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Hafeez, Sana, Tasmia Irum Noureen Shakir Baig, Muhammad Ali, Hania Hafeez, Ashley Nudrat et Hira Butt. « Prevalence of Diastasis Recti Abdominis in Females with Respect to Their Stage and Status of Pregnancy ». Pakistan Journal of Medical and Health Sciences 16, no 5 (30 mai 2022) : 1498–99. http://dx.doi.org/10.53350/pjmhs221651498.
Texte intégralRésumé :
Objective: To find the prevalence of diastasis recti abdominis in females with respect to their stage and status of pregnancy Methodology: A cross sectional study was conducted in Lahore General Hospital from September 2018 to January 2019.Child bearing female in the age group of 20-40 years. Child bearing females not willing to participate, menopausal females, females with any gynecological disorders and those who suffered from ectopic pregnancy were excluded from the study. The questionnaire distributed as hand-outs in selected hospitals. Data was collected in person/ through representatives appointed in every hospital. Results: There was no statistically significant association between previous pregnancy and presence of Diathesis Recti (P=0.566). A statistically significant association between status of pregnancy and presence of Diathesis Recti was present (p≤0.001). Conclusion The prevalence of Diathesis Recti was higher in the females who did not have a history of previous pregnancy.The presence of Diathesis Recti was the highest in females in their third trimester while those in the first and second trimester did not suffer from this condition. It was also seen that the non-pregnant females suffered more from the condition in comparison to the pregnant women. Keywords: Diathesis Recti, Pregnant females, Non-pregnant females, trimester.
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Hafeez, Sana, Tasmia Irum Noureen Shakir Baig, Muhammad Ali, Hania Hafeez, Ashley Nudrat et Hira Butt. « Prevalence of Diastasis Recti Abdominis in Females with Respect to Their Stage and Status of Pregnancy ». Pakistan Journal of Medical and Health Sciences 16, no 5 (30 mai 2022) : 1498–99. http://dx.doi.org/10.53350/pjmhs221651498.
Texte intégralRésumé :
Objective: To find the prevalence of diastasis recti abdominis in females with respect to their stage and status of pregnancy Methodology: A cross sectional study was conducted in Lahore General Hospital from September 2018 to January 2019.Child bearing female in the age group of 20-40 years. Child bearing females not willing to participate, menopausal females, females with any gynecological disorders and those who suffered from ectopic pregnancy were excluded from the study. The questionnaire distributed as hand-outs in selected hospitals. Data was collected in person/ through representatives appointed in every hospital. Results: There was no statistically significant association between previous pregnancy and presence of Diathesis Recti (P=0.566). A statistically significant association between status of pregnancy and presence of Diathesis Recti was present (p≤0.001). Conclusion The prevalence of Diathesis Recti was higher in the females who did not have a history of previous pregnancy.The presence of Diathesis Recti was the highest in females in their third trimester while those in the first and second trimester did not suffer from this condition. It was also seen that the non-pregnant females suffered more from the condition in comparison to the pregnant women. Keywords: Diathesis Recti, Pregnant females, Non-pregnant females, trimester.
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Bernardi, Antonio. « Alcune osservazioni sulle cause di tenuta del settore del franchising nelle fasi recessive ». ECONOMIA E DIRITTO DEL TERZIARIO, no 3 (juillet 2012) : 439–74. http://dx.doi.org/10.3280/ed2011-003003.
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La ricerca esamina le imprese che operano in franchising attraverso microdati raccolti da Assofranchising, la principale associazione italiana nel campo del franchising. Mediante tecniche esplorative e multivariate si dimostra che, ceteris paribus, un aumento della scala delle reti, basata sulla crescita delle risorse umane e materiali, ha un effetto positivo sull'efficienza aziendale attraverso il miglioramento di indicatori strategici di produttivitŕ. Questo fatto indica che le reti in franchising italiane, costituite principalmente ma non esclusivamente da parte delle piccole e medie imprese, anche se sono forti del vincolo associativo, non possono e non devono distogliere lo sguardo dal cercare ogni possibile espansione della loro dimensionalitŕ. Inoltre, questa strategia aiuta ad affrontare meglio le fasi di recessione economica, come l'attuale. The research examines companies operating under franchise through microdata collected from Assofranchising, the main Italian association in the field of franchising. By means of explorative and multivariate techniques it is shown that, other things being equal, an increase in the size of the networks, based on growth of human and material resources, has a positive effect on business efficiencies by improving strategic indicators of productivity. This fact indicates that the Italian franchise networks, consisting primarily but not exclusively by small and medium enterprises, even though they are strong of the associative link, cannot and should not divert their gaze from seeking any possible expansion of their dimensionality. Furthermore, this strategy helps to better address the downturn the economic cycle, like the present one
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Onger, Sergio. « La rappresentanza degli interessi imprenditoriali nella Brescia della Belle époque ». STORIA IN LOMBARDIA, no 2 (janvier 2022) : 51–70. http://dx.doi.org/10.3280/sil2020-002003.
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Le prime forme associative degli imprenditori italiani corrispondevano puntualmente alla struttura economica del Paese e riproducevano quindi il notevole peso degli interessi commerciali. La contiguità territoriale tra impianti industriali, reti distributive e reti creditizie favorivano la costituzione di associazioni con un forte radicamento locale. È questo il caso del Circolo commerciale, sorto a Brescia nel 1892 in modo spontaneo, geograficamente circoscritto e organizzativamente debole, nel quale erano rappresentati sia gli interessi industriali sia quelli commerciali, a dimostrazione di un basso grado di specializzazione settoriale. Al suo interno si trovavano imprenditori dell'industria, del commercio e della finanza, ma anche esponenti del ceto nobiliare che avevano iniziato a investire nell'azionariato industriale e bancario. Il Circolo divenne in pochi anni la centrale operativa di una élite di operatori economici di diverso orientamento politico che non intendevano l'azione associativa solo come difesa dei propri interessi, ma si sforzarono di collocarla nella prospettiva di una più ampia concezione ideologica, ponendosi traguardi comuni di progresso morale, civile e sociale.
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Gitta, Stefánia, Zoltán Magyar, Péter Tardi, Istvánné Füge, Melinda Járomi, Pongrác Ács, János Garai, József Bódis et Márta Hock. « A rectus diastasis prevalenciája, lehetséges rizikófaktorai és szövődményei ». Orvosi Hetilap 158, no 12 (mars 2017) : 454–60. http://dx.doi.org/10.1556/650.2017.30703.
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Abstract: Introduction: There is scant knowledge on diastasis recti which occurs mostly in 3rd trimester of pregnancy. Aim: Our aim was to assign the prevalence of diastasis recti and the possible risk factors and to investigate its association with some chronical diseases, like low back pain and urinary incontinence. Method: 200 women’s interrectus distance was measured who filled out a self-made diastasis recti questionnaire, the SF-36, Oswestry Disability Index and the International Consultation on Incontinence Modular Questionnaire – Urinary Incontinence Short Form questionnaires. Results: Prevalence of the condition was 46.5%. In case of risk factors, relationship between number of deliveries and interrectus distance was significant. We found a significant difference in quality of life, in presence of low back pain and urinary incontinence between the normal and the abnormal group. Conclusions: In line with the literature we found, that diastasis recti can predispose on serious sequelae, hence on decreased quality of life. Orv. Hetil., 2017, 158(12), 454–460.
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Poortinga, Wouter, Tatiana Calve, Nikki Jones, Simon Lannon, Tabitha Rees, Sarah E. Rodgers, Ronan A. Lyons et Rhodri Johnson. « Neighborhood Quality and Attachment ». Environment and Behavior 49, no 3 (27 juillet 2016) : 255–82. http://dx.doi.org/10.1177/0013916516634403.
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Various studies have shown that neighborhood quality is linked to neighborhood attachment and satisfaction. However, most have relied upon residents’ own perceptions rather than independent observations of the neighborhood environment. This study examines the reliability and validity of the revised Residential Environment Assessment Tool (REAT 2.0), an audit instrument covering both public and private spaces of the neighborhood environment. The research shows that REAT 2.0 is a reliable, easy-to-use instrument and that most underlying constructs can be validated against residents’ own neighborhood perceptions. The convergent validity of the instrument, which was tested against digital map data, can be improved for a number of miscellaneous urban form items. The research further found that neighborhood attachment was significantly associated with the overall REAT 2.0 score. This association can mainly be attributed to the property-level neighborhood quality and natural elements components. The research demonstrates the importance of private spaces in the outlook of the neighborhood environment.
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M. Daher, Liana, et Davide Nicolosi. « Mediazioni di cittadinanza : l'attivismo prosociale a favore dei migranti ». MONDI MIGRANTI, no 1 (mars 2022) : 117–35. http://dx.doi.org/10.3280/mm2022-001007.
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Le recenti iniziative di rivendicazione politica dei migranti evidenziano episodi di cittadinanza dal basso, all'interno dei quali è possibile osservare la presenza di movimenti collettivi o reti associative, quali, per esempio, Project20k e No Borders; ciò sembra rilevare una sovrapposizione tra aspetti volontaristici e aspetti relativi specificamente all'attivismo politico, prefigurando casi di cittadinanza mediata (Ambrosini, 2020a; Bartolotta, 2015). È possibile studiare questi casi attraverso il modello di attivismo prosociale, inteso come quella pluralità di forme attraverso le quali i cittadini si uniscono al fine di sostenere categorie sociali vulnerabili (Moro, 2010). Il presente lavoro mira ad analizzare tali processi di azione collettiva attraverso studi di caso di alcune reti di attivismo in difesa dei diritti dei migranti presenti in Sicilia, all'interno delle quali sono state condotte delle brevi campagne di interviste non strutturate rivolte ai membri del direttivo.
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Stull, Gregory W., Conrad C. Labandeira, William A. Dimichele et Dan S. Chaney. « The “seeds” on Padgettia readi are insect galls : reassignment of the plant to Odontopteris, the gall to Ovofoligallites n. gen., and the evolutionary implications thereof ». Journal of Paleontology 87, no 2 (mars 2013) : 217–31. http://dx.doi.org/10.1666/12-063r.1.
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The Early Permian (Asselian) Euramerican plant Padgettia readi Mamay is reassigned to Odontopteris Brongniart, as O. readi (Mamay) Stull et al. n. comb. Distinctive elongate structures on neuropteroid pinnules of this plant, previously interpreted as fructifications, are herein reinterpreted as foliar histoid galls, structurally analogous to blister or vein galls, and probably induced by an early lineage of hemipterans or mites. These distinctive features are assigned to the new gall ichnogenus Ovofoligallites Labandeira, n. ichnogen. n. ichnosp, as O. padgetti Labandeira. The Early Permian association between an Odontopteris host and Ovofoligallites gallers probably originated during the Middle Pennsylvanian as a similar, antecedent association between Macroneuropteris scheuchzeri (Hoffmann) Cleal, Shute, and Zodrow and the maker of U-shaped surface features long known as a distinctive, unattributed damage type, but now recognizable as a likely gall. The persistence of this association between the galler and certain medullosan pteridosperms into the Permian adds to the morphological richness of the Permian galler insect fauna. The Permian ecological expansion of galling insects resulted in colonization of new host plants, primarily through a shift from the consumption of entire, mostly pteridophyte axial organs during the Pennsylvanian to the partitioning of seed plant tissues in leaves and small branches in the Permian. The Ovofoligallites galler was part of a diverse Permian galler guild involving a variety of plant taxa, organs and tissues that overwhelmingly targeted multiple lineages of seed plants.
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Romero Caballero, Belén. « Las movidas ecosociales de Fortaleza de la Mujer Maya A. C. Con-fabulaciones, re-existencias y maniobras de retaguardia ». Arte y Políticas de Identidad 26 (30 juin 2022) : 172–94. http://dx.doi.org/10.6018/reapi.530061.
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Fortaleza de la Mujer Maya is a self-managed civil association founded by indigenous Tsotsil and Tseltal women, in February 1994, in San Cristóbal de las Casas (Mexico), in the geopolitical context of the uprising of the Zapatista Army of National Liberation. Although they are known nationally and internationally for their popular theater work, this has not been the only eco-social move. Reflect this, the workshops with women and children from different indigenous and peasant communities of Chiapas who, in 1994 and 1995, came to the city fleeing the violence of the armed conflict, or from previous migrations, because of forced expulsions caused by for religious intolerance. This article will try to show how the pareja and indissoluble articulation with practices located in an ontology and epistemology based on care and other maneuvers to sustain human and non-human life, with-fabled in the kuxlejal lekil, which have as a pedagogical device collective backbone of the popular arts, highlights the scope and particularity of their work as social actors, as well as their political commitment to the transformation of the material and visual culture of indigenous, mestizo and low-income women, and the politics of place. Fortaleza de la Mujer Maya es una asociación civil autogestionada fundada en febrero 1994 por mujeres indígenas tsotsiles y tseltales, en San Cristóbal de las Casas (México), en el contexto geopolítico del levantamiento del Ejército Zapatista de Liberación Nacional. Si bien, son conocidas a nivel nacional e internacional por su trabajo de teatro popular comunitario, esta no ha sido su única movida ecosocial. Dan cuenta de ello, los talleres con mujeres y niños de diferentes comunidades indígenas y campesinas chiapanecas que, en los años 1994 y 1995, llegaban a la ciudad huyendo de la violencia del conflicto armado, o procedentes de migraciones anteriores, consecuencia de expulsiones forzosas causadas por la intolerancia religiosa. Este artículo tratará de mostrar cómo la articulación pareja e indisoluble con unas prácticas situadas en una ontología y epistemología de los cuidados y otras maniobras de sostenimiento de la vida humana y no humana, con-fabulada en el lekil kuxlejal, que tienen como dispositivo pedagógico colectivo vertebrador el teatro y las artes populares, pone de manifiesto el alcance y la particularidad de su trabajo como actoras sociales, así como su compromiso político para la transformación de la cultura material y visual de las mujeres indígenas, mestizas o de escasos recursos, y las políticas del lugar.
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Starzec-Proserpio, Małgorzata, Montserrat Rejano-Campo, Agata Szymańska, Jacek Szymański et Barbara Baranowska. « The Association between Postpartum Pelvic Girdle Pain and Pelvic Floor Muscle Function, Diastasis Recti and Psychological Factors—A Matched Case-Control Study ». International Journal of Environmental Research and Public Health 19, no 10 (20 mai 2022) : 6236. http://dx.doi.org/10.3390/ijerph19106236.
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There is uncertainty regarding the association between abdominal morphology, pelvic floor function, and psychological factors in women with postpartum pelvic girdle pain (PGP). The aim of this case-control study was to evaluate the differences between women with and without persistent PGP regarding pelvic floor function, diastasis recti, and psychological factors 6–24 weeks postpartum. Pelvic floor manometry, palpation examination of abdominal muscles, the International Consultation on Incontinence Questionnaire Short Form, The Depression, Anxiety and Stress Scale—21, and the Pain Catastrophizing Scale were used. The PGP group presented with lower vaginal resting pressure (p < 0.001), more tenderness (p = 0.018) and impaired voluntary activation of pelvic floor muscles (p ≤ 0.001). Women with pain also had more distortion on the level of the anterior abdominal wall (p = 0.001) and more severe diastasis recti (p = 0.046) when compared to pain-free controls. Lower vaginal resting pressure was the strongest factor explaining PGP (OR 0.702, 95%CI 0.502–0.981). There were no differences in terms of the pelvic floor strength, endurance, severity of urinary incontinence and reported distress between the groups. Women with PGP 6–24 weeks postpartum differ in pelvic floor and abdominal muscle function from the pain-free controls. Vaginal resting pressure may be an important factor in pelvic girdle pain shortly postpartum. Further studies are needed to see a trend in changes over time.
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Corrado, Alessandra. « Semi, contadini e mercati : le reti per un'altra agricoltura ». SOCIOLOGIA URBANA E RURALE, no 87 (juin 2009) : 135–52. http://dx.doi.org/10.3280/sur2008-087008.
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- The search for control over resources, the re-appropriation of knowledge and the development of new relationships of exchange in local markets show the diffusion of original patterns for rural development. Moving from the case of the French association Réseau Semences Paysannes and of some Italian experiences, this paper aims to illustrate the new practices and strategies developed by small rural produces in order to cope with the expropriation process menacing their existence. These are considered as examples of peasant agriculture based on the capacity of re-socializing and re-localizing food. The paper concludes by outlining how these practices can challenge the techno-scientific system of knowledge, the institutional system of governance as well as the economic system of global market. Key words: peasant agriculture; peasant networks; biodiversity; participative selection; farmers markets; rural development practices.
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Campanella, Giovanna. « La ricerca del lavoro : problema di costi e di rigidità del mercato ? Uno studio di caso sui tirocini di formazione e orientamento ». ARGOMENTI, no 36 (janvier 2013) : 105–26. http://dx.doi.org/10.3280/arg2012-036005.
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Il saggio approfondisce le problematiche connesse alle forme associative tra Comuni, nel caso italiano, a partire dall'analisi del caso Veneto nella prospettiva europea. Tali forme di aggregazione possono essere efficacemente definite come esempi di reti intercomunali: un concetto che consente di spostare l'accento dalla staticità e rigidità della struttura organizzativa del singolo ente locale, alla flessibilità e funzionalità delle relazioni tra gli attori rispetto alle politiche che si intendono condividere e alle differenti logiche di rete che si implementano a seconda del modello di governance prescelto.
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Bernardi, Antonio. « Gruppi di reti di franchising e indicatori economici caratteristici ». ECONOMIA E DIRITTO DEL TERZIARIO, no 1 (octobre 2009) : 7–45. http://dx.doi.org/10.3280/ed2009-001001.
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- The research presents a cluster analysis of networks of franchising with data taken from the business register of the main Italian association in the sector. The basic processed information is the count of networks, national outlets, outlets abroad, employees and the level in revenues earned in various economic sectors where the franchising is active. The previous variables, after an examination by Explorative Data Analysis, were used for the construction of some characteristic ratios relating to aspects of dimensions, efficiency and strategy of the franchisors and franchisees. The ratios, after a screening for detection of uni-multivariate outliers, became the new variables for the cluster analysis, iterated with a different methodology in order to guarantee the stability of the results. The analysis revealed four types of networks, with specific patterns of connection that, in general but a few cases, are due to a good degree of symmetry and balance between the dynamics of franchisors and franchisees.
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Rossi, Giovanna, et Lucia Boccacin. « Reti associative di promozione sociale e capitale sociale. Una indagine quantitativa su scala nazionale ». SOCIOLOGIA E POLITICHE SOCIALI, no 1 (mars 2011) : 71–117. http://dx.doi.org/10.3280/sp2011-001004.
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Ullman, Elon D., Lauren M. Smith, Marjorie C. McCullagh et Richard L. Neitzel. « Hearing loss as a predictor for hearing protection attenuation among miners ». Occupational and Environmental Medicine 78, no 5 (12 janvier 2021) : 371–76. http://dx.doi.org/10.1136/oemed-2020-106838.
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ObjectiveThis study investigated risk factors for poor earplug fit, with a focus on the association between hearing loss and personal attenuation ratings (PARs).MethodsEarplug fit was assessed by obtaining PARs using a real ear at attenuation threshold (REAT) system. Hearing loss was assessed using the unoccluded hearing thresholds measured during the REAT testing and the results of a speech-in-noise test. Potential predictors of PARs were modelled using both simple and multiple linear regression. Hearing loss was the primary predictor of interest.ResultsData were collected from 200 workers at ten above-ground mining sites in the Midwestern USA. Workers reported wearing their hearing protection on average 73.9% of the time in a high noise environment (mean 8-hour time-weighted average noise exposure 85.5 dBA, range 65–103 dBA). One-quarter (26.7%) of workers were found to have a hearing loss (hearing threshold ≥25 dB across 1–4 kHz), and 42% reported symptoms of tinnitus. Workers with a hearing loss had a significantly lower PAR than those without a hearing loss (β=−5.1, SE=1.7).ConclusionsThe results of the adjusted regression models suggest that workers with hearing loss achieved significantly lower PARs than those without hearing loss. This association between hearing loss and hearing protection devices (HPD) fit brings into focus the potential benefit of fit checks to be included in hearing conservation programmes. Workers found to have hearing loss should be prioritised for fit testing, as their hearing impairment may be associated with poor HPD fit.
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Aldea, Mihaela, Arianna Marinello, Wael Zrafi, Fabrizio Tabbo, Florian Guisier, Damien Vasseur, Vincent Fallet et al. « Abstract 4019 : RET-MAP : An international multi-center study of patients with advanced non-small cell lung cancer and RET fusions ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 4019. http://dx.doi.org/10.1158/1538-7445.am2022-4019.
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Abstract Introduction: RET fusions (RET+) are identified in nearly 1% of advanced NSCLC (aNSCLC). We evaluated characteristics and outcomes of patients (pts) with RET+ aNSCLC. Methods: This is an international, multicenter, retrospective study evaluating clinical, biological, pathological and radiological data of pts with RET+ aNSCLC. Objective response rates (ORR), duration of response (DOR) and progression-free survival (PFS) were evaluated under double or single agent chemotherapy (CT), immunotherapy (ICI), CT-ICI, multityrosine kinase inhibitors (MTKi) and RET inhibitors (RETi). Overall survival (OS) was calculated from the start of first line therapy and compared between pts treated or not by RETi, after stratification by number of treatment lines. Results: A total of 71 pts was included from 11 centers. Median age was 60 [IQR 47-69], 58% were female, 93% had adenocarcinoma, 2 pts (3%) had squamous and 2 (3%) neuroendocrine carcinoma, 38 (53.5%) were tobacco consumers (median 18.5 PY [7.8-31.3]), 50 (70%) had stage IV disease at diagnosis. Fusion partners were KIF5B (35/49, 71%), CCDC6 (9/49, 18%), others (5/49, 10%). Median TMB was 2.76 [2.0-8.5], median PD-L1 5% [0-29]. The most frequent co-mutation was TP53 (18/58 cases, 31%). Median number of metastatic sites was 2 [1-3], most commonly lung (48%), bone (45%), pleura (41%) and nodes (35%). Brain metastases were found in 18% of cases at diagnosis and in 31% at last follow-up or death. Table reports outcomes by treatment. mOS was 50.6 months [95%CI 37.6 - NR]. Fifty-two pts received 1st generation RETi. The use of RETi improved OS in pts treated with ≤2 lines of therapy (NR vs 17.8 months, p=0.024) and in those receiving >2 lines (50.6 vs 12.7 months, p=0.0037). Pts responding to ICI had a median PD-L1 of 85% [15.5-90]. Conclusions: Pts with RET+ aNSCLC have mainly thoracic and bone disease. Despite smoking history, median TMB and PD-L1 expression are low. ICI may have a significant activity in selected cases. RETi improve OS. Outcomes by treatment First use of Doublet CT (N=46) Single agent CT (N=12) CT-ICI (N=9) ICI (N=19) MTKi (N=9) RETi (N=52) Line of treatment (median, range) 1 [1-1] 2 [2-3] 1 [1-2] 2 [2-3] 3 [1.5-3.5] 2 [1-3] ORR (N,%) 25/40 (62.5%) 3/12 (25%) 3/9 (33%) 7/17 (41%) 4/8 (50%) 36/45 (80%) mPFS (months, 95%CI) 7.89 [6.18-14] 2.81 [2.43-NR] 5.62 [2.79-NR] 3.71 [2.99-11.5] 2.76 [1.51-NR] 24.7 [16.2-NR] mDOR (months,95%CI) 11.83 [7.06-15.6] 8.90 [4.21-NR] 14.47 [10.25-NR] 20.47 [11.3-NR] 8.18 [1.64-NR] 24.74 [17.12-NR] Stopped for toxicity (N,%) 7/46 (15%) 1/12 (8%) 2/9 (22%) 4/18 (22%) 1/9 (11%) 14/50 (28%) Citation Format: Mihaela Aldea, Arianna Marinello, Wael Zrafi, Fabrizio Tabbo, Florian Guisier, Damien Vasseur, Vincent Fallet, Clarisse Audigier-Valette, Laura Mezquita, Antonio Calles, Giannis Mountzios, Marco Tagliamento, Judith Raimbourg, Safae Terrisse, Silvia Novello, Maria-Rosa Ghigna, Fabrice Barlesi, David Planchard, Benjamin Besse. RET-MAP: An international multi-center study of patients with advanced non-small cell lung cancer and RET fusions [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 4019.
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Kovalenko, Oleksii, et Mariia Kalista. « Phytosociology and biodiversity patterns of annual wetland communities of Pyriatynskyi National Nature Park (Poltava Oblast, Ukraine) ». Acta Botanica Croatica 78, no 2 (1 octobre 2019) : 155–63. http://dx.doi.org/10.2478/botcro-2019-0013.
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Abstract The results of a comparative structural analysis of the annual wetland herb vegetation syntaxa (class Isoëto-Nano-Juncetea) of Pyriatynskyi National Nature Park (Poltava Oblast, Ukraine) are presented. The systematic, biomorphological, ecological and geographical structures of syntaxa were studied using cluster, discriminant and factor analysis. The principal conformity of the floristic similarity dendrogram and the previously developed classification scheme were analysed. It was revealed that the leading factor of coenosis development is the soil moisture, while most parameters of these ecotopes are constant. The critical differentiation of Nano-Cyperion and Eleocharition ovatae alliances and the legitimacy of the recognition of the Radiolion linoidis alliance and Polygono recti-Juncetum juzepczukii association as separate syntaxa of the main ranks are emphasized.
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Davydova, Anastasia. « A Mediterranean element of the vegetation : Junco maritimi-Cladietum marisci – a new association for Ukraine ». Hacquetia 19, no 2 (1 décembre 2020) : 275–91. http://dx.doi.org/10.2478/hacq-2020-0010.
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AbstractCladium mariscus (L.) Pohl (Cyperaceae) is a rare species in Europe considered by several authors to be a relict of the early Holocene period. It is listed in the Red Data Book of Ukraine, Annexes of the Habitat Directive and the Bern Convention. Communities with domination of this species are included in the Green Data Book of Ukraine. Substantial differences in major ecological factors for Cladium mariscus communities in the western (carbonate bogs) and the southern (marshes and floating swamps of the northern Black Sea) regions of Ukraine were shown. The author carried out comparisons of relevés characterizing different communities with Cladium mariscus within Europe. Based on the results of TWINSPAN analysis, four associations were identified, confirmed by floristic indices and ecological data: Cladietum marisci Allorge 1921, Soncho maritimi-Cladietum marisci (Br.-Bl. & O. de Bolòs 1957) Cirujano 1980, Dorycnio recti-Cladietum marisci Gradstein & Smittenberg 1977 and Junco maritimi-Cladietum marisci (Br.-Bl. & O. de Bolòs 1957) Géhu & Biondi 1988. Thus, in addition to the association Cladietum marisci, a new one was indicated for Ukraine, Junco maritimi-Cladietum marisci.
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Basile, Carlo, et Carlo Lomonte. « Verità e leggende sulla fistola arterovenosa ». Giornale di Clinica Nefrologica e Dialisi 25, no 2 (5 octobre 2013) : 94–99. http://dx.doi.org/10.33393/gcnd.2013.1016.
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Studi di grandi dimensioni dimostrano un rischio di mortalità progressivamente crescente a seconda del tipo di accesso vascolare (VA), con il rischio più alto associato al catetere venoso centrale (CVC), seguito dai rischi associati alla protesi e, quindi, alla fistola arterovenosa (FAV). La presenza di una FAV ha un effetto negativo sulla funzione cardiaca, ma il suo esatto contributo alla morbidità cardiovascolare non è chiaro. È noto da tempo che un VA con un flusso inappropriatamente elevato può essere la causa di uno scompenso cardiaco ad alta gittata. Ancora più paradossalmente, ci possono essere benefici cardio-polmonari derivanti dalla presenza di una FAV. Tuttavia, pur sottolineando i reali benefici della creazione di una FAV, vogliamo anche sottolineare il pericolo legato a flussi elevati. La parola chiave nella scelta di un VA è “eleggibilità”. Un approccio del tipo “al primo posto viene il paziente e non la FAV, ma è meglio evitare un CVC, se possibile” potrebbe essere la scelta migliore.
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Malone, Caroline, et Simon Stoddart. « The neolithic site of San Marco, Gubbio (Perugia), Umbria : survey and excavation 1985–7 ». Papers of the British School at Rome 60 (novembre 1992) : 1–69. http://dx.doi.org/10.1017/s006824620000979x.
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RICOGNIZIONE E SCAVO DEL SITO NEOLITICO DI SAN MARCO, GUBBIO (PERUGIA), UMBRIA, 1985–7La ricognizione e lo scavo dell'insediamento di San Marco rappresenta uno dei pochi esempi di studio interdisciplinare compiuti nell'Italia centrale e riguardante un sito neolitico. Sono stati studiati in maniera approfondita i vari aspetti geologici ed ambientali del sito, collocato su un conoide alluvionale. Sono state inoltre ottenute date al 14C, eseguite con l'AMS direttamente su materiali organici associati con la sussistenza umana, che hanno permesso di attribuire il sito ad una prima fase dell'età neolitica (fine del sesto-inizio del quinto millennio a.C, date calibrate). L'industria litica mostra una chiara continuità con la precedente tecnologia epipaleolitica, mentre le ceramiche rinvenute possono essere attribuite alle correnti stilistiche della Ceramica Impressa e a quella di Sasso-Fiorano. Le analisi dei prodotti di sussistenza (fauna e resti botanici) rivelano un'economia basata principalmente sull'agricoltura, integrata a sua volta con prodotti ottenuti tramite attività di caccia e raccolta.
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Williams, Lauren, Karen Campbell, Gavin Abbott, David Crawford et Kylie Ball. « Is maternal nutrition knowledge more strongly associated with the diets of mothers or their school-aged children ? » Public Health Nutrition 15, no 8 (10 janvier 2012) : 1396–401. http://dx.doi.org/10.1017/s1368980011003430.
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AbstractObjectiveMaternal nutrition knowledge has frequently been identified as an important target for nutrition promotion interventions. The aim of the present study was to investigate whether maternal nutrition knowledge is more strongly associated with the mother's own diet or that of her child.DesignCross-sectional multivariate linear regression with interactions analyses of survey data.SettingSocio-economically disadvantaged neighbourhoods in Victoria, Australia.SubjectsFive hundred and twenty-three mothers and their children who participated in the Resilience for Eating and Physical Activity Despite Inequality (READI) study, a cross-sectional survey study conducted in 2009 among women and their children residing in socio-economically disadvantaged neighbourhoods.ResultsIn adjusted models, for three (vegetable, chocolate/lollies and soft drink consumption) out of the seven dietary outcomes assessed, there was a significant association between maternal nutrition knowledge and maternal diet, whereas for the children's diets none of the seven outcomes were associated with maternal nutrition knowledge. Statistical comparison of regression coefficients showed no difference between the maternal nutrition knowledge–maternal diet association and the maternal nutrition knowledge–child diet association.ConclusionsPromoting maternal nutrition knowledge may represent an important avenue for improving diet in mothers from socio-economically disadvantaged neighbourhoods, but more information is needed on how and when this knowledge is translated to benefits for their children's diet.
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Caligaris, Ottavio, Pier Giuseppe Giribone et Marco Neffelli. « Ricostruzione di superfici di volatilità mediante l’utilizzo di reti neurali auto-associative : un caso studio basato sull’analisi non lineare delle componenti principali ». Risk Management Magazine 3, no 2017 (15 février 2018) : 11–18. http://dx.doi.org/10.47473/2020rmm0047.
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Nuzzo, Valeria, et Valerio Speziale. « Il diritto del lavoro e la frantumazione dei confini dell'impresa ». SOCIOLOGIA DEL LAVORO, no 164 (décembre 2022) : 162–82. http://dx.doi.org/10.3280/sl2022-164009.
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Il saggio approfondisce il confronto tra giuslavoristi e sociologi del lavoro sui con-fini dell'impresa, sottolineando come l'assetto e la conformazione dell'impresa sia uno dei temi rimasti lungamente estraneo a tale dialogo. I cambiamenti organizza-tivi degli anni '90 inducono entrambi i settori a una riflessione, ma essi procedono per lo più paralleli, con richiami e citazioni reciproche estremamente rare ed episo-diche, in gran parte limitate al rinvio a una differente prospettiva di indagine. Solo negli ultimi anni tale confronto diventa più rilevante, quando si accentuano i fe-nomeni di outsourcing e si determina, con essi, una fuga dalla regolamentazione che vi si applica, grazie alla possibilità di organizzare la produzione sfruttando i differenziali regolativi e salariali esistenti fra le diverse aziende, fra i diversi settori industriali e anche fra diversi Paesi. Il saggio guarda, dunque, alle differenziazioni e alle asimmetrie che si sono prodotte sfruttando i confini e i differenziali ad essi associati, indagando sui diversi strumenti giuridici utilizzati, dall'appalto alle reti di impresa fino alle catene globali del valore.
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De Nicolò, Marco, Andrea Giuntini et Dino Mengozzi. « Spazi regionali, reti associative e mediazioni culturali : una discussione a proposito della storia delle Romagne / La storia regionale e la sua dimensione scientifica ». STORIA E PROBLEMI CONTEMPORANEI, no 80 (novembre 2020) : 239–49. http://dx.doi.org/10.3280/spc2019-080020.
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De Nicolò, Marco, Andrea Giuntini et Dino Mengozzi. « Spazi regionali, reti associative e mediazioni culturali : una discussione a proposito della storia delle Romagne / La storia regionale e la sua dimensione scientifica ». STORIA E PROBLEMI CONTEMPORANEI, no 80 (novembre 2020) : 239–49. http://dx.doi.org/10.3280/spc2020-080020.
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Zhang, Junwen, Jiaquan Zhu, Shiao Ding, Chunrong Bao, Zhaolei Jiang, Zi-Hui Tang et Ju Mei. « Analysis of the Synergistic Effects of Fasting Plasma Glucose and Hypertension on Cardiovascular Autonomic Neuropathy ». Cardiology 132, no 1 (2015) : 58–64. http://dx.doi.org/10.1159/000381013.
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Background: The purpose of this study was to evaluate the associations of fasting plasma glucose (FPG) and hypertension (HTN) with cardiovascular autonomic neuropathy (CAN) and to estimate the extent to which the synergistic effects of FPG and HTN affect outcomes in a Chinese population. Method: We conducted a large-scale, population-based study to analyze the association and interaction of the two factors with CAN in a sample of 2,092 Chinese people. Univariate and multiple linear regression (MLR) analyses were employed to detect these relationships. Interaction on an additive scale can be calculated by using the relative excess risk due to interaction, the proportion attributable to interaction (AP), and the synergy index (S). Result: After adjusting for confounding factors, MLR showed that FPG and HTN were independently associated with CAN (p < 0.001 for both). A significant synergistic effect of FPG and HTN on CAN was detected (p = 0.046, RETI = 0.733, 95% CI 0.059-1.450; AP = 0.167, 95% CI -0.033 to 0.367; S = 1.275, 95% CI 0.140-2.410). Conclusion: Our findings suggest that FPG and HTN are independently associated with CAN, and they offer evidence to support the hypothesis that FPG and HTN have synergistic effects that influence the progression of CAN.
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Hao, Hua, Sandrah P. Eckel, Anahita Hosseini, Eleanne D. S. Van Vliet, Eldin Dzubur, Genevieve Dunton, Shih Ying Chang et al. « Daily Associations of Air Pollution and Pediatric Asthma Risk Using the Biomedical REAI-Time Health Evaluation (BREATHE) Kit ». International Journal of Environmental Research and Public Health 19, no 6 (17 mars 2022) : 3578. http://dx.doi.org/10.3390/ijerph19063578.
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Background: Exposure to air pollution is associated with acute pediatric asthma exacerbations, including reduced lung function, rescue medication usage, and increased symptoms; however, most studies are limited in investigating longitudinal changes in these acute effects. This study aims to investigate the effects of daily air pollution exposure on acute pediatric asthma exacerbation risk using a repeated-measures design. Methods: We conducted a panel study of 40 children aged 8–16 years with moderate-to-severe asthma. We deployed the Biomedical REAI-Time Health Evaluation (BREATHE) Kit developed in the Los Angeles PRISMS Center to continuously monitor personal exposure to particulate matter of aerodynamic diameter < 2.5 µm (PM2.5), relative humidity and temperature, geolocation (GPS), and asthma outcomes including lung function, medication use, and symptoms for 14 days. Hourly ambient (PM2.5, nitrogen dioxide (NO2), ozone (O3)) and traffic-related (nitrogen oxides (NOx) and PM2.5) air pollution exposures were modeled based on location. We used mixed-effects models to examine the association of same day and lagged (up to 2 days) exposures with daily changes in % predicted forced expiratory volume in 1 s (FEV1) and % predicted peak expiratory flow (PEF), count of rescue inhaler puffs, and symptoms. Results: Participants were on average 12.0 years old (range: 8.4–16.8) with mean (SD) morning %predicted FEV1 of 67.9% (17.3%) and PEF of 69.1% (18.4%) and 1.4 (3.5) puffs per day of rescue inhaler use. Participants reported chest tightness, wheeze, trouble breathing, and cough symptoms on 36.4%, 17.5%, 32.3%, and 42.9%, respectively (n = 217 person-days). One SD increase in previous day O3 exposure was associated with reduced morning (beta [95% CI]: −4.11 [−6.86, −1.36]), evening (−2.65 [−5.19, −0.10]) and daily average %predicted FEV1 (−3.45 [−6.42, −0.47]). Daily (lag 0) exposure to traffic-related PM2.5 exposure was associated with reduced morning %predicted PEF (−3.97 [−7.69, −0.26]) and greater odds of “feeling scared of trouble breathing” symptom (odds ratio [95% CI]: 1.83 [1.03, 3.24]). Exposure to ambient O3, NOx, and NO was significantly associated with increased rescue inhaler use (rate ratio [95% CI]: O3 1.52 [1.02, 2.27], NOx 1.61 [1.23, 2.11], NO 1.80 [1.37, 2.35]). Conclusions: We found significant associations of air pollution exposure with lung function, rescue inhaler use, and “feeling scared of trouble breathing.” Our study demonstrates the potential of informatics and wearable sensor technologies at collecting highly resolved, contextual, and personal exposure data for understanding acute pediatric asthma triggers.
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Antoncecchi, Ettore, et Enrico Orsini. « Cardiologia 2019. Cosa c’è di nuovo ». Cardiologia Ambulatoriale, no 12020 (30 janvier 2020) : 1–10. http://dx.doi.org/10.17473/1971-6818-2020-1-1.
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Si può ben dire che il panorama scientifico 2019 è stato ricco di novità per la cardiologia. Sono stati presentati nei principali congressi internazionali e pubblicati sulle riviste più prestigiose i risultati di numerosi ed importanti trials, attesi da anni su tematiche differenti. La Società Europea di Cardiologia è stata attivissima, emanando ben cinque nuove linee guida, su diabete e malattie cardiovascolari, dislipidemie, embolia polmonare, tachicardie parossistiche sopraventricolari e sindromi coronariche croniche. Le società americane sono state più prudenti, per certi aspetti opportunamente, limitandosi ad emanare due nuovi documenti sulla prevenzione primaria e sulla fibrillazione atriale. Non sempre tuttavia novità è sinonimo di progresso reale. Numerosi trials su farmaci già sviluppati o in via di sviluppo hanno dato risultati negativi o solo modestamente positivi, tanto da non consentire di supportarne nuove indicazioni. Uno dei nuovi documenti di indirizzo della Società Europea di Cardiologia si è rivelato, come sarà discusso, sostanzialmente privo di reali innovazioni. Uno dei trials maggiormente attesi, ISCHEMIA, presentato all’American Heart Association ma non ancora pubblicato, ha dato un risultato che possiamo definire “nullo”. Soltanto una classe di nuovi farmaci antidiabetici, gli inibitori SGLT-2, hanno ricevuto conferme molteplici nel 2019, tanto da permetterne la collocazione fra gli agenti più attivi per la prevenzione cardiovascolare. Questo editoriale, non potendo passare in rassegna tutte le novità cardiologiche 2019, tratterà soltanto alcuni temi che gli autori reputano maggiormente significativi. Sperando di incontrare l’approvazione dei lettori di Cardiologia Ambulatoriale.
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Rajbhandari, Ajay, Dipendra Raj Pandeya, Madhur Dev Bhattarai et Ravi Malla. « Blood Glucose Levels in Patients with Coronary Artery Disease ». Medical Journal of Shree Birendra Hospital 11, no 1 (13 mars 2013) : 4–8. http://dx.doi.org/10.3126/mjsbh.v11i1.7758.
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Introduction: Diabetes Mellitus is a potent risk factor for Coronary Artery Diseases, but Impaired Glucose Tolerance is increasingly known risk factor for Coronary Artery Diseases. The aim of this study was to correlate blood glucose level in the patients with Coronary Artery Diseases with Acute Coronary Syndrome and to determine the relati onship of other risk factors. Methods: This was a cross-secti onal prospecti ve study of consecutive patients admitted in coronary care unit of Bir Hospital and Shaid Gangalal National Heart Center, with diagnosis of Acute Coronary Syndrome. Results: Total 209 patients were enrolled. 90.9% (190) had dyslipidemia, 78.5% were smokers with mean Standard Deviation of duration of smoking were 25.35 years. Abnormal waist to hip ratio in male and female are 56.3% and 76.1% respectively. 14.4 % (30) had Random Blood Glucose > 200mg%, 17.2 % had Impaired Fasting Glucose (110-126 mg% World Health Organizati on); 34.4% had Impaired Fasting Glucose (100-126 mg% American Diabeti c Associati on) 28.2% had Impaired Glucose Tolerance (postprandial blood glucose 140-200mg %).19.1% were old diabetes, 21.3% had recent diabetes mellitus, 52.7% had impaired glycemia.93.1% of total patients had Glucose Intolerance of any form. Conclusions: Almost all patients had diabetic or glucose intolerance of any form prior to coronary artery disease with acute coronary syndrome. This study consisted with Asian criteria of body mass index and Waist circumference for overweight or obesity. Medical Journal of Shree Birendra Hospital; Jan-June 2012/vol.11/Issue1/4-8 DOI: http://dx.doi.org/10.3126/mjsbh.v11i1.7758
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Antonietti, Alessandro, et Carlo Cipolli. « Pensiero, immagini mentali e creatività ; in diversi stati di vigilanza : il contributo della scuola di Marcello Cesa-Bianchi ». RICERCHE DI PSICOLOGIA, no 1 (mai 2021) : 45–64. http://dx.doi.org/10.3280/rip1-2021oa11597.
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Marcello Cesa-Bianchi ha svolto un ruolo importante nel favorire gli studi sperimentali degli psicologi italiani sulla funzione delle immagini visive all'interno del processo di pensiero creativo durante i diversi stati di vigilanza (veglia vigile, veglia rilassata, rêverie, addormentamento e sonno REM). Egli era partitodalla constatazione che la ricerca di soluzioni innovative per nuovi problemi artistici, scientifici o di vita quotidiana richiede una ricombinazione flessibile e creativa di alcune conoscenze pregresse. Questo articolo riporta le prove sperimentali a sostegno sia dell'assunto che le immagini mentali generate e trasformate intenzionalmente possono facilitare la soluzione dei problemi, sia delle successive ipotesisu come le strategie innovative e intuitive di manipolazione delle immagini mentali possano operare durante la veglia e altri stati di vigilanza. Dopo aver delineato sinteticamente i risultati degli studi in condizioni di veglia a sostegno di una stretta relazione tra la capacità di manipolare mentalmente le immagini in modo olistico e il pensiero creativo, vengono riportati i risultati di vari studi recenti i quali mostrano che l'intuizione (insight) che preannuncia la soluzione può avvenire durante il sonno così come nell'addormentamento, nella veglia rilassata e nella rêverie (mind wandering). Tutti questi stati di vigilanza favoriscono sia la diffusione dell'attivazione di nuclei di conoscenza episodica e semantica nelle reti associative (coinvolte anche nella produzione di sogni durante il sonno), sia la ristrutturazione della rappresentazione del problema attraverso il trasferimento di relazioni tra diversi tipi di informazioni. Soprattutto il sonno REM può funzionare come un periodo di incubazione in grado di aumentare i tassi di soluzione di compiti come la scoperta di regole matematiche nascoste e la risoluzione di anagrammi.Quasi tutti i risultati sperimentali confermano l'idea che un periodo di sonno – così come di veglia rilassata, rêverie o addormentamento – facilita la soluzione di problemi indipendentemente dalle loro caratteristiche artistiche, scientifiche o di vita quotidiana.
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Leirós-Rodríguez, Raquel, Vicente Romo-Pérez, Anxela Soto-Rodríguez et José L. García-Soidán. « Prevalencia de las limitaciones funcionales durante el envejecimiento en la población española y su relación con el índice de masa corporal (Prevalence of functional limitations during aging in a representative sample of Spanish population and its relati ». Retos, no 34 (1 février 2018) : 200–204. http://dx.doi.org/10.47197/retos.v0i34.58958.
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Objetivo: describir la prevalencia de las limitaciones funcionales y examinar las asociaciones entre IMC, edad, sexo y limitaciones funcionales. Material y Método: en este estudio transversal se emplearon los datos de 5.970 personas mayores de 65 años (rango de edad: 65-94 años) procedentes de la Encuesta Europea de Salud 2014 (EES14) realizados por el Instituto Nacional de Estadística y el Ministerio de Sanidad, Servicios Sociales e Igualdad del Gobierno español. Resultados: los datos mostraron que los hombres tenían una mejor percepción de sus limitaciones funcionales que las mujeres. En todas las variables analizadas, los hombres (sin importar la edad) reportaron menos limitaciones que las mujeres. El índice de masa corporal no obtuvo correlación significativa con el grado de limitación funcional en ninguna de las actividades evaluadas. Conclusiones: las mujeres de 75 años o más y los hombres a partir de los 85 años mostraron una gran dificultad para caminar, subir escaleras, agacharse y transportar cargas de peso medio. De hecho, la edad obtuvo correlaciones significativas con el grado de limitación funcional, al contrario que el índice de masa corporal.Abstract. Objective: to describe the prevalence of functional limitations and examine its association with BMI, age, and sex. Method: in this cross-sectional study, data from 5,970 people aged 65 and over (age range 65-94 years) was retrieved from the European Health Survey 2014 (EES14) conducted by the National Statistics Institute and the Ministry of Health, Services Social and Equality of the Spanish Government. Results: the data showed that men had a better perception of their functional limitations than women. In all variables analyzed, men (regardless of age) reported fewer limitations than women. Body mass index did not correlate significantly with the degree of functional limitation in any of the evaluated activities. Conclusions: women aged 75 years and over and men over 85 years of age showed great difficulty walking, climbing stairs, bending over, and carrying medium weight loads. In fact, age correlated significantly with the degree of functional limitation, unlike body mass index.
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Lorenzo, Guillermo, Jon S. Heiselman, Michael A. Liss, Michael I. Miga, Hector Gomez, Thomas E. Yankeelov, Thomas J. Hughes et Alessandro Reali. « Abstract 5064 : Patient-specific forecasting of prostate cancer growth during active surveillance using an imaging-informed mechanistic model ». Cancer Research 82, no 12_Supplement (15 juin 2022) : 5064. http://dx.doi.org/10.1158/1538-7445.am2022-5064.
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Abstract Active surveillance (AS) is a suitable management option for many newly-diagnosed prostate cancer (PCa) cases, which usually exhibit low to intermediate clinical risk. In AS, patients are closely monitored via multiparametric magnetic resonance imaging (mpMRI), prostate-specific antigen tests, and biopsies until these reveal an increase in PCa risk that warrants treatment. Thus, AS can contribute to reduce the current overtreatment of PCa and avoid treatment side-effects that may adversely impact patients’ lives without necessarily improving their longevity. However, current AS protocols rely on assessing PCa according to population-based studies, which complicates the design of personalized monitoring plans and the early detection of tumor progression. To address these issues, we propose to predict PCa growth using patient-specific forecasts based on an mpMRI-informed mechanistic model. Here, we present a preliminary study in a cohort of seven PCa patients who enrolled in AS and had three mpMRI scans over a period of 1.4 to 4.9 years. Our mechanistic model describes PCa growth in terms of tumor cell density dynamics, consisting of mobility and proliferation modeled via a diffusion process and a logistic law, respectively. We segment each patient’s prostate geometry on T2-weighted images and estimate tumor cell density from standard apparent diffusion coefficient (ADC) maps. To facilitate PCa modeling, we co-register each patient’s mpMRI datasets with a biomechanical elastic method that aligns the prostate segmentations across the imaging datasets. The model is initialized with the data from the first mpMRI scan. Model calibration relies on a nonlinear least-squares algorithm that minimizes the mismatch between ADC-measured and model-predicted tumor cell density at the second mpMRI date. For validation, we initialize the patient-specific calibrated model with the second mpMRI dataset and forecast PCa growth at the third mpMRI date, which we compare to the corresponding ADC-estimated tumor cell density. Model calibration resulted in a concordance correlation coefficient (CCC) > 0.99 for both tumor volume and global tumor cell count across the cohort. For each patient, the spatial fit of tumor cell density at the second scan date rendered a median Dice score and CCC of 0.79 and 0.52, respectively. Model validation resulted in CCCs of 0.88 and 0.81 for tumor volume and global tumor cell count across the cohort. Comparing the patient-specific ADC-estimated and model forecasts of tumor cell density at the third scan date, we obtained a median Dice score and CCC of 0.65 and 0.46, respectively. Thus, while improvement and further testing in larger cohorts are still needed, these results do suggest that our computational forecasting approach is a promising technology to predict the spatiotemporal growth of PCa during AS on a patient-specific basis. Citation Format: Guillermo Lorenzo, Jon S. Heiselman, Michael A. Liss, Michael I. Miga, Hector Gomez, Thomas E. Yankeelov, Thomas J. Hughes, Alessandro Reali. Patient-specific forecasting of prostate cancer growth during active surveillance using an imaging-informed mechanistic model [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 5064.
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Loghavi, Sanam, Courtney D. DiNardo, Koichi Takahashi, Rashmi Kanagal-Shamanna, Tomoyuki Tanaka, Ken Furudate, Nicholas J. Short et al. « Clonal Hematopoiesis and Its Implications for Flow Cytometric Assessment of Measurable Residual Disease in Patients with NPM1-mutated Acute Myeloid Leukemia ». Blood 136, Supplement 1 (5 novembre 2020) : 38–39. http://dx.doi.org/10.1182/blood-2020-139871.
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INTRODUCTION: NPM1 mutations (NPM1mut) occur in ∼30% of acute myeloid leukemia (AML) and frequently co-occur with mutations in other genes including those attributed to clonal hematopoiesis (CH) including DNMT3A and TET2, among others. CH mutations may persist beyond attaining NPM1mut-negative remission. Persistent CH may be associated with immunophenotypic alterations in myeloid progenitors detected by flow cytometry (FC) which poses an interpretive challenge in assessment of measurable residual disease (MRD) by FC. The aim of this study was to characterize the immunophenotypic alterations associated with persistent CH in the setting of NPM1mut clearance and to determine their possible clinical or biologic significance. METHODS: The cohort included 67 consecutive patients (pts) with NPM1mut AML treated at our institution between 01/2017 and 11/2019. FC assessment for MRD was performed an eight-color panel using FACSCanto II instruments (BD Biosciences, San Diego, CA) with a sensitivity of 10-3 to 10-4. Whole bone marrow (BM) DNA was interrogated for mutations with an 81-gene myeloid next-generation sequencing (NGS) panel using an Illumina MiSeq sequencer (Illumina, Inc., San Diego, CA, USA) with a sensitivity: 1% variant allelic frequency (VAF). RESULTS: Pts included 26 men and 41 women with a median age of 64 (range, 19-84) years with newly diagnosed NPM1mut AML. AML blasts had the following immunophenotype at baseline: promyelocytic-like phenotype (CD34-, CD117+, HLA-DR-) in 18 (27%), aberrant myeloid CD34-/CD117+/HLA-DR+ in 15 (22%), aberrant myeloid CD34+ in 13 (19%), myelomonocytic in 11 (16%), and monocytic in 10 (15%) cases. All pts had additional co-mutations at baseline (Fig 1). The most frequently co-mutated genes were DNMT3A (58%) FLT3 (51%), TET2 (27%), IDH2 (24%), PTPN11 (19%), IDH1 (18%), NRAS (16%), and SRSF2 (12%). Pts were treated with intensive (35;52%) and non-intensive induction regimens (32; 48%) (Fig 1); 22 (33%) received an allogeneic hematopoietic stem cell transplant as post-remission consolidation. We compared FC and NGS results in follow-up samples in pts achieving NPM1mut negative remission with adequate data available for comparison (n=50). 13 (26%) pts cleared all mutations whereas 37 (74%) had persistent CH. The most common mutations in the setting of residual CH involved DNMT3A (70%), TET2 (27%), IDH2 (19%) and IDH1 (11%). Among 37 pts with residual CH, 19 (51%) had no phenotypic alterations detected by FC while 17 (49%) had myeloid progenitors with alterations in intensity of antigen expression (increased CD13, CD123, CD117 and/or decreased CD38) or deviation from normal maturation but not diagnostic for AML MRD (herein referred to as pre-leukemic (PL) phenotype); 1 sample was MRD+ by FC. Mutation VAF of ≥5% was significantly more common (p=0.008) in cases with FC PL+ (100%) vs cases with normal FC phenotype (63%). IDH2 and SRSF2 mutation were exclusively observed in PL+CH+ cases with the former being statistically significant when compared with the FC-normal group (p=0.016). PL phenotype by FC did not correlate with intensity of induction therapy (41% treated with intensive regimens vs 59% non-intensive). The CH+/PL+ cohort had more pts ≥60 yrs old (67%) but the difference was not significant. There was no significant association between PL+ and residual mutation count. Presence of PL+ phenotype was not associated with a shorter relapse-free survival (RFS) (median not reached for both groups). CONCLUSIONS: Post-remission clonal hematopoiesis in the setting of NPM1mut clearance is common, and may result in immunophenotypic changes in myeloid progenitors, posing interpretive challenges for MRD assessment by FC. These alterations may be attributable to specific CH characteristics, such as IDH2 and SRSF2 mutations and VAF, but are not associated with a shorter RFS and thus should not be interpreted as residual AML or considered a high-risk attribute. Additional studies in other AML subtypes are warranted to further delineate these changes and their clinical significance. Figure 1 Disclosures DiNardo: Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Takeda: Honoraria; Jazz: Honoraria; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; MedImmune: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; Astellas: Research Funding. Kadia:JAZZ: Honoraria, Research Funding; Ascentage: Research Funding; Astra Zeneca: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Novartis: Honoraria; Cyclacel: Research Funding; Genentech: Honoraria, Research Funding; Amgen: Research Funding; Abbvie: Honoraria, Research Funding; Cellenkos: Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Konopleva:Sanofi: Research Funding; Eli Lilly: Research Funding; AstraZeneca: Research Funding; Rafael Pharmaceutical: Research Funding; Amgen: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Kisoji: Consultancy; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ascentage: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Cellectis: Research Funding; Agios: Research Funding; Ablynx: Research Funding. Kantarjian:Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria; Ascentage: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Ravandi:Macrogenics: Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding.
34
Muftuoglu, Muharrem, Li Li, Mahesh Basyal, Shaoheng Liang, Carissa J. Ball, Ken Chen, Prasanna Kumar, Arnaud Lesegretain, Naval Daver et Michael Andreeff. « Single-Cell Proteomics Identifies Leukemia Landscape Associated with Clinical Outcomes in R/R AML Treated with MDM2i (Milademetan) and FLT3i (Quizartinib) : Putative Role of CD68 and Diversity Index ». Blood 138, Supplement 1 (5 novembre 2021) : 3443. http://dx.doi.org/10.1182/blood-2021-154376.
Texte intégralRésumé :
Abstract Distinct mutations could differentially regulate cellular programs and alter the proteomic landscape in AML. Sequential acquisition of various mutations not only leads to clonal diversification but also alters the leukemia proteomic landscape through activation of mutation-specific gene programs. Characterization of AML proteomic profiles and diversity could be utilized as a measure of genetic imprint on leukemia proteome to inform clinical decision-making. We reasoned that diverse leukemia-specific proteomic profile could be indicative of the presence of multiple mutations activating numerous pathways, thus leading to a heterogenous clonal composition and more likely to therapy resistance. We aimed to test this hypothesis by assessing the proteomic profiles of FLT3-ITD AML patients treated with MDM2i (Milademetan) plus FLT3i (Quizartinib) (NCT03552029) and interrogate the association between proteomic landscape and therapy response. We assessed single-cell proteomic profiles of 35 sequentially collected samples for six selected patients treated with MDM2i+FLT3i using CyTOF, enabling us to assess expression of 51-parameters across leukemia compartments and identify leukemic clones with distinct proteomic profiles. Three patients achieved CRi while three patients did not respond. This allowed us to start interrogating proteomic signatures for their ability to predict response to therapy. We performed single-cell analysis and interrogated the phenotypic profiles of leukemia compartments to assess leukemia hierarchies, defined by spatial organization of leukemic subpopulations, and whether mutations in AML were associated with unique phenotypes. Notably, we found that NPM1-mutant (Mt) leukemia cells lacked CD34 expression, expressed high levels of CD99 and had patchy c-kit expression. Despite lacking a canonical marker, CD34, high-dimensional analysis positioned NPM1-Mt leukemia cells spatially in close proximity to CD34+ leukemia cells (NPM1 WT), indicating that NPM1 WT and Mt leukemia cells are closely related. CD34+ expressing cells most likely serve as the founding clone and acquisition of NPM1 mutation led to emergence of CD34- leukemia clones. As expected, all three patients who achieved CRi were NPM1-Mt and NPM1-Mt leukemia cells in CRi patients expressed CD68. Importantly, we also observed that CD68+ leukemia cells were eradicated in a NR patient where only a fraction of leukemia cells expressed CD68. This suggests that NPM1 mutations could activate unique cellular programs and induce distinct differentiation states (CD68), which could sensitize leukemia cells to MDM2+FLT3 inhibition. Altogether, NPM1 mutation status and CD68 expression level were associated with therapy response. Next, we mapped the response kinetics and quantified survived leukemia cells across multiple timepoints. Strikingly, MDM2i+FLT3i almost completely eliminated circulating blasts in responders (R) by day 8 while leukemia blasts persisted in NR (median blast %: 0.11 in R vs 19.8 in NR). This indicates that assessment of therapy response as early as day 8 could provide insights into the overall response and identify patients who will fail to achieve CR. Importantly, patients with reduced leukemia blasts at day 8 were also leukemia-free in BM at the end of cycle 1. Lastly, we sought to investigate the association between proteomic landscape diversity and therapy response, and quantified the number of leukemia subpopulations by unsupervised clustering. The median number of subpopulations detected in R vs NR at baseline were 3 and 9, respectively. We also utilized the inverse Simpson index to quantify the proteomic diversity of leukemia compartments and to further investigate the association between proteomic diversity and therapy outcome in an unbiased manner. The median diversity indices in R vs NR were 64 vs 212, revealing that patients with CR had restricted pre-treatment proteomic diversity. These findings suggest that a pre-treatment diverse phenotypic landscape could portend poor therapeutic outcome. Altogether, single-cell proteomic analysis identified correlates associated with overall clinical response in AML patients treated with MDM2i+FLT3i. Further validation is needed in a larger cohort of patients. Such approaches could be utilized in clinical-trial settings to predict therapy response with targeted agents and inform clinical decision-making. Disclosures Lesegretain: Daiichi-Sankyo Inc.: Current Employment. Daver: Amgen: Consultancy, Research Funding; Glycomimetics: Research Funding; Trovagene: Consultancy, Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Novimmune: Research Funding; ImmunoGen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Astellas: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Andreeff: AstraZeneca: Research Funding; Glycomimetics: Consultancy; Reata, Aptose, Eutropics, SentiBio; Chimerix, Oncolyze: Current holder of individual stocks in a privately-held company; Breast Cancer Research Foundation: Research Funding; Aptose: Consultancy; ONO Pharmaceuticals: Research Funding; Oxford Biomedica UK: Research Funding; Medicxi: Consultancy; Syndax: Consultancy; Karyopharm: Research Funding; Novartis, Cancer UK; Leukemia & Lymphoma Society (LLS), German Research Council; NCI-RDCRN (Rare Disease Clin Network), CLL Foundation; Novartis: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Research Funding; Senti-Bio: Consultancy; Amgen: Research Funding.
35
Maiti, Abhishek, Hagop M. Kantarjian, Guillermo Garcia-Manero, Marina Y. Konopleva, Srdan Verstovsek, Michael Andreeff, Gautam M. Borthakur et al. « Determinants of Outcomes of FLT3mut Acute Myeloid Leukemia with First Salvage Therapy ». Blood 134, Supplement_1 (13 novembre 2019) : 2641. http://dx.doi.org/10.1182/blood-2019-129621.
Texte intégralRésumé :
Background: Patients (pt) with relapsed or refractory acute myeloid leukemia (R/R AML) with FLT3mut have poor prognosis. FLT3 inhibitors (FLT3i) as single agent, and in combination improve outcomes in FLT3mut AML. However, recent clinical trials of FLT3i have had different inclusion criteria, and determinants of outcomes with FLT3i are not well known. Methods: We conducted a retrospective study to determine factors affecting outcomes in FLT3mut R/R AML with first salvage therapy. We reviewed medical records of R/R FLT3mut AML pts for data regarding prior therapy, salvage regimen and outcomes. Univariate analysis and multivariate Cox analysis were performed to evaluate the association of baseline covariates and outcomes. Evaluated baseline factors included ECOG PS, ELN cytogenetic risk group, FLT-ITD ratio, FLT3-D835 mutation, frontline therapy factors including intensive chemotherapy (IC), hypomethylating agent (HMA), or non-intensive chemotherapy (NIC)-based regimen, anthracycline use, FLT3i use, stem-cell transplantation (SCT), response to frontline therapy, salvage regimen related factors including IC vs. HMA vs NIC-based regimen, FLT3i use, SCT, AML mutations, etc. Efficacy endpoints of interest included CR/CRi per modified IWG criteria for AML, overall survival (OS) and duration of response (DOR). Results: Between June 2002 and July 2019 we identified 202 pts with R/R FLT3mut AML who received first salvage therapy at our institution with or without an FDA-approved or investigational FLT3i. The baseline characteristics are shown in Table 1 and treatment characteristics and outcomes are shown in Table 2. The median follow-up duration was 54 months (mo, 95% CI 46-89) and median OS 7.9 mo (95% CI 6.2-9.8). 53 out of 105 responding pts relapsed and median DOR was 3.6 mo (95% CI 2.7-5.8). Multivariate logistic regression analysis showed higher odds of achieving CR/CRi with salvage IC (OR 2.9), and IC+FLT3i (OR 8.1) compared to HMA, and RUNX1mut was associated with lower odds of achieving CR/CRi compared to RUNX1-WT (OR 0.06, Table 3). Single agent FLT3i as salvage therapy did not have significant association with CR/CRi or OS, as compared to HMA. Similarly, multivariate Cox model for analysis of factors associated with OS showed higher risk of death in pts who had received FLT3i in frontline setting (HR = 2.9) and pts with TET2mut (HR = 2.2, Table 4). Different salvage regimens of IC, NIC, HMA with or without FLT3i, and single agent FLT3i did not show survival benefit compared to HMA alone. Pairwise comparison between salvage regimens for OS censored at SCT (Fig. 1a-f) showed HMA improved OS compared to IC (median OS 10.2 vs 6.4 HR 0.64, 95% CI 0.36-0.99, p=0.046). Addition of FLT3i to HMA or IC did not yield significantly different OS compared to single agent FLT3i (Fig. 1 a-d). On univariate analysis, there was no significant difference in DOR between salvage HMA vs other salvage therapies including IC, NIC, single agent FLT3i, and IC with FLT3i. Covariates not associated with CR/CRi or OS on univariate analysis included ECOG PS, ELN cytogenetic risk group, frontline HMA or IC, prior anthracycline, prior SCT, response to prior regimen, FLT3-ITD ratio, FLT3-D835, and other recurrent AML mutations. Hence, these factors were not included in the multivariate models. Limitations of this study included retrospective nature and small sample sizes in subgroups. Conclusions: This multivariate analysis of a large cohort of R/R FLT3mut AML undergoing first salvage therapy showed association of RUNX1mut with lower odds of achieving CR/CRi, and frontline FLT3i use and TET2mut with worse OS. Both IC, and IC with FLT3i were associated with higher odds of achieving CR/CRi compared to HMAs. However, pairwise comparison of salvage regimens suggested improved OS with HMA compared to IC. Disclosures Maiti: Celgene: Other: research funding. Kantarjian:Astex: Research Funding; Takeda: Honoraria; BMS: Research Funding; Agios: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; Ariad: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Novartis: Research Funding. Garcia-Manero:Novartis: Research Funding; Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding; AbbVie: Research Funding. Konopleva:Ablynx: Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Amgen: Consultancy, Honoraria; Astra Zeneca: Research Funding; Agios: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Genentech: Honoraria, Research Funding. Verstovsek:Pharma Essentia: Research Funding; Celgene: Consultancy, Research Funding; Gilead: Research Funding; Promedior: Research Funding; CTI BioPharma Corp: Research Funding; Genetech: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Research Funding; Astrazeneca: Research Funding; Ital Pharma: Research Funding; Protaganist Therapeutics: Research Funding; Constellation: Consultancy; Pragmatist: Consultancy; Incyte: Research Funding; Roche: Research Funding; NS Pharma: Research Funding. Andreeff:AstaZeneca: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Eutropics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Aptose: Equity Ownership; Breast Cancer Research Foundation: Research Funding; NIH/NCI: Research Funding; CPRIT: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees. Borthakur:Strategia Therapeutics: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Incyte: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Cyclacel: Research Funding; Agensys: Research Funding; BMS: Research Funding; Bayer Healthcare AG: Research Funding; Janssen: Research Funding; AbbVie: Research Funding; Novartis: Research Funding; Cantargia AB: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy; GSK: Research Funding; Eisai: Research Funding; Merck: Research Funding; Arvinas: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; Eli Lilly and Co.: Research Funding; AstraZeneca: Research Funding; Oncoceutics, Inc.: Research Funding; PTC Therapeutics: Consultancy; Polaris: Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Celgene: Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Bioline RX: Research Funding. Daver:Abbvie: Consultancy, Research Funding; Agios: Consultancy; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Forty-Seven: Consultancy; Forty-Seven: Consultancy; Immunogen: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Astellas: Consultancy; Astellas: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz: Consultancy; Jazz: Consultancy; Servier: Research Funding; Servier: Research Funding; Karyopharm: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; NOHLA: Research Funding; NOHLA: Research Funding; Glycomimetics: Research Funding; Glycomimetics: Research Funding; Otsuka: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Celgene: Consultancy; Hanmi Pharm Co., Ltd.: Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Agios: Consultancy; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Pemmaraju:celgene: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; cellectis: Research Funding; incyte: Consultancy, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; sagerstrong: Research Funding; Daiichi-Sankyo: Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding. DiNardo:medimmune: Honoraria; agios: Consultancy, Honoraria; celgene: Consultancy, Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; jazz: Honoraria; syros: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Wierda:Miragen: Research Funding; Cyclcel: Research Funding; Gilead Sciences: Research Funding; Acerta Pharma Inc: Research Funding; Pharmacyclics LLC: Research Funding; Sunesis: Research Funding; GSK/Novartis: Research Funding; AbbVie: Research Funding; KITE pharma: Research Funding; Juno Therapeutics: Research Funding; Xencor: Research Funding; Janssen: Research Funding; Genentech: Research Funding; Loxo Oncology Inc.: Research Funding; Oncternal Therapeutics Inc.: Research Funding. Ravandi:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding; Xencor: Consultancy, Research Funding; Macrogenix: Consultancy, Research Funding; Selvita: Research Funding; Menarini Ricerche: Research Funding. Cortes:Biopath Holdings: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Merus: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; BiolineRx: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding.
36
Bucaram Levarone, Martha, Francisco Quinde Rosales, Joy Mayorga Ramos et Martha Bueno Quinonez. « Evaluation of the technical efficiency in the production of National Cocoa in the main cantons of the province of Guayas ». Universidad Ciencia y Tecnología 25, no 110 (24 août 2021) : 14–22. http://dx.doi.org/10.47460/uct.v25i110.471.
Texte intégralRésumé :
A comparative analysis of the technical efficiency in the production of national cocoa among the main producing cantons of the province of Guayas was carried out. For this, the study was based on an analysis with inductive reasoning and empirical-analytical paradigm, through the elaboration of surveys to 361 UPA's in the cantons of: Milagro, San Jacinto de Yaguachi, El Empalme, Alfredo Baquerizo Moreno, Naranjal and Simón Bolívar; these data served as the basis for the elaboration of the Data Envelopment Analysis (DEA) model. The results show that on average, the Simón Bolívar canton is the canton with the highest technical efficiency, with 50% of the total UPAs surveyed in the range of 70% and 99% effectiveness. Finally, regarding the observed averages of allocative efficiency, it can be concluded that Jujan has the highest average with 75%.
Keywords: Technical and Allocative Efficiency, National Cocoa, Enveloped Data Analysis, Non Parametric Method.
References
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37
Nishida, Yuki, Jo Ishizawa, Vivian Ruvolo et Michael Andreeff. « TP73 Isoforms (TAp73 and ΔNp73) Are Overexpressed in Acute Myeloid Leukemias and Potential Therapeutic Targets to Enhance Anti-Leukemia Activities of Bcl-2 and MDM2 Inhibitors ». Blood 132, Supplement 1 (29 novembre 2018) : 2629. http://dx.doi.org/10.1182/blood-2018-99-113900.
Texte intégralRésumé :
Abstract Background TP73 is one of the TP53 family transcription factors and generates two isoforms, the transactivation p73 (TAp73) and the N-terminally truncated ΔNp73. TAp73 shares a homologous N-terminal activation domain with p53 and has similar pro-apoptotic function to p53. ΔNp73 lacks an activation domain and has activities distinct from TAp73. ΔNp73 has a dominant negative effect on the DNA binding of TAp73 and more importantly, of p53, since the DNA binding domain is homologous with that of TAp73 and highly similar to that of p53. In acute myeloid leukemias (AML), TP73 has been reported to be expressed except in acute promyelocytic leukemias. However, the association of TP73 isoforms with clinical and genetic characteristics and the regulation of the isoforms in AML have not been explored. Results We determined copy numbers of ΔNp73 and TAp73 mRNA levels in 78 AML samples including 31 de novo AML using droplet digital PCR (ddPCR), which allows to determine the absolute quantity of the isoforms expressed, and investigated their clinical and biological relevance. ΔNp73 and TAp73 expression was detected in 93.6% and 98.7% of AML samples at variable levels (mean ± SEM, 10.6 ± 5.0, and 106.6 ± 33.7 copies/µL, for ΔNp73 and TAp73, respectively). ΔNp73 and TAp73 mRNA levels were highly correlated (R2 = 0.72, P < 0.0001). Normal peripheral blood mononuclear cells and CD34+ hematopoietic cells showed little or no ΔNp73 and TAp73 expression (0.09 ± 0.09 and 0.42 ± 0.35 copies/µL, respectively), demonstrating that expression of ΔNp73 and TAp73 is 100 - 1,000 fold higher in AML as compared to normal hematopoietic cells. These data collectively suggests that transcriptional systems of both isoforms in AML cells are abnormally activated. Disease status (de novo or relapsed/refractory) and cytogenetic abnormalities did not correlate with ΔNp73 and TAp73 levels. However, AML with IDH1/2 mutations had 8.5-fold lower ΔNp73 expression than those with wild-type IDH1/2 (1.8 ± 0.8 vs 15.4 ± 7.7 copies/µL, P = 0.0069), with a similar trend for TAp73 (49.0 ± 20.3 vs 138.6 ± 51.4 copies/µL, P = 0.056). For de novo AML samples, those with DNMT3a and NRAS mutations had significantly higher ΔNp73, but not TAp73, than those without these mutations (21.6 ± 18.2 vs 2.5 ± 1.2 copies/µL, P = 0.017 and 5.6 ± 2.5 vs 9.7 ± 8.0 copies/µL, P = 0.047, respectively). These findings suggest that ΔNp73 and TAp73 can be differentially regulated in AML based on mutation status. To further explore the regulation of TP73 isoforms, we used MDM2 inhibitor Nutlin-3a to induce p53 which is a transcriptional inducer of ΔNp73. Indeed, MDM2 inhibition increased p73 protein levels, and knockdown of both TAp73 and ΔNp73 in AML cells enhanced apoptosis induction by Nutlin-3a (specific annexin V induction by 5 uM Nutlin-3a, 21.9 ± 1.3% vs 61.3 ± 5.2%, P = 0.0084 in OCI-AML3 cells with vector control vs Shp73, respectively), possibly due to the silencing of ΔNp73. AML cells with IDH1/2 mutations are more dependent on Bcl-2 than those without (Chan, Nat Med 2015). Intriguingly, (R)-2HG, the oncometabolite of mutant IDH1/2, reduced both TAp73 and ΔNp73 in AML cells and increased susceptibility to the Bcl-2 inhibitor ABT-199. These results imply a potential mechanism that regulates p73 isoforms by histone methylation or other epigenetic modifications in AML. Conclusion Absolute quantitation of TP73 isoforms by ddPCR revealed high expression in AML cells compared to normal hematopoietic cells. The repressed expression of TP73 isoforms in AML cells with IDH1/2 mutations or by the oncometabolite (R)-2HG suggests that epigenetic modifications through (R)-2HG can regulate TP73 transcription and enhance the anti-leukemia effect by Bcl-2 inhibition. Finally, downregulation of TP73 isoforms enhances the efficacy of MDM2 inhibitor in AML, suggesting a potential therapeutic strategy to enhance MDM2 inhibitor-mediated p53 activation. Disclosures Andreeff: Amgen: Consultancy, Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Astra Zeneca: Research Funding; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; SentiBio: Equity Ownership; Reata: Equity Ownership; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding.
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Guerra, Veronica A., Yan Yuanqing, Joanne Hsu, Feng Wang, Mansour Alfayez, Kiyomi Morita, Xingzhi Song et al. « Comprehensive Analysis of Genotype and Prior Exposures in Therapy-Related Myeloid Neoplasms (t-MNs) ». Blood 134, Supplement_1 (13 novembre 2019) : 458. http://dx.doi.org/10.1182/blood-2019-127498.
Texte intégralRésumé :
Background: Therapy-related myeloid neoplasms (t-MNs) occur after exposures to chemotherapies and/or radiation therapies (CRT). However, true etiological association between CRT exposures and t-MN development is not clearly understood. We and others have recently revealed that selection of preleukemic mutant clones (TP53, PPM1D and others) under the selective pressure of CRT might play an important role in t-MN development (Wong et al. Nature 2014, Takahashi et al. Lancet Oncology 2017, Hsu et al. Cell Stem Cell 2018). For instance, PPM1D-mutated clone exhibited preferential expansion over wild-type clone only when exposed to cisplatin or etoposide, likely due to reduced apoptosis of mutant cells upon exposure to DNA damaging agents. In support of these findings, PPM1D-mutated t-MN patients had significantly frequent prior exposures to platinum and etoposide (Hsu et al. Cell Stem Cell 2018). These data led us to systematically analyze correlations between t-MN genotypes and prior exposures. Methods: We studied 471 patients (pts) with t-MNs (t-AML N = 188 and t-MDS N = 283) whose bone marrow or peripheral blood samples were analyzed by targeted next-generation sequencing. We performed extensive chart review to obtain history of prior exposures and analyzed correlation between CRT exposures and t-MN genotype. Results: Median age at diagnosis was 68 years (IQR:17-91) and the median latency from CRT exposures was 6 years (IQR: 0.1-45). (Table 1). The most frequent prior malignancies were breast cancer (20.8%), non-hodgkin's lymphoma (NHL) (20.3%) and prostate cancer (11.6%). Pts with NHL and multiple myeloma (MM) had significantly increased likelihood of developing t-MDS than t-AML (t-MDS vs. t-AML, 73.4% vs. 28.1%, P = .008 for NHL, 94.2% vs. 5.7%, P = < 0.001 for MM), whereas breast cancer pts developed t-AML more frequently than t-MDS (t-MDS vs. t-AML 43.8% vs. 56.1%, P < 0.001). Two hundred and eight (44.1%) pts had exposures to chemotherapy alone, 185 pts (39.2%) to chemo-radiotherapy, and 78 pts (16.5%) to radiotherapy alone. Eighty (16.9%) pts underwent autologous hematologic stem-cell transplant (auto-SCT). At least 1 driver mutation was detected in 392/471 (83.2%) t-MN pts and TP53 (36.3%), PPM1D (19.4%), TET2 (14.9%) and DNMT3A (14.6%%) were among the most frequently detected mutations. TP53 mutations were significantly more frequent in t-MDS than t-AML (43.8% vs. 25%; P=.000), while FLT3, NPM1, IDH1/2 mutations were more frequent in t-AML (14.9%, 7.4%, 9% respectively) than t-MDS (1.8%, 0%, 5.3%, 3.5% respectively) Correlation analysis of genotype and exposures confirmed previously known associations such as PPM1D mutations and platinum (log odds ratio [OR] 1.1, P = 0.01, false discovery rate [FDR] = 0.10), 11q23 rearrangement and topoisomerase II inhibitors (log OR 0.40, FDR = 0.71), and chromosome 7 abnormalities and alkylating agents (log OR 0.48, FDR =0.08). We found significant associations between TP53 mutations and immunomodulatory imide drugs (IMiDs, log OR = 0.98, , FDR =0.03); negative associations of alkylating agents with TET2 (log OR -0.93, FDR= 0.01) and NPM1 (log OR -3.31, FDR=0.003); and SRSF2 mutations with auto-SCT (log OR -2.24, FDR=0.03) and topoisomerase II inhibitors (log OR -2.42, FDR= 0.02). (Figure 1 Univariate analysis) We adjusted for the confounding effect from multiple exposures by multivariate logistic regression analysis (MLR) with modelbuilding by stepwise AIC or BIC selection criteria. MLR revealed a significant association of TP53 mutations with IMiDs (log OR = 1.07, P = 0.001), platinum (log OR = 0.61, P = 0.02), and vinca alkaloid (log OR = 0.62, P = 0.01). As well as a significant association between EZH2 mutations and vinca alkaloid (Log OR = 1.68, P = 0.009, Table 2). Conclusions: Comprehensive analysis of genotype and prior exposures in a large cohort of t-MNs revealed previously unknown associations, such as EZH2 mutations and vinka alkaloids, and TP53 mutations and IMiDs. The connection between TP53 mutations and IMiDs is consistent with the clonal selection of TP53 mutant clone with lenalidomide in 5q- syndrome (Jädersten et al. JCO 2011). These data provide a rationale for studying the mechanism of clonal selection of TP53-mutant or EZH2-mutant cells under IMiDs or vinka alkaloids. Further, this knowledge might be clinically useful for cancer pts with specific clonal hematopoiesis in reducing the risk of t-MNs by avoiding exposures to certain drugs. Disclosures DiNardo: notable labs: Membership on an entity's Board of Directors or advisory committees; agios: Consultancy, Honoraria; jazz: Honoraria; daiichi sankyo: Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; medimmune: Honoraria; syros: Honoraria. Konopleva:Eli Lilly: Research Funding; Ascentage: Research Funding; Forty-Seven: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Agios: Research Funding; Calithera: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; Astra Zeneca: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Ablynx: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Kisoji: Consultancy, Honoraria. Borthakur:Oncoceutics: Research Funding; Novartis: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Arvinas: Research Funding; Eli Lilly and Co.: Research Funding; GSK: Research Funding; Janssen: Research Funding; Incyte: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Cantargia AB: Research Funding; PTC Therapeutics: Consultancy; Tetralogic Pharmaceuticals: Research Funding; Eisai: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Bayer Healthcare AG: Research Funding; Polaris: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Oncoceutics, Inc.: Research Funding; Agensys: Research Funding; Strategia Therapeutics: Research Funding; Xbiotech USA: Research Funding; AstraZeneca: Research Funding; Cyclacel: Research Funding. Kantarjian:Pfizer: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Immunogen: Research Funding; Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Ariad: Research Funding; Astex: Research Funding; BMS: Research Funding; Agios: Honoraria, Research Funding; Novartis: Research Funding; Takeda: Honoraria; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Cyclacel: Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy.
39
Roman, Darwin, Hagop M. Kantarjian, Jorge E. Cortes, Gautam Borthakur, Guillermo Garcia-Manero, Marina Y. Konopleva, Courtney D. DiNardo et al. « Granulocyte Transfusions for Neutropenic Patients with Perirectal and Perineal Infections ». Blood 132, Supplement 1 (29 novembre 2018) : 2544. http://dx.doi.org/10.1182/blood-2018-99-117895.
Texte intégralRésumé :
Abstract Background: Granulocyte transfusions (GTX) in neutropenic patients (pts) have been used in an effort to treat infections not responding to antimicrobial therapy, but the efficacy and safety of GTX remains controversial. The objective of this study is to describe the outcome of pts with perirectal and perineal infections who received unirradiated GTX. Methods: We conducted a retrospective review of pts with hematological diseases with perirectal or perineal infections who received GTX between 2014 and 2018. Clinical response of infection was considered at 7 days if there was improvement in imaging studies, successful de-escalation to oral antimicrobials, or documentation of resolution on physical exam. The pre and post white blood cell count (WBC), absolute neutrophil count (ANC), and platelets (PLT) after GTX was assessed. A hematological response was defined as ANC >0.5x109/L, and sustained hematological response as ANC >0.5x109/L 48 hours after GTX. Statistical analysis was performed with SPSS. Paired sample t tests were used to compare pre and post GTX counts, and independent sample t tests were used to compare median ANC response between categorical variables. Pearson's correlation coefficient was used to analyze continuous variables. Overall survival was estimated by Kaplan-Meier and compared with log-rank. Granulocyte donors were relatives/friends of the pts and were mobilized using G-CSF and dexamethasone prior to apheresis. Results: 22 pts received a total of 148 GTX. Median number of GTX per patient was 4 (range 1-42). Median age of patient was 50 years (range 21-77). Seventeen pts had AML, 2 MDS, 2 ALL, and 1 had aplastic anemia. Six pts (27%) were in remission of their hematological disease at time of GTX. Median time from diagnosis of index infection to start of GTX was 7 days (range 1-24). Pts were receiving broad spectrum antibiotics including linezolid (9), meropenem (6), piperacillin tazobactam (5), ertapenem (4), and ceftazidime (4). Median number of antimicrobials per pt was 4 (range 2-5). Ten pts (45%) had clinical response of their infection at seven days post GTX. 20 pts (91%) achieved hematological response, all within 3 GTX, and 16 of them (73%) had sustained hematological response. All pts were able to resume chemotherapy. Median days from first GTX to next chemotherapy was 18.5. Difference between pre and post GTX WBC, ANC, and PLT were statistically significant (p<0.001). The median increase in WBC, ANC, and PLT was 0.20x109/L 0.26x109/L, and 3x109/L respectively. No association was found between gender (p=0.106), weight (p=0.169), age (p=0.616), number of GTX (p=0.133), or disease status (p=0.582) and median ANC increment. Day 7 clinical responders had a higher median ANC increment than those without response (1.349 vs 0.434, p=0.012), while no significant difference was found in mean number of GTX (p=0.073) or days to next chemotherapy (p=0.340). Disease status (p=0.069) or gender (p=0.746) did not predict day 7 response. There was no association between pts who held a 48-hr ANC response and day 7 response (p=0.489). Pts with sustained 48-hr response did not have a larger median ANC increment (p=0.068). Neither median ANC increment nor number of total GTX had a significant correlation with days to next chemotherapy (r -0.141 p=0.531, r 0.002 p=0.993). In 83 of the total 148 GTX (56%) ANC increased to >0.5x109/L. Day 7 responders did not have a higher percentage of successful transfusions than non-responders (p=0.236). All pts were alive 30 days after first GTX. 21 pts (96%) were alive at 90 days. With a median follow-up from the first GTX of 20.1 mo (3.77 to 40.6), 11 pts (50%) were still alive. Eleven pts have died, after a median of 33.57 weeks (14.29 to 161.57). There was trend for better 1 yr overall survival (OS) from time of first GTX for day 7 responders compared to non-responders (p=0.071). No serious adverse events were reported, including no transfusion association graft versus host disease, respiratory compromise, or anaphylaxis. Three pts had fever that was attributed to GTX and two had rash. Conclusion: Unirradiated GTXs were tolerated without any significant complications and successfully raised ANC in all pts with perirectal or perianal infections. This can translate to cost effectiveness and better quality of life in the form of decreased days of inpatient intravenous antibiotics and shorter hospital stays. Further, prospective studies are warranted to conform these results. Disclosures Cortes: Pfizer: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Arog: Research Funding. Konopleva:Stemline Therapeutics: Research Funding. DiNardo:Karyopharm: Honoraria; Medimmune: Honoraria; Abbvie: Honoraria; Agios: Consultancy; Celgene: Honoraria; Bayer: Honoraria. Daver:Pfizer: Consultancy; Daiichi-Sankyo: Research Funding; Sunesis: Consultancy; ARIAD: Research Funding; Karyopharm: Research Funding; Novartis: Consultancy; Incyte: Consultancy; Sunesis: Research Funding; Kiromic: Research Funding; Novartis: Research Funding; Alexion: Consultancy; Incyte: Research Funding; BMS: Research Funding; ImmunoGen: Consultancy; Karyopharm: Consultancy; Otsuka: Consultancy; Pfizer: Research Funding. Pemmaraju:Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Kadia:Novartis: Consultancy; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy; BMS: Research Funding; Jazz: Consultancy, Research Funding; Celgene: Research Funding; Abbvie: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Takeda: Consultancy; Amgen: Consultancy, Research Funding; BMS: Research Funding; Jazz: Consultancy, Research Funding; Celgene: Research Funding. Bose:Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; CTI BioPharma: Research Funding; Blueprint Medicines Corporation: Research Funding; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding. Andreeff:Amgen: Consultancy, Research Funding; Jazz Pharma: Consultancy; Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Reata: Equity Ownership; SentiBio: Equity Ownership; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Oncolyze: Equity Ownership; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Ravandi:Xencor: Research Funding; Seattle Genetics: Research Funding; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Sunesis: Honoraria; Xencor: Research Funding; Sunesis: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Macrogenix: Honoraria, Research Funding; Orsenix: Honoraria; Orsenix: Honoraria; Jazz: Honoraria; Abbvie: Research Funding; Jazz: Honoraria.
40
Guerra, Veronia, Jorge M. Ramos Perez, Danielle Hammond, Kelly S. Chien, Rashmi Kanagal-Shamanna, Kiran Naqvi, Koji Sasaki et al. « Outcomes of Chronic Myelomonocytic Leukemia (CMML) after Hypomethylating Agent (HMA) Failure ». Blood 136, Supplement 1 (5 novembre 2020) : 22–23. http://dx.doi.org/10.1182/blood-2020-139901.
Texte intégralRésumé :
Introduction: Hypomethylating agents (HMA) are effective therapies in chronic myelomonocytic leukemia (CMML), with an overall and complete (CR) response rates that range from 40-75% and 19-40% between studies, respectively. HMA therapy is associated with an overall survival (OS) of 12-24 months. However, the rate of HMA failure is 50% and is associated with a poor prognosis with an OS of 4-7 months. Defining predictors of HMA failure and optimal management of these patients (pts) is essential. Methods: We studied 157 pts with CMML treated with HMA between May 2010 and April 2020, whose bone marrow samples were analyzed by target next-generation sequencing. We performed chart review to obtain treatment responses and analyze correlations between clinical, cytogenetic and molecular characteristics and HMA failure. Primary objective was to determined risk factors associated with HMA failure. Secondary objectives include overall response rates (ORR) by 2015 IWG response criteria for MDS/MPN, overall survival (OS) and transformation-free survival (TFS) after HMA failure for CMML. Results: A total of 95 pts had HMA failure (61%), 59 pts (38%) with primary failure and 36 pts (23%) with secondary failure, with median time to HMA failure of 11 months (mo) (9 mo primary failure vs. 21 mo for secondary failure). Seventy-one pts (75%) were >65 years, and most pts were male (72%) with 16% having proliferative CMML (MP-CMML). Most patients had a normal karyotype (57%). Baseline characteristics are listed in Table 1. The most frequent mutations at diagnosis were TET2 (53%), SRSF2 (48%) and ASXL1 (46%). We analyzed the risk factors associated with HMA failure by logistic regression analysis. Univariate analysis (UVA) showed a significant association of ASXL1 mutation and HMA failure (Odds ratio OR 2.26, P value = 0.016). There was a tendency towards higher risk of failure in pts with MP-CMML (OR 1.57, p= 0.065) and SRSF2 mutation (OR 2.05, P=0.084) (Figure 1). The most common somatic mutations at HMA failure were ASXL1 (55%), SRSF2 (44%), TET2 (43%) and NRAS (32%) (Figure 2). Emergence of previously not detected mutations occurred in 59% of pts and included: NRAS (14%), ASXL1 (9%) and IDH1 (8%), with 18% of pts having cytogenetic evolution. IDH1 mutation was significantly associated with CMML blast transformation (Figure 2). The rate of CMML blast transformation after HMA failure was 14%. Of the 73 pts with CMML after HMA failure 45 received therapy and were eligible for response. Therapies included HMA single agent (47%), HMA combination therapy (ruxolitinib, rigosertib or ipilimumab) (24%), chemotherapy (13%) and other investigational therapies (16%). Pts with CMML blast transformation were included in AML protocols, with high-intensity chemotherapy (35%) or low-intensity therapies (65%). Among pts with CMML after HMA failure, the ORR was 16%, with 13% mCR and 2% HI and 13% progression to AML (Table 2). There was no difference in the ORR by therapy, or type of HMA failure with 16% with HMA single agent, 18% with HMA combination and 17% after chemotherapy, and ORR was 12% for primary failure and 21% for secondary failure. Of the 6 pts (13%) that underwent HSCT, no patient relapse and 1 pt died from infection 6 months after HSCT. A total of 40 pts died (55%), 12 pts from infections (30%), 4 pts progressive disease (10%), 3 pts due to other malignancies (8%) and 1 pt from bleeding (3%). With a median follow up of 20 months, the OS was 11 months for CMML and 5 mo for CMML blast transformation (p=0.002) (Figure 3 A). The OS after HMA failure was 23 mo for primary failure (23 mo for 1ry failure with lack of HI and 6 mo for 1ry failure with no response or progressive disease) and 6 mo for secondary failure (p= 0.120). Risk factors associated with worse OS by UVA included cytogenetic clonal evolution (Figure 3B), male gender, anemia, RUNX1 and TP53 mutations. Hematologic stem cell transplant was associated with improved OS (NR vs 6 months, HR 0.08, p=0.017). Conclusions: HMA failure occurs in 60% of pts with CMML and is associated with ASXL1 mutations. Emergence of mutations at progression are common (59%) and more frequently involve the RAS pathway, IDH1 and ASXL1 mutations. The rate of AML transformation in CMML with HMA therapy is 14%. HMA failure is associated with poor prognosis, with an OS of 11 months. Cytogenetic evolution, anemia, RUNX1 and TP53 mutations are associated with worse OS in pts whose disease experiences HMA failure. Disclosures Sasaki: Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding; Otsuka: Honoraria. Kadia:Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Cyclacel: Research Funding; Novartis: Honoraria; Astellas: Research Funding; Pulmotec: Research Funding; Cellenkos: Research Funding; Celgene: Research Funding; Amgen: Research Funding; JAZZ: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ascentage: Research Funding; Incyte: Research Funding; Astra Zeneca: Research Funding. DiNardo:Calithera: Research Funding; Novartis: Consultancy; ImmuneOnc: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Syros: Honoraria; Agios: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Honoraria. Konopleva:AstraZeneca: Research Funding; Ablynx: Research Funding; Amgen: Consultancy; AbbVie: Consultancy, Research Funding; Ascentage: Research Funding; Sanofi: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Forty-Seven: Consultancy, Research Funding; Eli Lilly: Research Funding; Rafael Pharmaceutical: Research Funding; Cellectis: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Agios: Research Funding; Calithera: Research Funding; Genentech: Consultancy, Research Funding; Kisoji: Consultancy. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: 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; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Ravandi:Astellas: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Pemmaraju:Plexxikon: Research Funding; AbbVie: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Cellectis: Research Funding; Blueprint Medicines: Honoraria; Celgene: Honoraria; Samus Therapeutics: Research Funding; DAVA Oncology: Honoraria; MustangBio: Honoraria; SagerStrong Foundation: Other: Grant Support; Affymetrix: Other: Grant Support, Research Funding; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Roche Diagnostics: Honoraria. Short:Amgen: Honoraria; AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding. Issa:Syndax: Research Funding; Celegene: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Kantarjian:Aptitute Health: Honoraria; Delta Fly: Honoraria; Ascentage: Research Funding; BioAscend: Honoraria; Janssen: Honoraria; BMS: Research Funding; Immunogen: Research Funding; Adaptive biotechnologies: Honoraria; Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Oxford Biomedical: Honoraria. Garcia-Manero:H3 Biomedicine: Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; Onconova: Research Funding; AbbVie: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Merck: Research Funding; Amphivena Therapeutics: Research Funding.
41
Montalban-Bravo, Guillermo, Rashmi Kanagal-Shamanna, Christopher B. Benton, Caleb Class, Kelly S. Chien, Koji Sasaki, Kiran Naqvi et al. « Genomic Context and TP53 Allele Frequency Define Prognostic Subgroups and Response Outcomes in TP53 Mutated Myelodysplastic Syndromes ». Blood 134, Supplement_1 (13 novembre 2019) : 1711. http://dx.doi.org/10.1182/blood-2019-124978.
Texte intégralRésumé :
INTRODUCTION: TP53 mutations are associated with adverse outcomes and shorter response to hypomethylating agents (HMA) in myelodysplastic syndromes (MDS). There is limited data evaluating the impact of the type, number, clonal size and patterns of TP53 mutations in response outcomes and prognosis. METHODS: We evaluated all patients with newly diagnosed myelodysplastic syndromes (MDS) treated at The University of Texas MD Anderson Cancer Center (MDACC) from 2013 to 2018. Genomic DNA was extracted from whole bone marrow aspirate samples and was subject to 28, 53 or 81-gene targeted PCR-based sequencing using a next generation sequencing (NGS) platform. Response assessment was performed following 2006 IWG criteria. The Kaplan-Meier product limit method was used to estimate survival outcomes for each clinical/demographic factor. Univariate Cox proportional hazards regression was used to identify any association with each of the variables and survival outcomes. RESULTS: 938 patients were evaluated including 261 (28%) with detectable TP53 mutations of which 189 (72%) received therapy: chemotherapy-based in 5 (3%) patients, single agent hypomethylating agents in 116 (61%) and hypomethylating agent in combination with novel agents in 65 (34%). Most (n=175, 67%) patients had one TP53 mutation with 75 (29%), 10 (4%) and 1 (0.4%) having 2, 3 and 4, respectively. TP53 dynamics on 18 patients with multiple TP53 mutations and longitudinal sequencing suggested both could present within the same clone in 8 (44%) patients. Median variant allele frequency (VAF) of all TP53 mutations was 39% (range 1-94%). TP53 deletion was more frequent in patients with mutated TP53 (31.8% vs 2.2%, p<0.001). Sixty-three patients (24%) suffered transformation to acute myeloid leukemia with a median transformation-free survival (TFS) of 10.6 months (95% CI 8.8-12.3). By univariate analysis the number of TP53 mutations (HR 2.03, 95% CI 1.3-3.05, p<0.001), TP53 mutation VAF (HR 1.02 increase per 1% VAF increase, 95% CI 1.01-1.02, p<0.001), TP53 deletion (HR 2.10, 95% CI 1.38-3.19, p<0.001) and complex karyotype (HR 2.58, 95% CI 1.70-3.91, p<0.001) were predictors of shorter TFS. By multivariate analysis only TP53 mutation VAF remained an independent predictor of shorter TFS (HR 1.02 increase per 1% VAF increase, 95% CI 1.00-1.03, p=0.005). With a median follow-up of 21.9 months (95% CI 20.3-25.6 months), there were no significant differences in ORR (58% vs 63%, p=0.303) or CR (27% vs 22%, p=0.288) based on the presence of TP53 mutation. Presence of TP53 deletion was associated with lower ORR (OR 0.53, p=0.021). Lower TP53 VAF correlated with higher ORR. Presence of TP53 abnormalities was associated with shorter response duration (HR 2.9, 95% CI 1.64-5.13, p<0.001). Longitudinal sequencing was available in 64 patients. TP53 VAF decreased more among responders (p=0.022) with subsequent increase of VAF at the time of relapse (Figure 1A). Presence of ³2 TP53 abnormalities was associated with shorter survival (HR 1.39, 95% CI 1.03-1.89, p=0.034, Figure 1B). TP53 VAF was associated with worse prognosis (HR 1.02 per 1% VAF increase, 95% CI 1.01-1.03, p<0.001). Patients could be classified into three prognostic groups based on TP53 VAF (Figure 1C). Integration of TP53 VAF and karyotypic complexity identified prognostic subgroups (Figure 1D). We developed a multivariable Cox model including TP53 VAF and IPSS-R categories with a corrected concordance index of 0.81 demonstrating a strong model fit. This model was used to generate a nomogram for overall survival (Figure 1E). CONCLUSION: This data suggests that the number and clonal size of TP53 mutations as well as other genomic events may help identify subgroups of patients with MDS with distinct prognosis and clinical outcomes. Figure 1 Disclosures Sasaki: Pfizer: Consultancy; Otsuka: Honoraria. Alvarado:Jazz Pharmaceuticals: Research Funding; Abbott: Honoraria. Kadia:Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Bioline RX: Research Funding; Celgene: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees. Ravandi:Selvita: Research Funding; Cyclacel LTD: Research Funding; Macrogenix: Consultancy, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Astellas Pharma: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Sun Pharma: Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding. Daver:Otsuka: Consultancy; Sunesis: Consultancy, Research Funding; Agios: Consultancy; Incyte: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Glycomimetics: Research Funding; Servier: Research Funding; BMS: Consultancy, Research Funding; Jazz: Consultancy; Abbvie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; NOHLA: Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Astellas: Consultancy; Immunogen: Consultancy, Research Funding; Celgene: Consultancy; Pfizer: Consultancy, Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:daiichi sankyo: Honoraria; agios: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; celgene: Consultancy, Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees; syros: Honoraria; medimmune: Honoraria; jazz: Honoraria. Jabbour:Takeda: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Cyclacel LTD: Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Borthakur:Novartis: Research Funding; Merck: Research Funding; Incyte: Research Funding; Eli Lilly and Co.: Research Funding; Janssen: Research Funding; Cantargia AB: Research Funding; Eisai: Research Funding; Agensys: Research Funding; Oncoceutics: Research Funding; Bayer Healthcare AG: Research Funding; NKarta: Consultancy; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xbiotech USA: Research Funding; Strategia Therapeutics: Research Funding; Tetralogic Pharmaceuticals: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Oncoceutics, Inc.: Research Funding; Arvinas: Research Funding; Polaris: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; GSK: Research Funding; Cyclacel: Research Funding; PTC Therapeutics: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding. Pemmaraju:cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Research Funding; plexxikon: Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; affymetrix: Research Funding; incyte: Consultancy, Research Funding; mustangbio: Consultancy, Research Funding; abbvie: Consultancy, Honoraria, Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria. Konopleva:Kisoji: Consultancy, Honoraria; Genentech: Honoraria, Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Ascentage: Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding. Bueso-Ramos:Incyte: Consultancy. Andreeff:BiolineRx: Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; AstaZeneca: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy. Kantarjian:Ariad: Research Funding; Amgen: Honoraria, Research Funding; Takeda: Honoraria; Daiichi-Sankyo: Research Funding; Agios: Honoraria, Research Funding; Astex: Research Funding; Jazz Pharma: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cyclacel: Research Funding; Novartis: Research Funding; Immunogen: Research Funding; AbbVie: Honoraria, Research Funding; BMS: Research Funding; Pfizer: Honoraria, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding.
42
Hammond, Danielle, Courtney D. DiNardo, Marina Konopleva, Gautam Borthakur, Jorge M. Ramos Perez, Veronica A. Guerra, Rashmi Kanagal-Shamanna et al. « Activity of Venetoclax-Based Therapy in CMML and CMML with Blast Transformation ». Blood 136, Supplement 1 (5 novembre 2020) : 36–37. http://dx.doi.org/10.1182/blood-2020-136385.
Texte intégralRésumé :
Introduction: There are no standard salvage options for patients (pts) with chronic myelomonocytic leukemia (CMML) after progressing on hypomethylating agents (HMA). Outcomes are especially poor after blast transformation (BT). Combination therapy with the BCL2 inhibitor venetoclax (VEN) has emerged as an efficacious treatment for pts with AML. To the best of our knowledge, the outcomes of VEN based therapies specifically in CMML, with or without BT, have not been reported. Methods: We retrospectively reviewed pts with CMML, both with and without BT, treated with VEN-based therapy at our institution from 2016 to present. Mutation testing at baseline (N=31) and loss of response was performed using an amplicon-based next-generation sequencing panel. Pts were stratified according to CPSS-Mol and whether VEN was given for chronic vs. transformed disease. Responses for CMML and CMML-BT were defined by IWG 2006 and ELN 2017 criteria, respectively. Cox proportional hazard regression and the Kaplan-Meir product limit method were used to study association of variables with survival. Overall survival was defined as the time from start of VEN therapy to death or last follow up and was not censored at date of transplant. Results: Thirty-two pts were identified: 17 CMML, 15 CMML-BT. Pt characteristics are shown in Figure 1A. The median age was 70 years in both groups; most pts were men with a PS of 0-1. The majority of pts treated for CMML had proliferative subtype (53%) and CPSS-Mol intermediate-2/high (76%) risk disease at diagnosis. Both groups were enriched for diploid karyotype (53 and 60%). Frequency of mutations prior VEN-based therapy are shown in Figure 1B; TET2 (71%), ASXL1 (55%), RUNX1 (45%), and NRAS (39%) were the most common. Forty-one percent (CMML) and 67% (BT) of pts had received ≥2 previous lines of therapy, and most (88% CMML, 87% BT) received VEN following HMA failure. The median per-cycle dosing of VEN was 100 mg x 14 days (CMML) and 200 mg x 21 days (BT). VEN was given in combination with HMA in 76% of the CMML group, whereas in the BT group it was partnered with HMA (47%), intensive chemotherapy (20%), or other agents (33%). Almost all pts were concurrently on a triazole antifungal. Forty-seven percent of pts in both groups required admission to hospital for infection and/or fever while on VEN. After a median of 1 (range 1-6 CMML, 1-16 BT) cycle in both groups, ORR was 59% (CR 0%, mCR 53%, PR 6%) in the CMML and 67% (CR/CRi 53%, MLFS 7%, PR 7%) in the BT group. Five out of the 7 pts in the BT group with CR/CRi responses and evaluable MRD by flow cytometry (sensitivity 0.01%) were MRD negative. Presence of a RAS pathway mutation was associated with lower likelihood of achieving CR (17% vs 83%, OR 5.5, 95% CI 0.92-33.2, p<0.001), NPM1 mutations with higher likelihood of CR (100% vs 14%, p=0.032) and RUNX1 with a trend to higher ORR (OR 4.13, 95% CI 0.84-29.28, p=0.081). Two pts had IDH mutations and both achieved CR. Thirty percent of responding pts in both groups were bridged directly to SCT. Four pts (24%) in the CMML group had leukemic transformation on VEN, all within the first 6 months on therapy. Excluding 1 outlier in the BT group, the median duration of response was 4.0 and 5.6 months in CMML and BT, respectively. Emergence of previously undetectable mutations at relapse on VEN occurred in 6 pts; half of these mutations involved the RAS pathway (Figure 1B). With a median follow-up of 10.9 and 23.4 months from initiation of VEN-based therapy, the median OS was 9.0 and 10.7 months in the CMML and BT groups, respectively (Figure 1C). Presence of RAS pathway mutations was associated with a trend to shorter survival among pts with BT (median OS 1 vs 14 months, p=0.059), but not in CMML (median OS 9.0 vs 3.5 months, p=0.076) (Figure 1D). Conclusions: Combination therapy with venetoclax has activity in both CMML and secondary AML arising out of CMML, even in the challenging setting of relapsed/refractory disease post HMA failure. It appears particularly useful as a means to clear excess marrow blasts and to serve as a bridge to allogeneic SCT. Without a subsequent consolidative strategy, however, response durations are short. RAS pathway mutations were associated with lower likelihood of CR and often emerge at relapse. NPM1 mutations predict for CR and RUNX1 mutations are associated with a trend to higher ORR. The high incidence of neutropenic infections in this cohort suggests that venetoclax dosing should be carefully tailored to minimize myelosuppression. Figure 1 Disclosures DiNardo: ImmuneOnc: Honoraria; Calithera: Research Funding; Novartis: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Takeda: Honoraria; Syros: Honoraria; Jazz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding. Konopleva:Amgen: Consultancy; Calithera: Research Funding; Rafael Pharmaceutical: Research Funding; Sanofi: Research Funding; Agios: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Stemline Therapeutics: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Kisoji: Consultancy; Cellectis: Research Funding; AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding; AstraZeneca: Research Funding; Ascentage: Research Funding; Eli Lilly: Research Funding. Borthakur:Treadwell Therapeutics: Consultancy; Polaris: Research Funding; Xbiotech USA: Research Funding; Nkarta Therapeutics: Consultancy; BioTherix: Consultancy; BioLine Rx: Consultancy; PTC Therapeutics: Consultancy; Argenx: Consultancy; FTC Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding. Sasaki:Otsuka: Honoraria; Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding; Pfizer Japan: Consultancy. Jabbour:Genentech: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding. Pemmaraju:Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding; DAVA Oncology: Honoraria; Celgene: Honoraria; Samus Therapeutics: Research Funding; Daiichi Sankyo: Research Funding; AbbVie: Honoraria, Research Funding; Plexxikon: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; LFB Biotechnologies: Honoraria; Cellectis: Research Funding; MustangBio: Honoraria; Pacylex Pharmaceuticals: Consultancy; SagerStrong Foundation: Other: Grant Support; Affymetrix: Other: Grant Support, Research Funding. Kadia:Pulmotec: Research Funding; Astra Zeneca: Research Funding; Cellenkos: Research Funding; BMS: Honoraria, Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Celgene: Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Cyclacel: Research Funding; Incyte: Research Funding. Ravandi:AstraZeneca: Consultancy, Honoraria; Macrogenics: Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding. Daver:Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: 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. Kantarjian:Janssen: Honoraria; Oxford Biomedical: Honoraria; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Delta Fly: Honoraria; BioAscend: Honoraria; Aptitute Health: Honoraria; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Amphivena Therapeutics: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Venetoclax for CMML
43
Montalban Bravo, Guillermo, Rashmi Kanagal-Shamanna, Koji Sasaki, Lucia Masarova, Kiran Naqvi, Elias Jabbour, Courtney D. DiNardo et al. « Clinicopathologic Correlates and Natural History of Atypical Chronic Myeloid Leukemia ». Blood 136, Supplement 1 (5 novembre 2020) : 54–56. http://dx.doi.org/10.1182/blood-2020-137176.
Texte intégralRésumé :
INTRODUCTION: Atypical chronic myeloid leukemia (aCML) is a rare subtype of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) associated with shorter survival and higher risk of transformation to acute myeloid leukemia (AML) than other MDS/MPNs. However, the clonal mechanisms underlying transformation to leukemia remain unclear. There is a need to develop predictive models and identify the optimal therapeutic management of these pts. METHODS: We evaluated all consecutive pts with aCML treated at the University of Texas MD Anderson Cancer Center from 2005 to 2020. Whole bone marrow (BM) DNA was subject to 28 or 81 gene targeted next-generation sequencing (NGS) analysis in a subset of pts. Variant allele frequency (VAF) estimates were used to evaluate clonal relationships within each sample using Pearson goodness-of-fit tests and VAF differences. Response to therapy was assessed following MDS/MPN IWG response criteria. Cox proportional hazards regression was used to study association of variables with survival. RESULTS: A total of 65 pts were identified. Median age was 67 years (range 46-89). Median WBC, Hgb and platelets were 44.5x109/L (5.9-474.9x109/L) 10.0g/dL (5.7-14.7g/dL) 93x109/L (12-560x109/L), respectively. Median neutrophil, promyelocyte, myelocyte and metamyelocyte percentages were 64%, 0%, 0% and 16%. Forty-one (63%) pts had normal karyotype, 5 (8%) trisomy 8, 2 (3%) i(17q) and 2 (3%) del(20q). Splenomegaly was observed in 26 (40%) pts and 7 (11%) had extramedullary disease. NGS data was available in 35 (54%) pts. The most frequently mutated genes included ASXL1 in 83%, SRSF2 in 68% and SETBP1 in 58%. Frequency and VAF of identified mutations is shown in Figure 1A. Mutations in SETBP1, SRSF2, TET2 and GATA2 tended to appear within dominant clones while other RAS pathway mutations were more likely to appear as minor clones. SRSF2 and SETBP1 tended to be co-dominant while ASXL1 appeared within minor clones in up to 50% of pts (Figure 1B). Therapy consisted of single agent hypomethylating agent (HMA) in 19 (29%), hydroxyurea in 8 (12%), HMA in combination with ruxolitinib in 7 (11%), other HMA combinations in 5 (8%), ruxolitinib single agent in 5 (8), induction chemotherapy in 3 (5%) and other investigational agents in 1 (2%) pts. Response outcomes by therapy are detailed in Figure 1C. With a median follow up of 35.6 months (95% CI 28.2-43.1) 18 (28%) of pts experienced transformation to AML within a median of 18 months (1-123 months). Median survival after transformation of 8.3 months (95% CI 5.5-11.0 months). NGS at the time of transformation was available in 12 (67%) pts with matched NGS at diagnosis of aCML and AML in 8 (44%) pts. Acquisition of new previously undetectable mutations was observed in 5 pts the most common involving signaling pathway mutations (Figure 1D). Acquisition of new cytogenetic abnormalities was observed in 9/14 pts (Figure 1D) the most frequent involving i(17q). The median OS was 25 months (95% CI 20.0-30.0) with pts who received intensive chemotherapy having significantly worse OS than those receiving HMA-based therapy or other agents such as ruxolitinib or hydroxyurea (p=0.012, Figure 1E). By multivariate analysis for survival, age, platelet count, BM blast percentage and serum LDH levels influenced prognosis. Based on these factors we developed a multivariable Cox model to generate a nomogram which assigned a score to each of the prognostic variables and allowed to predict 1-year and 3-year OS based on the total score among all prognostic variables (Figure 1F). CONCLUSIONS: aCML is characterized by high frequency of co-dominant SRSF2 and SETBP1 mutations. HMA therapy is associated with the best response outcomes. Clinicopathological features can help predict outcomes of these pts. Figure 1 Disclosures Sasaki: Daiichi Sankyo: Consultancy; Novartis: Consultancy, Research Funding; Pfizer Japan: Consultancy; Otsuka: Honoraria. Jabbour:Genentech: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding. DiNardo:Agios: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria; Novartis: Consultancy; MedImmune: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Konopleva:F. Hoffmann La-Roche: Consultancy, Research Funding; Ablynx: Research Funding; Eli Lilly: Research Funding; Kisoji: Consultancy; Sanofi: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Agios: Research Funding; Genentech: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; AbbVie: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Calithera: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Ascentage: Research Funding; Amgen: Consultancy; AstraZeneca: Research Funding; Cellectis: Research Funding. Pemmaraju:MustangBio: Honoraria; Incyte Corporation: Honoraria; Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Daiichi Sankyo: Research Funding; Affymetrix: Other: Grant Support, Research Funding; Plexxikon: Research Funding; Novartis: Honoraria, Research Funding; Samus Therapeutics: Research Funding; Cellectis: Research Funding; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria. Short:Takeda Oncology: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy; Amgen: Honoraria; Astellas: Research Funding. Issa:Novartis: Membership on an entity's Board of Directors or advisory committees; Syndax: Research Funding; Celegene: Research Funding. Kadia:Celgene: Research Funding; Abbvie: Honoraria, Research Funding; Novartis: Honoraria; Genentech: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Incyte: Research Funding; Cellenkos: Research Funding; BMS: Honoraria, Research Funding; Ascentage: Research Funding; Astra Zeneca: Research Funding; Cyclacel: Research Funding; Pulmotec: Research Funding; Astellas: Research Funding; JAZZ: Honoraria, Research Funding. Ravandi:Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: 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; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Borthakur:AstraZeneca: Research Funding; PTC Therapeutics: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Jannsen: Research Funding; Curio Science LLC: Consultancy; Novartis: Research Funding; Argenx: Consultancy; BioTherix: Consultancy; Polaris: Research Funding; BioLine Rx: Consultancy; Incyte: Research Funding; PTC Therapeutics: Research Funding; BioLine Rx: Research Funding; BMS: Research Funding; Cyclacel: Research Funding; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; FTC Therapeutics: Consultancy; Abbvie: Research Funding; GSK: Research Funding. Verstovsek:Gilead: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding; Genentech: Research Funding; Blueprint Medicines Corp: Research Funding; CTI Biopharma Corp: Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding; Novartis: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Promedior: Research Funding; Roche: Research Funding; Sierra Oncology: Consultancy, Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding. Kantarjian:Adaptive biotechnologies: Honoraria; Novartis: Honoraria, Research Funding; BioAscend: Honoraria; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Delta Fly: Honoraria; Janssen: Honoraria; Pfizer: Honoraria, Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Aptitute Health: Honoraria; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Oxford Biomedical: Honoraria. Bose:Blueprint Medicines Corporation: Honoraria, Research Funding; NS Pharma: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; CTI BioPharma: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Astellas Pharmaceuticals: Research Funding; Incyte Corporation: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer, Inc.: Research Funding; Constellation Pharmaceuticals: Research Funding; Promedior, Inc.: Research Funding. Garcia-Manero:Celgene: Consultancy, Honoraria, Research Funding; H3 Biomedicine: Research Funding; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Merck: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Amphivena Therapeutics: Research Funding.
44
Montalban-Bravo, Guillermo, Christopher B. Benton, Rashmi Kanagal-Shamanna, Koji Sasaki, Rita Assi, Tapan M. Kadia, Farhad Ravandi et al. « Landscape of TP53 Abnormalities and Their Clinical Relevance in Patients with Myelodysplastic Syndromes and Acute Myeloid Leukemia ». Blood 132, Supplement 1 (29 novembre 2018) : 2791. http://dx.doi.org/10.1182/blood-2018-99-119706.
Texte intégralRésumé :
Abstract INTRODUCTION: Mutations in TP53 can be detected in up to 16-19% patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). TP53 mutations confer adverse prognosis irrespective of currently available therapies. The clinical impact of the type, clonality and number of TP53 abnormalities is unclear. Preclinical data suggests some TP53 mutations may be associated with additional transactivation activity and increased oncogenicity. METHODS: We evaluated 1401 patients with previously untreated AML or MDS treated at The University of Texas MD Anderson Cancer Center from 2012 to 2016. Sequencing data was obtained by use of a 28 or 53-gene targeted PCR-based next generation sequencing platform. The following mutations in TP53 where defined as GOF based on available in vitro data: R172H, R175H, R270H, G245S, R248W, G248Q and R273H. Response was defined following 2003 IWG criteria for patients with AML and 2006 revised IWG criteria for patients with MDS. Generalized linear models were used to study the association of overall response (OR), complete response (CR) and risk factors. Kaplan-Meier produce limit method was used to estimate the median overall survival (OS). RESULTS: A total of 593 (42%) patients had MDS and 808 (56%) had AML. In a total of 984 (70%) patients, data on therapy with sufficient follow up and response evaluation was available, with 494 (35%) patients receiving therapy with hypomethylating agents (HMAs) and 373 (27%) with chemotherapy regimens. Among evaluated MDS pts, based on the Revised-IPSS prognostic model, 62 (11%) had very-low risk, 149 (25%) had low, 121 (20%) intermediate, 109 (18%) high and 152 (26%) very-high risk. A total of 167 (28%) pts with MDS and 223 (26%) pts with AML had complex karyotype. A total of 405 mutations in TP53 were detected among 151 (26%) and 161 (20%) patients with MDS and AML, respectively. Mutations included 332 (82%) missense, 26 (6%) nonsense, 34 (8%) frameshift insertions or deletions and 13 (3%) splice-site mutations. The most prevalent mutation was R273H (MDS: n=10, AML: n=9) followed by R248W (MDS: n=8, AML: n=8), Y220C (MDS: n=7, AML: n=8) and R175H (MDS: n=7, AML: n=6). Median variant allele frequency (VAF) of TP53 mutations was 39% (range 1-94). Among patients with TP53-mutant disease: 1 TP53 mutation was identified in 105 (70%) and 126 (78%) MDS and AML pts respectively, 2 in 44 (29%) and 34 (21%) and 3 in 2 (1%) and 1 (1%) respectively. The median difference in VAF among detectable mutations in pts with 2 TP53 mutations was 3.9% [95% CI 4.9-14%]. Among double TP53-mutant pts, known GOF mutations where always found in association with a LOF mutation with no pts having 2 detectable GOF mutations. Additionally, 66 (11%) MDS and 105 (13%) AML patients had TP53 deletions evidenced by presence of monosomy 17 or del(17p). Presence of a TP53 mutation was associated with loss of TP53 locus by cytogenetic abnormality (r=0.492, p<0.001). However, patients with multiple detectable TP53 mutations were less likely to have co-occurring chr17 abnormalities (79% vs 21%, OR 0.48, CI 0.29-0.81, p=0.01). Sequential bone marrow sequencing through the course of disease evolution was available in 75 pts. Dynamics of TP53 VAF at time or response and subsequent relapse in evaluable pts is shown in Figure A. Median follow up was 10.4 months (range 0-167 months) for MDS pts and 7.8 months (range 0-50) in AML pts. Presence of TP53 mutations with high VAF (defined as VAF > median VAF) was associated with significantly worse median OS (Figure B). Presence of more than 1 TP53 abnormality was not associated with worse OS, LFS or PFS in pts with MDS but predicted for shorter OS in pts with AML (Figure C). In addition, GOF were associated with worse OS than LOF mutations in pts with AML (Figure D), but not in MDS. Presence and number of TP53 mutations did not predict for response to HMAs. In addition, clearance of mutation at the time of response was associated with improved OS (HR 0.26, 95% CI 0.08-0.78, p=0.016). CONCLUSION: Presence of multiple TP53 abnormalities can be observed in up to 13% of patients with MDS or AML. The number of TP53 abnormalities does not seem to affect the survival of patients with MDS, but is associated with worse OS in AML. In addition, although GOF mutations do not seem to affect outcome of pts with MDS, these mutations were associated with worse OS than LOF in pts with AML. Clonal size of TP53 mutations as well as their clearance in therapy correlate with survival outcomes. Figure Figure. Disclosures Sasaki: Otsuka Pharmaceutical: Honoraria. Kadia:Jazz: Consultancy, Research Funding; Jazz: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Research Funding; Novartis: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Novartis: Consultancy; BMS: Research Funding; BMS: Research Funding; Celgene: Research Funding; Takeda: Consultancy. Ravandi:Astellas Pharmaceuticals: Consultancy, Honoraria; Abbvie: Research Funding; Jazz: Honoraria; Abbvie: Research Funding; Bristol-Myers Squibb: Research Funding; Jazz: Honoraria; Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Sunesis: Honoraria; Orsenix: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Xencor: Research Funding. Cortes:novartis: Research Funding. Daver:Novartis: Research Funding; Incyte: Consultancy; Karyopharm: Research Funding; Pfizer: Consultancy; ImmunoGen: Consultancy; Daiichi-Sankyo: Research Funding; Otsuka: Consultancy; BMS: Research Funding; Sunesis: Research Funding; Sunesis: Consultancy; Alexion: Consultancy; Novartis: Consultancy; Incyte: Research Funding; Kiromic: Research Funding; ARIAD: Research Funding; Karyopharm: Consultancy; Pfizer: Research Funding. DiNardo:Karyopharm: Honoraria; Medimmune: Honoraria; Bayer: Honoraria; Celgene: Honoraria; Agios: Consultancy; Abbvie: Honoraria. Jabbour:novartis: Research Funding. Pemmaraju:daiichi sankyo: Research Funding; samus: Research Funding; cellectis: Research Funding; abbvie: Research Funding; stemline: Consultancy, Honoraria, Research Funding; Affymetrix: Research Funding; novartis: Research Funding; plexxikon: Research Funding; celgene: Consultancy, Honoraria; SagerStrong Foundation: Research Funding. Konopleva:cellectis: Research Funding; Immunogen: Research Funding; Stemline Therapeutics: Research Funding; abbvie: Research Funding. Colla:Abbvie: Research Funding. Andreeff:Eutropics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Jazz Pharma: Consultancy; Aptose: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Consultancy, Patents & Royalties: MDM2 inhibitor activity patent, Research Funding; United Therapeutics: Patents & Royalties: GD2 inhibition in breast cancer ; Reata: Equity Ownership; Celgene: Consultancy; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Amgen: Consultancy, Research Funding; SentiBio: Equity Ownership.
45
Bruni, C., L. Chung, A. M. Hoffmann-Vold, S. Assassi, A. Gabrielli, D. Khanna, E. Bernstein et O. Distler. « AB0413 HIGH-RESOLUTION COMPUTED TOMOGRAPHY FOR THE SCREENING, RE-SCREENING AND FOLLOW-UP OF SYSTEMIC SCLEROSIS RELATED INTERSTITIAL LUNG DISEASE : RESULTS OF A EUSTAR-SCTC SURVEY ». Annals of the Rheumatic Diseases 80, Suppl 1 (19 mai 2021) : 1234.2–1235. http://dx.doi.org/10.1136/annrheumdis-2021-eular.849.
Texte intégralRésumé :
Background:High-resolution computed tomography (HRCT) is the gold standard diagnostic test for Interstitial lung disease (ILD), a significant cause of morbidity and mortality in systemic sclerosis (SSc). Different algorithms have been proposed for the screening of SSc-ILD, including the use of pulmonary function tests (Forced Vital Capacity - FVC, Lung Diffusion of Carbone Monoxyde - DLCO). A prior survey reported that 50-66% of general rheumatologists and SSc experts ordered HRCT for ILD screening in newly diagnosed SSc patients (1).Objectives:Given the recent availability of on-label treatment for SSc-ILD (2), the publication of consensus recommendations for the identification of SSc-ILD (3) and recent awareness programs for the use of HRCT to detect SSc-ILD, we aimed to re-evaluate the use of HRCT for screening, re-screening and follow-up of SSc-ILD.Methods:An invitation was sent to the European Scleroderma Trials and Research (EUSTAR) and Scleroderma Clinical Trials Consortium (SCTC) members, also advertised through social media. Answers were recorded between Nov 25th and Dec 31st 2020. Questions were asked on the use of chest HRCT at baseline, the re-screening of patients with a negative baseline HRCT and the follow-up of HRCT positive SSc-ILD patients. When HRCT was not routinely requested, additional details were collected about the parameters guiding its use. The results of the survey were tested for association with geographical origin, medical specialty, working environment, SSc referral institute and scientific group membership of the responders, using Chi-squared test.Results:205/630 (32.5%) physicians replied to the survey. Participants were widely distributed in terms of geographical origin (130 Europe, 23 Asia, 23 North America, 31 other continents), medical specialty (156 rheumatology, 21 internal medicine, 14 clinical immunology, 14 other), working environment (176 University Hospital, 12 community hospital, 17 other), SSc dedicated clinic (179 referral and 26 non-referral) and scientific group membership (98 EUSTAR, 42 SCTC, 42 EUSTAR and SCTC, 23 not declared).At SSc diagnosis, 95.7% of responders would perform HRCT: 66.7% as routine screening for ILD (67,4% of SSc referral and 62% for non-referral physicians) and 29% for diagnostic purposes (among the latter, if crackles on auscultation – 92.5%, FVC<80% predicted - 86.6%, FVC±DLCO relative decline reaching the current definition of ILD progression, 86.6% or dyspnea at rest/exercise - 85.1/83.3%).During follow-up, 78.8% of responders would repeat an HRCT in baseline negative cases: 20.3% as a yearly routine screening and 64.5% for diagnostic aims (decision on the latter group was more frequently driven by FVC±DLCO relative decline indicative of ILD progression– 90.6%, new onset or worsening of dyspnoea at rest/exercise – 80.5/86.6%, new onset or worsening of lung crackles on auscultation – 82.6%).Finally, 94.5% of responders would repeat a chest HRCT after SSc-ILD diagnosis: 36.8% as a yearly routine and 56.7% according to clinical evaluation (driven by new FVC±DLCO relative decline based ILD progression – 90.8%, new onset or worsening of dyspnoea at rest/exercise – 83.2/81.7%; 5.2% to evaluate treatment effects). We found no difference in the distribution of answers among groups.Conclusion:The use of baseline HRCT for the screening of SSc-ILD has slightly increased in non-referral and remained stable in referral centers compared to previous surveys, indicating that the implementation of guidelines might be successful and awareness programs should be continued. In addition, we provide new data on use of HRCT in re-screening and follow-up. The development of validated algorithms to further support the appropriate application of HRCT at follow-up is highly needed.References:[1]Bernstein EJ et al. Arthritis Rheumatol. 2018 Jun;70(6):971-972.[2]Distler O et al. N Engl J Med. 2019 Jun 27;380(26):2518-2528.[3]Hoffmann-Vold AM et al. The Lancet Rheumatology, Volume 2, Issue 2, e71 - e83.Disclosure of Interests:Cosimo Bruni Speakers bureau: Actelion, Consultant of: Eli Lilly, Grant/research support from: Foundation for Research in Rheumatology (FOREUM), Gruppo Italiano Lotta alla Sclerodermia (GILS), Fondazione Italiana per la Ricerca sull’Artrite (FIRA), New Horizon Fellowship, European Sclerodermia Trial and Reserach (EUSTAR) Group., Lorinda Chung Consultant of: Boehringer Ingelheim, Eicos, Mitsubishi Tanabe, Reata., Anna-Maria Hoffmann-Vold Consultant of: Actelion, ARXX therapeutics, Bayer, Boehringer-Ingelheim, Medscape, MSD, Lilly, Roche, Shervin Assassi Speakers bureau: Integrity Continuing Education, Consultant of: Boehringer Ingelheim, Novartis, and Corbus, Armando Gabrielli: None declared, Dinesh Khanna Consultant of: Acceleron, Actelion, Abbvie, Amgen, Bayer, Boehringer Ingelheim, CSL Behring, Corbus, Gilead, Galapagos, Genentech/Roche, GSK, Horizon, Merck, Mitsubishi Tanabe Pharma, Sanofi-Aventis, and United Therapeutics Leadership, Grant/research support from: NIH, Immune Tolerance Network, Bayer, BMS, Horizon, Pfizer, Employee of: Equity position – Chief Medical Officer, Eicos Sciences, Inc., Elana Bernstein Consultant of: Boehringer Ingelheim, Oliver Distler Consultant of: Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB., Grant/research support from: Abbvie, Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Baecon Discovery, Blade Therapeutics, Bayer, Boehringer Ingelheim, ChemomAb, Corbus Pharmaceuticals, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon (Curzion) Pharmaceuticals, Inventiva, iQvia, Italfarmaco, iQone, Kymera Therapeutics, Lilly, Medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Novartis, Pfizer, Roche, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB. Patent issued “mir-29 for the treatment of systemic sclerosis” (US8247389, EP2331143).
46
Mu-Mosley, Hong, Lauren B. Ostermann, Muharrem Muftuoglu, Wendy Schober, Nalini B. Patel, Abishek Vaidya, Challice L. Bonifant, Stephen Gottschalk, Mireya Paulina Velasquez et Michael Andreeff. « Transgenic Expression of IL15 in CD123-Specific BiTE-Secreting Engager T-Cells Results in Improved Anti-AML Activity ». Blood 134, Supplement_1 (13 novembre 2019) : 3917. http://dx.doi.org/10.1182/blood-2019-125928.
Texte intégralRésumé :
Background: CD123 is frequently expressed on hematologic malignancies including 96-98% of AML. CD123 has been a potential immunotherapeutic target in AML due to its association with leukemic stem cells that play an essential role in disease progression and relapse. Our previous study using T-cells secreting CD123/CD3-bispecific T-cell engagers (BiTEs) (CD123-ENG T-cells) showed a promising approach anti-AML activity, however T-cell persistence was limited. Interleukin-15 (IL15) has emerged as a candidate immunomodulator as it enhances T-cell expansion and persistence, and induces long-lasting memory T-cells. To improve the efficacy and persistence of CD123-ENG T-cells we developed IL15 expressing CD123-ENG T-cells. Here, we report on the characterization and efficacy of IL15-secreting CD123-ENG T cells in vitro and in vivo models of adult AML. Methods/Results: A cDNA encoding IL15 was cloned into retroviral vectors encoding CD123-ENG or CD19-ENG (CD123-ENG.IL15; CD19-ENG.IL15). ENG T-cells were generated from human peripheral blood mononuclear cells (PBMCs) from normal donors or T-cells from AML patients by retroviral transduction and in vitro expansion. Non-transduced (NT) T-cells and T-cells expressing CD123 (CD123-ENG T-cells) served as controls. IL15 production of CD19-ENG.IL15 and CD123-ENG.IL15 T cells was confirmed by ELISA (144-159 pg/ml vs 38 and 46 pg/ml of NT and CD123-ENG T cells, p<0.01, n=6). Both CD123-ENG and CD123-ENG.IL15 T-cells recognized CD123+ AML cells as judged by IL2 and interferon γ (IFNγ) production (p<0.01, n=5). In contrast, NT and CD19-ENG.IL15 T-cells did not, confirming specificity. In addition, CD123-ENG.IL15 and CD123-ENG T-cells induced killing of only CD123-positive target cells as well as of primary adult patients' AML blasts in luciferase- or 7AAD-based cytotoxicity assays (p<0.001, n=10). CD123-ENG.IL15 T-cells showed greater cytolytic activity than CD123-ENG T-cells as determined by luciferase activity (p=0.0002, n=3). In a Molm13 AML xenograft model, CD123-ENG.IL15 and CD123-ENG T-cells exhibited potent anti-leukemic activity as judged by bioluminescence imaging. Moreover, CD123-ENG.IL15 T cells had enhanced anti-leukemic activity and greater persistence in BMs, spleens, and livers in comparison to CD123-ENG T cells, resulting in improved anti-AML activity (Figure 1, p<0.01 vs CD123-ENG T-cell group, n=12 per group) and extended survival (Figure 2, p=0.0097 vs CD123-ENG T-cell group). Finally, AML PDX models and ENG T-cells were generated from AML blasts and T-cells from 3 patients with active AML. Infusion of autologous ENG T-cells (1.5x106 cells/mouse, n=7) in AML PDX#6697688 mouse model revealed significant reduction of leukemia burden in the CD123-ENG.IL15 or CD123-ENG T-cells mouse groups but not in the mouse group with NT or CD19-ENG.IL15 T-cells or PBS (p=0.004, n=6-8). We are currently monitoring survival of these PDX models. Conclusion: We here demonstrated that transgenic expression of IL15 in CD123-ENG T-cells results in improved expansion and persistence, and anti-AML activity. These results warrant further exploration of IL15-modified CD123-targeted T-cells as immunotherapy for AML. Disclosures Bonifant: Patents filed in the field of engineered cellular therapies: Patents & Royalties: Patents filed in the field of engineered cellular therapies. Gottschalk:EMD Serono: Honoraria; Inmatics: Membership on an entity's Board of Directors or advisory committees; ASSISI fundation of Memphis: Research Funding; TESSA Therapeutics: Other: Research Collaboration; ViraCyte: Consultancy; NHLBI: Research Funding; America Lebanese Syrian Associated Charities: Research Funding; California Institute for Regenerative Medicine: Research Funding; Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; MBIO: Other: St. Jude Children's Research Hospital has an existing exclusive license and ongoing partnership with Mustang Bio for the further clinical development and commercialization of this XSCID gene therapy; Sanofi: Honoraria; Tidal: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy. Velasquez:St. Jude: Patents & Royalties: Patent Applications in the Fields of Cell and Gene Therapy ; Rally! Foundation: Membership on an entity's Board of Directors or advisory committees. Andreeff:Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; AstaZeneca: Consultancy; Amgen: Consultancy; Eutropics: Equity Ownership; Aptose: Equity Ownership; Reata: Equity Ownership; 6 Dimensions Capital: Consultancy; Celgene: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; Cancer UK: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; BiolineRx: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; CPRIT: Research Funding; Oncoceutics: Equity Ownership; Oncolyze: Equity Ownership; Breast Cancer Research Foundation: Research Funding.
47
Rafei, Hind, Hagop M. Kantarjian, Koji Sasaki, Nicholas J. Short, Farhad Ravandi, Xuelin Huang, Joseph D. Khoury et al. « Impact of Cytogenetic Abnormalities (CA) on Outcome of Patients (Pts) with Relapsed/Refractory (R-R) Acute Lymphoblastic Leukemia (ALL) Treated with Inotuzumab Ozogamicin (INO) in Combination with Low-Intensity Chemotherapy (mini-hyper-CVD) with or without Blinatumomab : Results from a Phase 2 Study ». Blood 136, Supplement 1 (5 novembre 2020) : 45–47. http://dx.doi.org/10.1182/blood-2020-143401.
Texte intégralRésumé :
Background: The combination of INO with hyper-mini-CVD with or without blinatumomab offers a safe and effective treatment modality for pts with R-R ALL. However, the outcomes of some pts remain poor and the predictors of survival are not well understood. CA are frequently used as predictors of outcomes in leukemia. We present an exploratory analysis evaluating the relationship between baseline CA and outcome in pts with R-R ALL treated at our institution in a phase 2 study of INO in combination with mini-hyper-CVD with or without blinatumomab. Methods: Ninety-six pts with R-R ALL received low-intensity chemotherapy referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m2 x 4 doses). INO was given on Day 3 of each of the first 4 courses at 1.8-1.3 mg/m2 for course 1 followed by 1.3-1.0 mg/m2 for subsequent courses. From pt #68 onwards, INO was reduced and fractionated into biweekly doses (0.6 mg/m2 and 0.3 mg/m2 during course 1 and 0.3 mg/m2 and 0.3 mg/m2 during subsequent courses), and blinatumomab for up to 4 courses after INO therapy was added. By performing univariate and multivariate analyses of factors associated with survival, we identified 11q23 rearrangements and low hypodiploidy / near triploidy (Ho-Tr) as high-risk CA. Pts were categorized based on their CA as low-risk if they carry diploid, complex or other cytogenetics. Pts with 11q23 rearrangements and those with Ho-Tr were classified as having high-risk CA. Response rates and overall survival (OS) outcomes are compared between the two cytogenetic risk categories. Results: Pts characteristics are summarized in Table 1. Karyotype was diploid in 23 (24%) pts, complex in 12 (13%) pts, and other in 21 (22%) pts. Ten (10%) pts had Ho-Tr, 10 (10%) pts had KMT2A rearrangements, 3 (3%) pts had high hypertriploidy (HeH), 2 (2%) pts had near triploidy (Tt) and 15 (16%) pts had insufficient metaphases/ not determined karyotype. TP53 mutation was detected in a significantly higher proportion of pts with Ho-Tr (6 out of 7 tested pts or 86%) compared to pts with other cytogenetic abnormalities (10 out of 40 tested pts or 25%) (p=0.002). We performed univariate and multivariate analyses for the association of different cytogenetics with survival. By multivariate analysis, baseline cytogenetics independently associated with worse survival included Ho-Tr [HR= 18.262 (95% CI= 5.935-56.196); p<0.001], and KMT2A [HR= 3.744 (95% CI= 1.256-11.165); p=0.018]. Based on these findings, we stratified pts based on their CA into high-risk or low-risk disease. The overall response rate (ORR) was 73% in pts with high-risk CA compared to 82% in pts with low-risk CA (p=0.316). The complete remission (CR) rate was significantly higher in pts with low-risk CA compared to those with high-risk CA, 64% vs 36% (p=0.024). The rate of MRD negativity was numerically higher both at response as well as overall in the low-risk group compared to the high-risk group; 54% vs 44% and 86% vs 69%, respectively (Table 3). Four pts underwent allogeneic stem cell transplant (ASCT) in the high-risk group (17%), compared to 40 in the low risk group (55%) (p=0.003). At a median follow-up of 36 months, the median OS for pts with high-risk CA was 4 months compared to 23 months for pts with low-risk CA (p < 0.001) (Figure 1). The 3-year OS rates were 3% and 53%, respectively. Conclusion: Our analysis identified baseline KMT2A rearrangements and Ho-Tr as independent predictive of poor outcome in pts with R-R ALL treated with the combination therapy of INO with mini-hyper-CVD with or without blinatumomab. Pts with these poor-risk features should be considered for alternative strategies such as CAR T-cells therapies and clinical trials such as adding menin inhibitors to the regimen in pts with KMT2A rearrangement. Disclosures Rafei: United States Provisiona: Patents & Royalties: I have a filed patent. Kantarjian:BMS: Research Funding; AbbVie: Honoraria, Research Funding; Astex: Research Funding; Ariad: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Jazz Pharma: Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Research Funding; Takeda: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Research Funding; Agios: Honoraria, Research Funding. Sasaki:Novartis: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Otsuka: Honoraria; Pfizer Japan: Consultancy. Short:AstraZeneca: Consultancy; Takeda Oncology: Consultancy, Honoraria, Research Funding; Astellas: Research Funding; Amgen: Honoraria. Ravandi:Celgene: Consultancy, Honoraria; Macrogenics: Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Xencor: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Khouri:Bristol Myers Squibb: Research Funding; Pfizer: Research Funding. Kebriaei:Amgen: Other: Research Support; Novartis: Other: Served on advisory board; Ziopharm: Other: Research Support; Jazz: Consultancy; Pfizer: Other: Served on advisory board; Kite: Other: Served on advisory board. Jain:Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; Pfizer: Research Funding; Cellectis: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding. Verstovsek:Gilead: Research Funding; Genentech: Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; PharmaEssentia: Research Funding; AstraZeneca: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; Blueprint Medicines Corp: Research Funding; Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Celgene: Consultancy, Research Funding. Kadia:Pulmotec: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Novartis: Honoraria; Pfizer: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Cellenkos: Research Funding; Cyclacel: Research Funding; Incyte: Research Funding; Ascentage: Research Funding; Astellas: Research Funding; Amgen: Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding. Garcia-Manero:Onconova: Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Research Funding; Jazz Pharmaceuticals: Consultancy; H3 Biomedicine: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Merck: Research Funding. DiNardo:Takeda: Honoraria; Notable Labs: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; MedImmune: Honoraria; Syros: Honoraria; ImmuneOnc: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy; Agios: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Daver:Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: 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; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees. Yilmaz:Pfizer: Research Funding; Pint Pharma: Honoraria; Daicho Sankyo: Research Funding. Konopleva:Agios: Research Funding; Calithera: Research Funding; Ablynx: Research Funding; Eli Lilly: Research Funding; Kisoji: Consultancy; Amgen: Consultancy; Forty-Seven: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Rafael Pharmaceutical: Research Funding; Ascentage: Research Funding; Sanofi: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; AstraZeneca: Research Funding; Cellectis: Research Funding. O'Brien:Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc. Vaniam Group, AbbVie, Alexion, Verastem, Eisai, Juno Therapeutics, Vida Ventures: Consultancy; Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Consultancy, Research Funding; Kite, Regeneron, Acerta: Research Funding. Jabbour:BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; Pfizer: Other: Advisory role, Research Funding. OffLabel Disclosure: Blinatumomab and Inotuzumab as part of a clinical trial
48
Sasaki, Koji, Hagop M. Kantarjian, Elias Jabbour, Farhad Ravandi, Marina Y. Konopleva, Gautam M. Borthakur, William G. Wierda et al. « The Impact of Treatment Recommendation By Leukemia Artificial Intelligence Program (LEAP) on Survival in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) ». Blood 134, Supplement_1 (13 novembre 2019) : 1642. http://dx.doi.org/10.1182/blood-2019-130148.
Texte intégralRésumé :
INTRODUCTION: The survival of patients with chronic myeloid leukemia in chronic phase (CML-CP) is approaching that of general population after the approval of tyrosine-kinase inhibitors (TKI), particularly in younger patients who achieve remission. The optimal frontline TKI therapy in older patients in the context of comorbidity remains unknown. The aim of this study is to develop the LEukemia Artificial intelligence Program (LEAP) for treatment recommendations for patients with CML-CP. METHODS: From July 30, 2000 to November 25, 2014, 630 consecutive patients with newly diagnosed CML-CP were enrolled in frontline TKI therapy (imatinib 400 mg/day, imatinib 800 mg/day, nilotinib, dasatinib, and ponatinib). We included 101 social, demographic, clinical, chromosomal, and molecular variables such as the distance from home address to our institution, primary language, the European Treatment and Outcome Study (EUTOS) risk, the EUTOS long-term survival (ELTS) risk, and the severity of comorbidities by Adult Comorbidity Evaluation 27 (ACE-27). We developed an extreme gradient boosting decision tree model through ensemble learning after hyperparameter tuning. Hyperparameter optimization was calculated with Stampede2, a supercomputer located at Texas Advanced Computing Center, which was ranked as the 15th fastest supercomputer in June 2018. The extreme gradient boosting decision tree model was developed for the prediction of overall survival using only the training/validation cohort. We evaluated the final performance with the independent test cohort. A difference in hazard ratios of less than 0.005 between the best treatment option and alternative TKI therapy was considered as the LEAP recommendation. The test cohort was divided into the LEAP recommendation and the LEAP non-recommendation cohort by the LEAP recommendation. To confirm the association and causation of the LEAP recommendation with survival, we performed backward multivariate Cox regression, and inverse probability of treatment weighing (IPTW) to balance baseline difference of covariates. We calculated SHapley Additive exPlanations1 values to interpret the black box of the LEAP recommendation for the evaluation of the significance of variable for prediction. RESULTS: The whole cohort was randomly divided into a training/validation (N=504) cohort and a test cohort (N=126) at a 4:1 ratio (Figure 1). The training/validation cohort was used for 3-fold cross validation to develop the LEAP CML-CP model. The number of decision trees was 8417, 14659, and 14190 in the first, second, and third cross validation cohort, respectively (Figure 2). The accuracy of prediction at each iteration is shown in Supplemental Figure 1. The area under the curve (AUC) of the training in the first, second, and third cross validation cohort was 0.966, 0.978, and 0.977, respectively; the AUC of the validation in the first, second, and third cross validation cohort was 0.815, 0.832, and 0.742, respectively. The AUC in the test cohort was 0.819. We divided the test cohort (N=126) into the LEAP recommendation (N=94, 75%) and LEAP non-recommendation cohort (N=32, 25%) (Table 1). The LEAP did not recommend one particular TKI (P=0.128). Overall survival did not differ significantly by the type and dose of TKI (P=0.472) (Supplemental Figure 2). Patients in the LEAP recommendation cohort achieved higher rates of overall deep response (Table 2). In the test cohort, treatment consistent with the LEAP recommendation was associated with improved failure-free survival, transformation-free survival, event-free survival, and overall survival (P<0.001; P=0.002; P<0.001; P<0.001) (Figure 3). The median overall survival was 139 months (range, 3.7-216.1), and the median overall survival was 127 months and 148 months in the LEAP recommendation and LEAP non-recommendation cohorts, respectively (P=0.902). Backward multivariate Cox regression analysis and IPTW analysis confirmed the association and causation of improved OS with the LEAP recommendation, respectively (Supplemental Table 1; Supplemental Table 2). The SHAP values identified the presence and degrees of comorbidities and ELTS scores as top three importance for the prediction (Figure 4). Conclusion: The LEAP CML-CP recommendation improves overall survival in patients with CML-CP through higher tolerance, lower rates of progression, and higher rates of deep response. Disclosures Sasaki: Pfizer: Consultancy; Otsuka: Honoraria. Kantarjian:Jazz Pharma: Research Funding; Amgen: Honoraria, Research Funding; Cyclacel: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Takeda: Honoraria; BMS: Research Funding; Daiichi-Sankyo: Research Funding; Astex: Research Funding; Novartis: Research Funding; Immunogen: Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding. Ravandi:Cyclacel LTD: Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Macrogenix: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Xencor: Consultancy, Research Funding; Selvita: Research Funding. Konopleva:Agios: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Astra Zeneca: Research Funding; Ablynx: Research Funding; Amgen: Consultancy, Honoraria; Cellectis: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Eli Lilly: Research Funding; Forty-Seven: Consultancy, Honoraria; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Ascentage: Research Funding; Genentech: Honoraria, Research Funding; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding. Borthakur:AstraZeneca: Research Funding; Polaris: Research Funding; AbbVie: Research Funding; Incyte: Research Funding; Argenx: Membership on an entity's Board of Directors or advisory committees; NKarta: Consultancy; PTC Therapeutics: Consultancy; Oncoceutics, Inc.: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Merck: Research Funding; Eli Lilly and Co.: Research Funding; BioLine Rx: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Strategia Therapeutics: Research Funding; Arvinas: Research Funding; Janssen: Research Funding; BioTheryX: Membership on an entity's Board of Directors or advisory committees; Eisai: Research Funding; Xbiotech USA: Research Funding; Oncoceutics: Research Funding; Novartis: Research Funding; Bayer Healthcare AG: Research Funding; Agensys: Research Funding; FTC Therapeutics: Membership on an entity's Board of Directors or advisory committees; Cantargia AB: Research Funding; BMS: Research Funding; Tetralogic Pharmaceuticals: Research Funding. Wierda:Oncternal Therapeutics Inc.: Research Funding; Xencor: Research Funding; Cyclcel: Research Funding; Sunesis: Research Funding; GSK/Novartis: Research Funding; Miragen: Research Funding; KITE pharma: Research Funding; Loxo Oncology Inc.: Research Funding; Janssen: Research Funding; Juno Therapeutics: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Pharmacyclics LLC: Research Funding; Acerta Pharma Inc: Research Funding; Gilead Sciences: Research Funding. Takahashi:Symbio Pharmaceuticals: Consultancy. DiNardo:celgene: Consultancy, Honoraria; jazz: Honoraria; abbvie: Consultancy, Honoraria; agios: Consultancy, Honoraria; syros: Honoraria; medimmune: Honoraria; daiichi sankyo: Honoraria; notable labs: Membership on an entity's Board of Directors or advisory committees. Pemmaraju:plexxikon: Research Funding; novartis: Consultancy, Research Funding; celgene: Consultancy, Honoraria; cellectis: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; sagerstrong: Research Funding; incyte: Consultancy, Research Funding; affymetrix: Research Funding; mustangbio: Consultancy, Research Funding; samus: Research Funding; abbvie: Consultancy, Honoraria, Research Funding. Garcia-Manero:Amphivena: Consultancy, Research Funding; Helsinn: Research Funding; Novartis: Research Funding; AbbVie: Research Funding; Celgene: Consultancy, Research Funding; Astex: Consultancy, Research Funding; Onconova: Research Funding; H3 Biomedicine: Research Funding; Merck: Research Funding. Cortes:Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Astellas Pharma: Consultancy, Honoraria, Research Funding; Sun Pharma: Research Funding; Immunogen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Merus: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Forma Therapeutics: Consultancy, Honoraria, Research Funding; Biopath Holdings: Consultancy, Honoraria; BiolineRx: Consultancy.
49
Daver, Naval G., Jacqueline S. Garcia, Brian A. Jonas, Kevin R. Kelly, Sarit Assouline, Joseph M. Brandwein, Pierre Fenaux et al. « Updated Results from the Venetoclax (Ven) in Combination with Idasanutlin (Idasa) Arm of a Phase 1b Trial in Elderly Patients (Pts) with Relapsed or Refractory (R/R) AML Ineligible for Cytotoxic Chemotherapy ». Blood 134, Supplement_1 (13 novembre 2019) : 229. http://dx.doi.org/10.1182/blood-2019-123711.
Texte intégralRésumé :
Introduction: Elderly pts with R/R AML not eligible for cytotoxic therapy have limited therapeutic options, and dismal outcomes with available therapies. In preclinical studies, inhibition of BCL-2 and MDM2 with Ven and Idasa, respectively, has demonstrated potent synergistic apoptotic activity. In this ongoing, open-label, Phase Ib study, the safety, tolerability, and preliminary efficacy of Ven+cobimetinib (Arm A) and Ven+Idasa (Arm B) is being assessed in R/R AML (NCT02670044). Initial analysis indicated a tolerable safety profile for Ven+Idasa. Here, we present updated safety and efficacy results from Arm B. Methods: Pts (≥60 years) with R/R AML or secondary AML, previously treated for an antecedent hematologic disease but treatment naïve for AML, and ineligible for cytotoxic therapy/allogeneic stem cell transplant were enrolled. The maximum tolerated dose of Ven+Idasa was determined by two-dimensional dose escalation. Pts received Ven orally (PO) daily (400 or 600mg) + Idasa PO daily on Days (D) 1-5 (150mg, 200mg, or 400mg) in 28-day cycles. Responses were assessed according to revised International Working Group Response Criteria 2003. Pharmacokinetic (PK) analyses were performed on plasma samples on Cycles (C) 1 and 2, D1 and 5, and C4, D1. Exploratory assessments included minimal residual disease (MRD), assayed centrally at Covance Laboratories using 8-color flow cytometry. Data cut-off was June 21, 2019. Results: At data cut-off, 49 pts were treated with Ven+Idasa. Median age was 72 years (range 62-93); Eastern Cooperative Oncology Group performance status 0-1: 84%; refractory AML: 57%; relapsed AML: 33%; and secondary previously untreated AML: 10%; Intermediate-I or Intermediate-II European Leukemia Net (ELN) risk classification: 66%; adverse ELN classification: 30%; de novo (49%) versus secondary (51%) AML; and median prior lines of treatment: 1 (range 1-4). Most common adverse events (AEs; any grade) irrespective of attribution were diarrhea (90%) and nausea (78%); the most common grade ≥3 AEs were febrile neutropenia (45%), neutropenia (27%), and thrombocytopenia (25%; Table 1). Laboratory tumor lysis syndrome occurred in 3 pts; none resulted in treatment discontinuation. Ven and Idasa treatment discontinuation due to AEs were noted in 18% and 20%, respectively, most commonly due to infections. 30- and 60-day mortality rates were 6% and 17%, respectively. No apparent PK drug-drug interaction was found between Ven and Idasa; overlap in Ven and Idasa exposure was substantial over the doses tested. Anti-leukemic response rate (complete response [CR] + CR with incomplete platelet count recovery [CRp] + CR with incomplete blood count recovery [CRi] + partial response [PR] + morphologic leukemia-free state [MLFS]) across all dose levels was 41% (Table 2). Across the two Ven 600mg cohorts being considered for the recommended Phase II dose (RP2D), the anti-leukemic response rate was 50% (CR+CRp+CRi rate 29%). Median time to CR+CRp+CRi+PR was 1.4 months (range 1-3), with a median response (CR+CRp+CRi) duration of 4.9 months (range 0.6-9.7). Median overall survival in all pts and in the Ven 600mg cohorts was 4.4 months and 5.7 months, respectively, with a median follow-up of 3.4 months (range 0.03-18). Individual pt responses are shown in Figure 1. MRD negativity (<0.1%) was achieved in 45% (5/11) of pts with CR+CRp+CRi. Updated pre- and post-therapy mutation and BCL-2 family protein data and association with clinical response will be presented. Conclusions: The non-chemotherapy combination of Ven+Idasa demonstrated encouraging safety and efficacy in elderly pts with R/R AML who were ineligible for cytotoxic chemotherapy. The anti-leukemic response rate at the dose levels being considered for the RP2D was 50%, with a CR+CRp+CRi rate of 29%. Updated predictive biomarker data will be presented. Evaluation of Ven+Idasa RP2D is ongoing, and will be followed by dose expansion. Disclosures Daver: Otsuka: Consultancy; NOHLA: Research Funding; Jazz: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Astellas: Consultancy; BMS: Consultancy, Research Funding; Immunogen: Consultancy, Research Funding; Forty-Seven: Consultancy; Novartis: Consultancy, Research Funding; Agios: Consultancy; Abbvie: Consultancy, Research Funding; Celgene: Consultancy; Pfizer: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Hanmi Pharm Co., Ltd.: Research Funding; Genentech: Consultancy, Research Funding; Glycomimetics: Research Funding; Servier: Research Funding; Incyte: Consultancy, Research Funding. Garcia:Abbvie: Research Funding; Genentech: Research Funding. Jonas:AbbVie, Amgen, Celgene, GlycoMimetics, Jazz, Pharmacyclics, Tolero: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie, Accelerated Medical Diagnostics, AROG, Celgene, Daiichi Sankyo, Esanex, Forma, Genentech/Roche, GlycoMimetics, Incyte, LP Therapeutics, Pharmacyclics: Research Funding; AbbVie, Amgen, GlycoMimetics: Other: Travel expenses. Kelly:Novartis, Bayer, Janssen, Pharmacyclics, Celgene, Astrazeneca, Seattle Genetics: Honoraria, Speakers Bureau; Takeda: Research Funding; Genentech, Verastem: Consultancy. Assouline:Janssen: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria. Brandwein:Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharma: Consultancy, Honoraria; Otsuka: Honoraria; Roche: Research Funding; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding. Fenaux:Celgene Corporation: Honoraria, Research Funding; Astex: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Aprea: Research Funding. Olin:Ignyta: Research Funding; Clovis: Research Funding; Spectrum: Research Funding; Revolution Medicine: Consultancy; Jazz Pharmaceuticals: Consultancy, Honoraria; Pfizer: Research Funding; Genentech: Consultancy, Research Funding; Daiichi Sankyo: Research Funding; Astellas: Research Funding; Novartis: Research Funding; Mirati Therapeutics: Research Funding; MedImmune: Research Funding; AstraZeneca: Research Funding. Martinelli:Amgen: Consultancy, Other: trial grant; Ariad: Consultancy, Other: trial grant; Incyte: Consultancy, Other: trial grant; Pfizer: Consultancy, Other: trial grant; Roche: Consultancy, Other: trial grant; Celgene: Consultancy, Honoraria, Other: trial grant; Janssen: Consultancy, Other: trial grant; Abbvie: Consultancy, Honoraria, Other: trial grant; Novartis: Consultancy, Other: trial grant; Daiichi Sankyo: Consultancy, Honoraria. Pigneux:Novartis: Honoraria; Roche: Honoraria; Pfizer: Honoraria; F. Hoffmann-La Roche Ltd: Honoraria; Astellas: Honoraria; Daichi: Honoraria; Abbvie: Honoraria; Jazz: Honoraria; Amgen: Honoraria. Pollyea:Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: 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; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees. Powell:Rafael Pharmaceuticals: Consultancy, Research Funding; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Research Funding. Roboz:Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: 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; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Tafuri:Celgene: Research Funding; Novartis: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Yee:Agensys, Astex, Hoffman La Roche, MedImmune, Merck, Millenium, Roche/Genentech: Research Funding; Novartis, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas, Celgene, Otsuka, Shire, Takeda: Membership on an entity's Board of Directors or advisory committees. Dail:Genentech: Employment, Equity Ownership. Green:Genentech Inc.: Employment. Kirschbrown:Genentech, Inc.: Employment; F. Hoffman La Roche, Ltd.: Equity Ownership. Hong:Roche: Equity Ownership; Genentech Inc.: Employment, Equity Ownership. Ott:Roche: Employment, Equity Ownership. Onishi:Genentech, Inc.: Employment. Wang:Genentech, Inc.: Employment; Roche: Equity Ownership. Konopleva:Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Ascentage: Research Funding; Kisoji: Consultancy, Honoraria; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Ablynx: Research Funding; Astra Zeneca: Research Funding; Agios: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Calithera: Research Funding. Andreeff:Daiichi Sankyo, Inc.: Consultancy, Patents & Royalties: Patents licensed, royalty bearing, Research Funding; CLL Foundation: Membership on an entity's Board of Directors or advisory committees; NCI-RDCRN (Rare Disease Cliln Network): Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Membership on an entity's Board of Directors or advisory committees; German Research Council: Membership on an entity's Board of Directors or advisory committees; NCI-CTEP: Membership on an entity's Board of Directors or advisory committees; Cancer UK: Membership on an entity's Board of Directors or advisory committees; Center for Drug Research & Development: Membership on an entity's Board of Directors or advisory committees; NIH/NCI: Research Funding; CPRIT: Research Funding; Breast Cancer Research Foundation: Research Funding; Oncolyze: Equity Ownership; Oncoceutics: Equity Ownership; Senti Bio: Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Eutropics: Equity Ownership; Aptose: Equity Ownership; BiolineRx: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Consultancy; Celgene: Consultancy; Amgen: Consultancy; AstaZeneca: Consultancy; 6 Dimensions Capital: Consultancy; Reata: Equity Ownership. OffLabel Disclosure: Venetoclax (VEN; ABT-199/GDC-0199) is a highly selective, potent, oral B-cell lymphoma-2 (BCL-2) inhibitor. Idasanutlin (idasa; RG7388) is an orally available, small molecule antagonist of MDM2 (mouse double minute; Mdm2 p53 binding protein homolog).
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Reville, Patrick K., Graciela M. Nogueras González, Farhad Ravandi, Koji Sasaki, Gautam Borthakur, Guillermo Garcia-Manero, Naval Daver et al. « Predictors of Early Mortality, Response, and Survival in Newly Diagnosed Acute Myeloid Leukemia (AML) Using a Contemporary Academic Cohort ». Blood 136, Supplement 1 (5 novembre 2020) : 44–45. http://dx.doi.org/10.1182/blood-2020-141837.
Texte intégralRésumé :
Background Recent advances have led to higher response rates and improved survival in patients with newly diagnosed AML. However, early death, lack of response, and long term leukemia-free survival remain important challenges. Early mortality in AML has been reported to be as high as 20-30%. Similar to relapse risk, disease related factors (along with patient and treatment factors) may also contribute significantly to early mortality. Here we investigated predictors of early (4- and 8-week) mortality, response, relapse-free survival, and overall survival in a contemporary cohort from a single large academic medical center. Methods We analyzed all newly diagnosed patients with AML presenting to and treated at our institution from January 2012 to January 2020. For 4- and 8-week mortality and overall response rate (CR/CRi), logistic regression models were generated to identify factors associated with these outcomes. Kaplan-Meier methods were used to determine the median of the time to event outcomes. Cox proportional hazards modelswere used to identify any association with each of the variables and survival outcomes. Multivariate models were performed for all the outcomes, the models included variables with p<0.25 in the univariate analysis. Backward elimination methods were used to determine a final multivariate models for each outcome. Results Our cohort included 1576 consecutive patients (pts) with newly diagnosed AML with a median follow-up of 11 months (range 0 - 96). The median age is 66 (range: 17 - 94), with 66% of pts being ≥ 60 years (yrs) old. By 2017 ELN risk classification, 44% were classified as adverse, 31% intermediate, and 25% were favorable risk. To simplify induction regimens, we classified patients as receiving intensive (high dose Ara-C based), low intensity, and low intensity with venetoclax. 44% received intensive, 42% received low intensity, and 14% received low intensity with venetoclax therapy. The 4- and 8-week mortality rates were 5% and 11%, respectively. Among pts < 60 yrs the 4- and 8 week mortality rates were 3% and 5%, respectively; while those rates in pts ≥ 60 yrs were 6% and 14%, respectively. In the final reduced models the following factors are associated with both increased 4- and 8-week mortality: elevated baseline total bilirubin, age ≥ 60, and ELN intermediate and adverse risk classifications, when compared to ELN favorable. Elevated baseline WBC and bone marrow blasts were associated with 8-week but not 4-week mortality. Baseline platelet count ≥ 8k/µL was associated with reduced 4 and 8-week mortality. Among 97 pts who died between 4 and 8 weeks 87 patients (90%) had active disease or no response to their initial therapy, suggesting disease refractoriness as an important contributor to early death. The factors associated with decreased CR/CRi were increased baseline peripheral blasts, total bilirubin, serum creatinine, age ≥ 60, and ELN risk classifications when compared to favorable risk disease. Treatment with low intensity plus venetoclax and intensive therapy were associated with increased CR/CRi rates as was baseline platelet count ≥ 8k/µL. Median relapse-free survival for the cohort is 8 months (95% CI: 7- 9). Median overall survival for the cohort is 13 months (95% CI: 12- 14), with median OS for those ≥ 60 yrs: 10months (95%CI: 9- 11) and those < 60 yrs: 37months (95%CI: 24- 67). Factors associated with increased hazard of both relapse and death were increased baseline total bilirubin, creatinine, age ≥ 60, and ELN risk classifications when compared favorable disease. Factors associated with decreased hazard of both relapse and death were treatment with low intensity plus venetoclax and intensive therapy when compared to low intensity, and baseline hemoglobin ≥ 9 g/dl and platelet count ≥ 8k/µL. Conclusion In this study, using a contemporary cohort of consecutive, unselected AML patients, we identified parameters associated with early mortality, response, relapse-free, and overall survival. Compared to published historical data, patients at a high-volume academic center experienced lower early mortality and favorable long term outcomes. We identify both patient (i.e. baseline organ dysfunction) and disease (i.e. ELN risk) intrinsic characteristics that have a significant impact clinical outcomes in patients with AML. Further analysis including the impact mutational groups outside of ELN and treatment on or off investigational trials will be presented. Disclosures Ravandi: Xencor: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; BMS: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Sasaki:Novartis: Consultancy, Research Funding; Pfizer Japan: Consultancy; Otsuka: Honoraria; Daiichi Sankyo: Consultancy. Borthakur:FTC Therapeutics: Consultancy; BioLine Rx: Consultancy; BioTherix: Consultancy; Nkarta Therapeutics: Consultancy; Treadwell Therapeutics: Consultancy; Curio Science LLC: Consultancy; Oncoceutics: Research Funding; Xbiotech USA: Research Funding; Polaris: Research Funding; AstraZeneca: Research Funding; BMS: Research Funding; BioLine Rx: Research Funding; Cyclacel: Research Funding; GSK: Research Funding; Jannsen: Research Funding; Abbvie: Research Funding; Novartis: Research Funding; Incyte: Research Funding; PTC Therapeutics: Research Funding; PTC Therapeutics: Consultancy; Argenx: Consultancy. Garcia-Manero:Bristol-Myers Squibb: Consultancy, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onconova: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amphivena Therapeutics: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Merck: Research Funding. Daver:Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: 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; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. DiNardo:Novartis: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Jazz: Honoraria; ImmuneOnc: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Syros: Honoraria; MedImmune: Honoraria; Takeda: Honoraria; Calithera: Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees. Jabbour:Pfizer: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding. Pemmaraju:AbbVie: Honoraria, Research Funding; Incyte Corporation: Honoraria; Novartis: Honoraria, Research Funding; MustangBio: Honoraria; Daiichi Sankyo: Research Funding; SagerStrong Foundation: Other: Grant Support; DAVA Oncology: Honoraria; Cellectis: Research Funding; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; LFB Biotechnologies: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Blueprint Medicines: Honoraria; Roche Diagnostics: Honoraria; Celgene: Honoraria. Andreeff:Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy. Verstovsek:Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; PharmaEssentia: Research Funding; Sierra Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; Gilead: Research Funding; Promedior: Research Funding; Genentech: Research Funding; CTI Biopharma Corp: Research Funding; ItalPharma: Research Funding; Protagonist Therapeutics: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding. Jain:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Research Funding; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics: Research Funding; Aprea Therapeutics: Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:AbbVie: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Sanofi: Research Funding; Rafael Pharmaceutical: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Eli Lilly: Research Funding; Agios: Research Funding; Ablynx: Research Funding; Forty-Seven: Consultancy, Research Funding; Amgen: Consultancy; Calithera: Research Funding; Kisoji: Consultancy; Cellectis: Research Funding; AstraZeneca: Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding; Ascentage: Research Funding. Kantarjian:Abbvie: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Ascentage: Research Funding; BMS: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Immunogen: Research Funding; Jazz: Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sanofi: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive biotechnologies: Honoraria; Aptitute Health: Honoraria; BioAscend: Honoraria; Delta Fly: Honoraria; Janssen: Honoraria; Oxford Biomedical: Honoraria. Kadia:Cyclacel: Research Funding; Novartis: Honoraria; Incyte: Research Funding; Genentech: Honoraria, Research Funding; Cellenkos: Research Funding; Ascentage: Research Funding; Pulmotec: Research Funding; Astra Zeneca: Research Funding; Celgene: Research Funding; Abbvie: Honoraria, Research Funding; JAZZ: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Astellas: Research Funding; Amgen: Research Funding; Pfizer: Honoraria, Research Funding.