About 15% of classical Hodgkin lymphoma (cHL) patients remain refractory to first-line therapy and about one third of the responding patients relapse1. The standard of care for relapsed or refractory (R/R) cHL is salvage chemotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT)2.
Three novel agents effective in R/R cHL were introduced; brentuximab-vedotin (BV), anti-CD30 antibody-drug conjugate3 and the programmed-death-1 (PD-1) blocking antibodies, nivolumab and pembrolizumab4, 5 has been approved. The optimal line to incorporate these agents is an actual dilemma.
BV and PD1-blockers are effective in R/R cHL after ASCT. KEYNOTE-204 study reported that pembrolizumab treatment was associated with significantly longer PFS compared with BV (median:13.2 vs 8.3 months)6. In case of durable responses with PD1-blockers, cessation of the treatment may be an individualized decision and high response rates to re-treatment with PD1-blockers is an important advantage7. There is not obvious differences in the efficacy and toxicity of nivolumab and pembrolizumab8. We can conclude that PD1-blockers could be preferred over BV in patients who relapse following ASCT and who are naïve to BV and PD-1 blockade. For patients relapsing after ASCT with prior BV or PD1-blocker exposure, selection of the agent that has not been used previously could be recommended8.
BV and PD1-blockers are incorporated into the pre-ASCT salvage regimens in clinical trials. In the phase II BRaVE study, BV added to DHAP provided a complete metabolic response rate of 81% before ASCT, with a 2-year PFS and OS rates of 74% and 95%, respectively9. Similarly, pembrolizumab in combination with GVD provided an overall response rate (ORR) of 100%10. BV and nivolumab combination resulted in an ORR of 85%. The 3-year PFS rate for ASCT group was 91%11. Regarding these data, the need for ASCT will be an important point of debate in the next years.
In case of primary refractory disease, chemotherapy-based salvage regimens remain the standard. Combination treatment with BV and nivolumab resulted in a 21-month PFS of 65% in this group11, which may be a satisfactory option in the future.
Post-ASCT consolidation with BV is now standard of care in patients with risk factors defined by AETHERA trial12, which is supported by real-world data including pre-treated with and responsive to BV patients13.
Novel agents are not recommended in the front-line management of early-stage disease. ECHELON-1 study performed on treatment-naïve stage III/IV cHL patients reported 6-year PFS, and OS ratio were 82.3% and 93.9% for BV-AVD cohort versus 74.5% and 89.4% for ABVD cohort14. Beside advanced stage cases, BV-based therapies should be considered for elderly, unfit patients who cannot tolerate combination chemotherapies, as they are associated with longer duration of response compared to BV monotherapy8.
Giving decision about novel therapies, major adverse events, such as neuropathy for BV and immune related events for PD1-blockers. Optimal timing of BV and PD1-blockers and treatment strategies in case of resistance to novel agents are critical questions for the future of cHL management, which hopefully will be answered by the results of clinical trials and real-world data.
