Development of genetic prognostication models in newly diagnosed chronic lymphocytic leukaemia (CLL) patients

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in people of European ancestry with more than 10 new cases per day in the UK alone. CLL has a highly heterogeneous clinical course and most patients are diagnosed with early stage asymptomatic disease that does not initially require treatment. Some patients live with asymptomatic disease for several years while others progress quickly requiring treatment. CLL is inherently incurable and a significant cause of mortality and morbidity, including high risk of recurrent infections.
CLL therapy has been transformed by highly effective and well tolerated B-cell receptor signalling pathway inhibitors (BCRi) which improve patient outcomes for those with advanced disease. Given the success in treating symptomatic CLL, focus has recently shifted towards addressing whether pre-emptive treatment can improve outcomes for patients with early-stage asymptomatic disease but at high-risk of progressing. Preliminary results from the German CLL12 trial report remarkable improvements in outcomes for high-risk CLL patients treated early with the BCRi ibrutinib, where time to death was 4-5 times longer in high-risk patients treated early. Despite this success, current prognostication models are inadequate and identify only a minority of high-risk patients.

The aim of this project is to develop accurate prognostication models for early-stage CLL in order to identify high-risk patients who might benefit from earlier treatment. To this end, we recently published a genome-wide association study utilising early-stage CLL cases and identified two common germline genetic variants that significantly associate with high-risk CLL (Lin et al, 2021, Nature Communications, 12: 665. doi: 10.1038/s41467-020-20822-9). These variants have prognostic value equivalent to established clinical markers and provide proof of concept that the incorporation of germline genetic markers can significantly improve prognostication models for the...