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Background: Chimeric antigen receptor T-cell (CAR-T) therapies are available for patients with Non-Hodgkin Lymphoma (NHL); however, their use has been limited in accessibility due to nondisease factors., Patients & Methods: We conducted a retrospective study evaluating the influence of sociodemographic factors on access and outcomes after CAR-T therapy for adult patients with B-cell NHL in our institution treated between 2016 and 2023., Results: Among 154 patients treated with CAR-T, 43% were older than 65 years, 68% male, and 14% non-White (including Hispanic). Of those under 65, 66% had private insurance, while 82% over 65 had Medicare. Most patients (85%) were from in-state, 29% from areas below the national poverty level and 18% from nonmetropolitan areas. Distance to the treatment center was greater than 30, 60 or 120 miles for 52%, 40% and 29% of patients, respectively. No significant differences were found in the use of commercial versus investigational products among racial/ethnic minorities or those living >60 miles from the center. However, patients from nonmetropolitan areas and those below the national poverty level were less likely to receive commercial products. With a median follow-up of 11 months, the 1-year overall survival (OS) was 63.2% (95 th CI 59.9%-66.8%). Poverty was associated with lower 1-year OS (HR 0.4, 95 th CI 0.17-0.90, P = .031)., Conclusion: Our study shows that CAR-T therapy can be delivered across sociodemographic barriers and underscores the importance of considering social determinants of health to optimize access for all patients., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established., Methods: We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion., Results: Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR., Conclusion: CAR-T demonstrates clinical efficacy for patients with RT.

Background: Administration of anti-CD19 chimeric antigen receptor T-cell (CART19) immunotherapy for large B-cell lymphomas (LBCLs), a subset of non-Hodgkin lymphoma (NHL), involves high costs and access to specialized tertiary care centers. We investigated whether minority health populations (MHPs) have equal access to CART19 and whether their outcomes are similar to those of non-MHPs., Methods: We analyzed the prevalence and clinical outcomes of patients treated with commercial CART19 at two geographically and socioeconomically different institutions: the Abramson Cancer Center (ACC, Philadelphia, Pennsylvania) and the Knight Cancer Institute (KCI, Portland, Oregon)., Results: In the ACC catchment area, 8956 patients were diagnosed with NHL between 2015 and 2019 (latest available data from the state registry), including 17.9% MHPs. In the ACC, between 2018 and 2022 (CART became available in 2018), 1492 patients with LBCL were treated, and 194 received CART19. The proportion of MHPs was 15.7% for the entire LBCL cohort but only 6.7% for the CART19 cohort. During the same time, in the KCI catchment area, 4568 patients were diagnosed with NHL, including 4.2% MHPs. In the KCI, 396 patients with LBCL were treated, and 47 received CART19. The proportion of MHPs was 6.6% for the entire LBCL cohort and 4.2% for the CART19 cohort. The 3-month response, survival, and toxicities after CART19 infusion showed similar results, although the number of patients who were treated was limited., Conclusions: This study shows that the access of MHPs to tertiary centers for LBCL care was preserved but appeared reduced for commercial CART19 immunotherapy. Although clinical outcomes of MHPs seemed similar to those of non-MHPs, the small sample size precludes drawing firm conclusions. Further studies are needed. (Funded by the Laffey McHugh Foundation and others.).

Background: Peripheral T-cell lymphomas (PTCL) are a group of aggressive malignancies with inferior outcomes compared to B-cell non-Hodgkin lymphoma (NHL). Both allogeneic and autologous hematopoietic cell transplantation (HCT) are commonly employed for consolidation and salvage., Materials and Methods: We conducted a single-center review of all adult PTCL patients at OHSU who received HCT from 1991 to 2020 with responses assed by CIBMTR criteria., Results: 88 patients (autoHCT = 52, alloHCT = 36) were identified from the internal registry of ∼3800 autoHCT & alloHCT recipients in that time period. Median OS after autoHCT and alloHCT were 7.0 and 2.6 years. Median PFS after autoHCT and alloHCT was 3.9 vs 1.1 years. Post-HCT median OS for ALCL, AITL, and PTCL NOS were 14.9, 3.9, and 3.4 years, respectively. Median PFS after autoHCT performed while in CR vs. not in CR was 3.4 vs 4.2 years (P = 0.86); for alloHCT in CR vs. not CR 2.4 vs 0.7 years (P = 0.28). 1-year non-relapse mortality (NRM) for autoHCT and alloHCT were 6.1% and 22.2% (P = 0.2). 10/88 patients developed secondary malignancies including 4 skin cancers, 3 new lymphomas, and 2 MDS., Conclusion: Our experience with HCT for PTCL shows that HCT has acceptable toxicities and relatively long disease remissions. AutoHCT was most frequently utilized as planned remission consolidation while alloHCT was most often used late during salvage. Differences in response between autoHCT and alloHCT likely reflect differences in clinical setting and underlying disease natural history and biology., (Published by Elsevier Inc.)

Tisagenlecleucel (tisa-cel) is an approved CD19-directed chimeric antigen receptor T cell (CAR-T) therapy for relapsed/refractory B cell malignancies. Given potentially life-threatening toxicities, including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, inpatient tisa-cel infusion and toxicity monitoring are often considered; however, the toxicity profile of tisa-cel may be conducive to outpatient administration. Here we review the characteristics and outcomes of tisa-cel recipients treated in the outpatient setting. Patients age ≥18 years with B cell non-Hodgkin lymphoma who received tisa-cel between June 25, 2018, and January 22, 2021, at 9 US academic medical centers were included in a retrospective analysis. Six of the 9 representative centers (75%) had an outpatient program in place. A total of 157 patients were evaluable, including 93 (57%) in the outpatient treatment group and 64 (43%) in the inpatient treatment group. Baseline characteristics, toxicity and efficacy, and resource utilization were summarized. The most common lymphodepletion (LD) regimen was bendamustine in the outpatient group (65%) and fludarabine/cyclophosphamide (91%) in the inpatient group. The outpatient group had more patients with a Charlson Comorbidity Index of 0 (51% versus 15%; P < .001), fewer patients with an elevated lactate dehydrogenase (LDH) level above the normal range at the time of LD (32% versus 57%, P = .003) compared to the inpatient group, and a lower Endothelial Activation and Stress Index score (.57 versus 1.4; P < .001). Any-grade CRS and ICANS were lower in the outpatient group (29% versus 56% [P < .001] and 10% versus 16% [P = .051], respectively). Forty-two outpatient tisa-cel recipients (45%) required an unplanned admission, with a median length of stay of 5 days (range, 1 to 27 days), compared to 13 days (range, 4 to 38 days) in the inpatient group. The median number of tocilizumab doses administered was similar in the 2 groups as were the rate of intensive care unit (ICU) transfer (5% versus 8%; P = .5) and median length of ICU stay (6 days versus 5 days; P = .7). There were no toxicity-related deaths in the 30 days post-CAR-T infusion in either group. Progression-free survival and overall survival were similar in the 2 groups. With careful patient selection, outpatient tisa-cel administration is feasible and associated with similar efficacy outcomes as inpatient treatment. Outpatient toxicity monitoring and management may help optimize healthcare resource utilization., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Increased nitrate concentrations in groundwater and surface waters represent one of the most widespread and acute impacts of modern agriculture on the environment. However, there is often a fundamental gap in understanding how individual agricultural fields and practices contribute to this broad-scale issue. To practically address nutrient dynamics at individual agricultural sites, methods for assessing nitrogen loss to groundwater that are minimally invasive and thus can encourage farmer "buy in" are necessary. We present an approach that uses edge-of-field monitoring at multilevel samplers along with a once-per-year tracer application (bromide) to calculate nitrogen loss on an annual basis. Using appropriate spatio-temporal integrals of measured concentrations, a net loss of nitrogen to groundwater (per field area) can be calculated. This approach directly measures impacts of nitrogen leaching below the water table, while avoiding permanent in-field installations that can interfere with farm operations. We present an application of this technique to assess nitrogen loss to groundwater over 5 years for a commercial agricultural field in Sauk County, WI. Results from Field 19 indicate that nitrogen losses are similar to (or slightly below) previously reported values for corn and potato crops. In all years, however, we estimate that more than 25% (>60 kg/ha) of nitrogen applied leached as nitrate to groundwater. Use of this mass flux estimation method was most reliable when: (1) tracer is injected directly at the water table, limiting "smearing" within the vadose zone; and (2) nitrate concentrations from laboratory analysis were obtained, rather than using ion-selective electrodes or nitrate test strips., (© 2022 The Authors. Groundwater published by Wiley Periodicals LLC on behalf of National Ground Water Association.)

Static magnetic fields (SMF) have neuroprotective and behavioral effects in rats, however, little is known about the effects of SMF on cognition, motor function and the underlying neurochemical mechanisms. In this study, we focused on the effects of short-term (5-10d) and long-term (13-38d) SMF exposure on selective attention and motor coordination of rats, as well as associated alterations in expression level of neuroplasticity-related structural proteins and cryptochrome (CRY1) protein in the cortex, striatum and ventral midbrain. The results showed that 6d SMF exposure significantly enhanced selective attention without affecting locomotor activity in open field. All SMF exposures non-significantly enhanced motor coordination (Rotarod test). Neurochemical analysis demonstrated that 5d SMF exposure increased the expression of cortical and striatal CRY1 and synapsin-1 (SYN1), striatal total synapsins (SYN), and synaptophysin (SYP), growth associated protein-43 (GAP43) and post-synaptic density protein-95 (PSD95) in the ventral midbrain. Exposure to SMF for 14d increased PSD95 level in the ventral midbrain while longer SMF exposure elevated the levels of PSD95 in the cortex, SYN and SYN1 in all the examined brain areas. The increased expression of cortical and striatal CRY1 and SYN1 correlated with the short-lasting effect of SMF on improving selective attention. Collectively, SMF's effect on selective attention attenuated following longer exposure to SMF whereas its effects on neuroplasticity-related structural biomarkers were time- and brain area-dependent, with some protein levels increasing with longer time exposure. These findings suggest a potential use of SMF for treatment of neurological diseases in which selective attention or neuroplasticity is impaired., Competing Interests: Conflicts of interest The authors declare no conflicts of interest., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

CD19-targeted chimeric antigen receptor-engineered (CD19 CAR) T cells are novel therapies showing great promise for patients with relapsed or refractory (R/R) aggressive B-cell non-Hodgkin lymphoma (B-NHL). Single-arm studies showed significant variations in outcomes across distinct CD19 CAR T-cell products. To estimate the independent impact of the CAR T-cell product type on outcomes, we retrospectively analyzed data from 129 patients with R/R aggressive B-NHL treated with cyclophosphamide and fludarabine lymphodepletion followed by either a commercially available CD19 CAR T-cell therapy (axicabtagene ciloleucel [axicel] or tisagenlecleucel [tisacel]), or the investigational product JCAR014 on a phase 1/2 clinical trial (NCT01865617). After adjustment for age, hematopoietic cell transplantation-specific comorbidity index, lactate dehydrogenase (LDH), largest lesion diameter, and absolute lymphocyte count (ALC), CAR T-cell product type remained associated with outcomes in multivariable models. JCAR014 was independently associated with lower cytokine release syndrome (CRS) severity compared with axicel (adjusted odds ratio [aOR], 0.19; 95% confidence interval [CI]; 0.08-0.46), with a trend toward lower CRS severity with tisacel compared with axicel (aOR, 0.47; 95% CI, 0.21-1.06; P = .07). Tisacel (aOR, 0.17; 95% CI, 0.06-0.48) and JCAR014 (aOR, 0.17; 95% CI, 0.06-0.47) were both associated with lower immune effector cell-associated neurotoxicity syndrome severity compared with axicel. Lower odds of complete response (CR) were predicted with tisacel and JCAR014 compared with axicel. Although sensitivity analyses using either positron emission tomography- or computed tomography-based response criteria also suggested higher efficacy of axicel over JCAR014, the impact of tisacel vs axicel became undetermined. Higher preleukapheresis LDH, largest lesion diameter, and lower ALC were independently associated with lower odds of CR. We conclude that CD19 CAR T-cell product type independently impacts toxicity and efficacy in R/R aggressive B-NHL patients., (© 2022 by The American Society of Hematology.)

Background: Second autologous transplants (SAT) are routinely performed in the setting of myeloma relapse, though data on outcomes are lacking. We conducted a single-center review of all multiple myeloma patients at OHSU who received SAT (excluding tandems) with responses assessed by International Myeloma Working Group (IMWG) criteria., Results: Sixty-eight patients received SAT between 1999 and 2019. Risk by IMWG was available for 50 patients (10 high-risk). Median age at SAT was 61 (45-74). Median time between 1st and 2nd Autologous stem cell transplantation (ASCT) was 5.5 years (1.1 - 15.2). Median progression-free survival (PFS) after 1st ASCT (available for 53 pts) was 2.5 years (0.3 - 10). The average # of lines of therapy prior to SAT was 2.8 (1-14). SAT prep regimens (available for 67 pts) were: Fifty-one (87%) melphalan 200 mg/m 2 , 6 (9%) melphalan 140 mg/m 2 , 1 (2%) BEAM, 1 (2%) melphalan 200 mg/m 2 and bortezomib. All used PBSC mobilization. Median overall survival (OS) after SAT was 4.68 years, and median PFS was 1.72 years. By treatment era (1999-2009 vs. 2010-2019), median OS was 1.97 vs. 5.52 years (P = .15). When analyzed by IMWG group (standard/low vs. high risk) median PFS and OS were not significantly different (1.87 vs. 1.61 years and 3.58 vs. 5.91 years, respectively). Treatment-Related Mortality (TRM) occurred in 1 patient (2%)., Conclusion: Our experience with SAT for multiple myeloma (MM) shows that it has low TRM and is effective, with median OS >4.5 years, though with a shorter PFS than after 1st ASCT., Competing Interests: Disclosure The corresponding author has no conflicts of interest to report., (Copyright © 2021. Published by Elsevier Inc.)

Belumosudil, an investigational oral selective inhibitor of Rho-associated coiled-coil-containing protein kinase 2 (ROCK2), reduces type 17 and follicular T helper cells via downregulation of STAT3 and enhances regulatory T cells via upregulation of STAT5. Belumosudil may effectively treat patients with chronic graft-versus-host disease (cGVHD), a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2 randomized multicenter registration study evaluated belumosudil 200 mg daily (n = 66) and 200 mg twice daily (n = 66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions, and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR for belumosudil 200 mg daily and 200 mg twice daily was 74% (95% confidence interval [CI], 62-84) and 77% (95% CI, 65-87), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg daily and 200 mg twice daily was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil because of possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. This trial was registered at www.clinicaltrials.gov as #NCT03640481., (© 2021 by The American Society of Hematology.)