Prognostic Impact of PET after 2 Cycles of Escalated Beacopp Plus 2 Cycles of ABVD on Progression Free Survival in Early Unfavourable Hodgkin Lymphoma within the Phase 3 GHSG HD17 Trial

Background

Within the scope of the GHSG HD17 trial for early-stage unfavorable Hodgkin Lymphoma (HL) we used positron emission tomography (PET) after two cycles of eBEACOPP and 2 cycles of ABVD (“2+2”) to guide radiotherapy. As in our parallel trials HD16 (for early favourable stage HL) and HD18 (for advanced stage HL), we defined a Deauville score (DS) ≥3 as positive. However, both trials did not demonstrate DS3 as prognostic factor for an increased risk for relapse, while DS≥4 added prognostic information to GHSG baseline risk factors.

Aims

We investigated the prognostic impact of different cut-off values in early-stage unfavourable HL after standard therapy with 2+2 and IF-RT in our international phase 3 HD17 trial (NCT01356680).

Methods

Between January 2012 and March 2017 we recruited 1100 patients with newly diagnosed early-stage unfavourable HL aged 18-60 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 2x eBEACOPPesc and 2x ABVD. Patients in the standard arm were additionally treated with 30Gy involved-field radiotherapy (IFRT) while radiotherapy was omitted in the experimental arm, if a negative PET scan was demonstrated after 2+2. PET positive patients in the experimental arm were treated with 30 Gy involved-node radiotherapy (IS-RT). PET scan was centrally assessed by an expert panel blinded towards the randomization results. Primary objectives included non-inferiority of the chemotherapy-alone treatment in PET-negative patients and the impact of a positive PET-finding on the outcome in terms of progression free survival (PFS). We also explored if different cutoffs for PET positivity as defined by DS are associated with baseline characteristics and/or treatment outcomes.

Results

Among 979 randomized patients with regular PET after 2+2 651 (67%), 238 (24%) and 90 (9%) had DS1-2, 3 and 4 respectively. Median observation time was 45 months for PFS and 47 months for overall survival (OS). 5-year PFS was 97.3% in the standard group and 95.1% in the PET-guided group. The 5-year PFS difference between the two groups was -2.2% (95% CI, -5.3% to 0.9%) excluding the lower margin of -8%. The 5-year PFS estimation for PET negative patients (n=318) was 97.6 (95% CI, 94.0%-99.9%) compared to 94.2% (95% CI, 90.1%-96.6%) for the PET positive patients. The Hazard Ratio for this difference was 3.03 (95% CI, 1.1-8.3) thus confirming a positive PET scan as a significant risk factor after 2+2 chemotherapy. The prognostic impact was even more pronounced when the cutoff for PET positivity was changed from DS3 to DS4 (HR=10.19, 95% CI, 4.16-25.00).

In a multivariate analysis on clinical risk factors predicting DS4 after chemotherapy or a PFS event only bulky disease was associated with a higher likelihood of DS4 with a Hazard Ratio 0.781 (95%-HR CI 0.652-0.935). Overall survival rates at 5years were 98.8% in the standard group and 98.4% in the PET guided group.

Summary/Conclusion

In early-stage unfavourable HL, a positive PET scan represents a risk factor for PFS among patients treated with standard CMT, particularly when DS4 is considered as cutoff for positivity. Bulky disease is a risk factor for DS4 at the end of chemotherapy. Earlier identification of these higher risk patients (e.g. after 2 cycles) should be evaluated in order to modify the treatment strategy. Fortunately, only 9% of the patients had DS4 after 2+2 chemotherapy whereas the vast majority of patients showed a negative PET-result. Importantly, radiotherapy can be safely omitted without compromising the very good PFS and OS in these patients with newly diagnosed early unfavourable HL.