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2. EE82 A Cost-Utility Analysis of the MyPal eHealth Application, an ePro Intervention Aiming to Foster Palliative Care of Cancer Patients: Results From a Randomized Clinical Trial in 4 European Countries

Author

Naoum, P., primary, Athanasakis, K., additional, Radova, L., additional, Bonotis, P., additional, Scarfo, L., additional, Doubek, M., additional, Ghia, P., additional, Kazantzaki, E., additional, Pontikoglou, C., additional, Pospisilova, S., additional, Rosenquist, R., additional, Ekström Smedby, K., additional, and Pavi, E., additional

Published
2023
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3. Results of MOLTO, a multicenter, open label, phase II clinical trial evaluating venetoclax, atezolizumab and obinutuzumab combination in Richter syndrome

Author

Frustaci, A, Montillo, M, Rossi, D, Zinzani, P, Motta, M, Gaidano, G, Quaresmini, G, Scarfo, L, Pietrasanta, D, Coscia, M, Deodato, M, Zamprogna, G, Cairoli, R, Stussi, G, Zucca, E, Pileri, S, Zenz, T, Tedeschi, A, Frustaci, Anna Maria, Montillo, Marco, Rossi, Davide, Zinzani, Pier Luigi, Motta, Marina, Gaidano, Gianluca, Quaresmini, Giulia, Scarfo, Lydia, Pietrasanta, Daniela, Coscia, Marta, Deodato, Marina, Zamprogna, Giulia, Cairoli, Roberto, Stussi, Georg, Zucca, Emanuele, Pileri, Stefano, Zenz, Thorsten, Tedeschi, Alessandra, Frustaci, A, Montillo, M, Rossi, D, Zinzani, P, Motta, M, Gaidano, G, Quaresmini, G, Scarfo, L, Pietrasanta, D, Coscia, M, Deodato, M, Zamprogna, G, Cairoli, R, Stussi, G, Zucca, E, Pileri, S, Zenz, T, Tedeschi, A, Frustaci, Anna Maria, Montillo, Marco, Rossi, Davide, Zinzani, Pier Luigi, Motta, Marina, Gaidano, Gianluca, Quaresmini, Giulia, Scarfo, Lydia, Pietrasanta, Daniela, Coscia, Marta, Deodato, Marina, Zamprogna, Giulia, Cairoli, Roberto, Stussi, Georg, Zucca, Emanuele, Pileri, Stefano, Zenz, Thorsten, and Tedeschi, Alessandra

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

7. 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

8. Obinutuzumab plus chlorambucil versus ibrutinib in previously untreated chronic lymphocytic leukemia patients without TP53 disruptions: A real-life CLL campus study

Author

Visentin, A., Mauro, F. R., Catania, G., Fresa, Alberto, Vitale, C., Sanna, A., Mattiello, V., Cibien, F., Sportoletti, P., Gentile, M., Rigolin, G. M., Quaglia, F. M., Murru, R., Gozzetti, A., Molica, Serena, Marchetti, M., Pravato, S., Angotzi, F., Cellini, A., Scarfo, L., Reda, G., Coscia, M., Laurenti, Luca, Ghia, P., Foa, Robin, Cuneo, A., Trentin, L., Fresa A., Molica S., Laurenti L. (ORCID:0000-0002-8327-1396), Foa R., Visentin, A., Mauro, F. R., Catania, G., Fresa, Alberto, Vitale, C., Sanna, A., Mattiello, V., Cibien, F., Sportoletti, P., Gentile, M., Rigolin, G. M., Quaglia, F. M., Murru, R., Gozzetti, A., Molica, Serena, Marchetti, M., Pravato, S., Angotzi, F., Cellini, A., Scarfo, L., Reda, G., Coscia, M., Laurenti, Luca, Ghia, P., Foa, Robin, Cuneo, A., Trentin, L., Fresa A., Molica S., Laurenti L. (ORCID:0000-0002-8327-1396), and Foa R.

Abstract

One of the main issues in the treatment of patients with chronic lymphocytic leukemia (CLL) deals with the choice between continuous or fixed-duration therapy. Continuous ibrutinib (IB), the first-in-class BTK inhibitor, and obinutuzumab-chlorambucil (G-CHL) are commonly used therapies for elderly and/or comorbid patients. No head-to-head comparison has been carried out. Within the Italian campus CLL network, we performed a retrospective study on CLL patients without TP53 disruption treated with IB or G-CHL as first-line therapy. Patients in the G-CHL arm had a higher CIRS score and the worst renal function. The overall response rates between the G-CHL and IB arms were similar, but more complete remissions (CRs) were achieved with G-CHL (p = 0.0029). After a median follow-up of 30 months, the progression-free survival (PFS, p = 0.0061) and time to next treatment (TTNT, p = 0.0043), but not overall survival (OS, p = 0.6642), were better with IB than with G-CHL. Similar results were found after propensity score matching and multivariate analysis. While PFS and TTNT were longer with IB than with G-CHL in IGHV unmutated patients (p = 0.0190 and 0.0137), they were superimposable for IGHV mutated patients (p = 0.1900 and 0.1380). In the G-CHL arm, the depth of response (79% vs. 68% vs. 38% for CR, PR and SD/PD; p < 0.0001) and measurable residual disease (MRD) influenced PFS (78% vs. 53% for undetectable MRD vs. detectable MRD, p = 0.0203). Hematological toxicities were common in the G-CHL arm, while IB was associated with higher costs. Although continuous IB provides better disease control in CLL, IGHV mutated patients and those achieving an undetectable MRD show a marked clinical and economic benefit from a fixed-duration obinutuzumab-based treatment.

Published
2022

9. Ibrutinib dose intensity in high-risk chronic lymphocytic leukemia

Author

Forestieri, G., Terzi di Bergamo, L., Deodato, M., Frustaci, A. M., Moia, R., Deambrogi, C., Rasi, S., Autore, Francesco, Merli, Maria Clara, Mattarucchi, R., Fahrni, G., Scarfo', L., Gussetti, D., Bulian, P., Zanatta, A., Spina, V., Bruscaggin, A., Pini, K., Piffaretti, D., Pirosa, M. C., Salehi, M., Marques de Almeida, J., Passweg, J., Cavalli, F., Zucca, E., Gerber, B., Stussi, G., Gattei, V., Ghia, P., Gregor, M., Passamonti, F., Laurenti, Luca, Gaidano, G., Tedeschi, Alessandra, Rossi, Dario, Condoluci, A., Autore F., Merli M., Laurenti L. (ORCID:0000-0002-8327-1396), Tedeschi A., Rossi D., Forestieri, G., Terzi di Bergamo, L., Deodato, M., Frustaci, A. M., Moia, R., Deambrogi, C., Rasi, S., Autore, Francesco, Merli, Maria Clara, Mattarucchi, R., Fahrni, G., Scarfo', L., Gussetti, D., Bulian, P., Zanatta, A., Spina, V., Bruscaggin, A., Pini, K., Piffaretti, D., Pirosa, M. C., Salehi, M., Marques de Almeida, J., Passweg, J., Cavalli, F., Zucca, E., Gerber, B., Stussi, G., Gattei, V., Ghia, P., Gregor, M., Passamonti, F., Laurenti, Luca, Gaidano, G., Tedeschi, Alessandra, Rossi, Dario, Condoluci, A., Autore F., Merli M., Laurenti L. (ORCID:0000-0002-8327-1396), Tedeschi A., and Rossi D.

Abstract

NA

Published
2022

10. Minimal residual disease–driven treatment intensification with sequential addition of ibrutinib to venetoclax in R/R CLL

Author

Scarfo, L., Heltai, S., Albi, E., Scarano, E., Schiattone, L., Farina, L., Moia, R., Deodato, M., Ferrario, Alberto Alfredo, Motta, M., Reda, G., Sancetta, R., Coscia, M., Rivela, P., Laurenti, Luca, Varettoni, M., Perotta, E., Capasso, A., Ranghetti, P., Colia, M., Ghia, P., Ferrario A., Laurenti L. (ORCID:0000-0002-8327-1396), Scarfo, L., Heltai, S., Albi, E., Scarano, E., Schiattone, L., Farina, L., Moia, R., Deodato, M., Ferrario, Alberto Alfredo, Motta, M., Reda, G., Sancetta, R., Coscia, M., Rivela, P., Laurenti, Luca, Varettoni, M., Perotta, E., Capasso, A., Ranghetti, P., Colia, M., Ghia, P., Ferrario A., and Laurenti L. (ORCID:0000-0002-8327-1396)

Abstract

Undetectable measurable residual disease (uMRD) is achievable in patients with chronic lymphocytic leukemia (CLL) with the BCL2-inhibitor venetoclax alone or combined with the Bruton's tyrosine kinase inhibitor ibrutinib. This phase 2, multicenter, MRD-driven study was designed to discontinue treatment upon reaching uMRD4 (<10−4) in patients with relapsed/refractory CLL receiving venetoclax monotherapy or after the addition of ibrutinib. Primary end point of the study was proportion of uMRD4 with venetoclax ± ibrutinib. Secondary end points were overall response rate, partial response, complete response, progression-free survival, duration of response, overall survival, and safety of venetoclax ± ibrutinib. Patients with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. MRD+ patients added ibrutinib and continued both drugs up to Cycle 24 Day 28/uMRD4/progression/toxicity. After Cycle 24 Day 28, MRD+ patients continued ibrutinib. Thirty-eight patients (29% with TP53 aberrations; 79% with unmutated IGHV) started venetoclax. Overall response rate with venetoclax was 36 (95%) of 38 patients (20 complete; 16 partial response). Seventeen patients (45%) with uMRD4 at Cycle 12 Day 1 discontinued venetoclax. Nineteen (55%) MRD+ subjects added ibrutinib. After a median of 7 months (range, 3-10 months) of combined treatment, 16 (84%) of 19 achieved uMRD4, thus stopping both drugs. Two MRD+ patients at Cycle 24 Day 28 continued ibrutinib until progression/toxicity. After a median follow-up of 36.5 months, median progression-free survival was not reached; 10 patients progressed (4 restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, and 1 dropped out). Seven (22%) of 32 patients remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent grade 3 to 4 adverse event; no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33 (87%) of 38 patients, with venetoclax monotherapy or combined with ibrutinib

Published
2022

11. 'MOLTO', A MULTICENTER, OPEN LABEL, UNCONTROLLED, PHASE II CLINICAL TRIAL ON VENETOCLAX, ATEZOLIZUMAB, OBINUTUZUMAB (AVO) COMBINATION IN RICHTER TRANSFORMATION: SAFETY INTERIM ANALYSIS

Author

Frustaci, AM, Tedeschi, A, Zinzani, PL, Pietrasanta, D, Coscia, M, Zenz, T, Motta, M, Gaidano, G, Scarfo, L, Deodato, M, Zamprogna, G, Vitale, C, Cairoli, R, Rossi, D, Montillo, M, Frustaci, A, Tedeschi, A, Zinzani, P, Pietrasanta, D, Coscia, M, Zenz, T, Motta, M, Gaidano, G, Scarfo, L, Deodato, M, Zamprogna, G, Vitale, C, Cairoli, R, Rossi, D, and Montillo, M

Subjects
Hematology
Published
2021

12. 'MOLTO', A MULTICENTER, OPEN LABEL, UNCONTROLLED, PHASE II CLINICAL TRIAL ON VENETOCLAX, ATEZOLIZUMAB, OBINUTUZUMAB (AVO) COMBINATION IN RICHTER TRANSFORMATION: SAFETY INTERIM ANALYSIS

Author

Frustaci, A, Tedeschi, A, Zinzani, P, Pietrasanta, D, Coscia, M, Zenz, T, Motta, M, Gaidano, G, Scarfo, L, Deodato, M, Zamprogna, G, Vitale, C, Cairoli, R, Rossi, D, Montillo, M, Frustaci, AM, Zinzani, PL, Frustaci, A, Tedeschi, A, Zinzani, P, Pietrasanta, D, Coscia, M, Zenz, T, Motta, M, Gaidano, G, Scarfo, L, Deodato, M, Zamprogna, G, Vitale, C, Cairoli, R, Rossi, D, Montillo, M, Frustaci, AM, and Zinzani, PL

Published
2021

13. 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

14. Preexisting and treatment-emergent autoimmune cytopenias in patients with CLL treated with targeted drugs

Author

Vitale, C., Salvetti, Maria Cristina, Griggio, V., Porrazzo, M., Schiattone, L., Zamprogna, G., Visentin, A., Vassallo, F., Cassin, R., Rigolin, G. M., Murru, R., Laurenti, Luca, Rivela, P., Marchetti, M., Pennese, E., Gentile, Marino, Boccellato, E., Perutelli, F., Montalbano, M. C., De Paoli, L., Reda, G., Orsucci, L., Trentin, L., Cuneo, A., Tedeschi, Alessandra, Scarfo, L., Gaidano, G., Mauro, F. R., Foa, Robin, Boccadoro, M., Coscia, M., Salvetti C., Laurenti L. (ORCID:0000-0002-8327-1396), Gentile M., Tedeschi A., Foa R., Vitale, C., Salvetti, Maria Cristina, Griggio, V., Porrazzo, M., Schiattone, L., Zamprogna, G., Visentin, A., Vassallo, F., Cassin, R., Rigolin, G. M., Murru, R., Laurenti, Luca, Rivela, P., Marchetti, M., Pennese, E., Gentile, Marino, Boccellato, E., Perutelli, F., Montalbano, M. C., De Paoli, L., Reda, G., Orsucci, L., Trentin, L., Cuneo, A., Tedeschi, Alessandra, Scarfo, L., Gaidano, G., Mauro, F. R., Foa, Robin, Boccadoro, M., Coscia, M., Salvetti C., Laurenti L. (ORCID:0000-0002-8327-1396), Gentile M., Tedeschi A., and Foa R.

Abstract

Autoimmune cytopenias (AICs) affect 5% to 9% of patients with chronic lymphocytic leukemia (CLL). Targeted drugs—ibrutinib, idelalisib, and venetoclax—have a prominent role in the treatment of CLL, but their impact on CLL-associated AICs is largely unknown. In this study, we evaluated the characteristics and outcome of preexisting AICs and described the incidence, quality, and management of treatment-emergent AICs during therapy with targeted drugs in patients with CLL. We collected data from 572 patients treated with ibrutinib (9% in combination with an anti-CD20 monoclonal antibody), 143 treated with idelalisib-rituximab, and 100 treated with venetoclax (12% in combination with an anti-CD20 monoclonal antibody). A history of preexisting AICs was reported in 104 (13%) of 815 patients. Interestingly, 80% of patients whose AICs had not resolved when treatment with a targeted drug was started experienced an improvement or a resolution during therapy. Treatment-emergent AICs occurred in 1% of patients during ibrutinib therapy, in 0.9% during idelalisib therapy, and in 7% during venetoclax therapy, with an estimated incidence rate of 5, 6, and 69 episodes per 1000 patients per year of exposure in the 3 treatment groups, respectively. The vast majority of patients who developed treatment-emergent AICs had unfavorable biological features such as an unmutated IGHV and a del(17p) and/or TP53 mutation. Notably, despite AICs, 83% of patients were able to continue the targeted drug, in some cases in combination with additional immunosuppressive agents. Overall, treatment with ibrutinib, idelalisib, or venetoclax seems to have a beneficial impact on CLL-associated AICs, inducing an improvement or even a resolution of preexisting AICs in most cases and eliciting treatment-emergent AICs in a negligible portion of patients.

Published
2021

16. Computational analysis of the evolutionarily conserved Missing In Metastasis/Metastasis Suppressor 1 gene predicts novel interactions, regulatory regions and transcriptional control

Author

Petrov P., Sarapulov A. V., Eory L., Scielzo C., Scarfo' L., Smith J., Burt D. W., Mattila P. K., Petrov, P., Sarapulov, A. V., Eory, L., Scielzo, C., Scarfo', L., Smith, J., Burt, D. W., and Mattila, P. K.

Subjects
Evolution, Molecular, Polymorphism, Genetic, Protein Domains, Microfilament Proteins, Animals, Humans, Lizards, Regulatory Sequences, Nucleic Acid, Chickens, Conserved Sequence, Leukemia, Lymphoid, Neoplasm Proteins, Protein Binding
Abstract

Missing in Metastasis (MIM), or Metastasis Suppressor 1 (MTSS1), is a highly conserved protein, which links the plasma membrane to the actin cytoskeleton. MIM has been implicated in various cancers, however, its modes of action remain largely enigmatic. Here, we performed an extensive in silico characterisation of MIM to gain better understanding of its function. We detected previously unappreciated functional motifs including adaptor protein (AP) complex interaction site and a C-helix, pointing to a role in endocytosis and regulation of actin dynamics, respectively. We also identified new functional regions, characterised with phosphorylation sites or distinct hydrophilic properties. Strong negative selection during evolution, yielding high conservation of MIM, has been combined with positive selection at key sites. Interestingly, our analysis of intra-molecular co-evolution revealed potential regulatory hotspots that coincided with reduced potentiallypathogenic polymorphisms. We explored databases for the mutations and expression levels of MIM in cancer. Experimentally, we focused on chronic lymphocytic leukaemia (CLL), where MIM showed high overall expression, however, downregulation on poor prognosis samples. Finally, we propose strong conservation of MTSS1 also on the transcriptional level and predict novel transcriptional regulators. Our data highlight important targets for future studies on the role of MIM in different tissues and cancers.

Published
2019

17. Frontline treatment with the combination obinutuzumab±chlorambucil for chronic lymphocytic leukemia outside clinical trials: results of a multinational, multicenter study by ERIC and the Israeli CLL study group

Author

Herishanu Y, Shaulov A, Fineman R, BasiC-Kinda S, Aviv A, Wasik-Szczepanek E, Jaksic O, Zdrenghea M, Greenbaum U, Mandac I, Simkovic M, Morawska M, Benjamini O, Spacek M, Nemets A, Bairey O, Trentin L, Ruchlemer R, Laurenti L, Ciocan O, Doubek M, Shvidel L, Dali N, Miras F, De Meuter A, Dimou M, Mauro F, Coscia M, Bumbea H, Szasz R, Tadmor T, Gutwein O, Gentile M, Scarfo L, Tedeschi A, Sportoletti P, Vazquez E, Marquet J, Assouline S, Papaioannou M, Braester A, Levato L, Gregor M, Rigolin G, Loscertales J, Perez A, Nijziel M, Popov V, Collado R, Slavutsky I, Itchaki G, Ringelstein S, Goldschmidt N, Perry C, Levi S, Polliack A, and Ghia P

Abstract

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O±Clb in unfit patients with CLL, in a "real-world" setting. Patients with documented del(17p13.1)/TP53mutation were excluded. A total of 437 patients (median age, 75.9years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min)were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95%CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del(11q22.3) and/or IGHV-unmutated], lymph nodes of diameter >5cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a "real-world" setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del(11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease. This article is protected by copyright. All rights reserved.

Published
2020

18. 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

19. Frontline treatment with the combination obinutuzumab ± chlorambucil for chronic lymphocytic leukemia outside clinical trials: Results of a multinational, multicenter study by ERIC and the Israeli CLL study group

Author

Herishanu, Y., Shaulov, A., Fineman, R., Basic-Kinda, S., Aviv, A., Wasik-Szczepanek, E., Jaksic, O., Zdrenghea, M., Greenbaum, U., Mandac, I., Simkovic, M., Morawska, M., Benjamini, O., Spacek, M., Nemets, A., Bairey, O., Trentin, L., Ruchlemer, R., Laurenti, Luca, Stanca Ciocan, O., Doubek, M., Shvidel, L., Dali, N., Miras, F., De Meuter, A., Dimou, M., Mauro, F. R., Coscia, M., Bumbea, H., Szasz, R., Tadmor, T., Gutwein, O., Gentile, Marino, Scarfo, L., Tedeschi, Alessandra, Sportoletti, P., Gimeno Vazquez, E., Marquet, J., Assouline, S., Papaioannou, M., Braester, A., Levato, L., Gregor, M., Rigolin, G. M., Loscertales, J., Medina Perez, A., Nijziel, M. R., Popov, V. M., Collado, R., Slavutsky, I., Itchaki, G., Ringelstein, S., Goldschmidt, N., Perry, C., Levi, S., Polliack, A., Ghia, P., Laurenti L. (ORCID:0000-0002-8327-1396), Gentile M., Tedeschi A., Herishanu, Y., Shaulov, A., Fineman, R., Basic-Kinda, S., Aviv, A., Wasik-Szczepanek, E., Jaksic, O., Zdrenghea, M., Greenbaum, U., Mandac, I., Simkovic, M., Morawska, M., Benjamini, O., Spacek, M., Nemets, A., Bairey, O., Trentin, L., Ruchlemer, R., Laurenti, Luca, Stanca Ciocan, O., Doubek, M., Shvidel, L., Dali, N., Miras, F., De Meuter, A., Dimou, M., Mauro, F. R., Coscia, M., Bumbea, H., Szasz, R., Tadmor, T., Gutwein, O., Gentile, Marino, Scarfo, L., Tedeschi, Alessandra, Sportoletti, P., Gimeno Vazquez, E., Marquet, J., Assouline, S., Papaioannou, M., Braester, A., Levato, L., Gregor, M., Rigolin, G. M., Loscertales, J., Medina Perez, A., Nijziel, M. R., Popov, V. M., Collado, R., Slavutsky, I., Itchaki, G., Ringelstein, S., Goldschmidt, N., Perry, C., Levi, S., Polliack, A., Ghia, P., Laurenti L. (ORCID:0000-0002-8327-1396), Gentile M., and Tedeschi A.

Abstract

In recent years, considerable progress has been made in frontline therapy for elderly/physically unfit patients with CLL. The combination of obinutuzumab and chlorambucil (O-Clb) has been shown to prolong progression free survival (PFS, median PFS-31.5 months) and overall survival (OS) compared to chlorambucil alone. More recently, obinutuzumab given in combination with either ibrutinib or venetoclax improved PFS but not OS when compared to O-Clb. In this retrospective multinational, multicenter co-operative study, we evaluated the efficacy and safety of frontline treatment with O ± Clb in unfit patients with CLL, in a “real-world” setting. Patients with documented del (17p13.1)/TP53 mutation were excluded. A total of 437 patients (median age, 75.9 years; median CIRS score, 8; median creatinine clearance, 61.1 mL/min) were included. The clinical overall response rate was 80.3% (clinical complete and partial responses in 38.7% and 41.6% of patients, respectively). Median observation time was 14.1 months and estimated median PFS was 27.6 months (95% CI, 24.2-31.0). In a multivariate analysis, high-risk disease [del (11q22.3) and/or IGHV-unmutated], lymph nodes of diameter > 5 cm, obinutuzumab monotherapy and reduced cumulative dose of obinutuzumab, were all independently associated with shorter PFS. The median OS has not yet been reached and estimated 2-year OS is 88%. In conclusion, in a “real-world” setting, frontline treatment with O-Clb achieves PFS comparable to that reported in clinical trials. Inferior outcomes were noted in patients with del (11q22.3) and/or unmutated IGHV and those treated with obinutuzumab-monotherapy. Thus, O-Clb can be still considered as legitimate frontline therapy for unfit CLL patients with low-risk disease.

Published
2020

20. 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

21. No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(Immuno)therapy

Author

Baliakas, P. Mattsson, M. Hadzidimitriou, A. Minga, E. Agathangelidis, A. Sutton, L.-A. Scarfo, L. Davis, Z. Yan, X.-J. Plevova, K. Sandberg, Y. Vojdeman, F.J. Tzenou, T. Chu, C.C. Veronese, S. Mansouri, L. Smedby, K.E. Giudicelli, V. Nguyen-Khac, F. Panagiotidis, P. Juliusson, G. Anagnostopoulos, A. Lefranc, M.-P. Trentin, L. Catherwood, M. Montillo, M. Niemann, C.U. Langerak, A.W. Pospisilova, S. Stavroyianni, N. Chiorazzi, N. Oscier, D. Jelinek, D.F. Shanafelt, T. Darzentas, N. Belessi, C. Davi, F. Ghia, P. Rosenquist, R. Stamatopoulos, K.

Published
2018

22. UMBRALISIB MONOTHERAPY DEMONSTRATES EFFICACY AND SAFETY IN PATIENTS WITH RELAPSED/REFRACTORY MARGINAL ZONE LYMPHOMA: A MULTICENTER, OPEN-LABEL, REGISTRATION DIRECTED PHASE 2 STUDY

Author

Zinzani, P., primary, Samaniego, F., additional, Jurczak, W., additional, Lech-Maranda, E., additional, Ghosh, N., additional, Anz, B., additional, Patten, P., additional, Reeves, J., additional, Leslie, L.A., additional, Smolewski, P., additional, Chavez, J.C., additional, Scarfo, L., additional, Derenzini, E., additional, Burke, J.M., additional, Sharman, J., additional, Kolibaba, K., additional, O'Connor, O.A., additional, Cheah, C.Y., additional, Miskin, H.P., additional, Sportelli, P., additional, Weiss, M.S., additional, and Fowler, N.H., additional

Published
2019
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24. No improvement in long-term survival over time for chronic lymphocytic leukemia patients in stereotyped subsets #1 and #2 treated with chemo(immuno)therapy

Author

Baliakas, P, Mattsson, M, Hadzidimitriou, A, Minga, E, Agathangelidis, A, Sutton, LA, Scarfo, L, Davis, Z, Yan, XJ, Plevova, K, Sandberg, Yorick, Vojdeman, FJ, Tzenou, T, Chu, CC, Veronese, S, Mansouri, L, Smedby, KE, Giudicelli, V, Nguyen-Khac, F, Panagiotidis, P, Juliusson, G, Anagnostopoulos, A, Lefranc, MP, Trentin, L, Catherwood, M, Montillo, M, Niemann, CU, Langerak, Ton, Pospisilova, S, Stavroyianni, N, Chiorazzi, N, Oscier, D, Jelinek, DF, Shanafelt, T, Darzentas, N, Belessi, C, Davi, F, Ghia, P, Rosenquist, R, Stamatopoulos, K, Baliakas, P, Mattsson, M, Hadzidimitriou, A, Minga, E, Agathangelidis, A, Sutton, LA, Scarfo, L, Davis, Z, Yan, XJ, Plevova, K, Sandberg, Yorick, Vojdeman, FJ, Tzenou, T, Chu, CC, Veronese, S, Mansouri, L, Smedby, KE, Giudicelli, V, Nguyen-Khac, F, Panagiotidis, P, Juliusson, G, Anagnostopoulos, A, Lefranc, MP, Trentin, L, Catherwood, M, Montillo, M, Niemann, CU, Langerak, Ton, Pospisilova, S, Stavroyianni, N, Chiorazzi, N, Oscier, D, Jelinek, DF, Shanafelt, T, Darzentas, N, Belessi, C, Davi, F, Ghia, P, Rosenquist, R, and Stamatopoulos, K

Published
2018

25. A phase II multi-center trial of pentostatin plus cyclophosphamide with ofatumumab in older previously untreated chronic lymphocytic leukemia patients

Author

Tedeschi, A, Rossi, D, Motta, M, Quaresmini, G, Rossi, M, Coscia, M, Anastasia, A, Rossini, F, Cortelezzi, A, Nador, G, Scarfo, L, Cairoli, R, Frustaci, A, Dalceggio, D, Picardi, P, de Paoli, L, Orlandi, E, Rambaldi, A, Massaia, M, Gaidano, G, Montillo, M, Tedeschi A., Rossi D., Motta M., Quaresmini G., Rossi M., Coscia M., Anastasia A., Rossini F., Cortelezzi A., Nador G., Scarfo L., Cairoli R., Frustaci A. M., Dalceggio D., Picardi P., de Paoli L., Orlandi E., Rambaldi A., Massaia M., Gaidano G., Montillo M., Tedeschi, A, Rossi, D, Motta, M, Quaresmini, G, Rossi, M, Coscia, M, Anastasia, A, Rossini, F, Cortelezzi, A, Nador, G, Scarfo, L, Cairoli, R, Frustaci, A, Dalceggio, D, Picardi, P, de Paoli, L, Orlandi, E, Rambaldi, A, Massaia, M, Gaidano, G, Montillo, M, Tedeschi A., Rossi D., Motta M., Quaresmini G., Rossi M., Coscia M., Anastasia A., Rossini F., Cortelezzi A., Nador G., Scarfo L., Cairoli R., Frustaci A. M., Dalceggio D., Picardi P., de Paoli L., Orlandi E., Rambaldi A., Massaia M., Gaidano G., and Montillo M.

Published
2015

27. A PHASE II MULTI-CENTER TRIAL OF PENTOSTATIN PLUS CYCLOPHOSPHAMIDE WITH OFATUMUMAB (PCO) IN OLDER PREVIOUSLY UNTREATED CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) PATIENTS

Author

Montillo, M, Rossi, D, Motta, M, Quaresmini, G, Rossi, M, Coscia, M, Anastasia, A, Rossini, F, Cortellezzi, A, Nador, N, Scarfo, L, Cairoli, R, Frustaci, A, Dal Ceggio, D, Picardi, P, De Paoli, L, Orlandi, E, Rambaldi, A, Morra, M, Massaia, M, Tedeschi, A, Montillo M, Rossi D, Motta M, Quaresmini G, Rossi M, Coscia M, Anastasia A, Rossini F, Cortellezzi A, Nador N, Scarfo L, Cairoli R, Frustaci AM, Dal Ceggio D, Picardi P, De Paoli L, Orlandi E, Rambaldi A, Morra M, Massaia M, Tedeschi A, Montillo, M, Rossi, D, Motta, M, Quaresmini, G, Rossi, M, Coscia, M, Anastasia, A, Rossini, F, Cortellezzi, A, Nador, N, Scarfo, L, Cairoli, R, Frustaci, A, Dal Ceggio, D, Picardi, P, De Paoli, L, Orlandi, E, Rambaldi, A, Morra, M, Massaia, M, Tedeschi, A, Montillo M, Rossi D, Motta M, Quaresmini G, Rossi M, Coscia M, Anastasia A, Rossini F, Cortellezzi A, Nador N, Scarfo L, Cairoli R, Frustaci AM, Dal Ceggio D, Picardi P, De Paoli L, Orlandi E, Rambaldi A, Morra M, Massaia M, and Tedeschi A

Published
2014

28. Ibrutinib Treatment Mitigates Phenotypic Alterations of Non-Neoplastic Immune Cell Compartments in Chronic Lymphocytic Leukemia

Author

Griggio, V, Vitale, C, Todaro, M, Mauro, Fr, Salvetti, C, Pietrasanta, D, Vincelli, Id, Scarfo, L, Del Poeta, G, Gaidano, G, Gattei, V, Foà, R, Boccadoro, M, and Coscia, M

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Abstract

Background: Chronic lymphocytic leukemia (CLL) is characterized by phenotypic and functional defects of immune cells, which often emerge into increased susceptibility to infections and autoimmunity, and also contribute to immune evasion of cancer cells. Ibrutinib is a selective inhibitor of BTK that shows activity via its direct effects on crucial survival pathways in CLL cells. In addition to its anti-neoplastic effects, ibrutinib has also shown to have immunomodulatory properties. Currently available data are mainly limited to the activity exerted by ibrutinib on conventional T cells, whereas little is known on the effects induced on other non-neoplastic immune cell populations. Aim: The aim of this study was to evaluate the in vivo immunomodulatory effects of ibrutinib treatment on different immune compartments in patients with CLL Methods: We included 11 CLL patients with progressive disease (PD CLL) and eligible to ibrutinib therapy. PB samples were collected from patients at baseline and after 1, 6 and 12 months of treatment with ibrutinib. For comparison, we also analyzed 5 healthy donors (HD) and 6 treatment-naïve CLL patients with stable disease (SD CLL), who were not fulfilling criteria for treatment start. We assessed the percentages and the absolute numbers of CLL cells, T cells, γδ (Vδ1 and Vγ9Vδ2) T cells, T regulatory cells (Tregs), natural killer (NK) and NK-T cells by flow cytometry using population-specific markers. The expression of activation markers and immune checkpoint receptors (i.e. CD69, PD-1, CD96, TIGIT, NKG2D) was evaluated by flow cytometry as well. Results: Median age of patients was 69 years (range 44-75). The median lymphocyte count at study entry was 49 x 109/L (range 1,8-110) and the median number of previous treatment regimens was 2 (range 0-5). After 12 months of ibrutinib, 10 out of 11 (91%) patients achieved at least a partial response. The mean absolute number of CLL cells started to decrease by month 6 and became significantly lower than baseline value at 12 months of ibrutinib therapy. At the baseline, leukemic cells from PD CLL had significantly higher surface expression of the early activation marker CD69 and of the immune checkpoint molecule PD-1 compared to SD CLL and HD. After 6 months of treatment, the percentage of CLL cells expressing CD69 and PD-1 was normalized (reached values not significantly different from HD) (Fig 1A,B). We observed a gradual reduction of the total count of CD4+ and CD8+ T cells during ibrutinib treatment, becoming significant at 12 months. At the same timepoint, the expression of CD69, which was higher on T cells from PD CLL prior to therapy compared to SD CLL and HD, was normalized. Concurrently, a significant reduction in the surface levels of the inhibitory immune checkpoint molecule CD96 was observed (Fig 1C,D). Ibrutinib treatment had no impact on the absolute numbers of NK and NK-T cells. Compared to SD CLL and HD, NK cells from PD CLL showed a higher expression of CD69 before treatment start. In addition, they were characterized by increased levels of the immune checkpoints CD96 and TIGIT, and by reduced expression of the Fc receptor CD16, that is involved in the ADCC process, and the activating receptor NKG2D. After 6 months of treatment, the expression of CD69, CD16 and NKG2D on NK cells were restored (Fig 1E-G), whereas TIGIT and CD96 were not yet significantly modulated. Concerning the Tregs, a trend toward a reduction in the absolute number was detected after 12 months of ibrutinib treatment, compared to the baseline. The percentage of Tregs expressing the co-inhibitory molecule TIGIT was higher in PD CLL at the time of treatment start and was normalized by 12 months of ibrutinib therapy (Fig 1H). Lastly, we assessed ibrutinib effects on γδ T cells. The absolute numbers of both Vδ1 and Vγ9Vδ2 T cells remained unchanged during patients' treatment. Similar to conventional T lymphocytes, Vγ9Vδ2 T cells showed a decrease in the expression of CD96 after 12 months of ibrutinib administration (Fig 1I). Conclusions: our data suggest that the anti-tumor activity of ibrutinib is paralleled by a valuable immunomodulatory effect, leading to a partial recovery of phenotypic alterations that are hallmarks of immune exhaustion. Further studies to investigate the ability of ibrutinib to restore the functionality of the described immune cell compartments and to explore clinical correlations are currently ongoing on an enlarged cohort of treated patients. Figure 1. Figure 1. Disclosures Mauro: abbvie: Other: board member; janssen: Other: board member. Gaidano:Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Morphosys: Honoraria; Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Foà:ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD. Boccadoro:AbbVie: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding; Novartis: Honoraria, Research Funding. Coscia:Janssen, Karyopharm: Research Funding; Abbvie, Gilead, Shire: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Published
2018

29. THE IELSG-32 TRIAL: RANDOMIZED PHASE II TRIAL ON PRIMARY CHEMOTHERAPY WITH HIGH-DOSE METHOTREXATE AND HIGH-DOSE CYTARABINE WITH OR WITHOUT THIOTEPA, AND WITH OR WITHOUT RITUXIMAB, FOLLOWED BY BRAIN IRRADIATION VS HIGH-DOSE CHEMOTHERAPY SUPPORTED BY AUTOLOGOUS STEM CELLS TRANSPLANTATION FOR IMMUNOCOMPETENT PATIENTS WITH NEWLY DIAGNOSED PRIMARY CNS LYMPHOMA

Author

Ferreri, Ajm, Cwynarski, K, Pulczynski, E, Ponzoni, M, Politi, Ls, Ambrosetti, A, Vitolo, U, Ilariucci, F, Balzarotti, M, Fabbri, A, Tucci, A, Pisani, F, Levis, A, Cabras, Mg, D'Arco, M, Zaccaria, A, Angrilli, F, Guarini, Anna, Imola, M, Martelli, Maurizio, Cervetti, J, Zaja, F, Pinto, A, Liberati, M, Morra, E, Cortellazzo, Sf, Bassan, R, Foppoli, M, Citterio, G, Sassone, M, Scarfo, L, Cavalli, F, Finke, J, Reni, M, Zucca, E, and Illerhaus, G.

Published
2015

30. MAKING THE RIGHT CHOICE: THE ROLE OF FITNESS STATUS IN THE MANAGEMENT OF FIRST-LINE TREATMENT IN CHRONIC LYMPHOCYTIC LEUKEMIA PATIENTS (CLL FITNESS STUDY)

Author

Scarfo, L, Quaresmini, G, Mauro, Fr, Orlandi, E, Reda, G, Laurenti, L, Coscia, Marta, Ambrosetti, A, Murru, R, Trentin, L, Guelill, A, Visco, C, Morabito, F, Frustaci, A, Ciolli, S, Rossini, F, Cuneo, A, Gozzetti, A, Scortechini, I, Pane, F, Zinzani, Pl, Ferrara, F, Mannina, D, Marasca, R, Pierri, I, Specchia, G, Chiarenza, A, Zallio, F, Molica, S, De Paoli, L, Torreggiani, A, Brugiatelli, M, Semenzato, G, Innocenti, I, Picardi, P, Pizzolo, G, Foa, R, Rambaldi, A, and Ghia, P.

Published
2015

31. No Improvement In Long-Term Overall Survival After The Introduction Of Chemo(Immuno)Therapy For Chronic Lymphocytic Leukemia Patients Belonging To Stereotyped Subset #2

Author

Baliakas, Panagiotis, Mattsson, Mattias, Hadzidimitriou, A., Minga, E., Agathangelidis, A., Sutton, L. A., Scarfo, L., Davis, Z., Yan, X. J., Plevova, K., Sandberg, Y., Vojdeman, F. Juhl, Tzenou, T., Chu, C. C., Veroneze, S., Mansouri, Larry, Smedby, K. E., Giudicelli, V., Nguyen-Khac, F., Panagiotidis, P., Juliusson, G., Anagnostopoulos, A., Lefranc, M. P., Trentin, L., Catherwood, M., Montillo, M., Niemann, C. U., Langerak, A. W., Pospisilova, S., Stavroyianni, N., Chiorazzi, N., Oscier, D., Jelinek, D. F., Shanafelt, T., Darzentas, N., Belessi, C., Davi, F., Ghia, P., Rosenquist, Richard, Stamatopoulos, Kostas, Baliakas, Panagiotis, Mattsson, Mattias, Hadzidimitriou, A., Minga, E., Agathangelidis, A., Sutton, L. A., Scarfo, L., Davis, Z., Yan, X. J., Plevova, K., Sandberg, Y., Vojdeman, F. Juhl, Tzenou, T., Chu, C. C., Veroneze, S., Mansouri, Larry, Smedby, K. E., Giudicelli, V., Nguyen-Khac, F., Panagiotidis, P., Juliusson, G., Anagnostopoulos, A., Lefranc, M. P., Trentin, L., Catherwood, M., Montillo, M., Niemann, C. U., Langerak, A. W., Pospisilova, S., Stavroyianni, N., Chiorazzi, N., Oscier, D., Jelinek, D. F., Shanafelt, T., Darzentas, N., Belessi, C., Davi, F., Ghia, P., Rosenquist, Richard, and Stamatopoulos, Kostas

Published
2016

32. Ex Vivo Lymph Node Native Microenvironment Assay Shows Novel Antiproliferative Activity For Idelalisib And Ibrutinib On Cll Cells

Author

Ballesteros, J., Scarfo, L., Mattsson, Mattias, Xochelli, A., Ranghetti, P., Primo, D., Robles, A., Gorrochategui, J., Martinez Lopez, J., de la Serna, J., Gonzalez, M., Munugalavadla, V., Tannheimer, S., Rosenquist, Richard, Stamatopoulos, K., Ghia, P., Ballesteros, J., Scarfo, L., Mattsson, Mattias, Xochelli, A., Ranghetti, P., Primo, D., Robles, A., Gorrochategui, J., Martinez Lopez, J., de la Serna, J., Gonzalez, M., Munugalavadla, V., Tannheimer, S., Rosenquist, Richard, Stamatopoulos, K., and Ghia, P.

Published
2016

33. Different spectra of recurrent gene mutations in subsets of chronic lymphocytic leukemia harboring stereotyped B-cell receptors

Author

Sutton, LA, Young, E, Baliakas, P, Hadzidimitriou, A, Moysiadis, T, Plevova, K, Rossi, D, Kminkova, J, Stalika, E, Pedersen, LB, Malcikova, J, Agathangelidis, A, Davis, Z, Mansouri, L, Scarfo, L, Boudjoghra, M, Navarro, A, Muggen, Alice, Yan, XJ, Nguyen-Khac, F, Larrayoz, M, Panagiotidis, P, Chiorazzi, N, Niemann, CU, Belessi, C, Campo, E, Strefford, JC, Langerak, Ton, Oscier, D, Gaidano, G, Pospisilova, S, Davi, F, Ghia, P, Stamatopoulos, K, Rosenquist, R, Sutton, LA, Young, E, Baliakas, P, Hadzidimitriou, A, Moysiadis, T, Plevova, K, Rossi, D, Kminkova, J, Stalika, E, Pedersen, LB, Malcikova, J, Agathangelidis, A, Davis, Z, Mansouri, L, Scarfo, L, Boudjoghra, M, Navarro, A, Muggen, Alice, Yan, XJ, Nguyen-Khac, F, Larrayoz, M, Panagiotidis, P, Chiorazzi, N, Niemann, CU, Belessi, C, Campo, E, Strefford, JC, Langerak, Ton, Oscier, D, Gaidano, G, Pospisilova, S, Davi, F, Ghia, P, Stamatopoulos, K, and Rosenquist, R

Abstract

We report on markedly different frequencies of genetic lesions within subsets of chronic lymphocytic leukemia patients carrying mutated or unmutated stereotyped B-cell receptor immunoglobulins in the largest cohort (n=565) studied for this purpose. By combining data on recurrent gene mutations (BIRC3, MYD88, NOTCH1, SF3B1 and TP53) and cytogenetic aberrations, we reveal a subset-biased acquisition of gene mutations. More specifically, the frequency of NOTCH1 mutations was found to be enriched in subsets expressing unmutated immunoglobulin genes, i.e. #1, #6, #8 and #59 (22-34%), often in association with trisomy 12, and was significantly different (P<0.001) to the frequency observed in subset #2 (4%, aggressive disease, variable somatic hypermutation status) and subset #4 (1%, indolent disease, mutated immunoglobulin genes). Interestingly, subsets harboring a high frequency of NOTCH1 mutations were found to carry few (if any) SF3B1 mutations. This starkly contrasts with subsets #2 and #3 where, despite their immunogenetic differences, SF3B1 mutations occurred in 45% and 46% of cases, respectively. In addition, mutations within TP53, whilst enriched in subset #1 (16%), were rare in subsets# 2 and #8 (both 2%), despite all being clinically aggressive. All subsets were negative for MYD88 mutations, whereas BIRC3 mutations were infrequent. Collectively, this striking bias and skewed distribution of mutations and cytogenetic aberrations within specific chronic lymphocytic leukemia subsets implies that the mechanisms underlying clinical aggressiveness are not uniform, but rather support the existence of distinct genetic pathways of clonal evolution governed by a particular stereotyped B-cell receptor selecting a certain molecular lesion(s).

Published
2016

34. Histopathological EXAMINATION of BONE MARROW Biopsy (BMB) IN Primary Splenic B CELL Lymphomas of Marginal-ZONE ORIGIN (PSMZL). A Reliable Substitute for Spleen Pathology?

Author

PONZONI , MAURILIO, Kanellis G, Pouliou E, Scarfo L, Ferreri AJM, Doglioni C, Bikos V, Dagklis A, Anagnostopoulos A, Ghia P, Stamatopoulos K, Papadaki T., Ponzoni, Maurilio, Kanellis, G, Pouliou, E, Scarfo, L, Ferreri, Ajm, Doglioni, C, Bikos, V, Dagklis, A, Anagnostopoulos, A, Ghia, P, Stamatopoulos, K, and Papadaki, T.

Published
2009

36. REFINING PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH SOMATICALLY HYPERMUTATED B-CELL RECEPTORS : A NOVEL PROGNOSTIC INDEX ON BEHALF OF THE EUROPEAN RESEARCH INITIATIVE ON CLL (ERIC)

Author

Baliakas, Panagiotis, Hadzidimitriou, A., Mattsson, Mattias, Xochelli, Aliki, Sutton, L. A., Minga, E., Scarfo, L., Rossi, D., Davis, Z., Agathangelidis, A., Villamor, N., Parker, H., Kotaskova, J., Stalika, E., Plevova, K., Mansouri, Larry, Cortese, Diego, Navarro Lopez, A., Delgado, J., Larrayoz, M., Anagnostopoulos, A., Belessi, C., Smedby, K. E., Juliusson, G., Strefford, J. C., Pospisilova, S., Oscier, D., Gaidano, G., Campo, E., Ghia, P., Rosenquist, Richard, Stamatopoulos, Kostas, Baliakas, Panagiotis, Hadzidimitriou, A., Mattsson, Mattias, Xochelli, Aliki, Sutton, L. A., Minga, E., Scarfo, L., Rossi, D., Davis, Z., Agathangelidis, A., Villamor, N., Parker, H., Kotaskova, J., Stalika, E., Plevova, K., Mansouri, Larry, Cortese, Diego, Navarro Lopez, A., Delgado, J., Larrayoz, M., Anagnostopoulos, A., Belessi, C., Smedby, K. E., Juliusson, G., Strefford, J. C., Pospisilova, S., Oscier, D., Gaidano, G., Campo, E., Ghia, P., Rosenquist, Richard, and Stamatopoulos, Kostas

Published
2015

37. HIGHER-ORDER IMMUNOGLOBULIN SEQUENCE RELATIONS FOR MAJOR SUBSETS OF CHRONIC LYMPHOCYTIC LEUKEMIA : UNIQUENESS VERSUS EQUIVALENCE

Author

Agathangelidis, A., Bystry, V., Hadzidimitriou, A., Sutton, L. A., Minga, E., Kienle, D., Davis, Z., Yan, X. J., Shanafelt, T., Boudjogra, M., Plevova, K., Gounari, M., Xochelli, A., Navarro, A., Chatzouli, M., Pedersen, L. B., Baliakas, Panagiotis, Scarfo, L., Rossi, D., Veronese, S., Facco, M., Bikos, V., Karan-Djurasevic, T., Pavlovic, S., Mansouri, Larry, Poiron, C., Chu, C. C., Stalika, E., Giudicelli, V., Panagiotidis, P., Sudarikov, A., Anagnostopoulos, A., Trentin, L., Catherwood, M., Montillo, M., Gaidano, G., Campo, E., Geisler, C. H., Langerak, A. W., Pospisilova, S., Lefranc, M. P., Chiorazzi, N., Oscier, D., Jelinek, D. F., Stilgenbauer, S., Belessi, C., Davi, F., Rosenquist, Richard, Ghia, P., Darzentas, N., Stamatopoulos, Kostas, Agathangelidis, A., Bystry, V., Hadzidimitriou, A., Sutton, L. A., Minga, E., Kienle, D., Davis, Z., Yan, X. J., Shanafelt, T., Boudjogra, M., Plevova, K., Gounari, M., Xochelli, A., Navarro, A., Chatzouli, M., Pedersen, L. B., Baliakas, Panagiotis, Scarfo, L., Rossi, D., Veronese, S., Facco, M., Bikos, V., Karan-Djurasevic, T., Pavlovic, S., Mansouri, Larry, Poiron, C., Chu, C. C., Stalika, E., Giudicelli, V., Panagiotidis, P., Sudarikov, A., Anagnostopoulos, A., Trentin, L., Catherwood, M., Montillo, M., Gaidano, G., Campo, E., Geisler, C. H., Langerak, A. W., Pospisilova, S., Lefranc, M. P., Chiorazzi, N., Oscier, D., Jelinek, D. F., Stilgenbauer, S., Belessi, C., Davi, F., Rosenquist, Richard, Ghia, P., Darzentas, N., and Stamatopoulos, Kostas

Published
2015

38. Higher-order immunoglobulin sequence relations for major subsets of chronic lymphocytic leukemia: uniqueness versus equivalence

Author

Agathangelidis, Andreas, Bystry, V., Hadzidimitriou, A., Sutton, L. A., Minga, Eva, Kienle, D., Davis, Z., Yan, X. J., Shanafelt, T., Boudjogra, M., Plevova, K., Gounari, M., Xochelli, A., Navarro, A., Chatzouli, M., Pedersen, L. B., Baliakas, Panagiotis, Scarfo, L., Rossi, D., Veronese, S., Facco, M., Bikos, V., Karan-Đurašević, Teodora, Pavlović, S., Mansouri, L., Poiron, C., Chu, C. C., Stalika, E., Giudicelli, V., Panagiotidis, P., Sudarikov, A., Anagnostopoulos, Achilles, Trentin, L., Catherwood, M., Montillo, M., Gaidano, G., Campo, E., Geisler, C. H., Langerak, A. W., Pospisilova, S., Lefranc, M. P., Chiorazzi, N., Oscier, D., Jelinek, D. F., Stilgenbauer, S., Belessi, C., Davi, F., Rosenquist, R., Ghia, P., Darzentas, N., Stamatopoulos, K., Agathangelidis, Andreas, Bystry, V., Hadzidimitriou, A., Sutton, L. A., Minga, Eva, Kienle, D., Davis, Z., Yan, X. J., Shanafelt, T., Boudjogra, M., Plevova, K., Gounari, M., Xochelli, A., Navarro, A., Chatzouli, M., Pedersen, L. B., Baliakas, Panagiotis, Scarfo, L., Rossi, D., Veronese, S., Facco, M., Bikos, V., Karan-Đurašević, Teodora, Pavlović, S., Mansouri, L., Poiron, C., Chu, C. C., Stalika, E., Giudicelli, V., Panagiotidis, P., Sudarikov, A., Anagnostopoulos, Achilles, Trentin, L., Catherwood, M., Montillo, M., Gaidano, G., Campo, E., Geisler, C. H., Langerak, A. W., Pospisilova, S., Lefranc, M. P., Chiorazzi, N., Oscier, D., Jelinek, D. F., Stilgenbauer, S., Belessi, C., Davi, F., Rosenquist, R., Ghia, P., Darzentas, N., and Stamatopoulos, K.

Published
2015

40. Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and proliferation

Author

Fonte, E., primary, Agathangelidis, A., additional, Reverberi, D., additional, Ntoufa, S., additional, Scarfo, L., additional, Ranghetti, P., additional, Cutrona, G., additional, Tedeschi, A., additional, Xochelli, A., additional, Caligaris-Cappio, F., additional, Ponzoni, M., additional, Belessi, C., additional, Davis, Z., additional, Piris, M. A., additional, Oscier, D., additional, Ghia, P., additional, Stamatopoulos, K., additional, and Muzio, M., additional

Published
2015
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41. Not All IGHV3-21 CLL Are Equal : Subset #2 Displays a Distinctive Clinicobiological Profile with Remarkable Similarities to Subset #169, its Close Immunogenetic Relative

Author

Baliakas, Panagiotis, Hadzidimitriou, A., Sutton, L. A., Minga, E., Agathangelidis, A., Tsanousa, A., Scarfo, L., Davis, Z., Yan, X. J., Shanafelt, T., Plevova, K., Sandberg, Y., Vojdeman, F. J., Boudjogra, M., Tzenou, T., Chatzouli, M., Chu, C. C., Veronese, S., Gardiner, A., Mansouri, Larry, Smedby, K. E., Pedersen, L. B., Moreno, D., Van Lom, K., Giudicelli, V., Francova, H. S., Nguyen-Khac, F., Panagiotidis, P., Juliusson, G., Angelis, L., Anagnostopoulos, A., Lefranc, M. P., Trentin, L., Catherwood, M., Montillo, M., Geisler, C., Langerak, A. W., Pospisilova, S., Chiorazzi, N., Oscier, D., Jelinek, D., Darzentas, N., Belessi, C., Davi, F., Ghia, P., Rosenquist, Richard Brandell, Stamatopoulos, K., Baliakas, Panagiotis, Hadzidimitriou, A., Sutton, L. A., Minga, E., Agathangelidis, A., Tsanousa, A., Scarfo, L., Davis, Z., Yan, X. J., Shanafelt, T., Plevova, K., Sandberg, Y., Vojdeman, F. J., Boudjogra, M., Tzenou, T., Chatzouli, M., Chu, C. C., Veronese, S., Gardiner, A., Mansouri, Larry, Smedby, K. E., Pedersen, L. B., Moreno, D., Van Lom, K., Giudicelli, V., Francova, H. S., Nguyen-Khac, F., Panagiotidis, P., Juliusson, G., Angelis, L., Anagnostopoulos, A., Lefranc, M. P., Trentin, L., Catherwood, M., Montillo, M., Geisler, C., Langerak, A. W., Pospisilova, S., Chiorazzi, N., Oscier, D., Jelinek, D., Darzentas, N., Belessi, C., Davi, F., Ghia, P., Rosenquist, Richard Brandell, and Stamatopoulos, K.

Published
2014

43. Distinct patterns of novel gene mutations in poor-prognostic stereotyped subsets of chronic lymphocytic leukemia : the case of SF3B1 and subset #2

Author

Strefford, J. C., Sutton, Lesley Ann, Baliakas, Panagiotis, Agathangelidis, A., Malcikova, J., Plevova, K., Scarfo, L., Davis, Z., Stalika, E., Cortese, Diego, Cahill, Nicola, Pedersen, L. B., di Celle, P. F., Tzenou, T., Geisler, C., Panagiotidis, P., Langerak, A. W., Chiorazzi, N., Pospisilova, S., Oscier, D., Davi, F., Belessi, C., Mansouri, Larry, Ghia, P., Stamatopoulos, K., Rosenquist, Richard Brandell, Strefford, J. C., Sutton, Lesley Ann, Baliakas, Panagiotis, Agathangelidis, A., Malcikova, J., Plevova, K., Scarfo, L., Davis, Z., Stalika, E., Cortese, Diego, Cahill, Nicola, Pedersen, L. B., di Celle, P. F., Tzenou, T., Geisler, C., Panagiotidis, P., Langerak, A. W., Chiorazzi, N., Pospisilova, S., Oscier, D., Davi, F., Belessi, C., Mansouri, Larry, Ghia, P., Stamatopoulos, K., and Rosenquist, Richard Brandell

Abstract

Recent studies have revealed recurrent mutations of the NOTCH1, SF3B1 and BIRC3 genes in chronic lymphocytic leukemia (CLL), especially among aggressive, chemorefractory cases. Nevertheless, it is currently unknown whether their presence may differ in subsets of patients carrying stereotyped B-cell receptors and also exhibiting distinct prognoses. Here, we analyzed the mutation status of NOTCH1, SF3B1 and BIRC3 in three subsets with particularly poor prognosis, that is, subset # 1, # 2 and # 8, aiming to explore links between genetic aberrations and immune signaling. A remarkably higher frequency of SF3B1 mutations was revealed in subset # 2 (44%) versus subset # 1 and # 8 (4.6% and 0%, respectively; P<0.001). In contrast, the frequency of NOTCH1 mutations in subset # 2 was only 8%, lower than the frequency observed in either subset # 1 or # 8 (19% and 14%, respectively; P 0.04 for subset # 1 versus # 2). No associations were found for BIRC3 mutations that overall were rare. The apparent non-random association of certain mutations with stereotyped CLL subsets alludes to subset-biased acquisition of genomic aberrations, perhaps consistent with particular antigen/antibody interactions. These novel findings assist in unraveling specific mechanisms underlying clinical aggressiveness in poor-prognostic stereotyped subsets, with far-reaching implications for understanding their clonal evolution and implementing biologically oriented therapy., De tre första författarna delar första författarskapet.

Published
2013
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49. VENETOCLAX AND RITUXIMAB (VENR) FOR THE FRONT-LINE TREATMENT OF YOUNG PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AND AN UNFAVORABLE BIOLOGIC PROFILE. PRELIMINARY RESULTS OF THE GIMEMA VERITAS STUDY

Author

Mauro, F. R., Reda, G., Arena, V., Visentin, A., Coscia, M., Sportoletti, P., Laurenti, L., Gaidano, G., Marasca, R., Orsucci, L., Murru, R., Stelitano, C., Ilariucci, F., Mannina, D., Massaia, M., Gian Matteo Rigolin, Scarfo, L., Marchetti, M., Levato, L., Tani, M., Arcari, A., Musuraca, G., Deodato, M., Galieni, P., Patrizi, V. Belsito, Gottardi, D., Liberati, A. M., Pietrasanta, D., Molica, S., Cassin, R., Vitale, C., Ielo, C., Propris, M. S., Della Starza, I., Raponi, S., Nanni, M., Del Giudice, I., Paoloni, F., Fazi, P., Albano, F., Neri, A., Piciocchi, A., Trentin, L., Cuneo, A., Guarini, A., and Foa, R.

50. REFINING PROGNOSIS OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH SOMATICALLY HYPERMUTATED B-CELL RECEPTORS: A NOVEL PROGNOSTIC INDEX ON BEHALF OF THE EUROPEAN RESEARCH INITIATIVE ON CLL (ERIC)

Author

Baliakas, P., Hadzidimitriou, A., Mattsson, M., Xochelli, A., Sutton, L. A., Minga, E., Scarfo, L., Rossi, D., Davis, Z., Agathangelidis, A., Villamor, N., Parker, H., Kotaskova, J., Stalika, E., Plevova, K., Mansouri, L., Cortese, D., Navarro Lopez, A., Delgado, J., Larrayoz, M., Anagnostopoulos, A., Belessi, C., Smedby, K. E., Juliusson, G., Strefford, J. C., Sarka Pospisilova, Oscier, D., Gaidano, G., Campo, E., Ghia, P., Rosenquist, R., and Stamatopoulos, K.

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