Journal articles on the topic 'Vinceno Monti'

Abstracttitle SUMMARY /title Two letters of Gianfrancesco Malfatti (1731-1807) are published. The first one is addressed to Cassini de Thury (1784), the second one to Vincenzo Monti (1806). These letters also regard other important figures of the eighteenth century in Ferrara and of the Napoleonic Period, such as the physician Giuseppe Antonio Testa (1756-1814) and Giovanni Battista Costabili Containi (1756-1841).

SANTA SCOLASTICA: RICOGNIZIONE E SAGGI DI SCAVO DI UN SITO SANNITA PRESSO SAN VINCENZO AL VOLTURNOUn sito sulla parte bassa del pendio orientale di Monte Santa Croce venne esaminato come parte del programma di ricerca sugli insediamenti dipendenti dal monastero altomedievale di San Vincenzo al Volturno. Monte Santa Croce era stato precedentemente identificato come un centra sannita fortificato da mura poligonali dai resti consistenti visibili in cima. Ricognizioni passate avevano permesso il ritrovamento di materiale ceramico di età sannita ed altomedievale, mentre la tradizione orale locale associava il sito ad un convento dedicato a Santa Scolastica. Gli scavi hanno rivelato la presenza di una serie di strutture consistenti, probabilmente di quinto o quarto secolo AC, forse appartenenti ad un insediamento gerarchico situato a meta del pendio della montagna, intorno alia sommita fortificata e da essa dipendente. Siti di occupazioni successive sono noti grazie ad una ricognizione del 1993 a nord della montagna. La presenza di ceramica altomedievale rimane inspiegabile, e resta ancora da ricercare siti di insediamento altomedievale.

Carmelo Psaila (1871–1961), officially known as Dun Karm, has been acknowledged as Malta's national poet long before his death. He embodies the close relationship prevailing for long centuries between Italian culture and Maltese Literature. This essay seeks to unearth the basic characteristics of Dun Karm's poetry, in both Italian and Maltese, in the light of the Italian tradition, ranging from Dante to Monti and Manzoni. His initial identity is neoclassical, and as he moves ahead and gets more aware of his own environment, he assumes an ever growing romantic character. Various aspects of his style (vocabulary, rhythmic patterns, grammatical nuances) and metaphorical language show that there is a profound continuity between his writings in Italian and the subsequent ones in his own native tongue. Through a comparative analysis of his more typical poems, and with specific reference to Vincenzo Monti and Alessando Manzoni, the cultural personality of Dun Karm is identified and illustrated with numerous examples.

Tesi La sentenza Pescatore non decide né in merito alla controversia tra le parti relativa all’eredità di Vincenzo Pescatore, né in merito alla legge che governa la successione. Decide solo in merito alla richiesta della vedova della pronuncia di una anti-suit injunction nei confronti dei figli di Pescatore. Ciò nondimeno la sentenza è di particolare interesse per un giurista di civil law perché in molti punti della motivazione essa presenta una comparazione tra il diritto inglese e il diritto italiano in materia di principi fondamentali del diritto delle successioni.   The author’s view The Pescatore Judgement does not decide neither on claims concerning Vincenzo Pescatore’s inheritance, nor the question of the applicable law to the inheritance. It only decides on the widow’s claim of a anti-suit injunction toward Pescatore’s sons.  Nevertheles the Judgement is of great interest to a civilian jurist. The Judgement deals in many passages with a comparison between English law and Italian law concerning some basic issues of the succession law.

Il saggio presenta tutti i dati disponibili utili al ritrovamento di un testo per ora fantasma, quale la Risposta di Paolo Paruta (Venezia, 1540 - 1598) alla Lettera XXX dello pseudo-Dante, falso d’autore editando il quale nel 1547 il fiorentino Anton Francesco Doni scatenò una violenta polemica politica anti-veneziana. Nuove ricerche dimostrano come nella celebre biblioteca padovana di Gian Vincenzo Pinelli fosse conservata una copia della Risposta. Paruta e Pinelli, infatti, condividevano molti interessi e conoscenze negli ambienti della Padova e della Venezia del Secondo Cinquecento.

In the second half of the eighteenth century, archaeological activities in Rome intensified considerably under the pontificate of Pius VI (1775–99), and new excavations in the Roman Campagna and the Latium, together with the erection of the Museo Pio Clementino (1776–84), excited considerable interest in Roman learned and literary circles. A young poet who had moved to Rome from Romagna, Vincenzo Monti (1754–1828), obtained his first great success by celebrating the new discoveries in a memorable poem, La prosopopea di Pericle. In it, a newly found herm of Pericles sings of Pius's pontificate as a new golden age for the arts. Monti, who was to become Italy's most authoritative man of letters in the following decades, befriended in those years, and received considerable assistance from, the leading antiquarian of that age, Ennio Quirino Visconti (1751–1818). Their relationship and its legacy provide the subject of this paper, with emphasis on Monti's early poetry, its significance for the literary history of the neoclassical age, and its role in shaping a novel poetic style intended for the praise of ancient art.

Many factors need to be considered when preparing for new tree plantings. Careful planning and preparation is necessary to ensure success and reduced frustrations in the future. Site selection, rootstock and scion selection, planting density, quality of trees, tree planting, irrigation, nutrition, and disease control are all important factors that contribute to success of new grove establishment. This 3-page fact sheet is part of the 2018-2019 Florida Citrus Production Guide. Written by Mongi Zekri, Ute Albrecht, and Christopher Vincent, and published by the Horticultural Sciences Department, May 2018. HS1302/HS1302: 2022–2023 Florida Citrus Production Guide: Grove Planning and Establishment (ufl.edu)

This study was conducted to evaluate a behavioural assessment room (BAR) as a strategy in the management of people exhibiting acute behavioural disturbance in the St Vincent?s Hospital, Melbourne Emergency Department (ED). The study involved a retrospective audit of the data documented for BAR use over a 12-month period and a structured questionnaire of clinical and nonclinical emergency department staff. Patients managed in the BAR presented with various behaviours; 58% were substance induced. The median duration of stay in the room was 20 minutes, during which assessment and containment or ?behavioural resuscitation? proceeded. 98.5% of questionnaire respondents believed that the BAR created a safer environment for all ED patients, staff and others.

It is essential to accurately and safely resect all tumors during surgery for multiple lung metastases. Here, we report a case of hepatoblastoma (HB) with multiple pulmonary nodules that ultimately underwent complete resection using combined three-dimensional image reconstruction and indocyanine green (ICG) fluorescence guidance. A 1-year-old boy was diagnosed with HB and multiple lung metastases. After intensive chemotherapy, complete resection with subsegmentectomy (S5 + 6) and partial resection (S3, S8) were performed. More than 100 pulmonary nodules, which remained visible on computed tomography (CT) despite additional postoperative chemotherapy, were subjected to pulmonary resection. We used the SYNAPSE VINCENT software (Fujifilm Medical, Tokyo, Japan) to obtain three-dimensional images of the nodules. We numbered each nodule, and 33 lesions of the right lung were resected by multiple wedge resections through a right thoracotomy, with the aid of palpation and ICG fluorescence guidance. One month after the right metastasectomy, resection of 64 lesions in the left lung was performed via left thoracotomy. Postoperative CT showed complete clearance of the lung lesions, and the patient remained disease-free for 15 months after the treatment. This case study confirms that the combination of three-dimensional localization and ICG fluorescence guidance allows for accurate and safe resection of nearly 100 lung metastases.

Bougnères P. Efficacy of intermittent therapy in growth hormone-deficient children. Eur J Endocrinol 1994;130:459–62. ISSN 0804–4643 Eighty-six growth hormone-deficient children treated with extractive growth hormone were transferred to recombinant growth hormone (rGH): 57 children were transferred directly to rGH, but 29 experienced a 9.7 ± 1-month pause in growth hormone administration. The retrospective analysis of growth from 1 year before to 1 year after initiation of rGH showed that the interruption of growth hormone administration did not modify the final height gain. During the 2 years, children with continuous therapy gained 12.2 ± 0.5 cm with a cumulative growth hormone dose of 43 ± 3 U/kg, while those who paused gained 12.1 ±0.3 cm with a cumulative growth hormone dose of only 24 ± 2 U/kg (p < 0.0005). As expected, during the year preceding the onset of rGH, the children who paused gained less height than those treated continuously, but grew more rapidly during the first year of rGH administration. This was due to an important re-acceleration of growth rate at re-initiation of therapy after the pause. Our observation suggests that regimens of discontinuous rGH administration could be as efficient as continuous treatment. If confirmed in prospective randomized trials, this could have important consequences for improving the clinical efficiency of a given dose of rGH, as well as for the patient's comfort, secondary effects and cost of therapy. Pierre Bougnères, Service d'Endocrinologie Pédiatrique, Hôpital Saint Vincent de Paul, 82 avenue DenfertRochereau, 75014 Paris, France

IntroduzioneA dispetto delle attese e dei pronostici di molti, non c'è stato pareggio. Il voto ha prodotto un vincente: la coalizione di centro-sinistra formata dai partiti dell'Ulivo e da Rifondazione Comunista. Nelle elezioni del '94 il risultato non era stato così chiaro. Allora, emerse un «Parlamento diviso»: i Poli di Berlusconi vinsero nettamente alla Camera, ma sfiorarono solo la maggioranza assoluta dei seggi al Senato. Anche questa volta si rileva una differenza significativa tra Camera e Senato: al Senato i partiti dell'Ulivo da soli hanno quasi la maggioranza assoluta dei seggi mentre alla Camera non possono in ogni caso prescindere dal sostegno di Rc. Si può dire però che il sistema elettorale ha funzionato. Nonostante le sue imperfezioni la componente maggioritaria è riuscita a trasformare una maggioranza relativa di voti in una maggioranza assoluta di seggi consentendo così la formazione di un governo come diretta emanazione del verdetto elettorale. Si è inoltre realizzata l'attesa alternanza. Una alternanza atipica, visto che il governo entrante non sostituisce il governo installato dopo le elezioni del '94, ma un governo (quasi) tecnico già sostenuto in Parlamento dalla maggior parte dei partiti che hanno vinto le elezioni e che ora sostengono il governo Prodi. Questo articolo tratta delle cause della vittoria del centro-sinistra. Prima di mettere mano alla spiegazione, facciamo il punto sui risultati delle ultime elezioni mettendoli a confronto con quelli delle precedenti.

e13065 Background: Breast cancer associated with liver metastases (BCLM) occurs later in the progression of metastatic breast cancer and carries a poorer prognosis than bone or soft tissue metastases (Pagani). As systemic therapy begins to prolong progression, there is an inherent necessity for localized therapy directed at distant metastases. Further, there is some evidence to suggest that interventional techniques can prolong survival and palliate symptoms although data is lacking in this area (Hoe). Here we present findings describing the mortality benefit, adverse effects, and radiological response to Yttrium-90 (Y-90) radioembolization in BCLM patients. Methods: All patients with BCLM who received Y-90 radioembolization at St. Vincent Hospital from 2013-2018 were included in data collection. Digital chart review was utilized for data collection. To be eligible for the study, patients must have image or biopsy proven metastatic breast cancer to the liver, active unresectable disease not appropriate for ablation, ECOG performance status of 0-2, Bilirubin < 2.0 mg/dL, and no other evidence of liver disease. Patients with a life expectancy less than 2 months were excluded. Results: Twenty-five patients with BCLM underwent Y-90 radioembolization of hepatic metastases. Median survival after therapy was 495 days, or 16 months compared to the median survival rate of 4 months for BCLM patients reported by previous studies (Hoe). At 3 month follow up CT, 48% of patients experienced significant reduction in hepatic tumor burden, only 20% had worsening disease. 16% of patients reported abdominal pain. Median increase in bilirubin was 0.1. Median post procedural AST was 47, and ALT 40. Six patients experienced ascites requiring paracentesis, which occurred on average 14.3 months after Y-90 therapy. There were zero cases of pancreatitis and Radioembolization Induced Liver Disease (REILD). Conclusions: In patients with BCLM who undergo Y-90 radioembolization there seems to be a mortality benefit compared to traditional therapies. Further, there is a radiological reduction in tumor burden, and only minimal adverse effects.

AbstractStudy ObjectiveBurning mouth syndrome (BMS) is characterized by oral mucosal burning sensations, with normal clinical and laboratory results. Menstrual synchrony of migraines and epilepsy have been discussed; however, menstrual synchrony of BMS has not heretofore been described.MethodsCase Study: A 29 year old right-handed female exhibited intermittent BMS symptoms, one month after suffering a left parietal infarction. She describes the pain as a burningsensation, localized to the bilateral and anterior aspects of her tongue. It lasts for four days, starts three days prior to her menses, and occurs twice a month. She is unable to correlate any patterns or triggers that may cause to exacerbate her BMS. She denies any taste disturbances, hot-flashes, night sweats, and perspiration.ResultsAbnormalities during neurological examination were noted. Cranial nerves (CN) III, IV, and VI showed bilateral lateral first degree end-gaze unsustained nystagmus. CN IX and X showed decreased bilateral gag reflex. A right pronator drift with a right abductor digiti minimi sign was seen in the motor examination. The cerebellar examination was positive for bilateral dysmetria during the Finger-To-Nose examination, and exhibited Holmes rebound phenomena, right more than left. Sensory examination showed decreased light touch in the lower extremities, right more than left. Hoffman reflex was bilaterally positive. Mental status examinations demonstrated poor similarity interpretation and calculation ability. Her neuropsychiatric testing was normal, and included the Go-No-Go and Animal Fluency Testing. MRI of the brain exhibited gliosis/laminar necrosis in the left inferior parietal lobe, and an 8mm descent of cerebellar tonsils below the foramen magnum.ConclusionThe potential mechanism for catamenial BMS is manyfold. Estrogen and progesterone both have nociceptive properties. Premenstrual drop or reduction of estrogen and progesterone may act to disinhibit pain [Vincent 2008], with pain modulation being more effective during the ovulatory phase (high estrogen and low progesterone) [Rezaii 2012]. Depression in the presence of Late Luteal Phase Dysphoric Disorder may function to exacerbate the perception of underlying pain throughout the body, including the mouth and tongue. Decrease in estrogen and progesterone levels may also alter salivary output and composition. This may allow baseline reduction of proprioceptive input on the tongue, thus acting through Melzack and Wall’s Gate Control Theory of Pain to disinhibit small C fibers, which is perceived as burning pain [Melzack 1978]. Along with menses, olfactory ability drops, and food preferences are often reported to change [Keller 2013]. A decrease in estrogen and progesterone can also enhance trigeminal nerve sensitivity [Martin 2007], which exacerbates pain. This may indirectly influence or be associated with her BMS. Such observations justifies a trial of hormonal agents for therapy of BMS.Funding AcknowledgementsSmell and Taste Treatment and Research Foundation

Abstract Background: PDAC is a highly morbid disease with no validated biomarkers for first-line (1L) treatment selection. The PurIST single-sample molecular subtyping gene signature, initially described by Rashid et al. (Clin. Cancer Res., 2020), classifies PDAC tumors as basal or classical. Prior work showed that these subtypes are associated with prognosis and that basal subtype patients have significantly lower objective response rate to FOLFIRINOX (FFX) compared to classical subtype patients. This suggests potential implications for treatment with FFX versus gemcitabine and nab-paclitaxel (GnP). Here, we retrospectively demonstrate the clinical validity of PurIST implemented as a laboratory developed test (LDT) on the Tempus Labs sequencing platform using a real-world dataset of advanced PDAC patients. Methods: De-identified PDAC patients were selected from the Tempus Oncology Data Ecosystem under an IRB-approved protocol according to the following inclusion criteria: no systemic treatment, surgically unresectable/metastatic, available RNA-sequencing data from primary or metastatic tissue, and FFX or GnP as 1L systemic therapy with available outcomes. Sequencing was performed by the CAP/CLIA validated Tempus xT assay. The PurIST model was applied to normalized RNA-sequence abundance files to compute a basal or classical subtype label. Predefined statistical analysis parameters included 12-month survival rate and median overall survival (OS) in FFX treated patients. OS was compared using Kaplan-Meier estimates, hazard ratios, and log-rank statistical tests. Results: 258 PDAC patients (64.9 +/- 9.9 yrs, 42% female), were identified for analysis with median OS of 11.7 months (95% CI: 10.6-13.7) and 12-month censorship rate of 12.8%. 151 patients were treated with FFX and 107 with GnP. 42 patients (28%) receiving FFX and 31 patients (29%) receiving GnP were classified as basal. Among FFX treated patients, median OS was 14.4 months (95% CI: 12.5-16.9) in classical patients vs. 9.4 months (95% CI: 8.3-14.5) in basal patients (HR = 1.72, 95% CI = 1.2-2.6, p=0.006). The 12-month survival rate was significantly lower in basal patients receiving FFX vs. classical patients (33.3% vs. 59.4%, p=0.011). In basal patients, no difference in OS was observed between FFX and GnP groups (p=0.6). Classical patients receiving FFX had a 14.4 months median OS vs. 10.8 months for patients receiving GnP (p=0.046). Conclusions: In this real-world cohort, we validate the association between PurIST subtypes and PDAC patient survival when administered FFX or GnP. Among FFX-treated patients, classical patients had significantly better outcomes compared to basal patients. Moreover, classical patients appeared to have improved outcomes with FFX vs. GnP. These findings represent underlying biological PDAC differences and demonstrate the clinical validity of PurIST as a prognostic marker in PDAC patients when performed as an LDT on the Tempus xT platform. Ongoing evaluation of PurIST performance will be continuously monitored through the Tempus Oncology Data ecosystem. Citation Format: Stephane Wenric, James M. Davison, Yun E. Wang, Gregory M. Mayhew, Kirk Beebe, Hyunseok P. Kang, Michael V. Milburn, Vincent Chung, Tanios Bekaii-Saab, Charles M. Perou. Purity Independent Subtyping of Tumor (PurIST): Real-world data validation of a pancreatic ductal adenocarcinoma (PDAC) gene expression classifier and its prognostic implications [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A002.

O Rio Amazonas e sua imensa bacia hidrográfi ca ladeada por imponentes fl orestas, sempre exerceram um fascínio imenso em todos que ouviram falar dele. Desde o seu descobridor Vincente Pinzón, que em 1500 denominou-o de Rio Santa Maria del Mar Dulce, até os dias de hoje, aventureiros, biólogos, cartógrafos, geógrafos, indianistas e muitos outros cientistas percorreram suas águas à procura de informações que pudessem explicar a grandiosidade dessa obra da natureza. O fascínio do Rio-mar atraiu também o viajante italiano Gaetano Osculati, que em 26 de outubro de 1847 começou a sua viagem em canoa pelo Rio Napo, cuja nascente está no Equador, nas proximidades do monte Cotopaxi, e foz no Rio Solimões. Gaetano Osculati, espelhando-se em Orellana, faz o mesmo e ao fi nal da sua viagem de quatro anos, escreve Esplorazioni delle Regioni Equatoriali lungo il Napo ed il fi ume delle Amazzoni, publicado em Milão no ano de 1854, o qual utilizamos para recolher o léxico português inserido incidentalmente ou voluntariamente na obra. Ao escrever sobre o que observava, na falta de termos em italiano, o explorador se apropria de novas palavras, transcrevendo-as da maneira como as ouviu. Normalmente, há, nas nomeações existentes no interior da narrativa, uma estreita ligação entre o nomear e o narrar: ao nomear, o narrador concentra na palavra uma série de sinais linguísticos, a sua carga cultural, o seu saber e sua capacidade expressiva. Pretendemos, neste artigo, à luz das teorias de Alves (1990; 2010), Klajn (1972) e Nunes (1996), recolher, registrar e classifi car os empréstimos lexicais do português e do tupi, na obra de Gaetano Osculati, com o objetivo de contribuir para o estudo da Lexicologia histórica portuguesa e italiana, em especial recuperar os empréstimos lexicais portugueses utilizados pelo viajante italiano.

Abstract Background: Tumor Treating Fields (TTFields) are a novel, locoregional antimitotic treatment modality approved for glioblastoma and malignant pleural mesothelioma. Continuous, non-invasive low intensity, intermediate frequency (150-200 kHz) alternating electric fields are delivered to the tumor via skin-placed arrays. In vitro, TTFields (150 kHz), with or without chemotherapy, induced antiproliferative and anticlonogenic activity on pancreatic cancer cell lines. The phase 2 PANOVA study (NCT01971281) demonstrated that the combination of TTFields with nab-paclitaxel and gemcitabine (GnP) is well-tolerated, with promising efficacy in both metastatic and locally advanced pancreatic adenocarcinoma (LAPC). These data indicate that TTFields with GnP warrant phase 3 evaluation. Methods: PANOVA-3 (NCT03377491) is a prospective, randomized, phase 3 trial designed to investigate the efficacy and safety of TTFields concomitant with GnP in patients with LAPC. The planned enrollment is 556 patients. Eligibility criteria include unresectable LAPC (per National Comprehensive Cancer Network guidelines), Eastern Cooperative Oncology Group performance status of 0-2, and no prior progression or treatment. Patients will be stratified by performance status and geographical region, and randomly assigned 1:1 to TTFields plus GnP or GnP alone. Based on a recent protocol amendment, a smaller and lighter-weight (reduced from 6 to 2.7 lbs) TTFields device will be used. Standard doses of nab-paclitaxel (125 mg/m2) and gemcitabine (1000 mg/m2) will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) will be delivered ≥ 18 h/day until local disease progression per Response Evaluation Criteria in Solid Tumors V1.1. Follow-up will be performed every 4 weeks and a computed tomography scan of the chest and abdomen every 8 weeks. After local disease progression, patients will be followed every month until death. The primary endpoint is overall survival (OS). Secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, pain- and puncture-free survival rate, rate of resectability, quality of life, and toxicity. The sample size was estimated per log-rank test comparing time to event in patients treated with TTFields plus GnP with published clinical trial data on patients treated with GnP alone. PANOVA-3 is designed to detect a hazard ratio of 0.75 in OS. Type I error is set to 0.05 (2-sided) and power to 80%. The trial is currently recruiting at 104 sites in Austria, Belgium, Canada, China, Croatia, Czech Republic, France, Germany, Hong Kong, Hungary, Israel, Italy, Poland, Spain, Switzerland, and USA. Citation Format: Vincent J. Picozzi, Judith Finlay, Teresa Macarulla, Philip A. Philip, Carlos R. Becerra, Tomislav Dragovich. PANOVA-3: A phase 3 study of tumor treating fields with gemcitabine and nab-paclitaxel for front-line treatment of locally advanced pancreatic adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT234.

Abstract Background: Tumor Treating Fields (TTFields) therapy is a loco-regional antimitotic treatment approved for glioblastoma and malignant pleural mesothelioma. TTFields (150 kHz), with/without chemotherapy, induced antiproliferative and anticlonogenic activity in pancreatic cancer cell lines in vitro. The phase (ph) 2 PANOVA study (NCT01971281) demonstrated that TTFields therapy with gemcitabine and nab-paclitaxel (GnP) is well-tolerated, with promising efficacy in metastatic and locally advanced pancreatic adenocarcinoma (LAPC). Despite advances in the treatment of LAPC, prognosis is poor and available therapies negatively impact quality of life (QoL). As such, there is an unmet need for effective and tolerable treatments. Trial design: PANOVA-3 (NCT03377491) is a prospective, randomized, ph 3 trial investigating the efficacy and safety of TTFields therapy with GnP in patients (pts) with LAPC, with a planned enrollment of 556 pts. Pts with unresectable LAPC (per NCCN guidelines), ECOG PS of 0–2, and no prior treatment are eligible. Pts will be stratified by performance status and geographical region, and assigned 1:1 to TTFields therapy + GnP or GnP alone. Standard doses of GnP will be administered on days 1, 8, and 15 of a 28-day cycle. TTFields (150 kHz) generated by the NovoTTF-200T System, will be delivered ≥ 18 h/day until local disease progression per RECIST v1.1. Pt usage is tracked by the device. Follow-up will be performed every 4 wks; CT scans of the chest and abdomen will be taken every 8 wks. After local disease progression, pts will be followed every month until death. The primary endpoint is overall survival. QoL, pain-free survival, and puncture-free survival will be compared between TTFields therapy + GnP and GnP alone. Other secondary endpoints include progression-free survival (PFS), local PFS, objective response rate, 1-year survival rate, rate of resectability, and safety. Device Support Specialists (DSS) will provide technical and lifestyle integration training for pts and caregivers throughout TTFields therapy. The device manufacturer will also provide guidance on preventing and managing skin adverse events in line with published guidance, by means of DSS, field personnel, and various information resources. Furthermore, usage information from the NovoTTF-200T System is provided to both pts and physicians to facilitate discussions to optimize outcomes by maximizing time on therapy. Together, these novel support approaches help pts to confidently operate the NovoTTF-200T System with the knowledge that a multi-faceted support structure is available, ensuring TTFields therapy is seamlessly integrated into everyday life, increasing likelihood of high usage and ultimately optimizing pt outcomes. The trial is currently recruiting at 120 sites, globally. The DMC last reviewed the trial in August 2021, and suggested that the trial continue as planned. Citation Format: Vincent J. Picozzi, Teresa Macarulla, Philip Agop Philip, Carlos Roberto Becerra, Tomislav Dragovich. Tumor Treating Fields (TTFields) therapy concomitant with gemcitabine and nab-paclitaxel (GnP) for front-line treatment of locally advanced pancreatic cancer: the phase 3 PANOVA-3 study [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A021.

Abstract Background: Axi-cel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, is approved for the treatment of pts with relapsed/refractory LBCL with ≥ 2 prior systemic therapies. In the 2-year analysis of ZUMA-1 (NCT02348216), the multicenter, single-arm phase 1/2 study evaluating axi-cel in pts with refractory LBCL, the objective response rate (ORR) was 83%, including a complete response (CR) rate of 58%; 39% of pts had ongoing response with a median follow-up of 27.1 months (Locke et al. Lancet Oncol. 2019). EFS is emerging as a robust surrogate endpoint for OS in hematologic malignancies. A recent systematic analysis demonstrated a linear correlation between EFS and OS in pts with diffuse LBCL after first-line immunochemotherapy (Zhu et al. Leukemia. 2020). Here, we report updated survival findings from the phase 2 portion of ZUMA-1 after 4 years of follow-up, including an evaluation of the association of OS with EFS. Methods: Eligible pts had refractory LBCL (diffuse LBCL, primary mediastinal B cell lymphoma, transformed follicular lymphoma). After leukapheresis at enrollment, pts received low-dose conditioning chemotherapy (fludarabine and cyclophosphamide) followed by a target dose of 2×10 6 anti-CD19 CAR T cells/kg (Neelapu et al. N Engl J Med. 2017). The primary endpoint was ORR, with the first response assessment occurring 4 weeks following infusion. Additional endpoints included safety and translational evaluations. An exploratory analysis of OS by EFS at 12 and 24 months was performed. EFS was defined as the time from axi-cel infusion until disease progression, initiation of new lymphoma therapy (excluding stem cell transplant), or death from any cause. Comparisons of OS by EFS outcomes were analyzed via Kaplan-Meier estimates. Results: Of 111 enrolled pts, axi-cel was administered to 101 pts. As of August 11, 2020, median follow-up was 51.1 months. With over 4 years of follow-up, median OS was 25.8 months, and the 4-year OS rate was 44%. Median EFS in pts treated with axi-cel was 5.7 months, with a 12-month EFS rate of 43% (95% CI, 33-52) and a 24-month EFS rate of 38% (95% CI, 28-47). In pts with an EFS event by Month 12 (EFS12; n=57) vs those without EFS12 (n=44), 4-year OS rates were 7% (95% CI, 2-16) vs 91% (95% CI, 78-97), respectively. Among the 17 pts with EFS12 who were alive at Month 12, 13 (76%) died by Month 48, while among the 44 pts alive at Month 12 without EFS12, 4 (9%) died by Month 48. In pts with an EFS event by Month 24 (EFS24; n=62) vs those without EFS24 (n=39), 4-year OS rates were 13% (95% CI, 6-23) vs 92% (95% CI, 78-98), respectively. Among the 12 pts with EFS24 who were alive at Month 24, 4 (33%) died by Month 48, while among the 39 pts alive at Month 24 without EFS24, 3 (8%) died by Month 48. Since the 2-year analysis (Locke et al. Lancet Oncol. 2019), there have been no new safety signals reported, including no new serious adverse events, no axi-cel-related secondary malignancy, and no confirmed cases of replication-competent retrovirus. Overall, 26 pts received subsequent anti-cancer therapy; median time to next therapy was 8.7 months (range, 0.3 - 53.8). Immunoglobulin therapy was administered to 38 (38%) pts. Two pts in axi-cel-induced remission received allogeneic stem cell transplant; 1 pt was in CR and 1 pt was in partial response. Among treated pts, 58 (57%) have died, primarily due to progressive disease (46%; n=46), followed by other reasons (7%; n=7), adverse events (4%; n=4), and secondary malignancy (myelodysplastic syndrome, with onset on Day 574) unrelated to axi-cel (1%; n=1). Among pts without EFS12 and without EFS24, 1 pt each (2% and 3%, respectively) died due to disease progression &gt;24 months following axi-cel infusion; &gt;36 months, 2 pts each (5% for both) died due to disease progression (1 pt each [2% and 3%]) and other reasons (1 pt each [2% and 3%]. One pt (2%) without EFS12 died due to disease progression between 12 and 24 months. Updated findings with ≥5 years of follow-up, including translational correlations, will be presented. Conclusion: In this long-term survival analysis of ZUMA-1 with ≥4 years of follow-up, axi-cel demonstrated longer OS in pts without EFS events at Month 12 and Month 24 vs pts with events at these timepoints. These data support the use of EFS as a surrogate endpoint for long-term OS in refractory LBCL, and the relationship between EFS and 5-year OS will be presented. Disclosures Jacobson: Nkarta: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel support; Axis: Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Travel support, Research Funding; Clinical Care Options: Speakers Bureau; Celgene: Consultancy, Honoraria, Other: Travel support; Precision Biosciences: Consultancy, Honoraria, Other: Travel support; Lonza: Consultancy, Honoraria, Other: Travel support; Novartis Pharmaceuticals Corporation: Consultancy, Honoraria, Other: Travel support; Humanigen: Consultancy, Honoraria, Other: Travel support. Locke: Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Janssen: Consultancy, Other: Scientific Advisory Role; Gerson Lehrman Group: Consultancy; Novartis: Consultancy, Other, Research Funding; Legend Biotech: Consultancy, Other; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Emerging Therapy Solutions: Consultancy; Takeda: Consultancy, Other; Wugen: Consultancy, Other; EcoR1: Consultancy; Umoja: Consultancy, Other; Cowen: Consultancy; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding. Ghobadi: Atara: Consultancy; Amgen: Consultancy, Research Funding; Wugen: Consultancy; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Miklos: Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Patents & Royalties; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy. Oluwole: Kite, a Gilead Company: Consultancy, Research Funding; Janssen: Consultancy; Pfizer: Consultancy; Curio Science: Consultancy. Lin: Gamida Cell: Consultancy; Legend: Consultancy; Juno: Consultancy; Takeda: Research Funding; Merck: Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Bluebird Bio: Consultancy, Research Funding; Vineti: Consultancy; Sorrento: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Hill: Celgene (BMS): Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Gentenech: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Epizyme: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Timmerman: Spectrum Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Corvus: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Merck: Research Funding; TG Therapeutics: Current equity holder in publicly-traded company. Deol: Kite, a Gilead Company: Consultancy. Reagan: Seagen: Research Funding; Kite, a Gilead Company: Consultancy; Genentech: Research Funding; Curis: Consultancy. Stiff: Karyopharm: Consultancy, Honoraria; CRISPR Therapeutics: Consultancy, Honoraria; Kite, a Gilead Company: Research Funding; Amgen: Research Funding; Macrogenics: Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Research Funding; Gamida Cell: Research Funding; Seagen: Research Funding; Cellectar: Research Funding; Incyte: Research Funding; BioLineRX: Research Funding; Cellectar: Research Funding; Actinium: Research Funding; MorphoSys: Consultancy, Honoraria. Flinn: Celgene: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; AstraZeneca: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Rhizen Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Loxo: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Agios: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Karyopharm Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forma Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Infinity Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; ArQule: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Calithera Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Verastem: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Unum Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; AbbVie: Consultancy, Other: All Consultancy and Research Funding payments made to Sarah Cannon Research Institute, Research Funding; Kite, a Gilead Company: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Genentech: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; TG Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Roche: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Incyte: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Takeda: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Constellation Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Acerta Pharma: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Novartis: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Gilead Sciences: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Merck: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Seagen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Portola Pharmaceuticals: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; BeiGene: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Juno Therapeutics: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Janssen: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Nurix Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Pfizer: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Forty Seven: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Curis: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Iksuda Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; IGM Biosciences: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; MorphoSys: Consultancy, Other: All consultancy and research funding payments made to Sarah Cannon Research Institute, Research Funding; Great Point Partners: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Teva: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Trillium Therapeutics: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Triphase Research & Development Corp.: Other: All research funding payments made to Sarah Cannon Research Institute, Research Funding; Century Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Hutchison MediPharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Vincerx Pharma: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Sarah Cannon Research Institute: Current Employment; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Yingli Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Seagen: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Servier Pharmaceuticals: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute; Unum Therapeutics: Consultancy, Other: All consultancy payments made to Sarah Cannon Research Institute, Research Funding; Johnson & Johnson: Current holder of individual stocks in a privately-held company; Seattle Genetics: Research Funding. Farooq: Kite, a Gilead Company: Honoraria. Goy: MorphoSys: Honoraria, Other; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; OncLive Peer Exchange: Honoraria; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Michael J Hennessey Associates INC: Consultancy; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria; Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Medscape: Consultancy; Xcenda: Consultancy, Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Genentech/Hoffman la Roche: Research Funding; Infinity/Verastem: Research Funding; Janssen: Research Funding; Rosewell Park: Consultancy; LLC(Targeted Oncology): Consultancy; Hoffman la Roche: Consultancy; Xcenda: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Karyopharm: Research Funding; Phamacyclics: Research Funding; Constellation: Research Funding; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Muñoz: Bayer, Kite, a Gilead Company, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seagen, and Janssen, Millennium: Research Funding; Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics, Janssen, Seagen, Acrotech, Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/Bristol Myers Squibb, Genentech, and Roche: Speakers Bureau; Pharmacyclics, Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa, Alexion, Beigene, Fosun Kite, Innovent, Seagen, Debiopharm, Karyopharm, Genmab, ADC Therapeutics, Epizyme, Beigene, and Servier: Consultancy; Targeted Oncology, OncView, Kyowa, Physicians' Education Resource, and Seagen: Honoraria; OncView: Honoraria; Kyowa Kirin: Honoraria; Physicians' Education Resource: Honoraria. Siddiqi: Oncternal: Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics LLC, an AbbVie Company: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Speakers Bureau; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BeiGene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; TG Therapeutics: Research Funding. Shen: Atara: Current Employment, Current equity holder in publicly-traded company, Other: Leadership role, Patents & Royalties; Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Other: Leadership role, Patents & Royalties. Bot: Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support. Dong: GliaCure/Tufts: Consultancy, Patents & Royalties; Gilead: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Singh: Kite, a Gilead Company: Current Employment. Spooner: Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company. Karalliyadda: Kite, a Gilead Company: Current Employment; Gilead: Current equity holder in publicly-traded company. Kim: Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Zheng: Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding.

BackgroundAn interferon gene signature (IGS) is present in approximately 50% of early, treatment naive rheumatoid arthritis (eRA) patients. We previously demonstrated it negatively impacts on initial disease outcomes.ObjectivesTo 1) reproduce previous findings demonstrating the harmful effects of the IGS on early RA clinical outcomes, 2) identify which IFN class is responsible for the IGS and 3) seek evidence that IFN-α exposure contributes to harmful epigenetic footprint at disease onset.MethodsIn a large multicentre inception cohort (n=190) of eRA patients (RA-MAP TACERA) whole blood transcriptome, IGS (MxA, IFI44L, OAS1, ISG15, IFI6) and circulating interferons (IFN)-α, -β, -γ and -λ was examined at baseline and 6 months in conjunction with disease activity and clinical characteristics. A separate eRA cohort of paired methylome and transcriptome from CD4 T and CD19 B cells (n=41 for each) was used to explore any epigenetic influence of the IGS.ResultsThe baseline IGS reproducibly and significantly negatively impacts on 6-month clinical outcomes. In the high IGS cohort there was increased DAS-28 (p=0.025) and reduced probability of achieving a good EULAR response (p=0.034) at 6-months. In addition, the IGS in eRA is shown for the first time to predominantly reflect raised circulating IFN-α protein, not other classes of IFN and examination of whole blood upstream nucleic acid sensors expression suggest a RNA trigger. Both the IGS and IFN-α significantly fell in parallel at 6 months (p<0.0001), whereas other classes of IFN remained statistically static. There was a significant association with IFN-α and RF titre but not ACPA. Comparison of CD4 T and CD19 B cells between IGS high and low eRA patients demonstrated differentially methylated CPG sites and altered transcript expression of disease relevant genes e.g. PARP9, STAT1, EPTSI1 which was similarly, and persistently, altered 6 months in the separate TACERA cohort. Differentially methylated CPGs implicated altered transcription factor binding in B cells (GATA3, ETSI, NFATC2, EZH2) and T cells (p300, HIF1α) which cumulatively suggested IFN-α induced epigenetic changes promoting increased, and sustained, lymphocyte activation, proliferation and loss of anergy in the IGS high cohort.ConclusionWe validate that the IGS is a robust prognostic biomarker in eRA predicting poor therapeutic response. Its persistent harmful effects may be driven via epigenetic modifications. These data have relevance for other IFN-α states, such as COVID-19, but also provide a rationale for the initial therapeutic targeting of IFN-α signalling, such as with JAKi, at disease onset in stratified eRA subsets.ReferencesnilAcknowledgementsJDI is a National Institute for Health Research (NIHR) Senior Investigator. The authors acknowledge the support of TACERA Principal Investigators from all contributing NHS sites and the members of the TACERA Study Steering and Data Monitoring Committee. Additional acknowledgements include patient volunteers and administrative support from Ben Hargreaves. Newcastle researchers received infrastructural support via the Versus Arthritis Research into Inflammatory Arthritis Centre (Ref 22072), funding from The Medical Research Council; Academy of Medical Sciences; British Society of Rheumatology; The Wellcome Trust; JGW Patterson Foundation; Immune-Mediated Inflammatory Disease Biobank in the UK (IMID-Bio-UK), ANR and RTCure. This work was supported by the NIHR Newcastle Biomedical Research Centre at Newcastle Hospitals Foundation Trust and Newcastle University; views expressed are the authors’ and not necessarily those of the National Health Service, the National Institute of Health Research or the Department of Health.Disclosure of InterestsFaye Cooles Speakers bureau: Astrazeneca: December 2021, Jessica Tarn: None declared, Dennis Lendrem: None declared, Najib Naamane: None declared, Alice Lin: None declared, Ben Millar: None declared, Nicola Maney: None declared, Nishanthi Thalayasingam: None declared, Vincent Bondet: None declared, Darragh Duffy: None declared, Michael Barnes: None declared, Graham Smith: None declared, Sandra Ng: None declared, David Watson: None declared, Rafael Henkin: None declared, Andrew Cope: None declared, Louise Reynard: None declared, Arthur Pratt: None declared, RA-MAP Consortium: None declared, John Isaacs Speakers bureau: speaker/consulting fees from AbbVie, Gilead, Roche and UCB., Grant/research support from: JDI discloses research grants from Pfizer, Janssen and GSK.

Abstract SerpinA3N, a serine protease inhibitor, has been shown to ameliorate neuropathic pain by inhibiting leukocyte elastase activity (Vicuña et al., Nature Med 2015, 21:518-523). Patients with sickle cell disease (SCD) have activated leukocytes and experience neuropathic pain. We observed that SerpinA3N protein expression is significantly reduced in the dorsal root ganglion (DRG) of 5 month old homozygous HbSS-BERK sickle mice, compared to age-matched HbAA-BERK control mice expressing normal human hemoglobin A (p < 0.05). Since HbSS-BERK sickle mice demonstrate tonic hyperalgesia (Kohli et al., Blood 2010, 116:456-465), we hypothesize that decreased expression of SerpinA3N contributes to hyperalgesia by increasing elastase activity in these mice. We examined our hypothesis by using both genders of HbSS-BERK sickle and HbAA-BERK control mice, treated intravenously with and without sivelestat, a small molecule inhibitor of elastase. Mechanical, thermal and musculoskeletal/deep tissue hyperalgesia were analyzed before (considered baseline, BL) and after treatments. Elastase activity was determined using a fluorescent elastase substrate MeOSuc-AAPV-AMC (EMD Milipore). We observed that elastase activity is significantly increased in the DRG and lungs of male and female sickle mice compared to gender and age-matched control mice (p < 0.05 and < 0.005 for female and male DRG, respectively; p < 0.001 and < 0.05 for female and male lungs, respectively). Thus, decreased SerpinA3N expression perhaps contributes to increased elastase activity in sickle mice. Treatment of sickle mice with a single dose of 2 mg/Kg sivelestat led to a significant decrease in mechanical, heat and cold hyperalgesia for up to 24 hours compared to BL (p < 0.05), but no effect was noted in deep tissue hyperalgesia. Increasing the single dose to 4.5 mg/Kg led to a significant decrease in mechanical and thermal as well as deep tissue hyperalgesia for up to 24 hours in both genders compared to BL or saline treated mice (p < 0.05). Continuation of treatment with sivelestat 4.5 mg/Kg/day for 3 days led to significantly reduced hyperalgesia for up to 6 days in both genders of mice. These findings suggest that elastase activity contributes to nociceptive mechanisms, since hyperalgesia remained reduced for up to 3 days even after discontinuation of sivelestat. Reduced hyperalgesia following 3 days of sivelestat (4.5 mg/Kg/day) treatment was accompanied by a significant decrease in elastase activity in the DRG (p < 0.005) and lungs (p < 0.05) of both genders of sickle mice compared to saline treatment, but no histopathological changes were observed in lungs, kidney, liver, spleen and heart. Activating transcription factor 3 (ATF3), a marker of neuropathic pain, is elevated in the DRG of sickle as compared to control mice (Vincent et al., Blood 2013, 122:1853-1862). Sivelestat treatment significantly reduced ATF3-immunoreactivity compared to saline treatment in the DRG of sickle mice (p < 0.05), suggesting a decrease in neuronal injury which underlies neuropathic pain. None of the treatments had any effect on control mice. Sivelestat treatment showed no significant effect on serum tryptase or cutaneous mast cell degranulation in sickle or control mice. Thus, sivelestat specifically inhibits elastase activity. However, both elastase and tryptase activate protease-activated receptor-2 (PAR2) in the peripheral nervous system, stimulating the release of pro-nociceptive neuropeptides and activation of transient receptor potential vanilloid (TRPV) channels, leading to hyperalgesia. Since PAR-2 and TRPV channels are activated in sickle mice, it is likely that sivelestat treatment has an inhibitory effect on these mechanisms. It has been suggested that leukocytes, including activated neutrophils, contribute to acute lung injury (a common complication of SCD) and the pathogenesis of SCD (Zhang et al., Blood 2016, 127:801-809). Our observations that decreased SerpinA3N protein expression leads to increased elastase activity in DRG and lung in sickle mice suggest that this mechanism may contribute to sickle pathobiology and pain. In Japan, sivelestat is already approved for treatment of acute lung injury. Therefore, pharmacological inhibition of elastase may offer the advantage of treating chronic pain while concomitantly ameliorating one of the pathogenic mechanisms of SCD. Disclosures No relevant conflicts of interest to declare.

Abstract Background. Research in metastatic breast cancer is hampered by limited sample availability. Post-mortem tissue donation programs can help to overcome this problem but are logistically challenging and have thus far mainly focused on histopathological and genomic research. We here present the UPTIDER program (NCT04531696), aimed at the multilevel characterization of advanced breast cancer and generation of tumour models. Patients and Methods. Patients with stage IV breast cancer receiving their last line(s) of treatment are eligible for participation. Blood, urine and saliva samples are collected upon inclusion. Upon death, a post-mortem MRI (when possible) followed by a rapid autopsy is performed. Liquid biopsies from all body fluids and tissue samples from all macroscopically identified metastatic sites are collected. Samples are processed as mirrored biopsies in different conditions, such as fresh frozen for omics analyses, formalin fixed paraffin-embedded for histopathology, and slowly frozen in freezing medium or fresh for generation of xenograft and organoid models. Results. Since approval by the local Ethical Committee in November 2020, 22 patients have been enrolled and 15 autopsies have been performed. Mean interval between death and start of autopsy was 3h (range 2-6h), mean duration of the autopsies was 6h (4-9h). A post-mortem MRI was performed in 6 patients. Peripheral blood, central blood and bone marrow were collected from all patients; urine, ascites, cerebrospinal, pericardial and pleural fluid all in more than 2/3 of patients. On average, 232 (range 90-406) tissue samples of which 164 (45-303) pathological from 42 (15 – 79) metastases were collected for each patient. Most often sampled metastatic sites were lymph nodes, liver, bones, pleura and peritoneum. Samples from the primary tumour could be retrieved from all patients, either during the autopsy (n=6) or from historical archives. In total, 133 tumour samples were sent to collaborating partners for patient-derived xenograft creation. Already some have been successfully established and stored, including models derived from a patient with invasive lobular carcinoma (ILC) and one with metaplastic squamous cell carcinoma. When correlating microscopic and macroscopic findings, patients could largely be divided into three main categories. Eleven patients presented with overt and extensive disease burden, often characterized by diffuse visceral, pleural, peritoneal, bone and lymph node involvement. Two patients, both with ILC, presented with underestimated yet extensive disease burden. While gross examination and cross sectioning of organs did not reveal clear involvement, microscopical invasion of stomach and liver, amongst others, was found. Lastly, limited disease burden was seen in two patients, both with leptomeningeal involvement. In those patients, massive tumoral infiltration in the subarachnoid space and along the blood-brain barrier was seen microscopically, with no grey matter invasion. Conclusion. We successfully launched a new and comprehensive post-mortem tissue donation program for patients with metastatic breast cancer, enrolling ~ 1 patient per month. Post-mortem tumour samples already resulted in successful establishment of some patient-derived xenografts. From a clinical point of view, vast underestimation of the disease extent on imaging during life as well as macroscopically during the autopsy was observed in some patients with metastatic ILC. For patients with leptomeningeal metastasis, we showed that the highly aggressive nature of their disease might be explained by extensive meningeal infiltration disrupting the blood-brain barrier. Further insights into disease progression and heterogeneity will be generated by the ongoing multi-omics analyses. Citation Format: Tatjana Geukens, Maxim De Schepper, Karen Van Baelen, François Richard, Marion Maetens, Amena Mahdami, Ha-Linh Nguyen, Edoardo Isnaldi, Anirudh Pabba, Sophia Leduc, Imane Bachir, Maysam Hajipirloo, Emily Vanden Berghe, Sigrid Hatse, Eleonora Leucci, Maria Francesca Baietti, Georgios Sflomos, Cathrin Brisken, Patrick Derksen, Colinda Scheele, Vincent Vandecaveye, Ann Smeets, Ines Nevelsteen, Kevin Punie, Patrick Neven, Elia Biganzoli, Hans Wildiers, Wouter Van Den Bogaert, Giuseppe Floris, Christine Desmedt. Advancing research on metastatic breast cancer: the UPTIDER post-mortem tissue donation program [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-14-14.

Background Several agents have been investigated for beyond second-line treatment of chronic graft-versus-host disease (GVHD). Ruxolitinib has been recently approved for steroid-refractory acute GVHD, while a prospective randomized study is ongoing to examine its efficacy in steroid-resistant chronic GVHD (cGVHD). The present study evaluated the efficacy of Ruxolitinib in terms of 1) overall response rate (ORR), 2) clinical benefit (CB), 3) dose reduction of corticosteroid exposure, 4) failure-free survival (FFS) and 5) overall survival (OS), in patients heavily pretreated for steroid-resistant cGVHD. Patients and methods A total of 47 patients who developed cGVHD after HCT and treated with Ruxolitinib for cGVHD from March 2016 to April 2020, at three different sites (Princess Margaret Cancer Center, Canada; Vancouver General Hospital, Canada and Saint Vincent Hospital, Australia), were evaluated in the retrospective study. Patients and disease characteristics are as follows: median age 52 years; classical 35 (71%), overlap syndrome 14 (29%). Of note, 27 patients (57.4%) had a previous history of acute GVHD. The ORR and CB were assessed at months 3, 6 and 12, retrospectively. Responses were evaluated according to NIH scoring/staging/response assessment as part of standard clinical practice. CB was assessed considering clinical response as well as steroid dose reduction. For systemic steroid dose reduction, prednisone dose per kg per day was captured prior to Ruxolitinib start, at months 3, 6 and 12. Treatment failure was defined as 1) resistance requiring treatment switch, 2) non-relapse mortality (NRM), 3) relapse, 4) intolerance to treatment. FFS and OS were calculated from the day of starting Ruxolitinib therapy for cGVHD treatment. Results A total of 47 patients had moderate (11/47, 24.4%) to severe (33/47, 73.3%) cGVHD except one who had mild grade cGVHD with a high-risk feature (thrombocytopenia at the time of Ruxolitinib start). The median number of organ involvement was 3 (range 1-7). Over half of patients (63.8%) received Ruxolitinib as 4th line or beyond for cGVHD treatment, while median number of previous lines of therapy was 3 (range 1-9). All 47 patients (100%) had been previously treated with systemic steroids; other previous treatments included ECP therapy (53.2%), Imatinib (29.8%), Ibrutinib (23.4%), Rituximab (21.3%). Ruxolitinib was started at 10-15 mg daily as initial dose, then maintained at 20mg daily in two divided doses on months 3, 6 and 12.With a median follow-up duration of 12 months, ORR was attained in 35.7%, 36.0% and 35.0% at 3, 6 and 12 months, respectively (Figure A). Of note, ORR in patients with sclerotic changes was 56%, and 61.5% in those with lung involvement. Patients resistant to TKI (i.e. Imatinib or Ibrutinib) for cGVHD treatment showed similar ORR compared to those naïve to TKI therapy.The CB was observed in 53.5%, 66.7% and 72.2% at months 3, 6 and 12, respectively (Figure B). Patients resistant to TKI for cGVHD treatment did not show any difference in CB compared to those naïve to TKI therapy.In terms of prednisone dose reduction, by 12 months , half of patients (50.0%) could taper prednisone doses below 0.1mg/kg/day, while the proportion of patients on prednisone dose below 0.1mg/kg/day was 9.3%, 20.0%, 17.4%, and 50.0% at month 0, 3, 6 and 12, respectively (Figure C). The group who achieved CB at 3 months showed a significantly lower dose of prednisone at 12 months (0.078mg/kg/day) compared to those without clinical benefit at 3 months (0.197mg/kg/day; p=0.033; Figure D).Out of 37 patients evaluated, 11 failures (29.7%) were noted, including resistance requiring a switch to other therapy (n=7), NRM (n=2) and intolerance (n=2). The FFS rate at 1 year in the overall population was 68.5% (Figure E). The FFS at 1 year in those having CB at 3 months vs not was 86.5% vs 51.4% (p=0.025).The OS at 1 year was 90.9% (Figure F). The OS at 1 year in those having a CB at 3 months vs not was 100% vs 78.8% (p=0.053). Conclusion: This multicenter retrospective study revealed that Ruxolitinib is an effective treatment option for patients with cGVHD, with good ORR and CB. The achievement of CB in the first 3 months correlated well with steroid dose reduction. It suggests that Ruxolitinib is a feasible GVHD treatment option, even for patients who were heavily pretreated for cGVHD or failed previous TKI drug. Figure 1 Disclosures Hamad: Abbvie: Honoraria; Novartis: Honoraria. OffLabel Disclosure: Ruxolitinib treatment for steroid resistant chronic GVHD

INTRODUCTION Development of targeted therapies for chronic lymphocytic leukemia (CLL) including the anti-CD20 monoclonal antibody obinutuzumab (OBIN), Bruton's tyrosine kinase inhibitor ibrutinib (IBR), and Bcl-2 inhibitor venetoclax (VEN) offer highly effective treatment that avoids traditional cytotoxic chemotherapy. Both oral targeted agents (IBR and VEN) have high response rates and long progression-free survival (PFS) as single-agent monotherapy. Fixed duration combinations of IBR and VEN as well as VEN and anti-CD20 monoclonal antibodies have similarly high response rates and frequent achievement of undetectable minimal residual disease (uMRD) status, supporting that prolonged remission after fixed-duration treatment may be possible. Combination therapies have greater toxicities than monotherapy and the benefit of this approach is dependent on the durability of remissions. We conducted a phase 2 study of fixed-duration combination OBIN, IBR, and VEN in separate cohorts of treatment-naïve (TN) and relapsed/refractory (RR) CLL patients and report additional follow up (FU) for disease progression and survival. METHODS This study was conducted at the Ohio State University (OSU). Patients with TN or RR (≥1 prior treatment) CLL requiring therapy were eligible. Treatment was administered with OBIN, IBR, and VEN for 14 cycles (C) of 28 days. Drugs were started sequentially with OBIN starting C1, IBR C2, and VEN C3 with standard dose escalation. Final response was determined according to IWCLL 2008 criteria at 2 months after completing C14 (EOT). MRD was measured in the bone marrow and peripheral blood by standard 10-color flow cytometry with a cutoff of &lt;1x10-4 at EOT. The primary endpoint was the rate of complete remission (CR) with uMRD in the blood and the bone marrow at EOT. After EOT, patients were followed for safety and disease assessment every 3 months for the 2 years then every 6 months after that until initiation of alternative therapy, progressive disease (PD), or death. Patients unable to return to OSU for post-treatment visits were assessed locally. The Kaplan-Meier method was used to estimate PFS and overall survival (OS). RESULTS The study enrolled 50 patients including 25 TN and 25 RR in separate cohorts (Table 1). Enrollment completed in April of 2017 and data are presented as of July 6th 2020. Forty-three (86%) patients completed planned treatment and underwent EOT assessment. Seven patients did not complete treatment: 3 due to adverse events, 3 patient or physician preference, and 1 concomitant diagnosis of chronic myeloid leukemia. The overall response rate in an intention to treat analysis was 84% (95% CI: 64-95%) in TN and 88% (95% CI: 69-97%) in RR patients. A total of 14 (56%) TN and 11 (44%) RR patients had uMRD in both the blood and bone marrow and 7 (28%) in each group achieved a CR with uMRD. As of the data cut, 70% of patients remain in FU (18 TN, 17 RR). The median FU is 41.4 months (range 7.4-45.7) for TN and 38.8 months (range 0.03-45.9) for RR patients. The medians for PFS and OS were not reached (Figure 1). The 36- month estimated PFS is 95% (95% CI: 72-99%) for TN and 95% (95% CI: 69-99%) for RR patients. The 36-month estimated OS is 95% (95% CI: 72-99) for TN and 100% for RR patients. One TN patient discontinued treatment after C10 due to treatment-related neutropenic colitis and died 16.7 months after starting treatment. There were no other deaths. No TN and 2 RR patients developed PD at 24 and 37 months, corresponding to 10 and 22 months after EOT. Both had IGHV unmutated CLL with del(13q) and 1 prior treatment with chemoimmunotherapy. The first had a CR with MRD detectable in the bone marrow at EOT and developed immune thrombocytopenia. Bone marrow biopsy revealed 20% CLL. He was treated with IVIG, rituximab, and ibrutinib and remains on ibrutinib with control of his CLL. The second achieved a partial remission with MRD in the bone marrow and developed lymphocytosis. He continues in observation. CONCLUSIONS Fixed-duration OBIN, IBR, and VEN in combination results in high rates of overall response and uMRD status. This is the longest FU we are aware of after an IBR/VEN combination regimen and at 36 months remissions remain durable. Further FU is needed to evaluate the long-term durability, MRD kinetics, and factors that predict PFS. Disclosures Rogers: AstraZeneca: Consultancy, Other: Travel Funding; Janssen: Research Funding; Pharmacyclics: Consultancy; Genentech: Research Funding; Acerta Pharma: Consultancy; AbbVie: Consultancy, Research Funding. Hoffman:Pharmacyclics: Consultancy; AstraZeneca: Consultancy. Maddocks:Celgene: Consultancy, Honoraria; Karyopharm: Consultancy; Seattle Genetics: Consultancy, Honoraria; BMS: Consultancy, Research Funding; ADC Therapeutics, AstraZeneca: Consultancy; Morphosys: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria. Lozanski:Genentech, Novartis, Beckman Coulter: Research Funding. Woyach:Karyopharm: Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Morphosys: Research Funding; Loxo: Research Funding; Verastem: Research Funding; AbbVie: Research Funding. Byrd:Acerta Pharma: Research Funding; Syndax: Research Funding; Vincera: Research Funding; Novartis: Research Funding; Kartos Therapeutics: Research Funding; Trillium: Research Funding; Leukemia and Lymphoma Society: Other; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, BeiGene: Research Funding; Pharmacyclics LLC, an AbbVie Company, Gilead, TG Therapeutics, Novartis, Janssen: Speakers Bureau; Pharmacyclics LLC, an AbbVie Company, Janssen, Novartis, Gilead, TG Therapeutics: Other. OffLabel Disclosure: The three drugs described in this regimen are not approved for use in combination.

Abstract Introduction: Brexucabtagene autoleucel (brexu-cel) was approved by US FDA for relapsed/refractory (R/R) mantle cell lymphoma (MCL) on July 24, 2020 based on results from the pivotal ZUMA-2 (NCT02601313) study, in which an objective response rate (ORR) of 93% and a complete response (CR) rate of 67% were achieved among the 60 treated patients with at least 7 months of follow-up. The study had stringent eligibility criteria, including prior treatment with a BTK inhibitor (BTKi), and only allowed BTKi and/or corticosteroid for bridging therapy. We report here the safety and efficacy of brexu-cel in standard of care practice among centers in the US Lymphoma CAR-T Consortium. Methods: Fourteen centers participated in this retrospective study. Patients who underwent leukapheresis by 6/15/2021 with an intent to manufacture brexu-cel were included. Baseline clinical characteristics, bridging therapy, adverse events after brexu-cel infusion, and post-infusion outcome data were collected. Eligibility for ZUMA-2 was retrospectively determined based on characteristics at the time of leukapheresis. Duration of response (time from initial response to disease progression or death from any cause), progression-free survival (PFS; time from infusion to disease progression or death from any cause) and overall survival (OS; time from infusion to death from any cause) were analyzed using the Kaplan-Meier method. Results: At the data cut-off date of 7/9/2021, 107 patients underwent leukapheresis, among whom 93 (87%) completed brexu-cel infusion, 2 (2%) were waiting for infusion, and 12 (11%) did not receive infusion (manufacture failure n=6, organ dysfunction n=1, death n=5). Baseline clinical characteristics of the 93 infused patients are shown in Table 1. The median age was 67 years and 81% were male. 32% had high risk simplified MIPI, 77% had Ki-67≥30%, 45% had blastoid or pleomorphic variant, 46% had TP53 alteration, 29% had complex karyotype, and 7% had CNS involvement. The median number of prior lines of therapy was 3. Eighty-two percent had prior BTKi treatment, and 44% had refractory disease to the last line of therapy. Sixty-eight (73%) patients would not have met ZUMA-2 eligibility criteria. Reasons for ineligibility included ECOG PS ≥2 (n=8), CNS involvement by lymphoma (n=6), prior therapies (n=33), cytopenia (n=11), renal or hepatic dysfunction (n=13), other medical conditions (n=18), and active infection (n=2). Sixty (65%) of the 93 patients received bridging therapy, which included BTKi (n=27), venetoclax (n=14), chemotherapy (n=19), CD20 antibody (n=26), lenalidomide (n=3), corticosteroid (n=9), and radiotherapy (n=13). Only 13 (14%) patients received BTKi or corticosteroid alone as in ZUMA-2. Among 93 infused patients, cytokine release syndrome (CRS) rate was 88% (8% grade ≥3), and immune effector cell-associated neurotoxicity syndrome (ICANS) rate was 58% (33% grade ≥3). No grade 5 CRS or ICANS occurred. Medications used to manage CRS and ICANS were 71 (76%) for tocilizumab, 64 (69%) for steroid, and 16 (17%) for anakinra. Twenty-four (26%) patients required ICU admission, 9 patients required vasopressors, and 4 patients required mechanical ventilation. With a median follow-up of 3.0 months (range 0.1-9.6), day 30 response was evaluable in 81 patients, and the ORR was 86%, with 64% CR (Table 2). The ORR/CR rates were 94%/70% for blastoid or pleomorphic variants, 82%/50% for TP53 altered, 84%/61% for BTKi-exposed, 94%/76% for BTKi-naïve, and 88%/67% for those not meeting ZUMA-2 eligibility criteria. The ORR/CR rates were 87%/69% for patients who received bridging therapy and 85%/56% for those who did not. For patients who achieved a response at day 30, the rate of continued response at 3-month was 83.7% (95% CI 68.3%-92.0%). The 3-month PFS rate was 80.6% (95% CI 68.6%-88.4%), and the 6-month OS rate was 82.1% (95% CI 67.7%-90.5%). Conclusions: This multicenter retrospective study demonstrated encouraging safety and efficacy data of brexu-cel in R/R MCL in the real world practice. The CRS and ICANS incidences were comparable to those reported in ZUMA-2, but use of tocilizumab and steroid was more frequent than in ZUMA-2. Although 73% of the patients would have been ineligible for ZUMA-2, the ORR and CR rate were comparable to those reported in ZUMA-2. Longer follow-up is necessary to confirm long term safety and efficacy. YW, PJ and FLL are co-first authors, and YL, MW and MDJ are co-senior authors. Figure 1 Figure 1. Disclosures Wang: Novartis: Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; InnoCare: Research Funding; LOXO Oncology: Membership on an entity's Board of Directors or advisory committees, Research Funding; MorphoSys: Research Funding. Jain: Kite: Consultancy; Lilly: Membership on an entity's Board of Directors or advisory committees. Locke: Gerson Lehrman Group: Consultancy; Emerging Therapy Solutions: Consultancy; EcoR1: Consultancy; Cowen: Consultancy; GammaDelta Therapeutics: Consultancy, Other: Scientific Advisory Role; Kite, a Gilead Company: Consultancy, Other: Scientific Advisory Role, Research Funding; Umoja: Consultancy, Other; Janssen: Consultancy, Other: Scientific Advisory Role; Wugen: Consultancy, Other; Legend Biotech: Consultancy, Other; Takeda: Consultancy, Other; Novartis: Consultancy, Other, Research Funding; Moffitt Cancer Center: Patents & Royalties: field of cellular immunotherapy; Iovance Biotherapeutics: Consultancy, Other: Scientific Advisory Role; Calibr: Consultancy, Other: Scientific Advisory Role; Cellular Biomedicine Group: Consultancy, Other: Scientific Advisory Role; BMS/Celgene: Consultancy, Other: Scientific Advisory Role; Bluebird Bio: Consultancy, Other: Scientific Advisory Role; Amgen: Consultancy, Other: Scientific Advisory Role; Allogene Therapeutics: Consultancy, Other: Scientific Advisory Role, Research Funding. Munoz: Bayer, Gilead/Kite Pharma, Celgene, Merck, Portola, Incyte, Genentech, Pharmacyclics, Seattle Genetics, Janssen, and Millennium: Research Funding; Kite, a Gilead Company, Kyowa, Bayer, Pharmacyclics/Janssen, Seagen, Acrotech/Aurobindo, Beigene, Verastem, AstraZeneca, Celgene/BMS, Genentech/Roche.: Speakers Bureau; Targeted Oncology, OncView, Kyowa Kirin, Physicians' Education Resource, and Seagen: Honoraria; Pharmacyclics/Abbvie, Bayer, Kite, a Gilead Company, Pfizer, Janssen, Juno/Celgene, Bristol Myers Squibb, Kyowa Kirin, Alexion, Fosun Kite, Innovent, Seagen, BeiGene, Debiopharm, Epizyme, Karyopharm, ADC Therapeutics, Servier, and Genmab: Consultancy, Other: advisory role; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Maurer: BMS: Research Funding; Genentech: Research Funding; Morphosys: Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Nanostring: Research Funding. Beitinjaneh: Kite/Gilead: Other: Ad Board Event Attendee. Frank: Allogene Therapeutics: Research Funding; Kite-Gilead: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Research Funding. Dahiya: Miltenyi Biotech: Research Funding; Kite, a Gilead Company: Consultancy; Jazz Pharmaceuticals: Research Funding; Atara Biotherapeutics: Consultancy; BMS: Consultancy. McGuirk: Magenta Therapeutics: Consultancy, Honoraria, Research Funding; Gamida Cell: Research Funding; Novartis: Research Funding; Bellicum Pharmaceuticals: Research Funding; Fresenius Biotech: Research Funding; Astelllas Pharma: Research Funding; Novartis: Research Funding; Allovir: Consultancy, Honoraria, Research Funding; Pluristem Therapeutics: Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau; EcoR1 Capital: Consultancy. Goy: Vincerx pharma: Membership on an entity's Board of Directors or advisory committees; Michael J Hennessey Associates INC: Consultancy; Elsevier's Practice Update Oncology, Intellisphere, LLC(Targeted Oncology): Consultancy; Phamacyclics: Research Funding; Vincerx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Rosewell Park: Consultancy; Kite Pharma: Membership on an entity's Board of Directors or advisory committees; AbbVie/Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Incyte: Honoraria; Hoffman la Roche: Consultancy; LLC(Targeted Oncology): Consultancy; Xcenda: Consultancy, Honoraria; OncLive Peer Exchange: Honoraria; Infinity/Verastem: Research Funding; Genentech/Hoffman la Roche: Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medscape: Consultancy; Xcenda: Consultancy; Bristol Meyers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acerta: Consultancy, Research Funding; Bristol Meyers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie/Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Elsevier PracticeUpdate: Oncology: Consultancy, Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Genomic Testing Cooperative: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Physicians' Education Resource: Consultancy, Other: Meeting/travel support; MorphoSys: Honoraria, Other; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Research Funding; COTA (Cancer Outcome Tracking Analysis): Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees, Other: Leadership role; Hackensack Meridian Health, Regional Cancer Care Associates/OMI: Current Employment. Vose: Kite, a Gilead Company: Honoraria, Research Funding. Hill: Kite, a Gilead Company: Consultancy, Honoraria, Other: Travel Support, Research Funding; Celgene (BMS): Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Gentenech: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Incyte/Morphysis: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria; Epizyme: Consultancy, Honoraria. Oluwole: Pfizer: Consultancy; Curio Science: Consultancy; Janssen: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Deol: Kite, a Gilead Company: Consultancy. Shah: Jazz Pharmaceuticals: Research Funding; Incyte: Research Funding; Pfizer: Consultancy, Other: Expenses; Novartis: Consultancy, Other: Expenses; Bristol-Myers Squibb/Celgene: Consultancy, Other: Expenses; BeiGene: Consultancy, Honoraria; Amgen: Consultancy; Precision Biosciences: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Other: Expenses, Research Funding; Pharmacyclics/Janssen: Honoraria, Other: Expenses; Acrotech/Spectrum: Honoraria; Servier Genetics: Other; Adaptive Biotechnologies: Consultancy. Paludo: Karyopharm: Research Funding. Miklos: Pharmacyclics: Patents & Royalties; Adaptive Biotechnologies, Novartis, Juno/Celgene-BMS, Kite, a Gilead Company, Pharmacyclics-AbbVie, Janssen, Pharmacyclics, AlloGene, Precision Bioscience, Miltenyi Biotech, Adicet, Takeda: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics, Amgen, Kite, a Gilead Company, Novartis, Roche, Genentech, Becton Dickinson, Isoplexis, Miltenyi, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Biosciences, Adicet, Adaptive Biotechnologies: Research Funding; Kite, a Gilead Company, Amgen, Atara, Wugen, Celgene, Novartis, Juno-Celgene-Bristol Myers Squibb, Allogene, Precision Bioscience, Adicet, Pharmacyclics, Janssen, Takeda, Adaptive Biotechnologies and Miltenyi Biotechnologies: Consultancy. Ghobadi: Wugen: Consultancy; Atara: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding. Lin: Legend: Consultancy; Novartis: Consultancy; Gamida Cell: Consultancy; Vineti: Consultancy; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy; Takeda: Research Funding; Merck: Research Funding; Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Wang: Moffit Cancer Center: Honoraria; Chinese Medical Association: Honoraria; InnoCare: Consultancy, Research Funding; Epizyme: Consultancy, Honoraria; Hebei Cancer Prevention Federation: Honoraria; Newbridge Pharmaceuticals: Honoraria; Genentech: Consultancy; OMI: Honoraria; Physicians Education Resources (PER): Honoraria; Clinical Care Options: Honoraria; CAHON: Honoraria; VelosBio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; CStone: Consultancy; Loxo Oncology: Consultancy, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; DTRM Biopharma (Cayman) Limited: Consultancy; BGICS: Honoraria; Bayer Healthcare: Consultancy; Janssen: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria, Research Funding; Molecular Templates: Research Funding; Imedex: Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Dava Oncology: Honoraria; Oncternal: Consultancy, Research Funding; Lilly: Research Funding; Celgene: Research Funding; Anticancer Association: Honoraria; AstraZeneca: Consultancy, Honoraria, Research Funding; The First Afflicted Hospital of Zhejiang University: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; Scripps: Honoraria; Mumbai Hematology Group: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding. Jain: BMS, Kite/Gilead, Novartis, Precision Biosciences, Takeda: Consultancy.

Abstract Background EMMY is a large-scale epidemiological study to assess the epidemiology and real-life management of multiple myeloma (MM). Proteasome inhibitors (PI), immunomodulators (IMID) and anti-CD38, provide broad therapeutic solutions for the management of first-line Multiple Myeloma (MM). At more advanced stages, the therapeutic possibilities in patients already exposed to these 3 therapeutic classes are limited. The EMMY study allows to describe the characteristics and the real-life efficacy of treatments in tri-exposed patients. Methods EMMY is a descriptive, multicenter, national, non-interventional study conducted in 72 IFM (Intergroupe Francophone du Myélome, sponsor) centers in France. Any patient initiating treatment for MM over a 3-month observation period, from October to December, is included, since 2017. It is a dynamic cohort with the inclusion of 1000 additional patients each year (2765 patients included at the end of 2019). Data are updated annually from hospital records up to 2020. Patients with tri-exposure to the 3 classes IMID, IP and anti CD38 were identified, and the index date was defined as the initiation of the next line. The median time to next treatment (mTTNT), median progression-free survival (mPFS), and median overall survival (mOS) were estimated for these patients. Results are focused in patients refractory to the previous line (PL-Ref). Results After 3 years of data collection in EMMY, 491 patients (17.8%) were identified as tri-exposed in the cohort. The median age was 69.9 years [62.2-75.8] with 158 patients (32.2%) &lt; 65 years and 63 (12.8%) ≥ 80 years. When available, patients had ECOG 0 or 1 for 59.3% (n=211), high cytogenetic risk for 29.5% (RD) (n=65), an ISS of 1/2/3 for 25.3, 28.5 and 46.2% and at least one comorbidity for 32% (n=157). The patients were tri-exposed at the end of L2, L3, L4, L5 and L6+ for respectively 2%, 16.9%, 26.9%, 26.3% and 27% of them with a median time from diagnosis to the index date of 54.9 months (mo) [32.9 -89.7]. The proportion of patients early tri-exposed as of L3 or L4 increased over the years with respectively 9.8% (L3) and 15.7% (L4) in 2017 (n=51), 11% and 18.9% in 2018 (n=127), 17.1% and 26.8% in 2019 (n=164) and 24.5% and 37.4% in 2020 (n=147). Time from diagnosis to the index line decreased from 64.6 mo (2017) and 62.8 mo (2018) to 54.5 mo (2019) and 49.5 mo (2020). Half patients (52.5%) had previously received ASCT. At the index date, patients had previously been treated with bortezomib (98%), carfilzomib (21.2%), ixazomib (10.4%), lenalidomide (90.4%), thalidomide (35.8%), pomalidomide (61,9%), daratumumab (96.5%) and isatuximab (3.5%). In overall, 86% were refractory to anti-CD38, 51% refractory to 3 classes, and 31% to 2 classes. Of them, 89.2% (438) were refractory to the line prior to the index line (PL-Ref). The mPFS was 5,1 mo 95%CI [4.4 - 6.3] and the mTTNT 6.9 mo 95%CI [6.1 -8.2] for the whole cohort (n=481). In the 438 PL-Ref patients, mPFS was 4.8 mo 95%CI [4.1-6] and mTTNT was 6.6 mo 95%CI [5.5; 7.8] (Figure 1). The mOS was 17.7mo 95%CI [14.2 - 20.2] for the whole cohort with mOS of 16.6 mo 95%CI [13.1 - 19.8] in PL-Ref patients. Conclusion Advances in the management of myeloma are leading to the increasingly early use of combination treatments with IMID, PI and anti-CD38 antibodies in the treatment of multiple myeloma. As a result, patients are increasingly early exposed to these 3 major classes. The EMMY cohort confirms that patients are triple exposed to PIs, IMID, and anti CD38 at an increasingly early stage in the management of MM. Most of them were refractory to the last line and to anti-CD38 antibodies. The majority remains healthy with ECOG less than 2 and few comorbidities. Median PFS and TTNTs are approximately six months, lower than those observed with modern anti-BCMA immunotherapies. These results underline the importance of developing new therapeutic strategies in triple-exposed patients such as novel immunotherapy including bi-specific antibody/CART cells. Figure 1 Figure 1. Disclosures Perrot: Abbvie: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Honoraria, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hulin: Janssen: Honoraria; abbvie: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Celgene/BMS: Honoraria. Macro: takeda: Honoraria; abbvie: Honoraria; sanofi: Honoraria; celgene bms: Honoraria; janssen: Honoraria. Moreau: Abbvie: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Celgene BMS: Honoraria; Oncopeptides: Honoraria. Leleu: Roche: Honoraria; Pierre Fabre: Honoraria; Oncopeptides: Honoraria; Novartis: Honoraria; Mundipharma: Honoraria; Merck: Honoraria; Karyopharm Therapeutics: Honoraria; Janssen-Cilag: Honoraria; Gilead Sciences: Honoraria; Celgene: Honoraria; Carsgen Therapeutics Ltd: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Takeda: Honoraria, Other: Non-financial support; Amgen: Honoraria; AbbVie: Honoraria. Manier: Novartis: Consultancy, Research Funding; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene - Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Karlin: Takeda: Honoraria, Other: member of advisory board; oncopeptide: Honoraria; Celgene-BMS: Honoraria, Other: member of advisory board; Sanofi: Honoraria; GSK: Honoraria, Other: member of advisory board; Amgen: Honoraria, Other: travel support and advisory board ; Abbvie: Honoraria; Janssen: Honoraria, Other: member of advisory board, travel support. Vincent: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Rigaudeau: Takeda: Membership on an entity's Board of Directors or advisory committees. Boccaccio: celgene: Current holder of individual stocks in a privately-held company. Decaux: Amgen BMS Celgene Janssen Sanofi Takeda: Honoraria.

Abstract Introduction: Alliance for Clinical Trials in Oncology A041202 is a NCI National Clinical Trials Network phase 3 study (NCT01886872) comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) to determine whether ibrutinib-containing regimens are superior to chemoimmunotherapy (CIT) in terms of progression-free survival (PFS), and whether rituximab adds benefit to ibrutinib therapy. Initial results showed that ibrutinib-containing regimens had superior PFS to CIT, and that rituximab added to ibrutinib did not improve PFS over ibrutinib alone. Pts and Methods: Eligible pts on A041202 were those age ≥ 65 years with previously untreated, symptomatic CLL. Pts had a CrCl &gt; 40 mL/min, bilirubin &lt; 1.5 x ULN, and no significant life-limiting intercurrent illness or need for warfarin treatment. Pts were stratified on Rai stage, Zap-70 methylation performed centrally, and del(17)(p13.1) or del(11)(q22.3) by local interphase cytogenetics and were randomized 1:1:1 to each arm. Pts on Arm 1 who progressed could cross over to Arm 2. Here we present an updated analysis after the third planned interim analysis of Arms 2 and 3 versus Arm 1, and at the second planned interim analysis for Arms 3 vs 2. PFS and OS were estimated using the Kaplan-Meier method and corresponding hazard ratios with p-values were estimated using Cox proportional hazards models. These data encompass patient visits through April 2020 and were locked 15 February 2021. Results: Between 12/9/2013 and 5/16/2016, 547 pts were randomized (Arms 1: 183, 2: 182, and 3: 182). Baseline characteristics have previously been reported; briefly, median age was 71 years, 53% had unmethylated Zap-70, 61% were IGHV unmutated (performed in 66% of patients), 6% had del(17p) and 20% del(11q) by central FISH. Stimulated karyotype was performed centrally and revealed ≥ 3 abnormalities in 27%, and ≥ 5 in 11% of patients. With median follow-up of 55 months (mo), median PFS was 44 mo (95% CI 38-54) in Arm 1 and has not been reached in Arms 2 or 3 [Arm 2 vs 1 hazard ratio (HR): 0.36, 95% CI 0.26-0.52, p&lt;0.0001; Arm 3 vs 1 HR 0.36, 95% CI 0.25-0.51, p&lt;0.0001; Arms 3 vs 2 HR 0.99, 95% CI 0.66-1.48, p=0.96]. 48-month PFS estimates were 47%, 76% and 76% in Arms 1, 2, and 3 respectively (Figure 1). At this time, there are no significant differences in overall survival (OS) among arms (p=0.49). 48-month OS estimates were 84%, 85%, and 86% in Arms 1, 2, and 3, respectively (Figure 2). The benefit of ibrutinib regimens over CIT, with no additional benefit of rituximab when combined with ibrutinib, was consistent for all subgroups of patients defined by TP53 abnormalities, del(11q), complex karyotype, and IGHV (Figure 3). No significant interaction effects were observed between treatment arm and del(11q), complex karyotype, or IGHV. However, greater benefit of ibrutinib regimens over CIT was observed among patients with TP53 abnormalities than without (p&lt;0.001). Thus in Arm 1, PFS was significantly worse for those with TP53 abnormalities vs without (HR 5.32, 95% CI 3.05-9.27, p&lt;0.0001), but in Arms 2 and 3 combined, there was no significant difference in PFS by presence/absence of TP53 abnormalities (HR 0.99, 95% CI 0.51-1.91, p=0.98). Notable adverse events with ibrutinib include atrial fibrillation or flutter (afib) and hypertension (HTN). All grade afib was seen in 11 pts on BR (6%) and 67 pts on ibrutinib (19%). All grade HTN was seen in 95 pts on BR (54%) and 263 pts on ibrutinib (73%). Conclusions: This update of the A041202 trial continues to show that ibrutinib regimens prolong PFS over BR for older patients with treatment-naïve CLL. With longer follow-up, these benefits continue to be seen across subgroups, including those associated with higher risk disease. Strikingly, within the ibrutinib arms, there does not appear to be inferior PFS for patients with abnormalities in TP53, the highest risk feature seen in CLL, and a predictor of inferior PFS with ibrutinib in relapsed CLL. This differentiates ibrutinib (and perhaps BTKi in general) from other targeted therapy paradigms for treatment-naïve CLL. Similar to prior studies, rates of afib and HTN continue to increase with time on therapy. These data support the use of ibrutinib as initial therapy in CLL, and strengthen the rationale for use of ibrutinib for high risk disease. Support: U10CA180821, U10CA180882, U24CA196171, https://acknowledgments.alliancefound.org, Pharmacyclics, Inc Figure 1 Figure 1. Disclosures Woyach: Gilead Sciences Inc: Other: Data & Safety; AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy. Ruppert: Telios Pharma: Consultancy. Ding: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees. Bartlett: ADC Therapeutics: Consultancy, Research Funding; Roche/Genentech: Consultancy; Seagen: Consultancy, Research Funding; Autolus: Research Funding; Bristol Myers Squibb: Research Funding; Celgene: Research Funding; Forty Seven: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Kite, a Gilead Company: Research Funding; Merck: Research Funding; Millennium: Research Funding; Pharmacyclics: Research Funding. Brander: Pfizer: Consultancy, Other: Biosimilars outcomes research panel; Genentech: Consultancy, Research Funding; Verastem: Consultancy; Juno Therapeutics/Celgene/Bristol Myers Squibb: Research Funding; LOXO: Research Funding; TG Therapeutics: Consultancy, Research Funding; MEI Pharma: Research Funding; NCCN: Other: panel member; ArQule/Merck: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; DTRM: Research Funding; BeiGene: Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; ArQule: Research Funding; AbbVie: Consultancy, Other: informCLL registry steering committee, Research Funding; Novartis: Research Funding. Barr: Seattle Genetics: Consultancy; Bristol Meyers Squibb: Consultancy; AstraZeneca: Consultancy; Beigene: Consultancy; Genentech: Consultancy; Abbvie/Pharmacyclics: Consultancy; Gilead: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy. Rogers: Pharmacyclics LLC: Consultancy; Innate Pharma: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy; Acerta Pharma: Consultancy; AbbVie Inc.: Consultancy, Research Funding; Janssen Pharmaceuticals, Inc: Research Funding; ovartis Pharmaceuticals Corporation: Research Funding. Parikh: Pharmacyclics, MorphoSys, Janssen, AstraZeneca, TG Therapeutics, Bristol Myers Squibb, Merck, AbbVie, and Ascentage Pharma: Research Funding; Pharmacyclics, AstraZeneca, Genentech, Gilead, GlaxoSmithKline, Verastem Oncology, and AbbVie: Membership on an entity's Board of Directors or advisory committees. Coutre: Acerta: Other: Data Safety Monitoring Committee, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Beigene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Data Safety Monitoring Committee, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Larson: Epizyme: Consultancy; Astellas: Consultancy, Research Funding; Gilead: Research Funding; CVS/Caremark: Consultancy; Takeda: Research Funding; Novartis: Research Funding; Rafael Pharmaceuticals: Research Funding; Cellectis: Research Funding. Erba: AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Actinium: Research Funding; Amgen: Research Funding; Astellas: Research Funding; AbbVie: Research Funding; Omeros: Other: Advisory Board; Biosight: Other: Data monitoring committee. Blachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Owen: Genentech: Research Funding; Gilead: Honoraria; Janssen: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Merck: Honoraria; Servier: Honoraria; Incyte: Honoraria; Pharmacyclics: Research Funding. Abramson: Bristol-Myers Squibb Company: Consultancy, Research Funding; C4 Therapeutics: Consultancy; Morphosys: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; EMD Serono: Consultancy; Genmab: Consultancy; Bluebird Bio: Consultancy; Kymera: Consultancy; BeiGene: Consultancy; Incyte Corporation: Consultancy; Astra-Zeneca: Consultancy; Allogene Therapeutics: Consultancy; Seagen Inc.: Research Funding; AbbVie: Consultancy; Karyopharm: Consultancy; Genentech: Consultancy. Brown: Abbvie, Acerta/Astra-Zeneca, Beigene, Bristol-Myers Squibb/Juno/Celgene, Catapult, Eli Lilly, Genentech/Roche, Janssen, MEI Pharma, Morphosys AG, Nextcea, Novartis, Pfizer, Rigel: Consultancy; Invectys: Other: Data Safety Monitoring Committee Service; Gilead, Loxo/Lilly, SecuraBio, Sun, TG Therapeutics: Research Funding. Stone: Onconova: Consultancy; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Jazz: Consultancy; Arog: Consultancy, Research Funding; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Janssen: Consultancy; Innate: Consultancy; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; AbbVie: Consultancy; Actinium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Syros: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Byrd: Novartis, Trillium, Astellas, AstraZeneca, Pharmacyclics, Syndax: Consultancy, Honoraria; Vincerx Pharmaceuticals: Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees; Newave: Membership on an entity's Board of Directors or advisory committees.

Background: Axi-cel is an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of patients (pts) with relapsed/refractory large B cell lymphoma (LBCL) with ≥ 2 prior systemic therapies. ZUMA-1 is the multicenter, single-arm, registrational Phase 1/2 study of axi-cel in pts with refractory LBCL. In a 2-year analysis of ZUMA-1 (median follow-up, 27.1 months; N=101), axi-cel demonstrated objective response, complete response (CR), and ongoing response rates of 83%, 58%, and 39%, respectively (Locke et al. Lancet Oncol. 2019). Here, we present additional survival follow up and recovery of normal, polyclonal B cells from ongoing responders in ZUMA-1. Methods: Eligible pts with refractory large B cell lymphoma (diffuse large B cell lymphoma, primary mediastinal B cell lymphoma, transformed follicular lymphoma) underwent leukapheresis at enrollment and subsequently received low-dose conditioning chemotherapy (fludarabine and cyclophosphamide) followed by a target dose of 2 × 106 anti-CD19 CAR T cells/kg (Neelapu et al. NEJM. 2017; NCT02348216). The primary endpoint was objective response rate (ORR), and the first response assessment was 4 weeks post infusion. Response assessments were performed per protocol up to 24 months or disease progression, whichever occurred first. For pts in ongoing response beyond Month 24, response assessments continued per institutional standard-of-care (SOC). Blood levels of CAR T cells were quantified using polymerase chain reaction and B cells were characterized using flow cytometry in pts with ongoing responses and evaluable samples. Results: A total of 111 pts were enrolled, and axi-cel was administered to 101 pts. As previously reported in the ZUMA-1 2-year analysis, among pts who received axi-cel, the median time from axi-cel infusion to both objective response and CR was 1.0 month (range, 1 - 12 months; Locke et al. Lancet Oncol 2019). When the entire enrolled population (N = 111) was included on an intent-to-treat basis, the median manufacturing time was 17 days (range, 14 - 51; n = 110 as manufacturing was not feasible for 1 pt). Additionally, among the 111 pts, the median time from enrollment/leukapheresis to objective response and CR was 1.7 months (range, 0.7 - 12.9) and 1.9 months (range, 0.7 - 13.3), respectively. Responses have been durable, and with a minimum of 3 years of follow-up (median, 39.1 months), the median overall survival (OS) was 25.8 months, and the 3-year OS rate was 47%. Importantly, no axi-cel-related secondary malignancies have been reported. As previously reported, pts in ongoing response after 2 years had significantly greater peak CAR T cell expansion in blood 7 - 14 days after axi-cel infusion than did those with relapse (P = 0.014) or no response (P = 0.0003; Locke et al. Lancet Oncol 2019). Blood samples from 22 pts in ongoing response (per institutional SOC) at ≥ 3 years were available for analysis of CAR T cells and evaluation of B cell recovery. All evaluable pts had detectable B cells in blood at 3 years post axi-cel. Notably, 91% of pts in ongoing response at 3-year follow-up demonstrated recovery of polyclonal B cells measured by presence of both kappa and lambda light chains on non-malignant CD19+CD20+ B cells. The median kappa-lambda ratio of 1.6 and relative levels of key B cell subsets, including memory and naive B cell immunophenotypes, suggested reconstitution of B cell repertoire, consistent with published data from healthy individuals (Deneys et al. J Immunol Methods 2001; Scott et al. J Clin Pathol 2018). Additionally, 15/22 (68%) had both minimal levels of detectable CAR gene-marked cells and detectable polyclonal B cells in blood. Altogether, these findings support the hypothesis that persistence of functional CAR T cells is not necessary for durable remissions of LBCL. Overall survival and translational findings with ≥ 4 years of follow-up will be presented. Conclusions: Axi-cel produced rapid responses and longterm disease control in pts with refractory LBCL. Most responses occurred by the first assessment, and the brief time elapsed between enrollment and response supports both the speed and success of manufacturing. Furthermore, axi-cel-treated pts with ongoing responses at ≥ 3 years showed evidence of restoration of a normal B cell compartment and clearance of functional CAR T cells, a critical component of the long-term safety of CD19-directed CAR T cell therapies. Disclosures Locke: Kite, a Gilead Company: Consultancy, Research Funding; Wugen: Consultancy; Calibr: Consultancy; Allogene: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options; GammaDelta Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Ghobadi:Celegene: Consultancy; Wugen: Consultancy; Atara: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; EUSA: Consultancy. Miklos:Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Miltenyi Biotec: Research Funding; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding. Oluwole:Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Spectrum Pharmaceuticals: Consultancy; Bayer: Consultancy. Lin:Legend BioTech: Consultancy; Juno: Consultancy; Bluebird Bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Gamida Cells: Consultancy; Sorrento: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Merck: Research Funding; Vineti: Consultancy. Hill:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding. Timmerman:Merck: Research Funding; Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; BMS: Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Research Funding; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Bluebird Bio: Current equity holder in publicly-traded company; Genmab: Current equity holder in publicly-traded company; Valor: Research Funding. Deol:Novartis: Consultancy; Kite, a Gilead Company: Consultancy. Reagan:Kite, a Gilead Company: Consultancy; Curis: Consultancy; Seattle Genetics: Research Funding. Stiff:Kite, a Gilead Company: Research Funding; Delta-Fly: Research Funding; Gamida Cell: Research Funding; Atara: Research Funding; Unum: Research Funding; Macrogenics: Research Funding; Amgen: Research Funding. Flinn:Celgene: Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Curio Science: Consultancy; Merck: Research Funding; Constellation Pharmaceuticals: Research Funding; BeiGene: Consultancy, Research Funding; ArQule: Research Funding; Kite Pharma: Consultancy, Research Funding; Genentech, Inc.: Research Funding; Pfizer: Research Funding; Calithera Biosciences: Research Funding; Agios: Research Funding; Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Forty Seven: Research Funding; Forma Therapeutics: Research Funding; Loxo: Research Funding; F. Hoffmann-La Roche: Research Funding; Incyte: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Novartis: Research Funding; MorphoSys: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Johnson & Johnson: Other; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Gilead Sciences: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Iksuda Therapeutics: Consultancy; Great Point Partners: Consultancy; Curis: Research Funding; Nurix Therapeutics: Consultancy; Portola Pharmaceuticals: Research Funding; Acerta Pharma: Research Funding; Juno Therapeutics: Consultancy, Research Funding; Unum Therapeutics: Consultancy, Research Funding; Infinity Pharmaceuticals: Research Funding; IGM Biosciences: Research Funding; Takeda: Consultancy, Research Funding; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding. Farooq:Kite, a Gilead Company: Honoraria. Goy:COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Karyopharm: Research Funding; Genentech/Roche: Research Funding; Constellation: Research Funding; Bayer: Research Funding; CALBG: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Hackensack UMC and University of Nebraska: Research Funding; Infinity: Research Funding; Xcenda: Consultancy; Infinity Verastem: Research Funding; Morphosys: Research Funding; AbbVie: Research Funding; MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding. McSweeney:Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau; Colorado Blood Cancer Institute: Current Employment; Fred Hutchinson: Patents & Royalties. Munoz:Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Alexion: Consultancy; Beigene: Consultancy, Speakers Bureau; Fosunkite: Consultancy; Innovent: Consultancy; Acrotech/Aurobindo: Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Verastem: Speakers Bureau; AstraZeneca: Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AbbVie: Consultancy, Speakers Bureau; Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; Millenium: Research Funding; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau. Siddiqi:Oncternal: Research Funding; TG Therapeutics: Research Funding; Janssen: Speakers Bureau; Seattle Genetics: Speakers Bureau; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Research Funding; Juno: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding. Rossi:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Bot:Kite, a Gilead Company: Current Employment; Gilead Sciences: Consultancy, Current equity holder in publicly-traded company, Other: Travel support . Zheng:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Vezan:Merck: Current equity holder in publicly-traded company; Abbvie: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Honoraria, Other: Travel support. Bashir:Kite, a Gilead Company: Current Employment; OmniacPharmConsult Ltd: Current Employment, Current equity holder in private company. Kim:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Chu:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company; Amgen: Current equity holder in publicly-traded company; Celgene: Current equity holder in publicly-traded company. Neelapu:N/A: Other; Takeda Pharmaceuticals: Patents & Royalties; Acerta: Research Funding; Karus Therapeutics: Research Funding; Cellectis: Research Funding; Poseida: Research Funding; Unum Therapeutics: Other, Research Funding; Calibr: Other; Kite, a Gilead Company: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other: personal fees, Research Funding; Merck: Other: personal fees, Research Funding; Novartis: Other: personal fees; Celgene: Other: personal fees, Research Funding; Pfizer: Other: personal fees; Allogene Therapeutics: Other: personal fees, Research Funding; Adicet Bio: Other; Legend Biotech: Other; Precision Biosciences: Other: personal fees, Research Funding; Incyte: Other: personal fees; Cell Medica/Kuur: Other: personal fees.

Background: KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T cell therapy, is currently being evaluated in patients with relapsed/refractory (R/R) mantle cell lymphoma (MCL) who received 1 - 5 prior therapies (including a Bruton tyrosine kinase inhibitor) in the Phase 2, registrational, multicenter ZUMA-2 study. With a median follow-up of 12.3 months, we previously reported an objective response rate (ORR) of 93% (67% complete response [CR] rate) with KTE-X19 treatment in the 60 efficacy-evaluable patients in ZUMA-2 (Wang et al. N Engl J Med. 2020;382:1331). Here, we present an updated analysis of efficacy, safety, and pharmacology for all patients with a minimum follow-up of 1 year. Methods: Eligible patients with R/R MCL underwent leukapheresis and conditioning chemotherapy followed by a single infusion of KTE-X19 (2 × 106 CAR T cells/kg; Wang et al. N Engl J Med. 2020;382:1331). The primary endpoint was ORR (CR + partial response) as assessed by an Independent Review Committee according to the Lugano Classification (Cheson et al. J Clin Oncol. 2014;32:3059). Efficacy data are reported for the 60 treated patients with ≥ 1 year of follow-up; safety data are presented for all 68 treated patients. Results: As of December 31, 2019, the median follow-up was 17.5 months (range, 12.3 - 37.6). The ORR was 92% (95% CI, 81.6 - 97.2), with a CR rate of 67% (95% CI, 53.3 - 78.3). Of all efficacy-evaluable patients, 48% had ongoing responses at the data cutoff. Medians were not reached for duration of response, progression-free survival (PFS), or overall survival; 15-month estimates were 58.6% (95% CI, 42.5 - 71.7), 59.2% (95% CI, 44.6 - 71.2), or 76.0% (95% CI, 62.8 - 85.1), respectively. In patients who achieved a CR, the median PFS was not reached (15-month rate, 75.1% [95% CI, 56.8 - 86.5]); in those who achieved a partial response, the median PFS was 3.1 months (95% CI, 2.3 - 5.2). Median PFS was 1.1 months (95% CI, 0.9 - 3.0) in nonresponding patients. The first 28 patients treated had a median follow-up of 32.3 months (range, 30.6 - 37.6); 39.3% of these patients remain in remission with no further therapy. Common grade ≥ 3 adverse events were neutropenia (85%), thrombocytopenia (53%), anemia (53%), and infections (34%). Grade ≥ 3 cytopenias were reported in 60% of patients ≥ 30 days post-infusion. Grade ≥ 3 cytokine release syndrome (CRS; per Lee et al. [Blood. 2014;124:188]) occurred in 15% of patients; 59% received tocilizumab for management of CRS. Grade ≥ 3 neurologic events (NEs) were reported in 31% of patients, and 38% received steroids for NE management. All CRS events and most NEs (37/43) resolved, as previously reported. There were no Grade 5 CRS events or NEs, and no new Grade 5 events occurred with additional follow-up. As previously reported, there were 2 cases of Grade 2 cytomegalovirus infection, 1 case each of Grade ≥ 3 hypogammaglobulinemia and Grade ≥ 3 tumor lysis syndrome, and no cases of Epstein-Barr virus-associated lymphoproliferation, replication-competent retrovirus, hemophagocytic lymphohistiocytosis, or KTE-X19-related secondary cancers. Median peak CAR T cell levels and median area under the curve (Days 0 - 28) were 98.9 cells/µL (range, 0.2 - 2565.8) and 1394.9 cells/µL (range, 3.8 - 27,700) in patients with ongoing responses at 12 months, 202.6 cells/µL (range, 1.6 - 2589.5) and 2312.3 cells/µL (range, 19.0 - 27,200) in patients who were relapsed at 12 months, and 0.4 cells/µL (range, 0.2 - 95.9) and 5.5 cells/µL (range, 1.8 - 1089.1) in nonresponders. Of the 57 efficacy-evaluable patients with data available, 84% had B cells detectable by flow cytometry at baseline. Of those in ongoing responses at 12 months, 10 of 26 patients (38%) with evaluable samples had B cells detectable at 3 months, and 10 of 18 (56%) had detectable B cells at 12 months; gene-marked CAR T cells were no longer detectable at 12 months in 5 of 28 evaluable patients (17%). Conclusions: The ZUMA-2 study continues to demonstrate substantial and durable clinical benefit of KTE-X19 therapy with manageable safety in patients with R/R MCL. Within this patient population, which lacks curative treatment options, most patients achieved durable CR, and no new safety signals were reported. Although early CAR T cell expansion was higher in patients who achieved an objective response, those who later relapsed showed elevated CAR T cell levels pointing to alternate mechanisms of secondary treatment failure in MCL. Disclosures Wang: Verastem: Research Funding; Molecular Templates: Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Dava Oncology: Honoraria; Targeted Oncology: Honoraria; VelosBio: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; OncLive: Honoraria; Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Guidepoint Global: Consultancy; OMI: Honoraria, Other: Travel, accommodation, expenses; Nobel Insights: Consultancy; Acerta Pharma: Research Funding; Oncternal: Consultancy, Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; InnoCare: Consultancy; Beijing Medical Award Foundation: Honoraria; Lu Daopei Medical Group: Honoraria. Munoz:Merck: Research Funding; Portola: Research Funding; Incyte: Research Funding; AbbVie: Consultancy, Speakers Bureau; Genentech/Roche: Research Funding, Speakers Bureau; AstraZeneca: Speakers Bureau; Verastem: Speakers Bureau; Acrotech/Aurobindo: Speakers Bureau; Innovent: Consultancy; Fosunkite: Consultancy; Beigene: Consultancy, Speakers Bureau; Alexion: Consultancy; Juno/Celgene/BMS: Consultancy, Research Funding, Speakers Bureau; Janssen: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Bayer: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Honoraria, Research Funding, Speakers Bureau; Kyowa: Consultancy, Honoraria, Speakers Bureau; Millenium: Research Funding. Goy:MD Anderson: Research Funding; Regional Cancer Care Associates/OMI: Current Employment; Xcenda: Consultancy; AbbVie: Research Funding; Acerta: Consultancy, Honoraria, Other: leadership role, Research Funding; AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: leadership role, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Other: leadership role, Research Funding; Kite, a Gilead Company: Consultancy, Current equity holder in publicly-traded company, Honoraria, Other: leadership role, Research Funding; COTA: Consultancy, Current equity holder in publicly-traded company, Other: leadership role; Hackensack UMC and University of Nebraska: Research Funding; Infinity Verastem: Research Funding; Morphosys: Research Funding; Karyopharm: Research Funding; Infinity: Research Funding; Constellation: Research Funding; Genentech/Roche: Research Funding; CALBG: Research Funding; Bayer: Research Funding; PracticeUpdate Oncology: Consultancy; RCCA/OMI: Current Employment. Locke:Wugen: Consultancy; GammaDelta Therapeutics: Consultancy; Celgene/Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; Calibr: Consultancy; Allogene: Consultancy; Cellular Biomedicine Group: Other: Consultancy with grant options. Hill:Genentech: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding. Timmerman:Corvus: Current equity holder in publicly-traded company; Marker Therapeutics: Current equity holder in publicly-traded company; Bluebird Bio: Current equity holder in publicly-traded company; Kite, a Gilead Company: Consultancy, Other: Travel support, Research Funding; Immune Design: Honoraria; Celldex Therapeutics: Consultancy; BMS: Other: Travel support, Research Funding; Spectrum Pharmaceuticals: Research Funding; Merck: Research Funding; Valor: Research Funding; Genmab: Current equity holder in publicly-traded company. Holmes:Texas Oncology PA: Current Employment; Gilead/Kite, Celgene/Juno, Rigel, Karyopharm, Janssen, Dova: Consultancy; Gilead/Kite, Novartis, Autolus, Celgene/Juno/bluebird, Genentech, Inc., Rigel, Janssen, Unum, ADC Therapeutics, Seattle Genetics, Incyte, Verastem: Research Funding; Kite, Karyopharm, Seattle Genetics, Rigel, Dova: Speakers Bureau. Jaglowski:CRISPR: Consultancy; Novartis: Consultancy, Research Funding; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding. Flinn:Karyopharm Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Vincera Pharma: Consultancy; Iksuda Therapeutics: Consultancy; Janssen: Consultancy, Research Funding; Agios: Research Funding; ArQule: Research Funding; Infinity Pharmaceuticals: Research Funding; Unum Therapeutics: Consultancy, Research Funding; Forma Therapeutics: Research Funding; Forty Seven: Research Funding; Great Point Partners: Consultancy; Pfizer: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Novartis: Research Funding; Nurix Therapeutics: Consultancy; Curis: Research Funding; MorphoSys: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding; Incyte: Research Funding; Acerta Pharma: Research Funding; Genentech, Inc.: Research Funding; Gilead Sciences: Consultancy, Research Funding; F. Hoffmann-La Roche: Research Funding; AbbVie: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; IGM Biosciences: Research Funding; TG Therapeutics: Consultancy, Research Funding; Trillium Therapeutics: Research Funding; Triphase Research & Development Corp.: Research Funding; Verastem: Consultancy, Research Funding; Yingli Pharmaceuticals ≠: Consultancy, Research Funding; Rhizen Pharmaceuticals: Research Funding; Johnson & Johnson: Other; Teva: Research Funding; Seattle Genetics: Consultancy, Research Funding; Portola Pharmaceuticals: Research Funding; Constellation Pharmaceuticals: Research Funding; Merck: Research Funding; Celgene: Research Funding; Calithera Biosciences: Research Funding; BeiGene: Consultancy, Research Funding; Loxo: Research Funding; Kite Pharma: Consultancy, Research Funding; Curio Science: Consultancy. McSweeney:Fred Hutchinson: Patents & Royalties; Colorado Blood Cancer Institute: Current Employment; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding, Speakers Bureau. Miklos:Adaptive Biotech: Consultancy, Other: Travel support, Research Funding; Janssen: Consultancy, Other: Travel support; Pharmacyclics: Consultancy, Other: Travel support, Patents & Royalties, Research Funding; Novartis: Consultancy, Other: Travel support, Research Funding; Allogene Therapeutics Inc.: Research Funding; Juno-Celgene-Bristol-Myers Squibb: Consultancy, Other: Travel support, Research Funding; Kite-Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Miltenyi Biotec: Research Funding. Pagel:Gilead, Pharmacyclics LLC, an AbbVie Company, and AstraZeneca: Consultancy. Kersten:Novartis: Consultancy, Honoraria, Other: travel support; Kite, a Gilead Company: Consultancy, Honoraria, Other: travel support; Celgene: Research Funding; Roche: Research Funding; Takeda: Research Funding; Miltenyi: Consultancy, Honoraria, Other: travel support. Milpied:Celgene: Other: Travel support; Gilead Sciences: Other: consultancy or advisory role; Janssen: Honoraria; Sandoz: Honoraria, Other: consultancy or advisory role; Astellas: Honoraria; Roche: Honoraria, Other: Travel support. Fung:Takeda: Honoraria, Other: speakers' bureau, travel support; Sanotif: Honoraria, Other: speakers' bureau, travel support; Genentech: Honoraria, Other: speakers' bureau, travel support; AbbVie: Honoraria, Other: speakers' bureau, travel support; Kite, a Gilead Company: Honoraria, Other: speakers' bureau, travel support; AstraZeneca: Honoraria, Other: speakers' bureau, travel support; Janssen Oncology: Honoraria, Other: speakers' bureau, travel support. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Houot:Janssen: Honoraria; Gilead: Other: Personal fees; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Beitinjaneh:Jazz: Other: speaker's bureau; Kite, a Gilead Company: Honoraria, Other: consulting or advisory role, speaker's bureau, ; ATARA: Research Funding; Gilead: Research Funding. Peng:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Zheng:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Rossi:Kite, a Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company. Murugappan:Gilead Sciences: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment. Kloos:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Reagan:Curis: Consultancy; Seattle Genetics: Research Funding; Kite, a Gilead Company: Consultancy.

Two different solution contexts for the Math Is Going to the Dogs investigation are described this month: from Brenda Camaligan's fourth-grade students at Forked River School in Forked River, New Jersey; and from Walter Stark's fifth-grade class at Captain Vincent G. Fowler Elementary School in South Ozone Park, New York.

This 6-page fact sheet is part of the 2019–2020 Florida Citrus Production Guide. This chapter addresses the most important decisions that should be made before and immediately after planting and refers to other chapters with more detailed information. Generally, the most important factors before planting fall into site selection and grove planning and preparation. Planting and early tree care are also essential to long-term grove success. Coordinated planning of all aspects of grove establishment and careful planting establishment can set you up for success and reduced frustration in the future. Written by Christopher Vincent, Tripti Vashisth, Mongi Zekri, and Ute Albrecht, and published by the Horticultural Sciences Department, March 2019. HS1302/HS1302: 2022–2023 Florida Citrus Production Guide: Grove Planning and Establishment (ufl.edu)

AbstractThe Catholic Baron Willem Vincent van Wyttenhorst (I6I3-I674) from Utrecht was an enthusiastic collector of paintings. In his translation of Guarini's Il Pastor Fido, Hendrick Bloemaert even lauded Willem Vincent's 'Lofweerdigh cabinet' (commendable cabinet) of paintings. The inventory Wyttenhorst made of his collection between I65I and I659 affords insight into various aspects of the seventeenth-century art trade. Not only did he record the subject and maker of around I95 paintings, but also the price and often how he had acquired them. Part of the collection - in particular the finely painted works by Cornelis van Poelenburgh and Herman Saftleven - were auctioned in I722. Of Willem Vincent van Wyttenhorst's collection approximately 75 paintings can be traced to Herdringen Castle of the Von Fürstenberg family and several museums, making it possible to establish the relationship between the dimensions and the quality of execution, and the price they commanded in the seventeenth century. Willem Vincent acquired the greatest number of his paintings between I630 and I659, the majority of which were by contemporary masters, some of whom he knew personally. His collection also included several important sixteenth-century pictures by artists such as Cornelis Engebrechtszn, Jan van Scorel and Maerten van Heemskerck, which had come into his possession via his family or via that of his wife Wilhelmina van Bronckhorst. On the one hand, the Wyttenhorst collection is comparable to those of other aristocratic collectors and, on the other hand, to those of well-to-do connoisseurs such as Franciscus de la Boe Sylvius and Hendrick Bugge van Ring of Leiden. Its aristocratic character is evidenced by the prominent place occupied by family portraits: he owned a total of 4I likenesses, 29 of which were made for him and his wife. In I650 Bartholomeus van der Helst needed six weeks to portray Willem Vincent and his wife Wilhelmina van Bronckhorst for the amount of 330 guilders. Wyttenhorst appears to have preferred highly refined small paintings. Not a single genre was overlooked in the collection. Taking pride of place were approximately 90 pastoral scenes and Arcadian landscapes, which added to the collection's aristocratic aura. Furthermore, in keeping with his Catholic background, Willem Vincent had relatively many (25) paintings with religious subjects and devotional works. Striking is also the group of about 20 genre scenes with primarily peasant themes. The II flower and fruit still lifes listed in the inventory were purchased by Wilhelmina van Bronckhorst between I640 and I642 during her first marriage. Regrettably, the inventory only rarely indicates where the pictures hung. On the basis of the scant information, however, it emerges that Wilhelmina van Bronckhorst's cabinet was richly adorned with a variety of paintings. This cabinet also served as the 'Ahnengalerie' (gallery of forefathers) for the I9 family portraits by Cornelis van Poelenburgh. The exceptional status of the Wyttenhorst collection is reflected by the proportionally very modest number of eight anonymous paintings. Moreover, Willem Vincent describes ten copies, most of which he commissioned. The majority of painters mentioned by Wyttenhorst were active in Utrecht, while the overwhelming majority of non-Utrecht masters were active in Haarlem. Wyttenhorst owned about 90 paintings by Utrecht Italianates and related painters such as Poelenburgh, De Heus, Both, Berchem and Saftleven. He maintained intensive contact with Cornelis van Poelenburgh and Herman Saftleven, by whom he owned 57 and I8 paintings respectively. Among the Haarlem artists represented by a few works in his collection were Pieter de Molijn, Adriaen van Ostade and Wouwerman. Interestingly, the vast majority of the painters Wyttenhorst mentioned in his inventory are still known or even famous. The collection also comprised several collaborative efforts, such as Il Contento by Nicolaes Knüpfer, Jan Baptist Weenix and Jan Both. It is notable that Wyttenhorst regularly acquired work by young painters who had just barely begun; a good example is the painting he purchased in I638 from the then at most I8-year-old Nicolaes Berchem. A number of paintings were given to Willem Vincent by relatives and acquaintances. Some works entered his collection through exchange, for example via the Hague collector d'Arminvillers. He also bought the occasional painting from a private individual. In the case of 85 paintings, Wyttenhorst noted that he had bought them directly from a master. He also purchased from art dealers, in particular works by non-Northern Netherlandish painters via Dirck Matham. These were usually small, modestly priced paintings. In a few instances he acquired a painting at an auction, from an estate, at a market, kermis or from a pedlar. Incidentally, he acknowledged that the latter works were not highpoints in his collection. Thus, in amassing his collection, Willem Vincent used all of the channels available around the mid-seventeenth century. The prices of the paintings acquired by Wyttenhorst differed significantly. The cheapest was a panel of Three deer heads by Jacques Savery at 3 guilders, and the most expensive a Peasant kermis by Herman Saftleven at 500 guilders. A large number of works costing more than I00 guilders are explicitly described as history paintings. The finely executed Arcadian landscapes - often on copper - range in price from 30 to I50 guilders. The prices for works by Italianate painters do not differ much and appear to have depended mostly on their dimensions; the larger ones cost exactly twice as much as the smaller ones. The greatest variation in prices is found among the genre scenes. In the case of several paintings, Wyttenhorst noted that their value had exceeded the purchase price. Unfortunately, there is insufficient information to confirm the accuracy of all of his assertions. There are a few indications that the value of the Peasant sheds by the Saftleven brothers did, indeed, rise around the mid-seventeenth century. Willem Vincent's comment that Jacob Matham's flower and fruit still lifes had sharply increased in value between I642 and about I655 is also confirmed by contemporary sources. In addition to the I9 family portraits by Cornelis van Poelenburgh mentioned above, Wyttenhorst owned I7 landscapes by the artist ranging in price between 30 and 90 guilders. For the eight history paintings listed in the inventory, Willem Vincent paid amounts above I00 guilders, the most expensive being a Passion scene for 464 guilders. Alongside these originals, Wyttenhorst also owned several copies after Poelenburgh by Toussaint Gelton and by the master himself. Their prices serve as a good indication of the value attached to the originality of an invention. For these copies after originals - which also were (or had been) in the collection - approximately 1/4 of the price of the original was paid. Wyttenhorst owned several genre scenes and many landscapes by Herman Saftleven. Several of them are described in the inventory as Rhine landscapes. Willem Vincent's Saftlevens included a surprising number of pendants of two (and in one instance a series of four) paintings. On the whole, he appears to have paid more for works by Saftleven than by Poelenburgh. There is insufficient information to allow for a comparison of the prices Wyttenhorst paid for work by Poelenburgh and Saftleven and the value of their work in estate inventories or with the amounts they fetched at auction. However, this is possible with the landscapes by Pieter de Molijn and Dirck Verhaert. In the case of De Molijn, Wyttenhorst paid the master four times more than the price of I0 guilders most frequently given in estate inventories. An explanation for this enormous discrepancy could be that like Herman Saftleven, De Molijn produced work of diverging quality. He crafted both original, finely executed inventions for art collectors such as Willem Vincent van Wyttenhorst as well as small paintings for the open market, which were variations on a basic theme. For a painting by Dirck Verhaert, a Haarlem artist who simply followed popular trends, Wyttenhorst paid the modest amount of 6 guilders, a price that differs very little from the estimated values in estate inventories. On the basis of the above a tentative conclusion can be drawn regarding the services rendered by artists around the mid-seventeenth century who, incidentally, did not depend exclusively on the sale of their own paintings, but also relied on the sale of their pupils' work, the art trade, making assessments, restoration activities and apprenticeship fees. Should a painter like Poelenburgh, Berchem or De Molijn sell a few paintings per month for roughly 40 guilders, their earnings would soon exceed that of the 36 guilders in wages of a trained craftsman. However, this in no way applies to a minor artist such as Dirck Verhaert, who had to settle for 6 guilders per painting. Financial success was thus primarily the reserve of painters with talent and ingenuity. To win the patronage of discerning connoisseurs such as Willem Vincent van Wyttenhorst, an artist had to provide high-quality work and be innovative within a given genre.

The energy security of each Caribbean Community (CARICOM) member state is a key issue specifically addressed based on the energy demands of each nation. St. Vincent and the Grenadines (SVG) has the potential to strengthen its energy sector through the exploitation of immense untapped natural geothermal resources. Currently, SVG is planning to integrate base load power through a 10 Megawatt-electric (MWe) geothermal power plant (GPP1). The paper aims to highlight a detailed resource assessment profile of the renewables across SVG and the projected benefits of the proposed 10 MWe geothermal power potential, such as the positive economic development (displacing 149,000 bbls of crude oil), and the transition to a more climate-sensitive nation (displacing an estimated 0.172 million tCO2e/year). In addition, a volumetric method (Monte Carlo simulations) has been applied to reveal that the geothermal reservoir can sustain a minimum of 31 MWe, 34 MWe and 92 MWe over the lifespan of 25–30 years, for well 1 (SVG01), well 2 (SVG02) and well 3 (SVG03) respectively. Given the findings of the assessment and simulations, several policy approaches are identified as potential means of enhancing geothermal resource development and leveraging the resource for the islands’ sustainable energy demands. These include incentivization for public-private partnerships, information certainty, regulatory processes, and strengthened institutions.

This study examines how Marjan raised the folklore culture of Lutung Kasarung and Purbasari in his advertisements. This study uses the theory of semiotic analysis of Roland Barthes and the commodification of Vincent Mosco. The purpose of this study was to determine the commodification of culture in Marjan syrup advertisements in the month of Ramadan, the version of Kutukan Lutung Kasarung and Purbasari by using Roland Barthes Semiotics Analysis of Marjan Syrup Advertisements. The research method used is qualitative. By using Roland Barthes Semiotics as an analytical knife of this research. The results showed that using Roland Barthes' semiotic analysis, it was found that there was a commodification of culture in the Marjan syrup advertisement. The actual use of the folklore culture of Lutung Kasarung and Purbasari has absolutely nothing to do with industry or products. However, it is used as an exchange rate whether in an economic concept or not. Marjan brought the folklore of Purbasari into his advertisement because what Purbasari felt was very suitable with the circumstances we face in fasting. From the initial feeling of joy, then getting a big obstacle to getting back with patience, just like when we run fasting, welcome with joy, run with many trials after successfully being able to feel the day of victory.

On January 9th, 2020, the “World Health Organization” (WHO) declared the identification, by Chinese Health authorities, of a novel coronavirus, further classified as SARS-CoV-2 responsible of a diseases (COVID-19) ranging from asymptomatic cases to severe respiratory involvement. On March 9th, 2020, WHO declared COVID-19 a global pandemic. Italy is the second most affected country by COVID-19 infection after China. The “L. Spallanzani” National Institute for the Infectious Diseases, IRCCS has been the first Italian hospital to admit and manage patients affected by COVID-19. Hereby, we show our recommendations for the management of COVID-19 patients, based on very limited clinical evidences; these recomendations should be considered as expert opinions, which may be modified according to newly produced literature data. *for the INMI COVID-19 Treatment Group – ICOTREG Abdeddaim A, Agrati C, Albarello F, Antinori A, Ascoli Bartoli T, Baldini F, Bellagamba R, Bevilacqua N, Bibas M, Biava G, Boumis E, Busso D, Camici M, Capobianchi MR, Capone A, Caravella I, Cataldo A, Cerilli S, Chinello G, Cicalini S, Corpolongo A, Cristofaro M, D’Abramo A, Dantimi C, De Angelis G, De Palo MG, D’Offizi G, De Zottis F, Di Lorenzo R, Di Stefano F, Fusetti M, Galati V, Gagliardini R, Garotto G, Gebremeskel Tekle Saba, Giancola ML, Giansante F, Girardi E, Goletti D, Granata G, Greci MC, Grilli E, Grisetti S, Gualano G, Iacomi F, Iannicelli G, Ippolito G, Lepore L, Libertone R, Lionetti R, Liuzzi G, Loiacono L, Macchione M, Marchioni L, Mariano A, Marini MC, Maritti M, Mastrobattista A, Mazzotta V, Mencarini P, Migliorisi-Ramazzini P, Mondi A, Montalbano M, Mosti S, Murachelli S, Musso M, Nicastri E, Noto P, Oliva A, Palazzolo C, Palmieri F, Pareo C, Petrone A, Pianura E, Pinnetti C, Pontarelli A, Puro V, Rianda A, Rosati S, Sampaolesi A, Santagata C, Scarcia D’Aprano S, Scarabello A, Schininà V, Scorzolini L, Stazi GV, Taibi C, Taglietti F, Tonnarini R, Topino S, Vergori A, Vincenzi L, Visco-Comandini U, Vittozzi P, Zaccarelli M, Zaccaro G.

Background and Hypothesis: Autism Spectrum Disorder (ASD) is a common neurodevelopmental disorder with a prevalence of 2.76% among children ages 3-17 in the United States1. Some studies have linked total brain volume overgrowth or gyrification changes to ASD2,3,4. However, few have attempted to relate specific growth patterns to ASD. We hypothesize that regional differences in brain growth in subjects aged 12-24 months will correlate with diagnoses from the Autism Diagnostic Observation Schedule (ADOS). Project Methods: The subjects for this study came from the Infant Brain Imaging Study (IBIS)5. The CIVET pipeline was used to segment T1-weighted magnetic resonance images (MRIs) into surfaces using a non-linear classification method5,6,7. CIVET quality control outputs were used for validation and to select parameters for the tasks along with previous recommendations5,8. Analysis of Functional NeuroImages (AFNI) was used to convert the CIVET output format, and Connectome Workbench was used to calculate surface curvature. Using cortical reconstructions and surface curvatures from 12- and 24-month brains, anatomically-constrained Multimodal Surface Matching (aMSM) was applied to achieve point correspondence and generate individual cortical growth maps9,10. Results: Within the IBIS database, we found 38 individuals with ASD and 121 controls with T1weighted scans at both 12 and 24-month time points. Once individual growth maps have been generated for all subjects, Permutation Analysis of Linear Models (PALM)11 will be used to determine statistically significant differences in the cortical growth patterns of ASD versus control groups. Conclusion and Potential Impact: Research on autism may benefit from longitudinal studies of growth, as opposed to analysis of structural differences at later ages4. We concentrate on cortical growth before 24 months, which may serve as an earlier marker of ASD, when abnormal brain growth can be seen yet social deficits are not fully established5. [1] Zablotsky B, Black LI, Blumberg SJ. Estimated Prevalence of Children With Diagnosed Developmental Disabilities in the United States, 2014–2016. NCHS Data Brief 2017. https://www.cdc.gov/nchs/data/databriefs/db291.pdf (accessed April 29, 2019). [2] Libero LE, Schaer M, Li DD, Amaral DG, Nordahl CW. A Longitudinal Study of Local Gyrification Index in Young Boys With Autism Spectrum Disorder. Cereb Cortex. 2019;29(6):2575-87. [3] Raznahan A, Toro R, Daly E, Robertson D, Murphy C, Deeley Q, et al. Cortical anatomy in autism spectrum disorder: an in vivo MRI study on the effect of age. Cereb Cortex. 2010;20(6):1332-40. [4] Duret P, Samson F, Pinsard B, Barbeau EB, Bore A, Soulieres I, et al. Gyrification changes are related to cognitive strengths in autism. Neuroimage Clin. 2018;20:415-23. [5] Hazlett HC, Gu H, Munsell BC, Kim SH, Styner M, Wolff JJ, et al. Early brain development in infants at high risk for autism spectrum disorder. Nature. 2017;542(7641):348-51. [6] Shaw P, Malek M, Watson B, Sharp W, Evans A, Greenstein D. Development of cortical surface area and gyrification in attentiondeficit/hyperactivity disorder. Biol Psychiatry. 2012;72(3):191-7. [7] Ad-Dab’bagh, Y., Einarson, D., Lyttelton, O., Muehlboeck, J.-S., Mok, K., Ivanov, O., Vincent, R.D., Lepage, C., Lerch, J., Fombonne, E., and Evans, A.C. (2006). The CIVET Image-Processing Environment: A Fully Automated Comprehensive Pipeline for Anatomical Neuroimaging Research. In Proceedings of the 12th Annual Meeting of the Organization for Human Brain Mapping, M. Corbetta, ed. (Florence, Italy, NeuroImage). http://www.bic.mni.mcgill.ca/users/yaddab/Yasser-HBM2006-Poster.pdf [8] Shaw P, Kabani NJ, Lerch JP, Eckstrand K, Lenroot R, Gogtay N, et al. Neurodevelopmental trajectories of the human cerebral cortex. J Neurosci. 2008;28(14):3586-94. [9] Garcia KE, Robinson EC, Alexopoulos D, Dierker DL, Glasser MF, Coalson TS, et al. Dynamic patterns of cortical expansion during folding of the preterm human brain. Proc Natl Acad Sci U S A. 2018;115(12):3156-61. [10] Robinson EC, Garcia K, Glasser MF, Chen Z, Coalson TS, Makropoulos A, et al. Multimodal surface matching with higher-order smoothness constraints. Neuroimage. 2018;167:453-65. [11] Winkler AM, Ridgway GR, Webster MA, Smith SM, Nichols TE. Permutation inference for the general linear model. NeuroImage, 2014;92:381-397 (Open Access)

With issue 2 of volume 4, of this month, June 15, 2021, the Home Dialysis Bulletin (original journal title: Bulletin de la Dialyse à Domicile (BDD)) begins its fourth year of publication. Over the past three years, it has gradually become a benchmark medium for clinical research in the field of home dialysis for both nursing staff and nephrologists. It is referenced in Sherpa/Romeo [1], and each article has a CrossRef identifier. All articles benefit from perpetual archiving and have obtained the SEAL quality logo for open access journals from the referencer DOAJ [2]. The abstracts of articles have been viewed 33,840 times, and the French versions of articles have been downloaded in pdf format 19,164 times. It is widely read by caregivers and nephrologists regardless of the mode of exercise, as our recent survey revealed [3]. But dissemination outside the French-speaking world has also been growing steadily thanks to systematic bilingual publication, and 2,640 English versions of articles have been downloaded. Our privileged relations with the International Society for Peritoneal Dialysis (ISPD) [4] have enabled the translation and dissemination into French of international guidelines, when authorized.. The Bulletin de la Dialyse à Domicile appears to be one of the best supports for the development of home dialysis in France and Francophonie while maintaining close links with the English-speaking community.This success was made possible thanks to the work of the authors, whom we would like to thank for their support. Thanks also to the members of our editorial board. We also warmly thank our reviewers, who carry out the critical analysis of the published articles, usually within very short deadlines: Aguilera Didier (France), Azar Raymond (France), Bammens Bert (Belgium), Bataille Stanislas (France), Beaudreuil Séverine (France), Beaume Julie (France), Béchade Clémence (France), Ben Abdallah Taieb (Tunisia), Benamar Loubna (Morocco), Cassagne Brigitte (Switzerland), Caudwell Valérie (France), Chaffara Emmanuel (France), Chanliau Jacques (France), Collart Fredéric (Belgium), Courivaud Cécile (France), de Arteaga Javier (Argentina), Descot Lisa (France), Desitter Arielle (France), Divino José (USA), Durand Pierre-Yves (France), El Esper Najeh (France), Fabre Emmanuel (France), Faller Bernadette (France), Fessi Hafedh (France), Fibach Eitan (Israel), Francois Karlien (Belgium), Goffin Eric (Belgium), Grillon Antoine (France), Guillouet Sonia (France), Jager Rachel (France), Kieron Donovan (UK), Landru Isabelle (Fran ce), Lanot Antoine (France), Laruelle Eric (France), Mougel Sophie (France), Thierry Lobbedez (France), Laville Maurice (France), Morel Bertrand (France), Morelle Johann (Belgium), Mougel Sophie (France) , Nortier Joelle (Belgium), Padernoz Marie (France), Petitclerc Thierry (France), Pourcine Franck (France), Pouteau Lise-Marie (France), Poux Jean-Michel (France), Pujo Myriam (France), Querin Serge ( Belgium), Rodrigues Anabela (Portugal), Rostoker Guy (France), Rousseau-Gagnon Mathieu (Canada), Sanchez Emilio (Spain), Seret Guilaume (France), Simon Pierre (France), Sqalli Tarik (Morocco), Stéphanie Gentile ( France), Target Natalia (France), Testa Angelo (France), Touré Fatouma (France), Treille Serge (France), Urena Pablo (France), Van Biesen Wim (Belgium), Veniez Ghislaine (France), Vernier Isabelle ( France), Landi Vincent (France), Vrtovsnik François (France).More diffusion and improvement will only be possible if we continue to receive high-quality articles, and we hope that non-academics and academics, nurses and doctors will help us achieve this goal in the interest of all and of home dialysis ; so that these physicians and nurses teams will have easily accessible documentation at their disposal to enable them to exchange their knowledge in the service of patients, while sharing in both english and french language. 1 - https://v2.sherpa.ac.uk/id/publication/390072 - https://doaj.org/apply/seal/3 - Verger Christian, Max Dratwa, Pierre-Yves Durand, Jacques Chanliau, Eric Goffin, Thierry Petitclerc, Belkacem Issad, Ghislaine Veniez, Isabelle Vernier, Fatouma Toure, and Cécile Courivaud. 2020. «Assessment of the Interest of a French Language Journal Specializing in Home Dialysis». Bull Dial Domic 3 (4), 227-39. https://doi.org/10.25796/bdd.v3i4.58833.4 - https://ispd.org/

The ProjectThe Hand Up Linkage project focuses on the family as a communication context through which to explore the dynamics of intergenerational welfare dependency. In particular, it explores ways that creative life-course interventions might allow children in welfare dependent families to construct alternative realities for themselves and alternative views of their future. Formed through an alliance between a key Western Australian social welfare not-for-profit organisation, St Vincent de Paul WA (SVDPWA and also, in the context of volunteers, ‘Vinnies’), and Edith Cowan University, the project aims to address the organisation’s vision to provide “a hand up” (St Vincent 1) rather than ‘a hand out’, so that people can move forward with their lives without becoming dependent upon welfare. Prior to the start of the research, SVDPWA already had a whole of family focus in its outreach to poverty-impacted families including offering homework clubs and school holiday children’s camps run by their youth services division. Selected families supported by SVDPWA have been invited to participate in an in-depth interview for the project (Seidman), partly so that researchers can help identify “turning points” (King et al.) that might disrupt the communication of welfare dependency and inform more generalised intervention strategies; but also in order to explore the response to creative interventions within the children’s daily lives, including investigation of how strategies the child (and family) employed might help them to imagine alternative realities and futures for themselves. This paper closely examines the way that one 10 year old child from a non-English-speaking background family has employed alternative ways of viewing her life, through the camp program provided by the Linkage Partner St Vincent de Paul WA, and through reading novels such as Harry Potter and the Lemony Snicket Unfortunate Incidents series. Such activities help fuel hope for a different future which, in Snyder’s view has “two main components: the ability to plan pathways to desired goals despite obstacles, and agency or motivation to use those pathways” (Carr 96).The FamilyKani is a 10 year old girl living in a migrant sole parent family. The parents had moved to Australia from Bangladesh on student visas when Kani was 5 years old, however due to domestic violence the mother had recently separated from her husband, first into a women’s refuge then into private rental accommodation. The mother is in protracted negotiations with the Department of Immigration for permanent residency, which she had to recommence due to her separation. There are also family court negotiations for child custody and which restrict her leaving Australia. She receives no government benefits and minimal child support, works fulltime and pays full childcare fees for Kani’s 3 year old brother Adil and full primary school fees for Kani at a local religious school, given that Kani had experienced bullying and social aggression in previous schools. Kani was referred to SVDPWA by the women’s refuge and she began attending SVDPWA Kids’ Camps thereafter. (NB: Whilst the relevant specifics of this description are accurate, non-relevant material has been added or changed to protect the child’s and family’s identity.)Creative Life-Course InterventionsThe creative engagement that Kani experienced in the Hand Up project is constructed as one component in a larger model of creativity which includes “intrapersonal insights and interpretations, which often live only within the person who created them,” (Kaufman and Beghetto 4). Such an approach also acknowledges Csikszentmihalyi’s work on the concept of “flow”, whereby optimal experiences can result from positive absorption in a creative activity. Relevant Australian research such as the YouthWorx project has identified participatory engagement in creativity as one means of engaging with young people at risk (Hopkins; Podkalicka). The creative interventions in the Hand Up project take two forms; one is the predesigned and participatory creative activities delivered as part of the SVDPWA Kids’ Camp program. The second is a personalised intervention, identified by way of an in-depth interview with the child and parent, and is wholly dependent on the interests expressed by the child, the ability for the family to engage in that activity, and the budget restraints of the project.Reading as an Alternative RealityA key creative intervention embedded in the Hand Up Linkage project is determined by the interests expressed by the child during their in-depth interview. Also taken into account is the ability for the family to engage in that activity. For example, Kani’s mother works fulltime at a location which is an hour by public transport from home and does not have a car or driver’s license, so the choice of creative opportunity was restricted to a home-based activity or a weekend activity accessible by public transport. A further restriction is the limited budget available for this intervention in the project, along with an imperative that such interventions should be equitable between families and within families, and be of benefit to all the children in addition to the interviewed child. Fortunately, transport was not an issue because Kani expressed her interest very emphatically as books and reading. When asked what she liked doing most in life, Kani replied: “Reading. I like reading like big books, like really thick books and stuff. I have like 30 in my room. Like those really big books. And I'm starting to read Harry Potter now. Okay, the books that I like reading is Harry Potter, the entire set Roald Dahl books and the Baudelaire Orphans by Lemony Snicket. I like reading David Walliams. I like Little Women” (Kani). Her excitement in listing these books further animated the interview and was immediately emphasised because Kani took the interviewer (second author) and her mother into her room to demonstrate the truth of her statement. When asked again at the close of the interview “what’s a favourite thing that makes you feel good inside?” Kani’s answer was “Family and reading”. The energy and enthusiasm with which Kani talked about her reading and books made these the obvious choice as her creative intervention. However, participation in book-related courses or after-school activities was restricted by Kani’s mother’s transportation limitations. Taking into account how the financial constraints of her sole parent family impacted upon their capacity to buy books, and the joy that Kani clearly experienced from having books of her own, it was decided that a book voucher would be provided for her at a local bookstore easily accessible by bus. The research team negotiated with the bookstore to try to ensure that Kani could choose a book a month until the funds were expended so that the intervention would last most of the coming six months.What Kani was expressing in her love of books was partly related to the raw material they provide that help her to imagine the alternative reality of the fictional worlds she loved reading about. Kani’s passionate engagement in these alternative realities reflects theories of narrative immersion in one’s chosen medium: “One key element of an enjoyable media experience is that it takes individuals away from their mundane reality and into a story world. We call the process of becoming fully engaged in a story transportation into a narrative world” (Green et al. 311–12). Kani said: “Reading is everything, yeah. Like getting more books and like those kind of things and making me read more... ‘cause I really love reading, it’s like watching a movie. Do you know ... have you watched Harry Potter? … the book is nothing like the movie, nothing, they’ve missed so many parts so the book is more enjoyable than the movie. That’s why I like reading more. ‘Cause like I have my own adventures in my head.” This process of imagining her own adventures in her head echoes Green and Brock’s explanation of the process of being transported into alternative realities through reading as a result of “an integrative melding of attention, imagery, and feelings” (701).Constructing Alternative Realities for Herself and an Alternative Possible FutureLike many 10 year olds, Kani has a challenging time at school, exacerbated by the many school moves brought about by changes in her family circumstances. Even though she is in a school which supports her family’s faith, her experience is one of being made to feel an outsider: “all the boys and the girls in our class are like friends, they’re like ... it’s a group. But I’m not in their group. I have my friends in other classes and they’re [my classmates are] not happy with it, that’s why they tease me and stuff. And like whenever I play with my friends they’re like ... yeah”. The interviewer asked her what she liked about her special friends. “They’re fun. Creative like, enjoyable, yeah, those kind of things …they have lots of cool ideas like plans and stuff like that.” As Hawkins et al. argue, the capacity to develop and maintain good relationships with peers (and parents) is a key factor in helping children be resilient. It is likely that Kani also shares her creativity, ideas and plans with her friendship group as part of her shared contribution to its existence.A domestication of technology framework (Silverstone et al.) can be useful as part of the explanation for Kani’s use of imaginative experience in building her social relationships. Silverstone et al. argue that technology is domesticated via four interlocking activities: ‘appropriation’ (where it embraced, purchased, taken into the household), ‘objectification’ (where a physical space is found for it), ‘incorporation’ (the spaces through which it is inserted into the everyday activities of the household or users) and ‘conversion’ (whereby the experience and fact of the technology use – or lack of use – becomes material through which family members express themselves and their priorities to the social world beyond the home). Arguably, Kani ‘converts’ her engagement with books and associated imaginative experiences into social currency through which she builds relationships with the like-minded children with whom she makes friends. At the same time, those children feed into her ideas of what constitutes a creative approach to life and help energise her plans for the future.Kani’s views of her future (at the age of 10) are influenced by the traditional occupations favoured by high achieving students, and by the fact that her parents are themselves educational high achievers, entering Australia on student visas. “I want to be a doctor … my cousin wants to be a doctor too. Mum said lawyer but we want to be a doctors anywhere. We want to be a ...me and my cousin want to be doctors like ...we like being doctors and like helping people.” Noting the pressures on the household of the possible fees and costs of high school, Kani adds “I need to work even harder so I get a scholarship. ‘Cause like my mum can’t pay for like four terms, you know how much money that will be? Yeah.” Kani’s follow-on statement, partly to justify why she wants “a big house”, adds some poignancy to her reference to a cousin (one of many), who still lives in Bangladesh and whom Kani hasn’t seen since 2011. “Like I want to live with my mum and like yeah and like I live with my cousin too because like I have a cousin ... she’s a girl, yeah? And like yeah, she’s in Bangladesh, I haven’t seen her for very long time so yeah.” In the absence of her extended family overseas, Kani adds her pets to those with whom she shares her family life: “And my mum and my uncle and then our cat Dobby. I named it [for Harry Potter’s house elf] ...and the goldfish. The goldfish are Twinkle, Glitter, Glow and Bobby.”Kani’s mum notes the importance of an opportunity to dream a future into existence: “maybe she’s too young or she hasn’t really kind of made up her mind as yet as to what she wants to do in life but just going out and just you know doing stuff and just giving them the opportunity”. The SVDPWA Kids’ Camp is an important part of this “they [the refuge] kind of told us like ‘there’s this child camp’. … I was like yeah, sure, why not?” Providing Alternative Spaces at the SVDPWA Kids’ CampThe SVDPWA Kids’ Camps themselves constitute a creative intervention in offering visions of alternative realities to their young participants. Their benefit is delivered via anticipation, as well as the reality of the camp experience. As Kani said “I forget all about the things that’s just past, like all the hard things, you know like I go through and stuff and it just makes me forget it and it makes me like think about camp, things we’re going to do at camp”. The Kids’ Camps take place three times a year and are open to children aged between 8 and 13, with follow-on Teen Camps for older age groups. Once a child is part of the program she or he can continue to participate in successive camps while they are in the target age group. Consisting of a four day activity-based experience in a natural setting, conducted by Vinnies Youth and staffed by key SVDPWA employees and Youth volunteers, the camps offer children a varied schedule of activities in a safe and supported environment, with at least one volunteer for every two child participants. The camps are specifically made available to children from disadvantaged families and are provided virtually free to participants. (A nominal $10 enrolment fee is applied per child). Kani was initially reticent about attending her first camp. She explained: “I was shy, scared because I sleep with my mum so it’s different sleeping without Mum. I know it’s kind of embarrassing ‘cause, sleeping with my mum like, but I just get scared at night”. Kani went on to explain how the camp facilitators were able to allay her fears “I knew I was safe. And I had people I could talk to so yeah ...like the leader”. As one Vinnies Youth volunteer explains, the potential of offering children like Kani time out from the pressures of everyday life is demonstrated when “towards the end of every camp we always see that progression of, they came out of their shell … So I think it’s really just a journey for everyone and it’s understandable if they did feel stuck. It’s about what we can do to help them progress forward” (VY1). Kani was empowered to envision an alternative idea of herself at camp, one which was unexpectedly intuited by the research interviewer.When the interviewer closed the interview by expressing that it had been lovely to talk to Kani as she was “such a bundle of energy”, Kani grinned and replied “Do you know the warm fuzzies, yeah? [When positive thoughts about others are exchanged at the SVDPWA Kids’ Camp]. The bundle ... all the leaders say I’m a bundle of happiness”. The Kids’ Camp provided Kani with a fun and positive alternative reality to the one she experienced as a child handling the considerable challenges experienced by social isolation, domestic violence and parental separation, including the loss of her home, diminished connection to her overseas extended family, legal custody issues, and several school changes. Taking the role of cultural intermediary, by offering the possibility of alternative realities via their camp, SVDPWA offered Kani a chance that supported her work on creating a range of enticing possible futures for herself. This was in contrast to some commercial holiday camp experiences which might more centrally use their “cultural authority as shapers of taste and … new consumerist dispositions” (Nixon and Du Gay 497). Even so, Kani’s interview made clear that her experience with the SVDPWA Kids’ Camps were only part of the ways in which she was crafting a range of possible visions for her adult life, adding to this her love of books and reading, her fun, creative friends, and her vision for a successful future which would reunite her with her distant cousin and offer security to her mother. ConclusionUnderstandably, Kani at 10 lacks the critical insight required to interpret how her imaginative and creative life provides the raw materials from which she crafts her visions for the future. Further, the interviewer is careful not to introduce words like ‘creative’ into her work with the participant families, so that when Kani used it to talk about her friends she did so drawing upon her own store of descriptions and not as a result of having recently been reminded of creativity as a desirable attribute. The interview with this young person indicates, however, how greatly she values the imaginative and cultural inputs into her life and how she converts them in ways which help ensure access to further such creative currency. Apart from referencing her reading in the naming of her cat, Kani’s vision for herself reflects both the conventional idea of success (“a doctor”) and a very specific idea of her future living as an adult in house large enough to include her mum and her cousin.Kani’s love of reading, her pleasure in books, her choice of friends and her aspirations to scholarly excellence all offer her ways to escape the restricted options available to families who seek support from organisations such as SVDPWA. At the same time the Kids’ Camps themselves, like Kani’s books, provide an escape from the difficulties of the present. Kani’s appropriation of the cultural raw materials that she draws into her life, and her conversion of these inputs into a creative, social currency, offers her an opportunity to anticipate a better future, and some tools she can use to help bring it into existence.ReferencesCarr, A. Positive Psychology: The Science of Happiness and Human Strengths. 2nd ed. Hove, UK: Routledge, 2011.Csikszentmihalyi, M. Creativity: Flow and the Psychology of Discovery and Invention. New York: HarperCollins, 1996.Green, M., and T. Brock. “The Role of Transportation in the Persuasiveness of Public Narratives.”. Journal of Personality and Social Psychology 79 (2000): 701–21.———, T. Brock, and G. Kaufman. “Understanding Media Enjoyment: The Role of Transportation into Narrative Worlds." Communication Theory 14.4 (2004): 311–27.Hawkins, J.D., R. Kosterman, R.F. Catalano, K.G. Hill, and R.D. 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