Denileukin diftitox (ONTAK) as targeted therapy against steroid refractory graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT)

Abstract

Denileukin diftitox (ONTAK®) is a recombinant fusion protein composed of human interleukin-2 linked to the membrane translocation and catalytic domains of diphtheria toxin. ONTAK has potent selective killing activity against activated lymphocytes that express the high or intermediate affinity interleukin-2 receptor (IL-2R). Monoclonal antibodies that target the IL-2R have demonstrated clinical activity against acute GVHD. ONTAK may be superior to these agents because it does not rely on secondary effector mechanisms for cell kill, and entry of a few molecules into the cytoplasm may be sufficient to induce apoptosis. Furthermore, because ONTAK selectively destroys activated T-cells and spares resting lymphoid populations, valuable immune function and reconstitution potential may be preserved. We have completed a phase I study to assess the dosing of ONTAK in patients with steroid-refractory GVHD after allogeneic HSCT. Thirty patients (3 related donor, 27 unrelated donor) were treated for grade II (n = 10), grade III (n = 15), or grade IV (n = 5) steroid-refractory acute GVHD. Seven received ONTAK at dose level I (9 μg/kg IV on day 1 and 15), eighteen were treated on dose level II (9 μg/kg IV days 1,3,5,15,17,19), five were treated on dose level III (9 μg/kg IV days 1–5, 15–19). At dose level III, 4 of 5 subjects developed dose-limiting toxicity (1 acute renal failure, 3 hepatic transaminase elevation). Therefore, dose level II was deemed the maximum tolerated dose (MTD). In all patients, elevated transaminases resolved promptly upon withdrawal of ONTAK. Only 2 (7%) developed infusional reactions with transient hypotension. Twenty-four patients were evaluable for GVHD response. After 4 weeks, 8 (33%) had complete GVHD resolution (CR) of, 9(38%) had partial response (PR), for an overall response rate of 71%. Among the 9 PRs, 4 subsequently entered CR without additional GVHD therapy, resulting in an overall CR of 50%. Response was highest at the MTD, where 6 (46%) achieved CR, and 3 (23%) had PR, all of whom eventually converted to CR (overall CR = 69%). Of the 24 patients evaluable for GVHD response, 9(38%) are alive, with the longest survivor being GVHD free at 20 months. Our results show that ONTAK at a dose schedule of 9 μg/kg IV on days 1,3,5,15,17,19 is tolerable and has promising activity for steroid-refractory GVHD. Future studies using the MTD are warranted to investigate the potential role of ONTAK as primary treatment of acute GVHD.