Page 12 - Wondergem

Chapter 1
Introduction
Transformation is the development of high-grade, aggressive non-Hodgkin lymphoma (mostly diffuse large B cell lymphoma: DLBCL) in patients with an underlying indolent lymphoma. Transformation has been described in all subtypes of indolent B cell lymphoma (1). However, since follicular lymphoma is the most common indolent lymphoma, the incidence of transformation of follicular lymphoma enables studies on risk factors and outcome. Therefore, the focus of this thesis is transformation of follicular lymphoma.
Follicular lymphoma (FL) is the most common indolent B cell lymphoma worldwide, comprising approximately 20% of all non-Hodgkin lymphomas. The clinical course of FL is characterized by a continuous pattern of relapses with repeated but transient responses to therapy, resulting in a median overall survival (OS) of more than 10 years. However, there is a pronounced variability in OS, ranging from months to decades (2). A high follicular lymphoma prognostic index (FLIPI) and several clinical factors such as bulky disease, B symptoms and short response to therapy predict an aggressive disease course, including transformation of FL (3). However, the discriminative power has not been found consistent enough yet to guide treatment decisions.
Incidence of transformation of follicular lymphoma
The incidence of transformation in patients with FL varies considerably due to the use of different diagnostic methods, definition of transformation and the duration of follow up. The most recent studies, in which in the majority of patients the diagnosis was biopsy proven, report an incidence of 2% to 3% per patient per year (4,5). While Al Tourah et al report an ongoing risk of transformation, most authors have reported that the frequency of transformation is highest during the first years after diagnosis of FL (5) or even reaches a plateau after approximately 15 years (4,6-8).
Although the incidence of transformation in the rituximab era appears not to be substantially different from the pre-rituximab era, recently it was described by the authors of the National LymphoCare study that the incidence was less in patients who received rituximab maintenance therapy, however, transformation still occurs (4,6,7,9- 11). Most reports show that therapy early in the course of FL, or specific therapies (i.e. anthracyclines) do not meaningfully influence transformation risk (4,8,9,12). In conclusion, transformation of FL is an ongoing issue in the rituximab era.
Prediction of transformation of follicular lymphoma
Several clinical factors are associated with a higher risk of transformation, such as 10