Long Term Results of a Multicenter Prospective Trial By the Lysa Group Evaluating the RiPAD+C Regimen (Combination of Rituximab, Bortezomib, Doxorubicin, Dexamethasone and Chlorambucil) As First-Line Therapy for Elderly Mantle Cell Lymphoma Patients (MCL): Prognostic Value of FDG-PET/CT
Authors: Dubreuil Julien , Houot Roch , Le Gouill Steven , Mounier Christiane , Courby Stéphane , Dartigeas Caroline , Bouabdallah Krimo , Moles Marie Pierre , Magda Alexis , Tournilhac Olivier , Ojeda Uribe Mario , Bourre Jean Cyril , Bodet-Milin Caroline , Vuillez Jean-Philippe , Gressin Remy 
Published: November 2019

Abstract
Background:
Mantle cell lymphoma (MCL) is an aggressive lymphoma with variable 18Fluorine-Deoxyglucose (FDG) avidity. FDG - Positron Emission Tomography/Computed Tomography (FDG-PET/CT) is not yet recommended in MCL but many retrospective studies have underlined its prognostic impact either before any treatment or at interim or final time points of R-chemotherapy. The French LYSA/GOELAMS group published the results of a multicenter prospective phase II clinical trial evaluating the RiPAD + C front-line combination including one proteasome inhibitor (PS341-Velcade®) for elderly MCL patients(Houot, Le Gouill et al. 2012). The aim of the present study was to determine the prognostic value of FDG-PET/CT in this prospective cohort with a long follow up.
Method:
Patients between 65 and 80 years old were enrolled. They received 4 cycles of RiPAD+C regimen (every 35 days: Rituximab 375 mg/sqm D1, Velcade® 1.3 mg/sqm D1,4,8 and 11, Doxorubicin 9 mg/sqm D1 to D4, Dexamethasone 40 mg D1 to 4 and Chlorambucil 12 md D20 to D29) and 2 additional cyclesif they responded (IWR criteria). Three FDG-PET scans were performed: an initial pre-treatment, after 4 cycles (interim) and after 6 cycles (post-treatment). All available FDG-PET/CT were centrally reviewed by two experts, using visual international response assessment criteria proposed by IHP in Lymphoma and the Deauville five-point scale. The maximal standardized uptake value (SUVmax) and maximal standardized uptake value reduction (ΔSUVmax) of the most intense pathological area were measured.
Results:
From June 2007 to December 2008, 39 patients from 21 French centers were recruited. After 64 months follow-up for the 22 surviving patients, median overall survival (OS) has not been reached (the 3 year OS was 63,5%). Median progression free survival (PFS) is 22 months. Seventeen patients died either from lymphoma (n=13) or due to toxicity (n=4).
Seventy-eight FDG-PET/CT were performed (31 initial FDG-PET/CT; 28 interim, 19 post-treatment), in 39 patients. We reviewed 24 initial FDG-PET/CT, 27 interim, and 16 post-treatment. By univariate analysis: neither initial, interim nor post-treatment FDG-PET/CT were predictive of OS or PFS. The ΔSUVmax (> 65% vs ≤ 65%, or > 50% vs ≤ 50%) was also not predictive for OS or PFS (p= 0.48 to 0.92). However high SUVmax (>10 vs ≤10) and clinical prognostic scores (MIPI or the Goelams index) correlated with OS (p=0.09, p= 0.054 and p=0.16, respectively). In a multivariate analysis patients with a high prognostic score at diagnosis combined with a positive post-treatment FDG-PET/CT had very poor OS compared to other profiles (high index with a negative post-treatment FDG-PET/CT or low-intermediate index with a negative or positive FDG-PET/CT).
Conclusion:
This is the first prospective study evaluating the prognostic impact of FDG-PET/CT in a cohort of homogeneously treated MCL patients with a long time of follow up. Neither initial, interim or post-treatment FDG-PET/CT were predictive of PFS or OS. However we confirm, as previously described in a retrospective analysis (Bodet-Milin, Touzeau et al. 2010), that both high SUVmax at initial FDG-PET/CT and the MIPI score were prognostic for OS. Interestingly, a negative post-treatment FDG-PET/CT seemed to erase the adverse prognostic significance of a high MIPI score before treatment. These observations warrant further confirmation in large prospective clinical trials.

Disclosures
Le Gouill: Roche: Consultancy; Janssen: Consultancy. Dartigeas:Roche: Consultancy. Tournilhac:mundipharma: Honoraria, Other, Research Funding; GSK: Honoraria, Other, Research Funding; Roche: Honoraria, Other, Research Funding. Gressin:MundiPharma: Other.