210 - Associations Between Genetic Alterations in Follicular Lymphoma and Radiosensitivity

N. A. Wijetunga¹, E. S. Lebow², A. Chan³, J. Lee¹, B. Fregonese¹, V. Seshan³, C. Hajj², G. Cederquist¹, H. G. Hubbeling⁴, J. Ma¹, R. R. Sarkar¹, K. R. Tringale², P. K. Galera³, E. Joffe³, A. Dogan³, G. Salles³, B. S. Imber², and J. Yahalom¹; ¹Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, ²Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, ³Memorial Sloan Kettering Cancer Center, New York, NY, ⁴Department of Radiation Oncology, University of Pennsylvania, Philadelphia, PA

Purpose/Objective(s): Follicular lymphoma (FL) is typically indolent, but relapses and transformation to higher grade disease are common. FL is often radiosensitive and can show complete response (CR) even to very low dose radiotherapy (VLDRT, 4Gy). There are no known genetic markers of FL radiosensitivity. We sought to identify molecular signatures of FL radiosensitivity to help in unraveling its mechanism and aid in patient selection for VLDRT. Materials/

Methods: We analyzed our institutional database and identified 110 FL patients with 113 tumors treated with radiotherapy (RT) and MSK-IMPACT, a targeted exon sequencing panel incorporating germline genetic information. Hierarchical clustering was used to identify mutation signatures. We determined CR within 6 months of radiation, and local progression free survival (LPFS), censored at last follow-up, death, or starting an unplanned systemic therapy. Through logistic regression, Kaplan Meier analysis, and Cox proportional hazards regression, we identified gene mutations (mut) and signatures associated with CR to RT and LPFS.
Results: We found CREBBP to be the most frequently altered gene (66% of tumors). CREBBP mut was the only alteration associated with increased odds of CR (Odds ratio: 2.39 (95% CI: 1.06-5.37, p = 0.04), and this effect remained significant after adjusting for pelvic disease site (p=0.04). Mutations of BCL2, IRF8, and KMT2D were associated with decreased LPFS using log-rank testing (p<0.01, p=0.02, and p=0.043, respectively). We identified 5 signatures of altered genes, most of which showed altered CREBBP and relatively long LPFS; however, a signature with concurrent altered KMT2D, BCL2 translocation (t(14;18)) and BCL2 mut had significantly shorter LPFS than all other signatures (p < 0.01) and lower odds of CR relative to the other signatures (p= 0.028). In the VLDRT cohort, we found that CREBBP histone acetyltransferase (HAT) mut was associated with improved LPFS (n=39, 2y LPFS 52% vs 74%, HR:0.41 (95% CI: 0.18-0.93, p=0.03)), but this was not observed for tumors receiving radiation doses higher than 4Gy (n=44, HR: 1.27 (95% CI: 0.32-5.08), p=0.74)). We used multivariate modeling to verify that the effect of CREBBP HAT mut in the VLDRT cohort was still present after controlling for treatment strategy, prior chemoimmunotherapy, signature assignment, and BCL2 mut. Lastly, we observed that concurrent BCL2 mut and t(14;18) (BCL2 mut/t(14;18) ) and CREBBP HAT WT had a 2y LPFS of 13% whereas BCL2 mut/t(14;18) and CREBBP HAT mut had a 2y LPFS of 83% (p<0.01), and this relationship persisted on multivariate analysis.

Conclusion: Genetic signatures of radiosensitivity, and specifically alterations in the CREBBP HAT domain, may be incorporated into clinical decision making to improve patient and dose selection for VLDRT. This is the first study to demonstrate a specific gene associated with radiosensitivty in FL. Additional laboratory and prospective clinical studies are needed to validate and expand upon these findings.