbiome. Methods and Results: We retrospectively collected clinical data and antibiotic exposures from patients with acute lymphoblastic leukemia (ALL, n=91) and non-Hodgkin lymphoma (NHL, n=137) treated with investigational or commercial CD19 CAR T cells at Memorial Sloan Kettering Cancer Center (MSK) and the University of Pennsylvania (Penn). We considered any antibiotic exposure between day -30 and the day of CAR T cell infusion. We focused our analysis on anaerobe-targeting antibiotics used in the setting of neutropenic fever: piperacillin-tazobactam, imipenem-cilastatin, and meropenem (here referred to as "P-I-M"). We found that forty-seven (20.6%) of 228 patients were exposed to P-I-M in the four weeks before CAR T cell infusion. Patient characteristics at the time of CAR T cell infusion were similar between the P-I-M-exposed and not-exposed groups, although a worse performance status was observed in patients with NHL treated with P-I-M. We found that overall survival (OS) was significantly decreased following CAR T cell infusion in patients exposed to P-I-M (Fig 1A; OS HR, 2.58; 95% CI, 1.68 - 3.98; p= We also prospectively collected baseline fecal samples prior to cell infusion from CD19 CAR T cells recipients (n=48) at MSK and Penn. Samples were submitted for 16S RNA sequencing of the V4-V5 region on the Illumina MiSeq platform and the amplicon sequence variants (ASVs) were annotated according to the NCBI 16S database using BLAST. In comparison to healthy controls (n=30), we found that alpha-diversity was significantly lower in fecal samples from CAR T cell patients (p= 0.0023, Fig 1B) and the composition of fecal samples was significantly different (p= Conclusion: Our results suggest that exposure to antibiotics, in particular P-I-M, in the four weeks before therapy was associated with worse survival. Profiling of the baseline fecal microbiome samples by 16S revealed that CD19 CAR T cell patients presented with evidence of an altered fecal microbiome as measured by lower alpha-diversity and a composition that is distinct from that of healthy controls. Finally, we identified bacterial taxa that were associated with Day 100 CR and CAR-mediated toxicity. Our findings indicate that the intestinal microbiome can affect the efficacy of CD19 CAR T cell therapy and provides a rationale to target the intestinal microbiome to improve clinical outcomes of patients treated with cellular therapies. Figure 1 Figure 1. Disclosures Smith: Janssen: Consultancy, Honoraria. Gomes: Xbiome: Current Employment. Schluter: Postbiotics Plus LLC: Other: cofounder. Park: Kura Oncology: Consultancy; BMS: Consultancy; Servier: Consultancy; Autolus: Consultancy; Curocel: Consultancy; Artiva: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy; Novartis: Consultancy; Affyimmune: Consultancy; Intellia: Consultancy; Innate Pharma: Consultancy; Minerva: Consultancy; PrecisionBio: Consultancy. Palomba: Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Jain: Targeted Healthcare Communications: Consultancy; Bristol Myers Squibb: Other: for advisory board participation; CareDx: Other: for advisory board participation; CTI Biopharma: Research Funding; Syneos Health: Research Funding. Pennisi: Gilead Sciences: Consultancy. Perales: Miltenyi Biotec: Honoraria, Other; Novartis: Honoraria, Other; Omeros: Honoraria; NexImmune: Honoraria; Bristol-Myers Squibb: Honoraria; Merck: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Kite/Gilead: Honoraria, Other; Medigene: Honoraria; Nektar Therapeutics: Honoraria, Other; Cidara: Honoraria; Servier: Honoraria; Sellas Life Sciences: Honoraria; Karyopharm: Honoraria; MorphoSys: Honoraria; Equilium: Honoraria; Incyte: Honoraria, Other. Garfall: Amgen: Honoraria; CRISPR Therapeutics: Research Funding; GlaxoSmithKline: Honoraria; Janssen: Honoraria, Research Funding; Novartis: Research Funding; Tmunity: Research Funding. Landsburg: Triphase: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Incyte: Membership on an entity's Board of Directors or advisory committees; ADCT: Membership on an entity's Board of Directors or advisory committees; Curis: Research Funding; Takeda: Research Funding. Gerson: Kite: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; TG Therapeutics: Consultancy. Svoboda: Imbrium: Consultancy; Genmab: Consultancy; Astra Zeneca: Consultancy, Research Funding; Atara: Consultancy; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Incyte: Research Funding; Merck: Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; TG: Research Funding. Giralt: AMGEN: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; JAZZ: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Gill: Interius Biotherapeutics: Current holder of stock options in a privately-held company, Research Funding; Novartis: Other: licensed intellectual property, Research Funding; Carisma Therapeutics: Current holder of stock options in a privately-held company, Research Funding. Rivière: FloDesign Sonics: Other: Provision of Services; Centre for Commercialization of Cancer Immunotherapy: Other: Provision of Services; Fate Therapeutics: Other: Provision of Services, Patents & Royalties; The Georgia Tech Research Corporation (GTRC): Other: Provision of Services (uncompensated); Juno Therapeutics: Patents & Royalties. Porter: Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Wiley and Sons Publishing: Honoraria; Tmunity: Patents & Royalties; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; ASH: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; American Society for Transplantation and Cellular Therapy: Honoraria; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees. Schuster: Abbvie: Consultancy, Research Funding; Acerta Pharma: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; DTRM: Research Funding; Genetech: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Incyte: Research Funding; Juno Theraputics: Consultancy, Research Funding; Loxo Oncology: Consultancy; Merck: Research Funding; Nordic Nanovector: Consultancy; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Pharmaclcyclics: Research Funding; Tessa Theraputics: Consultancy; TG Theraputics: Research Funding. Sadelain: NHLBI Gene Therapy Resource Program: Other: Provision of Services (uncompensated); Fate Therapeutics: Other: Provision of Services (uncompensated), Patents & Royalties; Atara Biotherapeutics: Patents & Royalties; Ceramedix: Patents & Royalties; Mnemo Therapeutics: Patents & Royalties; Takeda Pharmaceuticals: Other: Provision of Services, Patents & Royalties; St. Jude Children's Research Hospital: Other: Provision of Services; Juno Therapeutics: Patents & Royalties; Minerva Biotechnologies: Patents & Royalties. Frey: Novartis: Research Funding; Kite Pharma: Consultancy; Sana Biotechnology: Consultancy; Syndax Pharmaceuticals: Consultancy. Brentjens: Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; BMS: Consultancy, Patents & Royalties, Research Funding; sanofi: Patents & Royalties; Caribou: Patents & Royalties. June: AC Immune, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Consultancy; Novartis: Patents & Royalties; Tmunity, DeCART, BluesphereBio, Carisma, Cellares, Celldex, Cabaletta, Poseida, Verismo, Ziopharm: Current equity holder in publicly-traded company. Pamer: Diversigen: Other: Advisory board; Bristol Myers Squibb, Celgene, Seres Therapeutics, MedImmune, Novartis and Ferring Pharmaceuticals: Honoraria. Peled: DaVolterra: Consultancy; MaaT Pharma: Consultancy; CSL Behring: Consultancy; Seres Therapeutics: Research Funding. Ruella: BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties; AbClon: Consultancy, Research Funding; Tmunity: Patents & Royalties; viTToria biotherapeutics: Research Funding. van den Brink: WindMILTherapeutics: Honoraria; Pluto Therapeutics: Current holder of stock options in a privately-held company, Other: has consulted, received honorarium from or participated in advisory boards ; Priothera: Research Funding; Forty-Seven, Inc.: Honoraria; MagentaTherapeutics: Honoraria; GlaskoSmithKline: Other: has consulted, received honorarium from or participated in advisory boards; Ceramedix: Other: has consulted, received honorarium from or participated in advisory boards ; Merck & Co, Inc: Honoraria; Synthekine (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Kite Pharmaceuticals: Other; Amgen: Honoraria; Frazier Healthcare Partners: Honoraria; Seres: Other: Honorarium, Intellectual Property Rights, Research Fundingand Stock Options; Rheos: Honoraria; Therakos: Honoraria; Jazz Pharmaceuticals: Honoraria; Notch Therapeutics: Honoraria; Nektar Therapeutics: Honoraria; Wolters Kluwer: Patents & Royalties; Juno Therapeutics: Other; DKMS (nonprofit): Other; Pharmacyclics: Other; Da Volterra: Other: has consulted, received honorarium from or participated in advisory boards; Novartis (Spouse): Other: has consulted, received honorarium from or participated in advisory boards; Lygenesis: Other: has consulted, received honorarium from or participated in advisory boards .

Background: Patients (pts) with cancer are at higher risk for complications and mortality related to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although mRNA vaccines have been granted Food and Drug Administration emergency use authorization (EUA) for prevention of COVID-19, the pivotal trials largely excluded pts with active cancer. Emerging data suggests suboptimal efficacy of these vaccines in pts with hematologic malignancies. There are also theoretical concerns that programmed cell death protein 1 inhibitors (PD-1i) could potentiate vaccine-related adverse events (AEs); conversely, these vaccines could activate the immune system, increasing the risk for immune-related reactions (IRRs) after PD-1i treatment. Pts with classic Hodgkin lymphoma (cHL) receiving PD-1i represent a unique cohort and should be investigated for safety and efficacy issues with SARS-CoV-2 vaccines. Methods: We conducted a retrospective analysis of pts with cHL who were treated with PD-1i within the past 12 months. Our primary objective was to determine the frequency of vaccine-related AEs and also subsequent IRRs to PD-1i after vaccination as reported in the medical records. Our secondary objective was to determine efficacy based on post-vaccine COVID-19 infection rates and by presence of adequate receptor binding domain (RBD) IgG antibody level to the SARS-CoV-2 spike protein. This assay was a clinically available institutional assay developed under EUA. While the level of antibody that is associated with immune protection has not yet been defined, we used RBD IgG > 0.700 AU as positive since it was previously correlated with virus neutralization titer in vitro. Results: From July 1, 2020 through June 31, 2021, we identified 27 pts who received PD-1i for cHL and were seen at the University of Pennsylvania. Seventeen (63%) pts received nivolumab and 10 (37%) received pembrolizumab. The median age was 42 years (23-86), median number of therapies was 4 (2-15), and 7 (26%) had prior history of COVID-19 infection (none required hospitalization). Twenty-three pts (85% of total) were vaccinated: 17 (74%) received Pfizer-BioNTech BNT162b2 and 6 (26%) had Moderna mRNA-1273 formulations. Of 19 (83%) pts who received at least one dose of PD-1i prior vaccine, the median time between last PD-1i infusion and first vaccine administration was 20 days (2-157). Of 19 (83%) pts who received any PD-1i after vaccine, the median time to infusion was 18 days (4-89). In pts who had prior COVID-19 infection, the median time between the prior infection and vaccine was 91 days (range 78-350). There were no unexpected toxicities noted and no severe adverse events or hospitalizations directly related to vaccination. No patient discontinued the vaccination series due to side effects. In 12 vaccinated pts who had vaccine-related AEs solicited by the medical provider, 7 (58%) developed injection site reaction/pain: grade 1 (6/12) and grade 2 (1/12). Six (50%) pts had systemic AEs: grade 1 fatigue (4/12), grade 2 fatigue (1/12), transient generalized lymphadenopathy (1/12), fever (1/12). No new IRRs occurred in pts receiving subsequent PD-1i after vaccination. Two weeks after second vaccination, 1 patient developed worsening cough with imaging suggestive of pneumonitis but improved with antibiotics. There were no post-vaccine COVID-19 infections noted. RBD IgG antibody levels were available in 12/23 (52%) of all vaccinated pts; 11/12 (92%) pts had positive antibody titers. The only patient who did not mount positive RBD IgG antibody titers received brentuximab vedotin concurrently with PD-1i prior to vaccination. There were insufficient events to correlate pre-vaccine factors with AEs or efficacy. Conclusion: Pts with relapsed/refractory cHL on PD-1i who received SARS-CoV-2 vaccines had no unexpected toxicities and tolerated subsequent PD-1i without new IRRs. The efficacy based on post-vaccination COVID-19 rates and RBD IgG levels is encouraging in these heavily pretreated pts. We plan an additional prospective component of this study using patient reported outcomes and long-term safety and efficacy follow-up. Disclosures Svoboda: Incyte: Research Funding; Genmab: Consultancy; Merck: Research Funding; Pharmacyclics: Consultancy, Research Funding; BMS: Consultancy, Research Funding; TG: Research Funding; Imbrium: Consultancy; Seattle Genetics: Consultancy, Research Funding; Astra Zeneca: Consultancy, Research Funding; Atara: Consultancy; Adaptive: Consultancy, Research Funding. Dwivedy Nasta: Roche: Research Funding; Merck: Other: Data safety monitoring board; Incyte: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; ATARA: Research Funding; Millenium: Research Funding; Rafael: Research Funding; Debiopharm: Research Funding. Ruella: AbClon: Consultancy, Research Funding; BMS, BAYER, GSK: Consultancy; Novartis: Patents & Royalties; Tmunity: Patents & Royalties; viTToria biotherapeutics: Research Funding. Landsburg: Triphase: Research Funding; Takeda: Research Funding; Curis: Research Funding; ADCT: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: DSMB member; Morphosys: Membership on an entity's Board of Directors or advisory committees. Barta: Seagen: Honoraria; Daiichi Sankyo: Honoraria; Acrotech: Honoraria; Kyowa Kirin: Honoraria. Gerson: TG Therapeutics: Consultancy; Kite: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy. Schuster: Loxo Oncology: Consultancy; Nordic Nanovector: Consultancy; Genentech/Roche: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Patents & Royalties, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Acerta Pharma/AstraZeneca: Consultancy; BeiGene: Consultancy; Juno Theraputics: Consultancy, Research Funding; Tessa Theraputics: Consultancy; Pharmaclyclics: Research Funding; Abbvie: Consultancy, Research Funding; Alimera Sciences: Consultancy; Adaptive Biotechnologies: Research Funding; Merck: Research Funding; Incyte: Research Funding; TG Theraputics: Research Funding; DTRM: Research Funding.

There is no consensus on the optimal therapy for primary CNS lymphoma. Conventional treatment modalities include chemotherapy and radiation therapy, which carry significant risks of morbidity and mortality. In systemic lymphomas, there are situations where non-Hodgkin lymphomas have resolved spontaneously. We now report the case of a nonimmunocompromised patient with primary CNS lymphoma who underwent a spontaneous remission with a durable response. This case suggests that not all patients with primary CNS lymphomas require aggressive treatment with chemotherapy and radiation therapy.

Patients with relapsed/refractory Hodgkin lymphoma (RR-HL) who progress or relapse following autologous stem cell transplantation (ASCT) have historically had a poor prognosis. Several novel agents, particularly brentuximab vedotin, have shown efficacy in this setting. However, there remains a paucity of data characterizing outcomes outside of clinical trials and how these novel agents impacted prognosis in general population of patients with RR-HL. Here, we conducted a retrospective analysis to evaluate outcomes in 87 patients with RR-HL with relapse post-ASCT. Treatment with novel agents (including brentuximab vedotin) was associated with significant improvement in median overall survival (OS) compared to patients who did not receive novel agents (85.6 vs 17.1 months; p

Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

Background: Current standard of care for most patients (pts) with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL) is systemic salvage chemotherapy followed by autologous stem cell transplant (ASCT). Given the treatment-related toxicities associated with ASCT and the expanding novel therapeutic options, it is desirable to identify pts with RR disease who may be cured by less toxic treatment approaches. We aimed to assess outcomes, evaluate treatment-related toxicities, and identify baseline characteristics for pts with RR cHL who were treated with radiation-based therapy as the initial salvage approach. Methods: We conducted a multicenter, retrospective study of pts with RR cHL who did not undergo consolidative ASCT as part of their first salvage therapy and instead were treated with either RT alone or in combination with systemic therapy. Pts who received systemic therapy as first salvage but did not proceed to ASCT and then received a RT-based salvage regimen were also included. We defined relapse as recurrence of disease after achievement of complete response (CR) and primary refractory disease as failure to achieve CR in response to frontline therapy. Responses were based on treating physician assessment using Revised Response Criteria for Malignant Lymphoma (Cheson et al, JCO 2014). Kaplan Meier survival analyses were performed using STATA 15.0 software. Toxicities were recorded using NCI Common Terminology Criteria for Adverse Events (CTCAE) v.5. Results: We identified 22 pts from 5 U.S centers with RR cHL who were treated between January 2009 and August 2019 with salvage RT alone or in combination with systemic therapy without consolidative ASCT. The pts' characteristics are summarized in Table 1. Both pts with relapsed (68%) and refractory (32%) disease were included. All pts with relapsed disease (N = 15) had localized relapse (stage I or II) and 67% had relapsed > 12 months after completion of frontline therapy. Three pts who received frontline RT had relapsed outside their prior RT volumes. The most common reason for not pursuing ASCT was that the relapsed or residual disease was localized (38%). Other reasons cited included age (11%), comorbidities (11%), and pt preference (11%). Pts with relapsed disease were more likely than pts with primary refractory disease to receive RT combined with systemic therapy as a salvage (60% vs 15%, p = 0.01). Out of 13, patients who received combined systemic therapy with RT, 77% (N = 10) received brentuximab vedotin (BV) and 23% received multi-agent chemotherapy. Median duration of BV treatment was 6 cycles. Four pts received multi-agent systemic salvage chemotherapy as first salvage but did not proceed to ASCT and then went on to receive a RT containing salvage regimen Among all 22 RR cHL pts, 82% achieved complete response (CR) and 14% had progressive disease after RT containing salvage regimen (Table 2). Of those achieving CR, 77% (95% CI: 44-92) remained disease free at 5 years. The 5-year PFS for the entire cohort was 68% (95% CI: 41-85). There was no difference in the 5-year PFS among those with primary refractory compared with relapsed disease as shown in Figure 1(c2=0.02, p=0.88). Furthermore, 5-year OS was 95% (95% CI: 69-99). In terms of toxicity, there were no deaths or hospitalizations attributed to complications from salvage therapy. The most common toxicities reported were cytopenias in 32% (N = 7) and peripheral neuropathy in 27% (N = 6). Only 3 pts experienced grade 3/4 adverse events. Systemic salvage therapy was discontinued in 3 pts due to toxicity. No long-term toxicities of RT were reported, but longer follow-up is needed. Conclusions: To the best of our knowledge, this is the first study to evaluate outcomes for patients with RR cHL in the United States who received RT-based salvage regimens without consolidative ASCT. In our study population of pts with localized relapse or refractory disease, 81% of pts achieved CR after this non-transplant approach and 5-year PFS was 68%. Our data provides evidence that RT alone or in combination with systemic therapy can be an effective and potentially less toxic treatment strategy for carefully selected pts. Further evaluation, including with prospective studies and long-term follow-up, is needed to corroborate these findings as well as to examine potential late effects. Disclosures Evens: Seattle Genetics: Consultancy, Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Epizyme: 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. Portell:Xencor: Research Funding; Roche/Genentech: Consultancy, Research Funding; Infinity: Research Funding; TG Therapeutics: Research Funding; AbbVie: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Bayer: Consultancy; BeiGene: Consultancy, Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding. Epperla:Pharmacyclics: Honoraria; Verastem Oncology: Speakers Bureau. Feldman:Seattle Genetics, Inc.: Consultancy, Honoraria, Other: Travel expenses, Research Funding, Speakers Bureau; Takeda: Honoraria, Other: Travel expenses; Celgene: Honoraria, Research Funding; Kite: Honoraria, Other: Travel expenses, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding; Corvus: Research Funding; Rhizen: Research Funding; Viracta: Research Funding; Trillium: Research Funding; Bayer: Consultancy, Honoraria; Abbvie: Honoraria; Pharmacyclics: Honoraria, Other, Speakers Bureau; Amgen: Research Funding; Cell Medica: Research Funding; Eisai: Research Funding; Kyowa Kirin: Consultancy, Research Funding; Pfizer: Research Funding; Portola: Research Funding; Janssen: Speakers Bureau; AstraZeneca: Consultancy. Landsburg:Triphase: Research Funding; Seattle Genetics: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Dwivedy Nasta:Roche: Research Funding; Rafael Pharmaceuticals: Research Funding; Incyte: Research Funding; Debiopharm: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Atara: Research Funding; Forty Seven: Research Funding. Gerson:Loxo: Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy. Barta:Pfizer: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria, Research Funding; Atara: Honoraria; Monsanto: Consultancy. Chong:KITE Pharma: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Tessa: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Schuster:Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding; AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria. Svoboda:Atara: Consultancy; Genmab: Consultancy; TG: Research Funding; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding; Imbrium: Consultancy; BMS: Consultancy, Research Funding; Astra-Zeneca: Consultancy, Research Funding; Adaptive: Consultancy.

Introduction: High-grade B cell lymphoma (HGBCL) with rearrangements of MYC in addition to either BCL2 or BCL6 (DHL) generally has a poor prognosis for response to conventional therapies. Nevertheless, current studies of responses to anti-CD19 CAR-T cell therapies (CAR-T) have not demonstrated poorer overall response rates (ORR) in patients with DHL (Locke Lancet Oncol 2019, Schuster NEJM 2019). Double expressor diffuse large B-cell lymphoma (DEL), which lacks the chromosomal rearrangements of DHL but overexpresses MYC and BCL2 proteins by immunohistochemistry, has been similarly associated with poor outcomes, including after autologous and allogeneic stem cell transplantation (Herrera JCO 2017; Kawashima Biol Blood Marrow Transplant, 2018). DEL and DHL each have a different cell of origin and biology; DEL is typically activated B cell-like phenotype, whereas DHL typically have germinal center-like phenotype. To our knowledge, the association of DEL and outcomes with CAR-T has not been assessed. We aimed to assess whether DEL is associated with outcome after CAR-T. Methods: We retrospectively reviewed the records of 75 consecutive patients with aggressive B-cell lymphomas treated with commercial CAR-T therapy at the University of Pennsylvania between April 2018 and October 2019. We included all patients with either diffuse large B cell lymphoma or HGBCL who had both: a) fluorescence in situ hybridization testing for MYC, BCL2 and BCL6 chromosomal rearrangements, and b) immunohistochemical staining (IHC) for MYC and BCL2. Patients who had both MYC and BCL2 and/or BCL6 chromosomal rearrangements were classified as DHL; patients with IHC expression of both MYC in > 40% and BCL2 in > 50% of tumor cells without meeting criteria for DHL were classified as DEL. Patient characteristics were collected. Fisher's exact test was used to compare overall response rate (ORR) and log-rank test was used for comparison of progression-free survival (PFS). Results: Seventy-five eligible cases of aggressive B-cell lymphoma were identified; 9 were excluded due to non-DLBCL or HGBCL subtype and 16 were excluded due to insufficient characterization of tissue to assess DHL and DEL status. Fifty patients were eligible for analysis; 18 patients (36%) met criteria for DEL, 10 patients (20%) met criteria for DHL, and the remaining 44% of patients had neither DEL nor DHL (non-DEL/DHL). Tisagenlecleucel was administered to 39 patients, whereas axicabtagene ciloleucel was administered to 11 patients. Median age at leukapheresis was 65 years (range: 35-81). LDH, administration of bridging therapy, and ECOG performance status (PS) did not significantly differ between the three groups. Median follow-up for the entire cohort was 15.9 months. For all patients, best ORR was 54% (27/50 patients), median PFS was 3.7 months (95%CI: 2.8-NE), and median OS was not reached. Best ORR was 56% (10/18) for DEL patients, 50% (5/10) for DHL patients, and 55% (12/22) for patients with non-DEL/DHL. ORR did not differ between these groups (p=1.0). There was no difference in PFS (see Figure, p=0.90), OS (p=0.61), or RD (p=0.38) between the three groups. At 16 months, 69% of responding DEL continue in CR (95%CI: 30-89%), 72% of non-DEL/DHL (95%CI: 35-90%) continue in CR, and 100% of DHL (95%CI: NE) continue in CR. Conclusions: The proportion of patients with DEL in our study was similar to that reported for patients with diffuse large B-cell lymphoma in the literature. There were no significant differences between DEL, DHL, and non-DEL/DHL groups with regard to the proportion of patients with elevated LDH, bridging therapy, or ECOG PS. Although DHL and DEL have a negative prognostic impact on response to salvage therapies and hematopoietic stem cell transplant, neither DHL nor DEL status was associated with inferior response to anti-CD19 commercial CAR-T products. We demonstrate that patients with DEL can achieve prolonged responses after CAR-T. Moreover, neither DEL nor DHL status appeared to impact PFS, OS, or RD outcomes after commercial CAR-T. Figure Disclosures Chong: BMS: Membership on an entity's Board of Directors or advisory committees; Tessa: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; KITE Pharma: Membership on an entity's Board of Directors or advisory committees. Landsburg:Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Triphase: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Morphosys: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Gerson:Loxo: Research Funding; Genentech: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy. Svoboda:Atara: Consultancy; Genmab: Consultancy; TG: Research Funding; Adaptive: Consultancy; Astra-Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Imbrium: Consultancy; Seattle Genetics: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Merck: Research Funding; Incyte: Research Funding. Dwivedy Nasta:Merck: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding; Debiopharm: Research Funding; Forty Seven: Research Funding; Incyte: Research Funding; Atara: Research Funding; Rafael Pharmaceuticals: Research Funding. Barta:Atara: Honoraria; Pfizer: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria, Research Funding; Monsanto: Consultancy. Garfall:Novartis: Research Funding; Tmunity: Consultancy, Other: Personal fees, Research Funding; Amgen: Research Funding; Kite Pharma: Other: Personal fees; Janssen: Consultancy, Research Funding; GSK: Consultancy; Surface Oncology: Consultancy. Ruella:UPenn/Novartis: Patents & Royalties; Abclon, BMS, NanoString: Consultancy; Abclon: Consultancy, Research Funding. Frey:Amgen: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria; Syntax: Consultancy, Honoraria. Porter:Incyte: Other: Advisory board; Novartis: Honoraria, Other: Advisory board, Patents & Royalties: CAR T cells for CD19+ malignancies, Research Funding; Janssen: Other: Advisory board; Genentech/Roche: Current equity holder in publicly-traded company, Other: Spouse employment (ended Sept 2020); her salary includes stock/options; Glenmark: Other: Advisory board; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; American Board of Internal Medicine: Other: Member, exam writing committee (end date Oct 2019); Tmunity: Patents & Royalties; Adicet bio: Other: Advisory board; Kite/Gilead: Other: Advisory board. Schuster:AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria; Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding.

Background: Patients (pts) with relapsed/refractory classical Hodgkin lymphoma (r/r cHL) who fail or cannot tolerate both brentuximab vedotin (BV) and PD-1 inhibitors (PD-1i) have limited treatment options. Hodgkin Reed-Sternberg cells and the pro-inflammatory tumor microenvironment are rich in therapeutic targets including those in the PI3K/AKT/mTOR and JAK/STAT pathways. Tumors resistant to PD-1i may be particularly enriched for JAK/STAT mutations (Zaretsky et al, NEJM 2016). Everolimus, an oral mTOR inhibitor, is active in r/r cHL pts with overall response rate (ORR) about 46% (Johnston et al, Exp Hematol Oncol 2018). Ruxolitinib, an oral JAK inhibitor, showed best ORR of only 19% in r/r cHL (Van Den Neste et al, Haematologica 2018). Pre-clinical studies have shown that co-treatment with mTOR and JAK inhibitors has synergistic activity against proliferation of JAK-mutated cell lines (Zhang et al, Oncotarget 2018). Methods: We designed an open label, investigator initiated, phase I/II trial using the combination of everolimus with itacitinib, an oral JAK inhibitor, for adult pts with r/r cHL. Eligible pts had to undergo at least 2 prior lines of therapy and autologous stem cell transplant (SCT) or be ineligible for SCT. Pts also had to either progress after treatment with, be intolerant of, or not a candidate for BV and PD-1i. Pts with a history pneumonitis requiring corticosteroids were excluded. Pts were treated with everolimus 5 mg daily for all dose levels and a starting dose of itacitinib at 300 mg daily with escalation to 400 mg daily or de-escalation to 200 mg daily using a traditional 3+3 design. Duration of therapy was planned for up to 24 cycles (each cycle lasting 28 days). All pts received PJP prophylaxis and after an amendment anti-viral prophylaxis. The primary objective of phase I was to evaluate dose-limiting toxicities (DLTs) of the novel combination and to establish a recommended phase II dose (RP2D). DLT was defined as the occurrence of any ≥ grade 3 non-hematological toxicity or selected grade 4 hematological toxicities occurring during Cycle 1. All DLTs were assessed using CTCAE v5 criteria. The primary objective of phase II was to evaluate the efficacy of the drug combination by investigator-based assessment using Lugano 2014 criteria (Cheson et al, JCO 2014). Enrollment began in 2/2019 with data cut off on 7/10/2020. Results: We enrolled 15 pts with r/r cHL with 14 pts evaluable for safety and response. Median age was 36 years (range 22-68), 71% were male, and median number of prior therapies was 5 (range 3-9). All pts had received prior BV and PD-1i, 64% had a prior auto-SCT, 14% had a prior allo-SCT, and 14% had prior anti-CD30 CAR T cells. There were no Cycle 1 DLTs in the phase I cohort, and the RP2D was determined as everolimus 5 mg and itacitinib 400 mg daily. Hematological adverse events (AEs) of any grade included thrombocytopenia (79%), neutropenia (43%), and anemia (36%). Most common non-hematological AEs were hyperlipidemia (29%), acneiform rash (21%) and stomatitis (14%). Notable grade 3 and 4 toxicities at least possibly related to the study treatment included thrombocytopenia (43%), neutropenia (21%), infection (7%), and hypertension (7%). There were no deaths related to study treatment and no patient discontinued therapy due to AEs. Six pts required dose modification for hematologic toxicities after the DLT period. The ORR in the combined phase I/II cohorts was 79% (95% CI: 49-95%) with a complete response rate 14% (95% CI: 2-43%). With median follow-up of 6.8 months (range 3.6-15.7), the overall survival was 92% (95% CI: 54-99%) with one patient dying of progressive disease at 2 months after discontinuing the study treatment due to progression. The median progression-free survival was estimated to be 3.8 months (95% CI: 1.8-not reached). Responses over 6 months are ongoing in several pts (Figure 1). Conclusion: The combination of everolimus and itacitinib is feasible and its efficacy compares favorably to historical reports for everolimus or JAK inhibitor monotherapy in r/r cHL. Our results suggest that the rational design for targeting multiple pathways can improve therapeutic outcomes in r/r cHL and warrants further investigation, particularly in pts with disease refractory to BV and PD-1i. Attempts to determine predictive biological markers of efficacy in long-term responders are ongoing. Figure 1 Disclosures Svoboda: Genmab: Consultancy; Adaptive: Consultancy; Astra-Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Imbrium: Consultancy; Incyte: Research Funding; Merck: Research Funding; Atara: Consultancy; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; TG: Research Funding. Barta:Pfizer: Honoraria; Janssen: Honoraria; Seattle Genetics: Honoraria, Research Funding; Atara: Honoraria; Monsanto: Consultancy. Landsburg:Seattle Genetics: Speakers Bureau; Takeda: Research Funding; Triphase: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Curis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Dwivedy Nasta:Debiopharm: Research Funding; Roche: Research Funding; Incyte: Research Funding; Forty Seven: Research Funding; Atara: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Rafael Pharmaceuticals: Research Funding. Hwang:Novartis: Research Funding; Tmunity Therapeutics: Research Funding. Gerson:Pharmacyclics: Consultancy; Genentech: Consultancy; Loxo: Research Funding; Abbvie: Consultancy. Chong:Novartis: Membership on an entity's Board of Directors or advisory committees; Tessa: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; KITE Pharma: Membership on an entity's Board of Directors or advisory committees. Hughes:Acerta Pharma and HOPA: Research Funding; AstraZeneca: Consultancy; Genzyme: Consultancy; Janssen: Consultancy; AbbVie: Consultancy. Ruella:Abclon: Consultancy, Research Funding; Abclon, BMS, NanoString: Consultancy; UPenn/Novartis: Patents & Royalties. Schuster:AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-La Roche, Juno/Celgene, Loxo Oncology, Nordic Nanovector, Novartis, Tessa Therapeutics: Consultancy, Honoraria; Novartis, Genentech, Inc./ F. Hoffmann-La Roche: Research Funding. OffLabel Disclosure: everolimus for relapsed and refractory Hodgkin lymphoma

Background Patients (pts) undergoing a solid organ (SOT) or allogeneic hematopoietic cell transplant (HCT) are at risk for developing Epstein-Barr virus-driven post-transplant lymphoproliferative disease (EBV+PTLD). There is a need for effective and well-tolerated therapies in pts with EBV+PTLD who have failed rituximab ± chemotherapy (CT). Tabelecleucel (tab-cel) is an investigational, off-the-shelf, allogeneic EBV-specific T-cell immunotherapy generated from healthy donors that is selected for a given pt from an existing library, based on human leukocyte antigen (HLA) restriction and matching. Objective Here, we report long-term outcomes using tab-cel through an ongoing US, multicenter Expanded Access Program (EAP) study (EBV-CTL-201, NCT02822495) in pts with relapsed/refractory (R/R) EBV+PTLD following HCT (n = 14) and SOT (n = 12). Methods Pts received tab-cel matched by ≥2/10 HLA alleles, including ≥1 HLA allele through which tab-cel exerts cytotoxicity (HLA restriction). In each 5-week cycle, pts received tab-cel 1.6–2 × 106 cells/kg intravenously on days 1, 8, and 15, with an imaging-based response assessment around day 28. Pts were treated until maximal response (with up to 4 tab-cel restrictions), unacceptable toxicity, or withdrawal of consent. Results herein reflect a data snapshot from June 3, 2019. Results All pts had received prior rituximab and 7/12 SOT pts received prior CT. Intermediate/high risk PTLD-prognostic index (PTLD-IPI; Choquet et al, Ann Hematol 2007) was noted in 79% and 42% of HCT and SOT pts, respectively. The results are presented in figure 1. While the median follow-up time in HCT pts was short, 3 pts were followed for over 12 months including 2 who were followed for more than 24 months. In pts responding to tab-cel, 1-year OS was 85.7% in HCT and 100% in SOT, and no deaths were attributable to EBV+PTLD progression. In a subset of study pts (HCT: n=11; SOT: n=11) with adequate ECOG, no CNS disease, and no PTLD-related ventilatory support who would have likely been eligible for Atara's ongoing Phase 3 studies, the ORR was 55% (HCT) and 82% (SOT), with a 2-yr OS of 79% (HCT) and 81% (SOT). The safety profile of tab-cel was consistent with previously published data. At the data snapshot for this abstract, no tab-cel-related adverse events led to treatment discontinuation or death. In addition, no cytokine release syndrome, organ rejection or tumor flare adverse events were reported in the EBV+PTLD pts treated with tab-cel in this EAP study. Conclusions The data demonstrate a high response rate for tab-cel in EBV+PTLD in both HCT and SOT after initial treatment failure. Longer term follow-up shows a favorable 2-year OS in this predominantly high-risk population for whom there are no approved alternative therapies. Similar outcomes were observed in the subset of pts potentially eligible for ongoing Phase 3 studies of tab-cel in R/R EBV+PTLD following SOT or HCT.

Background No consensus exists regarding the use of radiotherapy (RT) in conjunction with high-dose chemotherapy and autologous stem cell transplantation (HDC/ASCT) for patients with relapsed/refractory classical Hodgkin lymphoma (HL). The objectives of the current study were to characterize practice patterns and assess the efficacy and toxicity of RT at 2 major transplantation centers. Methods Eligible patients underwent HDC/ASCT from 2006 through 2015 using the combination of either carmustine (BCNU), etoposide, cytarabine, and melphalan (BEAM) or cyclophosphamide, BCNU, and etoposide (CBV). Results For the cohort of 189 patients, the 4-year overall survival rate was 80%, the progression-free survival rate was 67%, and the local control (LC) rate was 68%. RT was used within 4 months of ASCT for 22 patients (12%) and was given more often for disease that was early stage, primary refractory, or [18 F]fluorodeoxyglucose (FDG)-avid at the time of HDC/ASCT. Disease recurrence occurring after HDC/ASCT was associated with primary refractory disease and FDG-avidity at the time of HDC/ASCT. RT was not found to be associated with LC, progression-free survival, or overall survival on univariate analysis. In a model incorporating primary refractory HL and FDG-avid disease at the time of HDC/ASCT, RT was found to be associated with a decreased risk of local disease recurrence (hazard ratio, 0.3; P = .02). In patients with primary refractory HL and/or FDG-avid disease at the time of HDC/ASCT, the 4-year LC rate was 81% with RT versus 49% without RT (P = .03). There was one case of Common Terminology Criteria for Adverse Events grade ≥ 3 RT-related toxicity (acute grade 3 pancytopenia). Conclusions In patients undergoing ASCT for relapsed/refractory HL, peritransplantation RT was used more often for disease that was early stage, primary refractory, or FDG-avid after salvage conventional-dose chemotherapy. RT was associated with improved LC of high-risk localized disease and was well tolerated with modern techniques. Cancer 2017;123:1363-1371. © 2016 American Cancer Society.

Background Although classical Hodgkin lymphoma (cHL) is highly curable, 20%-30% of patients will not be cured with conventional treatments. The programmed death-1 (PD-1) inhibitors (PD-1i) nivolumab and pembrolizumab have been Food and Drug Administration-approved for relapsed/refractory (R/R) cHL. There is limited data on the real-world experience with PD-1i in cHL and it is unknown whether fewer selected patients treated with PD-1i derive benefits similar to those observed in published trials. Materials and methods We performed a multicenter, retrospective analysis of R/R cHL patients treated with PD-1i in the nontrial setting. The primary objective was to describe progression-free survival (PFS) and overall survival (OS) in this population. Secondary objectives were to characterize response rates, toxicities, discontinuation patterns, and post-PD-1i therapies. Results The study included 53 patients from nine U.S. centers. Overall response rate (ORR), complete response (CR), and partial response (PR) to PD-1i were 68%, 45%, and 23%, respectively. Twelve-month OS and PFS were 89% and 75%, respectively; median PFS was 29 months. Ninety-six percent of patients with CR continue to respond at a median follow-up of 20 months. Toxicities were similar to those previously described. Seventy percent of patients treated with systemic therapy after PD-1i demonstrated objective responses. Conclusion To our knowledge, this analysis is the first describing real-world experience with PD-1i in cHL patients in the U.S. Here, we demonstrate similar response rates compared to prior studies. The toxicity profile of PD-1i was similar to that seen in previous studies; we further describe toxicity patterns in those with prior autoimmune disease or allogeneic transplant. Post-PD-1i systemic therapies appear active. These results support the effectiveness and tolerability of PD-1i therapy in R/R cHL in a real-world setting. Implications for practice Two PD-1 inhibitors have recently been approved for patients with relapsed/refractory classical Hodgkin lymphoma based on results from nonrandomized clinical trials. However, to date, there have been no studies evaluating the effectiveness and toxicity profile of these drugs in the real-world setting in the U.S. The present study demonstrates that patients treated in a real-world context experience similar rates of overall effectiveness compared with published clinical trials. Patients who discontinue PD-1 inhibitors may experience clinical responses to subsequent treatment with systemic chemotherapy or targeted therapy. This study provides clinicians with further insight into the effectiveness and tolerability of PD-1 inhibitors and suggests that when patients progress while on these drugs, conventional systemic chemotherapy may be an effective treatment option.

Giant cell hepatitis (GCH) is a rare diagnosis in adults that is found in 0.25% of liver biopsies. GCH has been associated with multiple causes including drugs (6-mercaptopurine, methotrexate), toxins, viruses and autoimmune. GCH has been described in few patients with chronic lymphocytic leukemia (CLL). Here we describe three patients diagnosed with GCH thought to be related to underlying CLL and its management. All of our patients were treated with a combination of immunosuppression as well as CLL-directed therapy to address CLL and concomitant liver disease. GCH is a rare manifestation of active CLL and should be ruled out with prompt liver biopsy in patients with CLL with persistent transaminitis without another attributable cause. Prompt treatment of GCH with immunosuppression is required to prevent long-term liver toxicity. If transaminitis does not improve with immunosuppression alone, the addition of CLL directed therapy should be considered in patients who carry this diagnosis to prevent long-term liver toxicity.

e18503 Background: Chimeric antigen receptor T-cell therapy (CAR-T) is a novel therapy only available at specialized centers. Because patients prefer treatment close to home and provider continuity, preferences may result in unequal access. Sharing follow-up (f/u) with a local provider could increase willingness to travel, but its appeal to patients is unknown. Methods: We conducted a choice-based conjoint analysis to determine the clinical and care delivery factors that patients with diffuse-large B cell lymphoma (DLBCL) value when deciding whether to travel for CAR-T. We recruited from 13 sites within an integrated health system and asked participants to make choices between 12 pairs of treatment options that varied on 5 attributes: travel time, oncologist continuity, whether shared f/u was offered, two-year overall survival (OS), and intensive care unit (ICU) admission rate. Preferences for specific attributes were determined using a generalized estimating equation model with treatment choice as the outcome and the attributes as the variables. Each attribute’s coefficient (importance weight [IW]) represented its value to participants: higher IWs indicated greater value; negative IWs indicated undesirable attributes. Results: We invited 489 patients and 303 (62%) responded. IWs ranged from -0.56 to 1.15 (total cohort) and -2.83 to 2.50 (when modeled by race). Treatments at cancer centers ≥60 minutes away were valued less than those 30 minutes away without collaborative f/u; but were desirable if shared f/u care was offered (Table). Black respondents valued treatments ≥60 minutes away less despite shared f/u care. Participants also valued oncologist continuity (IW 1.15 [0.99, 1.32]), greater OS (IW 0.71 [0.63, 0.79] per 5 percentage point increase), and lower ICU admission rates (IW -0.21 [-0.25, -0.17] per 5 percentage point increase). Oncologist continuity was more highly valued by Black than by White respondents (IW 2.50 [1.74, 3.27] vs 1.09 [0.92, 1.25]). Conclusions: Patients with DLBCL are more likely to select CAR-T therapy at distant cancer centers if f/u care is shared locally. This could represent a strategy to expand access to CAR-T. Travel remains a barrier for Black patients despite shared f/u, suggesting the need to investigate targeted strategies that promote equitable access to CAR-T. [Table: see text]

e19568 Background: Anti-CD19 chimeric antigen receptor modified T-cell therapies (CAR-T) have expanded the treatment possibilities for many patients with relapsed/refractory (R/R) aggressive large B-cell lymphomas (B-NHL) but fails to achieve remissions in a considerable proportion of patients. In this study, we examined whether response to systemic therapy prior to CAR T-cell infusion is associated with outcome. Methods: We analyzed a retrospective dataset of R/R B-NHL patients (pts) treated with commercially available CAR-T at the University of Pennsylvania treated from April 2018 to August 2020. 18F-FDG PET/CT scans obtained directly prior to and after CAR-T therapy were re-evaluated for response by an independent radiologist using the Lugano 2014 criteria. Association between pre-therapy and post-therapy responses were examined using Fisher’s exact test. Results: 50 pts with aggressive R/R B-NHL were enrolled. 34 pts received tisagenlecleucel and 16 received axi-cel. Median age was 61 (range 29-82), and 27 pts (54%) were men. Most pts (n = 48, 96%) had ECOG performance status of 0-1, with a median number of 3 prior therapies (range 1-11). 14 (28%) of pts had LDH elevation at time of CAR T cell infusion. Median time from pre-therapy PET/CT to infusion was 47 days (range: 6-155). Median PFS was 3.4 months. Prior to CAR T cell infusion, responses were as follows: 12 complete response (CR), 9 partial response (PR), 8 stable disease (SD) and 21 progressive disease (PD). Post-therapy responses were: 20 CR, 5 PR, 2 SD, and 23 PD. 67% of pts with a CR pre-therapy had continued CR after CAR T-cell infusion, whereas 32% pf pts without a CR had a CR after infusion (p < 0.05). There was a trend toward CR/PR immediately prior to CAR T cell infusion being significantly associated with CR after CAR-T. We found that high metabolic tumor volume ( > 350cc vs ≤350cc) was associated with poorer PFS (log rank, p = 0.05). We did not find elevated LDH or use of bridging therapy to be associated with response to CAR-T. Conclusions: This is the largest report of lymphoma patients treated with CAR-T while in remission to date and suggests the importance of optimizing clinical response prior to CAR-T. Although patients in CR were excluded from the registrational trials, it is notable that patients in CR prior to CAR-T had a high rate of CR post CAR T cells despite the absence of active lymphoma on imaging. Longer follow-up is needed to confirm these early observations.

7539 Background: Lenalidomide (len) plus rituximab is now a standard-of-care option for indolent B-cell non-Hodgkin lymphomas (iNHL) and mantle cell lymphomas (MCL). We previously demonstrated the efficacy of len plus rituximab in patients (pts) with rituximab-refractory iNHL and MCL (Chong et al. Clin Can Res 2015). We now report the longest experience to date with this regimen. Methods: We conducted an open-label phase II trial in pts with iNHL or MCL and rituximab resistance, defined as failure to respond or progression of disease within 6 months (mo) of rituximab or a rituximab-containing regimen. Pts received len 10 mg daily for 8 weeks, followed by 4 weekly doses of rituximab 375 mg/m2 and continued len maintenance until disease progression, toxicity or pt choice. Results: 50 pts (30 FL, 14 MCL, 2 MZL, 4 SLL) were treated between 2008-2012. Median follow-up was 10.5 years (yr). Pts received a median of 3 prior therapies (range: 1–7). Progression free survival (PFS) for all pts at 5 and 10 yrs was 20.0% [95%CI 8-35] & 13% [95%CI 3-30%]; 5- and 10-yr response duration (RD) was 27% [95% CI 12-46] and 18% [95% CI 4-40], respectively; 5- and 10-yr overall survival (OS) was 58% [95%CI 43-70] and 45% [95%CI 30-58], respectively. 5-yr OS from the time pts were deemed rituximab-resistant is 64.0% and 10-yr OS 51.9%. For pts with FL, 5- and 10-yr PFS were both 13%, and 5- and 10-yr OS were 60% and 40%. For MCL, 5- and 10-yr PFS were both 25% and 5- and 10-yr OS were 50% and 36%. At 10.5 yr, 4 pts (2 FL, 1 MCL, 1 MZL) remain in complete remission (CR), 3 of whom discontinued len at 7.0-yr, 8.8-yr and 10.1-yr in CR. 1 pt with FL discontinued study in CR after 11.6-yr but continues on commercial len at 5 mg daily. The most common grade 1–2 adverse events (AEs) requiring dose reductions were neuropathy (n = 3) and diarrhea (n = 5), which all resolved with dose reduction. The most common grade 3–4 AEs requiring dose reductions were neutropenia (n = 6, 12%) and tumor flare (n = 3, 6%). Pts discontinued therapy due to toxicity at a median of 4.9 mo (range 0.3–25.7) from len start due to grade 3–4 rash (n = 2), grade 2 abdominal pain (n = 1), and grade 3–4 thrombocytopenia (n = 2). Only 1 patient discontinued len after > 1 yr (25.7 mo) due to persistent diarrhea. The pt who developed grade 2 abdominal pain was retreated with len without recurrence of pain and sustained a second CR for 5 yrs. 5 (10%) pts developed secondary cancers at a median of 15.5 mo (range: 0.8–50.5) from starting len, including 2 hematological (acute myeloid leukemia, B-acute lymphoblastic leukemia) and 3 solid cancers (NSCLC, renal cell carcinoma, prostate cancer). Prior to enrollment, 4/5 of the patients with secondary cancers had received alkylating agents and 3/5 had received anthracyclines. Conclusions: These data represent the longest reported outcomes for len plus rituximab in NHLs. We demonstrate durable responses and a manageable safety profile with rituximab plus low-dose len. Clinical trial information: NCT00783367.