Phase II Trial of Response Adapted Ultra Low Dose (ULD) Orbital Radiation Therapy for Indolent B Cell Lymphoma
Authors: Pinnix Chelsea C. , Dabaja Bouthaina S. , Gunther Jillian R. , Fang Penny , Wu Susan , Nastoupil Loretta , Strati Paolo , Nair Ranjit , Ahmed Sairah , Steiner Raphael E , Malpica-Castillo Luis , Chihara Dai , Jain Preetesh , Fayad Luis , Westin Jason R. , Neelapu Sattva S. , Rodriguez Maria Alma , Hagemeister Fredrick B. , Lee Hun Ju , Wang Michael , Samaniego Felipe , Fowler Nathan H. , Flowers Christopher R. , Feng Lei , Chi Linda , Esmaeli Bita 
Published: November 2021

Abstract
Introduction: The standard of care for patients with stage IE indolent B-cell lymphoma (BCL) of the ocular adnexa is external beam radiotherapy (RT) to 24-30 Gy. Even with these moderate doses, ocular morbidity is common. Indolent BCL is radiosensitive, with reports of complete response (CR) to 4 Gy. We sought to evaluate the efficacy of a response adapted strategy for the treatment of orbital indolent BCL with upfront ultra-low dose (ULD) orbital RT (4 Gy) and an additional 20 Gy for incomplete responders.
Methods: We conducted a phase II single arm study in patients with stage I-IV indolent BCL involving the orbit. Patients were treated with ULD RT to 4 Gy in 2 fractions to the affected orbit(s). Response was assessed clinically and/or radiographically 3 months after ULD RT. Patients with a CR were observed. Patients without CR were evaluated in 3-4 month intervals and offered an additional 20 Gy if they had two consecutive visits with no tumor reduction. The primary endpoint was local control (LC) within the RT field defined from the last day of RT. Secondary endpoints included CR rate, freedom from distant relapse (for stage I patients) and overall survival. We hypothesized that this response adapted strategy would yield equivalent LC to that of standard therapy (24 Gy up front).
CR was defined as clinical and/or radiographic resolution of orbital disease. In patients with pre-therapy PET-CT avid disease, CR was defined as a 5PS of 1-3 with or without a residual mass. Partial response (PR) was defined as a decrease in clinical or radiographic disease burden by ≥50% by sum of the disease parameters. Minimal response (MR) was defined as &lt; 50% in orbital disease burden. Stable disease (SD) and progressive disease (PD) were defined as no change or increasing disease, respectively.
Results: Between July 2015 and January 2021, 51 patients were enrolled. The median age was 63 years (range 29-88); 62% were female (n=31). Diagnoses included MALT lymphoma (65%, n=33), follicular lymphoma (FL) (24%, n=12), and unclassified low-grade BCL (12%, n=6). Thirty-two patients (63%) had disease confined to one or both orbits at enrollment (stage I); 37 (73%) had newly diagnosed, untreated lymphoma.
All patients received 4 Gy in 2 fractions to the affected orbit(s) (bilateral, n=8). Treatment was well tolerated without grade 3 or higher toxicity.
One patient did not return for follow up. For 50 evaluable patients, at a median follow up of 21.9 months (95% CI 16.2 - 27.6), 44 patients achieved a CR to ULD therapy (88%) at a median time of 3.4 months (IQR 3, 3.9). Nine patients (20%) had residual disease at the first follow up visit but subsequently had resolution of orbital lymphoma in future follow up. No patient who experienced CR to ULD RT had an in-field orbital relapse (freedom from local relapse rate = 100%, Figure 1a). At the time of follow up #3, 7 patients had not experienced CR and had evidence of disease (Figure 2). Among these 7 patients, 1 achieved CR with continued observation (without intervening therapy) and 2 are being observed with stable disease. Ultimately 4 patients were recommended additional RT to 20 Gy; two patients received the recommended RT, one refused additional RT, one was treated with rituximab for systemic disease progression. After an additional 20 Gy, one patient has stable disease at 21 months and the other patient has pending follow-up.
Of the 50 evaluable patients, 31 had stage I disease (MALT = 25, FL=4, low grade BCL =2) that was either untreated (n=25) or had relapsed or progressed in the orbit (n=6) after rituximab (n=2), surgical excision (n=2) or contralateral RT (n=2). Twenty-eight stage I patients (90%) had a CR to ULD RT; of these, the 2-year freedom from local recurrence rate was 100% (Figure 1b) and the freedom from distant relapse rate was 87% (Figure 1b). Distant relapses in the mediastinum, lung, contralateral orbit and mesentery were salvaged successfully with bendamustine/rituximab, rituximab, contralateral 4 Gy orbital RT and rituximab, respectively. None of the 3 patients that did not completely respond to ULD RT experienced distant relapse.
Conclusions: In the first prospective study evaluating this novel approach of response adapted ULD orbital RT, orbital outcomes were compelling with minimal toxicity. Additional follow up is required to evaluate long term LC. Response adapted ULD orbital RT is an effective and promising strategy for the definitive management of indolent BCL of the ocular adnexa.
Figure 1 Figure 1.

Disclosures
Pinnix: Merck Inc: Research Funding. Nastoupil: Bristol Myers Squibb/Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Other: DSMC, Research Funding; MorphoSys: Honoraria; Gilead/Kite: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Epizyme: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; IGM Biosciences: Research Funding; TG Therapeutics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Denovo Pharma: Other: DSMC; ADC Therapeutics: Honoraria; Bayer: Honoraria; Caribou Biosciences: Research Funding. Strati: Astrazeneca-Acerta: Research Funding; Roche-Genentech: Consultancy. Ahmed: Seagen: Research Funding; Tessa Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Xencor: Research Funding. Steiner: Rafael Pharmaceuticals: Research Funding; BMS: Research Funding; Seattle Genetics: Research Funding. Jain: kite: Consultancy; Lilly: Consultancy. Westin: Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; MorphoSys: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Umoja: Consultancy; Iksuda Therapeutics: Consultancy; Curis: Research Funding; Morphosys: Research Funding; 47 Inc: Research Funding. Neelapu: Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene Therapeutics, Cell Medica/Kuur, Incyte, Precision Biosciences, Legend Biotech, Adicet Bio, Calibr, Unum Therapeutics and Bluebird Bio: Honoraria; Takeda Pharmaceuticals and related to cell therapy: Patents & Royalties; Kite, a Gilead Company, Bristol Myers Squibb, Merck, Poseida, Cellectis, Celgene, Karus Therapeutics, Unum Therapeutics (Cogent Biosciences), Allogene, Precision BioSciences, Acerta and Adicet Bio: Research Funding; Kite, a Gilead Company, Merck, Bristol Myers Squibb, Novartis, Celgene, Pfizer, Allogene, Kuur, Incyte, Precision BioSciences, Legend, Adicet Bio, Calibr, and Unum Therapeutics: Other: personal fees. Wang: BioInvent: Research Funding; Celgene: Research Funding; Molecular Templates: Research Funding; Lilly: Research Funding; VelosBio: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Oncternal: Consultancy, Research Funding; Loxo Oncology: Consultancy, Research Funding; Juno: Consultancy, Research Funding; InnoCare: Consultancy, Research Funding; Genentech: Consultancy; DTRM Biopharma (Cayman) Limited: Consultancy; CStone: Consultancy; Bayer Healthcare: Consultancy; BGICS: Honoraria; The First Afflicted Hospital of Zhejiang University: Honoraria; Scripps: Honoraria; Physicians Education Resources (PER): Honoraria; OMI: Honoraria; Newbridge Pharmaceuticals: Honoraria; Mumbai Hematology Group: Honoraria; Moffit Cancer Center: Honoraria; Miltenyi Biomedicine GmbH: Consultancy, Honoraria; Kite Pharma: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Imedex: Honoraria; Hebei Cancer Prevention Federation: Honoraria; Epizyme: Consultancy, Honoraria; Dava Oncology: Honoraria; Clinical Care Options: Honoraria; Chinese Medical Association: Honoraria; CAHON: Honoraria; BeiGene: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Research Funding; Anticancer Association: Honoraria; Acerta Pharma: Consultancy, Honoraria, Research Funding. Samaniego: Arog: Research Funding; Imbrium: Membership on an entity's Board of Directors or advisory committees. Fowler: BostonGene, Corp: Current Employment, Current holder of stock options in a privately-held company; Bristol Myers Squibb, F. Hoffmann-La Roche Ltd, TG Therapeutics and Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding. Flowers: Karyopharm: Consultancy; SeaGen: Consultancy; Genentech/Roche: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Acerta: Research Funding; Biopharma: Consultancy; Genmab: Consultancy; 4D: Research Funding; Denovo: Consultancy; Spectrum: Consultancy; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy; Epizyme, Inc.: Consultancy; Bayer: Consultancy, Research Funding; Gilead: Consultancy, Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; EMD: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Janssen: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Nektar: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding.