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The approval of brentuximab vedotin (BV) and checkpoint inhibitors (CPI) has revolutionized the management of relapsed/refractory classical Hodgkin lymphoma (cHL) patients. In recent years these agents have rapidly moved to earlier lines of therapy, including post-autologous hematopoietic cell transplant (auto-HCT) consolidation, pre-HCT salvage, and the frontline treatment setting. This shift in practice means that double-refractory (refractory to both BV and CPI) cHL is becoming an increasingly common clinical problem. In patients who are not eligible for clinical trials, conventional cytotoxic and targeted therapies (off label) may be a potential option. In patients who are transplant eligible, early referral to allogeneic HCT should be considered given the significant improvement in transplant outcomes in the contemporary era. Cellular therapy options including CD30.chimeric antigen receptor T cells, Epstein-Barr virus-directed cytotoxic T cells, and CD16A/30 bispecific natural killer cell engagers appear promising and are currently in clinical trials.

Double-refractory Hodgkin lymphoma: tackling relapse after brentuximab vedotin and checkpoint inhibitors