This study provides an overview of established processes as well as recent progress in emerging technologies for advanced oxidation processes (AOPs). In addition to a discussion of major reaction ...mechanisms and formation of by-products, data on energy efficiency were collected in an extensive analysis of studies reported in the peer-reviewed literature enabling a critical comparison of various established and emerging AOPs based on electrical energy per order (EEO) values. Despite strong variations within reviewed EEO values, significant differences could be observed between three groups of AOPs: (1) O3 (often considered as AOP-like process), O3/H2O2, O3/UV, UV/H2O2, UV/persulfate, UV/chlorine, and electron beam represent median EEO values of <1 kWh/m3, while median energy consumption by (2) photo-Fenton, plasma, and electrolytic AOPs were significantly higher (EEO values in the range of 1–100 kWh/m3). (3) UV-based photocatalysis, ultrasound, and microwave-based AOPs are characterized by median values of >100 kWh/m3 and were therefore considered as not (yet) energy efficient AOPs. Specific evaluation of 147 data points for the UV/H2O2 process revealed strong effects of operational conditions on reported EEO values. Besides water type and quality, a major influence was observed for process capacity (lab-vs. pilot-vs. full-scale applications) and, in case of UV-based processes, of the lamp type. However, due to the contribution of other factors, correlation of EEO values with specific water quality parameters such as UV absorbance and dissolved organic carbon were not substantial. Also, correlations between EEO and compound reactivity with OH-radicals were not significant (photolytically active compounds were not considered). Based on these findings, recommendations regarding the use of the EEO concept, including the upscaling of laboratory results, were derived.
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•Short summary of radical generation mechanisms and application of AOPs.•First comparison of published EEO values across different AOPs.•Critical consideration of influencing factors on reported EEO values within UV/H2O2.•Proposal for proper use of the EEO-concept.•Discussion of major oxidation by-product formation mechanisms.
Patients with relapsed or refractory mantle-cell lymphoma who have disease progression during or after the receipt of Bruton's tyrosine kinase (BTK) inhibitor therapy have a poor prognosis. KTE-X19, ...an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, may have benefit in patients with relapsed or refractory mantle-cell lymphoma.
In a multicenter, phase 2 trial, we evaluated KTE-X19 in patients with relapsed or refractory mantle-cell lymphoma. Patients had disease that had relapsed or was refractory after the receipt of up to five previous therapies; all patients had to have received BTK inhibitor therapy previously. Patients underwent leukapheresis and optional bridging therapy, followed by conditioning chemotherapy and a single infusion of KTE-X19 at a dose of 2×10
CAR T cells per kilogram of body weight. The primary end point was the percentage of patients with an objective response (complete or partial response) as assessed by an independent radiologic review committee according to the Lugano classification. Per the protocol, the primary efficacy analysis was to be conducted after 60 patients had been treated and followed for 7 months.
A total of 74 patients were enrolled. KTE-X19 was manufactured for 71 patients and administered to 68. The primary efficacy analysis showed that 93% (95% confidence interval CI, 84 to 98) of the 60 patients in the primary efficacy analysis had an objective response; 67% (95% CI, 53 to 78) had a complete response. In an intention-to-treat analysis involving all 74 patients, 85% had an objective response; 59% had a complete response. At a median follow-up of 12.3 months (range, 7.0 to 32.3), 57% of the 60 patients in the primary efficacy analysis were in remission. At 12 months, the estimated progression-free survival and overall survival were 61% and 83%, respectively. Common adverse events of grade 3 or higher were cytopenias (in 94% of the patients) and infections (in 32%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 15% and 31% of patients, respectively; none were fatal. Two grade 5 infectious adverse events occurred.
KTE-X19 induced durable remissions in a majority of patients with relapsed or refractory mantle-cell lymphoma. The therapy led to serious and life-threatening toxic effects that were consistent with those reported with other CAR T-cell therapies. (Funded by Kite, a Gilead company; ZUMA-2 ClinicalTrials.gov number, NCT02601313.).
In this study, we comparatively investigated the degradation of 12 trace organic chemicals (TOrCs) during UV/H2O2 and UV/peroxydisulfate (PDS) processes. Second-order rate constants for the reactions ...of iopromide, phenytoin, caffeine, benzotriazole, and primidone with sulfate radical (SO4•−) were determined for the first time. Experiments were conducted in buffered pure water and wastewater effluent with spiked TOrCs. UV/PDS degraded all TOrCs more efficiently than UV/H2O2 in buffered pure water due to the higher yield of SO4•− than that of hydroxyl radical (•OH) at the same initial molar dose of PDS and H2O2, respectively. UV/PDS showed higher selectivity toward TOrCs removal than UV/H2O2 in wastewater effluent. Compounds with electron-rich moieties, such as diclofenac, venlafaxine, and metoprolol, were eliminated faster in UV/PDS whereas UV/H2O2 was more efficient in degrading compounds with lower reactivity to SO4•−. The fluence-based rate constants (kobs−UV/H2O2) of TOrCs in wastewater effluent linearly increased as a function of initial H2O2 dose during UV/H2O2, possibly due to the constant scavenging impact of the wastewater matrix on •OH. However, exponential increase of kobs−UV/PDS with increasing PDS dose was observed for most compounds during UV/PDS, suggesting the decreasing scavenging effect of the water matrix (electron-rich site of effluent organic matter (EfOM)) after initial depletion of SO4•− at low PDS dose. Fulvic and humic-like fluorophores appeared to be more persistent during UV/H2O2 compared to aromatic protein and soluble microbial product-like fluorophores. In contrast, UV/PDS efficiently degraded all identified fluorophores and showed less selectivity toward the fluorescent EfOM components. Removal pattern of TOrCs during pilot-scale UV/PDS was consistent with lab-scale experiments, however, overall removal rates were lower due to the presence of higher concentration of EfOM and nitrite.
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•A comparative investigation on the efficiency of UV/H2O2 and UV/PDS.•Degradation kinetics of 12 trace organic chemicals.•Higher steady state concentration of SO4•− compared to •OH in pure water.•Selective property of SO4•− favouring oxidation of electron-rich organic moieties.•Pilot-scale validation of UV/PDS in wastewater treatment plant effluent.
Brexucabtagene autoleucel (KTE-X19) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy is approved for the treatment of relapsed/refractory mantle cell lymphoma (MCL). Outcomes after ...a 3-year follow-up in the pivotal ZUMA-2 study of KTE-X19 in relapsed/refractory MCL are reported, including for subgroups by prior therapy (bendamustine and type of Bruton tyrosine kinase inhibitor BTKi) or high-risk characteristics.
Patients with relapsed/refractory MCL (one to five prior therapies, including prior BTKi exposure) received a single infusion of KTE-X19 (2 × 10
CAR T cells/kg).
After a median follow-up of 35.6 months, the objective response rate among all 68 treated patients was 91% (95% CI, 81.8 to 96.7) with 68% complete responses (95% CI, 55.2 to 78.5); medians for duration of response, progression-free survival, and overall survival were 28.2 months (95% CI, 13.5 to 47.1), 25.8 months (95% CI, 9.6 to 47.6), and 46.6 months (95% CI, 24.9 to not estimable), respectively. Post hoc analyses showed that objective response rates and ongoing response rates were consistent among prespecified subgroups by prior BTKi exposure or high-risk characteristics. In an exploratory analysis, patients with prior bendamustine benefited from KTE-X19, but showed a trend toward attenuated T-cell functionality, with more impact of bendamustine given within 6 versus 12 months of leukapheresis. Late-onset toxicities were infrequent; only 3% of treatment-emergent adverse events of interest in ZUMA-2 occurred during this longer follow-up period. Translational assessments revealed associations with long-term benefits of KTE-X19 including high-peak CAR T-cell expansion in responders and the predictive value of minimal residual disease for relapse.
These data, representing the longest follow-up of CAR T-cell therapy in patients with MCL to date, suggest that KTE-X19 induced durable long-term responses with manageable safety in patients with relapsed/refractory MCL and may also benefit those with high-risk characteristics.
Sex-mismatched hematopoietic cell transplantation is linked to increased graft-versus-host disease and mortality in myeloablative conditioning. Here we evaluated outcomes of 1,041 adult transplant ...recipients at two centers between 2006 and 2013 and investigated how the effect of sex-mismatching differed in myeloablative, reduced-intensity, and non-myeloablative total lymphoid irradiation with anti-thymocyte globulin conditioning. Among patients who underwent myeloablative conditioning, male recipients with female donors had increased chronic graft-versus-host disease (hazard ratio 1.83, P<0.01), increased non-relapse mortality (hazard ratio 1.84, P=0.022) and inferior overall survival (hazard ratio 1.59, P=0.018). In contrast, among patients who received reduced-intensity conditioning, male recipients with female donors had increased acute graft-versus-host disease (hazard ratio 1.96, P<0.01) but no difference in non-relapse mortality or overall survival. Among the patients who underwent total lymphoid irradiation with anti-thymocyte globulin, male recipients with female donors showed no increase in graft-versus-host disease or non-relapse mortality. Notably, only in the cohort receiving total lymphoid irradiation with anti-thymocyte globulin were male recipients with female donors significantly associated with reduced relapse (hazard ratio 0.64, P<0.01), and allo-antibody responses against H-Y antigens were predictive of reduced relapse. In the cohort given total lymphoid irradiation with anti-thymocyte globulin, the graft-versus-leukemia effect resulted in superior overall survival in recipients of sex-mismatched grafts (HR 0.69, P=0.037). In addition, only in the cohort treated with total lymphoid irradiation with anti-thymocyte globulin were female recipients with male donors associated with reduced relapse (hazard ratio 0.59, P<0.01) and superior survival (hazard ratio 0.61, P=0.014) compared with sex-matched pairs. We conclude that the risks and benefits of sex-mismatched transplants appear to differ according to conditioning strategy and this could affect donor selection.
This study investigated the removal of 15 trace organic chemicals (TOrCs) occurring at ambient concentrations from municipal wastewater treatment plant effluent by advanced oxidation using UV/H2O2 at ...pilot-scale. Pseudo first-order rate constants (kobs) for photolytic as well as combined oxidative and photolytic degradation observed at pilot-scale were validated with results from a bench-scale collimated beam device. No significant difference was determined between pilot- and lab-scale performance. During continuous pilot-scale operation at constant UV fluence of 800 mJ/cm2 and H2O2 dosage of 10 mg/L, the removal of various TOrCs was investigated. The average observed removal for photo-susceptible (kUV>10−3 cm2/mJ; like diclofenac, iopromide and sulfamethoxazole), moderately photo-susceptible (10−4<kUV<10−3 cm2/mJ; like climbazole, tramadol, sotalol, citalopram, benzotriazole, venlafaxine and metoprolol), and most photo-resistant (kUV<10−4 cm2/mJ; like primidone, carbamazepine and gabapentin) compounds was 90%, 49% and 37% including outliers, respectively. The poorly reactive compound TCEP was not significantly eliminated during pilot-scale experiments. Additionally, based on removal kinetics of photo-resistant TOrCs, continuous pilot-scale operation revealed high variations of OH-radical exposure determined from removal kinetics of photo-resistant TOrCs, primarily due to nitrite concentration fluctuations in the feed water. Furthermore, a correlation between OH-radical exposure and scavenging capacity could be determined and verified by mechanistic modeling using UV fluence, H2O2 dosage, and standard water quality parameters (i.e., DOC, NO3−, NO2− and HCO3−) as model input data. This correlation revealed the possibility of OH-radical exposure prediction by water matrix parameters and proved its applicability for pilot-scale operations.
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•Comparison of UV/H2O2 efficiency at pilot- and laboratory scale.•Removal assessment of 15 trace organic chemicals (TOrCs).•Ambient TOrC concentrations in municipal wastewater effluent (no spiking).•Scavenger capacity is dominated by nitrite concentration fluctuations.•Mechanistic modeling of OH-radical exposure by water matrix and process parameters.
ZUMA-1 demonstrated a high rate of durable response and a manageable safety profile with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in patients ...with refractory large B-cell lymphoma. As previously reported, prespecified clinical covariates for secondary end point analysis were not clearly predictive of efficacy; these included Eastern Cooperative Oncology Group performance status (0 vs 1), age, disease subtype, disease stage, and International Prognostic Index score. We interrogated covariates included in the statistical analysis plan and an extensive panel of biomarkers according to an expanded translational biomarker plan. Univariable and multivariable analyses indicated that rapid CAR T-cell expansion commensurate with pretreatment tumor burden (influenced by product T-cell fitness), the number of CD8 and CCR7+CD45RA+ T cells infused, and host systemic inflammation, were the most significant determining factors for durable response. Key parameters differentially associated with clinical efficacy and toxicities, with both theoretical and practical implications for optimizing CAR T-cell therapy. This trial was registered at www.clinicaltrials.gov as #NCT02348216.
•Axi-cel durable responses were associated with low baseline tumor burden, low systemic inflammation, and high product CCR7+CD45RA+ T cells.•Distinct sets of factors associated with durable response, grade ≥3 cytokine release syndrome, and grade ≥3 neurologic events.
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In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after ...the failure of conventional therapy.
In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×10
anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments.
Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response.
In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216 .).
Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the ...single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication.
Data were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution's guidelines. Responses were assessed as per Lugano 2014 classification.
Of 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel-treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis.
The safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.
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