Introduction: We previously reported initial (n=30) efficacy results of a frontline study of pembrolizumab + AVD (Lynch et al Blood 2023, ASH 2023) in classic Hodgkin lymphoma (CHL). Despite finding surprisingly high rates of positive interim and EOT PET/CT compared to historical data, observed outcomes were excellent. Herein we present updated clinical data for our full 50-patient study including interim and end of treatment (EOT) MRD testing by PhasED-Seq
Methods: We examined additional long-term follow up pembrolizumab combined with concurrent AVD in untreated CHL as previously described (NCT03331341). Samples were analyzed for ctDNA at baseline, post cycle 1 (if available), post cycle 2, and end of treatment. ctDNA levels were quantified as haploid genome equivalents/mL plasma using PhasED-Seq (Kurtz et al. Nat Biotech 2021).
Results: 50 patients were enrolled between Feb 1, 2019, and Apr 13, 2023, with a median follow up of 3.1 years, 3-year PFS and OS were 98% and 100%, respectively. Among advanced stage patients (n=38), 3-year PFS and OS were 97% and 100% respectively.
In patients where samples were available for analysis, baseline ctDNA was detectable in 11/12 (92%) of early-stage patients, and 36/37 (97%) of advanced stage patients. 7/8 (88%) early-stage patients had undetectable MRD (uMRD) at C3D1, and all cleared ctDNA by EOT and none have relapsed to date. Among advanced stage patients, 22/29 (76%) of samples at C2D1 and 29/35 (83%) samples at C3D1 had uMRD. In contrast, the PET CR rate at C3D1 in advanced stage patients was only 58%. At EOT, 31/34 (91%) advanced stage samples had uMRD compared to a PET CR rate of 73%. The only patient in the study to relapse had a negative interim PET but did not clear ctDNA at any timepoint. Two additional patients had minute amounts of ctDNA detectable at the end of treatment after levels dropped >20,000 fold when compared to baseline. Both patients have not relapsed 3 years and 14 months after completion of treatment, respectively. Some timepoints did not have plasma samples available, and no samples were drawn for sequencing during follow-up,
Conclusion: Pembrolizumab + AVD continues to demonstrate durable efficacy in previously untreated CHL. No patient who has cleared ctDNA as measured by PhasED-Seq has relapsed to date despite high rates of interim-PET positivity. The role of PhasED-Seq will be further examined in the upcoming Phase 2 MRD-adapted PRECISE-HL study in untreated advanced stage CHL.
Ryan Lynch, Stefan K. Alig, Chaitra Ujjani, Christina Poh, Edus H. Warren, Stephen Smith, Mazyar Shadman, Brian Till, Vikram M. Raghunathan, Yolanda Tseng, Susan Ottemiller, Bonnie Joy, Melissa Fessel, Hongyan Du, Jackie Vandermeer, Alyssa Kelly, Heather Rasmussen, Jenna Voutsinas, Ash A. Alizadeh, Ajay K. Gopal