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To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.apergo.2005.02.001 Byline: Paul Salmon (a)(b), Neville Stanton (a)(b), Guy Walker (a)(b), Damian Green (a)(b) Keywords: Situation awareness; Measurement; C4i systems Abstract: The construct of situation awareness (SA) has become a core theme within the human factors (HF) research community. Consequently, there have been numerous attempts to develop reliable and valid measures of SA but there is a lack of techniques developed specifically for the assessment of SA in command, control, communication, computers and intelligence (C4i) environments. During the design, development and evaluation of novel systems, technology and procedures, valid and reliable situation awareness measurement techniques are required for the assessment of individual and team SA, in order to determine the improvements (or in some cases decrements) resulting from proposed design and technological interventions. The paper presents a review of existing situation awareness measurement techniques for their suitability for use in the assessment of SA in C4i environments. Seventeen SA measures were evaluated against a set of HF methods criteria. It was concluded that current SA measurement techniques are inadequate by themselves for use in the assessment of SA in C4i environments, and a multiple-measure approach utilising different approaches is recommended. Author Affiliation: (a) Defence Technology Centre for Human Factors Integration (DTC-HFI), Brunel University, UK (b) BIT Lab, School of Engineering and Design, Uxbridge, Middlesex UB8 3PH, UK Article History: Received 8 June 2004; Accepted 1 February 2005

γ-Secretase inhibitors (GSIs) increase B cell maturation antigen (BCMA) density on malignant plasma cells and enhance antitumour activity of BCMA chimeric antigen receptor (CAR) T cells in preclinical models. We aimed to evaluate the safety and identify the recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat (LY3039478) for individuals with relapsed or refractory multiple myeloma. We conducted a phase 1, first-in-human trial combining crenigacestat with BCMA CAR T-cells at a single cancer centre in Seattle, WA, USA. We included individuals aged 21 years or older with relapsed or refractory multiple myeloma, previous autologous stem-cell transplant or persistent disease after more than four cycles of induction therapy, and Eastern Cooperative Oncology Group performance status of 0–2, regardless of previous BCMA-targeted therapy. To assess the effect of the GSI on BCMA surface density on bone marrow plasma cells, participants received GSI during a pretreatment run-in, consisting of three doses administered 48 h apart. BCMA CAR T cells were infused at doses of 50 × 106 CAR T cells, 150 × 106 CAR T cells, 300 × 106 CAR T cells, and 450 × 106 CAR T cells (total cell dose), in combination with the 25 mg crenigacestat dosed three times a week for up to nine doses. The primary endpoints were the safety and recommended phase 2 dose of BCMA CAR T cells in combination with crenigacestat, an oral GSI. This study is registered with ClinicalTrials.gov, NCT03502577, and has met accrual goals. 19 participants were enrolled between June 1, 2018, and March 1, 2021, and one participant did not proceed with BCMA CAR T-cell infusion. 18 participants (eight [44%] men and ten [56%] women) with multiple myeloma received treatment between July 11, 2018, and April 14, 2021, with a median follow up of 36 months (95% CI 26 to not reached). The most common non-haematological adverse events of grade 3 or higher were hypophosphataemia in 14 (78%) participants, fatigue in 11 (61%), hypocalcaemia in nine (50%), and hypertension in seven (39%). Two deaths reported outside of the 28-day adverse event collection window were related to treatment. Participants were treated at doses up to 450 × 106 CAR+ cells, and the recommended phase 2 dose was not reached. Combining a GSI with BCMA CAR T cells appears to be well tolerated, and crenigacestat increases target antigen density. Deep responses were observed among heavily pretreated participants with multiple myeloma who had previously received BCMA-targeted therapy and those who were naive to previous BCMA-targeted therapy. Further study of GSIs given with BCMA-targeted therapeutics is warranted in clinical trials. Juno Therapeutics—a Bristol Myers Squibb company and the National Institutes of Health. [ABSTRACT FROM AUTHOR]

• A comprehensive summary of the 2019 BMT CTN Myeloma Intergroup Minimal Residual Disease (MRD) and Immune Profiling (IP) workshop is provided. • MRD is a prognostic biomarker and should be incorporated into trial designs. • IP provides insight into disease biology and response to treatment. The Blood and Marrow Transplant Clinical Trials Network (BMT CTN) Myeloma Intergroup has organized an annual workshop focused on minimal residual disease (MRD) testing and immune profiling (IP) in multiple myeloma since 2016. In 2019, the workshop took place as an American Society of Hematology (ASH) Friday Scientific Workshop titled "Immune Profiling and Minimal Residual Disease Testing in Multiple Myeloma." This workshop focused on 4 main topics: the molecular and immunologic evolution of plasma cell disorders, development of new laboratory- and imaging-based MRD assessment approaches, chimeric antigen receptor T cell therapy research, and statistical and regulatory issues associated with novel clinical endpoints. In this report, we provide a summary of the workshop and discuss future directions. [ABSTRACT FROM AUTHOR]

Highlights • 90Y-ibritumomab tiuxetan–based NMA allogeneic HCT yielded excellent long-term outcomes in patients with indolent B-NHL. • Long-term PFS was also observed in patients with MCL who were early responders. • No survival was observed beyond 8 years in DLBCL regardless of early response. • Improved strategies needed for aggressive histologies. ABSTRACT Nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) can provide prolonged remissions in patients with advanced B cell lymphoma (B-NHL) via the graft-versus-lymphoma effect, although inferior results are seen in patients with chemoresistant, bulky, or aggressive disease. Radioimmunotherapy can safely induce responses in B-NHL with minimal nonhematologic toxicity. Initial results of 90Y-ibritumomab tiuxetan–based allografting demonstrated early safety and disease control in nonremission patients but with short follow-up. Here we report the long-term outcomes of patients treated on this study with specific emphasis on patients achieving early remissions. Eleven of 40 patients were alive at a median follow-up of 9 years (range, 5.3 to 10.2). Fourteen (35%) deaths were due to disease progression and 14 (35%) deaths to complications from HCT. One patient died of a Merkel cell carcinoma. The 5-year overall and progression-free survival for patients with indolent B-NHL was 40% and 27.5%, respectively. None of the patients with diffuse large B cell lymphoma was a long-term disease-free survivor regardless of early remission status. 90Y-ibritumomab tiuxetan–based allografting represents a viable option in patients with indolent histologies. Improved strategies are needed for aggressive B-NHL. The original trial was registered at www.clinicaltrials.gov as NCT00119392. [ABSTRACT FROM AUTHOR]

Circulating plasma cells (CPCs) have been detected in patients with multiple myeloma (MM) at various stages of disease and associated with worse outcomes. Little data exist regarding the impact of CPCs at the time of autologous peripheral blood stem cell (PBSC) collection on outcomes, and the impact of maintenance therapy after autologous stem cell transplantation (ASCT) on prognosis in patients with CPC-containing collections. All patients with MM who underwent first ASCT at Fred Hutchinson Cancer Research Center from 2012 to 2015 and had evaluation for CPCs at the time of PBSC collection were included in our analysis. Seven-color flow cytometry was used to detect the presence of CPCs. Kaplan-Meier estimates were used to generate overall survival (OS) and progression-free survival (PFS) rates from the time of ASCT. A multivariate analysis, including receipt of maintenance therapy post-ASCT, high-risk cytogenetics, and international staging system (ISS) stage, was included in a Cox proportional hazards regression model for associations with OS and PFS. We identified 227 patients with MM who underwent ASCT; of these, 144 (63.4%) patients had routine assessment of CPCs at the time of PBSC collection. One hundred seventeen (81.3%) patients did not have CPCs and 27 (18.8%) did have CPCs. The presence of CPCs was highly associated with poorer PFS ( P  = .031 by log-rank analysis), but did not affect OS. The median PFS for those patients without CPCs was 39.4 months (95% confidence interval [CI], 31.1 to not reached), while the median PFS for those patients with CPCs was 16.5 months (95% CI, 13.7 to not reached). A subgroup analysis of patients achieving very good partial response (VGPR) or better at time of collection, showed the median PFS for patients without CPCs was 38.3 months (95% CI, 29 to not reached), as compared with those patients with CPCs, where it was only 16.5 months (95% CI, 12 months to not reached; P  = .02). There was no statistically significant difference in PFS or OS among those patients achieving partial response at the time of collection. In a Cox proportional hazards model, adjusting for post-ASCT maintenance therapy, high-risk cytogenetics, and ISS stage at time of initial diagnosis, there was a 43% higher risk of progression or death among the patients with CPCs ( P  = .04). The presence of CPCs at the time of autologous PBSC collection is a negative prognostic factor for risk of early relapse or death despite the advent of novel agents and maintenance strategies. The impact of CPCs was most significant among patients achieving a VGPR or better at time of collection. The presence of CPCs denotes a unique group of high-risk MM patients for whom alternative treatment strategies are needed to overcome resistance to current standard therapies. [ABSTRACT FROM AUTHOR]

Autologous stem cell transplantation (ASCT) is standard therapy for mantle cell lymphoma (MCL) in remission after induction chemotherapy, with the best results for patients in complete remission (CR). We hypothesized that evaluation of minimal residual disease (MRD) before ASCT could further stratify outcomes for these patients. Patients with MCL who underwent ASCT in clinical CR between 1996 and 2011 with pretransplantation MRD testing were eligible. Presence of a clonal IgH rearrangement, t(11; 14) by PCR or positive flow cytometry from blood or bone marrow, was considered positive. An adjusted proportional hazards model for associations with progression-free (PFS) and overall survival (OS) was performed. Of 75 MCL patients in CR, 8 (11%) were MRD positive. MRD positivity was associated with shorter OS and PFS. The median OS for MRD-negative patients was not reached, with 82% survival at 5 years, whereas for the MRD-positive patients, median OS was 3.01 years (hazard ratio [HR], 4.04; P = .009), with a median follow-up of 5.1 years. The median PFS for MRD-negative patients was not reached with 75% PFS at 5 years, whereas for MRD-positive patients, it was 2.38 years (HR, 3.69; P = .002). MRD positivity is independently associated with poor outcomes after ASCT for MCL patients in CR. [ABSTRACT FROM AUTHOR]

Relapse is least common in patients with indolent B cell (iB) malignancies (ie, iB non-Hodgkin lymphoma [NHL]) who undergo nonmyeloablative allogeneic transplantation (NMAT) in complete remission (CR). However, for the many patients unable to achieve this state, outcomes are poorly described and methods to improve results are unknown. We sought to describe the long-term follow-up and predictive factors for these poor-risk patients unable to achieve CR before NMAT. We identified and evaluated patients with iB-NHL including chronic lymphocytic leukemia treated with fludarabine/total body irradiation–based NMAT that had evidence of persistent disease before NMAT. From December 1998 to April 2009, 89 patients were identified, most commonly with small/chronic lymphocytic lymphoma (n = 62) and follicular lymphoma (n = 24). Pretransplant anti-CD20 radioimmunotherapy (RIT) using standard yttrium-90-ibritumomab tiuxetan was administered to 18 patients (20%) who more frequently had chemoresistant disease (81% versus 39%, P = .003), disease bulk > 5 cm (61% versus 15%, P < .001), thrombocytopenia < 25k/μL (33% versus 7%, P = .002), and Hematopoietic Cell Transplant Comorbidity Index scores ≥ 3 (72% versus 37%, P = .006). After adjusting for these imbalances, RIT-treated patients had improved rates of progression-free survival (PFS) (hazard ratio [HR] = .4; 95% confidence interval [CI], .2 to .9, P = .02) and overall survival (OS) (HR = .3; 95% CI, .1 to .8, P = .008) compared with the non-RIT group. The 3-year adjusted estimates of PFS and OS for the RIT and non-RIT groups were 71% and 87% versus 44% and 59%, respectively. The use of RIT was the only factor independently associated with improved PFS and OS. Rates of nonrelapse mortality and graft-versus-host disease (GVHD) were similar between the 2 groups, although over 70% of patients developed clinically significant acute or chronic GVHD. In conclusion, despite relatively high rates of GVHD, patients with persistent iB-NHL can derive durable benefit from NMAT. [ABSTRACT FROM AUTHOR]

We treated patients under age 50 years with iodine-131 (131I)-anti-CD45 antibody combined with fludarabine and 2 Gy total body irradiation to create an improved hematopoietic cell transplantation (HCT) strategy for advanced acute myeloid leukemia or high-risk myelodysplastic syndrome patients. Fifteen patients received 332 to 1561 mCi of 131I, delivering an average of 27 Gy to bone marrow, 84 Gy to spleen, and 21 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no dose-limiting toxicity was observed. Marrow doses were arbitrarily capped at 43 Gy to avoid radiation-induced stromal damage; however, no graft failure or evidence of stromal damage was observed. Twelve patients (80%) developed grade II graft-versus-host disease (GVHD), 1 patient developed grade III GVHD, and no patients developed grade IV GVHD during the first 100 days after HCT. Of the 12 patients with chronic GVHD data, 10 developed chronic GVHD, generally involving the skin and mouth. Six patients (40%) are surviving after a median of 5.0 years (range, 4.2 to 8.3 years). The estimated survival at 1 year was 73% among the 15 treated patients. Eight patients relapsed, 7 of whom subsequently died. The median time to relapse among these 8 patients was 54 days (range, 26 to 1364 days). No cases of nonrelapse mortality were observed in the first year after transplantation. However, 2 patients died in remission from complications of chronic GVHD and cardiomyopathy, at 18 months and 14 months after transplantation, respectively. This study suggests that patients may tolerate myeloablative doses >28 Gy delivered to the liver using 131I-anti-CD45 antibody in addition to standard reduced-intensity conditioning. Moreover, the arbitrary limit of 43 Gy to the marrow may be unnecessarily conservative, and continued escalation of targeted radioimmunotherapy doses may be feasible to further reduce relapse. [ABSTRACT FROM AUTHOR]

Highlights: [•] The abundance and dispersal of a major riverine cyanobacterial bloom is reported. [•] Drought, low river flow and river regulation infrastructure had marked effects. [•] The genetic potential of the bloom for toxin production was established by PCR. [•] Analysis for toxins indicated most were below detection limits. [•] The risk of future blooms in rivers due to climate change is considerable. [Copyright &y& Elsevier]

Abstract: Outcomes with autologous hematopoietic cell transplantation (auto HCT) for relapsed and/or refractory mantle cell lymphoma (MCL) are typically poor. We hypothesized that certain factors could predict which patients experience a favorable outcome with this approach. We thus developed a predictive score from a cohort of 67 such patients using 3 factors independently associated with progression-free survival (PFS): (1) simplified Mantle Cell Lymphoma International Prognostic Index score before auto HCT (hazard ratio [HR], 2.9; P = .002); (2) B symptoms at diagnosis (HR, 2.7; P = .005); and (3) remission quotient, calculated by dividing the time, in months, from diagnosis to auto HCT by the number of prior treatments (HR, 1.4; P = .02). The estimated 5-year PFS for favorable-risk patients (n = 23) and unfavorable-risk patients (n = 44) were 58% (95% confidence interval [CI], 34% to 75%) and 15% (95% CI, 6% to 28%), respectively. These factors also independently predicted overall survival. In summary, we have defined 3 simple factors that can identify patients with relapsed/refractory MCL who derive a durable benefit from salvage auto HCT. [Copyright &y& Elsevier]

Introduction The efficacy and safety of palliative radiotherapy (RT) is well established for patients with multiple myeloma (MM). However, little is known regarding the safety of RT as consolidation or cytoreduction among MM patients undergoing autologous stem cell transplant (ASCT). Objectives Given that many MM patients undergo ASCT as part of treatment, we sought to characterize the safety and toxicity profile of peri-transplant RT among patients with MM that underwent ASCT at a large, tertiary-care stem cell transplant center. Methods Eligible patients included those 18 years or older with a confirmed diagnosis of MM that underwent ASCT between January 2009 and June 2018 at the Fred Hutchinson Cancer Research Center. Peri-transplant RT was defined as RT deployed within 3 months of ASCT for the explicit purpose of disease consolidation or cytoreduction, including treating lesions at risk for pathologic fracture. We excluded patients that underwent tandem autologous-allogeneic stem cell transplant and patients that received RT for disease relapse post-transplant. Transplant-related toxicity and infectious complications were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Results Of 785 MM patients that underwent ASCT, 23 (2.9%) received RT, post-stem cell collection, at our institution in the peri-transplant setting. Demographics, disease characteristics, and treatment data are depicted in figure 1. Seven patients (30%) received RT to treat lesions at risk for pathologic fracture. A total of 18 patients (78%) were hospitalized within 30 days of transplant. Among these patients, 12 patients (52%) experienced grade 3 regimen-related toxicities requiring hospitalization, most frequently nausea, vomiting, and mucositis; 2 patients (9%) experienced grade 2 autologous-pseudo GVHD requiring oral steroids. Twelve patients (52%) experienced grade 3 infectious complications, the majority of which were neutropenic fever. The median time to neutrophil engraftment was 16 days (range 13-20), and the median time to platelet engraftment was 11 days (range 8-14); within this group, subjects who received RT to the hip or pelvic region had similar engraftment times. Conclusion In this analysis of the MM patients who underwent ASCT at our institution, we observed the expected degree of transplant-related toxicity among peri-transplant RT recipients, with most patients requiring hospitalization post-transplant for gastrointestinal toxicity. Peri-transplant RT, including irradiation of the hip or pelvic region (where the majority of hematopoiesis occurs), did not impact on engraftment or incidence of infectious complications. Future work is needed to evaluate whether peri-transplant RT improves disease remission among MM patients that undergo ASCT, and we are in the process of updating disease response rates in these patients. [ABSTRACT FROM AUTHOR]