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Recent developments for patients with R/R FL
Epigenetic changes also contribute to immune dysregula- tion via suppression of major histocompatibility complex expression and tumor infiltrating lymphocyte content.
Tazemetostat represents the most successful epigenetic therapy to date in FL.63 Activating mutations in EZH2 occur in about 20% of FL, and result in aberrant silencing of differentiation genes, allowing continued survival and proliferation of FL (Figure 2). Tazemetostat inhibits EZH2, allowing for normal transcription of repressed genes. In phase I and II studies evaluating tazemetostat monotherapy, the overall response rate was 69% in EZH2-mutant FL, with a median PFS of 13.8 months. Tazemetostat also demonstrated activity in EZH2 wild- type FL with an overall response rate of 35% and PFS of 11.1 months. Tazemetostat was well tolerated, with only 4% of patients suffering a serious treatment-related adverse event, a favorable profile for combination thera- pies. Other EZH2 inhibitors are in early development.
Other epigenetically targeted agents are also under investigation. Histone deacetylase inhibitors counteract the epigenetic impact of CREBBP and EP300 mutations (Figure 2), and have demonstrated activity in FL. Four phase II studies have documented response rates of 47- 64% with abexinostat or vorinostat, but with significant
hematologic and gastrointestinal tract toxicity.64-67 In each of these studies, higher response rates to histone deacety- lase inhibition were seen in FL than in other types of non- Hodgkin lymphoma, suggesting a particular sensitivity to epigenetic modulation. As yet no studies have evaluated whether mutations in EP300 or CREBBP predict for response in FL, and this may be worth exploring; howev- er, it is interesting to note that in a study of the histone deacetylase inhibitor panobinostat in diffuse large B-cell lymphoma, CREBBP or EP300 mutations were not associ- ated with response.68 Additional in vivo work suggests that inhibitors of the demethylase KDM5 may restore normal histone methylation and gene expression in KMT2D- mutant disease, another gene commonly affected in FL.69
Immunotherapies: early successes and promising potential
Single-agent anti-CD20 therapy remains viable for selected patients
In patients with relapsed disease and low tumor burden following initial anti CD20-containing therapy, re-chal- lenge with monoclonal antibodies, including rituximab
Figure 2. Epigenetic dynamics in follicular lymphoma. Frequent epigenetic mutations in follicular lymphoma result in repression of mature B-cell differentiation fac- tors and cell regulators, preventing terminal differentiation and exit from the cell cycle. This allows a germinal center phenotype, genomic instability, and cellular pro- liferation to persist. (A) Activating mutations in EZH2 result in aberrant trimethylation of lysine 27 in histone 3 (H3K27me3), resulting in transcriptional silencing and lymphomagenesis. Tazemetostat inhibits EZH2, restoring normal H3K27 methylation. (B) Loss-of-function mutations in the histone acetyltransferases CREBBP and EP300 result in decreased acetylation of histones H3K27 and H3K18, shifting the balance toward histone deacetylation by HDAC3. Histone deacetylase inhibitors prevent this deacetylation. (C) KMT2D is a histone methyltransferase and is frequently inactivated in follicular lymphoma, favoring demethylation of H3K4 and repres- sion of key differentiation genes. Inhibitors of the demethylase KDM5 restore normal H3K4 methylation and gene expression in KMT2D-mutant lymphoma. HDAC: histone deacetylase.
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