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Axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) are CD19-directed chimeric antigen receptor (CAR) T cell therapies approved for the treatment of relapsed/refractory aggressive B cell lymphomas. We present a multicenter retrospective study among centers that prescribe either commercial product to evaluate usage patterns, safety and efficacy outcomes, and resource utilization. Data collection included all patients from 8 US centers who underwent apheresis between May 1, 2018, and July 31, 2019. Patient selection, toxicity management, and disease assessment followed institutional practices. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to American Society for Transplantation and Cellular Therapy consensus criteria, and tumor responses were assessed according to the Lugano 2014 classification scheme. A total of 260 patients underwent apheresis, including 168 (65%) for axi-cel and 92 (35%) for tisa-cel. Among the infused patients, the median age was 59 years for axi-cel recipients and 67 years for tisa-cel recipients (P.001). The median time from apheresis to infusion was 28 days for axi-cel recipients and 45 days for tisa-cel recipients (P.001). Sixty-one percent of the axi-cel recipients and 43% of the tisa-cel recipients would have been ineligible for the ZUMA-1 and JULIET trials, respectively. Grade ≥3 CRS occurred in 9% of axi-cel recipients and in 1% of tisa-cel recipients (P = .017), and grade ≥3 ICANS was seen in 38% of axi-cel recipients and 1% of tisa-cel recipients (P.001). Inpatient cell therapy infusion was common (92% in axi-cel recipients, 37% in tisa-cel recipients). The day 90 overall response rate was 52% in the axi-cel group and 41% in the tisa-cel group (P = .113), with complete response in 44% and 35%, respectively (P = .319). Twelve-month progression-free survival (42% versus 32%; P = .206) and overall survival (62% versus 59%; P = .909) rates were comparable in the axi-cel and tisa-cel groups. Baseline characteristics differed between the 2 groups, although response rates and survival outcomes were comparable, albeit lower than those in the pivotal trials. Safety and resource utilization appear to be key differentiators between axi-cel and tisa-cel.

Summary Background In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort. Methods In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0–1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov , NCT02445248 , and is ongoing. Findings Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8–43·8), the overall response rate was 53·0% (95% CI 43·5–62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3–4 adverse events were anaemia (45 [39%]), decreased neutrophil count (39 [34%]), decreased white blood cell count (37 [32%]), decreased platelet count (32 [28%]), cytokine release syndrome (26 [23%]), neutropenia (23 [20%]), febrile neutropenia (19 [17%]), hypophosphataemia (15 [13%]), and thrombocytopenia (14 [12%]). The most common treatment-related serious adverse events were cytokine release syndrome (31 [27%]), febrile neutropenia (seven [6%]), pyrexia (six [5%]), pancytopenia (three [3%]), and pneumonia (three [3%]). No treatment-related deaths were reported. Interpretation Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk–benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy). Funding Novartis Pharmaceuticals.

Summary Background Patients with chronic lymphocytic leukaemia and high-risk features have poorer outcomes on ibrutinib than those without high-risk features. The aim of this study was to assess the benefit of adding ublituximab, an anti-CD20 monoclonal antibody, to ibrutinib therapy in this population. Methods We did a randomised, phase 3, multicentre study (GENUINE) of patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia with at least one of 17p deletion, 11q deletion, or TP53 mutation, at 119 clinics in the USA and Israel. Eligible patients had received at least one previous chronic lymphocytic leukaemia therapy and had an Eastern Cooperative Oncology Group performance status of 2 or lower. We randomised patients (1:1) using permuted block randomisation with a block size of four and stratified by previous lines of therapy (one vs two or more) to receive ibrutinib alone or ibrutinib in combination with ublituximab. Treatment allocation was not masked to patients or investigators. Ibrutinib was given orally daily at 420 mg for all cycles. Ublituximab was given intravenously in 28-day cycles, with increasing doses during cycle 1 (≤150 mg on day 1, 750 mg on day 2, and 900 mg on days 8 and 15) and continuing at 900 mg on day 1 of cycles 2–6. After cycle 6, ublituximab was given at 900 mg every three cycles. The study was initially designed with co-primary endpoints of progression-free survival and overall response rate but due to protracted patient accrual, the protocol was amended to have a single primary endpoint of independent review committee-assessed overall response rate (defined as the proportion of patients who had a partial response, complete response, or complete response with incomplete marrow recovery according to the 2008 International Workshop on CLL criteria) in the intention-to-treat population. Safety was evaluated in the population of patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov , NCT02301156 , and the final analysis is presented. Findings 224 patients were assessed for eligibility, of whom 126 patients were enrolled and randomly assigned to receive ublituximab plus ibrutinib (n=64) or ibrutinib alone (n=62) between Feb 6, 2015, and Dec 19, 2016. After a median follow-up of 41·6 months (IQR 36·7–47·3), the overall response rate was 53 (83%) of 64 patients in the ublituximab plus ibrutinib group and 40 (65%) of 62 patients in the ibrutinib group (p=0·020). 117 patients, including 59 in the ublituximab plus ibrutinib group and 58 in the ibrutinib group, received at least one dose of treatment and were included in safety analyses. Most adverse events were grade 1 or 2. The most common grade 3 and 4 adverse events were neutropenia (11 [19%] patients in the ublituximab plus ibrutinib group and seven [12%] in the ibrutinib group), anaemia (five [8%] and five [9%]), and diarrhoea (six [10%] and three [5%]). The most common serious adverse events were pneumonia (six [10%] in the ublituximab plus ibrutinib group and four [7%] in the ibrutinib group), atrial fibrillation (four [7%] and one [2%]), sepsis (four [7%] and one [2%]), and febrile neutropenia (three [5%] and one [2%]). Two patients in the ublituximab plus ibrutinib group died due to adverse events (one cardiac arrest and one failure to thrive), neither of which were treatment-related. Five patients in the ibrutinib group died due to adverse events, including one cardiac arrest, one cerebral infarction, one intracranial haemorrhage, one Pneumocystis jirovecii pneumonia infection, and one unexplained death; the death due to cardiac arrest was considered to be treatment-related. Interpretation The addition of ublituximab to ibrutinib resulted in a statistically higher overall response rate without affecting the safety profile of ibrutinib monotherapy in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia. These findings provide support for the addition of ublituximab to Bruton tyrosine kinase inhibitors for the treatment of these patients. Funding TG Therapeutics.

Follicular lymphoma (FL) is generally considered an indolent disease, although patients with relapsing FL experience progressively shorter durations of response to second or later lines of therapy. The ongoing ELARA trial in adult patients with relapsed/refractory (r/r) FL treated with tisagenlecleucel demonstrated an overall response rate of 86.2% and a complete response rate of 69.1%, with no treatment-related deaths. Tisagenlecleucel was administered in the outpatient setting in 18% of patients in ELARA; however, there is limited knowledge concerning the impact of inpatient versus outpatient tisagenlecleucel administration on healthcare resource utilization (HCRU) among patients with r/r FL. Here, we present the first HCRU analysis among patients with r/r FL who received tisagenlecleucel in the Phase II, single-arm, multicenter ELARA trial. HCRU was characterized using hospitalization data from day 1 to month 2 after tisagenlecleucel infusion. Information on length of stay, facility use, and discharge was assessed in patients who received tisagenlecleucel in the outpatient or inpatient setting. All costs were inflated to 2020 US dollars. As of August 3, 2021 (20-month median follow-up), 17/97 (18%) r/r FL patients were infused in an outpatient setting. Patients infused in the outpatient setting generally had favorable Eastern Cooperative Oncology Group performance status and Follicular Lymphoma International Prognostic Index scores, and less bulky disease at baseline. However, the outpatients had higher proportions of patients with grade 3A FL, primary refractory disease, and5 lines of prior therapy compared with inpatients. Forty-one percent of patients treated in the outpatient setting did not require hospitalization within 30 days after infusion, and outpatients who did require hospitalization had a shorter average length of stay compared with inpatients (5 versus 13 days). No outpatients required intensive care unit (ICU) admission, whereas 9% of inpatients were admitted to the ICU. The mean postinfusion hospitalization costs were $7477 and $40,054 in the outpatient and inpatient settings, respectively. Efficacy between both groups was similar. Tisagenlecleucel can be safely administered to some patients in the outpatient setting, which may reduce HCRU for patients with r/r FL.

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

Axicabtagene ciloleucel (YESCARTA; Kite Pharma, a Gilead Company, Los Angeles CA) and tisagenlecleucel (KYMRIAH; Novartis Pharmaceuticals Corp., Basel, Switzerland) are two CD19-directed chimeric antigen receptor (CAR) T cell products currently approved by the US Food and Drug Administration; the European Medicines Agency; Health Canada; Ministry of Health, Labor and Welfare (Japan); and Therapeutic Goods Administration (Australia) for treatment of specific subtypes of relapsed/refractory aggressive B cell non-Hodgkin lymphoma (NHL). Although this approval has been transformative in the use of cellular immunotherapy in lymphoma, there are concerns regarding appropriate use of this novel therapy and of short- and long-term toxicities. To address these issues, representatives of the American Society of Transplantation and Cellular Therapy convened to recognize and address key issues surrounding the clinical application of CD19 CAR T cell therapy in B cell lymphomas, in collaboration with worldwide experts. The aim of this article is to provide consensus opinion from experts in the fields of hematopoietic cell transplantation, cellular immunotherapy, and lymphoma regarding key clinical questions pertinent to the use of CD19 CAR T cell products for the treatment of NHL. As the clinical practice using CAR T cells grows worldwide, we anticipate that this guidance will be relevant for hematology/oncology physicians who care for patients with lymphomas.

Context: Despite the marked efficacy of covalent BTK inhibitors (BTKi) in CLL/SLL, the development of resistance and discontinuation for adverse events can lead to treatment failure. Low oral bioavailability or short half-life of these agents can lead to suboptimal BTK target coverage and ultimately result in acquired resistance in some patients (pts). Pirtobrutinib (LOXO-305) is a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal, low nM potency. Objective: To evaluate pirtobrutinib safety and efficacy in pts with CLL/SLL. Design: BRUIN is an ongoing multi-center phase 1/2 trial (NCT03740529). Enrollment was initiated 21 March 2019. Setting: Global: community hospitals, and academic medical centers. Patients: As of 27 September 2020, 323 previously treated pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other B-cell lymphomas) were enrolled. Interventions: Oral pirtobrutinib (7 dose escalation levels: 25–300mg once daily) in 28-day cycles. Main Outcomes Measures: Determining the maximum tolerated dose/recommended phase 2 dose (RP2D), safety profile, and efficacy based on response assessment using disease-specific criteria (iwCLL2018 for CLL/SLL) per protocol. Results: Pirtobrutinib demonstrated high oral exposures, with doses ≥100mg QD exceeding BTK IC90 for the entirety of the dosing interval. No DLTs occurred. The only treatment-emergent adverse events, regardless of attribution or grade seen in ≥10% of pts (n=323), were fatigue (20%), diarrhea (17%), and contusion (13%). An RP2D of 200 mg QD was selected for future studies. The ORR (per iwCLL 2018) was 63%, with 69 PRs, 19 PR-Ls, 45 SDs, 1 PD, and 5 discontinued prior to first response assessment. Responses deepened over time among pts with ≥10 months of follow-up (n=29; 86% ORR). ORR was not influenced by the reason for prior BTKi discontinuation (i.e., progression vs intolerance) or other classes of prior therapy received (including a covalent BTK and a BCL2 inhibitor). The longest followed responding pt continues on treatment for 17.8+ months. Conclusions: Pirtobrutinib showed promising efficacy in pre-treated CLL/SLL pts, was well-tolerated, and exhibited a wide therapeutic index.

Context Follicular lymphoma (FL) often presents with recurrent relapses. Treatment options for patients (pts) with FL who have received ≥2 prior lines of therapy are limited, and prognosis is poor. The safety and efficacy of mosunetuzumab, a full-length, fully humanized IgG1 CD20/CD3 bispecific antibody is currently being investigated in an ongoing open-label, multicenter, Phase I/Ib, dose-escalation and expansion trial in relapsed/refractory (R/R) B-cell lymphoma (GO29781; NCT02500407). Objective To present updated data from the R/R FL cohort. Methods Pts received intravenous mosunetuzumab step-up doses in cycle (C) 1, days (D) 1 and 8, then the target dose on D15 and D1 of each subsequent 21-day cycle (Group B); treatment continued for ≤17 cycles. Results As of January 21, 2020, mosunetuzumab 0.4/1.0/2.8 mg to 1/2/13.5 mg (C1D1/8/15 dose levels) was given to 62 pts with FL who received ≥2 prior systemic therapies. Pts had a median age of 59 (27–85) years, median number of 3 (2–11) prior therapies; 33 pts (53%) were double refractory, 30 (48%) had progression of disease within 24 months of first-line treatment (POD24), and four (6%) received prior chimeric antigen receptor T-cell (CAR-T) therapy. Overall response rate (ORR) and CR rate were 68% and 50%, respectively. In high-risk pts, consistent CR rates were observed: 55% (18/33) in pts with double refractory disease, 53% (16/30) in pts who had POD24, 78% (7/9) in pts with PI3Ki refractory FL, and 50% (2/4) in those who received prior CAR-T therapy. Twenty-six pts with a CR (74%) remained in remission (median time on study: 14.4 months). In responders (n=42), median duration of response was 20.4 months (95% CI: 11.7–not reached), and median progression-free survival was 11.8 months (95% CI: 7.3–21.9). Adverse events (AEs) and serious AEs were reported in 60 (97%) and 22 pts (35%), respectively. The most common grade (Gr) ≥3 AEs included hypophosphatemia (23%) and neutropenia (21%). Fourteen pts (23%) experienced CRS1; events were mostly Gr 1 or 2, reversible, and occurred largely during C1. Conclusions A high CR rate, durable responses, and a manageable safety profile were observed with mosunetuzumab monotherapy in heavily pre-treated pts with FL, including high-risk pts.

Context Tisagenlecleucel demonstrated durable responses and manageable safety in adult patients with r/r diffuse large B-cell lymphoma. Objective Determine the efficacy and safety of tisagenlecleucel in adult patients with r/r FL. Design ELARA (NCT03568461) is an international, multicenter, single-arm, phase 2 trial of tisagenlecleucel treatment. Patients or Other Participants Adult (≥18 years) patients with r/r FL (grades 1–3A) after ≥2 lines of therapy or whose disease relapsed after autologous stem cell transplant were eligible. As of September 28, 2020, 98 patients were enrolled. Interventions Bridging therapy was permitted, and disease status was reassessed prior to infusion. Patients received tisagenlecleucel (0.6–6×10 8 CAR+ viable T-cells) after lymphodepleting chemotherapy. Main Outcomes Measures Primary endpoint was complete response rate (CRR) by central review (Lugano 2014 criteria). Secondary endpoints included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), safety, and cellular kinetics. Results Ninety-seven patients received tisagenlecleucel (median follow-up, 10.6 months). Median age at study entry was 57 years (range, 29-73), 85% had stage III–IV disease, 60% had a FLIPI score ≥3, 65% had bulky disease, and 42% had LDH > upper limit of normal. Median number of prior therapies was 4 (range, 2–13); 78% of patients were refractory to their last treatment, and 60% progressed ≤2 years of initial anti-CD20-containing treatment. Among 94 patients evaluable for efficacy, CRR was 66% (95% CI, 56%–75%), and ORR was 86% (95% CI, 78%–92%). Estimated DOR (CR) and PFS rates at 6 months were 94% (95% CI, 82%–98%) and 76% (95% CI, 65%–84%), respectively. Of 97 patients evaluable for safety, 65% experienced grade ≥3 adverse events ≤8 weeks post-infusion, most commonly neutropenia (28%) and anemia (13%). Any-grade cytokine release syndrome (Lee scale) occurred in 49% of patients. Any-grade neurological events (per CTCAE v4.03) occurred in 9% of patients. Three patients died from disease progression. C(max) and AUC(0–28d) for tisagenlecleucel were similar between responders and nonresponders. C(max) was achieved at a median of 10 days in responders and 12.9 days in nonresponders. Conclusions Tisagenlecleucel demonstrated efficacy and a favorable safety profile in patients with r/r FL. The study was funded by Novartis.

Tumor-initiating cells with reprogramming plasticity and/or de-differentiation attributes have been thought to initiate primary tumor development as well as to regenerate secondary tumors in metastatic organs; however, the molecular mechanisms are not fully understood. We previously found that breast tumor-initiating cell marker, CD44, directs multicellular aggregation and cluster formation of circulating tumor cells (CTCs), which further enhance stemness and survival of such cells, enabling metastatic colonization to the lungs. To further elucidate the molecular network underlying CTC cluster formation, we performed global proteomic profiling and discovered that the tetraspanin protein CD81, which is normally enriched in exosomes (small extracellular vesicles), is a new driver of cancer initiation and metastasis as a facilitator and target of CD44. Loss of CD81 compromises tumorigenicity and mammosphere formation of triple negative breast cancer (TNBC) cells. Assisted by machine learning-based algorithms and mutagenesis approach, we found that CD81 interacts with CD44 on the cellular membrane through their extracellular regions. Notably, genetic knockout of CD44 or CD81 results in loss of both CD81 and CD44 in secreted exosomes, a state which abolishes exosome-induced self-renewal of recipient cells, such as mammosphere formation. In addition, RNA sequencing analysis showed that CD81 knockdown up-regulates expression of a cell differentiation marker, SEMA7a, whose down-regulation partially rescues mammosphere formation inhibition by CD81 depletion. Clinically, CD81 expression was observed in >80% of CTCs and specifically enriched and co-expressed along with CD44 in clustered CTCs of breast cancer patients. Mimicing the phenotypes of CD44 deficiency, loss of CD81 also inhibited tumor cell aggregation and lung metastasis of TNBC in both human and mouse tumor models, supporting the clinical significance of CD81 in association with patient outcomes. Our study highlights a new driving role of CD81 in cancer exosome-induced stemness, clustered CTCs, and metastasis initiation of TNBC, reported for the first time to our knowledge.

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

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

Anthropogenic nitrogen (N) and phosphorus (P) inputs can alter the stoichiometry of senesced plant tissues, a key trait controlling nutrient cycling. However, it is unclear how fertilization rate affects plant litter tissue chemistry under varied N:P supply ratios. In a 2-year study, we investigated the effects of N and P supply rates at three N:P input ratios (4:1, 16:1, and 60:1) on the chemical constitution and N:P stoichiometry of the litter of two grasses: Leymus chinensis and Stipa krylovii. We further evaluated the differential responses of chemical constitution and N:P stoichiometry in leaf and culm litter of L. chinensis. Combined N and P fertilization increased soil acidity and plant-available N, but decreased plant-available P, especially when fertilization occurred at N:P ratio = 60:1. Litter N and P concentrations showed positive response to N and P inputs, and N concentration increased with fertilization rate under N:P ratio = 4:1, but P concentration decreased under N:P ratio = 60:1. Furthermore, we found stronger responses of N and P in L. chinensis and culms than in S. krylovii and leaves. Stoichiometric responses became more positive with increasing N and P fertilization level at each ratio. Nitrogen and P inputs also significantly improved potassium, copper, and sodium concentrations in senesced shoots independent of fertilization rates except for sodium at N:P ratio = 16:1, which had weaker responses in L. chinensis and leaves than in S. krylovii and culms. The effects of N and P inputs on other elements were primarily influenced by species and organs, but were also idiosyncratically affected by input levels at each ratio. These results indicate that decreasing evenness of N and P inputs may have increasingly severe non-linear impacts on nutrient cycling and that these impacts will be greater in L. chinensis-dominated ecosystems compared to those dominated by S. krylovii.

PURPOSE/OBJECTIVE(S) Most patients (pts) with relapsed/refractory (RR) cHL undergo salvage chemotherapy (CT) followed by curative-intent autologous stem cell transplant (ASCT). For failure post-ASCT, allogeneic stem cell transplant is considered in select cases. Given the morbidity of transplants, it is beneficial to assess if RT-based regimens can offer potential cure in RR cHL with less toxicity and without consolidative transplant. MATERIALS/METHODS We reviewed medical records of RR cHL pts salvaged between 2009 and 2019 with either RT alone or in combination with systemic therapy (ST) for 2nd line therapy and beyond (i.e., post-ASCT). We defined relapse as recurrence after complete response (CR) and refractory as failure to achieve CR after frontline/salvage therapy. Response and toxicity were assessed by Lugano criteria and CTCAEv.5, respectively. Kaplan Meier survival and univariate Cox regression analyses were performed. RESULTS We identified 26 pts (10 in RT vs. 16 in RT + ST) of which 88% had localized disease prior to RT-based salvage. All relapsed pts (n = 12) had localized relapse (stage I/II), and 50% had relapse > 1 yr after finishing frontline therapy. Relapsed pts who received frontline RT (n = 2) failed outside of prior fields. Reasons to forgo 2nd line therapy of ST followed by ASCT (n = 13) were localized disease/pt preference (92%) and comorbidities (8%). Most relapsed (67%) and refractory (64%) pts got RT + ST with 81% receiving brentuximab vedotin and 19% receiving pembrolizumab. Five pts received cytotoxic CT and then RT-based salvage, forgoing intended ASCT primarily due to refractory disease. After RT-based salvage (median dose 36 Gy (30-45)), 85% of pts achieved CR (70% in RT vs. 94% RT + ST) and 15% had progressive disease (30% in RT vs. 6% in RT + ST). 86% of pts with CR remained disease-free at 5 yrs. With a median follow up of 4.9 yrs, 5 yr PFS and OS for the entire cohort was 72% (95% CI: 56-92) and 92% (95% CI: 82-100), respectively. No significant difference in PFS was found between relapsed vs. refractory disease (HR = 0.7; 95% CI: 0.2-2.9; P = 0.6) or RT vs. RT + ST (HR = 1.8, 95% CI: 0.4-7.1; P = 0.4). Failures (n = 8) were categorized as isolated locoregional (outside of RT field) (38%), isolated distant (25%), combined local/locoregional/distant (25%); and local/locoregional (13%). Three grade (G) 3 and 0 ≥G4 events were reported. G2-3 ST-related toxicities included cytopenias (n = 2, 13%) and neuropathy (5, 31%), resulting in discontinuation/dose-reduction in 5 pts and hospitalization in 1. G2 RT-related toxicities included radiation pneumonitis (2, 8%), dermatitis (6, 23%), esophagitis (9, 35%), and hypothyroidism (5, 19%). CONCLUSION In this retrospective study, most RR cHL pts with localized disease achieved CR after RT-based salvage with low toxicity and without consolidative transplant. With a 5 yr PFS of 72%, RT-based salvage regimens appear effective and well-tolerated options for select RR cHL pts.

Common buckthorn (Rhamnus cathartica L.) is a prolific invader of forest understories throughout eastern North America. Its ability to invade is partially attributable to its relatively high shade tolerance and ability to capture light both early and late in the growing season because of its phenological differences from native species. Competitors that mitigate this phenological advantage by casting shade early and late in the growing season may therefore increase biotic resistance against invasion. However, controlled comparisons between buckthorn and other woody understory species are scarce and to what extent buckthorn’s phenology is truly exceptional is incompletely known. Here, we compare the spring and autumn phenologies of five shade tolerant, native woody species (Sambucus canadensis, Sambucus racemosa, Corylus americana, Cornus racemosa, and Acer saccharum) to those of buckthorn in two common garden experiments. Spring phenology of buckthorn was often comparable to the five native species considered. All native species broke bud no later than 7 days after buckthorn, with S. racemosa reaching spring phenophases consistently earlier than buckthorn. In contrast to spring, buckthorn fall phenology was distinct in comparison to some natives but not all. Native species started to senesce up to 20 days earlier than buckthorn, but both Sambucus species senesced slowly and held their leaves equally long as buckthorn. These findings illustrate that buckthorn does not possess unique phenology amongst understory species. Forest communities rich in deciduous shrubs or trees that are phenologically similar to buckthorn (particularly S. racemosa) likely limit buckthorn's critical spring and fall carbon gains and exert greater biotic resistance to invasion by buckthorn.

The treatment landscape for chronic lymphocytic leukemia (CLL) is changing rapidly. Novel targeted agents such as ibrutinib, venetoclax, and idelalisib have had a significant effect on first-line, relapsed/refractory, and high-risk disease. Despite these advances, there are continuous needs for new treatment options, especially for patients in whom these novel therapies fail or those who cannot tolerate these novel therapies. In 2011, Porter et al reported the first successful use of autologous chimeric antigen receptor T cells (CARTs) directed against cluster of differentiation (CD)19 in 3 refractory CLL patients. Several groups have since shown success with similar approaches in various settings of CLL, including failure of ibrutinib treatment and in patients who relapse after allogeneic stem cell transplantation. Although CD19-directed CART therapy holds great promise in CLL and other diseases, many challenges and questions remain including: optimization of the lymphodepletion regimen before CART infusion, optimal dosing of CART, a determination of the most effective CART product (T-cell subset[s]) as well as the optimal combinations and therapeutic sequences, and managing treatment-associated adverse events. Clinical trials addressing these challenges are in process. In this timely review, we analyze current state of CART therapy in CLL and attempt answering remaining questions.

Carbon fibre reinforced polymers (CFRP) offer superior weight-specific mechanical properties. However, their brittle failure behaviour limits the structural integrity and damage tolerance in case of impact and crash events. Furthermore, the electrical conductivity is insufficient for certain applications (e.g. lightning strike protection, signal transfer, grounding). Former material concepts tried to resolve these deficits by modifying the resin system, but could not prove sufficient enhancements. A novel approach is the incorporation of highly conductive and ductile continuous metal filaments into the CFRP, thus merging electrical and load-bearing functions within the metal fibres. In this context, the present study focuses on optimising the structural and electrical performance of such hybrid composites with shares of metal fibres up to 20 vol.%. Fundamental experiments are carried out on unidirectional as well as on multiaxial (hybrid) laminates. Synchronous improvements of the electrical conductivity, the impact and penetration resistance, the notched properties as well as a pseudo-ductile behaviour can be verified. Additionally, the application of integrated metastable austenitic steel fibres for non-destructive health monitoring by measurement of deformation-induced phase transformations is introduced and discussed.

Ibrutinib, idelalisib, and venetoclax are approved for treating CLL patients in the United States. However, there is no guidance as to their optimal sequence.We conducted a multicenter, retrospective analysis of CLL patients treated with kinase inhibitors (KIs) or venetoclax. We examined demographics, discontinuation reasons, overall response rates (ORR), survival, and post-KI salvage strategies. Primary endpoint was progression-free survival (PFS).A total of 683 patients were identified. Baseline characteristics were similar in the ibrutinib and idelalisib groups. ORR to ibrutinib and idelalisib as first KI was 69% and 81%, respectively. With a median follow-up of 17 months (range 1-60), median PFS and OS for the entire cohort were 35 months and not reached. Patients treated with ibrutinib (versus idelalisib) as first KI had a significantly better PFS in all settings; front-line [hazard ratios (HR) 2.8, CI 1.3-6.3, P = 0.01], relapsed-refractory (HR 2.8, CI 1.9-4.1, P0.001), del17p (HR 2.0, CI 1.2-3.4, P = 0.008), and complex karyotype (HR 2.5, CI 1.2-5.2, P = 0.02). At the time of initial KI failure, use of an alternate KI or venetoclax had a superior PFS when compared with chemoimmunotherapy. Furthermore, patients who discontinued ibrutinib due to progression or toxicity had marginally improved outcomes if they received venetoclax (ORR 79%) versus idelalisib (ORR 46%) (PFS HR .6, CI.3-1.0, P = 0.06).In the largest real-world experience of novel agents in CLL, ibrutinib appears superior to idelalisib as first KI. Furthermore, in the setting of KI failure, alternate KI or venetoclax therapy appear superior to chemoimmunotherapy combinations. The use of venetoclax upon ibrutinib failure might be superior to idelalisib. These data support the need for trials testing sequencing strategies to optimize treatment algorithms.

Introduction CD19 directed CAR T cells have potent activity in relapsed/refractory (R/R) aggressive B-cell lymphomas (B-NHL) leading to the FDA approval of axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel). Initial reports on commercial use of axi-cel suggest many patients (pts) would not have met eligibility criteria for ZUMA-1, yet outcomes and toxicities appeared similar. Limited data on the "real world" use of tisa-cel is available. We performed a multicenter retrospective study to evaluate efficacy, safety, and patterns of use in 8 US centers that had the option of prescribing either commercial product for R/R B-NHL. Results As of 7/31/2019, 242 pts underwent apheresis for axi-cel or tisa-cel. Of these, 163 (67%) underwent apheresis for axi-cel, and 79 (33%) for tisa-cel. 14 (9%) axi-cel and 3 (4%) tisa-cel pts died prior to CAR T-cell infusion from lymphoma progression, and 1 (1%) tisa-cel pt was not infused for other reasons. Detailed baseline pt characteristics were available for 180/242 pts (Figure 1). Median age at apheresis was 58 years (range: 18-85) for axi-cel and 67 years (range: 36-88) for tisa-cel. ECOG PS was 0-1 in 86% of axi-cel and 94% of tisa-cel pts. The median number of prior therapies was 3 (range: 2-11) for axi-cel and 4 (range: 2-9) for tisa-cel pts. Bridging therapy was given in 61% of axi-cel and 72% of tisa-cel pts. Median time from apheresis to CAR T-cell infusion was 28 days for axi-cel and 44 days for tisa-cel. CAR T-cell infusion was inpatient in 100% of axi-cel and 39% of tisa-cel pts. Safety was evaluable in 213 pts. CRS was graded according to institutional practices (CARTOX (38%), Penn scale (31%), ASTCT (19%), and Lee scale (11%)). NEs were graded per CARTOX (80%), ASTCT (19%), or CTCAE V4.03 (1%). Grade ≥3 CRS and NEs occurred in 13% and 41% of axi-cel pts and 1% and 3% of tisa-cel pts. The median onset of CRS and NEs was 2 and 6 days in axi-cel, and 3 and 5 days in tisa-cel treated pts, respectively. Tocilizumab was administered in 62% of axi-cel pts with 57% receiving steroids. In tisa-cel pts, tocilizumab was administered in 13% of cases, with 7% receiving steroids. Response assessment was performed for infused pts at day 30 and/or day 90, or in those with clinical progression. Of 120 axi-cel pts evaluable at day 30, the ORR was 72% with 43% achieving a CR. Of the 32 tisa-cel pts evaluable at day 30, the ORR was 59% with 44% achieving a CR. At day 90, the ORR for axi-cel was 52% with 39% achieving a CR, while for tisa-cel the ORR was 48% with 39% achieving a CR. Conclusions Efficacy outcomes in the commercial setting appear similar to responses seen in the pivotal clinical trials. Though different toxicity grading scales were employed, tisa-cel appears to be associated with less CRS and NEs. Updated analyses of usage patterns and outcomes with uniform ASTCT toxicity grading will be presented at the meeting.

Groundwater resources are under increasing threats from contamination and overuse, posing direct threats to human and environmental health. The purpose of this study is to better understand drivers of, and relationships between, well and aquifer characteristics, sampling frequencies, and microbiological contamination indicators (specifically E. coli) as a precursor for improving knowledge and tools to assess aquifer vulnerability and well contamination within Ontario, Canada. A dataset with 795, 023 microbiological testing observations over an eight-year period (2010 to 2017) from 253,136 unique wells across Ontario was employed. Variables in this dataset include date and location of test, test results (E. coli concentration), well characteristics (well depth, location), and hydrogeological characteristics (bottom of well stratigraphy, specific capacity). Association rule analysis, univariate and bivariate analyses, regression analyses, and variable discretization techniques were utilized to identify relationships between E. coli concentration and the other variables in the dataset. These relationships can be used to identify drivers of contamination, their relative importance, and therefore potential public health risks associated with the use of private wells in Ontario. Key findings are that: i) bedrock wells completed in sedimentary or igneous rock are more susceptible to contamination events; ii) while shallow wells pose a greater risk to consumers, deep wells are also subject to contamination events and pose a potentially unanticipated risk to health of well users; and, iii) well testing practices are influenced by results of previous tests. Further, while there is a general correlation between months with the greatest testing frequencies and concentrations of E. coli occurring in samples, an offset in this timing is observed in recent years. Testing remains highest in July while peaks in adverse results occur up to three months later. The realization of these trends prompts a need to further explore the bases for such occurrences.

Private well users are responsible for managing and maintaining the quality of their drinking water source. Previous studies in Canada have reported low testing rates among well users, a cornerstone of well stewardship behaviours that can prevent the consumption of contaminated groundwater. To improve well stewardship, it is important to understand the interactions between, and the impacts of, various factors that may influence behaviours. Accordingly, the objective of the current study was to investigate the impact of socio-demographics, property characteristics, and experiences with well construction and acute gastrointestinal illness (AGI) (i.e., previous experiences) on levels of awareness, attitudes, risk perceptions, and beliefs (i.e., risk domains) among private well users in Ontario. A link to a province-wide online survey was circulated between May and August 2018 and novel "risk domain" scoring protocols were developed to classify and summarize response data. The survey was undertaken by 1228 respondents, of which 1030 completed the survey in full. Results indicate a low level of waterborne pathogen awareness, with 50.8% of respondents unaware of any groundwater associated pathogens. Respondents' geographic location, gender, and well type were significantly associated with well users' attitudes and perceptions of risk regarding their personal well water supply and the quality and quantity of local groundwater sources. Higher levels of awareness and lower risk perception scores (i.e., lower perceptions of risk) were associated with residential presence during well construction (p 0.001 and p = 0.017, respectively). Previous case(s) of AGI within the respondent's household were significantly associated with negative attitudes towards their well water (p 0.001) and higher risk perception scores (p = 0.025) with respect to the quantity of local groundwater sources. Results may be used to identify critical experiential control points (e.g., during well construction or after a physician confirmed AGI diagnosis) and develop improved risk management and communication strategies aimed at private well users.

Forest light availability strongly regulates understory community composition, and low availability may confer resistance to invasion by exotic species, yet common buckthorn (Rhamnus cathartica L.) invades North American temperate forests with a broad range of light habitats. It is unclear to what extent buckthorn’s success is due to high mid-season shade tolerance versus shade avoidance permitted by early leaf out and late senescence. We used buckthorn seedlings planted into a forest diversity experiment in Cloquet, Minnesota, USA and a combined buckthorn physiology-canopy light model to test (1) how buckthorn germination, growth, and survival depend on canopy shading and (2) how canopy species richness and phenology affect light availability and buckthorn performance. Based on the mean of May, August, and October light measurements, we found that canopies that permitted ≤3% transmission of incoming light had almost complete mortality of buckthorn and that growth of surviving buckthorn was strongly tied to light availability, but not canopy richness. Compared to deciduous canopies or deciduous-evergreen mixtures, evergreen canopies restricted light availability the most and led to the smallest and least likely to survive buckthorn. Our canopy models further indicated a tight linkage between buckthorn performance and spring and autumn light availability, but not summer light availability. We conclude that spring and autumn light availability are key regulators of buckthorn performance and that buckthorn relies on shade avoidance via an extended phenology to succeed in temperate forests. Consequently, we suggest species with extended spring or autumn canopy cover offer the greatest resistance to invasion, and communities which are often leafless during such periods are most vulnerable to invasion by buckthorn and similar invasive shrubs.