Value of assessing liver enlargement as a group a parameter in chronic lymphocytic leukemia (CLL) clinical trials: Retrospective review of data from multiple trials for incidence of liver enlargement and impact on response assessment.

e19517 Background: iwCLL 2018 criteria defines liver enlargement as one of the important group A parameters for staging and overall response assessment (ORA). However, the authors acknowledge that given the impact of numerous medical conditions, liver size by physical examination or CT scan is not a reliable measure of hepatic involvement by CLL and should only be considered if hepatomegaly is clearly attributable to lymphoid involvement. The criteria even define partial response and progression categories as 50% decrease or increase, respectively, but no specific size or other criteria for assessing lymphoid involvement are proposed. Focal lesions in liver may be a sign of involvement by CLL but are assessed separately, as extranodal disease. Hepatomegaly may be non-specific with possible causes including metabolic, infectious, neoplastic, toxic, hereditary, vascular, and miscellaneous other causes. 20-30% of a general population may have non-alcoholic fatty liver enlargement. In the literature hepatomegaly by palpation has been defined as a portion of the liver below the costal margin and the cut-off for normal liver on imaging is considered < 16 cm in mid-clavicular line. However, there are various anatomic variations with no consensus on the size criteria for liver enlargement. Methods: Independent review data from seven phase II/III CLL trials for frontline therapies as well as in relapsed/refractory setting, were retrospectively analyzed. Data included the independent review assessment results of a total of 22224 timepoints (TPs) of 2223 subjects (2223 baseline (BL) and 20001 post-BL TPs). The data were analyzed for the incidence of subjects with liver enlargement at baseline, post-BL assessment of liver and its impact on ORA. Liver assessment in all trials was qualitative, and the criteria for enlargement was based on the reviewer’s judgement; no size limit was defined. Results: Only 7 out of 2223 subjects (0.3%) had liver enlargement at baseline. Liver assessment of these subjects at post-BL did not cause an upgrade or downgrade of the ORA. None of the 2223 subjects had liver progression at post-BL TPs. Conclusions: Based on the data analysis of a large sample size, it is evident that assessment of liver enlargement as a group A parameter in CLL clinical trials, does not impact the ORA. Liver is rarely even assessed as enlarged by independent reviewers, since hepatomegaly may be caused by various other medical conditions besides CLL. No size or other criteria help distinguish between liver enlargement from CLL versus other causes. We recommend removing liver enlargement as a group A parameter for response assessment as it complicates the assessment paradigm without adding any value to it. Liver involvement should only be assessed for focal lesions, as extranodal disease.