Chronic lymphocytic leukemia : Studies from genetics to epidemiology with focus on the impact of different treatments

The progress in our understanding of the biology and pathophysiology of chronic lymphocytic leukemia (CLL), as well as the development of new treatments, necessitates additional research on; (i) the impact of different therapies within subgroups of CLL patients, (ii) solid epidemiological data on the prevalence of CLL and on comorbidities within the CLL population, and (iii) new means of prognostication, as the value of traditional prognostic markers is uncertain when applied to new treatments. In paper I we studied the efficacy of chemo(immuno)therapy in stereotyped subsets #1 and #2. We could demonstrate that the improvement in survival seen over time in CLL in general, was not observed in these two subgroups. This suggests that alternative treatment options should be explored in these patients, and that subset assignment can be used as a predictive tool. In paper II we could demonstrate a significant rise (56%) in the prevalence of CLL in Sweden from 2000 to 2015. We then developed a model to estimate the future prevalence of CLL. Applying this, we estimated a further increase in the absolute number of CLL patients with approximately 70% over the next 20 years, a rise with important health-economic impact. In paper III we showed that 32% of all CLL patients were diagnosed with at least one cardiovascular disease (CVD) within 10 years before diagnosis, as well as 37% before start of treatment. Of these, 81% had ≥3 concomitant CVD diagnoses. Within 5 years after start of treatment, an additional 28% of patients (without previous CVD) were diagnosed with a CVD. This is particularly important considering the known cardiovascular side-effects of BTK-inhibitors. In paper IV we studied clonal dynamics in 10 patients with high-risk CLL during treatment with ibrutinib, with a long-term clinical follow-up. Seven out of 10 displayed major clonal shifts and 5 of these experienced disease progression, which was not seen in the 3 patients without clonal shifts. We suggest further studies of clonal shifts as a new means of prognostication in patients treated with BTK-inhibitors. We conclude that; (i) CLL patients of subsets #1 and #2 do not benefit of “old” treatments and should be explored for alternatives, (ii) the prevalence in CLL is higher than previously described with an expected continuing rise, (iii) the burden of cardiovascular comorbidities in CLL is high, and (iv) the occurrence of clonal shifts during ibrutinib treatment suggests inferior outcome