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With the emerging application of novel targeted agents in the induction, maintenance and salvage strategies, management of aggressive mantle cell lymphoma is being transformed from high-intensity chemo-immunotherapy applicable to only selected patients, to more personalized treatment incorporating novel agents that are effective and accessible for the majority of the patients. This review summarizes risk-stratified management paradigm for aggressive mantle cell lymphoma, providing context for clinical applications of novel agents and cellular therapy including stem cell transplant and CAR-T.

Although chemotherapy has been a mainstay of the frontline treatment of mantle cell lymphoma (MCL) for many years, novel agents-including Bruton kinase inhibitors, immunomodulatory agents, and BCL2 inhibitors-have shown promise in patients with relapsed and refractory disease, and they are also being studied in the frontline setting. This review summarizes the current clinical data for using these novel agents in untreated MCL, both in combination with chemotherapy and singly, and discusses some of the trials currently under way to assess their future potential.

PURPOSESARS-CoV-2 (COVID-19) is a systemic infection. Patients with cancer are immunocompromised and may be vulnerable to COVID-related morbidity and mortality. The objectives of this study were to determine if patients with cancer have worse outcomes compared with patients without cancer and to identify demographic and clinical predictors of morbidity and mortality among patients with cancer.METHODSWe used data from adult patients who tested positive for COVID-19 and were admitted to two New York–Presbyterian hospitals between March 3 and May 15, 2020. Patients with cancer were matched 1:4 to controls without cancer in terms of age, sex, and number of comorbidities. Using Kaplan-Meier curves and the log-rank test, we compared morbidity (intensive care unit admission and intubation) and mortality outcomes between patients with cancer and controls. Among those with cancer, we identified demographic and clinical predictors of worse outcomes using Cox proportional hazard models.RESULTSWe included 585 patients who were COVID-19 positive, of whom 117 had active malignancy, defined as those receiving cancer-directed therapy or under active surveillance within 6 months of admission. Presenting symptoms and in-hospital complications were similar between the cancer and noncancer groups. Nearly one half of patients with cancer were receiving therapy, and 45% of patients received cytotoxic or immunosuppressive treatment within 90 days of admission. There were no statistically significant differences in morbidity or mortality ( P = .894) between patients with and without cancer.CONCLUSIONWe observed that patients with COVID-19 and cancer had similar outcomes compared with matched patients without cancer. This finding suggests that a diagnosis of active cancer alone and recent anticancer therapy do not predict worse COVID-19 outcomes and therefore, recommendations to limit cancer-directed therapy must be considered carefully in relation to cancer-specific outcomes and death.

Background: Brexucabtagene autoleucel (brexu-cel) is the first CD19 chimeric antigen receptor T-cell (CAR T) therapy approved for use in patients (pts) with relapsed mantle cell lymphoma (MCL). The ZUMA-2 trial demonstrated that brexu-cel induces durable remissions in these pts with an ORR of 85% (59% CR), estimated 12-month PFS rate of 61%, and similar toxicity profile to other CAR T therapies (Wang et al, NEJM 2020). We conducted a multicenter, retrospective study of pts treated with commercial brexu-cel to evaluate its safety and efficacy in the non-trial setting. Methods: We reviewed records of pts with relapsed MCL across 12 US academic medical centers. Pts who underwent leukapheresis between July 2020 and June 2021 with the intent to proceed to commercial brexu-cel were included. Baseline demographic and clinical characteristics were summarized using descriptive statistics. Survival curves were generated using the Kaplan-Meier method, and univariate models were fit to identify predictors of post-CAR T outcomes. Results: Fifty-five pts underwent leukapheresis. There were 3 manufacturing failures. Baseline characteristics of the 52 pts who received brexu-cel are summarized in Table 1. Median age was 66 yrs (range: 47-79 yrs) and 82% were male. Twenty of 29 (69%) pts with known baseline MIPI were intermediate or high risk. Seven pts had a history of CNS involvement. The median number of prior therapies was 3 (range: 2-8), including prior autologous stem cell transplant (ASCT) in 21 (40%) and prior allogeneic transplant in 2 pts (1 with prior ASCT and 1 without). Fifty percent had relapsed within 24 months of their initial therapy. All pts had previously received a Bruton's tyrosine kinase inhibitor (BTKi), including 29 (56%) with disease progression on a BTKi. Forty (77%) pts received bridging therapy (17 BTKi, 10 BTKi + venetoclax, 6 chemo, 3 venetoclax, 2 XRT only, 1 steroids only, 1 lenalidomide + rituximab). The ORR was 88% (CR 69%) among patients who received brexu-cel. Two pts had PD on initial restaging and 3 died prior to first response assessment (without evidence of relapse). Seven pts have not completed restaging due to limited follow-up (< 3 months) and were not included in the response assessment. Five pts have progressed, including 2 with CR and 1 with PR on initial restaging. With a median follow-up of 4.2 months, the estimated 6-month PFS and OS rates were 82.7% and 89.0%, respectively. All 7 pts with prior CNS involvement were alive without relapse at last follow-up. The incidence of cytokine release syndrome (CRS) was 84% (10% grade ≥ 3) with a median time to max grade of 5 days (range: 0-10 days). There were no cases of grade 5 CRS. The incidence of neurotoxicity (NT) was 57% (31% grade ≥ 3) with a median time to onset of 7 days (range: 4-15 days). NT occurred in 4/7 pts with prior CNS involvement (3 grade 3, 1 grade 4). Grade 5 NT occurred in 1 pt who developed cerebral edema and died 8 days after infusion. Thirty-five pts received tocilizumab, 33 received steroids, 7 received anakinra, and 1 received siltuximab for management of CRS and/or NT. Post-CAR T infections occurred in 8 pts, including two grade 5 infectious AEs (covid19 on day +80 and septic shock on day +40 after infusion). Rates of grade ≥ 3 neutropenia and thrombocytopenia were 38% and 37%, respectively. Among pts with at least 100 days of follow-up and lab data available, 5/34 (15%) had persistent grade ≥ 3 neutropenia and 4/34 (12%) had persistent grade ≥ 3 thrombocytopenia at day +100. Five pts have died, with causes of death being disease progression (2), septic shock (1), NT (1), and covid19 (1). Univariate analysis did not reveal any significant associations between survival and baseline/pre-CAR T MIPI, tumor pathologic or cytogenetic features, prior therapies, receipt of steroids/tocilizumab, or pre-CAR T tumor bulk. Conclusions: This analysis of relapsed MCL pts treated with commercial brexu-cel reveals nearly identical response and toxicity rates compared to those reported on ZUMA-2. Longer follow-up is required to confirm durability of response, but these results corroborate the efficacy of brexu-cel in a population of older adults with high-risk disease features. While all 7 pts with prior CNS involvement are alive and in remission, strategies to mitigate the risk of NT in this setting need to be evaluated. Further studies to define the optimal timing of CAR T, bridging strategies, and salvage therapies for post-CAR T relapse in MCL are warranted. Figure 1 Figure 1. Disclosures Gerson: TG Therapeutics: Consultancy; Kite: Consultancy; Abbvie: Consultancy; Pharmacyclics: Consultancy. Sawalha: TG Therapeutics: Consultancy, Research Funding; Celgene/BMS: Research Funding; BeiGene: Research Funding; Epizyme: Consultancy. Bond: Kite/Gilead: Honoraria. Karmali: Janssen/Pharmacyclics: Consultancy; BeiGene: Consultancy, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Takeda: Research Funding; Genentech: Consultancy; AstraZeneca: Speakers Bureau; Roche: Consultancy; Karyopharm: Consultancy; Epizyme: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; EUSA: Consultancy. Torka: TG Therapeutics: Membership on an entity's Board of Directors or advisory committees. Chow: ADC Therapeutics: Current holder of individual stocks in a privately-held company, Research Funding; AstraZeneca: Research Funding. Shadman: Abbvie, Genentech, AstraZeneca, Sound Biologics, Pharmacyclics, Beigene, Bristol Myers Squibb, Morphosys, TG Therapeutics, Innate Pharma, Kite Pharma, Adaptive Biotechnologies, Epizyme, Eli Lilly, Adaptimmune , Mustang Bio and Atara Biotherapeutics: Consultancy; Mustang Bio, Celgene, Bristol Myers Squibb, Pharmacyclics, Gilead, Genentech, Abbvie, TG Therapeutics, Beigene, AstraZeneca, Sunesis, Atara Biotherapeutics, GenMab: Research Funding. Ghosh: Genentech: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharma: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; TG Therapeutics: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genmab: Consultancy, Honoraria; Epizyme: Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding, Speakers Bureau; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria; Adaptive Biotech: Consultancy, Honoraria; AbbVie: Honoraria, Speakers Bureau. Moyo: Seattle Genetics: Consultancy. Fenske: TG Therapeutics: Consultancy, Speakers Bureau; Servier Pharmaceuticals: Consultancy; Seattle Genetics: Speakers Bureau; Sanofi: Speakers Bureau; Pharmacyclics: Consultancy; MorphoSys: Consultancy; Kite (Gilead): Speakers Bureau; KaryoPharm: Consultancy; CSL Therapeutics: Consultancy; Bristol-Myers Squibb: Speakers Bureau; Biogen: Consultancy; Beigene: Consultancy; AstraZeneca: Speakers Bureau; ADC Therapeutics: Consultancy; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy. Grover: Genentech: Research Funding; Novartis: Consultancy; ADC: Other: Advisory Board; Kite: Other: Advisory Board; Tessa: Consultancy. Maddocks: Seattle Genetics: Divested equity in a private or publicly-traded company in the past 24 months; BMS: Divested equity in a private or publicly-traded company in the past 24 months; Pharmacyclics: Divested equity in a private or publicly-traded company in the past 24 months; Novatis: Divested equity in a private or publicly-traded company in the past 24 months; Janssen: Divested equity in a private or publicly-traded company in the past 24 months; Morphosys: Divested equity in a private or publicly-traded company in the past 24 months; ADC Therapeutics: Divested equity in a private or publicly-traded company in the past 24 months; Karyopharm: Divested equity in a private or publicly-traded company in the past 24 months; Beigene: Divested equity in a private or publicly-traded company in the past 24 months; Merck: Divested equity in a private or publicly-traded company in the past 24 months; KITE: Divested equity in a private or publicly-traded company in the past 24 months; Celgene: Divested equity in a private or publicly-traded company in the past 24 months. Jacobson: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support; Celgene: Consultancy, Honoraria, Other: Travel support; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Lonza: Consultancy, Honoraria, Other: Travel support; AbbVie: Consultancy, Honoraria; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Nkarta: Consultancy, Honoraria; Axis: Speakers Bureau; Clinical Care Options: Speakers Bureau. Cohen: Janssen, Adaptive, Aptitude Health, BeiGene, Cellectar, Adicet, Loxo/Lilly, AStra ZenecaKite/Gilead: Consultancy; Genentech, Takeda, BMS/Celgene, BioInvent, LAM, Astra Zeneca, Novartis, Loxo/Lilly: Research Funding.

BACKGROUND: We previously reported early efficacy and 5-year follow-up of a multicenter phase 2 study of lenalidomide plus rituximab as initial treatment for MCL (NEJM 2015:373:1835; Blood 2018:132:2016), which was highly effective (ORR 92%, CR 64%) and well tolerated, with durable responses (5-year PFS and OS of 64% and 77% respectively). Here we present 7-year follow up analysis. METHODS: This study included both induction and maintenance with lenalidomide (L) and rituximab (R). During induction, patients received lenalidomide 20 mg daily on days 1-21 of a 28-day cycle for 12 cycles, followed by maintenance with dose reduction to 15 mg. Patients received rituximab weekly for four weeks during cycle 1, then once every other cycle. Treatment continued until progression of disease, with an option to stop therapy after 3 years. RESULTS: A total of 38 subjects requiring therapy were enrolled at 4 centers from 7/2011 to 4/2014. Median age was 65 with MIPI scores evenly distributed between low-, intermediate-, and high-risk groups. As of July 2020, the median follow-up was 86 months with range of 73-105 months. Two patients were inevaluable - one withdrew consent and the other was intolerant of tumor flare during induction. Nineteen (53%) of the evaluable 36 patients remain in remission, including 12 (33%) beyond 7 years. Of the patients in remission, 12 (33%) remain on treatment, including 4 on both L+R (at 100, 97, 96, and 92 months of treatment), 7 on R alone (105, 101, 98, 97, 92, 84, and 77 months), and 1 on L alone (72 months), while 7 patients in remission opted to stop therapy after at least 3 years of study treatment due to side effects or patient preference. Fourteen patients had progression: 3 had primary refractory disease and 11 relapsed following initial responses (5 CRs with PFS of 18, 38, 39, 49, and 72 months, 6 PRs with PFS at 14, 25, 28, 43, 44 and 92 months). Eleven evaluable patients have died, 8 from lymphoma progression and 3 from unrelated comorbidities. Eleven total patients stopped therapy while in remission: 7 remain in ongoing remission while off treatment for 0, 11, 15, 17, 29, 51, and 55 months, 1 progressed after 19 months off of therapy, and 3 died of causes unrelated to lymphoma. Median PFS and DOR have not been reached. The 7-year PFS rate was estimated at 60.3% (95% CI = 41.1%, 75.0%) with 7-year OS rates at 73.2% (95% CI = 55.9%, 84.6%). Interestingly, MIPI score ≤6.2 was predictive of increased overall survival (p = 0.04), with 7-year OS rates of 80.6% in this group versus 57.1% in patients with MIPI >6.2, while there was no difference in PFS between the two groups. Ki67 CONCLUSIONS: Lenalidomide and rituximab as initial treatment for MCL can achieve high rates of complete responses with durable remissions in both elderly and younger patients, with many patients maintain remissions now extending beyond 7 years. Toxicity was not significantly affected by continuous treatment, and close follow up was able to limit toxicity for those who wished to remain on therapy. It is notable that this combination offers a chemotherapy-free initial approach which compares favorably in outcome to conventional outpatient chemotherapy-based regimens such as bendamustine-rituximab, VR-CAP, and R-CHOP with rituximab maintenance. Further evaluation of this active regimen in larger, randomized frontline trials comparing novel agents with chemoimmunotherapy is warranted. (ClinicalTrials.gov - NCT01472562) Figure Disclosures Martin: Janssen: Consultancy; Bayer: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Karyopharm: Consultancy, Research Funding; Sandoz: Consultancy; I-MAB: Consultancy; Kite: Consultancy; Incyte: Consultancy; Teneobio: Consultancy; Celgene: Consultancy. Shah:NCCN: Vice-Chair, Acute Lymphoblastic Leukemia Working Group: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Precision Biosciences, Novartis, AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Kite/Gilead, Celgene/Juno/BMS, Novartis, Pfizer, Amgen, Spectrum/Acrotech, Precision Biosciences, Beigene, AstraZeneca, Pharmacyclics/Jansen, Adaptive: Honoraria; Moffitt Cancer Center: Current Employment; Kite/Gilead, Jazz, Incyte: Research Funding. 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. Smith:Acerta: Research Funding; Celgene: Consultancy, Research Funding; BMS: Consultancy; Pharmacyclics: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; Janssen: Consultancy; FortySeven: Research Funding; TG Therapeutics: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding. Svoboda:Astra-Zeneca: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Imbrium: Consultancy; Incyte: Research Funding; Merck: Research Funding; Pharmacyclics: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; TG: Research Funding; Genmab: Consultancy; Adaptive: Consultancy; Atara: Consultancy. Furman:AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy; Genentech: Consultancy; Sunesis: Consultancy; TG Therapeutics: Consultancy, Research Funding; Verastem: Consultancy; Incyte: Consultancy; Pharmacyclics: Consultancy; Oncotarget: Consultancy; Loxo Oncology: Consultancy; Janssen: Consultancy, Speakers Bureau; Acerta: Consultancy; Abbvie: Consultancy. Rutherford:Seattle Genetics: Consultancy; Genentech/Roche: Research Funding; Dova: Consultancy; Heron: Consultancy; Karyopharm: Consultancy, Research Funding; Juno: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; LAM Therapeutics: Research Funding; Kite: Consultancy; Regeneron: Research Funding. Allan:Acerta, Genentech, Abbvie, Sunesis, Ascentage, Pharmacyclics, Janssen, AstraZeneca, BeiGene: Consultancy; Abbvie, Janssen, AstraZeneca, Pharmacyclics: Honoraria; Celgene, Genentech, Janssen, TG Therapeutics: Research Funding. Leonard:Sutro: Consultancy; Gilead/Kite: Consultancy; Roche/Genentech: Consultancy; BMS/Celgene: Consultancy; Regeneron: Consultancy; ADC Therapeutics: Consultancy; Bayer: Consultancy; MEI Pharma: Consultancy; GenMab: Consultancy; Karyopharm: Consultancy; AstraZeneca: Consultancy; Epizyme: Consultancy; Miltenyi: Consultancy. Ruan:AstraZeneca: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pharmacyclics: Research Funding; Kite Pharma: Consultancy; Seattle Genetics: Research Funding; Juno: Consultancy; BMS: Consultancy, Research Funding. OffLabel Disclosure: This presentation will discuss the use of lenalidomide in untreated mantle cell lymphoma

Background: New York City has been at the epicenter of the SARS-CoV-2 (COVID-19) pandemic. Immunocompromised cancer patients may be more vulnerable to COVID-related morbidity and mortality. The objectives of this study were to determine if patients with cancer have worse outcomes compared to their noncancer counterparts and to identify potential demographic and clinical predictors of morbidity and mortality among cancer patients. Methods: We used data from a retrospective observational cohort of adult patients who tested positive for COVID-19 at New York-Presbyterian hospitals between March 3 and April 25, 2020. Patients with active cancer were matched 1:4 to noncancer controls on age, gender, and diabetes status. Using Kaplan-Meier curves and the log-rank test, we compared morbidity (intensive care unit admission and intubation) and mortality outcomes between cancer patients and controls. We identified demographic and clinical predictors of worse outcomes using Cox Proportional Hazard models. Hazard ratios and 95% confidence intervals were calculated for all estimates. Results: We included 445 COVID-19 positive adult patients of whom 89 had active malignancy. Among cancer patients, the median age was 72 years, 54% were male, and 52% were non-white. Presenting symptoms were similar between cancer and noncancer groups. Nearly half of cancer patients were on active treatment including cytotoxic and immunosuppressive therapy, and 40.9% of patients received cytotoxic treatment within 90 days of admission. Both patients with and without cancer received hydroxychloroquine in similar proportions (64% vs. 65.5%), and more cancer patients received remdesivir (7.9% vs. 3.7%). Overall, age (HR 1.14; 95% CI 1.00-1.29; p=0.049), male sex (HR 1.43; 95% CI 1.04-1.96, p=0.07), dyspnea on presentation (HR 1.81, 95% CI 1.3-2.58; p=0.0005), and bilateral lung infiltrates (HR 1.94; 95% CI 1.30-2.89; p=0.001) were associated with worse outcomes. Observed complications were similar for cancer and noncancer patients, including myocardial infarction (3.4% vs. 4.2%), vasopressor requirements (24.7% vs. 26.2%), bacteremia (9% vs. 10.4%), and venous thromboembolic events (7.9% vs. 7.3%), respectively. There were no statistically significant differences in morbidity or mortality between cancer and noncancer patients (p=0.287). Conclusion: We demonstrate that COVID-19 hospitalized patients with active malignancies have comparable morbidity and mortality to patients without cancer. In contrast to previous findings, we observed no differences in risk of ICU admission, intubation, or death between cancer and noncancer patients. Our findings suggest that active malignancy may not be a contributive risk factor in comparison to other significant comorbidities that may be more responsible for the unfavorable prognosis of COVID-19 in cancer patients. We should consider the consequences of limiting care for cancer patients on cancer-specific outcomes and mortality in the context of COVID-19. Citation Format: Gagandeep Brar, Laura C. Pinheiro, Michael Shusterman, Brandon Swed, Evgeniya Reshentnyak, Orysya Soroka, Frank Chen, Samuel Yamshon, John Vaughn, Peter Martin, Doru Paul, Manuel Hidalgo, Manish A. Shah. COVID-19 severity and outcomes in hospitalized patients with cancer at a New York City tertiary medical center: A matched cohort study [abstract]. In: Proceedings of the AACR Virtual Meeting: COVID-19 and Cancer; 2020 Jul 20-22. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(18_Suppl):Abstract nr S10-01.

IMiDs are a class of biologic agents with immunomodulatory, anti-angiogenic, and direct anti-cancer activities. This review summarizes current data on clinical development and application of IMiDs in non-Hodgkin lymphoma (NHL) subtypes, focusing primarily on lenalidomide, with additional discussion on managing common side effects. Improved upon the prototype thalidomide, the second-generation compound lenalidomide has enhanced immunological and anti-cancer properties with fewer side effects, while next-generation small molecule cereblon/E3 ubiquitin ligase modulator CC-122 is in early clinical studies. Lenalidomide is FDA-approved for treatment of relapsed/refractory mantle cell lymphoma as a single agent, as well as in combination with rituximab for R/R follicular lymphoma and marginal zone lymphoma. In addition, numerous clinical trials of lenalidomide, as single agent, in combination with anti-CD20 antibodies, or in combination with chemoimmunotherapy regimens, have shown promise in aggressive and indolent NHL in both the upfront and relapsed/refractory setting. As clinical trials with lenalidomide continue to find success in both indolent and aggressive lymphomas, IMiDs are poised to be important building blocks for combinatorial strategies with antibodies, chemotherapy, novel target agents, and emerging immunotherapy involving immune checkpoint inhibitors and chimeric antigen receptor T cell (CAR-T) therapy. Delineation of treatment-specific and disease-specific biomarkers is an important research objective to gain insight into potential mechanisms of action, and to guide future clinical development.

Background: Post-transplant lymphoproliferative disorders (PTLD) are a diverse group of lymphoid neoplasms arising after solid organ (SOT) or hematopoietic stem cell transplant (HSCT). They may resemble lymphomas in immunocompetent patients (monomorphic); present as destructive, heterogeneous lesions (polymorphic); or be non-destructive but mass-forming (non-destructive, previously known as 'early lesions'). PTLDs are often associated with Epstein-Barr virus (EBV) infection or reactivation, which likely functions as a driver in these cases. Non-destructive lesions may be challenging to diagnose in the absence of EBV. However, a significant fraction of PTLDs are EBV(-), including a subset of non-destructive lesions. The pathogenesis of these remains to be fully elucidated. Human herpesvirus 6 (HHV-6) reactivation is common during transplantation, occurring in up to 70% of HSCT and 80% of SOT patients. While it has been hypothesized that HHV-6 may play a role in PTLD, particularly in EBV(-) cases, the role of HHV-6 in the pathogenesis of PTLD remains underexplored. Methods: Following IRB approval, pathology archives at Weill Cornell/New York Presbyterian Hospital were searched to identify patients with a tissue diagnosis of PTLD and correlated with clinical information. A tissue microarray was constructed from blocks with sufficient tissue. Standard immunohistochemistry (IHC) and in situ hybridization for EBV-encoded RNA (EBER) were performed, and IHC conditions were optimized for antibodies against HHV-6 gp60/110 (Millipore Sigma, MAB853) and p41 (Santa Cruz Biotechnologies, 9A5D12). Statistical comparisons utilized Student's t-test and Fisher's exact test. Results: We identified 79 patients from 6/23/94-6/6/19 with a tissue diagnosis of PTLD. Morphologic subtype could be determined in 74, including 8 patients with non-destructive lesions. Compared to monomorphic or polymorphic, patients with non-destructive PTLDs were significantly younger (median age 9, p While tissue testing failed on blocks > 20 years old, 13 PTLD cases from 12 patients had sufficient evaluable material for HHV-6 testing (Table 2). 9/12 patients had a SOT (8 renal, 1 heart) and 3 had HSCT. HHV-6 was identified in 5/13 lesions (38%), all of which were in SOT patients (Figure 1). EBER was detected in 8/13 lesions (62%). When stratified by PTLD subtype, 3/3 non-destructive PTLDs were HHV-6+ (100%). Two were EBER(-) and the remaining case only showed scattered EBER+ cells. Unfortunately, material was not available for testing the EBER+ non-destructive lesions. 2/9 of the monomorphic lesions tested (22%) were positive for both HHV-6 and EBER. While the series is limited, the association between HHV-6 and non-destructive lesions, compared to other types of PTLD, appears significant (p Conclusions: Non-destructive, monomorphic and polymorphic PTLDs show significant differences in timing, patient demographics and transplant type, suggesting that they may differ in associated risk factors affecting their pathogenesis. Confirming prior studies, we find non-destructive lesions tend to occur in younger patients, often following SOT as compared to HSCT and with a median time from transplantation of ~50 months. In addition, the presence of HHV-6 in the absence of (or with limited) EBV in the 3 non-destructive lesions tested raises the possibility that HHV-6 may play a role in the pathogenesis of this PTLD subtype that has yet to be defined. These findings are intriguing given the frequent reactivation of HHV-6 seen in transplant populations. HHV-6 has been variably associated with post-transplant complications including pneumonitis, delayed hematopoietic engraftment and graft versus host disease and thus received relatively more attention in the HSCT population. A causative role for HHV-6 in PTLD remains speculative, but these findings raise the possibility that clinicians treating the SOT population should also consider aggressively identifying and treating HHV-6 reactivation. Disclosures Rutherford: AstraZeneca: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Heron: Consultancy, Honoraria; Janssen Scientific Affairs: Consultancy, Honoraria; Juno Therapeutics Inc: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Verastem: Consultancy, Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees.

We describe the case of a 61-year-old man from the Dominican Republic admitted with diarrhoea, fevers and weight loss who was found to have lab studies and imaging (including radiolabeled somatostatin positron emission tomography/CT scan) initially consistent with a metastatic neuroendocrine tumour. However, after weeks of workup and multiple inconclusive biopsies, he was diagnosed with disseminated extrapulmonary tuberculosis. Here we examine the data for neuroendocrine tumour and tuberculosis labs and imaging to delineate where these studies overlap. We also analyse the biases and pitfalls in this case that led to a protracted diagnosis.

Background: Lenalidomide is an immunomodulatory agent FDA approved for the treatment of multiple myeloma (MM) and relapsed/refractory mantle cell lymphoma (MCL). More recently, lenalidomide has been shown to enhance the activity of rituximab and has shown activity in first-line and refractory MCL, diffuse large B-Cell lymphoma (DLBCL), and indolent NHL, both as a single agent and in combination with rituximab. In patients with MM treated with lenalidomide, there is a well-documented risk of venous thromboembolism (VTE), cited as 0.7-0.8 events per 100 patient-cycles. However, this risk has never been well-defined in patients with B-cell NHL treated with lenalidomide and remains an important clinical question. We present preliminary findings of a systematic review and meta-analysis determining rates of venous thrombosis in patients with B-cell NHL treated with lenalidomide. We also present subgroup analyses comparing those patients treated with single-agent lenalidomide and those treated with lenalidomide in combination with chemotherapy or biologic agents. Aims: Study aims were to assess rates of VTE in B-cell NHL patients treated with lenalidomide Methods: We conducted a systematic literature search to identify studies in the MEDLINE (1946 to January 2017), EMBASE (1980 to January 2017), and Web of Science Core Collection using the OVID engine, and reviewed the footnotes of all included studies for additional potential studies. We reviewed all abstracts using a structured format and reviewed candidate articles to ensure that they included prospective enrollment of patients with newly diagnosed or relapsed/refractory B-cell NHL, treatment with lenalidomide, and that the number of cycles of lenalidomide given, as well as safety data including rates of VTE, were reported. Two reviewers independently assessed articles for eligibility and extracted data. A VTE event was prospectively defined as Grade II or greater venous thrombosis, and primary outcome defined as VTE events per patient cycle. This was subsequently converted to VTE events per 100 patient cycles for ease of use. The authors were contacted directly if the study would otherwise have met eligibility criteria but did not report all outcomes. Results: 1719 citations were identified in our initial literature search. Of these, 24 articles were deemed eligible. In total, our review identified 8270 cycles of lenalidomide received by patients with B-cell NHL with 65 VTE events, with an event rate of 0.78 per 100 patient-cycles, a rate very consistent with that of lenalidomide in the treatment of MM. In subgroup analyses, the rate of VTE in patients treated with single-agent lenalidomide was 1.56 per 100 patient/cycles versus 0.41 in patients treated with lenalidomide + biologics with a relative risk (RR) of 3.78 (95% CI: 2.04-7.02, p There was no significant difference in rates of VTE between patients treated with lenalidomide + chemotherapy or lenalidomide + biologics. In addition, there was no statistically significant difference between patients treated for DLBCL, MCL, or indolent lymphoma, although our analysis was inadequately powered to detect such a difference. Further risk stratification by disease and patient characteristics, as well as pooled estimates and forest plot creation, is ongoing and will be included in our final report. Conclusion: Rates of thrombosis in patients with B-cell lymphoma treated with lenalidomide are significantly greater in patients treated with single-agent lenalidomide vs those treated with lenalidomide in combination with either chemotherapy or biologic agents. This is consistent with the findings of a phase II trial by Leonard et al. comparing single-agent lenalidomide and lenalidomide + rituximab in follicular lymphoma that showed a differential risk of thrombosis, although statistical significance was not reached in that study. Rates of thrombosis in patients treated with lenalidomide for B-cell NHL are comparable to rates of VTE in MM. These data inform the consideration of strategies for monitoring and prophylaxis in specific clinical settings. Disclosures Leonard: Celgene: Consultancy, Research Funding; Roche: Consultancy. Ruan: Cell Medica: Research Funding; Pharmacyclics: Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Background Although indolent non-Hodgkin lymphomas (iNHLs) are responsive to initial therapy, patients have a relapsing and progressive disease course and most remain incurable with current treatments. Lenalidomide is an immunomodulatory agent that enhances rituximab-mediated antibody-dependent cellular cytotoxicity. In lymphoma cell lines, animal models, and in several phase II trials, combining lenalidomide and rituximab (R2) resulted in improved antitumor activity relative to either agent alone. However, the immunological mechanisms remain unclear. Here we provide updated results from a phase II trial investigating the clinical activity of R2 in previously untreated and relapsed/refractory (R/R) patients with iNHL. We also present an analysis of immunologic correlative data that may provide insight into the therapy's mechanism-of-action and may also predict response. Aims Study aims were to assess: the clinical activity of the R2 regimen in previously untreated and R/R iNHL patients and, assess the potential of serum cytokine levels to predict response. Methods Patients had previously untreated (n=15) or R/R (n=30) iNHL with measurable disease, and ECOG Performance Status ² 2. Lenalidomide (20 mg/day) was administered on days 1–21 of a 28-day cycle and continued until disease progression, rituximab 375 mg/m2 IV was administered on day 15 of cycle 1 and repeated weekly for a total of 4 doses. The primary clinical endpoint was overall response rate (ORR). Secondary endpoints included response duration (DR), overall survival, progression-free survival (PFS), and safety. The correlative serum cytokine samples were obtained from patients at baseline, D15 (prior to treatment with rituximab), D30 and D60. IL-1, 2, 6, 8, 10, 12, GM-CSF, IFN-γ, TNF-α , CXCL-10/IP-10 levels were measured at each time point using a Meso Scale Discovery multi-plex cytokine assay. The cytokine levels at each time point were then correlated with response using a two-sided T test. Results Of the 30 R/R patients, 22 had follicular lymphoma (FL), the median age was 60 years, median number of prior therapies was 3 (range 1–11), and 50% were refractory to rituximab. Of the 15 previously untreated patients, 12 had FL and the median age was 58. For the 27 evaluable R/R patients, the ORR was 74%, including 12 patients (44%) with a CR. At a median follow-up of 34 months, median PFS was 12.4 months, the median DR and time to next therapy (TTNT) were 15.4 and 37.4 months respectively with 7 remissions that are ongoing including three that have lasted more than 48 months. Of the 15 previously untreated patients 13 are evaluable for response; the ORR was 92% with 6 of 13 (42%) having a CR. At a median follow-up of 18 months the median PFS is 14.5 months; the median DR has not been reached. The correlative analyses showed that there was a significant increase in IFN-γ, GM-CSF, CXCL-10 and IL-2 at Day 15 with a 652, 494, 737, and 242% increase respectively above baseline which correlated with patients who had a CR (p < 0.05), Table. IL-1, 6, 8, 10, 12, and TNF-α were also measured, but did not predict CR at any time point. Phenotypic and functional analyses are ongoing. There was no significant difference in the percent increase in cytokine levels in previously untreated versus R/R patients. Conclusion The R2 regimen has considerable activity in patients with both untreated or R/R iNHL, particularly those with FL. A significant increase in the serum levels of IFN-γ, GM-CSF, IL-2 and CXCL-10/IP-10 after 2 weeks of lenalidomide alone correlates with achievement of CR. Disclosures: Off Label Use: The use of lenalidomide for the treatment of indolent NHL will be discussed which is not an FDA approved indication. Tuscano:Celgene: Honoraria, Research Funding.