Combined Modality Low-Dose Radiation Therapy (2 Gy x 2) and Single-Agent Rituximab Immunotherapy in the Treatment of Indolent Non-Hodgkin Lymphoma
Authors: Brocklehurst Samantha , Desai Neil , Shah Jennifer L , Rizvi Syed , Ramakrishnan Geethakumari Praveen , Kumar Kiran A 
Published: November 2019

Introduction
Low-dose involved site radiation therapy (ISRT) of 2 Gy x 2 is effective in terms of palliation and local control for indolent Non-Hodgkin Lymphoma (NHL), with >80% response rate (Hoskin et al., Lancet 2014). It is commonly used in patients for whom radiation-related toxicity is of concern due to location, volume of disease, or poor performance status, and because of the ease of re-treatment if necessary. An alternative treatment for these patients is rituximab monotherapy, which is well-tolerated and has a good initial response rate but poor long-term response rate (Ardeshna et al., Lancet 2014). To date, no study has examined the efficacy of low-dose ISRT with single-agent rituximab in patients for whom treatment-related toxicity is a concern. We hypothesize that this combination is an effective treatment modality for indolent NHL that may result in the optimal balance of local and systemic disease control with minimal toxicity.
Methods
From a prospectively maintained clinical database of patients treated with radiation therapy (RT) at UT-Southwestern Medical Center, we performed an IRB-approved, retrospective review of 40 treated sites from 34 patients with indolent B-cell lymphoma (predominantly follicular, marginal zone, and mucosal associated lymphoid tissue) treated with low-dose ISRT (2 Gy x 2) between 2013-2019. Of primary interest, 7 patients received single-agent rituximab (median 4 cycles) either concurrently or within a short interval (median 18 days) of their ISRT, with a median follow-up of 13 months. Of the remaining patients, 14 received RT alone and 13 received combination therapy (predominantly bendamustine-rituximab or R-CHOP).
Of the patients who received a combination of low-dose ISRT and single-agent rituximab, treated sites included parotid (3), brain (2), orbit (1), and pre-sacral space (1). The median ECOGperformance status was 1 (range, 1-2), the median age was 75 (range, 21-87), and 4/7 patients were female. The majority of patients were stage I (5), and remaining were stage II (1) and stage III (1). Nopatients had prior RT or systemic therapies.
The primary outcome was response rate, categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD).Secondary outcomes included progression free survival (PFS), overall survival (OS), symptom relief, and acute and long-term toxicities. Treatment response and disease control were determined by radiographic studies and/or physical examinations. SPSS Statistics software was used for statistical analysis.
Results
In all patients who received low-dose ISRT, the progression-free survival and overall survival at 1-year was 58% and 82%, respectively.
In the patients who received combined low-dose ISRT and single-agent rituximab, the response rate was 100% (7/7), of which 5 had CR, 1 had PR and 1 had SD at the time of latest follow-up. For patients with multiple lesions (stage II-III), there was a 100% CR rate of un-irradiated lesions as well. There were no distal failures or deaths.
Of note, 1 patient had progression of disease locally and a second had progression of disease distally initially after ISRT, both of which resolved as SD and CR, respectively, after the administration of rituximab. Also, 1 patient had progression of disease locally while receiving rituximab maintenance therapy, which resolved as CR after treatment with ISRT.
Two patients experienced acute toxicities, 1 with mild diarrhea from presacral RT that resolved within days and 1 with dysgeusia from parotid RT that resolved within 2 months. Only 1 patient noted long-term toxicity from RT, in the form of dry mouth from about 50% reduction in saliva post-RT to the left parotid gland.
All 7 patients presented with symptoms, of which 6 noted improvement. The remaining 1 patient had stable symptoms, as well as SD, with significant improvement in her initial condition confounded by a lower presenting ECOG and C2 fracture from a symptomatic fall prior to RT.
Conclusion
In patients with indolent lymphoma, combined low-dose ISRT of 2 Gy x 2 with single-agent rituximab appears to provide effective palliation and disease control with minimal toxicity. This combination is a promising new treatment paradigm, particularly for patients in whom radiation or chemotherapy related toxicities are of concern, and warrants evaluation in a larger prospective series.

Disclosures
No relevant conflicts of interest to declare.