Simultaneous Sessions II: Hodgkin lymphoma - Clinical
In our HD16 study for early-stage favorable Hodgkin lymphoma (HL), we used PET after 2 cycles of ABVD to guide involved-field radiotherapy (IFRT). As in our parallel HD18 trial, we defined a Deauville score (DS) ≥3 as positive. However, HD18 showed that DS3 did not indicate an increased risk of treatment failure in advanced-stage HL, while DS≥4 added prognostic information to baseline risk factors.
We investigated whether these results also hold true in the context of early-stage favorable HL patients treated with ABVD and IFRT in our international HD16 trial (NCT00736320).
Between November 2009 and December 2015, we recruited 1150 patients with newly diagnosed, early-stage favorable HL aged 18-75 years from Germany, Switzerland, Austria, and the Netherlands for this randomized, parallel-group phase 3 trial. Patients were randomly assigned to receive standard combined-modality treatment (CMT) with 2xABVD and 20 Gy IFRT or PET-guided treatment, where IFRT was restricted to patients with DS ≥3 after 2xABVD. PET was centrally assessed by an expert panel blinded towards the randomization result. A central objective of the trial was to prospectively test whether a DS ≥3 was associated with impairment in progression-free survival (PFS) among patients treated with CMT (i.e. those randomized to the standard group and those from the PET-guided randomization group with DS ≥3). We also explored the association of DS with baseline characteristics and treatment outcomes considering different cutoffs for positivity. We analyzed survival outcomes according to Kaplan-Meier, using Cox regression for comparisons.
Among 1007 randomized patients with regular PET, 667 (66%), 218 (22%) and 122 (12%) had DS 1-2, 3 and 4, respectively. Of those, 693 were assigned to treatment with CMT (353, 218 and 122 with DS 1-2, 3 and 4, respectively). Clinical stage II and bulky disease at initial staging were associated with an unfavorable DS after 2xABVD. CT-based complete remission as final treatment outcome after IFRT was observed in 344/348 patients (99%) with interim DS1-2, 209/214 (98%) with DS3, and 108/117 (92%) with DS4 (p = 0.016 for DS1-2 vs. 3-4; p = 0.0012 for DS1-3 vs. 4). Of note, all six progressions in this trial occurred in the DS4 subgroup. With a median follow-up of 46 months, the estimated 5-year PFS was 93.2% (90.2-96.2) among patients with DS1-2, 92.8% (88.8-96.9) for those with DS3 and only 80.9% (72.2-89.7) in the DS4 subgroup. Considering DS ≥3 as cutoff, the PFS difference was just statistically significant (HR 1.71 [1.00-2.93], p = 0.047). An analysis adjusting for baseline stratification factors led to similar, but non-significant results (HR 1.73 [0.99-3.02], p = 0.055). With DS4 as cutoff, the difference became more pronounced, indicating a threefold risk for treatment failure in patients with DS4 after chemotherapy (HR adjusted for baseline factors 2.94 [1.63-5.31], p = 0.0004). Overall survival was on a high level with no differences between any subgroups defined by DS (5-year overall survival 98.2% [96.7-99.8] for DS1-2, 98.6% [96.0-100] for DS3, 96.5% [92.3-100] for DS4).
In early-stage favorable HL, a positive PET after 2xABVD is associated with a larger tumor volume and represents a risk factor for PFS among patients treated with standard CMT, particularly when DS4 is considered as cutoff for positivity. PET-guided treatment intensification in this high-risk subgroup might help to reduce the frequency of relapses.