Baseline PET-Derived Metabolic Tumor Volume Metrics Did Not Predict Outcomes in Follicular Lymphoma Patients Treated with First-Line Immunochemotherapy and Antibody Maintenance in the Phase III GALLIUM Study

Abstract

Introduction: Evidence suggests that baseline 18fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography-derived parameters, such as metabolic tumor volume (MTV) and maximum standardized uptake value (SUVmax), may predict progression-free survival (PFS) in patients (pts) with follicular lymphoma (FL) treated with first-line R-CHOP immunochemotherapy. However, data from pts routinely treated with bendamustine or antibody maintenance are lacking, and several methods have been used to evaluate PET metrics for tumor burden in pts with lymphoma. This prospective exploratory analysis assessed the prognostic value of baseline MTV, total glycolytic activity (TLG), and SUVmax for PFS and overall survival (OS) in pts with FL treated with first-line obinutuzumab (GA101; G) or rituximab (R) plus chemotherapy (chemo) in the Phase III GALLIUM study (NCT01332968; Marcus et al. N Engl J Med 2017), using two published methods for measuring tumor burden. Methods: Pts ≥18 years with previously untreated FL (grade 1-3a) and advanced disease (Stage III/IV or Stage II with tumor diameter ≥7cm) requiring treatment were randomized 1:1 to receive 6-8 cycles of G (1000mg intravenous [IV] on days [D] 1, 8, and 15 of cycle [C] 1 and D1, C2-6 or 8) or R (375mg/m2 IV on D1) plus standard chemo (CHOP, bendamustine, or CVP). Responding pts received the same antibody as maintenance every 2 months for up to 2 years. After an early protocol amendment, PET imaging at baseline and end of induction (EOI) was mandatory in the first 170 pts and optional thereafter. Independent reviewers segmented FDG-avid tumors applying thresholds of I) standardized uptake value (SUV)max ≥2.5, and II) SUVmax ≥41% of lesional maximum SUV and a minimum volume of 1mL, using MIM software. Results were analyzed for the PET intent-to-treat population. MTV, TLG, and SUVmax were split into quartiles: Q1, <25%; Q2, 25-49%; Q3, 50-74%; and Q4, 75-100%, based on their distribution in the available population. Investigator-assessed PFS and OS were estimated using Kaplan-Meier methods (data cut-off, February 12, 2018). Hazard ratios refer to stratified log-rank tests comparing Q2, Q3, and Q4 with Q1, adjusted for the randomization stratification factors FLIPI score and chemo regimen. Multivariable Cox analyses were also undertaken to investigate whether baseline MTV quartiles and other covariates were prognostic for PFS. Statistical significance at 0.05 was determined using the Wald test. Results: Of 1202 enrolled FL pts, 609 had a baseline PET scan and 521 had baseline PET scans available for all quantitative assessments by central review; 303 pts (58%) received bendamustine, 179 (34%) CHOP, and 39 (8%) CVP. After a median follow-up of 57 months, none of the 3 baseline PET parameters (MTV or TLG measured by either method or SUVmax) significantly predicted PFS (Table). Multivariable analysis, which included baseline pt and disease characteristics, confirmed that MTV did not predict PFS. Consistent with the primary analysis, receipt of G-chemo was an independent predictor of improved PFS. Conclusions: Contrary to previous reports, these prospective data from the Phase III GALLIUM study show that baseline quantitative PET metrics do not predict PFS or OS in FL pts receiving first-line immunochemotherapy (of whom the majority received bendamustine) followed by antibody maintenance treatment, irrespective of the measurement method applied. Conversely, a previously reported analysis from GALLIUM suggests that PET-complete metabolic response at EOI assessed using Lugano 2014 criteria is a strong predictor of long-term outcome in these pts. Table. Table. Disclosures Barrington: EPSRC: Research Funding; Department of Health (England): Research Funding; F.Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees; National Institute of Health Research: Research Funding; MRC: Research Funding; CRUK: Research Funding. Trotman:Janssen: Other: Unremunerated member of Ad Board, Research Funding; Celgene: Other: Unremunerated member of Ad Board, Research Funding; PCYC: Research Funding; Takeda: Other: Unremunerated member of Ad Board; F. Hoffman-La Roche: Other: Travel to meeting, Unremunerated member of Ad Board, Research Funding; Beigene: Research Funding. Sahin:Roche: Employment, Equity Ownership. Belada:Janssen-Cilag: Consultancy, Research Funding; Gilead Sciences: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Celgene: Research Funding; Roche: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Davies:Janssen: Consultancy, Honoraria; GSK: Research Funding; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Kite: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria, Research Funding; Pfizer: Research Funding. MacEwan:Consultant Radiologist/ Nuc Med Physician: Consultancy. Owen:Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Honoraria, Research Funding; Merck: Honoraria; Janssen: Honoraria, Research Funding; Teva: Honoraria; AbbVie: Research Funding. Ptáčník:F. Hoffman-La Roche: Honoraria. Hiddemann:F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy, Research Funding. Marcus:Roche: Consultancy, Other: Travel support and lecture fees ; Gilead: Consultancy; F. Hoffman-La Roche: Other: Travel support and lecture fees. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Mattiello:Roche: Employment. Zeuner:F. Hoffman-La Roche: Employment, Equity Ownership. Meignan:F. Hoffman-La Roche Ltd: Honoraria.

Baseline SUV_max is related to tumor cell proliferation and patient outcome in follicular lymphoma

“…While TMTV, a surrogate marker of tumor cell burden, was unrelated to baseline SUVmax or patient outcomes in our series, TMTV >510 cm 3 has been associated with a higher risk of treatment failure in FL patients. 6 However, this discrepancy could be related to the absence of maintenance treatment in the study by Meignan et al 6 Considering that the long-term results of the PRIMA study showed improved PFS in FL patients receiving rituximab maintenance (10.5 years compared to 4.1 years without maintenance treatment) 33 , and the GALLIUM study 34 showed an additional benefit of obinutuzumab over rituximab for PFS, anti-CD20 maintenance could mitigate the prognostic value of TMTV at baseline. Accordingly, TMTV had no prognostic value in either arm (rituximab or obinutuzumab) of the GALLIUM study.…”

Intratumoral T cells have a differential impact on FDG-PET parameters in follicular lymphoma

“…4,5 However, FDG-PET analysis of the phase 3 GALLIUM study (58% treated by bendamustine induction), in which all patients received anti-CD20 antibody maintenance, found no association with either TMTV or SUV max . 6 Intriguingly, high pretherapy SUV max was associated with shorter PFS in nonanthracycline-treated (mainly bendamustine or lenalidomide) but not in anthracycline (R-CHOP)-treated patients in another study. 7 The predictive utility of a pretherapy T-effector gene signature in patients treated with CHOP/CVP (cyclophosphamide, vincristine, prednisone)-rituximab/obinutuzumab is reversed in patients treated with bendamustine-rituximab (B-R)/obinutuzumab.…”

“…Pretherapy FDG-PET scans were assessed for SUV max , TMTV, and total lesion glycolysis (TLG), using customized software (MIM Software, Cleveland, OH). 6,14,15 Biopsy samples (formalin-fixed, paraffinembedded tissue and tumor-infiltrating lymphocytes [TILs] from deaggregated nodes) were used for multiplex gene hybridization, immunohistochemistry, T-cell receptor (TCR) repertoire sequencing and flow cytometry as published. 12,[16][17][18][19] Cryopreserved TILs were used to assess cellular glucose uptake by intratumoral CD4 1 T cells, CD8 1 T cells, and CD19 1 B cells, by using the fluorescently Data are expressed as the number (percentage) of patients in the subgroups, unless otherwise stated.…”

Time for an individualized approach to first-line management of follicular lymphoma

“…Indeed, a large body of data from the GALLIUM study suggests no association of maximum standardized glucose uptake value (SUVmax) with either histological transformation 11 or PFS. 12 There is marked heterogeneity in FDG uptake within patients which reflects metabolic activity of the malignant B cells as well as that of the microenvironment. 13 Likewise, the isolated analysis of bone marrow or blood infiltration is not appropriate for the diagnosis of FL.…”

“…17 The utility of PET has been demonstrated by identifying disseminated disease ultimately associated with a poorer outcome if treated as localized on the basis of CT-based staging. 17 The prognostic value of total metabolic tumor volume at diagnosis in FL remains debated 12,18 and the predictive value of automated software solutions for measuring total metabolic tumor volume 19 needs to be validated in prospective studies before being utilized in a standard manner in clinical practice. The prognostic value of end-of-induction PET response after first-line immunochemotherapy for FL 20,21,22 is now clear and provides a platform for PET-adapted therapies in current clinical trials.…”