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1. Report of Consensus Panel 3 from the 11th International Workshop on Waldenström's Macroglobulinemia: Recommendations for Molecular Diagnosis in Waldenström's Macroglobulinemia

Author

Garcia-Sanz, R, primary, Varettoni, M, additional, Jiménez, C, additional, Ferrero, S, additional, Poulain, S, additional, San-Miguel, JF, additional, Guerrera, ML, additional, Drandi, D, additional, Bagratuni, T, additional, McMaster, M, additional, Roccaro, AM, additional, Roos-Weil, D, additional, Leiba, M, additional, Li, Y, additional, Qiu, L, additional, Hou, J, additional, De Larrea, C Fernandez, additional, Castillo, JJ, additional, Dimopoulos, M, additional, Owen, RG, additional, Treon, SP, additional, and Hunter, ZR, additional

Published
2023
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2. Report of consensus panel 2 from the 11th international workshop on Waldenström's macroglobulinemia on the management of relapsed or refractory WM patients

Author

D'Sa, S, primary, Matous, JV, additional, Advani, R, additional, Buske, C, additional, Castillo, JJ, additional, Gatt, M, additional, Kapoor, P, additional, Kersten, MJ, additional, Leblond, V, additional, Leiba, M, additional, Palomba, ML, additional, Paludo, J, additional, Qiu, L, additional, Sarosiek, S, additional, Shadman, M, additional, Talaulikar, D, additional, Tam, CS, additional, Tedeschi, A, additional, Thomas, SK, additional, Tohidi-Esfahani, I, additional, Trotman, J, additional, Varettoni, M, additional, Vos, JMI, additional, Garcia-Sanz, R, additional, San-Miguel, J, additional, Dimopoulos, MA, additional, Treon, SP, additional, and Kastritis, E, additional

Published
2023
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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

4. SARS-CoV-2 Infection in Patients with Waldenstrom's Macroglobulinemia: A Multicenter International Cohort Study

Author

Defrancesco, I., Ferretti, V. V., Morel, P., Kyriakou, C., Kastritis, E., Tohidi-Esfahani, I., Tedeschi, A., Buske, C., Garcia-Sanz, R., Vos, J. M. I., Peri, V., Margiotta Casaluci, G., Ferrari, A., Piazza, F., Oostvogels, R., Lovato, E., Montes, L., Fornecker, L. M., Grunenberg, A., Dimopoulos, M. A., Tam, C. S., D'Sa, S., Leblond, V., Trotman, J., Passamonti, F., Arcaini, L., and Varettoni, M.

Published
2023

6. Antiviral treatment in patients with indolent B-cell lymphomas associated with HCV infection: a study of the Fondazione Italiana Linfomi

Author

Arcaini, L., Vallisa, D., Rattotti, S., Ferretti, V.V., Ferreri, A.J.M., Bernuzzi, P., Merli, M., Varettoni, M., Chiappella, A., Ambrosetti, A., Tucci, A., Rusconi, C., Visco, C., Spina, M., Cabras, G., Luminari, S., Tucci, M., Musto, P., Ladetto, M., Merli, F., Stelitano, C., d'Arco, A., Rigacci, L., Levis, A., Rossi, D., Spedini, P., Mancuso, S., Marino, D., Bruno, R., Baldini, L., and Pulsoni, A.

Published
2014
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7. 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

8. 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

9. P1256: A NOVEL DROP-OFF DIGITAL PCR ASSAY FOR CXCR4 MUTATION SCREENING IN IGM GAMMOPATHIES: FIRST DATA FROM THE FONDAZIONE ITALIANA LINFOMI BIO-WM STUDY

Author

Drandi, D., primary, Ferrante, M., additional, Zibellini, S., additional, Marcheselli, L., additional, Cappello, E., additional, Borriero, M., additional, Ragaini, S., additional, Dogliotti, I., additional, Varraso, C., additional, Cavallo, F., additional, Ferrari, A., additional, Merli, M., additional, Zamprogna, G., additional, Laurenti, L., additional, Tomasetti, S., additional, Cencini, E., additional, Loseto, G., additional, Finotto, S., additional, Marchetti, M., additional, Re, F., additional, Sica, A., additional, Olivieri, J., additional, Jimenez, C., additional, Puig, N., additional, Cavalloni, C., additional, García-Sanz, R., additional, Varettoni, M., additional, and Ferrero, S., additional

Published
2022
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10. Updated results of the aspen trial from a cohort of patients with wild-type myd88 waldenstrom macroglobulinemia (myd88wt wm).

Author

Buske C., Dimopoulos M., Garcia Sanz R., Lee H.-P., Trneny M., Varettoni M., Opat S., D'Sa S., Owen R.G., Cull G., Mulligan S., Czyz J., Castillo J., Motta M., Siddiqi T., Gironella Mesa M., Granell Gorrochategui M., Talaulikar D., Zinzani P.L., Askari E., Grosicki S., Oriol A., Kloczko J., Tedeschi A., Leblond V., Chan W.Y., Schneider J., Cohen A., Huang J., Tam C.S., Buske C., Dimopoulos M., Garcia Sanz R., Lee H.-P., Trneny M., Varettoni M., Opat S., D'Sa S., Owen R.G., Cull G., Mulligan S., Czyz J., Castillo J., Motta M., Siddiqi T., Gironella Mesa M., Granell Gorrochategui M., Talaulikar D., Zinzani P.L., Askari E., Grosicki S., Oriol A., Kloczko J., Tedeschi A., Leblond V., Chan W.Y., Schneider J., Cohen A., Huang J., and Tam C.S.

Abstract

Introduction: Inhibitors of Bruton's tyrosine kinase (BTK) have shown significant activity in patients with MYD88 mutation-positive (MYD-88mut+) WM. However, lower response rates and shorter progression-free survival have been reported in patients with WM who lack such mutations (N Engl J Med. 2015;372:1430). The ASPEN trial (NCT03053440) evaluated zanubrutinib, a potent and selective BTK inhibitor, in patients with MYD88WT WM. Here, we present the safety and efficacy of zanubrutinib in these patients. Method(s): At study entry, bone marrow MYD88 mutations were assessed by a central laboratory (NeoGenomics). Based on these results, patients were assigned to cohort 1 (MYD88mut+) or cohort 2 (MYD88WT or unknown mutation status). Patients received zanubrutinib 160 mg twice daily until disease progression. Result(s): In total, 28 patients were enrolled in cohort 2, of which 26 were centrally confirmed as MYD88WT. Median age of patients was 72 years; five patients were treatment-naive and 23 patients had relapsed/refractory (>=1 prior therapy) WM. Most patients had intermediate-risk (39.3%) or high-risk (42.9%) disease, as defined by the International Prognostic Scoring System for WM. At median follow-up of 17.9 months, two patients discontinued zanubrutinib due to adverse events (AEs), and six experienced disease progression; there were no cases of disease transformation. In patients with confirmed MYD88WT, the overall response rate by independent review was 80.8%, with a major response rate of 50.0%, including a very good partial response rate of 26.9%. The progression-free survival event-free rate at 12 months was 72.4%. The most frequently reported AEs were diarrhea, anemia, contusion, pyrexia, and upper respiratory tract infection. Major hemorrhage was reported in two patients, and atrial fibrillation was reported in one patient. There were no fatal AEs. Conclusion(s): Zanubrutinib showed clinically meaningful antitumor activity, including achieving major responses

Published
2022

11. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenstrom's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study

Author

Buske, C, Tedeschi, A, Trotman, J, Garcia-Sanz, R, MacDonald, D, Leblond, V, Mahe, B, Herbaux, C, Matous, JV, Tam, CS, Heffner, LT, Varettoni, M, Palomba, ML, Shustik, C, Kastritis, E, Treon, SP, Ping, J, Hauns, B, Arango-Hisijara, I, Dimopoulos, MA, Buske, C, Tedeschi, A, Trotman, J, Garcia-Sanz, R, MacDonald, D, Leblond, V, Mahe, B, Herbaux, C, Matous, JV, Tam, CS, Heffner, LT, Varettoni, M, Palomba, ML, Shustik, C, Kastritis, E, Treon, SP, Ping, J, Hauns, B, Arango-Hisijara, I, and Dimopoulos, MA

Abstract

PURPOSE The double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenström’s macroglobulinemia (WM). Here, we present the final analysis from iNNOVATE. METHODS Patients had confirmed symptomatic WM, either previously untreated or previously treated; patients with prior rituximab had at least a minor response to their last rituximab-based regimen. Patients were randomly assigned to once-daily ibrutinib 420 mg plus rituximab or placebo plus rituximab (n = 75 per arm). The primary end point was progression-free survival (PFS). Secondary end points included response rate, time to next treatment, hemoglobin improvement, overall survival, and safety. RESULTS With a median follow-up of 50 (range, 0.5-63) months, median (95% CI) PFS was not reached (57.7 months to not evaluable) with ibrutinib-rituximab versus 20.3 months (13.0 to 27.6) with placebo-rituximab (hazard ratio, 0.250; P < .0001). PFS benefit was regardless of prior treatment status, MYD88 and CXCR4 mutation status, or key patient characteristics. Higher response rates (partial response or better) were observed with ibrutinib-rituximab (76% v 31% with placebo-rituximab; P < .0001) and were sustained over time. Median time to next treatment was not reached with ibrutinib-rituximab versus 18 months with placebo-rituximab. More patients receiving ibrutinib-rituximab versus placebo-rituximab had sustained hemoglobin improvement (77% v 43%; P < .0001). Median overall survival was not reached in either arm. Ibrutinib-rituximab maintained a manageable safety profile; the prevalence of grade $ 3 adverse events of clinical interest generally decreased over time. CONCLUSION In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib-rituximab showed ongoing superiority across clinical outcomes in patients with WM regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics.

Published
2022

12. How Age, Comorbidities and Concomitant Medications Influence Ibrutinib Management and Survival in Waldenstrom Macroglobulinemia

Author

Frustaci, A, Piazza, F, Ferrero, S, Reda, G, Rizzi, R, Orsucci, L, Ferrarini, I, Deodato, M, Laurenti, L, Puccini, B, Barate, C, Varettoni, M, Merli, M, Cencini, E, Greco, A, Gini, G, Ferrari, A, Borella, C, Lista, E, Gentile, M, Murru, R, Motta, M, Rezzonico, F, Tani, M, Sportoletti, P, Zamprogna, G, Torri, V, Cairoli, R, Tedeschi, A, Frustaci, A, Piazza, F, Ferrero, S, Reda, G, Rizzi, R, Orsucci, L, Ferrarini, I, Deodato, M, Laurenti, L, Puccini, B, Barate, C, Varettoni, M, Merli, M, Cencini, E, Greco, A, Gini, G, Ferrari, A, Borella, C, Lista, E, Gentile, M, Murru, R, Motta, M, Rezzonico, F, Tani, M, Sportoletti, P, Zamprogna, G, Torri, V, Cairoli, R, and Tedeschi, A

Published
2022

13. 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

14. Use of BTK inhibitors with focus on ibrutinib in mantle cell lymphoma: An expert panel opinion statement

Author

Zinzani, Pier Luigi, Martelli, Maurizio, Ferrero, S, Gentile, Massimo, Laurenti, Luca, Romana Mauro, Francesca, Sportoletti, Paolo, Tedeschi, Alessandra, Varettoni, M, Visco, Carlo, Laurenti, Luca (ORCID:0000-0002-8327-1396), Zinzani, Pier Luigi, Martelli, Maurizio, Ferrero, S, Gentile, Massimo, Laurenti, Luca, Romana Mauro, Francesca, Sportoletti, Paolo, Tedeschi, Alessandra, Varettoni, M, Visco, Carlo, and Laurenti, Luca (ORCID:0000-0002-8327-1396)

Abstract

The introduction of Bruton's tyrosine kinase (BTK) inhibitors transformed the management of patients with mantle cell lymphoma (MCL). Ibrutinib, the first-in-class BTK inhibitor is now approved in more than 80 countries and there are over 20 new BTK inhibitors in development. In addition, novel agents show potential clinical activity (alone and in combination) and are in the approval phase and/or being studied in ongoing clinical trials. How does the practicing clinician decide on the optimal therapeutic strategy for this highly heterogenous disease? In July 2020 a group of experts from Italy, convened a meeting to address and provide clarification on a series of outstanding issues in the treatment of MCL with the view of providing clinical guidance on its management. This expert opinion statement represents the panel's collective analysis, evaluation, and recommendations and is made up of a series of questions and answers (in the form of a review of the pertinent literature) designed to replicate those posed by practicing clinicians in Italy but which are applicable to clinical settings worldwide.

Published
2022

15. Use of BTK inhibitors with special focus on ibrutinib in Waldenström macroglobulinemia: An expert panel opinion statement

Author

Ferrero, S, Gentile, Massimo, Laurenti, Luca, Mauro, Francesca Romana, Martelli, Maurizio, Sportoletti, Paolo, Visco, Carlo, Zinzani, Pier Luigi, Tedeschi, Alessandra, Varettoni, M, Laurenti, Luca (ORCID:0000-0002-8327-1396), Ferrero, S, Gentile, Massimo, Laurenti, Luca, Mauro, Francesca Romana, Martelli, Maurizio, Sportoletti, Paolo, Visco, Carlo, Zinzani, Pier Luigi, Tedeschi, Alessandra, Varettoni, M, and Laurenti, Luca (ORCID:0000-0002-8327-1396)

Abstract

The pivotal role that ibrutinib plays in the management of Waldenström macroglobulinemia (WM) is undisputed but there are ongoing questions regarding its positioning in the therapeutic algorithm of WM as well as in some peculiar clinical situations. A panel of experts from Italy was convened to provide real world recommendations on the use of BTK inhibitors in lymphoproliferative diseases in general, and in patients with WM in particular. This position paper represents the panel's collective analysis, evaluation, and opinions and is made up of a series of questions frequently asked by practicing clinicians and answers based on currently available evidence.

Published
2022

16. 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

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

Author

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

Abstract

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

Published
2022

20. 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

21. Ibrutinib Plus Rituximab Versus Placebo Plus Rituximab for Waldenström's Macroglobulinemia: Final Analysis From the Randomized Phase III iNNOVATE Study

Author

Buske, C. Tedeschi, A. Trotman, J. García-Sanz, R. MacDonald, D. Leblond, V. Mahe, B. Herbaux, C. Matous, J.V. Tam, C.S. Heffner, L.T. Varettoni, M. Palomba, M.L. Shustik, C. Kastritis, E. Treon, S.P. Ping, J. Hauns, B. Arango-Hisijara, I. Dimopoulos, M.A.

Subjects
immune system diseases, hemic and lymphatic diseases
Abstract

PURPOSE: The double-blind, randomized, placebo-controlled phase III iNNOVATE study showed sustained efficacy of ibrutinib-rituximab in Waldenström's macroglobulinemia (WM). Here, we present the final analysis from iNNOVATE. METHODS: Patients had confirmed symptomatic WM, either previously untreated or previously treated; patients with prior rituximab had at least a minor response to their last rituximab-based regimen. Patients were randomly assigned to once-daily ibrutinib 420 mg plus rituximab or placebo plus rituximab (n = 75 per arm). The primary end point was progression-free survival (PFS). Secondary end points included response rate, time to next treatment, hemoglobin improvement, overall survival, and safety. RESULTS: With a median follow-up of 50 (range, 0.5-63) months, median (95% CI) PFS was not reached (57.7 months to not evaluable) with ibrutinib-rituximab versus 20.3 months (13.0 to 27.6) with placebo-rituximab (hazard ratio, 0.250; P < .0001). PFS benefit was regardless of prior treatment status, MYD88 and CXCR4 mutation status, or key patient characteristics. Higher response rates (partial response or better) were observed with ibrutinib-rituximab (76% v 31% with placebo-rituximab; P < .0001) and were sustained over time. Median time to next treatment was not reached with ibrutinib-rituximab versus 18 months with placebo-rituximab. More patients receiving ibrutinib-rituximab versus placebo-rituximab had sustained hemoglobin improvement (77% v 43%; P < .0001). Median overall survival was not reached in either arm. Ibrutinib-rituximab maintained a manageable safety profile; the prevalence of grade ≥ 3 adverse events of clinical interest generally decreased over time. CONCLUSION: In the final analysis of iNNOVATE with a median follow-up of 50 months, ibrutinib-rituximab showed ongoing superiority across clinical outcomes in patients with WM regardless of MYD88 or CXCR4 mutation status, prior treatment, and key patient characteristics.

Published
2022

24. ROMIDEPSIN‐CHOEP PLUS UP‐FRONT STEM‐CELL TRANSPLANTATION IN PERIPHERAL T‐CELL LYMPHOMA (PTCL): FIRST ANALYSIS OF THE PHASE II FIL‐PTCL13 STUDY

Author

Chiappella, A., primary, Carniti, C., additional, Re, A., additional, Castellino, C., additional, Evangelista, A., additional, Ciancia, R., additional, Orsucci, L., additional, Pinto, A., additional, Usai, S. V., additional, Arcari, A., additional, Ilariucci, F., additional, Rossi, F. G., additional, Benedetti, F., additional, Flenghi, L., additional, Ghiggi, C., additional, Molinari, A. L., additional, Stefoni, V., additional, Volpetti, S., additional, Zilioli, V. R., additional, Ballerini, F., additional, Bruna, R., additional, Cavallo, F., additional, Musuraca, G., additional, Patti, C., additional, Re, F., additional, Tani, M., additional, Varettoni, M., additional, Zanni, M., additional, Dodero, A., additional, Pileri, S. A., additional, Ciccone, G., additional, and Corradini, P., additional

Published
2021
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25. Efficacy of idelalisib and rituximab in relapsed/refractory chronic lymphocytic leukemia treated outside of clinical trials. A report of the Gimema Working Group

Author

Rigolin, G. M., Cavazzini, F., Piciocchi, A., Arena, V., Visentin, A., Reda, G., Zamprogna, G., Cibien, F., Vitagliano, O., Coscia, M., Farina, L., Gaidano, G., Murru, R., Varettoni, M., Paolini, R., Sportoletti, P., Pietrasanta, D., Molinari, A. L., Quaglia, F. M., Laurenti, L., Marasca, R., Marchetti, M., Mauro, F. R., Crea, E., Vignetti, M., Gentile, M., Montillo, M., Foa, R., Cuneo, A., Chiarenza, A., Perbellini, O., Mannina, D., Sancetta, R., Olivieri, A., Molica, S., Pane, F., Patti, C., Iliariucci, F., Gozzetti, A., Califano, C., Galieni, P., Augello, A. F., Vallisa, D., Cura, F., Frustaci, A. M., Fazi, P., Trentin, L., and Ferrara, F.

Subjects
Male, Oncology, Cancer Research, idelalisib, law.invention, 0302 clinical medicine, Randomized controlled trial, Recurrence, law, Original Research Articles, Antineoplastic Combined Chemotherapy Protocols, 80 and over, Original Research Article, Chronic, Aged, 80 and over, Leukemia, real‐world evidence, Hematology, General Medicine, Middle Aged, Lymphocytic, Survival Rate, 030220 oncology & carcinogenesis, Female, Rituximab, Refractory Chronic Lymphocytic Leukemia, Idelalisib, chronic lymphocytic leukemia, real-world evidence, Aged, Disease-Free Survival, Humans, Leukemia, Lymphocytic, Chronic, B-Cell, Purines, Quinazolinones, medicine.drug, medicine.medical_specialty, NO, 03 medical and health sciences, Internal medicine, medicine, Survival rate, Performance status, business.industry, B-Cell, Clinical trial, Settore MED/15 - MALATTIE DEL SANGUE, Regimen, business, 030215 immunology
Abstract

Because the efficacy of new drugs reported in trials may not translate into similar results when used in the real‐life, we analyzed the efficacy of idelalisib and rituximab (IR) in 149 patients with relapsed/refractory chronic lymphocytic leukemia treated at 34 GIMEMA centers. Median progression‐free survival (PFS) and overall survival were 22.9 and 44.5 months, respectively; performance status (PS) ≥2 and ≥3 previous lines of therapy were associated with shorter PFS and overall survival (OS). 48% of patients were on treatment at 12 months; the experience of the centers (≥5 treated patients) and PS 0–1 were associated with a significantly longer treatment duration (p = 0.015 and p = 0.002, respectively). TP53 disruption had no prognostic significance. The overall response rate to subsequent treatment was 49.2%, with median OS of 15.5 months and not reached in patients who discontinued, respectively, for progression and for toxicity (p

Published
2021

26. UPDATED RESULTS OF THE ASPEN TRIAL FROM A COHORT OF PATIENTS WITH MYD88 WILD-TYPE (MYD88(WT)) WALDENSTROM MACROGLOBULINEMIA (WM)

Author

Zinzani, P, Dimopoulos, M, Sanz, RG, Lee, H, Trneny, M, Varettoni, M, Opat, S, D'Sa, S, Owen, R, Cull, G, Mulligan, S, Czyz, J, Castillo, J, Motta, M, Siddiqi, T, Mesa, MG, Gorrochategui, MG, Talaulikar, D, Askari, E, Grosicki, S, Oriol, A, Rule, S, Kloczko, J, Tedeschi, A, Buske, C, Leblond, V, Chan, W, Schneider, J, Cohen, A, Huang, J, and Tam, C

Published
2021

27. Zanubrutinib for the treatment of MYD88 wild-type Waldenstrom macroglobulinemia: A substudy of the phase 3 ASPEN trial.

Author

Trotman J., Rule S., Kloczko J., Tedeschi A., Buske C., Leblond V., Chan W.Y., Michel J., Schneider J., Tan Z., Cohen A., Huang J., Tam C.S., Opat S., Dimopoulos M., Sanz R.G., Lee H.-P., Trneny M., Varettoni M., D'Sa S., Owen R.G., Cull G., Mulligan S., Czyz J., Castillo J.J., Motta M., Siddiqi T., Mesa M.G., Gorrochategui M.G., Talaulikar D., Zinzani P.L., Askari E., Grosicki S., Oriol A., Trotman J., Rule S., Kloczko J., Tedeschi A., Buske C., Leblond V., Chan W.Y., Michel J., Schneider J., Tan Z., Cohen A., Huang J., Tam C.S., Opat S., Dimopoulos M., Sanz R.G., Lee H.-P., Trneny M., Varettoni M., D'Sa S., Owen R.G., Cull G., Mulligan S., Czyz J., Castillo J.J., Motta M., Siddiqi T., Mesa M.G., Gorrochategui M.G., Talaulikar D., Zinzani P.L., Askari E., Grosicki S., and Oriol A.

Abstract

Patients with Waldenstrom macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/ refractory; 5 treatment-naive) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.Copyright © 2020 by The American Society of Hematology

Published
2021

28. 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

29. 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

30. 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

31. 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

32. 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

35. Consensus treatment recommendations from the tenth International Workshop for Waldenström Macroglobulinaemia

Author

Castillo, J.J. Advani, R.H. Branagan, A.R. Buske, C. Dimopoulos, M.A. D'Sa, S. Kersten, M.J. Leblond, V. Minnema, M.C. Owen, R.G. Palomba, M.L. Talaulikar, D. Tedeschi, A. Trotman, J. Varettoni, M. Vos, J.M. Treon, S.P. Kastritis, E.

Subjects
hemic and lymphatic diseases
Abstract

Waldenström macroglobulinaemia is an indolent B-cell lymphoma with clearly defined criteria for diagnosis, initiation of therapy, and response, which was established by consensus panels at previous International Workshops for Waldenström Macroglobulinaemia (IWWM). The treatment options for Waldenström macroglobulinaemia continued to be researched after the publication of the eighth IWWM consensus recommendations in 2016, and at the tenth IWWM in New York, USA (October, 2018) an international consensus panel was formed to update treatment recommendations. Participants were selected as members of the consensus panel based on their expertise on Waldenström macroglobulinaemia. The initial live discussion took place during the tenth IWWM meeting and two separate teleconferences were held in June, 2019, and January, 2020, to refine recommendations. No external or financial support was received for the elaboration of these recommendations. According to these updated consensus recommendations, alkylating drugs (bendamustine, cyclophosphamide) and proteasome inhibitors (bortezomib, carfilzomib, ixazomib), both in combination with rituximab, as well as BTK inhibitors (ibrutinib), alone or in combination with rituximab, are preferred first-line therapy options for symptomatic patients with Waldenström macroglobulinaemia. In previously treated patients with Waldenström macroglobulinaemia who had an initial durable response, reuse of a previous regimen or another primary therapy regimen are acceptable options. Novel BTK inhibitors (acalabrutinib, zanubrutinib, tirabrutinib) and the BCL2 antagonist venetoclax appear safe and active, and represent emerging options for the treatment of Waldenström macroglobulinaemia. The choice of therapy should be guided by the patient's clinical profile, genomic features, and drug availability. © 2020 Elsevier Ltd

Published
2020

36. Consensus statement on the management of waldenström macroglobulinemia patients during the COVID-19 pandemic

Author

Talaulikar, D. Advani, R.H. Branagan, A.R. Buske, C. Dimopoulos, M.A. D'Sa, S. Kersten, M.J. Leblond, V. Minnema, M.C. Owen, R.G. Palomba, M.L. Tedeschi, A. Trotman, J. Varettoni, M. Vos, J.M. Treon, S.P. Kastritis, E. Castillo, J.J.

Subjects
education
Abstract

In the light of the COVID-19 pandemic, the International Workshop on Waldenström Macroglobulinemia (IWWM) Treatment Recommendations Panel felt the need to provide a consensus statement for the management of Waldenström Macroglobulinemia (WM) patients during this challenging time. We followed the current recommendations by the American Society of Hematology, which have been modified accordingly to fit the specific realities associated with the management of WM. In this Consensus Statement, the Panel addresses questions related to treatment initiation, preferred therapies, minimizing visit to clinics and infusions centers, supportive care and guidance for WM patients in clinical trials. Finally, we also provide information on timing and appropriateness of testing and management of COVID-19 infected patients, as well as ways to get physicians and patients involved in registry studies that could help others. Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association. This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Published
2020

37. Zanubrutinib for the treatment of MYD88 wild-type Waldenström macroglobulinemia: A substudy of the phase 3 ASPEN trial

Author

Dimopoulos, M. Sanz, R.G. Lee, H.-P. Trneny, M. Varettoni, M. Opat, S. D'Sa, S. Owen, R.G. Cull, G. Mulligan, S. Czyz, J. Castillo, J.J. Motta, M. Siddiqi, T. Mesa, M.G. Gorrochategui, M.G. Talaulikar, D. Zinzani, P.L. Askari, E. Grosicki, S. Oriol, A. Rule, S. Kloczko, J. Tedeschi, A. Buske, C. Leblond, V. Trotman, J. Chan, W.Y. Michel, J. Schneider, J. Tan, Z. Cohen, A. Huang, J. Tam, C.S. ASPEN investigators

Abstract

Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/ refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440. © 2020 by The American Society of Hematology

Published
2020

38. Updated results of the aspen trial from a cohort of patients with MYD88 wild-type waldenstrom macroglobulinemia.

Author

Schneider J., Tam C.S., Chan W.Y., Ro S., Huang J., Cohen A., Dimopoulos M., Garcia Sanz R., Lee H.-P., Trneny M., Varettoni M., Opat S., D'Sa S., Owen R.G., Cull G., Mulligan S., Czyz J., Castillo J., Motta M., Siddiqi T., Gironella Mesa M., Granell Gorrochategui M., Talaulikar D., Zinzani P.L., Askari E., Grosicki S., Oriol A., Rule S., Kloczko J., Tedeschi A., Buske C., Leblond V., Schneider J., Tam C.S., Chan W.Y., Ro S., Huang J., Cohen A., Dimopoulos M., Garcia Sanz R., Lee H.-P., Trneny M., Varettoni M., Opat S., D'Sa S., Owen R.G., Cull G., Mulligan S., Czyz J., Castillo J., Motta M., Siddiqi T., Gironella Mesa M., Granell Gorrochategui M., Talaulikar D., Zinzani P.L., Askari E., Grosicki S., Oriol A., Rule S., Kloczko J., Tedeschi A., Buske C., and Leblond V.

Abstract

Background: Inhibitors of Bruton tyrosine kinase (BTK) have shown significant activity in patients with Waldenstrom macroglobulinemia (WM) harboring a mutation in the MYD88 gene. However, lower response rates and shorter progression-free survival have been reported in patients with WM who lack such mutations (N Engl J Med. 2015;372:1430). Zanubrutinib (BGB-3111; ZANU) is an investigational, next-generation BTK inhibitor designed to maximize BTK occupancy and minimize off-target inhibition of TEC-and EGFR-family kinases. The ASPEN trial evaluated ZANU, a potent and selective BTK inhibitor, in patients with WM. Aim(s): To evaluate the efficacy and safety of ZANU in patients who have WM with MYD88 wild-type (MYD88WT) mutation status. Method(s): In the ASPEN trial, bone marrow MYD88 mutations were assessed at study entry by a central laboratory (NeoGenomics) using a wild-type-blocking polymerase chain reaction method. This MYD88 mutation assay detects all mutations in the region encompassing amino acid Ala260-Pro278, which includes the predominant mutation in WM (MYD88L265P), with enhanced sensitivity (Int J Lab Hematol. 2016;38:133). Based on the results of the MYD88 mutation assay, patients were assigned to cohort 1 (MYD88 mutation) or cohort 2 (MYD88WT or mutation unknown). All cohort 2 patients received ZANU 160 mg twice daily until disease progression. Result(s): In total, 28 patients (n = 26 MYD88WT; n = 2 MYD88 mutation status unknown) were enrolled into cohort 2. The median age was 72 years and 42.9% were > 75 years old; 5 patients were treatment-naive (TN), and 23 patients were relapsed/refractory (R/R; >=1 prior therapy). Most patients had intermediate- (39.3%) or high-risk (42.9%) disease by International Prognostic Scoring System for WM. With a median follow- up of 17.9 months, 2 patients discontinued ZANU due to adverse events, and 6 patients experienced disease progression; there were no cases of disease transformation. In 26 confirmed MYD88WT patients, th

Published
2020

39. 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

40. Zanubrutinib for the treatment of MYD88 wild-type Waldenstrom macroglobulinemia: a substudy of the phase 3 ASPEN trial

Author

Dimopoulos, M, Garcia Sanz, R, Lee, H-P, Trneny, M, Varettoni, M, Opat, S, D'Sa, S, Owen, RG, Cull, G, Mulligan, S, Czyz, J, Castillo, JJ, Motta, M, Siddiqi, T, Gironella Mesa, M, Granell Gorrochategui, M, Talaulikar, D, Zinzani, PL, Askari, E, Grosicki, S, Oriol, A, Rule, S, Kloczko, J, Tedeschi, A, Buske, C, Leblond, V, Trotman, J, Chan, WY, Michel, J, Schneider, J, Tan, Z, Cohen, A, Huang, J, Tam, CS, Dimopoulos, M, Garcia Sanz, R, Lee, H-P, Trneny, M, Varettoni, M, Opat, S, D'Sa, S, Owen, RG, Cull, G, Mulligan, S, Czyz, J, Castillo, JJ, Motta, M, Siddiqi, T, Gironella Mesa, M, Granell Gorrochategui, M, Talaulikar, D, Zinzani, PL, Askari, E, Grosicki, S, Oriol, A, Rule, S, Kloczko, J, Tedeschi, A, Buske, C, Leblond, V, Trotman, J, Chan, WY, Michel, J, Schneider, J, Tan, Z, Cohen, A, Huang, J, and Tam, CS

Abstract

Patients with Waldenström macroglobulinemia (WM) lacking activating mutations in the MYD88 gene (MYD88WT) have demonstrated relatively poor outcomes to ibrutinib monotherapy, with no major responses reported in a phase 2 pivotal study. Zanubrutinib is a novel, selective Bruton tyrosine kinase (BTK) inhibitor designed to maximize BTK occupancy and minimize off-target activity. The ASPEN study consisted of a randomized comparison of zanubrutinib and ibrutinib efficacy and safety in patients with WM who have the MYD88 mutation, as well as a separate cohort of patients without MYD88 mutation (MYD88WT) or with unknown mutational status who received zanubrutinib. Results from the latter single-arm cohort are reported herein. Efficacy endpoints included overall, major and complete (CR) or very good partial response (VGPR) rates, progression-free survival (PFS), duration of response (DOR), and overall survival (OS). Twenty-eight patients (23 relapsed/refractory; 5 treatment-naïve) were enrolled, including 26 with centrally confirmed MYD88WT disease and 2 with unknown MYD88 mutational status. At a median follow-up of 17.9 months, 7 of 26 MYD88WT patients (27%) had achieved a VGPR and 50% a major response (partial response or better); there were no CRs. At 18 months, the estimated PFS and OS rates were 68% and 88%, respectively, while the median DOR had not been reached. Two patients discontinued zanubrutinib due to adverse events. Treatment-emergent hypertension, atrial fibrillation, and major hemorrhages were reported in 3, 1 and 2 patients (including 1 concurrent with enoxaparin therapy), respectively. Results of this substudy demonstrate that zanubrutinib monotherapy can induce high quality responses in patients with MYD88WT WM. This trial is registered on www.clinicaltrials.gov as NCT #03053440.

Published
2020

41. Validation of a survival-risk score (SRS) in relapsed/refractory CLL patients treated with idelalisib–rituximab

Author

Gentile, Marino, Martino, E. A., Visentin, A., Coscia, M., Reda, G., Sportoletti, P., Mauro, F. R., Laurenti, Luca, Varettoni, M., Murru, R., Chiarenza, A., Vigna, E., Mendicino, F., Lucia, E., Bossio, S., Recchia, A. G., Moia, R., Pietrasanta, D., Loseto, G., Consoli, U., Scortechini, I., Rossi, Federica Maria, Zucchetto, A., Al-Janazreh, H., Vitale, C., Tripepi, G., D'Arrigo, G., Angeletti, I., Bomben, R., Neri, A., Cutrona, G., Fronza, G., Di Raimondo, F., Gaidano, G., Cuneo, A., Foa, Robin, Ferrarini, M., Trentin, L., Gattei, V., Morabito, Francesco, Gentile M., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi F. M., Foa R., Morabito F., Gentile, Marino, Martino, E. A., Visentin, A., Coscia, M., Reda, G., Sportoletti, P., Mauro, F. R., Laurenti, Luca, Varettoni, M., Murru, R., Chiarenza, A., Vigna, E., Mendicino, F., Lucia, E., Bossio, S., Recchia, A. G., Moia, R., Pietrasanta, D., Loseto, G., Consoli, U., Scortechini, I., Rossi, Federica Maria, Zucchetto, A., Al-Janazreh, H., Vitale, C., Tripepi, G., D'Arrigo, G., Angeletti, I., Bomben, R., Neri, A., Cutrona, G., Fronza, G., Di Raimondo, F., Gaidano, G., Cuneo, A., Foa, Robin, Ferrarini, M., Trentin, L., Gattei, V., Morabito, Francesco, Gentile M., Laurenti L. (ORCID:0000-0002-8327-1396), Rossi F. M., Foa R., and Morabito F.

Abstract

N/a

Published
2020

42. Younger patients with Waldenström Macroglobulinemia exhibit low risk profile and excellent outcomes in the era of immunotherapy and targeted therapies

Author

Varettoni, M., Ferrari, A., Frustaci, A. M., Ferretti, V. V., Rizzi, R., Motta, M., Piazza, F., Merli, M., Benevolo, G., Visco, C., Laurenti, L., Ferrero, S., Gentile, M., Del Fabro, V., Abbadessa, A., Klersy, C., Musto, P., Fabbri, N., Deodato, M., Dogliotti, I., Greco, C., Corbingi, A., Luminari, S., Arcaini, L., Rizzi R., Piazza F., Merli M., Laurenti L. (ORCID:0000-0002-8327-1396), Gentile M., Varettoni, M., Ferrari, A., Frustaci, A. M., Ferretti, V. V., Rizzi, R., Motta, M., Piazza, F., Merli, M., Benevolo, G., Visco, C., Laurenti, L., Ferrero, S., Gentile, M., Del Fabro, V., Abbadessa, A., Klersy, C., Musto, P., Fabbri, N., Deodato, M., Dogliotti, I., Greco, C., Corbingi, A., Luminari, S., Arcaini, L., Rizzi R., Piazza F., Merli M., Laurenti L. (ORCID:0000-0002-8327-1396), and Gentile M.

Abstract

We analyzed 160 young Waldenström Macroglobulinemia (WM) patients with a median age of 49 years (range 23-55 years), diagnosed between January 2000 and January 2019 in 14 Italian centers. At diagnosis, 70% of patients were asymptomatic. With a median follow-up of 5.6 years, 57% have been treated. As initial therapy 79% of patients received chemo-immunotherapy, 13% a chemo-free induction and 8% chemotherapy only. At relapse or progression, 6% underwent an autologous stem cell transplantation. Overall, 19% of patients received ibrutinib during the course of the disease. According to IPSSWM, 63% were classified as low risk, 27% as intermediate risk and 10% as high risk. Five-year OS was shorter in high-risk as compared with low or intermediate risk patients (92.9% vs 100% P =.002). According to revised IPSSWM, 92% were classified as very low or low risk and 8% as intermediate risk, with a shorter 5-year OS in the latter group (87.5% vs 100%, P =.028). The OS of young WM patients was not significantly reduced as compared with age-matched, sex-matched and calendar year-matched general population. Early diagnosis, absence of high-risk features in symptomatic patients and high efficacy of modern treatments are the main determinants of the excellent outcome of young WM patients.

Published
2020

43. 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

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