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Follicular lymphoma (FL) is typically indolent, but relapses and transformation to higher grade disease are common. Ionizing radiation therapy (RT) is guideline-preferred for localized disease; FL can be exquisitely radiosensitive, as demonstrated by the potential for complete response (CR) to very low dose RT (VLDRT, 4Gy). Clinicodemographic factors associated with durable FL response to RT are crude, and there are no known genetic markers of FL radiosensitivity.  We sought to identify genetic signatures of FL radiosensitivity to aid in patient and dose selection for VLDRT.

We analyzed a single institution database of FL patients (all stages) treated with RT between 2005-2021 and identified 98 patients with 101 tumors treated with RT, and each having preexisting MSK-IMPACT, a targeted exon sequencing panel assaying up to 505 genes. We identified an additional cohort of 12 patients with biopsy tissue available for which we performed de novo MSK-IMPACT. We identified gene alteration signatures, and using logistic regression and Kaplan Meier analysis, we associated the presence of gene alterations with best response to RT between 2-6 months using Lugano criteria and local progression (LP), respectively. Lastly, we used LASSO Cox regression to derive a single model relating gene alterations to LP.

The median RT dose was 4Gy (range: 4-36Gy), and most tumors were early stage and treated with curative intent (Table 1). We identified 5 signatures of altered genes with a BCL2 altered signature without CREBBP alterations having significantly shorter LP after RT (p=0.02). From LASSO regression modeling, CREBBP and BCL2 made the largest contribution to observed LP after RT. Coding mutations occurring within CREBBP were associated with increased odds of CR (OR: 3.02 (95% CI: 1.25-7.33, p=0.014) and improved LP (median LP 136 vs 31 months, p=0.02). Mutations of the histone acetyltransferase (HAT) domain, responsible for transcriptional regulation (Figure 1A), show a significant association with reduced LP risk after RT (HR:0.37 (95% CI: 0.15-0.89, p=0.019))(Figure 1B). This effect was observed for tumors receiving VLDRT (n=56) (p=0.05) and in our de novo cohort (p=0.05).

Table 1. Tumor and Treatment Characteristics

Figure 1. CREBBP Mutations and Local Progression

Alterations in the HAT domain of CREBBP, which are likely associated with loss of function, appear to be associated with better response to RT. Adjuvants targeting histone acetylation may have a role in increasing radiosensitivity during FL treatment. Genetic signatures of radiosensitivity can be further explored to clarify additive effects of alterations on treatment response, and they may be incorporated into clinical decision making to improve patient and dose selection for RT.