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This study aimed to assess the frequency of and the contributing factors for second primary malignancies (SPMs) and Richter's transformations (RTs) following first-line treatment of chronic lymphocytic leukemia within four phase II/III trials of the GCLLSG evaluating fludarabine (F) vs F+cyclophosphamide (FC), chlorambucil vs F, FC without or with rituximab, and bendamustine+R (BR). Among 1458 patients, 239 (16.4%) experienced either an SPM (N = 191) or a RT (N = 75). Solid tumors (N = 115; 43.2% of all second neoplasias) appeared most frequently, followed by RTs (N = 75; 28.2%). Patients showed a 1.23-fold increased risk of solid tumors in comparison to the age-matched general population from the German cancer registry. Age >65 (hazard ratio (HR) 2.1; P<0.001), male sex (HR 1.7; P = 0.01), co-morbidities (HR 1.6; P = 0.01) and number of subsequent treatments ≤ 1 (HR 12.1; P<0.001) showed an independent adverse prognostic impact on SPM-free survival. Serum thymidine kinase ±10 U/l at trial enrollment (HR 3.9; P = 0.02), non-response to first-line treatment (HR 3.6; P<0.001) and number of subsequent treatments ≤ 1 (HR 30.2; P<0.001) were independently associated with increased risk for RT.