Outcome and feasibility of radiotherapy bridging in large B-cell lymphoma patients receiving CD19 CAR T in the UK.

Radiotherapy (RT) has potential synergistic effects with chimeric antigen receptor (CAR) T but is not widely used as bridging therapy due to logistical challenges and lack of standardised protocols. We analysed RT bridging in a multicentre national cohort of large B-cell lymphoma patients approved for 3L axicabtagene ciloleucel or tisagenlecleucel across 12 UK centres. Of 763 approved patients, 722 were leukapheresed, 717 had data available on bridging therapy. 169/717 (24%) received RT bridging, 129 as single modality and 40 as combined modality treatment (CMT). Of 169 patients, 65.7% had advanced stage, 36.9% bulky disease, 86.5% elevated LDH, 41.7% international prognostic index (IPI) ≥3 and 15.2% double/triple hit at the time of approval. Use of RT bridging varied from 11% to 32% between centres and increased over time. Vein-to-vein time and infusion rate did not differ between bridging modalities. RT-bridged patients had favourable outcomes with 1-year progression-free survival (PFS) of 56% for single modality and 47% for CMT (1-year PFS 43% for systemic bridging). This is the largest cohort of LBCL patients receiving RT bridging prior to CAR T reported to date. Our results show that RT bridging can be safely and effectively used even in advanced stage and high-risk disease, with low dropout rates and excellent outcomes.

Improved outcomes of large B-cell lymphoma patients treated with CD19 CAR T in the UK over time.

The success of CD19 Chimeric antigen receptor (CAR) T-cell therapy in large B-cell lymphoma (LBCL) has been partially offset by toxicity and logistical challenges, which off-the-shelf agents like CD20xCD3 bispecific antibodies might potentially overcome. However, when using CAR T outcomes as the 'standard-of-care comparator̕ for relapsed/refractory (r/r) LBCL, a potential learning curve with implementing a novel, complex therapy like CAR T needs to be considered. To address this, we analysed 726 UK patients intended to be treated with CD19 CAR T for r/r LBCL and compared outcomes between the first year of the national CAR T programme (Era 1; 2019) and the more recent treatment era (Era 2; 2020-2022). We identified significant improvements for Era 2 versus Era 1 in dropout rate (17% vs. 27%, p = 0.001), progression-free survival (1-year PFS 50% vs. 32%, p < 0.001) and overall survival (1-year OS 60% vs. 40%, p < 0.001). We also observed increased use of bridging therapy, improvement in bridging outcomes, more tocilizumab/corticosteroid use, reduced high-grade cytokine release syndrome (4% vs. 9%, p = 0.01) and intensive care unit admissions (20% vs. 32%, p = 0.001). Our results demonstrate significant improvement in CAR T outcomes over time, highlighting the importance of using up-to-date clinical data when comparing CAR T against new treatment options for r/r LBCL.

Comparison of bacterial colonization on absorbable non-coated suture with Triclosan- or Chlorhexidine-coated sutures: a randomized controlled study.

OBJECTIVE: The oral cavity is a colossal reservoir for the bacteria. The healing of tissues is compromised after flap surgery, particularly in the presence of sutures, as they can act as repositories for bacteria, ultimately leading to surgical site infections. Hence, antibacterial-coated sutures have been considered as an alternative to reduce the risk of these infections and further improve the wound healing of the tissues after flap surgery. Since minimal information is available on the effect of antibacterial-coated sutures on periodontal tissues, this study aims to clinically and microbiologically assess the antibacterial efficacy of Triclosan (TCS) and Chlorhexidine-coated sutures (CCS) on periodontal tissues compared to non-coated sutures (NCS). PATIENTS AND METHODS: A total of 75 subjects with moderate to severe periodontitis were included in the study and randomly allocated to one of the three groups, (TCS, CCS, and NCS groups) equally. Suture removal was performed on postoperative day 8, and parameters such as wound healing and post-operative pain were evaluated. The retrieved suture samples were subjected to microbiological analysis and the bacteria were identified quantitatively and qualitatively. RESULTS: Intragroup analysis of the wound healing index and post-operative pain for all the groups showed a significant improvement (p<0.01), from day 8 to day 30. Intergroup analysis of the wound healing index revealed significant wound healing (p<0.05) on day 15 and day 30. For post-operative pain, intergroup analyses showed significantly low pain scores (p<0.01) for the TCS group. Microbiologic analysis of aerobic colony counts in both anterior and posterior regions revealed significantly (p<0.01) least colony counts in TCS and highest colony counts in NCS groups, respectively. Although anaerobic colony counts were not statistically significant, relatively fewer colony counts were identified in the TCS group. Whereas, relatively higher anaerobic colony counts were seen in the CCS group in the anterior region and in the NCS group in the posterior region. Qualitative assessment revealed higher amounts of Streptococcus and Staphylococcus species in all the three groups (TCS, CCS, and NCS groups). CONCLUSIONS: Antibacterial-coated sutures, particularly Triclosan-coated sutures, are effective in reducing bacterial accumulation compared to non-coated sutures. Therefore, these sutures can be effectively utilized in periodontal flap surgery.

CAR T in patients with large B-cell lymphoma not fit for autologous transplant.

Large B-cell lymphoma (LBCL) patients with comorbidities and/or advanced age are increasingly considered for treatment with CD19 CAR T, but data on the clinical benefit of CAR T in the less fit patient population are still limited. We analysed outcomes of consecutive patients approved for treatment with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) by the UK National CAR T Clinical Panel, according to fitness for autologous stem cell transplant (ASCT). 81/404 (20%) of approved patients were deemed unfit for ASCT. Unfit patients were more likely to receive tisa-cel versus axi-cel (52% vs. 48%) compared to 20% versus 80% in ASCT-fit patients; p < 0.0001. The drop-out rate from approval to infusion was significantly higher in the ASCT-unfit group (34.6% vs. 23.5%; p = 0.042). Among infused patients, response rate, progression-free and overall survival were similar in both cohorts. CAR T was well-tolerated in ASCT-unfit patients with an incidence of grade ≥3 cytokine release syndrome and neurotoxicity of 2% and 11%, respectively. Results from this multicentre real-world cohort demonstrate that CD19 CAR T can be safely delivered in carefully selected older patients and patients with comorbidities who are not deemed suitable for transplant.

Microbial community day-to-day dynamics during a spring algal bloom event in a tributary of Three Gorges Reservoir.

The microbial food-loop is critical to energy flow in aquatic food webs. We tested the hypothesis that species composition and relative abundance in a microbial community would be modified by the development of toxic algal blooms either by enhanced carbon production or toxicity. This study tracked the response of the microbial community with respect to composition and relative abundance during a 7-day algal bloom event in the Three Gorges Reservoir in May 2018. Chlorophyll a biomass, microscopic identification and cell counting of algae and algal abundance (ind. L-1) and carbon, nutrient concentrations (total phosphorus and nitrogen, dissolved total phosphorus and nitrogen), and DNA high throughput sequencing were measured daily. Algal density (1.2 × 109 ind. L-1) and Chlorophyll a (219 µg L-1) peaked on May 20th-21st, when the phytoplankton community was dominated by Chlorella spp. and Microcystis spp. The concentrations of both dissolved total nitrogen and phosphorus declined during the bloom period. Based on DNA high throughput sequencing data, the relative abundance of eukaryotic phytoplankton, microzooplankton (20-200 µm), mesozooplankton (>200 µm), and fungal communities varied day by day while the prokaryotic community revealed a more consistent structure. Enhanced carbon production during the bloom was closely associated with increased heterotrophic microbial composition in both the prokaryotic and eukaryotic communities. A storm event, however, that caused surface cooling and deep mixing of the water column greatly modified the composition and relative abundance of species in the microbial loop. The high temporal variability and dynamics observed in this study suggest that many factors, and not just algal blooms, were interacting to determine the composition and relative abundance of species of the microbial loop.

Diffuse large B cell lymphoma (DLBCL) in patients older than 65 years: analysis of 3 year Real World data of practice patterns and outcomes in England.

BACKGROUND: We wished to examine treatment and outcome patterns in older diffuse large B-cell lymphoma (DLBCL) patients, with a focus on the effect of route-to-diagnosis to outcome. METHODS: Data were extracted from Public Health England's National Cancer Registration and Analysis Service between 2013 and 2015 included route-to-diagnosis, disease characteristics and survival for 9186 patients ≥65 years. Systemic Anti-Cancer Therapy data identified front-line regimens, cycles and doses. RESULTS: Route-to-diagnosis were emergency (34%), NHS urgent cancer pathway (rapid haemato-oncologist review <2 weeks), (29%) and standard GP referral (25%). The most common regimen was R-CHOP (n = 4392). 313 patients received R-miniCHOP (7% of R-CHOP). For all patients, 3-year overall survival (OS) for 65-79 years was 57% and for ≥80 years was 32%. Three-year OS for R-CHOP-treated patients diagnosed via emergency presentation was 54% (adjusted hazard ratio (HR) 1.63, p < 0.01) and 75% (adjusted HR 0.81, p < 0.01) on the NHS urgent cancer pathway (reference HR:1.00: GP referrals). 3-year OS was 54% for both R-miniCHOP and R-CHOP in ≥80 years. CONCLUSIONS: Our comprehensive population analysis is the first to show that the NHS urgent cancer pathway is associated with a superior survival after adjusting for multiple confounders. Equivalent survival for R-CHOP and R-mini-CHOP was demonstrated in those ≥80 years.

Global patterns of care in advanced stage mycosis fungoides/Sezary syndrome: a multicenter retrospective follow-up study from the Cutaneous Lymphoma International Consortium.

BACKGROUND: Advanced-stage mycosis fungoides (MF)/Sézary syndrome (SS) patients are weighted by an unfavorable prognosis and share an unmet clinical need of effective treatments. International guidelines are available detailing treatment options for the different stages but without recommending treatments in any particular order due to lack of comparative trials. The aims of this second CLIC study were to retrospectively analyze the pattern of care worldwide for advanced-stage MF/SS patients, the distribution of treatments according to geographical areas (USA versus non-USA), and whether the heterogeneity of approaches has potential impact on survival. PATIENTS AND METHODS: This study included 853 patients from 21 specialist centers (14 European, 4 USA, 1 each Australian, Brazilian, and Japanese). RESULTS: Heterogeneity of treatment approaches was found, with up to 24 different modalities or combinations used as first-line and 36% of patients receiving four or more treatments. Stage IIB disease was most frequently treated by total-skin-electron-beam radiotherapy, bexarotene and gemcitabine; erythrodermic and SS patients by extracorporeal photochemotherapy, and stage IVA2 by polychemotherapy. Significant differences were found between USA and non-USA centers, with bexarotene, photopheresis and histone deacetylase inhibitors most frequently prescribed for first-line treatment in USA while phototherapy, interferon, chlorambucil and gemcitabine in non-USA centers. These differences did not significantly impact on survival. However, when considering death and therapy change as competing risk events and the impact of first treatment line on both events, both monochemotherapy (SHR = 2.07) and polychemotherapy (SHR = 1.69) showed elevated relative risks. CONCLUSION: This large multicenter retrospective study shows that there exist a large treatment heterogeneity in advanced MF/SS and differences between USA and non-USA centers but these were not related to survival, while our data reveal that chemotherapy as first treatment is associated with a higher risk of death and/or change of therapy and thus other therapeutic options should be preferable as first treatment approach.

Novel cost effective full scale mussel shell bioreactors for metal removal and acid neutralization.

Acid mine drainage (AMD) impacted waters are a worldwide concern for the mining industry and countries dealing with this issue; both active and passive technologies are employed for the treatment of such waters. Mussel shell bioreactors (MSB) represent a passive technology that utilizes waste from the shellfish industry as a novel substrate. The aim of this study is to provide insight into the biogeochemical dynamics of a novel full scale MSB for AMD treatment. A combination of water quality data, targeted geochemical extractions, and metagenomic analyses were used to evaluate MSB performance. The MSB raised the effluent pH from 3.4 to 8.3 while removing up to ∼99% of the dissolved Al, and Fe and >90% Ni, Tl, and Zn. A geochemical gradient was observed progressing from oxidized to reduced conditions with depth. The redox conditions helped define the microbial consortium that consists of a specialized niche of organisms that influence elemental cycling (i.e. complex Fe and S cycling). MSB technology represents an economic and effective means of full scale, passive AMD treatment that is an attractive alternative for developing economies due to its low cost and ease of implementation.

Microbiologic contamination of a positive- and a neutral- displacement needleless intravenous access device in clinical use.

The use of a positive-displacement needleless intravenous access device was associated with lower microbial contamination rates compared with a neutral-displacement device when used on central venous catheters in hemato-oncology patients. In addition, rates of central line-associated bloodstream infection did not differ when either device was used.

Greatly reduced risk of EBV reactivation in rituximab-experienced recipients of alemtuzumab-conditioned allogeneic HSCT.

EBV-associated post-transplant lymphoproliferative disease (PTLD) remains an important complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT). We retrospectively analysed the incidence and risk factors for EBV reactivation in 186 adult patients undergoing consecutive allo-HSCT with alemtuzumab T-cell depletion at a single centre. The cumulative incidence of EBV reactivation was 48% (confidence interval (CI) 41-55%) by 1 year, with an incidence of high-level EBV reactivation of 18% (CI 13-24%); 8 patients were concurrently diagnosed with PTLD. Amongst patients with high-level reactivation 31/38 (82%) developed this within only 2 weeks of first EBV qPCR positivity. In univariate analysis age⩾50 years was associated with significantly increased risk of EBV reactivation (hazard ratio (HR) 1.54, CI 1.02-2.31; P=0.039). Furthermore, a diagnosis of non-Hodgkin lymphoma (NHL) was associated with greatly reduced risk of reactivation (HR 0.10, CI 0.03-0.33; P=0.0001) and this was confirmed in multivariate testing. Importantly, rituximab therapy within 6 months prior to allo-HSCT was also highly predictive for lack of EBV reactivation (HR 0.18, CI 0.07-0.48; P=0.001) although confounding with NHL was apparent. Our data emphasise the risk of PTLD associated with alemtuzumab. Furthermore, we report the clinically important observation that rituximab, administered in the peri-transplant period, may provide effective prophylaxis for PTLD.

Transfusion in CMV seronegative T-depleted allogeneic stem cell transplant recipients with CMV-unselected blood components results in zero CMV transmissions in the era of universal leukocyte reduction: a U.K. dual centre experience.

OBJECTIVES: To establish rates of cytomegalovirus (CMV) transmission with use of CMV-unselected (CMV-U), leukocyte-reduced blood components transfused to CMV-seronegative patient/CMV-seronegative donor (CMV neg/neg) allogeneic stem cell transplantation (SCT) recipients including those receiving T-depleted grafts. BACKGROUND: CMV infection remains a major cause of morbidity following SCT. CMV-seronegative SCT recipients are particularly at risk of transfusion transmitted CMV (TT-CMV) and until recently they have received blood components from CMV-seronegative donors with significant resource implications. Although leukocyte reduction of blood components is reported to minimise risk of TT-CMV, its efficacy in high-risk situations, such as in T-depleted transplant recipients, is unknown. METHODS: We retrospectively analysed the incidence of TT-CMV in CMV neg/neg allogeneic SCT recipients transfused with CMV-U, leukocyte-reduced blood components in two transplantation centres in the UK. Patients were monitored for CMV infection by weekly CMV polymerase chain reaction testing. Leukocyte reduction of blood components was in accordance with current UK standards. RESULTS: Among 76 patients, including 59 receiving in vivo T-depletion, no episodes of CMV infection were detected. Patients were transfused with 1442 CMV-unselected, leukocyte-reduced components, equating to 1862 donor exposures. CONCLUSIONS: Our findings confirm the safety of leukocyte reduction as a strategy in preventing TT-CMV in high-risk allogeneic SCT recipients.

EBV-associated post-transplant lymphoproliferative disorder following in vivo T-cell-depleted allogeneic transplantation: clinical features, viral load correlates and prognostic factors in the rituximab era.

EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based allo-SCT is a relatively uncommon and challenging clinical problem but has not received detailed study in a large cohort. Quantitative-PCR (qPCR) monitoring for EBV reactivation post allo-SCT is now commonplace but its diagnostic and predictive value remains unclear. Sixty-nine patients with PTLD following Alemtuzumab-based allo-SCT were studied. Marked clinicopathological heterogeneity was evident; lymphadenopathy was frequently absent, whereas advanced extranodal disease was common. The median viral load at clinical presentation was 49 300 copies/mL (50-65 200 000 copies/mL) and, notably, 23% and 45% of cases, respectively, had 10 000 and 40 000 copies/mL. The overall response rate to rituximab as first-line therapy was 70%. For rituximab failures, chemotherapy was ineffectual but DLIs were successful. A four-parameter prognostic index predicted response to therapy (OR 0.30 (0.12-0.74); P=0.009] and PTLD mortality (hazard ratio (HR) 1.81 (1.12-2.93) P=0.02) on multivariate analysis. This is the largest detailed series of EBV-associated PTLD after allo-SCT. At clinical presentation, EBV-qPCR values are frequently below customary thresholds for pre-emptive therapy, challenging current paradigms for monitoring and intervention. A four-point score identifies a proportion of patients at risk of rituximab-refractory disease for whom alternative therapy is needed.

Post-transplant T cell chimerism predicts graft versus host disease but not disease relapse in patients undergoing an alemtuzumab based reduced intensity conditioned allogeneic transplant.

In this multicentre retrospective study we have studied the impact of T cell chimerism on the outcome of 133 patients undergoing an alemtuzumab based reduced intensity conditioning allograft (RIC). The median age of the patients was 50 years (range 42-55 years). 77 patients were transplanted using an HLA identical sibling donor while 56 patients received a fully matched volunteer unrelated donor graft. 64 patients had a lymphoid malignancy and 69 were transplanted for a myeloid malignancy. 38 patients (29%) relapsed with no significant difference in risk of relapse between patients developing full donor and mixed donor chimerism in the T-cell compartment on D+90 and D+180 post transplant. Day 90 full donor T cell chimerism correlated with an increased incidence of acute GVHD according to NIH criteria (p=0.0004) and the subsequent development of chronic GVHD. Consistent with previous observations, our results confirmed a correlation between the establishment of T cell full donor chimerism and acute GVHD in T deplete RIC allografts. However our study failed to identify any correlation between T cell chimerism and relapse risk and challenge the use of pre-emptive donor lymphocyte infusions (DLI) in patients with mixed T cell chimerism transplanted using an alemtuzumab based RIC regimen.