PET-Guided Brecadd in Older Patients with Advanced-Stage Classic Hodgkin Lymphoma: Results of the Phase 2 Part of the GHSG HD21 Trial

B ackground: PET-adapted therapy with four or six cycles of brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine and dexamethasone (4-6x BrECADD) is highly effective in patients up to 60 years with Advanced-stage classic Hodgkin lymphoma (AS-cHL; Borchmann P et al. The Lancet 2024). However, highly effective treatments are still an unmet need for older patients with AS-cHL. Here we report feasibility, safety and efficacy of PET-guided BrECADD as first-line treatment of AS-cHL in patients 61-75 years of age, who have been treated within the GHSG HD21 study. Methods: We designed a phase II single-arm cohort within the international HD21 trial (NCT02661503) for patients with AS-cHL aged 61-75 years to receive BrECADD. PET/CT restaging was done after 2x BrECADD (PET2). If PET2 was negative (i.e. Deauville score (DS) 1-3), treatment was reduced to a total of 4x BrECADD, while patients with PET2-positive lymphoma residuals (DS >3) were scheduled to receive 6x BrECADD. Consolidation radiotherapy was recommended for PET-positive residuals after central review of PET/CT at end of chemotherapy (EOT). The primary endpoint for this cohort was the complete response (CR) rate after EOT according to central review. Secondary endpoints included adverse events, treatment-related morbidity (TRMB, defined as the occurrence of relevant acute non-hematologic organ toxicity ≥ grade 3 or relevant hematologic toxicity grade 4), feasibility, progression-free survival (PFS) and overall survival (OS). Results: Between June 2020 and April 2023, 85 patients with AS-cHL were enrolled in the HD21 Older Cohort. Following disconfirmation of cHL by expert pathology review in one patient, the final ITT population consisted of 84 patients. Median age was 66.5 years (range: 61-75, IQR 63-70) and a majority had Eastern Cooperative Oncology Group (ECOG) performance status ≥1 (52%, range 0-2), stage IV (54%), B-symptoms (75%) and an IPS ≥3 (73%). Comorbidities were reported in 87% of patients with a mean Cumulative Illness Rating Scale-Geriatric (CIRS-G) sum score of 3.7 (SD: 2.7, range 0-10). All patients in the ITT cohort started trial treatment. Most patients were PET-2-negative (48/80, 60%) according to central review and therefore scheduled for a total of 4x BrECADD. Overall, 85% of patients received the scheduled number of cycles and 12% of patients received consolidating radiotherapy. Neutropenic fever occurred in 54% of patients and the TRMB rate was 77% (95%CI: 67-86). Sensory neuropathy of any grade occurred in 38% of patients, with grade >2 in one patient (1%). There were eight patients without centrally evaluated response assessment at EOT. Of the 76 patients with central response evaluation at EOT, 66/76 (87%), 9/76 (12%) and 1/76 (1%) had CR, partial remission or progressive disease, respectively. After a median follow-up of 23 months, PFS estimates at 1 year (1y) and 2 years (2y) were 95.1% (95%CI: 90-100) and 91.5% (95%CI: 85-98), respectively. Corresponding 1y-OS and 2y-OS rates were 96.2 (95%CI: 92-100) and 90.7% (95%CI: 83-98). No death was attributed to study treatment. Eleven second primary malignancies were reported during follow-up, most of which were other lymphomas (n=6). Conclusions: PET-guided BrECADD is feasible and safe in older patients but requires more frequent dose adjustments than in younger patients. Importantly, BrECADD resulted in an exceptionally high 2-year PFS rate, which is in the range observed for younger patients in HD21. We thus recommend PET-guided BrECADD as treatment strategy for newly diagnosed AS-cHL patients 61-75 years of age.