Final results of a phase 1 study of loncastuximab tesirine in relapsed/refractory B-cell non-Hodgkin lymphoma.

The prognosis for patients with relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) remains poor, with a need for alternatives to current salvage therapies. Loncastuximab tesirine (ADCT-402) is an antibody-drug conjugate comprising a humanized anti-CD19 monoclonal antibody conjugated to a pyrrolobenzodiazepine dimer toxin. Presented here are final results of a phase 1 dose-escalation and dose-expansion study in patients with R/R B-NHL. Objectives were to determine the maximum tolerated dose (MTD) and recommended dose(s) for expansion and evaluate safety, clinical activity, pharmacokinetics, and immunogenicity of loncastuximab tesirine. Overall, 183 patients received loncastuximab tesirine, with 3 + 3 dose escalation at 15 to 200 µg/kg and dose expansion at 120 and 150 µg/kg. Dose-limiting toxicities (all hematologic) were reported in 4 patients. The MTD was not reached, although cumulative toxicity was higher at 200 µg/kg. Hematologic treatment-emergent adverse events were most common, followed by fatigue, nausea, edema, and liver enzyme abnormalities. Overall response rate (ORR) in evaluable patients was 45.6%, including 26.7% complete responses (CRs). ORRs in patients with diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma, and follicular lymphoma were 42.3%, 46.7%, and 78.6%, respectively. Median duration of response in all patients was 5.4 months and not reached in patients with DLBCL (doses ≥120 µg/kg) who achieved a CR. Loncastuximab tesirine had good stability in serum, notable antitumor activity, and an acceptable safety profile, warranting continued study in B-NHL. The recommended dose for phase 2 was determined as 150 µg/kg every 3 weeks for 2 doses followed by 75 µg/kg every 3 weeks. This trial was registered at www.clinicaltrials.gov as #NCT02669017.

Impact of positron emission tomography - computed tomography status on progression-free survival for relapsed follicular lymphoma patients undergoing autologous stem cell transplantation.

The optimum management approach for patients with relapsed or refractory follicular lymphoma remains uncertain. Autologous stem cell transplantation (autoSCT) is considered a standard option in suitable, younger patients with relapsed follicular lymphoma. AutoSCT is associated with very durable remissions in a minority of subjects, but also with significant, well-established toxicities. Although positron emission tomography (PET) status prior to autoSCT is an established prognostic factor in diffuse large B-cell lymphoma and Hodgkin lymphoma, no data exist in follicular lymphoma. We describe survival outcomes according to pre-transplant PET status, classified by the Lugano criteria into complete metabolic remission (CMR) versus non-CMR, in 172 patients with relapsed or refractory follicular lymphoma within a national, multicenter, retrospective British Society of Blood and Marrow Transplantation and Cellular Therapy registry study. The median number of lines of therapy prior to SCT was three (range, 1-6). The median follow-up after SCT was 27 months (range, 3-70). The median progression-free survival for all patients after autoSCT was 28 months (interquartile range, 23- 36). There was no interaction between age at transplantation, sex, number of months since last relapse, Karnofsky performance status or comorbidity index and achieving CMR prior to autoSCT. Superior progression-free survival was observed in 115 (67%) patients obtaining CMR versus 57 (33%) non-CMR patients (3-year progression-free survival 50% vs. 22%, P=0.011) and by pre-SCT Deauville score (continuous variable 1-5, hazard ratio [HR]=1.32, P=0.049). PET status was independently associated with progression-free status (non-CMR HR=2.02, P=0.003), overall survival (non-CMR HR=3.08, P=0.010) and risk of relapse (non-CMR HR=1.64, P=0.046) after autoSCT by multivariable analysis. Our data suggest that pre- SCT PET status is of clear prognostic value and may help to improve the selection of patients for autoSCT.

Psychosis secondary to thyrotoxicosis that persisted post-thyroidectomy: a case report.

BACKGROUND: This case report is of a patient with psychosis secondary to thyrotoxicosis that persisted and reemerged after definitive treatment of thyroidectomy, which is a unique occurrence in the literature. CASE PRESENTATION: This patient is a male between 30 and 35 years of age with a history of Graves Disease and no past psychiatric history who was admitted to the hospital due to psychosis secondary to thyrotoxicosis. The thyrotoxicosis was treated with surgical removal, but the psychotic symptoms persisted after surgery and normalization of standard thyroid functional measures. The symptoms were of sufficient significance for inpatient psychiatric hospitalization, a rare occurrence. Ultimately after an extended stay in the psychiatric unit, the patient's symptoms stabilized with a second-generation antipsychotic, and the patient was discharged from the psychiatric unit. CONCLUSION: This case is evidence that the link between psychosis and hyperthyroidism is still poorly understood due to the patient's psychotic symptoms persisting after the definitive treatment of thyroidectomy and the fact that it required anti-psychotic medications for normalization.

Guideline for the first-line management of Classical Hodgkin Lymphoma - A British Society for Haematology guideline.

This guideline was compiled according to the British Society for Haematology (BSH) process at BSH Guidelines Process 2016 (b-s-h.org.uk). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Recommendations are based on a review of the literature using Medline, PubMed/Medline and Cochrane searches beginning from 2013 up to January 2021. The following search terms were used: [Hodgkin lymphoma OR Hodgkin disease] NOT non-Hodgkin; AND [chemotherapy OR radiotherapy]; AND [elderly]; AND [teenage OR adolescent OR young adult]; AND [pregnancy]. Filters were applied to include only publications written in English, studies carried out in humans, clinical conferences, congresses, clinical trials, clinical studies, meta-analyses, multicentre studies and randomised controlled trials. References pre-2013 were taken from the previous version of this guideline.1 Review of the manuscript was performed by the British Society for Haematology (BSH) Guidelines Committee Haematology Oncology Taskforce, the BSH Guidelines Committee and the Haematology Oncology sounding board of BSH.

A national service for delivering CD19 CAR-Tin large B-cell lymphoma - The UK real-world experience.

CD19 CAR-T have emerged as a new standard treatment for relapsed/refractory (r/r) large B-cell lymphoma (LBCL). CAR-T real-world (RW) outcomes published to date suggest significant variability across countries. We provide results of a large national cohort of patients intended to be treated with CAR-T in the UK. Consecutive patients with r/r LBCL approved for CAR-T by the National CAR-T Clinical Panel between December 2018 and November 2020 across all UK CAR-T centres were included. 404/432 patients were approved [292 axicabtagene ciloleucel (axi-cel), 112 tisagenlecleucel (tisa-cel)], 300 (74%) received the cells. 110/300 (38.3%) patients achieved complete remission (CR) at 6 months (m). The overall response rate was 77% (52% CR) for axi-cel, 57% (44% CR) for tisa-cel. The 12-month progression-free survival was 41.8% (axi-cel) and 27.4% (tisa-cel). Median overall survival for the intention-to-treat population was 10.5 m, 16.2 m for infused patients. The incidence of grade ≥3 cytokine release syndrome and neurotoxicity were 7.6%/19.6% for axi-cel and 7.9%/3.9% for tisa-cel. This prospective RW population of CAR-T eligible patients offers important insights into the clinical benefit of CD19 CAR-T in LBCL in daily practice. Our results confirm long-term efficacy in patients receiving treatment similar to the pivotal trials, but highlight the significance of early CAR-T failure.

Oxymetazoline vs ofloxacin vs ciprofloxacin/dexamethasone- effects of drops on tympanostomy tube postoperative otorrhea.

OBJECTIVE: To assess for differences in postoperative otorrhea rates after tympanostomy with tube placement surgery comparing use of oxymetazoline, ofloxacin, or ciprofloxacin/dexamethasone drops prescribed in the postoperative period. METHODS: A retrospective review was conducted of 516 pediatric patients who had either bilateral or unilateral myringotomy with tube placement performed during the year 2018. Information collected from each surgery included whether there was effusion at time of surgery, type of effusion, whether an adenoidectomy was performed the same time or prior, prior history of tube placement, style of tube placed, type of drop given or prescribed on the day of surgery. Demographic information including age, sex, race, weight was recorded as well. Finally, the postoperative visit was analyzed for presence of otorrhea in the ears that had surgery. Univariate analysis was conducted to see if there was any association between the three different drops and presence of otorrhea postoperatively. RESULTS: Postoperative otorrhea was present in 50 of the 516 patients (9.7 %). We observed no significant difference between the type of drop used and postoperative otorrhea being present (p = 0.179), but prior placement of tubes was significantly correlated to postoperative otorrhea (p < 0.001). There was no relationship between type of tube used, prior tube placement, or history of adenoidectomy with type of ear drop used. CONCLUSION: Overall, there is no significant difference in the rate of postoperative otorrhea when choosing between oxymetazoline, ofloxacin, or ciprofloxacin/dexamethasone drops for use in the postoperative period after tympanostomy tube placement.

Electrochemistry of redox-active molecules confined within narrow carbon nanotubes.

Confinement of molecules within nanocontainers can be a powerful tool for controlling the states of guest-molecules, tuning properties of host-nanocontainers and triggering the emergence of synergistic properties within the host-guest systems. Among nanocontainers, single-walled carbon nanotubes - atomically thin cylinders of carbon, with typical diameters below 2 nm and lengths reaching macroscopic dimensions - are ideal hosts for a variety of materials, including inorganic crystals, and organic, inorganic and organometallic molecules. The extremely high aspect ratio of carbon nanotubes is complemented by their functional properties, such as exceptionally high electrical conductivity and thermal, chemical and electrochemical stability, making carbon nanotubes ideal connectors between guest-molecules and macroscopic electrodes. The idea of harnessing nanotubes both as nanocontainers and nanoelectrodes has led to the incorporation of redox-active species entrapped within nanotube cavities where the host-nanotubes may serve as conduits of electrons to/from the guest-molecules, whilst restricting the molecular positions, orientations, and local environment around the redox centres. This review gives a contemporary overview of the status of molecular redox chemistry within ultra-narrow carbon nanotubes (nanotubes with diameters approaching molecular dimensions) highlighting the opportunities, pitfalls, and gaps in understanding of electrochemistry in confinement, including the role of nanotube diameter, size and shape of guest-molecules, type of electrolyte, solvent and other experimental conditions.

Safety of decreasing ureteral stent duration following radical cystectomy.

PURPOSE: We aim to assess the safety of decreasing ureteral stenting duration following Radical Cystectomy with Urinary Diversion (RCUD). MATERIALS AND METHODS: We analyzed a prospectively and retrospectively collected dataset for cystectomy patients at our tertiary center. Adult patient who underwent RCUD for malignancy from January 2013 to February 2018 were included. Patients with a history of abdominal/pelvic radiation and continent diversions were excluded. The patient population was divided to late stent removal group (LSR-POD 14) and early stent removal group (ESR-POD5). Our endpoints were total stent duration, 90-day readmission, 90-day total-UTI, 90-day urinary-readmissions, complications and Ureteroenteric Stricture (UES) rates. Statistical methods included t test, Chi-squared test and multivariate logistic regression. RESULTS: One hundred and seventy-eight patients were included in the final analysis after inclusion/exclusion criteria were applied. The LSR (n = 74) and ESR (n = 104) groups were similar in preoperative characteristics except higher intracorporeal ileal conduit formation in ESR. The duration of stenting decreased significantly from approximately 15.5-5 days (P < 0.001). The LSR had higher 90-day overall readmission rates (OR = 2.57, 95% CI 1.19-5.53, P = 0.016) and total-UTIs (OR = 2.36, 95%CI 1.11-5.04, P = 0.026). With a median follow-up of 9.8 months, UES was similar between the two groups. CONCLUSION: Shorter ureteral stent duration is a safe and non-inferior option following RCUD. It allows for stent removal prior to discharge and less outpatient visits. In addition, decreasing stent duration was linked decreased readmissions and total-UTIs without increased risk of UES. However, future studies are needed to establish causality and promote stent duration change.

Lymph node core biopsies reliably permit diagnosis of lymphoproliferative diseases. Real-World Experience from 554 sequential core biopsies from a single centre.

INTRODUCTION: Whilst excision biopsy is traditionally preferred, advances in radiological and histological techniques warrant a re-look at core biopsy as a viable primary diagnostic method. METHOD: Over a 3-year period, all patients who underwent core biopsy to investigate lymphoma at our centre were included. RESULTS: 554 consecutive patients were included (40.1% prior lymphoma and 59.4% new presentations). Three or more cores were taken in 420 (75.8%) cases. Median time from request to biopsy and biopsy to histology report was 2 (0-40) days and 7 (1-24) days, respectively. 510/544 (93.8%) biopsies were diagnostic. There was no difference in whether the biopsy was diagnostic based on indication (new vs. relapsed lymphoma) (P = .445), whether biopsy was PET-directed (P = .507), for T-cell lymphoma (P = .468) or nodal vs. extra-nodal (P = .693). Thirty-eight patients (6.9%) required a second biopsy due to inadequate tissue. In a patient experience survey, only 13.9% reported any complications (1 self-limiting minor bleeding, 4 bruising) whilst 16.7% reported any discomfort beyond 12 hours. CONCLUSION: Core biopsy performed by experienced radiologists and analysed by expert haemato-pathologists is a reliable, well-tolerated method for diagnosing lymphoma and confirming relapse. Multiple cores can be obtained under local anaesthetic yielding sufficient material in the majority of cases.

Treatment of classical Hodgkin lymphoma in young adults aged 18-30 years with a modified paediatric Hodgkin lymphoma protocol. Results of a multicentre phase II clinical trial (CRUK/08/012).

This phase II trial was designed to determine the safety and efficacy of a modified paediatric risk-stratified protocol in young adults (18-30 years) with classical Hodgkin Lymphoma. The primary end-point was neurotoxicity rate. The incidence of grade 3 neurotoxicity was 11% (80% CI, 5-19%); a true rate of neuropathy of >15% cannot be excluded. Neuropathy and associated deterioration in quality of life was largely reversible. The overall response rate was 100% with 40% complete remission (CR) rate. Twelve months disease-free survival (DFS) was 91%. We demonstrate that a risk-stratified paediatric combined modality treatment approach can be delivered to young adults without significant irreversible neuropathy.

Obinutuzumab for the First-Line Treatment of Follicular Lymphoma.

BACKGROUND: Rituximab-based immunochemotherapy has improved outcomes in patients with follicular lymphoma. Obinutuzumab is a glycoengineered type II anti-CD20 monoclonal antibody. We compared rituximab-based chemotherapy with obinutuzumab-based chemotherapy in patients with previously untreated advanced-stage follicular lymphoma. METHODS: We randomly assigned patients to undergo induction treatment with obinutuzumab-based chemotherapy or rituximab-based chemotherapy. Patients with a response received maintenance treatment for up to 2 years with the same antibody that they had received in induction. The primary end point was investigator-assessed progression-free survival. RESULTS: A total of 1202 patients with follicular lymphoma underwent randomization (601 patients in each group). After a median follow-up of 34.5 months (range, 0 to 54.5), a planned interim analysis showed that obinutuzumab-based chemotherapy resulted in a significantly lower risk of progression, relapse, or death than rituximab-based chemotherapy (estimated 3-year rate of progression-free survival, 80.0% vs. 73.3%; hazard ratio for progression, relapse, or death, 0.66; 95% confidence interval [CI], 0.51 to 0.85; P=0.001). Similar results were seen with regard to independently reviewed progression-free survival and other time-to-event end points. Response rates were similar in the two groups (88.5% in the obinutuzumab group and 86.9% in the rituximab group). Adverse events of grade 3 to 5 were more frequent in the obinutuzumab group than in the rituximab group (74.6% vs. 67.8%), as were serious adverse events (46.1% vs. 39.9%). The rates of adverse events resulting in death were similar in the two groups (4.0% in the obinutuzumab group and 3.4% in the rituximab group). The most common adverse events were infusion-related events that were considered by the investigators to be largely due to obinutuzumab in 353 of 595 patients (59.3%; 95% CI, 55.3 to 63.2) and to rituximab in 292 of 597 patients (48.9%; 95% CI, 44.9 to 52.9; P<0.001). Nausea and neutropenia were common. A total of 35 patients (5.8%) in the obinutuzumab group and 46 (7.7%) in the rituximab group died. CONCLUSIONS: Obinutuzumab-based immunochemotherapy and maintenance therapy resulted in longer progression-free survival than rituximab-based therapy. High-grade adverse events were more common with obinutuzumab-based chemotherapy. (Funded by F. Hoffmann-La Roche; GALLIUM ClinicalTrials.gov number, NCT01332968 .).

The architecture of neoplastic follicles in follicular lymphoma; analysis of the relationship between the tumor and follicular helper T cells.

CD4+ T-follicular helper cells are essential for the survival, proliferation, and differentiation of germinal center B cells and have been implicated in the pathogenesis of follicular lymphoma (FL). To further define the role of these cells in FL, we used multiparameter confocal microscopy to compare the architecture of normal and neoplastic follicles and next generation sequencing to analyze the T-cell receptor repertoire in FL lymph nodes (LN). Multiparameter analysis of LN showed that the proportion of T-follic-ular helper cells (TFH) in normal and neoplastic follicles is the same and that the previously reported increase in TFH numbers in FL is thus due to an increase in the number and not content of follicles. As in normal germinal centers, TFH were shown to have a close spatial correlation with proliferating B cells in neoplastic follicles, where features of immunological synapse formation were observed. The number of TFH in FL correlate with the rate of B-cell proliferation and TFH co-localized to activation induced cytidine deaminase expressing proliferating B cells. T-cell receptor repertoire analysis of FL LN revealed that follicular areas are significantly more clonal when compared to the rest of the LN. These novel findings show that neoplastic follicles and germinal centers share important structural features and provide further evidence that TFH may play a role in driving B-cell proliferation and genomic evolution in TFH Our results also suggest that targeting this interaction would be an attractive therapeutic option.

The role of obinutuzumab in the management of follicular lymphoma.

The outcomes for follicular lymphoma (FL) have improved significantly in recent years. This has been driven by an improved understanding of the pathobiology of FL and the development of therapeutic anti-CD20 antibodies. Combining rituximab with chemotherapy, coupled with its use as maintenance therapy, has contributed to significant improvements in disease control and progression-free survival. However, FL remains incurable and almost all patients invariably relapse. Therefore, there remains a need to develop novel therapeutic options and optimize existing regimens. Obinutuzumab (a first-in-class, glycoengineered, humanized type 2 anti-CD20 antibody) has been evaluated in a number of clinical trials. In this review, we will summarize the evaluable results of clinical trials investigating the efficacy of obinutuzumab in the treatment of FL.

In vitro and in vivo evidence for uncoupling of B-cell receptor internalization and signaling in chronic lymphocytic leukemia.

B-cell receptor activation, occurring within lymph nodes, plays a key role in the pathogenesis of chronic lymphocytic leukemia and is linked to prognosis. As well as activation of downstream signaling, receptor ligation triggers internalization, transit to acidified endosomes and degradation of ligand-receptor complexes. Herein, we investigated the relationship between these two processes in normal and leukemic B cells. We found that leukemic B cells, particularly anergic cases lacking the capacity to initiate downstream signaling, internalize and accumulate ligand in acidified endosomes more efficiently than normal B cells. Furthermore, ligation of either surface CD79B, a B-cell receptor component required for downstream signaling, or surface Immunoglobulin M (IgM) by cognate agonistic antibody, showed that the two molecules internalize independently of each other in leukemic but not normal B cells. Since association with surface CD79B is required for surface retention of IgM, this suggests that uncoupling of B-cell receptor internalization from signaling may be due to the dissociation of these two molecules in leukemic cells. A comparison of lymph node with peripheral blood cells from chronic lymphocytic leukemia patients showed that, despite recent B-cell receptor activation, lymph node B cells expressed higher levels of surface IgM. This surprising finding suggests that the B-cell receptors of lymph node- and peripheral blood-derived leukemic cells might be functionally distinct. Finally, long-term therapy with the Bruton's tyrosine kinase inhibitors ibrutinib or acalabrutinib resulted in a switch to an anergic pattern of B-cell receptor function with reduced signaling capacity, surface IgM expression and more efficient internalization.