OBJECTIVES: Chronic lymphocytic leukemia (CLL) is the most frequent form of leukemia in the US and Europe. The disease ant treatment landscapes are changing rapidly due to emergence of new treatments with significant impact of prognosis and progress in diagnostic technologies. The projected economic burden for CLL is expected to exceed $50 billion by 2030. The objective of this study was to understand the trends in observational research in relation to current unmet needs in CLL. METHODS: Systematic literature review was conducted in PubMed from 2001-2015 to identify observational studies published globally. Search was limited to studies in English and clinical trials were excluded. Studies reporting on 11 research related topics including treatments, epidemiology, transplantation, and using real world data (RWD – database or CLL-registries) were identified. The trends of research were studied by three five-year periods ending 2005, 2010 and 2015. RESULTS: Of 387 titles and abstracts screened, 82 studies were published in 2001-2005, 131 in 2006-2010 and 174 in 2011-2015 periods. A total of 135 studies reported on prognosis, 92 on genetic mutations, 78 on treatments, 75 on epidemiology, 43 on risk factors, 30 on transplantation, 21 each on imaging and safety, 17 using data from CLL-registries, 4 on prevention and 2 on HRQoL. Significant chronological trends were observed with research on prognosis, treatments, epidemiology, risk factors and transplantation. Research using RWD, evaluating safety and characterizing HRQoL was limited. CONCLUSIONS: More robust evidence using RWD is needed. Research on safety and HRQoL are also important to monitor and improve care and identify unmet needs. More research is also needed to understand and distinguish the roles for chemotherapy, monoclonal antibodies and kinase inhibitors as single agents and for combination therapy strategies in the context of genetic markers, in addition to the roles of bone marrow and stem cell transplantation.