A Prospective Study of the Prognostic Impact of 18[F]-FDG-PET and Molecular Response in Patients with Relapsed Indolent Non-Hodgkin Lymphoma (NHL) Following Iodine-131-Rituximab Radio-Immunotherapy (RIT).
Authors: Bishton Mark J. , Hicks Rod , Westerman David Alan , Prince Miles , Wolf Max , Seymour John Francis 
Published: October 2019

Abstract
Aims. RIT with an anti-CD20 monoclonal antibody conjugated to a beta-emitting radioisotope may overcome rituximab resistance in B-cell NHL, delivering radiation not only to tumor cells that bind the antibody but also, due to a cross-fire effect, to neighboring unbound tumor cells. PET has emerged as a major imaging modality for response assessment of aggressive NHL, and recent data suggests PET has excellent sensitivity and specificity in indolent NHL. In follicular NHL, high molecular response rates for BCL-2 re-arrangements occurs following first-line treatment with RIT. Outcomes following molecular remission, and the impact of PET response post RIT at relapse, are unknown. We present the prospectively collected data for patients (pts)at a single institution enrolled in a multi-center phase II trial of 131-I labelled rituximab treatment of patients with relapsed or refractory indolent B-cell NHL.
Methods. All pts were required to have histologically proven relapsed or refractory indolent CD20 positive B-cell NHL. The administered activity of 131I-rituximab was estimated to deliver a whole-body radiation absorbed dose of 0.75 Gy. Post treatment surveillance PET-CT scans were performed at baseline, 3, 6, and 12 months after RIT. In patients with follicular NHL, multiplex nested PCR with a sensitivity of 1 in 10−4 for the major and minor breakpoint regions of the Bcl-2 rearrangement were performed on BM and PB prior to treatment. If positive this was followed by repeat BM and PB at 3, 6 and 12 months, and then only at suspected relapse. The influence of metabolic and PCR responses to 131I-rituximab on event free survival (EFS) and overall survival (OS) were then evaluated. Relapses after 1 year were established with a dedicated CT and PET when clinically suspected.
Results. 29 pts [follicular (24), small lymphocytic (2), marginal zone (3)] had a response rate of 83%. At 3-months, 15/27 (56%) evaluable pts achieved a complete metabolic response (CMR). The 3-month PET status predicted outcome with median time to progression (TTP) of 15 months for CMR (n = 15), 11 months for PMR (n =7) and three months for non-responders (n=5) (P=0.001). CT response status at 3-months did not display as clear a separation of categories, with a median TTP of 24 months for CR (n=9), 12 months for PR (n=10) and six months for non-responders (n=9) (P=0.0023). 5/11 evaluable pts with Bcl-2 re-arrangements achieved a complete molecular response (CMolR) with a median TTP of 24 months, and six remained positive with a median TTP of 6 months (P=0.0025).
Conclusions. 131I-rituximab is able to induce metabolic and molecular responses in pts with relapsed indolent NHL. Although CT CR predicts TTP, the lack of a PET response conveys the most robust prediction of lack of treatment benefit. PET provides statistically superior prognostic stratification, although both modalities are able to identify good responders from poor-responders. Patients with Bcl-2 re-arrangements at salvage RIT who become PCR negative have a significantly prolonged TTP.