Follicular lymphoma : clinical and biological factors associated with response to therapy and overall prognosis

Sammanfattning: Follicular lymphoma (FL) is a heterogeneous group of malignancies within the adaptive immune system. The clinical course is highly variable. Treatment includes different chemotherapy regimens as well as the anti-CD20 monoclonal antibody rituximab which has significantly improved the prognosis for patients with all types of B cell lymphomas. The majority of patients with FL respond well to therapy but eventually relapse and generalized disease is still considered incurable. On the other hand, a substantial number appear to have such an indolent disease that the benefit from treatment is unclear. In the clinical setting one challenge is to identiy FL patients in need of therapy upfront as opposed to those who can be managed with active expectancy. Seemingly of importance in addition to the clinical status of the host are characteristics of the tumour cells as well as of the immune cells in the surrounding microenvironment. A greater understanding of the complex intra- and intercellular signaling provides new potential targets for therapeutical intervention. The aim of this thesis was to gain increased insight in clinical and immunological factors of prognostic importance, in indolent lymphoma in general and in FL in particular. This was done by investigation of the long-term outcome in patients treated with rituximab-based immunotherapy and of the validity of the prognostic tools developed in patients receiving standard chemotherapy-based treatment. We also made a study on the interaction of rituximab and the immunomodulator lenalidomide with the healthy immune system during therapy. In paper I we evaluated the late effects of rituximab monotherapy and rituximab with interferon-α2a in 321 previously untreated symptomatic indolent lymphoma patients. After a median follow-up of 10 years more than one third had never required chemotherapy and 73% were still alive. In papers II and III we investigated the two prognostic models m7-FLIPI and PRIMA-PI, both recently developed on cohorts of FL patients treated with a combination of rituximab and CHOP/CVP. The clinicogenetic m7-FLIPI model was not valid in our cohort treated with rituximab with or without interferon. The PRIMA-PI on the other hand, although based on only two parameters – beta2-microglobulin and bone marrow involvement, was a useful tool in differentiating a small group of patients with very poor prognosis, that should be considered for a new or more intensive and hopefully more effective therapeutic approach. In paper IV we followed the changing composition of immune cells in blood in FL patients randomized to therapy with rituximab with or without lenalidomide. Cells were sampled at baseline, after 2 weeks of lenalidomide (combination arm), 24 hours after first rituximab dose and at follow-up weeks 10 and 23 and analysed by flow cytometry. With lenalidomide alone a transient increase in monocyte and NK cell fractions appeared, the latter decreasing again after first rituximab infusion. Post-treatment effects included an increased fraction of T cells as a group and an increased CD4/CD8 ratio. A high proportion of monocytes at baseline was associated with clinical response at week 10 as were a larger fraction of naïve T cells in the rituximab monotherapy treatment arm. Possibly lenalidomide may help overcome the negative impact of few naïve cells, by a beneficial effect on their activity.