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Marginal zone lymphoma (MZL) is challenging to treat, with many patients relapsing following initial treatment. We report the long-term efficacy and safety of copanlisib, a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor, in the subset of 23 patients with relapsed/ refractory MZL treated in the phase 2 CHRONOS-1 study (#NCT01660451, Part B; www.clinicaltrials.gov). Patients had a median of 3 prior lines of therapy, including rituximab and alkylating agents, and received IV copanlisib 60 mg on days 1, 8, and 15 of 28-day cycles for a median of 23 weeks. The objective response rate was 78.3% (18/23; 3 complete responses and 15 partial responses). The median duration of response was 17.4 months (median follow-up, 9.4 months), and median time to response was 2.1 months. Median progression-free survival was 24.1 months (median follow-up, 10.3 months), and median overall survival was not reached (median follow-up, 28.4 months). The most common all-grade treatment-emergent adverse events (TEAEs) included fatigue (52.2%, 12/23), diarrhea, and transient, infusion-related hyperglycemia (each 47.8%, 11/23). Nineteen patients (82.6%) had grade 3/4 TEAEs, most commonly transient, infusion-related hyperglycemia and hypertension (each 39.1%, 9/23). TEAEs led to dose reduction or dose interruptions /delays in 9 patients (39.1%) and 18 patients (78.3%), respectively. Patients with activated PI3K/B-cell antigen receptor signaling had improved response rates. Overall, copanlisib demonstrated strong efficacy, with a short time to objective response, improved objective response rate with longer treatment duration, durable responses, and manageable safety, in line with previous reports. These data provide rationale for long-term treatment with copanlisib in patients with relapsed/refractory MZL. © 2021 by The American Society of Hematology

Safety profiles of oral PI3K inhibitors have resulted in US FDA black box warnings regarding fatal/serious toxicities. The approved intravenous PI3K inhibitor copanlisib has low incidence of severe toxicities and no black box warnings, but chronic treatment effects were unknown. We provide an update on safety and efficacy of copanlisib with a minimum 2-year follow-up of the CHRONOS-1 study. A total of 142 patients with histologically confirmed indolent B-cell lymphoma who had relapsed after or were refractory to ≥2 prior treatments received intravenous copanlisib 60 mg on days 1, 8, and 15 (28-day cycle). The primary efficacy endpoint was objective response rate (ORR) after ≥4 cycles (independent assessment). The predominant histology was follicular lymphoma (n = 104). The ORR was 60.6% (seven additional complete responses since primary analysis). Secondary endpoints of median duration of response, progression-free survival, and overall survival were 14.1 months (median follow-up, 16.1 months), 12.5 months (median follow-up, 14.0 months), and 42.6 months (median follow-up, 31.5 months), respectively. Median safety follow-up was 6.7 months; 26% of patients received treatment for >1 year. Common treatment-emergent adverse events (TEAEs) (all grade/grade 3/grade 4) were transient hyperglycemia (50.0%/33.1%/7.0%), diarrhea (35.2%/8.5%/0%), transient hypertension (29.6%/23.9%/0%), and neutropenia (28.9%/9.2%/14.8%). Serious AEs were largely unchanged, with no new cases of pneumonitis (4.2%), diarrhea (2.8%), or grade 5 events. Note, TEAEs showed no evidence for increased incidence or worsening following longer exposure in patients treated >1 year. Long-term follow-up of patients with relapsed/refractory indolent B-cell lymphoma treated with intravenous copanlisib demonstrated durable, enhanced responses without evidence of worsening TEAEs, as reported for orally administered PI3K inhibitors. © 2019 The Authors. American Journal of Hematology published by Wiley Periodicals, Inc.

SSCI-VIDE+CARE+SGI:AGF:PAN; National audience; Dans un contexte où les normes environnementales se durcissent de plus en plus, la réduction des émissions de polluants et/ou de gaz à effet de serre, en particulier les NOx et le CO2, est un enjeu majeur. Dans le domaine du post traitement automobile, l’usage de biocarburants a été développé pour limiter l’empreinte carbone de ces technologies de combustion. Cependant des études récentes montrent que l’utilisation de bioDiesel soumet la ligne de post-traitement à des poisons inorganiques, notamment Na et K, qui peuvent affecter la nature, la réactivité et la durabilité des catalyseurs [1]. En conséquence des études sont nécessaires pour évaluer les effets de ces poisons inorganiques sur la chaine de post traitement. L’objectif de ce travail consiste donc à empoisonner un catalyseur de référence d’oxydation diesel (DOC) et d’analyser l’impact de ces impuretés (Na, K et Ca) sur les propriétés d'adsorption des systèmes catalytiques en présence de molécule modèle (NO, CO).Des tests d’adsorption/désorption de NO sur les catalyseurs frais et empoisonnés suivis d’une étude in-situ par spectroscopie de réflexion diffuse en infra rouge à transformée de Fourrier ont été réalisée en présence de mélange NO+O2 et NO+C3H6+O2 à 250ºC.Les spectres obtenus après l’adsorption de NO montrent la formation de nouveaux sites d’adsorption en présence des impuretés. Par ailleurs, en présence de NO+O2/He, la formation de NO2 dans la phase gaz a été observé et l’adsorption de NO sous la forme des nitrates est favorisée notamment en présence des impuretés [2]. Ces tendances s’expliquent par le caractère basique des impuretés alcalines et leurs propriétés d’électrodonneur qui favorisent l’interaction avec le NO. En présence du mélange NO+C3H6+O2, les spectres montrent la formation d’acétates et de formates, espèces intermédiaires formées lors de l’oxydation totale du propène (Figure 1). Nous notons également la présence de bandes caractéristiques des isocyanates et cyanides. Ces résultats indiquent que la réduction de NO par le propène a lieu à la surface du catalyseur entre les espèces carbonées et les espèces nitrates [3].En accord avec la littérature [4], en présence de Na, l’intensité des pics correspondants aux intermédiaires carbonées diminue, ce qui se traduit par une faible vitesse de disparition du C3H6 (Tableau 1). Par contre, lorsque le catalyseur est empoisonné au K, nous observons un phénomène inverse, avec une augmentation de l’intensité des pics correspondants aux espèces intermédiaires crées lors de la réduction de NO par le C3H6. Enfin, dans le cas du catalyseur empoisonné au Ca, nous notons une forte adsorption des nitrates au détriment des intermédiaires carbonés ce qui affecte la vitesse de réduction du NO par le C3H6.En conclusion, l’étude in-situ par spectroscopie diffuse en réflexion par infra rouge à transformée de Fourrier a permis d’identifier les sites d’adsorption sur le catalyseur de référence (nitrates, acétates, isocyanates et cyanides). Ensuite l’impact des impuretés inorganiques sur la nature des sites d’adsorption a pu être évaluer et relier aux vitesses des réactions catalytiques de surface.

SSCI-VIDE+CARE+JGR:SGI:LRE:AGF; National audience; Preparación de catalizadores Diesel NOx Trap por via coloidalJ. M. García-Vargasa,*, S. Gila, L. Retailleaua, L. Veyreb, C. Thieuleuxb, A. Giroir-Fendleraa Université Claude Bernard Lyon 1, CNRS, IRCELYON, 2 avenue Albert Einstein, Villeurbanne, F-69622, France.b , ICL, C2P2 UMR 5265, CPE Lyon, 43 Bd du 11 Novembre 1918, F-69616 Villeurbanne, France.*Autor principal: jesus.vargas@ircelyon.univ-lyon1.fr1. IntroducciónHoy en día, la legislación relativa a la emisión de contaminantes por parte de vehículos a motor ha llevado al empleo de diferentes sistemas catalíticos para tratar los gases que emiten, consiguiendo así cumplir con los requerimientos en cuanto a niveles máximos de emisión. Dichos límites han disminuido de forma continuada en los últimos años, convirtiendo la reducción de las emisiones de óxidos de nitrógeno (NOx) por parte de los vehículos diésel en uno de los principales desafíos tecnológicos. Se han planteado diferentes tecnologías para resolver esta problemática, siendo una de estas el uso de catalizadores Diesel NOx Trap (DNT) que permiten almacenar NOx en forma de nitratos durante el funcionamiento normal del motor y posteriormente reducirlos a N2 mediante la inyección durante cortos periodo de tiempo de un agente reductor. Estos catalizadores han mostrado buen rendimiento pero baja durabilidad1. En el presente trabajo se muestra la aplicación de un nuevo método de preparación de catalizadores DNT Pt/Pd/Rh por vía coloidal, procedimiento que se ha utilizado con éxito en la obtención de partículas metálicas muy dispersas, con tamaños de entre 1 y 2 nm, al preparar catalizadores de Ni2 y Pt3.2. ExperimentalDos catalizadores Pt/Pd/Rh fueron preparados con diferente carga de metal mediante la impregnación de coloides metal-Si, mezclando complejos organometálicos de Pt, Pd y Rh en THF con octilsilano, que fue utilizado como agente estabilizante, en atmósfera de H2. Un oxido mixto BaO/CeO2/Al2O3-La2O3 fue seleccionado como soporte. Más detalles acerca del procedimiento utilizado pueden ser encontrados en la literatura2. Los experimentos catalíticos fueron realizados con 10 mg de catalizador usando SiC como inerte para conseguir un GHSV = 52.000 h-1, con un caudal total de 10 l h-1. La composición del alimento fue 14% O2, 4% H2O, 1500 ppm CO, 430 ppm C3H6, 100 ppm NO, usando He como balance. Los catalizadores preparados fueron caracterizados mediante análisis ICP, BET, DRX, TPR, TEM y TPD-NO2. Así mismo fue analizada la actividad de los catalizadores después de envejecimiento, tratando los materiales a 1050°C durante 10 h en atmosfera de N2 con un 10% de H2O. Además de los catalizadores preparados, se testó en las mismas condiciones un catalizador comercial usado como referencia.Tabla 1. Composición de los catalizadores y resultados TPD-NO2.Catalizador %Ce %Al %La %Ba %Mg %Pt %Pd %Rh NOx desorbido (mol/g)Pt/Pd/Rh 4/2/129.1128.511.641.08245 ppm0.490.200.15306 NO2/54 NOPt/Pd/Rh 14/3/129.1128.511.641.08245 ppm0.36719 ppm358 ppm354 NO2/35 NOReferencia com.40.8317.841.130.860.760.650.300.16600 NO2/204 NOCatalysis for a moresustainable worldOviedo, June 26 – 28, 2017 O/P 3. Resultados y discusiónLa composición de los catalizadores preparados y del catalizador de referencia aparece en la Tabla 1. Los análisis DRX no mostraron la presencia de picos de difracción correspondientes a los metales nobles, lo que indica una buena dispersión que fue confirmada mediante análisis TEM, con tamaños de partícula en torno a 1 nm. Experimentos TPD de NO2 fueron realizados, mostrando la Tabla 1 la cantidad de NOx adsorbidos por los catalizadores frescos y el de referencia, siendo la capacidad de adsorción de este catalizador mayor. Comparando los dos catalizadores preparados, el catalizador con una mayor proporción de Pt (Pt/Pd/Rh 14/3/1) fue capaz de adsorber más NO2, apareciendo los picos de desorción a temperaturas mayores, lo que implica una mayor fortaleza de dicha adsorción. La actividad catalítica fue evaluada en términos de conversión y velocidad de reacción. El catalizador preparado con la menor proporción de Pt (Pt/Pd/Rh 4/2/1) fue el más activo tanto en la combustión de C3H6 como en la de CO, mientras que el otro catalizador preparado mostró una actividad similar a la del catalizador de referencia. En cuanto a la conversión de NO (Figura 1), el catalizador que presentó mayor conversión fue el preparado con mayor proporción de Pt, siendo los dos catalizadores preparados más activos que el de referencia. La resistencia al envejecimiento fue también evaluada en términos de actividad catalítica, siendo el catalizador Pt/Pd/Rh 14/3/1 el menos afectado, con valores de conversión de C3H6 y CO cercanos a los del catalizador fresco.Figura 1. Conversión de NO.4. ConclusionesLa proporción de metales nobles ha mostrado una clara influencia en la actividad y propiedades de catalizadores Diesel NOx Trap preparados por vía coloidal, método eficaz a la hora de obtener catalizadores con gran dispersión de metal. El catalizador preparado con una menor proporción de Pt mostro la mayor actividad en la combustión de CO y C3H6, incluso al compararlo con un catalizador comercial. Sin embargo, la presencia de una mayor proporción de Pt favorece la resistencia a la desactivación hidrotermal.Referencias1. E. Rohart, V. Bellière-Baca, K. Yokota, V. Harlé, C. Pitois, Top. Catal. 42 (2007) 71-75.2. D. Baudouin, K.C. Szeto, P. Laurent, … , C. Thieuleux, J. Am. Chem. Soc. 134 (2012) 20624-20627.3. P. Laurent, D. Baudouin, B. Fenet, L. Veyre, S. Donet, C. Coperet, C. Thieuleux, New J. Chem. 38 (2014) 5952-5956

Purpose: Phosphatidylinositol 3-kinase (PI3K) signaling is critical for the proliferation and survival of malignant B cells. Copanlisib, a pan-class I PI3K inhibitor with predominant activity against PI3K-a and -d isoforms, has demonstrated efficacy and a manageable safety profile in patients with indolent lymphoma. Patients and Methods: In this phase II study, 142 patients with relapsed or refractory indolent lymphoma after two or more lines of therapy were enrolled to receive copanlisib 60 mg intravenously on days 1, 8, and 15 of a 28-day cycle. The primary end point was objective response rate; secondary end points included duration of response, progression-free survival, and overall survival. In addition, safety and gene expression were evaluated. Results: Median age was 63 years (range, 25 to 82 years), and patients had received a median of three (range, two to nine) prior regimens. The objective response rate was 59% (84 of 142 patients); 12% of patients achieved a complete response. Median time to response was 53 days. Median duration of response was 22.6 months, median progression-free survival was 11.2 months, and median overall survival had not yet been reached. The most frequent treatment-emergent adverse events were transient hyperglycemia (all grades, 50%; grade 3 or 4, 41%) and transient hypertension (all grades, 30%; grade 3, 24%). Other grade $3 events included decreased neutrophil count (24%) and lung infection (15%). High response rates to copanlisib were associated with high expression of PI3K/B-cell receptor signaling pathway genes. Conclusion: PI3K-α and -δ inhibition by copanlisib demonstrated significant efficacy and a manageable safety profile in heavily pretreated patients with relapsed or refractory indolent lymphoma. © 2017 by American Society of Clinical Oncology.

SSCI-VIDE+CARE+JGR:SGI:AGF; International audience; None

SSCI-VIDE+CARE+JGR:SGI:LRE:AGF; International audience; 1. IntroductionPresently, catalysts are widely employed in the abatement of pollutants from automobiles, being the three-way catalyst (TWC) the most common system used in the gasoline powered vehicles, due to its capacity to achieve the elimination of CO, HC and NO simultaneously. Pt/Rh containing catalysts dominated the automobile exhaust converter market for many years. However, Pd is more abundant and cheap, and has therefore drawn much attention. In addition, the Pd catalysts developed demonstrated significantly improved light-off and NOx conversion activities compared to the commercial Pt/Rh TWCs [1]. Generally, the particle size has a great effect in the catalytic activity of Pd in the TWC, showing smaller particles a higher activity, especially for the oxidation of CO and HC; probably due to a higher presence of Pd (I) species [2]. In this work, we apply a novel colloidal procedure in the catalysts preparation of a Pd/Rh TWC, procedure that has proven to be successful in order to obtain very small metal particles (1-2 nm) when preparing Ni [3] or Pt [4] catalysts.2. ExperimentalPd, Rh and four Pd/Rh catalysts with different impregnation order were prepared by impregnation of metal-Si colloids, mixing Pd and/or Rh organometallic complexes in THF with octylsilane as a stabilizing agent, in the presence of H2; using a standard TWC washcoat. More details about the procedure followed can be found elsewhere [3]. After impregnation, the catalyst was stabilized at 650 °C for 2 h under a flow of N2 with 10% of H2O. Light off tests were carried out using 40 mg of catalyst and SiC as inert in order to reach a GHSV = 52.000h-1 with a total flow of 10 l h-1. The feed gas composition was 4% CO2, 3% H2O, 0.86 % O2, 3000 ppm C3H6, 2300 ppm H2, 1500 ppm NO, 700 ppm CO, using He as balance. 3. Results and discussionMetal particle size was analyzed using the TEM technique, showing all the catalysts metal particles sizes around 1 nm both for Pd and Rh. No differences in particle size were observed depending in the impregnation order or comparing monometallic with bimetallic catalysts. The actual metal content was analyzed by ICP, Table 1.Table 1: Main characterization and catalytic results.Catalyst%Pd%RhT50 (°C) C3H6-CO2T50 (°C) CO-CO2T50 (°C) NO-N2Pd/Washcoat0.51 - 313184-454304Rh/Washcoat- 0.06 297228-412313Pd/Rh/Washcoat0.70 0.05 296173-434299Rh/Pd/Washcoat0.76 0.06 304177-451299Pd-Rh/Washcoat0.67 0.09 301177-447306Pd/Washcoat+Rh/Washcoat0.27 0.05 310183-457314Great differences were observed depending on the metal, as can be observed in Figure 1. At 100 ºC a decrease of the concentration of H2 and NO for the Pd catalyst was obtained, probably due to the concurrence of the H2 SCR reaction, while in the case of the Rh catalyst no catalytic activity was observed until 200 °C. This different behaviour is probably due to the higher H2 adsorption capacity of Pd compared to Rh, what increases the reactivity of this molecule. At about 150 °C it can be observed a decrease in the O2 and CO concentration also for the Pd catalyst, while the NO concentration rises to its initial value. This is probably due to the beginning of the oxidation of CO towards CO2 and also to the oxidation of H2 towards H2O, being this reaction competitive with the H2 SCR. In the case of the Rh catalyst, the oxidation of both CO and H2 did not start until reaching a temperature of 200-220 °C, showing therefore a lower activity in these oxidative reactions. In addition, two different peaks were obtained in the CO conversion for the Pd catalyst, while only one peak with a slight shoulder was observed for the Rh one, what yields a bigger range of temperature in which there are conversion of CO for the first catalyst. This is due to the higher activity of Pd in the CO oxidation at low temperature, and also to the higher activity of Rh in the reforming of C3H6 at medium temperatures (350-450 °C), what yields CO and H2 as products, as can be observed in the increase of the concentration of these compounds at such temperatures.Figure 1: Concentration (dark colors) and Conversion (light colors) vs Temp.: a) Pd/Washcoat b) Rh/Washcoat.Moreover, obtained results showed that the impregnation order had an important influence on the behaviour of the catalysts, showing the catalyst where Rh was impregnated in the last place the conversion and concentration profiles more similar to the Rh catalyst. In Table 1 it can be observed the temperature needed to reach 50% of conversion in the C3H6-CO2, CO-CO2 and NO-N2 reactions for each one of the catalysts prepared. Pd/Rh and Rh/Pd showed the better catalytic behavior, needing lower temperatures to reach the 50% of conversion of NO towards N2 and also the highest temperature range to reach at least a 50% of conversion of CO. In addition, Pd/Rh was the catalyst with the lowest T50 in the conversion of C3H6 to CO2.4. ConclusionsThis new colloidal procedure has shown to be useful in order to obtain Pd and Rh particles of size around 1 nm in a TWC catalyst. A higher activity at low temperature in the H2 SCR and CO oxidation was observed for the Pd/Washcoat catalyst compared with the Rh/Washcoat catalyst. Catalyst prepared impregnating in the first place Rh and after that Pd showed the higher catalytic activity in the three main reactions in which are involved the TWC.

SSCI-VIDE+CARE+PAN:JGR:LRE:SGI:AGF; International audience; None

SSCI-VIDE+CARE+PAN:JGR:LRE:SGI:AGF; National audience; None

SSCI-VIDE+CARE+SGI:JGR:LRE:AGF; International audience; None