Radioimmunotherapy with 90Y-Ibritumomab Tiuxetan (Zevalin®) as Consolidation of First Remission in Patients with Advanced Stage Follicular Lymphoma: A ’Real-Time’ MBR RQ-PCR Analysis.
Authors: Goff Lindsey , Summers Karin , Iqbal Sameena , Kuhlmann Jens , Kunz Michael , Hagenbeek Anton , Lister Andrew , Rohatiner Ama 
Published: October 2019

Abstract
Introduction: The randomized phase 3 First-line Indolent Trial (FIT) was conducted in newly diagnosed patients (pts) with stage III or IV follicular lymphoma (FL) to investigate the use of 90Y-ibritumomab tiuxetan (Zevalin) given as consolidation of first complete (CR/CRu) or partial remission (PR). Bcl-2 status was evaluated using ’real-time’ quantitative PCR (RQ-PCR) for the major breakpoint region (MBR) Bcl2-IgH rearrangement at the time of randomization and at follow up (after treatment with Zevalin or observation).
Methods: Peripheral blood samples were available for RQ-PCR analysis from 77 centers for 414 pts with grade 1 or 2 FL, in CR/CRu (n=216) or PR (n=198) following initial therapy. Pts were randomized to receive either Zevalin (n=208) or no further treatment (control; n=206). Initial therapies included CVP, CHOP/CHOP-like regimen, fludarabine combinations, chlorambucil and rituximab + chemotherapy. Zevalin treatment comprised rituximab 250 mg/m2 on day -7 and day 0, followed on day 0 by Zevalin 0.4 mCi/kg (maximum dose: 32mCi). Peripheral blood samples were analyzed using standard methodology (Summers et al J Clin Oncol2001;19:420), a result of 1 in 105 being regarded as negative. Only pts for whom clinical data, a peripheral blood sample at the time of randomization, and at least 1 follow-up sample (post-treatment for Zevalin arm; post-randomization for control arm) were available have been included in this analysis. Because not all pts with FL have an MBR rearrangement, the analysis was limited to those showing RQ-PCR positivity at some point.
Results: Overall, 127/291 pts (44%) who fulfilled the above criteria were RQ-PCR positive at the time of randomization, ie, 68/141 (46%) and 59/150 (39%) in the Zevalin and control arms, respectively. Progression-free survival (PFS) of the control arm served as an internal control and benchmark. In the control arm, the 59 pts who were RQ-PCR positive at time of randomization had a median PFS of 8.2 months, compared with 2.4 years for the 91 pts who were RQ-PCR negative. In the Zevalin arm, the 73 pts who were RQ-PCR negative at the time of randomization had a median PFS of 3.1 years compared with 3.2 years for the 68 pts who were RQ-PCR positive. At the time of the follow-up evaluation, 61/68 pts (90%) who received Zevalin consolidation and 21/59 pts (36%) in the control arm converted from RQ-PCR positive to negative status. The 61 Zevalin-treated pts who converted had a median PFS of 3.4 years compared with 2 years for the 21 pts who converted in the control arm (p<0.005). Clinical evidence of recurrent lymphoma was observed in 24/61 (39%) and 16/21 (76%) of pts who converted to RQ-PCR negative status in the Zevalin and control arms, respectively.
Conclusion: Conversion to RQ-PCR negativity was observed in both arms but was more frequent in the Zevalin arm. Treatment with Zevalin consolidation resulted in 90% of pts converting from RQ-PCR positive to negative status; this was associated with significant prolongation of PFS compared with the control arm.