Open Access

Thomas Chatzikonstantinou, Lydia Scarfò, Georgios Karakatsoulis, Eva Minga, Dimitra Chamou, Gloria Iacoboni, Jana Kotaskova, Christos Demosthenous, Lukas Smolej, Stephen Mulligan, Miguel Alcoceba, Salem Al-Shemari, Thérèse Aurran-Schleinitz, Francesca Bacchiarri, Mar Bellido, Fontanet Bijou, Anne Calleja, Angeles Medina, Mehreen Ali Khan, Ramona Cassin, Sofia Chatzileontiadou, Rosa Collado, Amy Christian, Zadie Davis, Maria Dimou, David Donaldson, Gimena Dos Santos, Barbara Dreta, Maria Efstathopoulou, Shaimaa El-Ashwah, Alicia Enrico, Alberto Fresa, Sara Galimberti, Andrea Galitzia, Rocío García-Serra, Eva Gimeno, Isabel González-Gascón-y-Marín, Alessandro Gozzetti, Valerio Guarente, Eleftheria Hatzimichael, Yair Herishanu, José-Ángel Hernández-Rivas, Luca Inchiappa, Ozren Jaksic, Susanne Janssen, Elżbieta Kalicińska, Laribi Kamel, Volkan Karakus, Arnon P. Kater, Bonnie Kho, Maria Kislova, Eliana Konstantinou, Maya Koren-Michowitz, Ioannis Kotsianidis, Robert J. Kreitman, Jorge Labrador, Deepesh Lad, Mark-David Levin, Ilana Levy, Thomas Longval, Alberto Lopez-Garcia, Juan Marquet, Lucia Martin-Rodríguez, Marc Maynadié, Stanislava Maslejova, Carlota Mayor-Bastida, Biljana Mihaljevic, Ivana Milosevic, Fatima Miras, Riccardo Moia, Marta Morawska, Roberta Murru, Uttam Kumar Nath, Almudena Navarro-Bailón, Ana C. Oliveira, Jacopo Olivieri, David Oscier, Irina Panovska-Stavridis, Maria Papaioannou, Tomas Papajík, Zuzana Kubova, Punyarat Phumphukhieo, Cheyenne Pierie, Anna Puiggros, Lata Rani, Gianluigi Reda, Gian Matteo Rigolin, Rosa Ruchlemer, Marcos Daniel de Deus Santos, Mattia Schipani, Annett Schiwitza, Yandong Shen, Martin Simkovic, Svetlana Smirnova, Dina Sameh Abdelrahman Soliman, Martin Spacek, Tamar Tadmor, Kristina Tomic, Eric Tse, Theodoros Vassilakopoulos, Andrea Visentin, Candida Vitale, Julia von Tresckow, George Vrachiolias, Vojin Vukovic, Renata Walewska, Ewa Wasik-Szczepanek, Zhenshu Xu, Munci Yagci, Lucrecia Yañez, Mohamed Yassin, Jana Zuchnicka, Maria Angelopoulou, Darko Antic, Bella Biderman, Mark Catherwood, Rainer Claus, Marta Coscia, Antonio Cuneo, Fatih Demirkan, Blanca Espinet, Gianluca Gaidano, Olga B. Kalashnikova, Luca Laurenti, Eugene Nikitin, Gerassimos A. Pangalis, Panagiotis Panagiotidis, Viola Maria Popov, Sarka Pospisilova, Paolo Sportoletti, Niki Stavroyianni, Constantine Tam, Livio Trentin, Anastasia Chatzidimitriou, Francesc Bosch, Michael Doubek, Paolo Ghia, Kostas Stamatopoulos

• Background Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs). The only predictor for MDS andBackground Patients with chronic lymphocytic leukemia (CLL) have a higher risk of developing other malignancies (OMs) compared to the general population. However, the impact of CLL-related risk factors and CLL-directed treatment is still unclear and represents the focus of this work. Methods We conducted a retrospective international multicenter study to assess the incidence of OMs and detect potential risk factors in 19,705 patients with CLL, small lymphocytic lymphoma, or high-count CLL-like monoclonal B-cell lymphocytosis, diagnosed between 2000 and 2016. Data collection took place between October 2020 and March 2022. Findings In 129,254 years of follow-up after CLL diagnosis, 3513 OMs were diagnosed (27.2 OMs/1000 person-years). The most common hematological OMs were Richter transformation, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Non-melanoma skin (NMSC) and prostate cancers were the most common solid tumors (STs). The only predictor for MDS and AML development was treatment with fludarabine and cyclophosphamide with/without rituximab (FC ± R) (OR = 3.7; 95% CI = 2.79–4.91; p < 0.001). STs were more frequent in males and patients with unmutated immunoglobulin heavy variable genes (OR = 1.77; 95% CI = 1.49–2.11; p < 0.001/OR = 1.89; 95% CI = 1.6–2.24; p < 0.001). CLL-directed treatment was associated with non-melanoma skin and prostate cancers (OR = 1.8; 95% CI = 1.36–2.41; p < 0.001/OR = 2.11; 95% CI = 1.12–3.97; p = 0.021). In contrast, breast cancers were more frequent in untreated patients (OR = 0.17; 95% CI = 0.08–0.33; p < 0.001). Patients with CLL and an OM had inferior overall survival (OS) than those without. AML and MDS conferred the worst OS (p < 0.001).…