Effect of Adding Ibritumomab Tiuxetan (Zevalin) Radioimmunotherapy Consolidation to Three Cycles of CHOP Plus Involved-Field Radiotherapy for Limited-Stage Aggressive Diffuse B-Cell Lymphoma (SWOG 0313)
Authors: Miller Thomas P. , Unger Joseph M , Spier Catherine , Stea Baldassarre , Press Oliver W. , Friedberg Jonathan W. , LeBlanc Michael , Fisher Richard I 
Published: October 2019

Abstract
The 5-year survival rate of patients with limited disease (LD) and aggressive histologies of non-Hodgkin lymphoma (NHL) who have at least one adverse risk factor is about 70% after treatment with three cycles of CHOP followed by involved-field radiotherapy (CHOP(3) plus IFRT). We have previously reported the effect of adding four infusions of rituximab to CHOP(3) plus IFRT demonstrating an improved estimated overall 5-year survival (OS) of 82% (Persky et al. J Clin Oncol26:2258, 2008). In this study we test the effect of adding ibratumomab tiuxetan consolidation to CHOP(3) plus IFRT in 40 evaluable patients. Patients had a biopsy diagnosis (no FNA allowed) of diffuse aggressive B-cell NHL without any follicular component and high risk LD. High risk LD is defined, using the stage-modified International Prognostic Index, as stage I with at least one adverse risk factor (age > 60 years, elevated LDH and a performance status of 2) OR non-bulky stage II disease. Patients with stage I and no risk factors were excluded because their survival exceeds 90% at 10 years using standard therapy. Patients with bulky stage II disease were not eligible because their prognosis is similar to advanced disease. CHOP chemotherapy was given at standard doses on days 1, 22, and 43. IFRT was given as previously described (above) starting on day 64 to include 40 – 46 Gy. The rituximab plus ibritumomab tiuxetan regimen was given 3 – 6 weeks following completion of IFRT over a period of 7 – 9 days. Rituximab, 250 mg/m2 was given on day 1 followed within 4 hours by 5 mCi of In-111 ibritumomab tiuxetan followed by whole body gamma camera images to assess biodistribution of the ibritumomab tiuxetan. Scans were obtained at 2 – 24 hours and at 48 – 72 hours. Following acceptable biodistribution, rituximab is repeated on days 7, 8, or 9 followed within 4 hours by Y-90 ibritumomab tiuxetan, 0.4 mCi/kg, not to exceed 32 mCi total dose. Forty patients are eligible. Patients have been followed for a median of 24 months (range 1 – 50 months). During this time there have been only three events recorded (progression or death from any cause). Estimated 2-year progression-free survival is 91% (95% CI: 81%-100%) and 2-year OS is 95% (95% CI: 87%-100%). Toxicity has been reversible with no treatment related deaths. There were 9 grade 3 and 10 grade 4 hematologic events, but only 3 episodes of febrile neutropenia and only one patient requiring platelet support. Other grade 3 toxicities were mostly gastrointestinal symptoms including mucositis and nausea/vomiting or flu-like symptoms. We conclude that patients with aggressive histologies of NHL and high-risk LD treated with CHOP(3) plus IFRT followed by ibritumomab tiuxetan consolidation result in outcome that compares favorably to our historical experience in the short term. Longer follow-up will determine whether these patients exhibit a pattern of late recurrences as seen in our prior experiences.