SB2 is a biosimilar of infliximab (IFX), which is approved for rheumatoid arthritis (RA), ankylosing spondylitis (AS), adult and pediatric Crohn’s disease (CD), adult and pediatric ulcerative colitis (UC), psoriatic arthritis (PsA), and plaque psoriasis (PsO). The drug approval process in Korea includes post-marketing surveillance (PMS) studies to re-examine the safety and effectiveness of approved new medications. This was a prospective, multi-center, open-label, observational, phase 4 PMS study of IFX-naïve patients or patients switched from reference IFX or another IFX-biosimilar to SB2 in all approved indications. The primary endpoint was to evaluate the safety of SB2 reported as adverse events (AEs) and adverse drug reactions (ADRs). The secondary endpoint was to evaluate the effectiveness measured as investigators' overall effectiveness assessment, categorized as improved, stable, or worsened. Furthermore, disease-specific activity scores were collected for each indication [28-joint Modified Disease Activity Score (DAS28) for RA, Korean Bath Ankylosing Spondylitis Disease Activity Index (KBASDAI), Crohn’s Disease Activity Index (CDAI), and Full Mayo Score for UC]. In the safety and effectiveness analysis, 180 and 128 patients were included, respectively. Most patients (83.9%) were IFX-naïve patients and 16.1% were switched patients. RA (48.9%) and AS (31.1%) were the most frequent indications. Overall, 23 (12.8%) patients reported AEs and 14 (7.8%) patients reported ADRs. Serious adverse events (SAEs) were reported by 3 (1.7%) patients. As per investigators’ overall effectiveness assessments, SB2 was effective in 94.6% (105/111) of IFX-naïve patients and 82.4% (14/17) of switched patients. In IFX-naïve patients, disease activity scores decreased significantly from baseline to week 30 (week 24 for AS); mean (SD) changes of disease scores for each indication were DAS28 − 1.9 (0.79) for RA, KBASDAI − 3.8 (1.68) for AS, CDAI − 200.4 (112.47) for CD, and Full Mayo Score − 6.6 (2.92) for UC. The persistence rate of SB2 treatments was 88.3% with median treatment duration of 30.1 weeks. This PMS study of the IFX-biosimilar SB2 in Korea confirmed the safety and effectiveness of SB2 in major indications.

In those with a partial response on initial day 28 post CAR-T therapy imaging, clinical uncertainty remains as half of these patients will ultimately have relapsed disease. In this study we utilize imaging biomarkers by 18F-FDG PET/CT imaging at pre CAR-T therapy baseline and day 28 in 24 patients achieving a partial response on day 28 to determine factors that may predict response. We demonstrate that a lower day 28 SUVmax may predict favorable progression free survival and overall survival. Additionally, lower TMV, both at baseline and day 28, may also be predictive of longer progression free survival and overall survival, while lower tumor lesion glycolysis at baseline, but not day 28 is significantly associated with a best overall response of complete response.Background: CD19 directed CAR-T therapy for Large B-cell lymphoma (LBCL) has shown great therapeutic response in patients with relapsed/refractory disease with response rates of 60-80%. However, in patients with a partial response (PR) on initial day 28 post CAR-T therapy imaging, clinical uncertainty remains as half of these patients will ultimately have relapsed disease. Patients: In 24 patients receiving CD19 directed CAR-T therapy for relapsed/refractory LBCL achieving a PR on day 28, we utilize imaging biomarkers by 18F-FDG PET/CT imaging at pre CAR-T therapy baseline and day 28 to determine factors that may predict best overall response (B-OR), progression free survival (PFS), and overall survival (OS). Methods: Out of 75 patients receiving CAR-T therapy at a single institution, we retrospectively identified and reviewed 25 (33%) as achieving a PR on day 28. PR was defined using the 2014 Lugano classification system. All patients received standard of care CD19 directed CAR-T therapy with axicabtagene ciloleucel. Two indepen-dent nuclear medicine physicians measured baseline (pre-CAR-T therapy) and day 28 PET/CT SUVmax, SUVmean and TMV (cm3) of each lesion (node, organ or marrow uptake, if any) using ROVER software. All statistical tests were two-sided and conducted at the 0.05 level of significance. R version 1.3.1099 (R-studio) was used for statistical model-ing. Conclusion: We demonstrate that a higher day 28 SUVmax was significantly higher in those with a B-OR of PR and in our modeling, a lower day 28 SUVmax may predict favorable PFS and OS. Additionally, lower TMV, both at baseline and day 28, may also be predictive of longer PFS and OS, while lower TLG at baseline, but not day 28 is significantly associated with a B-OR of CR. While further study is warranted, these imaging biomarkers may allow for early identification of those with a day 28 PR at highest risk for relapse leading to early intervention to improve long term outcomes.

Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation disorder. Use of chimeric antigen receptor T-cell therapy (CAR-T) is associated with cytokine release syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) and secondary HLH. However, application of HLH scoring systems (H-score, HLH-2004 criteria) are not validated in this setting. We analyzed the utility of applying the H-score and the HLH-2004 criteria to identify patients with possible HLH post-CAR-T for Relapsed/Refractory Diffuse Large B-cell Lymphoma. Only two of four patients with post CAR-T HLH met five or more of the diagnostic criteria for HLH by HLH 2004 criteria. In contrast all four post CAR-T HLH patients had a high H-score (>169); however, an additional ten patients that did not have HLH also had a high H-score. Thus, in this patient population, both scoring systems were demonstrated to have low prognostic significance in differentiating between high grade CRS and HLH.

Introduction: CD19 Chimeric Antigen Receptor T-cell (CAR-T) therapy is now a commonly used treatment for relapsed/refractory (R/R) Large B-cell Lymphoma (LBCL). However, predictors of long-term response remain poorly defined. In particular, partial response (PR) at first tumor assessment at Day 28 (D28) is a source of uncertainty both for clinicians and patients. In the pivotal CAR-T trials for LBCL, approximately half of these patients eventually achieved a complete remission (CR), while the other half experienced progressive disease (PD) (Neelapu et al, NEJM 2017). Herein, we present real-world data on 24 patients achieving a PR on D28 by PET/CT imaging following CAR-T therapy for R/R LBCL. We explore whether differences between baseline and D28 PET/CT imaging might predict progression free survival (PFS), overall survival (OS), best overall response rate (B-ORR), or last overall response rate (L-ORR).

Introduction:The spread of SARS-CoV-2 virus continues to pose a major public health threat. Patients with cancer are thought to be at increased risk from SARS-COV-2 infection due to the immunodeficiency that results from the underlying neoplasm and treatment. The immune response to this infection has been the subject of great interest, with an extreme variation in clinical severity between infected individuals. Variation in the immune cell response (B, T, and NK lymphocytes, monocytes, and myeloid derived suppressor cells (MDSCs), among others) and their function have been hypothesized to be responsible for this range of presentation. Methods:Two patients with a history of hematologic malignancies were matched with three non-cancer patients with similar baseline clinical characteristics and severity of COVID related illness. The critical group (CG) was defined as those requiring mechanical ventilation (MV) due to COVID related respiratory failure and the non-critical group (NCG) were hospitalized but did not require MV. All samples studied were obtained from peripheral blood and processed within 4-hours of collection. Peripheral blood mononuclear cell (PBMC) were isolated using ficoll density gradient separation. Flowcytometric analysis using CytekTM Aurora was done on fresh PBMC samples. Thirty antibody-based flow markers were used to identify 54 distinct immune cell populations. IRB approval was obtained. Results: Critical Group (CG):The CG included case 1, a 47 year-old (y.o.) female (F) with a history (hx) of acute myeloid leukemia and had an matched related donor allogeneic hematopoietic stem cell transplant (alloHSCT) 10-years prior remaining in remission, with hematologic recovery, and off immunosuppressants treated with remdesivir and coritcosteroids for COIVD directed therapy; and case 2, a 55 y.o. F with a hx of HIV treated with corticosteroids for COIVD directed therapy (see Figure 1a). Non-Critical Group (NCG):The NCG included case 3, a 73 y.o male (M) with hx of relapsed/refractory Philadelphia chromosome negative Acute Lymphoblastic Leukemia with loss of CD19 and CD22 expression following treatment with blinatumumab and inotuzumab, and most recently treated with decitabine/venetoclax; case 4, a 66 y.o. M with hx of cardiomyopathy; and case 6, a 54 y.o. M with hx of obesity. None of the NCG cases were treated with COVID directed therapy. See Table 1 for further clinical information. Immunophenotypic expression:Flow cytometry gating strategy done as outlined in Fig 1a. Case 1 had a high proportion of B-cells, CD8+ T-cells, and cells with exhaustion markers (CD8+CD94+ T-cells, CD4+PD1+ T-cells, CD4+PD1+CD94+ T-cells, PD1-CD94+ NK T-cells, Lag3+Cd11b- non-TB leukocytes) and MDSC immunophenotypes compared with matched case 2. Case 3 also had a high proportion of exhaustion markers (Lag3+CD39 low B-cells, CD8+PD1+ T-cells, CD8+CD94+PD1+ T-cells, CD4+PD1+CD94+ T-cells, PD1+CD94+ NK T-cells, PD1-CD94+ NK T-cells, Lag3+CD11b+, Lag3+CD11b- non-TB leukocytes) and high expression of immunosuppressive Treg and all MDSC; although high expression of granulocytic MDSC. Case 2 had a significant number of exhaustion and immunosuppressive cells as well. Cases 4 and 5 had a higher predominance of all T-cell subtypes and also had variable expression of exhaustion and immunosuppressive immunophenotypes (See Fib 1b). Conclusion:In our study of one critical and one non-critical patient with a history of hematologic malignancy matched with three non-cancer patients we demonstrate the high predominance of exhaustion markers (Lag3,PD1,CD94) and immunosuppressive cell types (Treg, granulocytic and monocytic MDSC). These findings are consistent with the fact that both CG and NCG, as hospitalized patients, represent the most severely ill COVID patient cohort. Of notable interest to the cancer population, cases 1 and 3 had a significant number of exhaustion and immunosuppressive immunophenotypes, suggestive of baseline exhaustion following alloHSCT even years after engraftment in case 1 and attenuated functional immunity in a patient undergoing active treatment in case 3. Interestingly, case 3 had lower expression of all MDSC, a known treatment effect of decitabine. Paired cytokine measurement and its effect on immunophenotype is underway. Additionally, we plan to present an atlas of the peripheral immune cell response on fifteen additional non-cancer COVID patients. Disclosures No relevant conflicts of interest to declare.

In the relapsed/refractory setting for treatment of large B-cell lymphoma (LBCL), chimeric antigen receptor T-cell (CAR-T) therapy has emerged as an effective treatment modality. Patients often have aggressive disease that requires prompt treatment in the form of bridging therapy (BT) for disease stabilisation while CAR-T cells are manufactured. Patients (n = 75) undergoing CAR-T therapy infusion for LBCL at our institution were identified. A total of 52 (69·3%) received BT and 23 (30·7%) received no BT (NBT). BT modalities included systemic BT (SBT) in 28 patients, radiation BT (RBT) in 14, and high-dose steroid BT (HDS) in 10. There was no difference in incidence of cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome between BT and NBT (P = 0·18 and P = 0·53 respectively). Prolonged cytopenias at Day 180 were more common in BT than NBT (50% vs. 13·3%, P = 0·04). The SBT and RBT subgroups had more cytopenias at Day 180 compared to the HDS and NBT subgroups (58·3% and 57·1% vs. 20% and 13·3% respectively, P = 0·04). Disease response at last follow-up, progression-free survival and overall survival were similar between BT, NBT, and BT subgroups. In summary, BT can be safely considered in patients undergoing CAR-T therapy. However, those undergoing BT with SBT or RBT are at higher risk of prolonged cytopenias after CAR-T therapy.

PURPOSE:Our purpose was to evaluate cosmetic changes after 5-fraction adjuvant stereotactic partial breast irradiation (S-PBI). METHODS AND MATERIALS:Seventy-five women with in situ or invasive breast cancer stage 0, I, or II, with tumor size ≤3 cm, were enrolled after lumpectomy in a phase 1 dose escalation trial of S-PBI into cohorts receiving 30, 32.5, 35, 37.5, or 40 Gy in 5 fractions. Before S-PBI, 3 to 4 gold fiducial markers were placed in the lumpectomy cavity for tracking with the Synchrony respiratory tracking system. S-PBI was delivered with a CyberKnife robotic radiosurgery system. Patients and physicians evaluated global cosmesis using the Harvard Breast Cosmesis Scale. Eight independent panelists evaluated digital photography for global cosmesis and 10 subdomains at baseline and follow-up. McNemar tests were used to evaluate change in cosmesis, graded as excellent/good or fair/poor, from baseline to year 3. Wilcoxon signed rank tests were used to evaluate change in subdomains. Cohen's kappa (κ) statistic was used to estimate interobserver agreement (IOA) between raters, and Fleiss' κ was used to estimate IOA between panelists. RESULTS:Median cosmetic follow-up was 5, 5, 5, 4, and 3 years for the 30, 32.5, 35, 37.5, and 40 Gy cohorts. Most patients reported excellent/good cosmesis at both baseline (86.3%) and year 3 (89.8%). No dose cohort had significantly worsened cosmesis by year 3 on McNemar analysis. No cosmetic subdomain had significant worsening by year 3. IOA was fair for patient-physician (κ = 0.300, P < .001), patient-panel (κ = 0.295, P < .001), physician-panel (κ = 0.256, P < .001), and individual panelists (Fleiss κ = 0.327, P < .001). CONCLUSIONS:Dose escalation of S-PBI from 30 to 40 Gy in 5 fractions for early stage breast cancer was not associated with a detectable change in cosmesis by year 3. S-PBI is a promising modality for treatment of early stage breast cancer.

Introduction:Chimeric antigen receptor T-cell (CAR-T) therapy has become an important treatment modality for patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL). However, many of these patients have aggressive disease and require a form of bridging therapy (BT) for disease control during CAR-T manufacturing. There is limited data in the literature on the most appropriate form of BT and the impact of BT on clinical outcomes. Methods:We retrospectively analyzed data on 75 patients that received CAR-T therapy at our institution. BT was defined as therapy administered between apheresis and CAR-T infusion. 52 patients received bridging therapy (BT) and 23 did not receive BT (NBT). BT included 10 high dose (HD) steroids, 28 chemotherapy-based regimen (CT), and 14 radiation therapy (RT). CT included cytotoxic chemotherapy, immunotherapy, and targeted therapy. IRB approval was obtained for this study. Statistical analysis was conducted with SAS v9.4. Univariate analysis Cox proportional hazard model was used and p-values for response rate were generated from Fisher's exact test. The methods of generalized linear model and logistic regression were used to associate the toxicity grades and cytopenias with BT, respectively. Results:Many patient and disease characteristics between BT and NBT groups were similar, with minor, non-statistically significant differences (See Fig. 1a). Although while the incidence of stage III/IV patients in the BT and NBT group was comparable (p=0.79), in subgroup analysis, there were significantly more stage III/IV patients in the CT subgroup and NBT than in the RT and HD steroids subgroups (p=0.03). There was a higher incidence of bulky disease (≥10cm) in the BT and all BT subgroups versus (vs) NBT, although this was not significant (p=0.58 and p=0.92). The number of prior lines of therapy was comparable between the BT and NBT groups (p=0.99). However, in subgroup analysis there were significantly more patients in the CT subgroup and NBT that received ≥4 lines of therapy compared with RT and HD steroids subgroups (p=0.02). There was no significant difference in overall response rate (ORR) at last follow up between BT vs NBT and BT subgroups vs NBT with approximately 50% being in complete remission in all cases (p=0.48 and p=0.54). Progression free survival (PFS) and overall survival (OS) were similar in the BT vs NBT (one-year rates of 67% vs 64% and 83% vs 75%, respectively) and this was not statistically significant (p=0.52 and 0.89), see Fig. 1b and 1c. In subgroup analysis PFS was comparable in the BT subgroups (CT 69% and HD steroids 68%) vs NBT group (67%) while RT was lower (51%), although this was not statistically significant (p=0.54). In subgroup analysis OS was slightly worse in the BT subgroups (CT 77%, RT 76%, and HD steroids 72%) vs NBT group (83%) although was not statistically significant (p=0.93). The development of cytokine release syndrome (CRS) was comparable in the BT vs NBT group and in BT subgroups vs NBT (p=0.18 and p=0.53). The median grade of immune effector cell-associated neurotoxicity syndrome (ICANS) was higher in BT than NBT (grade 2 vs 0) and trended towards statistical significance (p=0.09). The development of cytopenias at day +180 following CAR-T therapy was significantly higher in BT (50%) vs NBT (13.3%) and was statistically significant (p= 0.038). Subgroup analysis also showed significantly increased cytopenias at day +180 in CT (58.3%) and RT (57.1%) subgroups (p= 0.04). Conclusion:In our single-institution experience, BT prior to CAR-T therapy is feasible and may preserve CAR-T candidacy in patients with rapidly progressive LBCL. BT does not appear to significantly affect ORR, PFS, and OS. The incidence of CRS was comparable, although there was a higher incidence of ICANS in BT, which trended towards significance, and could be contributed to higher tumor bulk in the BT group. BT patients receiving CT and RT for BT were more likely to experience prolonged cytopenias, likely due to the myelosuppressive impact of BT and previous lines of chemo-immunotherapy agents. In conclusion, in high-risk patients with advanced and/or aggressive disease, BT may provide disease stabilization to CAR-T with a similar toxicity profile compared to NBT patients, although BT patients are more likely to experience prolonged cytopenias after CAR-T therapy. Disclosures Kansagra: Alnylam Pharmaceuticals, Bristol Myers Squibb /Celgene, GlaxoSmithKline, Janssen, Pharmacyclics, Takeda Pharmaceuticals, Pfizer, Karyopharm Therpeutics:Other: Advisory Board.Hardy:Incyte Corporation:Other: Advisory Board Member;American Gene Technologies:Other: DSMB Member;Kite/Gilead:Other: Advisory Board Member.

Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a rapidly-advancing treatment modality for relapsed/refractory (R/R) large B-cell lymphoma (LBCL) with response rates approaching 60–80%.1, 2 The registrational clinical trials that lead to the approval of CAR-T in R/R LBCL, as well as ongoing trials, have excluded patients with previous allogeneic haematopoietic cell transplantation (alloHCT) from trial participation.3-8 To date, limited clinical data exists describing the safety and efficacy of standard-of-care CAR-T therapies following alloHCT. There are a number of potential concerns with CAR-T infusion in the context of previous alloHCT; namely, CAR-T manufacturing failure, risk of high-grade graft-versus-host disease (GVHD), and potential for increased risk of CAR-T toxicities, e.g. cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Here, we present our experience with post-alloHCT CAR-T with axicabtagene ciloleucel (Axi-cel) in seven patients with R/R LBCL that were heavily pretreated (see Fig 1A for specific regimens and clinical timeline). Of note, case 4 received tisagenlecleucel (Tisa-cel) prior to alloHCT on a clinical trial. All patients underwent lymphodepletion with cyclophosphamide and fludarabine before Axi-cel infusion. None of the products administered were out of specification per the United States Food and Drug Administration (FDA) label. All patients were off immunosuppression at the time of Axi-cel infusion with no evidence of GVHD. CRS was graded by the 2014 Lee criteria and ICANS was graded by Common Terminology Criteria for Adverse Events (CTCAE), version 4.9 Institutional Review Board approval was obtained for this retrospective study. Patient age ranged from 28 to 70 years, with LBCL Stages II–IV, and transplant stem cell graft donors included one matched unrelated (MUD), two matched related (MRD), and four haploidentical (Table I). Cases 1, 3, and 5 experienced Stage I–II acute GVHD peri-transplant, all managed conservatively and resolved prior to CAR-T. Donor chimerism was near 100% donor in all cases prior to CAR-T apheresis. Cases 4 and 5 each had two donor lymphocyte infusions (DLIs) months prior to Axi-cel infusion. The time elapsed between alloHCT and CAR-T therapy ranged from 5 months to 13 years. Only case 3 experienced high-grade (>2) CRS or ICANS. Following CAR-T infusion, cases 1, 2, and 6 experienced acute GVHD, with cases 1 and 6 being managed conservatively (psoralen and ultraviolet A, and oral steroids) and case 2 being severe, although not biopsy confirmed and in the setting of checkpoint inhibitor therapy (Fig 1b,c). Following CAR-T, all evaluable cases had 100% donor chimerism (unfractionated). Four patients (cases 1, 4, 5, 7) achieved a complete remission (CR), one (case 3) had a partial response (PR), and two (cases 2 and 6) had progressive disease (PD). Five of the seven cases had cytopenias at day +30, which persisted in two at day +90. At last follow-up, cases 1, 5, and 7 had no evidence of disease (NED), cases 2, 3, and 4 died due to PD, and case 6 was undergoing salvage therapy for PD. GVHD Pre-CAR-T Chimerism Pre-CAR-T (unfractionated) As our centre's experience with CAR-T has matured, with now >100 treated patients, we have had seven patients with R/R LBCL with safe administration of CAR-T products following alloHCT. Manufacturing failure occurred in one instance (case 2) due to the product being out of specifications for release, and manufacturing was successful on the second attempt. In our experience, the use of CAR-T in patients with R/R LBCL following alloHCT has been safe and without significantly increased incidence of high-grade GVHD. Three of seven cases developed GVHD following CAR-T; however, one was in the setting of programmed cell death protein 1 (PD-1) monoclonal antibody therapy and the other two were confined to cutaneous GVHD that responded well to therapy. All three cases experiencing post-CAR-T GVHD had a time elapsed from alloHCT to CAR-T infusion of <10 months, whereas the four cases not experiencing GVHD had >12 months of elapsed time. Interestingly, the two cases that had DLI prior to CAR-T did not develop GVHD. Kochenderfer et al.10 and Park et al.11 previously reported no incidence of GVHD in CAR-T following alloHCT, from donor-derived CAR-T and acute lymphoblastic leukaemia, respectively. Thus, while the risk of GVHD following CAR-T in our experience has been greater than previously reported, we believe that CAR-T therapy following alloHCT remains safe, particularly when given >12 months after alloHCT. Furthermore, the incidence of GVHD observed in our present series is comparable to that previously reported for patients with LBCL undergoing alloHCT.12, 13 Although our present sample size is small, we did not observe a difference in CAR-T response or incidence of GVHD between MRD, MUD, and haploidentical alloHCT. In regard to toxicity, there were no treatment-related deaths and the incidence and severity of CRS and ICANS with CAR-T following alloHCT does not appear to be increased. Only case 3 experienced CRS and ICANS greater than grade 2 and this was in the setting of bulky disease with a high tumour burden. Cytopenias were present at day +30 in five of the seven patients, but persisted in only two patients at day +90 and none experienced clinically significant infections following CAR-T. Although by their very nature, patients with LBCL undergoing alloHCT have extremely aggressive and refractory disease, four of seven achieved a best response of CR. Interestingly, case 4 had CAR-T both prior to and after alloHCT (Tisa-cel clinical trial and commercially available Axi-cel, respectively), and achieved a better response (CR at day +30) with the post-alloHCT CAR-T infusion (CD19 expression was confirmed by immunohistochemistry on biopsy following relapse). However, this raises an important question of whether CAR-T cells manufactured from donor-derived engrafted lymphocytes may have greater efficacy given the possibility of graft-versus-lymphoma effect.14 Brudno et al.15 demonstrated the safe use of donor-derived T cells for manufacturing of true allogeneic CAR-T cells. However, obtaining mononuclear cells from the patient with high donor chimerism offers logistical advantage over truly donor-derived T cells, especially in the case of an unrelated donor. In summary, our present case series demonstrates that CAR-T therapy can be a safe and well-tolerated treatment modality in R/R LBCL following alloHCT, although ultimately, its efficacy compared to pure autologous CAR-T requires further study. Forat Lutfi, Jonathan Siglin, Ali Bukhari, and Noa Holtzman wrote the manuscript and constructed the tables/figures. Moaath Mustafa Ali, Dong Won Kim, Gabriela Sanchez-Petitto, and David Gottlieb assisted with reviewing and compiling medical records of patients involved, as well as manuscript editing. Kathleen Ruehle, Eilzabeth Hutnick, Natalie Gahres, and Kim Hankey were responsible for identifying the patients in our study and maintaining the CAR-T IRB-approved database at our medical centre. Seung T. Lee, Mehmet H. Kocoglu, Jean A. Yared, and Nancy M. Hardy were involved with the writing, editing, and review of this manuscript. Aaron P. Rapoport and Saurabh Dahiya were the primary individuals behind the idea for this manuscript and involved in its writing and editing. All authors had key roles in the creation of this manuscript, as noted above, and this is reflected in the order of authorship. There are no conflicts of interest by any authors involved in this manuscript.

Introduction Chimeric antigen receptor T-cell (CAR-T) therapy has emerged as a powerful therapy for relapsed and refractory (R/R) B-cell malignancies. A growing body of research suggests that CAR-T therapy can be safe and effective in patients who have previously received allogeneic hematopoietic stem cell transplantation (alloHSCT). "Pseudo-allogeneic" CAR-T therapy refers to manufacture of engineered T-cells collected from an alloHSCT recipient exhibiting 100% donor chimerism. This CAR-T approach poses theoretical risks due to alloreactivity and increased CAR-T toxicity. Most studies to date in this area have enrolled patients with leukemia. We present here a single-center experience with pseudo-allogeneic CAR-T following alloHSCT in 6 patients with large B-cell lymphoma (LBCL). Patients and Methods Patients with R/R LBCL who underwent treatment with axicabtagene ciloleucel (axi-cel) CAR-T after prior alloHSCT were identified. All patients underwent lymphodepletion with cyclophosphamide and fludarabine prior to CAR-T infusion. CAR-T toxicities, namely cytokine release syndrome (CRS) and immune effector-cell associated neurotoxicity syndrome (ICANS) were graded in accordance with the 2019 American Society for Transplantation and Cellular Therapy (ASTCT) consensus grading. Results Six patients who underwent axi-cel CAR-T due to post-alloHSCT R/R LBCL were identified. All patients had stage ≥II disease. At the time of CAR-T apheresis, all patients had ≥95% donor chimerism and were off immunosuppression, without evidence of GVHD. Manufacturing failure occurred in only one patient (case 2) due to low viability and upon second apheresis, manufacture was successful. All 6 pseudo-allogeneic CAR-T therapy patients tolerated infusion and did not show increased incidence or severity of CRS or ICANS compared to our center's experience with standard CAR-T patients, with only one patient experiencing greater than grade 2 toxicity. Three of six patients developed graft-versus-host disease (GVHD); however, one case was in the setting of PD-1 blockade and two were isolated cutaneous manifestations. There was no incidence of severe GVHD. All three cases of GVHD underwent CAR-T within ten months after alloHSCT, whereas the three patients without GVHD were >1 year post-HSCT at time of CAR-T. Two cases who had donor lymphocyte infusions prior to CAR-T did not develop GVHD. In terms of efficacy, three patients achieved a complete remission. There was no perceptible relationship between the development of GVHD and the response to CAR-T. Four of six had cytopenias at day 30 after CAR-T, with only two exhibiting persistent cytopenias at day 90. Lastly, in this small sample size, no differences were seen in incidence of GVHD or treatment response between haploidentical, matched-related, and matched-unrelated alloHSCT donors. Conclusion In our experience, pseudo-allogeneic CAR-T therapy following alloHSCT appears to be a safe and well-tolerated treatment modality for R/R B-cell lymphoma. The efficacy of this modality will need to be borne out in further studies. Disclosures No relevant conflicts of interest to declare.

BACKGROUND:There is growing interest in the effect of postoperative analgesics on oncological outcomes after cancer surgery. We investigated the impact of tramadol after breast cancer surgery on recurrence and mortality and explored the mechanism by which tramadol affects cultured breast cancer cells in vitro. METHODS:Electronic medical records of patients who underwent breast cancer surgery between November 2005 and December 2010 at Severance Hospital in Korea were reviewed. Cox regression analyses were used to identify factors related to postoperative recurrence and mortality. We performed the sensitivity test with propensity score matching to adjust for selection bias. In addition, we investigated the effects of tramadol on human breast adenocarcinoma (Michigan Cancer Foundation-7 [MCF-7]) cells via assessment of cell viability, clonogenic assay, and cell cycle analysis in vitro. RESULTS:Of 2588 breast cancer patients, 36.4% had received tramadol. Those who received tramadol had a 0.71-fold decreased risk of recurrence and a 0.56-fold decrease in mortality. The MCF-7 cell viability assays showed that tramadol had an anti-proliferative effect by cell cycle arrest, suppressing colony formation, and regulation of oestrogen and progesterone receptors. Tramadol induced apoptosis of MCF-7 cells via extracellular signal-regulated kinases by decreasing of 5-hydroxytryptamine (HT)2B receptor and transient receptor potential vanilloid-1 expression. CONCLUSIONS:After breast cancer surgery, patients who received tramadol had a decreased risk of postoperative recurrence and mortality. The anti-tumour effect of tramadol appears to involve inhibition of proliferation, induction of apoptosis, and effects on 5-HT2B receptor and TRPV-1.

Methimazole is a thionamide drug that inhibits the synthesis of thyroid hormones by blocking the oxidation of iodine in the thyroid gland. We report a case of methimazole-induced recurrent pleural effusion. A 67-year-old female with recently diagnosed Graves' disease on methimazole 20mg daily was admitted with dyspnea and new onset atrial fibrillation with rapid ventricular rate. Chest X-ray revealed a unilateral right pleural effusion, which was consistent with a transudate on thoracocentesis. She was managed as a case of congestive heart failure and methimazole dose was increased to 30 mg daily. She was readmitted twice with recurrent right pleural effusion. The fluid revealed an exudative process on repeat thoracocentesis. CT scan of the chest with contrast showed mediastinal lymphadenopathy and a diffuse ground glass process involving the right lower lobe suggestive of pneumonitis. Bronchoalveolar lavage showed neutrophil predominant fluid, and cytology and adenosine deaminase were negative. Patient also had an endobronchial ultrasound guided biopsy of the lymph nodes (EBUS). She was treated empirically with steroids 40 mg for 10 days and the methimazole was also discontinued. The antinuclear antibodies (ANA) came back positive with a speckled pattern; antineutrophil cytoplasmic antibody (c-ANCA) and antimyeloperoxidase were also positive. The effusion resolved but recurred on rechallenge with methimazole. She was referred for urgent thyroidectomy. The patient's repeat chest X-ray showed complete resolution of the pleural effusion after stopping the methimazole. Few weeks later, repeat ANCA and antimyeloperoxidase antibody were both negative. Our case report highlights the importance of the recognition of a rare side effect of methimazole. Timely diagnosis would ensure that appropriate treatment is given.

BACKGROUND Propofol is an anaesthetic that resembles alpha-tocopherol and it has been suggested that it protects against ischaemia-reperfusion injury in liver transplantation. Living-donor liver transplantation (LDLT) presents an opportunity to test this hypothesis in both donors and recipients. OBJECTIVES We compared clinical outcomes after LDLT following anaesthesia with propofol and desflurane against desflurane alone. DESIGN A randomised, parallel study. SETTING Single-centre trial, study period June 2014 and May 2017. PATIENTS Sixty-two pairs of adult donors and recipients who underwent LDLT. INTERVENTION Patients were randomised to receive either desflurane balanced anaesthesia or propofol total intravenous anaesthesia combined with desflurane anaesthesia. MAIN OUTCOME MEASURES The primary outcome was peak liver transaminase levels during the first 7 days after surgery. Liver function was assessed at 10 different time-points (before surgery, 1 h after reperfusion, upon arrival in the ICU, and daily until postoperative day 7). Creatinine was measured to evaluate the incidence of acute kidney injury. TNF-alpha, IL-1 beta, IL-6 and TGF-beta 1 were assessed in 31 donors after induction, at hepatectomy and at the end of surgery and in 52 recipients after induction, and 1, 3 and 24 h after reperfusion. RESULTS Peak liver transaminase levels were not significantly different between the two groups. Liver function tests and creatinine were also similar between groups at all time-points. There was no difference in the incidence of postoperative complications, including acute kidney injury. With the exception of higher TNF-alpha in donors of the Propofol group at hepatectomy (0.60 +/- 0.29 vs. 1.03 +/- 0.53, P = 0.01) cytokine results were comparable between the two groups. CONCLUSION Despite the simultaneous administration of propofol infusion in both donors and recipients, no improvement in laboratory or surgical outcome was observed after LDLT compared with patients who received desflurane anaesthesia alone.

133 Background: 20% of men with prostate cancer (PCa) are diagnosed with high-risk disease. The optimal therapy for these patients, prostatectomy followed by adjuvant radiation therapy (ART) or definitive radiation with androgen deprivation (DRT), is still unclear. Previous randomized trials failed to accrue; therefore we sought to answer this using an IRB-approved retrospective cohort study. Methods: High-risk PCa was defined using NCCN criteria. Adjuvant radiation was defined as radiotherapy started within 6 months of prostatectomy. Biochemical progression-free survival (BPFS), castrate resistance-free survival (CRFS), distant metastasis-free survival (DMFS), prostate cancer-specific survival (PCSS), and overall survival (OS) were calculated using Kaplan-Meier estimates. Biochemical failure was defined using the AUA definition in the ART group and by the Phoenix definition in the DRT group. Castrate resistance was defined as ≥2 episodes of rising PSA with testosterone <50 ng/ml or rising PSA despite second line anti-androgen. Statistical analysis was performed using log rank and Cox testing. Results: 60 men with high-risk PCa treated between 1992-2011 were included in the ART group and 154 men were included in the DRT group. 58% of men in the ART group received short course of androgen depravation therapy (ADT). Nearly all men received 2 years of ADT in the DRT group. The median follow up for the ART group was 62 months and 55 months for the DRT group. Men in ART group were younger (p<0.0001) and had a lower pre-treatment PSA (p=0.0338). Log rank testing revealed the ART group had worse BPFS (5 year: 57% vs. 71%; p=0.008), but there was no difference in the other endpoints including CRFS (p=0.9693), DMFS (p=0.7345), PCSS (p=0.5481), or OS (p=0.2557). On multivariable analysis ADT use, ADT length, type of treatment, and stage were not predictive of BRFS whereas Gleason score was (p=.0001). Conclusions: This study suggests that for high-risk PCa patients there is no difference between DRT and ART with regards to BPFS, CRFS, DMFS, PCSS, or OS. Therefore, over a short follow-up period, there does not appear to be a difference between these approaches. Prospective trials are required to validate this finding.

e16553 Background: Our pilot study, which analyzed DAB2IP expression in 46 patients' biopsies and had short follow up, showed that DAB2IP reduction correlates with worse outcome in patients with high-risk prostate cancer treated with radiation therapy and androgen deprivation. With longer follow up and increased sample size, we hypothesized that pretreatment tumor status of DAB2IP would also predict worse prostate cancer-specific survival (PCSS). Methods: Immunohistochemistry of pretreatment biopsies was scored by an expert genitourinary pathologist. PCSS was defined as death due to prostate cancer, radiation toxicity, or unknown cause with distant metastasis or castration resistance. Other endpoints analyzed include freedom from biochemical failure (FFBF), castration resistance-free survival (CRFS), and distant metastasis-free survival (DMFS). Results: 79 patients with NCCN-defined high-risk prostate cancer treated with radiotherapy from 2005-2012 at our institution were evaluated. 28% (22/79) of pretreatment biopsies revealed DAB2IP-reduction while 72% (57/79) retained DAB2IP expression. The median follow up times were 4.8 years and 5.3 years for patients in the DAB2IP-reduced group and DAB2IP-retained group, respectively. Patients with reduced DAB2IP were statistically more likely to have higher T stage (p = 0.0149), pretreatment PSA (p = 0.0379), and Gleason scores (p = 0.0048). Patients with reduced DAB2IP also demonstrated worse outcome compared to patients retaining DAB2IP, including FFBF (4-year: 34% vs. 92%; p < 0.0001), CRFS (4-year: 58% vs. 96%; p = 0.0039), DMFS (4-year: 58% vs. 100%; p = 0.0006), and PCSS (5-year: 83% vs. 100%; p = 0.0102). Univariate analysis showed T stage, N stage, and Gleason score were statistically significant variables. Pretreatment tumor DAB2IP status remained significant in the multivariable analysis. Conclusions: This study suggests that about one-fourth of men with high-risk prostate cancer have decreased DAB2IP tumor expression. This subpopulation with reduced DAB2IP has a suboptimal response and worse PCSS following radiation therapy and androgen deprivation. Further study into improving treatment response and survival in this subpopulation is warranted.

533 Background: Renal cell carcinoma (RCC) has traditionally been refractory to radiotherapy with conventional fractionation, although recent evidence suggests a response to higher doses per fraction. We evaluated local control of extra-cranial metastases from RCC treated with stereotactic ablative radiotherapy (SABR). Methods: RCC patients with extra-cranial metastases treated with SABR were retrospectively enrolled from a single institution between 2005 and 2015. A total of 188 lesions were identified from 91 patients. Radiation (8-60Gy) was delivered in 1-5 fractions (fx) using stereotactic guidance. Local control (LC) was determined by imaging according to RECIST 1.1. Results: Median age at the time of treatment was 62.4 years. Metastases were detected in bone (39.9%), lung (14.9%), liver (9.6%), lymph nodes (11.7%) and other sites (23.9%). Ninety-seven (51.6%) lesions reached curative intent while 91 (48.4%) only reached palliative intent. The most common radiation regimens were 20Gy/1fx, 30Gy/3fx, and 40Gy/5fx. One-year overall survival was 76.5% with a median follow up of 10.7 months. Patients treated with curative SABR showed a 2-fold median survival as compared to those treated with palliative therapy (3.97 year vs 1.43 year, p<0.05). LC rates at 1 and 2 years were 91.4% and 89.7%, respectively. For the patients that failed, median time to local failure was 6.6 months. LC at 1 year significantly improved when treatment was curative (96.1% vs 84.9%, p<0.05), while it decreased in a re-irradiation setting (94.8% vs 46.7%, p<0.05). The median biological equivalent dose (BED) for the lesions that failed was 103Gy, corresponding to 6Gy x 5fx, and was significantly lowered compared to controlled lesions (BED 134Gy). Although 79% of patients developed new lesions within 1 year following SABR, 34.8% did not switch systemic therapy. Switching systemic therapy was delayed in patients treated with curative as compared to palliative SABR (13.4 vs 2.5 months, p<0.05). Conclusions: SABR improved LC of extra-cranial RCC metastases and delayed change to systemic therapy. SABR may complement systemic therapy to improve outcome in the present patient population.

Objectives/Hypothesis No previous ultrasound (US) studies have investigated the diagnostic accuracy of specific US‐based diagnostic protocol for cervical lymph node (LN) lesions in a tuberculosis‐endemic area. This study aimed to assess the accuracy of US‐based diagnosis of cervical LNs in a tuberculosis‐endemic area. Study Design This was a retrospective cohort study. Methods We enrolled 495 consecutive patients who underwent US examination of the LNs in the neck. A single radiologist carried out the US examination, and established a US‐based diagnosis at the time of the examination in each of the patients. We calculated the diagnostic accuracy of US for LNs in the neck by using the final results as a reference standard. Results Of 476 study cases, the number of tuberculous, nontuberculous benign, malignant, and indeterminate US category cases was 74, 224, 152, and 26, respectively. Confirmed diagnoses in these cases were as follow: tuberculous LN (n = 69), nontuberculous benign LN (n = 249), and malignant LN (n = 158). The sensitivity, specificity, positive and negative predictive values, and accuracy of tuberculous, malignant, and nontuberculous benign US categories were 90.9%, 96.4%, 81.1%, 98.4%, and 95.6%; 92.8%, 96.6%, 93.4%, 96.3%, and 95.3%; and 92.2%, 95.0%, 95.1%, 92.0%, and 93.6%, respectively. All US categories showed a high sensitivity and specificity. Conclusions The present US‐based diagnostic protocol for cervical LNs in a tuberculosis‐endemic area may be useful. Level of Evidence 4. Laryngoscope , 125:1113–1117, 2015

A 61-year-old man with relapsing-remitting multiple sclerosis developed extranodal large B-cell lymphoma of the stomach following monthly natalizumab infusions for 6 years. Development of lymphoproliferative disorders increases with chronic use of immunosuppression. Cases of primary central nervous system lymphoma as well as one case of peripheral T-cell lymphoma have previously been reported with natalizumab use. Given the absence of a known association between multiple sclerosis and extranodal presentations of diffuse large B-cell lymphoma, a causal association with natalizumab administration cannot be excluded.