PET Adapted Salvage Therapy for Advanced Hodgkin Lymphomas: Towards the Suppression of Positive Interim PET Unfavorable Prognosis? a Report of the Goelams Multicentric Phase 2 Trial LH2007

Introduction : Continuous improvement in the management of Hodgkin Lymphoma (HL) has brought to favorable outcome for the majority of patients. However, patients with advanced stages still present unsatisfactory results with ABVD. The GOELAMS group conducted a prospective multicentric phase 2 trial for advanced stage HL with front-line therapy by VABEM and early salvage therapy followed by ASCT in case of absence of complete metabolic response to test a global PET adapted strategy with early salvage (LH 2007 trial, NCT00920153).

Patients & Methods :  Patients with advanced stage according to prognostic system score (PSS>3) received VABEM in front-line and interim 18F-FDG PET restaging using visual analysis after 2 courses. In case of negative PET-2 patients continued their therapy with a third course. In case of positive interim PET they underwent early salvage therapy by platin, gemcitabine and dexamethasone combination followed by intensification in case of metabolic response.

Results : 51 patients were included in the advanced arm. Median age was 40.5 years (range 18.2-64.8). Ann Arbor stage was IV in 35 (78%). B symptoms were observed in 44 (88%) patients; bulky disease in 22 (43%) of cases. The complete remission rate at the end of the strategy was 88% (n=45/51), with 34/37 patients in CR after 3 VABEM courses and 11/12 patients in CR after salvage therapy and ASCT. The metabolic complete response rate after 2 VABEM courses was 76% (37 above 49 assessable patients). The median follow up is 4.2 years  (range: 0.02-5.8). Estimated 2-yrs EFS and OS (n=51) were respectively 82.3% (IC95% 72.5% to 93.5%)  and 92.1% (IC95% 85% to 99.8%). 9 events occurred during the first 2 years and led to 4 deaths. The comparison by the one sample log-rank test of the observed EFS to a reference curve with a 2years EFS of 70% was statistcally significant (p=0.0004). No difference was observed in 2yrs-EFS and OS depending on interim PET-2 status. 2yrs-EFS and 2yrs-OS were respectively 83.7% (IC 95 72.6%-96.5%) and 97.2% (IC95 92.0%-100.0%) for PET-2 negative population vs 91.7% (IC 95 77.3%-100%) and 91.7% (IC95 77.3%-100.0%) for PET-2 positive population.

Discussion & conclusion : VABEM is an efficient first line treatment choice for Advanced HL. We demonstrate here that a PET-guided strategy with early salvage therapy and intensification for interim PET-2 positive patients is safe and feasible and that this global strategy permits to obtain interesting results in a population of patients associated with poor prognosis. Finally, we suggest that salvage by non-cross-resistant drugs and intensification may erase the unfavourable prognostic of positive interim PET-2 status in HL.