Total Metabolic Tumor Volume and Tumor Dissemination Are Independent Prognostic Factors in Advanced Hodgkin Lymphoma

Abstract

Background: The AHL2011 study demonstrated that a PET-driven strategy allows to deescalate treatment to 4 x ABVD in PET negative patients after 2 cycles of escalated BEACOPP (BEACOPPesc) without loss of tumor control in patients with advanced Hodgkin lymphoma (HL) compared to a non PET-monitored treatment delivering 6 x BEACOPPesc (Casasnovas RO et al, Lancet Oncol 2019). The interim PET results after 2 (PET2) and 4 (PET4) cycles of chemotherapy were found to influence patients PFS and OS independently of IPS. To further refine the patients outcome prediction we evaluate the prognostic value of baseline Total Metabolic Tumor Volume (TMTV) and tumor dissemination (SDmax) in Ann Arbor stage III-IV patients included in the AHL2011 trial. Patients and methods: 634 patients enrolled in the AHL2011 trial with stage Ann Arbor III or IV were included in the study. According to the AHL2011 trial, patients were randomized in a standard arm (6 x BEACOPPesc) or a PET-driven arm (2 x BEACOPPesc and 4 x ABVD in negative PET2 patients or 4 x BEACOPPesc in positive PET2 patients). For each patient, a semi automatic tumor segmentation was retrospectively performed in baseline PET to calculate TMTV using the 41% of SUVmax threshold and compute the maximum distance between the delineated lesions normalized by body surface area (SDmax). Optimal thresholds for TMTV and SDmax were calculated using X-Tile and ROC curve approaches in a randomly assigned training (n=317) and validation sets (n=317). The per protocol PET2 and PET4 responses were analyzed using the modified Deauville criteria (positive if residual uptake >140% background liver). Multivariate analysis included treatment arm, TMTV, SDmax, international prognosis score (IPS), PET2, and PET4 as covariates. The median follow-up was 5.6y. Results : Median TMTV and SDmax were 215 ml and 0.221 m-1 in the whole population and similar in both randomized arms and in the training and validation sets. Optimal cutoffs were 220ml for TMTV (312 patients [49%] had High TMTV) and 0.330 m-1 for SDmax (149 patients [24%] had High SDmax) and similar in the training and validation sets. 5-year PFS for patients with TMTV>220ml was 84.1% vs 90.2% in low TMTV patients (p=0.02) in the whole population (in the training set: 83% vs 89%, p=0.088 ; in the validation set : 86% vs 92% p=0.11). 5-year PFS was significantly lower in patients with SDmax>0.333 m-1 (78.8% vs 89.7%; HR=2.15 [95%CI: 1.38-3.35], p=0.0005) in the whole population (in the training set: 77% vs 89%; p=0.0037); in the validation set: 81% vs 91; p=0.046). The combination of TMTV and SDmax allows to identify two subgroups of patients, those having both low TMTV and low SDmax (n= 281; 44%) and those having high TMTV and/or SDmax (5-year PFS: 92% vs 83.4%; HR=2.24 [95%CI: 1.39-3.62], p=0.0007) (figure 1). In multivariate analysis, high TMTV (p=0.034), high SDmax (p=0.0002), PET2 (p=0.02) and PET4 (p<0.001) positivity retained independent prognostic value for predicting PFS. Conclusion: Tumor burden (TMTV) and dissemination (SDmax) assessed on baseline 18FDG PET allow to predict, independently of early reponse to treatment, the outcome of patients with advanced HL. These two parameters overcome the prognosis value of IPS and could be included into new prognostic scores to tailor personalized therapy in advanced Hodgkin Lymphoma. Figure 1 : PFS according to TMTV and SDmax in stage III-IV HL patients enrolled in the AHL2011 study Figure 1 Figure 1. Disclosures Brice: Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria; MSD: Honoraria. Ghesquieres: Janssen: Honoraria; Mundipharma: Consultancy, Honoraria; Roche: Consultancy; Celgene: Consultancy, Honoraria; Gilead Science: Consultancy, Honoraria. Stamatoullas-Bastard: Takeda: Consultancy. André: AbbVie: Other: Travel/accomodation/expenses; Roche: Other: Travel/accomodation/expenses, Research Funding; Johnson & Johnson: Research Funding; Incyte: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Celgene: Other: Travel/accomodation/expenses; Takeda: Consultancy, Research Funding. Rossi: ROCHE: Honoraria, Research Funding; Takeda: Honoraria; JANSSEN: Honoraria; ABBVIE: Honoraria. Casasnovas: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.

Prognostic Value of Baseline Tumor Burden and Tumor Dissemination Extracted From 18F-FDG PET/CT in a Cohort of Adult Patients With Early or Advanced Hodgkin Lymphoma

“…Regarding TMTV, this PET feature was confirmed in our study as prognostic factor for PFS in the univariate analysis, which is consistent with almost all studies assessing baseline TMTV as risk factor in HL, 10–12,14–18 especially the recent studies including patients treated with escalated BEACOPP 13,19,20 . The presence of a bulky tumor was not a predictor of a poor outcome in our study, confirming that quantifying the volume rather than the single largest diameter of the mass gives a more relevant prognosis information.…”

Prognostic value of lesion dissemination in doxorubicin, bleomycin, vinblastine, and dacarbazine‐treated, interimPET‐negative classical Hodgkin Lymphoma patients: A radio‐genomic study

“…Kanoun et al. recently provided confirmatory data about the prognostic role of Dmax among patients initially treated with BEACOPP within the AHL2011 randomized trial 37 . Also, regarding the cut‐off value of Dmax that was defined at 20 cm in our study further validation is needed.…”

“…recently provided confirmatory data about the prognostic role of Dmax among patients initially treated with BEACOPP within the AHL2011 randomized trial. 37 Also, regarding the cut‐off value of Dmax that was defined at 20 cm in our study further validation is needed. Indeed, our data should be considered as a proof of concept about the prognostic role of Dmax in cHL patients and to identify subgroups of patients that could have the greater utility from the use of Dmax, that is, iPET negative patients.…”

Dmax: A simple and reliable PET/CT‐derived new biomarker of lymphoma outcome?

“…Their combination with MTV in predictive models showed a significant improvement of the prognostic value of the only tumor burden estimation (by MTV). [12][13][14] The study published by Durmo et al 15 tested the capacity of D max to predict treatment outcome in a retrospective cohort of patients with classical HL treated with ABVD regimen confirming the prognostic role of this biomarker in this type of lymphoma. In a multivariate analysis including the most common clinical parameters and baseline PET metrics (MTV, TLG and SUVmax), D max resulted the only independent predictor of PFS.…”

“…These two parameters have been proposed substantially as complementary biomarkers to MTV. Their combination with MTV in predictive models showed a significant improvement of the prognostic value of the only tumor burden estimation (by MTV) 12–14 …”