Clinical and tumour biology studies of Diffuse Large B-cell Lymphoma : with emphasis on comorbidity, toxicity and outcome

Abstract: Diffuse large B-cell lymphoma (DLBCL) is curable in around 70% when treated with standard immunochemotherapy R- CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). Treatment related toxicity affecting survivors is a clinical problem as well as comorbidities influencing the possibility to give adequate treatment. The relevance of follow-up time and follow-up measures can be debated, follow-up time in Sweden has been reduced to two years due to studies showing an OS survival comparable to standard population among DLBCL achieving EFS24.The main objective of this thesis is to study known side-effects of treatment and comorbidities and explore outcome in DLBCL in order to improve clinical treatment and follow-up decisions. In Paper I we explored whether the omission of vincristine (VCR) due to neurotoxicity affect outcome (DFS,OS). In 541 patients omission of VCR was made in 95 (17.6%). There was no impact on outcome measures in the whole cohort irrespective of treatment cycle for the omission nor was there a difference in the elderly (≥70 years) group. In Paper II we studied the occurrence of different autoimmune disorders (AID) in 612 DLBCL and analysed whether AID affects treatment outcome. We found a high occurrence of AID among DLBCL patients (17.3%) compared to the general population (3-10%). AID did not affect EFS/LSS or OS in the whole cohort but women with B-cell response AID had a worse OS compared to other women (p=0.013). In Paper III we established event free survival at 24 months (EFS24) in a Swedish DLBCL cohort and analysed factors governing OS and compared OS with an age and gender matched standard population. 71.6% achieved EFS24 and OS was marginally lower than the standard population. Age was the only factor affecting OS in multivariate analysis and EFS24 patients<60 years had a comparable OS to the standard population. In older ages (>60years) there was a trend for worse OS driven by a significant difference in OS among those 60-69 years. Among DLBCL achieving EFS24, 22.4% died of cardiovascular disease and 16% from other malignancies. In Paper IV we explored whether advanced serum protein analysis can be used to measure doxorubicin (DXR) related cardiac/cardiovascular (CVD) disease in DLBCL patients. We found two proteins, SPON-1 associated with CVD at diagnosis and IL-1RT1 associated with emerging CVD after treatment. Compared to the general population and to a matched cohort DLBCL patients had a high occurrence of CVD at diagnosis, 33.4%. After treatment 22.6% developed CVD.