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Patients with relapsed or refractory large B-cell lymphoma after first-line treatment who are not intended for haematopoietic stem-cell transplantation (HSCT) have poor outcomes and limited treatment options. We assessed the antitumour activity and safety of lisocabtagene maraleucel, an autologous, CD19-directed chimeric antigen receptor (CAR) T-cell product, as second-line treatment in adults with relapsed or refractory large B-cell lymphoma not intended for HSCT.PILOT, an open-label, phase 2 trial done at 18 clinical sites in the USA, included adults aged 18 years or older who had relapsed or refractory large B-cell lymphoma and PET-positive disease, had received first-line therapy containing an anthracycline and a CD20-targeted agent, were not intended for HSCT by their physician, and met at least one prespecified transplantation not intended criterion. Patients received lymphodepleting chemotherapy (intravenous fludarabine 30 mg/mBetween July 26, 2018, and Sept 24, 2021 (data cutoff for the primary analysis), 74 patients underwent leukapheresis and 61 received lisocabtagene maraleucel (efficacy and safety sets); median age was 74 years (IQR 70-78), 24 (39%) patients were women versus 37 (61%) men, and 54 (89%) patients were White. 16 (26%) of 61 patients had an Eastern Cooperative Oncology Group performance status of 2, 33 (54%) had refractory disease, 13 (21%) relapsed within 1 year of first-line therapy, and 15 (25%) relapsed after 12 months of first-line therapy. Median on-study follow-up was 12·3 months (IQR 6·1-18·0). 49 (80% [95% CI 68-89]; p0·0001) patients had an overall response. The most common grade 3 or worse treatment-emergent adverse events were neutropenia (29 [48%] patients), leukopenia (13 [21%]), and thrombocytopenia (12 [20%]). Lisocabtagene maraleucel-related serious treatment-emergent adverse events were reported in 13 (21%) patients. There were no treatment-related deaths. Cytokine release syndrome occurred in 23 (38%; grade 3 in one) patients and neurological events in 19 (31%; grade 3 in three) patients, with no grade 4 events or deaths.These results support lisocabtagene maraleucel as a potential second-line treatment in patients with large B-cell lymphoma for whom HSCT is not intended.Juno Therapeutics, a Bristol-Myers Squibb company.

The mechanism(s) of acquisition of extended-spectrum cephalosporin-resistant Enterobacteriaceae (ESCRE) on inpatient hospital units dedicated to hematopoietic stem cell transplantation (HSCT) is unclear. The objectives of this study were to determine whether ESCRE organisms are transmitted among patients housed on a HSCT unit, clarify the mechanisms involved, and determine whether routine surveillance for ESCRE carriage and contact isolation for ESCRE carriers is beneficial. The study was conducted on a 30-bed inpatient unit dedicated to the care of patients with hematologic malignancies and HSCT recipients. To investigate whether ESCRE organisms may be transmitted vertically to subsequent room occupants, presumably through contamination of room surfaces, we (1) cultured 6 high touch areas in 10 rooms before and 9 rooms after terminal cleaning that had been occupied by patients with ESCRE carriage, (2) determined the in vitro survivals of our most common clinical ESCRE species, and (3) followed the subsequent room occupants of 54 consecutive ESCRE colonized patients for the development of inpatient acquired ESCRE carriage. To investigate whether ESCRE organisms are transmitted horizontally among inpatients we (1) sequenced 60 available ESCRE Escherichia coli isolates obtained from unit inpatients and searched for identities using complete-genome multisequence locus typing (cgMLST) and (2) retrospectively tabulated the cumulative rates of acquired ESCRE carriage in 356 patients admitted for a first HSCT before (200 patients) or after (156 patients) institution of universal ESCRE stool surveillance and contact isolation for carriers. No ESCRE organisms were cultured from patient rooms before or after terminal cleaning. In vitro, few, if any, ESCRE organisms survived longer than 2 hours. Nine of the subsequent occupants of a room in which a patient with ESCRE carriage had resided were detected with ESCRE carriage, only 2 of whom carried the same species as that of the prior occupant. DNA sequencing and cgMLST determination of the 60 E. coli isolates showed 53 cgMLST strains. Seven of the 53 strains were shared by 2 patients. After institution of universal ESCRE surveillance/isolation there was a significant decline in acquired ESCRE carriage among HSCT recipients. We conclude that vertical transmission of ESCRE organisms through room contamination appears to be uncommon on modern HSCT units. Conversely, our results are consistent with the horizontal spread of ESCRE organisms, probably mediated by intermediate vectors such as personnel or shared equipment. Further studies are needed to better define the magnitude of and risk factors for ESCRE horizontal transfers and the benefits of ESCRE surveillance/isolation.

Patients with multiple myeloma can now be treated with chimeric antigen receptor T-cell (CAR-T) therapy. We studied how CAR-T therapy is used for multiple myeloma. We also studied things that could help make this therapy easier for doctors to use. The CAR-T process takes 13 steps and 177 days. It begins with the choice to use the therapy and ends about 100 days after it is used. The process uses 46 different healthcare professionals and ten different locations. We found several possible changes that can improve this process. Of these changes, three stand out. First, improved teamwork between members of the care team can help them prepare for and resolve possible problems. Second, reducing insurance red tape will make it easier to provide CAR-T therapy to patients. Third, allowing use of CAR-T therapy in places other than hospitals can help more patients receive this therapy. If applied, these three things may lower the time needed to treat patients by 14.4% and may reduce costs by 13.2%.

Current information is limited on the incidence, risk factors, and consequences of extended-spectrum cephalosporin resistant Enterobacteriaceae (ESCRE) carriage in patients undergoing therapy for newly-diagnosed acute leukemia.We monitored 300 consecutive patients who submitted a first stool within the first week of initial hospitalization for initial and hospital acquired ESCRE carriage. Selected available isolates underwent DNA sequencing for determination of strain typing and resistance genes.19 (6%) patients had ESCRE in their initial stool, and there was continued risk for new acquisition throughout their multiple hospitalizations. Patients with AML had more acquired carriage during their initial hospitalization. Increased hospitalizations and male sex were risk factors for detected acquired ESCRE carriage. ESCRE stool carriage was predictive for ESCRE BSI but not for overall survival. Sequencing revealed that E. coli ESCRE isolates contained primarily ESBL, while Enterobacter spp. and Citrobacter spp. showed primarily AmpC genes. The antibiotic sensitivity patterns for ESCRE BSI isolates reflected these genome findings.ESCRE carriage is common in patients with acute leukemia undergoing repeated hospitalizations and increases the risk for ESCRE BSI. ESCRE genera express differing resistance genes which may be predictive for empiric antibiotic efficacy.

Background Few therapies are approved for hospitalized patients with severe coronavirus disease 2019 (COVID-19). Ibrutinib, a once-daily Bruton tyrosine kinase inhibitor, may mitigate COVID-19–induced lung damage by reducing inflammatory cytokines. The multicenter, randomized, double-blind phase 2 iNSPIRE study evaluated ibrutinib for prevention of respiratory failure in hospitalized patients with severe COVID-19. Methods Adult patients with severe COVID-19 requiring hospitalization and supplemental oxygen but without respiratory failure were randomized 1:1 (stratified by remdesivir prescription) to ibrutinib 420 mg or placebo once daily for up to 28 days plus standard of care (SOC), including remdesivir and/or dexamethasone. Results Forty-six patients were randomized to ibrutinib plus SOC (n = 22) or placebo plus SOC (n = 24). The primary endpoint (proportion of patients alive and without respiratory failure through day 28) was not met, with no statistically significant difference adjusting for remdesivir prescription (86% with ibrutinib plus SOC vs 79% with placebo plus SOC; adjusted difference, 5.8% [80% confidence interval, –9.2% to 20.4%]; P = .599). Secondary endpoints also showed no statistically significant improvement with ibrutinib plus SOC. Median treatment duration was 14 days for ibrutinib and placebo. Adverse events were similar with ibrutinib plus SOC vs placebo plus SOC (overall: 55% vs 50%; serious: 18% vs 13%) and were consistent with the known safety profile of ibrutinib. Conclusions Addition of ibrutinib to SOC did not improve the proportion of patients alive and without respiratory failure through day 28 in hospitalized patients with severe COVID-19. Ibrutinib had a manageable safety profile, with similar safety to placebo. Clinical Trials Registration NCT04375397.

7062 Background: Pts with R/R LBCL after first-line (1L) treatment (tx) who are unable to undergo high-dose chemotherapy (HDCT) and HSCT have poor outcomes and limited tx options. PILOT (NCT03483103) evaluated liso-cel, an autologous, CD19-directed chimeric antigen receptor (CAR) T cell product, as 2L tx in pts with R/R LBCL not intended for HSCT. Methods: Eligible pts were adults with R/R LBCL after 1L tx who were not deemed candidates for HDCT and HSCT by their physician and met ≥ 1 frailty criteria: age ≥ 70 yr, ECOG PS = 2, DLCO ≤ 60%, LVEF < 50%, CrCl < 60 mL/min, or ALT/AST > 2 × ULN. Bridging tx was allowed. Pts received lymphodepletion with cyclophosphamide and fludarabine, followed 2–7 days later by liso-cel at a target dose of 100 × 106 CAR+ T cells. Cytokine release syndrome (CRS) was graded per Lee 2014 criteria and neurological events (NE) per NCI CTCAE, version 4.03. Primary endpoint was ORR per independent review committee (IRC); all pts had ≥ 6 mo follow-up (f/u) from first response. Results: Of 74 pts leukapheresed, 61 received liso-cel and 1 received nonconforming product. Common reasons for pre-infusion dropout included death and loss of eligibility (5 each). For liso-cel–treated pts, median age was 74 yr (range, 53–84; 79% ≥ 70 yr) and 69%, 26%, and 5% met 1, 2, and 3 frailty criteria, respectively; 26% had ECOG PS = 2 and 44% had HCT-CI score ≥ 3. After 1L tx, 54% were chemotherapy refractory, 21% relapsed ≤ 12 mo, and 25% relapsed > 12 mo; 51% of pts received bridging chemotherapy. Median (range) on-study f/u was 12.3 mo (1.2–26.5). ORR and CR rate was 80% and 54%, respectively. Median DOR and PFS was 12.1 mo and 9.0 mo, respectively. Median OS has not been reached (Table). Most frequent tx-emergent AEs (TEAE) were neutropenia (51%), fatigue (39%), and CRS (38%), with grade (gr) 3 CRS in 1 pt (2%) and no gr 4/5 CRS. Any-grade NEs were seen in 31%, gr 3 in 5% (n = 3), and no gr 4/5 NEs; 7% received tocilizumab, 3% corticosteroids, and 20% both for tx of CRS/NEs. Overall, gr ≥ 3 TEAEs occurred in 79%, with gr 5 in 2 pts (both due to COVID-19). Two pts (3%) had gr 3/4 infections and 15 (25%) had gr ≥3 neutropenia at Day 29. Conclusions: In the PILOT study, liso-cel as 2L tx in pts with LBCL who met ≥ 1 frailty criteria and for whom HSCT was not intended demonstrated substantial and durable overall and complete responses, with no new safety concerns. Clinical trial information: NCT03483103. [Table: see text]

6567 Background: PILOT (NCT03483103) evaluated liso-cel, an autologous, CD19-directed, CAR T cell product, as 2L tx in pts with R/R LBCL not intended for HSCT. We analyzed changes in health-related quality of life (QOL) with respect to functioning and symptoms in PILOT. Methods: Adults with R/R LBCL after first-line tx were eligible. Pts were deemed not candidates for high-dose chemotherapy and HSCT by their physician and met ≥ 1 frailty criteria: age ≥ 70 yr, ECOG PS = 2, DLCO ≤ 60%, LVEF < 50%, CrCl < 60 mL/min, or ALT/AST > 2 × ULN. Pts completed EORTC QLQ-C30, FACT-LymS, and EQ-5D-5L (health utility index [HUI] and VAS) at screening (baseline [BL]), pre-tx (within 7 days before lymphodepletion), preinfusion on day of liso-cel infusion (Day 1), post-tx on Days 29, 60, 90, 180, 270, 365, 545, and 730/end of study, or at PD. The PRO-evaluable set included all pts with BL and ≥ 1 post-BL assessments. Linear mixed-effects models for repeated measures assessed the least squares (LS) mean change from BL for visits with ≥ 10 pts. Meaningful change from BL was calculated using responder definitions (in points): 10 for EORTC QLQ-C30, 3 for FACT-LymS, 0.08 for EQ-5D-5L HUI, and 7 for EQ-VAS. Results: Among the PRO-evaluable set, completion rates were high (≥ 80%) across most visits for all measures. For EORTC QLQ-C30, mean BL fatigue was meaningfully worse than in a general noncancer population (difference of > 10 points). Overall LS mean changes through Day 545 showed significant improvements in EORTC QLQ-C30 fatigue and pain, FACT-LymS, and EQ-VAS (Table). Improvement for lymphoma symptoms was also clinically meaningful. Fatigue improvement was clinically meaningful with a more sensitive minimal important difference of 4 (Cocks et al, 2012). Significant worsening was not observed for any outcome. In individual patient-level analysis, 70% of pts demonstrated meaningful improvement in FACT-LymS at month 6. Conclusions: Liso-cel meaningfully improved fatigue and FACT-LymS scores without negatively impacting other QOL measures. These data support the clinical evidence of liso-cel as a potential new 2L tx in pts with R/R LBCL not intended for HSCT. Clinical trial information: NCT03483103. [Table: see text]

Background: CAR T cell therapies are generally administered in an inpt setting owing to concerns of AE management. Infusion and monitoring of pts who receive CAR T cell therapy at nonuniversity medical centers (NMC) and in outpt settings have not been studied specifically. Liso-cel is an autologous CD19-directed, defined composition, 4-1BB CAR T cell product administered at equal target doses of CD8 + and CD4 + CAR + T cells. In TRANSCEND NHL 001 (NCT02631044) in pts with third- or later-line LBCL, liso-cel treatment showed an ORR of 73% (CR rate, 53%), with grade ≥ 3 cytokine release syndrome (CRS) in 2%, and grade ≥ 3 neurological events (NE) in 10% of pts (Abramson et al. Lancet 2020). We report outcomes of liso-cel in pts with R/R LBCL across inpt and outpt settings at NMCs in the United States treated in the OUTREACH study (NCT03744676). Methods: The study enrolled pts at NMCs, including those with university affiliations and centers naïve to CAR T cell therapy. Adults with R/R PET-positive LBCL after ≥ 2 lines of therapy and ECOG PS ≤ 1 were eligible. Pts with grade 3-4 cytopenias, mild to moderate organ function (LVEF ≥ 40%; serum CrCl > 30 mL/min), secondary CNS lymphoma, and prior autologous HSCT were eligible. After leukapheresis and lymphodepleting chemotherapy (LDC), pts received liso-cel at a target dose of 100 × 10 6 CAR + T cells. Primary endpoint was incidence of grade ≥ 3 CRS, NEs, prolonged cytopenias (Day 29 grade ≥ 3 lab values), and infections. Secondary endpoints included safety, ORR, CR rate, duration of response (DOR), and liso-cel PK. B-cell depletion analyses were exploratory. AEs, including NEs, were graded using NCI CTCAE v4.03; CRS was graded per Lee criteria (2014). NEs were defined as investigator-identified neurological AEs related to liso-cel. All study sites had a multidisciplinary CAR T cell therapy team and standard operating procedures (SOP) for outpt monitoring of toxicity and admission for CRS/NE management. Results: At data cutoff, 71 pts were treated with liso-cel at NMCs; 52 and 19 were monitored as outpts and inpts, respectively. Median age was 65 years (range, 28-83; ≥ 65 years, 51%; ≥ 75 years, 18%); 65% of pts had de novo DLBCL, 68% had screening ECOG PS of 1, 82% were chemotherapy refractory, 31% had ≥ 3 prior therapies, and 48% had markers of high tumor burden (pre-LDC LDH ≥ 500 U/L or SPD ≥ 50 cm 2). Demographics and baseline disease characteristics were generally similar in outpts and inpts, respectively, with differences of ≥ 20% noted in incidences of high-grade B-cell lymphoma (4% vs 42%) and DLBCL transformed from indolent lymphoma (29% vs 0%). Overall, any-grade CRS occurred in 39% of pts (no grade ≥ 3) and NEs in 32% (grade 3-4, 10%); 27% received tocilizumab and/or corticosteroids for CRS or NEs. Incidences of any-grade CRS and NEs were similar in outpts and inpts, while grade ≥ 3 NEs, infections, and prolonged cytopenias were numerically higher in outpts, but similar to pivotal trial observations (Table). The most common treatment-emergent AEs were neutropenia (68%), leukopenia (45%), CRS (39%), anemia (38%), thrombocytopenia (37%), and fatigue (35%). No grade 5 AEs were reported. Early (study Day ≤ 4) and overall hospitalization occurred in 33% and 69% of outpts, respectively; median time to hospitalization was 5.0 days (range 2-141) in outpts. The median (range) length of initial hospital stay after liso-cel administration was 6.0 days (1-28; n = 36) for outpts versus 10.0 days (0-31; n = 19) for inpts; 31% of outpts were not hospitalized. All pts were efficacy evaluable. The ORR was 77% and the CR rate was 51%. Median DOR was 14.8 months (95% CI, 3.9‒not reached [NR]) for outpts and was NR (95% CI, 2.0‒NR) for inpts at a median follow-up of 8.1 months and 11.3 months, respectively (Table). PK profiles were similar in outpts and inpts. Target depletion of CD19 + B cells in peripheral blood was also similar between oupts and inpts, and was maintained over the period of 1 year. Conclusions: Pts with R/R LBCL were successfully treated with liso-cel in outpt and inpt settings at NMCs and monitored for CAR T cell therapy-related toxicities using SOPs and multidisciplinary teams. Liso-cel demonstrated durable clinical activity with a favorable safety profile in both outpts and inpts. Incidences of severe CRS and NEs were low, as was tocilizumab and/or corticosteroid use. These data support liso-cel administration at NMCs and in the outpt setting. Figure 1 Figure 1. Disclosures Bachier: Novartis: Membership on an entity's Board of Directors or advisory committees; Mana: Membership on an entity's Board of Directors or advisory committees; Nkarta: Membership on an entity's Board of Directors or advisory committees; Autolus: Membership on an entity's Board of Directors or advisory committees; CRISPR: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Varela: Kite: Speakers Bureau; Nexlmmune: Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cherry: BMS: Membership on an entity's Board of Directors or advisory committees; Genetech: Membership on an entity's Board of Directors or advisory committees; Jazz: Membership on an entity's Board of Directors or advisory committees. Fanning: Sanofi: Speakers Bureau; Takeda: Speakers Bureau; ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Genmab: Membership on an entity's Board of Directors or advisory committees; TG Pharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees. Essell: Gilead: Current Employment, Speakers Bureau; BMS: Speakers Bureau. Yimer: Texas Oncology: Current Employment; Pharmacyclics: Speakers Bureau; Amgen: Speakers Bureau; Sanofi: Speakers Bureau; GSK: Speakers Bureau; Beigene: Speakers Bureau; Janssen: Speakers Bureau; Astrazeneca: Speakers Bureau; Karyopharm: Current equity holder in publicly-traded company, Speakers Bureau. Sharman: AstraZeneca: Consultancy; AbbVie: Consultancy; BMS: Consultancy; TG Therapeutics: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; Lilly: Consultancy. Espinola: BMS: Current Employment, Current equity holder in publicly-traded company. Mailley: BMS: Current Employment, Current equity holder in publicly-traded company. Avilion: BMS: Current Employment, Current equity holder in publicly-traded company. Ogasawara: Bristol Myers Squibb: Current Employment, Current equity holder in publicly-traded company. Ou: BMS: Current Employment. Shaughnessy: Sanofi: Honoraria, Speakers Bureau; Kite: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau.

CAR-T therapies represent a novel advance in oncology, albeit at list prices that exceed $373,000 (and that does not capture their total cost to the healthcare system). Since initial product approval in 2017, stakeholders and observers have attempted to investigate clinical and financial impacts of CAR-T therapies, and potential approaches to optimizing access and use by eligible patients. Most existing research is from a single stakeholder perspective - patients, providers, or payers - limiting the ability to draw broader conclusions on trends and offer prospective recommendations. To address this knowledge gap, we sought to identify and describe critical success factors for optimal delivery of CAR-T therapies. We undertook a qualitative study based on interviews with multiple US-based stakeholders including clinicians, financial and operations staff, and payer-insurers. Interviewees--which included oncologists (n=6), facility financial and operational personnel (n=4), and coverage and reimbursement decision-makers from US health plans (n=3)--completed structured, live, hour-long, interviews covering clinical, administrative, and general topics on patient access to CAR-T therapies. All clinicians had experience with ≥1 FDA-approved CAR-T therapies in both registered clinical trials and clinical practice; financial and operational personnel were affiliated with the same facilities as the clinicians, and also had real-world experience with these therapies; payer representatives were directors from a large national commercial plan, regional integrated delivery network, and a Medicare administrative contractor, respectively. Consensus facility feedback (i.e., clinicians, operational personnel) was that CAR-T is effective, and that their administrative processes had been optimized through care team coordination and experience-based efficiencies; in contrast, 2 of 3 payer interviewees expressed that, while CAR-T therapies have shown efficacy, their real-world benefits and applicability are less well-defined. Facility interviewees noted that: (1) reimbursement from commercial insurers is higher than from Medicare, with the latter associated with per-patient net-neutral or negative margins; (2) when possible, differential reimbursement between inpatient and outpatient settings may drive patient management towards outpatient care; and (3) negative-margin cases are currently deemed acceptable due to nonclinical factors (i.e., competitive pressure within a geographic region, anticipated branding/marketing value) and relatively small treated populations. From payer interviewees, CAR-T cost and perceived cost-to-value have made health plans more receptive to considering outcomes-based contracting, capitated provider payments, or other mitigation methods. Left unoptimized, these factors may adversely impact patient access to, and long-term provider attractiveness of, CAR-T therapies. All interviewees agreed that as the CAR-T marketplace grows, a strong preference exists for manufacturers to develop and communicate for their therapies durable outcomes data, clear and comprehensive reimbursement information, and competitive pricing. With the potential for many approved products in a single indication, and/or a single approval for indications with relatively large eligible patient populations, interviewees also conveyed interest in compelling health economic data. Facility interviewees also acknowledged that if it remains an overall net-negative margin service, new providers will be less able to start CAR-T programs and smaller programs may encounter sustainability issues, collectively jeopardizing patient access to these life-changing therapies. Overall, findings from this study suggest that during the continued maturation of the landscape, stakeholders will need to be proactive to ensure that CAR T-cell therapies can be maintained amidst financial and operational pressures. Several CAR-T therapy options for multiple myeloma are on the immediate horizon, likely increasing demand among eligible patients. Accordingly, the need to link real-world evidence of the clinical value and institutional investment burden of these therapies to reimbursement is imperative, both to insulate payers and enable clinicians to provide innovative therapies. Figure 1 Figure 1. Disclosures Faber: Amgen: Honoraria; Adaptive: Honoraria; Cardinal Health: Honoraria; Celgene: Honoraria; Astra Zeneca: Honoraria; GlaxoSmith Kline: Honoraria; Janssen: Honoraria; Juno: Honoraria; Karyopharm: Honoraria; Kite: Honoraria; Takeda: Honoraria; Sanofi Genzyme: Honoraria. Hunter: BMS: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Deol: Kite, a Gilead Company: Consultancy. Crivera: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Riccobono: Legend Biotech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Garrett: Legend Biotech USA: Current Employment. Jackson: Memorial Sloan Kettering Cancer Center: Consultancy; Janssen: Current Employment. Fowler: Amgen: Ended employment in the past 24 months; Janssen: Current Employment. Berger: Janssen Scientific Affairs: Consultancy, Research Funding. Lorden: Janssen Scientific Affairs: Consultancy, Research Funding. Stewart: Janssen Scientific Affairs: Consultancy, Research Funding.