Main Session
Sep
28
PQA 04 - Breast Cancer, Patient Reported Outcomes/QoL/Survivorship, Functional Radiation Medicine, Hematologic Malignancies, Palliative Care, and International/Global Oncology
3806 - Phase I HyDEF Trial: Hypofractionated and Dual Equivalent Fractionated Bridging Radiation Therapy in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma Undergoing T-Cell Redirection Therapy
Presenter(s)
James Ninia, MD, MS - Yale Therapeutic Radiology, New Haven, CT
A. Rybkin1, J. G. Ninia1, K. B. Roberts1, S. Huntington2, S. Kothari2, N. Bar2, S. Seropian2, I. Isufi2, G. El Fakhri3, R. Lim3, D. J. Carlson4, and T. J. Robinson4; 1Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT, 2Department of Internal Medicine (Hematology), Yale University School of Medicine, New Haven, CT, 3Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, 4Department of Therapeutic Radiology, Yale School of Medicine, New Haven, CT
Purpose/Objective(s):
Radiation (RT) is increasingly used as a bridging therapy to improve outcomes for patients with high-risk relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL) undergoing CAR T therapy. However, the optimal fractionation strategy remains unknown. We conducted the first-in-kind dual fractionation trial design in which the same tumor is treated with radiobiologically equivalent doses of once-daily (hypofractionated, QD) and twice-daily (hyperfractionated, BiD) radiation, enabling a direct intra-tumoral comparison of fractionation schedules. Single-cell T-cell functional assays, cytokine profiling, and a novel ctDNA methylation assay were obtained before and after radiation therapy to investigate the impact of bridging radiation on host T-cell fitness. Herein, we report data from the first trial patient.Materials/Methods:
The primary endpoint is feasibility and safety defined as the absence of 30% or more grade = 3 acute toxicities. Dual fractionation was planned by dividing the tumor volumetrically in half, then expanding each half by 5 mm to PTV, thereby generating a “hot match line” oriented away from critical organs-at-risk. The hypofractionated portion was treated in 13 fractions, 2.5 Gy/fx (32.5 Gy total), and hyperfractionated portion treated to 1.4 Gy/fx (36.4 Gy total). The tumor volumes were contoured on daily CBCT throughout treatment to assess volumetric response.Results:
The total tumor volume reduced by 56% at RT end (day 13), by 73% at post-RT PET, and by 98% at 60-day PET. SUVmax was reduced from 40 to 16 on pre- and post-treatment PET, respectively. The rate of daily volumetric reduction (cm3 per day) appeared similar in the BiD (11.7) and QD (12.5) volumes between days 1 and 13 of treatment. However, between simulation and RT start, there was rapid progression of the tumor mass, particularly in the BiD region that partially confounded direct comparison. The patient tolerated the treatment well with improvement in tumor-related pain and ability to taper off steroids. He reported only grade 1 fatigue. Patient CD4 and CD8 peripheral T-cells each demonstrated improvements in polyfunctional strength index scores post- vs. pre- radiation therapy as assessed by single cell cytokine secretion ex-vivo using the IsoPlexis technology, driven by the ability of activated T-cells to secrete TNF-alpha, MIP-1b, IL-8, and granzyme B. Serum cytokine and methylated ctDNA assays are pending.Conclusion:
We report the first patient treated safely and effectively on the HyDEF phase I clinical trial, establishing a fundamentally new approach to radiation planning, delivery, and investigation. This trial will continue to accrue and mature in both clinical and correlative endpoints.