Dose-Dense Brentuximab Vedotin Plus Ifosfamide, Carboplatin, and Etoposide (ICE) in Second Line Treatment of Relapsed/Refractory Classical Hodgkin Lymphoma: 5-Year Long Term Follow up

Background: Classical Hodgkin lymphoma (CHL) patients (pts) requiring second line therapy may still be cured with multiagent salvage chemotherapy followed by autologous stem cell transplant (ASCT). We previously published results of a phase I/II clinical trial which showed that dose-dense brentuximab vedotin (Bv) combined with ICE was highly active in this setting (Lynch RC et al, Lancet Haematology 2021) We present 5-year long term follow-up from this study (#NCT02227199).

Methods: Pts ≥ 18 years old with first relapse or primary refractory CD30+ CHL were eligible. Treatment included Bv on Days 1 and 8 at either 1.2 or 1.5 mg/kg (based on 3+3 dose-escalation schema; capped at 150 mg), ifosfamide and mesna 5 g/m² each on Day 2, carboplatin AUC 5 (capped at 800 mg) on Day 2, and etoposide 100 mg/m² daily on Days 1-3. Two 21-day cycles were given with G-CSF support. Bv 1.5 mg/kg was selected as the phase II dose based on reported dose escalation data (Lynch et al. Lancet Haematology 2021). PET was performed after Cycle 2, with response assigned per Cheson 2007. Stem cells were collected after Cycle 2 at the discretion of the treating investigator. The primary endpoint was to estimate the MTD and CR rate after 2 cycles. Secondary endpoints included PFS and OS.

Results: Between October 15, 2014 and February 10, 2020, 45 pts enrolled and completed study treatment, including 42 pts who received treatment at the MTD of 1.5 mg/kg on day 1 and 8 of each cycle. Median age was 31 (range, 21-61). 43 pts were evaluable for efficacy. Overall response rate (ORR) and CR for all enrolled pts were 91% and 74%, respectively. Among primary refractory pts, ORR and CR were 86% and 68%, respectively. Thirty-seven pts (82%) proceeded with ASCT. Only 2 pts did not proceed with ASCT due to inadequate response to salvage therapy. One was eventually lost to follow up, and the other died after subsequently declining therapy for chronic phase CML).

With an updated median follow up of 5.2 years, 5-year PFS was 77% (95% CI 66-91), and 5-year OS was 91% (82-100).

Five pts relapsed post ASCT, two of whom subsequently had an allogeneic transplant and are in CR. Three pts remain alive after relapse with ongoing therapy.

Five pts developed second malignancies, two of which were excised skin cancers (basal cell carcinoma, melanoma). Three pts developed non-skin cancers (lung adenocarcinoma, myelodysplastic syndrome, chronic phase CML) and all have succumbed to these second malignancies.

Overall, five pts have died since enrollment on the study due to second cancers (3), study treatment (1), or complications of ASCT (1).

Conclusions: As the field of CHL shifts to incorporate PD1-inhibitors in the front-line setting, the Bv-ICE regimen may provide primary refractory patients an effective salvage treatment option.

Lynch:SeaGen, Foresight Diagnostics, Abbvie, Janssen: Consultancy; Merck: Honoraria; TG Therapeutics, Incyte, Bayer, Cyteir, Genentech, SeaGen, Rapt, Merck, Janssen: Research Funding. Cassaday:Amgen: Consultancy, Research Funding; Autolus: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Research Funding; Jazz: Consultancy; Kite/Gilead: Consultancy, Honoraria, Research Funding; PeproMene Bio: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Research Funding; Seagen: Ended employment in the past 24 months; Servier: Consultancy, Research Funding; Vanda Pharmaceuticals: Research Funding. Smith:Genentech: Consultancy, Research Funding; Epizyme: Consultancy; Enterome: Research Funding; De Novo Biopharma: Research Funding; Merck Sharp and Dohme Corp: Research Funding; Lumanity: Consultancy; Karyopharm: Consultancy; Incyte: Consultancy, Research Funding; Kymera Therapeutics: Research Funding; AstraZeneca: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Coherus Biosciences (spouse): Consultancy; abbvie: Consultancy; ADC therapeutics: Consultancy, Research Funding; BMS (spouse): Research Funding; KITE pharma: Consultancy; Bayer: Research Funding; Ignyta (spouse): Research Funding; Millenium/Takeda: Consultancy. Cowan:Adaptive Biotechnologies: Consultancy, Research Funding; HopeAI: Consultancy, Current holder of stock options in a privately-held company; Harpoon: Research Funding; Abbvie: Research Funding; BMS: Consultancy, Research Funding; Juno/Celgene: Research Funding; Caelum: Research Funding; Nektar: Research Funding; Sanofi: Consultancy, Research Funding; Regeneron: Research Funding; IgM biosciences: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Sebia: Consultancy. Warren:Roche Diagnostics: Other: Travel Support. Shadman:Vincerx: Research Funding; Fate therapeutics: Consultancy; Bristol Myers Squibb (spouse): Current Employment; Koi Biotherapeutics: Current holder of stock options in a privately-held company; Eli Lilly: Consultancy; Kite Pharma: Consultancy; Morphosys/Incyte: Consultancy, Research Funding; Merck: Consultancy; Mustang Bio: Research Funding; Nurix: Consultancy; Genentech: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Janssen: Consultancy; BeiGene: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; AbbVie: Consultancy, Research Funding. Till:Bristol Myers Squibb: Research Funding; Mustang Bio: Consultancy, Patents & Royalties, Research Funding. Ujjani:Abbvie, Astrazeneca, Beigene, Genentech, Jansen, Lilly, Pharmacyclics: Honoraria; AbbVie, Astrazeneca, Lilly, PCYC: Research Funding. Gopal:Merck: Consultancy, Honoraria, Research Funding; I-Mab bio: Research Funding; IgM Bio: Research Funding; Takeda: Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Astra Zeneca: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Research Funding; BMS: Research Funding; SeaGen: Research Funding; Teva: Research Funding; Genmab: Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Morphosys/Incyte: Consultancy, Honoraria; ADCT: Consultancy, Honoraria; Acrotech: Consultancy, Honoraria; Merck: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Cellectar: Consultancy, Honoraria; Compliment: Consultancy, Current holder of stock options in a privately-held company, Honoraria; Epizyme: Consultancy, Honoraria; Lilly: Consultancy, Honoraria; Caribou: Consultancy, Honoraria; Fresenius-Kabi: Consultancy, Honoraria; Scitek: Consultancy, Honoraria; Sana: Consultancy, Honoraria.