Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL). Histological transformation (HT) refers to the evolution of a clinically indolent NHL to an aggressive one. The rates of HT in published series range from 10% to 60%. There are no specific clinical characteristics that can predict transformation. Some molecular parameters associated with transformation are: p53 expression, expression of c-MYC, BCL-6 mutations. This suggests that multiple alternative mechanisms are likely to be involved in the pathogenesis of HT.
We report a prospective, multicenter (39 Spanish member institutions of Grupo Oncológico para Tratamiento de Linfomas-GOTEL-), observational study designed to collect data on disease presentation, treatment and clinical outcomes of HT. Inclusion criteria for this analysis were initial diagnosis of grade 1-3a FL and enrolment from 1990 to 2016. HT was defined as refractory/recurrent disease with clinical or pathologic diagnosis. Whole exome sequencing of the HT samples has been performed and compared with samples from patients with LF without transformation.
Of the 975 evaluable patients, 64 had HT. Characteristics associated with an increased risk of HT were: the presence of B symptoms (p = 0.001), increased LDH (p = 0.02), high Follicular Lymphoma International Prognostic Index (FLIPI) (p = 0.01) and poor perfomance status (p = 0.01). In this group of patients, the cumulative incidence rate of HT at 5 years was 7.3%; the rate of HT remained constant, reaching a plateau after 14 years. Expectant management also predicted for a higher risk of HT (p = 0.0001). The median survival from transformation was 5 years. Regarding molecular characteristics, we found that all patients with HT had more than 4 mutations at diagnosis of FL in a group of 14 genes that are frequently mutated in patients with HT: CSMD3, DTX1, FOXO1, LRP1B, NOTCH2, PIM1, POU2F2, ATM, BCL7A, HIST1H1E, IRF8, PCLO, EZH2 and TNFAIP3.
There are clinical (increased LDH, B symptoms, high FLIPI, poor performance status) and molecular factors (more than 4 mutations in specific genes) at diagnosis correlate with an increased risk of HT. These predictors of HT could help to develop targeted therapies to prevent HT in high risk patients or improve current salvage approaches.
Clinical trial identification
GOTEL trial of histological transformation
Legal entity responsible for the study
GOTEL (Grupo Oncológico para el Tratamiento y Estudio de Linfomas)
All authors have declared no conflicts of interest.