Different impact of NOTCH1 and SF3B1 mutations on the risk of chronic lymphocytic leukemia transformation to Richter syndromeRichter syndrome (RS) represents the development of an aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL), in the context of chronic lymphocytic leukaemia (CLL). At least two types of RS exist: (i) transformation of CLL into a clonally related DLBCL, that accounts for~80% of cases; and (ii) development of a DLBCL unrelated to the CLL clone. Clonally related RS and clonally unrelated RS are distinct disorders (Rossi et al, 2011a). Clinically, transformation into a clonally related RS is frequently lethal with an expected survival of a few months, while CLL patients developing a clonally unrelated RS display a survival probability in the range of de novo DLBCL (Rossi et al, 2011a). Biologically, clonally related RS frequently acquire genetic lesions of TP53, MYC and NOTCH1, which are otherwise absent or exceptional in clonally unrelated RS (Rossi et al, 2011a).NOTCH1 and SF3B1 mutations are predictors of poor outcome in CLL (Puente et al, 2011;Rossi et al, 2011bRossi et al, , 2012Wang et al, 2011;Quesada et al, 2012). Here, we investigated a large multi-institutional series of 605 CLL patients to verify whether NOTCH1 and SF3B1 mutations at diagnosis may help in the identification of CLL at high risk of RS transformation.The study was approved by the Ethical Committee of the Ospedale Maggiore della Carità di Novara associated with the Amedeo Avogadro University of Eastern Piedmont (Protocol Code 59/CE; Study Number CE 8/11). Patients provided informed consent in accordance with local Institutional Review Board requirements and the Declaration of Helsinki. CLL was diagnosed according to National Cancer Institutes-International Workshop on CLL criteria (Hallek et al, 2008). RS diagnosis was histologically-proven (Müller-Hermelink et al, 2008). NOTCH1, SF3B1, TP53 and IGHV mutations were analysed by Sanger sequencing (Rossi et al, 2012). Probes (Abbott) used for fluorescent in situ hybridization analysis were: LSI13 and LSID13S319, CEP12, LSIp53 and LSIATM (Rossi et al, 2011a). CD38 expression was analysed by flow cytometry, utilizing a cut-off of 30% to define positivity (Rossi et al, 2009). VH CDR3 subset analysis and nomenclature were according to Murray et al (2008). Clonal relationship between CLL/DLBCL paired samples was established by comparing IGHV-D-J sequences. Time-toevent analysis utilized the Kaplan-Meier method. The cumulative incidence of RS development was calculated accounting for death as a competing risk, and was compared across groups with the Gray's test. The association between exposure variables and outcome was estimated by univariate and multivariate Cox regression analysis. Further details are reported in Supplementary Methods.Features of the CLL cohort are reported in Table SI. At CLL presentation, NOTCH1 mutations occurred in 12·2% patients, being mostly represented (82·4%) by a recurrent two bp frameshift deletion (c.7544_7545delCT). SF3B1 mutat...