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1. The time to first treatment is an independent predictor of overall survival in chronic lymphocytic leukemia

Author

Morabito, Francesco, Tripepi, G., Mauro, F. R., Laurenti, Luca, Reda, G., Moia, R., Condoluci, A., Vincelli, I., Chiarenza, A., Vigna, E., Martino, E. A., Bruzzese, Maria Antonella, Mezzatesta, S., Laureana, R., Cutrona, G., Di Raimondo, F., Fronza, G., Zucchetto, A., Bomben, R., Rossi, Federica Maria, Olivieri, J., Zaja, F., Rossi, Dario, Gaidano, G., Del Principe, M. I., Ilariucci, F., Del Poeta, G., Ferrarini, M., Neri, A., Gattei, V., Gentile, M., Morabito F., Laurenti L. (ORCID:0000-0002-8327-1396), Bruzzese A., Rossi F. M., Rossi D., Morabito, Francesco, Tripepi, G., Mauro, F. R., Laurenti, Luca, Reda, G., Moia, R., Condoluci, A., Vincelli, I., Chiarenza, A., Vigna, E., Martino, E. A., Bruzzese, Maria Antonella, Mezzatesta, S., Laureana, R., Cutrona, G., Di Raimondo, F., Fronza, G., Zucchetto, A., Bomben, R., Rossi, Federica Maria, Olivieri, J., Zaja, F., Rossi, Dario, Gaidano, G., Del Principe, M. I., Ilariucci, F., Del Poeta, G., Ferrarini, M., Neri, A., Gattei, V., Gentile, M., Morabito F., Laurenti L. (ORCID:0000-0002-8327-1396), Bruzzese A., Rossi F. M., and Rossi D.

Abstract

NA

Published
2023

2. Clinical impact of TP53 disruption in chronic lymphocytic leukemia patients treated with ibrutinib: a campus CLL study

Author

Bomben, R., Rossi, Federica Maria, Vit, F., Bittolo, T., Zucchetto, A., Papotti, R., Tissino, E., Pozzo, F., Degan, M., Polesel, J., Bulian, P., Marasca, R., Reda, G., Laurenti, Luca, Olivieri, J., Chiarenza, A., Laureana, R., Postorino, M., Del Principe, M. I., Cuneo, A., Gentile, M., Morabito, Francesco, Fronza, G., Tafuri, A., Zaja, F., Foa, Robin, Di Raimondo, F., Del Poeta, G., Gattei, V., Rossi F. M., Laurenti L. (ORCID:0000-0002-8327-1396), Morabito F., Foa R., Bomben, R., Rossi, Federica Maria, Vit, F., Bittolo, T., Zucchetto, A., Papotti, R., Tissino, E., Pozzo, F., Degan, M., Polesel, J., Bulian, P., Marasca, R., Reda, G., Laurenti, Luca, Olivieri, J., Chiarenza, A., Laureana, R., Postorino, M., Del Principe, M. I., Cuneo, A., Gentile, M., Morabito, Francesco, Fronza, G., Tafuri, A., Zaja, F., Foa, Robin, Di Raimondo, F., Del Poeta, G., Gattei, V., Rossi F. M., Laurenti L. (ORCID:0000-0002-8327-1396), Morabito F., and Foa R.

Abstract

NA

Published
2023

3. Efficacy of front-line ibrutinib versus fludarabine, cyclophosphamide, and rituximab in patients with chronic lymphocytic leukemia: A retrospective multicenter “Real-World” study

Author

Levi, S., Bronstein, Y., Goldschmidt, N., Morabito, Francesco, Ziv-Baran, T., Del Poeta, G., Bairey, O., Del Principe, M. I., Fineman, R., Mauro, F. R., Gutwein, O., Reda, G., Ruchlemer, R., Sportoletti, P., Laurenti, Luca, Shvidel, L., Coscia, M., Tadmor, T., Varettoni, M., Aviv, A., Murru, R., Braester, A., Chiarenza, A., Visentin, A., Pietrasanta, D., Loseto, G., Zucchetto, A., Bomben, R., Olivieri, J., Neri, A., Rossi, Dario, Gaidano, G., Trentin, L., Foa, Robin, Cuneo, A., Perry, C., Gattei, V., Gentile, M., Herishanu, Y., Morabito F., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi D., Foa R., Levi, S., Bronstein, Y., Goldschmidt, N., Morabito, Francesco, Ziv-Baran, T., Del Poeta, G., Bairey, O., Del Principe, M. I., Fineman, R., Mauro, F. R., Gutwein, O., Reda, G., Ruchlemer, R., Sportoletti, P., Laurenti, Luca, Shvidel, L., Coscia, M., Tadmor, T., Varettoni, M., Aviv, A., Murru, R., Braester, A., Chiarenza, A., Visentin, A., Pietrasanta, D., Loseto, G., Zucchetto, A., Bomben, R., Olivieri, J., Neri, A., Rossi, Dario, Gaidano, G., Trentin, L., Foa, Robin, Cuneo, A., Perry, C., Gattei, V., Gentile, M., Herishanu, Y., Morabito F., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi D., and Foa R.

Abstract

NA

Published
2023

5. Chronic lymphocytic leukemia management in Italy during the COVID-19 pandemic: a Campus CLL report

Author

Cuneo, A., Scarfo, L., Reda, G., Varettoni, M., Quaglia, F. M., Marchetti, M., De Paoli, L., Re, F., Pietrasanta, D., Rigolin, G. M., Orsucci, L., Ibatici, A., Gattei, V., Mauro, F. R., Trentin, L., Laurenti, L., Marasca, R., Foa, R., Angeletti, I., Chiurazzi, F., Del Poeta, G., Rosaria De Paolis, M., Farina, L., Ferrari, A., Gentile, M., Gottardi, D., Gozzetti, A., Leone, M., Levato, L., Maccaferri, M., Malerba, L., Motta, M., Murru, R., Nocilli, L., Olivieri, J., Stefoni, V., Cuneo, A., Scarfo', L., Reda, G., Varettoni, M., Quaglia, F. M., Marchetti, M., De Paoli, L., Re, F., Pietrasanta, D., Rigolin, G. M., Orsucci, L., Ibatici, A., Gattei, V., Mauro, F. R., Trentin, L., Laurenti, L., Marasca, R., Foa, R., Angeletti, I., Chiurazzi, F., Del Poeta, G., Rosaria De Paolis, M., Farina, L., Ferrari, A., Gentile, M., Gottardi, D., Gozzetti, A., Leone, M., Levato, L., Maccaferri, M., Malerba, L., Motta, M., Murru, R., Nocilli, L., Olivieri, J., and Stefoni, V.

Subjects
Aged, Aged, 80 and over, Betacoronavirus, COVID-19, Coronavirus Infections, Disease Management, Humans, Italy, Leukemia, Lymphocytic, Chronic, B-Cell, Middle Aged, Pandemics, Pneumonia, Viral, SARS-CoV-2, Chronic lymphocytic leukemia, Biochemistry, chemistry.chemical_compound, Pandemic, 80 and over, Viral, Chronic, Disease management (health), Letter to Blood, Leukemia, Hematology, Lymphocytic, Ibrutinib, CLL, COVID-19, Campus CLL, medicine.medical_specialty, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Immunology, Cancer therapy, NO, Internal medicine, medicine, business.industry, B-Cell, Pneumonia, Cell Biology, Campus CLL, medicine.disease, Settore MED/15 - MALATTIE DEL SANGUE, chemistry, business, CLL
Published
2020
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6. Do age, fitness, and concomitant medications influence management and outcomes of patients with CLL treated with ibrutinib?

Author

Tedeschi, A, Frustaci, A, Mauro, F, Chiarenza, A, Coscia, M, Ciolli, S, Reda, G, Laurenti, L, Varettoni, M, Murru, R, Barate, C, Sportoletti, P, Greco, A, Borella, C, Rossi, V, Deodato, M, Biagi, A, Zamprogna, G, Pelle, A, Lapietra, G, Vitale, C, Morelli, F, Cassin, R, Fresa, A, Cavalloni, C, Postorino, M, Ielo, C, Cairoli, R, Di Raimondo, F, Montillo, M, Del Poeta, G, Tedeschi A., Frustaci A. M., Mauro F. R., Chiarenza A., Coscia M., Ciolli S., Reda G., Laurenti L., Varettoni M., Murru R., Barate C., Sportoletti P., Greco A., Borella C., Rossi V., Deodato M., Biagi A., Zamprogna G., Pelle A. C., Lapietra G., Vitale C., Morelli F., Cassin R., Fresa A., Cavalloni C., Postorino M., Ielo C., Cairoli R., Di Raimondo F., Montillo M., Del Poeta G., Tedeschi, A, Frustaci, A, Mauro, F, Chiarenza, A, Coscia, M, Ciolli, S, Reda, G, Laurenti, L, Varettoni, M, Murru, R, Barate, C, Sportoletti, P, Greco, A, Borella, C, Rossi, V, Deodato, M, Biagi, A, Zamprogna, G, Pelle, A, Lapietra, G, Vitale, C, Morelli, F, Cassin, R, Fresa, A, Cavalloni, C, Postorino, M, Ielo, C, Cairoli, R, Di Raimondo, F, Montillo, M, Del Poeta, G, Tedeschi A., Frustaci A. M., Mauro F. R., Chiarenza A., Coscia M., Ciolli S., Reda G., Laurenti L., Varettoni M., Murru R., Barate C., Sportoletti P., Greco A., Borella C., Rossi V., Deodato M., Biagi A., Zamprogna G., Pelle A. C., Lapietra G., Vitale C., Morelli F., Cassin R., Fresa A., Cavalloni C., Postorino M., Ielo C., Cairoli R., Di Raimondo F., Montillo M., and Del Poeta G.

Abstract

Functional reserve of organs and systems is known to be relevant in predicting immunochemotherapy tolerance. Age and comorbidities, assessed by the cumulative illness rating scale (CIRS), have been used to address chemotherapy intensity. In the ibrutinib era, it is still unclear whether age, CIRS, and Eastern Cooperative Oncology Group performance status (ECOG-PS) retain their predictive role on treatment vulnerability. In this series of 712 patients with chronic lymphocytic leukemia (CLL) treated with ibrutinib outside clinical trials, baseline ECOG-PS and neutropenia resulted as the most accurate predictors of treatment feasibility and outcomes. Age did not independently influence survival and ibrutinib tolerance, indicating that not age per se, but age-related conditions, may affect drug management. We confirmed the role of CIRS . 6 as a predictor of a poorer progression- and event-free survival (PFS, EFS). The presence of a severe comorbidity was significantly associated with permanent dose reductions (PDRs), not translating into worse outcomes. As expected, del(17p) and/or TP53mut and previous therapies affected PFS, EFS, and overall survival. No study so far has analyzed the influence of concomitant medications and CYP3A inhibitors with ibrutinib. In our series, these factors had no impact, although CYP3A4 inhibitors use correlated with Cox regression analysis, with an increased risk of PDR. Despite the limitation of its retrospective nature, this large study confirmed the role of ECOG-PS as the most accurate predictor of ibrutinib feasibility and outcomes, and importantly, neutropenia emerged as a relevant tool influencing patients’ vulnerability. Although CIRS > 6 retained a significant impact on PFS and EFS, its value should be confirmed by prospective studies.

Published
2021

7. Pre-transplant persistence of minimal residual disease does not contraindicate allogeneic stem cell transplantation for adult patients with acute myeloid leukemia

Author

Buccisano, F, Maurillo, L, Piciocchi, A, Del Principe, M I, Picardi, A, Cerretti, R, Cudillo, L, De Angelis, G, Sarlo, C, Cefalo, M, Ditto, C, Di Veroli, A, Mariotti, B, Nasso, D, De Bellis, E, Del Poeta, G, Voso, M T, Sconocchia, G, Lo Coco, F, Arcese, W, Amadori, S, and Venditti, A

Published
2017
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11. Thrombotic and bleeding complications in patients with chronic lymphocytic leukemia and severe COVID-19: a study of ERIC, the European Research Initiative on CLL

Author

Antic, D., Milic, N., Chatzikonstantinou, T., Scarfo, L., Otasevic, V., Rajovic, N., Allsup, D., Alonso Cabrero, A., Andres, M., Baile Gonzales, M., Capasso, A., Collado, R., Cordoba, R., Cuellar-Garcia, C., Correa, J. G., De Paoli, L., De Paolis, M. R., Del Poeta, G., Dimou, M., Doubek, M., Efstathopoulou, M., El-Ashwah, S., Enrico, A., Espinet, B., Farina, L., Ferrari, A., Foglietta, M., Lopez-Garcia, A., Garcia-Marco, J. A., Garcia-Serra, R., Gentile, Marino, Gimeno, E., da Silva, M. G., Gutwein, O., Hakobyan, Y. K., Herishanu, Y., Hernandez-Rivas, J. A., Herold, T., Itchaki, G., Jaksic, O., Janssens, A., Kalashnikova, O. B., Kalicinska, E., Kater, A. P., Kersting, S., Koren-Michowitz, M., Labrador, J., Lad, D., Laurenti, Luca, Fresa, Alberto, Levin, M. -D., Mayor Bastida, C., Malerba, L., Marasca, R., Marchetti, M., Marquet, J., Mihaljevic, B., Milosevic, I., Miras, F., Morawska, M., Motta, M., Munir, T., Murru, R., Nunes, R., Olivieri, J., Pavlovsky, M. A., Piskunova, I., Popov, V. M., Quaglia, F. M., Quaresmini, G., Reda, G., Rigolin, G. M., Shrestha, A., Simkovic, M., Smirnova, S., Spacek, M., Sportoletti, P., Stanca, O., Stavroyianni, N., Te Raa, D., Tomic, K., Tonino, S., Trentin, L., Van Der Spek, E., van Gelder, M., Varettoni, M., Visentin, A., Vitale, C., Vukovic, Vladimir, Wasik-Szczepanek, E., Wrobel, T., Segundo, L. Y. S., Yassin, M., Coscia, M., Rambaldi, A., Montserrat, E., Foa, Robin, Cuneo, A., Carrier, M., Ghia, P., Stamatopoulos, K., Gentile M., Laurenti L. (ORCID:0000-0002-8327-1396), Fresa A., Vukovic V. (ORCID:0000-0002-9561-7825), Foa R., Antic, D., Milic, N., Chatzikonstantinou, T., Scarfo, L., Otasevic, V., Rajovic, N., Allsup, D., Alonso Cabrero, A., Andres, M., Baile Gonzales, M., Capasso, A., Collado, R., Cordoba, R., Cuellar-Garcia, C., Correa, J. G., De Paoli, L., De Paolis, M. R., Del Poeta, G., Dimou, M., Doubek, M., Efstathopoulou, M., El-Ashwah, S., Enrico, A., Espinet, B., Farina, L., Ferrari, A., Foglietta, M., Lopez-Garcia, A., Garcia-Marco, J. A., Garcia-Serra, R., Gentile, Marino, Gimeno, E., da Silva, M. G., Gutwein, O., Hakobyan, Y. K., Herishanu, Y., Hernandez-Rivas, J. A., Herold, T., Itchaki, G., Jaksic, O., Janssens, A., Kalashnikova, O. B., Kalicinska, E., Kater, A. P., Kersting, S., Koren-Michowitz, M., Labrador, J., Lad, D., Laurenti, Luca, Fresa, Alberto, Levin, M. -D., Mayor Bastida, C., Malerba, L., Marasca, R., Marchetti, M., Marquet, J., Mihaljevic, B., Milosevic, I., Miras, F., Morawska, M., Motta, M., Munir, T., Murru, R., Nunes, R., Olivieri, J., Pavlovsky, M. A., Piskunova, I., Popov, V. M., Quaglia, F. M., Quaresmini, G., Reda, G., Rigolin, G. M., Shrestha, A., Simkovic, M., Smirnova, S., Spacek, M., Sportoletti, P., Stanca, O., Stavroyianni, N., Te Raa, D., Tomic, K., Tonino, S., Trentin, L., Van Der Spek, E., van Gelder, M., Varettoni, M., Visentin, A., Vitale, C., Vukovic, Vladimir, Wasik-Szczepanek, E., Wrobel, T., Segundo, L. Y. S., Yassin, M., Coscia, M., Rambaldi, A., Montserrat, E., Foa, Robin, Cuneo, A., Carrier, M., Ghia, P., Stamatopoulos, K., Gentile M., Laurenti L. (ORCID:0000-0002-8327-1396), Fresa A., Vukovic V. (ORCID:0000-0002-9561-7825), and Foa R.

Abstract

Background: Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment-related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods: This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results: A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C-reactive protein to albumin ratio were poor prognostic factors for thrombosis occu

Published
2022

13. S136: CONSTITUTIVE VLA-4 ACTIVATION IN CHRONIC LYMPHOCYTIC LEUKEMIA. THE OTHER SIDE OF BCR AUTONOMOUS SIGNALING.

Author

Tissino, E., primary, Bomben, R., additional, Maity, P. C., additional, Pozzo, F., additional, Forestieri, G., additional, Nicolò, A., additional, Härzschel, A., additional, Bittolo, T., additional, Rossi, F. M., additional, Datta, M., additional, Zaja, F., additional, Capasso, G., additional, D’Arena, G., additional, Chiarenza, A., additional, Di Raimondo, F., additional, Jumaa, H., additional, Rossi, D., additional, Del Poeta, G., additional, Hartmann, T. N., additional, Zucchetto, A., additional, and Gattei, V., additional

Published
2022
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14. P596: CLINICAL IMPACT OF TP53 DISRUPTION IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS TREATED WITH A BCR INHIBITOR. A CAMPUS CLL EXPERIENCE

Author

Bomben, R., primary, Rossi, F. M., additional, Vit, F., additional, Bittolo, T., additional, Zucchetto, A., additional, Papotti, R., additional, Tissino, E., additional, Pozzo, F., additional, Degan, M., additional, Zaina, E., additional, Cattarossi, I., additional, Nanni, P., additional, Marasca, R., additional, Reda, G., additional, Laurenti, L., additional, Olivieri, J., additional, Chiarenza, A., additional, Ballotta, L., additional, Cuneo, A., additional, Gentile, M., additional, Morabito, F., additional, Tafuri, A., additional, Zaja, F., additional, Foà, R., additional, Di Raimondo, F., additional, Del Poeta, G., additional, and Gattei, V., additional

Published
2022
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15. Thrombotic and bleeding complications in patients with chronic lymphocytic leukemia and severe COVID-19: a study of ERIC, the European Research Initiative on CLL

Author

Antic D, Milic N, Chatzikonstantinou T, Scarfò L, Otasevic V, Rajovic N, Allsup D, Alonso Cabrero A, Andres M, Baile Gonzales M, Capasso A, Collado R, Cordoba R, Cuéllar-García C, Correa JG, De Paoli L, De Paolis MR, Del Poeta G, Dimou M, Doubek M, Efstathopoulou M, El-Ashwah S, Enrico A, Espinet B, Farina L, Ferrari A, Foglietta M, Lopez-Garcia A, García-Marco JA, García-Serra R, Gentile M, Gimeno E, da Silva MG, Gutwein O, Hakobyan YK, Herishanu Y, Hernández-Rivas JÁ, Herold T, Itchaki G, Jaksic O, Janssens A, Kalashnikova OB, Kalicińska E, Kater AP, Kersting S, Koren- Michowitz M, Labrador J, Lad D, Laurenti L, Fresa A, Levin MD, Mayor Bastida C, Malerba L, Marasca R, Marchetti M, Marquet J, Mihaljevic B, Milosevic I, Mirás F, Morawska M, Motta M, Munir T, Murru R, Nunes R, Olivieri J, Pavlovsky MA, Piskunova I, Popov VM, Quaglia FM, Quaresmini G, Reda G, Rigolin GM, Shrestha A, Šimkovič M, Smirnova S, Špaček M, Sportoletti P, Stanca O, Stavroyianni N, Te Raa D, Tomic K, Tonino S, Trentin L, Van Der Spek E, van Gelder M, Varettoni M, Visentin A, Vitale C, Vukovic V, Wasik-Szczepanek E, Wróbel T, Segundo LYS, Yassin M, Coscia M, Rambaldi A, Montserrat E, Foà R, Cuneo A, Carrier M, Ghia P, Stamatopoulos K.

Subjects
Age, Anticoagulation therapy, Bleeding, CLL, COVID-19, D-dimer, LMWH, Thromboprophylaxis, Thrombosis
Abstract

Background: Patients with chronic lymphocytic leukemia (CLL) may be more susceptible to COVID-19 related poor outcomes, including thrombosis and death, due to the advanced age, the presence of comorbidities, and the disease and treatment- related immune deficiency. The aim of this study was to assess the risk of thrombosis and bleeding in patients with CLL affected by severe COVID-19. Methods: This is a retrospective multicenter study conducted by ERIC, the European Research Initiative on CLL, including patients from 79 centers across 22 countries. Data collection was conducted between April and May 2021. The COVID-19 diagnosis was confirmed by the real-time polymerase chain reaction (RT-PCR) assay for SARS- CoV-2 on nasal or pharyngeal swabs. Severe cases of COVID-19 were defined by hospitalization and the need of oxygen or admission into ICU. Development and type of thrombotic events, presence and severity of bleeding complications were reported during treatment for COVID-19. Bleeding events were classified using ISTH definition. STROBE recommendations were used in order to enhance reporting. Results: A total of 793 patients from 79 centers were included in the study with 593 being hospitalized (74.8%). Among these, 511 were defined as having severe COVID: 162 were admitted to the ICU while 349 received oxygen supplementation outside the ICU. Most patients (90.5%) were receiving thromboprophylaxis. During COVID-19 treatment, 11.1% developed a thromboembolic event, while 5.0% experienced bleeding. Thrombosis developed in 21.6% of patients who were not receiving thromboprophylaxis, in contrast to 10.6% of patients who were on thromboprophylaxis. Bleeding episodes were more frequent in patients receiving intermediate/therapeutic versus prophylactic doses of low-molecular-weight heparin (LWMH) (8.1% vs. 3.8%, respectively) and in elderly. In multivariate analysis, peak D-dimer level and C- reactive protein to albumin ratio were poor prognostic factors for thrombosis occurrence (OR = 1.022, 95%CI 1.007‒1.038 and OR = 1.025, 95%CI 1.001‒1.051, respectively), while thromboprophylaxis use was protective (OR = 0.199, 95%CI 0.061‒0.645). Age and LMWH intermediate/therapeutic dose administration were prognostic factors in multivariate model for bleeding (OR = 1.062, 95%CI 1.017-1.109 and OR = 2.438, 95%CI 1.023-5.813, respectively). Conclusions: Patients with CLL affected by severe COVID-19 are at a high risk of thrombosis if thromboprophylaxis is not used, but also at increased risk of bleeding under the LMWH intermediate/therapeutic dose administration.

Published
2022

18. SF3B1-mutated chronic lymphocytic leukemia shows evidence of NOTCH1 pathway activation including CD20 downregulation

Author

Pozzo, F, Bittolo, T, Tissino, E, Vit, F, Vendramini, E, Laurenti, L, D'Arena, G, Olivieri, J, Pozzato, G, Zaja, F, Chiarenza, A, Di Raimondo, F, Zucchetto, A, Bomben, R, Rossi, Fm, Del Poeta, G, Dal Bo, M, Gattei, V., Pozzo, F, Bittolo, T, Tissino, E, Vit, F, Vendramini, E, Laurenti, L, D'Arena, G, Olivieri, J, Pozzato, G, Zaja, F, Chiarenza, A, Di Raimondo, F, Zucchetto, A, Bomben, R, Rossi, Fm, Del Poeta, G, Dal Bo, M, and Gattei, V.

Subjects
Down-Regulation, Article, NOTCH1, immune system diseases, hemic and lymphatic diseases, Humans, CD20, Receptor, Notch1, Antigens, Chronic, neoplasms, CLL, SF3B1, Notch1, Leukemia, B-Cell, Antigens, CD20, Phosphoproteins, Prognosis, Leukemia, Lymphocytic, Chronic, B-Cell, Lymphocytic, Settore MED/15 - MALATTIE DEL SANGUE, embryonic structures, Mutation, cardiovascular system, RNA Splicing Factors, Receptor
Abstract

Chronic lymphocytic leukemia (CLL) is characterized by a low CD20 expression, in part explained by an epigenetic-driven downregulation triggered by mutations of the NOTCH1 gene. In the present study, by taking advantage of a wide and well-characterized CLL cohort (n=537), we demonstrate that CD20 expression is downregulated in SF3B1-mutated CLL in an extent similar to NOTCH1-mutated CLL. In fact, SF3B1-mutated CLL cells show common features with NOTCH1-mutated CLL cells, including a gene expression profile enriched of NOTCH1-related gene sets and elevated expression of the active intracytoplasmic NOTCH1. Activation of the NOTCH1 signaling and down-regulation of surface CD20 in SF3B1-mutated CLL cells correlate with over-expression of an alternatively spliced form of DVL2, a component of the Wnt pathway and negative regulator of the NOTCH1 pathway. These findings are confirmed by separately analyzing the CD20-dim and CD20-bright cell fractions from SF3B1-mutated cases as well as by DVL2 knock-out experiments in CLL-like cell models. Altogether, the clinical and biological features that characterize NOTCH1-mutated CLL may also be recapitulated in SF3B1-mutated CLL, contributing to explain the poor prognosis of this CLL subset and providing the rationale for expanding novel agents-based therapies to SF3B1-mutated CLL.

Published
2020

19. Effectiveness of ibrutinib as first-line therapy for chronic lymphocytic leukemia patients and indirect comparison with rituximab-bendamustine: Results of study on 486 cases outside clinical trials

Author

Morabito, F., Tripepi, G., Del Poeta, G., Mauro, F. R., Reda, G., Sportoletti, P., Laurenti, L., Coscia, M., Herishanu, Y., Bossio, S., Varettoni, M., Murru, R., Chiarenza, A., Visentin, A., Condoluci, A., Moia, R., Pietrasanta, D., Loseto, G., Consoli, U., Scortechini, I., Rossi, F. M., Zucchetto, A., Al-Janazreh, H., Vigna, E., Martino, E. A., Cassin, R., D'Arrigo, G., Galimberti, S., Rago, A., Angeletti, I., Biagi, A., Del Giudice, I., Bomben, R., Neri, A., Fronza, G., Monti, P., Menichini, P., Olivieri, J., Cutrona, G., Rossi, D., Cuneo, A., Di Raimondo, F., Gaidano, G., Polliack, A., Trentin, L., Foa, R., Ferrarini, M., Gattei, V., Gentile, M., Morabito F., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi F. M., Galimberti S., Monti P. (ORCID:0000-0002-2586-1881), Rossi D., Foa R., Gentile M., Morabito, F., Tripepi, G., Del Poeta, G., Mauro, F. R., Reda, G., Sportoletti, P., Laurenti, L., Coscia, M., Herishanu, Y., Bossio, S., Varettoni, M., Murru, R., Chiarenza, A., Visentin, A., Condoluci, A., Moia, R., Pietrasanta, D., Loseto, G., Consoli, U., Scortechini, I., Rossi, F. M., Zucchetto, A., Al-Janazreh, H., Vigna, E., Martino, E. A., Cassin, R., D'Arrigo, G., Galimberti, S., Rago, A., Angeletti, I., Biagi, A., Del Giudice, I., Bomben, R., Neri, A., Fronza, G., Monti, P., Menichini, P., Olivieri, J., Cutrona, G., Rossi, D., Cuneo, A., Di Raimondo, F., Gaidano, G., Polliack, A., Trentin, L., Foa, R., Ferrarini, M., Gattei, V., Gentile, M., Morabito F., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi F. M., Galimberti S., Monti P. (ORCID:0000-0002-2586-1881), Rossi D., Foa R., and Gentile M.

Abstract

n/a

Published
2021

20. Comparison of ibrutinib and idelalisib plus rituximab in real-life relapsed/resistant chronic lymphocytic leukemia cases

Author

Morabito, Francesco, Tripepi, G., Del Poeta, G., Mauro, F. R., Reda, G., Sportoletti, P., Laurenti, Luca, Coscia, M., Herishanu, Y., Bossio, S., Varettoni, M., Murru, R., Chiarenza, A., Visentin, A., Condoluci, A., Moia, R., Pietrasanta, D., Loseto, G., Consoli, U., Scortechini, I., Rossi, Federica Maria, Zucchetto, A., Al-Janazreh, H., Vigna, E., Martino, E. A., Mendicino, F., Cassin, R., D'Arrigo, G., Galimberti, Sofia, Rago, A., Angeletti, I., Biagi, A., Del Giudice, I., Bomben, R., Neri, A., Fronza, G., Monti, Paolo, Menichini, P., Cutrona, G., Jaksic, O., Rossi, Dario, Di Raimondo, F., Cuneo, A., Gaidano, G., Polliack, A., Trentin, L., Foa, Robin, Ferrarini, M., Gattei, V., Gentile, Marino, Morabito F., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi F. M., Galimberti S., Monti P. (ORCID:0000-0002-2586-1881), Rossi D., Foa R., Gentile M., Morabito, Francesco, Tripepi, G., Del Poeta, G., Mauro, F. R., Reda, G., Sportoletti, P., Laurenti, Luca, Coscia, M., Herishanu, Y., Bossio, S., Varettoni, M., Murru, R., Chiarenza, A., Visentin, A., Condoluci, A., Moia, R., Pietrasanta, D., Loseto, G., Consoli, U., Scortechini, I., Rossi, Federica Maria, Zucchetto, A., Al-Janazreh, H., Vigna, E., Martino, E. A., Mendicino, F., Cassin, R., D'Arrigo, G., Galimberti, Sofia, Rago, A., Angeletti, I., Biagi, A., Del Giudice, I., Bomben, R., Neri, A., Fronza, G., Monti, Paolo, Menichini, P., Cutrona, G., Jaksic, O., Rossi, Dario, Di Raimondo, F., Cuneo, A., Gaidano, G., Polliack, A., Trentin, L., Foa, Robin, Ferrarini, M., Gattei, V., Gentile, Marino, Morabito F., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi F. M., Galimberti S., Monti P. (ORCID:0000-0002-2586-1881), Rossi D., Foa R., and Gentile M.

Abstract

Objectives: To compare the capacity of ibrutinib (IB) and idelalisib-rituximab (IDELA-R) of prolonging overall survival (OS) as in CLL patients, previously treated with chemotherapy only. Methods: A real-life cohort of 675 cases has been identified and investigated in the database of the groups participating in the study. Results: At an unadjusted univariate analysis, a significant death risk reduction was observed favoring IB (IDELA-R vs IB HR = 0.5, 95% CI = 0.36-0.71) although with some limitations due to the non-randomized and retrospective nature of the study and to the lower number of patients in the IDELA-R group (112 cases) related to the current prescribing practice. To overcome the potential problem of confounding by indication, we adjusted the association between the type of therapy and mortality for all variables significantly associated with OS at Cox univariate analysis. Furthermore, those variables, differently distributed between the two study groups, were introduced into the multivariate Cox model to improve the effectiveness of the analysis. By introducing all these variables into the multiple Cox regression model, we confirmed the protective effect of IB vs IDELA-R (HR = 0.67, 95% CI = 0.45-0.98, P =.04) independent of potential confounders. Conclusions: Although our analysis presents some constraints, that is, the unavailability of additional potential confounders, and the retrospective nature of the study, this observation may be of help for the daily clinical practice, particularly in the absence of randomized trials comparing the two schedules.

Published
2021

21. Prognostic impact and risk factors of infections in patients with chronic lymphocytic leukemia treated with ibrutinib

Author

Mauro, F. R., Giannarelli, D., Visentin, A., Reda, G., Sportoletti, P., Frustaci, A. M., Chiarenza, A., Ciolli, S., Vitale, C., Laurenti, L., De Paoli, L., Murru, R., Gentile, M., Rigolin, G. M., Levato, L., Giordano, A., Del Poeta, G., Stelitano, C., Ielo, C., Noto, A., Guarente, V., Molica, S., Coscia, M., Tedeschi, A., Gaidano, G., Cuneo, A., Foa, R., Martelli, M., Girmenia, C., Gentile, G., Trentin, L., Laurenti L. (ORCID:0000-0002-8327-1396), Gentile M., Molica S., Tedeschi A., Foa R., Martelli M., Gentile G., Mauro, F. R., Giannarelli, D., Visentin, A., Reda, G., Sportoletti, P., Frustaci, A. M., Chiarenza, A., Ciolli, S., Vitale, C., Laurenti, L., De Paoli, L., Murru, R., Gentile, M., Rigolin, G. M., Levato, L., Giordano, A., Del Poeta, G., Stelitano, C., Ielo, C., Noto, A., Guarente, V., Molica, S., Coscia, M., Tedeschi, A., Gaidano, G., Cuneo, A., Foa, R., Martelli, M., Girmenia, C., Gentile, G., Trentin, L., Laurenti L. (ORCID:0000-0002-8327-1396), Gentile M., Molica S., Tedeschi A., Foa R., Martelli M., and Gentile G.

Abstract

Ibrutinib represents extraordinary progress in the treatment of chronic lymphocytic leukemia (CLL). However, treatment-related adverse events limit the benefit of this agent. This obser-vational, multicenter study focused on the incidence, risk factors, and prognostic impact of infections in 494 patients with CLL treated with an ibrutinib-based treatment. Ibrutinib was given to 89 (18%) previously untreated patients (combined with rituximab, 24) and 405 (82%) relapsed/refractory patients. Pneumonia (PN), grade ≥3 non-opportunistic infections (NOI), and opportunistic infections (OI) were recorded in 32% of patients with an overall incidence rate per 100 person-year of 15.3% (PN, 10%; NOI, 3.3%; OI, 2%). Infections were the reason for the permanent discontinuation of ibrutinib in 9% of patients. Patients who experienced pneumonia or a severe infection showed a significantly inferior survival than those who were infection-free (p < 0.0001). A scoring system based on the three factors associated with a significant and independent impact on infections—PN or severe infection in the year before starting ibrutinib, chronic obstructive pulmonary disease, ≥2 prior treatments—identified patients with a two-to threefold increase in the rate of infections. In conclusion, the results of this study highlight the adverse impact of infectious events on the outcomes of CLL patients treated with ibrutinib.

Published
2021

22. Management of chronic lymphocytic leukemia in Italy during a one year of the COVID-19 pandemic and at the start of the vaccination program. A Campus CLL report

Author

Cuneo, A., Rigolin, G. M., Coscia, M., Quaresmini, G., Scarfo, L., Mauro, F. R., Motta, M., Quaglia, F. M., Trentin, L., Ferrario, Alberto Alfredo, Laurenti, Luca, Reda, G., Ferrari, A., Pietrasanta, D., Sportoletti, P., Re, F., De Paoli, L., Foglietta, M., Giordano, A., Marchetti, M., Farina, L., Del Poeta, G., Varettoni, M., Chiurazzi, F., Marasca, R., Malerba, L., Ibatici, A., Tisi, Maria Chiara, Stefoni, V., Leone, M., Barate, C., Olivieri, J., Murru, R., Gentile, Marino, Sanna, A., Gozzetti, A., Gattei, V., Gottardi, D., Derenzini, E., Levato, L., Orsucci, L., Penna, G., Chiarenza, A., Foa, Robin, Ferrario A., Laurenti L. (ORCID:0000-0002-8327-1396), Tisi M. C., Gentile M., Foa R., Cuneo, A., Rigolin, G. M., Coscia, M., Quaresmini, G., Scarfo, L., Mauro, F. R., Motta, M., Quaglia, F. M., Trentin, L., Ferrario, Alberto Alfredo, Laurenti, Luca, Reda, G., Ferrari, A., Pietrasanta, D., Sportoletti, P., Re, F., De Paoli, L., Foglietta, M., Giordano, A., Marchetti, M., Farina, L., Del Poeta, G., Varettoni, M., Chiurazzi, F., Marasca, R., Malerba, L., Ibatici, A., Tisi, Maria Chiara, Stefoni, V., Leone, M., Barate, C., Olivieri, J., Murru, R., Gentile, Marino, Sanna, A., Gozzetti, A., Gattei, V., Gottardi, D., Derenzini, E., Levato, L., Orsucci, L., Penna, G., Chiarenza, A., Foa, Robin, Ferrario A., Laurenti L. (ORCID:0000-0002-8327-1396), Tisi M. C., Gentile M., and Foa R.

Abstract

n/a

Published
2021

23. Assessment of the 4-factor score: Retrospective analysis of 586 CLL patients receiving ibrutinib. A campus CLL study

Author

Morabito, Francesco, Tripepi, G., Del Poeta, G., Mauro, F. R., Reda, G., Sportoletti, P., Laurenti, Luca, Coscia, M., Herishanu, Y., Varettoni, M., Murru, R., Chiarenza, A., Visentin, A., Condoluci, A., Moia, R., Pietrasanta, D., Loseto, G., Consoli, U., Scortechini, I., Rossi, Federica Maria, Zucchetto, A., Vigna, E., Martino, E. A., Mendicino, F., Botta, C., Caracciolo, D., Cassin, R., D'Arrigo, G., Galimberti, Sofia, Rago, A., Angeletti, I., Biagi, A., Del Giudice, I., Bomben, R., Neri, A., Fronza, G., Cutrona, G., Rossi, Dario, Di Raimondo, F., Cuneo, A., Gaidano, G., Polliack, A., Trentin, L., Foa, Robin, Ferrarini, M., Gattei, V., Gentile, Marino, Morabito F., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi F. M., Galimberti S., Rossi D., Foa R., Gentile M., Morabito, Francesco, Tripepi, G., Del Poeta, G., Mauro, F. R., Reda, G., Sportoletti, P., Laurenti, Luca, Coscia, M., Herishanu, Y., Varettoni, M., Murru, R., Chiarenza, A., Visentin, A., Condoluci, A., Moia, R., Pietrasanta, D., Loseto, G., Consoli, U., Scortechini, I., Rossi, Federica Maria, Zucchetto, A., Vigna, E., Martino, E. A., Mendicino, F., Botta, C., Caracciolo, D., Cassin, R., D'Arrigo, G., Galimberti, Sofia, Rago, A., Angeletti, I., Biagi, A., Del Giudice, I., Bomben, R., Neri, A., Fronza, G., Cutrona, G., Rossi, Dario, Di Raimondo, F., Cuneo, A., Gaidano, G., Polliack, A., Trentin, L., Foa, Robin, Ferrarini, M., Gattei, V., Gentile, Marino, Morabito F., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi F. M., Galimberti S., Rossi D., Foa R., and Gentile M.

Abstract

n/a

Published
2021

24. Survival risk score for real-life relapsed/refractory chronic lymphocytic leukemia patients receiving ibrutinib. A campus CLL study

Author

Gentile, Marino, Morabito, Francesco, Del Poeta, G., Mauro, F. R., Reda, G., Sportoletti, P., Laurenti, Luca, Coscia, M., Herishanu, Y., Recchia, A. G., Varettoni, M., Murru, R., Chiarenza, A., Condoluci, A., Moia, R., Pietrasanta, D., Loseto, G., Consoli, U., Scortechini, I., Rossi, Federica Maria, Zucchetto, A., Fraticelli, V., Vigna, E., Botta, C., Tripepi, G., Arrigo, G. D., Rago, A., Angeletti, I., Biagi, A., Del Giudice, I., Bomben, R., Rigolin, G. M., Rossi, Dario, Di Raimondo, F., Gaidano, G., Polliack, A., Cuneo, A., Foa, Robin, Gattei, V., Gentile M., Morabito F., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi F. M., Rossi D., Foa R., Gentile, Marino, Morabito, Francesco, Del Poeta, G., Mauro, F. R., Reda, G., Sportoletti, P., Laurenti, Luca, Coscia, M., Herishanu, Y., Recchia, A. G., Varettoni, M., Murru, R., Chiarenza, A., Condoluci, A., Moia, R., Pietrasanta, D., Loseto, G., Consoli, U., Scortechini, I., Rossi, Federica Maria, Zucchetto, A., Fraticelli, V., Vigna, E., Botta, C., Tripepi, G., Arrigo, G. D., Rago, A., Angeletti, I., Biagi, A., Del Giudice, I., Bomben, R., Rigolin, G. M., Rossi, Dario, Di Raimondo, F., Gaidano, G., Polliack, A., Cuneo, A., Foa, Robin, Gattei, V., Gentile M., Morabito F., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi F. M., Rossi D., and Foa R.

Abstract

N/A

Published
2021

28. Treatment of chronic lymphocytic leukemia in the new drugs era: the state of art in the Italian landscape

Author

Morelli, F, Innocenti, I, Autore, F, Fresa, F, Tomasso, A, Piciocchi, A, Frustaci, Am, Trentin, L, Mauro, Fr, Schiattone, L, Visentin, A, Del Poeta, G, Reda, G, Rigolin, Gm, Ibatici, A, Ciolli, S, Vitale, C, Sportoletti, P, Murru, R, Levato, L, Gentile, M, D’Arena, G, Coscia, M, Villa, Mr, Fontana, R, Efremov, D, Tedeschi, A, Scarfò, L, Cuneo, A, Foà, R, and Laurenti, L

Published
2020

31. COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus

Author

Scarfo, L, Chatzikonstantinou, T, Rigolin, GM, Quaresmini, G, Motta, M, Vitale, C, Garcia-Marco, JA, Hernandez-Rivas, JA, Miras, F, Baile, M, Marquet, J, Niemann, CU, Reda, G, Munir, T, Gimeno, E, Marchetti, M, Quaglia, FM, Varettoni, M, Delgado, J, Iyengar, S, Janssens, A, Marasca, R, Ferrari, A, Cuellar-Garcia, C, Itchaki, G, Spacek, M, De Paoli, L, Laurenti, L, Levin, M-D, Lista, E, Mauro, FR, Simkovic, M, Van Der Spek, E, Vandenberghe, E, Trentin, L, Wasik-Szczepanek, E, Ruchlemer, R, Bron, D, De Paolis, MR, Del Poeta, G, Farina, L, Foglietta, M, Gentile, M, Herishanu, Y, Herold, T, Jaksic, O, Kater, AP, Kersting, S, Malerba, L, Orsucci, L, Popov, VM, Sportoletti, P, Yassin, M, Pocali, B, Barna, G, Chiarenza, A, dos Santos, G, Nikitin, E, Andres, M, Dimou, M, Doubek, M, Enrico, A, Hakobyan, Y, Kalashnikova, O, Ortiz Pareja, M, Papaioannou, M, Rossi, D, Shah, N, Shrestha, A, Stanca, O, Stavroyianni, N, Strugov, V, Tam, C, Zdrenghea, M, Coscia, M, Stamatopoulos, K, Rossi, G, Rambaldi, A, Montserrat, E, Foa, R, Cuneo, A, Ghia, P, Scarfo, L, Chatzikonstantinou, T, Rigolin, GM, Quaresmini, G, Motta, M, Vitale, C, Garcia-Marco, JA, Hernandez-Rivas, JA, Miras, F, Baile, M, Marquet, J, Niemann, CU, Reda, G, Munir, T, Gimeno, E, Marchetti, M, Quaglia, FM, Varettoni, M, Delgado, J, Iyengar, S, Janssens, A, Marasca, R, Ferrari, A, Cuellar-Garcia, C, Itchaki, G, Spacek, M, De Paoli, L, Laurenti, L, Levin, M-D, Lista, E, Mauro, FR, Simkovic, M, Van Der Spek, E, Vandenberghe, E, Trentin, L, Wasik-Szczepanek, E, Ruchlemer, R, Bron, D, De Paolis, MR, Del Poeta, G, Farina, L, Foglietta, M, Gentile, M, Herishanu, Y, Herold, T, Jaksic, O, Kater, AP, Kersting, S, Malerba, L, Orsucci, L, Popov, VM, Sportoletti, P, Yassin, M, Pocali, B, Barna, G, Chiarenza, A, dos Santos, G, Nikitin, E, Andres, M, Dimou, M, Doubek, M, Enrico, A, Hakobyan, Y, Kalashnikova, O, Ortiz Pareja, M, Papaioannou, M, Rossi, D, Shah, N, Shrestha, A, Stanca, O, Stavroyianni, N, Strugov, V, Tam, C, Zdrenghea, M, Coscia, M, Stamatopoulos, K, Rossi, G, Rambaldi, A, Montserrat, E, Foa, R, Cuneo, A, and Ghia, P

Abstract

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79–7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.

Published
2020

32. COVID-19 severity and mortality in patients with chronic lymphocytic leukemia: a joint study by ERIC, the European Research Initiative on CLL, and CLL Campus

Author

Scarfo, L., Chatzikonstantinou, T., Rigolin, G. M., Quaresmini, G., Motta, M., Vitale, C., Garcia-Marco, J. A., Hernandez-Rivas, J. A., Miras, F., Baile, M., Marquet, J., Niemann, C. U., Reda, G., Munir, T., Gimeno, E., Marchetti, M., Quaglia, F. M., Varettoni, M., Delgado, J., Iyengar, S., Janssens, A., Marasca, R., Ferrari, A., Cuellar-Garcia, C., Itchaki, G., Spacek, M., De Paoli, L., Laurenti, Luca, Levin, M. -D., Lista, E., Mauro, F. R., Simkovic, M., Van Der Spek, E., Vandenberghe, E., Trentin, L., Wasik-Szczepanek, E., Ruchlemer, R., Bron, D., De Paolis, M. R., Del Poeta, G., Farina, L., Foglietta, M., Gentile, Marino, Herishanu, Y., Herold, T., Jaksic, O., Kater, A. P., Kersting, S., Malerba, L., Orsucci, L., Popov, V. M., Sportoletti, P., Yassin, M., Pocali, B., Barna, G., Chiarenza, A., dos Santos, G., Nikitin, E., Andres, M., Dimou, M., Doubek, M., Enrico, A., Hakobyan, Y., Kalashnikova, O., Ortiz Pareja, M., Papaioannou, M., Rossi, Dario, Shah, N., Shrestha, A., Stanca, O., Stavroyianni, N., Strugov, V., Tam, C., Zdrenghea, M., Coscia, M., Stamatopoulos, K., Rossi, G., Rambaldi, A., Montserrat, E., Foa, Robin, Cuneo, A., Ghia, P., Laurenti L. (ORCID:0000-0002-8327-1396), Gentile M., Rossi D., Foa R., Scarfo, L., Chatzikonstantinou, T., Rigolin, G. M., Quaresmini, G., Motta, M., Vitale, C., Garcia-Marco, J. A., Hernandez-Rivas, J. A., Miras, F., Baile, M., Marquet, J., Niemann, C. U., Reda, G., Munir, T., Gimeno, E., Marchetti, M., Quaglia, F. M., Varettoni, M., Delgado, J., Iyengar, S., Janssens, A., Marasca, R., Ferrari, A., Cuellar-Garcia, C., Itchaki, G., Spacek, M., De Paoli, L., Laurenti, Luca, Levin, M. -D., Lista, E., Mauro, F. R., Simkovic, M., Van Der Spek, E., Vandenberghe, E., Trentin, L., Wasik-Szczepanek, E., Ruchlemer, R., Bron, D., De Paolis, M. R., Del Poeta, G., Farina, L., Foglietta, M., Gentile, Marino, Herishanu, Y., Herold, T., Jaksic, O., Kater, A. P., Kersting, S., Malerba, L., Orsucci, L., Popov, V. M., Sportoletti, P., Yassin, M., Pocali, B., Barna, G., Chiarenza, A., dos Santos, G., Nikitin, E., Andres, M., Dimou, M., Doubek, M., Enrico, A., Hakobyan, Y., Kalashnikova, O., Ortiz Pareja, M., Papaioannou, M., Rossi, Dario, Shah, N., Shrestha, A., Stanca, O., Stavroyianni, N., Strugov, V., Tam, C., Zdrenghea, M., Coscia, M., Stamatopoulos, K., Rossi, G., Rambaldi, A., Montserrat, E., Foa, Robin, Cuneo, A., Ghia, P., Laurenti L. (ORCID:0000-0002-8327-1396), Gentile M., Rossi D., and Foa R.

Abstract

Chronic lymphocytic leukemia (CLL) is a disease of the elderly, characterized by immunodeficiency. Hence, patients with CLL might be considered more susceptible to severe complications from COVID-19. We undertook this retrospective international multicenter study to characterize the course of COVID-19 in patients with CLL and identify potential predictors of outcome. Of 190 patients with CLL and confirmed COVID-19 diagnosed between 28/03/2020 and 22/05/2020, 151 (79%) presented with severe COVID-19 (need of oxygen and/or intensive care admission). Severe COVID-19 was associated with more advanced age (≥65 years) (odds ratio 3.72 [95% CI 1.79–7.71]). Only 60 patients (39.7%) with severe COVID-19 were receiving or had recent (≤12 months) treatment for CLL at the time of COVID-19 versus 30/39 (76.9%) patients with mild disease. Hospitalization rate for severe COVID-19 was lower (p < 0.05) for patients on ibrutinib versus those on other regimens or off treatment. Of 151 patients with severe disease, 55 (36.4%) succumbed versus only 1/38 (2.6%) with mild disease; age and comorbidities did not impact on mortality. In CLL, (1) COVID-19 severity increases with age; (2) antileukemic treatment (particularly BTK inhibitors) appears to exert a protective effect; (3) age and comorbidities did not impact on mortality, alluding to a relevant role of CLL and immunodeficiency.

Published
2020

33. SF3B1-mutated chronic lymphocytic leukemia shows evidence of NOTCH1 pathway activation including CD20 downregulation

Author

Pozzo, F., Bittolo, T., Tissino, E., Vit, F., Vendramini, E., Laurenti, Luca, D'Arena, G., Olivieri, J., Pozzato, G., Zaja, F., Chiarenza, A., Di Raimondo, F., Zucchetto, A., Bomben, R., Rossi, Federica Maria, Del Poeta, G., Dal Bo, M., Gattei, V., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi F. M., Pozzo, F., Bittolo, T., Tissino, E., Vit, F., Vendramini, E., Laurenti, Luca, D'Arena, G., Olivieri, J., Pozzato, G., Zaja, F., Chiarenza, A., Di Raimondo, F., Zucchetto, A., Bomben, R., Rossi, Federica Maria, Del Poeta, G., Dal Bo, M., Gattei, V., Laurenti L. (ORCID:0000-0002-8327-1396), and Rossi F. M.

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by a low CD20 expression, in part explained by an epigenetic-driven downregulation triggered by mutations of the NOTCH1 gene. In the present study, by taking advantage of a wide and well-characterized CLL cohort (n=537), we demonstrate that CD20 expression is downregulated in SF3B1-mutated CLL in an extent similar to NOTCH1-mutated CLL. In fact, SF3B1-mutated CLL cells show common features with NOTCH1-mutated CLL cells, including a gene expression profile enriched of NOTCH1-related gene sets and elevated expression of the active intracytoplasmic NOTCH1. Activation of the NOTCH1 signaling and down-regulation of surface CD20 in SF3B1-mutated CLL cells correlate with over-expression of an alternatively spliced form of DVL2, a component of the Wnt pathway and negative regulator of the NOTCH1 pathway. These findings are confirmed by separately analyzing the CD20-dim and CD20-bright cell fractions from SF3B1-mutated cases as well as by DVL2 knock-out experiments in CLL-like cell models. Altogether, the clinical and biological features that characterize NOTCH1-mutated CLL may also be recapitulated in SF3B1-mutated CLL, contributing to explain the poor prognosis of this CLL subset and providing the rationale for expanding novel agents-based therapies to SF3B1-mutated CLL.

Published
2020

34. CD49d promotes disease progression in chronic lymphocytic leukemia: New insights from CD49d bimodal expression

Author

Tissino, E., Pozzo, F., Benedetti, D., Caldana, C., Bittolo, T., Rossi, Federica Maria, Bomben, R., Nanni, P., Chivilo, H., Cattarossi, I., Zaina, Elisabetta, Norris, K., Polesel, J., Gentile, Marino, Tripepi, G., Moia, R., Santinelli, E., Innocenti, Idanna, Olivieri, J., D'Arena, G., Laurenti, Luca, Zaja, F., Pozzato, G., Chiarenza, A., Di Raimondo, F., Rossi, Dario, Pepper, C., Hartmann, T. N., Gaidano, G., Del Poeta, G., Gattei, V., Zucchetto, A., Rossi F. M., Zaina E., Gentile M., Innocenti I., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi D., Tissino, E., Pozzo, F., Benedetti, D., Caldana, C., Bittolo, T., Rossi, Federica Maria, Bomben, R., Nanni, P., Chivilo, H., Cattarossi, I., Zaina, Elisabetta, Norris, K., Polesel, J., Gentile, Marino, Tripepi, G., Moia, R., Santinelli, E., Innocenti, Idanna, Olivieri, J., D'Arena, G., Laurenti, Luca, Zaja, F., Pozzato, G., Chiarenza, A., Di Raimondo, F., Rossi, Dario, Pepper, C., Hartmann, T. N., Gaidano, G., Del Poeta, G., Gattei, V., Zucchetto, A., Rossi F. M., Zaina E., Gentile M., Innocenti I., Laurenti L. (ORCID:0000-0002-8327-1396), and Rossi D.

Abstract

CD49d is a remarkable prognostic biomarker of chronic lymphocytic leukemia (CLL). The cutoff value for the extensively validated 30% of positive CLL cells is able to separate CLL patients into 2 subgroups with different prognoses, but it does not consider the pattern of CD49d expression. In the present study, we analyzed a cohort of 1630 CLL samples and identified the presence of ∼20% of CLL cases (n 5 313) characterized by a bimodal expression of CD49d, that is, concomitant presence of a CD49d1 subpopulation and a CD49d2 subpopulation. At variance with the highly stable CD49d expression observed in CLL patients with a homogeneous pattern of CD49d expression, CD49d bimodal CLL showed a higher level of variability in sequential samples, and an increase in the CD49d1 subpopulation over time after therapy. The CD49d1 subpopulation from CD49d bimodal CLL displayed higher levels of proliferation compared with the CD49d2 cells; and was more highly represented in the bone marrow compared with peripheral blood (PB), and in PB CLL subsets expressing the CXCR4dim/CD5bright phenotype, known to be enriched in proliferative cells. From a clinical standpoint, CLL patients with CD49d bimodal expression, regardless of whether the CD49d1 subpopulation exceeded the 30% cutoff or not, experienced clinical behavior similar to CD49d1 CLL, both in chemoimmunotherapy (n 5 1522) and in ibrutinib (n 5 158) settings. Altogether, these results suggest that CD49d can drive disease progression in CLL, and that the pattern of CD49d expression should also be considered to improve the prognostic impact of this biomarker in CLL.

Published
2020

35. Front-Line Therapy for Elderly Chronic Lymphocytic Leukemia Patients: Bendamustine Plus Rituximab or Chlorambucil Plus Rituximab? Real-Life Retrospective Multicenter Study in the Lazio Region

Author

Autore, Francesco, Innocenti, Idanna, Corrente, Francesco, Del Principe, M. I., Rosati, S., Falcucci, P., Fresa, Alberto, Conte, Eliana, Limongiello, M. A., Renzi, D., De Padua, L., Andriani, A., Pisani, F., Cimino, G., Tafuri, A., Montanaro, M., Mauro, F. R., Del Poeta, G., Laurenti, Luca, Autore F., Innocenti I., Corrente F., Fresa A., Conte E., Laurenti L. (ORCID:0000-0002-8327-1396), Autore, Francesco, Innocenti, Idanna, Corrente, Francesco, Del Principe, M. I., Rosati, S., Falcucci, P., Fresa, Alberto, Conte, Eliana, Limongiello, M. A., Renzi, D., De Padua, L., Andriani, A., Pisani, F., Cimino, G., Tafuri, A., Montanaro, M., Mauro, F. R., Del Poeta, G., Laurenti, Luca, Autore F., Innocenti I., Corrente F., Fresa A., Conte E., and Laurenti L. (ORCID:0000-0002-8327-1396)

Abstract

Previous studies investigated the efficacy and the safety of bendamustine (B) vs. chlorambucil (Chl) associated with rituximab (R) in fludarabine-ineligible patients with treated and untreated chronic lymphocytic leukemia (CLL). We conducted a retrospective multicenter study in the Lazio region to further evaluate and compare the efficacy and the toxicity of Chl-R and B-R regimen in CLL patients over the age of 65. We enrolled 192 untreated CLL patients: 111 treated with B-R and 81 with Chl-R. The overall response rates (ORR; 93.6% in B-R and 86.5% in Chl-R) were not statistically different between the two groups, such as progression-free survival (PFS), time to retreatment (TTR), and overall survival (OS). The B-R group showed a higher hematological (p = 0.007) and extra-hematological (p = 0.008) toxicity. When comparing the toxicities according to age, we noted that the extra-hematological toxicity was higher in patients over the age of 75 who were treated with B-R than those treated with Chl-R (p = 0.03). This retrospective study confirms the feasibility of B-R and Chl-R in elderly untreated CLL patients. Currently, patients who are over 75 and unfit are usually treated with Chl-R. This scheme allows achieving the same ORR, PFS, TTR, and OS when compared with B-R because of hematological and extra-hematological toxicities due to B, in which a greater dose reduction has been shown in comparison to Chl.

Published
2020

37. The prognostic value of cytogenetics is reinforced by the kind of induction/consolidation therapy in influencing the outcome of acute myeloid leukemia – analysis of 848 patients

Author

Visani, G, Bernasconi, P, Boni, M, Castoldi, GL, Ciolli, S, Clavio, M, Cox, MC, Cuneo, A, Del Poeta, G, Dini, D, Falzetti, D, Fanin, R, Gobbi, M, Isidori, A, Leoni, F, Liso, V, Malagola, M, Martinelli, G, Mecucci, C, Piccaluga, PP, Petti, MC, Rondelli, R, Russo, D, Sessarego, M, Specchia, G, Testoni, N, Torelli, G, Mandelli, F, and Tura, S

Published
2001
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