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Key Points The NGS-MRD assay detected clonotypic DNA in 100% of CSF samples from patients who had lymphoma with parenchymal CNS involvement.Clonotypic DNA in CSF was present in 36% of newly diagnosed aggressive lymphomas and was associated with a 29% risk of CNS recurrence., Visual Abstract, The diagnosis of parenchymal central nervous system (CNS) invasion and prediction of risk for future CNS recurrence are major challenges in the management of aggressive lymphomas, and accurate biomarkers are needed to supplement clinical risk predictors. For this purpose, we studied the results of a next-generation sequencing (NGS)–based assay that detects tumor-derived DNA for clonotypic immunoglobulin gene rearrangements in the cerebrospinal fluid (CSF) of patients with lymphomas. Used as a diagnostic tool, the NGS-minimal residual disease (NGS-MRD) assay detected clonotypic DNA in 100% of CSF samples from 13 patients with known CNS involvement. They included 7 patients with parenchymal brain disease only, whose CSF tested negative by standard cytology and flow cytometry, and 6 historical DNA aliquots collected from patients at a median of 39 months before accession, which had failed to show clonal rearrangements using standard polymerase chain reaction. For risk prognostication, we prospectively collected CSF from 22 patients with newly diagnosed B-cell lymphomas at high clinical risk of CNS recurrence, of whom 8 (36%) had detectable clonotypic DNA in the CSF. Despite intrathecal prophylaxis, a positive assay of CSF was associated with a 29% cumulative risk of CNS recurrence within 12 months of diagnosis, in contrast with a 0% risk among patients with negative CSF (P = .045). These observations suggest that detection of clonotypic DNA can aid in the diagnosis of suspected parenchymal brain recurrence in aggressive lymphoma. Furthermore, the NGS-MRD assay may enhance clinical risk assessment for CNS recurrence among patients with newly diagnosed lymphomas and help select those who may benefit most from novel approaches to CNS-directed prophylaxis.

Most patients receiving CAR T-cell therapy (CAR-T) for aggressive B-cell lymphoma (B-NHL) will not experience a durable remission. There are several novel agents approved for the treatment relapsed, refractory aggressive B-NHL; however, it remains unclear how to sequence these therapies pre- and post-CAR-T (peri-CAR-T). We conducted a multicenter retrospective analysis for the purpose of describing peri-CAR-T practice patterns and survival predictors for patients receiving CD19-directed CAR-T. Patients (n=514) from thirteen centers treated with CAR-T for aggressive B-NHL between 2015-2021 were included. Clinical characteristics, CAR-T outcomes and treatment regimens administered pre- and post-CAR-T were collected. Survival curves were constructed using Kaplan Meier method. Multivariate Cox regression was used to determine the impact of variables on survival outcomes. For all patients receiving CAR-T, a greater number lines of therapy prior to CAR-T apheresis and receipt of bridging therapy were predictive of inferior progression-free survival (PFS) and overall survival (OS). From time of CAR-T infusion, median PFS and OS were 7.6 and 25.6 months (n=514). From time of progression post-CAR-T (n=254), median OS was 5.5 months. The median PFS of treatments given in the first-line post-CAR-T failure (n=167) was just 2.8 months. Patients with refractory disease at day 30 had inferior OS and were less likely to receive subsequent treatment(s) compared to other patients with CAR-T failure. AlloHCT for select patients at any time following CAR-T failure (n=16) led to durable responses in over half at one-year. These data provide a benchmark for future clinical trials in patients with progression post-CAR-T, an unmet clinical need.

Ollila et al address a challenging problem: can the risk for central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma be predicted better on a molecular basis? They report that most tumors with CNS recurrence have recognizable molecular features that fall into two categories: those that resemble primary CNS lymphoma and those that resemble high-grade lymphoma. These data suggest that it is time to revisit identification of patients who may benefit from CNS prophylaxis, while highlighting how challenging that is.

Prophylaxis is commonly used to prevent central nervous sy stem (CNS) relapse in diffuse large B-cell lymphoma (DLBCL), with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013 and 2019. Prophylaxis was administered intrathecally(IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7%) had CNS relapse after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4% vs 6.8%, P = .4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected vs observed CNS relapse rates were nearly identical (5.8% vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated, and reconsideration of prophylaxis strategies in DLBCL is of critical need.

This retrospective case series study examines immune response of adults with hematologic malignant disease who were vaccinated with 1 of 3 FDA-authorized COVID-19 vaccines between February and April of 2021.

Introduction: Treatment of older patients (pts) with PCNSL is challenging due to the prevalence of comorbidities, frailty, and complexities with delivery of chemotherapy (CT). The optimal induction CT and consolidation regimens for older PCNSL pts is unknown. Moreover, there are few large scale prognostication studies available, including analysis of geriatric assessments (GA). We analyzed detailed characteristics, treatment patterns and outcomes with prognostication across 17 academic centers. Methods: We conducted a large, RW retrospective study of newly diagnosed PCNSL pts (1/2008-1/2019) ages ≥ 60 years (yrs). Survival rates were estimated by Kaplan-Meier with differences assessed by log rank test. We detailed Cumulative Index Rating Scale-Geriatric (CIRS-G) scores & other GAs. Univariate associations were derived via Cox model with variables p Results: Among 491 initial cases, n=450 cases were verified for diagnosis & follow-up. Clinical features included: median age 71 yrs (60-88); male 47%; elevated LDH 30%; creatinine clearance 1 site). Cerebral involvement predominated in 75% with deep structure involvement in 20% & cerebellum in 5%. CSF involvement was documented in 13% of pts (unchecked in 26%). For GA at diagnosis, the median CIRS-G score was 6 (range 0-27) and impaired self-care activities of daily living (ADLs) were noted in 36%. Furthermore, geriatric syndrome (ie, dementia, delirium, depression, and/or falls) was present in 45% of pts. Induction therapy included CT in 91% of pts (of whom 82% had rituximab (Rtx)) and radiation therapy (RT) in 8%. The most common chemotherapy regimens were: high-dose methotrexate (HD MTX) or HD MTX with Rtx (MR) in 38%; HD MTX/procarbazine/vincristine (MPV) +/- Rtx 30%; HD MTX/temozolomide/Rtx (MTR) 22%; Rtx alone 2%; and HD MTX/cytarabine/thiotepa/Rtx (MATRIX) in 2%. Median MTX dosing for all pts was 3.5 g/m2 (range 1-8 g/m2), and by 3 most common regimens (all g/m2): MTR 5.1; MR 5.4; MPV 3.1 (P With 42 month median follow-up (1-125), 3-yr PFS & OS for all pts were 38% & 52%, respectively (Fig 1A/1B). On MVA, factors associated with inferior PFS were: advancing age (continuous HR 1.05, P Conclusions: Older pts with PCNSL have suboptimal outcomes, with 2/3 progressing in the first several years. GA is an important prognostic tool, and could be used to stratify pts in future investigations. In addition, use of Rtx, increasing MTX dose, and the MTR regimen were associated with improved outcomes. Disclosures Reddy: Genentech: Research Funding; Abbvie: Consultancy; KITE Pharma: Consultancy; Celgene: Consultancy; BMS: Consultancy, Research Funding. Bachanova:Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; FATE: Research Funding; BMS: Research Funding; Incyte: Research Funding. Bond:Seattle Genetics: Honoraria. Goldlust:COTA: Other; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel; Tocagen: Membership on an entity's Board of Directors or advisory committees, Other: travel; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding, Speakers Bureau; Boston Biomedical: Consultancy; Cortice Bio: Consultancy, Other: travel; WEX: Consultancy, Other: travel. Spurgeon:Beigene: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy; Bristol-Myers Squibb: Research Funding; Genentech: Research Funding; Gilead: Research Funding; Acerta: Research Funding; AstraZeneca: Research Funding; Genmab: Research Funding; VelosBio: Consultancy, Research Funding; Cardinal Health: Honoraria; Verastem: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Karmali:Takeda: Research Funding; Karyopharm: Honoraria; AstraZeneca: Speakers Bureau; BeiGene: Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Martin:Celgene: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Sandoz: Consultancy; I-MAB: Consultancy; Teneobio: Consultancy; Beigene: Consultancy; Cellectar: Consultancy; Incyte: Consultancy; Kite: Consultancy; Morphosys: Consultancy; Karyopharm: Consultancy, Research Funding; Regeneron: Consultancy. Smith:Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding; FortySeven: Research Funding; Karyopharm: Consultancy, Research Funding; Pharmacyclics: Research Funding; BMS: Consultancy; Janssen: Consultancy; Celgene: Consultancy, Research Funding; Acerta: Research Funding. Rubenstein:Kymera: Research Funding. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy; Pharmacyclics LLC: Consultancy; Roche Laboratories Inc: Consultancy; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding. Evens:Merck: Consultancy, Honoraria, Research Funding; Research To Practice: Honoraria, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria, Research Funding; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Mylteni: Consultancy, Honoraria.

Background Primary CNS lymphoma (PCNSL) is a rare non-Hodgkin lymphoma that is often associated with immunosuppressed states. The Epstein-Barr Virus (EBV) may play a role in tumor pathogenicity in some cases. The objective of this study was to examine the patient characteristics, tumor pathology, and survival outcomes associated with EBV tumor status in patients with PCNSL. Methods This was a retrospective subset analysis from 17 academic medical centers that included 439 patients of ages 60 years and above with PCNSL (David K et al. ASH 2020). The associations between EBV status and clinical or demographical variables were tested by Fisher's exact test, Wilcoxon rank-sum test, or CMH trend test. Kaplan-Meier estimator was used to estimate survival probability. Survival difference between groups was tested by log-rank test for statistical significance. Confidence interval of survival rate was calculated using Greenwood's formula. Results A total of 247 patients with available EBV status were included in this analysis. Median age was 71 (range 60-84) and 44.5% were male. Notably, none of the patients were HIV-positive. Twenty-five patients (10.1%) had EBV positive tumors as detected by EBER (EBV-encoded RNA) in-situ hybridization or LMP1 immunohistochemistry (IHC), 17 of which were solid organ transplant (SOT)-related post-transplant lymphoproliferative disorders (PTLD) and 8 of which were not PTLD. All EBV-positive non-PTLDs were diffuse large B-cell lymphoma. Three (15%) SOT-related PTLDs were EBV-negative. Patient characteristics analyzed included age at diagnosis, sex, ECOG performance status, history of prior or concurrent malignancies, history of solid organ transplant or autoimmune disease, history of allogeneic stem cell transplant, and immunosuppressive treatment. Of these, only a history of solid organ transplant or autoimmune disease (P Tumor characteristics analyzed included expression of C-MYC, BCL2, CD5, cell of origin markers (BCL6, MUM1, CD10), and CD20 through IHC, C-MYC and BCL2 translocation through FISH, histology, and involvement of brain parenchyma, CSF, spinal cord, and eyes. EBV-positive tumors were associated with low C-MYC (p=0.047) and BCL6 (p=0.0006) expression on immunohistochemistry, but not other factors. There were no significant differences in tumor characteristics between those with EBV-positive PTLD and EBV-positive non-PTLD. Among patients with PTLD, 30% (n=6) did not receive primary chemotherapy, and the most common treatment regimens were high-dose methotrexate (HD-MTX) with or without rituximab (n=5) and rituximab alone (n=3). However, there was no significant difference in outcomes among PTLD patients who received chemotherapy or those who did not. Among EBV-positive non-PTLD patients, only 12.5% (n=1) did not receive primary chemotherapy and the most common treatment regimens were methotrexate/rituximab/temozolomide (n=3) and HD-MTX with or without rituximab (n=3). There was no difference in overall or progression free survival between patients with EBV-positive and EBV-negative tumors, or in outcomes among SOT-related PTLD patients regardless of EBV status. However, patients with EBV-positive non-PTLD PCNSL had better overall survival compared to patients with EBV-positive PTLD and EBV-negative tumors (p=0.033, Figure). Conclusions In this large observational study of older patients with PCNSL, the incidence of EBV positive tumors was overall low and was most commonly associated with SOT-related PTLD. Mycophenolate mofetil was the most common immunosuppressive medication. In those without PTLD, there were no patient or tumor factors that were associated with EBV status. Unexpectedly, non-PTLD EBV-positive PCNSL had superior outcomes to EBV-positive PTLD and EBV-negative PCNSL. Future studies of EBV-positive non-PTLDs are warranted to further evaluate the potential impact of EBV latency and the immune response on the tumor microenvironment. Disclosures Reddy: BMS: Consultancy, Research Funding; Celgene: Consultancy; Abbvie: Consultancy; Genentech: Research Funding; KITE Pharma: Consultancy. Bachanova:Karyopharma: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; FATE: Research Funding; Incyte: Research Funding; Gamida Cell: Membership on an entity's Board of Directors or advisory committees, Research Funding. Bond:Seattle Genetics: Honoraria. Goldlust:Tocagen: Membership on an entity's Board of Directors or advisory committees, Other: travel; BMS: Membership on an entity's Board of Directors or advisory committees, Other: travel; WEX: Consultancy, Other: travel; Cortice Bio: Consultancy, Other: travel; Boston Biomedical: Consultancy; COTA: Other; Novocure: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: travel, Research Funding, Speakers Bureau. Spurgeon:Gilead: Research Funding; Genentech: Research Funding; Cardinal Health: Honoraria; Bristol-Myers Squibb: Research Funding; VelosBio: Consultancy, Research Funding; Acerta: Research Funding; Janssen: Consultancy, Research Funding; AstraZeneca: Research Funding; Pharmacyclics: Consultancy; Beigene: Research Funding; Verastem: Research Funding; Genmab: Research Funding. Epperla:Verastem Oncology: Speakers Bureau; Pharmacyclics: Honoraria. Karmali:AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; Takeda: Research Funding; BeiGene: Speakers Bureau; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Naik:Celgene: Other: advisory board; Sanofi: Other: advisory board. Smith:Janssen: Consultancy; Celgene: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; BMS: Consultancy; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding; Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding. Rubenstein:Kymera: Research Funding. Kahl:BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy; AbbVie: Consultancy; Genentech: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy. Evens:Abbvie: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; MorphoSys: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; Merck: Consultancy, Honoraria, Research Funding; Epizyme: Consultancy, Honoraria, Research Funding; Mylteni: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria, Research Funding. Martin:Kite: Consultancy; Morphosys: Consultancy; Regeneron: Consultancy; Incyte: Consultancy; Cellectar: Consultancy; Beigene: Consultancy; Bayer: Consultancy; I-MAB: Consultancy; Sandoz: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy, Research Funding; Teneobio: Consultancy; Celgene: Consultancy.

Cutaneous T-cell lymphoma (CTCL) poses unique treatment challenges, given its range of presentations and numerous systemic therapy options. These options often lack comparative evidence or are characterized by low response rates and short remission duration in relapsed/refractory disease. The approval of mogamulizumab, a humanized, glycoengineered IgG1κ monoclonal antibody targeting the chemokine receptor type 4 (CCR4) chemokine receptor, brings a novel tool into the spectrum of treatment options for advanced CTCL and adult T-cell leukemia/lymphoma (ATLL). CCR4 is expressed in almost all cases of ATLL, and in a majority of CTCLs, particularly when blood involvement is present. In a Phase III randomized trial, mogamulizumab was associated with 28% overall response rate among patients with relapsed CTCL, median progression-free survival of 7.7 months, and median duration of remission of 14.1 months. Responses are more frequent among patients with Sezary syndrome and within the blood compartment. Common adverse effects include rash and infusion reactions, which are usually low grade. Sentinel reports indicate that exposure to mogamulizumab may result in severe or refractory graft vs host disease after allogeneic bone marrow transplantation, highlighting the need for vigilance and expert management. Further research may establish incremental efficacy of combining mogamulizumab with cytotoxic or immunomodulatory agents in CTCL, ATLL, and possibly other lymphomas and even solid tumors.

Heparin-induced thrombocytopenia (HIT) remains a difficult clinical diagnosis, even with the under-utilized standardized scoring systems, like the '4T' score, to aid in clinical decision-making. Our quality improvement study sought to assess the use of '4T' score, improve the use of HIT antibody (HITA) testing and improvement management of possible HIT by implementing an in-line calculator with guidance within our electronic medical record (EMR) at our institution. We retrospectively reviewed patient charts between October 2017 and October 2018, assessing practices before and after implementation of the '4T' in-line calculator in April 2018. HITA were ordered inappropriately (for 4T4) in 141 (67%) of 210 instances (75 before and 66 after). We found no statistically significant difference in positive predictive value (PPV) or 4T documentation in provider notes after its implementation. We were able to identify problematic areas in HIT management, such as the ordering of non-heparin anticoagulants, and implement additional changes addressing these problems.

The search for research funding is challenging. This narrative describes how passions for research and bicycling led to a successful fundraising event.

Cancers of unknown primary (CUP) are histologically confirmed malignancies but for which further investigation cannot identify a primary site. Improvements in histopathologic modalities for diagnosis have lessened the frequency of CUPs to 3%–5% of all malignancies compared with historical estimates of 5%–10%. Despite this, there is an ongoing debate as to whether CUPs are malignancies where the primary is not found or if they are otherwise a fully separate entity. Improvements in molecular analysis holds promise for improved identification and treatment of CUPs with mixed preliminary results. Here we present a woman with CUP and metastases in her brain and lung. We performed genomic profiling to compare the molecular makeup of each site in order to establish treatment targets. Key Points Cancer of unknown primary remains a diagnostic and therapeutic challenge. Molecular analysis may provide improvements in diagnosis and novel treatment options. Different sites of metastatic disease have subtle variations in molecular profile. Sequencing of different sites may offer therapeutic options that are either already approved or available in clinical trial.

In aggressive lymphomas, discrepancies in survival reported from experimental and observational studies may reflect selective non-enrolment of high-risk patients in trials. We examined the association between time from diagnosis to chemotherapy and overall survival in diffuse large B-cell (DLBCL), Burkitt (BL), mantle cell (MCL) and peripheral T-cell lymphoma (PTCL), using National Cancer Data Base records of 130 549 patients treated in 2004-2014. Across the histologies, patients who started chemotherapy within 7 days of diagnosis had more often high International Prognostic Index (IPI) or advanced-stage disease. The discrepancy in 3-year survival between groups treated within 7 or >30 days from diagnosis ranged from 14% in BL to 30% in MCL. After adjusting for the IPI, time to treatment was significantly associated with shorter overall survival. Using the group treated >30 days from diagnosis as reference, patients treated within 7 days had a hazard ratio of 1·38 [95% confidence interval (CI), 1·28-1·48] in DLBCL, 1·42 (95% CI, 1·22-1·66) in BL, 2·23 (95% CI, 1·79-2·78) in MCL and 1·46 (95% CI, 1·18-1·81) in PTCL. Time from diagnosis to treatment may reflect high-risk features uncaptured by standard prognostic assessments. Clinical trials should accommodate patients who need urgent therapy to improve external validity and detect treatment effects in high-risk groups.

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

Background: Recent studies reported low rates of seroconversion response to COVID-19 vaccination in patients (pts) with hematologic malignancies (HMs). Vaccine choice among the 3 FDA-authorized products (BNT162b2/Pfizer-BioNTech, mRNA-1273/Moderna, or Ad26.COV2.S/J&J), prior therapy, and disease-specific factors may affect seroconversion. Addressing these factors may improve seroconversion rates and identify pts at risk of severe COVID-19 infection despite vaccination. Methods: We conducted a retrospective study of adults with HMs vaccinated in our center between 2/2021 and 7/2021, excluding pts with prior COVID-19 infection. Seroconversion was assessed by the qualitative SARS-CoV-2 Total Antibody Test (IgG/IgM against Receptor Binding Domain [RBD], Wondfo USA, Willowbrook, IL). A subset of samples was tested by the semi-quantitative Abbott AdviseDx SARS-CoV-2 IgG II assay (IgG against RBD). For univariate associations (UVA) we used Fisher's exact test for categorical variables, and fractional polynomial fits for continuous variables to examine non-linearity. Multivariable analysis (MVA) used a robust Poisson model reporting risk ratio (RR) with 95% confidence intervals (CI). Results: Among 239 eligible pts, median age was 70 (range, 28-94), and 112 (47%) were female. HMs included aggressive B-cell lymphomas (n=74, 31%), indolent B-cell lymphomas (n=52, 22%), chronic lymphocytic leukemia (CLL, n=30, 13%), other lymphomas (n-19, 8%), plasma cell neoplasms (n=43, 18%), and myeloid cancers (n=21, 9%); 140 pts (59%) received BNT162b2/Pfizer, 74 (31%) mRNA-1273/Moderna, and 23 (10%) Ad26.COV2.S/J&J vaccines (2 pts had undetermined vaccine type). HM was active in 100 pts (42%), whereas 108 (45%) pts were in remission after treatment, and 31 (13%) on watchful waiting (WW, never treated); 141 (59%) had a prior exposure to an anti-B-cell monoclonal antibody, and 22 (9%) prior stem cell transplantation. Overall, 99 pts (41%; binomial 95% CI, 35-48%) showed post-vaccination seroconversion upon testing at median 10 weeks from first vaccine. Seroconversion was significantly less frequent among pts with lymphomas compared with plasma cell or myeloid neoplasms (overall P=.020; Fig A). It was also less frequent after prior anti-B-cell antibody exposure (29% vs 59%, P In a MVA (Fig. J), vaccination with mRNA-1273 remained significantly associated with higher rate of seroconversion compared with BNT162b2 (RR=0.59; 95%CI, 0.44-0.79) or Ad26.COV2.S (RR=0.35; 95%CI, 0.16-0.77). Higher seroconversion rate was also associated with remission (RR=1.98; 95%CI, 1.42-2.76) or WW status (RR=1.72; 95%CI 1.02-2.89) compared with active disease, and higher lymphocyte count. Exposure to anti-B-cell antibodies remained associated with lack of seroconversion (RR=0.66; 95%CI, 0.44-0.99). Seroconversion was borderline less frequent in CLL than lymphomas, and higher with plasma cell or myeloid disorders. Results were similar in the subset of pts (n=191) with prior treatment, adjusting for time from last chemotherapy(data not shown). The anti-COVID-19 IgG titers on semiquantitative test (n=47, all after mRNA-based vaccines) were also lower in pts with active disease compared with those in remission (P=.065) or under WW (P=.028), and in those with prior anti-B-cell antibody (P=.0095). Conclusions: Pts with HMs demonstrate overall low rates of seroconversion after vaccination against COVID-19, particularly when they have active disease or are on/after B-cell depleting monoclonal antibody therapy. The mRNA vaccines (particularly mRNA-1273) appear to have elicited superior responses compared with the adenovirus-based product. Pts with active HMs or those within 2 years of last therapy should be particularly aware of the risk of infection despite vaccines and should be considered for strategies to enhance anti-COVID-19 immunity regardless of age. Figure 1 Figure 1. Disclosures Olszewski: TG Therapeutics: Research Funding; PrecisionBio: Research Funding; Celldex Therapeutics: Research Funding; Acrotech Pharma: Research Funding; Genentech, Inc.: Research Funding; Genmab: Research Funding.

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

Background: CNS invasion in aggressive lymphoma (including diffuse large B-cell [DLBCL], double-hit [DHL], Burkitt [BL] and plasmablastic lymphoma [PBL]) remains a major diagnostic and therapeutic challenge. Parenchymal CNS invasion requires a brain biopsy to diagnose, and conventional CSF evaluations lack sensitivity. Furthermore, determining which patients (pts) without CNS disease at diagnosis might be at high risk of future CNS relapse, and thus would most benefit from aggressive CNS prophylaxis, is difficult. Predictors that use clinical variables (e.g. the CNS-IPI) can select a high-risk group with ~10% risk of CNS relapse, but ~50% of events occur in low/intermediate-risk groups. We evaluated a novel CSF assay that detects clonotype-specific cell-free DNA (cfDNA) by next-generation sequencing (NGS) combined with multiplex PCR (Chang T et al, BMC Cancer 2020). This assay can identify minimal residual disease (MRD) in the plasma of pts with DLCBL and can predict systemic relapse (Roschewski et al, Lancet Oncol 2015). Methods: To examine the diagnostic sensitivity of the NGS-MRD assay in the CSF, we prospectively collected CSF from 6 pts with lymphomas who had known parenchymal or leptomeningeal CNS invasion. We also tested stored DNA from historical CSF samples of 8 pts with CNS lymphoma who tested negative by conventional IGH-PCR. We then enrolled 19 pts with newly diagnosed high-risk lymphomas without CNS invasion to examine the prognostic value of the NGS-MRD assay in the CSF collected at diagnosis. In the two-step assay, tumor-specific clonotype sequences were first identified from genomic DNA in primary tumor specimens using NGS of rearranged IGK, IGH (VJ or DJ), and IGL loci. Tumor-specific clonotypes were then selected for tracking in the CSF (split into acellular CSF fluid and cell pellet) and in paired plasma samples. The assay quantitated copy numbers of each tracked sequence per mL of acellular CSF or per 106 cells in the pellet, as well as tumor clonotype frequency (%) per all B-cells. Results: The NGS-MRD detected tumor-specific clonotype in 100% of CSF samples from pts with known CNS lymphoma (n=6; Fig A), including pts with isolated parenchymal-only CNS disease that was not detected by CSF cytology, flow cytometry, or IGH-PCR. For pts with CNS parenchymal disease, median cfDNA copy count in the CSF fluid was 2 /mL (range, 0.4-929) and median clonotype frequency was 9.0% (range, 0.03-68.9%). For pts with leptomeningeal disease, these values were 2233 /mL (1.2-5620) and 37% (1.7-98.4%), respectively (Fig. B). Furthermore, the NGS-MRD assay detected tumor clonotypes in DNA isolates from 6 historical CSF samples (collected in 2014-2018) of pts with known CNS disease, in which lymphoma was not detectable by conventional IGH-PCR (2 additional historical samples failed DNA quality check). Among 19 newly diagnosed pts with no known CNS invasion (median age 57, 42% women, median LDH 352 IU/L), 12 (63%) had DLBCL with high risk of CNS relapse by virtue of high CNS-IPI or epidural tumor, and 7 had other high-risk histologies (2 DHL, 2 BL, HIV+ PBL, and 2 lymphoblastic leukemias). The CSF NGS-MRD assay was positive for tumor-specific clonotype in 8 pts (42%). Median cfDNA copy count in the CSF fluid was 3 /mL (range, 0.9-15.6) and median clonotype frequency was 18.6% (range, 1.4-28.5%). We observed no significant correlation between the amount of cfDNA and number of red cells /mL of CSF (a measure of potential CSF contamination by blood during collection procedure; Fig. C) or between the amount of cfDNA in plasma and in CSF (Fig. D). With median follow-up of 11 months, no pts with negative baseline NGS-MRD assay in CSF relapsed, whereas 2 of 10 with a positive assay had a CNS relapse (12-month incidence, 29%; Fig. E), despite both pts having negative CNS imaging, CSF cytology, flow cytometry, and IGH-PCR at diagnosis. Conclusions: In this proof-of-concept study, the NGS-MRD CSF assay showed 100% sensitivity for diagnosing intraparenchymal CNS invasion in aggressive lymphomas that were not detected in the CSF using conventional methods. In a prospective cohort of newly diagnosed pts without baseline CNS invasion but at high clinical risk for CNS relapse, the assay identified lymphoma-derived cfDNA in 42% of cases. The 100% sensitivity and 100% negative predictive value of the assay for subsequent CNS relapse warrants further prospective evaluation as a potential tool for personalizing CNS-directed prophylaxis. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech, Inc.: Research Funding. Mullins:Adaptive Biotechnologies: Current Employment, Other: shareholder.

Introduction Relapses involving the central nervous system (CNSrel) occur in ~5% of patients (pts) with aggressive non-Hodgkin lymphoma (NHL) in the rituximab era (Ghose et al, Clin LML 2015) with rates exceeding 10% in high risk groups (Villa et al, Ann Onc 2010; Schmitz et al, JCO 2016). CNSrel are generally thought to occur in the first 4-6 months from diagnosis. Prophylaxis (PPx) administration, route, and frequency are not standardized, and the impact of PPx on CNSrel risk is incompletely understood. Methods We performed a multicenter retrospective analysis of pts with aggressive NHL (excluding Burkitt's) without known CNS involvement (inv) who received single-route CNS PPx with during front-line (FL) anthracycline-based therapy (tx) from 2013-2019 across 19 US academic institutions. Recipients of chemotherapy for prior CLL or indolent NHL were ineligible. Method, frequency, and outcomes of CNS PPx administration were evaluated, with significance assessed by various statistical methods via two-tailed P Results 1030 patients were identified who met eligibility criteria. Clinical features included median age 61 years (yrs; range 16-86), 40.9% female, ECOG PS 0-1 82.8%, elevated LDH 65.3%, >1 extranodal (EN) site 42.3%, stage 3/4 disease 79.2%. NHL histologies included diffuse large B cell (DLBCL; 75.2%), high grade B cell (16.3%), transformed follicular lymphoma (5.6%) and 3% other; among pts with DLBCL, 46.4% had germinal center (GCB) subtype and 40.5% had non-GCB. 26.2% (n=210) of evaluable pts had double-hit lymphoma (DHL). Among pts with known HIV status, 7.2% (n=65) were HIV-positive. 85.7% had EN inv; common sites included bone (35.4%), liver (13.7%), gastrointestinal (12.7%), lung (11.8%), and marrow (11.5%). FL regimens included RCHOP (45.9%), REPOCH (46.5% total; 79.1% with dose-adjustment), 7.6% other. PPx was given intravenously (IV) in 20% of pts vs 77% intrathecally (IT), over a median 2.9 vs 4.1 doses respectively; see Table 1 for factors associated with PPx route. PPx was generally well-tolerated, with 10.7% PPx-related toxicity reported; see Table 2. CNSrel after FL tx was 5.3% overall without significant difference by PPx route (7% IV vs 5% IT, p=0.178). This lack of difference between PPx routes was observed in all subgroup analyses performed, including by: age, stage, histology, number of EN sites, individual EN site inv, elevated LDH, CNS-IPI, DHL status, HIV status, FL regimen, number of PPx doses. There was no significant difference in anatomic site(s) of CNSrel by PPx route. CNSrel occurred bimodally: 24% by end of FL tx vs 76% delayed (average 2.3 yrs, range 0.4-5.2 yrs). Rates of CNSrel were significantly higher with CNS-IPI high vs moderate risk (8.3 vs 4.1%, p=0.03; Figure 1), elevated LDH (6.9 vs 2.6%, p=0.007) and multiple inv EN sites (7.5% for 2+ vs 4% for 0-1, p=0.01); each additional EN site further increased risk (p=0.03 for trend; Figure 2). Increased CNSrel was noted in pts with testis (13.7 vs 5%, p=0.004) and liver inv (11.1 vs 4.6%, p=0.002) vs those without inv at respective sites. No significant difference was noted at other EN sites, including renal/adrenal (4.8 vs 5.6%, p=0.71), marrow (8.9 vs 5.1%, p=0.09), or lung (8.6 vs 5.1%, p=0.12). All EN site-CNSrel correlations were unchanged when accounting for PPx route. With median follow-up of 2.3 yrs, median PFS and OS for the overall group have not been reached; 2-yr PFS and OS were 70 and 85% respectively. PFS and OS were each predicted by CNS-IPI (p Conclusion Use of single-route ppx demonstrated similar CNSrel vs established outcomes for this population in the rituximab era, with no difference by PPx route. CNSrel remains a rare but devastating complication, with greater risk even after single-route PPx in those with higher EN burden and inv of key EN sites. Disclosures Kahl: Acerta: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy. Spinner:Notable Labs: Honoraria. Advani:Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding; Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy. Voorhees:AstraZeneca: Research Funding. Grover:Genentech: Research Funding; Tessa: Consultancy. Huntington:Genentech: Consultancy; Novartis: Consultancy; Celgene: Consultancy, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Honoraria; Bayer: Consultancy, Honoraria; DTRM: Research Funding; Astrazeneca: Honoraria; AbbVie: Consultancy. Spurgeon:Beigene: Research Funding; Gilead: Research Funding; Genentech: Research Funding; Bristol-Myers Squibb: Research Funding; Pharmacyclics: Consultancy; Janssen: Consultancy, Research Funding; VelosBio: Consultancy, Research Funding; Cardinal Health: Honoraria; Verastem: Research Funding; Genmab: Research Funding; AstraZeneca: Research Funding; Acerta: Research Funding. Olszewski:Spectrum Pharmaceuticals: Research Funding; Genentech, Inc.: Research Funding; Adaptive Biotechnologies: Research Funding; TG Therapeutics: Research Funding. Landsburg:Seattle Genetics: Speakers Bureau; 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; Takeda: Research Funding; Triphase: Research Funding. Kamdar:Roche: Research Funding. Caimi:Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding; Verastem: Other: Advisory Board; Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Celgene: Speakers Bureau. Karmali:Takeda: Research Funding; BeiGene: Speakers Bureau; AstraZeneca: Speakers Bureau; Karyopharm: Honoraria; Gilead/Kite: Honoraria, Other, Research Funding, Speakers Bureau; BMS/Celgene/Juno: Honoraria, Other, Research Funding, Speakers Bureau. Stephens:Pharmacyclics: Consultancy; Innate: Consultancy; Verastem: Research Funding; Karyopharm: Consultancy, Research Funding; Janssen: Consultancy; Gilead: Research Funding; Arqule: Research Funding; Juno: Research Funding; MingSight: Research Funding; Acerta: Research Funding; Beigene: Consultancy. Smith:Genentech/Roche: Consultancy, Other: Support of parent study and funding of editorial support, Research Funding; TG Therapeutics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy; BMS: Consultancy; Karyopharm: Consultancy, Research Funding; FortySeven: Research Funding; Pharmacyclics: Research Funding; Acerta: Research Funding. Khan:Celgene: Research Funding; Pharmacyclics: Honoraria; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Honoraria. Cohen:Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding; Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy. Portell:Bayer: Consultancy; Xencor: Research Funding; BeiGene: Consultancy, Research Funding; Infinity: Research Funding; Roche/Genentech: Consultancy, Research Funding; Amgen: Consultancy; Janssen: Consultancy; Pharmacyclics: Consultancy; AbbVie: Research Funding; TG Therapeutics: Research Funding; Kite: Consultancy, Research Funding; Acerta/AstraZeneca: Research Funding.

Using data from the National Cancer Data Base, 2010–2015, we examined characteristics and outcomes of T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL, N=622) relative to unspecified diffuse large B-cell lymphoma (DLBCL-NOS, N=91,588) and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL, N=2,240). Socio-demographic characteristics of patients with THRLBCL resembled more NLPHL than DLBCL-NOS. Five-year overall survival in THRLBCL was 66% (95%CI, 60–71%). Adjusting for clinical and socio-economic covariates, THRLBCL was associated with better survival than DLBCL-NOS (adjusted hazard ratio, 0.80; 95%CI, 0.67–0.94). This association was similar in academic and community hospitals and consistent in a model stratified by the revised International Prognostic Index. Prognostic factors in THRLBCL included age, comorbidity index, and extranodal primary site, but not stage. Adjusted odds of prior NLPHL were 18.2 higher for THRLBCL (95% confidence interval [CI], 7.2–45.7) than DLBCL-NOS. These large-scale epidemiologic data support the relationship between THRLBCL and NLPHL, and suggest improved prognosis with modern rituximab-based immunochemotherapy.

[Figure][1] These images were captured from the peripheral blood smear of a 56-year-old patient with Child-Pugh C alcoholic cirrhosis, ongoing alcohol abuse, and chronic macrocytic anemia with baseline hemoglobin 7 to 8 g/dL. Laboratory work suggested a hemolytic process, with a mixed

Clinicopathologic features are poor at predicting the risk of CNS relapse after initial treatment in DLBCL, or at guiding CNS prophylactic therapy. However, mutational profiles may correlate with primary extranodal disease, including primary CNS lymphoma (Ollila T, Curr Treat Options Oncol 2018). We hypothesized that specific genomic profiles in DLBCL would also correlate with CNS relapse or with systemic-only (non-CNS) relapse. We examined 26 DLBCLs with CNS-only (n=13) or systemic-only relapse (n=13) using a 592 gene next-generation sequencing (NGS) assay (Illumina NextSeq, average coverage depth >750x; Caris Life Sciences) performed on formalin-fixed tissue. We also determined cell of origin (COO) by IHC; MYC/BCL2/BCL6 rearrangements by FISH, and karyotype by cytogenetics. We used the novel LymphGen genomic DLBCL classifier (Wright GW, Cancer Cell 2020) to group tumors into the MCD, ST2, EZB, BN2, and A53 subtypes. We then constructed a simplified hierarchical classifier (hc) usable with common clinical multigene NGS panels to identify 3 relevant subtypes: (1) hc-MCD subtype (defined as MYD88L265P or >2 mutations in CD79B, PIM1, ETV6, BTG1, TBL1XR1, or PRDM1), (2) hc-TP53 subtype characterized by TP53 mutations +/- complex karyotype, and (3) hc-GCB subtype with ≥2 mutations in BCL2, CREBBP, EZH2, KMT2D, TNFRSF14, GNA13, MEF2B, or PTEN. We compared prevalence of these subtypes between our groups and a reference dataset of unselected DLBCL tumors combining data from Chapuy (Nat Medicine 2018; n=135; dbGaP phs000450) and Reddy (Cell 2018; n=1001; EGA: EGAS00001002606). There was no difference between DLBCL with CNS-only or systemic recurrence in any standard clinicopathologic characteristics, including COO, FISH, or karyotype. The LymphGen MCD subtype was significantly more frequent in DLBCL with CNS-only relapse compared with reference datasets (39% vs. 7%, P=.001), but not in DLBCL with systemic relapse (P=.05). Conversely, the ST2 subtype was more frequent in DLBCL with systemic relapse (23% vs. 3%, P=.010) and completely absent in CNS relapse (0%). The A53 or EZB subtypes did not significantly differ between any groups. The simplified NGS classifier identified 96% of LymphGen MCD cases and 100% of A53 cases. The hc-MCD subtype was also significantly associated with CNS relapse (46% vs. 18%, P=.018) but not with systemic relapse (P=.26), whereas hc-TP53 and hc-GCB subtypes did not differ from the reference dataset (P=.15 and P=.70, respectively). Our data demonstrate that the MCD DLBCL subtype is specifically associated with the risk of CNS relapse. Full molecular classification of DLBCL is not yet incorporated into current clinical practice, as it requires integration of single nucleotide, structural chromosomal variants, and copy alterations. We show that a meaningful molecular predictor signature for the MCD subtype can be obtained from clinically validated multigene NGS assays. If validated, this signature may prove useful for selecting patients for CNS-directed prophylactic therapy. Citation Format: Thomas A. Ollila, Habibe Kurt, Jozal Waroich, John Vatkevich, Ashlee Sturtevant, Nimesh Patel, Diana O. Treaba, Patrycja M. Dubielecka, Adam J. Olszewski. Genomic subtypes correlate with the risk of central nervous system (CNS) recurrence in diffuse large B-cell lymphoma (DLBCL) [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr PO-38.

Management of primary testicular lymphoma (PTL), a rare disease accounting for less than 2% of non-Hodgkin lymphomas, poses unique challenges [1]. PTL arises from an immune-privileged anatomic site...

Diffuse large B-cell lymphoma (DLBCL) arises from extranodal organs in about 30% of cases. Its prognosis and risk of recurrence in the central nervous system (CNS) vary according to the primary site of origin. Recent studies begin to clarify these differences using molecular classification. Testicular, breast, and uterine DLBCL (as well as possibly primary cutaneous DLBCL, leg-type) share a high prevalence of the non-germinal center B-cell (non-GCB) phenotype and the MYD88/CD79B-mutated (MCD) genotype. These biologic features, which resemble primary CNS lymphoma, may underlie their stage-independent propensity for CNS involvement. Management of these lymphomas should involve CNS prophylaxis, preferably using systemic high-dose methotrexate to prevent intraparenchymal recurrence. Involvement of the kidneys, adrenal glands, ovary, bone marrow, lung, or pleura usually indicates disseminated disease, conferring worse prognosis. Involvement of these sites is often associated with high CNS-International Prognostic Index (IPI), concurrent MYC and BCL2 or BCL6 rearrangements, or intravascular lymphoma—risk factors warranting CNS prophylaxis. In contrast, craniofacial, thyroid, localized bone, or gastric lymphomas have a variable prevalence of the non-GCB phenotype and lack MYD88 mutations. Their outcomes with standard immunochemotherapy are excellent, and the risk of CNS recurrence is low. We recommend individualized consideration of CNS prophylaxis based on the CNS-IPI score and anatomical proximity in cases of epidural, orbital, or skull involvement. Rituximab-containing immunochemotherapy is a standard approach for all extranodal DLBCLs. Surgery is no longer required for any primary site, but routine consolidative radiation therapy is recommended for testicular lymphoma. Radiation therapy also appears to be associated with better progression-free survival in primary bone DLBCL. Future studies should better distinguish primary from secondary sites of extranodal involvement, and investigate the association of newly identified genotypes with the risk of CNS or systemic recurrence.

Background: Allogeneic stem cell transplant (allo-SCT) is a cornerstone in the treatment of Acute Myeloid Leukemia (AML) exerting much of its therapeutic efficacy through the graft-versus-leukemia effect. The administration of immunoregulatory cells via engrafted donor lymphocytes is essential to the eradication of residual malignancy and long-term survival. Many patients, however, either do not have an allo-SCT donor or cannot withstand the toxicity of allo-SCT. Previous studies have shown durable responses in AML patients following donor lymphocyte infusions in the absence of engraftment in both the frontline and relapsed setting (Dey et al, BJH 2005, Colvin et al, BBMT 2009, Ai et al, Blood 2010). In this clinical trial we propose a role for donor leukocyte infusions (DLI) in the absence of engraftment. Without the need for engraftment patients will not need to receive high dose chemotherapy or radiation and the toxicities that accompany these therapies. Instead, allogeneic donor cells are infused into patient with relapsed/refractory (R/R) AML to serve as a potent immune stimulator. Prior to DLI, patients will receive fractionated dosing of gemtuzumab ozogamicin (GO). GO is an anti-CD-33 antibody drug conjugate approved in combination with induction therapy for de novo AML and in R/R disease. Patients who demonstrate a CR or CRi to therapy will go on to have up to 2 additional GO + DLI treatments. Bone marrow and blood samples will be obtained from patients before, during, and after treatment to determine immune effector cells (both donor and patient), cytokine release profiles, and extracellular vesicle components. Study Design and Methods: Our study, BrUOG 345 [NCT03374332], evaluates the combination of fractionated GO with non-engraftment DLI in the treatment of patients with R/R AML. Adults patients 18 years of age and older with histologically confirmed R/R AML who have had recurrence or progression after at least 1 prior standard treatment are eligible. Enrollees must have no active systemic infections and have adequate lung, liver, cardiac, and renal function with an ECOG PS 0-1. Fractionated GO 6-9mg/m2 will be administered on days 1, 4, and 7 followed by infusion of 1-2x108 CD3 cells/kg from a 0-3/6 HLA mismatched related donor cell. Patients that are in CR or CRi can receive up to 2 additional treatments with GO+DLI (Figure 1). The primary objective of the phase 1 portion is to determine the maximum tolerated dose (MTD) of DLI in combination with GO while the primary objective of Phase 2 portion is to assess the response rate after one cycle of fractionated GO followed by non-engraftment DLI in patients with relapsed/refractory AML. The study will initially utilize a 3+3 design in Phase 1 to determine if 1-2x108 CD3 cells/kg can be safely administered with GO. This study will target a response rate of 57% considered to be interesting enough to warrant further study in a randomized setting. With this hypothesis in mind, the phase 2 portion of the study will use Simon's two-stage design. The null hypothesis that the true response rate (CR and CRi) is only 29% will be tested against a one-sided alternative. In the first stage, 9 subjects will be accrued. Patients treated at MTD in the Phase 1 portion of the study will be included in this cohort. If there are 3 or fewer responses in these 9 patients, the study will be stopped for futility. Otherwise, 6 additional subjects will be accrued for a total of 15. The null hypothesis will be rejected if 7 or more responses are observed in 15 patients. This design yields a type I error rate of 0.1 and power of 80% if the true response rate is 57%. A continuous assessment of toxicity will be utilized for the Phase 2 portion of this study. Sequential boundaries will be used to monitor dose-limiting toxicity rate for patients after the initial MTD is determined. Accrual will be halted if excessive numbers of dose-limiting toxicities are seen. The primary outcome of the Phase 2 portion is the CR/CRi rate following GO and non-engraftment DLI. Secondary outcomes will include survival, both progression-free (PFS) and overall (OS) until two years post treatment, and dose limiting toxicities until 16 weeks post-infusion. Additional lab correlative studies will be performed including CD33 expression before, during, and after GO infusion and T-cell activation markers, antigen presenting cell/macrophage amounts, cytokine release profiles, and extracellular vesicle measurements (Figure 1). Disclosures Olszewski: TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech: Research Funding. Reagan:Pfizer: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees.

Background: CNS involvement in aggressive lymphomas (including diffuse large B-cell lymphoma, DLBCL) is associated with poor survival, requiring aggressive CNS-directed therapy to avert dismal outcomes. Early detection of clinically occult CNS invasion is thus critical. Clinical risk factors have low specificity to select patients for CNS prophylaxis, and routine evaluations of the CSF by cytology or flow cytometry have low sensitivity (Doolittle et al., Blood 2008). Moreover, most CNS recurrences of DLBCL occur in the brain parenchyma and remain occult on CSF examination. There is a high unmet need for an accurate method to identify subclinical CNS invasion and help non-invasively diagnose parenchymal disease. Clonotype-specific cell-free DNA (cfDNA) can be detected in the plasma of patients with DLBCL using high-throughput sequencing (HTS) combined with multiplex PCR, and cfDNA reappearance after therapy precedes systemic recurrence (Roschewski et al., Lancet Oncol. 2015). However, clonotypic cfDNA has not been systematically evaluated in the CSF compartment. Because of the blood-brain barrier that isolates CSF from plasma, clonotypic cfDNA might hold promise as a sensitive method of CNS lymphoma detection. Therefore, we sought to evaluate the ability of HTS-based cfDNA assay in the CSF to detect CNS invasion. Methods: We collected CSF samples from consenting patients with aggressive lymphomas who either had clinically overt CNS disease, or who were newly diagnosed and without evident CNS disease, but at high clinical risk. Genomic DNA from primary tumors (formalin-fixed paraffin-embedded [FFPE] tissue; Fig. A) was analyzed for tumor-specific clonotype using a quantitative HTS of rearranged IGK, IGH (VJ or DJ), or IGL loci, as previously described (Carlson CS et al., Nat Commun. 2013). Clonotypes in each primary tumor were selected for subsequent tracking in the CSF based on frequency relative to other B cells and all nucleated cells, as well as distribution. HTS of B-cell receptor (BCR) was performed on 5 mL CSF centrifuged at 1000x for 5 min at 4°C and separated into acellular portion for cfDNA, and a cell pellet suspension. Clonotype copy numbers are expressed per mL for acellular fluid, and per 106 cells for cell pellets. Results: The HTS assay identified median 3 (range, 2-6) dominant immunoglobulin sequences in each primary FFPE lymphoma sample (N=9), with median dominant clonotype frequency 39.0% (range, 22.0-97.9%) and median copy count 753,618 per 106 cells (range 47,455-1,407,748). In the CSF, the HTS/ASO-PCR assay detected the dominant clonotype in 5 out of 9 samples (Table), including all cases (N=3) with overt CNS disease, and 2 without known CNS invasion (sensitivity=100% and specificity=67% for clinically overt disease). Of note, the cfDNA assay detected tumor-specific clonotype in the CSF of a patient with primary CNS lymphoma (PCNSL) who had negative CSF evaluations by flow cytometry and IGH PCR. In the cell-free CSF, median detectable cfDNA clonotype copy count was 1,649/mL (range, 2-5,620), and in the CSF cell suspension it was 389,558 per 106 cells (range, 10,373-1,181,171). Copy counts were significantly higher (P=.004 for cfDNA in CSF fluid, P=.004 for cell suspension) in patients with overt leptomeningeal involvement (positive CSF cytology) than those with parenchymal or clinically occult disease (Fig. B). The 2 cases with positive CSF cfDNA but negative clinical staging and CSF cytology were notable for high risk of CNS dissemination due to ruptured epidural tumor with spinal cord compression, or double-hit histology (MYC-IGH and BCL2-IGH rearrangements) with extensive extranodal invasion of kidneys, pleura, and liver. Both patients were recommended CNS-directed prophylaxis based on clinical risk. Conclusions: HTS of BCR loci in the CSF of patients with aggressive lymphomas can identify intraparenchymal CNS or leptomeningeal disease with high sensitivity. More importantly, it can detect intraparenchymal involvement not identifiable using traditional means of CSF analysis (flow cytometry, standard IGH PCR). Detection of cfDNA in CSF of some high-risk patients without overt CNS disease will be further explored in a larger sample. It suggests that pre-treatment HTS of BCR loci could be prospectively tested to predict the risk of CNS recurrence, with a future potential to enable more sensitive and specific selection of patients for CNS prophylaxis therapy. Disclosures Olszewski: Spectrum Pharmaceuticals: Research Funding; TG Therapeutics: Research Funding; Adaptive Biotechnologies: Research Funding; Genentech: Research Funding. Reagan:Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding. Mullins:Adaptive Biotechnologies: Employment.

Background: Ibritumomab tiuxetan (IbT) is a radioimmunoconjugate linking rituximab with 90Y isotope. IbT is approved for treatment of relapsed/refractory indolent B-cell lymphomas, or for consolidation after chemotherapy in follicular lymphoma (FL), yet its use has been limited by concern about treatment-related myeloid neoplasms (tMDS/AML: acute myeloid leukemia and myelodysplastic syndrome). The risk of tMDS/AML may differ among older patients who experience significant competing mortality. Our objective was to use population-based data to examine real-life patterns of use of IbT, and associated incidence of tMDS/AML among older patients with B-cell lymphomas. Methods: From the SEER-Medicare registry, which covers about 28% of the United States population, we selected fee-for-service Medicare beneficiaries >60 years [y] old, with B-cell lymphomas diagnosed between 2001-2015, who received systemic therapy. We identified the use of IbT, purine analogues, alkylating agents, and rituximab. We defined tMDS/AML as myeloid neoplasms diagnosed >2 months from the start of first-line therapy for lymphoma, or use of tMDS/AML-directed chemotherapy. We estimated incidence rate and incidence rate ratio (IRR) for tMDS/AML after IbT exposure using a time-split survival model. By matching IbT recipients with non-recipients according to age, sex, lymphoma histology, and observation time from the start of lymphoma therapy, we compared the cumulative incidence function of tMDS/AML using competing risk models stratified by matched groups. We fitted the univariate model, and model adjusting for prior exposure to purine analogues or alkylators. Results: Among 43,945 Medicare beneficiaries (median age of 76 y) treated for diffuse large B-cell (DLBCL, 48%), FL (22%), mantle cell (7%), marginal zone (10%), or unspecified B-cell lymphoma (14%), 428 (1%) received IbT, at median 18 months from first-line chemotherapy (interquartile range [IQR], 8-34). IbT was used most frequently in FL (50%) and DLBCL (23%), and was applied as first-line treatment in 30 patients (7%). With median follow-up of 8.5 y, 618 cases of tMDS/AML were recorded (15 among IbT recipients, and 603 among non-recipients). Median latency from the start of first-line lymphoma therapy to tMDS/AML was 38 months (IQR, 18-65). The cumulative incidence rate of tMDS/AML after IbT exposure was 2.8% at 5y (95%CI, 1.2-4.4) and 3.9% at 10y (95%CI, 1.8-6.0). No tMDS/AML was observed among patients who received IbT as first-line treatment, before chemotherapy exposure. In the time-split survival analysis, the incidence of tMDS/AML was 0.39 per 100 person-years (95%CI, 0.18-0.60) without IbT exposure, and 1.02 (95%CI, 0.56-1.71) after IbT exposure, with an IRR of 3.22 (95%CI, 1.80-5.26). There was no significant heterogeneity in the IRR by lymphoma histology (Mantel-Haenszel test of homogeneity, P=.47). In the matched analysis (Fig A), the cumulative incidence of tMDS/AML was significantly higher among patients receiving IbT (subhazard ratio [SHR], 2.16; 95%CI, 1.32-3.55). However, the association became non-significant after adjusting for prior exposure to myelotoxic chemotherapy (SHR, 1.58; 95%CI, 0.93-2.68). Prior exposures to a purine analogue (SHR 3.83; 95%CI, 2.96-4.95) or an alkylator (SHR, 1.39; 95%CI, 1.11-1.75) remained significantly associated with increased risk of tMDS/AML. Median overall survival after tMDS/AML diagnosis was 0.6y (95%CI, 0.5-0.7), and it did not differ according to IbT exposure status (P=.62; Fig B). Conclusions: The cumulative incidence of secondary tMDS/AML in this large population-based cohort is similar to reports from clinical trials (Czuczman et al. J Clin Oncol. 2007), and lower than in some prior observational series (Epperla N, et al., Br J Haematol 2017). Our results support the use of IbT for older patients with indolent lymphomas. Exposure to IbT was associated with an increased incidence of tMDS/AML, but it was no longer significant after adjustment for prior exposure to myelotoxic chemotherapy. This result suggests that the increased incidence of tMDS/AML is a cumulative effect of IbT with other myelotoxic agents. Caution should thus be exercised when using IbT after exposure to chemotherapy. The fact that no tMDS/AML were observed in patients receiving IbT as first line therapy suggests that earlier use of IbT may be preferable from the point of view of the tMDS/AML risk. Disclosures Olszewski: Genentech: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding; Adaptive Biotechnologies: Research Funding. OffLabel Disclosure: Ibritumumab tiuxetan - for treatment of any B-cell lymphoma in any setting

Background: Nodal and splenic marginal zone lymphomas (NMZL/SMZL) are rare, usually disseminated, and typically diagnosed in older patients (median age 69 years). They are increasingly treated with first-line bendamustine/rituximab (BR) based on phase 3 trials that pooled various B-cell indolent lymphomas (Rummel et al., Lancet 2013). However, NMZL and SMZL have unique biology and clinical course. In this context, without histology-specific evidence, the risk/benefit ratio of BR over single-agent rituximab (R) in SMZL/NMZL is uncertain. Our objective was to examine treatment patterns, and to compare survival and toxicity outcomes of BR versus (vs.) R, using population-based data. Methods: Using Medicare claims linked to cancer registry data covering ~34% of the US population (SEER-Medicare), we identified all SMZL/NMZL patients age ≥65 who received 1st line R or BR between 2009-2016 (after approval of bendamustine) and had complete Medicare records. We used a propensity score to generate "pseudo-randomized" cohorts (pooled, including NMZL and SMZL, and histology -specific for NMZL and SMZL), balancing patient and disease characteristics: age, sex, race, comorbidities (including kidney disease and heart failure), performance status, lymphoma stage, B symptoms, prior splenectomy, anemia (including autoimmune hemolytic), transfusions, hospitalizations, and time from diagnosis to therapy. In the balanced pseudo-randomized cohorts, we compared event-free survival (EFS, defined as 2nd line chemotherapy, splenectomy, hospice, or death) and overall survival (OS) from the start of therapy, risk of major toxicities (hospitalization, transfusions), and inflation-adjusted Medicare spending. Outcome models report hazard ratios (HR) or risk ratios (RR) with 95% confidence intervals (95%CI), and marginal means for costs. Results: Among 1,315 patients (901 with NMZL and 414 with SMZL), median age was 78 years [y], and there were 52% women. About half of patients received first-line R every year, but the proportion treated with BR increased from 4% in 2009 to 23% in 2016 (Fig. A). In the pooled NMZL/SMZL cohort of patients receiving BR or R (N=926), those treated with BR were on average younger, more likely to have NMZL, stage 2-4 lymphoma, and B symptoms. With median follow-up 3.8 y, median EFS was 4.3 y (95%CI, 3.5-5.1) for NMZL, and 4.5 y (95%CI, 3.8-6.5) for SMZL. Median OS was 5.7 y (95%CI, 4.9-6.7) in NMZL, and 5.2 y (95%CI, 4.4-6.7) in SMZL. After balancing the confounders, there was no significant difference in either EFS (HR for BR, 1.00; 95%CI, 0.76-1.30, P=.98) or OS (HR, 1.14; 95%CI, 0.85-1.53; P=.38). Toxicities were higher with BR, including hospitalizations (RR, 1.46; 95%CI, 1.14-1.87; P=.003) and transfusions (RR, 2.35; 95%CI, 1.55-3.56; P50% of BR patients would need to have an unobserved risk factor doubling their mortality to explain lack of OS benefit. We then fitted separate propensity score models in NMZL and SMZL. In the comparative NMZL cohort (N=609), 434 patients (71%) received R, and 175 (29%) received BR. We observed no significant difference in either EFS (HR for BR, 0.93; 95%CI, 0.68-1.29; P=.67; Fig. B) or OS (HR, 1.16; 95%CI, 0.82-1.63; P=.40), whereas toxicities and costs were consistently higher with BR. In the comparative SMZL cohort (N=317), 272 patients (86%) received R, and 45 (14%) received BR. Again, there was no significant difference in EFS (HR for BR, 0.84; 95%CI, 0.46-1.53; P=.56; Fig. C) or OS (HR, 0.92; 95%CI, 0.46-1.83; P=.80). Results for toxicities and costs were again consistent. Conclusions: Among older patients with SMZL and NMZL treated in the community, the use of first-line BR is increasing. However, in this large observational study, BR was not associated with any significant EFS or OS benefit over single-agent R, while it increased toxicities and costs. Without a formal randomized histology-specific study, single-agent R may offer a favorable risk/benefit ratio as a first-line therapy for older NMZL/SMZL patients at average risk, reserving BR for those with compelling clinical circumstances. Our results may however be affected by bias due to unobserved confounding, and may not be applicable to younger patients. Disclosures Olszewski: Adaptive Biotechnologies: Research Funding; Genentech: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Research Funding. OffLabel Disclosure: Rituximab with bendamustine is off-label for marginal zone lymphoma

Inferior vena cava (IVC) filter is a medical device placed in patients with proven pulmonary embolism or those with risk of embolization. Although many IVC filters are designed for removal after patient recovery, in many instances they are never retrieved. We present a case of a 22-year-old woman who underwent placement of an IVC filter as a prophylactic measure following a C-6 spinal injury that rendered her a quadriplegic. A tyne from the filter later fractured and embolized to the right ventricle, leading to perforation and subsequent large symptomatic pericardial effusion. The tyne was retrieved through a subxiphoid pericardial window, and the patient had an uneventful recovery. She later underwent retrieval of the entire filter.

Background: Among many causes of thrombocytopenia acquired during hospitalization, heparin-induced thrombocytopenia (HIT), an immune complex-mediated thrombogenic state with high morbidity and mortality, is one of the most feared etiologies. The clinical '4T' score is an established method to assess risk for HIT and guide immediate management(Lo, Juhl et al. 2006). However, the 4T score is not consistently used by clinicians, leading to potential over-testing and suboptimal management of suspected HIT. Our objective in this Quality Improvement (QI) project was to implement a mandatory 4T calculator (4TC) into the electronic medical record (EMR) to improve the positive predictive value of HIT antibody (HITA) testing, decrease the incidence of testing of low-risk patients, and to improve clinical management of suspected HIT. Methods: We developed a 4TC that assisted clinicians by integrating EMR-derived data on heparin exposure and the five most recent platelet counts with a link to an online calculator as well as clinical suggestions (Figure). As a part of this QI project, clinicians were required to enter the calculated 4T score before ordering a polyspecific HITA assay, which serves as the screening test for HIT in our institution. We reviewed laboratory records for all HITA tests performed over a six-month period, including 3 months before and after the implementation of a "hard stop" for HITA order in the EMR. We extracted data on the ordering hospital service team, 4T score documented in notes (if any), as well as quality of care indicators including rates of clinically recommended heparin cessation and initiation of alternative anticoagulation in the subgroup of patients with intermediate or high 4T score at the time of HITA order. In this QI project, we refrained from any statistical testing and summarized pre-specified outcome measures: incidence of HITA testing, positive predictive value of the HITA assay, and quality of care indicators. Results: We identified 99 (53 prior to the 4TC and 46 post) cases of HITA orders in the study period, among which there were 4 cases of confirmed HIT (either with positive IgG or positive serotonin-release assay [SRA]). Three HIT cases occurred after the 4TC was implemented. After the implementation of the 4TC, the positive predictive value for the HITA assay increased from 9% to 21%. The rate of clinically appropriate heparin order discontinuation increased from 72% to 88%, as did the initiation of alternative anticoagulation from 14% to 27%. HITA assay was most commonly ordered by the internal medicine service (35% of tests), non-cardiac intensive care service (30%), coronary care and cardiothoracic surgery services (21%), neurology (5%), and general surgery/other services (9%). Implementation of the 4TC did not significantly change this distribution, but the overall incidence of HITA orders decreased from 4.0 to 3.4 per 1000 admissions. We observed a high frequency of confirmatory SRA testing requested (18%), which is the reflex confirmatory test performed at our institution, even in cases of negative polyspecific HITA or HIT IgG. Conclusions: Addition of a 4T score calculator into the EMR which provides immediate feedback on patient's prior heparin exposure and recent platelet counts allows clinicians to consistently use the 4T score when considering HIT. Importantly, it also helps to educate non-hematologists on the proper management of HIT. Improved predictive value of the HITA assay suggests that our 4TC led to ordering HITA in a more appropriate patient population. We also demonstrated improved quality of care for suspected HIT, with increased rates of heparin cessation and initiation of alternative anticoagulation in patients with intermediate or high pre-test probability. Identifying clinical teams that order a disproportionate number of HITA assays will help us to direct education to improve clinical management. This QI project has led to other areas of improvement, particularly with regard to rational ordering of the SRA. At only three months of review since implementation of the 4TC, we have noted an improvement in the management of suspected HIT and a slight reduction in the incidence of testing. With continued review, we hope to demonstrate further improvement, as practitioners continue to use the 4TC and rely on clinical rationale rather than reflexive laboratory testing when evaluating thrombocytopenia in the hospital. Disclosures Olszewski: TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding; Genentech: Research Funding. Reagan:Alexion: Honoraria; Takeda Oncology: Research Funding; Pfizer: Research Funding.

Background: Recent studies (Maurer et al., JCO 2018, Olszewski et al., BJH 2018) have identified short diagnosis-to-treatment interval (DTI) of less than 15 days as a high-risk feature in B-cell lymphomas, independently of other clinical factors. T-cell lymphomas (TCL) pose a challenge because of their heterogeneity, rarity, and poor outcomes. Patients who respond to initial induction chemotherapy frequently proceed to consolidative high-dose chemotherapy with stem cell transplantation (SCT). Our objective was to examine the association between short DTI, receipt of SCT, and survival in 4 most common types of aggressive NK/TCL: peripheral TCL not otherwise specified (PTCL), angioimmunoblastic TCL (AITL), anaplastic large-cell TCL (ALCL), and extranodal NK-/T-cell lymphoma, nasal type (ENKTL). Methods: From the National Cancer Data Base, a registry containing >80% of lymphomas diagnosed in the US, we selected patients age 18 to 70, diagnosed with PTCL, AITL, ALCL, or ENKTL in 2004-2014, who received multi-agent chemotherapy within 120 days of diagnosis. Short DTI was defined as less than 15 days from diagnosis to start of chemotherapy. We analyzed the use of SCT as part of first course of treatment (before relapse) in a hierarchical logistic model adjusting for age, sex, race/ethnicity, TCL histology, stage, extranodal origin, and type of hospital (academic or community), reporting adjusted odds ratios (OR) with 95% confidence intervals (CI). Overall survival (OS) from start of chemotherapy was examined using Cox models adjusting for the same variables, reporting adjusted hazard ratios (HR). To investigate the differential impact of early mortality, we conducted sensitivity analyses in pre-specified subgroups excluding patients who died within 3 or 6 months of starting chemotherapy, and in the subset who underwent SCT (after presumably favorable response to initial chemotherapy). Results: Among 8,194 patients (Table; median age 54 years, 38% women), median DTI was 22 days (interquartile range, 11 to 38). The proportion undergoing SCT (11% overall) varied by histology, and was higher in academic centers (17%) compared with other types of hospitals (7%, P3 months from the start of chemotherapy (OR, 0.78; 95%CI, 0.65-0.94, P=.012). With a median follow-up of 10.1 years, survival varied by histology, and was significantly worse for patients with short DTI in PTCL, ALCL and ENKTL, but not in AITL (Fig. A-D). Worse prognosis with short DTI persisted in the subsets patients who survived >3 months (overall HR, 1.32; 95%CI, 1.14-1.33; P6 months (overall HR, 1.14; 95%CI, 1.04-1.25; P=.005) from the start of chemotherapy. However, in the subgroup of patients who successfully underwent SCT, a short DTI was no longer prognostic (Fig. E; HR, 0.91; 95%CI, 0.66-1.26; P=.57). Conclusions: Patients with TCL who need to start chemotherapy within 15 days of diagnosis have a lower likelihood of undergoing subsequent SCT. This association is not fully explained by early mortality, and may reflect a more aggressive biology, including worse response to standard chemotherapy-a hypothesis supported by the fact that achievement of SCT nullifies the poor prognostic value of short DTI. Short DTI is thus a novel risk factor in TCL that identifies a high-risk population well suited to experimental treatment strategies, and clinical researchers should strive to enroll these patients. Outcomes from clinical trials in which subjects start therapy after a screening period lasting >15 days from diagnosis should not be uncritically extrapolated to patients who start urgent chemotherapy in general practice. Further research should examine molecular characteristics and response rates to chemotherapy among patients with TCL who require immediate treatment upon diagnosis. Disclosures Reagan: Takeda Oncology: Research Funding; Alexion: Honoraria; Pfizer: Research Funding. Olszewski:Genentech: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding; TG Therapeutics: Research Funding.

Introduction In the treatment of acute myeloid leukemia, initial induction guidelines frequently include performing a day 14 bone marrow biopsy to assess response. A second induction is then recommended for patients with morphologic residual leukemia (≥5% blasts). Recent retrospective reviews have shown no difference in complete response (CR) rates amongst patients with residual leukemia based on day 14 marrow assessment who were and were not given a second induction. In our single center retrospective study, we compared patients with residual blast counts ≥5% to identify differences in leukemia free survival (LFS) and overall survival (OS) in those who did and did not receive a second induction. In addition we examined the cytogenetic profile of Day 14 and remission bone marrows. Methods: Consecutively treated patients with newly diagnosed primary and secondary AML over the age of 18 who received daunorubicin based induction with a curative intent from 2006 to 2014 were obtained via cancer center medical records. Outcome data was followed until May 1st 2015. We reviewed demographic (age, sex, ECOG PS, co-morbidities) as well as AML specific data (daunorubicin dose, use of etoposide, initial bone marrow blast count, initial white blood cell count, bone marrow blast count at day 14, cytogenetic stratification, CR rate, allogeneic stem cell transplant, LFS and OS). Patients included in survival analysis were required to have an initial and day 14 bone marrow biopsy with morphologic identification of residual leukemia on the day 14 marrow. Cytogenetic risk stratification was based on NCCN guidelines. Morphological CR was defined based on International Working Group criteria (Cheson, JCO, 2003). Positive (PPV) and negative predictive value (NPV) for CR were calculated by considering a BM of less than 5% at Day 14 a positive screening test for obtaining CR. Data was analyzed using Mann Whitney U test and chi square analysis as appropriate. LFS and OS were estimated using the Kaplan Meier method and compared using the log rank test. All calculations and graphs were obtained using STATA/SE 12.1. Results: Of the 91 patients initially identified, 67 had Day 14 marrows performed and 31 had residual blast counts ≥5%. For our overall cohort, we found a PPV of 76% and NPV of 65% for Day 14 marrows in determination of CR, which is in line with previous studies. No statistical differences were seen between the groups (Table 1), although patients who were reinduced trended toward higher initial white blood cell counts while those who were not reinduced trended towards improved CR rates. Comparing patients with residual disease at Day 14 who were or were not reinduced, we found no statistical difference for LFS and OS between the two groups (p 0.87 and 0.96 respectively). Interestingly, in comparing cytogenetics, two patients with unfavorable cytogenetics on initial BM converted to normal/intermediate cytogenetics after induction despite a residual blast count greater than 5%. Both obtained CR, one with and one without reinduction. Another patient with unfavorable cytogenetics at day 14 obtained CR with normal cytogenetics without reinduction. Conclusions: Although of limited size, our study suggests that reinduction based on Day 14 marrow is of limited use in predicting LFS and OS in AML. Better methods to determine residual leukemia following initial induction therapy are required in order to help guide treatment decisions. | | No Reinduction (n=17) | Reinduction (n=14) | p value | | ------------------------------------------------------- | ---------------------------- | ------------------------- | ------- | | Age (Median) | 63 | 57.5 | 0.46 | | Male:Female | 8:9 | 8:6 | 0.58 | | ECOG PS 0 1 | 11 6 | 10 4 | 0.69 | | Initial WBC (Median) | 5.2 | 11.7 | 0.06 | | Initial % Bone Marrow Blast (Median) | 0.53 | 0.48 | 0.56 | | DNR Dose 60mg/m2 90mg/m2 | 11 6 | 8 6 | 0.67 | | Etoposide Given | 5 | 4 | 0.96 | | Cytogenetic Risk Intermediate Unfavorable | 9 8 | 7 7 | 0.87 | | Complete Response | 10 | 4 | 0.09 | | Allo-SCT | 7 | 8 | 0.38 | Table 1. Demographics of patients with and without reinduction chemotherapy with residual disease on repeat bone marrow biopsy ![Figure 1.][1] Figure 1. Kaplan-Meier Curve for Overall Survival ![Figure 2.][1] Figure 2. Kaplan-Meier Curve for Leukemia Free Survival Disclosures No relevant conflicts of interest to declare. [1]: pending:yes