Relapsed and Primary Refractory Diffuse Large B-Cell Lymphoma: Improving Outcome by Incorporating Involved Field Radiotherapy into a Comprehensive Second-Line High-Dose Therapy Strategy.
Authors: Hoppe Bradford S. , Yahalom Joachim , Kewalramani Tarun , Hamlin Paul A. , Rice David , Filippa Daniel , Maragulia Jocelyn , Weaver Alandra , Moskowitz Craig H. 
Published: April 2020

Abstract
Primary refractory or relapse patients (pts) who have not achieved complete response after salvage or re-induction therapy carry poor prognosis even if additional high-dose chemotherapy is given. In a cohort of 171 pts with relapsed or refractory DLBCL, treated at MSKCC between 1/1/1994 to 9/1/2006 with ICE (ifosfamide, carboplatin, etoposide)-based salvage chemotherapy (44% received ICE+ Rituximab) followed by high dose chemotherapy with autologous stem cell rescue (HDT/ASCR), all pts had post-ICE functional imaging (FI) (Gallium or PET scan). All pts were required to have improvement on CT scan after ICE to be eligible for HDT/ASCR. Involved field radiotherapy (IFRT) was given (prior to HDT/ASCR) to sites of previously unirradiated bulky disease (&gt;5 cm) or to sites with residual nodal masses of more than 2 cm in size following ICE. IFRT was administered within two weeks in 1.5 Gy fractions twice daily to a total dose of 30 Gy if given alone, or to a dose of 18 Gy if given in combination with 12 Gy fractionated total body irradiation. At a median follow-up of 57 months for surviving pts, there were no treatment-related deaths, and the 5-year progression-free survival (PFS) and overall survival (OS) for the entire cohort was 51% and 57%, respectively. Following ICE-based cytoreduction, FI was positive in 65 pts (38%) and they had an inferior 5 yr PFS (30% vs 61%, p=0.001) and OS (37% vs 67%, p&lt;0.001) compared to those with a negative test. In the pts with positive FI scan, IFRT was delivered to all positive sites based on FI in 40 pts, while 25 pts had incomplete or no IFRT coverage to the positive sites. Eleven pts could not receive further IFRT, due to a history of prior IFRT as part of initial front-line treatment. In pts with positive FI, complete IFRT coverage had an improved 5yr-PFS (44% vs 19%; p=0.05). In a Cox regression multivariate analysis of the pts with positive FI, two factors remained independently significant for inferior PFS: 1. higher age-adjusted second-line IPI scores, and 2. no IFRT, or inadequate IFRT (incomplete coverage of all positive areas). Adequate radiation reduced the risk of progression/relapse by approximately 50%.
Conclusion: Patients with positive FI following ICE have a worse PFS compared with pts with negative FI to ICE. Higher adjusted IPI scores are associated with even worse outcomes in this group of pts. If all sites of abnormal FI post-ICE can receive IFRT prior to HDT/ASCR, PFS is likely to improve.
Multivariate Analysis Patients HR 95% CI P value Abbreviations: HR-Hazard Ratio; CI-Confidence Interval; sAAIPI-age-adjusted second-line IPI score IFRT: incomplete coverage 25 1.00 reference IFRT: complete coverage 40 0.51 0.26, 1.02 0.057 sAAIPI: 0 11 1.00 reference sAAIPI: 1 22 3.98 1.13, 13.98 0.031 sAAIPI: 2&3 24 3.42 1.00, 11.79 0.051