Introduction: PET-guided treatment is standard of care to treat patients diagnosed with advanced-stage classical Hodgkin Lymphoma (AS-cHL) in several countries. Here, we investigate the role of metabolic tumor volume (MTV) for the response assessment of patients treated for AS-cHL.
Methods: The investigator-initiated phase III trials HD18 (NCT00515554) and HD21 (NCT02661503) randomized patients between 18-60 years with newly diagnosed AS-cHL to receive BEACOPP (HD21 standard arm, HD18) or BrECADD (HD21 experimental arm). All patients received two cycles of chemotherapy followed by response assessment after two cycles (PET-2). MTV after two cycles (MTV-2) encompassed all lymphoma tissue with standard uptake value > 4. To exclude confounding of PET-guided treatment, we first analyzed MTV-2 in patients treated in control arms of HD18 who received 6 cycles of BEACOPP irrespective of PET-2 (C6-Cohort). Cox-regression models and Kaplan Meier estimates were used to analyze impact of MTV-2 on progression-free survival (PFS). Findings were validated in the full ITT cohorts of HD18 and HD21.
Results: A total of 645 patients were included in the C6-Cohort, of these 471 (64.6%) were rated as DS1-3 in PET-2 and 569 (88.2%) had no residual MTV-2. Compared to patients with DS1-3 (5y-PFS 93.5%; CI95: 91.2-95.9), Patients with measurable MTV-2 had significantly inferior PFS (5y-PFS 77.5%; HR 3.62, CI95: 1.94-6.76), while patients without detectable MTV-2 and DS4 had similarly high PFS (5y-PFS 89.3%; HR 1.65; CI95: 0.8-3.38). In line with these results, in the analyzed ITT cohorts of HD18 (n = 1756) and HD21 (n= 1211), patients with DS4 but with completely resolved MTV-2 had similar outcomes as patients with DS1-3 (HD18: HR 1.12, CI95: 0.69-1.80; HD21: HR 1.03, CI95: 0.55-1.95), whereas patients with measurable MTV-2 featured higher risk of progression (HD18: HR 2.98, CI95: 1.92-4.64; HD21: HR 4.44, CI95: 2.78-7.09). Results were similar in both trial arms of HD21 (BEACOPP vs. BrECADD) and frequency of measurable MTV-2 was similar in HD18 post-amendment and HD21.
Conclusion: Complete resolution of MTV after two cycles of first-line chemotherapy for AS-cHL occurs in a vast majority of patients and associates with favorable prognosis, irrespective of DS. Approximately 10% had measurable MTV-2 (i.e. any lesion with SUV > 4) and face high risk of progression. Our results advocate implementation of quantitative biomarkers to refine response assessment in AS-cHL.
Justin Ferdinandus, Helen Kaul, Gundolf Schneider, Michael Fuchs, Hans-Theodor Eich, Johannes Rosenbrock, Christian Baues, Katrin S. Roth, Alexander Drzezga, Lutz van Heek, Markus Dietlein, Peter Borchmann, Carsten Kobe