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2. Comparison between azacitidine and decitabine as front-line therapy in elderly acute myeloid leukemia patients not eligible for intensive chemotherapy

Author

Maurillo, L., Spagnoli, A., Candoni, A., Papayannidis, C., Borlenghi, E., Lazzarotto, D., Fianchi, L., Sciumè, M., Zannier, M.E., Buccisano, F., Del Principe, M.I., Mancini, V., Breccia, M., Fanin, R., Todisco, E., Lunghi, M., Palmieri, R., Fracchiolla, N., Musto, P., Rossi, G., and Venditti, A.

Published
2023
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3. Decoding the historical tale: COVID-19 impact on haematological malignancy patients—EPICOVIDEHA insights from 2020 to 2022

Author

Salmanton-Garcia, J., Marchesi, F., Farina, F., Weinbergerova, B., Itri, F., Davila-Valls, J., Martin-Perez, S., Glenthoj, A., Hersby, D. S., Gomes da Silva, M., Nunes Rodrigues, R., Lopez-Garcia, A., Cordoba, R., Bilgin, Y. M., Falces-Romero, I., El-Ashwah, S., Emarah, Z., Besson, C., Kohn, M., Van Doesum, J., Ammatuna, E., Marchetti, M., Labrador, J., Zambrotta, G. P. M., Verga, L., Jaksic, O., Nucci, M., Piukovics, K., Cabirta-Touzon, A., Jimenez, M., Arellano, E., Espigado, I., Blennow, O., Nordlander, A., Meers, S., van Praet, J., Aiello, T. F., Garcia-Vidal, C., Fracchiolla, N., Sciume, M., Seval, G. C., Zak, P., Buquicchio, C., Tascini, C., Grafe, S. K., Schonlein, M., Adzic-Vukicevic, T., Bonuomo, V., Cattaneo, C., Nizamuddin, S., Cernan, M., Plantefeve, G., Prin, R., Szotkovski, T., Collins, G. P., Dargenio, M., Petzer, V., Wolf, D., Colovic, N., Prezioso, L., Valkovic, T., Passamonti, F., Mendez, G. -A., Sili, U., Vena, A., Bavastro, M., Limongelli, A., Duarte, R. F., Ledoux, M. -P., Cvetanoski, M., Stojanoski, Z., Machado, M., Batinic, J., Magliano, G., Biernat, M. M., Pantic, N., Poulsen, C. B., Cuccaro, A., Del Principe, M. I., Kulasekararaj, A., Ormazabal-Velez, I., Busca, A., Demirkan, F., Ijaz, M., Klimko, N., Stoma, I., Khostelidi, S., Fernandez, N., Omrani, A. S., Bergantim, R., De Jonge, N., Fouquet, G., Navratil, M., Abu-Zeinah, G., Samarkos, M., Maertens, J., De Ramon, C., Guidetti, A., Magyari, F., Gonzalez-Lopez, T. J., Lahmer, T., Finizio, O., Ali, N., Pinczes, L. I., Lavilla-Rubira, E., Romano, A., Merelli, M., Delia, M., Calbacho, M., Meletiadis, J., Antic, D., Hernandez-Rivas, J. -A., Marques de Almeida, J., Al-Khabori, M., Hoenigl, M., Tisi, M. C., Khanna, N., Barac, A., Eisa, N., Di Blasi, R., Lievin, R., Miranda-Castillo, C., Bahr, N. C., Lamure, S., Papa, M. V., Yahya, A., Aujayeb, A., Novak, J., Erben, N., Fernandez-Galan, M., Ribera-Santa Susana, J. -M., Rinaldi, I., Fazzi, R., Piedimonte, M., Dulery, R., Gonzaga, Y., Soto-Silva, A., Sapienza, G., Serris, A., Drgona, Groh, A., Serrano, L., Gavriilaki, E., Tragiannidis, A., Prattes, J., Coppola, N., Otasevic, V., Mladenovic, M., Mitrovic, M., Miskovic, B., Jindra, P., Zompi, S., Sacchi, M. V., Krekeler, C., Infante, M. S., Garcia-Bordallo, D., Colak, G. M., Mayer, J., Nygaard, M., Hanakova, M., Racil, Z., Bonanni, Matteo, Koehler, P., Rahimli, L., Cornely, O. A., Pagano, Livio, Martin-Vallejo, F. J., Zdziarski, P., Zarrinfer, H., Wittig, J., Win, S., Wai-Man, V., Visek, B., Vinh, D. C., Vehreschild, M., Varricchio, G., Tsirigotis, P., Torres-Tienza, A., Tanase, A. D., Tafuri, A., Stamouli, M., Sramek, J., Soussain, C., Shirinova, A., Schubert, J., Schalk, E., Salehi, M. R., Saleh, M., Rosati, G., Roldan, E., Reizine, F., Rego, M., Regalado-Artamendi, I., Popova, M., Pinto, F., Philippe, L., Orth, H. M., Ommen, H. -B., Obr, A., Nunez-Martin-Buitrago, L., Noel, N., Neuhann, J., Nadali, G., Nacov, J. A., Munhoz Alburquerque, A. M., Mitra, M. E., Mikulska, M., Mellinghoff, S., Mechtel, B., Martin-Gonzalez, J. -A., Malak, S., Loureiro-Amigo, J., Lorenzo De La Pena, L., Liberti, G., Landau, M., Lacej, I., Kolditz, M., Kho, C. S., Khedr, R. A., Karthaus, M., Karlsson, L. K., Jimenez-Lorenzo, M. -J., Izuzquiza, M., Hoell-Neugebauer, B., Herbrecht, R., Heath, C. H., Guolo, F., Grothe, J., Giordano, A., Gerasymchuk, S., Garcia-Sanz, R., Garcia-Pouton, N., Funke, V. A. M., Fung, M., Flasshove, C., Fianchi, Luana, Essame, J., Egger, M., Drenou, B., Dragonetti, G., Desole, M., Della Pepa, R., Deau Fischer, B., De Kort, E., De Cabo, E., Danion, F., Daguindau, E., Cushion, T., Cremer, L., Criscuolo, Marianna, Cordini, G., Cingolani, Antonella, Ciceri, F., Chowdhury, F. R., Chelysheva, E., Chauchet, A., Chai, L. Y. A., Ceesay, M. M., Busch, E., Brehon, M., Borducchi, D. M. M., Booth, S., Bologna, S., Berg Venemyr, C., Bailen-Almorox, R., Antoniadou, A., Anastasopoulou, A. N., Altuntas, F., Bonanni M., Pagano L. (ORCID:0000-0001-8287-928X), Fianchi L., Criscuolo M., Cingolani A. (ORCID:0000-0002-3793-2755), Salmanton-Garcia, J., Marchesi, F., Farina, F., Weinbergerova, B., Itri, F., Davila-Valls, J., Martin-Perez, S., Glenthoj, A., Hersby, D. S., Gomes da Silva, M., Nunes Rodrigues, R., Lopez-Garcia, A., Cordoba, R., Bilgin, Y. M., Falces-Romero, I., El-Ashwah, S., Emarah, Z., Besson, C., Kohn, M., Van Doesum, J., Ammatuna, E., Marchetti, M., Labrador, J., Zambrotta, G. P. M., Verga, L., Jaksic, O., Nucci, M., Piukovics, K., Cabirta-Touzon, A., Jimenez, M., Arellano, E., Espigado, I., Blennow, O., Nordlander, A., Meers, S., van Praet, J., Aiello, T. F., Garcia-Vidal, C., Fracchiolla, N., Sciume, M., Seval, G. C., Zak, P., Buquicchio, C., Tascini, C., Grafe, S. K., Schonlein, M., Adzic-Vukicevic, T., Bonuomo, V., Cattaneo, C., Nizamuddin, S., Cernan, M., Plantefeve, G., Prin, R., Szotkovski, T., Collins, G. P., Dargenio, M., Petzer, V., Wolf, D., Colovic, N., Prezioso, L., Valkovic, T., Passamonti, F., Mendez, G. -A., Sili, U., Vena, A., Bavastro, M., Limongelli, A., Duarte, R. F., Ledoux, M. -P., Cvetanoski, M., Stojanoski, Z., Machado, M., Batinic, J., Magliano, G., Biernat, M. M., Pantic, N., Poulsen, C. B., Cuccaro, A., Del Principe, M. I., Kulasekararaj, A., Ormazabal-Velez, I., Busca, A., Demirkan, F., Ijaz, M., Klimko, N., Stoma, I., Khostelidi, S., Fernandez, N., Omrani, A. S., Bergantim, R., De Jonge, N., Fouquet, G., Navratil, M., Abu-Zeinah, G., Samarkos, M., Maertens, J., De Ramon, C., Guidetti, A., Magyari, F., Gonzalez-Lopez, T. J., Lahmer, T., Finizio, O., Ali, N., Pinczes, L. I., Lavilla-Rubira, E., Romano, A., Merelli, M., Delia, M., Calbacho, M., Meletiadis, J., Antic, D., Hernandez-Rivas, J. -A., Marques de Almeida, J., Al-Khabori, M., Hoenigl, M., Tisi, M. C., Khanna, N., Barac, A., Eisa, N., Di Blasi, R., Lievin, R., Miranda-Castillo, C., Bahr, N. C., Lamure, S., Papa, M. V., Yahya, A., Aujayeb, A., Novak, J., Erben, N., Fernandez-Galan, M., Ribera-Santa Susana, J. -M., Rinaldi, I., Fazzi, R., Piedimonte, M., Dulery, R., Gonzaga, Y., Soto-Silva, A., Sapienza, G., Serris, A., Drgona, Groh, A., Serrano, L., Gavriilaki, E., Tragiannidis, A., Prattes, J., Coppola, N., Otasevic, V., Mladenovic, M., Mitrovic, M., Miskovic, B., Jindra, P., Zompi, S., Sacchi, M. V., Krekeler, C., Infante, M. S., Garcia-Bordallo, D., Colak, G. M., Mayer, J., Nygaard, M., Hanakova, M., Racil, Z., Bonanni, Matteo, Koehler, P., Rahimli, L., Cornely, O. A., Pagano, Livio, Martin-Vallejo, F. J., Zdziarski, P., Zarrinfer, H., Wittig, J., Win, S., Wai-Man, V., Visek, B., Vinh, D. C., Vehreschild, M., Varricchio, G., Tsirigotis, P., Torres-Tienza, A., Tanase, A. D., Tafuri, A., Stamouli, M., Sramek, J., Soussain, C., Shirinova, A., Schubert, J., Schalk, E., Salehi, M. R., Saleh, M., Rosati, G., Roldan, E., Reizine, F., Rego, M., Regalado-Artamendi, I., Popova, M., Pinto, F., Philippe, L., Orth, H. M., Ommen, H. -B., Obr, A., Nunez-Martin-Buitrago, L., Noel, N., Neuhann, J., Nadali, G., Nacov, J. A., Munhoz Alburquerque, A. M., Mitra, M. E., Mikulska, M., Mellinghoff, S., Mechtel, B., Martin-Gonzalez, J. -A., Malak, S., Loureiro-Amigo, J., Lorenzo De La Pena, L., Liberti, G., Landau, M., Lacej, I., Kolditz, M., Kho, C. S., Khedr, R. A., Karthaus, M., Karlsson, L. K., Jimenez-Lorenzo, M. -J., Izuzquiza, M., Hoell-Neugebauer, B., Herbrecht, R., Heath, C. H., Guolo, F., Grothe, J., Giordano, A., Gerasymchuk, S., Garcia-Sanz, R., Garcia-Pouton, N., Funke, V. A. M., Fung, M., Flasshove, C., Fianchi, Luana, Essame, J., Egger, M., Drenou, B., Dragonetti, G., Desole, M., Della Pepa, R., Deau Fischer, B., De Kort, E., De Cabo, E., Danion, F., Daguindau, E., Cushion, T., Cremer, L., Criscuolo, Marianna, Cordini, G., Cingolani, Antonella, Ciceri, F., Chowdhury, F. R., Chelysheva, E., Chauchet, A., Chai, L. Y. A., Ceesay, M. M., Busch, E., Brehon, M., Borducchi, D. M. M., Booth, S., Bologna, S., Berg Venemyr, C., Bailen-Almorox, R., Antoniadou, A., Anastasopoulou, A. N., Altuntas, F., Bonanni M., Pagano L. (ORCID:0000-0001-8287-928X), Fianchi L., Criscuolo M., and Cingolani A. (ORCID:0000-0002-3793-2755)

Abstract

Background: The COVID-19 pandemic heightened risks for individuals with hematological malignancies due to compromised immune systems, leading to more severe outcomes and increased mortality. While interventions like vaccines, targeted antivirals, and monoclonal antibodies have been effective for the general population, their benefits for these patients may not be as pronounced. Methods: The EPICOVIDEHA registry (National Clinical Trials Identifier, NCT04733729) gathers COVID-19 data from hematological malignancy patients since the pandemic's start worldwide. It spans various global locations, allowing comprehensive analysis over the first three years (2020–2022). Findings: The EPICOVIDEHA registry collected data from January 2020 to December 2022, involving 8767 COVID-19 cases in hematological malignancy patients from 152 centers across 41 countries, with 42% being female. Over this period, there was a significant reduction in critical infections and an overall decrease in mortality from 29% to 4%. However, hospitalization, particularly in the ICU, remained associated with higher mortality rates. Factors contributing to increased mortality included age, multiple comorbidities, active malignancy at COVID-19 onset, pulmonary symptoms, and hospitalization. On the positive side, vaccination with one to two doses or three or more doses, as well as encountering COVID-19 in 2022, were associated with improved survival. Interpretation: Patients with hematological malignancies still face elevated risks, despite reductions in critical infections and overall mortality rates over time. Hospitalization, especially in ICUs, remains a significant concern. The study underscores the importance of vaccination and the timing of COVID-19 exposure in 2022 for enhanced survival in this patient group. Ongoing monitoring and targeted interventions are essential to support this vulnerable population, emphasizing the critical role of timely diagnosis and prompt treatment in preventing severe

Published
2024

4. NPM1-mutated myeloid neoplasm with low percentage of blasts

Author

Falini, B., Chiusolo, Patrizia, Fianchi, Luana, Pagano, Livio, Chiusolo P. (ORCID:0000-0002-1355-1587), Fianchi L., Pagano L. (ORCID:0000-0001-8287-928X), Falini, B., Chiusolo, Patrizia, Fianchi, Luana, Pagano, Livio, Chiusolo P. (ORCID:0000-0002-1355-1587), Fianchi L., and Pagano L. (ORCID:0000-0001-8287-928X)

Abstract

n/a

Published
2024

5. CPX-351 exploits the gut microbiota to promote mucosal barrier function, colonization resistance, and immune homeostasis

Author

Renga, G., Nunzi, E., Stincardini, C., Pariano, M., Puccetti, M., Pieraccini, G., Di Serio, C., Fraziano, M., Poerio, N., Oikonomou, V., Mosci, P., Garaci, E., Fianchi, Luana, Pagano, Livio, Romani, L., Fianchi L., Pagano L. (ORCID:0000-0001-8287-928X), Renga, G., Nunzi, E., Stincardini, C., Pariano, M., Puccetti, M., Pieraccini, G., Di Serio, C., Fraziano, M., Poerio, N., Oikonomou, V., Mosci, P., Garaci, E., Fianchi, Luana, Pagano, Livio, Romani, L., Fianchi L., and Pagano L. (ORCID:0000-0001-8287-928X)

Abstract

CPX-351, a liposomal combination of cytarabine plus daunorubicin, has been approved for the treatment of adults with newly diagnosed, therapy-related acute myeloid leukemia (AML) or AML with myelodysplasia-related changes, because it improves survival and outcome of patients who received hematopoietic stem cell transplant compared with the continuous infusion of cytarabine plus daunorubicin (referred to as “7 + 3” combination). Because gut dysbiosis occurring in patients with AML during induction chemotherapy heavily affects the subsequent phases of therapy, we have assessed whether the superior activity of CPX-351 vs “7 + 3” combination in the real-life setting implicates an action on and by the intestinal microbiota. To this purpose, we have evaluated the impact of CPX-351 and “7 + 3” combination on mucosal barrier function, gut microbial composition and function, and antifungal colonization resistance in preclinical models of intestinal damage in vitro and in vivo and fecal microbiota transplantation. We found that CPX-351, at variance with “7 + 3” combination, protected from gut dysbiosis, mucosal damage, and gut morbidity while increasing antifungal resistance. Mechanistically, the protective effect of CPX-351 occurred through pathways involving both the host and the intestinal microbiota, namely via the activation of the aryl hydrocarbon receptor–interleukin-22 (IL-22)–IL-10 host pathway and the production of immunomodulatory metabolites by anaerobes. This study reveals how the gut microbiota may contribute to the good safety profile, with a low infection-related mortality, of CPX-351 and highlights how a better understanding of the host-microbiota dialogue may contribute to pave the way for precision medicine in AML.

Published
2024

6. AVALON: The Italian cohort study on real-life efficacy of hypomethylating agents plus venetoclax in newly diagnosed or relapsed/refractory patients with acute myeloid leukemia

Author

Todisco, E, Papayannidis, C, Fracchiolla, N, Petracci, E, Zingaretti, C, Vetro, C, Martelli, M, Zappasodi, P, Di Renzo, N, Gallo, S, Audisio, E, Griguolo, D, Cerchione, C, Selleri, C, Mattei, D, Bernardi, M, Fumagalli, M, Rizzuto, G, Facchini, L, Basilico, C, Manfra, I, Borlenghi, E, Cairoli, R, Salutari, P, Gottardi, M, Molteni, A, Martini, V, Lunghi, M, Fianchi, L, Cilloni, D, Lanza, F, Abruzzese, E, Cascavilla, N, Rivellini, F, Ferrara, F, Maurillo, L, Nanni, J, Romano, A, Cardinali, V, Gigli, F, Roncoroni, E, Federico, V, Marconi, G, Volpi, R, Sciumè, M, Tarella, C, Rossi, G, Martinelli, G, Todisco E, Papayannidis C, Fracchiolla N, Petracci E, Zingaretti C, Vetro C, Martelli MP, Zappasodi P, Di Renzo N, Gallo S, Audisio E, Griguolo D, Cerchione C, Selleri C, Mattei D, Bernardi M, Fumagalli M, Rizzuto G, Facchini L, Basilico CM, Manfra I, Borlenghi E, Cairoli R, Salutari P, Gottardi M, Molteni A, Martini V, Lunghi M, Fianchi L, Cilloni D, Lanza F, Abruzzese E, Cascavilla N, Rivellini F, Ferrara F, Maurillo L, Nanni J, Romano A, Cardinali V, Gigli F, Roncoroni E, Federico V, Marconi G, Volpi R, Sciumè M, Tarella C, Rossi G, Martinelli G, Todisco, E, Papayannidis, C, Fracchiolla, N, Petracci, E, Zingaretti, C, Vetro, C, Martelli, M, Zappasodi, P, Di Renzo, N, Gallo, S, Audisio, E, Griguolo, D, Cerchione, C, Selleri, C, Mattei, D, Bernardi, M, Fumagalli, M, Rizzuto, G, Facchini, L, Basilico, C, Manfra, I, Borlenghi, E, Cairoli, R, Salutari, P, Gottardi, M, Molteni, A, Martini, V, Lunghi, M, Fianchi, L, Cilloni, D, Lanza, F, Abruzzese, E, Cascavilla, N, Rivellini, F, Ferrara, F, Maurillo, L, Nanni, J, Romano, A, Cardinali, V, Gigli, F, Roncoroni, E, Federico, V, Marconi, G, Volpi, R, Sciumè, M, Tarella, C, Rossi, G, Martinelli, G, Todisco E, Papayannidis C, Fracchiolla N, Petracci E, Zingaretti C, Vetro C, Martelli MP, Zappasodi P, Di Renzo N, Gallo S, Audisio E, Griguolo D, Cerchione C, Selleri C, Mattei D, Bernardi M, Fumagalli M, Rizzuto G, Facchini L, Basilico CM, Manfra I, Borlenghi E, Cairoli R, Salutari P, Gottardi M, Molteni A, Martini V, Lunghi M, Fianchi L, Cilloni D, Lanza F, Abruzzese E, Cascavilla N, Rivellini F, Ferrara F, Maurillo L, Nanni J, Romano A, Cardinali V, Gigli F, Roncoroni E, Federico V, Marconi G, Volpi R, Sciumè M, Tarella C, Rossi G, and Martinelli G

Abstract

Background: Venetoclax in combination with hypomethylating agents (HMA) is revolutionizing the therapy of acute myeloid leukemia (AML). However, evidence on large sets of patients is lacking, especially in relapsed or refractory leukemia. Methods: AVALON is a multicentric cohort study that was conducted in Italy on patients with AML who received venetoclax-based therapies from 2015 to 2020. The study was approved by the ethics committee of the participating institution and was conducted in accordance with the Declaration of Helsinki. The effectiveness and toxicity of venetoclax + HMA in 190 (43 newly diagnosed, 68 refractory, and 79 relapsed) patients with AML are reported here. Results: In the newly diagnosed AML, the overall response rate and survival confirmed the brilliant results demonstrated in VIALE-A. In the relapsed or refractory AML, the combination demonstrated a surprisingly complete remission rate (44.1% in refractory and 39.7% in relapsed evaluable patients) and conferred to treated patients a good expectation of survival. Toxicities were overall manageable, and most incidents occurred in the first 60 days of therapy. Infections were confirmed as the most common nonhematologic adverse event. Conclusions: Real-life data show that the combination of venetoclax and HMA offers an expectation of remission and long-term survival to elderly, newly diagnosed patients, and to relapsed or chemoresistant AML, increasing the chance of cure through a different mechanism of action. The venetoclax + HMA combination is expected to constitute the base for triplet combinations and integration of target therapies. Our data contribute to ameliorate the understanding of venetoclax + HMA effectiveness and toxicities in real life.

Published
2023

7. Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium

Author

Sánchez-Maldonado, J. M., Campa, D., Springer, J., Badiola, J., Niazi, Y., Moñiz-Díez, A., Hernández-Mohedo, F., González-Sierra, P., Ter Horst, R., Macauda, A., Brezina, S., Cunha, C., Lackner, M., López-Nevot, M. A., Fianchi, L., Pagano, L., López-Fernández, E., Potenza, L., Luppi, M., Moratalla, L., Rodríguez-Sevilla, J. J., Fonseca, J. E., Tormo, M., Solano, C., Clavero, E., Romero, A., Li, Y., Lass-Flörl, C., Einsele, H., Vazquez, L., Loeffler, J., Hemminki, K., Carvalho, A., Netea, M. G., Gsur, A., Dumontet, C., Canzian, F., Försti, A., Jurado, M., and Sainz, J.

Published
2020
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8. P25 EFFECT OF DARATUMUMAB ON STEM CELL YIELDS IN PATIENTS WITH NEWLY DIAGNOSED MULTIPLE MYELOMA: REPORT FROM THE MULTIPLE MYELOMA LAZIO GROUP

Author

Fazio, F., primary, Passucci, M., additional, Lisi, C., additional, Micozzi, J., additional, Fianchi, L., additional, Di Landro, F., additional, Za, T., additional, Gumenyuk, S., additional, Ferraro, S., additional, Anaclerico, B., additional, De Padua, L., additional, Annibali, O., additional, Rago, A., additional, Piciocchi, A., additional, Bongarzoni, V., additional, Cupelli, L., additional, Mengarelli, A., additional, De Stefano, V., additional, Martelli, M., additional, and Petrucci, M.T., additional

Published
2023
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9. Optimal Duration of CPX-351 Treatment and Best Timing for Consolidation with Allogeneic Stem Cell Transplantation: Evidence from a Large Real-World Italian Study

Author

Guolo, F, Fianchi, L, Martelli, M, Chiusolo, P, Lussana, F, Grimaldi, F, Pilo, F, Rondoni, M, Fili, C, Capelli, D, Breccia, M, Mastaglio, S, Bocchia, M, Fumagalli, M, Galimberti, S, Mancini, V, Piccioni, A, Maurillo, L, Palmieri, R, Corbingi, A, Vetro, C, Sperotto, A, Gigli, F, Zappasodi, P, Mulé, A, Borlenghi, E, Dargenio, M, Lessi, F, Cerrano, M, Isidori, A, Brunetti, L, Papayannidis, C, Lunghi, M, Alati, C, Gatani, S, Mannelli, F, Fracchiolla, N, Gottardi, M, Cairoli, R, Ferrara, F, Lemoli, R, Venditti, A, Pagano, L, Todisco, E, Guolo, Fabio, Fianchi, Luana, Martelli, Maria Paola, Chiusolo, Patrizia, Lussana, Federico, Grimaldi, Francesco, Pilo, Federica, Rondoni, Michela, Fili, Carla, Capelli, Debora, Breccia, Massimo, Mastaglio, Sara, Bocchia, Monica, Fumagalli, Monica, Galimberti, Sara, Mancini, Valentina, Piccioni, Anna Lina, Maurillo, Luca, Palmieri, Raffaele, Corbingi, Andrea, Vetro, Calogero, Sperotto, Alessandra, Gigli, Federica, Zappasodi, Patrizia, Mulé, Antonio, Borlenghi, Erika, Dargenio, Michelina, Lessi, Federica, Cerrano, Marco, Isidori, Alessandro, Brunetti, Lorenzo, Papayannidis, Cristina, Lunghi, Monia, Alati, Caterina, Gatani, Samuele, Mannelli, Francesco, Fracchiolla, Nicola, Gottardi, Michele, Cairoli, Roberto, Ferrara, Felicetto, Lemoli, Roberto Massimo, Venditti, Adriano, Pagano, Livio, Todisco, Elisabetta, Guolo, F, Fianchi, L, Martelli, M, Chiusolo, P, Lussana, F, Grimaldi, F, Pilo, F, Rondoni, M, Fili, C, Capelli, D, Breccia, M, Mastaglio, S, Bocchia, M, Fumagalli, M, Galimberti, S, Mancini, V, Piccioni, A, Maurillo, L, Palmieri, R, Corbingi, A, Vetro, C, Sperotto, A, Gigli, F, Zappasodi, P, Mulé, A, Borlenghi, E, Dargenio, M, Lessi, F, Cerrano, M, Isidori, A, Brunetti, L, Papayannidis, C, Lunghi, M, Alati, C, Gatani, S, Mannelli, F, Fracchiolla, N, Gottardi, M, Cairoli, R, Ferrara, F, Lemoli, R, Venditti, A, Pagano, L, Todisco, E, Guolo, Fabio, Fianchi, Luana, Martelli, Maria Paola, Chiusolo, Patrizia, Lussana, Federico, Grimaldi, Francesco, Pilo, Federica, Rondoni, Michela, Fili, Carla, Capelli, Debora, Breccia, Massimo, Mastaglio, Sara, Bocchia, Monica, Fumagalli, Monica, Galimberti, Sara, Mancini, Valentina, Piccioni, Anna Lina, Maurillo, Luca, Palmieri, Raffaele, Corbingi, Andrea, Vetro, Calogero, Sperotto, Alessandra, Gigli, Federica, Zappasodi, Patrizia, Mulé, Antonio, Borlenghi, Erika, Dargenio, Michelina, Lessi, Federica, Cerrano, Marco, Isidori, Alessandro, Brunetti, Lorenzo, Papayannidis, Cristina, Lunghi, Monia, Alati, Caterina, Gatani, Samuele, Mannelli, Francesco, Fracchiolla, Nicola, Gottardi, Michele, Cairoli, Roberto, Ferrara, Felicetto, Lemoli, Roberto Massimo, Venditti, Adriano, Pagano, Livio, and Todisco, Elisabetta

Published
2023

10. Passive pre-exposure immunization by tixagevimab/cilgavimab in patients with hematological malignancy and COVID-19: matched-paired analysis in the EPICOVIDEHA registry

Author

Marchesi, F., Salmanton-Garcia, J., Buquicchio, C., Itri, F., Besson, C., Davila-Valls, J., Martin-Perez, S., Fianchi, Luana, Rahimli, L., Tarantini, G., Grifoni, F. I., Sciume, M., Labrador, J., Cordoba, R., Lopez-Garcia, A., Fracchiolla, N. S., Farina, F., Ammatuna, E., Cingolani, Antonella, Garcia-Bordallo, D., Grafe, S. K., Bilgin, Y. M., Dargenio, M., Gonzalez-Lopez, T. J., Guidetti, A., Lahmer, T., Lavilla-Rubira, E., Mendez, G. -A., Prezioso, L., Schonlein, M., Van Doesum, J., Wolf, D., Hersby, D. S., Magyari, F., Van Praet, J., Petzer, V., Tascini, C., Falces-Romero, I., Glenthoj, A., Cornely, O. A., Pagano, Livio, Fianchi L., Cingolani A. (ORCID:0000-0002-3793-2755), Pagano L. (ORCID:0000-0001-8287-928X), Marchesi, F., Salmanton-Garcia, J., Buquicchio, C., Itri, F., Besson, C., Davila-Valls, J., Martin-Perez, S., Fianchi, Luana, Rahimli, L., Tarantini, G., Grifoni, F. I., Sciume, M., Labrador, J., Cordoba, R., Lopez-Garcia, A., Fracchiolla, N. S., Farina, F., Ammatuna, E., Cingolani, Antonella, Garcia-Bordallo, D., Grafe, S. K., Bilgin, Y. M., Dargenio, M., Gonzalez-Lopez, T. J., Guidetti, A., Lahmer, T., Lavilla-Rubira, E., Mendez, G. -A., Prezioso, L., Schonlein, M., Van Doesum, J., Wolf, D., Hersby, D. S., Magyari, F., Van Praet, J., Petzer, V., Tascini, C., Falces-Romero, I., Glenthoj, A., Cornely, O. A., Pagano, Livio, Fianchi L., Cingolani A. (ORCID:0000-0002-3793-2755), and Pagano L. (ORCID:0000-0001-8287-928X)

Abstract

Only few studies have analyzed the efficacy of tixagevimab/cilgavimab to prevent severe Coronavirus disease 2019 (COVID-19) and related complications in hematologic malignancies (HM) patients. Here, we report cases of breakthrough COVID-19 after prophylactic tixagevimab/cilgavimab from the EPICOVIDEHA registry). We identified 47 patients that had received prophylaxis with tixagevimab/cilgavimab in the EPICOVIDEHA registry. Lymphoproliferative disorders (44/47, 93.6%) were the main underlying HM. SARS-CoV-2 strains were genotyped in 7 (14.9%) cases only, and all belonged to the omicron variant. Forty (85.1%) patients had received vaccinations prior to tixagevimab/cilgavimab, the majority of them with at least two doses. Eleven (23.4%) patients had a mild SARS-CoV-2 infection, 21 (44.7%) a moderate infection, while 8 (17.0%) had severe infection and 2 (4.3%) critical. Thirty-six (76.6%) patients were treated, either with monoclonal antibodies, antivirals, corticosteroids, or with combination schemes. Overall, 10 (21.3%) were admitted to a hospital. Among these, two (4.3%) were transferred to intensive care unit and one (2.1%) of them died. Our data seem to show that the use of tixagevimab/cilgavimab may lead to a COVID-19 severity reduction in HM patients; however, further studies should incorporate further HM patients to confirm the best drug administration strategies in immunocompromised patients.

Published
2023

11. Nirmatrelvir/ritonavir in COVID-19 patients with haematological malignancies: a report from the EPICOVIDEHA registry

Author

Salmanton-Garcia, J., Marchesi, F., Gomes da Silva, M., Farina, F., Davila-Valls, J., Bilgin, Y. M., Glenthoj, A., Falces-Romero, I., Van Doesum, J., Labrador, J., Buquicchio, C., El-Ashwah, S., Petzer, V., Van Praet, J., Schonlein, M., Dargenio, M., Mendez, G. -A., Meers, S., Itri, F., Giordano, A., Pinczes, L. I., Espigado, I., Stojanoski, Z., Lopez-Garcia, A., Prezioso, L., Jaksic, O., Vena, A., Fracchiolla, N. S., Gonzalez-Lopez, T. J., Colovic, N., Delia, M., Weinbergerova, B., Marchetti, M., Marques de Almeida, J., Finizio, O., Besson, C., Biernat, M. M., Valkovic, T., Lahmer, T., Cuccaro, A., Ormazabal-Velez, I., Batinic, J., Fernandez, N., De Jonge, N., Tascini, C., Anastasopoulou, A. N., Dulery, R., Del Principe, M. I., Plantefeve, G., Papa, M. V., Nucci, M., Jimenez, M., Aujayeb, A., Hernandez-Rivas, J. -A., Merelli, M., Cattaneo, C., Blennow, O., Nordlander, A., Cabirta, A., Varricchio, G., Sacchi, M. V., Cordoba, R., Arellano, E., Grafe, S. K., Wolf, D., Emarah, Z., Ammatuna, E., Hersby, D. S., Martin-Perez, S., Nunes Rodrigues, R., Rahimli, L., Pagano, Livio, Cornely, O. A., Piukovics, K., De Ramon, C., Danion, F., Yahya, A., Guidetti, A., Garcia-Vidal, C., Sili, U., Meletiadis, J., De Kort, E., Verga, L., Serrano, L., Erben, N., Di Blasi, R., Tragiannidis, A., Ribera-Santa Susana, J. -M., Ommen, H. -B., Busca, A., Coppola, N., Bergantim, R., Dragonetti, Giulia, Criscuolo, Marianna, Fianchi, Luana, Bonanni, Matteo, Soto-Silva, A., Mikulska, M., Machado, M., Shan Kho, C., Hassan, N., Gavriilaki, E., Cordini, G., Chi, L. Y. A., Eggerer, M., Hoenigl, M., Prattes, J., Jimenez-Lorenzo, M. -J., Zompi, S., Zambrotta, G. P. M., Colak, G. M., Garcia-Pouton, N., Aiello, T. F., Prin, R., Stamouli, M., Samarkos, M., Pagano L. (ORCID:0000-0001-8287-928X), Dragonetti G., Criscuolo M., Fianchi L., Bonanni M., Salmanton-Garcia, J., Marchesi, F., Gomes da Silva, M., Farina, F., Davila-Valls, J., Bilgin, Y. M., Glenthoj, A., Falces-Romero, I., Van Doesum, J., Labrador, J., Buquicchio, C., El-Ashwah, S., Petzer, V., Van Praet, J., Schonlein, M., Dargenio, M., Mendez, G. -A., Meers, S., Itri, F., Giordano, A., Pinczes, L. I., Espigado, I., Stojanoski, Z., Lopez-Garcia, A., Prezioso, L., Jaksic, O., Vena, A., Fracchiolla, N. S., Gonzalez-Lopez, T. J., Colovic, N., Delia, M., Weinbergerova, B., Marchetti, M., Marques de Almeida, J., Finizio, O., Besson, C., Biernat, M. M., Valkovic, T., Lahmer, T., Cuccaro, A., Ormazabal-Velez, I., Batinic, J., Fernandez, N., De Jonge, N., Tascini, C., Anastasopoulou, A. N., Dulery, R., Del Principe, M. I., Plantefeve, G., Papa, M. V., Nucci, M., Jimenez, M., Aujayeb, A., Hernandez-Rivas, J. -A., Merelli, M., Cattaneo, C., Blennow, O., Nordlander, A., Cabirta, A., Varricchio, G., Sacchi, M. V., Cordoba, R., Arellano, E., Grafe, S. K., Wolf, D., Emarah, Z., Ammatuna, E., Hersby, D. S., Martin-Perez, S., Nunes Rodrigues, R., Rahimli, L., Pagano, Livio, Cornely, O. A., Piukovics, K., De Ramon, C., Danion, F., Yahya, A., Guidetti, A., Garcia-Vidal, C., Sili, U., Meletiadis, J., De Kort, E., Verga, L., Serrano, L., Erben, N., Di Blasi, R., Tragiannidis, A., Ribera-Santa Susana, J. -M., Ommen, H. -B., Busca, A., Coppola, N., Bergantim, R., Dragonetti, Giulia, Criscuolo, Marianna, Fianchi, Luana, Bonanni, Matteo, Soto-Silva, A., Mikulska, M., Machado, M., Shan Kho, C., Hassan, N., Gavriilaki, E., Cordini, G., Chi, L. Y. A., Eggerer, M., Hoenigl, M., Prattes, J., Jimenez-Lorenzo, M. -J., Zompi, S., Zambrotta, G. P. M., Colak, G. M., Garcia-Pouton, N., Aiello, T. F., Prin, R., Stamouli, M., Samarkos, M., Pagano L. (ORCID:0000-0001-8287-928X), Dragonetti G., Criscuolo M., Fianchi L., and Bonanni M.

Abstract

Background: Nirmatrelvir/ritonavir treatment decreases the hospitalisation rate in immunocompetent patients with COVID-19, but data on efficacy in patients with haematological malignancy are scarce. Here, we describe the outcome of nirmatrelvir/ritonavir treatment in a large cohort of the latter patients. Methods: This is a retrospective cohort study from the multicentre EPICOVIDEHA registry (NCT04733729) on patients with haematological malignancy, who were diagnosed with COVID-19 between January and September 2022. Patients receiving nirmatrelvir/ritonavir were compared to those who did not. A logistic regression was run to determine factors associated with nirmatrelvir/ritonavir administration in our sample. Mortality between treatment groups was assessed with Kaplan–Meier survival plots after matching all the patients with a propensity score. Additionally, a Cox regression was modelled to detect factors associated with mortality in patients receiving nirmatrelvir/ritonavir. Findings: A total of 1859 patients were analysed, 117 (6%) were treated with nirmatrelvir/ritonavir, 1742 (94%) were treated otherwise. Of 117 patients receiving nirmatrelvir/ritonavir, 80% had received ≥1 anti-SARS-CoV-2 vaccine dose before COVID-19 onset, 13% of which received a 2nd vaccine booster. 5% were admitted to ICU. Nirmatrelvir/ritonavir treatment was associated with the presence of extrapulmonary symptoms at COVID-19 onset, for example anosmia, fever, rhinitis, or sinusitis (aOR 2.509, 95%CI 1.448–4.347) and 2nd vaccine booster (aOR 3.624, 95%CI 1.619–8.109). Chronic pulmonary disease (aOR 0.261, 95%CI 0.093–0.732) and obesity (aOR 0.105, 95%CI 0.014–0.776) were not associated with nirmatrelvir/ritonavir use. After propensity score matching, day-30 mortality rate in patients treated with nirmatrelvir/ritonavir was 2%, significantly lower than in patients with SARS-CoV-2 directed treatment other than nirmatrelvir/ritonavir (11%, p = 0.036). No factor was observed explaining the mort

Published
2023

12. Infectious complications during monoclonal antibodies treatments and cell therapies in Acute Lymphoblastic Leukemia

Author

Quattrone, Martina, Di Pilla, Alessia, Pagano, Livio, Fianchi, Luana, Quattrone M., Di Pilla A., Pagano L. (ORCID:0000-0001-8287-928X), Fianchi L., Quattrone, Martina, Di Pilla, Alessia, Pagano, Livio, Fianchi, Luana, Quattrone M., Di Pilla A., Pagano L. (ORCID:0000-0001-8287-928X), and Fianchi L.

Abstract

Infections represent one of the most frequent complications during the treatment of patients with Acute Lymphoblastic Leukemia (ALL): of these, almost half develop an infectious event in the majority of cases in induction. The new monoclonal and bispecific antibodies and CAR-T, besides offering new perspectives in the overall survival and disease-free survival of patients, may also transform the epidemiology of infections in ALL by improving the toxicity of treatments. In this review, we examined studies published in the literature over the past 12 years and described the infectious complications of therapy with Blinatumomab, Inotuzumab, Rituximab and CAR-T in adult and pediatric patients with ALL. Infections are less frequent than in traditional chemotherapy treatment with vincristine, corticosteroids and anthracyclines, which has been the backbone of therapy for patients with ALL for years. On the other hand, the infection scenario in the CAR-T setting is quite peculiar: In these patients, infections are more frequent in the first month after infusion and are predominantly bacterial. As the time moves away from day zero, viral infections become more frequent, occurring mainly in patients who have had prolonged cytopenia and major cytokine release syndrome.

Published
2023

13. Multicenter Observational Retrospective Study on Febrile Events in Patients with Acute Myeloid Leukemia Treated with Cpx-351 in “Real-Life”: The SEIFEM Experience

Author

Fianchi, Luana, Guolo, F., Marchesi, F., Cattaneo, C., Gottardi, M., Restuccia, F., Candoni, A., Ortu La Barbera, E., Fazzi, R., Pasciolla, C., Finizio, O., Fracchiolla, N., Delia, M., Lessi, F., Dargenio, M., Bonuomo, V., Del Principe, M. I., Zappasodi, P., Picardi, M., Basilico, C., Piedimonte, M., Minetto, P., Giordano, A., Chiusolo, Patrizia, Prezioso, L., Buquicchio, C., Melillo, L. M. A., Zama, D., Farina, F., Mancini, V., Terrenato, I., Rondoni, M., Urbino, I., Tumbarello, Mario, Busca, A., Pagano, Livio, Fianchi L., Chiusolo P. (ORCID:0000-0002-1355-1587), Tumbarello M. (ORCID:0000-0002-9519-8552), Pagano L. (ORCID:0000-0001-8287-928X), Fianchi, Luana, Guolo, F., Marchesi, F., Cattaneo, C., Gottardi, M., Restuccia, F., Candoni, A., Ortu La Barbera, E., Fazzi, R., Pasciolla, C., Finizio, O., Fracchiolla, N., Delia, M., Lessi, F., Dargenio, M., Bonuomo, V., Del Principe, M. I., Zappasodi, P., Picardi, M., Basilico, C., Piedimonte, M., Minetto, P., Giordano, A., Chiusolo, Patrizia, Prezioso, L., Buquicchio, C., Melillo, L. M. A., Zama, D., Farina, F., Mancini, V., Terrenato, I., Rondoni, M., Urbino, I., Tumbarello, Mario, Busca, A., Pagano, Livio, Fianchi L., Chiusolo P. (ORCID:0000-0002-1355-1587), Tumbarello M. (ORCID:0000-0002-9519-8552), and Pagano L. (ORCID:0000-0001-8287-928X)

Abstract

In the present study, we aimed to evaluate the absolute risk of infection in the real-life setting of AML patients treated with CPX-351. The study included all patients with AML from 30 Italian hematology centers of the SEIFEM group who received CPX-351 from July 2018 to June 2021. There were 200 patients included. Overall, 336 CPX-351 courses were counted: all 200 patients received the first induction cycle, 18 patients (5%) received a second CPX-351 induction, while 86 patients (26%) proceeded with the first CPX-351 consolidation cycle, and 32 patients (10%) received a second CPX-351 consolidation. A total of 249 febrile events were recorded: 193 during the first or second induction, and 56 after the first or second consolidation. After the diagnostic work-up, 92 events (37%) were classified as febrile neutropenia of unknown origin (FUO), 118 (47%) were classifiable as microbiologically documented infections, and 39 (17%) were classifiable as clinically documented infections. The overall 30-day mortality rate was 14% (28/200). The attributable mortality–infection rate was 6% (15/249). A lack of response to the CPX-351 treatment was the only factor significantly associated with mortality in the multivariate analysis [p-value: 0.004, OR 0.05, 95% CI 0.01–0.39]. Our study confirms the good safety profile of CPX-351 in a real-life setting, with an incidence of infectious complications comparable to that of the pivotal studies; despite prolonged neutropenia, the incidence of fungal infections was low, as was infection-related mortality.

Published
2023

14. COVID-19 in adult acute myeloid leukemia patients: a long-term follow-up study from the European Hematology Association survey (EPICOVIDEHA)

Author

Marchesi F, Salmanton-García J, Emarah Z, Piukovics K, Nucci M, López-García A, Ráčil Z, Farina F, Popova M, Zompi S, Audisio E, Ledoux MP, Verga L, Weinbergerová B, Szotkovski T, Da Silva MG, Fracchiolla N, De Jonge N, Collins G, Marchetti M, Magliano G, García-Vidal C, Biernat MM, Van Doesum J, Machado M, Demirkan F, Al- Khabori M, Žák P, Víšek B, Stoma I, Méndez GA, Maertens J, Khanna N, Espigado I, Dragonetti G, Fianchi L, Del Principe MI, Cabirta A, Ormazabal- Vélez I, Jaksic O, Buquicchio C, Bonuomo V, Batinić J, Omrani AS, Lamure S, Finizio O, Fernández N, Falces-Romero I, Blennow O, Bergantim R, Ali N, Win S, Van Praet J, Tisi MC, Shirinova A, Schönlein M, Prattes J, Piedimonte M, Petzer V, Navrátil M, Kulasekararaj A, Jindra P, Sramek J, Glenthøj A, Fazzi R, De Ramón-Sánchez C, Cattaneo C, Calbacho M, Bahr NC, El-Ashwah S, Cordoba R, Hanakova M, Zambrotta G, Sciumè M, Booth S, Rodrigues RN, Sacchi MV, García-Poutón N, Martín- González JA, Khostelidi S, Gräfe S, Rahimli L, Ammatuna E, Busca A, Corradini P, Hoenigl M, Klimko N, Koehler P, Pagliuca A, Passamonti F, Cornely OA, Pagano L and EPICOVIDEHA working group.

Subjects
AML Covid 19
Abstract

Patients with acute myeloid leukemia (AML) are at high risk of dying from coronavirus disease 2019 (COVID-19). The optimal management of AML patients with COVID-19 has not been established. Our multicenter study included 388 adult AML patients diagnosed with COVID-19 between February 2020 and October 2021. The vast majority were receiving or had received AML treatment in the preceding 3 months. COVID-19 was severe in 41.2% and critical in 21.1% of cases. The chemotherapeutic schedule was modified in 174 patients (44.8%), delayed in 68 and permanently discontinued in 106. After a median follow-up of 325 days, 180 patients (46.4%) had died ; death was attributed to COVID-19 (43.3%), AML (26.1%) or to a combination of both (26.7%), whereas in 3.9% of cases the reason was unknown. Active disease, older age, and treatment discontinuation were associated with death, whereas AML treatment delay was protective. Seventy-nine patients had a simultaneous AML and COVID-19 diagnosis, with better survival when AML treatment could be delayed (80% ; P

Published
2023

15. Polymorphisms within the TNFSF4 and mapkapk2 loci influence the risk of developing invasive aspergillosis: A two-stage case control study in the context of the aspbiomics consortium

Author

Sanchez-Maldonado, J. M., Moniz-Diez, A., Ter Horst, R., Campa, D., Cabrera-Serrano, A. J., Martinez-Bueno, M., Garrido-Collado, M. P., Hernandez-Mohedo, F., Fernandez-Puerta, L., Lopez-Nevot, M. A., Cunha, C., Gonzalez-Sierra, P. A., Springer, J., Lackner, M., Alcazar-Fuoli, L., Fianchi, L., Aguado, J. M., Pagano, L., Lopez-Fernandez, E., Clavero, E., Potenza, L., Luppi, M., Moratalla, L., Solano, C., Sampedro, A., Cuenca-Estrella, M., Lass-Florl, C., Canzian, F., Loeffler, J., Li, Y., Einsele, H., Netea, M. G., Vazquez, L., Carvalho, A., Jurado, M., Sainz, J., Fianchi L., Pagano L. (ORCID:0000-0001-8287-928X), Sanchez-Maldonado, J. M., Moniz-Diez, A., Ter Horst, R., Campa, D., Cabrera-Serrano, A. J., Martinez-Bueno, M., Garrido-Collado, M. P., Hernandez-Mohedo, F., Fernandez-Puerta, L., Lopez-Nevot, M. A., Cunha, C., Gonzalez-Sierra, P. A., Springer, J., Lackner, M., Alcazar-Fuoli, L., Fianchi, L., Aguado, J. M., Pagano, L., Lopez-Fernandez, E., Clavero, E., Potenza, L., Luppi, M., Moratalla, L., Solano, C., Sampedro, A., Cuenca-Estrella, M., Lass-Florl, C., Canzian, F., Loeffler, J., Li, Y., Einsele, H., Netea, M. G., Vazquez, L., Carvalho, A., Jurado, M., Sainz, J., Fianchi L., and Pagano L. (ORCID:0000-0001-8287-928X)

Abstract

Here, we assessed whether 36 single nucleotide polymorphisms (SNPs) within the TNFSF4 and MAPKAPK2 loci influence the risk of developing invasive aspergillosis (IA). We conducted a two-stage case control study including 911 high-risk patients diagnosed with hematological malignancies that were ascertained through the aspBIOmics consortium. The meta-analysis of the discovery and replication populations revealed that carriers of the TNFSF4rs7526628T/T genotype had a significantly increased risk of developing IA (p = 0.00022). We also found that carriers of the TNFSF4rs7526628T allele showed decreased serum levels of TNFSF14 protein (p = 0.0027), and that their macrophages had a decreased fungicidal activity (p = 0.048). In addition, we observed that each copy of the MAPKAPK2rs12137965G allele increased the risk of IA by 60% (p = 0.0017), whereas each copy of the MAPKAPK2rs17013271T allele was estimated to decrease the risk of developing the disease (p = 0.0029). Mechanistically, we found that carriers of the risk MAPKAPK2rs12137965G allele showed increased numbers of CD38+IgM-IgD-plasmablasts in blood (p = 0.00086), whereas those harboring two copies of the allele had decreased serum concentrations of thymic stromal lymphopoietin (p = 0.00097). Finally, we also found that carriers of the protective MAPKAPK2rs17013271T allele had decreased numbers of CD27-IgM-IgD-B cells (p = 0.00087) and significantly lower numbers of CD14+ and CD14+CD16-cells (p = 0.00018 and 0.00023). Altogether, these results suggest a role of the TNFSF4 and MAPKAPK2 genes in determining IA risk.

Published
2021

17. Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes.

Author

Garcia-Manero G., Santini V., Almeida A., Platzbecker U., Jonasova A., Silverman L.R., Falantes J., Reda G., Buccisano F., Fenaux P., Buckstein R., Campelo M.D., Larsen S., Valcarcel D., Vyas P., Giai V., Oliva E.N., Shortt J., Niederwieser D., Mittelman M., Fianchi L., Torre I.L., Zhong J., Laille E., De Menezes D.L., Skikne B., Beach C.L., Giagounidis A., Garcia-Manero G., Santini V., Almeida A., Platzbecker U., Jonasova A., Silverman L.R., Falantes J., Reda G., Buccisano F., Fenaux P., Buckstein R., Campelo M.D., Larsen S., Valcarcel D., Vyas P., Giai V., Oliva E.N., Shortt J., Niederwieser D., Mittelman M., Fianchi L., Torre I.L., Zhong J., Laille E., De Menezes D.L., Skikne B., Beach C.L., and Giagounidis A.

Abstract

PURPOSE Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia. METHODS Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS Two hundred sixteen patients received CC-486 (n 5 107) or placebo (n 5 109). The median age was 74 years, median platelet count was 25 3 109/L, and absolute neutrophil count was 1.3 3 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (P5.0002), with median durations of 11.1 and 5.0 months. Reductions of $ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had $ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC- 486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P 5 .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC- 486, n 5 16; placebo, n 5 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 3 109/L. CONCLUSION CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation of

Published
2022

18. Neutralizing monoclonal antibodies in haematological patients paucisymptomatic for COVID-19: The GIMEMA EMATO-0321 study

Author

Marasco, V., Piciocchi, A., Candoni, A., Pagano, Livio, Guidetti, A., Musto, P., Bruna, R., Bocchia, M., Visentin, A., Turrini, M., Tucci, A., Pilerci, S., Fianchi, Luana, Salvini, M., Galimberti, S., Coviello, E., Selleri, C., Luppi, M., Crea, E., Fazi, P., Passamonti, F., Corradini, P., Pagano L. (ORCID:0000-0001-8287-928X), Fianchi L., Marasco, V., Piciocchi, A., Candoni, A., Pagano, Livio, Guidetti, A., Musto, P., Bruna, R., Bocchia, M., Visentin, A., Turrini, M., Tucci, A., Pilerci, S., Fianchi, Luana, Salvini, M., Galimberti, S., Coviello, E., Selleri, C., Luppi, M., Crea, E., Fazi, P., Passamonti, F., Corradini, P., Pagano L. (ORCID:0000-0001-8287-928X), and Fianchi L.

Abstract

COVID-19 continues to be a relevant issue among patients with haematological malignancies (HM). Vaccines are frequently not effective in subjects on active treatment. In this multicentre retrospective study of Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA), we collected data from 91 paucisymptomatic HM patients treated with anti-spike neutralizing monoclonal antibodies (nMoAbs) to determine time to viral clearance, referencing it to the expected value of 28 days from an historical group of untreated paucisymptomatic patients. Secondary endpoints included rate of hospitalization, intensive care unit (ICU) admission, COVID-19 related death and safety. SARS-CoV-2 molecular swab negativity was obtained in 86 patients (95%), with a median time of 18 days (IQR 13–26; p < 0.0001). We did not find significant variations according to age, diagnosis, treatment type, vaccination status or nMoAbs type. Rate of hospitalization due to COVID-19 progression was 12% (11/91), with 2 patients (2.2%) requiring ICU admission. With a median follow-up of 2.33 months, the overall mortality was 5.5% (5/91), with 3 deaths due to COVID-19. Side effects were rare and self-limiting. Our data suggest that nMoAbs can limit the detrimental effect of immunosuppressive treatments on COVID-19 clinical progression and time to viral clearance. The original trial was registered at www.clinicaltrials.gov as #NCT04932967.

Published
2022

19. Long-term follow-up of cladribine treatment in hairy cell leukemia: 30-year experience in a multicentric Italian study

Author

Pagano, Livio, Criscuolo, Marianna, Broccoli, A., Piciocchi, A., Varettoni, M., Galli, Eugenio, Anastasia, A., Cantonetti, M., Trentin, L., Kovalchuk, S., Orsucci, L., Frustaci, A., Spolzino, A., Volpetti, S., Annibali, O., Storti, Sergio, Stelitano, C., Marchesi, F., Offidani, M., Casadei, B., Nizzoli, M. E., De Luca, M. L., Fianchi, Luana, Motta, M., Guarnera, L., Simonetti, E., Visentin, A., Vassallo, F., Deodato, M., Sarlo, C., Olivieri, A., Falini, B., Pulsoni, A., Tiacci, E., Zinzani, P. L., Pagano L. (ORCID:0000-0001-8287-928X), Criscuolo M., Galli E., Storti S. (ORCID:0000-0002-4374-3985), Fianchi L., Pagano, Livio, Criscuolo, Marianna, Broccoli, A., Piciocchi, A., Varettoni, M., Galli, Eugenio, Anastasia, A., Cantonetti, M., Trentin, L., Kovalchuk, S., Orsucci, L., Frustaci, A., Spolzino, A., Volpetti, S., Annibali, O., Storti, Sergio, Stelitano, C., Marchesi, F., Offidani, M., Casadei, B., Nizzoli, M. E., De Luca, M. L., Fianchi, Luana, Motta, M., Guarnera, L., Simonetti, E., Visentin, A., Vassallo, F., Deodato, M., Sarlo, C., Olivieri, A., Falini, B., Pulsoni, A., Tiacci, E., Zinzani, P. L., Pagano L. (ORCID:0000-0001-8287-928X), Criscuolo M., Galli E., Storti S. (ORCID:0000-0002-4374-3985), and Fianchi L.

Abstract

Hairy cell leukemia (HCL) is a rare lymphoproliferative disease with an excellent prognosis after treatment with cladribine (2CDA), although relapse may occur during follow-up. The aim of the study is to review the efficacy, safety, long-term remission rate, and overall survival (OS) in those patients who received 2CDA as first-line treatment. We retrospectively reviewed data of HCL patients treated with 2CDA between March 1991 and May 2019 at 18 Italian Hematological centers: 513 patients were evaluable for study purpose. The median age was 54 years (range 24–88) and ECOG was 0 in 84.9% of cases. A total of 330 (64.3%) patients received 2CDA intravenously and 183 (35.7%) subcutaneously. ORR was 91.8%: CR was obtained in 335 patients (65.3%), PR in 96 (18.7%), and hematological response in 40 (7.8%) patients; in 42 (8.2%) no response was observed. Hemoglobin value (p = 0.044), frequency of circulating hairy cells (p = 0.039), recovery of absolute neutrophil count (p = 0.006), and normalization of spleen (p ≤ 0.001) were associated with CR compared to PR in univariable analysis. At a median follow-up of 6.83 years (range 0.04–28.52), the median time to relapse was 12.2 years. A significant difference in duration of response was identified between patients that obtained a CR and PR (19.4 years versus 4.8 years, p < 0.0001). Non-hematological grade 3 or higher early toxicity was reported in 103 (20.1%) patients. Median OS was not reached: 95.3%, 92.4%, and 81.8% of patients were estimated to be alive at 5, 10, and 15 years, respectively. Forty-nine patients died (9.5%), following an infection in 14 cases (2.7%), natural causes in 14 (2.7%), cardiovascular events in 13 (2.5%), a second neoplasm in 6 (1.2%), and progression of HCL in 2 cases (0.4%). Following treatment of HCL with 2CDA, 80% of patients are estimated to be alive 15 years after diagnosis.

Published
2022

20. High Incidence of Invasive Fungal Diseases in Patients with FLT3-Mutated AML Treated with Midostaurin: Results of a Multicenter Observational SEIFEM Study

Author

Cattaneo, C., Marchesi, F., Terrenato, I., Bonuomo, V., Fracchiolla, N. S., Delia, M., Criscuolo, Marianna, Candoni, A., Prezioso, L., Facchinelli, D., Pasciolla, C., Del Principe, M. I., Dargenio, M., Buquicchio, C., Mitra, M. E., Farina, F., Borlenghi, E., Nadali, G., Gagliardi, V. P., Fianchi, Luana, Sciume, M., Menna, P., Busca, A., Rossi, G., Pagano, Livio, Criscuolo M., Fianchi L., Pagano L. (ORCID:0000-0001-8287-928X), Cattaneo, C., Marchesi, F., Terrenato, I., Bonuomo, V., Fracchiolla, N. S., Delia, M., Criscuolo, Marianna, Candoni, A., Prezioso, L., Facchinelli, D., Pasciolla, C., Del Principe, M. I., Dargenio, M., Buquicchio, C., Mitra, M. E., Farina, F., Borlenghi, E., Nadali, G., Gagliardi, V. P., Fianchi, Luana, Sciume, M., Menna, P., Busca, A., Rossi, G., Pagano, Livio, Criscuolo M., Fianchi L., and Pagano L. (ORCID:0000-0001-8287-928X)

Abstract

The potential drug-drug interactions of midostaurin may impact the choice of antifungal (AF) prophylaxis in FLT3-positive acute myeloid leukemia (AML) patients. To evaluate the incidence of invasive fungal diseases (IFD) during the treatment of FLT3-mutated AML patients and to correlate it to the different AF prophylaxis strategies, we planned a multicenter observational study involving 15 SEIFEM centers. One hundred fourteen patients treated with chemotherapy + midostaurin as induction/reinduction, consolidation or both were enrolled. During induction, the incidence of probable/proven and possible IFD was 10.5% and 9.7%, respectively; no statistically significant difference was observed according to the different AF strategy adopted. The median duration of neutropenia was similar in patients with or without IFD. Proven/probable and possible IFD incidence was 2.4% and 1.8%, respectively, during consolidation. Age was the only risk factor for IFD (OR, 95% CI, 1.10 [1.03–1.19]) and complete remission achievement after first induction the only one for survival (OR, 95% CI, 5.12 [1.93–13.60]). The rate of midostaurin discontinuation was similar across different AF strategies. The IFD attributable mortality during induction was 8.3%. In conclusion, the 20.2% overall incidence of IFD occurring in FLT3-mutated AML during induction with chemotherapy + midostaurin, regardless of AF strategy type, was noteworthy, and merits further study, particularly in elderly patients.

Published
2022

23. Treatment of Philadelphia-negative myeloproliferative neoplasms in accelerated/blastic phase with azacytidine. Clinical results and identification of prognostic factors

Author

Andriani, A, Elli, E, Trape, G, Villiva, N, Fianchi, L, Di Veroli, A, Niscola, P, Centra, A, Anaclerico, B, Montanaro, G, Martini, V, Aroldi, A, Carmosino, I, Voso, M, Breccia, M, Montanaro, M, Foa, R, Latagliata, R, Andriani A., Elli E., Trape G., Villiva N., Fianchi L., Di Veroli A., Niscola P., Centra A., Anaclerico B., Montanaro G., Martini V., Aroldi A., Carmosino I., Voso M. T., Breccia M., Montanaro M., Foa R., Latagliata R., Andriani, A, Elli, E, Trape, G, Villiva, N, Fianchi, L, Di Veroli, A, Niscola, P, Centra, A, Anaclerico, B, Montanaro, G, Martini, V, Aroldi, A, Carmosino, I, Voso, M, Breccia, M, Montanaro, M, Foa, R, Latagliata, R, Andriani A., Elli E., Trape G., Villiva N., Fianchi L., Di Veroli A., Niscola P., Centra A., Anaclerico B., Montanaro G., Martini V., Aroldi A., Carmosino I., Voso M. T., Breccia M., Montanaro M., Foa R., and Latagliata R.

Abstract

There have been some reports on a possible role of azacytidine (AZA) in the treatment of accelerated/blastic phase evolved from Philadelphia-negative myeloproliferative neoplasms (MPN-AP/BP), but results are conflicting. In this study, we analyzed a cohort of 39 patients with MPN-AP/BP treated frontline with AZA at the standard dosage (75 mg/m2). Median time from diagnosis to AP/BP evolution was 92.3 months (IR 29.9-180.1). All patients were evaluable for hematologic response: two patients (5.2%) died early after AZA initiation, 13 patients (33.3%) had a progressive or stable disease, nine (23.1%) had a hematologic improvement (HI), seven (17.9%) achieved a partial response (PR), and eight (20.5%) a complete response (CR). Overall, 24 patients achieved a clinical hematologic response (HI + PR + CR), with an overall response rate of 61.5%. Median overall survival (OS) from AZA start of the whole cohort was 13.5 months (95% CI, 8.2-18.7). There was no difference in median OS among patients with HI, PR, or CR (P =.908). These three subgroups as “responders” having been considered, a significantly better OS was observed in responder compared with nonresponder patients, with a median OS of 17.6 months (95% CI, 10.1-25.0) versus 4.1 months (95% CI, 0.4-10.0) (P =.001) Only female gender was significant for both achievement of response (.010) and OS duration (P =.002). In conclusion, AZA is useful for the management of MPN-AP/BP, with an overall response rate (HI + PR + CR) of 61.5% and a longer OS in responders.

Published
2019

25. Toxic iron species in lower-risk myelodysplastic syndrome patients : course of disease and effects on outcome

Author

Hoeks, Marlijn, Bagguley, Tim, van Marrewijk, Corine, Smith, Alex, Bowen, David, Culligan, Dominic, Kolade, Seye, Symeonidis, Argiris, Garelius, Hege, Spanoudakis, Michail, Langemeijer, Saskia, Roelofs, Rian, Wiegerinck, Erwin, Tatic, Aurelia, Killick, Sally, Panagiotidis, Panagiotis, Stanca, Oana, Hellström-Lindberg, Eva, Cermak, Jaroslav, van der Klauw, Melanie, Wouters, Hanneke, van Kraaij, Marian, Blijlevens, Nicole, Swinkels, Dorine W., de Witte, Theo, Stauder, R., Walder, A., Pfeilstöcker, M., Schoenmetzler-Makrai, A., Burgstaller, S., Thaler, J., Mandac Rogulj, I., Krejci, M., Voglova, J., Rohon, P., Jonasova, A., Cermak, J., Mikulenkova, D., Hochova, I., Jensen, P. D., Holm, M. S., Kjeldsen, L., Dufva, I. H., Vestergaard, H., Re, D., Slama, B., Fenaux, P., Choufi, B., Cheze, S., Klepping, D., Salles, B., de Renzis, B., Willems, L., De Prost, D., Gutnecht, J., Courby, S., Siguret, V., Tertian, G., Pascal, L., Chaury, M., Wattel, E., Guerci, A., Legros, L., Itzykson, R., Ades, L., Isnard, F., Sanhes, L., Benramdane, R., Stamatoullas, A., Amé, S., Beyne-Rauzy, O., Gyan, E., Platzbecker, U., Badrakan, C., Germing, U., Lübbert, M., Schlenk, R., Kotsianidis, I., Tsatalas, C., Pappa, V., Galanopoulos, A., Michali, E., Panagiotidis, P., Viniou, N., Katsigiannis, A., Roussou, P., Terpos, E., Kostourou, A., Kartasis, Z., Pouli, A., Palla, K., Briasoulis, V., Hatzimichael, E., Vassilopoulos, G., Symeonidis, A., Kourakli, A., Zikos, P., Anagnostopoulos, A., Kotsopoulou, M., Megalakaki, K., Protopapa, M., Vlachaki, E., Konstantinidou, P., Stemer, G., Nemetz, A., Gotwin, U., Cohen, O., Koren, M., Levy, E., Greenbaum, U., Gino-Moor, S., Price, M., Ofran, Y., Winder, A., Goldshmidt, N., Elias, S., Sabag, R., Hellman, I., Ellis, M., Braester, A., Rosenbaum, H., Berdichevsky, S., Itzhaki, G., Wolaj, O., Yeganeh, S., Katz, O., Filanovsky, K., Dali, N., Mittelman, M., Malcovati, L., Fianchi, L., vd Loosdrecht, A., Matthijssen, V., Herbers, A., Pruijt, H., Aboosy, N., de Vries, F., Velders, G., Jacobs, E., Langemeijer, S., MacKenzie, M., Lensen, C., Kuijper, P., Madry, K., Camara, M., Almeida, A., Vulkan, G., Stanca Ciocan, O., Tatic, A., Savic, A., Pedro, C., Xicoy, B., Leiva, P., Munoz, J., Betes, V., Benavente, C., Lozano, M., Martinez, M., Iniesta, P., Bernal, T., Diez Campelo, M., Tormo, D., Andreu Lapiedra, R., Sanz, G., Hesse Sundin, E., Garelius, H., Karlsson, C., Antunovic, P., Jönsson, A., Brandefors, L., Nilsson, L., Kozlowski, P., Hellstrom-Lindberg, E., Grövdal, M., Larsson, K., Wallvik, J., Lorenz, F., Ejerblad, E., Culligan, D., Craddock, C., Kolade, S., Cahalin, P., Killick, S., Ackroyd, S., Wong, C., Warren, A., Drummond, M., Hall, C., Rothwell, K., Green, S., Ali, S., Bowen, D., Karakantza, M., Dennis, M., Jones, G., Parker, J., Bowen, A., Radia, R., Das-Gupta, E., Vyas, P., Nga, E., Creagh, D., Ashcroft, J., Mills, J., Bond, L., Life Course Epidemiology (LCE), and VU University medical center

Subjects
Adult, Male, 0301 basic medicine, Cancer Research, medicine.medical_specialty, Iron Overload, Iron, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], Vascular damage Radboud Institute for Health Sciences [Radboudumc 16], Ferroportin, Lower risk, Gastroenterology, Article, Cancer development and immune defence Radboud Institute for Health Sciences [Radboudumc 2], 03 medical and health sciences, 0302 clinical medicine, Hepcidin, Internal medicine, Humans, Medicine, Blood Transfusion, Prospective Studies, Aged, Soluble transferrin receptor, biology, business.industry, Transferrin saturation, Hematology, Middle Aged, Erythroferrone, Prognosis, 3. Good health, Survival Rate, Ferritin, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Oncology, Myelodysplastic Syndromes, 030220 oncology & carcinogenesis, biology.protein, Erythropoiesis, Female, business, Myelodysplastic syndrome, Follow-Up Studies, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Red blood cell transfusions (RBCT) remain the cornerstone of supportive care in lower-risk myelodysplastic syndrome (LRMDS) [1]. Transfusion dependency in LRMDS patients is associated with inferior outcomes, mainly attributed to severe bone marrow failure [2]. However, iron toxicity, due to frequent RBCT or ineffective erythropoiesis, may be an additional negative prognostic factor [3,4,5,6]. Recently, much progress has been made in unraveling the iron metabolism. The peptide hormone hepcidin is the key regulator by inhibiting iron uptake through degradation of ferroportin, a cellular iron exporter [7]. Erythroferrone and GDF15, produced by erythroblasts, inhibit hepcidin production, which leads to increased uptake and cellular release of iron for the purpose of erythropoiesis [8]. The pathophysiology of iron metabolism in MDS is still not completely understood. Exceedingly high reactive oxygen species (ROS) levels are associated with iron toxicity, disease development, and progression in MDS patients [9,10,11,12]. Malondialdehyde (MDA), resulting from lipid peroxidation of polyunsaturated fatty acids, is a biomarker of oxidative stress [10, 12]. Currently, little is known about the prognostic impact of ROS in MDS patients. The aim of this study is twofold: (1) describe iron and oxidative stress parameters over time in LRMDS patients and (2) to assess their effect on overall and progression-free survival. The EUMDS registry prospectively collects observational data on newly diagnosed LRMDS patients from 148 centers in 16 countries in Europe and Israel as of January 2008. All patients provided informed consent. Clinical data were collected at baseline and at each six-monthly follow-up visit. Serum samples were collected prospectively at each visit from 256 patients included in six participating countries. Conventional iron parameters were measured with routine assays. We additionally analyzed hepcidin, growth differentiation factor 15 (GDF15), soluble transferrin receptor (sTfR), non-transferrin bound iron (NTBI), labile plasma iron (LPI), and MDA. Subjects were prospectively followed until death, loss to follow-up, or withdrawal of consent. All iron parameters were measured centrally at the department of Laboratory Medicine of the Radboudumc, Nijmegen, The Netherlands. Serum samples were collected just prior to transfusion in transfusion-dependent patients and stored at −80 °C. Details on the assays and reference ranges of hepcidin, GDF15, sTfR, NTBI, LPI, and MDA are provided in the supplement. The Spearman rank test was used to evaluate correlations between iron parameters. We stratified the results by transfusion dependency per visit and the presence of ring sideroblasts. When evaluating temporal changes in iron parameters, with linear quantile mixed models, we excluded patients from the timepoint they received iron chelation therapy. Overall survival (OS) was defined as the time from MDS diagnosis to death or, in case of progression-free survival, to date of progression or death; patients still alive at the end of follow-up were censored. Time-dependent Kaplan–Meier curves and cox proportional hazards models were used. In total, 256 consecutive patients, were included in this study. Over five six-monthly visits, 1040 samples were collected. Table 1 describes the patient characteristics. Most patients without ring sideroblasts were transfusion-independent at diagnosis (nonRS-TI; 55.9%), 18.8% with ring sideroblasts were transfusion-independent (RS-TI), 18.4% without ring sideroblasts were transfusion-dependent (nonRS-TD), and 7% with ring sideroblasts were transfusion-dependent patients (RS-TD). The median follow-up time was 6.6 years (95% CI 5.9–7.0). LPI was positively correlated with transferrin saturation (TSAT) (r = 0.15, p < 0.001, Fig. S1). LPI values increased exponentially at TSAT values above 80%. This effect was most pronounced in the transfusion-dependent groups, but also observed in the RS-TI group. MDA was weakly correlated with NTBI (r = 0.09, p = 0.069) and negatively correlated with hemoglobin level (r = −0.1, p = 0.033). GDF15 and hepcidin were negatively correlated in the RS-TI and nonRS-TD group and significantly negatively correlated in the RS-TD group (r = −0.34, p = 0.007, Fig. S2). Serum ferritin levels were elevated in all subgroups with a mean value of 858 µg/L at visit 5. The highest serum ferritin levels were observed in the RS-TD group (mean value at visit 5: 2092 µg/L, Table S1). Serum ferritin increased significantly per visit in the RS-TD group (beta 454.46 µg/L; 95% CI 334.65–574.27), but not in the other groups (Table S2). All subgroups, except for the nonRS-TI, had elevated TSAT levels. TSAT levels were most markedly increased in the RS-TD group with a mean TSAT of 88% at visit 5 (Table S1). In both transfusion-dependent groups the median increase per visit was significant (Table S2). LPI was elevated in the RS-TD group exclusively with a mean value of 0.59 µmol/L at visit 5 (Table S1). NTBI was elevated in all subgroups, with the highest values in the RS-TD group (Table S1). The increase in median NTBI level was significant in both transfusion-dependent groups (Table S2). Hepcidin levels were markedly elevated in the nonRS-TD group. Interestingly, hepcidin levels were lower in the RS-TD group, probably reflecting ineffective erythropoiesis, likewise supported by lower hepcidin/ferritin ratios in RS groups (Table S1). Median hepcidin levels increased over time in the transfusion-dependent subgroups only (Table S2). GDF15 levels, analyzed in the light of its potential role in hepcidin suppression, were increased in all subgroups (Table S1). The RS subgroups had higher GDF15 levels compared to the nonRS groups, reflecting increased erythropoiesis. Mean sTfR levels were within the reference range in all subgroups except for the RS-TI group, which showed elevated levels, reflecting...

Published
2021

26. Topic: AS04-MDS Biology and Pathogenesis/AS04d-Somatic mutations

Author

Chiusolo, P., primary, Marchetti, C., additional, Rossi, M., additional, Minnella, G., additional, Salutari, V., additional, Fagotti, A., additional, Di Stefano, M.G., additional, Giammarco, S., additional, Metafuni, E., additional, Fianchi, L., additional, Scambia, G., additional, and Sica, S., additional

Published
2021
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29. Toxic iron species in lower-risk myelodysplastic syndrome patients: course of disease and effects on outcome

Author

Hoeks, M. Bagguley, T. van Marrewijk, C. Smith, A. Bowen, D. Culligan, D. Kolade, S. Symeonidis, A. Garelius, H. Spanoudakis, M. Langemeijer, S. Roelofs, R. Wiegerinck, E. Tatic, A. Killick, S. Panagiotidis, P. Stanca, O. Hellström-Lindberg, E. Cermak, J. van der Klauw, M. Wouters, H. van Kraaij, M. Blijlevens, N. Swinkels, D.W. de Witte, T. Stauder, R. Walder, A. Pfeilstöcker, M. Schoenmetzler-Makrai, A. Burgstaller, S. Thaler, J. Mandac Rogulj, I. Krejci, M. Voglova, J. Rohon, P. Jonasova, A. Cermak, J. Mikulenkova, D. Hochova, I. Jensen, P.D. Holm, M.S. Kjeldsen, L. Dufva, I.H. Vestergaard, H. Re, D. Slama, B. Fenaux, P. Choufi, B. Cheze, S. Klepping, D. Salles, B. de Renzis, B. Willems, L. De Prost, D. Gutnecht, J. Courby, S. Siguret, V. Tertian, G. Pascal, L. Chaury, M. Wattel, E. Guerci, A. Legros, L. Itzykson, R. Ades, L. Isnard, F. Sanhes, L. Benramdane, R. Stamatoullas, A. Amé, S. Beyne-Rauzy, O. Gyan, E. Platzbecker, U. Badrakan, C. Germing, U. Lübbert, M. Schlenk, R. Kotsianidis, I. Tsatalas, C. Pappa, V. Galanopoulos, A. Michali, E. Panagiotidis, P. Viniou, N. Katsigiannis, A. Roussou, P. Terpos, E. Kostourou, A. Kartasis, Z. Pouli, A. Palla, K. Briasoulis, V. Hatzimichael, E. Vassilopoulos, G. Symeonidis, A. Kourakli, A. Zikos, P. Anagnostopoulos, A. Kotsopoulou, M. Megalakaki, K. Protopapa, M. Vlachaki, E. Konstantinidou, P. Stemer, G. Nemetz, A. Gotwin, U. Cohen, O. Koren, M. Levy, E. Greenbaum, U. Gino-Moor, S. Price, M. Ofran, Y. Winder, A. Goldshmidt, N. Elias, S. Sabag, R. Hellman, I. Ellis, M. Braester, A. Rosenbaum, H. Berdichevsky, S. Itzhaki, G. Wolaj, O. Yeganeh, S. Katz, O. Filanovsky, K. Dali, N. Mittelman, M. Malcovati, L. Fianchi, L. vd Loosdrecht, A. Matthijssen, V. Herbers, A. Pruijt, H. Aboosy, N. de Vries, F. Velders, G. Jacobs, E. Langemeijer, S. MacKenzie, M. Lensen, C. Kuijper, P. Madry, K. Camara, M. Almeida, A. Vulkan, G. Stanca Ciocan, O. Tatic, A. Savic, A. Pedro, C. Xicoy, B. Leiva, P. Munoz, J. Betes, V. Benavente, C. Lozano, M. Martinez, M. Iniesta, P. Bernal, T. Diez Campelo, M. Tormo, D. Andreu Lapiedra, R. Sanz, G. Hesse Sundin, E. Garelius, H. Karlsson, C. Antunovic, P. Jönsson, A. Brandefors, L. Nilsson, L. Kozlowski, P. Hellstrom-Lindberg, E. Grövdal, M. Larsson, K. Wallvik, J. Lorenz, F. Ejerblad, E. Culligan, D. Craddock, C. Kolade, S. Cahalin, P. Killick, S. Ackroyd, S. Wong, C. Warren, A. Drummond, M. Hall, C. Rothwell, K. Green, S. Ali, S. Karakantza, M. Dennis, M. Jones, G. Parker, J. Bowen, A. Radia, R. Das-Gupta, E. Vyas, P. Nga, E. Creagh, D. Ashcroft, J. Mills, J. Bond, L. the EUMDS Registry Participants

Published
2021

30. Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes.

Author

Skikne B., Lopes de Menezes D., Beach C.L., Giagounidis A., Garcia-Manero G., Santini V., Almeida A., Platzbecker U., Jonasova A., Silverman L.R., Falantes J., Reda G., Buccisano F., Fenaux P., Buckstein R., Diez Campelo M., Larsen S., Valcarcel D., Vyas P., Giai V., Oliva E.N., Shortt J., Niederwieser D., Mittelman M., Fianchi L., La Torre I., Zhong J., Laille E., Skikne B., Lopes de Menezes D., Beach C.L., Giagounidis A., Garcia-Manero G., Santini V., Almeida A., Platzbecker U., Jonasova A., Silverman L.R., Falantes J., Reda G., Buccisano F., Fenaux P., Buckstein R., Diez Campelo M., Larsen S., Valcarcel D., Vyas P., Giai V., Oliva E.N., Shortt J., Niederwieser D., Mittelman M., Fianchi L., La Torre I., Zhong J., and Laille E.

Abstract

PURPOSE: Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia. METHOD(S): Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULT(S): Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 x 109/L, and absolute neutrophil count was 1.3 x 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (P = .0002), with median durations of 11.1 and 5.0 months. Reductions of >= 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had >= 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 x 109/L. CONCLUSION(S): CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further e

Published
2021

31. Phase III, Randomized, Placebo-Controlled Trial of CC-486 (Oral Azacitidine) in Patients With Lower-Risk Myelodysplastic Syndromes

Author

Garcia-Manero, G, Santini, V, Almeida, A, Platzbecker, U, Jonasova, A, Silverman, LR, Falantes, J, Reda, G, Buccisano, F, Fenaux, P, Buckstein, R, Campelo, MD, Larsen, S, Valcarcel, D, Vyas, P, Giai, V, Oliva, EN, Shortt, J, Niederwieser, D, Mittelman, M, Fianchi, L, La Torre, I, Zhong, J, Laille, E, de Menezes, DL, Skikne, B, Beach, CL, Giagounidis, A, Garcia-Manero, G, Santini, V, Almeida, A, Platzbecker, U, Jonasova, A, Silverman, LR, Falantes, J, Reda, G, Buccisano, F, Fenaux, P, Buckstein, R, Campelo, MD, Larsen, S, Valcarcel, D, Vyas, P, Giai, V, Oliva, EN, Shortt, J, Niederwieser, D, Mittelman, M, Fianchi, L, La Torre, I, Zhong, J, Laille, E, de Menezes, DL, Skikne, B, Beach, CL, and Giagounidis, A

Abstract

PURPOSE: Treatment options are limited for patients with lower-risk myelodysplastic syndromes (LR-MDS). This phase III, placebo-controlled trial evaluated CC-486 (oral azacitidine), a hypomethylating agent, in patients with International Prognostic Scoring System LR-MDS and RBC transfusion-dependent anemia and thrombocytopenia. METHODS: Patients were randomly assigned 1:1 to CC-486 300-mg or placebo for 21 days/28-day cycle. The primary end point was RBC transfusion independence (TI). RESULTS: Two hundred sixteen patients received CC-486 (n = 107) or placebo (n = 109). The median age was 74 years, median platelet count was 25 × 109/L, and absolute neutrophil count was 1.3 × 109/L. In the CC-486 and placebo arms, 31% and 11% of patients, respectively, achieved RBC-TI (P = .0002), with median durations of 11.1 and 5.0 months. Reductions of ≥ 4 RBC units were attained by 42.1% and 30.6% of patients, respectively, with median durations of 10.0 and 2.3 months, and more CC-486 patients had ≥ 1.5 g/dL hemoglobin increases from baseline (23.4% v 4.6%). Platelet hematologic improvement rate was higher with CC-486 (24.3% v 6.5%). Underpowered interim overall survival analysis showed no difference between CC-486 and placebo (median, 17.3 v 16.2 months; P = .96). Low-grade GI events were the most common adverse events in both arms. In the CC-486 and placebo arms, 90% and 73% of patients experienced a grade 3-4 adverse event. Overall death rate was similar between arms, but there was an imbalance in deaths during the first 56 days (CC-486, n = 16; placebo, n = 6), most related to infections; the median pretreatment absolute neutrophil count for the 16 CC-486 patients was 0.57 × 109/L. CONCLUSION: CC-486 significantly improved RBC-TI rate and induced durable bilineage improvements in patients with LR-MDS and high-risk disease features. More early deaths occurred in the CC-486 arm, most related to infections in patients with significant pretreatment neutropenia. Further evaluation

Published
2021

32. OUTCOMES OF RELAPSED OR REFRACTORY AND NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA AFTER HYPOMETHYLATING AGENT AND VENETOCLAX. THE ITALIAN REAL-LIFE EXPERIENCE BEFORE PUBLIC HEALTH REIMBURSEMENT (AVALON STUDY)

Author

Todisco, E, Papayannidis, C, Fracchiolla, N, Cerchione, C, Marconi, G, Petracci, E, Zingaretti, C, Vetro, C, Martelli, M, Zappasodi, P, Di Renzo, N, Cignetti, A, Lussana, F, Mattei, D, Ciceri, F, Facchini, L, Selleri, C, Fumagalli, M, Audisio, E, Griguolo, D, Basilico, C, Manfra, I, Borlenghi, E, Cairoli, R, Salutari, P, Gottardi, M, Molteni, A, Martini, V, Lunghi, M, Fianchi, L, Cilloni, D, Lanza, F, Abruzzese, E, Cascavilla, N, Rivellini, F, Ferrara, F, Maurillo, L, Nanni, J, Romano, A, Cardinali, V, Gigli, F, Vincenzo, F, Volpi, R, Sciume, M, Tarella, C, Rossi, G, Martinelli, G, Todisco, E, Papayannidis, C, Fracchiolla, N, Cerchione, C, Marconi, G, Petracci, E, Zingaretti, C, Vetro, C, Martelli, M, Zappasodi, P, Di Renzo, N, Cignetti, A, Lussana, F, Mattei, D, Ciceri, F, Facchini, L, Selleri, C, Fumagalli, M, Audisio, E, Griguolo, D, Basilico, C, Manfra, I, Borlenghi, E, Cairoli, R, Salutari, P, Gottardi, M, Molteni, A, Martini, V, Lunghi, M, Fianchi, L, Cilloni, D, Lanza, F, Abruzzese, E, Cascavilla, N, Rivellini, F, Ferrara, F, Maurillo, L, Nanni, J, Romano, A, Cardinali, V, Gigli, F, Vincenzo, F, Volpi, R, Sciume, M, Tarella, C, Rossi, G, and Martinelli, G

Published
2021

33. Disseminated geosmithia argillacea infection in a patient with ph-positive acute lymphoblastic leukemia. Case report and literature review

Author

Giordano, A., Di Landro, Francesca, De Carolis, Elena, Criscuolo, Marianna, Dragonetti, Giulia, Fianchi, Luana, Pagano, Livio, Di Landro F., De Carolis E. (ORCID:0000-0003-4757-7256), Criscuolo M., Dragonetti G., Fianchi L., Pagano L. (ORCID:0000-0001-8287-928X), Giordano, A., Di Landro, Francesca, De Carolis, Elena, Criscuolo, Marianna, Dragonetti, Giulia, Fianchi, Luana, Pagano, Livio, Di Landro F., De Carolis E. (ORCID:0000-0003-4757-7256), Criscuolo M., Dragonetti G., Fianchi L., and Pagano L. (ORCID:0000-0001-8287-928X)

Abstract

Invasive fungal infection (IFI) remains the major complication in patients with either acute leukemia, allogeneic stem cell transplantation setting, or both, especially regarding pulmonary lo-calization. We report an experience of a 74-year-old Caucasian male with a Philadelphia-positive (BCR-ABL p190) Common B-acute lymphoblastic leukemia (ALL) who developed a pulmonary infection due to Geosmithia argillacea. Furthermore, we describe the management of this complication and the results of microbiological tests useful to guide the treatment. All cases reported show failure of voriconazole treatment. In the majority of cases a good susceptibility to posaconazole has been reported, which seems to have a good clinical impact; however, only L-AmB shows a clinical effect to produce quick clinical improvement and so it should be a drug of choice. A literature revision shows that only a few papers have thus far described this infection, at present only one case was reported in a hematological setting like a gastrointestinal graft versus host disease in an allogeneic HSCT recipient. The severity of clinical conditions in hematological malignancy settings requires improving the management of this emerging invasive fungal infection. Indeed, a molecular diag-nostic approach with a tight laboratory collaboration and targeted therapy should become the gold standard.

Published
2021

34. Extramedullary Involvement in Acute Myeloid Leukemia. A Single Center Ten Years' Experience

Author

Fianchi, Luana, Quattrone, Martina, Criscuolo, Marianna, Bellesi, Silvia, Dragonetti, Giulia, Maraglino, Alessio Maria Edoardo, Bonanni, Matteo, Chiusolo, Patrizia, Sica, Simona, Pagano, Livio, Fianchi L., Quattrone M., Criscuolo M., Bellesi S., Dragonetti G., Maraglino A. M. E., Bonanni M., Chiusolo P. (ORCID:0000-0002-1355-1587), Sica S. (ORCID:0000-0003-2426-3465), Pagano L. (ORCID:0000-0001-8287-928X), Fianchi, Luana, Quattrone, Martina, Criscuolo, Marianna, Bellesi, Silvia, Dragonetti, Giulia, Maraglino, Alessio Maria Edoardo, Bonanni, Matteo, Chiusolo, Patrizia, Sica, Simona, Pagano, Livio, Fianchi L., Quattrone M., Criscuolo M., Bellesi S., Dragonetti G., Maraglino A. M. E., Bonanni M., Chiusolo P. (ORCID:0000-0002-1355-1587), Sica S. (ORCID:0000-0003-2426-3465), and Pagano L. (ORCID:0000-0001-8287-928X)

Abstract

The incidence, risk factors, and prognostic significance of extramedullary involvement (EMI) in adult patients with acute myeloid leukemia (AML) have not been established yet. This study analyzed clinical and biological characteristics, the impact on prognosis, and the cumulative incidence of EMI in a monocentric retrospective series. All adult patients diagnosed with AML observed in our institution between January 2010 and December 2017 were included in the analysis. Overall, 346 AMLs were analyzed. The incidence of EMI was 11% (38 patients). The involved sites were: Skin (66%), central nervous system (CNS) (23%), pleura (7%), lymph nodes (5%), peritoneum (2%), spleen (2%), pancreas (2%), breasts (2%) and bones (2%). Most patients (91%) had only one EMI site, while 9% had multiple sites affected at the same time. Twenty-four (63%) patients showed signs of EMI at presentation, while extramedullary relapse occurred in 10 patients (26%); 4 patients had EMI both at presentation and relapse. EMI had a significantly higher frequency in patients with monocytic and myelo-monocytic leukemia subtypes (p<0,0001), CD117-negative (p=0,03) at flow cytometry analysis, MLL rearrangements (p=0.001), trisomy 8 (p=0,02). An analysis regarding treatment, overall survival (OS), and disease-free survival (DFS) was performed only on the 28 patients who experienced EMI at the onset of their disease; one EMI patient receiving best supportive care was excluded from OS analysis. The other 27 patients were treated with: Conventional chemotherapy (21 patients), hypomethylating agents (5 patients), and low dose cytarabine (1 patient); 8 patients only (28.5%) received an allogeneic stem cell transplantation (allo-HSCT). After induction therapy, complete remission (CR) rate was 22%, with a median DFS of 7.4 months. The median OS of all 27 EMI patients was 11.6 months (range 2-79); this resulted significantly longer for the 8 EMI patients who undergone allo-HSCT than those (19 patients) who did

Published
2021

38. Polymorphisms within the ARNT2 and CX3CR1 Genes Are Associated with the Risk of Developing Invasive Aspergillosis

Author

Lupiañez, C B, Martínez-Bueno, M, Sánchez-Maldonado, J M, Badiola, J, Cunha, C, Springer, J, Lackner, M, Segura-Catena, J, Canet, L M, Alcazar-Fuoli, L, López-Nevot, M A, Fianchi, L, Aguado, J M, Pagano, L, López-Fernández, E, Alarcón-Riquelme, M, Potenza, L, Gonçalves, S M, Luppi, M, Moratalla, L, Solano, C, Sampedro, A, González-Sierra, P, Cuenca-Estrella, M, Lagrou, K, Maertens, J A, Lass-Flörl, C, Einsele, H, Vazquez, L, PCRAGA Study Group, Loeffler, J, Ríos-Tamayo, R, Carvalho, A, Jurado, M, and Sainz, J

Subjects
0301 basic medicine, host immunity, Genotype, 030106 microbiology, Immunology, Population, CX3C Chemokine Receptor 1, Single-nucleotide polymorphism, ARNT2, CX3CR1, genetic susceptibility, invasive aspergillosis, Biology, Aspergillosis, Microbiology, Polymorphism, Single Nucleotide, Risk Assessment, 03 medical and health sciences, medicine, Genetic predisposition, Basic Helix-Loop-Helix Transcription Factors, Humans, Genetic Predisposition to Disease, Allele, education, Invasive Pulmonary Aspergillosis, education.field_of_study, Haplotype, Aryl Hydrocarbon Receptor Nuclear Translocator, PCRAGA Study Group, medicine.disease, Hematologic Diseases, 3. Good health, Settore MED/15 - MALATTIE DEL SANGUE, 030104 developmental biology, Infectious Diseases, Aspergillus, Case-Control Studies, Expression quantitative trait loci, Parasitology
Abstract

Invasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients. We genotyped selected SNPs in a cohort of 500 hematological patients (103 of those had been diagnosed with proven or probable IA), and we evaluated their association with the risk of developing IA. The association of the most interesting markers of IA risk was then validated in a replication population, including 474 subjects (94 IA and 380 non-IA patients). Functional experiments were also performed to confirm the biological relevance of the most interesting markers. The meta-analysis of both populations showed that carriers of the ARNT2rs1374213G, CX3CR1rs7631529A, and CX3CR1rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing IA according to a log-additive model (P value from the meta-analysis [PMeta] = 9.8 · 10-5, PMeta = 1.5 · 10-4, and PMeta =7.9 · 10-5, respectively). Haplotype analysis also confirmed the association of the CX3CR1 haplotype with AG CGG with an increased risk of IA (P = 4.0 · 10-4). Mechanistically, we observed that monocyte-derived macrophages (MDM) from subjects carrying the ARNTR2rs1374213G allele or the GG genotype showed a significantly impaired fungicidal activity but that MDM from carriers of the ARNT2rs1374213G and CX3CR1rs9823718G or CX3CR1rs7631529A alleles had deregulated immune responses to Aspergillus conidia. These results, together with those from expression quantitative trait locus (eQTL) data browsers showing a strong correlation of the CX3CR1rs9823718G allele with lower levels of CX3CR1 mRNA in whole peripheral blood (P = 2.46 · 10-7) and primary monocytes (P = 4.31 · 10-7), highlight the role of the ARNT2 and CX3CR1 loci in modulating and predicting IA risk and provide new insights into the host immune mechanisms involved in IA development. ispartof: INFECTION AND IMMUNITY vol:88 issue:4 ispartof: location:United States status: published

Published
2020

39. Fungal infections in recipients of hematopoietic stem cell transplants: results of the SEIFEM B-2004 study - Sorveglianza Epidemiologica Infezioni Fungine Nelle Emopatie Maligne

Author

Pagano, L., Caira, M., Nosari, A., Van Lint, M.T., Candoni, A., Offidani, M., Aloisi, T., Irrera, G., Bonini, A., Picardi, M., Caramatti, C., Invernizzi, R., Mattei, D., Melillo, L., de Waure, C., Reddiconto, G., Fianchi, L., Valentini, C.G., Girmenia, C., Leone, G., and Aversa, F.

Subjects
Mycoses -- Causes of, Mycoses -- Health aspects, Mycoses -- Care and treatment, Mycoses -- Research, Organ transplant recipients -- Health aspects, Organ transplant recipients -- Patient outcomes, Hematopoietic stem cells -- Transplantation, Hematopoietic stem cells -- Methods, Hematopoietic stem cells -- Complications and side effects, Health, Health care industry
Published
2007

40. A phase iii placebo-controlled trial of CC-486 in patients with red blood cell transfusiondependent (RBC-TD) anemia and thrombocytopenia due to IPSS lower-risk myelodysplastic syndromes (LR-MDS).

Author

Laille E., Fianchi L., Zhong J., La Torre I., Giagounidis A., Beach C., Skikne B., Garcia-Manero G., Santini V., Almeida A., Platzbecker U., Jonasova A., Silverman L., Falantes J., Reda G., Buccisano F., Fenaux P., Buckstein R., Diez Campelo M., Larsen S., Valcarcel D., Vyas P., Giai V., Oliva E.N., Shortt J., Niederwieser D., Mittelman M., Laille E., Fianchi L., Zhong J., La Torre I., Giagounidis A., Beach C., Skikne B., Garcia-Manero G., Santini V., Almeida A., Platzbecker U., Jonasova A., Silverman L., Falantes J., Reda G., Buccisano F., Fenaux P., Buckstein R., Diez Campelo M., Larsen S., Valcarcel D., Vyas P., Giai V., Oliva E.N., Shortt J., Niederwieser D., and Mittelman M.

Abstract

Background: MDS is characterized by bone marrow dysplasia and peripheral cytopenias of variable severity. Treatment (Tx) options are limited for LR-MDS patients (pts) with low blast counts but high-risk disease features (eg, RBC-TD anemia and thrombocytopenia). The phase III placebo (PBO)-controlled QUAZAR Lower-risk MDS trial (NCT01566695) assessed CC-486, an oral hypomethylating agent, in pts who were RBC-TD and thrombocytopenic at study entry. Aim(s): Describe clinical outcomes from the QUAZAR Lower-risk MDS trial. Method(s): Eligible pts were age >=18 yrs, with IPSS LR-MDS, average RBC transfusion requirement of >=2 units (U)/28 days (d) for 56d, and 2 platelet (PLT) counts <=75 x 109/L taken >=21d apart. Pts were randomized 1:1 to CC-486 300 mg or PBO QD for 21d per 28d Tx cycle (C). The primary endpoint was RBC transfusion independence (TI) lasting >=56d (IWG 2006). Key secondary endpoints were overall survival (OS), >=84d RBC-TI, and hematologic improvement in erythroid and PLT lineages (HI-E, HI-P). Planned enrollment was 386 pts. An imbalance of early deaths in the CC-486 arm led to a decision to close enrollment; the final sample size (N = 216) allowed comparison of RBC-TI between Tx arms with ~99% power. Result(s): At data cutoff all pts (CC-486 n = 107; PBO n = 109) completed >=12 mo of Tx or discontinued before 12 mo. Baseline (BL) characteristics were similar between Tx arms. Median age was 74 yrs (30-89), Hgb 8.1 g/dL (5.4-10.9), PLT count 25x109/L (5-73), ANC 1.3x109/L (0.1-25), and transfusion requirement 6.7 U/56d. All pts had IPSS INT-1 MDS. Significantly more pts in the CC-486 arm achieved RBC-TI for >=56d (31%, vs. 11% with PBO; P = 0.0002) (Table 1). Median RBC-TI durations in the CC-486 and PBO arms were 11.1 and 5.0 mo, respectively (P = 0.42). In the CC-486 and PBO arms, 42% and 31%, respectively, had RBC transfusion reductions of >=4 U from BL, sustained for a median of 10.0 and 2.3 mo (P = 0.0001). While HI-E rates were comparable (P = 0.1

Published
2020

41. Host immune genetic variations influence the risk of developing acute myeloid leukaemia: results from the NuCLEAR consortium

Author

Sánchez-Maldonado, J M, Campa, D, Springer, J, Badiola, J, Niazi, Y, Moñiz-Díez, A, Hernández-Mohedo, F, González-Sierra, P, Ter Horst, R, Macauda, A, Brezina, S, Cunha, C, Lackner, M, López-Nevot, M A, Fianchi, Luana, Pagano, Livio, López-Fernández, E, Potenza, L, Luppi, M, Moratalla, L, Rodríguez-Sevilla, J J, Fonseca, J E, Tormo, M, Solano, C, Clavero, E, Romero, A, Li, Y, Lass-Flörl, C, Einsele, H, Vazquez, L, Loeffler, J, Hemminki, K, Carvalho, A, Netea, M G, Gsur, A, Dumontet, C, Canzian, F, Försti, A, Jurado, M, Sainz, J, Fianchi, L, Pagano, L (ORCID:0000-0001-8287-928X), Sánchez-Maldonado, J M, Campa, D, Springer, J, Badiola, J, Niazi, Y, Moñiz-Díez, A, Hernández-Mohedo, F, González-Sierra, P, Ter Horst, R, Macauda, A, Brezina, S, Cunha, C, Lackner, M, López-Nevot, M A, Fianchi, Luana, Pagano, Livio, López-Fernández, E, Potenza, L, Luppi, M, Moratalla, L, Rodríguez-Sevilla, J J, Fonseca, J E, Tormo, M, Solano, C, Clavero, E, Romero, A, Li, Y, Lass-Flörl, C, Einsele, H, Vazquez, L, Loeffler, J, Hemminki, K, Carvalho, A, Netea, M G, Gsur, A, Dumontet, C, Canzian, F, Försti, A, Jurado, M, Sainz, J, Fianchi, L, and Pagano, L (ORCID:0000-0001-8287-928X)

Abstract

The purpose of this study was to conduct a two-stage case control association study including 654 acute myeloid leukaemia (AML) patients and 3477 controls ascertained through the NuCLEAR consortium to evaluate the effect of 27 immune-related single nucleotide polymorphisms (SNPs) on AML risk. In a pooled analysis of cohort studies, we found that carriers of the IL13rs1295686A/A genotype had an increased risk of AML (PCorr = 0.0144) whereas carriers of the VEGFArs25648T allele had a decreased risk of developing the disease (PCorr = 0.00086). In addition, we found an association of the IL8rs2227307 SNP with a decreased risk of developing AML that remained marginally significant after multiple testing (PCorr = 0.072). Functional experiments suggested that the effect of the IL13rs1295686 SNP on AML risk might be explained by its role in regulating IL1Ra secretion that modulates AML blast proliferation. Likewise, the protective effect of the IL8rs2227307 SNP might be mediated by TLR2-mediated immune responses that affect AML blast viability, proliferation and chemorresistance. Despite the potential interest of these results, additional functional studies are still warranted to unravel the mechanisms by which these variants modulate the risk of AML. These findings suggested that IL13, VEGFA and IL8 SNPs play a role in modulating AML risk.

Published
2020

42. Polymorphisms within the ARNT2 and CX3CR1 Genes Are Associated with the Risk of Developing Invasive Aspergillosis

Author

Lupianez, C. B., Martinez-Bueno, M., Sanchez-Maldonado, J. M., Badiola, J., Cunha, C., Springer, J., Lackner, M., Segura-Catena, J., Canet, L. M., Alcazar-Fuoli, L., Lopez-Nevot, M. A., Fianchi, Luana, Aguado, J. M., Pagano, Livio, Lopez-Fernandez, E., Alarcon-Riquelme, M., Potenza, L., Goncalves, S. M., Luppi, M., Moratalla, L., Solano, C., Sampedro, A., Gonzalez-Sierra, P., Cuenca-Estrella, M., Lagrou, K., Maertens, J. A., Lass-Florl, C., Einsele, H., Vazquez, L., Loeffler, J., Rios-Tamayo, R., Carvalho, A., Jurado, M., Sainz, J., Fianchi L., Pagano L. (ORCID:0000-0001-8287-928X), Lupianez, C. B., Martinez-Bueno, M., Sanchez-Maldonado, J. M., Badiola, J., Cunha, C., Springer, J., Lackner, M., Segura-Catena, J., Canet, L. M., Alcazar-Fuoli, L., Lopez-Nevot, M. A., Fianchi, Luana, Aguado, J. M., Pagano, Livio, Lopez-Fernandez, E., Alarcon-Riquelme, M., Potenza, L., Goncalves, S. M., Luppi, M., Moratalla, L., Solano, C., Sampedro, A., Gonzalez-Sierra, P., Cuenca-Estrella, M., Lagrou, K., Maertens, J. A., Lass-Florl, C., Einsele, H., Vazquez, L., Loeffler, J., Rios-Tamayo, R., Carvalho, A., Jurado, M., Sainz, J., Fianchi L., and Pagano L. (ORCID:0000-0001-8287-928X)

Abstract

Invasive aspergillosis (IA) is a life-threatening infection that affects an increasing number of patients undergoing chemotherapy or allo-transplantation, and recent studies have shown that genetic factors contribute to disease susceptibility. In this two-stage, population-based, case-control study, we evaluated whether 7 potentially functional single nucleotide polymorphisms (SNPs) within the ARNT2 and CX3CR1 genes influence the risk of IA in high-risk hematological patients. We genotyped selected SNPs in a cohort of 500 hematological patients (103 of those had been diagnosed with proven or probable IA), and we evaluated their association with the risk of developing IA. The association of the most interesting markers of IA risk was then validated in a replication population, including 474 subjects (94 IA and 380 non-IA patients). Functional experiments were also performed to confirm the biological relevance of the most interesting markers. The meta-analysis of both populations showed that carriers of the ARNT2rs1374213G, CX3CR1rs7631529A, and CX3CR1rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing IA according to a log-additive model (P value from the meta-analysis [PMeta] = 9.8 · 10-5, PMeta = 1.5 · 10-4, and PMeta =7.9 · 10-5, respectively). Haplotype analysis also confirmed the association of the CX3CR1 haplotype with AG CGG with an increased risk of IA (P = 4.0 · 10-4). Mechanistically, we observed that monocyte-derived macrophages (MDM) from subjects carrying the ARNTR2rs1374213G allele or the GG genotype showed a significantly impaired fungicidal activity but that MDM from carriers of the ARNT2rs1374213G and CX3CR1rs9823718G or CX3CR1rs7631529A alleles had deregulated immune responses to Aspergillus conidia. These results, together with those from expression quantitative trait locus (eQTL) data browsers showing a strong correlation of the CX3CR1rs9823718G allele with lower levels of CX3CR1

Published
2020

43. Treatment of primary plasma cell leukemia with high doses of cyclophosphamide, bortezomib, and dexamethasone followed by double autologous HSCT

Author

Pagano, Livio, Maraglino, Alessio Maria Edoardo, Fianchi, Luana, Criscuolo, Marianna, Rossi, Elena, Za, Tommaso, Chiusolo, Patrizia, Bonanni, Matteo, Dragonetti, Giulia, Bacigalupo, Andrea, Sica, Simona, De Stefano, Valerio, Pagano L. (ORCID:0000-0001-8287-928X), Maraglino A. M. E., Fianchi L., Criscuolo M., Rossi E. (ORCID:0000-0002-7572-9379), Za T., Chiusolo P. (ORCID:0000-0002-1355-1587), Bonanni M., Dragonetti G., Bacigalupo A. (ORCID:0000-0002-9119-567X), Sica S. (ORCID:0000-0003-2426-3465), De Stefano V. (ORCID:0000-0002-5178-5827), Pagano, Livio, Maraglino, Alessio Maria Edoardo, Fianchi, Luana, Criscuolo, Marianna, Rossi, Elena, Za, Tommaso, Chiusolo, Patrizia, Bonanni, Matteo, Dragonetti, Giulia, Bacigalupo, Andrea, Sica, Simona, De Stefano, Valerio, Pagano L. (ORCID:0000-0001-8287-928X), Maraglino A. M. E., Fianchi L., Criscuolo M., Rossi E. (ORCID:0000-0002-7572-9379), Za T., Chiusolo P. (ORCID:0000-0002-1355-1587), Bonanni M., Dragonetti G., Bacigalupo A. (ORCID:0000-0002-9119-567X), Sica S. (ORCID:0000-0003-2426-3465), and De Stefano V. (ORCID:0000-0002-5178-5827)

Abstract

nd

Published
2020

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