Other malignancies in the history of CLL: an international multicenter study conducted by ERIC, the European Research Initiative on CLL, in HARMONY

Abstract

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. 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 March2022. 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). OMs in CLL impact on OS. Treatment for CLL increased the risk for AML/MDS, prostate cancer, and NMSC. FCR was associated with increased risk for AML/MDS. AbbVie, and EU/EFPIAInnovative Medicines Initiative Joint Undertaking HARMONY grant n° 116026.