MEPED as salvage therapy for relapsed/refractory Hodgkin's lymphoma incorporating edited non-oncogene addiction: mTOR as bottleneck

Dennis Christoph Harrer ^1* Florian Lüke ¹ Tobias Pukrop ¹ Lina Ghibelli ² Albrecht Reichle ¹ Daniel Heudobler ¹

• ¹ University Medical Center Regensburg, Regensburg, Germany
• ² University of Rome Tor Vergata, Roma, Lazio, Italy

Rescue therapies of relapsed/refractory (r/r) Hodgkin's lymphoma (HL), in >2 nd to 6 th line entail major, still unresolved problems. The MEPED regimen encompasses agonists of nuclear receptors, pioglitazone and dexamethasone, counterbalancing HL homeostasis, inhibitors of HL stress responses with everolimus and COX-2 inhibitor, and an instigator of stress responses, low dose metronomic treosulfan. CR (6 of 7 patients) and long-term cCR also in patients receiving no consolidating allogeneic stem cell transplantation highlight MEPED as a potent salvage therapy in advanced refractory HL. MEPED edits everolimus activities this way that mTORC1 becomes a nononcogene addiction bottleneck, finally determining long-term therapy outcome. The implications of the therapeutic paradigm shift towards editing of HL tissue and particularly mTOR addiction, could prove to be profound for clinical practice, both for outcome and treatment tolerability. The long-term results of MEPED treatment indicate the urgent evaluation of the schedule in a multicenter trial for r/r HL.