Incidence, Risk Factors and Prognosis of Transformation in Follicular Lymphoma: a Multicentre Retrospective Analysis of 1763 Patients from the Geltamo Spanish Lymphoma Cooperative Group
Authors: Alonso* Sara , Alcoceba* Miguel , Magnano Laura , Andrade Marcio , García-Álvarez María , Mercadal Santiago , Rodríguez Guillermo , Garcia Olga , Sancho Juan-Manuel , Salar Antonio , Pasarolls Francesc , Terol Maria Jose , Grande Carlos , González de Villambrosia Sonia , Cordoba Raul , Novelli Silvana , López Lourdes , Montalbán Carlos , de Cabo Erik , Infante Maria Stefania , Pardal Emilia , Lopez-Jimenez Javier , Antelo Beatriz , Arranz Reyes , González Marcos , Martín Alejandro , López-Guillermo‡ Armando , Caballero‡ Maria Dolores 
Published: October 2019

Abstract
INTRODUCTION Follicular lymphoma (FL) may, over time, transform into an aggressive lymphoma, usually diffuse large B-cell lymphoma (DLBCL). Transformed follicular lymphomas (tFL) have a worse prognosis due to poorer response to treatment than primary DLBCL. The incidence of transformation is estimated in ~3% per year, although it varies largely between different studies (24%-70% overall). These differences are mainly due to different criteria to define tFL, to lack of evidence of tFL by biopsy, absence of clonality studies discarding secondary de novo NHL, studies performed in the pre-Rituximab era, or different follow-up times among studies. With all this pitfalls, the actual incidence of transformation remains an open question. The aim of the present study is to analyse the incidence and prognostic impact of transformation in patients with FL in a large retrospective series of the Spanish group of Lymphomas (GELTAMO).
PATIENTS&METHODS A total of 1763 patients from 19 Spanish centres diagnosed of FL between 2000 and 2011 were recruited in the study. Data were obtained from the database of centres willing to participate in this study. True tFL (FL to DLBCL) were recorded. From the original cohort, FL IIIb, composite FL+DLBCL, discordant FL (FL in bone marrow and DLBCL in adenopathy or viceversa), and downgrading tFL (DLBCL at diagnosis and relapse of FL) were excluded. Patients with inadequate follow-up were not considered. Therefore, 1611 patients (grade I, II, and IIIa) were finally included. This study was approved by the Salamanca University Hospital Ethic Committee.
RESULTS One hundred and ten patients (median follow up of 6 years) were transformed to DLBCL. Cumulative incidence of transformation at 5, 10, and 15 years was of 5%, 9%, and 14%, respectively. With a median follow up of 75.9 months (2 to 179), median time to transformation was 66 months, ranged 1-179. Considering survival from diagnosis of FL, tFL patients had a shorter OS than non-transformed (19% vs. 69%, p<0,0001). Most of the tFL patients (92%) have previously received treatment for FL, 63% of them with Rituximab. Median number of treatment lines before transformation was 2 (1-7). Factors influencing risk of tFL in the multivariate analysis included non-response to first line therapy (PR, p<0.001, HR:2,5 95% CI:1.5-4.2; others, p<0.0001, HR: 8,1 95% CI: 4.1-16.0), and FLIPI>2 (p=0.002, HR: 2,1 95% CI: 1.3-3.4).
In the multivariate analysis, factors predicting decreased OS after transformation included non-achievement of CR after first line therapy (p<0,001, HR:4.3 95% CI:2-9.1), and elevated LDH at the moment of transformation (p=0,003, HR:3 95% CI:1.5-6.3).
We analyzed separately the role of autologous stem cell transplantation (ASCT) in transformed FL patients. Patients that received ASCT were significantly younger (<70 years) p<0,001, had a better performance status (ECOG <2) (p=0,008) and had achieved a better response (CR) (p<0,001) than those who did not receive ASCT. All of them in our series were treated with rituximab based regimens at transformation. When we analyzed those patients that were eligible for ASCT (younger than 70), patients that received ASCT showed a better OS after transformation than those who did not (51% vs 26% at 5 years, p=0,004). Interestingly, patients who achieve CR to first line therapy at transformation did not beneficiate of ASCT (54% vs 66% at 5 years, p=0,8) while those who do not achieve CR did (50% vs 16% at 5 years, p=0,008).
CONCLUSIONS In this series, one of the largest reported in the rituximab era, high risk FLIPI (>=2) and non-response to FL first line therapy were associated with a higher risk of transformation.Only non-response to transformed FL treatment therapy and a high LDH at transformation were associated with a worse OS after transformation in the multivariate analysis. Autologous transplantation in transformed patients could have a benefit in terms of OS after transformation, but after the introduction of immunochemotherapy strategies, perhaps patients responding to treatment after transformation do not beneficiate from this strategy. *Equal contribution; ‡Equal senior contribution

Disclosures
Sancho: CELLTRION, Inc.: Research Funding.