2763 - Safety and Feasibility of Hypofractionated Radiation Therapy for Relapsed/Refractory Lymphoma: Extended Follow-Up of a Phase I Trial

Purpose/Objective(s): Radiation therapy (RT) improves local control in relapsed/refractory Hodgkin/non-Hodgkin lymphoma (RRL). To increase access to RT and decrease time to next line therapy, we evaluated the safety and tolerability of hypofractionated RT for RRL using a design in which the biologically equivalent dose is held constant across dose levels (DLs) while reducing the number of fractions.

Materials/Methods: In this i3+3 phase I trial of RRL (ECOG = 2 with = 5 lesions), DLs were: D1 (42 Gy/10 fx) D2, 39.2 Gy/7 fx; D3, 34 Gy/5 fx; and D4, 30 Gy/3 fx. Dose-limiting toxicity (DLT) was any grade 3 or 4 toxicities within 1 week of completing RT. To meet planning constraints or per clinician discretion, per protocol dose de-escalation was permitted to 75% of prescribed dose. After 12 patients with no DLTs, an expansion cohort was treated at D4. The primary endpoint was DLT. Secondary endpoints included overall survival (OS), progression-free survival (PFS), and local control (LC), estimated using the Kaplan-Meier method. Univariable and multivariable Cox proportional hazards models were used to assess predictors of OS.

Results: The final dose level (D4) was reached after 12 patients; an additional 11 patients were enrolled in the expansion cohort (de-escalation to 23.4Gy/3 fx, n=11). The 23 patients received a median of 2 (range 1-11) prior lines of systemic therapy. 16/23 patients (70%) were treated with definitive intent, with 4/16 (25%) receiving RT as a bridge to further therapy (CAR-T cell, n=3). The most common histologies were diffuse large B-cell lymphoma (14/23, 61%) and follicular lymphoma (4/23, 17%). Acute toxicities occurred in 17/23 patients (74%); grade 1 in 4 patients (17%), grade 2 in 12 patients (52%), and grade 3 in 1 patient (4%), with no grade 4 or 5 toxicities. The most common acute toxicities were fatigue, nausea, odynophagia, and pain. There were no acute DLTs. Late grade 3 toxicities (>3 months post-RT) occurred in 5 patients (22%), of which 2 (9%) were attributable to RT (gastritis and radiation dermatitis). At a median follow-up of 26 months, the 2-year OS was 56.5% (95% CI 38.4-83.2%), PFS 38.5% (95% CI 21.9-67.8%), and LC 72.6% (95% CI 54.3-97.0%). On univariable Cox regression, the number of prior lines of systemic therapy was the only significant predictor of OS (HR 1.34, 95% CI 1.08-1.67, p=0.008). This remained significant on multivariable analysis adjusting for age and performance status (adjusted HR 1.51, 95% CI 1.12-2.05, p=0.007).

Conclusion: This phase I prospective trial demonstrates the safety of hypofractionated RT for RRL. With no DLTs, the final regimen of 23.4-30 Gy in 3 fx had 72.6% LC and minimal toxicity (9% grade 3+ attributable to RT). These results support further investigation of hypofractionation to improve access to RT while reducing time to next line therapy.