Somatic Mutation Profile Analyzed By Next-Generation Sequencing in Relapsed/Refractory Follicular Lymphoma Treated with Idelalisib
Authors: Robert Philippine , Rossi Cédric , Aucagne Romain , Chapusot Caroline , Ramla Selim , Noel Robin , Bouabdallah Reda , Avenin Morgan , Xerri Luc , Toussaint Elise , Chenard Marie-Pierre , Fornecker Luc Mathieu , Chauchet Adrien , Bedgedjian Isabelle , Quinquenel Anne , Nasri Saviz , Marchal Aude , Delmer Alain Jacques , Bouteloup Juliette , Bastie Jean-Noel , Martin Laurent , Callanan Mary , Casasnovas Olivier 
Published: November 2019

Purpose
Follicular lymphoma (FL) accounting for 20% of non-Hodgkin lymphoma, is currently considered treatable but not curable despite more effective treatment options. Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase δ (PI3Kδ) that blocks PI3Kδ-AKT signaling and promotes apoptosis, is approved for patients with relapsed/refractory (R/R) FL who have received ≥ 2 prior systemic therapies. Previous studies suggest that somatic tumor mutations identified at relapse may have an impact on the response to targeted therapies (Bartlett N et al., Blood 2018). The goal of this study was to analyze the lymphoma mutational profile to identify the prognostic value of mutations in R/R follicular lymphoma patients treated with idelalisib.
Methods
We performed a retrospective multicenter study of patients (pts) with relapsed follicular lymphoma and no evidence of transformation, having received at least 2 prior regimens before idelalisib treatment. Patients received idelalisib 150mg BID until progression or toxicity. Next-generation sequencing (NGS) of 51 genes was performed either at FL diagnosis and/or at relapse prior idelalisib therapy. The primary endpoint was to analyze the relationship between the mutational status and the duration of response (DOR) to idelalisib. DOR was measured from the time of initial response until documented lymphoma progression. According to DOR pts were classified as: refractory (response &lt; 1 month), short-responder (1 month ≤ DOR ≤ 12 months) and long-responder (&gt; 12 months).
Results
24 pts with R/R FL were enrolled with a median age of 62.5 years (range: 57-86). Patients had received a median of 3 prior treatments (range: 2-7). FL was refractory to rituximab in 16 pts (67%), to alkylating agents in 11 pts (46%) and to 2 or more prior treatments in 11 pts (46%). Twelve (50%) had refractory disease to the last therapy before idelalisib. Pts received idelalisib during a median of 5.5 months (range: 0.5-31). Overall response rate was 83% (n=20) including 3 (15%) complete response and 17 (85%) partial response. The median DOR was 9.5 months (range: 0-28). Eleven pts were short-responders and 9 long-responders. Four pts (17%) had refractory disease to idelalisib. Median progression-free survival and overall survival were 11.5 (range: 1-30) and 16.5 months (range: 1-56) respectively. Three pts (12.5%) are still continuing idelalisib. Twenty-one pts (87.5%) discontinued treatment mostly due to progressive disease (n=14) and adverse events (n=5); 3 pts remained progression-free after idelalisib discontinuation and observation with a median follow-up of 23 months (range: 20-24).
All the pts had at least one mutation detectable for one of the targeted genes in both diagnosis (n=17) and relapse (n=20) samples. The median number of targeted genes with non-silent mutations per patient was 7 at diagnosis (range: 2-11) and 6 at relapse (range: 3-28). The most frequent genes found in 10% of patients (≥ 2) or more at diagnosis and at relapse are listed in Figure 1.
The mutational profile at diagnosis predominantly included mutations in epigenetics gene family, KTM2D (n=16; 94%), EP300 (n=9; 52%), ARID1A (n=6; 35%), KTM2A (n=5; 29%) and CREBBP (n=4; 23%). The m7-FLIPI score (Pastore A et al., Lancet Oncology 2015) at diagnosis helped identifying pts with low-risk (n=12; 71%) and high-risk (n=5; 29%) of idelalisib treatment failure. The median m7-FLIPI score in the refractory group was 1.25 compared to 0.26 in the short responder group and 0.04 in the long responder group. All long responder patients had low-risk m7-FLIPI.
The mutational profile at relapse was significantly enriched in mutations of TNFAIP3 (n=7; 35%) and NFKBIE (n=4; 20%), affecting the NF-kB inhibitor pathway, and mutations of transcription factors, TP53 (n=10; 50%), MEF2B (n=5; 25%), FOXO1, STAT6 and IRF4 (n=4; 20% each).
Overall the mutational profile of the 3 sub-groups according to DOR was detailed in Figure 2. The genes more frequently mutated in refractory pts were: EP300 (n=3/4; 75%), B2M (n=2/4; 50%), FBXW7 (n=2/4; 50%), CARD11, CXCR4 and MYD88 (n=1/4; 25% each).
Conclusion
The m7FLIPI at diagnosis identifies patients with higher risk of treatment failure in patients with R/R FL treated with idelalisib. Patients with idelalisib refractory disease have more frequently mutations of EP300, B2M, FBXW7, which suggests they could be related to resistance to idelalisib.

Disclosures
No relevant conflicts of interest to declare.